Ivermectin for COVID-19: real-time meta analysis of 105

studies
@CovidAnalysis, July 22, 2024, Version 231 — GidMK response
[Link]

PRINCIPLE, TOGETHER, ACTIV-6, GidMK, Scott Alexander, Strongyloides, Popp, TLDR

Abstract Ivermectin for COVID-19 [Link]

October 2024
Statistically significant lower risk is seen for mortality, ventilation, Improvement, Studies, Patients Relative Risk

ICU admission, hospitalization, recovery, cases, and viral All studies 60% 105 220,423

clearance. All remain significant for higher quality studies. 64 Primary outcome 51% 105 220,380

studies from 58 independent teams in 27 different countries show

significant improvements. Mortality 47% 53 123,452

Ventilation 35% 20 37,217

Meta analysis using the most serious outcome shows 61% [50- ICU admission 40% 15 28,149
69%] and 85% [77-90%] lower risk for early treatment and Hospitalization 34% 30 122,275

prophylaxis, with similar results for higher quality studies, primary Recovery 38% 39 13,227

outcomes, peer-reviewed studies, and for RCTs. Cases 81% 16 13,696

Viral clearance 42% 32 4,378

Results are very robust — in worst case exclusion sensitivity

analysis 63 of 105 studies must be excluded to avoid finding RCTs 52% 52 17,642

statistically significant efficacy.

Peer-reviewed 59% 89 133,335

No treatment or intervention is 100% effective. All practical,

effective, and safe means should be used based on risk/benefit Prophylaxis 85% 17 19,764
Early 61% 40 136,434
analysis. Multiple treatments are typically used in combination,
Late 40% 48 64,225
which may be significantly more effective. Pharmacokinetics show
0 0.5 1 1.5+
significant inter-individual variability 1. Efficacy may vary depending Favors Favors
on the manufacturer 2. after exclusions ivermectin control

Over 20 countries adopted ivermectin for COVID-19. The evidence base is much larger and has much lower conflict of interest
than typically used to approve drugs.

3-7
All data to reproduce this paper and sources are in the appendix. Multiple other meta analyses show efficacy .

100% Evolution of COVID-19 clinical evidence [Link]

October 2024
Effective

50% Ivermectin
p<0.0000000001
1202

4202
3202
2202
0202

0%

Acetaminophen
p=0.00000029
-50%
Harmful meta analysis results (pooled effects)
IVERMECTIN FOR COVID-19 — HIGHLIGHTS

Ivermectin reduces risk with very high confidence for mortality, ventilation, ICU admission, hospitalization,
progression, recovery, cases, viral clearance, and in pooled analysis.

≥
4th treatment shown effective with 3 clinical studies in August 2020, now with p < 0.00000000001 from 105
studies, and recognized in 23 countries.

Outcome specific analyses and combined evidence from all studies, incorporating treatment delay, a primary
confounding factor.

Real-time updates and corrections, transparent analysis with all results in the same format, consistent protocol for
95 treatments.
Ivermectin COVID-19 early treatment and prophylaxis studies [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] hosp. 0/60 2/56 14mg OT​1 CT​2
Espitia-Hernandez 70% 0.30 [0.16-0.55] recov. time 28 (n) 7 (n) 12mg CT​2
Carvallo 85% 0.15 [0.02-1.28] death 1/32 3/14 36mg CT​2
Mahmud (DB RCT) 86% 0.14 [0.01-2.75] death 0/183 3/183 12mg CT​2
Szente Fonseca -14% 1.14 [0.75-1.66] hosp. 340 (n) 377 (n) 24mg
Cadegiani 78% 0.22 [0.01-4.48] death 0/110 2/137 42mg CT​2
Ahmed (DB RCT) 85% 0.15 [0.01-2.70] symptoms 0/17 3/19 48mg
Chaccour (DB RCT) 96% 0.04 [0.00-1.01] symptoms 12 (n) 12 (n) 28mg
Ghauri 92% 0.08 [0.01-0.88] no recov. 0/37 7/53 48mg
Babalola (DB RCT) 64% 0.36 [0.10-1.27] viral+ 40 (n) 20 (n) 24mg OT​1
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] death 0/55 4/57 24mg
Bukhari (RCT) 82% 0.18 [0.07-0.46] viral+ 4/41 25/45 12mg
Mohan (DB RCT) 62% 0.38 [0.08-1.75] no recov. 2/40 6/45 28mg RIVET-COV
Biber (DB RCT) 70% 0.30 [0.03-2.76] hosp. 1/47 3/42 36mg
Elalfy 87% 0.13 [0.06-0.27] viral+ 7/62 44/51 36mg CT​2
López-Me.. (DB RCT) 67% 0.33 [0.01-8.11] death 0/200 1/198 84mg
Roy 6% 0.94 [0.52-1.93] recov. time 14 (n) 15 (n) n/a CT​2
Chahla (CLUS. RCT) 87% 0.13 [0.03-0.54] no disch. 2/110 20/144 24mg
Mourya 89% 0.11 [0.05-0.25] viral+ 5/50 47/50 48mg
Loue (QR) 70% 0.30 [0.04-2.20] death 1/10 5/15 14mg
Merino (QR) 74% 0.26 [0.11-0.57] hosp. 77,381 (all patients) 24mg censored, see notes CS​5
Faisal (RCT) 68% 0.32 [0.14-0.72] no recov. 6/50 19/50 48mg
Aref (RCT) 63% 0.37 [0.22-0.61] recov. time 57 (n) 57 (n) n/a
Krolewiecki (RCT) -152% 2.52 [0.11-58.1] ventilation 1/27 0/14 168mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] death 4/250 3/251 24mg
Reis (DB RCT) 12% 0.88 [0.49-1.55] death 21/679 24/679 84mg TOGETHER impossible data, see notes
Buonfrate (DB RCT) -211% 3.11 [0.13-73.3] hosp. 1/28 0/31 336mg COVER
Mayer 55% 0.45 [0.32-0.63] death 3,266 (n) 17,966 (n) 151mg
Borody 92% 0.08 [0.01-0.79] death 0/600 6/600 96mg MD​3 CT​2 SC​4
Abbas (DB RCT) -4% 1.04 [0.07-16.4] death 1/99 1/103 84mg
de Jesús Ascenci.. 59% 0.41 [0.36-0.47] death/hosp. 7,898 (n) 20,150 (n) 12mg CT​2
Manomai.. (DB RCT) 43% 0.57 [0.20-1.46] no recov. 3/36 6/36 48mg
de la Ro.. (DB RCT) -187% 2.87 [0.12-67.5] misc. 1/30 0/26 36mg
Rezai (DB RCT) -5% 1.05 [0.07-16.7] death 1/268 1/281 84mg
Mirahma.. (DB RCT) 67% 0.33 [0.03-3.14] ventilation 1/131 3/130 24mg
Schilling (RCT) 67% 0.33 [0.01-7.97] hosp. 0/45 1/45 168mg PLATCOV
Bramante (DB RCT) -197% 2.97 [0.12-72.7] death 1/408 0/396 90mg COVID-OUT OT​1
Mikamo (DB RCT) -205% 3.05 [0.12-74.7] progression 1/502 0/527 63mg
Siripongbo.. (RCT) 0% 1.00 [0.07-15.3] progression 1/30 1/30 168mg FINCOV CT​2
Wijewic.. (DB RCT) -196% 2.96 [0.12-72.0] death 1/127 0/122 96mg

Early treatment 61% 0.39 [0.31-0.50] 67/16,019 240/43,034 61% lower risk
Tau​2 = 0.17, I​2 = 50.3%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (1m)

Shouman (RCT) 91% 0.09 [0.03-0.23] symp. case 15/203 59/101 36mg
Carvallo 96% 0.04 [0.00-0.63] cases 0/131 11/98 14mg see notes CT​2
Behera 54% 0.46 [0.29-0.71] cases 41/117 145/255 42mg
Carvallo 100% 0.00 [0.00-0.02] cases 0/788 237/407 48mg see notes CT​2
Hellwig (ECO.) 78% 0.22 [0.06-0.76] cases ecological 14mg
Bernigaud 99% 0.01 [0.00-0.10] death 0/69 150/3,062 84mg
Alam 91% 0.09 [0.04-0.25] cases 4/58 44/60 12mg
IVERCOR PREP 73% 0.27 [0.15-0.48] cases 13/389 61/486 48mg MD​3
Chahla (RCT) 95% 0.05 [0.00-0.80] m/s case 0/117 10/117 48mg CT​2
Behera 83% 0.17 [0.12-0.23] cases 45/2,199 133/1,147 42mg
Tanioka (ECO.) 88% 0.12 [0.03-0.46] death ecological 14mg
Seet (CLUS. RCT) 50% 0.50 [0.33-0.76] symp. case 32/617 64/619 12mg OT​1
Morgenstern (PSM) 80% 0.20 [0.01-4.15] hosp. 0/271 2/271 56mg
Mondal 88% 0.12 [0.01-0.55] symp. case 128 (n) 1,342 (n) n/a
Samajdar 80% 0.20 [0.11-0.38] cases 12/164 29/81 n/a
Kerr (PSM) 70% 0.30 [0.19-0.46] death 25/3,034 79/3,034 56mg
Desort-H.. (DB RCT) 96% 0.04 [0.02-0.11] high v. load 4/200 99/199 203mg SAIVE

Prophylaxis 85% 0.15 [0.10-0.23] 191/8,485 1,123/11,279 85% lower risk

Tau​2 = 0.52, I​2 = 83.3%, p < 0.0001

All studies 72% 0.28 [0.22-0.35] 258/24,504 1,363/54,313 72% lower risk
1 2
OT: ivermectin vs. other treatment CT: study uses combined treatment
3
MD: minimal detail available currently 4
SC: study uses synthetic control arm 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+
5
CS: censored, see details
T 2
0 33 I2 72 7% < 0 0001 Effect extraction pre specified see appendix Favors ivermectin Favors control
 Tau​2 = 0.33, I​2 = 72.7%, p < 0.0001 Effect extraction pre-specified, see appendix Favors ivermectin Favors control
A

Timeline of COVID-19 ivermectin studies (pooled effects) [Link]

October 2024
100%

nitcemrevi lortnoc
srovaF
50%

0%
srovaF

1202

2202

3202

4202
-50% 0202
-100%

August 2020: efficacy (pooled outcomes)

September 2020: efficacy (specific outcome)
December 2020: efficacy (RCT pooled)
December 2020: efficacy (RCT specific) B
Figure 1. A. Random effects meta-analysis excluding late treatment. This plot shows pooled effects, see the specific
outcome analyses for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect
extraction is pre-specified, using the most serious outcome reported. Simplified dosages are shown for comparison, these
are the total dose in the first four days for treatment, or the monthly dose for prophylaxis, for a 70kg person. For details of
effect extraction and full dosage information see the appendix. B. Timeline of results in ivermectin studies. The marked
≥
dates indicate the time when efficacy was known with a statistically significant improvement of 10% from 3 studies for≥
pooled outcomes, one or more specific outcome, pooled outcomes in RCTs, and one or more specific outcome in RCTs.
Efficacy based on RCTs only was delayed by 3.6 months, compared to using all studies. Efficacy based on specific outcomes
was delayed by 1.3 months, compared to using pooled outcomes.

Introduction

Immediate treatment recommended. SARS-CoV-2 infection primarily begins in the upper respiratory tract and may
progress to the lower respiratory tract, other tissues, and the nervous and cardiovascular systems, which may lead to
cytokine storm, pneumonia, ARDS, neurological injury 8-16 and cognitive deficits 10,15, cardiovascular complications 17-
19
, organ failure, and death. Minimizing replication as early as possible is recommended.

Many treatments are expected to modulate infection. SARS-CoV-2 infection and replication involves the complex
interplay of 50+ host and viral proteins and other factors A,20-24, providing many therapeutic targets for which many
existing compounds have known activity. Scientists have predicted that over 8,000 compounds may reduce COVID-19
risk 25, either by directly minimizing infection or replication, by supporting immune system function, or by minimizing
secondary complications.

Extensive supporting research. Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with
activity against many viruses including H7N7 26, Dengue 27-29, HIV-1 28, Simian virus 40 30, Zika 29,31,32, West Nile 32,
Yellow Fever 33,34, Japanese encephalitis 33, Chikungunya 34, Semliki Forest virus 34, Human papillomavirus 35, Epstein-
Barr 35, BK Polyomavirus 36, and Sindbis virus 34.

Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins 26,28,30,37, shows spike-ACE2 disruption at
1nM with microfluidic diffusional sizing 38, binds to glycan sites on the SARS-CoV-2 spike protein preventing
interaction with blood and epithelial cells and inhibiting hemagglutination 39,40, shows dose-dependent inhibition of
wildtype and omicron variants 41, exhibits dose-dependent inhibition of lung injury 42,43, may inhibit SARS-CoV-2 via
IMPase inhibition 29, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation 44, inhibits
SARS-CoV-2 3CLpro 45, may inhibit SARS-CoV-2 RdRp activity 46, may minimize viral myocarditis by inhibiting NF-
κB/p65-mediated inflammation in macrophages 47, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET
formation 48, may inhibit SARS-CoV-2 by disrupting CD147 interaction 49-52, shows protection against inflammation,
cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 53,54, may
be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell
proliferation that leads to lung damage 55, may minimize SARS-CoV-2 induced cardiac damage 56,57, increases
Bifidobacteria which play a key role in the immune system 58, has immunomodulatory 59 and anti-inflammatory 60,61
properties, and has an extensive and very positive safety profile 62.

Analysis. We analyze all significant controlled studies of ivermectin for COVID-19. Search methods, inclusion criteria,
effect extraction criteria (more serious outcomes have priority), all individual study data, PRISMA answers, and
statistical methods are detailed in Appendix 1. We present random effects meta-analysis results for all studies, studies
within each treatment stage, mortality, ventilation, ICU admission, hospitalization, recovery, cases, viral clearance,
peer-reviewed studies, Randomized Controlled Trials (RCTs), and after exclusion of lower quality studies.

Treatment timing. Figure 2 shows stages of possible treatment for COVID-19. Prophylaxis refers to regularly taking
medication before becoming sick, in order to prevent or minimize infection. Early Treatment refers to treatment
immediately or soon after symptoms appear, while Late Treatment refers to more delayed treatment.

Figure 2. Treatment stages.

Preclinical Research

Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses
including H7N7 26, Dengue 27-29, HIV-1 28, Simian virus 40 30, Zika 29,31,32, West Nile 32, Yellow Fever 33,34, Japanese
encephalitis 33, Chikungunya 34, Semliki Forest virus 34, Human papillomavirus 35, Epstein-Barr 35, BK Polyomavirus 36,
and Sindbis virus 34.

Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins 26,28,30,37, shows spike-ACE2 disruption at
1nM with microfluidic diffusional sizing 38, binds to glycan sites on the SARS-CoV-2 spike protein preventing
interaction with blood and epithelial cells and inhibiting hemagglutination 39,40, shows dose-dependent inhibition of
wildtype and omicron variants 41, exhibits dose-dependent inhibition of lung injury 42,43, may inhibit SARS-CoV-2 via
IMPase inhibition 29, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation 44, inhibits
SARS-CoV-2 3CLpro 45, may inhibit SARS-CoV-2 RdRp activity 46, may minimize viral myocarditis by inhibiting NF-
κB/p65-mediated inflammation in macrophages 47, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET
formation 48, may inhibit SARS-CoV-2 by disrupting CD147 interaction 49-52, shows protection against inflammation,
cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-19 53,54, may
be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell
proliferation that leads to lung damage 55, and may minimize SARS-CoV-2 induced cardiac damage 56,57.

30 In Silico studies support the efficacy of ivermectin 44,46,55,63-89.

24 In Vitro studies support the efficacy of ivermectin 29,35,38,39,41,45,53,56,57,59,90-103.

14 In Vivo animal studies support the efficacy of ivermectin 42,43,47,53,61,95,99,104-110.

7 studies investigate novel formulations of ivermectin that may be more effective for COVID-19 92,105,106,110-113.

Preclinical research is an important part of the development of treatments, however results may be very different in
clinical trials. Preclinical results are not used in this paper.

Results

Table 1 summarizes the results of random-effects meta analysis for all stages combined, for Randomized Controlled
Trials, for peer-reviewed studies, with different exclusions, and for specific outcomes. Table 2 shows results by
treatment stage. Figure 3 plots individual results by treatment stage. Figure 4, 5, 6, 7, 8, 9, 10, and 11 show forest
plots for random effects meta-analysis of all studies with pooled effects, and for specific outcomes: mortality, ICU
admission, mechanical ventilation, hospitalization, recovery, cases, and viral clearance. Figure 12 shows results for
peer reviewed trials only, and the supplementary data contains peer reviewed and individual outcome results after
exclusions.

Improvement Studies Patients Authors

****
All studies 60% [52-67%] p < 0.0001 105 220,423 1,206
****
After exclusions 65% [58-72%] p < 0.0001 70 202,821 831

Peer-reviewed studies 59% [50-67%] p < 0.0001 **** 89 133,335 1,099

****
Randomized Controlled Trials 52% [37-63%] p < 0.0001 52 17,642 762
****
RCTs after exclusions 60% [45-71%] p < 0.0001 39 12,977 532

Mortality 47% [34-58%] p < 0.0001 **** 53 123,452 638

Ventilation 35% [17-50%] p = 0.00063 *** 20 37,217 300

**
ICU admission 40% [12-58%] p = 0.0078 15 28,149 225
****
Hospitalization 34% [21-44%] p < 0.0001 30 122,275 454

Recovery 38% [29-46%] p < 0.0001 **** 39 13,227 463

****
Cases 81% [71-87%] p < 0.0001 16 13,696 144
****
Viral 42% [29-52%] p < 0.0001 32 4,378 460

RCT mortality 26% [3-44%] p = 0.027 * 20 7,864 348

RCT cases 87% [56-96%] p = 0.00092 *** 4 2,173 39

**
RCT viral 19% [6-31%] p = 0.0064 24 3,279 402

Table 1. Random effects meta-analysis for all stages combined, for Randomized Controlled
Trials, for peer-reviewed studies, with different exclusions, and for specific outcomes. Results
show the percentage improvement with treatment and the 95% confidence interval. * p<0.05
** *** ****
p<0.01 p<0.001 p<0.0001.
 Early treatment Late treatment Prophylaxis

All studies 61% [50-69%] **** 40% [26-51%] **** 85% [77-90%] ****

After exclusions 69% [61-76%] **** 48% [32-60%] **** 84% [73-91%] ****

Peer-reviewed studies 60% [48-69%] **** 42% [26-55%] **** 83% [73-90%] ****

Randomized Controlled Trials 55% [39-67%] **** 28% [12-41%] ** 89% [57-97%] **

RCTs after exclusions 65% [53-74%] **** 34% [14-50%] ** 89% [57-97%] **

Mortality 39% [11-58%] * 43% [26-56%] **** 90% [50-98%] **

Ventilation 19% [-16-44%] 47% [28-61%] ****

ICU admission 52% [3-76%] * 35% [2-57%] *

Hospitalization 53% [27-69%] *** 18% [5-29%] ** 67% [54-77%] ****

Recovery 55% [34-69%] **** 27% [17-35%] ****

Cases 81% [71-87%] ****

Viral 43% [29-55%] **** 37% [7-58%] *

RCT mortality 14% [-40-47%] 31% [5-50%] *

RCT cases 87% [56-96%] ***

RCT viral 21% [7-34%] ** 10% [-43-44%]

Table 2. Random effects meta-analysis results by treatment stage. Results show the
percentage improvement with treatment, the 95% confidence interval, and the number of studies
for the stage. * p<0.05 **
p<0.01 ***
p<0.001 ****
p<0.0001.

Efficacy in COVID-19 ivermectin studies (pooled effects) [Link]

October 2024
Prophylaxis
Early treatment

Late treatment

All studies
0 0.25 0.5 0.75 1 1.25 1.5+

Favors ivermectin Favors control

Figure 3. Results by treatment stage.

All 105 ivermectin COVID-19 studies [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] hosp. 0/60 2/56 14mg OT​1 CT​2
Espitia-Hernandez 70% 0.30 [0.16-0.55] recov. time 28 (n) 7 (n) 12mg CT​2
Carvallo 85% 0.15 [0.02-1.28] death 1/32 3/14 36mg CT​2
Mahmud (DB RCT) 86% 0.14 [0.01-2.75] death 0/183 3/183 12mg CT​2
Szente Fonseca -14% 1.14 [0.75-1.66] hosp. 340 (n) 377 (n) 24mg
Cadegiani 78% 0.22 [0.01-4.48] death 0/110 2/137 42mg CT​2
Ahmed (DB RCT) 85% 0.15 [0.01-2.70] symptoms 0/17 3/19 48mg
Chaccour (DB RCT) 96% 0.04 [0.00-1.01] symptoms 12 (n) 12 (n) 28mg
Ghauri 92% 0.08 [0.01-0.88] no recov. 0/37 7/53 48mg
Babalola (DB RCT) 64% 0.36 [0.10-1.27] viral+ 40 (n) 20 (n) 24mg OT​1
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] death 0/55 4/57 24mg
Bukhari (RCT) 82% 0.18 [0.07-0.46] viral+ 4/41 25/45 12mg
Mohan (DB RCT) 62% 0.38 [0.08-1.75] no recov. 2/40 6/45 28mg RIVET-COV
Biber (DB RCT) 70% 0.30 [0.03-2.76] hosp. 1/47 3/42 36mg
Elalfy 87% 0.13 [0.06-0.27] viral+ 7/62 44/51 36mg CT​2
López-Me.. (DB RCT) 67% 0.33 [0.01-8.11] death 0/200 1/198 84mg
Roy 6% 0.94 [0.52-1.93] recov. time 14 (n) 15 (n) n/a CT​2
Chahla (CLUS. RCT) 87% 0.13 [0.03-0.54] no disch. 2/110 20/144 24mg
Mourya 89% 0.11 [0.05-0.25] viral+ 5/50 47/50 48mg
Loue (QR) 70% 0.30 [0.04-2.20] death 1/10 5/15 14mg
Merino (QR) 74% 0.26 [0.11-0.57] hosp. 77,381 (all patients) 24mg censored, see notes CS​5
Faisal (RCT) 68% 0.32 [0.14-0.72] no recov. 6/50 19/50 48mg
Aref (RCT) 63% 0.37 [0.22-0.61] recov. time 57 (n) 57 (n) n/a
Krolewiecki (RCT) -152% 2.52 [0.11-58.1] ventilation 1/27 0/14 168mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] death 4/250 3/251 24mg
Reis (DB RCT) 12% 0.88 [0.49-1.55] death 21/679 24/679 84mg TOGETHER impossible data, see notes
Buonfrate (DB RCT) -211% 3.11 [0.13-73.3] hosp. 1/28 0/31 336mg COVER
Mayer 55% 0.45 [0.32-0.63] death 3,266 (n) 17,966 (n) 151mg
Borody 92% 0.08 [0.01-0.79] death 0/600 6/600 96mg MD​3 CT​2 SC​4
Abbas (DB RCT) -4% 1.04 [0.07-16.4] death 1/99 1/103 84mg
de Jesús Ascenci.. 59% 0.41 [0.36-0.47] death/hosp. 7,898 (n) 20,150 (n) 12mg CT​2
Manomai.. (DB RCT) 43% 0.57 [0.20-1.46] no recov. 3/36 6/36 48mg
de la Ro.. (DB RCT) -187% 2.87 [0.12-67.5] misc. 1/30 0/26 36mg
Rezai (DB RCT) -5% 1.05 [0.07-16.7] death 1/268 1/281 84mg
Mirahma.. (DB RCT) 67% 0.33 [0.03-3.14] ventilation 1/131 3/130 24mg
Schilling (RCT) 67% 0.33 [0.01-7.97] hosp. 0/45 1/45 168mg PLATCOV
Bramante (DB RCT) -197% 2.97 [0.12-72.7] death 1/408 0/396 90mg COVID-OUT OT​1
Mikamo (DB RCT) -205% 3.05 [0.12-74.7] progression 1/502 0/527 63mg
Siripongbo.. (RCT) 0% 1.00 [0.07-15.3] progression 1/30 1/30 168mg FINCOV CT​2
Wijewic.. (DB RCT) -196% 2.96 [0.12-72.0] death 1/127 0/122 96mg

Early treatment 61% 0.39 [0.31-0.50] 67/16,019 240/43,034 61% lower risk
Tau​2 = 0.17, I​2 = 50.3%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (4d)

Gorial 71% 0.29 [0.01-5.76] death 0/16 2/71 14mg
Kishoria (RCT) -8% 1.08 [0.57-2.02] no disch. 11/19 7/13 12mg
Podder (RCT) 16% 0.84 [0.55-1.12] recov. time 32 (n) 30 (n) 14mg
Khan 87% 0.13 [0.02-1.00] death 1/115 9/133 12mg
Chachar (RCT) 10% 0.90 [0.44-1.83] no recov. 9/25 10/25 36mg
Soto-Becerra 17% 0.83 [0.71-0.97] death 92/203 1,438/2,630 14mg
Rajter (PSM) 46% 0.54 [0.27-0.99] death 13/98 24/98 14mg
Hashim (SB RCT) 92% 0.08 [0.00-1.44] death 0/59 6/70 28mg CT​2
Camprubí 40% 0.60 [0.18-2.01] ventilation 3/13 5/13 14mg
Spoorthi 21% 0.79 [0.64-0.98] recov. time 50 (n) 50 (n) n/a CT​2
Budhiraja 99% 0.01 [0.00-0.15] death 0/34 103/942 n/a
Okumuş (DB RCT) 33% 0.67 [0.27-1.64] death 6/30 9/30 56mg
Shahbazn.. (DB RCT) -197% 2.97 [0.13-70.5] death 1/35 0/34 14mg
Lima-Morales 78% 0.22 [0.12-0.41] death 15/481 52/287 12mg CT​2
Beltran .. (DB RCT) 14% 0.86 [0.29-2.56] death 5/36 6/37 12mg
Pott-Junior (RCT) 85% 0.15 [0.01-1.93] ventilation 1/27 1/4 14mg censored, see notes
Huvemek (DB RCT) 32% 0.68 [0.38-1.23] no improv. 13/50 19/50 84mg
Ahsan 50% 0.50 [0.28-0.90] death 17/110 17/55 21mg CT​2
Abd-Elsalam (RCT) 25% 0.75 [0.17-3.06] death 3/82 4/82 36mg
Hazan 86% 0.14 [0.01-2.15] death 0/24 synthetic 24mg CT​2 SC​4
Elavarasi 20% 0.80 [0.61-1.06] death 48/283 311/1,475 n/a
Rezk 80% 0.20 [0.01-4.13] death 0/160 2/160 72mg
Lim (RCT) 69% 0.31 [0.09-1.11] death 3/241 10/249 112mg I-TECH
Ozer 75% 0.25 [0.06-1.13] death 2/60 8/60 28mg
Ferreira -5% 1.05 [0.32-3.43] death 3/21 11/81 n/a
Jamir (ICU) -53% 1 53 [0 88-2 67] death 32/76 69/190 n/a ICU patients
Jamir (ICU) 53% 1.53 [0.88 2.67] death 32/76 69/190 n/a ICU patients
Baguma 97% 0.03 [0.00-11.7] death 7 (n) 474 (n) n/a
Mustafa 64% 0.36 [0.12-1.14] death 3/73 42/371 varies
Shimizu 100% 0.00 [0.00-0.01] death 0/39 8/49 14mg
Zubair -9% 1.09 [0.33-3.64] death 5/90 5/98 12mg
Thairu (PSM) 88% 0.12 [0.01-2.14] death 0/21 4/26 56mg
Efimenko (PSM) 69% 0.31 [0.20-0.48] death 1,072 (n) 40,536 (n) n/a self-censored, see notes OT​1
Soto -41% 1.41 [1.16-1.76] death 280/484 374/934 n/a
Ravikirti 3% 0.97 [0.74-1.24] death 53/171 254/794 varies
George (RCT) 30% 0.70 [0.25-1.93] death 5/35 8/39 24mg
Naggie (DB RCT) -202% 3.02 [0.12-74.1] death 1/708 0/724 168mg ACTIV-6
Rezai (DB RCT) 31% 0.69 [0.35-1.39] death 13/311 18/298 84mg
Qadeer 58% 0.42 [0.31-0.56] viral+ 35/105 84/105 48mg
Aref (RCT) 74% 0.26 [0.12-0.55] recov. time 49 (n) 47 (n) n/a LONG COVID
Ochoa-Ja.. (DB RCT) 57% 0.43 [0.07-2.50] death 2/37 4/38 28mg
Sarojvisut (RCT) -104% 2.04 [0.19-22.3] ICU 2/157 1/160 112mg
Munir 48% 0.52 [0.22-1.21] death 92 (n) 908 (n) n/a
Llenas-García 17% 0.83 [0.38-1.84] death 10/96 12/96 14mg
Wada (DB RCT) 19% 0.81 [0.44-1.38] progression 19/106 23/106 14mg
Osati 32% 0.68 [0.45-0.92] death 448 (n) 849 (n) n/a
Hayward (RCT) -1% 1.01 [0.61-1.68] death/hosp. 34/2,157 27/1,806 73mg PRINCIPLE
Varnaseri (DB RCT) 82% 0.18 [0.04-0.78] ventilation 2/55 11/55 84mg
Hashmi (RCT) 15% 0.85 [0.45-1.62] death 81 (n) 69 (n) 56mg REMAP-CAP ICU patients

Late treatment 40% 0.60 [0.49-0.74] 742/8,774 2,998/55,451 40% lower risk
Tau​2 = 0.25, I​2 = 79.7%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (1m)

Shouman (RCT) 91% 0.09 [0.03-0.23] symp. case 15/203 59/101 36mg
Carvallo 96% 0.04 [0.00-0.63] cases 0/131 11/98 14mg see notes CT​2
Behera 54% 0.46 [0.29-0.71] cases 41/117 145/255 42mg
Carvallo 100% 0.00 [0.00-0.02] cases 0/788 237/407 48mg see notes CT​2
Hellwig (ECO.) 78% 0.22 [0.06-0.76] cases ecological 14mg
Bernigaud 99% 0.01 [0.00-0.10] death 0/69 150/3,062 84mg
Alam 91% 0.09 [0.04-0.25] cases 4/58 44/60 12mg
IVERCOR PREP 73% 0.27 [0.15-0.48] cases 13/389 61/486 48mg MD​3
Chahla (RCT) 95% 0.05 [0.00-0.80] m/s case 0/117 10/117 48mg CT​2
Behera 83% 0.17 [0.12-0.23] cases 45/2,199 133/1,147 42mg
Tanioka (ECO.) 88% 0.12 [0.03-0.46] death ecological 14mg
Seet (CLUS. RCT) 50% 0.50 [0.33-0.76] symp. case 32/617 64/619 12mg OT​1
Morgenstern (PSM) 80% 0.20 [0.01-4.15] hosp. 0/271 2/271 56mg
Mondal 88% 0.12 [0.01-0.55] symp. case 128 (n) 1,342 (n) n/a
Samajdar 80% 0.20 [0.11-0.38] cases 12/164 29/81 n/a
Kerr (PSM) 70% 0.30 [0.19-0.46] death 25/3,034 79/3,034 56mg
Desort-H.. (DB RCT) 96% 0.04 [0.02-0.11] high v. load 4/200 99/199 203mg SAIVE

Prophylaxis 85% 0.15 [0.10-0.23] 191/8,485 1,123/11,279 85% lower risk

Tau​2 = 0.52, I​2 = 83.3%, p < 0.0001

All studies 60% 0.40 [0.33-0.48] 1,000/33,278 4,361/109,764 60% lower risk
1 2
OT: ivermectin vs. other treatment CT: study uses combined treatment
3
MD: minimal detail available currently 4
SC: study uses synthetic control arm 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+
5
CS: censored, see details
Tau​2 = 0.48, I​2 = 85.8%, p < 0.0001 Effect extraction pre-specified, see appendix Favors ivermectin Favors control

Figure 4. Random effects meta-analysis for all studies. This plot shows pooled effects, see the specific outcome analyses
for individual outcomes. Analysis validating pooled outcomes for COVID-19 can be found below. Effect extraction is pre-
specified, using the most serious outcome reported. Simplified dosages are shown for comparison, these are the total dose
in the first four days for treatment, or the monthly dose for prophylaxis, for a 70kg person. For details of effect extraction and
full dosage information see the appendix.
All 53 ivermectin COVID-19 mortality results [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Carvallo 85% 0.15 [0.02-1.28] 1/32 3/14 36mg CT​2
Mahmud (DB RCT) 86% 0.14 [0.01-2.75] 0/183 3/183 12mg CT​2
Cadegiani 78% 0.22 [0.01-4.48] 0/110 2/137 42mg CT​2
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] 0/55 4/57 24mg
López-Me.. (DB RCT) 67% 0.33 [0.01-8.11] 0/200 1/198 84mg
Loue (QR) 70% 0.30 [0.04-2.20] 1/10 5/15 14mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] 4/250 3/251 24mg
Reis (DB RCT) 12% 0.88 [0.49-1.55] 21/679 24/679 84mg TOGETHER impossible data, see notes
Mayer 55% 0.45 [0.32-0.63] 3,266 (n) 17,966 (n) 151mg
Borody 92% 0.08 [0.01-0.79] 0/600 6/600 96mg MD​3 CT​2 SC​4
Abbas (DB RCT) -4% 1.04 [0.07-16.4] 1/99 1/103 84mg
de Jesús Ascenci.. 15% 0.85 [0.68-1.06] 101/7,898 303/20,150 12mg CT​2
Rezai (DB RCT) -5% 1.05 [0.07-16.7] 1/268 1/281 84mg
Bramante (DB RCT) -197% 2.97 [0.12-72.7] 1/408 0/396 90mg COVID-OUT OT​1
Wijewic.. (DB RCT) -196% 2.96 [0.12-72.0] 1/127 0/122 96mg

Early treatment 39% 0.61 [0.42-0.89] 132/14,185 356/41,152 39% lower risk
Tau​2 = 0.11, I​2 = 37.9%, p = 0.01

Improvement, RR [CI] Treatment Control Dose (4d)

Gorial 71% 0.29 [0.01-5.76] 0/16 2/71 14mg
Khan 87% 0.13 [0.02-1.00] 1/115 9/133 12mg
Soto-Becerra 17% 0.83 [0.71-0.97] 92/203 1,438/2,630 14mg
Rajter (PSM) 46% 0.54 [0.27-0.99] 13/98 24/98 14mg
Hashim (SB RCT) 92% 0.08 [0.00-1.44] 0/59 6/70 28mg CT​2
Budhiraja 99% 0.01 [0.00-0.15] 0/34 103/942 n/a
Okumuş (DB RCT) 33% 0.67 [0.27-1.64] 6/30 9/30 56mg
Shahbazn.. (DB RCT) -197% 2.97 [0.13-70.5] 1/35 0/34 14mg
Lima-Morales 78% 0.22 [0.12-0.41] 15/481 52/287 12mg CT​2
Beltran .. (DB RCT) 14% 0.86 [0.29-2.56] 5/36 6/37 12mg
Ahsan 50% 0.50 [0.28-0.90] 17/110 17/55 21mg CT​2
Abd-Elsalam (RCT) 25% 0.75 [0.17-3.06] 3/82 4/82 36mg
Hazan 86% 0.14 [0.01-2.15] 0/24 synthetic 24mg CT​2 SC​4
Elavarasi 20% 0.80 [0.61-1.06] 48/283 311/1,475 n/a
Rezk 80% 0.20 [0.01-4.13] 0/160 2/160 72mg
Lim (RCT) 69% 0.31 [0.09-1.11] 3/241 10/249 112mg I-TECH
Ozer 75% 0.25 [0.06-1.13] 2/60 8/60 28mg
Ferreira -5% 1.05 [0.32-3.43] 3/21 11/81 n/a
Jamir (ICU) -53% 1.53 [0.88-2.67] 32/76 69/190 n/a ICU patients
Baguma 97% 0.03 [0.00-11.7] 7 (n) 474 (n) n/a
Mustafa 64% 0.36 [0.12-1.14] 3/73 42/371 varies
Shimizu 100% 0.00 [0.00-0.01] 0/39 8/49 14mg
Zubair -9% 1.09 [0.33-3.64] 5/90 5/98 12mg
Thairu (PSM) 88% 0.12 [0.01-2.14] 0/21 4/26 56mg
Efimenko (PSM) 69% 0.31 [0.20-0.48] 1,072 (n) 40,536 (n) n/a self-censored, see notes OT​1
Soto -41% 1.41 [1.16-1.76] 280/484 374/934 n/a
Ravikirti 3% 0.97 [0.74-1.24] 53/171 254/794 varies
George (RCT) 30% 0.70 [0.25-1.93] 5/35 8/39 24mg
Naggie (DB RCT) -202% 3.02 [0.12-74.1] 1/708 0/724 168mg ACTIV-6
Rezai (DB RCT) 31% 0.69 [0.35-1.39] 13/311 18/298 84mg
Ochoa-Ja.. (DB RCT) 57% 0.43 [0.07-2.50] 2/37 4/38 28mg
Munir 48% 0.52 [0.22-1.21] 92 (n) 908 (n) n/a
Llenas-García 17% 0.83 [0.38-1.84] 10/96 12/96 14mg
Osati 32% 0.68 [0.45-0.92] 448 (n) 849 (n) n/a
Hashmi (RCT) 15% 0.85 [0.45-1.62] 81 (n) 69 (n) 56mg REMAP-CAP ICU patients

Late treatment 43% 0.57 [0.44-0.74] 613/5,929 2,810/52,987 43% lower risk
Tau​2 = 0.29, I​2 = 81.1%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (1m)

Bernigaud 99% 0.01 [0.00-0.10] 0/69 150/3,062 84mg
Tanioka (ECO.) 88% 0.12 [0.03-0.46] ecological 14mg
Kerr (PSM) 70% 0.30 [0.19-0.46] 25/3,034 79/3,034 56mg

Prophylaxis 90% 0.10 [0.02-0.50] 25/3,103 229/6,096 90% lower risk

Tau​2 = 1.39, I​2 = 76.5%, p = 0.005

All studies 47% 0.53 [0.42-0.66] 770/23,217 3,395/100,235 47% lower risk

1 2 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment CT: study uses combined treatment
3 4
MD: minimal detail available currently SC: study uses synthetic control arm
T 2
0 30 I2 79 9% < 0 0001 Favors ivermectin Favors control
Tau​2 = 0.30, I​2 = 79.9%, p < 0.0001 Favors ivermectin Favors control

Figure 5. Random effects meta-analysis for mortality.

All 20 ivermectin COVID-19 mechanical ventilation results [Link]

Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Cadegiani 94% 0.06 [0.00-0.99] 0/110 9/137 42mg CT​1
Ravikirti (DB RCT) 79% 0.21 [0.03-1.72] 1/55 5/57 24mg
Krolewiecki (RCT) -152% 2.52 [0.11-58.1] 1/27 0/14 168mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] 4/250 3/251 24mg
Reis (DB RCT) 23% 0.77 [0.43-1.36] 19/679 25/679 84mg TOGETHER impossible data, see notes
de Jesús Ascenci.. 9% 0.91 [0.70-1.18] 77/7,898 216/20,150 12mg CT​1
Mirahma.. (DB RCT) 67% 0.33 [0.03-3.14] 1/131 3/130 24mg

Early treatment 19% 0.81 [0.56-1.16] 103/9,150 261/21,418 19% lower risk
Tau​2 = 0.04, I​2 = 14.4%, p = 0.25

Improvement, RR [CI] Treatment Control Dose (4d)

Rajter (PSM) 64% 0.36 [0.12-1.10] 4/98 11/98 14mg
Camprubí 40% 0.60 [0.18-2.01] 3/13 5/13 14mg
Shahbazn.. (DB RCT) -94% 1.94 [0.18-20.4] 2/35 1/34 14mg
Lima-Morales 52% 0.48 [0.20-1.18] 8/434 11/287 12mg CT​1
Pott-Junior (RCT) 85% 0.15 [0.01-1.93] 1/27 1/4 14mg censored, see notes
Abd-Elsalam (RCT) 0% 1.00 [0.21-4.81] 3/82 3/82 36mg
Lim (RCT) 59% 0.41 [0.13-1.30] 4/241 10/249 112mg I-TECH
Ozer (PSM) 13% 0.87 [0.11-5.58] 3/60 2/60 28mg
Shimizu 48% 0.52 [0.29-0.93] 39 (n) 49 (n) 14mg
Rezai (DB RCT) 50% 0.50 [0.24-1.07] 311 (n) 298 (n) 84mg
Ochoa-Ja.. (DB RCT) -34% 1.34 [0.42-4.23] 7/37 5/38 28mg
Hayward (RCT) -151% 2.51 [0.26-24.2] 3/2,149 1/1,801 73mg PRINCIPLE
Varnaseri (DB RCT) 82% 0.18 [0.04-0.78] 2/55 11/55 84mg

Late treatment 47% 0.53 [0.39-0.72] 40/3,581 61/3,068 47% lower risk
Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001

All studies 35% 0.65 [0.50-0.83] 143/12,731 322/24,486 35% lower risk

1 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

CT: study uses combined treatment

Tau​2 = 0.04, I​2 = 14.3%, p = 0.00063 Favors ivermectin Favors control

Figure 6. Random effects meta-analysis for mechanical ventilation.

All 15 ivermectin COVID-19 ICU results [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Ravikirti (DB RCT) 14% 0.86 [0.28-2.67] 5/55 6/57 24mg
Mayer 66% 0.34 [0.22-0.51] 3,266 (n) 17,966 (n) 151mg
Rezai (DB RCT) -9% 1.09 [0.07-17.3] 268 (n) 281 (n) 84mg

Early treatment 52% 0.48 [0.24-0.97] 5/3,589 6/18,304 52% lower risk
Tau​2 = 0.15, I​2 = 32.8%, p = 0.04

Improvement, RR [CI] Treatment Control Dose (4d)

Khan 89% 0.11 [0.01-0.80] 1/115 11/133 12mg
Camprubí 33% 0.67 [0.13-3.35] 2/13 3/13 14mg
Pott-Junior (RCT) 85% 0.15 [0.01-1.93] 1/27 1/4 14mg censored, see notes
Lim (RCT) 22% 0.78 [0.27-2.20] 6/241 8/249 112mg I-TECH
Ozer (PSM) 49% 0.51 [0.09-2.50] 6/60 3/60 28mg
Shimizu 43% 0.57 [0.32-1.02] 39 (n) 49 (n) 14mg
Rezai (DB RCT) 16% 0.84 [0.52-1.36] 311 (n) 298 (n) 84mg
Ochoa-Ja.. (DB RCT) -37% 1.37 [0.53-3.57] 8/37 6/38 28mg
Sarojvisut (RCT) -104% 2.04 [0.19-22.3] 2/157 1/160 112mg
Llenas-García -4% 1.04 [0.51-2.11] 96 (n) 96 (n) 14mg
Hayward (RCT) -319% 4.19 [0.49-35.8] 5/2,149 1/1,801 73mg PRINCIPLE
Varnaseri (DB RCT) 83% 0.17 [0.05-0.53] 3/55 18/55 84mg

Late treatment 35% 0.65 [0.43-0.98] 34/3,300 52/2,956 35% lower risk
Tau​2 = 0.15, I​2 = 34.1%, p = 0.041

All studies 40% 0.60 [0.42-0.88] 39/6,889 58/21,260 40% lower risk

0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

Tau​2 = 0.18, I​2 = 43.4%, p = 0.0078 Favors ivermectin Favors control

Figure 7. Random effects meta-analysis for ICU admission.

All 30 ivermectin COVID-19 hospitalization results [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] hosp. 0/60 2/56 14mg OT​1 CT​2
Szente Fonseca -14% 1.14 [0.75-1.66] hosp. 340 (n) 377 (n) 24mg
Cadegiani 98% 0.02 [0.00-0.33] hosp. 0/110 27/137 42mg CT​2
Biber (DB RCT) 70% 0.30 [0.03-2.76] hosp. 1/47 3/42 36mg
Merino (QR) 74% 0.26 [0.11-0.57] hosp. 77,381 (all patients) 24mg censored, see notes CS​5
Vallejos (DB RCT) 33% 0.67 [0.34-1.28] hosp. 14/250 21/251 24mg
Reis (DB RCT) 17% 0.83 [0.63-1.10] hosp. 79/679 95/679 84mg TOGETHER impossible data, see notes
Buonfrate (DB RCT) -211% 3.11 [0.13-73.3] hosp. 1/28 0/31 336mg COVER
Borody 93% 0.07 [0.04-0.13] hosp. 5/600 70/600 96mg MD​3 CT​2 SC​4
de Jesús Ascenci.. 48% 0.52 [0.48-0.58] hosp. 485/7,898 2,360/20,150 12mg CT​2
Rezai (DB RCT) -36% 1.36 [0.65-2.84] hosp. 268 (n) 281 (n) 84mg
Mirahma.. (DB RCT) 46% 0.54 [0.21-1.42] hosp. 6/131 11/130 24mg
Schilling (RCT) 67% 0.33 [0.01-7.97] hosp. 0/45 1/45 168mg PLATCOV
Bramante (DB RCT) 61% 0.39 [0.08-2.00] hosp. 2/206 5/202 90mg COVID-OUT OT​1

Early treatment 53% 0.47 [0.31-0.73] 593/10,662 2,595/22,981 53% lower risk
Tau​2 = 0.35, I​2 = 83.3%, p = 0.00067

Improvement, RR [CI] Treatment Control Dose (4d)

Gorial 42% 0.58 [0.45-0.75] hosp. time 16 (n) 71 (n) 14mg
Khan 40% 0.60 [0.44-0.81] hosp. time 115 (n) 133 (n) 12mg
Spoorthi 16% 0.84 [0.74-0.96] hosp. time 50 (n) 50 (n) n/a CT​2
Shahbazn.. (DB RCT) 15% 0.85 [0.74-0.97] hosp. time 35 (n) 34 (n) 14mg
Lima-Morales 67% 0.33 [0.22-0.47] hosp. 44/481 89/287 12mg CT​2
Beltran .. (DB RCT) -20% 1.20 [0.77-1.87] hosp. time 36 (n) 37 (n) 12mg
Abd-Elsalam (RCT) 20% 0.80 [0.63-1.03] hosp. time 82 (n) 82 (n) 36mg
Hazan 93% 0.07 [0.00-1.02] hosp. 0/24 synthetic 24mg CT​2 SC​4
Lim (RCT) -5% 1.05 [0.94-1.19] hosp. time 241 (n) 249 (n) 112mg I-TECH
Ozer (PSM) -9% 1.09 [0.99-1.22] hosp. time 60 (n) 60 (n) 28mg
Zubair -8% 1.08 [0.91-1.29] hosp. time 90 (n) 98 (n) 12mg
Naggie (DB RCT) -5% 1.05 [0.43-2.58] hosp. 10/817 9/774 168mg ACTIV-6
Rezai (DB RCT) -11% 1.11 [1.03-1.21] hosp. time 311 (n) 298 (n) 84mg
Varnaseri (DB RCT) 33% 0.67 [0.52-0.85] hosp. time 55 (n) 55 (n) 84mg

Late treatment 18% 0.82 [0.71-0.95] 54/2,413 98/2,228 18% lower risk
Tau​2 = 0.06, I​2 = 88.3%, p = 0.008

Improvement, RR [CI] Treatment Control Dose (1m)

Morgenstern (PSM) 80% 0.20 [0.01-4.15] hosp. 0/271 2/271 56mg
Kerr (PSM) 67% 0.33 [0.23-0.46] hosp. 44/3,034 99/3,034 56mg

Prophylaxis 67% 0.33 [0.23-0.46] 44/3,305 101/3,305 67% lower risk

Tau​2 = 0.00, I​2 = 0.0%, p < 0.0001

All studies 34% 0.66 [0.56-0.79] 691/16,380 2,794/28,514 34% lower risk
1 2
OT: ivermectin vs. other treatment CT: study uses combined treatment
3
MD: minimal detail available currently 4
SC: study uses synthetic control arm 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+
5
CS: censored, see details
Tau​2 = 0.14, I​2 = 91.9%, p < 0.0001 Favors ivermectin Favors control

Figure 8. Random effects meta-analysis for hospitalization.

All 39 ivermectin COVID-19 recovery results [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 46% 0.54 [0.40-0.73] no recov. 27/60 47/56 14mg OT​1 CT​2
Espitia-Hernandez 70% 0.30 [0.16-0.55] recov. time 28 (n) 7 (n) 12mg CT​2
Mahmud (DB RCT) 94% 0.06 [0.04-0.09] no recov. 72/183 100/180 12mg CT​2
Ghauri 92% 0.08 [0.01-0.88] no recov. 0/37 7/53 48mg
Babalola (DB RCT) 41% 0.59 [0.33-1.05] ∆Spo2 38 (n) 18 (n) 24mg OT​1
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] no disch. 0/55 4/57 24mg
Mohan (DB RCT) 62% 0.38 [0.08-1.75] no recov. 2/40 6/45 28mg RIVET-COV
López-Me.. (DB RCT) 15% 0.85 [0.56-1.25] no recov. 36/200 42/198 84mg
Roy 6% 0.94 [0.52-1.93] recov. time 14 (n) 15 (n) n/a CT​2
Chahla (CLUS. RCT) 87% 0.13 [0.03-0.54] no disch. 2/110 20/144 24mg
Faisal (RCT) 68% 0.32 [0.14-0.72] no recov. 6/50 19/50 48mg
Aref (RCT) 63% 0.37 [0.22-0.61] recov. time 57 (n) 57 (n) n/a
Abbas (DB RCT) 36% 0.64 [0.43-0.96] no recov. 26/99 42/103 84mg
Manomai.. (DB RCT) 43% 0.57 [0.20-1.46] no recov. 3/36 6/36 48mg
Rezai (DB RCT) -2% 1.02 [0.96-1.08] no recov. 268 (n) 281 (n) 84mg
Mirahma.. (DB RCT) 39% 0.61 [0.26-1.42] no recov. 8/131 13/130 24mg
Mikamo (DB RCT) 4% 0.96 [0.78-1.20] no recov. 502 (n) 527 (n) 63mg
Siripongbo.. (RCT) 39% 0.61 [0.28-1.29] symp. score 30 (n) 30 (n) 168mg FINCOV CT​2

Early treatment 55% 0.45 [0.31-0.66] 182/1,938 306/1,987 55% lower risk
2 2
Tau​ = 0.49, I​ = 93.3%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (4d)

Gorial 71% 0.29 [0.01-5.76] no recov. 0/16 2/71 14mg
Kishoria (RCT) -8% 1.08 [0.57-2.02] no disch. 11/19 7/13 12mg
Podder (RCT) 16% 0.84 [0.55-1.12] recov. time 32 (n) 30 (n) 14mg
Khan 87% 0.13 [0.02-1.00] no recov. 1/115 9/133 12mg
Chachar (RCT) 10% 0.90 [0.44-1.83] no recov. 9/25 10/25 36mg
Hashim (SB RCT) 41% 0.59 [0.46-0.77] recov. time 70 (n) 70 (n) 28mg CT​2
Spoorthi 21% 0.79 [0.64-0.98] recov. time 50 (n) 50 (n) n/a CT​2
Shahbazn.. (DB RCT) 32% 0.68 [0.47-1.00] recov. time 35 (n) 34 (n) 14mg
Lima-Morales 59% 0.41 [0.30-0.55] no recov. 75/481 118/287 12mg CT​2
Beltran .. (DB RCT) -37% 1.37 [0.33-5.70] no disch. 4/36 3/37 12mg
Rezk 33% 0.67 [0.35-1.27] no recov. 14/145 20/138 72mg
Lim (RCT) -2% 1.02 [0.85-1.23] no recov. 116/241 116/247 112mg I-TECH
Thairu (PSM) 55% 0.45 [0.31-0.67] no disch. 61 (n) 26 (n) 56mg
George (RCT) 19% 0.81 [0.52-1.27] recov. time 35 (n) 39 (n) 24mg
Naggie (DB RCT) 2% 0.98 [0.89-1.09] recovery 708 (n) 724 (n) 168mg ACTIV-6
Rezai (DB RCT) 24% 0.76 [0.60-0.96] no recov. 311 (n) 298 (n) 84mg
Aref (RCT) 74% 0.26 [0.12-0.55] recov. time 49 (n) 47 (n) n/a LONG COVID
Sarojvisut (RCT) 4% 0.96 [0.82-1.12] recov. time 157 (n) 160 (n) 112mg
Wada (DB RCT) 60% 0.40 [0.13-1.24] no recov. 4/107 10/107 14mg
Hayward (RCT) 16% 0.84 [0.78-0.92] no recov. 2,157 (n) 1,806 (n) 73mg PRINCIPLE
Varnaseri (DB RCT) 28% 0.72 [0.66-0.78] recov. time 55 (n) 55 (n) 84mg

Late treatment 27% 0.73 [0.65-0.83] 234/4,905 295/4,397 27% lower risk
Tau​2 = 0.04, I​2 = 77.5%, p < 0.0001

All studies 38% 0.62 [0.54-0.71] 416/6,843 601/6,384 38% lower risk

1 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment
2
CT: study uses combined treatment
Tau​2 = 0.11, I​2 = 89.4%, p < 0.0001 Favors ivermectin Favors control

Figure 9. Random effects meta-analysis for recovery results only.

All 16 ivermectin COVID-19 case results [Link]
Improvement, RR [CI] Treatment Control Dose (1m)
October 2024
Shouman (RCT) 91% 0.09 [0.03-0.23] symp. case 15/203 59/101 36mg
Carvallo 96% 0.04 [0.00-0.63] cases 0/131 11/98 14mg see notes CT​2
Behera 54% 0.46 [0.29-0.71] cases 41/117 145/255 42mg
Carvallo 100% 0.00 [0.00-0.02] cases 0/788 237/407 48mg see notes CT​2
Hellwig (ECO.) 78% 0.22 [0.06-0.76] cases ecological 14mg
Bernigaud 55% 0.45 [0.22-0.91] cases 7/69 692/3,062 84mg
Alam 91% 0.09 [0.04-0.25] cases 4/58 44/60 12mg
IVERCOR PREP 73% 0.27 [0.15-0.48] cases 13/389 61/486 48mg MD​3
Chahla (RCT) 84% 0.16 [0.04-0.46] cases 4/117 25/117 48mg CT​2
Behera 83% 0.17 [0.12-0.23] cases 45/2,199 133/1,147 42mg
Seet (CLUS. RCT) 50% 0.50 [0.33-0.76] symp. case 32/617 64/619 12mg OT​1
Morgenstern (PSM) 74% 0.26 [0.10-0.71] cases 5/271 18/271 56mg
Mondal 88% 0.12 [0.01-0.55] symp. case 128 (n) 1,342 (n) n/a
Samajdar 80% 0.20 [0.11-0.38] cases 12/164 29/81 n/a
Kerr (PSM) 44% 0.56 [0.53-0.58] cases population-based cohort 56mg
Desort-H.. (DB RCT) 96% 0.04 [0.02-0.11] high v. load 4/200 99/199 203mg SAIVE

Prophylaxis 81% 0.19 [0.13-0.29] 182/5,451 1,617/8,245 81% lower risk

Tau​2 = 0.51, I​2 = 91.9%, p < 0.0001

All studies 81% 0.19 [0.13-0.29] 182/5,451 1,617/8,245 81% lower risk

1 2 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment CT: study uses combined treatment
3
MD: minimal detail available currently
Tau​2 = 0.51, I​2 = 91.9%, p < 0.0001 Favors ivermectin Favors control

Figure 10. Random effects meta-analysis for COVID-19 case results.

All 32 ivermectin COVID-19 viral clearance results [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] viral+ 0/60 2/56 14mg OT​1 CT​2
Espitia-Hernandez 97% 0.03 [0.01-0.10] viral+ 0/28 7/7 12mg CT​2
Mahmud (DB RCT) 39% 0.61 [0.44-0.83] viral+ 14/183 36/180 12mg CT​2
Ahmed (DB RCT) 76% 0.24 [0.07-0.91] viral+ 11/22 20/23 48mg
Chaccour (DB RCT) 95% 0.05 [0.01-0.50] viral load 12 (n) 12 (n) 28mg
Babalola (DB RCT) 64% 0.36 [0.10-1.27] viral+ 40 (n) 20 (n) 24mg OT​1
Ravikirti (DB RCT) -12% 1.12 [0.89-1.40] viral+ 42/55 39/57 24mg
Bukhari (RCT) 82% 0.18 [0.07-0.46] viral+ 4/41 25/45 12mg
Mohan (DB RCT) 24% 0.76 [0.53-1.09] viral+ 21/40 31/45 28mg RIVET-COV
Biber (DB RCT) 62% 0.38 [0.14-0.90] viral+ 8/47 17/42 36mg
Elalfy 87% 0.13 [0.06-0.27] viral+ 7/62 44/51 36mg CT​2
Mourya 89% 0.11 [0.05-0.25] viral+ 5/50 47/50 48mg
Aref (RCT) 79% 0.21 [0.07-0.71] viral+ 3/57 14/57 n/a
Krolewiecki (RCT) 66% 0.34 [0.10-1.16] decay rate 20 (n) 14 (n) 168mg
Vallejos (DB RCT) -5% 1.05 [0.88-1.21] viral+ 137/250 131/251 24mg
Reis (DB RCT) 0% 1.00 [0.68-1.47] viral+ 106/142 123/165 84mg TOGETHER impossible data, see notes
Buonfrate (DB RCT) 20% 0.80 [0.36-1.76] viral load 28 (n) 29 (n) 336mg COVER
Manomai.. (DB RCT) 5% 0.95 [0.62-1.45] viral+ 19/36 20/36 48mg
de la Ro.. (DB RCT) 2% 0.98 [0.81-1.18] viral load 30 (n) 26 (n) 36mg
Rezai (DB RCT) -23% 1.23 [0.92-1.67] viral+ 268 (n) 281 (n) 84mg
Schilling (RCT) -9% 1.09 [0.88-1.27] viral rate 45 (n) 45 (n) 168mg PLATCOV
Siripongbo.. (RCT) 6% 0.94 [0.65-1.35] viral+ 30 (n) 30 (n) 168mg FINCOV CT​2
Wijewic.. (DB RCT) 51% 0.49 [0.26-0.93] viral load 80 (n) 81 (n) 96mg

Early treatment 43% 0.57 [0.45-0.71] 377/1,626 556/1,603 43% lower risk
Tau​2 = 0.19, I​2 = 84.6%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (4d)

Kishoria (RCT) -8% 1.08 [0.57-2.02] viral+ 11/19 7/13 12mg
Khan 73% 0.27 [0.12-0.58] viral time 115 (n) 133 (n) 12mg
Camprubí -25% 1.25 [0.43-3.63] viral+ 5/13 4/13 14mg
Okumuş (DB RCT) 80% 0.20 [0.05-0.81] viral+ 2/16 5/8 56mg
Pott-Junior (RCT) 1% 0.99 [0.04-26.3] viral+ 27 (n) 3 (n) 14mg censored, see notes
Rezk 27% 0.73 [0.57-0.93] viral time 160 (n) 160 (n) 72mg
Thairu (PSM) 95% 0.05 [0.00-0.85] viral+ 0/21 10/26 56mg
Qadeer 58% 0.42 [0.31-0.56] viral+ 35/105 84/105 48mg
Wada (DB RCT) -4% 1.04 [0.76-1.43] viral+ 106 (n) 106 (n) 14mg

Late treatment 37% 0.63 [0.42-0.93] 53/582 110/567 37% lower risk
Tau​2 = 0.20, I​2 = 77.7%, p = 0.019

All studies 42% 0.58 [0.48-0.71] 430/2,208 666/2,170 42% lower risk

1 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment
2
CT: study uses combined treatment
Tau​2 = 0.19, I​2 = 83.7%, p < 0.0001 Favors ivermectin Favors control

Figure 11. Random effects meta-analysis for viral clearance.

All 89 ivermectin COVID-19 peer reviewed studies [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] hosp. 0/60 2/56 14mg OT​1 CT​2
Espitia-Hernandez 70% 0.30 [0.16-0.55] recov. time 28 (n) 7 (n) 12mg CT​2
Carvallo 85% 0.15 [0.02-1.28] death 1/32 3/14 36mg CT​2
Mahmud (DB RCT) 86% 0.14 [0.01-2.75] death 0/183 3/183 12mg CT​2
Szente Fonseca -14% 1.14 [0.75-1.66] hosp. 340 (n) 377 (n) 24mg
Cadegiani 78% 0.22 [0.01-4.48] death 0/110 2/137 42mg CT​2
Ahmed (DB RCT) 85% 0.15 [0.01-2.70] symptoms 0/17 3/19 48mg
Chaccour (DB RCT) 96% 0.04 [0.00-1.01] symptoms 12 (n) 12 (n) 28mg
Ghauri 92% 0.08 [0.01-0.88] no recov. 0/37 7/53 48mg
Babalola (DB RCT) 64% 0.36 [0.10-1.27] viral+ 40 (n) 20 (n) 24mg OT​1
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] death 0/55 4/57 24mg
Mohan (DB RCT) 62% 0.38 [0.08-1.75] no recov. 2/40 6/45 28mg RIVET-COV
Biber (DB RCT) 70% 0.30 [0.03-2.76] hosp. 1/47 3/42 36mg
Elalfy 87% 0.13 [0.06-0.27] viral+ 7/62 44/51 36mg CT​2
López-Me.. (DB RCT) 67% 0.33 [0.01-8.11] death 0/200 1/198 84mg
Chahla (CLUS. RCT) 87% 0.13 [0.03-0.54] no disch. 2/110 20/144 24mg
Mourya 89% 0.11 [0.05-0.25] viral+ 5/50 47/50 48mg
Loue (QR) 70% 0.30 [0.04-2.20] death 1/10 5/15 14mg
Faisal (RCT) 68% 0.32 [0.14-0.72] no recov. 6/50 19/50 48mg
Aref (RCT) 63% 0.37 [0.22-0.61] recov. time 57 (n) 57 (n) n/a
Krolewiecki (RCT) -152% 2.52 [0.11-58.1] ventilation 1/27 0/14 168mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] death 4/250 3/251 24mg
Reis (DB RCT) 12% 0.88 [0.49-1.55] death 21/679 24/679 84mg TOGETHER impossible data, see notes
Buonfrate (DB RCT) -211% 3.11 [0.13-73.3] hosp. 1/28 0/31 336mg COVER
Mayer 55% 0.45 [0.32-0.63] death 3,266 (n) 17,966 (n) 151mg
Abbas (DB RCT) -4% 1.04 [0.07-16.4] death 1/99 1/103 84mg
de Jesús Ascenci.. 59% 0.41 [0.36-0.47] death/hosp. 7,898 (n) 20,150 (n) 12mg CT​2
Manomai.. (DB RCT) 43% 0.57 [0.20-1.46] no recov. 3/36 6/36 48mg
de la Ro.. (DB RCT) -187% 2.87 [0.12-67.5] misc. 1/30 0/26 36mg
Rezai (DB RCT) -5% 1.05 [0.07-16.7] death 1/268 1/281 84mg
Mirahma.. (DB RCT) 67% 0.33 [0.03-3.14] ventilation 1/131 3/130 24mg
Schilling (RCT) 67% 0.33 [0.01-7.97] hosp. 0/45 1/45 168mg PLATCOV
Bramante (DB RCT) -197% 2.97 [0.12-72.7] death 1/408 0/396 90mg COVID-OUT OT​1
Mikamo (DB RCT) -205% 3.05 [0.12-74.7] progression 1/502 0/527 63mg
Siripongbo.. (RCT) 0% 1.00 [0.07-15.3] progression 1/30 1/30 168mg FINCOV CT​2
Wijewic.. (DB RCT) -196% 2.96 [0.12-72.0] death 1/127 0/122 96mg

Early treatment 60% 0.40 [0.31-0.52] 63/15,364 209/42,374 60% lower risk
Tau​2 = 0.15, I​2 = 46.9%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (4d)

Kishoria (RCT) -8% 1.08 [0.57-2.02] no disch. 11/19 7/13 12mg
Podder (RCT) 16% 0.84 [0.55-1.12] recov. time 32 (n) 30 (n) 14mg
Khan 87% 0.13 [0.02-1.00] death 1/115 9/133 12mg
Chachar (RCT) 10% 0.90 [0.44-1.83] no recov. 9/25 10/25 36mg
Rajter (PSM) 46% 0.54 [0.27-0.99] death 13/98 24/98 14mg
Hashim (SB RCT) 92% 0.08 [0.00-1.44] death 0/59 6/70 28mg CT​2
Camprubí 40% 0.60 [0.18-2.01] ventilation 3/13 5/13 14mg
Spoorthi 21% 0.79 [0.64-0.98] recov. time 50 (n) 50 (n) n/a CT​2
Okumuş (DB RCT) 33% 0.67 [0.27-1.64] death 6/30 9/30 56mg
Shahbazn.. (DB RCT) -197% 2.97 [0.13-70.5] death 1/35 0/34 14mg
Lima-Morales 78% 0.22 [0.12-0.41] death 15/481 52/287 12mg CT​2
Beltran .. (DB RCT) 14% 0.86 [0.29-2.56] death 5/36 6/37 12mg
Pott-Junior (RCT) 85% 0.15 [0.01-1.93] ventilation 1/27 1/4 14mg censored, see notes
Ahsan 50% 0.50 [0.28-0.90] death 17/110 17/55 21mg CT​2
Abd-Elsalam (RCT) 25% 0.75 [0.17-3.06] death 3/82 4/82 36mg
Hazan 86% 0.14 [0.01-2.15] death 0/24 synthetic 24mg CT​2 SC​3
Elavarasi 20% 0.80 [0.61-1.06] death 48/283 311/1,475 n/a
Rezk 80% 0.20 [0.01-4.13] death 0/160 2/160 72mg
Lim (RCT) 69% 0.31 [0.09-1.11] death 3/241 10/249 112mg I-TECH
Ozer 75% 0.25 [0.06-1.13] death 2/60 8/60 28mg
Ferreira -5% 1.05 [0.32-3.43] death 3/21 11/81 n/a
Jamir (ICU) -53% 1.53 [0.88-2.67] death 32/76 69/190 n/a ICU patients
Mustafa 64% 0.36 [0.12-1.14] death 3/73 42/371 varies
Shimizu 100% 0.00 [0.00-0.01] death 0/39 8/49 14mg
Zubair -9% 1.09 [0.33-3.64] death 5/90 5/98 12mg
Thairu (PSM) 88% 0.12 [0.01-2.14] death 0/21 4/26 56mg
Efimenko (PSM) 69% 0.31 [0.20-0.48] death 1,072 (n) 40,536 (n) n/a self-censored, see notes OT​1
Soto -41% 1.41 [1.16-1.76] death 280/484 374/934 n/a
George (RCT) 30% 0.70 [0.25-1.93] death 5/35 8/39 24mg
Naggie (DB RCT) -202% 3 02 [0 12-74 1] death 1/708 0/724 168mg ACTIV-6
 Naggie (DB RCT) 202% 3.02 [0.12 74.1] death 1/708 0/724 168mg ACTIV 6
Rezai (DB RCT) 31% 0.69 [0.35-1.39] death 13/311 18/298 84mg
Qadeer 58% 0.42 [0.31-0.56] viral+ 35/105 84/105 48mg
Aref (RCT) 74% 0.26 [0.12-0.55] recov. time 49 (n) 47 (n) n/a LONG COVID
Ochoa-Ja.. (DB RCT) 57% 0.43 [0.07-2.50] death 2/37 4/38 28mg
Sarojvisut (RCT) -104% 2.04 [0.19-22.3] ICU 2/157 1/160 112mg
Munir 48% 0.52 [0.22-1.21] death 92 (n) 908 (n) n/a
Llenas-García 17% 0.83 [0.38-1.84] death 10/96 12/96 14mg
Wada (DB RCT) 19% 0.81 [0.44-1.38] progression 19/106 23/106 14mg
Hayward (RCT) -1% 1.01 [0.61-1.68] death/hosp. 34/2,157 27/1,806 73mg PRINCIPLE
Varnaseri (DB RCT) 82% 0.18 [0.04-0.78] ventilation 2/55 11/55 84mg

Late treatment 42% 0.58 [0.45-0.74] 584/7,764 1,182/49,572 42% lower risk
Tau​2 = 0.34, I​2 = 82.0%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (1m)

Shouman (RCT) 91% 0.09 [0.03-0.23] symp. case 15/203 59/101 36mg
Behera 54% 0.46 [0.29-0.71] cases 41/117 145/255 42mg
Carvallo 100% 0.00 [0.00-0.02] cases 0/788 237/407 48mg see notes CT​2
Hellwig (ECO.) 78% 0.22 [0.06-0.76] cases ecological 14mg
Bernigaud 99% 0.01 [0.00-0.10] death 0/69 150/3,062 84mg
Alam 91% 0.09 [0.04-0.25] cases 4/58 44/60 12mg
Chahla (RCT) 95% 0.05 [0.00-0.80] m/s case 0/117 10/117 48mg CT​2
Behera 83% 0.17 [0.12-0.23] cases 45/2,199 133/1,147 42mg
Seet (CLUS. RCT) 50% 0.50 [0.33-0.76] symp. case 32/617 64/619 12mg OT​1
Morgenstern (PSM) 80% 0.20 [0.01-4.15] hosp. 0/271 2/271 56mg
Mondal 88% 0.12 [0.01-0.55] symp. case 128 (n) 1,342 (n) n/a
Samajdar 80% 0.20 [0.11-0.38] cases 12/164 29/81 n/a
Kerr (PSM) 70% 0.30 [0.19-0.46] death 25/3,034 79/3,034 56mg

Prophylaxis 83% 0.17 [0.10-0.27] 174/7,765 952/10,496 83% lower risk

Tau​2 = 0.50, I​2 = 84.8%, p < 0.0001

All studies 59% 0.41 [0.33-0.50] 821/30,893 2,343/102,442 59% lower risk

1 2 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment CT: study uses combined treatment
3
SC: study uses synthetic control arm
Tau​2 = 0.52, I​2 = 86.3%, p < 0.0001 Effect extraction pre-specified, see appendix Favors ivermectin Favors control

Figure 12. Random effects meta-analysis for peer-reviewed trials. Zeraatkar et al. analyze 356 COVID-19 trials, finding no
significant evidence that preprint results are inconsistent with peer-reviewed studies. They also show extremely long peer-
review delays, with a median of 6 months to journal publication. A six month delay was equivalent to around 1.5 million
deaths during the first two years of the pandemic. Authors recommend using preprint evidence, with appropriate checks for
potential falsified data, which provides higher certainty much earlier. Davidson et al. also showed no important difference
between meta analysis results of preprints and peer-reviewed publications for COVID-19, based on 37 meta analyses
including 114 trials. Effect extraction is pre-specified, using the most serious outcome reported, see the appendix for details.
Analysis validating pooled outcomes for COVID-19 can be found below.

Randomized Controlled Trials (RCTs)

Results restricted to Randomized Controlled Trials (RCTs) are shown in Figure 13, 14, 15, and 16, Table 1, and Table 2.
The supplementary data contains RCT results after exclusions.

Efficacy in COVID-19 ivermectin studies (pooled effects) [Link]

October 2024
RCTs
Non-RCTs
0 0.25 0.5 0.75 1 1.25 1.5+

Favors ivermectin Favors control

Figure 13. Randomized Controlled Trials. The distribution of results for RCTs is similar to the distribution for all other
studies.
All 52 ivermectin COVID-19 Randomized Controlled Trials [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] hosp. 0/60 2/56 14mg OT​1 CT​2
Mahmud (DB RCT) 86% 0.14 [0.01-2.75] death 0/183 3/183 12mg CT​2
Ahmed (DB RCT) 85% 0.15 [0.01-2.70] symptoms 0/17 3/19 48mg
Chaccour (DB RCT) 96% 0.04 [0.00-1.01] symptoms 12 (n) 12 (n) 28mg
Babalola (DB RCT) 64% 0.36 [0.10-1.27] viral+ 40 (n) 20 (n) 24mg OT​1
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] death 0/55 4/57 24mg
Bukhari (RCT) 82% 0.18 [0.07-0.46] viral+ 4/41 25/45 12mg
Mohan (DB RCT) 62% 0.38 [0.08-1.75] no recov. 2/40 6/45 28mg RIVET-COV
Biber (DB RCT) 70% 0.30 [0.03-2.76] hosp. 1/47 3/42 36mg
López-Me.. (DB RCT) 67% 0.33 [0.01-8.11] death 0/200 1/198 84mg
Chahla (CLUS. RCT) 87% 0.13 [0.03-0.54] no disch. 2/110 20/144 24mg
Faisal (RCT) 68% 0.32 [0.14-0.72] no recov. 6/50 19/50 48mg
Aref (RCT) 63% 0.37 [0.22-0.61] recov. time 57 (n) 57 (n) n/a
Krolewiecki (RCT) -152% 2.52 [0.11-58.1] ventilation 1/27 0/14 168mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] death 4/250 3/251 24mg
Reis (DB RCT) 12% 0.88 [0.49-1.55] death 21/679 24/679 84mg TOGETHER impossible data, see notes
Buonfrate (DB RCT) -211% 3.11 [0.13-73.3] hosp. 1/28 0/31 336mg COVER
Abbas (DB RCT) -4% 1.04 [0.07-16.4] death 1/99 1/103 84mg
Manomai.. (DB RCT) 43% 0.57 [0.20-1.46] no recov. 3/36 6/36 48mg
de la Ro.. (DB RCT) -187% 2.87 [0.12-67.5] misc. 1/30 0/26 36mg
Rezai (DB RCT) -5% 1.05 [0.07-16.7] death 1/268 1/281 84mg
Mirahma.. (DB RCT) 67% 0.33 [0.03-3.14] ventilation 1/131 3/130 24mg
Schilling (RCT) 67% 0.33 [0.01-7.97] hosp. 0/45 1/45 168mg PLATCOV
Bramante (DB RCT) -197% 2.97 [0.12-72.7] death 1/408 0/396 90mg COVID-OUT OT​1
Mikamo (DB RCT) -205% 3.05 [0.12-74.7] progression 1/502 0/527 63mg
Siripongbo.. (RCT) 0% 1.00 [0.07-15.3] progression 1/30 1/30 168mg FINCOV CT​2
Wijewic.. (DB RCT) -196% 2.96 [0.12-72.0] death 1/127 0/122 96mg

Early treatment 55% 0.45 [0.33-0.61] 53/3,572 126/3,599 55% lower risk
Tau​2 = 0.07, I​2 = 11.6%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (4d)

Kishoria (RCT) -8% 1.08 [0.57-2.02] no disch. 11/19 7/13 12mg
Podder (RCT) 16% 0.84 [0.55-1.12] recov. time 32 (n) 30 (n) 14mg
Chachar (RCT) 10% 0.90 [0.44-1.83] no recov. 9/25 10/25 36mg
Hashim (SB RCT) 92% 0.08 [0.00-1.44] death 0/59 6/70 28mg CT​2
Okumuş (DB RCT) 33% 0.67 [0.27-1.64] death 6/30 9/30 56mg
Shahbazn.. (DB RCT) -197% 2.97 [0.13-70.5] death 1/35 0/34 14mg
Beltran .. (DB RCT) 14% 0.86 [0.29-2.56] death 5/36 6/37 12mg
Pott-Junior (RCT) 85% 0.15 [0.01-1.93] ventilation 1/27 1/4 14mg censored, see notes
Huvemek (DB RCT) 32% 0.68 [0.38-1.23] no improv. 13/50 19/50 84mg
Abd-Elsalam (RCT) 25% 0.75 [0.17-3.06] death 3/82 4/82 36mg
Lim (RCT) 69% 0.31 [0.09-1.11] death 3/241 10/249 112mg I-TECH
George (RCT) 30% 0.70 [0.25-1.93] death 5/35 8/39 24mg
Naggie (DB RCT) -202% 3.02 [0.12-74.1] death 1/708 0/724 168mg ACTIV-6
Rezai (DB RCT) 31% 0.69 [0.35-1.39] death 13/311 18/298 84mg
Aref (RCT) 74% 0.26 [0.12-0.55] recov. time 49 (n) 47 (n) n/a LONG COVID
Ochoa-Ja.. (DB RCT) 57% 0.43 [0.07-2.50] death 2/37 4/38 28mg
Sarojvisut (RCT) -104% 2.04 [0.19-22.3] ICU 2/157 1/160 112mg
Wada (DB RCT) 19% 0.81 [0.44-1.38] progression 19/106 23/106 14mg
Hayward (RCT) -1% 1.01 [0.61-1.68] death/hosp. 34/2,157 27/1,806 73mg PRINCIPLE
Varnaseri (DB RCT) 82% 0.18 [0.04-0.78] ventilation 2/55 11/55 84mg
Hashmi (RCT) 15% 0.85 [0.45-1.62] death 81 (n) 69 (n) 56mg REMAP-CAP ICU patients

Late treatment 28% 0.72 [0.59-0.88] 130/4,332 164/3,966 28% lower risk
2 2
Tau​ = 0.03, I​ = 13.6%, p = 0.0018

Improvement, RR [CI] Treatment Control Dose (1m)

Shouman (RCT) 91% 0.09 [0.03-0.23] symp. case 15/203 59/101 36mg
Chahla (RCT) 95% 0.05 [0.00-0.80] m/s case 0/117 10/117 48mg CT​2
Seet (CLUS. RCT) 50% 0.50 [0.33-0.76] symp. case 32/617 64/619 12mg OT​1
Desort-H.. (DB RCT) 96% 0.04 [0.02-0.11] high v. load 4/200 99/199 203mg SAIVE

Prophylaxis 89% 0.11 [0.03-0.43] 51/1,137 232/1,036 89% lower risk

Tau​2 = 1.57, I​2 = 92.6%, p = 0.0017

All studies 52% 0.48 [0.37-0.63] 234/9,041 522/8,601 52% lower risk

1 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment
2
CT: study uses combined treatment Effect extraction pre-specified
Tau​2 = 0.45, I​2 = 64.2%, p < 0.0001 (most serious outcome, see appendix) Favors ivermectin Favors control
Figure 14. Random effects meta-analysis for Randomized Controlled Trials only. Effect extraction is pre-specified, using the
most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be found
below.

All 20 ivermectin COVID-19 RCT mortality results [Link]

Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Mahmud (DB RCT) 86% 0.14 [0.01-2.75] 0/183 3/183 12mg CT​2
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] 0/55 4/57 24mg
López-Me.. (DB RCT) 67% 0.33 [0.01-8.11] 0/200 1/198 84mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] 4/250 3/251 24mg
Reis (DB RCT) 12% 0.88 [0.49-1.55] 21/679 24/679 84mg TOGETHER impossible data, see notes
Abbas (DB RCT) -4% 1.04 [0.07-16.4] 1/99 1/103 84mg
Rezai (DB RCT) -5% 1.05 [0.07-16.7] 1/268 1/281 84mg
Bramante (DB RCT) -197% 2.97 [0.12-72.7] 1/408 0/396 90mg COVID-OUT OT​1
Wijewic.. (DB RCT) -196% 2.96 [0.12-72.0] 1/127 0/122 96mg

Early treatment 14% 0.86 [0.53-1.40] 29/2,269 37/2,270 14% lower risk
Tau​2 = 0.00, I​2 = 0.0%, p = 0.57

Improvement, RR [CI] Treatment Control Dose (4d)

Hashim (SB RCT) 92% 0.08 [0.00-1.44] 0/59 6/70 28mg CT​2
Okumuş (DB RCT) 33% 0.67 [0.27-1.64] 6/30 9/30 56mg
Shahbazn.. (DB RCT) -197% 2.97 [0.13-70.5] 1/35 0/34 14mg
Beltran .. (DB RCT) 14% 0.86 [0.29-2.56] 5/36 6/37 12mg
Abd-Elsalam (RCT) 25% 0.75 [0.17-3.06] 3/82 4/82 36mg
Lim (RCT) 69% 0.31 [0.09-1.11] 3/241 10/249 112mg I-TECH
George (RCT) 30% 0.70 [0.25-1.93] 5/35 8/39 24mg
Naggie (DB RCT) -202% 3.02 [0.12-74.1] 1/708 0/724 168mg ACTIV-6
Rezai (DB RCT) 31% 0.69 [0.35-1.39] 13/311 18/298 84mg
Ochoa-Ja.. (DB RCT) 57% 0.43 [0.07-2.50] 2/37 4/38 28mg
Hashmi (RCT) 15% 0.85 [0.45-1.62] 81 (n) 69 (n) 56mg REMAP-CAP ICU patients

Late treatment 31% 0.69 [0.50-0.95] 39/1,655 65/1,670 31% lower risk
Tau​2 = 0.00, I​2 = 0.0%, p = 0.023

All studies 26% 0.74 [0.56-0.97] 68/3,924 102/3,940 26% lower risk

1 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment
2
CT: study uses combined treatment
Tau​2 = 0.00, I​2 = 0.0%, p = 0.027 Favors ivermectin Favors control

Figure 15. Random effects meta-analysis for RCT mortality results.

All 4 ivermectin COVID-19 RCT case results [Link]

Improvement, RR [CI] Treatment Control Dose (1m)
October 2024
Shouman (RCT) 91% 0.09 [0.03-0.23] symp. case 15/203 59/101 36mg
Chahla (RCT) 84% 0.16 [0.04-0.46] cases 4/117 25/117 48mg CT​2
Seet (CLUS. RCT) 50% 0.50 [0.33-0.76] symp. case 32/617 64/619 12mg OT​1
Desort-H.. (DB RCT) 96% 0.04 [0.02-0.11] high v. load 4/200 99/199 203mg SAIVE

Prophylaxis 87% 0.13 [0.04-0.44] 55/1,137 247/1,036 87% lower risk

Tau​2 = 1.31, I​2 = 92.5%, p = 0.00092

All studies 87% 0.13 [0.04-0.44] 55/1,137 247/1,036 87% lower risk

1 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment
2
CT: study uses combined treatment
Tau​2 = 1.31, I​2 = 92.5%, p = 0.00092 Favors ivermectin Favors control

Figure 17. Random effects meta-analysis for RCT case results.

 All 24 ivermectin COVID-19 RCT viral clearance results [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] viral+ 0/60 2/56 14mg OT​1 CT​2
Mahmud (DB RCT) 39% 0.61 [0.44-0.83] viral+ 14/183 36/180 12mg CT​2
Ahmed (DB RCT) 76% 0.24 [0.07-0.91] viral+ 11/22 20/23 48mg
Chaccour (DB RCT) 95% 0.05 [0.01-0.50] viral load 12 (n) 12 (n) 28mg
Babalola (DB RCT) 64% 0.36 [0.10-1.27] viral+ 40 (n) 20 (n) 24mg OT​1
Ravikirti (DB RCT) -12% 1.12 [0.89-1.40] viral+ 42/55 39/57 24mg
Bukhari (RCT) 82% 0.18 [0.07-0.46] viral+ 4/41 25/45 12mg
Mohan (DB RCT) 24% 0.76 [0.53-1.09] viral+ 21/40 31/45 28mg RIVET-COV
Biber (DB RCT) 62% 0.38 [0.14-0.90] viral+ 8/47 17/42 36mg
Aref (RCT) 79% 0.21 [0.07-0.71] viral+ 3/57 14/57 n/a
Krolewiecki (RCT) 66% 0.34 [0.10-1.16] decay rate 20 (n) 14 (n) 168mg
Vallejos (DB RCT) -5% 1.05 [0.88-1.21] viral+ 137/250 131/251 24mg
Reis (DB RCT) 0% 1.00 [0.68-1.47] viral+ 106/142 123/165 84mg TOGETHER impossible data, see notes
Buonfrate (DB RCT) 20% 0.80 [0.36-1.76] viral load 28 (n) 29 (n) 336mg COVER
Manomai.. (DB RCT) 5% 0.95 [0.62-1.45] viral+ 19/36 20/36 48mg
de la Ro.. (DB RCT) 2% 0.98 [0.81-1.18] viral load 30 (n) 26 (n) 36mg
Rezai (DB RCT) -23% 1.23 [0.92-1.67] viral+ 268 (n) 281 (n) 84mg
Schilling (RCT) -9% 1.09 [0.88-1.27] viral rate 45 (n) 45 (n) 168mg PLATCOV
Siripongbo.. (RCT) 6% 0.94 [0.65-1.35] viral+ 30 (n) 30 (n) 168mg FINCOV CT​2
Wijewic.. (DB RCT) 51% 0.49 [0.26-0.93] viral load 80 (n) 81 (n) 96mg

Early treatment 21% 0.79 [0.66-0.93] 365/1,486 458/1,495 21% lower risk
2 2
Tau​ = 0.07, I​ = 68.3%, p = 0.0053

Improvement, RR [CI] Treatment Control Dose (4d)

Kishoria (RCT) -8% 1.08 [0.57-2.02] viral+ 11/19 7/13 12mg
Okumuş (DB RCT) 80% 0.20 [0.05-0.81] viral+ 2/16 5/8 56mg
Pott-Junior (RCT) 1% 0.99 [0.04-26.3] viral+ 27 (n) 3 (n) 14mg censored, see notes
Wada (DB RCT) -4% 1.04 [0.76-1.43] viral+ 106 (n) 106 (n) 14mg

Late treatment 10% 0.90 [0.56-1.43] 13/168 12/130 10% lower risk
Tau​2 = 0.09, I​2 = 42.1%, p = 0.66

All studies 19% 0.81 [0.69-0.94] 378/1,654 470/1,625 19% lower risk

1 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment
2
CT: study uses combined treatment
Tau​2 = 0.06, I​2 = 64.8%, p = 0.0064 Favors ivermectin Favors control

Figure 16. Random effects meta-analysis for RCT viral clearance results.

RCTs have many potential biases. RCTs help to make study groups more similar and can provide a higher level of
evidence, however they are subject to many biases 116, and analysis of double-blind RCTs has identified extreme levels
of bias 117. For COVID-19, the overhead may delay treatment, dramatically compromising efficacy; they may
encourage monotherapy for simplicity at the cost of efficacy which may rely on combined or synergistic effects; the
participants that sign up may not reflect real world usage or the population that benefits most in terms of age,
comorbidities, severity of illness, or other factors; standard of care may be compromised and unable to evolve quickly
based on emerging research for new diseases; errors may be made in randomization and medication delivery; and
investigators may have hidden agendas or vested interests influencing design, operation, analysis, reporting, and the
potential for fraud. All of these biases have been observed with COVID-19 RCTs. There is no guarantee that a specific
RCT provides a higher level of evidence.

Conflicts of interest for COVID-19 RCTs. RCTs are expensive and many RCTs are funded by pharmaceutical
companies or interests closely aligned with pharmaceutical companies. For COVID-19, this creates an incentive to
show efficacy for patented commercial products, and an incentive to show a lack of efficacy for inexpensive
treatments. The bias is expected to be significant, for example Als-Nielsen et al. analyzed 370 RCTs from Cochrane
reviews, showing that trials funded by for-profit organizations were 5 times more likely to recommend the
experimental drug compared with those funded by nonprofit organizations. For COVID-19, some major philanthropic
organizations are largely funded by investments with extreme conflicts of interest for and against specific COVID-19
interventions.
RCTs for novel acute diseases requiring rapid treatment. High quality RCTs for novel acute diseases are more
challenging, with increased ethical issues due to the urgency of treatment, increased risk due to enrollment delays,
and more difficult design with a rapidly evolving evidence base. For COVID-19, the most common site of initial
infection is the upper respiratory tract. Immediate treatment is likely to be most successful and may prevent or slow
progression to other parts of the body. For a non-prophylaxis RCT, it makes sense to provide treatment in advance and
instruct patients to use it immediately on symptoms, just as some governments have done by providing medication
kits in advance. Unfortunately, no RCTs have been done in this way. Every treatment RCT to date involves delayed
treatment. Among the 95 treatments we have analyzed, 64% of RCTs involve very late treatment 5+ days after onset.
No non-prophylaxis COVID-19 RCTs match the potential real-world use of early treatments. They may more accurately
represent results for treatments that require visiting a medical facility, e.g., those requiring intravenous administration.

RCT bias for widely available treatments. RCTs have a bias against finding an effect for interventions that are widely
available — patients that believe they need the intervention are more likely to decline participation and take the
intervention. RCTs for ivermectin are more likely to enroll low-risk participants that do not need treatment to recover,
making the results less applicable to clinical practice. This bias is likely to be greater for widely known treatments, and
may be greater when the risk of a serious outcome is overstated. This bias does not apply to the typical
pharmaceutical trial of a new drug that is otherwise unavailable.

Non-RCT studies have been shown to be reliable. Evidence shows that non-RCT studies can also provide reliable
results. Concato et al. found that well-designed observational studies do not systematically overestimate the
magnitude of the effects of treatment compared to RCTs. Anglemyer et al. summarized reviews comparing RCTs to
observational studies and found little evidence for significant differences in effect estimates. Lee et al. showed that
only 14% of the guidelines of the Infectious Diseases Society of America were based on RCTs. Evaluation of studies
relies on an understanding of the study and potential biases. Limitations in an RCT can outweigh the benefits, for
example excessive dosages, excessive treatment delays, or Internet survey bias may have a greater effect on results.
Ethical issues may also prevent running RCTs for known effective treatments. For more on issues with RCTs see 122,123.

Using all studies identifies efficacy 7+ months faster (8+ months for low-cost treatments). Currently, 48 of the
treatments we analyze show statistically significant efficacy or harm, defined as ≥10% decreased risk or >0%
increased risk from ≥3 studies. Of these, 29 have been confirmed in RCTs, with a mean delay of 7.1 months. When
considering only low cost treatments, 25 have been confirmed with a delay of 8.2 months. For the 19 unconfirmed
treatments, 4 have zero RCTs to date. The point estimates for the remaining 15 are all consistent with the overall
results (benefit or harm), with 13 showing >20%. The only treatment showing >10% efficacy for all studies, but <10%
for RCTs is sotrovimab.

Summary. We need to evaluate each trial on its own merits. RCTs for a given medication and disease may be more
reliable, however they may also be less reliable. For off-patent medications, very high conflict of interest trials may be
more likely to be RCTs, and more likely to be large trials that dominate meta analyses.

Exclusions

To avoid bias in the selection of studies, we analyze all non-retracted studies. Here we show the results after
excluding studies with critical issues likely to alter results, non-standard studies, and studies where very minimal
detail is currently available. Our bias evaluation is based on analysis of each study and identifying when there is a
significant chance that limitations will substantially change the outcome of the study. We believe this can be more
valuable than checklist-based approaches such as Cochrane GRADE, which may underemphasize serious issues not
captured in the checklists, overemphasize issues unlikely to alter outcomes in specific cases (for example, lack of
blinding for an objective mortality outcome, or certain specifics of randomization with a very large effect size), or be
subject to bias. However, they can also be very high quality 5.

A team of researchers has analyzed the data in ivermectin studies and identified several studies with concerns.
Retracted studies are not in this analysis. All other studies that the team has identified are excluded here. For more
details see the response section.
Detailed description of issues with Reis, Naggie, Bramante, Hayward, López-Medina, Vallejos, Beltran Gonzalez can
be found in the study notes section.

Soto-Becerra is a database analysis covering anyone with ICD-10 COVID-19 codes, which includes asymptomatic
PCR+ patients. Therefore many patients in the control group are likely asymptomatic with regards to SARS-CoV-2, but
in the hospital for another reason. For those that had symptomatic COVID-19, there is also likely significant
confounding by indication. KM curves show that the treatment groups were in more serious condition, with more than
the total excess mortality at 30 days occurring on day 1. All treatments are worse than the control group at 30 days,
while at the latest followup all treatments show lower mortality than control. The machine learning system used also
appears over-parameterized and likely to result in significant overfitting and inaccurate results. There is also no real
control group in this study - patients receiving the treatments after 48 hours were put in the control group. Authors
also state that outcomes within 24 hours were excluded, however the KM curves show significant mortality at day 1
(only for the treatment groups). Several protocol violations have also been reported in this study 132. Note that this
study provides both 30 day mortality and weighted KM curves up to day 43 for ivermectin, we use the day 43 results
as per our protocol. IVERCOR PREP reports prophylaxis results, however only very minimal details are currently
available in a news report and an online presentation. Hellwig analyze African countries and COVID-19 cases in
October 2020 as a function of whether widespread prophylactic use of ivermectin is used for parasitic infections.
Tanioka perform a similar analysis for COVID-19 mortality in January 2021. These studies are excluded because they
are not clinical trials. Shahbaznejad had only one death that occurred in a patient that was critically ill at the time of
admission and died within the first 24 hours. Galan perform an RCT comparing ivermectin and other treatments with
very late stage severe condition hospitalized patients, not showing significant differences between the treatments.
Authors were unable to add a control arm due to ethical issues. The closest control comparison we could find is Baqui
et al., which shows 43% hospital mortality in the northern region of Brazil where the study was performed, from which
we can estimate the mortality with ivermectin in this study as 47% lower, RR 0.53. Further, the study is restricted to
more severe cases, hence the expected mortality, and therefore the benefit of treatment, may be higher. Kishoria
restrict inclusion to patients that did not respond to standard treatment, provide no details on the time of the
discharge status, and there are very large unadjusted differences in the groups, with over twice as many patients in
the ivermectin group with age >40, and all patients over 60 in the ivermectin group. Angkasekwinai does not make
sense as reported, for details see 141.

Summarizing, the studies excluded are as follows, and the resulting forest plot is shown in Figure 18. The
supplementary data shows results after restrictions and exclusions.

Abbas, very minimal patient information, three different results for the recovery outcome, selective omission of the
statistically significant recovery p-value, and other inconsistencies.

Ahsan, unadjusted results with no group details.

Beltran Gonzalez, major inconsistencies reported and the data is no longer available 144, although the authors state
that it is available, and have shared it with an anti-treatment group.

Borody, preliminary report with minimal details.

Buonfrate, significant unadjusted group differences, with 3 times as many patients in the ivermectin arms having the
baseline visit in a hospital setting, and arm C having large differences in baseline gender, weight, cough, pyrexia, and
anosmia, excessive dose for arm C.

Cadegiani, control group retrospectively obtained from untreated patients in the same population.

Carvallo, concern about potential data issues.

Carvallo (B), concern about potential data issues.

Carvallo (C), minimal details of groups provided.

de Jesús Ascencio-Montiel, unadjusted results with alternate outcome adjusted results showing significant changes
with adjustments. Excluded results: death, mechanical ventilation, hospitalization, progression.

de la Rocha, data mismatch, no response from authors.

Elavarasi, unadjusted results with no group details.

Ferreira, unadjusted results with no group details; substantial unadjusted confounding by indication likely.

Hashmi, baseline severity favors control, post-hoc outcome and SAP changes, see discussion.

Hazan (B), study uses a synthetic control arm.

Hellwig, not a typical trial, analysis of African countries that used or did not use ivermectin prophylaxis for parasitic
infections.

IVERCOR PREP, minimal details provided.

Kishoria, excessive unadjusted differences between groups.

López-Medina, strong evidence of patients in the control group self-medicating, ivermectin widely used in the
population at that time, and the study drug identity was concealed by using the name D11AX22.

Mikamo, very low risk group with almost no progression leaves little room for improvement, unbalanced baseline
dyspnea and high symptom scores, design and post-hoc changes favor null result.

Mustafa, unadjusted results with no group details.

Qadeer, minimal baseline details provided.

Ravikirti, exclusion of patients in less severe condition, data/analysis concerns.

Reis, multiple anomalies as per detailed analysis.

Rezai, multiple critical issues, see study page.

Rezai (B), multiple critical issues, see study page.

Roy, no serious outcomes reported and fast recovery in treatment and control groups, there is little room for a
treatment to improve results.

Samajdar, minimal details provided; unadjusted results with no group details; results may be significantly affected by
survey bias.

Schilling, post-hoc change to exclude patients treated before high viral load, population very low risk, recovering
quickly without treatment, high baseline immunity, 2.2x greater baseline antibody negative for the treatment arm.

Siripongboonsitti, data consistency issues, very low risk patients/variants with almost no progression, all patients
received known effective antiviral, baseline differences.

Soto, substantial unadjusted confounding by indication likely; substantial confounding by time possible due to
significant changes in SOC and treatment propensity near the start of the pandemic.

Soto-Becerra, substantial unadjusted confounding by indication likely; includes PCR+ patients that may be
asymptomatic for COVID-19 but in hospital for other reasons.

Szente Fonseca, result is likely affected by collinearity across treatments in the model.

Tanioka, not a typical trial, analysis of African countries that used or did not use ivermectin prophylaxis for parasitic
infections.

Thairu, significant confounding by time possible due to separation of groups in different time periods.

Zubair, substantial unadjusted confounding by indication likely; unadjusted results with no group details.
70 ivermectin COVID-19 studies after exclusions [Link]
Improvement, RR [CI] Treatment Control Dose (4d)
October 2024
Chowdhury (RCT) 81% 0.19 [0.01-3.96] hosp. 0/60 2/56 14mg OT​1 CT​2
Espitia-Hernandez 70% 0.30 [0.16-0.55] recov. time 28 (n) 7 (n) 12mg CT​2
Mahmud (DB RCT) 86% 0.14 [0.01-2.75] death 0/183 3/183 12mg CT​2
Ahmed (DB RCT) 85% 0.15 [0.01-2.70] symptoms 0/17 3/19 48mg
Chaccour (DB RCT) 96% 0.04 [0.00-1.01] symptoms 12 (n) 12 (n) 28mg
Ghauri 92% 0.08 [0.01-0.88] no recov. 0/37 7/53 48mg
Babalola (DB RCT) 64% 0.36 [0.10-1.27] viral+ 40 (n) 20 (n) 24mg OT​1
Ravikirti (DB RCT) 89% 0.11 [0.01-2.05] death 0/55 4/57 24mg
Bukhari (RCT) 82% 0.18 [0.07-0.46] viral+ 4/41 25/45 12mg
Mohan (DB RCT) 62% 0.38 [0.08-1.75] no recov. 2/40 6/45 28mg RIVET-COV
Biber (DB RCT) 70% 0.30 [0.03-2.76] hosp. 1/47 3/42 36mg
Elalfy 87% 0.13 [0.06-0.27] viral+ 7/62 44/51 36mg CT​2
Chahla (CLUS. RCT) 87% 0.13 [0.03-0.54] no disch. 2/110 20/144 24mg
Mourya 89% 0.11 [0.05-0.25] viral+ 5/50 47/50 48mg
Loue (QR) 70% 0.30 [0.04-2.20] death 1/10 5/15 14mg
Merino (QR) 74% 0.26 [0.11-0.57] hosp. 77,381 (all patients) 24mg censored, see notes CS​3
Faisal (RCT) 68% 0.32 [0.14-0.72] no recov. 6/50 19/50 48mg
Aref (RCT) 63% 0.37 [0.22-0.61] recov. time 57 (n) 57 (n) n/a
Krolewiecki (RCT) -152% 2.52 [0.11-58.1] ventilation 1/27 0/14 168mg
Vallejos (DB RCT) -33% 1.33 [0.30-5.72] death 4/250 3/251 24mg
Mayer 55% 0.45 [0.32-0.63] death 3,266 (n) 17,966 (n) 151mg
de Jesús Ascenci.. 59% 0.41 [0.36-0.47] death/hosp. 7,898 (n) 20,150 (n) 12mg CT​2
Manomai.. (DB RCT) 43% 0.57 [0.20-1.46] no recov. 3/36 6/36 48mg
Mirahma.. (DB RCT) 67% 0.33 [0.03-3.14] ventilation 1/131 3/130 24mg
Bramante (DB RCT) -197% 2.97 [0.12-72.7] death 1/408 0/396 90mg COVID-OUT OT​1
Wijewic.. (DB RCT) -196% 2.96 [0.12-72.0] death 1/127 0/122 96mg

Early treatment 69% 0.31 [0.24-0.39] 39/13,042 200/39,971 69% lower risk
Tau​2 = 0.08, I​2 = 36.2%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (4d)

Gorial 71% 0.29 [0.01-5.76] death 0/16 2/71 14mg
Podder (RCT) 16% 0.84 [0.55-1.12] recov. time 32 (n) 30 (n) 14mg
Khan 87% 0.13 [0.02-1.00] death 1/115 9/133 12mg
Chachar (RCT) 10% 0.90 [0.44-1.83] no recov. 9/25 10/25 36mg
Rajter (PSM) 46% 0.54 [0.27-0.99] death 13/98 24/98 14mg
Hashim (SB RCT) 92% 0.08 [0.00-1.44] death 0/59 6/70 28mg CT​2
Camprubí 40% 0.60 [0.18-2.01] ventilation 3/13 5/13 14mg
Spoorthi 21% 0.79 [0.64-0.98] recov. time 50 (n) 50 (n) n/a CT​2
Budhiraja 99% 0.01 [0.00-0.15] death 0/34 103/942 n/a
Okumuş (DB RCT) 33% 0.67 [0.27-1.64] death 6/30 9/30 56mg
Shahbazn.. (DB RCT) -197% 2.97 [0.13-70.5] death 1/35 0/34 14mg
Lima-Morales 78% 0.22 [0.12-0.41] death 15/481 52/287 12mg CT​2
Pott-Junior (RCT) 85% 0.15 [0.01-1.93] ventilation 1/27 1/4 14mg censored, see notes
Huvemek (DB RCT) 32% 0.68 [0.38-1.23] no improv. 13/50 19/50 84mg
Abd-Elsalam (RCT) 25% 0.75 [0.17-3.06] death 3/82 4/82 36mg
Rezk 80% 0.20 [0.01-4.13] death 0/160 2/160 72mg
Lim (RCT) 69% 0.31 [0.09-1.11] death 3/241 10/249 112mg I-TECH
Ozer 75% 0.25 [0.06-1.13] death 2/60 8/60 28mg
Jamir (ICU) -53% 1.53 [0.88-2.67] death 32/76 69/190 n/a ICU patients
Baguma 97% 0.03 [0.00-11.7] death 7 (n) 474 (n) n/a
Shimizu 100% 0.00 [0.00-0.01] death 0/39 8/49 14mg
Efimenko (PSM) 69% 0.31 [0.20-0.48] death 1,072 (n) 40,536 (n) n/a self-censored, see notes OT​1
George (RCT) 30% 0.70 [0.25-1.93] death 5/35 8/39 24mg
Naggie (DB RCT) -202% 3.02 [0.12-74.1] death 1/708 0/724 168mg ACTIV-6
Aref (RCT) 74% 0.26 [0.12-0.55] recov. time 49 (n) 47 (n) n/a LONG COVID
Ochoa-Ja.. (DB RCT) 57% 0.43 [0.07-2.50] death 2/37 4/38 28mg
Sarojvisut (RCT) -104% 2.04 [0.19-22.3] ICU 2/157 1/160 112mg
Munir 48% 0.52 [0.22-1.21] death 92 (n) 908 (n) n/a
Llenas-García 17% 0.83 [0.38-1.84] death 10/96 12/96 14mg
Wada (DB RCT) 19% 0.81 [0.44-1.38] progression 19/106 23/106 14mg
Osati 32% 0.68 [0.45-0.92] death 448 (n) 849 (n) n/a
Hayward (RCT) -1% 1.01 [0.61-1.68] death/hosp. 34/2,157 27/1,806 73mg PRINCIPLE
Varnaseri (DB RCT) 82% 0.18 [0.04-0.78] ventilation 2/55 11/55 84mg

Late treatment 48% 0.52 [0.40-0.68] 177/6,742 427/48,465 48% lower risk
Tau​2 = 0.28, I​2 = 66.3%, p < 0.0001

Improvement, RR [CI] Treatment Control Dose (1m)

Shouman (RCT) 91% 0.09 [0.03-0.23] symp. case 15/203 59/101 36mg
Behera 54% 0.46 [0.29-0.71] cases 41/117 145/255 42mg
Bernigaud 99% 0 01 [0 00-0 10] death 0/69 150/3 062 84mg
 Bernigaud 99% 0.01 [0.00 0.10] death 0/69 150/3,062 84mg
Alam 91% 0.09 [0.04-0.25] cases 4/58 44/60 12mg
Chahla (RCT) 95% 0.05 [0.00-0.80] m/s case 0/117 10/117 48mg CT​2
Behera 83% 0.17 [0.12-0.23] cases 45/2,199 133/1,147 42mg
Seet (CLUS. RCT) 50% 0.50 [0.33-0.76] symp. case 32/617 64/619 12mg OT​1
Morgenstern (PSM) 80% 0.20 [0.01-4.15] hosp. 0/271 2/271 56mg
Mondal 88% 0.12 [0.01-0.55] symp. case 128 (n) 1,342 (n) n/a
Kerr (PSM) 70% 0.30 [0.19-0.46] death 25/3,034 79/3,034 56mg
Desort-H.. (DB RCT) 96% 0.04 [0.02-0.11] high v. load 4/200 99/199 203mg SAIVE

Prophylaxis 84% 0.16 [0.09-0.27] 166/7,013 785/10,207 84% lower risk

Tau​2 = 0.56, I​2 = 87.3%, p < 0.0001

All studies 65% 0.35 [0.28-0.42] 382/26,797 1,412/98,643 65% lower risk

1 2 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2+

OT: ivermectin vs. other treatment CT: study uses combined treatment
3
CS: censored, see details
Tau​2 = 0.35, I​2 = 76.7%, p < 0.0001 Effect extraction pre-specified, see appendix Favors ivermectin Favors control

Figure 18. Random effects meta-analysis excluding studies with significant issues. Effect extraction is pre-specified, using
the most serious outcome reported, see the appendix for details. Analysis validating pooled outcomes for COVID-19 can be
found below.

Heterogeneity

Heterogeneity in COVID-19 studies arises from many factors including:

Treatment delay. The time between infection or the onset of symptoms and treatment may critically affect how well a
treatment works. For example an antiviral may be very effective when used early but may not be effective in late stage
disease, and may even be harmful. Oseltamivir, for example, is generally only considered effective for influenza when
used within 0-36 or 0-48 hours 171,172. Baloxavir marboxil studies for influenza also show that treatment delay is
critical — Ikematsu et al. report an 86% reduction in cases for post-exposure prophylaxis, Hayden et al. show a 33
hour reduction in the time to alleviation of symptoms for treatment within 24 hours and a reduction of 13 hours for
treatment within 24-48 hours, and Kumar et al. report only 2.5 hours improvement for inpatient treatment.

Treatment delay Result

Post-exposure prophylaxis 86% fewer cases 173

<24 hours -33 hours symptoms 174

24-48 hours -13 hours symptoms 174

Inpatients -2.5 hours to improvement 175

Table 3. Studies of baloxavir marboxil for influenza show that

early treatment is more effective.

Figure 19 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19 studies
from 95 treatments, showing that efficacy declines rapidly with treatment delay. Early treatment is critical for COVID-
19.
 Efficacy by treatment delay in COVID-19 studies

%001
[Link]
October 2024

%57
%05
ycacffiE
%52
%0

p<0.00000000001
mixed-effects meta-regression, most serious sufficiently powered outcome
%52-

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Treatment delay (days since onset)

Figure 19. Early treatment is more effective. Meta-regression showing efficacy as a

function of treatment delay in COVID-19 studies from 95 treatments.

Patient demographics. Details of the patient population including age and comorbidities may critically affect how well
a treatment works. For example, many COVID-19 studies with relatively young low-comorbidity patients show all
patients recovering quickly with or without treatment. In such cases, there is little room for an effective treatment to
improve results, for example as in López-Medina et al.

Variants. Efficacy may depend critically on the distribution of SARS-CoV-2 variants encountered by patients. Risk
varies significantly across variants 176, for example the Gamma variant shows significantly different characteristics 177-
180
. Different mechanisms of action may be more or less effective depending on variants, for example the degree to
which TMPRSS2 contributes to viral entry can differ across variants 181,182.

Regimen. Effectiveness may depend strongly on the dosage and treatment regimen. Higher dosages have been found
to be more successful for ivermectin 183. Method of administration may also be critical. Guzzo show that the plasma
concentration of ivermectin is much higher when administered with food (Figure 20: geometric mean AUC 2.6 times
higher). Many ivermectin studies specify fasting, or they do not specify administration. Fasting administration is
expected to reduce effectiveness for COVID-19 due to lower plasma and tissue concentrations. Note that this is
different to anthelmintic use in the gastrointestinal tract where fasting is recommended.
 Figure 20. Ivermectin plasma concentration is significantly higher when
administered with a meal. The graph shows mean plasma concentration (ng/ml)
profiles following single oral doses of 30mg (fed and fasted administration), from
Guzzo.

Other treatments. The use of other treatments may significantly affect outcomes, including supplements, other
medications, or other interventions such as prone positioning. Treatments may be synergistic 91,93,98,101,169,184-189,
therefore efficacy may depend strongly on combined treatments.

Medication quality. The quality of medications may vary significantly between manufacturers and production batches,
which may significantly affect efficacy and safety. Williams et al. analyze ivermectin from 11 different sources,
showing highly variable antiparasitic efficacy across different manufacturers. Xu et al. analyze a treatment from two
different manufacturers, showing 9 different impurities, with significantly different concentrations for each
manufacturer.

Effect measured. Across all studies there is a strong association between different outcomes, for example improved
recovery is strongly associated with lower mortality. However, efficacy may differ depending on the effect measured,
for example a treatment may be more effective against secondary complications and have minimal effect on viral
clearance.

Meta analysis. The distribution of studies will alter the outcome of a meta analysis. Consider a simplified example
where everything is equal except for the treatment delay, and effectiveness decreases to zero or below with increasing
delay. If there are many studies using very late treatment, the outcome may be negative, even though early treatment
is very effective. All meta analyses combine heterogeneous studies, varying in population, variants, and potentially all
factors above, and therefore may obscure efficacy by including studies where treatment is less effective. Generally, we
expect the estimated effect size from meta analysis to be less than that for the optimal case. Looking at all studies is
valuable for providing an overview of all research, important to avoid cherry-picking, and informative when a positive
result is found despite combining less-optimal situations. However, the resulting estimate does not apply to specific
cases such as early treatment in high-risk populations. While we present results for all studies, we also present
treatment time and individual outcome analyses, which may be more informative for specific use cases.

Ivermectin. Ivermectin studies vary widely in all the factors above, which makes the consistently positive results even
more remarkable. A failure to detect an association after combining heterogeneous studies does not mean the
treatment is not effective (it may only work in certain cases), however the reverse is not true — an identified
association is valid, although the magnitude of the effect may be larger for more optimal cases, and lower for less
optimal cases. Note that trial with a design favoring null results have become common, and are likely to dominate
future trials. For example, the Together Trial tested ivermectin in locations known to have a high degree of self-
medication, up to 7 days from onset (while claiming to be an early treatment trial), and using low doses compared to
clinical recommendations for the dominant variant. The ACTIV-6 trial had a median treatment delay of 6 days and very
low risk patients.

Pooled Effects

Pooled effects are no longer required to show efficacy as of September 2020. This section validates the use of
pooled effects for COVID-19, which enables earlier detection of efficacy, however note that pooled effects are no
longer required for ivermectin as of September 2020. Efficacy is now known for ivermectin based on specific
outcomes for all studies and when restricted to RCTs. Efficacy based on specific outcomes was delayed by 1.3
months, compared to using pooled outcomes.

Combining studies is required. For COVID-19, delay in clinical results translates into additional death and morbidity,
as well as additional economic and societal damage. Combining the results of studies reporting different outcomes is
required. There may be no mortality in a trial with low-risk patients, however a reduction in severity or improved viral
clearance may translate into lower mortality in a high-risk population. Different studies may report lower severity,
improved recovery, and lower mortality, and the significance may be very high when combining the results. "The
studies reported different outcomes" is not a good reason for disregarding results.

Specific outcome and pooled analyses. We present both specific outcome and pooled analyses. In order to combine
the results of studies reporting different outcomes we use the most serious outcome reported in each study, based on
the thesis that improvement in the most serious outcome provides comparable measures of efficacy for a treatment.
A critical advantage of this approach is simplicity and transparency. There are many other ways to combine evidence
for different outcomes, along with additional evidence such as dose-response relationships, however these increase
complexity.

Using more information. Another way to view pooled analysis is that we are using more of the available information.
Logically we should, and do, use additional information. For example dose-response and treatment delay-response
relationships provide significant additional evidence of efficacy that is considered when reviewing the evidence for a
treatment.

Ethical and practical issues limit high-risk trials. Trials with high-risk patients may be restricted due to ethics for
treatments that are known or expected to be effective, and they increase difficulty for recruiting. Using less severe
outcomes as a proxy for more serious outcomes allows faster collection of evidence.

Improvement across outcomes. For many COVID-19 treatments, a reduction in mortality logically follows from a
reduction in hospitalization, which follows from a reduction in symptomatic cases, which follows from a reduction in
PCR positivity. We can directly test this for COVID-19.

Validating pooled outcome analysis for COVID-19. Analysis of the the association between different outcomes across
studies from all 95 treatments we cover confirms the validity of pooled outcome analysis for COVID-19. Figure 21
shows that lower hospitalization is very strongly associated with lower mortality (p < 0.000000000001). Similarly,
Figure 22 shows that improved recovery is very strongly associated with lower mortality (p < 0.000000000001).
Considering the extremes, Singh et al. show an association between viral clearance and hospitalization or death, with
p = 0.003 after excluding one large outlier from a mutagenic treatment, and based on 44 RCTs including 52,384
patients. Figure 23 shows that improved viral clearance is strongly associated with fewer serious outcomes. The
association is very similar to Singh et al., with higher confidence due to the larger number of studies. As with Singh et
al., the confidence increases when excluding the outlier treatment, from p = 0.00000053 to p = 0.000000028.
 Lower hospitalization is associated with lower mortality

%001
%57
ytilatrom ni tnemevorpmI
%05
%52
[Link]
%0 October 2024

mixed-effects meta-regression
slope 0.84 [95% CI 0.74 to 0.95] p<0.00000000001
%52-

-25% 0% 25% 50% 75% 100%

Improvement in hospitalization

Figure 21. Lower hospitalization is associated with lower mortality, supporting

pooled outcome analysis.

Improved recovery is associated with lower mortality

%001
%57
ytilatrom ni tnemevorpmI
%05
%52

[Link]
October 2024
%0

mixed-effects meta-regression
slope 0.79 [95% CI 0.61 to 0.97] p<0.00000000001
%52-

-25% 0% 25% 50% 75% 100%

Improvement in recovery

Figure 22. Improved recovery is associated with lower mortality, supporting pooled
outcome analysis.
 Improved viral clearance is associated with fewer serious outcomes

%001
semoctuo suoires ni tnemevorpmI
%57
%05
%52
[Link]
%0 October 2024

mixed-effects meta-regression
slope 0.9 [95% CI 0.58 to 1.2] p=0.000000028
%52-

-25% 0% 25% 50% 75% 100%

Improvement in viral clearance

Figure 21. Improved viral clearance is associated with fewer serious outcomes,
supporting pooled outcome analysis.

Pooled outcomes identify efficacy 5 months faster (6 months for RCTs). Currently, 48 of the treatments we analyze
≥
show statistically significant efficacy or harm, defined as 10% decreased risk or >0% increased risk from 3 studies. ≥
89% of these have been confirmed with one or more specific outcomes, with a mean delay of 5.1 months. When
restricting to RCTs only, 56% of treatments showing statistically significant efficacy/harm with pooled effects have
been confirmed with one or more specific outcomes, with a mean delay of 6.4 months. Figure 24 shows when
treatments were found effective during the pandemic. Pooled outcomes often resulted in earlier detection of efficacy.
Time when COVID-19 studies showed efficacy [Link]
October 2024
HCQ
Zinc
Pooled outcomes
Metformin
Specific outcome
Ivermectin
RCT pooled
Colchicine
RCT specific
PPIs ↑risk
Vitamin C Statistically significant
Antiandrogens ≥10% improvement
Vitamin D
≥3 studies
Exercise
Acetaminophen ↑risk
Antihistamine H1RAs
Melatonin
Nigella Sativa
Povidone-Iodine
Curcumin
Sleep
Casirivimab/i..
Probiotics
Budesonide
Hydrogen Peroxide
Bamlanivimab/e..
Diet
Quercetin
Molnupiravir
Famotidine
Fluvoxamine
Alkalinization
Montelukast
Phthalocyanine
Sunlight
Vitamin B12
Regdanvimab
0202

1202

3202

4202
Paxlovid
Sodium Bicarbonate
Evusheld
Azvudine

Figure 24. The time when studies showed that treatments were effective, defined as statistically significant improvement
≥ ≥
of 10% from 3 studies. Pooled results typically show efficacy earlier than specific outcome results. Results from all studies
often shows efficacy much earlier than when restricting to RCTs. Results reflect conditions as used in trials to date, these
depend on the population treated, treatment delay, and treatment regimen.

Limitations. Pooled analysis could hide efficacy, for example a treatment that is beneficial for late stage patients but
has no effect on viral clearance may show no efficacy if most studies only examine viral clearance. In practice, it is rare
for a non-antiviral treatment to report viral clearance and to not report clinical outcomes; and in practice other sources
of heterogeneity such as difference in treatment delay is more likely to hide efficacy.

Summary. Analysis validates the use of pooled effects and shows significantly faster detection of efficacy on average.
However, as with all meta analyses, it is important to review the different studies included. We also present individual
outcome analyses, which may be more informative for specific use cases.

Discussion

Publication bias. Publishing is often biased towards positive results, which we would need to adjust for when
analyzing the percentage of positive results. For ivermectin, there is strong evidence of a growing negative publication
bias.

As Scott Alexander said in November 2021, "if you say anything in favor of ivermectin you will be cast out of civilization
and thrown into the circle of social hell reserved for Klan members and 1/6 insurrectionists. All the health officials in
the world will shout 'horse dewormer!' at you and compare you to Josef Mengele." In many locations, publishing
positive ivermectin results is not conducive to maintaining employment or friendships. This can be seen in the design
of recent trials, and the extreme measures taken to avoid presenting statistically significant positive results, as
detailed in the study notes below.
One method to evaluate bias is to compare prospective vs. retrospective studies, although this method has become
less useful with ivermectin due to the increase of prospective studies with designs favoring null results. Prospective
studies are likely to be published regardless of the result, while retrospective studies are more likely to exhibit bias. For
example, researchers may perform preliminary analysis with minimal effort and the results may influence their
decision to continue. Retrospective studies also provide more opportunities for the specifics of data extraction and
adjustments to influence results. Figure 25 shows a scatter plot of results for prospective and retrospective studies.
Prospective studies show 59% [48-68%] improvement in meta analysis, compared to 61% [49-70%] for retrospective
studies, showing no significant difference. Bryant also perform a funnel plot analysis, which they found did not
suggest evidence of publication bias.

Efficacy in COVID-19 ivermectin studies (pooled effects) [Link]

October 2024
Prospective
Retrospective
0 0.25 0.5 0.75 1 1.25 1.5+

Favors ivermectin Favors control

Figure 25. Prospective vs. retrospective studies. The diamonds show the results of random effects meta-analysis.

There is substantial evidence that journals are rejecting and delaying the publication of positive studies, for example
by accepting a paper for review, holding it for some time, and then rejecting it without review 192,193. One group
performed prophylaxis and early treatment studies, with only the less positive study being formally published to
date 129,133, suggesting a negative publication bias. Dr. Eli Schwartz's 194 double blind RCT was rejected without review
by The Lancet and Clinical Infectious Diseases 195. Authors of Efimenko do not plan to submit the very positive results
to a journal, and have self-censored the conference publication, providing further evidence of a negative publication
bias. Trials with pending and possibly delayed publication often involve researchers that may be restricted due to
politics — publishing positive results may be incompatible with continued employment, whereas negative results can
receive priority treatment at certain well-known journals, support the positions of employers or funding organizations,
and receive substantial press. For more details of censorship and negative publication bias in ivermectin research
see 197-199.

News coverage of ivermectin studies is extremely biased. Only studies with designs favoring null results have received
significant press coverage in western media 124,125,128, all of which have multiple critical issues as discussed below,
but ignored by the press.

Physician case series results. Table 4 shows the reported results of physicians that use early treatments for COVID-
19, compared to the results for a non-treating physician (this physician reportedly prescribed early treatment for
themself, but not for patients 200). The treatments used vary between physicians. Almost all report using ivermectin
and/or HCQ, and most use additional treatments in combination. These results are subject to selection and
ascertainment bias and more accurate analysis requires details of the patient populations and followup, however
results are consistently better across many teams, and consistent with the extensive controlled trial evidence that
shows a significant reduction in risk with many early treatments, and improved results with the use of multiple
treatments in combination.
 LATE TREATMENT

Physician / Team Location Patients Hospitalization Mortality

Dr. David Uip (*) Brazil 2,200 38.6% (850) Ref. 2.5% (54) Ref.

EARLY TREATMENT - 40 physicians/teams

Physician / Team Location Patients Hospitalization Improvement Mortality Improvement

Dr. Roberto Alfonso Accinelli

Peru 1,265 0.6% (7) 77.5%
0/360 deaths for treatment within 3 days

Dr. Mohammed Tarek Alam

Bangladesh 100 0.0% (0) 100.0%
patients up to 84 years old

Dr. Oluwagbenga Alonge Nigeria 310 0.0% (0) 100.0%

Dr. Raja Bhattacharya

India 148 1.4% (2) 44.9%
up to 88yo, 81% comorbidities

Dr. Flavio Cadegiani Brazil 3,450 0.1% (4) 99.7% 0.0% (0) 100.0%

Dr. Alessandro Capucci Italy 350 4.6% (16) 88.2%

Dr. Shankara Chetty South Africa 8,000 0.0% (0) 100.0%

Dr. Deborah Chisholm USA 100 0.0% (0) 100.0%

Dr. Ryan Cole USA 400 0.0% (0) 100.0% 0.0% (0) 100.0%

Dr. Marco Cosentino

vs. 3-3.8% mortality during period; earlier Italy 392 6.4% (25) 83.5% 0.3% (1) 89.6%
treatment better

Dr. Jeff Davis USA 6,000 0.0% (0) 100.0%

Dr. Dhanajay India 500 0.0% (0) 100.0%

Dr. Bryan Tyson & Dr. George Fareed USA 20,000 0.0% (6) 99.9% 0.0% (4) 99.2%

Dr. Raphael Furtado Brazil 170 0.6% (1) 98.5% 0.0% (0) 100.0%

Rabbi Yehoshua Gerzi Israel 860 0.1% (1) 99.7% 0.0% (0) 100.0%

Dr. Heather Gessling USA 1,500 0.1% (1) 97.3%

Dr. Ellen Guimarães Brazil 500 1.6% (8) 95.9% 0.4% (2) 83.7%

Dr. Syed Haider USA 4,000 0.1% (5) 99.7% 0.0% (0) 100.0%

Dr. Mark Hancock USA 24 0.0% (0) 100.0%

Dr. Sabine Hazan USA 1,000 0.0% (0) 100.0%

Dr. Mollie James USA 3,500 1.1% (40) 97.0% 0.0% (1) 98.8%

Dr. Roberta Lacerda Brazil 550 1.5% (8) 96.2% 0.4% (2) 85.2%

Dr. Katarina Lindley USA 100 5.0% (5) 87.1% 0.0% (0) 100.0%

Dr. Ben Marble USA 150,000 0.0% (4) 99.9%

Dr. Edimilson Migowski Brazil 2,000 0.3% (7) 99.1% 0.1% (2) 95.9%

Saudi
Dr. Abdulrahman Mohana 2,733 0.0% (0) 100.0%
Arabia

Dr. Carlos Nigro Brazil 5,000 0.9% (45) 97.7% 0.5% (23) 81.3%

Dr. Benoit Ochs Luxembourg 800 0.0% (0) 100.0%

Dr. Ortore Italy 240 1.2% (3) 96.8% 0.0% (0) 100.0%

Dr. Valerio Pascua

one death for a patient presenting on the 5th day Honduras 415 6.3% (26) 83.8% 0.2% (1) 90.2%
in need of supplemental oxygen

Dr. Sebastian Pop Romania 300 0.0% (0) 100.0%

 Dr. Brian Proctor USA 869 2.3% (20) 94.0% 0.2% (2) 90.6%

Dr. Anastacio Queiroz Brazil 700 0.0% (0) 100.0%

Dr. Didier Raoult France 8,315 2.6% (214) 93.3% 0.1% (5) 97.6%

Dr. Karin Ried

Turkey 237 0.4% (1) 82.8%
up to 99yo, 73% comorbidities, av. age 63

Dr. Roman Rozencwaig

Canada 80 0.0% (0) 100.0%
patients up to 86 years old

Dr. Vipul Shah India 8,000 0.1% (5) 97.5%

Dr. Silvestre Sobrinho Brazil 116 8.6% (10) 77.7% 0.0% (0) 100.0%

Dr. Unknown Brazil 957 1.7% (16) 95.7% 0.2% (2) 91.5%

Dr. Vladimir Zelenko USA 2,200 0.5% (12) 98.6% 0.1% (2) 96.3%

Mean improvement with early treatment

238,381 Hospitalization 94.4% Mortality 94.9%
protocols

Table 4. Physician results with early treatment protocols compared to no early treatment. (*) Dr. Uip reportedly prescribed early
treatment for himself, but not for patients 200.

Funnel plot analysis. Funnel plots have traditionally been used for analyzing publication bias. This is invalid for COVID-
19 acute treatment trials — the underlying assumptions are invalid, which we can demonstrate with a simple
example. Consider a set of hypothetical perfect trials with no bias. Figure 26 plot A shows a funnel plot for a
simulation of 80 perfect trials, with random group sizes, and each patient's outcome randomly sampled (10% control
event probability, and a 30% effect size for treatment). Analysis shows no asymmetry (p > 0.05). In plot B, we add a
single typical variation in COVID-19 treatment trials — treatment delay. Consider that efficacy varies from 90% for
treatment within 24 hours, reducing to 10% when treatment is delayed 3 days. In plot B, each trial's treatment delay is
randomly selected. Analysis now shows highly significant asymmetry, p < 0.0001, with six variants of Egger's test all
showing p < 0.05 201-208. Note that these tests fail even though treatment delay is uniformly distributed. In reality
treatment delay is more complex — each trial has a different distribution of delays across patients, and the
distribution across trials may be biased (e.g., late treatment trials may be more common). Similarly, many other
variations in trials may produce asymmetry, including dose, administration, duration of treatment, differences in SOC,
comorbidities, age, variants, and bias in design, implementation, analysis, and reporting.

B: Simulated perfect trials

A: Simulated perfect trials
with varying treatment delay
p > 0.05
p < 0.0001
0

0
0.352

0.358
Standard Error

Standard Error
0.703

0.716
1.055

1.074
1.406

1.433

-3 -2 -1 0 1 2 -4 -3 -2 -1 0 1 2
Log Risk Ratio Log Risk Ratio

Figure 26. Example funnel plot analysis for simulated perfect trials.
In Vitro evidence on required concentration. Some authors claim that Caly showed that therapeutic concentrations
are not easily reached in humans. This is incorrect. The authors explain why their in vitro study cannot be used to
determine the effective dose in vivo, and state that the concentration required is very unlikely to be an issue 209. The
study used monkey kidney cells (the only choice at the time of the experiments), which lack adaptive immune
responses and do not produce interferon. Authors also note that ivermectin accumulates in lung and other tissues,
that subsequent experiments with lung cells show many times greater concentrations, and that the average lung
concentration shown in modeling studies exceeds the effective level shown in their research. Tissue concentrations of
ivermectin can be much higher than plasma concentration 210,211. Authors note that ivermectin works with the immune
system and a 1:1 ratio of drug to virus is unlikely to be required. In Bray, authors reply that "ivermectin's key direct
target in mammalian cells is a not a viral component, but a host protein important in intracellular transport; the fact
that it is a host-directed agent (HDA) is almost certainly the basis of its broad-spectrum activity against a number of
different RNA viruses in vitro. The way a HDA can reduce viral load is by inhibiting a key cellular process that the virus
hijacks to enhance infection by suppressing the host antiviral response. Reducing viral load by even a modest amount
by using a HDA at low dose early in infection can be the key to enabling the body's immune system to begin to mount
the full antiviral response before the infection takes control." In further research, authors note that they find efficacy for
prophylactic use, and that smaller repeated doses are more efffective than a single larger dose 209. Moreover, there are
now 24 In Vitro studies that support the efficacy of ivermectin for COVID-19 29,35,38,39,41,45,53,56,57,59,90-103.

Strongyloides.

SEE ALSO
Do Strongyloides Worms Explain Positive Ivermectin Trials?
Strongyloides Hypothesis: Summary Conclusions and What's Next
Did Use Of Ivermectin In Latin America Sabotage Clinical Trials and Confuse The World Of Medicine?

One theory for the beneficial effect of ivermectin for COVID-19 is related to strongyloides and the use of steroids —
control group patients with strongyloides may be at risk due to steroid use, while ivermectin patients are protected.
While this mechanism may contribute to efficacy in some cases, it is inconsistent with the data. If this was the case,
we would expect to see greater benefit in late stage trials where steroids are used more often, and we would expect to
see greater benefit for outcomes that occur after steroids are used. However, we see a very strong opposite effect for
treatment time, and we see comparable or stronger efficacy for earlier outcomes.

The theory has gained renewed interest based on a new analysis Bitterman. However, this analysis is confounded by
treatment delay, dose, conflicts of interest, and other factors, and the effect disappears when analyzing all studies, all
RCTs, or all mortality results, as shown in Figure 27.

Although the first author has responded to the confounders on Twitter, we do not see mention of them in the paper.
Author is also aware that the larger sets of all trials, all RCTs, or all mortality results do not show the effect, however
we also do not see this mentioned in the paper. These omissions suggest investigator bias. Author claims they could
not discuss these issues due to publication delays, however the paper was accepted Jan 31, 2022, and author was
aware of the issues months before, for example discussing treatment delay and dose in Nov 2021. These confounders
are also basic and not really possible to miss.

The meta analysis for Hashim includes critical patients, however these patients were always allocated to the
treatment arm for ethical reasons, therefore including them is not logical and introduces substantial bias. According
to the author response, this appears to have been known, suggesting investigator bias. Authors include Shahbaznejad
where the only death was a critical patient that died within 24 hours of admission.

Although authors note following PRISMA guidelines, we do not see registration of the protocol or discussion thereof.
We note that the current protocol is the result of multiple changes to the original methodology as posted on Twitter:
from 3 groups to 2 groups, altering the included studies, and switching from using one source for prevalence
estimates to selecting estimate sources on a per study basis, which allows potential bias in the selection. Notably, this
resulted in moving the Together Trial (Brazil) into the low prevalence category.
Author's results rely on trials with a very small number of mortality events — the high stronglyoides prevalance group
has trials with 1, 3, 4, and 13 events. Authors do mention limitations due to the small number of events and the
reliability of strongyloides estimates.

Authors indicate no conflicts of interest, however the first author has been an investigator on a Pfizer trial, which may
be NCT04092452, showing completion in January 2022 215,216.

Efficacy by strongyloides prevalance in COVID-19 ivermectin studies

%001
[Link]
October 2024
%57
%05
ycacffiE
%52
%0

slope -0.27 [95% CI -1.7 to 1.2] p=0.71

prevalence from Buonfrate et al., most serious sufficiently powered outcome
%52-

0% 5% 10% 15% 20%

Strongyloides prevalence A

Efficacy by strongyloides prevalance in COVID-19 ivermectin RCTs

%001

[Link]
October 2024
%57
%05
ycacffiE
%52
%0

slope -1.4 [95% CI -3.5 to 0.74] p=0.2

prevalence from Buonfrate et al., most serious sufficiently powered outcome
%52-

0% 5% 10% 15% 20%

Strongyloides prevalence B
 Efficacy by strongyloides prevalance in COVID-19 ivermectin mortality results

%001
[Link]
October 2024

%57
%05
ycacffiE
%52
%0

prevalence from Buonfrate et al.

slope -0.6 [95% CI -2.9 to 1.7] p=0.61
%52-

0% 5% 10% 15% 20%

Strongyloides prevalence C
Figure 27. Mixed-effects meta-regression showing efficacy as a function of
strongyloides prevalence. A. all studies. B. all RCTs. C. all mortality results.

The following refers to the first author's analysis posted earlier on Twitter. The author selected 10 of the 105 studies,
with 3 in a high strongyloides prevalence group where a greater benefit is seen. This was used to draw strong
conclusions about the mechanism of ivermectin efficacy.

There are several limitations to this analysis. One of the 3 studies does not mention steroids in the list of SOC
medications, while a second reports 6% usage for the control group. Author has added a fourth paper in a revised
grouping with 11 studies.

We perfomed a similar analysis for all studies (except the 2 ecological studies), which shows no significant effect, with
the high prevalence group actually showing lower improvement (49% [34-61%] vs. 65% [57-71%] for the low
prevalence group). Details can be found in the supplementary data. Results are similar when restricting to mortality
results or when restricting to RCTs.

Why does the smaller analysis with 11 studies show a greater benefit in high strongyloides prevalence regions? The
effect is based on relatively few events - 1, 3, 4, and 13 respectively for the high prevalence group. More importantly,
the result is confounded by treatment delay and dose.

Treatment delay. All meta analyses combine heterogeneous studies which results in limitations. For example in
pooled analysis we combine hospitalization and mortality. In terms of evaluating efficacy for COVID-19 treatments,
reduction in hospitalization reasonably leads to reduction in mortality for high-risk populations. Both are indicators of
efficacy, and both are valuable. In the largest series of COVID-19 treatment trials, hospitalization and mortality
estimates are very similar. The same does not apply to treatment delay for antivirals. A trial showing efficacy with early
treatment provides no information on late treatment, and a trial showing no efficacy with late treatment provides no
information on early treatment. Ivermectin, as with many COVID-19 treatments, shows a strong treatment delay
relationship — early treatment shows significantly higher efficacy.

The high prevalence group in the 11 study analysis has more early treatment trials, and the low prevalence group has
more late treatment trials. The result is confounded by treatment delay, and reflects the greater efficacy of early
treatment.

Only one trial in the high prevalence group is classified as late treatment, I-TECH, which was very close to the cutoff.
Moreover, of all trials in the 11 trial analysis, this one uses the highest dose.
Dose. The average dosage used in the high prevalence group is about twice the dose in the low prevalence group, and
would be close to three times higher if the Together Trial was not moved to the low prevalence group. The result is
confounded by dose, and reflects the greater efficacy of higher dosages.

Variants. Efficacy may vary based on variants. Notably, the Gamma variant was most common for one trial in the low
prevalance group. This variant shows dramatically different characteristics 180, and clinicians report that significantly
higher dosage and/or earlier treatment is required, as may be expected for variants where the peak viral load is
significantly higher and/or reached earlier 177,178.

Conflicts of interest. Two trials have very high (>$US1B) negative conflicts of interest which may introduce bias
towards null effects. The trial in the low prevalance group shows a lower effect size. The trial in the high prevalence
group also shows a lower effect size for the primary outcome. This trial shows a larger mortality effect, however with
only one event this has very low significance.

Summary. In summary, the greater benefit in high strongyloides prevalence regions is only seen with the small subset
of 11 trials and is not seen with all trials, or after restriction to mortality results, or restriction to RCTs. Within the 11
trial sample, all trials except one in the low prevalence group have confounding due to treatment delay and/or low
dosage, where a lower effect size is expected. The only remaining trial in the group is unpublished, has an unknown
treatment delay (a significant percentage of patients may have been treated very late), has very high negative conflicts
of interest, and the Gamma variant was most common, in addition to other issues.

Conflicts of interest. Pharmaceutical drug trials often have conflicts of interest whereby sponsors or trial staff have a
financial interest in the outcome being positive. Ivermectin for COVID-19 lacks this because it is off-patent, has many
manufacturers, and is very low cost. In contrast, most COVID-19 ivermectin trials have been run by physicians on the
front lines with the primary interest of finding the best methods to save human lives and minimize the collateral
damage caused by COVID-19. While pharmaceutical companies are careful to run trials under optimal conditions (for
example, restricting patients to those most likely to benefit, only including patients that can be treated soon after
onset when necessary, ensuring accurate dosing), many ivermectin trials do not represent the optimal conditions for
efficacy.

Two ivermectin trials to date involve very large financial conflicts of interest 124,128 — companies closely involved with
the trial or organizers stand to lose billions of dollars if ivermectin efficacy becomes more widely known. The design of
these trials favors producing a null outcome as detailed in 124,128. Note that biasing an RCT to produce a false positive
result is difficult (suppressing adverse events is relatively easy 217), but biasing a trial to produce a false negative result
is very easy — for example, in a trial of an antiviral that works within the first 24 hours of symptom onset, trial
organizers only need to avoid treating people within the first 24 hours; or with a disease like COVID-19, organizers
only need to select a low-risk population where most people recover quickly without treatment. We note that, even
under the very suboptimal designs, these trials produced positive results, although without statistical significance.

Designed to fail. Several major trials have been designed in a way that favors finding no effect, with a number of
methods including late treatment, selecting low-risk patients, fasting administration, very high conflict of interest
medication sourcing, and dosing below current clinical practice. For discussion see 218. One patient reported their
experience with one of the remote outpatient ivermectin/fluvoxamine trials: they were offered enrollment 7 days after
symptoms (receipt of medication would be even later), were offered $400 to participate, and reportedly target healthy
people 219. Details of issues with several trials are included in the study notes.

Drug interactions. Other treatments may reduce the efficacy of ivermectin, for example dexamethasone may interfere
with the pharmacokinetics of ivermectin, significantly reducing plasma concentration and efficacy 220.

Notes. The 105 studies are from 95 independent research teams. 5 studies compare against other treatments rather
than placebo. Currently ivermectin shows better results than these other treatments, however ivermectin may show
greater improvement when compared to placebo. 18 of 105 studies combine treatments, for example ivermectin +
doxycycline. The results of ivermectin alone may differ. 5 of 52 RCTs use combined treatment, three with doxycycline,
and one with iota-carrageenan. 2 of 105 studies currently have minimal published details available.
Reviews. Many reviews cover ivermectin for COVID-19, presenting additional background on mechanisms,
formulations, and related results, including 3,40,48-52,54,60,197,212,221-253.

Limitations. Summary statistics from meta analysis necessarily lose information. As with all meta analyses, studies
are heterogeneous, with differences in treatment delay, treatment regimen, patient demographics, variants, conflicts
of interest, standard of care, and other factors. We provide analyses for specific outcomes and by treatment delay,
and we aim to identify key characteristics in the forest plots and summaries. Results should be viewed in the context
of study characteristics.

Some analyses classify treatment based on early or late administration, as done here, while others distinguish
between mild, moderate, and severe cases. Viral load does not indicate degree of symptoms — for example patients
may have a high viral load while being asymptomatic. With regard to treatments that have antiviral properties, timing
of treatment is critical — late administration may be less helpful regardless of severity.

Details of treatment delay per patient is often not available. For example, a study may treat 90% of patients relatively
early, but the events driving the outcome may come from 10% of patients treated very late. Our 5 day cutoff for early
treatment may be too conservative, 5 days may be too late in many cases.

Comparison across treatments is confounded by differences in the studies performed, for example dose, variants, and
conflicts of interest. Trials with conflicts of interest may use designs better suited to the preferred outcome.

In some cases, the most serious outcome has very few events, resulting in lower confidence results being used in
pooled analysis, however the method is simpler and more transparent. This is less critical as the number of studies
increases. Restriction to outcomes with sufficient power may be beneficial in pooled analysis and improve accuracy
when there are few studies, however we maintain our pre-specified method to avoid any retrospective changes.

Studies show that combinations of treatments can be highly synergistic and may result in many times greater efficacy
than individual treatments alone 91,93,98,101,169,184-189. Therefore standard of care may be critical and benefits may
diminish or disappear if standard of care does not include certain treatments.

This real-time analysis is constantly updated based on submissions. Accuracy benefits from widespread review and
submission of updates and corrections from reviewers. Less popular treatments may receive fewer reviews.

No treatment or intervention is 100% available and effective for all current and future variants. Efficacy may vary
significantly with different variants and within different populations. All treatments have potential side effects.
Propensity to experience side effects may be predicted in advance by qualified physicians. We do not provide medical
advice. Before taking any medication, consult a qualified physician who can compare all options, provide personalized
advice, and provide details of risks and benefits based on individual medical history and situations.

Meta analyses. Typical meta analyses involve subjective selection criteria, effect extraction rules, and study bias
evaluation, which can be used to bias results towards a specific outcome. In order to avoid bias we include all studies
and use a pre-specified method to extract results from all studies (we also present results after exclusions). The
results to date are overwhelmingly positive, very consistent, and very insensitive to potential selection criteria, effect
extraction rules, and/or bias evaluation. Additional meta analyses confirming the effectiveness of ivermectin can be
found in Kory, Lawrie, Bryant, Nardelli, Hariyanto, Ragó. Kory et al. also review epidemiological data and provide
suggested treatment regimens.

Evidence base. The evidence supporting ivermectin for COVID-19 far exceeds the typical amount of evidence used for
the approval of treatments. Lee shows that only 14% of the guidelines of the Infectious Diseases Society of America
were based on RCTs. Table 5 and Table 6 compare the amount of evidence for ivermectin compared to that used for
other COVID-19 approvals, and that used by WHO for the approval of ivermectin for scabies and strongyloidiasis.
Table 7 compares US CDC recommendations for ibuprofen and ivermectin.
 Indication Studies Patients Status

Strongyloidiasis 255 5 591 Approved

Scabies 255 10 852 Approved

COVID-19 105 220,423

Pending
COVID-19 RCTs 52 17,642

Table 5. WHO ivermectin approval status.

Medication Studies Patients Improvement Status

Molnupiravir (UK) 1 775 50% Approved

Budesonide (UK) 1 1,779 17% Approved

Remdesivir (USA EUA) 1 1,063 31% Approved

Casiri/imdevimab (USA EUA) 1 799 66% Approved

Ivermectin evidence 105 220,423 60% [52-67%] Pending

Table 6. Evidence base used for other COVID-19 approvals compared with the
ivermectin evidence base.

Ivermectin Ivermectin
Ibuprofen
(for scabies) (for COVID-19)

Lives saved 0 0 >500,000

Deaths per year ~450 <1 <1

CDC recommended Yes Yes No

10 RCTs 52 RCTs
Based on 0 RCTs
852 patients 17,642 patients

Table 7. Comparison of CDC recommendations 255.

Merck, FDA, NIH, WHO

WHO.

WHO updated their treatment recommendations on 3/30/2021 256. For ivermectin they reported a mortality odds ratio
of 0.19 [0.09-0.36] based on 7 studies with 1,419 patients. They do not specify which trials they included. The report
is inconsistent, with a forest plot that only shows 4 studies with mortality results. WHO's recommendation has not
been updated for 1280 days.

Despite this extremely positive result, they recommended only using ivermectin in clinical trials. The analysis contains
many flaws 257:

• Of the 105 studies (52 RCTs), they only included 16.

• They excluded all 17 prophylaxis studies (4 RCTs).

• There was no protocol for data exclusion.

• Trials included in the original UNITAID search protocol were excluded.

• They excluded all epidemiological evidence, although WHO has considered such evidence in the past.

• They combine early treatment and late treatment studies and do not provide heterogeneity information. As above,
early treatment is more successful, so pooling late treatment studies will obscure the effectiveness of early
treatment. They chose not to do subgroup analysis by disease severity across trials, although treatment delay is
clearly a critical factor in COVID-19 treatment, the analysis is easily done (as above), and it is well known that the
studies for ivermectin and many other treatments clearly show greater effectiveness for early treatment.

• WHO downgraded the quality of trials compared to the UNITAID systematic review team and a separate
international expert guideline group that has long worked with the WHO 5.

• They disregarded their own guidelines that stipulate quality assessments should be upgraded when there is
evidence of a large magnitude effect (which there is), and when there is evidence of a dose-response relationship
(which there is). They claim there is no dose-response relationship, while the UNITAID systematic review team
found a clear relationship, along with individual studies 183.

• Their risk of bias assessments do not match the actual risk of bias in studies. For example they classify López-
Medina as low risk of bias, however this study has many issues making the results unreliable 258, even prompting an
open letter from over 170 physicians concluding that the study is fatally flawed 259. Beltran Gonzalez is also
classified as low risk of bias, but is a study with very late stage severe condition high-comorbidity patients. There is
a clear treatment delay-response relationship and very late stage treatment is not expected to be as effective as
early treatment. Conversely, much higher quality studies were classified as high risk of bias.

• Although WHO's analysis is called a "living guideline", it is rarely updated and very out of date. As of May 14, 2021,
four of the missing RCTs are known to WHO and labeled "RCTs pending data extraction" 260. We added these 4, 4, 2,
and one month earlier.

• A single person served as Methods Chair, member of the Guidance Support Collaboraton Committee, and member
of the Living Systematic Review/NMA team.

• Public statements from people involved in the analysis suggest substantial bias. For example, a co-chair reportedly
said that "the data available was sparse and likely based on chance" 261. The clinical team lead refers to their
analysis of ivermectin as "fighting this overuse of unproven therapies ... without evidence of efficacy" 261, despite the
extensive evidence of efficacy from the 105 studies by 1,206 scientists with 220,423 patients. People involved may
be more favorable to late stage treatment of COVID-19, for example the co-chair recommended treating severe
COVID-19 with remdesivir 262.

In summary, although WHO's analysis predicts that over 2 million fewer people would be dead if ivermectin was used
from early in the pandemic, they recommend against use outside trials. This appears to be based primarily on
excluding the majority of the evidence, and by assigning bias estimates that do not match the actual risk of bias in
studies.

Use early in the pandemic was proposed by Kitasato University including the co-discoverer of ivermectin, Dr. Satoshi
Ōmura. They requested Merck conduct clinical trials of ivermectin for COVID-19 in Japan, because Merck has priority
to submit an application for an expansion of ivermectinʼs indications. Merck declined 245.

Merck.

Merck has recommended against ivermectin 263, however this recommendation has not been updated for 1334 days.
They stated that there is "no scientific basis for a potential therapeutic effect against COVID-19 from pre-clinical
studies". This is contradicted numerous studies, including Jitobaom, Li, Fauquet, Boschi, Shahin, Abd-Elmawla, Ma,
Vottero, Mody, Parvez, Gao, Zhang, DiNicolantonio, Zhao, Liu (B), Liu (C), Munson, Yan, de Oliveira Só, Agamah,
Oranu, Chellasamy, Umar, Alvarado, Aminpour, Parvez (B), Francés-Monerris, González-Paz, González-Paz (B), Rana,
Muthusamy, Qureshi, Schöning, Bello, Udofia, Choudhury, Kern, Saha, Eweas, Francés-Monerris (B), Kalhor,
Swargiary, Maurya, Lehrer, Suravajhala, García-Aguilar, De Forni, Saha (B), Jitobaom (B), Croci, Zheng, Delandre,
Segatori, Jitobaom (C), Mountain Valley MD, Yesilbag, Jeffreys, Surnar, Caly, Uematsu, Albariqi, Errecalde, Madrid,
de Melo, Arévalo, Chaccour, Zaidi, Wehbe, Jans (B), Heidary, Zatloukal, Kalfas.

They state that there is "no meaningful evidence for clinical activity or clinical efficacy in patients with COVID-19
disease". This is contradicted by numerous studies including de Jesús Ascencio-Montiel, Babalola, Hashim,
Chowdhury, Espitia-Hernandez, Mahmud, Chaccour (B), Ghauri, Ravikirti (B), Bukhari, Mohan, Elalfy, Chahla,
Mourya, Loue, Merino, Faisal, Aref, Mayer, Manomaipiboon, Khan, Budhiraja, Okumuş, Lima-Morales, Huvemek,
Baguma, Shimizu, Aref (B), Varnaseri, Behera, Bernigaud, Alam, Chahla (B), Behera (B), Seet, Morgenstern, Mondal,
Kerr.

They also claim that there is "a concerning lack of safety data in the majority of studies". Safety analysis is found in
Guzzo, Kory, Descotes, Errecalde, Madrid, and safety data can be found in most studies, including López-Medina,
Vallejos, Shahbaznejad, Kishoria, Carvallo (C), Hazan (B), Szente Fonseca, Zubair, Babalola, Biber, Chowdhury,
Espitia-Hernandez, Mahmud, Chaccour (B), Ghauri, Bukhari, Mohan, Elalfy, Mourya, Loue, Aref, Khan, Okumuş,
Lima-Morales, Huvemek, Chahla (B), Behera (B), Seet, Morgenstern, Ahmed, Krolewiecki, Gorial, Camprubí,
Spoorthi, Pott-Junior, Abd-Elsalam, George, Shouman (B), Bhattacharya.

Merck has a number of conflicts of interest:

• Merck has committed to give ivermectin away for free "as much as needed, for as long as needed" in the Mectizan®
Donation Program 311, to help eliminate river blindness.

• Merck has their own new COVID-19 treatments MK-7110 (formerly CD24Fc) 312 and Molnupiravir (MK-4482) 313,314.
Merck has a ~$US1.2B agreement to supply molnupiravir to the US government, if it receives EUA or approval 315.
Over $US10B in near-term orders are expected if approved 316.

• Ivermectin is off-patent, there are many manufacturers, and Merck is unlikely to be able to compete with low cost
manufacturers.

• Promoting the use of low cost off-patent medications compared to new products may be undesirable to some
shareholders.

• Japan requested Merck conduct clinical trials early in the pandemic and they declined. Merck may be reluctant to
admit this mistake 245.

For other concerns regarding Merck's statement and prior actions related to Vioxx, see Scheim (E).

FDA.

The US FDA recommended against ivermectin on March 5, 2021, however they stated that "The FDA has not reviewed
data to support use of ivermectin in COVID-19 patients to treat or to prevent COVID-19". There is still no indication
that the FDA has reviewed the clinical trials 1305 days later.

The FDA notes that they "received multiple reports of patients who have required medical support and been
hospitalized after self-medicating with ivermectin intended for horses". The number of reports was 4 318. For
comparison, acetaminophen overdose results in ~33,000 yearly hospitalizations in the USA (~12,000
unintentional) 319. The FDA's recommendation may increase cases of self-medication with animal ivermectin, because
it reduces the percentage of prescribing physicians.
They state that "Ivermectin is not an anti-viral", however many studies contradict this Caly, Buonfrate, Qadeer, Thairu,
Babalola, Biber, Chowdhury, Espitia-Hernandez, Mahmud, Bukhari, Mohan, Elalfy, Mourya, Aref, Khan, Okumuş,
Ahmed, Wijewickrema, Rezk, including 11 RCTs.

They note that "some initial research is underway", however there had been many studies completed and published
prior to the FDA recommendation: López-Medina, Beltran Gonzalez, Hellwig, Cadegiani, Carvallo (C), Babalola, Biber,
Hashim, Chowdhury, Espitia-Hernandez, Mahmud, Chaccour (B), Ghauri, Ravikirti (B), Bukhari, Mohan, Elalfy, Khan,
Budhiraja, Okumuş, Lima-Morales, Behera, Bernigaud, Alam, Chahla (B), Ahmed, Gorial, Camprubí, Spoorthi,
Shouman (B), Podder, Chachar, Rajter, including 17 RCTs.

Sep 3, 2021: The FDA revised their statement slightly. They removed the false claim that invermectin is not an antiviral,
and they removed the statement that they have not reviewed the data. However, there is still nothing to indicate that
they have reviewed the clinical trials. Indeed, they state "currently available data do not show ivermectin is effective
against COVID-19" and "ivermectin has not been shown to be safe or effective for these indications", which are both
false.

NIH.

Update: NIH has updated the recommendation, based heavily on the Together Trial, while making no mention of the
impossible data, blinding, randomization, and protocol failures, or that the co-principal investigator privately reported
that "There is a clear signal that IVM works in COVID patients".

NIH has reported that there is insufficient evidence to recommended for or against ivermectin 325. A table with
summaries of 7 studies is provided, dated Dec 16, 2021, and they reference another 23 studies without analysis,
however there are 105 studies to date. No quantitative analysis is provided. The NIH recommendation is "insufficient
evidence", indicating that they must review new evidence immediately. Lack of updates suggest bias.

The likely members of the panel have been revealed by FOIA requests 326. In the first request, all but two member
names were redacted 327, however all are visible in a second request 328. Major conflicts of interest have been
reported 326,329. 7 of 9 panel members appear to have conflicts of interest. Submit Corrections or Updates

• Merck: advisory board, consultant, research support 330,331

• Gilead (maker of remdesivir): consultant, research support 332,333 "Aadimora

Prof. Adaora Adimora
AA has received consulting fees from Viiv, and Gilead and her institution has
(adimora@[Link])
received funding from Gilead for her research"

• Open Payments shows $62,000 from Merck and $88,000 from Gilead 334

• Merck: advisory board 330,331

Prof. Roger Bedimo • Gilead: honoraria 333

([Link]@[Link])
• Open Payments shows $149,000 from Merck, $76,000 from Sanofi, and
$23,000 from Gilead 335

Prof. Rajesh Gandhi • Gilead: grants, advisory board, personal fees 336,337 "Dr. Gandhi reports
(rgandhi@[Link]) grants and personal fees from Gilead, personal fees from Merck, grants and
personal fees from Theratechnologies, grants from ViiV, grants from
Janssen."

• Merck: advisory board and personal fees 333,336,337

• Janssen: grants 336

 • Open Payments shows $45,000 from Merck and $10,000 from Gilead 338

• Merck: advisory board 330,331

Prof. David Glidden
([Link]@[Link])
• Gilead: consultant 330,333

• Merck: grants 339 (deleted from current version 340) "Roy M. Gulick, MD,
MPH, has disclosed that he has received grants for clinical research from
Abbott, Boehringer Ingelheim, Merck, Pfizer, Schering, and Tibotec, and has
received grants for educational activities from Gilead and Monogram. Dr.
Gulick has also disclosed that he has served as an ad-hoc advisor or
consultant to Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead,
GlaxoSmithKline, Pfizer, Schering, and Tibotec", principal investigator on
A5391 with funding in part from Merck 341

Prof. Roy Gulick

• Pfizer: grants and ad-hoc advisor or consultant 339 (deleted from current
(rgulick@[Link])
version 340

• Gilead: grants and ad-hoc advisor or consultant 339 (deleted from current
version 340

• GlaxoSmithKline: ad-hoc advisor or consultant 339 (deleted from current

version 340

• NIAID/NIH: grants 342,343

• Gilead: grants, travel/meeting support 330,333,337

• AbbVie, NIH: grants 337

• Vir Biotechnology: advisory board, stockholder 330

Prof. Susanna Naggie
([Link]@[Link])
• Ivermectin trial grant: $155 million grant after the insufficient evidence
recommendation 331

• Open Payments shows $2.4 million from AbbVie, $1.2 million from Gilead,
$34,000 from Janssen, and $19,000 from Merck 344

• Merck: consultant 333,337

• Genentech: consultant 333

Prof. Andrew Pavia
([Link]@[Link]) • GlaxoSmithKline: consultant 337

• Open Payments shows $14,000 from Pfizer, $5,000 from Merck, and
$4,000 from Janssen 345

Perspective

Results compared with other treatments. SARS-CoV-2 infection and replication involves a complex interplay of 50+
host and viral proteins and other factors 20-24, providing many therapeutic targets. Over 8,000 compounds have been
predicted to reduce COVID-19 risk 25, either by directly minimizing infection or replication, by supporting immune
system function, or by minimizing secondary complications. Figure 28 shows an overview of the results for ivermectin
in the context of multiple COVID-19 treatments, and Figure 29 shows a plot of efficacy vs. cost for COVID-19
treatments.

Efficacy in COVID-19 studies (pooled effects) [Link]

October 2024
Regdanvimab
Ivermectin
PVP-I
Diet

Alkalinization
Melatonin
Vitamin D
Metformin
Zinc

HCQ
Vitamin C
Paxlovid independent trials refused

Molnupiravir mutagenic/teratogenic

Remdesivir worse w/longer followup

Conv. Plasma
Cannabidiol
Acetaminophen
PPIs
0 0.25 0.5 0.75 1 1.25 1.5+

Lower risk Increased risk

Figure 28. Scatter plot showing results within the context of multiple COVID-19 treatments. Diamonds shows the results of
random effects meta-analysis. 0.6% of 8,000+ proposed treatments show efficacy 346.

Efficacy vs. cost for COVID-19 treatments Lifestyle / free [Link]

No prescription October 2024
Prescription required Regdanvimab $2,100
Ivermectin High-cost
Thermotherapy

50% Diet PVP-I

pH+ Quercetin
Melatonin Bamlanivimab/e.. Ensovibep >$2,000
N. Sativa NaHCO₃
Curcumin Tixagevimab/c.. Casirivimab/i.. $2,100
Exercise Fluvox. H1RAs
H. Peroxide Vitamin A Vitamin D
Sunlight
Azvudine Antiandro.. Nitric Oxide Bebtelovimab
Metformin HCQ Zinc
Sleep Sotrovimab $2,100
Probiotics Colchicine Budesonide
25% NAC Vilobelimab $6,350
Vitamin C
Amubarvimab/r..
rewoL

Famotidine Paxlovid
ksir

Favipiravir
Molnupiravir
Aspirin
mutagenic/teratogenic
Acebilustat >$2,000
Remdesivir $3,120
0% Ibuprofen
COVID-19 involves the interplay of 50+ host/viral proteins/ Conv. Plasma $5,000
Sargramostim >$2,000
rehgiH

Vitamin B9
factors, modulated by many treatments. 0.6% of 8,000+ Trimodulin >$2,000
ksir

Cannabidiol
Losartan proposed treatments show efficacy with ≥3 studies. Lufotrelvir >$2,000
BMS mAbs -36% >$2,000
Acetaminophen -28% Protocols combine treatments, none are 100% effective. Glenzocimab -60% >$2,000
-25+% PPIs -46% c19early analyzes over 4,800 studies for 95 treatments. Donidalorsen -151% >$2,000

$0 $1,000 $2,000+

Treatment cost (US$)

Figure 29. Efficacy vs. cost for COVID-19 treatments.

Conclusion

Ivermectin is an effective treatment for COVID-19. Treatment is more effective when used early. Meta analysis using
the most serious outcome shows 61% [50-69%] and 85% [77-90%] lower risk for early treatment and prophylaxis, with
similar results for higher quality studies, primary outcomes, peer-reviewed studies, and for RCTs. Statistically
significant lower risk is seen for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral
clearance. All remain significant for higher quality studies. 64 studies from 58 independent teams in 27 different
countries show significant improvements. Results are very robust — in worst case exclusion sensitivity analysis 63 of
105 studies must be excluded to avoid finding statistically significant efficacy.

Optimal use of ivermectin may involve synergy with combined treatments, administration taking into account the
lipophilic nature, and sublingual, spray, or inhaled formulations for direct treatment to the respiratory tract.
Pharmacokinetics show significant inter-individual variability 1. Injectable formulations may reduce variability and
provide much faster onset of action 99. Liposomal formulations show increased antiviral activity and lower
cytotoxicity 94. Synergistic results are seen with polytherapy 91,93,98. Efficacy varies depending on the manufacturer 2,
underdosed and contaminated tablets are common 347,348, and fake tablets with no active ingredient have been
reported 226.

Responses

TLDR.

As Scott Alexander says: "if you say anything in favor of ivermectin you will be cast out of civilization and thrown into
the circle of social hell reserved for Klan members and 1/6 insurrectionists. All the health officials in the world will
shout 'horse dewormer!' at you and compare you to Josef Mengele." The extreme politicization means we can only
evaluate the data directly.

With 105 controlled studies, 52 RCTs, and extensive supporting evidence, few people have the time and experience to
analyze all or most of the evidence. However, the PRINCIPLE trial 127 provides a single large trial showing efficacy.
Despite being perhaps the most biased trial, with extreme bias against showing efficacy in the design, operation,
analysis, and reporting, authors failed to eliminate the efficacy and hid the results for 600 days (810 days from the
expected announcement time, which resulted in a pause and continuation with even greater bias).

PRINCIPLE showed 36% lower ongoing persistent COVID-19 specific symptoms, p<0.0001 127, and the primary
recovery outcome shows superiority of ivermectin with significantly faster recovery and a probability of superiority >
0.999. While authors make an unprecedented claim that the results are not clinically relevant, 2 days faster recovery
and 36% lower long COVID are both highly clinically relevant. Moreover, from all 95 treatments we cover, improved
recovery is very significantly associated with lower mortality, p < 0.0000000000001, as shown in Figure 30. These
highly positive results are despite very late treatment, a relatively low-risk population, and poor administration —
based on analysis of all trials we expect significantly better results with recommended usage.
 Improved recovery is associated with lower mortality

%001
%57
ytilatrom ni tnemevorpmI
%05
%52
[Link]
%0 October 2024

mixed-effects meta-regression
slope 0.79 [95% CI 0.61 to 0.97] p<0.00000000001
%52-

-25% 0% 25% 50% 75% 100%

Improvement in recovery

Figure 30. Improved recovery is associated with lower mortality. Meta-regression

across 95 treatments.

36% lower ongoing persistent COVID-19 specific symptoms, p<0.0001 127. The primary outcome
PRINCIPLE shows superiority of ivermectin with significantly faster recovery and a probability of superiority >
0.999.

"There is a clear signal that IVM works in COVID patients.. that would be significant if more patients
TOGETHER
were added.." - co-principal investigator 124.

99%, 98%, 97% superiority for time unwell, progression @14,7 days 125 (note: the clinical
ACTIV-6 progression results were modified in the journal version, with no explanation for over 700 days, and
the 600µg/kg results also differ without explanation).

61% lower hospitalization (ivermectin vs. placebo, unreported) 126. Authors detail why the
COVID-
hypoxemia results are unusable, however analysis of the data shows that the ER results are similarly
OUT
uninformative and do not appear to be related to symptoms.

Table 8. Summary of widely discussed ivermectin RCTs.

Primary outcome analysis.

We use fixed pre-specified effect extraction to avoid bias and to focus on the most clinically relevant results. For
comparison, we have also performed analysis using the primary outcome of studies (shown in the supplementary
data), with results showing similar effect sizes. Prophylaxis results are very similar with 100% (17 of 17) positive
effects. Early treatment shows 85% (34 of 40) positive effects, improved due to the very small event count negative
serious outcomes in Krolewiecki, Vallejos, and Buonfrate no longer having priority. Late treatment shows 71% (34 of
48) positive effects, reduced slightly, primarily due to viral clearance results being the primary outcome in some
studies, and viral clearance being less successful with late treatment. Overall, the primary outcome analysis shows
81% (85 of 105) positive effects, which is currently identical to the results of the main protocol analysis.
BBC.

The team referenced in this article is unreliable. Dr. Kyle Sheldrick posted a schedule A statement as a result of a
defamation lawsuit admitting to false and defamatory claims regarding one of the world's most highly published and
respected critical care physicians 349; Dr. Nick Brown has called for trials for crimes against humanity for scientists
that "tried to scam the world with their fake treatments" including vitamin D 350,351. Gideon Meyerowitz-Katz has
posted many false claims detailed below 352.

Update: authors indicated that their data would be available "soon" as of Sep 14, 2021, however it has not been
released over 1,100 days later 353, therefore it is not possible to analyze their methods regarding ivermectin research
in detail. However, Dr. Sheldrick posted false and defamatory accusations regarding a highly respected physician that
has saved countless lives before and during the pandemic. In this case, detailed methods were published, revealing
highly flawed analysis, and a basic misunderstanding of statistics, as detailed by multiple statisticians 354,355. Author
deleted the blog post. Further, we note that the team's disregard for major issues with the Together Trial, ACTIV-6,
López-Medina et al., and Beltran Gonzalez et al. suggest substantial bias.

A BBC article raises questions due to data issues in some studies, based on an analysis from a team of researchers.
One of the researchers reports that data in some trials could have been manipulated, while noting that human error
can not be ruled out. Others in the team directly accuse authors of malfeasance. Regardless of the cause, concern
over these studies is valid. Currently, 2 studies have been retracted, one was withdrawn by a preprint server, and
another has been reported as pending retraction, although the journal reports that no retraction is pending. None of
these studies are in our analysis.

Existence of some lower quality studies is typical in large evidence bases. The percentage of studies with issues is not
greater than reported averages, and is not close to removing evidence of efficacy (and may actually improve evidence
as detailed below). We performed an absolute worst case sensitivity analysis, where positive studies are excluded in
order of the effect size, with the largest effect first. 60%, or 63 of 105 studies must be excluded to avoid finding
statistically significant efficacy (this is in addition to the four papers not in this analysis).

The summary statistics from meta analysis necessarily obscure most of the information in the evidence base. For
those that have read all of the research, knowledge of efficacy is supported by extensive additional information,
including for example relationships between outcomes within a study, dose-response relationships within and across
studies, treatment delay-efficacy relationships within and across studies, variant-efficacy relationships, etc. Notably,
removal of Elgazzar, Samaha, and Niaee improve the treatment delay-efficacy and dose-response relationships and
may further increase confidence when considering all information.

Concerns about Cadegiani, Carvallo, Carvallo (B), Carvallo (C) have also been reported. All of these studies are
excluded in our exclusion analysis.

Studies Prophylaxis Early treatment Late treatment Patients Authors

With GMK/BBC exclusions 70 84% [73-91%] 69% [61-76%] 48% [32-60%] 202,821 831

RCTs w/GMK/BBC exc. 39 89% [57-97%] 65% [53-74%] 34% [14-50%] 12,977 532

Percentage improvement with ivermectin treatment after exclusion of all studies reported by this team

We note that, while malfeasance cannot be ruled out, reported concerns may also be caused by typos, data collection
errors not affecting analyzed outcomes, and expected results from multiple tests. Authors, without any prior
registration or statistical analysis plan, perform thousands of statistical tests across data in the studies and report
results without correcting for multiple tests. For example, reporting the occurrence of a 1 in 1,000 event as evidence
of randomization failure, while performing more than this number of tests across studies.

This group often dismisses studies based on an arbitrary statistical significance threshold for a specific outcome, a
misunderstanding of statistics 356, and indefensible as a pre-filter in meta analysis.
This group has made many claims unsupported by the data. For Niaee, one author claimed the study "made a HUGE
difference". It has no effect on early treatment or prophylaxis. For late treatment, which is not recommended, the
change was relatively minor. For Elgazzar, the author claimed that it could be "the most consequential medical fraud
ever committed". There was almost no difference in our analysis after removing this paper (excluding 1 of 108 studies
has very little effect, and the exclusion actually improves the treatment delay-response relationship).

Statements by the group suggest significant bias. The main author first referred to ivermectin as "something else to
debunk" in December 2020, and later as a "horse dewormer". Another group member has called for charging
scientists that recommend vitamin D with "crimes against humanity".

The group has made claims about all ivermectin evidence based on the existence of some studies with issues. It is
inappropriate to generalize about the entire group of 1206 scientists and researchers based on the mistakes or
actions of a few individuals.

This group has focused on finding issues in papers reporting large positive effects, which introduces a significant
bias. Notably, the few studies that contribute most to minimizing the effects in meta analysis include studies with very
high conflicts of interest and many reported protocol violations and data issues, however this group disregards all of
these issues.

The article claims "The largest and highest quality ivermectin study published so far is the Together trial" which "found
no benefit", however this study has not been published, is one of the lowest quality trials with many documented
design, execution, and analysis issues, has extremely high conflicts of interest, there is a history of inaccurate
reporting prior to publication for a previous treatment in the same trial, and the trial actually reported 18% lower
mortality (not statistically significant).

The article reports that 26 studies were examined, however there are 108 studies, authors have not reported their
results for all 26, and authors have not provided their data after repeated requests. Currently they have not even
provided a list of the 26 studies.

The group has an excessive focus on RCTs, which have a fundamental bias against finding an effect for interventions
like ivermectin that are widely known and easily available — patients that believe they need treatment are more likely
to decline participation and take the treatment 357 (this does not apply to the typical pharmaceutical trial of a new drug
that is otherwise unavailable and unfamiliar).

The main author of the group is also against vitamin D. Of the 122 vitamin D COVID-19 treatment studies, author
suggests only one trial is worth looking at 358. This gives us a simple case to examine potential bias. Murai is a small
trial providing no statistically significant effects (mortality p = 0.43, other outcomes are positive while also not
significant). Author acknowledges that the trial is too small for a conclusion. More importantly, this trial provides no
information about whether vitamin D reduces the risk of a serious COVID-19 case, because the patients in this trial
already had a serious COVID-19 case (90% already on oxygen treatment at baseline). Author does not mention this.
The trial also has poorly matched arms in terms of gender, ethnicity, hypertension, diabetes, and baseline ventilation,
all favoring the control group. Further, this study uses an inappropriate form of vitamin D — cholecalciferol. In reality
physicians would use calcifediol or calcitriol with late stage treatment, because they avoid a very long delay for
conversion. We are unaware of a reason to use cholecalciferol in this case (other than to produce a null result). In
summary, author's chosen study is the study providing the least useful information from the 122 vitamin D treatment
studies to date, suggesting biased analysis.

We fully support this team's effort to clean up the evidence base. This is extremely valuable and improves the integrity
of the evidence base (and the accuracy if done equally for all studies). We hope this or other teams can do the same
for all treatments. However the analysis plan should be published, details of all tests should be provided, results
should be corrected for multiple testing, results for all studies and tests should be provided, and equal attention
should be given to studies with non-statistically significant results, especially those with major reported data issues
that have been disregarded by this team (for example data suggesting substantial protocol violations including
confounding by time in Reis and control arm use of treatments in López-Medina).
For coverage of other errors in the BBC article, and illumination of the stark contrast between Dr. Lawrie's response to
the BBC before publication and what they chose to report, see BiRD Group, Elijah, Lawrie (B), Campbell.

More details can be found in the following response regarding the main author of this group.

GidMK.

On September 6, 2021, author is on video saying "what this web site does is it goes through all of those 10 things,
finds the positive one, and only reports the positive one ... they'll pick a number that is the lowest number" 363
@46:48. This is false, we report individual outcome analyses, and for pooled results we use the most serious
outcome with a detailed protocol. Notably, author knows this is false, having posted the protocol on Twitter a month
earlier. Moreover, in most cases there could be no ambiguity on the most serious outcome even without a detailed
protocol. At the time of author's statement, the most serious outcome was actually the worst of multiple reported
outcomes 26% of the time.

Author indicated their data would be released "soon" on Sep 14, 2021. The data was used for conclusions in the BBC
and BMJ along with a message that data transparency is needed. No data has been released over 1,100 days later 353.

TLDR
As a quick way to assess reliability, consider that author describes the Together Trial as "incredibly well-done" and a
“masterpiece of science". The trial actually reported multiple impossible numbers, has refused to release data despite
pledging to do so, has extreme conflicts of interest, and had blinding failure, randomization failure, and multiple
protocol violations as detailed below. Author similarly disregards major issues with many other trials, including ACTIV-
6, López-Medina et al., and Beltran Gonzalez et al. This suggests substantial bias.

SEE ALSO
The Potemkin Argument: How Scott Alexander and GidMK Caricatured the Work of Honest Scientists
The Potemkin Argument, part I (extension): The Sullying of Babalola et al.

Incorrect, misleading, hyperbolic, and unsupported statements have been made by an influential anti-treatment
Twitter personality, journalist, and PhD student known for defending Monsanto Roundup against carcinogenic claims
(later settled for $US 11 billion). Author is notable as the only known researcher that reports having read a majority of
the 108 (including retracted) studies, but does not find the evidence to be positive. However, their opinion appears to
have been formed before reading the studies — they first referred to ivermectin as "something else to debunk". We
note that the author has made valuable contributions identifying significant issues with some studies, which has
helped to improve the quality of the ivermectin evidence base, and has improved the dose-response and treatment
delay-response relationships.

Analysis with GMK's recommended exclusions can be found in the supplementary data, which shows 46% [33-56%]
improvement, p = 0.0000000083.

Author has been paid for writing anti-treatment articles, and has also referred to ivermectin as a "horse dewormer".
Author has experienced personal tragedy with multiple family members having died of COVID-19, which may
introduce a bias against acknowledging errors in treatment advice.

Author's attempt to discredit the scientists performing ivermectin research centers on the false assertion that
excluding a small number of lower quality trials results in a negative outcome. It should be clear from the forest plot
that this is not possible, but we can be more specific. We perform a worst case sensitivity analysis, where positive
studies are excluded in order of the effect size, with the largest effect first. How many studies do we need to exclude
before the meta analysis RR has a confidence interval exceeding 1.0? 60%, or 63 of 105 studies must be excluded to
avoid finding statistically significant efficacy. As with all data in this paper, this analysis will automatically update as
the evidence base evolves. Also note that this is after exclusion of withdrawn papers - one has never been in this
analysis, the second was removed on the same day it was withdrawn, and the other two were removed in advance of
retraction based on author's notification that retraction is pending (only one has been retracted, the journal for Niaee
et al. has reported that no retraction is pending).

Author claims that we include several papers that are already excluded in the 11 exclusion analyses.

Author claims that there is a greater percentage of low quality studies for ivermectin and COVID-19 compared to other
treatments. This is unsupported for such a large evidence base, and does not match previous studies.

Author often makes a basic error by equating positive effects that are not statistically significant at a specific level with
"no effect", a misunderstanding of statistics 356. For example, if a study reports 50% improvement with a p value of
0.1, we cannot say that the study shows the treatment is ineffective, or in the words of the author shows "no benefit at
all". Author repeatedly makes false claims in this way.

On Sep 14, 2021, author indicated that their team had reviewed about 30 ivermectin studies and their data would be
available soon, however it has not been released three years later.

Author appears to favor pharmaceutical company affiliated/operated trials. For example, the author has no problem
with the lack of IPD for many pharmaceutical affiliated COVID-19 trials that support the author's treatment positions,
yet considers the lack of IPD in a positive ivermectin trial to be problematic. Author believes the pharmaceutical
affiliated Together Trial is the highest quality trial so far, yet not only have the authors declined to release IPD that they
previously pledged to release, there was not even a preprint when GMK made the statement, and the trial has many
critical and serious flaws, extremely high conflicts of interest, and a history of inaccurate reporting prior to publication
for another treatment arm. GMK has subsequently published a paper with one of the original co-lead's of the Together
Trial (who later joined the trial DSMC).

Author has disregarded treatment delay in analysis, which results in incorrect conclusions. For example, author claims
that the RECOVERY trial proved that another treatment is not effective, and would provide definitive data if the same
was done for ivermectin. The trial provided valuable data on very late use (9 days after symptoms) with an excessively
high dose and very late stage patients. However, it did not provide information on early treatment. Oseltamivir, for
example, is generally only considered effective for influenza when used within 0-36 or 0-48 hours 171,172. Paxlovid was
tested with a maximum of 3 days from symptom onset (the mean delay is unknown). For ivermectin, author believes
the PRINCIPLE trial will provide strong data on efficacy, however this trial includes low risk patients less than 15 days
from symptom onset, and may only provide information on late treatment in a low risk population with lower risk
variants. Figure 31 shows a mixed-effects meta-regression for efficacy as a function of treatment delay in COVID-19
studies from 95 treatments. Efficacy declines rapidly with treatment delay.
 Efficacy by treatment delay in COVID-19 studies

100%
[Link]
October 2024

75%

ton taL
era
e
rpe ert
50%

a
ne emt
Efficacy

n
se
ev ser t
25%

t
u
a
stl
it
0%

p<0.00000000001
mixed-effects meta-regression, most serious sufficiently powered outcome
-25%

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Treatment delay (days since onset)

Figure 31. GMK believes that results for treatment delayed 9 days from symptom onset provides definitive information on
treatment efficacy. However early treatment is critical for antivirals, as shown with antivirals for other respiratory diseases,
and in meta-regression of studies from 95 COVID-19 treatments.

Author has an unwarranted focus on a specific outcome (mortality) and a specific subset of trials (RCTs). This would
be reasonable in many cases when sufficient high-quality data is available, however this is not the case for off-patent
COVID-19 treatment trials, where RCTs often involve delayed treatment, low-risk patients where mortality is rare, or
very high conflicts of interest. Widely accepted and effective (for specific variants) treatments like
casirivimab/imdevimab, bamlanivimab, and sotrovimab were all approved without statistically significant mortality
benefits. Other outcomes are also important — accelerating viral clearance, and reducing cases, hospitalization, ICU
admission, ventilation, etc. are all very valuable, for example reducing serious "long COVID" problems, reducing
transmission of the virus, and reducing the burden on the healthcare system. These outcomes are also likely to
correlate with reduced mortality among larger or higher-risk populations. We note that there is extensive evidence for
the mortality outcome when not restricting to RCTs. RCTs have mostly been run with relatively low risk populations
where mortality is low, leading to limited statistical significance. However RCTs are inherently biased towards low
mortality and towards not finding an effect in this case — ivermectin is well-known to be beneficial for COVID-19 and
is easily available, therefore participants that believe they may be at serious risk are more likely to decline participation
in the RCT and take the recommended medications. Patients that do choose to participate are also more likely to have
low adherence. This bias of RCTs is likely to be even larger in locations where ivermectin is widely used in the
community and very easily obtained, which correlates with the observed RCT results.

Author suggests that we have chosen the wrong outcome in some cases. While mistakes are possible, for example
we corrected errors with Espitia-Hernandez et al. and Jain et al., the claims made suggest that the author has not
read the studies and/or our protocol carefully. Details are below. We note that the author disregards the existence of
the individual outcome analyses and the primary outcome analysis.

Most errors have not been corrected by the author over three years later. Many false, misleading, and defamatory
statements continue to be available, highly-ranked in search results, and highly influential. Other errors include:

• that excluding Elgazzar et al. completely changes the results and could be "the most consequential medical fraud
ever committed". Excluding 1 of 108 studies has very little effect, and the exclusion improves the treatment delay-
response relationship.

• that Niaee et al. "made a HUGE difference". It has no effect on early treatment or prophylaxis. For late treatment,
which is not recommended, the change was minor, and the exclusion improves the treatment delay-response
relationship.
• making basic errors suggesting very superficial reading of studies, for example claiming the RR in Szente Fonseca
is the risk of being treated.

• making basic errors suggesting very superficial reading of this paper, for example claiming that a result for
prophylaxis studies is based on the number of patients from all studies.

• equating a high degree of COVID-19 in a country partially adopting a treatment with a lack of efficacy, disregarding
obvious confounding such as heavily affected areas being more likely to adopt treatment (analysis of results in
regions or time periods adopting treatment, while not equivalent to controlled studies, is more informative and
shows efficacy 278,364-366).

• confusing heterogeneity due to dose, treatment delay, etc. and due to bias.

• disregarding treatment delay to dilute or obscure effects by including late treatment (author has also used this
method with other treatments).

• disregarding the existence of specific outcome analyses, RCT analysis, and exclusion-based sensitivity analysis.

• suggesting that efficacy over longer periods is not possible because ivermectin has a half-life of "about a day".
Author disregards known efficacy for other conditions over much longer periods, and mischaracterizes the half-life.
Antiparasitic efficacy can persist for several months after a single dose 367. Plasma half-life is longer in some
studies, and significant plasma concentration can persist for over 2 weeks in some patients 368. More importantly,
ivermectin is highly lipophilic and may accumulate in the lung and other tissues where concentrations may be many
times higher 369,370.

• misunderstanding funnel plot analysis and explanations other than selective reporting (and providing no evidence of
unreported negative studies, while there is substantial evidence of difficulty publishing positive studies 192,193).

• suggesting that it is not reasonable to combine evidence from mortality and hospitalization (for example), but
happily combining late treatment and early treatment in order to obscure efficacy. If a treatment reduces disease
severity requiring hospitalization, reduced mortality in at-risk populations logically follows, whereas lack of efficacy
several days after onset can not be extrapolated to early treatment — treatments for a viral infection are often less
effective when delayed.

• making serious claims about individual studies without contacting authors (for example claiming patients were
excluded for reaching the endpoint too quickly in one study, whereas authors report exclusions due to baseline
negative status).

• author is unaware of different variants, suggesting that results should be identical for treatment at a given delay,
even when the predominant variants have markedly different peak viral load, time to peak viral load 177-179, and
mortality (for example Gamma vs. non-Gamma aHR 4.73 [1.15-19.41] 180).

The cases where author suggests we have chosen the wrong outcome indicate that the author has not read the
studies and/or our protocol carefully:

• suggesting that the risk of a good outcome should be selectively used instead of the risk of a bad outcome (author
would like to do this when it reduces the effect size). This is similar to using the risk of surviving instead of the risk
of death. 99% survival may only be a 4% improvement over 95% survival, but most people would appreciate the
80% lower risk of death.

• suggesting that hospitalization time should be used for symptomatic recovery in a study where discharge is based
on viral clearance (and only tested weekly).

• suggesting that a specific symptom such as cough should be used (author would prefer a less positive result for the
study).

• suggesting that viral load is more important than symptomatic results.

• suggesting that mortality should be used in populations with zero mortality (for low-risk populations with no
mortality, reduction in mortality is not possible, this does not mean a reduction in hospitalization, for example, is
not valuable).

• suggesting that unadjusted results should be used in a study where the adjustments clearly make a significant
difference (author wants to cherry-pick unadjusted cough results).
• suggesting that, for example, in a study of viral load where all patients recover, it is not valuable if treated patients
recover faster (or are less likely to transmit the virus to others).

• suggesting that study selected outcomes should have priority rather than using a consistent pre-specified protocol,
disregarding the added bias and the fact that this actually improves results for ivermectin (for example the very
small event count negative serious outcomes in Krolewiecki, Vallejos, and Buonfrate would no longer have priority).

• suggesting that cough is a more important symptom than low SpO2 or fever. Cough can persist for a long time after
more serious symptoms resolve, and persistent cough may be caused by many conditions.

• suggesting that combined low dose treatment results should be used in a study that had a combined
ivermectin/doxycycline arm (single dose ivermectin, 5 days doxycline) and an ivermectin arm with treatment for 5
days.

We note that this personality has an extensive history of incorrect advice, including for example:

• claiming that flu is more dangerous than COVID-19

• claiming that SARS-CoV-2 is not airborne

• claiming that it's impossible to improve immune system functioning

• even believing and propagating a made up story that claimed ivermectin overdose was causing gunshot victims to
wait at an ER

Author has taken a public position against early treatments for COVID-19 since at least July 2020. Given this
longstanding and influential negative position, they may tend to view information with a negative filter and
confirmation bias, and may be reluctant to admit errors. They acknowledge not having read all of the studies (and
appear to have very superficially read others). They submitted zero feedback to us, suggesting that they know their
comments are incorrect or that they have a motivation other than correcting errors. Author claims that they could not
contact us, however there are over 50 feedback links throughout this article. We also note that the author is not open
to critical feedback and routinely blocks Twitter users correcting mistakes or expressing anything critical on their feed.
Reports suggest that the author also pre-emptively blocks people that have not even interacted with them, but are
connected to other users reporting on their errors. Author ackowledges using a tool called MegaBlock that blocks all
people that liked a specific tweet.

The author is also against vitamin D. Of the 122 vitamin D COVID-19 treatment studies, author suggests only one trial
is worth looking at 358. This gives us a simple case to examine potential bias. Murai is a small trial providing no
statistically significant effects (mortality p = 0.43, other outcomes are positive while also not significant). Author
acknowledges that the trial is too small for a conclusion. More importantly, this trial provides no information about
whether vitamin D reduces the risk of a serious COVID-19 case, because the patients in this trial already had a serious
COVID-19 case (90% already on oxygen treatment at baseline). Author does not mention this. The trial also has poorly
matched arms in terms of gender, ethnicity, hypertension, diabetes, and baseline ventilation, all favoring the control
group. Further, this study uses an inappropriate form of vitamin D — cholecalciferol. In reality physicians would use
calcifediol or calcitriol with late stage treatment, because they avoid a very long delay for conversion. We are unaware
of a reason to use cholecalciferol in this case (other than to produce a null result). In summary, author's chosen study
is one of least useful studies from the 122 studies to date, suggesting biased analysis.

Based on many comments, author appears to focus on superficial criteria such as typesetting and quality of writing.
While many of the studies have been performed by non-native English speakers with minimal budgets, this does not
imply the researchers are less reliable. Indeed, the author is highly critical of the program used to create a graph, for
example, but is unable to see flaws in high budget high conflict of interest trials, even when they prompt >100
scientists to write an open letter requesting retraction 259.

Three years later, the author has still not contacted us, making content-free comments on Twitter such as calling us
"sh*tty". Other individuals pointing out errors with detailed and careful feedback get similar treatment, such as being
called a "d*ckhead" and being blocked.

More details can be found in the BBC response.

Scott Alexander.

Feb 2, 2023 update: Scott acknowledges that his analysis was incorrect, that the topic is outside his "expertise and
competence level", and that his self-and-GidMK-filtered subset of a 29 study subset of 105 studies actually shows
much stronger efficacy than previously claimed. Scott further acknowledges several false and defamatory claims,
while standing by others. Scott acknowledges that the strongyloides theory is not very strong. Scott now relies on
publication bias to discredit the 653 scientists reporting efficacy, without even reading many of their studies.

For publication bias, author is saying that the statistically significant positive studies were chance events, i.e., there
are actually >1,000 ivermectin studies, but there is an extremely strong bias towards publishing only the positive
studies.

This is in direct opposition to the evidence on publication bias. High profile journals refuse to publish positive
ivermectin studies, while negative ivermectin studies are guaranteed acceptance, widespread press, and fame, just as
Scott has received fame for his negative article. As Scott said in November 2021, "if you say anything in favor of
ivermectin you will be cast out of civilization and thrown into the circle of social hell reserved for Klan members and
1/6 insurrectionists. All the health officials in the world will shout 'horse dewormer!' at you and compare you to Josef
Mengele." Ivermectin has the strongest negative publication bias we have ever seen.

Scott finally points at our overview of efficacy across treatments, claiming that multiple effective treatments is proof of
publication bias. As if somehow the existence of several effective treatments is impossible.

Scientists have identified over 2,000 compounds potentially beneficial for COVID-19. It is trivial to disable SARS-CoV-2
in vitro, hundreds of compounds do so, many with existing known and positive safety records. What is the chance that
none of these can safely reach the location of SARS-CoV-2 infection? In the nasopharynx, oropharynx? Lung? Other
tissues?

Is it really surprising that PVP-I for example, very effective in vitro, can be applied to the nasopharynx/oropharynx in
effective concentrations, and is helpful, especially if used before infection spreads further?

Are there really no inputs to the human system that improve functioning of the immune system?

Does Scott really believe that paxlovid, casirivimab/imdevimab, sotrovimab, tixagevimab/cilgavimab, bebtelovimab,
ensovibep, molnupiravir, and remdesivir are actually ineffective, all were approved in error because hundreds of other
studies were not published?

While Scott dismisses the work of over 9,700 scientists reporting statistically significant positive effects of low cost
treatments (over 600 for ivermectin), he appears to have blind faith in trials having perhaps the highest moral and
financial conflicts in the history of medicine, while simultaneously missing many critical issues (ACTIV-6, TOGETHER,
COVID-OUT, PRINCIPLE) creating unreliable results, and signs of efficacy despite best efforts to avoid it.

Extreme moral conflicts arise for authors and institutions that played a critical role in the suppression of early
treatments — they share responsibility for the results of any mistakes that impacted policies. The extreme financial
conflicts come from authors and institutions associated with companies where billions of dollars of profit relies on no
effective inexpensive treatments existing.

We challenge Scott to do a more serious analysis. For example: examine all of the studies rather than only 28%;
directly examine studies rather than relying on a personality that thinks a study treating patients 9 days after onset is
conclusive (a study so extremely late that 17% were on ventilation/ECMO); take into account major issues with studies
like ACTIV-6, TOGETHER, COVID-OUT, and PRINCIPLE; and review the ~100 additional supporting papers for
understanding of the mechanisms of action, censorship, and other issues.

Previous response: For a much better and more thorough analysis of Scott Alexander's essay, including numerous
errors, extreme bias, incorrect statistical analysis, contradictory standards, and failure to make corrections, see the
Potemkin Argument series. Part 21 illustrates the potentially catastrophic result of humanity's difficulty in objectively
creating and evaluating scientific evidence related to critical world problems.
 SEE ALSO
The Potemkin Argument: Index
The Potemkin Argument, Part 2: The Devil's Advocate
The Potemkin Argument, Part 3: The Misportrayal of Dr. Flavio Cadegiani
The Potemkin Argument, Part 4: How Scott Alexander and GidMK Caricatured the Work of Honest Scientists
The Potemkin Argument, Part 5: The Sullying of Babalola et al.
The Potemkin Argument, Part 6: The Erratic Disciples of Dr. John Carlisle
The Potemkin Argument, Part 7: Scott Alexander's Statistical Power Struggle
The Potemkin Argument, Part 8: Scott's Synthetic Scorn
The Potemkin Argument, Part 9: Scott's Observational Opprobrium
The Potemkin Argument, Part 10: The Ballad of Lopez-Medina
The Potemkin Argument, Part 11: TOGETHER vs. Carvallo, A Tale of Two Studies
The Potemkin Argument, part 12: Bayes Wept
The Potemkin Argument, Part 13: Consequentialism for Me, Deonticism for Thee
The Potemkin Argument, part 14: Achilles' Analytical Heel
The Potemkin Argument, Interlude I: Scott Alexander and the Worm of Inconsistency
The Potemkin Argument, Part 16: Worm Games
The Potemkin Argument, Part 17: Viral Funnel Plot Blues
The Potemkin Argument, Part 18: Scott's Scientific Takeaway
The Potemkin Argument, part 19: My Scientific Takeaway -or- Why You Still Can't Box Intelligence
The Potemkin Argument, Part 20: Scott's Sociological Takeaway—or—The Bret and Pierre Special
The Potemkin Argument, Part 21: The Political Takeaway
Ivermectin: Much Less Than You Needed To Know

The analysis by SSC / Scott Alexander has a number of major issues. For many other uncorrected errors in SSC's
analysis, see [Link], [Link] (E).

Analysis with SSC's recommended exclusions can be found in the supplementary data.

Update: after exclusions chosen by SSC, exclusions by GMK, excluding all late treatment, and excluding all
prophylaxis studies, SSC found the results in Figure 32, showing statistically significant efficacy of ivermectin with p =
0.04. The method for computing this p value is not specified. We used the same event results and performed random-
effects inverse variance DerSimonian and Laird meta analysis as shown in Figure 33, finding much higher significance
with p = 0.005. We note that the effect extraction appears biased against ivermectin, choosing the excessive dose arm
in Buonfrate, and using the post-hoc exclusion in López-Medina. The Krolewiecki treatment count appears to have
been scaled for the different group sizes. We do not know where SSC's Mahmud counts are from.

Figure 32. SSC's analysis. SSC reports p = 0.04, with an unspecified method.
 Figure 33. Random-effects meta analysis per SSC's chosen results, finding much higher significance.

Author appears to be against all treatments, labeling them all "unorthodox" and "controversial", even those approved
by western health authorities, including casirivimab/imdevimab, bamlanivimab, sotrovimab, and paxlovid. Update:
author's original article still refers to all treatments we follow as unorthodox and controversial, however they report
that they actually recommend fluvoxamine, paxlovid, casirivimab/imdevimab, bamlanivimab/etesevimab, and
sotrovimab, and suggest that they support all western health authority approved treatments which additionally
includes remdesivir, budesonide, bebtelovimab, tixagevimab/cilgavimab, and molnupiravir. Author also has positive
comments for zinc (but reports there is no proof). i.e., author appears to actually support at least 11 of the 95
treatments we follow. We note that the methodology is the same for all treatments.

We encourage the author to at least direct readers to government approved treatments, for which there are several in
the author's country, and many more in other countries (including ivermectin). While approved treatments in a specific
country may not be as effective (or as inexpensive) as current evidence-based protocols combining multiple
treatments, they are better than dismissing everything as "unorthodox". Elimination of COVID-19 is a race against viral
evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants — we need to embrace
all safe and effective means.

The third-party analysis that author references for the strongyloides theory is confounded by treatment delay and
dosage — the high prevalence group has more early treatment trials and a higher average dose, i.e., the analysis
reflects the greater efficacy of early treatment and the greater efficacy of higher dosage. More details can be found in
the strongyloides section.

Author refers to studies with positive but not statistically significant results as "negative" 273, or "[the] original outcome
would also have shown ivermectin not working" 128, which are incorrect conclusions 356. Update: author believes this
means we abandon statistical significance. We do not know where this comes from — all of our results report
confidence intervals, and the first two words of this paper are "statistically significant". What is incorrect is making a
negative conclusion based on an insignificant result. For example, if one study reports 50% lower mortality without
reaching statistical signifiance, this does not mean that the treatment is useless. Consider if there are 10 studies all
reporting ~50% lower mortality, the combined evidence may be strong even if each individual result is not statistically
significant.

Author notes that: "if you say anything in favor of ivermectin you will be cast out of civilization and thrown into the
circle of social hell reserved for Klan members and 1/6 insurrectionists", suggesting an environment that may bias the
information that the author sees, and could unconsciously bias analysis. We note that similar environments influence
the design, operation, and publication of some existing (and many upcoming) ivermectin trials.

Author looks at 29 of the 105 studies, which we note is much better than most commenters, but still ignores the
majority of studies, including the prophylaxis studies.
The author finds efficacy at p = 0.04 in their analysis of 11 of the 29 studies they looked at. We note that simply
looking at the other 76 studies will result in much higher confidence in efficacy. We also note that even at p = 0.04 with
11 independent studies, a rational risk-benefit analysis results in immediate adoption into protocols (pending stronger
data with other combinations of treatments), and immediate collection of more data from sources without conflicts of
interest.

However, ultimately the author at least partially supports the two prevailing theories that are commonly used by those
against treatment. These theories require disregarding extensive contradictory evidence:

The steps required to accept the no-significant-effect outcome are extreme — one needs to find a reason to exclude
most of the studies, disregard the strong treatment-delay response relationship, and disregard all prophylaxis studies.
Even after this, the result is still positive, just not statistically signficant. This does not support a negative
recommendation. Widely accepted and effective (subject to dependence on viral variants) treatments like
casirivimab/imdevimab, bamlanivimab, and sotrovimab were all approved without statistically significant mortality
benefits.

The steps required to accept the strongyloides-mechanism-only conclusion are also extreme - we need to disregard
the majority of outcomes occuring before steroid use, and disregard the strong treatment-delay response relationship
which is contradictory. Figure 27 shows analysis by strongyloides prevalence. The third-party analysis referenced by
the author is confounded by treatment delay and dosage.

Author seems biased against believing any large effect size. We note that large effect sizes have been seen in several
COVID-19 treatments approved by western health authorities, including paxlovid which the author is very positive
about, and also that better results may be expected when studies combine multiple effective treaments with
complementary mechanisms of action (as physicians that treat COVID-19 early typically do). Update: author confirms
this bias but appears to disregard it for paxlovid.

Author is suspicious about a study based on the country of the researchers, and also appears biased against non-
native speakers, with comments such as "unreadable" for one paper, compared to "written up very nicely in real
English" for another. Update: author confirms being biased against certain countries.

Author calls a physician that has reported zero deaths and 5 hospitalizations with 2,400 COVID-19 patients "a crazy
person" that "put his patients on every weird medication he could think of".

Author disregards the dramatically higher mortality for Gamma vs non-Gamma variants (aHR 4.73 [1.15-19.41] 180),
instead concluding that higher mortality indicates fraud in one instance, while in another instance assuming that the
related confounding by time in the Together Trial is not significant.

Author's review of the 29 studies appears relatively cursory, for example author appears unaware that the ivermectin
dosage is very different in the ivermectin + doxycycline arm of Ahmed.

Author appears to accept the analysis and accusations of GMK as correct, however that author is often incorrect.

Author is concerned that we detail problems with López-Medina, while correctly noting that the outcomes in this trial
are actually positive and in favor of ivermectin (while not statistically significant in isolation).

Author is concerned that we specifically comment on Reis, López-Medina. We note that it has been others that have
focused on these trials — we comment on them because they have received special attention, including being held up
as sole evidence overriding all other trials, despite having major issues.

Author claims that nobody can find issues with Vallejos, which suggests that they have not read the study, or our
analysis.
Elgazzar.

This study was withdrawn and was removed from this analysis on the same day. There was no significant change
(excluding 1 of 108 studies has very little effect, and the exclusion actually improves the treatment delay-response
relationship).

Samaha.

This study was removed from this analysis within an hour of notification that it was pending retraction. There was no
significant change in the results, and the exclusion improves the dose-response relationship.

Merino.

This preprint was censored by the original preprint host. Censors claim that the government treatment program,
which used approved medications and saved over 500 people from hospitalization, was unethical. In part they also
indicate that studies of "the effects of a medication on a disease outcome" are outside the scope of their site.

The author's response (not provided by the censors) can be found here: [Link] (F). Author's provide the data and
code for the study, and the results have been independently verified.

Pott-Junior.

This paper appears to have been censored at the request of the journal's founding editor 374. An external review is
mentioned but is not provided, and there is no reply from the authors, or indication that the authors were notified.
Conclusions in this study are limited due to the small size, however we should consider all information in the context
of the full body of research.

Efimenko.

The conference publication for this analysis was self-censored by the authors, not due to any error in the analysis, but
because authors believe ivermectin "has proven to be ineffective in clinical trials". This is incorrect, 64 studies show
statistically significant positive results for one or more outcomes (37 prospective and 27 retrospective studies,
including 27 Randomized Controlled Trials).

Carvallo.

Concerns have been raised about Carvallo. There appears to be some valid concerns with potential data issues, and
this study is excluded in the exclusion analysis. There is no significant change in results, with only a minor reduction in
prophylaxis efficacy to 84% [73-91%]. However, it is difficult to trust information from the personality reporting the
concerns. The author suggests that the study may not have happened at all, claiming for example that the team could
not have afforded the medications without funding, and that a busy clinician would not have enough time. However,
with just basic checks, the author would know that a drug company has confirmed donating the medications, that
they confirmed authorization for the study was received, that the main hospital for the study requested additional
supplies, and that the hospital confirmed ethics committee approval. For additional details see O'Reilly. We also note
that the combined treatment in this study has been independently shown to be effective, and the complementary
mechanisms of action support improved efficacy of the combination 376.

Study Notes

For discussion of all studies see [Link]. A few studies have received special attention, with some considering
them to be very strong evidence overriding the other 104 studies. We note limitations of these studies here.

PRINCIPLE.

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): an open, randomised, controlled, adaptive platform
trial of short- and longer-term outcomes
 SEE ALSO
The Last of The "Big Seven" Fraudulent Ivermectin Trials Has Finally Been Published
Ivermectin and the Research Cartel
Four Years Later – The Toughest COVID Pill to Swallow
Can Scientific Misconduct Be Criminally Prosecuted?

Significantly improved recovery and significantly lower risk of long COVID with ivermectin, despite very late treatment,
low-risk patients, and poor administration.

36% lower ongoing persistent COVID-19 specific symptoms, p<0.0001 (details below). The primary recovery outcome
shows superiority of ivermectin (probability of superiority > 0.999), missing from the abstract (details below). The p
values for sustained recovery, early sustained recovery, alleviation of all symptoms, and sustained alleviation are all <
0.0001.

The efficacy seen for ivermectin here is despite the trial being the most clearly designed to fail trial, with major bias in
design, operation, analysis, and reporting. This trial is a great example of bias in clinical trials which will be covered in
detail in the future.

Molnupiravir Ivermectin
PANORAMIC 377,378 PRINCIPLE 379

Investigator Prof. Chris Butler Prof. Chris Butler

Delay
≤5 days from onset ≤14 days from onset
median 2 days median unknown

Population 50+ or 18+ w/comorbidities 18+ (mid-trial change)

Treatment 5 days, 2x per day 3 days, 1x per day, dose below real-world use

Per recommendation (with or Directed to take opposite of recommendation for COVID-19 -

Administration 1,380
without food) without food, greatly reducing concentration

Patients 25,783 3,963 (inc. concurrent control)

Publication
4 months 19 months (26 months from expected end)
delay

Enrollment Dec 2021 - Apr 2022 May 2021 - Jul 2022

Mutagenic Yes No

381 382
Cost $707 <$1

>$7.2B sales to date 383, estimated ~$0 (potential, unlikely competitive with low cost
Merck profit
$18 to produce 384 manufacturers)

Design better for showing efficacy

Design better for hiding efficacy [Link]

Severity Issue

CRITICAL 1. 36% lower long COVID hidden in appendix

CRITICAL 2. False claims for long-term outcomes and recovery

CRITICAL 3. Significantly improved recovery is strongly associated with significantly lower mortality

CRITICAL 4. Superiority of ivermectin hidden

 CRITICAL 5. Mid-trial allowance of mAbs/antivirals invalidates hospitalization/death data

CRITICAL 6. Superiority of budesonide not hidden

CRITICAL 7. Budesonide press release within 12 days

CRITICAL 8. Similar results, opposite conclusion

CRITICAL 9. Pre-specified "meaningful effect" only for interim futility

CRITICAL 10. Meaningful effect was 1.5 days for other arms

CRITICAL 11. Pre-specified "meaningful effect" probability changed 0.01->0.25

CRITICAL 12. Hospitalization/death probability of meaningful effect

CRITICAL 13. 10x lower accuracy in reported results

CRITICAL 14. Adverse event data missing

CRITICAL 15. Mortality results missing for concurrent control arm

CRITICAL 16. Details of hospitalizations and deaths not provided

CRITICAL 17. False claim on administration

CRITICAL 18. Results delayed 600 days

CRITICAL 19. Authors coverage of prior research extremely biased and cherry-picked

CRITICAL 20. Very late treatment

21. Inclusion changed from 50+ to 18+ w/COVID dyspnea or comorbidity before start of
CRITICAL
ivermectin arm

CRITICAL 22. Mid-trial change to include lower risk patients

CRITICAL 23. Exteme conflict of interest

CRITICAL 24. Pause due to supply but medicine was stored at every study site

CRITICAL 25. Supply issue contradicated by manufacturer

CRITICAL 26. Design favors null result in contrast to molnupiravir trial by the same chief investigator

CRITICAL 27. Other arm results not released over 1,500 days later

CRITICAL 28. Inclusion changed from 7 to 14 days

CRITICAL 29. "Gate-keeping" protection of serious outcome evaluation

CRITICAL 30. Long delay between registration and enrollment

CRITICAL 31. Subject to participant fraud

CRITICAL 32. Inconsistent analysis - Bayesian vs. frequentist statistics

CRITICAL 33. Age 65+ reduced from 47% to 16% for ivermectin

SERIOUS 34. Delivery delay reduces perceived effect

SERIOUS 35. Recovery subgroup forest plot for all arms except ivermectin

SERIOUS 36. Even faster recovery with greater baseline severity

SERIOUS 37. Lack of recovery inverted to reduce effect size

SERIOUS 38. Slow delivery

SERIOUS 39. Administration on an empty stomach

SERIOUS 40. Mismatch with original proposal

SERIOUS 41. Eligibility criteria worse than concurrent favipiravir arm

SERIOUS 42. Recruitment questions varied

MAJOR 43. Ivermectin from source chosen has shown lower efficacy

MAJOR 44. Ability to pickup medication quickly removed from information sheet

MAJOR 45. Only three different doses, lower μg/kg dose for higher weights

MINOR 46. Duration == 7 missing

COMMENT 47. Efficacy not due to open label design

Responses: authors have not responded to any of these issues.

36% lower long COVID hidden in appendix. Page 358 in the appendix shows 36% lower ongoing persistent COVID-
19 specific symptoms (p<0.0001) when combining the individual symptom results. The paper reports a 28% reduction
(p=0.015), not mentioned in the abstract or conclusion. This appears to be a one of any symptom analysis, effectively
increasing the weight of the more common “fatigue”, reducing the perceived effect (the difference does not appear to
be due to adjustments - the adjustments in Table S6 to Table S39 make minimal difference). This is for very late and
poorly administered treatment taken by only 89% of patients in a relatively low-risk population - benefits may be much
greater with recommended usage and in high-risk patients.

False claims for long-term outcomes and recovery. Authors claim that ivermectin is "unlikely to provide clinically
meaningful improvement in recovery, hospital admissions, or longer-term outcomes", which is contradicted by their
results. 36% (or the 28% from the author's calculation) lower long COVID is clearly clinical and very meaningful - it
would represent an enormous global reduction in morbidity if adopted. The significantly faster recovery is also clearly
clinically meaningful.

Significantly improved recovery is strongly associated with significantly lower mortality. Authors report highly
statistically significant improved recovery but claim no clinical relevance. Across all 95 treatments we cover, improved
recovery is very significantly associated with lower mortality, p<0.000000001 (from all studies that report both).
Superiority of ivermectin hidden. The protocol states "If the Bayesian posterior probability of superiority (a log
hazards ratio greater than 0 corresponding to quicker recovery) for a treatment versus Usual Care is sufficiently large
(e.g. ≥ 0.99), the null hypothesis will be rejected and the intervention will be deemed superior..". The intervention is
superior (probability > 0.9999), yet there was no press release and immediate call for use, and this is not even
mentioned in the abstract or conclusion.

Mid-trial allowance of mAbs/antivirals invalidates hospitalization/death data. Authors note: "From 16 Dec 2021, a
minority of extremely clinically vulnerable patients could also access antiviral treatment or a monoclonal antibody
infusion". However, there is no information on treatments provided or procedures for determining eligibility. This
change invalidates hospitalization/death data after 16 Dec 2021. Hospitalization/death events occured in a small
minority of patients and are expected to be strongly biased towards the extremely clinically vulnerable patients.
Patients randomized to usual care are more likely to obtain alternative treatment. During the trial extension period
sotrovimab was the most common treatment, with paxlovid and molnupiravir also being used 421. Sotrovimab showed
very high efficacy during this period 422,423. It is normal to provide details of other treatments used in cases like this,
the lack of disclosure suggests that the data confirms alternative treatment use significantly biased the results.

Superiority of budesonide not hidden. The same trial's budesonide arm did not hide the superiority: "There was a
benefit in time to first self-reported recovery ... with a probability of superiority greater than 0·999, meeting the
prespecified superiority threshold of 0·99" (in the abstract).

Budesonide press release within 12 days. The superiority for recovery for budesonide was announced within 12 days
of trial completion 417,424. Slow but perhaps acceptable. Ethical and moral obligations mandate release as soon as
possible. However for ivermectin, the results were hidden for around 600 days, and then misrepresented.

Similar results, opposite conclusion. Of the 6 arms reporting results (HCQ is still missing), three show superiority on
the primary recovery outcome. Comparing ivermectin and budesonide, which both show probability of superiority
>0.999 and similar results - several individual recovery results are better for ivermectin than budesonide - concurrent
and COVID+: time to allevation of all symptoms, time to sustained alleviation of all symptoms, WHO5 wellbeing at day
28, all concurrent: time to allevation of all symptoms, time to sustained alleviation of all symptoms, and time to initial
reduction of severity all show better results for ivermectin than budesonide. However the conclusions for each are the
opposite - for budesonide authors concluded superiority, for ivermectin they conclude that ivermectin "is unlikely to
provide clinically meaningful improvement in recovery". Note improvements are higher with ivermectin and the
primary recovery outcome for several subgroups related to baseline severity - illness duration, baseline severity, and
respiratory illness.

Pre-specified "meaningful effect" only for interim futility. The protocol (even the post-hoc versions) only mentions
clinically meaningful effects in terms of interim futility analyses: "If the Bayesian posterior probability of a clinically
meaningful treatment effect is sufficiently small (e.g. < 0.01) for the first co-primary endpoint (time to recovery), the
intervention arm may be dropped from the study for futility". In the body of the paper authors do note that the pre-
specified HR of ≥1.2 was only for futility evaluation, however the abstract drops this, implying that there was a pre-
specified HR of 1.2 for superiority.

Meaningful effect was 1.5 days for other arms. Authors did not mention a "meaningful effect" for budesonide, but
added a "meaningful effect" of 1.5 days for colchicine, azithromycin, and doxycycline - which was sufficient to ensure
very low probabilities for those arms. For ivermectin they show an improvement of 2.06 days, i.e., clinically meaningful
according to the authors for all prior arms (for most other people, smaller improvements are also clinically
meaningful, and as above the improvements translate into lower mortality for high-risk patients). Additionally, the poor
design of the trial means the actual improvement for recommended usage is likely much greater.

Pre-specified "meaningful effect" probability changed 0.01->0.25. In June 2022, in view of interim (if not all at the
time) results, authors changed the 0.01 probability to 0.25 (just above the 0.22 for the one outcome at the time).
Authors note this change is only for ivermectin and favipiravir, and will return to 0.01 for future arms (appendix page
169). Authors claim a rationale for the change is in "Appendix A" but this appears to be missing.
Hospitalization/death probability of meaningful effect. For hospitalization/death authors previously used a threshold
of 2% for calculating the probability of meaningful effect. For ivermectin they changed it to 20%. Consider the families
of 20% or 2% of COVID-19 deaths, perhaps 4 million or 400,000 people based on an estimated 20 million total. Do
they believe those deaths were not clinically meaningful?

10x lower accuracy in reported results. For budesonide authors reported key results with 10x greater accuracy, for
example 10.9 vs. 13.3 days time to recovery, wherease for ivermectin all times are reported as integers, e.g., 14 vs. 16
days. This may be used to hide differences and to reduce efficacy (e.g., 3.6 vs. 5.4 becomes 4 vs. 5 and 3.6 vs. 4.4
becomes 4 vs. 4).

Adverse event data missing. Other than a count of hospitalizations, no adverse event data was reported.

Mortality results missing for concurrent control arm. Authors do not provide the main mortality results for the
concurrent control arm.

Details of hospitalizations and deaths not provided. Authors provide no details on the hospitalizations and deaths.
Given the remote nature of the trial, the enrollment of very late stage patients, the very low event rate, and the very
delayed time between patients signing up and actual enrollment indicated by some participants, many of the
hospitalizations may have happened before medication was delivered and taken. This is supported by the subgroup
analysis showing that patients >7 days from onset (likely >8-9 days to treatment initiation) contributed more to the
ivermectin events.

False claim on administration. Authors falsely claim that "the influence of food on absorption is not known" 380. Guzzo
et al. 1 show that the plasma concentration of ivermectin is much higher when administered with food (geometric
mean AUC 2.6 times higher). This is from 2002 and well-known among ivermectin researchers.

Results delayed 600 days. Results were delayed around 600 days from the expected announcement time, with no
reasonable excuse for hiding such positive results (or any results).

Authors coverage of prior research extremely biased and cherry-picked. Authors perform extreme cherry-picking on
their discussion of previous research, and even then highly misrepresent those studies. For example, authors discuss
the TOGETHER trial, without mentioning the known impossible data, refusal to release data despite pledging to,
external sharing of results during the trial, randomization/blinding failure, and many protocol violations; and without
mentioning that the principal investigator said that "There is a clear signal that IVM works in COVID patients.." in
private 124.

Very late treatment. Patients were enrolled up to 14 days after the onset of symptoms. Extensive research for COVID-
19 and other viral diseases show that early antiviral treatment is critical.

Inclusion changed from 50+ to 18+ w/COVID dyspnea or comorbidity before start of ivermectin arm. Inclusion was
originally 50+ w/comorbidity or 65+, but was changed to 18+ w/COVID dyspnea or comorbidity or 65+ before the start
of the ivermectin arm. The move to low-risk patients was specific to the ivermectin and favipiravir arms only 425.

Mid-trial change to include lower risk patients. Inclusion criteria were modified mid-trial to allow enrolling anyone
18+, i.e. very low risk patients. This change is first seen in protocol 9.0 on July 12, 2021 401

Exteme conflict of interest. The chief investigator is also chief investigator for the PANORAMIC molnupiravir trial, with
overlapping dates, and 7.2B+ financial conflict of interest between the two treatments.

Pause due to supply but medicine was stored at every study site. The trial claimed to pause due to a supply problem
but medicine was stored at every site 412, It is unlikely that all sites would have run out, if there was no supply in some
locations, recruitment could have continued at other locations.

Supply issue contradicated by manufacturer. The trial was paused with a reported supply issue, however the
manufacturer stated that there were no supply issues.
Design favors null result in contrast to molnupiravir trial by the same chief investigator. Treatment delay, inclusion
criteria, dosing, administration, and target size all show a design better for efficacy for molnupiravir, and worse for
efficacy for ivermectin. Both trials have the same chief investigator and overlapping dates.

Other arm results not released over 1,500 days later. The HCQ arm results have not been released over 1,500 days
later 413.

Inclusion changed from 7 to 14 days. Inclusion was originally within 7 days of symptoms, but was changed to 14
days, compared to the molnupiravir trial which was started with 5 days 426.

"Gate-keeping" protection of serious outcome evaluation. Authors declare a "gate-keeping" strategy to prevent
evaluation of hospitalization/death if the recovery time difference is not significant 380. Authors claim benefit for serious
outcomes is unlikely without statistically significant benefit for recovery time, which is not logical, especially with low
prevalence of progression - consider for example an intervention that prevented progression to mortality by 100%, but
has no effect on resolution of a specific symptom, e.g., cough. The trial did not always have this gate-keeping strategy
- protocol 4.0 had hospitalization/death as the primary outcome and protocol 5.0 added the new strategy (this was a
post-hoc change for azithromycin and doxycycline related to the recruitment of low-risk patients and low event rates).

Long delay between registration and enrollment. One participant reports filling out a form for the trial at the time of
receiving a positive PCR result and not being called until much later on day 11 of COVID to complete enrollment 427. A
second participant reports waiting 9 days after online registration to receive an enrollment phone call 428,429.

Subject to participant fraud. There is no requirement for participants to have a face-to-face visit as part of trial
participation. The self-reported design and the potential lack of professional medical examination results for many
patients opens this kind of remote trial to participant fraud, which may be significant due to extreme politicization in
the study country. Participant fraud has been reported for two other remote trials 430,431, involving submission of fake
surveys and repeated signups. Authors do not provide any information on attempts to limit participant fraud.

Inconsistent analysis - Bayesian vs. frequentist statistics. The protocol specifies Bayesian analysis which is used for
some outcomes. However, authors have used frequentist statistics for other outcomes, with no known reason. This
results in avoiding reporting Bayesian probability of superiority showing superiority of treatment for those outcomes.

Age 65+ reduced from 47% to 16% for ivermectin. From the non-concurrent to concurrent populations (Table 1), we
can see a dramatic change in the population. 47% of patients were over 65 in the control group prior to the ivermectin
arm. For ivermectin this was reduced to 16% (focusing on low-risk patients is one method to reduce the chance of
showing a benefit).

Delivery delay reduces perceived effect. Recovery is defined as the time from randomization, however there are
additional delays between randomization and delivery, and between delivery and the patient taking the medication.
This has the effect of reducing the perceived effect of treatment. For example, the median time to alleviation of all
symptoms was 4 and 5 days respectively, or 20% faster with treatment. If the delay until treatment is one day, this
becomes 3 and 4 days, for 25% improvement, with progressively greater improvement with longer delays. The patient
information sheet for molnupiravir states that medication will be delivered by the next day 378,432, while the patient
information sheet for ivermectin has deleted "next day" only stating that medication will be delivered 433.

Recovery subgroup forest plot for all arms except ivermectin. The main paper shows a forest plot with subgroups of
the primary recovery outcome for all arms (colchicine, budesonide, azithromycin, doxycycline) except ivermectin. For
ivermectin, authors only show the hospitalization/death forest plot in the main paper. The recovery results show
superiority of ivermectin.

Even faster recovery with greater baseline severity. Figure S2a shows that longer duration, at least one baseline
major severity item, and respiratory illness all show greater improvement for recovery, consistent with the greater
room for improvement in more severe cases. If authors truly believed that HR 1.2 is a required and valid threshold,
they should not be ruling out use for higher-risk cases.
Lack of recovery inverted to reduce effect size. Authors report the number of patients fully recovered at 3, 6, 12
months. It is typical to compare the risk of bad outcomes (failure to recover, hospitalization, death, etc.), however
authors compare good outcomes. Authors method shows a significant improvement of 6% at 12 months, however
the typical analysis shows a much larger 18% reduction in failure to recover. Consider a recovery rate of 90% in the
control group, by the author's method it would be impossible for any intervention to create the HR ≥1.2 that they
added.

Slow delivery. The patient information sheet for molnupiravir states that medication will be delivered by the next
day 378,432, while the patient information sheet for ivermectin has deleted "next day" only stating that medication will
be delivered 433.

Administration on an empty stomach. Authors instructed patients that "no food should be taken two hours before or
after administration" 380. Guzzo et al. 1, from 2002 and well known to ivermectin investigators, shows that the plasma
concentration of ivermectin is much higher when administered with food (geometric mean AUC 2.6 times higher).

Mismatch with original proposal. The original proposal for the trial starts with: "COVID-19 disproportionately affects
people over 50 years old with comorbidities and those over 65 years old. The infection causes considerable morbidity
and mortality in this population group in particular." 434, yet authors later modified the trial to include anyone 18+.

Eligibility criteria worse than concurrent favipiravir arm. In addition to inferior eligibility compared with molnupiravir,
eligibility was even inferior to the concurrent favipiravir arm, with ivermectin further favoring a null result. As of July 8,
2021 favipiravir started at 50+ while ivermectin started at 18+ w/dyspnea or comorbidity as per the trial newsletter 435.

Recruitment questions varied. Recruitment questions varied, for example the video instructions for ambulatory care
show the system asking about only two symptons - cough and fever. Notably, cough may be less responsive to
treatment and increased enrollment based on cough may reduce the chance of showing efficacy 436.

Ivermectin from source chosen has shown lower efficacy. Authors chose to source ivermectin from Edenbridge,
which ranked 7 out of 11 brands in In Vitro tests for antiparasitic efficacy 2, requiring 5 days compared to 2 days for
the best performing brand, and 3 days for 4 other brands.

Ability to pickup medication quickly removed from information sheet. Earlier versions of the patient information
sheet (e.g., v3.1 437) allowed patients to pickup the medication from a local pharmacy instead of waiting for delivery.
This was removed sometime before the ivermectin arm and the sheet now only lists delivery, excluding the possibility
of very quick pickup of the medication after enrollment 438.

Only three different doses, lower μg/kg dose for higher weights. Only three different doses were used: 45-64kg
(18mg), 65-84kg (24mg), and ≥84kg (30mg) 380
. Patients with higher weights will have progressively lower μg/kg
dosing.

Duration == 7 missing. The subgroup forest plot shows illness duration <7 and >7, without specifying what happens
≤
with == 7. The papers for other arms shows 7 and >7.

Efficacy not due to open label design. Some people with strong prior claims of no efficacy have claimed that the
efficacy here is due to the open label design. Moustgaard et al. showed there was no evidence to support this from
analysis of 142 meta-analyses covering 1,153 trials. However, in this case we have multiple arms from the same exact
trial that show this is not the case (which authors acknowledge in the paper, noting no evidence from the other arms).
Moreover, any effect would be reversed because at the time and in the study country, the government and almost all
media claimed that ivermectin was ineffective (and contrary information was censored).

The PANORAMIC trial for molnupiravir and the PRINCIPLE trial for ivermectin provide a good example of extreme bias
in trial design. For molnupiravir investigators randomized 25,000 patients a median of 2 days from onset 385. For
ivermectin, they allow inclusion up to 14 days after onset — a delay incompatible with the recommended use of
antiviral treatments, and incompatible with current real-world protocols. This delay alone would normally be more
than enough to guarantee a null effect for an early treatment. However, authors also bias the population, treatment
dose and duration, treatment administration, and sample size to favor a null result with ivermectin.
PANORAMIC and PRINCIPLE have the same chief investigator and primary contact 377,379, and the molnupiravir and
ivermectin arms overlap in time.

It is unclear why results were not released December 2021, why a reported supply issue was contradicted by the
manufacturer, why the trial continued, and why results were delayed 19 months 386.

Ivermectin was added to the PRINCIPLE trial on May 12, 2021 387 (June 2021 according to 388), and favipiravir on April
26, 2021 387. 4,731 patients were enrolled as of April 8, 2021 389, by which time the azithromycin, doxycycline, and
budesonide arms had completed. The colchicine arm had been running for one month and was later terminated with
156 patients. With an estimated enrollment of 1,000 per arm for ivermectin, favipiravir, and concurrent control, the
trial would end when total enrollment reached around 8,000.

8,010 patients were enrolled and ivermectin was removed from the list of treatments under investigation on the
website on or before Dec 2, 2021 390,391, suggesting that enrollment was complete and results would be available
shortly thereafter.

By Dec 9 ivermectin was added back to the list 392 with a note that the arm was paused due to supply issues.
MedPage Today reported on the pause on Dec 14 393. Notably, Merck's statement at the time shows a significantly
softer stance compared to their previous comments 393,394.

The reported supply issue is unusual - trials normally secure medication in advance, the reported trial manufacturer
stated there were no supply issues 395, investigators did not respond to journalist queries, there was reportedly no
response to Freedom of Information requests 396, alternate sources of ivermectin in the specified dosage were readily
available, and there was no need for an identical match in appearance. The trial manufacturer was Edenbridge 397,
participants received standard standard foil strips 398,399.

The trial later restarted the ivermectin arm. As of January 27, 2022, the trial was paused without explanation. As of
February 11, 2022, the trial was open intermittently (twice daily between Sunday and Thursday), a change which
further decreases the chance of participants receiving relatively early treatment. Delaying and restarting the trial at a
later time may also reduce observed efficacy due to less severe variants in combination with the trial design.

We are pre-specifying subgroup analysis for enrollment up to Dec 2, 2021, for treatment within 2 days of onset, and
for treatment of high risk patients (as originally defined by the trial).
 PRINCIPLE trial timeline

Date Change

March 22, 2020 ≤

Inclusion 7 days, age 50+ w/comorbidity or 65+.

June 16, 2020 ≤

Inclusion changed to 14 days.

February 14, 2021 Inclusion changed to 18+ w/COVID dyspnea or comorbidity or 65+ 400.

May 12, 2021 Ivermectin listed as current intervention in protocol 387.

388
June 2021 Ivermectin added according to web site .

Jul 12, 2021 Inclusion changed to 18+ 401.

December 2021 Anticipated completion of ivermectin arm.

391,402,403
December 3, 2021 Ivermectin arm ends, removed from web site between Dec 2 and Dec 3 .

December 2021 No press release or rapid top-tier publication, indicating positive results.

December 9, 2021 Ivermectin added back to web site with claim of pause due to supply issues.

Trial does not respond to MedPage Today regarding supply problems. A statement from Merck is
dramatically different to their previous position and is consistent with them knowing that a trial
December 14, 2021
they cannot ignore has positive results and them being unsure if they can suppress the
results 404.

The trial supplier, Edenbridge, denies any supply issue. Prof. Chris Butler declines to
December 25, 2021 405 398,399
comment . The trial used standard widely available tablets .

Prof. Paul Little, TSC chair, is removed from the trial in protocol version 13 406. The TSC is
January 14, 2022
responsible for reporting ethical issues.

407
January 27, 2022 Trial paused without explanation .

Trial only open intermittently (twice daily between Sunday and Thursday), adding further
February 11, 2022
enrollment delays 408.

409
July 8, 2022 Extended ivermectin arm ends .

July 2022 No press release or rapid top-tier publication, indicating positive results.

Sometime between May 2 and June 2, authors add a note on the web site indicating that, against
protocol, they are delaying and will release in a rigorous and transparent way after extended 1
June 2, 2023
year followup ends in July 410,411. Note that the analysis code for professional trials is written and
tested in advance.

Links to the protocol, amendments, and other supporting documents were removed from the
November 6, 2023
web site.

Still no results or update. A link was added to a version 14 of the protocol dated August 8, 2022
(after all arms had completed). The link does not work, pointing to an internal University of
December 2023
Oxford site. The latest version available is 13.0, dated January 14, 2022 406 (during the ivermectin
arm, after the expected end in December 2021).
 PRINCIPLE trial treatments

Treatment Treatment patients Duration Results delay

HCQ 393-408 412 2 months over 1,500 days 413

414 415
Azithromycin 540 6 months 56 days

Budesonide 416 1,073 4 months 12 days 417

Doxycycline 418 780 5 months 42 days 415

419 420
Colchicine 156 3 months 120 days

Ivermectin 2,157 14 months 600 days (810 days from ~1,000 per arm enrollment)

Favipiravir ~2,250 15 months 780 days (1,000 days from ~1,000 per arm enrollment)

Together Trial.

Effect of Early Treatment with Ivermectin among Patients with Covid-19

Extreme COI, impossible data, blinding broken, randomization/blinding failure, uncorrected errors, protocol violations,
no response from authors, refusal to release data

SEE ALSO
The TOGETHER Files 1: The Andrew Hill connection - How the principal investigator leaked interim results to a privat…
Fraudulent Trial On Ivermectin Published By The World's Top Medical Journal
The False, Sinister, and Duplicitous Statements of the TOGETHER Ivermectin Trial Investigators
10 Questions for the TOGETHER Trial Investigators
The Potemkin Argument, Part VII: TOGETHER vs. Carvallo, A Tale of Two Studies
Did the Placebo Group in the TOGETHER Trial Take Ivermectin?
Demonstrating Randomization Failure in the TOGETHER Trial
FDA Reveals Concerns About the Conduct of the TOGETHER Trial, Joining Other Regulators
When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable …

Many major issues including multiple impossible numbers, blinding broken, randomization failure, and many
protocol violations, as detailed below. We provide more detailed analysis of this study due to widespread incorrect
press. Submit Updates or Corrections

Private comments: Public comments:

"There is a clear signal that IVM works in COVID patients.. that “There was no indication that ivermectin
would be significant if more patients were added.. you will hear me is clinically useful” — Ed Mills, Together
retract previous statements where I had been previously negative" Trial co-principal investigator.
— Ed Mills, Together Trial co-principal investigator 440.
"..the question of whether this study was
"I’m not interested in this question as its not the correct way to stopped too early in light of the political
interpret the outcome" — Ed Mills, responding to a per-protocol ramifications of needing to demonstrate
death count request 441. that the efficacy is really unimpressive..
really could be raised.." — Frank Harrell,
"F*ck you" "F*ck off" "Glory to Satan" "You are one of these
"I totally agree with Frank" — Ed Mills 442.
f*ckers.." "You f*cking *sshole" — Ed Mills, responding to various
emails on the trial and ivermectin research 441.
Severity Issue

CRITICAL 1. Blinding broken

CRITICAL 2. Blinding failure

CRITICAL 3. Patient counts for reported period impossible

CRITICAL 4. Placebo counts vs. fluvoxamine not possible

CRITICAL 5. Impossible baseline data

CRITICAL 6. Randomization violation, significant confounding by time

CRITICAL 7. Data pledge violation, unavailable over 1,100 days from protocol, over 900 days from publication

CRITICAL 8. DSMC not independent

CRITICAL 9. Extreme conflicts of interest

CRITICAL 10. Three conflicting death counts

CRITICAL 11. Placebo adverse event conflicts with fluvoxamine arm

CRITICAL 12. Conflicting adverse event counts

CRITICAL 13. 3-day dosing patients before March 23 missing

CRITICAL 14. Multiple false statements by investigators

CRITICAL 15. Investigators not responding to concerns

CRITICAL 16. ICODA reports never having the data

CRITICAL 17. Indications of ivermectin use in the placebo arm

CRITICAL 18. Conflicting and inconsistent PP/ITT groups

CRITICAL 19. Refusal to release per-protocol mortality and hospitalization data

CRITICAL 20. Conflicting descriptions of the placebo group

CRITICAL 21. Failure of NEJM to publish letters reporting errors and issues

CRITICAL 22. Placebo tablets may not match treatment tablets

CRITICAL 23. Viral load protocol violation, high Ct may hide efficacy

CRITICAL 24. 162 control patients missing onset data vs. 1 for peginterferon lambda

CRITICAL 25. Contradictory inclusion/exclusion of vaccinated patients, changes, and confounding

CRITICAL 26. Impossible data in the metformin arm

CRITICAL 27. Conflicting information on FTX funding

28. Metformin/fluvoxamine conclusions opposite of COVID-OUT, but matching earlier studies on

CRITICAL
each team

CRITICAL 29. Author claims results from 653 researchers should be censored for false information

CRITICAL 30. Paper silently modified without notification or explanation

CRITICAL 31. Team selected dose below what they believe is required

CRITICAL 32. Viral clearance results mismatch

CRITICAL 33. FDA concerns regarding trial conduct for peginterferon lambda

CRITICAL 34. Co-principal investigator agrees with political need to demonstrate poor efficacy

CRITICAL 35. Private comments on efficacy contradict public comments

CRITICAL 36. Mid-trial change adds patients showing lower efficacy

CRITICAL 37. Funding from Gates Foundation

CRITICAL 38. Conflicting reports on trial end date

CRITICAL 39. Expression of concern

SERIOUS 40. Side-effect prevalence consistent with treatment error

SERIOUS 41. Screening to treatment delay unknown

SERIOUS 42. 317 unknown onset patients, onset required for inclusion

SERIOUS 43. Unknown onset patients treated late

SERIOUS 44. Conflicting comorbidity counts

 SERIOUS 45. Unexplained >6 month delay

SERIOUS 46. Placebo patients receiving an injection not blinded

SERIOUS 47. Major imputation error

SERIOUS 48. Single dose results missing

SERIOUS 49. Incorrect conclusion

SERIOUS 50. Missing age information

SERIOUS 51. Mid-trial protocol changes

SERIOUS 52. COI: designed by Cytel

SERIOUS 53. COI: co-principal investigator works for Cytel and the Gates Foundation

SERIOUS 54. COI: pharma funding and denial of independent investigator

SERIOUS 55. COI: Gates Foundation

SERIOUS 56. COI: Certara

SERIOUS 57. COI: MMS Holdings

SERIOUS 58. COI: analysis company works closely with Pfizer

SERIOUS 59. COI: Fast Grants funding closely related to companies that censored scientific research

SERIOUS 60. Unexpected differences in missing data

SERIOUS 61. Out of funding claim contradicted by funder

SERIOUS 62. Misrepresentation of dosing recommendation

MAJOR 63. Unknown onset patients show statistically significanct efficacy

MAJOR 64. Mean delay likely excluding unknown onset

MAJOR 65. Per-protocol placebo much more effective

MAJOR 66. Multiple conflicting randomization protocols

MAJOR 67. Dominated by Gamma variant with different characteristics, no discussion

68. Incorrect dose reporting, patients at higher risk due to BMI may have received lower per kg
MAJOR
doses, and show lower efficacy

MAJOR 69. Conflicting target enrollment and reasons for termination

MAJOR 70. Primary outcome subject to bias, selected after single dose arm

MAJOR 71. Reported terminated due to futility, but threshold not reached

MAJOR 72. Subgroup analysis protocol violations

MAJOR 73. Many pre-specified outcomes missing

MAJOR 74. Single-dose recruiting continued after change

MAJOR 75. Funding list incorrect, missing Gates Foundation and Unitaid

MAJOR 76. Statistical analysis plan dated after trial start

MAJOR 77. Imputation protocol violation

MAJOR 78. Expected analyses missing

MAJOR 79. Conflicting reasons for dose change

MAJOR 80. Details of placebo unspecified

MAJOR 81. Antigen test requirement

MAJOR 82. Bayesian probability of superiority, featured for FLV, hidden in appendix

MAJOR 83. Two different per-protocol counts

UNKNOWN 84. Source of ivermectin unspecified (fluvoxamine source specified)

UNKNOWN 85. 100% adherence reported for 3-day placebo

UNKNOWN 86. No confirmation of placebo manufacturing

Author responses
83. modified without explanation
No response for all other items

Blinding broken. Leaked documents show that blinding was broken, with interim results available not only within the
team, but shared externally with a group of 90+ people, many from other ivermectin trials, in meetings organized by
Dr. Andrew Hill. Unreleased leaked emails also indicate sharing with higher-up individuals at the NIH. As below,
protocol changes were made mid-trial to add additional bias against ivermectin 463.

Blinding failure. Ivermectin/placebo blinding was done by assigning a letter to each group that was only known to the
pharmacist. If a patient received a 3-dose treatment, investigators immediately know that the patient is more likely to
be in the treatment group than the control group, because 3-dose placebo was relatively rare (~46% from PP). If a
patient received non-3-day treatment, investigators immediately know that the patient is not an ivermectin treatment
patient. Moreover, by observing the frequency of allocations, investigators can easily determine which letter
corresponds to active ivermectin 3-day treatment, thereby removing all blinding. For example, consider 3-dose-
ivermectin and 3-dose-placebo being identified by the letters G and K. If allocations to date have been G:11 and K:20,
there is a very high probability that K is ivermectin. Note that this blinding failure is only obvious because the journal
required the authors to restrict to the 3-day placebo group. Also note that it would have been trivial to avoid if desired,
for example by using a unique identifier for all medication bottles. Note that there may be additional reasons for
blinding failure, for example the paper specifies identically shaped bottles, but does not appear to specify identical
appearance tablets 464, and patients receiving a placebo injection.

Patient counts for reported period impossible. Authors claim the ivermectin and control patients were all from on or
after March 23, 2021, however independent analyses of the enrollment graph (contained in this presentation 465)
require including patients prior to this date to reach the reported numbers 452,466. The enrollment graph shows much
higher enrollment to ivermectin near the start of the trial. The only way that the number of placebo patients can be the
same as the number of treatment patients is if placebo patients were taken from an earlier period 461,467, which
creates a nonconcurrent control group 468 and substantial confounding by time as below.

Placebo counts vs. fluvoxamine not possible. The IVM placebo arm has 679 patients and the FLV arm has 756. The
679 should be shared between the arms, with 77 extra patients for FLV. For FLV, there were 34 placebo patients
requiring mechanical ventilation, for IVM there was only 25, indicating that 9 of the extra 77 placebo patients for FLV
had mechanical ventilation, a much higher percentage during a period that had lower deaths and CFR (and included
vaccinated patients). Placebo all-cause hospitalization shows 95/679 for IVM and 99/756 for FLV, i.e., only 4 of the
extra 77 patients were hospitalized, but the paper reports an additional 9 patients with mechanical ventilation.

Impossible baseline data. Analysis of baseline data by Marinos shows conflicting data and points to data being
changed to hide randomization failure and incomparable groups. For details see 469.

Randomization violation, significant confounding by time. Unequal randomization, significant confounding by time.
The trial reports [Link] randomization, however independent analysis shows much higher enrollment in the
ivermectin treatment arm towards the start of the trial 452,470. This introduces very significant confounding by time due
to the major change in the distribution of variants. Zavascki show dramatically higher mortality for Gamma vs non-
Gamma variants (28 day mortality from symptom onset aHR 4.73 [1.15-19.41]). Many more patients were randomized
to ivermectin vs. placebo in the first few weeks, for example the first week shows 82 ivermectin vs. 28 placebo
patients, 2.9x higher. The period of excess ivermectin enrollment coincides closely with a period of significantly higher
deaths and CFR in Brazil.
Data pledge violation, unavailable over 1,100 days from protocol, over 900 days from publication. The trial
registration states that data was to be available at termination and upon request 471, however authors have not
responded to a request for the data. Even funders of the trial have been unable to access the data 472. Requests can be
sent to thetogethertrial@[Link], let us know the outcome. For a detailed timeline of requests and the denial to
release data see 473 (appendix A).

DSMC not independent. Reviewer 1 of the protocol notes that the DSMC is not independent 474. Prof. Thorlund is Vice
President of the contract research organisation (CRO, Cytel), professor at the sponsoring university, and an author of
the protocol. Dr. Häggström is an employee of the CRO. [Link] (E), [Link] (O)
reveals many other conflicts. Prof. Thorlund has written >100 papers with Prof. Mills. Prof. Singh has written 29 papers
with Prof. Mills. Prof. Orbinski has written 9 papers with Prof. Mills. The first version of the web site showed Prof. Mills
and Prof. Thorlund as joint leads. Emails pointed to a company MTEK Sciences, founded by Prof. Mills and Prof.
Thorlund (MTEK is hypothesized to stand for Mills, Thorlund, Edward, Kristian). MTEK received grants from the Gates
Foundation. MTEK also employed Dr. Häggström. MTEK was acquired by Cytel in 2019. Dr. Häggström works for the
Gates Foundation. Two members of the DSMC have published a paper with members of a well known anti-ivermectin
research group 476 and Dr. Hill, whose meta analysis has reports of external influence 477-479. The trial protocol reports
that "an independent DSMC will be established, composed of scientists of unrivalled reputation and expertise, without
involvement with this research protocol."

Extreme conflicts of interest. Disclosed conflicts of interest include: Pfizer, Merck, Bill & Melinda Gates Foundation,
Australian Government, Medicines Development for Global Health, Novaquest, Regeneron, Astrazeneca, Daichi
Sankyo, Commonwealth Science and Research Organization, and Card Research. Many conflicts of interest appear
unreported. For example, Unitaid is a sponsor 480,481.

Three conflicting death counts. In the original paper, Table 3 shows 21 and 24 deaths, while Table S6 shows 20 and
25 482. In Table 3, death and grade 5 events showed the same 21/24 numbers, but different effect sizes, with 0.81
being closer to the 20/25 counts and the previously reported number. This is consistent with one death being moved
between arms after manuscript generation, but not updated in Table S6 or the Table 3 AE RR. This cannot be
explained by the safety population excluding patients with zero doses because the AE control deaths are higher. In
email, a co-principal investigator suggested that the discrepancy was due to one being COVID-19 deaths and the
other being all-cause deaths 440. That explanation does not fit the data because one arm increases while the other arm
decreases. Both co-principal investigators report in the paper that "they had full access to all the trial data and vouch
for the accuracy and completeness of the data and for the fidelity of the trial to the protocol." A third set of death
counts, 20 and 24, with RR 0.84, was presented by a co-principal investigator on Mar 18, 2022 483. In total, 4 different
death relative risks have been presented: Mar 18, 2022 presentation: 0.84, Mar 30 paper: 0.88 (T3), 0.81 (T3 AE), and
0.80 (TS6, presented as 20 and 25 only without group sizes). 6 days after publication, the paper was updated, with no
information given on what was changed. In this version, a "respiratory, thoracic and mediastinal disorders" death was
removed from the control arm and an "infections and infestations" death was added to the ivermectin arm. The paper
still indicates RR 0.81 for death AE.

Placebo adverse event conflicts with fluvoxamine arm. For FLV, there were 11 grade 1 AEs, for IVM there were 12,
with 77 less patients. For FLV, there were 50 grade 3 AEs, for IVM there were also 50, meaning the 77 extra patients
had 0% grade 3 AEs vs. an expected 7.4%. For FLV, there were 54 CKD patients according to Figure 3 and eTable1 (2
according to Table 1). For IVM there was 5.

Conflicting adverse event counts. Table 3 and Table S6 adverse event counts do not match for any grade, e.g., grade
1/2 in Table S6 shows 82 for IVM, while Table 3 shows 65 484. The Apr 5 update changed the grade 5 events without
explanation, however the other grades remain conflicting.

3-day dosing patients before March 23 missing. The co-principal investigator wrote on March 6 that 3-day dosing
was being administered, and that the clinicaltrials entry was out of date at that time 485. This earlier start of the 3-dose
arm would resolve an oustanding major inconsistency. Analysis of the trial randomization shows that reaching the 3-
day placebo count requires patients from March 4 486, and it would be logical for the 3-day placebo and 3-day active
arms to have started on the same day. This reinforces existing concerns as to which patients were included in the
analysis, and adds additional questions regarding what happened to the patients prior to March 23, and if patients
were treated prior to ethics approval. Ethics approval for the dose change was received on March 21 according to the
paper 487, with the regulator document dated March 15 488.

Multiple false statements by investigators. There has been multiple false statements by investigators raising
questions about their ethics and the reliability of their work 441.

Investigators not responding to concerns. After details of major data errors and protocol violations became known,
investigators appear to have stopped responding to all researchers regarding serious concerns with the trial 441,489
(and have still not responded to us).

ICODA reports never having the data. Investigators report that the data is available via ICODA: "The final trial dataset
will be accessible by written request to the study principal investigators (G Reis or EJ Mills). There are no contractual
agreements to limit access to final trial data. All data collected by the TOGETHER Trial will be shared with the
International COVID-19 Data Alliance". Not only has there been no reports of successful access to the data, but an
ICODA manager reports that they have never had the data 490.

Indications of ivermectin use in the placebo arm. Recent ivermectin use was not in the exclusion criteria, however
community use was widespread. Ivermectin was available OTC, was recommended by the government for COVID-19,
and had nine times higher sales 491. Authors claim they ensured patients did not use ivermectin via "extensive
screening", but do not explain why this was not an exclusion criterion, or how this unwritten exclusion was ensured
even though there is extensive missing data related to written exclusion criteria. Similar unwritten exclusions were not
mentioned for other arms 492, a primary investigator previously stated such an exclusion should not be an issue 493,
and it is not mentioned in the interview sheets 494. After publication, a co-principal investigator reportedly wrote that
"even if some patients did access IVM, the fact that it is blinded should still maintain balance", which is incorrect,
placebo patients taking ivermectin are expected to improve, treatment patients that already have significant tissue
distributions may have positive, neutral, or negative responses to additional treatment. Further, there are contradictory
reports of how patients with prior ivermectin use were handled, and there is an indication that patients who had taken,
or "were likely to take" ivermectin for COVID-19 were re-allocated to fluvoxamine or placebo 495.

Conflicting and inconsistent PP/ITT groups. Conflicting and inconsistent decreases in PP vs. ITT groups between
different tables and between the treatment and control arms 473.

Refusal to release per-protocol mortality and hospitalization data. Refusal to release per-protocol mortality and
hospitalization results although they were reported for fluvoxamine and their importance was emphasized by
coauthor Dr. Boulware 473.
Conflicting descriptions of the placebo group. There are multiple conflicting statements regarding the placebo
group 473.

Failure of NEJM to publish letters reporting errors and issues. NEJM has refused to publish any of the many letters
submitted by scientists reporting errors and critical issues with the trial. For details see 473.

Placebo tablets may not match treatment tablets. Authors do not specify the appearance of the placebo tablets,
suggesting that they may not match the treatment tablets, providing an additional reason for blinding failure. A
Brazilian investigator reports that, at the time of the trial, there was only one likely placebo manufacturer, and they
reportedly did not receive a request to produce identical placebo tablets 464. They also report that compounded
ivermectin in Brazil is considered unreliable.

Viral load protocol violation, high Ct may hide efficacy. The protocol has change in viral load as an outcome,
however only viral clearance is reported, and without any details (for example, using a high Ct value would have
limited relevance). Notably, the same trial did report viral load results for a commercial drug where one of the principal
investigators is a founder of the company 496.

162 control patients missing onset data vs. 1 for peginterferon lambda. 162 control patients are missing time from
onset (Figure 2), however for peginterferon lambda (which overlaps with ivermectin in time) authors claim only one
control patient is missing time from onset 496 (page 25).

Contradictory inclusion/exclusion of vaccinated patients, changes, and confounding. The trial changed from
including vaccinated patients to excluding them on Mar 21, 2021 497,498, and on Jul 5 the exclusion was changed to
specify >14 days. As discussed, meeting the reported placebo counts likely requires taking placebo patients from the
earlier period, which has significant confounding due to variant changes. The vaccine inclusion change adds
additional confounding, which also favors the placebo group. The original vaccine inclusion criterion is shown in both
the protocol and the [Link] record 499,500. Note that the paper, master protocol, Brazilian protocol, and trial
registration report contradictory information on vaccine inclusion/exclusion and changes over time 501.

Impossible data in the metformin arm. Data for the primary outcome in the metformin arm of this trial appears to be
impossible 502. For example, considering the metformin arm and the ITT population: 24 were hospitalized and 8 had
an ER visit (tables S2/S3), therefore the number for combined ER or hospitalization must be between 24 and 32.
However, authors report 34 events for ER/hospitalization.

Conflicting information on FTX funding. There is conflicting information and statements regarding FTX funding of the
trial 503.

Metformin/fluvoxamine conclusions opposite of COVID-OUT, but matching earlier studies on each team. The
Together trial and COVID-OUT both tested metformin and fluvoxamine. Notably, they came to opposite conclusions. In
Together, authors found efficacy for fluvoxamine, but the metformin results were so negative that the trial was
terminated early. In COVID-OUT it was the opposite, authors (although not the journal editor) found efficacy for
metformin, while the fluvoxamine results were so negative that the trial was terminated early 504. Note that the
Together authors include researchers that found fluvoxamine effective in earlier studies, while the COVID-OUT authors
include researchers that found metformin effective in earlier studies.

Author claims results from 653 researchers should be censored for false information. 64 studies by 653 scientists
report statistically significant positive results for ivermectin treatment of COVID-19 505. One author claimed that a
report of positive results is "disinformation" and distributed a request to report and censor the author 506-508. While
discussion is warranted for all studies, a call for censorship of results is extreme and raises questions. Author provides
no basis for the results of the 653 scientists being wrong and warranting of censorship, and there is no indication that
author has even read most of the studies. Author cherry-picked two of 105 studies, (COVID-OUT and ACTIV-6 125,126,
both very high COI studies with an extensive list of issues and very delayed treatment) and claimed that "no benefit of
ivermectin was observed" 509. In addition to ignoring the 64 studies reporting statistically significant positive results,
ACTIV-6 510 reported a posterior probability that ivermectin is effective of 99%, 98%, and 97% for mean time unwell,
clinical progression @14 days, and clinical progression @7 days (even though none of the pre-specified primary
outcomes were reported, and noting that these preprint results were changed without explanation), and COVID-OUT
showed 61% lower hospitalization with ivermectin vs. placebo (not including metformin), although this was not
reported.

Paper silently modified without notification or explanation. Apr 5: The paper was silently updated, with no indication
or explanation of the changes. Changes include: age range, placebo description, per-protocol count, and death
counts (as above). May 5: The paper was silently updated again. A new summary notes that authors attempted to
screen for previous ivermectin use, contradicting both the discussion section, where authors claim they ensured no
use for COVID-19, and the exclusion criteria and interview forms, which do not specify ivermectin use.

Team selected dose below what they believe is required. Dr. Craig Rayner, a senior investigator on the trial,
previously published research indicating that a higher dose is required 511, raising the question of why the dose and
fasting administration was chosen, for both the single day and 3 day dose regimens. Clinical equipoise 512 raises
ethical questions about running a trial where the invesigators do not believe the chosen dose is effective. Krolewiecki
show an antiviral effect only with plasma concentrations above 160ng/mL. Figure S5 shows that the authors expected
the mean concentration to be well below this level 513. Dosage requirements are likely to vary significantly depending
on many factors including the variant encountered, time of administration, mode of administration, patient genetics,
concomitant medications, SOC, and the distribution of the infection in different tissues. However, the dose used is far
below what is recommended by clinicians for post-infection treatment with the Gamma variant — about 2.5 - 6.5x
lower, depending on the recommendation and which estimate of fasting/fed administration is used. The trial used
fasting administration, however Merck's product information reports that "administration of 30mg ivermectin following
a highfat meal resulted in an approximate 2.5-fold increase in bioavailability relative to administration of 30mg
ivermectin in the fasted state." 514.

Viral clearance results mismatch. In Figure S3, the numbers in the table do not match the graph, for example day 0 to
day 3 for ivermectin shows a 30% decline in viral detection in the table, while the graph shows only a 4% decline 515.
Table 3 results do not match either of these results. For example at day 3, table 3 reports 7.4% clearance for
ivermectin. In Table 3, about 15% more patients have viral clearance results in the control arm, suggesting likely
confounding by time. Authors provide no details on which patients were tested in each arm, however the confounding
may be very significant. Notably, a July 2021 change adds viral load testing for the IV arms 516, suggesting that
placebo viral results may have a significant number of patients from a very different time period 516 where patient
characteristics 517, viral variants, and outcomes may be very different.

FDA concerns regarding trial conduct for peginterferon lambda. The peginterferon lambda arm of this trial generated
positive results, however the FDA denied a request for a pre-EUA meeting, citing concerns about the conduct of the
trial 518. Reportedly, the "FDA will not consider an EUA application based on results generated from the TOGETHER
study" 518. Details of the FDA's concerns were not provided.

Co-principal investigator agrees with political need to demonstrate poor efficacy. Frank Harrell commented that
"..the question of whether this study was stopped too early in light of the political ramifications of needing to
demonstrate that the efficacy is really unimpressive.. really could be raised..", and co-principal investigator Prof. Ed
Mills responded "I totally agree with Frank" 442.

Private comments on efficacy contradict public comments. Co-principal investigator Prof. Ed Mills said the following
in private communication: "There is a clear signal that IVM works in COVID patients.. that would be significant if more
patients were added.. you will hear me retract previous statements where I had been previously negative" 440, while
public comments are contradictory, e.g. “There was no indication that ivermectin is clinically useful”.

Mid-trial change adds patients showing lower efficacy. Authors modified the inclusion criteria mid-trial to allow
adding more low-risk patients <50 519. Comparison with the metformin placebo arm shows many more patients <50
≥
were included in the later part of the trial. Notably, the primary outcome shows much higher efficacy for patients 50,
≥
which would be statistically significant if there was about 50% more patients 50.

Funding from Gates Foundation. Analysis suggests funding of the ivermectin arm in part by the Gates Foundation by
way of Certara and Prof. Rayner 520, in addition to previously disclosed funding of the overall trial. Authors list only
FastGrants and Rainwater in the ivermectin paper. The Gates Foundation was cited as a funder on the web site until
Sep 13, 2021 521 (after completion of the trial). Correspondence regarding fluvoxamine and fluoxetine notes that
Certara support for the TOGETHER study was funded by the Gates Foundation 522.

Conflicting reports on trial end date. There are conflicting reports on when enrollment into the ivermectin and
fluvoxamine arms ended 523, with the master protocol showing the end as July 26 and the web site confirming an end
in July. However, the papers report August 5 and 6.

Expression of concern. An expression of concern was posted for the metformin arm in 2024 524.

Side-effect prevalence consistent with treatment error. The side effects (e.g., gastrointestinal side effects were lower
in the ivermectin arm) suggest that many ivermectin patients may not have received authentic ivermectin, or that
placebo patients may have taken ivermectin. For comparison, there was a 3.6 times greater incidence of diarrhea in
the treatment arm in Lim.

Screening to treatment delay unknown. Most Together Trial master protocols show an additional day delay in already
late treatment for most patients. The Aug 5, 2021 protocol published with the metformin paper 526, shows treatment
administration one day after screening, baseline, and randomization (Table 2, schedule of study activities). This can
also be found in the protocol dated Mar 11, 2021 527. The protocol attached to the ivermectin paper, dated Feb 15,
2021, shows a different schedule, stating that the treatment should be administered on the same day of
randomization. There is no explanation of when this change was made, how the overlapping metformin and
ivermectin arms could use different schedules, or how this change was implemented (there are many tasks in the
screening and baseline visits). There is no reporting for how many patients received treatment on the same day. The
form for the first treatment visit asks if there were clinical events including >6hr ER visits since the baseline visit, which
would not be possible if this visit was immediately after randomization. Time of first treatment was recorded 494, but
no information has been reported. According to Forrest, WhatsApp messaging and video was used for recruitment,
raising the question of how medication was delivered in cases where recruitment was done online. The Brazilian
versions of the protocol do not match the master protocol, with all showing administration on the same day. The first
Brazilian version of the protocol stated the drug "must be administered on the same day", however in March 2021 and
later versions, this was changed to "should be administered on the same day".

317 unknown onset patients, onset required for inclusion. Figure 2 shows that the time from onset was unknown for
317 patients, however time from onset is required for the inclusion criteria.

Unknown onset patients treated late. After imputation, the percentage of patients in the late treatment subgroup
went from 46% to 56%. 87% of the unknown patients were predicted to be in the late group. This is reasonable and
expected — patients that do not recall when the onset was are more likely to have had onset further in the past. What
is not clear is how these patients could be enrolled in the trial, how many of these patients had onset >7 days, how
this very late 317 patient subgroup could show much greater efficacy as above, and why authors did not report this
result, analyze this in greater detail, or recommend further research.

Conflicting comorbidity counts. The companion fluvoxamine arm ran from Jan 20 to Aug 5, 2021, while this trial ran
from March 23 to Aug 6, 2021 — most control patients should be shared, with an additional 10% for fluvoxamine
from the earlier start. The Aug 6 presentation, which has a date of 9:38am Aug 6 local trial time 529, shows 678
placebo patients, indicating that either 0 or 1 placebo patients were randomized on Aug 6. Zero patients should have
been randomized on Aug 6, because authors cannot add patients after unblinding. The fluvoxamine control arm
shows 16/756 control patients with asthma. The ivermectin control arm has a subset of these patients (679), but
shows a much higher prevalence of asthma (60 patients). This might be possible due to imputation if there was a very
high percentage of missing data, however imputation does not appear to be a good explanation. For example,
placebo CKD goes from 2 to 5 (FLV->IVM). First, it is not logical to impute CKD on patients based on the other
variables. Second, the protocol specifies imputation only with up to 20% missing data, making it unlikely that
imputation would add 150% of CKD patients. Third, the degree of change between FLV and IVM varies dramatically,
with IVM reporting 666%, 275%, 150%, and 43% more patients for CPD, asthma, CKD, and CCD, without any clear
explanation for similar differences in the percentage of missing data (all were collected on the same interview form).

Unexplained >6 month delay. The paper was delayed over 6 months with no explanation. The companion fluvoxamine
arm, completed at the same time, was published Aug 23, 2021. The very long delay, high profile of the topic, and
other issues above raise questions. The paper was submitted to NEJM in Sep 2021 530. COI forms suggest that
additional authors were added after submission and the corresponding author changed from Prof. Mills to Dr.
Rayner 531, whose conflicts include Pfizer, Merck, the Gates Foundation, and the Australian Goverment.

Placebo patients receiving an injection not blinded. One-day placebo patients, which study documents repeatedly
report as being included in the placebo group, would include those receiving a single injection, and are therefore not
blinded 473.

Major imputation error. In the paper authors use imputation in Table 1 but not in Figure 2. Authors also released a
version of Figure 2 with imputation 532, where the numbers for age and BMI now match the imputed numbers in Table
1. However, the time from onset numbers are very different, with the treatment arm showing 302 patients for 0-3 days,
and the imputed version of Figure 2 showing 367 533.

Single dose results missing. Results for the single dose ivermectin arm have not been reported.

Incorrect conclusion. The conclusion states that ivermectin "did not result in a lower incidence of [hospitalization] or
of [ER observation >6hr]". This is incorrect, hospitalization was 17% lower, which is not statistically significant with the
sample size and typical statistical analysis. For the Bayesian analysis the authors use, the ITT probability of superiority
for ivermectin was 79.4%, which is a positive result, the opposite of the conclusion.

Missing age information. According to Figure 2, 98 patients are missing age information 534.

Mid-trial protocol changes. There were several mid-trial protocol changes on July 5, 2021 535. The number of patients
for viral load analysis was reduced, only for the ivermectin arm. All-cause, cardiovascular, and respiratory death
outcomes were deleted (all-cause was reported). Exclusions were modified to allow enrolling patients vaccinated
within the last 14 days. Inclusion criteria were modified to allow enrolling healthy young people — the criterion "fever
>38C at baseline" was added, allowing enrollment independent of increased risk.

COI: designed by Cytel. The trial was designed by Cytel, a company that helps pharmaceutical companies get
approval and that works very closely with Pfizer 536,537. Cytel's software and services are used by the top 30
pharmaceutical companies 538.

COI: co-principal investigator works for Cytel and the Gates Foundation. A co-principal investigator works for Cytel
and the Gates Foundation 539: "The majority of the time I work for a company called Cytel, where I design clinical trials,
predominantly for the Bill & Melinda Gates Foundation".
COI: pharma funding and denial of independent investigator. Reportedly, the first author's center is funded by
pharmaceutical companies, and independent investigators tried to participate in the trial but were denied 540.

COI: Gates Foundation. The Gates Foundation is a founding partner of GAVI, which took out Google ads telling people
not to use ivermectin 541, and a major funder of Unitaid, which may have modified the results of the Hill meta analysis
in a way that prevented adoption 477-479.

COI: Certara. One of the senior investigators was Dr. Craig Rayner, President of Integrated Drug Development at
Certara - another company with a similar mission to MMS Holdings. They state on their website that: "Since 2014, our
customers have received over 90% of new drug and biologic approvals by the FDA." One of their clients is Pfizer 542.

COI: MMS Holdings. The trial is associated with MMS Holdings 465, whose mission includes helping pharmaceutical
companies get approval and designing scientific studies that help them get approval. One of their clients is Pfizer 543.

COI: analysis company works closely with Pfizer. All analyses were done by Cytel. Cytel is a statistical modelling
company that helps pharmaceutical companies get approval — they work very closely with Pfizer 537. Cytel's software
and services are used by the top 30 pharmaceutical companies 538.

COI: Fast Grants funding closely related to companies that censored scientific research. Fast Grants funding is
closely related to tech companies that censored ivermectin and other early treatment research. These companies
have a strong conflict of interest in not admitting that their censorship was harmful 544,545.

Unexpected differences in missing data. Age is unknown for 98 patients, however according to Figure 2, BMI is
missing for only 11 patients, smoking status is unknown for only 2 patients, lung disease is unknown for only one
patient, and cardiovascular disease is known for all patients.

Out of funding claim contradicted by funder. A co-principal investigator has reported that the trial was stopped
because they ran out of funding, however this is contradicted by the Rainwater Foundation, which reported that they
would have given more money to finish the trial if the investigators had asked 546.

Misrepresentation of dosing recommendation. Investigators have misrepresented an email from the FLCCC
regarding recommended dosing 546.

Unknown onset patients show statistically significanct efficacy. For the known time since onset subgroups, both
groups show worse results than the overall results 547, with the missing 317 patients showing significant efficacy RR
0.51, p = 0.02 (compared to 1.00 and 1.14 for known patients).

Mean delay likely excluding unknown onset. The reported mean number of days from symptoms to randomization
probably only includes known onset patients and therefore is likely to significantly underestimate the actual average
(in addition to not including the time between randomization and treatment).

Per-protocol placebo much more effective. The 3-dose per-protocol placebo group shows greater efficacy 461,548.
This could be consistent with placebo patients accidently receiving treatment.

Multiple conflicting randomization protocols. [Link] (AP) reviewed the randomization protocol, finding three
different algorithms, and conflicting versions in the papers.

Dominated by Gamma variant with different characteristics, no discussion. The trial took place in an area of Brazil
and time when the Gamma variant was dominant. Brazilian clinicians report that this variant is much more virulent,
and that significantly higher dosage and/or earlier treatment is required, as may be expected for variants where the
peak viral load is significantly higher and/or reached earlier 177,178.

Incorrect dose reporting, patients at higher risk due to BMI may have received lower per kg doses, and show lower
efficacy. The paper reports 400μg/kg for 3 days, however the protocol indicates that this was only up to 90kg,
meaning that the dose received for higher-risk high BMI patients was even further reduced from dosage which is
 ≥
already far below clinician recommendations for the dominant variant 550. 50% of patients had BMI 30. Much greater
efficacy was seen in the low BMI subgroup (RR 0.77 vs 0.98).

Conflicting target enrollment and reasons for termination. There are conflicting target enrollment numbers. The
protocol showed 800 patients per arm as of Mar 21, 2021 (after the trial started) 551,552, the co-principal investigator
reported 800 per arm in an interview published June 14, 2021 553, and the protocol changed to 681 on June 22 554.
However, the trial record from Jan indicates 2724 (681*4) patients 499, suggesting that the 800 goal was later, and
was kept for fluvoxamine but reverted for ivermectin. The fluvoxamine arm which started two months earlier was
terminated at the same time, and was terminated due to superiority 555 after 741/756 patients. Note that Gamma was
declining significantly around the termination point, which likely favors improved efficacy if the trial continued, given
the late treatment and dosage used. The co-principal investigator reports three different reasons for stopping the
trial 556: a) because they ran out of money, b) because third parties were not supportive, and c) it was done by the
DSMC and was out of their control.

Primary outcome subject to bias, selected after single dose arm. The subjective "emergency room visit for >6 hours"
criterion shows higher risk (RR 1.16), while hospitalization is lower (RR 0.83 all-cause, RR 0.84 COVID-19). The
primary outcome results were set on March 21, 2021, after the single dose ivermectin arm. Given the known public
biases of some investigators, this may have been specifically chosen to reduce efficacy. Authors claim that the 6hr
threshold did not include waiting time, however the emergency visit form has no mention of waiting time, only
recording presentation and discharge times 494.

Reported terminated due to futility, but threshold not reached. The trial was reportedly terminated due to futility 557,
however the futility thresholds were 20%, 40% and 60%, and all published probabilities are >60% (ITT 79.4%).
Additionally, the fluvoxamine arm did not have the higher 60% threshold, only using 40%. Note the DSMC was not
independent as below.

Subgroup analysis protocol violations. The presented subgroup analysis is inconsistent with plans and with the
fluvoxamine paper, including not presenting pre-specified subgroups, presenting subgroups that were not pre-
specified, presenting different subgroups to the contemporary fluvoxamine paper, and modifying subgroup
definitions 558.

Many pre-specified outcomes missing. Many outcomes specified in the protocol appear to be missing, including the
co-primary outcome of COVID-19 mortality (only all-cause mortality is provided, specific AE details not provided), time
to clinical failure, days with respiratory symptoms, mortality due to pulmonary complications, cardiovascular
mortality, COVID-19 symptom scale assessment, WHO clinical worsening scale assessment, and 14 day mortality.

Single-dose recruiting continued after change. The trial had requested moving to 3-dose treatment by Feb 15/19,
when only 19 patients had been recruited, however the trial continued recruiting an additional 59 patients to single
dose treatment 559.

Funding list incorrect, missing Gates Foundation and Unitaid. The paper does not include the Bill and Melinda Gates
Foundation or Unitaid as funders, however the protocol shows the Gates Foundation 560 and the web site shows
Unitaid 480.

Statistical analysis plan dated after trial start. The statistical analysis plan appears to be dated after the trial
started 561.

Imputation protocol violation. The protocol specifies multiple imputation with up to 20% of missing data, however
imputation was done with time from symptom onset, which has >23% missing data 562.

Expected analyses missing. Authors do not provide time from onset analysis for either mortality or hospitalization,
only the combined measure including the ER visits where anomalous results are seen. Authors do not provide per-
protocol or mITT results for mortality or hospitalization. Per-protocol mortality results were provided for the
companion fluvoxamine trial.
Conflicting reasons for dose change. Conflicting reasons have been given for the change from 1-day to 3-day dosing.
In email from March 6, the co-principal investigator says the change was "based on emerging trials from Andrew Hill's
synthesis" 563. The paper says the change was made "on the basis of feedback from advocacy groups". Neither of
these match the report that the dosing change was made at the request of one of the trial funders 441.

Details of placebo unspecified. The placebo appears to be unspecified in the paper and protocol. The initial trial
announcement indicated the placebo was vitamin C 536, which would be an active treatment according to the results
of 72 studies (mortality RR 0.81 [0.72-0.90]). The metformin arm reports using talc, however fluvoxamine and
ivermectin do not appear to report details of the placebo, which could potentially be different, for example based on
manufacturer limitations for matching active treatment tablets.

Antigen test requirement. The protocol indicates that patients with a negative test may be included if they become
positive a few days later, potentially resulting in a long unreported delay between randomization and treatment,
depending on how investigators interpreted the protocol. The requirement for a positive antigen test excludes the
possibility of early treatment in many cases - tests have very high false negative rates in the early stages of infection,
and symptoms may appear before the test becomes positive.

Bayesian probability of superiority, featured for FLV, hidden in appendix. The bayesian probability of superiority
figure, featured in the main paper for FLV, MET, HCQ, was hidden in the appendix for IVM 564.

Two different per-protocol counts. Figure 1 shows 228 per-protocol for the control arm, while Table 2 shows 288.
This was modified in the Apr 5 update without explanation.

Source of ivermectin unspecified (fluvoxamine source specified). Authors do not specify the source of the ivermectin
used in the trial, whereas they do specify the source for the fluvoxamine arm (Luvox, Abbott). Depending on the
source, Ivermectin has been reported to be of unreliable quality in Brazil.

100% adherence reported for 3-day placebo. Reported numbers indicate that there was 100% adherence among
288 patients assigned to 3-day placebo, which is unexpected 441,486.

No confirmation of placebo manufacturing. A local Brazilian investigator reports that, at the time of the trial, there
was only one likely placebo manufacturer, and they reportedly did not receive a request to produce identical placebo
tablets 464. They also report that compounded ivermectin in Brazil is considered unreliable. The protocol reports that
"the study medication used will come from pharmaceutical plants that hold a commercial authorization for their
production, already approved by ANVISA."

The following comments are prior to the publication and may be out of date. We note that authors claim they have not
included patients prior to the time period for the 3 dose ivermectin patients, however this conflicts with previously
reported data as per the analyses above.

The trial randomization chart does not match the protocol, suggesting major problems and indicating substantial
confounding by time. For example, trial week 43, the first week for 3 dose ivermectin, shows ~3x patients assigned to
ivermectin vs. placebo 443. Treatment efficacy can vary significantly over time, for example due to overall improvement
in protocols, changes in the distribution of variants, or changes in public awareness and treatment delays. Zavascki
show dramatically higher mortality for Gamma vs non-Gamma variants (28 day mortality from symptom onset aHR
4.73 [1.15-19.41]), and the prevalence of the Gamma variant varied dramatically throughout the trial 444. This
introduces confounding by time, which is common in COVID-19 retrospective studies and has often obscured efficacy
(many retrospectives have more patients in the treatment group earlier in time when overall treatment protocols were
significantly worse).

According to this analysis 443, the total number of patients for the ivermectin and placebo groups do not appear to
match the totals in the presentation (the numbers for the fluvoxamine arm match) — reaching the number reported
for ivermectin would require including some of the patients assigned to single dose ivermectin. Reaching the placebo
number requires including placebo patients from the much earlier ivermectin single dose period, and from the early
two week period when zero ivermectin patients were assigned. If these earlier participants were accidently included in
the control group, this would dramatically change the results in favor of the control group according to the changes in
Gamma variant prevalence.

An investigator from Brazil notes that the gamma variant became prevailing in the state of Minas Gerais later than in
the rest of the country, with the time when gamma prevailed for the trial locations being more closely aligned with the
start of the ivermectin arm 445. Due to the substantial differences in disease course and risk between the variants,
authors need to consider only patients recruited during the same time period.

Treatment delay is currently unknown, however the protocol allows very late inclusion and a companion trial reported
mostly late treatment. Overall mortality is high for 18+ outpatients. Results may be impacted by late treatment, poor
SOC, and may be specific to local variants 177,178,446. Treatment was administered on an empty stomach, greatly
reducing expected tissue concentration 1 and making the effective dose about 1/5th of current clinical practice. The
trial was conducted in Minas Gerais, Brazil which had substantial community use of ivermectin 447, and prior use of
ivermectin is not listed in the exclusion criteria.

This trial uses a soft primary outcome, easily subject to bias and event inflation in both arms (e.g., observe >6 hours
independent of indication). There is also an unusual inclusion criteria: "patients with expected hospital stays of <= 5
days". This is similar to "patients less likely to need treatment beyond SOC to recover", and would make it very easy to
reduce the effect seen. This is not in either of the published protocols.

RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that
believe they need treatment are more likely to decline participation and take the intervention 357, i.e. RCTs are more
likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical
pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin
is widely known and used.

The same trial's results for a previous treatment were initially reported as RR 1.0 [0.45-2.21] 448, while the final paper
reported something very different — HR 0.76 [0.30-1.88] 449.

Trial design, analysis, and presentation, along with previous public and private statements suggest investigator bias.
Design: including very late treatment, additional day before administration, operation in a region with high community
use, specifying administration on an empty stomach, limiting treatment to 3 days, using soft inclusion criterion and a
soft primary outcome, easily subject to bias. Analysis: authors perform analysis excluding events very shortly after
randomization for fluvoxamine but not ivermectin, and report viral load results for fluvoxamine but not ivermectin.
Presentation: falsely describing positive but not statistically significant effects as "no effect, what so ever" 356,450. Prior
statements: [Link].
The local Brazilian investigator also reports that nitazoxanide was tested in the same location, however very few
patients reportedly experienced urine discoloration, while all are expected to experience this side effect. They also
suggest that 6-hour observation is a poor choice because it is almost impossible to stay less than 6 hours in Brazil.

For additional issues see: [Link], [Link], [Link], [Link] (C),

[Link], [Link] (B), [Link] (L), [Link] (M),
[Link] (N), [Link] (M), Marinos, Marinos (B). Protocols, approvals, and statistical analysis plans can be
found here [Link].

ACTIV-6.

Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A
Randomized Clinical Trial

Extreme COI, data inconsistencies, uncorrected errors, no response from authors, participant fraud, refusal to release
data

SEE ALSO
ACTIV-6 Trial on Ivermectin: NIH Scientists Behaving Badly
The Story Of A Real ACTIV-6 Patient
ACTIV-6 Dosing & Timing: A Fox In The Henhouse

≥
RCT low-risk outpatients with very late treatment (median 6 days, 25% 8 days) in the USA, showing 98% probability
of efficacy for clinical progression at day 14, a treatment delay-response relationship, and significant efficacy for
patients with severe symptoms at baseline. The posterior probability ivermectin is effective was 99%, 98%, 97% for
mean time unwell and clinical progression @14 and 7 days. All exceed the pre-specified threshold for superiority 565.
Note that the clinical progression results exceeding the superiority threshold in the preprint 566 changed in the journal
version for the 400µg/kg arm, with no explanation for over 700 days). The 600µg/kg arm was reported separately 567.
When not specified, comments refer to the 400µg/kg arm. We provide more detailed analysis of this study due to
widespread incorrect press.

There was one death reported in each of the 400µg/kg and 600µg/kg ivermectin arms. For 400µg/kg, the patient did
not take ivermectin. For 600µg/kg, authors note that the death was accidental.

There are many critical issues as below. Design, presentation, and analysis shows a strong negative bias. Submit
Updates or Corrections

Severity Issue

CRITICAL 1. Impossible data

CRITICAL 2. 16% of patients missing (600µg/kg)

CRITICAL 3. Randomization failure - higher severity in ivermectin arms

CRITICAL 4. Adverse events consistent with potential medication error

CRITICAL 5. Superiority found, not reported

CRITICAL 6. Mismatch in number of patients receiving medication

CRITICAL 7. Adverse events similar for active and placebo

CRITICAL 8. Adverse event count mismatch

CRITICAL 9. Participant fraud

CRITICAL 10. 0.4% AE for newly added patients versus 8.0%

CRITICAL 11. Interim analyses not reported, likely showed superiority

CRITICAL 12. Death incorrectly reported in mITT, medication not received

CRITICAL 13. Ivermectin source unknown, specified for other trial medications

CRITICAL 14. More patients took medication than received it

CRITICAL 15. Non-identical placebo

CRITICAL 16. Post-hoc protocol

CRITICAL 17. Clinical progression results changed

CRITICAL 18. Primary outcome not reported, closest reported shows superiority

CRITICAL 19. Pre-specified primary 14 day outcomes not reported, clinical status shows 30% benefit

CRITICAL 20. Hospitalization/death mismatch

CRITICAL 21. 90 day followup results not provided

CRITICAL 22. Very late treatment

23. Key clinical question consistent with unreported pre-specified primary outcome but not the
CRITICAL
reported outcome

CRITICAL 24. Patients with symptoms >7 days included

CRITICAL 25. Data unavailable over 800 days from publication

CRITICAL 26. Outcomes reported do not match protocol

CRITICAL 27. Primary outcomes changed after publication

CRITICAL 28. Different hosp./urgent care numbers between paper and presentation

CRITICAL 29. Post-hoc primary outcome measured on day 3

CRITICAL 30. Dose below 400μg/kg

CRITICAL 31. Effective dose ~130μg/kg, administration on empty stomach

CRITICAL 32. Clinical progression details for other arms but not ivermectin

CRITICAL 33. COVID-19 mortality/hospitalization not reported

CRITICAL 34. Many pre-specified outcomes missing

CRITICAL 35. Full protocol unavailable before October 2022

CRITICAL 36. IDMC not independent, extreme conflict of interest

CRITICAL 37. Reported primary outcome low relevance

CRITICAL 38. Shipping and PCR delays largely enforce late treatment

CRITICAL 39. Very slow shipping

CRITICAL 40. Blinding failure

CRITICAL 41. Extreme conflicts of interest

CRITICAL 42. Treatment delay-response relationship

CRITICAL 43. Asymptomatic patients included

CRITICAL 44. Disingenuous conclusion

CRITICAL 45. Significant missing data, not mentioned in paper

CRITICAL 46. Statistically significant efficacy for severe patients removed

CRITICAL 47. Statistical analysis plan dated after trial end

CRITICAL 48. 31% more severe cases in the ivermectin arm

CRITICAL 49. Many conflicting exclusion counts

CRITICAL 50. Population incorrect

CRITICAL 51. Early treatment incorrect

CRITICAL 52. Author claims results from 653 researchers should be censored for false information

SERIOUS 53. Bias due to false positive antigen tests

SERIOUS 54. Participant pickup delay

SERIOUS 55. Randomization failure

SERIOUS 56. Low risk patients

SERIOUS 57. No adherence data or per-protocol analysis

 SERIOUS 58. Skeptical prior not justified

SERIOUS 59. Missing symptom severity mismatch

SERIOUS 60. Not enough tablets provided

SERIOUS 61. Monotherapy with no SOC for most patients

SERIOUS 62. Over 2x greater severe dyspnea at baseline for ivermectin

SERIOUS 63. Safety conclusion removed, suggests bias

64. Authors suggest high-income country healthcare is better, however almost all patients received
SERIOUS
no active SOC

SERIOUS 65. Placebo unspecified

SERIOUS 66. No breakdown of severe outcomes

SERIOUS 67. Missing subgroup counts

MAJOR 68. Overlapping fluticasone placebo shows very different event numbers

MAJOR 69. Overlapping fluticasone placebo shows unexpected baseline numbers

MAJOR 70. Inconsistent calendar time subgroups

UNKNOWN 71. Outcome graph presented does not match either medication tested

Responses: authors have not responded to any of these issues.

Impossible data. There are major data mismatches 571. For the ivermectin 600 arm [Link] (CT) indicates
that 718 patients started and 708 completed the arm 572, while the paper claims that only 668 were randomized to
ivermectin, of which 66 did not even receive the medication 573. Baseline age, ethnicity, and race data all differ
between CT and the paper, for example CT indicates 3 patients in the ivermectin arm were American Indian or Alaska
Native, whereas the paper shows 9, despite reporting on a much smaller number of patients. Many results also differ
between CT and the paper. A second version of the paper makes some values match but adds new data problems as
below.

16% of patients missing (600µg/kg). Naggie (C) confirms that 16% of patients were missing in the 600µg/kg paper.
It's not clear how the trial could have such a large error for the number of patients randomized, why the correction
took over a year, or why the many other errors have not been corrected.

Randomization failure - higher severity in ivermectin arms. The most severe baseline symptom reported is severe
dyspnea. For both 600μg/kg and 400μg/kg, the ivermectin arm has higher incidence of severe dyspnea, which is
statistically significant across both arms (p = 0.02). This suggests that known and potentially unknown blinding
failures are material.

Adverse events consistent with potential medication error. Placebo adverse events are expected to be similar for the
400μg/kg and 600μg/kg arms. The populations are similar and patients are not taking any study treatments. The
600μg/kg arm has a lower overall hospitalization rate. However, the 600μg/kg placebo arm reports 44/604 (7.3%)
adverse events, while the 400μg/kg arm reports only 27/774 (3.5%), over 2 times higher. This is a significant increase
in adverse events, p = 0.002, without explanation or discussion. Comparing 400μg/kg and 600μg/kg, adverse events
are over 2x higher for both the active and placebo arms. The overall increase in adverse events with the higher dosage
(total 3x higher) matches expectations, however we expect the increase in the active treatment arm, not both active
and placebo arms. One hypothesis is that patient arm classifications are incorrect, i.e., many patients received the
opposite of their designated arm. This kind of error is possible in all placebo controlled trials and happened for
example in López-Medina (discovered and excluded in that case). This hypothesis is consistent with both the adverse
events and the 600μg/kg results, with the very small remaining effect explainable by the 10% non-matching placebo
patients. We recommend that participants retain any leftover tablets for analysis.
Superiority found, not reported. Day 7 and day 14 clinical progression results and mean time unwell show superiority
of ivermectin (note: 400μg/kg arm, preprint version 566, clinical progression results were changed without explanation
in the journal version). The protocol indicates superiority for OR < 0.9 and posterior probability > 0.95 565. In the
presentation 568, author shows a slide containing these results while stating "this was, um, not statistically significant"
(@22:36). These results were seen despite 107 patients having no symptoms at baseline and the use of the skeptical
prior 575.

Mismatch in number of patients receiving medication. The first version of the 600µg/kg paper reports that 138
patients did not receive the study medication, while the second (which includes many patients incorrectly excluded in
the first version) claims that only 27 did not receive the medication (from Figure 1 in each version).

Adverse events similar for active and placebo. For the 600μg/kg arm authors report that 9% of patients experienced
an adverse event, similar to placebo (7%, no significant difference). However significantly more side effects are
expected at this dosage (the total dosage is 3x greater due to the longer duration). The 600μg/kg arm in Buonfrate
reports much higher adverse events. Overall reporting is higher in this trial, which may include lower severity items,
especially within "general disorders". However looking specifically at eye disorders, a known side effect of higher
doses of ivermectin, Buonfrate show 46% vs. 3% for ivermectin vs. control. The lack of higher side effects for
ivermectin in ACTIV-6 suggests that patients may not have taken authentic ivermectin at the dosage reported. GMK 352
notes that data was self-reported by patients in ACTIV-6. Highly inaccurate reporting by patients would also apply to
the symptomatic results, similarly invalidating the trial.

Adverse event count mismatch. The paper reports 44 of 604 placebo patients had an adverse event in the 600µg/kg
arm 573 (44 of 724 in the second version), whereas clinicaltrials shows 5 of 724 placebo patients had an adverse
event 572.

Participant fraud. A paper on the operation of the trial 431 reveals that there was participant fraud - authors identified
participants that signed up repeatedly, and participants that withdrew when not randomized to their preferred arm.
Authors indicate that they tried to prevent repeat signups but provide no details on the algorithms or the evaluation
thereof. It is possible that they only caught a small fraction of the fraud, and possible that improvements to detection
were added only later in the trial during or after the ivermectin arms. It is likely that individuals were gaming the
system related to the politicization and extreme financial implications. This information was not disclosed previously.
Patients were allowed to specify treatments that they accept or decline to be a part of. One author indicates this was
most commonly used by patients to specify only ivermectin 576, which may be related to fraud targeting ivermectin.
There are known paid groups of individuals targeting ivermectin, and it would be simple to bias results towards null
without having to break the blinding. Participant fraud has also been reported for a similar remote trial 430 where
known fake surveys were submitted. The self-reported design and absence of professional medical examination
opens these kind of trials to participant fraud, which may be significant due to extreme politicization in the study
country.
0.4% AE for newly added patients versus 8.0%. The first version of the 600µg/kg paper reports that 8.0% of patients
had an adverse event (96/1206, eTable2). The second version reports 97/1430 indicating that only 0.4% of the added
patients had an adverse event.

Interim analyses not reported, likely showed superiority. The original protocol specified interim analyses every 200
patients, this was later modified to every 300 patients. However the paper claims "Because the rate of enrollment was
so rapid, it was not possible to complete the interim analyses". This is not realistic — the analysis code is written and
tested in advance for trials like ACTIV-6 which have professional statisticians. Based on the clinical progression results
showing superiority, it is likely that one or more of the interim analyses showed superiority on the original primary
outcome.

Death incorrectly reported in mITT, medication not received. Authors report one death in the ivermectin 400µg/kg
arm in the mITT population (817 patients that received the drug within 7 days), however in the presentation 568
(@21:15) author reports that the patient that died did not receive the drug because they were admitted prior to
receipt. The reported mITT death is therefore incorrect. Similarly, at least one and potentially many or all
hospitalizations may have occurred before receiving the drug.

Ivermectin source unknown, specified for other trial medications. Authors do not specify who provided the
ivermectin and ivermectin placebo tablets. This information is specified for the other ACTIV-6 medications (fluticasone
and fluvoxamine). For both other medications, active and placebo were provided by the same source.

More patients took medication than received it. The first version of the 600µg/kg paper reports that 566 of 602
treatment patients took the medication (eTable 2), however Figure 1 shows that only 536 of 602 received the
medication.

Non-identical placebo. The protocol states that the ivermectin placebo tablets will be identical to the ivermectin
tablets. However, the papers state only that packaging was identical, suggesting that a decision was made at some
point to use non-identical tablets. This was only done for ivermectin, both fluvoxamine and fluticasone papers report
using identical placebos. The protocol changelist notes that ivermectin and matched placebo information was
updated in version 2.0 (version 2.0 is not available).

Post-hoc protocol. An incorrect post-hoc protocol is included with the paper published October 21, 2022 which
differs significantly from the pre-specified protocol 565. The post-hoc protocol is dated December 20, 2021, long after
the trial started and after scheduled interim analyses that likely showed superiority as above. Metadata shows the
author of the protocol files to be Jenny Jackman. The protocol for the ivermectin arm is included with the fluticasone
NEJM paper, and is dated May 25, 2021. Neither protocol matches the reported outcomes, however the post-hoc
version has been modified to be closer.

Clinical progression results changed. The preprint 566 and journal version show very different clinical progression
results, with no acknowledgement or explanation. See also 577.

Primary outcome not reported, closest reported shows superiority. The protocol shows the primary symptom
outcome using a longitudinal statistical model with an ordinal variable based on symptom count and
hospitalization/death measured daily until day 14 565 (see section 10.6.1). This outcome is not reported. The closest
reported outcome is clinical progression at 14 days, which shows superiority of ivermectin, OR 0.73 [0.52-0.98],
posterior probability of efficacy 98%, which exceeds the pre-specified threshold for superiority (note: changed without
explanation as above).
Pre-specified primary 14 day outcomes not reported, clinical status shows 30% benefit. The pre-specified primary
14 day outcomes 565 are still not reported in the journal version. However, authors now show the clinical status graphs
in eFigure 2, which shows 30% benefit for ivermectin for limited activity at 14 days.

Hospitalization/death mismatch. Results show 10 and 9 events for hospitalization/death, however eFigure 1A shows
4 and 3.

90 day followup results not provided. Authors do not provide the PROMIS-29 results, stating that this is due to the 90
day followup. The 90 day followup period ended 169 days before publication (38 days before the preprint publication).
The protocol also specifies 7, 14, and 28 day PROMIS-29 results.

Very late treatment. Patients were treated a median of 6 days late, with 25+% 8+ days late. Extensive research for
COVID-19 and other viral diseases show that early antiviral treatment is critical. While authors recommend (and are
performing) further study, they do not recommend or perform the obvious step of doing an early treatment trial, as is
done for NIH recommended treatments like Paxlovid, suggesting a strong negative bias with a goal of maintaining late
treatment and obtaining poor results.

Key clinical question consistent with unreported pre-specified primary outcome but not the reported outcome.
Authors report the key clinical questions for ACTIV-6 as being "How to help someone feel better faster with newly
diagnosed mild-moderate COVID-19?" and "How to prevent hospitalizations or death in someone with newly
diagnosed mild-moderate COVID-19?" 568. The pre-specified but unreported primary symptom outcome provides a
measure for feeling better faster, however the reported post-hoc primary outcome is very poorly matched. For
example, a treatment that resolves serious symptoms 10x faster, but does not speed up 100% resolution of cough for
three consecutive days, would show zero benefit in the post-hoc primary outcome. Cough may persist long after viral
clearance 578. Note also that the trial does not address "newly diagnosed" patients, but rather very late treatment a
median of 6 days after symptoms. The very late treatment also minimizes the chance of preventing the initiation of
viral cough.

Patients with symptoms >7 days included. The trial specifies symptoms ≤7 days, however subgroup results show
symptoms ≤9, 11, and 13 days, and the Q3 for the ivermectin arm was 8 days, indicating 25% of patients with a
treatment delay of ≥8 days. The difference is likely due to the authors not considering receipt of medication or
treatment time in inclusion, i.e., due to shipping delays. However, ≤7 days treatment delay already makes the results
inapplicable to real-world usage where antivirals are used early.

Data unavailable over 800 days from publication. Data for the study is unavailable over 800 days after publication.

Outcomes reported do not match protocol. The reported outcomes are very different to the trial registration 579 and
the pre-specified protocol 565. The trial registration shows three primary outcomes, of which zero are reported in the
paper. The pre-specified protocol shows the primary outcome using a longitudinal statistical model with an ordinal
variable based on symptom count and hospitalization/death measured daily until day 14.

Primary outcomes changed after publication. The primary outcomes were changed from day 14 to day 28 on June
25, 2022, after publication 580. Two of the three primary outcomes were changed to match what was reported, while
the third remains unreported, and none of the pre-specified primary outcomes have been reported to date.

Different hosp./urgent care numbers between paper and presentation. The paper and the later presentation show
different numbers for hospitalization and urgent care/ER. In the presentation, a hospitalization was moved from the
placebo arm to the ivermectin arm 568 (@21:44). The HRs did not change.

Post-hoc primary outcome measured on day 3. The new primary outcome of sustained 100% recovery for 3 days is
measured on day 3 rather than day 1 568 (@19:10). We are unaware of any reason to use day 3 rather than the day of
100% recovery, other than to reduce the observed efficacy. Both the pre-specified 565 and post-hoc protocols include a
secondary outcome of "symptom resolution, defined as first of at least three consecutive days without symptoms".
Dose below 400μg/kg. The abstract states that patients received 400μg/kg. This is incorrect, section 16.3.3 in the
protocol shows that the actual dose was always below 400μg/kg, unless patients weighed exactly 35kg or 70kg, as
shown below 575. Dosage was as low as 269μg/kg for 52kg. When considering administration as below, the average
dose administered is equivalent to ~130μg/kg as used in practice. Authors state: "ivermectin was dosed by weight to
achieve a goal dose of 400μg/kg, but the maximum dose of ivermectin provided by the study was 35mg. While almost
42% of participants had a weight of more than 88kg and thus did not achieve the goal dose, more than 75% of
participants had a weight of less than 100kg and so received at least 90% of the target dose". This is incorrect - the
goal dose varied between ~300-400μg/kg, and the percentage that received 90+% of 400μg/kg is likely < 40%.

Effective dose ~130μg/kg, administration on empty stomach. Authors instructed patients to take ivermectin on an
empty stomach (not done for fluvoxamine). Guzzo show that the plasma concentration of ivermectin is much higher
when administered with food (geometric mean AUC 2.6 times higher). "Ivermectin should be taken on an empty
stomach with water" (protocol section 16.3.3). This is not mentioned in the paper or the supplementary appendix,
only in the protocol. This makes the average effective dose administered equivalent to ~130μg/kg for administration
with a meal (as used in clinical protocols).

Clinical progression details for other arms but not ivermectin. Authors provide clinical progression details for
fluticasone (Table S3, Figure S5) and fluvoxamine (eFigure 3), but not for ivermectin. This may be related to authors
not reporting any of the pre-specified primary outcomes — the same table would reveal 2 of the 3 pre-specifed
primary outcome results.

COVID-19 mortality/hospitalization not reported. Authors only report all-cause mortality and hospitalization. Notably,
the baseline hospitalization and mortality rate for non-COVID-19 causes may account for the death and many of the
hospitalizations. This may also explain why authors report only 28 day mortality/hospitalization in violation of the
protocol where the primary outcomes specify 14 days 579. Additionally, adverse events show only one case of
aggravated COVID-19 pneumonia for ivermectin, versus 3 for placebo.

Many pre-specified outcomes missing. Authors do not report 565:

• OR describing the overall difference in symptoms and clinical events over 14 days (primary outcome)

• Overall clinical progression OR (only specific day 7, 14, 28 values are provided)

• Time to first urgent care, emergency care, hospitalization or death

• Risk and time to event for each component of the composite

• Mean and median time to symptom freedom

• Overall QOL OR

• Day 7, 14, 28, 90 QOL OR

• Mean difference in QOL scores at day 7, 14, 28, 90

• Mean and median time to symptom resolution (only a new sustained resolution measure is reported, which is not in
the protocol)
• Day 90 mean and median symptom count

Full protocol unavailable before October 2022. The pre-specified protocol 565 is missing the appendix which includes
contraindications, exclusions, formulation, appearance, packaging, dispensing, dosing, and dose rationale.

IDMC not independent, extreme conflict of interest. The IDMC vice chair was reportedly on the NIH panel that did not
recommend treatment despite strong evidence, and provided no quantitative analysis, no reference to the majority of
the research, and no updates for new research for a very long period 581. While not reviewing most of the evidence, the
panel concluded that there was "insufficient evidence".

Reported primary outcome low relevance. The reported primary outcome (which matches neither the trial
registration or the protocol) is of relatively low relevance being based on sustained absence of all symptoms, where
symptoms includes many things that may be found after viral clearance and may be unrelated to COVID-19, including
fatigue, headache, and cough (which may remain for some time). Authors may have searched for the outcome that
shows the least benefit. The 3-day sustained definition further adds two days for all participants, reducing efficacy.
Authors should report data for more significant symptoms such as dyspnea, fever, and loss of sense of taste/smell.

Shipping and PCR delays largely enforce late treatment. Authors required positive PCR before randomization, and
shipped medication to participants. The delay before PCR results become positive, delay in receiving PCR results, and
the shipping delay largely ensure that patients will not be treated early.

Very slow shipping. While one day or faster shipping should have been possible (~$11,000 funding per patient 582),
≤
the shipping delays in this trial appear to be very long based on the 7 days inclusion criterion and subgroup analysis
up to 13 days. One participant in the ivm-600 arm shared their experience showing 6 days from signing up until arrival
of the medication, resulting in a total of 11 days treatment delay 583. COVID-19 is an acute disease (which may or may
not be mild). Participants cannot be expected to wait 1-2 days or longer for treatment. Chances are that patients feel
better by the time medication arrives and do not take the medication, which may explain why adherence is not
reported, or their condition became worse and they found alternative immediate care elsewhere.

Blinding failure. The placebo arm included multiple regimens matching different treatment arms, hence some
participants will know they are not in the ivermectin arm, and others will know that there is a higher probability of
them being in the ivermectin arm than the placebo arm. This may be more important given the politicization in the
study country. The fluticasone arm and matching placebo use an inhaler, the fluvoxamine arm uses 10 days treatment.
Matched placebo analysis should be provided.

Extreme conflicts of interest. This trial has extreme conflicts of interest, being funded by an organization that chose
not to recommend treatment while providing no quantitative analysis, no reference to the majority of the research, and
no updates for new research for a very long period 581. Further, a majority of the panel providing the recommendation
has major conflicts of interest 581. Also see [Link] (E), [Link] (F). The ACTIV executive
committee was chaired by employees of J&J and NIH, and is now chaired by employees of Pfizer and NIH. Other
members of the committee are from NIAID (Dr. Fauci), FDA, and Pfizer 569,586.

Treatment delay-response relationship. Subgroup results for treatment delays 13, 11, 9, 7, and 5 show monotonically
improving results (less than 1% probability due to chance). ≤3 days may have very few patients, and is within
confidence limits for monotonically improving results. Improved efficacy for earlier treatment matches extensive
results for ivermectin and other COVID-19 treatments 587, however authors ignore this trend, claiming only a lack of
statistical significance for one specific binary threshold (which may have few patients on one side), and authors have
not initiated an early treatment trial.

Asymptomatic patients included. Study inclusion required >2 symptoms, however the subgroup analysis includes
109 patients with no symptoms, where results favored placebo. The primary outcome may reach statistical
significance without these patients.

Disingenuous conclusion. The conclusion states that treatment did not lower mortality of hospitalization, however it
is impossible to lower zero mortality. While authors do not indicate COVID-19 versus other hospitalization, statistically
significant reduction in hospitalization would require at minimum 79% efficacy, but for COVID-19 hospitalization it is
likely impossible based on expected non-COVID-19 hospitalizations. The trial is underpowered by design due to
selection of a low-risk population. Note that among the 90 severe cases, statistically significant efficacy is reported.

Significant missing data, not mentioned in paper. The paper does not mention missing data, however in the
presentation 568 (@44:20) authors report close to 10% missing survey data. One author indicates there was less then
10% missing survey data through day 14. However, the presentation also shows clinical progression graphs (@22:10)
that contradict this, showing 650/614 patients at day 14, which is over 20% missing data.

Statistically significant efficacy for severe patients removed. The statistically significant HR 1.86 [1.10-3.16] efficacy
for severe patients at baseline (using the post-hoc primary outcome) was noted in the text of the preprint 566, but has
been deleted in the journal version (only seen in the appendix eFigure 3).

Statistical analysis plan dated after trial end. The statistical analysis plan included with the journal paper is dated
after the end of the trial.

31% more severe cases in the ivermectin arm. There were 31% more severe cases in the ivermectin arm at baseline
(39 control vs. 51 ivermectin).

Many conflicting exclusion counts. Comparing the two versions of the 600µg/kg paper shows many conflicts in
excluded patients. 10 had a drug allergy to ivermectin in the first while only 7 did in the second. 11 were on warfarin in
the first version while only 4 were in the second version. 9 were hospitalized in the last 10 days in the first version
while only one was in the second version. 7 had current use of ivermectin in the first version while only 4 had current
or recent use in the second version. The second version claims 78 were exluded for symptom onset >7 days which is
not in the first version, and both versions show patients up to 10 days from onset included (eFigure 2). In the second
version, 17 fewer patients were eligible but elected not to continue.

Population incorrect. The visual abstract reports the population as patients experiencing two or more symptoms for 7
days or less. This is incorrect and refers to the time of enrollment, not the time of intervention. The study actually
includes a subgroup of patients 13 days from onset, and 107 patients that had no symptoms at baseline (eFigure 3).

Early treatment incorrect. The abstract and paper claim to study "treatment of early mild to moderate COVID-19." This
is incorrect, treatment was very late, median 6 days, 25+% 8+ days, and with subgroup results up to 13 days. For
influenza and oseltamivir or baloxavir, treatment is typically considered early within 24-48 hours 588.

Author claims results from 653 researchers should be censored for false information. 64 studies by 653 scientists
report statistically significant positive results for ivermectin treatment of COVID-19 505. One author claimed that a
report of positive results is "disinformation" and distributed a request to report and censor the author 506-508. While
discussion is warranted for all studies, a call for censorship of results is extreme and raises questions. Author provides
no basis for the results of the 653 scientists being wrong and warranting of censorship, and there is no indication that
author has even read most of the studies. Author cherry-picked two of 105 studies, (COVID-OUT and ACTIV-6 125,126,
both very high COI studies with an extensive list of issues and very delayed treatment) and claimed that "no benefit of
ivermectin was observed" 509. In addition to ignoring the 64 studies reporting statistically significant positive results,
ACTIV-6 510 reported a posterior probability that ivermectin is effective of 99%, 98%, and 97% for mean time unwell,
clinical progression @14 days, and clinical progression @7 days (even though none of the pre-specified primary
outcomes were reported, and noting that these preprint results were changed without explanation), and COVID-OUT
showed 61% lower hospitalization with ivermectin vs. placebo (not including metformin), although this was not
reported.

Bias due to false positive antigen tests. Authors accept positive antigen tests for enrollment, where the false positive
rate varies depending on the prevalence of COVID-19. If the false positive rate significantly affects the results, we
would expect the observed efficacy to vary with COVID-19 prevalence, with lower prevalence leading to higher false
positives leading to lower observed efficacy (as more patients did not actually have COVID-19). The change in COVID-
19 prevalence and efficacy over time follows this pattern in both the 400μg/kg and 600μg/kg arms. Results may be
significantly affected by the inclusion of patients that do not have COVID-19 but had false positive antigen tests 589.
Participant pickup delay. A paper on the operation of the trial 431 reveals that delivery was increasingly made to
centralized pickup locations and not directly to the participant. Authors indicate they use shipping logs and participant
notification of drug receipt. This is unclear because if delivery was based on participant confirmation there would be
no need to determine delivery based on shipping logs. This suggests that in at least some cases, delivery time may
not have accounted for the time for participant pickup. Therefore, the actual treatment delay may be even longer than
reported. This information was not disclosed previously.

Randomization failure. The treatment and control groups were drawn from different populations. Patients were
allowed to select which medication they would like to test, while the control group contains patients assigned to other
medications, some of which specifically requested that medication 590. Additionally, drug-specific exclusions further
modify the populations.

Low risk patients. Authors focus on patients at low risk of COVID-19 severe outcomes, which ensures an
underpowered trial, with only one death which may not be due to COVID-19. All-cause mortality and hospitalization
become less meaningful, with a significant contribution from non-COVID-19 causes.

No adherence data or per-protocol analysis. Authors provide no adherence data. Non-adherence may de-power the
trial and may harm randomization.

Skeptical prior not justified. The skeptical prior, which reduces the observed efficacy in the post-hoc primary
outcome, is not justified based on the studies to date. The skeptical prior was pre-specified. Authors may argue that
the prior is justified because the trial was designed to avoid showing efficacy.

Missing symptom severity mismatch. The first version of the 600µg/kg paper reports that 2.4% of patients had
missing symptom severity (eFigure 4). In the second version 32% of the newly added patients are missing symptom
severity.

Not enough tablets provided. Participants were supplied 15 7mg tablets and instructed to take the number of tablets
to approximate 400μg/kg, however not enough tablets were provided for patients with higher weights, indicating that
higher risk patients received lower dosage. 41% of patients had BMI >30 and subgroups include BMI 50. In the journal
version authors confirm that 42% of patients exceeded 88kg and did not receive the intended dose.

Monotherapy with no SOC for most patients. Authors perform monotherapy and the standard of care for most
patients in the study country included no active treatments. Other treatments were very rare - remdesivir 0.3%,
monoclonal antibodies 3%, and paxlovid 0.1%. However, extensive and growing research shows greater and
synergistic benefits from polytherapy. Many studies use polytherapy and/or the standard of care includes multiple
active treatments.

Over 2x greater severe dyspnea at baseline for ivermectin. There was over 2x greater severe dyspnea in the
ivermectin arm at baseline (1.65% vs. 0.71%), which may be very important for analyzing mortality and
hospitalization. Notably, the opposite is the case for fluticasone. The ivermectin placebo arm has less severe dyspnea
than fluticasone, despite being larger.

Safety conclusion removed, suggests bias. Authors included the conclusion "Ivermectin at 400 μg/kg was safe and
without serious adverse events as compared with placebo" in the abstract 566. This was deleted in the JAMA paper 591.

Authors suggest high-income country healthcare is better, however almost all patients received no active SOC.
Authors suggest the operation in a high-income country with an associated healthcare system is a notable strength,
however the study country provided no active treatment for almost all patients in the study, in contrast to many lower
income countries that provide multiple treatments. Remdesivir, monoclonal antibodies, and paxlovid are very difficult
to obtain and rarely used for outpatients in the study country. High income countries also may have significantly
higher conflicts of interest.

Placebo unspecified. Authors do not specify placebo details, only that packaging was identical. If the tablets were not
identical, this would be an additional reason for blinding failure.
No breakdown of severe outcomes. Notably, no details are provided for the hospitalization and mortality events,
which may have been more likely among patients with extremely late treatment, or influenced by the higher baseline
severity in the ivermectin arm. No severe outcome results are provided for (relatively) early treatment.

Missing subgroup counts. No subgroup counts are provided for several subgroups including treatment delay, while
≤
they are provided for baseline symptoms and vaccination status. The number of patients with symptoms 3 days may
have been very small given the design of the trial. Authors suggest that there are no discrete categories to count the
number of participants. While the graph shows estimates from a smoothed model, there are discrete numbers of
participants in each group, for example patients treated within 3 days.

Overlapping fluticasone placebo shows very different event numbers. The ivermectin and fluticasone arms have
79% overlap in time (Jun 23, 2021 - Feb 4, 2022 vs. Aug 10, 2021 - Feb 12, 2022). The ivermectin placebo arm is 20%
larger, suggesting approximately 20% more events. However, hospitalization is 3x larger (9 vs. 3), and combined
hospitalization, urgent care, ER, and death is 2.2x larger (28 vs. 13).

Overlapping fluticasone placebo shows unexpected baseline numbers. The ivermectin and fluticasone arms have
79% overlap in time (Jun 23, 2021 - Feb 4, 2022 vs. Aug 10, 2021 - Feb 12, 2022). The ivermectin placebo arm is 20%
larger, suggesting approximately 20% more patients for each characteristic. However, ivermectin placebo has less
Latino patients than fluticasone and over 2x COPD patients.

Inconsistent calendar time subgroups. The calendar time subgroups for ivermectin and fluticasone are identical,
from Oct 15, 2021 to Feb 1, 2022, however these do not match the reported recruitment periods.

Outcome graph presented does not match either medication tested. In the ACTIV-6 presentation 568 (@9:22) an
outcome graph is shown, however there is no indication what treatment it is for. The deaths and hospitalizations do
not match those reported for either ivermectin or fluticasone.

Efficacy was higher over calendar time, which may reflect higher efficacy with more recent variants. Efficacy was
higher for vaccinated patients.

Data: Team comments:

Posterior probability ivermectin is effective: “No differences were observed in relief of

mild-to-moderate COVID-19
Mean time unwell: 99% symptoms” 568 (@24:22)
Clinical progression @14 days: 98%
Clinical progression @7 days: 97% “No evidence of improvement in time to
recovery” 569
565
All exceed the pre-specified threshold for superiority . (Clinical
progression results showing superiority in the preprint 566 have been "The posterior probability for treatment
changed without explanation). benefit did not meet prespecified
 thresholds for clinical events or on the
COVID Clinical Progression Scale" (in the
preprint)

What can be done better? This long list of issues details the flaws prohibiting any negative conclusion about early
treatment. In fact, the results are extremely positive given the conditions. Despite extreme and obvious measures used
to avoid showing efficacy, efficacy was still found. Running a better trial is a simple matter of avoiding the issues
above. How do you ensure early treatment with high-risk patients? One example would be pre-enrolling nursing home
patients, providing treatment packages in advance, and instructing local medical staff to initiate randomization,
treatment, and monitoring immediately on symptoms. This would likely be cheaper to run, and easily extended to also
study prophylaxis.

For additional issues see 570.

COVID-OUT.

Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19

COVID-OUT remote RCT, showing no significant differences compared to a combined metformin/placebo "control"
group. Results for other treatments are listed separately - metformin, fluvoxamine.

Authors include metformin patients in the control group, allowing details of adjustments to affect results. Using
standard treatment vs. placebo analysis shows 61% lower hospitalization, or 75% lower for patients with onset ≤5
days (not statistically significant with only 7 and 5 events). These results are not reported in the paper or the
supplementary appendix, readers need to request the data. Authors note that "hospitalization is perhaps the most
accurate and well-documented end point".

There are many major issues as detailed below. We provide more detailed analysis of this study due to widespread
incorrect press. Submit Updates or Corrections

Severity Issue

CRITICAL 1. Ivermectin vs. placebo analysis - 61% lower hospitalization

CRITICAL 2. Severity mismatch for ivermectin treatment but not for any other medication or control

CRITICAL 3. ER results unreliable, not related to symptoms

CRITICAL 4. Mismatch with reported death and symptoms

CRITICAL 5. Ivermectin vs. placebo symptoms consistent with efficacy

CRITICAL 6. Multiple outcomes missing, including time to recovery

CRITICAL 7. Hypoxemia results unreliable but prioritized

CRITICAL 8. Adverse events suggest authentic ivermectin not taken

CRITICAL 9. Major event counts differ between paper and registry

CRITICAL 10. Baseline data differs between paper and registry

CRITICAL 11. Control group includes metformin, adjustment protocol violation

CRITICAL 12. Primary outcome changes

CRITICAL 13. All 7 secondary outcomes deleted

14. Metformin/fluvoxamine conclusions opposite of Together Trial, but matching earlier studies
CRITICAL
on each team

CRITICAL 15. Author claims results from 653 researchers should be censored for false information

CRITICAL 16. Administration on an empty stomach

CRITICAL 17. Results delayed 6 months (including life-saving metformin results)

CRITICAL 18. Subject to participant fraud

SERIOUS 19. Fewer comorbidities for serious outcomes

 SERIOUS 20. Control arm results very different between treatments

SERIOUS 21. COVID-19 specific symptoms hidden in appendix

SERIOUS 22. Authors claim placebo is not better than the treatments

SERIOUS 23. Incorrect claim that no treatment reduced severity

SERIOUS 24. False conclusion

SERIOUS 25. Trial outcomes modified

SERIOUS 26. Very high percentage of missing data

SERIOUS 27. Medication delivery varied significantly

SERIOUS 28. Treatment 3 days for ivermectin, 14 days for metformin and fluvoxamine

SERIOUS 29. SAP dated after trial

SERIOUS 30. Test requirement and delivery prohibits early treatment

SERIOUS 31. Conclusion modified by journal

SERIOUS 32. Symptom results contradictory

SERIOUS 33. Adherence very low

SERIOUS 34. Inconsistent blinding statements

SERIOUS 35. Author indicates a best guess can be used for onset

MAJOR 36. Ivermectin from source chosen has shown lower efficacy

MAJOR 37. Highest mean age for ivermectin, lowest for placebo

MAJOR 38. Adherence subgroups analysed but not reported

UNKNOWN 39. Maximum symptom duration not clear

UNKNOWN 40. No discontinuation due to hospitalization for ivermectin

COMMENT 41. Authors indicate up to 5 day delay in real-world usage

Author responses
17. Results sent to the US government 592. Note most people live outside the US, and there was no action.
No response for all other items

Ivermectin vs. placebo analysis - 61% lower hospitalization. Authors include metformin patients in the control
group, allowing details of adjustments to affect results. Using standard treatment (ivermectin only) vs. placebo
analysis shows more favorable results for ivermectin, with 61% lower hospitalization, or 75% lower for patients with
≤
onset 5 days (not statistically significant with only 7 and 5 events). Authors note that "hospitalization is perhaps the
most accurate and well-documented end point".

Severity mismatch for ivermectin treatment but not for any other medication or control. The table shows the
percentage of patients reporting severe dyspnea for each active treatment and respective control. We expect that
patients reporting ER visits would be more likely to experience severe dyspnea. This is true for all cases except for
ivermectin treatment, suggesting unlucky randomization for ivermectin treatment, or a potential data error. The
percentages are with respect to the total number of patients reporting symptom data in each case.

Ivermectin Ivermectin Metformin Metformin Fluvoxamine Fluvoxamine

active control active control active control

ER 0.0% 9.1% 13.3% 10.0% 10.0% 14.3%

Non-
6.1% 6.9% 8.0% 7.8% 6.4% 8.4%
ER

ER results unreliable, not related to symptoms. Authors detail why the main hypoxemia results are unreliable,
however the ER results appear to be similarly uninformative. ER visits do not appear to be related to symptoms. The
mean total COVID-19 symptom score for patients reporting an ER visit is 55 compared to 56 for patients reporting no
ER visit (or hospitalization/death). Visualization of the ER patient symptoms raises the question of why most of them
went to the ER. Of the 26 patients reporting an ER visit and symptom data, only one ever reported severe dyspnea, 5
more reported at most moderate dyspnea, 11 more reported at most mild dyspnea, and 9 reported no dyspnea at any
time. ER patients were less likely to report severe or moderate dyspnea. The decision to go to the ER appears to be
more of a personal preference rather than based on symptoms. Patients that signed up for the trial may be especially
concerned about PASC for example, and seek help based on potential future problems rather than current symptoms.

Maximum dyspnea severity ER patients Non-ER/hosp./death patients

Severe 3.8% 6.5%

Moderate 19.2% 22.2%

D1 D14 D1 D14 D1 D14 D1 D14 D1 D14

D1 D14 D1 D14 D1 D14 D1 D14 D1 D14

D1 D14 D1 D14 D1 D14 D1 D14 D1 D14

D1 D14 D1 D14 D1 D14 D1 D14 D1 D14

D1 D14 D1 D14 D1 D14 D1 D14 D1 D14

D1 D14

Mismatch with reported death and symptoms. There was only one death for a patient that was treated very late (7
days). The patient was not hospitalized. The death is reported within 14 days, however the patient reported symptom
data for all 14 days, showing substantial recovery several days prior, with only 2 of 14 symptoms remaining and
reported as mild. Data suggests that the death was not due to COVID-19.
 D1 D14

Ivermectin vs. placebo symptoms consistent with efficacy. Authors include metformin patients in the control group,
allowing details of adjustments to affect results. Using standard treatment vs. placebo analysis gives the mean
COVID-19 symptom scores below, matching expectation for an effective treatment with the low-risk fast recovering
population (note that administration on an empty stomach is expected to delay the time when therapeutic effects may
be reached).

Multiple outcomes missing, including time to recovery. Multiple outcomes are missing, for example time to recovery
(where ACTIV-6 showed superiority of ivermectin): "Time to meaningful recovery (symptoms or severity improved by
one category and sustained for at least 36 hours)" (protocol page 91). Notably, the definition is less biased than the
ACTIV-6 definition, including improvement by one category, making allowance for mild fatigue and cough, and
requiring 36 hours sustained rather than 3 days. More notably, the result is not reported.

Hypoxemia results unreliable but prioritized. Authors detail why the hypoxemia results are unreliable 593 @28:30,
however they are still prioritized in the presentation, and included in the abstract without mentioning that these results
are unreliable.

Adverse events suggest authentic ivermectin not taken. Adverse events were notably not reported in the paper, other
than to note none were serious. Partial information is contained in Table S2 and Figure S5. Notably, there is no
significant increase for ivermectin for any of the expected side effects, in contrast to other trials, e.g. 525. These results
are unexpected if patients received and took authentic ivermectin at the dosage indicated. Adverse events have been
reported to [Link], which shows only one adverse avent (neuropathy) for all 410 ivermectin patients, which
does not match Table S2 594.

Major event counts differ between paper and registry. The main outcome event numbers are different between the
paper and the [Link] registry. Some differences are expected - clinicaltrials shows events for each arm while
the paper hides information by using control groups with other treatments instead of placebo comparisons. However,
expected matches are different. For example, the paper shows 8/652 hospitalization or death for metformin, while the
registry shows 18/652 for all treatment groups with metformin 594. It appears that authors attempted to submit the
combined data that hides the individual arm results (which show lower hospitalization for ivermectin versus placebo)
but their submission was not allowed and they subsequently submitted false data. For discussion see 595.

Baseline data differs between paper and registry. The baseline data is different between the paper and the
[Link] registry. For example, for ivermectin the paper shows 19/410 Asian patients, while the registry shows
13/410 594. For metformin, the numbers are 25/663 and 18/663.
Control group includes metformin, adjustment protocol violation. The "control" group includes patients receiving
metformin, which is known to be beneficial for COVID-19 596. Authors present adjusted results however they do not
appear to fully account for metformin efficacy. For example, the adjusted result for ivermectin ER/hosp./death is close
to the unadjusted result, while a greater difference would be expected based on the metformin efficacy reported
(which is not expected to be doubled in the metformin + ivermectin arm). The trial has 5 treatments arms, but is
presented as if there was 3, which adds complexity, makes the results subject to potential interactions between
treatments, and introduces the potential for investigator bias in adjustments. Notably, the protocol specifies primary
and secondary adjustments (page 74), and the paper reports only one set of adjustments, which matches neither the
primary or secondary adjustments in the protocol.

Primary outcome changes. The primary outcome was changed around and after the end of recruitment 597,598.

All 7 secondary outcomes deleted. All 7 secondary outcomes were deleted in the [Link] registry on April
18, 2023 598.

Metformin/fluvoxamine conclusions opposite of Together Trial, but matching earlier studies on each team. The
Together trial and COVID-OUT both tested metformin and fluvoxamine. Notably, they came to opposite conclusions. In
Together, authors found efficacy for fluvoxamine, but the metformin results were so negative that the trial was
terminated early. In COVID-OUT it was the opposite, authors (although not the journal editor) found efficacy for
metformin, while the fluvoxamine results were so negative that the trial was terminated early 504. Note that the
Together authors include researchers that found fluvoxamine effective in earlier studies, while the COVID-OUT authors
include researchers that found metformin effective in earlier studies.

Author claims results from 653 researchers should be censored for false information. 64 studies by 653 scientists
report statistically significant positive results for ivermectin treatment of COVID-19 505. One author claimed that a
report of positive results is "disinformation" and distributed a request to report and censor the author 506-508. While
discussion is warranted for all studies, a call for censorship of results is extreme and raises questions. Author provides
no basis for the results of the 653 scientists being wrong and warranting of censorship, and there is no indication that
author has even read most of the studies. Author cherry-picked two of 105 studies, (COVID-OUT and ACTIV-6 125,126,
both very high COI studies with an extensive list of issues and very delayed treatment) and claimed that "no benefit of
ivermectin was observed" 509. In addition to ignoring the 64 studies reporting statistically significant positive results,
ACTIV-6 510 reported a posterior probability that ivermectin is effective of 99%, 98%, and 97% for mean time unwell,
clinical progression @14 days, and clinical progression @7 days (even though none of the pre-specified primary
outcomes were reported, and noting that these preprint results were changed without explanation), and COVID-OUT
showed 61% lower hospitalization with ivermectin vs. placebo (not including metformin), although this was not
reported.

Administration on an empty stomach. Authors instructed patients to take ivermectin on an empty stomach, but other
treatments with food. Guzzo show that the plasma concentration of ivermectin is much higher when administered
with food (geometric mean AUC 2.6 times higher). "Ivermectin or matching placebo should be taken by mouth on an
empty stomach with water. 1 hour before or 2 hours after a meal. All other agents should be taken by mouth at the
end of a balanced snack or small meal."

Results delayed 6 months (including life-saving metformin results). Results were delayed for 6 months with no
explanation, with followup ending Feb 14, 2022. Results were not presented until July 8 599, and they were still not
available to the public due to a news embargo for over a month. Embargo and delay of clinical trial results during a
pandemic is not consistent with a goal of minimizing mortality and morbidity. Notably authors report very positive
results for metformin (although journal editors changed the conclusion as below).

Subject to participant fraud. The self-reported design and absence of professional medical examination opens this
kind of remote trial to participant fraud, which may be significant due to extreme politicization in the study country.
Participant fraud has been reported for two other remote trials with a shared author 430,431, involving submission of
fake surveys and repeated signups.

Fewer comorbidities for serious outcomes. Patients experiencing serious outcomes are expected to be more likely to
have comorbidities, however the opposite is seen.
 Outcome Comorbidity prevalence

Non-ER/hosp./death 53%

ER 45%

Hospitalization 12.5%

Death 0%

Control arm results very different between treatments. Control arm results are very different between treatments, for
example considering hospitalization/death, this was 1.0% for ivermectin treatment vs. 2.7% for metformin control,
however it was 1.3% for the ivermectin control. The metformin arm started earlier, however the difference in
outcomes is very large given that most patients are in the shared period.

COVID-19 specific symptoms hidden in appendix. Authors present results for all symptoms in Figure 2, and for
COVID-19 symptoms in the appendix Figure S4. Notably, the COVID-19 specific results are better for ivermectin and
especially for fluvoxamine.

Authors claim placebo is not better than the treatments. Authors state: Neither overall symptoms nor Covid-19–
specific symptoms were reduced faster with placebo than with any of the trial drugs. This may be true, Figure S4
shows symptoms were reduced faster with all treatments (with ivermectin and fluvoxamine showing greater
improvement than metformin), but the reverse claim is very unusual — placebo is not expected to be better. Note that
the graphs and data refer to the control groups including other treatments, while the statement refers to placebo only.

Incorrect claim that no treatment reduced severity. Authors claim that "None of the trial drugs resulted in a lower
severity of symptoms than identically matched placebo." The intended meaning — compared to the "control" groups
used, since that is the data reported — is incorrect, multiple results show lower severity in the treatment groups in
terms of the symptom scores and severity resulting in hospitalization. Individual results may not reach statistical
significance, however ER/hosp./death does in the larger metformin group.

False conclusion. Authors claim "None of the three medications that were evaluated prevented the occurrence of
hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19." Taking the literal
wording, this is false, there were no deaths with fluvoxamine. Taking the likely meaning (no treatment reduced
incidence of these events), this is false, reduced incidence is seen in several results (mostly without statistical
significance).

Trial outcomes modified. Trial outcomes were changed on January 20, 2022 600, and again on March 2, 2022 601.

Very high percentage of missing data. There is a very high percentage of missing data. 25% of patients have zero
symptom data reported for all 14 days in the data file. This does not match the paper which reports 20% of patients
did not contribute symptom data (Figure 2).

Medication delivery varied significantly. Medication delivery varied significantly over the trial. In this presentation 602,
author indicates that delivery was initially local, later via FedEx, was much slower in August, there were delays due to
team bandwidth issues, and they only realized they could use FedEx same day delivery in September.

Treatment 3 days for ivermectin, 14 days for metformin and fluvoxamine. Treatment was 14 days for metformin and
fluvoxamine, but only 3 days for ivermectin.

SAP dated after trial. The SAP is dated February 14, 2022, which authors note is one day before unblinding. However,
the protocol notes that the statisticians are unblinded: "There is one unblinded statistician with two unblinded
supporting statisticians on the study team", and "All analyses will be carried out by the un-blinded statisticians". The
protocol also notes that the SAP will be developed by unblinded statisticians in one case, and blinded in a second
case: "detailed statistical analysis plan will be developed by the unblinded statisticians", and "statistical analysis plan
will be developed by the blinded statistician."
Test requirement and delivery prohibits early treatment. The requirement for a positive test and delivery of
medication introduces substantial delay and largely excludes the possibility of early treatment. The protocol requires
verifiable results using a local laboratory standard which excludes most home antigen tests (supplementary data page
5). Note that the trial results do not generalize to real-world usage, where clinicians recommend treatment
immediately on symptoms.

Conclusion modified by journal. Author statements indicate that the conclusion was modified by the journal 603,604.

Symptom results contradictory. Authors consider only metformin results to be positive (the journal editor considers
none to be positive), however the symptom results in Figure S4 show the opposite: ivermectin and fluvoxamine show
faster improvement (without statistical significance), while no difference is seen for metformin.

Adherence very low. Adherence was very low, with 77% overall reporting 70+% adherence, and 85% for ivermectin
reporting 70+% adherence. An author has claimed 85% took all doses but that is contradicted by the 20% reported
"Total Interruption or Discontinuation" in Table S2. Numbers for 100% adherence are not provided.

Inconsistent blinding statements. Protocol page 12 states that "The research team statisticians will remain blinded",
while the supplementary data page 40 states that "There is one unblinded statistician with two unblinded supporting
statisticians on the study team".

Author indicates a best guess can be used for onset. One author suggests that investigators can use a "best guess"
if a patient gives a range for time of onset, which would allow a biased investigator to present an incorrect lower
average time from onset 605.

Ivermectin from source chosen has shown lower efficacy. Authors chose to source ivermectin from Edenbridge,
which ranked 7 out of 11 brands in In Vitro tests for antiparasitic efficacy 2, requiring 5 days compared to 2 days for
the best performing brand, and 3 days for 4 other brands.

Highest mean age for ivermectin, lowest for placebo. All treatment groups show the same median age (46) in the
paper, however the [Link] registry shows the mean ages, and the mean is notably higher in the ivermectin
only group (48) versus all other groups, suggesting a skew towards older patients specifically in the ivermectin only
group. The control median age for ivermectin is 45 in the paper, while the placebo mean age in the registry is 42, while
no other group has a mean age below 46. There is a large difference between the ivermectin and placebo mean ages
(48 vs. 42), which is hidden in the paper which shows median 46 vs. 45 ivermectin vs. control

Adherence subgroups analysed but not reported. Authors indicate they performed subgroup analysis by
adherence 593 @18:30, however these results have not been reported.

Maximum symptom duration not clear. The procol excludes patients with >7 days of symptoms, i.e. patients 7 days
from onset are included. The paper claims "less than 7 days" in one instance and "within 7 days" in another. The
presentation reports "<7 days" 593.

No discontinuation due to hospitalization for ivermectin. Table S2 shows 9 placebo patients discontinued treatment
due to hospitalization, compared to zero for ivermectin. While ivermectin patients only received 3 days treatment, they
received placebo tablets for the remaining days. If this number is only counting discontinuation during the first three
days, the result highlights that treatment was stopped before any patients were hospitalized. The protocol notes
"Study drug will be stopped at the time of hospitalization for any reason".

Authors indicate up to 5 day delay in real-world usage. Authors note up to 11 days treatment delay with a remote
clinical trial compared to up to 5 day for "real-world use" 593 @43:00, where the 5 days derives from testing and
medical system delays. However, logical real-world use, as used in many locations, is to have the treatment on hand
to take immediately.
López-Medina et al.

Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical
Trial

SEE ALSO
The Publication of Fraudulent Ivermectin Trials by the High Impact Medical Journals
The Potemkin Argument, Part VI: The Ballad of Lopez-Medina
More Fraud Uncovered In The Lopez-Medina Ivermectin Trial Published In JAMA

Phone survey based RCT with low risk patients, 200 ivermectin and 198 control, showing lower mortality, lower
disease progression, lower treatment escalation, and faster resolution of symptoms with treatment, without reaching
statistical significance. Authors find the results of this trial alone do not support the use of ivermectin. However the
effects are all positive, especially for serious outcomes which are unable to reach statistical significance with the very
small number of events in the low risk population.

An open letter, signed by >100 physicians, concluding this study is fatally flawed can be found at [Link].

With the low risk patient population, there is little room for improvement with an effective treatment - 59/57%
(IVM/control) recovered within the first 2 days to either "no symptoms" or "not hospitalized and no limitation of
activities"; 73/69% within 5 days. Less than 3% of all patients ever deteriorated.

The primary outcome was changed mid-trial, it was originally clinical deterioration, which is more meaningful, and
shows greater benefit. The new outcome of resolution of symptoms includes "not hospitalized and no limitation of
activities" as a negative outcome and is not very meaningful in terms of assessing how much treatment reduces
serious outcomes. Using this measure could completely invalidate results - for example a treatment that eliminates all
COVID-19 symptoms but has a temporary minor adverse event could be seen as worse.

Authors state that "preliminary reports of other randomized trials of ivermectin as treatment for COVID-19 with
positive results have not yet been published in peer-reviewed journals", however there were 8 peer-reviewed RCTs with
positive effects published prior to this paper(and 19 total peer-reviewed studies with positive effects).

Authors advised taking ivermectin on an empty stomach, reducing lung tissue concentration by ~2.5x 1.

76 patients were excluded due to control patients receiving ivermectin. However, there was a similar percentage of
adverse events like diarrhea, nausea, and abdominal pain in both treatment and control groups. These are potential
non-serious side effects of treatment and suggest that it is possible that many more control patients received some
kind of treatment.

No pre-registered protocol documentation has been found, the same organization is associated with other COVID
trials with extremely high financial conflicts of interest with this trial, and the official registration shows a different
code to the paper (IVE-PA_CEIP vs. PI-CEP-1390) 607.

Ivermectin was widely used in the population and available OTC at the time of the study. The paper claims that
patients were excluded if they used ivermectin within the last 5 days, however this conflicts with the trial registration
which shows that use of ivermectin within the previous 2 days was an exclusion criterion. A post-hoc change to 5 days
was made on December 16, 2020 608,609, which is after enrollment ended (July 15 to November 30, 2020). Ivermectin
may retain efficacy far beyond 2 or 5 days. Note that, with 75% of patients having symptoms for 4+ days at baseline,
the trial registration allows patients to take ivermectin for a few days after symptoms and then join the placebo arm
two days later 610.

The study reports 11.5% blurry vision with ivermectin, consistent with known side effects. However, the study also
reports 11.6% blurry vision in the placebo group, which is not consistent with expected side effects of placebo. One
possible explanation is that many placebo patients received ivermectin.
This study reportedly has an ethical issue whereby participants were told the study drug was "D11AX22" 611. The
editor-in-chief of JAMA initially offered to help with this issue, but later indicated that "JAMA does not review consent
forms", however the lead author reportedly confirmed the issue 612-614.

The study protocol specifically allows "the use of other treatments outside of clinical trials". The paper provides no
information on what other treatments were used, but other treatments were commonly used at the time. Additionally,
the control group did about 5x better than anticipated for deterioration, also suggesting that the control patients used
some kind of treatment. Patients that enroll in such a study may be more likely to learn about and use other
treatments, especially since they do not know if they are receiving the study medication.

The study protocol was amended 4 times. Amendments 2-4 are provided but amendment 1 is missing. Amendment 2
increased the inclusion criteria to within 7 days of onset, including more later stage patients and reducing the
expected effectiveness. The trial protocol lists “the duration of supplemental oxygen” as an outcome but the results
for this outcome are missing.

RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that
believe they need treatment are more likely to decline participation and take the intervention 357, i.e., RCTs are more
likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical
pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin
was available OTC and very widely known and used.

Grants and/or personal fees, including in some cases during the conduct of the study, were provided by Sanofi
Pasteur, GlaxoSmithKline, Janssen, Merck, and Gilead. For more details see 615.

For other confounding issues see 616 and additional issues can be found in the comments of the article 617. Re-analysis
of the raw data has been reported to show a significant positive effect 618.

Vallejos et al.

Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind,

placebo-controlled trial

SEE ALSO
The Publication of Fraudulent Ivermectin Trials by the High Impact Medical Journals

With only 7% hospitalization, this trial is underpowered. The trial primarily includes low-risk patients that recover
quickly without treatment, leaving minimal room for improvement with treatment. 74 patients had symptoms for >= 7
days. Among the 7 patients requiring ventilation, authors note that the earlier requirement in the ivermectin group may
be due to those patients having higher severity at baseline. However, authors know the answer to this - it is unclear
why it is not reported. There were more adverse events in the placebo group than the ivermectin group, suggesting a
possible issue with dispensing or non-trial medication usage. 25+% of patients were hospitalized within 2/3 days for
the placebo/treatment groups (Figure S2).

The companion prophylaxis study IVERCOR PREP has reported results in the press and an online presentation 619,620,
however these results have not yet been formally published. The prophylaxis study results are very positive and
statistically significant, and would be expected to receive priority publication due to the predicted impact on the
pandemic and confirmation of previous prophylaxis studies. The lack of formal publication suggests a negative
publication bias that may be due to politicization in the authors' location.

Authors pre-specify multivariate analysis but do not present it, however multivariate analysis could significantly
change the results. Consider for example if just a few extra patients in the ivermectin group were in severe condition
based on baseline SpO2. The lower mean SpO2 in the ivermectin group, and the shorter time to ventilation, are
consistent with this being the case. Additionally, there are 14% more male patients in the ivermectin group.
An extremely large percentage of patients (55%) were excluded based on ivermectin use in the last 7 days. However,
ivermectin may retain efficacy much longer (for example antiparasitic activity may persist for months 367). A significant
number of patients may also misrepresent their prior and future usage — the population is clearly aware of ivermectin,
and patients with progressing disease may be motivated to take it, knowing that they may be in the control group.
Another report states that 12,000 patients were excluded for recent use of ivermectin 621).

RCTs have a fundamental bias against finding an effect for interventions that are widely available — patients that
believe they need treatment are more likely to decline participation and take the intervention 357, i.e., RCTs are more
likely to enroll low-risk participants that do not need treatment to recover (this does not apply to the typical
pharmaceutical trial of a new drug that is otherwise unavailable). This trial was run in a community where ivermectin
was very widely known and used.

For other issues see [Link] (K).

Beltran Gonzalez et al.

Efficacy and Safety of Ivermectin and Hydroxychloroquine in Patients with Severe COVID-19: A Randomized Controlled
Trial

Another study reports results on a larger group of patients in the same hospital, showing ivermectin mortality RR 0.81
[0.53-1.24] 623.

Questions have been raised about this study and the early termination of the study and discontinuation of treatments,
because the hospital statistics show a dramatically lower (~75%) case fatality rate during the period of the study 624
(data from [Link]).

Date Cases Deaths CFR

3/2020 2 1 50%

4/2020 4 1 25%

5/2020 13 1 8%

6/2020 37 2 5%

7/2020 65 5 8%

8/2020 79 23 29%

9/2020 54 12 22%

10/2020 62 21 34%

11/2020 80 26 33%

12/2020 41 13 32%

Several other inconsistencies have been reported 144.

Although the data from this study is reported to be available and has been shared with an anti-treatment group,
independent researchers have been unable to obtain the data for verification 144,626.

Popp et al.

Ivermectin for preventing and treating COVID-19

SEE ALSO
 The Publication of Fraudulent Ivermectin Meta-Analyses and Editorials by the High-Impact Medical Journals
The uses and abuses of systematic reviews: the case of ivermectin in Covid-19
Rapid Response: Ivermectin in Covid-19

This meta analysis is designed to exclude most studies. Authors select a small subset of studies, with a majority of
results based on only 1 or 2 studies. Authors split up studies which dilutes the effects and results in a lack of
statistical significance for most outcomes. Authors perform 16+ meta analyses with very few studies in each analysis,
and do not combine the evidence from all studies. However, we can consider the probability of the observed results
across all outcomes.

Authors find positive results for 11 of 12 primary efficacy outcomes with events, or 16 of 18 including secondary
outcomes. One of the primary outcomes and two of the secondary outcomes show statistically significant
improvements in isolation. If we assume independence, the probability that 11+ of 12 primary efficacy outcomes were
positive for an ineffective treatment is p = 0.003. For 16+ of 18 outcomes we get p = 0.0007. This simple analysis does
not take into account the magnitude of positive effects, or the dependence due to some studies contributing multiple
outcomes, however observation suggests that a full analysis of the combined evidence is likely to show efficacy.

The study is entirely retrospective in the current version. The protocol is dated April 20, 2021, and the most recent
study included is from March 9, 2021. The protocol was modified after publication in order to include a close to null
result (Beltran Gonzalez "patients discharged without respiratory deterioration or death at 28 days"), so the current
protocol is dated July 28, 2021.

Authors excluded many studies by requiring results at a specific time, for example mortality, ventilation, etc. required
results at exactly 28 days. Authors excluded all prophylaxis studies by requiring results at exactly 14 days.

Studies comparing with other medications were excluded, however these studies confirm efficacy of ivermectin. The
only case where they could overstate the efficacy of ivermectin is if the other medication was harmful. There is some
evidence of this for excessive dosage/very late stage use, however that does not apply to any of the studies here.

Studies using combined treatment were excluded, even when it is known that the other components have minimal or
no effect. 3 of 4 RCTs with combined treatment use doxycycline in addition, which was shown to have no significant
effect in Butler (B). Other studies were excluded by requiring PCR confirmation.

Authors are inconsistent regarding active comparators. They state that hydroxychloroquine “does not work”, yet
excluded trials comparing ivermectin to a drug they hold to be inactive. On the other hand, remdesivir was an
acceptable comparator, although it is considered to be effective standard of care in some locations 235.

Authors fail to recognize that Risk of Bias (RoB) domains such as blinding are far less important for the objective
outcome of mortality.

Authors include Beltran Gonzalez as "moderate" COVID-19, however patients in this study were in severe condition
(baseline SatO2 83).

Fordham summarizes several problems:

• unsupported assertions of adverse reactions to ivermectin, and the outdated claim that unsafe dosing would be
needed to be effective;

• a demand for PCR or antigen testing, without analysis of reliability and not universally available even in developed
countries at the start of the pandemic;

• contradictions in the exclusion criteria, including placebo and approved SoC comparators, but rejecting
hydroxychloroquine, though held to be ineffective (and an approved SoC in some jurisdictions);

• inclusion of “deemed active” comparators whilst excluding “potentially active” ones;

• exclusion of combination therapies, though the norm among practising clinicians;

• the rejection of other than RCTs when the objective is a “complete evidence profile”;
• arbitrary time-points for outcome measures, excluding non-compliant trials;

• fragmentation of data by location of care under varying hospitalisation criteria;

• the resulting focus on a small fraction of the available clinical evidence, with most comparisons based on single
studies with no meta-analysis possible;

• a resulting inpatient mortality comparison with fewer patients than a June 2020 confounder-matched study;

• no conclusion on the headline mortality outcome, when multiple lines of evidence from elsewhere (including the
WHO) point to significant mortality advantage.

Cochrane was reputable in the past, but is now controlled by pharmaceutical interests. For example, see the news
related to the expulsion of founder Dr. Gøtzsche and the associated mass resignation of board members in protest 628-
630
. For another example of bias see [Link].

The BiRD group gave the following early comment: "Yesterday’s Cochrane review surprisingly doesn’t take a pragmatic
approach comparing ivermectin versus no ivermectin, like in the majority of other existing reviews. It uses a granular
approach similar to WHO’s and the flawed Roman et al paper, splitting studies up and thereby diluting effects.
Consequently, the uncertain conclusions add nothing to the evidence base. A further obfuscation of the evidence on
ivermectin and an example of research waste. Funding conflicts of interests of the authors and of the journal
concerned should be examined."

For dicussion of issues added in the updated version see Popp.

Revisions

Please submit updates and corrections at [Link]

7/22: We added Wijewickrema.

6/13: We added Hashmi.

5/3: We added Varnaseri.

4/18: We added Shahin, Gao.

3/30: Updated discussion of pooled outcomes.

3/29: We added Siripongboonsitti.

3/9: Discussion updates.

2/29: We added Hayward.

2/23: RCT discussion updates.

2/12: We added Oranu.

1/24/2024: We updated the introduction.

12/27: We added Mikamo.

9/23: Preclinical updates.

8/10: Preclinical updates.

7/25: We added Osati.

7/17: We updated the introduction.

6/11: We added Llenas-García.

6/6: We added Wada.

4/21: We added Munir.

4/18: We updated Desort-Henin to the published version.

2/23: We updated Schilling to the journal version.

2/2: Scott Alexander response updates.

1/6/2023: We added Desort-Henin, Sarojvisut.

12/20: We updated the discussion of heterogeneity and RCTs.

12/15: We added the ACTIV-6 600µg/kg arm Naggie (B).

12/9: We updated de la Rocha to the journal version.

10/27: We added Ochoa-Jaramillo.

10/21: We updated the ACTIV-6 trial to the journal version.

9/23: We added Aref (B).

9/9: We added Qadeer.

8/18: We added Bramante.

7/26: We added Schilling.

6/24: We added Mirahmadizadeh.

6/16: We updated the ACTIV-6 analysis.

6/16: We added Rezai, Rezai (B).

6/12: We added Naggie.

6/1: We updated the Together Trial analysis.

5/30: We added George.

5/30: We updated the Together Trial analysis.

5/27: We added de la Rocha.

4/25: SSC discussion updates.

4/17: We added a section on preclinical research.

4/16: We added discussion of the NIH recommendation.

4/9: We updated the Together Trial analysis.

4/8: We added Ravikirti.

4/5: We added preprint discussion based on Zeraatkar, and updated the Together Trial analysis.

4/2: We updated the Together Trial analysis.

3/30: We updated Reis to the journal version.

3/21: Strongyloides discussion updates.

3/3: We updated Beltran Gonzalez to the journal version.

3/2: We added Soto.

2/28: We added Efimenko.

2/25: We added Thairu.

2/23: We updated Mayer to the journal version.

2/18: We updated Lim to the journal version.

2/2: We added Manomaipiboon.

1/28: We added de Jesús Ascencio-Montiel.

1/21: We added Zubair.

1/17: We added an explanation of why funnel plot analysis is not valid in this case.

1/16: We added RCT viral clearance analysis and corrected missing symptomatic case results in the case analysis.
1/15: We updated Kerr to the journal version.

1/15: We corrected hospitalization group sizes in Buonfrate.

1/13: We added Abbas, Baguma.

1/11: We updated Kerr to the latest results, and added discussion of Beltran Gonzalez.

1/7/2022: We updated Buonfrate to the journal version, and we updated Kerr to the latest results.

12/31: We added Shimizu.

12/29: We added Mustafa.

12/26: We updated Kerr to the revised version of the paper.

12/16: We added Jamir.

12/11: We added Kerr.

12/8: We added analysis of the number of independent research groups reporting statistically significant positive
results.

12/5: We added Ferreira.

12/5: We added Rezk.

12/3: A note on Bernigaud: continuity correction uses the reciprocal of the contrasting arm Sweeting, as detailed in
the appendix. We previously limited the size of the control group when showing the total number of patients, however
this was confusing for people that did not read the details, as discussed below. The full group size has always been
used when computing the RR.

12/1: Strongyloides discussion updates.

11/30: We corrected Ghauri to use the event counts.

11/24: We added Ozer.

11/24: SSC discussion updates.

11/21: Strongyloides discussion updates.

11/20: Strongyloides discussion updates.

11/19: We added analysis by strongyloides prevalence, and updated it to match the revised classification used in the
comparable analysis.

11/19: We added additional exclusion analyses in the supplementary data.

11/18: We incorrectly included López-Medina as a study not reporting use of steroids, however they report 6% usage
in the control group.

11/18: We added Samajdar.

11/17: SSC response.

11/16: Discussion updates.

11/12: We now show the number of studies reporting statistically significant results for any outcome, primary
outcomes, and the most serious outcome.

11/9: Discussion updates.

11/5: We added discussion of strongyloides, comparison with the recent molnupiravir approval, and notes on
recruitment for remote outpatient delayed treatment trials.

11/3: We added Lim.

11/3: Discussion updates.

10/29: Discussion updates including GMK vitamin D analysis.

10/28: Discussion updates.

10/26: We updated the GMK response.

10/24: We added additional exclusion analyses for individual outcomes.

10/21: We added Borody.

10/19: Discussion updates.

10/18: Ghauri was updated to the journal version.

10/16: We added a summary plot for all results.

10/13: We added primary outcome analysis and additional exclusion analyses. Niaee et al. has been reported as
pending retraction and has been removed. 10/27 update: the journal has reported that this is incorrect — no
retraction is pending.

10/11: Discussion updates. Niaee et al. exclusion. Updates to the study notes including discussion of Vallejos et al.
and additional issues in the Together Trial. Discussion of inherent bias in RCTs for widely available interventions.

10/8: Discussion updates.

10/7: Samaha et al. has been reported as pending retraction and has been removed. There was no significant change
in the results.

10/4: Merck discussion updates.

9/29: We corrected a display error causing a few points to be missing in Figure 3.

9/27: We added Mayer.

9/24: We added a graph of variants over time for the Together Trial discussion and corrected outcome discussion for
Popp et al.

9/22: Discussion updates.

9/20: Discussion updates.

9/18: We added Buonfrate, and updated discussion of the Together Trial.

9/17: We added study notes.

9/15: Discussion updates.

9/14: FDA discussion updates.

9/9: We added sensitivity analysis to compute the minimum number of studies that need to be excluded in order to
avoid showing efficacy. Discussion updates.

9/7: Discussion updates.

9/6: We corrected Espitia-Hernandez to use the reported recovery time and added missing recovery and viral
clearance results.

9/3: We updated discussion and excluded Carvallo et al. in the exclusion analysis.

8/27: We updated Morgenstern (B) with the journal version of the article.

8/26: We updated Mohan with the journal version of the article.

8/16: We updated Reis with event counts.

8/15: We updated discussion and made the abstract more concise.

8/12: We added Reis, Elavarasi.

8/8: We updated discussion in the responses.

8/6: We updated Behera (B) with the journal version of the article.

8/5: We added Mondal.

8/4: We added discussion of the FDA recommendation.

8/3: We added discussion in the responses section.

8/2: We added analysis restricted to serious outcomes and analysis restricted to recovery, and we added discussion in
the responses section.
7/31: We added discussion in the responses section related to in vitro evidence and therapeutic concentrations.

7/29: We added discussion in the responses section.

7/20: We updated Hashim with the journal version of the article.

7/16: We updated Ravikirti (B) with the journal version of the article.

7/15: Elgazzar et al. was withdrawn by the preprint server and has been removed.

7/9: We added Hazan (B).

7/8: We updated Cadegiani to the journal version.

7/6: We previously limited the size of the control group for Bernigaud when calculating the total number of patients,
however this was confusing for many people that did not read the details. We now show the original counts and note
the larger size of the control group in the text.

7/3: We added Vallejos.

7/2: We updated Niaee et al. to the journal version.

6/21: We added more information to the abstract.

6/19: We updated Bryant to the journal version.

6/19: Beltran Gonzalez was incorrectly included in the peer-reviewed analysis.

6/18: We added Krolewiecki.

6/15: We added Aref.

6/7: We added Hariyanto.

6/5: We added Ahsan.

6/2: We added Abd-Elsalam.

5/31: Biber was updated to the preprint.

5/26: Samaha et al. was updated to the journal version.

5/18: We added analysis of Merck's recommendation.

5/17: We added Szente Fonseca.

5/15: We updated the discussion of the WHO analysis.

5/13: We updated Mahmud to the journal version.

5/10: We added Faisal.

5/10: We added additional information in the abstract.

5/8: We added Merino.

5/7: We updated Shahbaznejad to the journal version, which includes additional outcomes not reported earlier.

5/6: We updated Chahla to the Research Square preprint.

5/6: We added a comparison of CDC recommendations.

5/6: We added mechanical ventilation and ICU admission analysis.

5/6: We updated discussion based on peer review including discussion of heterogeneity, exclusion based sensitivity
analysis, and search criteria.

5/5: We updated Okumuş to the journal paper.

5/5: We previously limited the size of the control group in Bernigaud to be the same as the treatment group for
calculation of the total number of patients. This is now also reflected and noted in the forest plots.

5/4: We added Loue.

4/30: We added analysis of the WHO meta analysis and updated Kory to the journal version.

4/28: We added the WHO meta analysis results for comparison.

4/27: We added analysis restricted to hospitalization results and a comparison with the evidence base used in the
approval of other COVID-19 treatments.

4/26: We added notes on heterogeneity.

4/25: We updated Biber to the latest results reported at the International Ivermectin for Covid Conference.

4/18: We updated Morgenstern to the preprint.

4/16: We added Morgenstern.

4/14: We added Seet.

4/10: We added Kishoria.

4/9: We corrected a duplicate entry for Bukhari.

4/7: We identified studies where minimal detail is currently available in the forest plots.

4/5: We added Mourya.

4/4: We added event counts to the forest plots.

3/31: We updated Chahla (B) to the preprint.

3/30: We added Chahla.

3/28: We highlighted and added discussion for studies that use combined treatments.

3/26: We added Tanioka.

3/25: We added Huvemek.

3/17: We added Nardelli.

3/12: We added Bryant, Roy.

3/10: We added Pott-Junior.

3/6: We added Chowdhury and we identify studies that compare with another treatment.

3/5: We added discussion of pooled effects (we show both pooled effects and individual outcome results).

3/4: We added López-Medina, and we added more information in the abstract.

3/3: We updated the graphs to indicate the time period for the dosage column, now showing the dosage over one
month for prophylaxis and over four days for other studies.

3/2: We updated IVERCOR PREP with the latest results Vallejos (B).

2/27: We added analysis restricted to peer reviewed studies.

2/24: We added a comparison of the evidence base and WHO approval status for the use of ivermectin with scabies
and COVID-19. We updated Okumuş with the Research Square preprint.

2/23: We added Beltran Gonzalez.

2/18: We updated Babalola to the journal version of the paper.

2/17: We added Elalfy, and we added analysis restricted to viral clearance outcomes, and mortality results restricted
to RCTs.

2/16: We updated Behera to the journal version of the paper.

2/15: We added Behera (B).

2/14: We added analysis restricted to COVID-19 case outcomes, and we added additional results in the abstract.

2/12: We added Biber.

2/11: We added more details on the analysis of prospective vs. retrospective studies.

2/10: We added Lima-Morales.

2/5: We updated Bukhari to the preprint.

2/2: We added Mohan.

1/26: We updated Shouman (B) with the journal version of the article.

1/25: We updated IVERCOR PREP with the recently released results.

1/19: We added Shahbaznejad and Samaha et al. Chaccour (B) was updated to the journal version of the paper.

1/17: We added Bukhari.

1/16: We moved the analysis with exclusions to the main text, and added additional commentary.

1/15: We added the effect measured for each study in the forest plots.

1/12: We added Okumuş.

1/11: We added Chahla (B).

1/10: We put all prophylaxis studies in a single group.

1/9: We added Ravikirti (B). Due to the much larger size of the control group in Bernigaud, we limited the size of the
control group to be the same as the treatment group for calculation of the total number of patients.

1/7: We added direct links to the study details in the chronological plots.

1/6: We added Babalola.

1/5: We added direct links to the study details in the forest plots.

1/2/2021: We added dosage information and we added the number of patients to the forest plots.

12/31: We added additional details about the studies in the appendix.

12/29: We added meta analysis excluding late treatment.

12/27: We added the total number of authors and patients.

12/26: We added IVERCOR PREP, Carvallo (B).

12/17: We added Alam.

12/16: We added Ghauri.

12/11: We added Soto-Becerra.

12/7: We added Chaccour (B).

12/2: We added Ahmed.

11/26/2020: Initial revision.

Appendix 1. Methods and Data

We perform ongoing searches of PubMed, medRxiv, Europe PMC, [Link], The Cochrane Library, Google
Scholar, Research Square, ScienceDirect, Oxford University Press, the reference lists of other studies and meta-
analyses, and submissions to the site [Link], which regularly receives submissions of studies upon publication.
Search terms are ivermectin and COVID-19 or SARS-CoV-2. Automated searches are performed twice daily, with all
matches reviewed for inclusion. All studies regarding the use of ivermectin for COVID-19 that report a comparison
with a control group are included in the main analysis. Sensitivity analysis is performed, excluding studies with major
issues, epidemiological studies, and studies with minimal available information. This is a living analysis and is
updated regularly.

We extracted effect sizes and associated data from all studies. If studies report multiple kinds of effects then the most
serious outcome is used in pooled analysis, while other outcomes are included in the outcome specific analyses. For
example, if effects for mortality and cases are both reported, the effect for mortality is used, this may be different to
the effect that a study focused on. If symptomatic results are reported at multiple times, we used the latest time, for
example if mortality results are provided at 14 days and 28 days, the results at 28 days have preference. Mortality
alone is preferred over combined outcomes. Outcomes with zero events in both arms are not used, the next most
serious outcome with one or more events is used. For example, in low-risk populations with no mortality, a reduction
in mortality with treatment is not possible, however a reduction in hospitalization, for example, is still valuable. Clinical
outcomes are considered more important than viral test status. When basically all patients recover in both treatment
and control groups, preference for viral clearance and recovery is given to results mid-recovery where available. After
most or all patients have recovered there is little or no room for an effective treatment to do better, however faster
recovery is valuable. If only individual symptom data is available, the most serious symptom has priority, for example
difficulty breathing or low SpO2 is more important than cough. When results provide an odds ratio, we compute the
relative risk when possible, or convert to a relative risk according to 646. Reported confidence intervals and p-values
were used when available, using adjusted values when provided. If multiple types of adjustments are reported
propensity score matching and multivariable regression has preference over propensity score matching or weighting,
which has preference over multivariable regression. Adjusted results have preference over unadjusted results for a
more serious outcome when the adjustments significantly alter results. When needed, conversion between reported
p-values and confidence intervals followed Altman, Altman (B), and Fisher's exact test was used to calculate p-values
for event data. If continuity correction for zero values is required, we use the reciprocal of the opposite arm with the
sum of the correction factors equal to 1 642. Results are expressed with RR < 1.0 favoring treatment, and using the risk
of a negative outcome when applicable (for example, the risk of death rather than the risk of survival). If studies only
report relative continuous values such as relative times, the ratio of the time for the treatment group versus the time
for the control group is used. Calculations are done in Python (3.12.6) with scipy (1.14.1), pythonmeta (1.26), numpy
(1.26.4), statsmodels (0.14.3), and plotly (5.24.1).

Forest plots are computed using PythonMeta 649 with the DerSimonian and Laird random effects model (the fixed
effect assumption is not plausible in this case) and inverse variance weighting. Results are presented with 95%
confidence intervals. Heterogeneity among studies was assessed using the I2 statistic. Mixed-effects meta-regression
results are computed with R (4.4.0) using the metafor (4.6-0) and rms (6.8-0) packages, and using the most serious
sufficiently powered outcome. Forest plots show simplified dosages for comparison, these are the total dose in the
first four days for treatment, and the monthly dose for prophylaxis, for a 70kg person. For full dosage details see
below. For all statistical tests, a p-value less than 0.05 was considered statistically significant. Grobid 0.8.0 is used to
parse PDF documents.

We have classified studies as early treatment if most patients are not already at a severe stage at the time of
treatment (for example based on oxygen status or lung involvement), and treatment started within 5 days of the onset
of symptoms. If studies contain a mix of early treatment and late treatment patients, we consider the treatment time
of patients contributing most to the events (for example, consider a study where most patients are treated early but
late treatment patients are included, and all mortality events were observed with late treatment patients). We note that
a shorter time may be preferable. Antivirals are typically only considered effective when used within a shorter
timeframe, for example 0-36 or 0-48 hours for oseltamivir, with longer delays not being effective 171,172.

We received no funding, this research is done in our spare time. We have no affiliations with any pharmaceutical
companies or political parties.

Note that the size of the control group in Bernigaud is significantly larger than the treatment group. We previously
limited the size to be the same as that of the treatment group for calculation of the number of patients, however this
was confusing to many people that did not read the details.

A summary of study results is below. Please submit updates and corrections at [Link]

Early treatment.

Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the
first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other
outcomes are used in outcome specific analyses.

Abbas, 12/31/2021, Double Blind Randomized risk of death, 4.0% higher, RR 1.04, p = 1.00, treatment 1 of 99
Controlled Trial, placebo-controlled, China, peer- (1.0%), control 1 of 103 (1.0%).
reviewed, 3 authors, study period May 2021 -
August 2021, dosage 300μg/kg days 1-5, excluded deterioration of 2 or more points, 40.5% lower, RR 0.59, p =
in exclusion analyses: very minimal patient 0.54, treatment 4 of 99 (4.0%), control 7 of 103 (6.8%), NNT 36.
information, three different results for the recovery
escalation of care, 14.9% lower, RR 0.85, p = 0.82, treatment 9
outcome, selective omission of the statistically
of 99 (9.1%), control 11 of 103 (10.7%), NNT 63.
significant recovery p-value, and other
inconsistencies.
fever during study, 17.9% lower, RR 0.82, p = 0.58, treatment 15
of 99 (15.2%), control 19 of 103 (18.4%), NNT 30.

risk of no recovery, 35.6% lower, RR 0.64, p = 0.04, treatment 26

of 99 (26.3%), control 42 of 103 (40.8%), NNT 6.9, primary
outcome.

recovery time, 30.8% lower, relative time 0.69, p = 0.08,

treatment 99, control 103, primary outcome.

Ahmed, 12/2/2020, Double Blind Randomized risk of unresolved symptoms, 85.0% lower, RR 0.15, p = 0.09,
Controlled Trial, Bangladesh, peer-reviewed, mean treatment 0 of 17 (0.0%), control 3 of 19 (15.8%), NNT 6.3,
age 42.0, 15 authors, average treatment delay 3.83 relative risk is not 0 because of continuity correction due to zero
days, dosage 12mg days 1-5, the ivermectin + events (with reciprocal of the contrasting arm), day 7, fever,
doxycycline group took only a single dose of ivermectin (5 days), primary outcome.
ivermectin.
risk of unresolved symptoms, 62.7% lower, RR 0.37, p = 0.35,
treatment 1 of 17 (5.9%), control 3 of 19 (15.8%), NNT 10, day
7, fever, ivermectin (1 day) + doxycycline.

risk of no viral clearance, 75.6% lower, HR 0.24, p = 0.03,

treatment 11 of 22 (50.0%), control 20 of 23 (87.0%), NNT 2.7,
adjusted per study, inverted to make HR<1 favor treatment, day
7, ivermectin (5 days).

risk of no viral clearance, 56.5% lower, HR 0.43, p = 0.22,

treatment 16 of 23 (69.6%), control 20 of 23 (87.0%), NNT 5.8,
adjusted per study, inverted to make HR<1 favor treatment, day
7, ivermectin (1 day) + doxycycline.

risk of no viral clearance, 63.0% lower, HR 0.37, p = 0.02,

treatment 5 of 22 (22.7%), control 14 of 23 (60.9%), NNT 2.6,
adjusted per study, inverted to make HR<1 favor treatment, day
14, ivermectin (5 days).

risk of no viral clearance, 41.2% lower, HR 0.59, p = 0.19,

treatment 9 of 23 (39.1%), control 14 of 23 (60.9%), NNT 4.6,
adjusted per study, inverted to make HR<1 favor treatment, day
14, ivermectin (1 day) + doxycycline.

time to viral-, 23.6% lower, relative time 0.76, p = 0.02,

treatment 22, control 23, ivermectin (5 days).

time to viral-, 9.4% lower, relative time 0.91, p = 0.27, treatment

23, control 23, ivermectin (1 day) + doxycycline.

Aref, 6/15/2021, Randomized Controlled Trial, relative duration of fever, 63.2% lower, relative time 0.37, p <
Egypt, peer-reviewed, 7 authors, study period 0.001, treatment 57, control 57, primary outcome.
February 2021 - March 2021, dosage not specified,
trial NCT04716569 (history). relative duration of dyspnea, 56.4% lower, relative time 0.44, p <
0.001, treatment 57, control 57.
 relative duration of anosmia, 68.8% lower, relative time 0.31, p <
0.001, treatment 57, control 57.

relative duration of cough, 64.3% lower, relative time 0.36, p <

0.001, treatment 57, control 57.

risk of no viral clearance, 78.6% lower, RR 0.21, p = 0.004,

treatment 3 of 57 (5.3%), control 14 of 57 (24.6%), NNT 5.2.

time to viral-, 35.7% lower, relative time 0.64, p < 0.001,

treatment 57, control 57.

Babalola, 1/6/2021, Double Blind Randomized adjusted risk of viral+ at day 5, 63.9% lower, RR 0.36, p = 0.11,
Controlled Trial, Nigeria, peer-reviewed, baseline treatment 40, control 20, adjusted per study, inverted to make
oxygen required 8.3%, 10 authors, study period RR<1 favor treatment.
May 2020 - November 2020, dosage 12mg or 6mg
q84h for two weeks, this trial compares with relative ∆SpO 2 (unadjusted), 41.5% better, RR 0.59, p = 0.07,
another treatment - results may be better when treatment 38, control 18, figure 3.
compared to placebo.

risk of no viral clearance, 58.0% lower, HR 0.42, p = 0.01,

treatment 20, control 20, inverted to make HR<1 favor
treatment, 12mg - Cox proportional hazard model.

risk of no viral clearance, 40.5% lower, HR 0.60, p = 0.12,

treatment 20, control 20, inverted to make HR<1 favor
treatment, 6mg - Cox proportional hazard model.

time to viral-, 49.2% lower, relative time 0.51, p = 0.02,

treatment 20, control 20, 12mg, primary outcome.

time to viral-, 34.4% lower, relative time 0.66, p = 0.08,

treatment 20, control 20, 6mg.

Biber, 2/12/2021, Double Blind Randomized risk of hospitalization, 70.2% lower, RR 0.30, p = 0.34,
Controlled Trial, placebo-controlled, Israel, peer- treatment 1 of 47 (2.1%), control 3 of 42 (7.1%), NNT 20.
reviewed, 10 authors, study period 12 May, 2020 -
31 October, 2020, average treatment delay 4.0 risk of no viral clearance, 61.6% lower, RR 0.38, p = 0.02,
days, dosage 12mg days 1-3, 15mg for patients treatment 8 of 47 (17.0%), control 17 of 42 (40.5%), NNT 4.3,
≥70kg, trial NCT04429711 (history). adjusted per study, inverted to make RR<1 favor treatment, odds
ratio converted to relative risk, Ct>30, multivariable, day 8.

risk of no viral clearance, 39.0% lower, RR 0.61, p = 0.09,

treatment 13 of 47 (27.7%), control 21 of 42 (50.0%), NNT 4.5,
adjusted per study, inverted to make RR<1 favor treatment, odds
ratio converted to relative risk, Ct>30, multivariable, day 6,
primary outcome.

risk of no viral clearance, 73.0% lower, RR 0.27, p = 0.008,

treatment 3 of 23 (13.0%), control 14 of 29 (48.3%), NNT 2.8,
culture viability.

risk of no viral clearance, 70.2% lower, RR 0.30, p = 0.14,

treatment 2 of 47 (4.3%), control 6 of 42 (14.3%), NNT 10.0,
non-infectious samples (Ct>30 or non-viable culture), day 10.
 risk of no viral clearance, 82.1% lower, RR 0.18, p = 0.01,
treatment 2 of 47 (4.3%), control 10 of 42 (23.8%), NNT 5.1,
non-infectious samples (Ct>30 or non-viable culture), day 8.

risk of no viral clearance, 75.6% lower, RR 0.24, p = 0.02,

treatment 3 of 47 (6.4%), control 11 of 42 (26.2%), NNT 5.0,
non-infectious samples (Ct>30 or non-viable culture), day 6.

risk of no viral clearance, 65.1% lower, RR 0.35, p = 0.05,

treatment 4 of 28 (14.3%), control 9 of 22 (40.9%), NNT 3.8,
non-infectious samples (Ct>30 or non-viable culture), day 4.

risk of no viral clearance, 51.9% lower, RR 0.48, p = 0.08,

treatment 7 of 47 (14.9%), control 13 of 42 (31.0%), NNT 6.2,
Ct>30, day 10.

risk of no viral clearance, 57.9% lower, RR 0.42, p = 0.02,

treatment 8 of 47 (17.0%), control 17 of 42 (40.5%), NNT 4.3,
Ct>30, day 8.

risk of no viral clearance, 44.7% lower, RR 0.55, p = 0.049,

treatment 13 of 47 (27.7%), control 21 of 42 (50.0%), NNT 4.5,
Ct>30, day 6.

risk of no viral clearance, 31.9% lower, RR 0.68, p = 0.16,

treatment 13 of 28 (46.4%), control 15 of 22 (68.2%), NNT 4.6,
Ct>30, day 4.

Borody, 10/19/2021, retrospective, Australia, risk of death, 92.3% lower, RR 0.08, p = 0.03, treatment 0 of
preprint, 2 authors, study period 1 June, 2021 - 30 600 (0.0%), control 6 of 600 (1.0%), NNT 100, relative risk is not
September, 2021, dosage 24mg days 1-10, this trial 0 because of continuity correction due to zero events (with
uses multiple treatments in the treatment arm reciprocal of the contrasting arm).
(combined with zinc and doxycycline) - results of
individual treatments may vary, excluded in risk of hospitalization, 92.9% lower, RR 0.07, p < 0.001,
exclusion analyses: preliminary report with minimal treatment 5 of 600 (0.8%), control 70 of 600 (11.7%), NNT 9.2,
details. primary outcome.

Bramante, 8/18/2022, Double Blind Randomized risk of death, 197.1% higher, RR 2.97, p = 1.00, treatment 1 of
Controlled Trial, placebo-controlled, USA, peer- 408 (0.2%), control 0 of 396 (0.0%), continuity correction due to
reviewed, 37 authors, average treatment delay 4.6 zero event (with reciprocal of the contrasting arm), day 28.
days, dosage 430μg/kg days 1-3, this trial
compares with another treatment - results may be risk of death/hospitalization, 26.7% lower, RR 0.73, p = 0.66,
better when compared to placebo, trial treatment 4 of 406 (1.0%), control 5 of 394 (1.3%), NNT 352,
NCT04510194 (history) (COVID-OUT). odds ratio converted to relative risk.

risk of progression, 36.8% higher, RR 1.37, p = 0.33, treatment

23 of 406 (5.7%), control 16 of 394 (4.1%), odds ratio converted
to relative risk, combined ER, hospitalization, death.

risk of progression, 3.7% higher, RR 1.04, p = 0.78, treatment

105 of 407 (25.8%), control 96 of 391 (24.6%), odds ratio
converted to relative risk, combined hypoxemia, ER,
hospitalization, death, primary outcome.
 risk of hospitalization, 60.8% lower, RR 0.39, p = 0.28, treatment
2 of 206 (1.0%), control 5 of 202 (2.5%), NNT 66, IVM vs.
placebo.

risk of hospitalization, 74.6% lower, RR 0.25, p = 0.37, treatment

1 of 137 (0.7%), control 4 of 139 (2.9%), NNT 47, IVM vs.
≤
placebo, 5 days from onset.

risk of hospitalization, 70.1% lower, RR 0.30, p = 0.12, treatment

3 of 406 (0.7%), control 5 of 202 (2.5%), NNT 58, IVM and
IVM+MF vs. placebo.

risk of hospitalization, 41.8% lower, RR 0.58, p = 0.50, treatment

3 of 406 (0.7%), control 5 of 394 (1.3%), NNT 189, IVM and
IVM+MF vs. placebo and MF.

Bukhari, 1/16/2021, Randomized Controlled Trial, risk of no viral clearance, 82.4% lower, RR 0.18, p < 0.001,
Pakistan, preprint, 10 authors, study period 15 treatment 4 of 41 (9.8%), control 25 of 45 (55.6%), NNT 2.2, day
March, 2020 - 15 June, 2020, dosage 12mg single 7, primary outcome.
dose, trial NCT04392713 (history).
risk of no viral clearance, 38.7% lower, RR 0.61, p < 0.001,
treatment 24 of 41 (58.5%), control 43 of 45 (95.6%), NNT 2.7,
day 3.

Buonfrate, 9/6/2021, Double Blind Randomized risk of hospitalization, 210.7% higher, RR 3.11, p = 0.47,
Controlled Trial, Italy, peer-reviewed, 18 authors, treatment 1 of 28 (3.6%), control 0 of 31 (0.0%), continuity
study period 31 July, 2020 - 8 June, 2021, average correction due to zero event (with reciprocal of the contrasting
treatment delay 4.0 days, dosage 1200μg/kg days arm), arm B.
1-5, arm B 600µg/kg, arm C 1200µg/kg, trial
NCT04438850 (history) (COVER), excluded in risk of hospitalization, 610.0% higher, RR 7.10, p = 0.11,
exclusion analyses: significant unadjusted group treatment 3 of 30 (10.0%), control 0 of 31 (0.0%), continuity
differences, with 3 times as many patients in the correction due to zero event (with reciprocal of the contrasting
ivermectin arms having the baseline visit in a arm), arm C, very high dose, poorly tolerated with low
hospital setting, and arm C having large differences compliance.
in baseline gender, weight, cough, pyrexia, and
anosmia, excessive dose for arm C.
relative change in viral load, RR 0.80, p = 0.59, treatment mean
2.5 (±2.2) n=28, control mean 2.0 (±4.4) n=29, day 7, arm B,
primary outcome.

relative change in viral load, RR 0.69, p = 0.07, treatment mean

2.9 (±1.6) n=30, control mean 2.0 (±2.1) n=29, day 7, arm C,
primary outcome.

Cadegiani, 11/4/2020, prospective, Brazil, peer- risk of death, 78.3% lower, RR 0.22, p = 0.50, treatment 0 of
reviewed, 4 authors, average treatment delay 2.9 110 (0.0%), control 2 of 137 (1.5%), NNT 68, relative risk is not
days, dosage 200μg/kg days 1-3, this trial uses 0 because of continuity correction due to zero events (with
multiple treatments in the treatment arm (combined reciprocal of the contrasting arm), control group 1.
with AZ, nitazoxanide (82), HCQ (22),
spironolactone (66), dutasteride (4)) - results of risk of mechanical ventilation, 94.2% lower, RR 0.06, p = 0.005,
individual treatments may vary, excluded in treatment 0 of 110 (0.0%), control 9 of 137 (6.6%), NNT 15,
exclusion analyses: control group retrospectively relative risk is not 0 because of continuity correction due to zero
obtained from untreated patients in the same events (with reciprocal of the contrasting arm), control group 1.
population.
 risk of hospitalization, 98.0% lower, RR 0.02, p < 0.001,
treatment 0 of 110 (0.0%), control 27 of 137 (19.7%), NNT 5.1,
relative risk is not 0 because of continuity correction due to zero
events (with reciprocal of the contrasting arm), control group 1.

Carvallo (C), 9/15/2020, prospective, Argentina, risk of death, 85.4% lower, RR 0.15, p = 0.08, treatment 1 of 32
peer-reviewed, mean age 55.7, 3 authors, dosage (3.1%), control 3 of 14 (21.4%), NNT 5.5, moderate/severe
36mg days 1, 8, dose varied depending on patient patients, the only treatment death was a patient already in the
condition - mild 24mg, moderate 36mg, severe ICU before treatment, primary outcome.
48mg, this trial uses multiple treatments in the
treatment arm (combined with dexamethasone,
enoxaparin, and aspirin) - results of individual
treatments may vary, excluded in exclusion
analyses: minimal details of groups provided.

Chaccour (B), 12/7/2020, Double Blind Randomized risk of symptoms, 96.0% lower, OR 0.04, p < 0.05, treatment
Controlled Trial, Spain, peer-reviewed, 24 authors, 12, control 12, logistic regression, chance of presenting any
study period 31 July, 2020 - 11 September, 2020, symptom, RR approximated with OR.
average treatment delay 1.0 days, dosage 400μg/kg
single dose, trial NCT04390022 (history). viral load, 94.6% lower, relative load 0.05, p < 0.01, treatment
12, control 12, day 7 mid-recovery, average of gene E and gene
N, data in supplementary appendix.

risk of no viral clearance, 8.0% lower, RR 0.92, p = 1.00,

treatment 12, control 12, primary outcome.

Chahla, 3/30/2021, Cluster Randomized Controlled risk of no discharge, 86.9% lower, RR 0.13, p = 0.004, treatment
Trial, Argentina, peer-reviewed, 9 authors, study 2 of 110 (1.8%), control 20 of 144 (13.9%), NNT 8.3, adjusted
period September 2020 - January 2021, dosage per study, inverted to make RR<1 favor treatment, odds ratio
24mg days 1, 8, 15, 22, trial NCT04784481 converted to relative risk, logistic regression, multivariable,
(history). primary outcome.

Chowdhury, 7/14/2020, Randomized Controlled risk of hospitalization, 80.6% lower, RR 0.19, p = 0.23,
Trial, Bangladesh, peer-reviewed, 6 authors, study treatment 0 of 60 (0.0%), control 2 of 56 (3.6%), NNT 28,
period 2 May, 2020 - 5 June, 2020, dosage relative risk is not 0 because of continuity correction due to zero
200μg/kg single dose, this trial compares with events (with reciprocal of the contrasting arm).
another treatment - results may be better when
compared to placebo, this trial uses multiple risk of no recovery, 46.4% lower, RR 0.54, p < 0.001, treatment
treatments in the treatment arm (combined with 27 of 60 (45.0%), control 47 of 56 (83.9%), NNT 2.6, mid-
doxycycline) - results of individual treatments may recovery day 5.
vary, trial NCT04434144 (history).

recovery time, 15.2% lower, relative time 0.85, p = 0.07,

treatment 60, control 56.

risk of no viral clearance, 80.6% lower, RR 0.19, p = 0.23,

treatment 0 of 60 (0.0%), control 2 of 56 (3.6%), NNT 28,
relative risk is not 0 because of continuity correction due to zero
events (with reciprocal of the contrasting arm), primary
outcome.

time to viral-, 4.3% lower, relative time 0.96, p = 0.23, treatment

60, control 56.

de Jesús Ascencio-Montiel, 1/24/2022, risk of death/hospitalization, 59.0% lower, RR 0.41, p < 0.001,
retrospective, Mexico, peer-reviewed, 10 authors, treatment 7,898, control 20,150, adjusted per study,
dosage 6mg days 1-2, this trial uses multiple multivariable, primary outcome.
treatments in the treatment arm (combined with
risk of death/hospitalization, 71.0% lower, RR 0.29, p < 0.001,
AZ, acetaminophen, aspirin) - results of individual
treatment 5,557, control 12,526, adjusted per study, with phone
treatments may vary.
call followup, multivariable.

risk of death, 15.0% lower, RR 0.85, p = 0.16, treatment 101 of

7,898 (1.3%), control 303 of 20,150 (1.5%), NNT 445,
unadjusted, excluded in exclusion analyses: unadjusted results
with alternate outcome adjusted results showing significant
changes with adjustments.

risk of mechanical ventilation, 9.1% lower, RR 0.91, p = 0.51,

treatment 77 of 7,898 (1.0%), control 216 of 20,150 (1.1%),
NNT 1031, unadjusted, excluded in exclusion analyses:
unadjusted results with alternate outcome adjusted results
showing significant changes with adjustments.

risk of hospitalization, 47.6% lower, RR 0.52, p < 0.001,

treatment 485 of 7,898 (6.1%), control 2,360 of 20,150 (11.7%),
NNT 18, unadjusted, excluded in exclusion analyses: unadjusted
results with alternate outcome adjusted results showing
significant changes with adjustments.

risk of progression, 41.8% lower, RR 0.58, p < 0.001, treatment

435 of 7,898 (5.5%), control 1,906 of 20,150 (9.5%), NNT 25,
unadjusted, ER, excluded in exclusion analyses: unadjusted
results with alternate outcome adjusted results showing
significant changes with adjustments.

de la Rocha, 5/23/2022, Double Blind Randomized risk of progression to serious adverse events, 186.7% higher,
Controlled Trial, placebo-controlled, Mexico, peer- RR 2.87, p = 1.00, treatment 1 of 30 (3.3%), control 0 of 26
reviewed, 21 authors, study period 1 July, 2020 - 29 (0.0%), continuity correction due to zero event (with reciprocal
January, 2021, dosage 12mg days 1-3, trial of the contrasting arm).
NCT04407507 (history), excluded in exclusion
analyses: data mismatch, no response from viral load, 2.4% lower, relative load 0.98, p = 0.64, treatment
authors. mean 33.74 (±4.77) n=30, control mean 32.94 (±7.74) n=26, day
14.

viral load, 7.8% lower, relative load 0.92, p = 0.04, treatment

mean 30.64 (±3.74) n=30, control mean 28.25 (±4.21) n=26,
mid-recovery, day 5.

Elalfy, 2/16/2021, retrospective, Egypt, peer- risk of no viral clearance, 86.9% lower, RR 0.13, p < 0.001,
reviewed, 15 authors, dosage 18mg days 1, 4, 7, treatment 7 of 62 (11.3%), control 44 of 51 (86.3%), NNT 1.3,
10, 13, <90kg 18mg, 90-120kg 24mg, >120kg day 15, primary outcome.
30mg, this trial uses multiple treatments in the
treatment arm (combined with nitazoxanide, risk of no viral clearance, 58.1% lower, RR 0.42, p < 0.001,
ribavirin, and zinc) - results of individual treatments treatment 26 of 62 (41.9%), control 51 of 51 (100.0%), NNT 1.7,
may vary. day 7.

Espitia-Hernandez, 8/15/2020, retrospective, recovery time, 70.0% lower, relative time 0.30, p < 0.001,
Mexico, peer-reviewed, mean age 45.1, 5 authors, treatment 28, control 7.
dosage 6mg days 1-2, 8-9, this trial uses multiple
treatments in the treatment arm (combined with risk of viral+ at day 10, 97.2% lower, RR 0.03, p < 0.001,
azithromycin and cholecalciferol) - results of treatment 0 of 28 (0.0%), control 7 of 7 (100.0%), NNT 1.0,
individual treatments may vary. relative risk is not 0 because of continuity correction due to zero
events (with reciprocal of the contrasting arm), primary
outcome.
Faisal, 5/10/2021, Randomized Controlled Trial, risk of no recovery, 68.4% lower, RR 0.32, p = 0.005, treatment
Pakistan, peer-reviewed, 3 authors, study period 5 6 of 50 (12.0%), control 19 of 50 (38.0%), NNT 3.8, 6-8 days,
April, 2020 - 30 May, 2020, dosage 12mg days 1-5. mid-recovery, primary outcome.

risk of no recovery, 27.3% lower, RR 0.73, p = 0.11, treatment 24

of 50 (48.0%), control 33 of 50 (66.0%), NNT 5.6, 3-5 days.

risk of no recovery, 75.0% lower, RR 0.25, p = 0.09, treatment 2

of 50 (4.0%), control 8 of 50 (16.0%), NNT 8.3, 9-10 days.

Ghauri, 12/15/2020, retrospective, Pakistan, peer- risk of fever, 92.2% lower, RR 0.08, p = 0.04, treatment 0 of 37
reviewed, 6 authors, dosage 12mg days 1-6. (0.0%), control 7 of 53 (13.2%), NNT 7.6, relative risk is not 0
because of continuity correction due to zero events (with
reciprocal of the contrasting arm), day 14.

risk of fever, 86.4% lower, RR 0.14, p < 0.001, treatment 2 of 37

(5.4%), control 21 of 53 (39.6%), NNT 2.9, day 10.

risk of fever, 55.7% lower, RR 0.44, p < 0.001, treatment 13 of 37

(35.1%), control 42 of 53 (79.2%), NNT 2.3, day 7.

risk of fever, 42.2% lower, RR 0.58, p < 0.001, treatment 21 of 37

(56.8%), control 52 of 53 (98.1%), NNT 2.4, day 5.

Kamal, 9/1/2020, Randomized Controlled Trial, trial Estimated 100 patient RCT with results unknown and over 4
NCT04425707 (history). years late.

Krolewiecki, 6/18/2021, Randomized Controlled risk of mechanical ventilation, 151.9% higher, RR 2.52, p = 1.00,
Trial, Argentina, peer-reviewed, 23 authors, study treatment 1 of 27 (3.7%), control 0 of 14 (0.0%), continuity
period 18 May, 2020 - 9 September, 2020, average correction due to zero event (with reciprocal of the contrasting
treatment delay 3.5 days, dosage 600μg/kg days 1- arm).
5, trial NCT004381884 (history).
risk of progression, 3.7% higher, RR 1.04, p = 1.00, treatment 2
of 27 (7.4%), control 1 of 14 (7.1%).

viral decay rate, RR 0.34, p = 0.09, treatment 20, control 14,

relative mean viral decay rate (corrigendum table 2, all treatment
patients vs. all control patients), primary outcome.

Loue, 4/17/2021, retrospective quasi-randomized risk of death, 70.0% lower, RR 0.30, p = 0.34, treatment 1 of 10
(patient choice), France, peer-reviewed, 2 authors, (10.0%), control 5 of 15 (33.3%), NNT 4.3.
dosage 200μg/kg single dose.
risk of severe case, 55.0% lower, RR 0.45, p = 0.11, treatment 3
of 10 (30.0%), control 10 of 15 (66.7%), NNT 2.7.

López-Medina, 3/4/2021, Double Blind Randomized risk of death, 66.8% lower, RR 0.33, p = 0.50, treatment 0 of
Controlled Trial, Colombia, peer-reviewed, median 200 (0.0%), control 1 of 198 (0.5%), NNT 198, relative risk is not
age 37.0, 19 authors, study period 15 July, 2020 - 0 because of continuity correction due to zero events (with
30 November, 2020, average treatment delay 5.0 reciprocal of the contrasting arm).
days, dosage 300μg/kg days 1-5, excluded in
exclusion analyses: strong evidence of patients in risk of escalation of care, 60.8% lower, RR 0.39, p = 0.11,
the control group self-medicating, ivermectin widely treatment 4 of 200 (2.0%), control 10 of 198 (5.1%), NNT 33,
used in the population at that time, and the study odds ratio converted to relative risk.
drug identity was concealed by using the name
D11AX22.
 risk of escalation of care with post-hoc <12h exclusion, 34.3%
lower, RR 0.66, p = 0.52, treatment 4 of 200 (2.0%), control 6 of
198 (3.0%), NNT 97, odds ratio converted to relative risk.

risk of deterioration by >= 2 points on an 8-point scale, 43.1%

lower, RR 0.57, p = 0.37, treatment 4 of 200 (2.0%), control 7 of
198 (3.5%), NNT 65, odds ratio converted to relative risk,
primary outcome.

risk of fever post randomization, 24.8% lower, RR 0.75, p = 0.38,

treatment 16 of 200 (8.0%), control 21 of 198 (10.6%), NNT 38,
odds ratio converted to relative risk.

risk of unresolved symptoms at day 21, 15.3% lower, RR 0.85, p

= 0.53, treatment 36 of 200 (18.0%), control 42 of 198 (21.2%),
NNT 31, inverted to make RR<1 favor treatment, odds ratio
converted to relative risk, Cox proportional-hazard model.

lack of resolution of symptoms, 6.5% lower, HR 0.93, p = 0.53,

treatment 200, control 198, inverted to make HR<1 favor
treatment, post-hoc primary outcome.

Mahmud, 10/9/2020, Double Blind Randomized risk of death, 85.7% lower, HR 0.14, p = 0.25, treatment 0 of
Controlled Trial, Bangladesh, peer-reviewed, 15 183 (0.0%), control 3 of 183 (1.6%), NNT 61, relative risk is not
authors, study period 1 June, 2020 - 30 August, 0 because of continuity correction due to zero events (with
2020, average treatment delay 4.0 days, dosage reciprocal of the contrasting arm).
12mg single dose, this trial uses multiple
treatments in the treatment arm (combined with risk of progression, 57.0% lower, HR 0.43, p < 0.001, treatment
doxycycline) - results of individual treatments may 16 of 183 (8.7%), control 32 of 180 (17.8%), NNT 11, adjusted
vary, trial NCT04523831 (history). per study, Cox regression.

risk of no recovery, 94.0% lower, HR 0.06, p < 0.001, treatment

72 of 183 (39.3%), control 100 of 180 (55.6%), NNT 6.2,
adjusted per study, day 7, Cox regression.

risk of no recovery, 38.5% lower, RR 0.61, p = 0.005, treatment

40 of 183 (21.9%), control 64 of 180 (35.6%), NNT 7.3, day 11.

risk of no recovery, 96.0% lower, HR 0.04, p < 0.001, treatment

42 of 183 (23.0%), control 67 of 180 (37.2%), NNT 7.0, adjusted
per study, day 12, Cox regression.

time to recovery, 27.0% lower, HR 0.73, p = 0.003, treatment

183, control 180, Cox regression, primary outcome.

risk of no viral clearance, 39.0% lower, HR 0.61, p = 0.002,

treatment 14 of 183 (7.7%), control 36 of 180 (20.0%), NNT 8.1,
adjusted per study, Cox regression.

Manomaipiboon, 2/2/2022, Double Blind risk of no recovery, 43.5% lower, RR 0.57, p = 0.26, treatment 3
Randomized Controlled Trial, placebo-controlled, of 36 (8.3%), control 6 of 36 (16.7%), NNT 12, adjusted per
Thailand, peer-reviewed, mean age 48.6, 8 authors, study, odds ratio converted to relative risk, resolution of
study period 10 October, 2021 - 15 December, symptoms, Table S2, day 28.
2021, dosage 12mg days 1-5, trial NCT05076253
(history).
 recovery time, 15.3% lower, RR 0.85, p = 0.56, treatment 36,
control 36, inverted to make RR<1 favor treatment, time to
resolution of symptoms.

risk of no viral clearance, 5.0% lower, RR 0.95, p = 1.00,

treatment 19 of 36 (52.8%), control 20 of 36 (55.6%), NNT 36,
day 14, primary outcome.

risk of no viral clearance, 3.3% lower, RR 0.97, p = 1.00,

treatment 29 of 36 (80.6%), control 30 of 36 (83.3%), NNT 36,
day 7.

Mayer, 9/23/2021, retrospective, Argentina, peer- risk of death, 55.1% lower, RR 0.45, p < 0.001, treatment 3,266,
reviewed, 14 authors, dosage 540μg/kg days 1-5, control 17,966, adjusted per study, odds ratio converted to
mean prescribed dose. relative risk, Figure 3, multivariable.

risk of ICU admission, 65.9% lower, RR 0.34, p < 0.001,

treatment 3,266, control 17,966, adjusted per study, odds ratio
converted to relative risk, Figure 3, multivariable.

risk of death, 27.6% lower, RR 0.72, p = 0.03, treatment 3,266,

control 17,966, odds ratio converted to relative risk, unadjusted.

risk of ICU admission, 26.0% lower, RR 0.74, p = 0.13, treatment

3,266, control 17,966, odds ratio converted to relative risk,
unadjusted.

Merino, 5/3/2021, retrospective quasi-randomized risk of hospitalization, 74.4% lower, RR 0.26, p < 0.001, model
(patients receiving kit), population-based cohort, 7, same time period, patients receiving kit.
Mexico, preprint, 7 authors, dosage 6mg bid days
1-2. risk of hospitalization, 68.4% lower, RR 0.32, p < 0.001, model 1,
different time periods, administrative rule.

Mikamo, 9/26/2022, Double Blind Randomized COVID-19 pneumonia, 205.0% higher, RR 3.05, p = 0.49,
Controlled Trial, placebo-controlled, multiple treatment 1 of 502 (0.2%), control 0 of 527 (0.0%), continuity
countries, peer-reviewed, 19 authors, study period correction due to zero event (with reciprocal of the contrasting
12 November, 2021 - 7 August, 2022, dosage arm), Table S8.
300μg/kg days 1-3, trial NCT05056883 (history),
excluded in exclusion analyses: very low risk group use of therapeutic agents, oxygen, transfer, hospitalization,
with almost no progression leaves little room for death, 214.9% higher, RR 3.15, p = 0.36, treatment 3 of 502
improvement, unbalanced baseline dyspnea and (0.6%), control 1 of 527 (0.2%).
high symptom scores, design and post-hoc
changes favor null result.
risk of no improvement, 4.0% higher, HR 1.04, p = 0.62,
treatment 502, control 527, 168hr, improving trend, primary
outcome.

risk of no recovery, 4.0% lower, HR 0.96, p = 0.72, treatment

502, control 527, 168hr, clinical resolution, Figure S3.

risk of no recovery, 4.0% lower, HR 0.96, p = 0.64, treatment

502, control 527, 240hr, clinical resolution, Figure S3.
Mirahmadizadeh, 6/23/2022, Double Blind risk of mechanical ventilation, 66.9% lower, RR 0.33, p = 0.37,
Randomized Controlled Trial, placebo-controlled, treatment 1 of 131 (0.8%), control 3 of 130 (2.3%), NNT 65,
Iran, peer-reviewed, 12 authors, study period 9 24mg.
April, 2021 - 20 May, 2021, dosage 24mg single
dose, 12mg and 24mg arms. risk of mechanical ventilation, 33.3% lower, RR 0.67, p = 1.00,
treatment 2 of 130 (1.5%), control 3 of 130 (2.3%), NNT 130,
12mg.

risk of hospitalization, 45.9% lower, RR 0.54, p = 0.22, treatment

6 of 131 (4.6%), control 11 of 130 (8.5%), NNT 26, 24mg,
primary outcome.

risk of hospitalization, 27.3% lower, RR 0.73, p = 0.63, treatment

8 of 130 (6.2%), control 11 of 130 (8.5%), NNT 43, 12mg,
primary outcome.

risk of no recovery, 38.9% lower, RR 0.61, p = 0.27, treatment 8

of 131 (6.1%), control 13 of 130 (10.0%), NNT 26, day 28,
24mg.

risk of no recovery, 30.8% lower, RR 0.69, p = 0.50, treatment 9

of 130 (6.9%), control 13 of 130 (10.0%), NNT 32, day 28,
12mg.

Mohan, 2/2/2021, Double Blind Randomized risk of no discharge at day 14, 62.5% lower, RR 0.38, p = 0.27,
Controlled Trial, India, peer-reviewed, 27 authors, treatment 2 of 40 (5.0%), control 6 of 45 (13.3%), NNT 12,
study period 28 July, 2020 - 29 September, 2020, 24mg.
average treatment delay 5.0 days, dosage 400μg/kg
single dose, 200μg/kg also tested, trial risk of clinical worsening, 32.5% lower, RR 0.68, p = 0.72,
CTRI/2020/06/026001 (RIVET-COV). treatment 3 of 40 (7.5%), control 5 of 45 (11.1%), NNT 28,
24mg.

risk of no viral clearance, 23.8% lower, RR 0.76, p = 0.18,

treatment 21 of 40 (52.5%), control 31 of 45 (68.9%), NNT 6.1,
day 5, 24mg, primary outcome.

risk of no viral clearance, 10.3% lower, RR 0.90, p = 0.65,

treatment 20 of 36 (55.6%), control 26 of 42 (61.9%), NNT 16,
day 7, 24mg.

Mourya, 4/1/2021, retrospective, India, peer- risk of no viral clearance, 89.4% lower, RR 0.11, p < 0.001,
reviewed, 5 authors, dosage 12mg days 1-7. treatment 5 of 50 (10.0%), control 47 of 50 (94.0%), NNT 1.2,
primary outcome.

Ravikirti (B), 1/9/2021, Double Blind Randomized risk of death, 88.7% lower, RR 0.11, p = 0.12, treatment 0 of 55
Controlled Trial, India, peer-reviewed, 11 authors, (0.0%), control 4 of 57 (7.0%), NNT 14, relative risk is not 0
study period 1 August, 2020 - 31 October, 2020, because of continuity correction due to zero events (with
average treatment delay 6.1 days, dosage 12mg reciprocal of the contrasting arm).
days 1, 2.
risk of mechanical ventilation, 79.3% lower, RR 0.21, p = 0.10,
treatment 1 of 55 (1.8%), control 5 of 57 (8.8%), NNT 14.

risk of ICU admission, 13.6% lower, RR 0.86, p = 0.80, treatment

5 of 55 (9.1%), control 6 of 57 (10.5%), NNT 70.
 risk of no hospital discharge, 88.7% lower, RR 0.11, p = 0.12,
treatment 0 of 55 (0.0%), control 4 of 57 (7.0%), NNT 14,
relative risk is not 0 because of continuity correction due to zero
events (with reciprocal of the contrasting arm).

risk of no viral clearance, 11.6% higher, RR 1.12, p = 0.35,

treatment 42 of 55 (76.4%), control 39 of 57 (68.4%).

Reis, 8/6/2021, Double Blind Randomized risk of death, 12.0% lower, RR 0.88, p = 0.68, treatment 21 of
Controlled Trial, Brazil, peer-reviewed, 27 authors, 679 (3.1%), control 24 of 679 (3.5%), NNT 226.
study period 23 March, 2021 - 6 August, 2021,
dosage 400μg/kg days 1-3, impossible data, see risk of mechanical ventilation, 23.0% lower, RR 0.77, p = 0.38,
notes, trial NCT04727424 (history) (TOGETHER), treatment 19 of 679 (2.8%), control 25 of 679 (3.7%), NNT 113.
excluded in exclusion analyses: multiple anomalies
as per detailed analysis.
risk of hospitalization, 17.0% lower, RR 0.83, p = 0.19, treatment
79 of 679 (11.6%), control 95 of 679 (14.0%), NNT 42.

extended ER observation or hospitalization, 10.0% lower, RR

0.90, p = 0.42, treatment 100 of 679 (14.7%), control 111 of 679
(16.3%), NNT 62, primary outcome.

viral clearance, no change, RR 1.00, p = 1.00, treatment 106 of

142 (74.6%), control 123 of 165 (74.5%), day 7.

viral clearance, 31.6% higher, RR 1.32, p = 0.46, treatment 148,

control 170, inverted to make RR<1 favor treatment, day 3.

Rezai, 6/16/2022, Double Blind Randomized risk of death, 4.9% higher, RR 1.05, p = 1.00, treatment 1 of 268
Controlled Trial, placebo-controlled, Iran, peer- (0.4%), control 1 of 281 (0.4%).
reviewed, mean age 35.5, 29 authors, study period
19 February, 2021 - 30 August, 2021, dosage risk of ICU admission, 9.0% higher, RR 1.09, p = 0.95, treatment
400μg/kg days 1-3, trial IRCT20111224008507N4, 268, control 281.
excluded in exclusion analyses: multiple critical
issues, see study page.
risk of hospitalization, 36.0% higher, RR 1.36, p = 0.41,
treatment 268, control 281.

risk of no recovery, 2.0% higher, RR 1.02, p = 0.49, treatment

268, control 281, inverted to make RR<1 favor treatment, post-
hoc primary outcome.

risk of no recovery, 13.2% lower, RR 0.87, p = 0.09, treatment

mean 3.87 (±0.18) n=268, control mean 4.46 (±0.18) n=281,
cough.

risk of no recovery, 16.7% lower, RR 0.83, p = 0.81, treatment

mean 2.5 (±0.51) n=268, control mean 3.0 (±0.92) n=281,
tachypnea.

risk of no viral clearance, 23.5% higher, RR 1.23, p = 0.16,

treatment 268, control 281, inverted to make RR<1 favor
treatment.

Roy, 3/12/2021, retrospective, database analysis, relative time to clinical response of wellbeing, 5.6% lower,
India, preprint, 5 authors, dosage not specified, this relative time 0.94, p = 0.87, treatment 14, control 15, primary
trial uses multiple treatments in the treatment arm outcome.
(combined with doxycycline) - results of individual
treatments may vary, excluded in exclusion
analyses: no serious outcomes reported and fast
recovery in treatment and control groups, there is
little room for a treatment to improve results.

Schilling, 7/19/2022, Randomized Controlled Trial, risk of hospitalization, 66.7% lower, RR 0.33, p = 1.00,
Thailand, peer-reviewed, median age 27.0, 38 treatment 0 of 45 (0.0%), control 1 of 45 (2.2%), NNT 45,
authors, study period 30 September, 2021 - 18 relative risk is not 0 because of continuity correction due to zero
April, 2022, average treatment delay 2.0 days, events (with reciprocal of the contrasting arm).
dosage 600μg/kg days 1-7, trial NCT05041907
(history) (PLATCOV), excluded in exclusion risk of progression, 85.7% lower, RR 0.14, p = 0.24, treatment 0
analyses: post-hoc change to exclude patients of 45 (0.0%), control 3 of 45 (6.7%), NNT 15, relative risk is not
treated before high viral load, population very low 0 because of continuity correction due to zero events (with
risk, recovering quickly without treatment, high reciprocal of the contrasting arm), hospitalization or progression
baseline immunity, 2.2x greater baseline antibody to COVID-19 rhabdomyolysis.
negative for the treatment arm.

relative clearance rate, 9.1% worse, RR 1.09, p = 0.36, treatment

45, control 45, primary outcome.

Siripongboonsitti, 3/29/2024, Randomized risk of progression, no change, RR 1.00, p = 1.00, treatment 1 of

Controlled Trial, Thailand, peer-reviewed, 5 authors, 30 (3.3%), control 1 of 30 (3.3%), chest xray progression, day 6.
study period 7 December, 2022 - 3 February, 2023,
dosage 600μg/kg days 1-5, this trial uses multiple risk of progression, 66.7% lower, RR 0.33, p = 1.00, treatment 0
treatments in the treatment arm (combined with of 30 (0.0%), control 1 of 30 (3.3%), NNT 30, relative risk is not
niclosamide) - results of individual treatments may 0 because of continuity correction due to zero events (with
vary, trial TCTR20230403007 (FINCOV), excluded in reciprocal of the contrasting arm), chest xray progression, day
exclusion analyses: data consistency issues, very 3.
low risk patients/variants with almost no
progression, all patients received known effective
risk of no recovery, 39.4% lower, RR 0.61, p = 0.19, treatment
antiviral, baseline differences.
30, control 30, combined symptoms.

risk of no recovery, 70.0% lower, RR 0.30, p = 0.048, treatment

30, control 30, mid-recovery, day 3, cough.

risk of no recovery, 14.3% lower, RR 0.86, p = 0.38, treatment

30, control 30, mid-recovery, day 3, sore throat.

risk of no recovery, 66.7% lower, RR 0.33, p = 0.41, treatment

30, control 30, inverted to make RR<1 favor treatment, mid-
recovery, day 3, runny nose.

risk of no recovery, 50.0% lower, RR 0.50, p = 0.32, treatment

30, control 30, inverted to make RR<1 favor treatment, day 6,
cough.

relative Ct improvement, 6.1% better, RR 0.94, p = 0.75,

treatment median 9.15 IQR 9.7 n=30, control median 8.59 IQR
8.24 n=30, E gene, mid-recovery, day 5, primary outcome.

Szente Fonseca, 10/31/2020, retrospective, Brazil, risk of hospitalization, 13.9% higher, RR 1.14, p = 0.53,
peer-reviewed, mean age 50.6, 10 authors, average treatment 340, control 377, adjusted per study, odds ratio
treatment delay 4.6 days, dosage 12mg days 1-2, converted to relative risk, control prevalence approximated with
excluded in exclusion analyses: result is likely overall prevalence, primary outcome.
affected by collinearity across treatments in the
model.
 Vallejos, 7/2/2021, Double Blind Randomized risk of death, 33.5% higher, RR 1.33, p = 0.70, treatment 4 of
Controlled Trial, Argentina, peer-reviewed, 29 250 (1.6%), control 3 of 251 (1.2%), odds ratio converted to
authors, study period 19 August, 2020 - 22 relative risk.
February, 2021, average treatment delay 4.0 days,
dosage 12mg days 1-2, <80kg 12mg, 80-110kg risk of mechanical ventilation, 33.5% higher, RR 1.33, p = 0.70,
18mg, >110kg 24mg. treatment 4 of 250 (1.6%), control 3 of 251 (1.2%), odds ratio
converted to relative risk.

risk of hospitalization, 33.0% lower, RR 0.67, p = 0.23, treatment

14 of 250 (5.6%), control 21 of 251 (8.4%), NNT 36, odds ratio
converted to relative risk, primary outcome.

risk of no viral clearance, 5.0% higher, RR 1.05, p = 0.55,

treatment 137 of 250 (54.8%), control 131 of 251 (52.2%),
inverted to make RR<1 favor treatment, odds ratio converted to
relative risk, day 3.

risk of no viral clearance, 26.8% higher, RR 1.27, p = 0.29,

treatment 38 of 250 (15.2%), control 30 of 251 (12.0%),
inverted to make RR<1 favor treatment, odds ratio converted to
relative risk, day 12.

Wijewickrema, 7/22/2024, Double Blind risk of death, 196.1% higher, RR 2.96, p = 1.00, treatment 1 of
Randomized Controlled Trial, Sri Lanka, peer- 127 (0.8%), control 0 of 122 (0.0%), continuity correction due to
reviewed, 11 authors, study period 29 July, 2021 - zero event (with reciprocal of the contrasting arm).
17 March, 2022, dosage 24mg days 1-5, trial
SLCTR/2021/020. viral load, 51.2% lower, relative load 0.49, p = 0.03, treatment
80, control 81, relative viral load (copies/mL), day 10, primary
outcome.

Late treatment.

Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the
first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other
outcomes are used in outcome specific analyses.

Abd-Elsalam, 6/2/2021, Randomized Controlled risk of death, 25.0% lower, RR 0.75, p = 0.70, treatment 3 of 82
Trial, Egypt, peer-reviewed, 16 authors, study (3.7%), control 4 of 82 (4.9%), NNT 82, odds ratio converted to
period March 2020 - October 2020, dosage 12mg relative risk, logistic regression, primary outcome.
days 1-3.
risk of mechanical ventilation, no change, RR 1.00, p = 1.00,
treatment 3 of 82 (3.7%), control 3 of 82 (3.7%).

hospitalization time, 19.6% lower, relative time 0.80, p = 0.09,

treatment 82, control 82.

Ahsan, 4/29/2021, retrospective, Pakistan, peer- risk of death, 50.0% lower, RR 0.50, p = 0.03, treatment 17 of
reviewed, 10 authors, dosage 150μg/kg days 1-2, 110 (15.5%), control 17 of 55 (30.9%), NNT 6.5.
150-200µg/kg, this trial uses multiple treatments in
the treatment arm (combined with doxycycline) -
results of individual treatments may vary, excluded
in exclusion analyses: unadjusted results with no
group details.
Aref (B), 9/19/2022, Randomized Controlled Trial, recovery time, 74.0% lower, relative time 0.26, p < 0.001,
placebo-controlled, Egypt, peer-reviewed, 9 treatment 49, control 47, anosmia.
authors, study period 1 March, 2021 - 30 April,
2021, dosage 2 puffs of 70 μg/mL nasal ivermectin,
trial NCT04951362 (history).

Baguma, 12/28/2021, retrospective, Uganda, risk of death, 96.8% lower, RR 0.03, p = 0.31, treatment 7,
preprint, 16 authors, study period March 2020 - control 474, adjusted per study, inverted to make RR<1 favor
October 2021, dosage not specified. treatment, odds ratio converted to relative risk, multivariable,
control prevalance approximated with overall prevalence.

Beltran Gonzalez, 2/23/2021, Double Blind risk of death, 14.4% lower, RR 0.86, p = 1.00, treatment 5 of 36
Randomized Controlled Trial, Mexico, peer- (13.9%), control 6 of 37 (16.2%), NNT 43.
reviewed, mean age 53.8, 13 authors, average
treatment delay 7.0 days, dosage 12mg single risk of respiratory deterioration or death, 8.6% lower, RR 0.91, p
dose, 18mg for patients >80kg, excluded in = 1.00, treatment 8 of 36 (22.2%), control 9 of 37 (24.3%), NNT
exclusion analyses: major inconsistencies reported 48.
and the data is no longer available, although the
authors state that it is available, and have shared it
risk of no hospital discharge, 37.0% higher, RR 1.37, p = 0.71,
with an anti-treatment group.
treatment 4 of 36 (11.1%), control 3 of 37 (8.1%).

hospitalization time, 20.0% higher, relative time 1.20, p = 0.43,

treatment 36, control 37, primary outcome.

Budhiraja, 11/18/2020, retrospective, India, risk of death, 99.1% lower, RR 0.009, p = 0.04, treatment 0 of
preprint, 12 authors, dosage not specified. 34 (0.0%), control 103 of 942 (10.9%), NNT 9.1, relative risk is
not 0 because of continuity correction due to zero events (with
reciprocal of the contrasting arm), unadjusted, primary
outcome.

Camprubí, 11/11/2020, retrospective, Spain, peer- risk of mechanical ventilation, 40.0% lower, RR 0.60, p = 0.67,
reviewed, 9 authors, average treatment delay 12.0 treatment 3 of 13 (23.1%), control 5 of 13 (38.5%), NNT 6.5.
days, dosage 200μg/kg single dose.
risk of ICU admission, 33.3% lower, RR 0.67, p = 1.00, treatment
2 of 13 (15.4%), control 3 of 13 (23.1%), NNT 13, ICU at day 8.

risk of no improvement at day 8, 33.3% higher, RR 1.33, p =

1.00, treatment 4 of 13 (30.8%), control 3 of 13 (23.1%).

risk of no viral clearance, 25.0% higher, RR 1.25, p = 1.00,

treatment 5 of 13 (38.5%), control 4 of 13 (30.8%), tests done
between days 3-5, primary outcome.

Chachar, 9/30/2020, Randomized Controlled Trial, risk of no recovery at day 7, 10.0% lower, RR 0.90, p = 0.50,
India, peer-reviewed, 6 authors, dosage 36mg, treatment 9 of 25 (36.0%), control 10 of 25 (40.0%), NNT 25,
12mg stat, 12mg after 12 hours, 12mg after 24 primary outcome.
hours.

Efimenko, 2/28/2022, retrospective, propensity risk of death, 69.2% lower, OR 0.31, p < 0.001, treatment 1,072,
score matching, USA, peer-reviewed, 6 authors, control 40,536, propensity score matching, RR approximated
study period 1 January, 2020 - 11 July, 2021, with OR.
dosage not specified, this trial compares with
another treatment - results may be better when
compared to placebo.
Elavarasi, 8/12/2021, retrospective, India, peer- risk of death, 19.6% lower, RR 0.80, p = 0.12, treatment 48 of
reviewed, 31 authors, study period April 2021 - 283 (17.0%), control 311 of 1,475 (21.1%), NNT 24, unadjusted.
June 2021, dosage not specified, excluded in
exclusion analyses: unadjusted results with no
group details.

Ferreira, 11/26/2021, retrospective, Brazil, peer- risk of death, 5.0% higher, RR 1.05, p = 1.00, treatment 3 of 21
reviewed, 5 authors, study period 12 March, 2020 - (14.3%), control 11 of 81 (13.6%).
8 July, 2020, average treatment delay 7.0 days,
dosage not specified, excluded in exclusion risk of death/intubation, 54.3% higher, RR 1.54, p = 0.37,
analyses: unadjusted results with no group details; treatment 6 of 21 (28.6%), control 15 of 81 (18.5%).
substantial unadjusted confounding by indication
likely.
risk of death/intubation/ICU, 62.4% higher, RR 1.62, p = 0.27,
treatment 8 of 21 (38.1%), control 19 of 81 (23.5%).

George, 5/27/2022, Randomized Controlled Trial, risk of death, 30.4% lower, RR 0.70, p = 0.55, treatment 5 of 35
India, peer-reviewed, 15 authors, study period June (14.3%), control 8 of 39 (20.5%), NNT 16, 24mg.
2020 - February 2021, dosage 24mg single dose,
trial CTRI/2020/05/025068. risk of death, 2.6% higher, RR 1.03, p = 1.00, treatment 8 of 38
(21.1%), control 8 of 39 (20.5%), 12mg.

recovery time, 18.7% lower, relative time 0.81, p = 0.37,

treatment mean 4.82 (±4.35) n=35, control mean 5.93 (±5.93)
n=39, 24mg.

recovery time, 6.2% lower, relative time 0.94, p = 0.78,

treatment mean 5.56 (±5.42) n=38, control mean 5.93 (±5.93)
n=39, 12mg.

risk of progression, 33.1% lower, RR 0.67, p = 0.41, treatment 6

of 35 (17.1%), control 10 of 39 (25.6%), NNT 12, 24mg.

risk of progression, 17.9% lower, RR 0.82, p = 0.79, treatment 8

of 38 (21.1%), control 10 of 39 (25.6%), NNT 22, 12mg.

Gorial, 7/8/2020, retrospective, Iraq, preprint, 9 risk of death, 71.0% lower, RR 0.29, p = 1.00, treatment 0 of 16
authors, dosage 200μg/kg single dose, trial (0.0%), control 2 of 71 (2.8%), NNT 36, relative risk is not 0
NCT04343092 (history). because of continuity correction due to zero events (with
reciprocal of the contrasting arm).

hospitalization time, 42.0% lower, relative time 0.58, p < 0.001,

treatment 16, control 71.

risk of no recovery, 71.0% lower, RR 0.29, p = 1.00, treatment 0

of 16 (0.0%), control 2 of 71 (2.8%), NNT 36, relative risk is not
0 because of continuity correction due to zero events (with
reciprocal of the contrasting arm), primary outcome.

Hashim, 10/26/2020, Single Blind Randomized risk of death, 91.7% lower, RR 0.08, p = 0.03, treatment 0 of 59
Controlled Trial, Iraq, peer-reviewed, 7 authors, (0.0%), control 6 of 70 (8.6%), NNT 12, relative risk is not 0
study period 1 July, 2020 - 14 October, 2020, because of continuity correction due to zero events (with
dosage 200μg/kg days 1-2, some patients received reciprocal of the contrasting arm), excluding non-randomized
a third dose on day 8, this trial uses multiple critical patients, primary outcome.
treatments in the treatment arm (combined with
doxycycline) - results of individual treatments may risk of death, 67.1% lower, RR 0.33, p = 0.16, treatment 2 of 70
vary, trial NCT04591600 (history). (2.9%), control 6 of 70 (8.6%), NNT 18, odds ratio converted to
relative risk, including critical patients that were always
 allocated to treatment.

risk of progression, 83.1% lower, RR 0.17, p = 0.07, treatment 1

of 59 (1.7%), control 7 of 70 (10.0%), NNT 12, excluding non-
randomized critical patients.

risk of progression, 57.4% lower, RR 0.43, p = 0.20, treatment 3

of 70 (4.3%), control 7 of 70 (10.0%), NNT 18, odds ratio
converted to relative risk, including critical patients that were
always allocated to treatment.

recovery time, 40.7% lower, relative time 0.59, p < 0.001,

treatment 70, control 70.

Hashmi, 6/13/2024, Randomized Controlled Trial, risk of death, 14.9% lower, RR 0.85, p = 0.64, treatment 81,
Pakistan, preprint, 2 authors, study period 11 June, control 69, adjusted per study, non-critical/critical combined.
2021 - 9 September, 2022, dosage 200μg/kg days
1-5, trial NCT02735707 (history) (REMAP-CAP), risk of death, 22.5% lower, OR 0.78, p = 0.59, treatment 44,
excluded in exclusion analyses: baseline severity control 45, adjusted per study, inverted to make OR<1 favor
favors control, post-hoc outcome and SAP treatment, non-critical, day 90, RR approximated with OR.
changes, see discussion.

risk of death, 5.7% lower, OR 0.94, p = 0.91, treatment 37,

control 24, adjusted per study, inverted to make OR<1 favor
treatment, critical, day 90, RR approximated with OR.

intubation, ECMO, death, 23.7% lower, OR 0.76, p = 0.57,

treatment 44, control 45, adjusted per study, inverted to make
OR<1 favor treatment, non-critical, RR approximated with OR.

intubation, ECMO, death, 16.0% lower, OR 0.84, p = 0.72,

treatment 37, control 24, adjusted per study, inverted to make
OR<1 favor treatment, critical, RR approximated with OR.

organ support-free days, 3.8% lower, OR 0.96, p = 0.93,

treatment 44, control 45, inverted to make OR<1 favor
treatment, non-critical, RR approximated with OR.

organ support-free days, 6.4% higher, OR 1.06, p = 0.89,

treatment 37, control 24, inverted to make OR<1 favor
treatment, critical, RR approximated with OR.

Hayward, 2/29/2024, Randomized Controlled Trial, risk of death/hospitalization, 1.0% higher, HR 1.01, p = 0.97,
placebo-controlled, United Kingdom, peer- treatment 34 of 2,157 (1.6%), control 27 of 1,806 (1.5%),
reviewed, 25 authors, study period 23 June, 2021 - concurrent and eligible, primary outcome.
1 July, 2022, dosage 350μg/kg days 1-3, trial
ISRCTN86534580 (PRINCIPLE). risk of mechanical ventilation, 151.4% higher, RR 2.51, p = 0.63,
treatment 3 of 2,149 (0.1%), control 1 of 1,801 (0.1%).

risk of ICU admission, 319.0% higher, RR 4.19, p = 0.23,

treatment 5 of 2,149 (0.2%), control 1 of 1,801 (0.1%).

time to sustained recovery, 16.0% lower, HR 0.84, p < 0.001,

treatment 2,157, control 1,806, inverted to make HR<1 favor
treatment, concurrent and eligible.
early sustained recovery, 23.1% lower, HR 0.77, p < 0.001,
treatment 2,154, control 1,805, inverted to make HR<1 favor
treatment, concurrent and eligible.

sustained alleviation, 17.4% lower, HR 0.83, p < 0.001,

treatment 1,826, control 1,535, inverted to make HR<1 favor
treatment, concurrent and eligible.

alleviation of all symptoms, 16.0% lower, HR 0.84, p < 0.001,

treatment 2,154, control 1,805, inverted to make HR<1 favor
treatment, concurrent and eligible.

first reported recovery, 13.0% lower, HR 0.87, p < 0.001,

treatment 2,157, control 1,806, inverted to make HR<1 favor
treatment, concurrent and eligible, primary outcome.

no recovery at 3/6/12 months, 28.0% lower, HR 0.72, p = 0.02,

treatment 94 of 1,941 (4.8%), control 109 of 1,624 (6.7%), NNT
54.

risk of no recovery, 17.6% lower, RR 0.82, p = 0.001, treatment

417 of 1,848 (22.6%), control 420 of 1,533 (27.4%), NNT 21,
day 365.

risk of PASC, 36.3% lower, RR 0.64, p < 0.001, treatment 1,886,

control 1,567, all symptoms combined.

risk of PASC, 63.2% higher, RR 1.63, p = 1.00, treatment 2 of

1,507 (0.1%), control 1 of 1,230 (0.1%), ongoing/persistent,
fever.

risk of PASC, 72.7% lower, RR 0.27, p = 0.33, treatment 1 of

1,819 (0.1%), control 3 of 1,489 (0.2%), NNT 683,
ongoing/persistent, cough.

risk of PASC, 50.1% lower, RR 0.50, p = 0.04, treatment 15 of

1,886 (0.8%), control 25 of 1,567 (1.6%), NNT 125,
ongoing/persistent, dyspnea.

risk of PASC, 35.3% higher, RR 1.35, p = 0.74, treatment 5 of

1,808 (0.3%), control 3 of 1,468 (0.2%), ongoing/persistent,
chest pain.

risk of PASC, 25.2% lower, RR 0.75, p = 0.36, treatment 21 of

1,831 (1.1%), control 23 of 1,501 (1.5%), NNT 259,
ongoing/persistent, smell.

risk of PASC, 58.7% lower, RR 0.41, p = 0.42, treatment 2 of

1,821 (0.1%), control 4 of 1,503 (0.3%), NNT 640,
ongoing/persistent, diarrhoea.

risk of PASC, 70.2% lower, RR 0.30, p < 0.001, treatment 10 of

1,739 (0.6%), control 27 of 1,400 (1.9%), NNT 74,
ongoing/persistent, headache.
risk of PASC, 29.8% lower, RR 0.70, p = 0.25, treatment 23 of
1,739 (1.3%), control 27 of 1,433 (1.9%), NNT 178,
ongoing/persistent, muscle ache.

risk of PASC, 47.1% lower, RR 0.53, p = 0.03, treatment 19 of

1,724 (1.1%), control 30 of 1,441 (2.1%), NNT 102,
ongoing/persistent, generally unwell.

risk of PASC, 20.1% lower, RR 0.80, p = 0.19, treatment 66 of

1,876 (3.5%), control 69 of 1,567 (4.4%), NNT 113,
ongoing/persistent, fatigue.

risk of PASC, 28.5% lower, RR 0.72, p < 0.001, treatment 1,513,

control 1,238, adjusted per study, all symptoms combined.

risk of PASC, 39.9% lower, RR 0.60, p = 0.01, treatment 46 of

1,435 (3.2%), control 51 of 1,136 (4.5%), relatedness (yes +
unsure) 9.1% (treatment) 11.2% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
cough.

risk of PASC, 41.6% lower, RR 0.58, p < 0.001, treatment 96 of

1,513 (6.3%), control 106 of 1,238 (8.6%), relatedness (yes +
unsure) 14.4% (treatment) 18.5% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
shortness of breath.

risk of PASC, 22.2% lower, RR 0.78, p = 0.27, treatment 39 of

1,426 (2.7%), control 36 of 1,117 (3.2%), relatedness (yes +
unsure) 7.6% (treatment) 8.4% (control) , NNT 205, adjusted per
study and for relatedness, moderate/major symptoms at 12
months, chest pain.

risk of PASC, 38.0% lower, RR 0.62, p = 0.02, treatment 46 of

1,427 (3.2%), control 44 of 1,140 (3.9%), relatedness (yes +
unsure) 7.7% (treatment) 10.3% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
palpitations.

risk of PASC, 11.5% higher, RR 1.12, p = 0.52, treatment 77 of

1,403 (5.5%), control 57 of 1,131 (5.0%), relatedness (yes +
unsure) 13.2% (treatment) 12.9% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
smell.

risk of PASC, 36.4% lower, RR 0.64, p = 0.02, treatment 51 of

1,375 (3.7%), control 51 of 1,116 (4.6%), relatedness (yes +
unsure) 1.1% (treatment) 1.4% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
taste.

risk of PASC, 22.1% lower, RR 0.78, p = 0.37, treatment 26 of

1,290 (2.0%), control 25 of 1,057 (2.4%), relatedness (yes +
unsure) 4.8% (treatment) 5.3% (control) , NNT 286, adjusted per
study and for relatedness, moderate/major symptoms at 12
months, ear ache.
risk of PASC, 9.6% higher, RR 1.10, p = 0.73, treatment 37 of
1,325 (2.8%), control 25 of 1,089 (2.3%), relatedness (yes +
unsure) 6.7% (treatment) 7.4% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
sore throat.

risk of PASC, 34.8% lower, RR 0.65, p = 0.12, treatment 24 of

1,308 (1.8%), control 27 of 1,077 (2.5%), relatedness (yes +
unsure) 6.0% (treatment) 6.9% (control) , NNT 149, adjusted per
study and for relatedness, moderate/major symptoms at 12
months, hoarse voice.

risk of PASC, 16.6% higher, RR 1.17, p = 0.42, treatment 60 of

1,341 (4.5%), control 46 of 1,082 (4.3%), relatedness (yes +
unsure) 8.3% (treatment) 7.4% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
tinnitus.

risk of PASC, 34.7% lower, RR 0.65, p = 0.29, treatment 13 of

1,382 (0.9%), control 12 of 1,139 (1.1%), relatedness (yes +
unsure) 2.2% (treatment) 3.0% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
vomiting.

risk of PASC, 46.5% higher, RR 1.46, p = 0.12, treatment 44 of

1,439 (3.1%), control 25 of 1,175 (2.1%), relatedness (yes +
unsure) 5.9% (treatment) 5.8% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
abdominal pain.

risk of PASC, 1.6% lower, RR 0.98, p = 0.95, treatment 33 of

1,416 (2.3%), control 24 of 1,167 (2.1%), relatedness (yes +
unsure) 4.4% (treatment) 5.1% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
diarrhoea.

risk of PASC, 43.8% higher, RR 1.44, p = 0.23, treatment 30 of

1,417 (2.1%), control 17 of 1,160 (1.5%), relatedness (yes +
unsure) 4.5% (treatment) 4.6% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
reduced appetite.

risk of PASC, 89.8% higher, RR 1.90, p = 0.27, treatment 11 of

1,375 (0.8%), control 4 of 1,129 (0.4%), relatedness (yes +
unsure) 1.8% (treatment) 2.2% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
weight loss.

risk of PASC, 41.3% lower, RR 0.59, p < 0.001, treatment 89 of

1,287 (6.9%), control 94 of 973 (9.7%), relatedness (yes +
unsure) 13.2% (treatment) 16.2% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
anxiety.

risk of PASC, 38.6% lower, RR 0.61, p < 0.001, treatment 95 of

1,298 (7.3%), control 92 of 992 (9.3%), relatedness (yes +
unsure) 13.7% (treatment) 17.4% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
depression.

risk of PASC, 49.0% lower, RR 0.51, p < 0.001, treatment 129 of

1,376 (9.4%), control 143 of 1,105 (12.9%), relatedness (yes +
unsure) 19.6% (treatment) 27.3% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
brain fog.

risk of PASC, 32.9% lower, RR 0.67, p = 0.08, treatment 37 of

1,187 (3.1%), control 33 of 874 (3.8%), relatedness (yes +
unsure) 7.1% (treatment) 9.2% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
confusion.

risk of PASC, 41.9% lower, RR 0.58, p < 0.001, treatment 78 of

1,278 (6.1%), control 81 of 964 (8.4%), relatedness (yes +
unsure) 12.5% (treatment) 15.7% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
headache.

risk of PASC, 45.4% lower, RR 0.55, p = 0.001, treatment 53 of

1,254 (4.2%), control 54 of 955 (5.7%), relatedness (yes +
unsure) 11.5% (treatment) 15.8% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
dizziness.

risk of PASC, 73.5% lower, RR 0.27, p = 0.10, treatment 3 of

1,105 (0.3%), control 3 of 802 (0.4%), relatedness (yes +
unsure) 0.4% (treatment) 1.1% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
fainting.

risk of PASC, 38.7% lower, RR 0.61, p = 0.02, treatment 42 of

1,200 (3.5%), control 39 of 894 (4.4%), relatedness (yes +
unsure) 7.9% (treatment) 10.7% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
numbness.

risk of PASC, 42.1% lower, RR 0.58, p < 0.001, treatment 123 of

1,288 (9.5%), control 121 of 982 (12.3%), relatedness (yes +
unsure) 13.9% (treatment) 18.5% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
sleeping problems.

risk of PASC, 11.8% lower, RR 0.88, p = 0.37, treatment 99 of

1,180 (8.4%), control 88 of 967 (9.1%), relatedness (yes +
unsure) 15.1% (treatment) 16.1% (control) , NNT 141, adjusted
per study and for relatedness, moderate/major symptoms at 12
months, body pains.

risk of PASC, 32.2% lower, RR 0.68, p < 0.001, treatment 136 of

1,220 (11.1%), control 146 of 1,034 (14.1%), relatedness (yes +
unsure) 16.1% (treatment) 19.0% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
joint pains.
 risk of PASC, 30.2% lower, RR 0.70, p < 0.001, treatment 205 of
1,398 (14.7%), control 209 of 1,181 (17.7%), relatedness (yes +
unsure) 24.1% (treatment) 28.3% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
fatigue.

risk of PASC, 31.9% lower, RR 0.68, p = 0.006, treatment 91 of

1,208 (7.5%), control 89 of 997 (8.9%), relatedness (yes +
unsure) 14.5% (treatment) 18.1% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
weakness.

risk of PASC, 35.9% lower, RR 0.64, p < 0.001, treatment 99 of

1,211 (8.2%), control 107 of 1,002 (10.7%), relatedness (yes +
unsure) 14.3% (treatment) 17.4% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
generally unwell.

risk of PASC, 9.2% lower, RR 0.91, p = 0.81, treatment 16 of

1,066 (1.5%), control 11 of 855 (1.3%), relatedness (yes +
unsure) 3.0% (treatment) 3.8% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
fever.

risk of PASC, 42.4% lower, RR 0.58, p = 0.21, treatment 10 of

1,065 (0.9%), control 11 of 853 (1.3%), relatedness (yes +
unsure) 3.0% (treatment) 3.7% (control) , adjusted per study
and for relatedness, moderate/major symptoms at 12 months,
rashes.

risk of PASC, 10.0% lower, RR 0.90, p = 0.62, treatment 47 of

1,090 (4.3%), control 41 of 873 (4.7%), NNT 260, adjusted per
study, moderate/major symptoms at 12 months, other.

Hazan (B), 7/7/2021, retrospective, USA, peer- risk of death, 86.2% lower, RR 0.14, p = 0.04, NNT 6.9, relative
reviewed, 7 authors, dosage 12mg days 1, 4, 8, this risk is not 0 because of continuity correction due to zero events
trial uses multiple treatments in the treatment arm (with reciprocal of the contrasting arm).
(combined with doxycycline, zinc, vitamin D,
vitamin C) - results of individual treatments may risk of hospitalization, 93.5% lower, RR 0.07, p = 0.001, NNT
vary, trial NCT04949230 (history), excluded in 3.3, relative risk is not 0 because of continuity correction due to
exclusion analyses: study uses a synthetic control zero events (with reciprocal of the contrasting arm), primary
arm. outcome.

Huvemek, 3/25/2021, Double Blind Randomized risk of no improvement, 31.6% lower, RR 0.68, p = 0.28,
Controlled Trial, Bulgaria, preprint, 1 author, treatment 13 of 50 (26.0%), control 19 of 50 (38.0%), NNT 8.3,
average treatment delay 7.0 days, dosage 400μg/kg patients with improvement on WHO scale, day 7.
days 1-3, trial EudraCT2020-002091-12.
risk of no improvement, 31.8% lower, RR 0.68, p = 0.21,
treatment 15 of 50 (30.0%), control 22 of 50 (44.0%), NNT 7.1,
patients with improvement on WHO scale, day 6.

risk of no improvement, 36.0% lower, RR 0.64, p = 0.10,

treatment 16 of 50 (32.0%), control 25 of 50 (50.0%), NNT 5.6,
patients with improvement on WHO scale, day 5.
 risk of no improvement, 34.5% lower, RR 0.66, p = 0.07,
treatment 19 of 50 (38.0%), control 29 of 50 (58.0%), NNT 5.0,
patients with improvement on WHO scale, day 4.

Jamir, 12/13/2021, retrospective, India, peer- risk of death, 53.0% higher, RR 1.53, p = 0.13, treatment 32 of
reviewed, 6 authors, study period June 2020 - 76 (42.1%), control 69 of 190 (36.3%), adjusted per study,
October 2020, dosage not specified. multivariable Cox regression.

Khan, 9/24/2020, retrospective, Bangladesh, peer- risk of death, 87.1% lower, RR 0.13, p = 0.02, treatment 1 of
reviewed, median age 35.0, 8 authors, dosage 115 (0.9%), control 9 of 133 (6.8%), NNT 17.
12mg single dose.
risk of ICU admission, 89.5% lower, RR 0.11, p = 0.007,
treatment 1 of 115 (0.9%), control 11 of 133 (8.3%), NNT 14.

risk of progression, 83.5% lower, RR 0.17, p < 0.001, treatment

3 of 115 (2.6%), control 21 of 133 (15.8%), NNT 7.6.

risk of no recovery, 87.1% lower, RR 0.13, p = 0.02, treatment 1

of 115 (0.9%), control 9 of 133 (6.8%), NNT 17.

hospitalization time, 40.0% lower, relative time 0.60, p < 0.001,

treatment 115, control 133.

time to viral-, 73.3% lower, relative time 0.27, p < 0.001,

treatment 115, control 133.

Kishoria, 8/31/2020, Randomized Controlled Trial, risk of no hospital discharge, 7.5% higher, RR 1.08, p = 1.00,
India, peer-reviewed, 7 authors, dosage 12mg treatment 11 of 19 (57.9%), control 7 of 13 (53.8%).
single dose, excluded in exclusion analyses:
excessive unadjusted differences between groups. risk of no viral clearance, 7.5% higher, RR 1.08, p = 1.00,
treatment 11 of 19 (57.9%), control 7 of 13 (53.8%), day 3,
primary outcome.

risk of no viral clearance, 220.0% higher, RR 3.20, p = 0.45,

treatment 1 of 5 (20.0%), control 0 of 6 (0.0%), continuity
correction due to zero event (with reciprocal of the contrasting
arm), day 5.

Lim, 11/3/2021, Randomized Controlled Trial, risk of death, 69.0% lower, RR 0.31, p = 0.09, treatment 3 of
Malaysia, peer-reviewed, 26 authors, study period 241 (1.2%), control 10 of 249 (4.0%), NNT 36.
31 May, 2021 - 9 October, 2021, average treatment
delay 5.1 days, dosage 400μg/kg days 1-5, trial risk of death, 75.2% lower, RR 0.25, p = 0.02, treatment 3 of 52
NCT04920942 (history) (I-TECH). (5.8%), control 10 of 43 (23.3%), NNT 5.7, among patients
progressing to severe cases (mostly before treatment ended).

risk of mechanical ventilation, 59.0% lower, RR 0.41, p = 0.17,

treatment 4 of 241 (1.7%), control 10 of 249 (4.0%), NNT 42.

risk of ICU admission, 22.0% lower, RR 0.78, p = 0.79, treatment

6 of 241 (2.5%), control 8 of 249 (3.2%), NNT 138.

risk of progression, 31.1% lower, RR 0.69, p = 0.29, treatment

14 of 241 (5.8%), control 21 of 249 (8.4%), NNT 38,
death/IMV/NIV/high flow (WHO severe cases).
 risk of progression, 25.0% higher, RR 1.25, p = 0.25, treatment
52 of 241 (21.6%), control 43 of 249 (17.3%), primary outcome.

hospitalization time, 5.5% higher, relative time 1.05, p = 0.38,

treatment 241, control 249.

risk of no recovery, 2.5% higher, RR 1.02, p = 0.86, treatment

116 of 241 (48.1%), control 116 of 247 (47.0%), day 5.

Lima-Morales, 2/10/2021, prospective, Mexico, risk of death, 77.7% lower, RR 0.22, p < 0.001, treatment 15 of
peer-reviewed, 10 authors, average treatment delay 481 (3.1%), control 52 of 287 (18.1%), NNT 6.7, adjusted per
7.2 days, dosage 12mg single dose, this trial uses study, odds ratio converted to relative risk, multivariate.
multiple treatments in the treatment arm (combined
with azithromycin, montelukast, and aspirin) - risk of mechanical ventilation, 51.9% lower, RR 0.48, p = 0.15,
results of individual treatments may vary. treatment 8 of 434 (1.8%), control 11 of 287 (3.8%), NNT 50.

risk of hospitalization, 67.4% lower, RR 0.33, p < 0.001,

treatment 44 of 481 (9.1%), control 89 of 287 (31.0%), NNT 4.6,
adjusted per study, odds ratio converted to relative risk,
multivariate.

risk of no recovery, 58.6% lower, RR 0.41, p < 0.001, treatment

75 of 481 (15.6%), control 118 of 287 (41.1%), NNT 3.9,
adjusted per study, inverted to make RR<1 favor treatment, odds
ratio converted to relative risk, recovery at day 14 after
symptoms, multivariate.

Llenas-García, 5/10/2023, retrospective, Spain, risk of death, 16.7% lower, RR 0.83, p = 0.82, treatment 10 of
peer-reviewed, 11 authors, study period 23 96 (10.4%), control 12 of 96 (12.5%), NNT 48.
February, 2020 - 14 March, 2021, average
treatment delay 6.0 days, dosage 200μg/kg single risk of oxygen therapy, 18.4% lower, RR 0.82, p = 0.37,
dose. treatment 31 of 96 (32.3%), control 38 of 96 (39.6%), NNT 14.

risk of progression, 23.0% lower, OR 0.77, p = 0.52, treatment

96, control 96, adjusted per study, in-hospital mortality or
respiratory support, multivariable, primary outcome, RR
approximated with OR.

risk of ICU admission, 4.0% higher, OR 1.04, p = 0.92, treatment

96, control 96, adjusted per study, multivariable, RR
approximated with OR.

Munir, 4/21/2023, retrospective, Pakistan, peer- risk of death, 48.2% lower, OR 0.52, p = 0.13, treatment 92,
reviewed, 3 authors, study period March 2021 - control 908, adjusted per study, multivariable, RR approximated
March 2022, dosage not specified. with OR.

Mustafa, 12/29/2021, retrospective, Pakistan, peer- risk of death, 63.7% lower, RR 0.36, p = 0.09, treatment 3 of 73
reviewed, 7 authors, dosage varies, excluded in (4.1%), control 42 of 371 (11.3%), NNT 14.
exclusion analyses: unadjusted results with no
group details.
Naggie, 6/12/2022, Double Blind Randomized risk of death, 202.3% higher, RR 3.02, p = 0.49, treatment 1 of
Controlled Trial, placebo-controlled, USA, peer- 708 (0.1%), control 0 of 724 (0.0%), continuity correction due to
reviewed, 28 authors, study period 23 June, 2021 - zero event (with reciprocal of the contrasting arm), 600µg/kg,
4 February, 2022, average treatment delay 6.0 days, day 28.
dosage 600μg/kg days 1-6, trial NCT04885530
(history) (ACTIV-6). risk of death, 194.7% higher, RR 2.95, p = 1.00, treatment 1 of
817 (0.1%), control 0 of 774 (0.0%), continuity correction due to
zero event (with reciprocal of the contrasting arm), 400µg/kg,
day 28.

risk of death/hospitalization, 256.9% higher, RR 3.57, p = 0.11,

treatment 7 of 708 (1.0%), control 2 of 722 (0.3%), 600µg/kg,
day 28.

risk of hospitalization, 5.3% higher, RR 1.05, p = 1.00, treatment

10 of 817 (1.2%), control 9 of 774 (1.2%), 400µg/kg, day 28.

risk of progression, 68.4% lower, RR 0.32, p = 0.36, treatment 1

of 817 (0.1%), control 3 of 774 (0.4%), NNT 377, 400µg/kg,
aggravated C19 pneumonia, eTable 2.

risk of progression, 3.0% lower, RR 0.97, p = 0.53, treatment 39

of 708 (5.5%), control 42 of 722 (5.8%), NNT 324, adjusted per
study, urgent or emergency care visits, hospitalizations, or
death, 600µg/kg.

risk of progression, 20.0% higher, RR 1.20, p = 0.32, treatment

32 of 817 (3.9%), control 28 of 774 (3.6%), adjusted per study,
urgent or emergency care visits, hospitalizations, or death,
400µg/kg.

clinical progression, 29.0% higher, OR 1.29, p = 0.30, treatment

708, control 724, mid-recovery, 600µg/kg, day 7, RR
approximated with OR.

clinical progression, 150.0% higher, OR 2.50, p = 0.007,

treatment 708, control 724, 600µg/kg, day 14, RR approximated
with OR.

clinical progression, 150.0% higher, OR 2.50, p = 0.03,

treatment 708, control 724, 600µg/kg, day 28, RR approximated
with OR.

clinical progression, 24.0% lower, OR 0.76, p = 0.07, treatment

817, control 774, mid-recovery, 400µg/kg, day 7, RR
approximated with OR.

clinical progression, 27.0% lower, OR 0.73, p = 0.05, treatment

817, control 774, 400µg/kg, day 14, RR approximated with OR.

clinical progression, 10.0% lower, OR 0.90, p = 0.57, treatment

817, control 774, 400µg/kg, day 28, RR approximated with OR.

time to recovery, 2.0% lower, HR 0.98, p = 0.71, treatment 708,

control 724, inverted to make HR<1 favor treatment, 600µg/kg,
post-hoc primary outcome.
 risk of limited activity, 30.5% lower, RR 0.70, p = 0.14, treatment
30 of 805 (3.7%), control 41 of 765 (5.4%), NNT 61, eFigure 2,
400µg/kg, day 14.

time to recovery, 6.5% lower, HR 0.93, p = 0.18, treatment 817,

control 774, inverted to make HR<1 favor treatment, 400µg/kg,
post-hoc primary outcome.

time to recovery, 46.2% lower, HR 0.54, p = 0.02, treatment 39,

control 51, inverted to make HR<1 favor treatment, 400µg/kg,
severe, recovery.

Ochoa-Jaramillo, 10/21/2022, Double Blind risk of death, 57.0% lower, HR 0.43, p = 0.35, treatment 2 of 37
Randomized Controlled Trial, placebo-controlled, (5.4%), control 4 of 38 (10.5%), NNT 20, Cox proportional
Colombia, peer-reviewed, 8 authors, study period hazards.
10 December, 2020 - 9 December, 2021, average
treatment delay 8.8 days, dosage 400μg/kg single risk of mechanical ventilation, 34.0% higher, HR 1.34, p = 0.62,
dose, trial NCT04602507 (history). treatment 7 of 37 (18.9%), control 5 of 38 (13.2%), Cox
proportional hazards.

risk of ICU admission, 37.0% higher, HR 1.37, p = 0.52,

treatment 8 of 37 (21.6%), control 6 of 38 (15.8%), Cox
proportional hazards, primary outcome.

Okumuş, 1/12/2021, Double Blind Randomized risk of death, 33.3% lower, RR 0.67, p = 0.55, treatment 6 of 30
Controlled Trial, Turkey, peer-reviewed, 15 authors, (20.0%), control 9 of 30 (30.0%), NNT 10.
study period May 2020 - September 2020, dosage
200μg/kg days 1-5, 36-50kg - 9mg, 51-65kg - risk of no improvement at day 10, 42.9% lower, RR 0.57, p =
12mg, 66-79kg - 15mg, >80kg 200μg/kg, trial 0.18, treatment 8 of 30 (26.7%), control 14 of 30 (46.7%), NNT
NCT04646109 (history). 5.0.

risk of no improvement at day 5, 15.8% lower, RR 0.84, p = 0.60,

treatment 16 of 30 (53.3%), control 19 of 30 (63.3%), NNT 10,
primary outcome.

risk of no viral clearance, 80.0% lower, RR 0.20, p = 0.02,

treatment 2 of 16 (12.5%), control 5 of 8 (62.5%), NNT 2.0, day
10.

Osati, 7/16/2023, retrospective, Tanzania, preprint, risk of death, 31.5% lower, OR 0.68, p = 0.02, treatment 448,
median age 60.0, 22 authors, study period 26 control 849, adjusted per study, inverted to make OR<1 favor
March, 2021 - 30 July, 2022, dosage not specified. treatment, multivariable, RR approximated with OR.

Ozer, 11/23/2021, prospective, USA, peer-reviewed, risk of death, 75.0% lower, RR 0.25, p = 0.09, treatment 2 of 60
12 authors, dosage 200μg/kg days 1, 3. (3.3%), control 8 of 60 (13.3%), NNT 10.0, PSM.

risk of mechanical ventilation, 12.6% lower, RR 0.87, p = 0.20,

treatment 3 of 60 (5.0%), control 2 of 60 (3.3%), adjusted per
study, odds ratio converted to relative risk, propensity score
matching, multivariable.

ventilation time, 83.3% lower, relative time 0.17, p = 0.002,

treatment 60, control 60.

risk of ICU admission, 48.7% lower, RR 0.51, p = 0.42, treatment

6 of 60 (10.0%), control 3 of 60 (5.0%), adjusted per study, odds
ratio converted to relative risk, propensity score matching,
 multivariable.

ICU time, 70.6% lower, relative time 0.29, p < 0.001, treatment
60, control 60.

hospitalization time, 9.0% higher, relative time 1.09, p = 0.09,

treatment 60, control 60, adjusted per study, propensity score
matching, multivariable.

Podder, 9/3/2020, Randomized Controlled Trial, recovery time from enrollment, 16.1% lower, relative time 0.84,
Bangladesh, peer-reviewed, 4 authors, study period p = 0.34, treatment 32, control 30.
1 May, 2020 - 31 July, 2020, average treatment
delay 7.0 days, dosage 200μg/kg single dose.

Pott-Junior, 3/9/2021, Randomized Controlled Trial, risk of mechanical ventilation, 85.2% lower, RR 0.15, p = 0.25,
Brazil, peer-reviewed, 10 authors, study period 1 treatment 1 of 27 (3.7%), control 1 of 4 (25.0%), NNT 4.7.
July, 2020 - 1 December, 2020, average treatment
delay 8.0 days, dosage 200μg/kg single dose, dose risk of ICU admission, 85.2% lower, RR 0.15, p = 0.25, treatment
varies in three arms 100, 200, 400μg/kg, trial 1 of 27 (3.7%), control 1 of 4 (25.0%), NNT 4.7.
NCT04431466 (history).

relative improvement in Ct value, 0.8% better, RR 0.99, p = 1.00,

treatment 27, control 3.

risk of no viral clearance, 11.1% higher, RR 1.11, p = 1.00,

treatment 10 of 27 (37.0%), control 1 of 3 (33.3%), primary
outcome.

Qadeer, 8/31/2022, prospective, Pakistan, peer- risk of no viral clearance, 58.3% lower, RR 0.42, p < 0.001,
reviewed, median age 55.4, 6 authors, study period treatment 35 of 105 (33.3%), control 84 of 105 (80.0%), NNT
1 November, 2020 - 30 May, 2021, dosage 12mg 2.1, mid-recovery, day 10.
days 1-5, excluded in exclusion analyses: minimal
baseline details provided. risk of no viral clearance, 20.0% lower, RR 0.80, p < 0.001,
treatment 84 of 105 (80.0%), control 105 of 105 (100.0%), NNT
5.0, day 7.

risk of no viral clearance, 98.6% lower, RR 0.01, p < 0.001,

treatment 0 of 105 (0.0%), control 35 of 105 (33.3%), NNT 3.0,
relative risk is not 0 because of continuity correction due to zero
events (with reciprocal of the contrasting arm), day 14.

Rajter, 10/13/2020, retrospective, propensity score risk of death, 46.0% lower, RR 0.54, p = 0.045, treatment 13 of
matching, USA, peer-reviewed, 6 authors, dosage 98 (13.3%), control 24 of 98 (24.5%), NNT 8.9, adjusted per
200μg/kg single dose. study, odds ratio converted to relative risk, PSM.

risk of death, 66.9% lower, RR 0.33, p = 0.03, treatment 26 of

173 (15.0%), control 27 of 107 (25.2%), NNT 9.8, adjusted per
study, odds ratio converted to relative risk, multivariate, primary
outcome.

risk of mechanical ventilation, 63.6% lower, RR 0.36, p = 0.10,

treatment 4 of 98 (4.1%), control 11 of 98 (11.2%), NNT 14,
matched cohort excluding intubated at baseline.

Ravikirti, 4/6/2022, retrospective, India, preprint, 7 risk of death, 2.8% lower, RR 0.97, p = 0.82, treatment 53 of
authors, study period 1 April, 2021 - 15 May, 2021, 171 (31.0%), control 254 of 794 (32.0%), NNT 100, odds ratio
dosage varies, excluded in exclusion analyses: converted to relative risk.
exclusion of patients in less severe condition,
data/analysis concerns.

Rezai (B), 6/16/2022, Double Blind Randomized risk of death, 30.8% lower, RR 0.69, p = 0.36, treatment 13 of
Controlled Trial, placebo-controlled, Iran, peer- 311 (4.2%), control 18 of 298 (6.0%), NNT 54.
reviewed, mean age 53.8, 29 authors, study period
19 February, 2021 - 14 August, 2021, average risk of mechanical ventilation, 50.0% lower, RR 0.50, p = 0.07,
treatment delay 7.18 days, dosage 400μg/kg days treatment 311, control 298.
1-3, trial IRCT20111224008507N5, excluded in
exclusion analyses: multiple critical issues, see
risk of ICU admission, 16.0% lower, RR 0.84, p = 0.47, treatment
study page.
311, control 298.

hospitalization time, 11.5% higher, relative time 1.11, p = 0.009,

treatment mean 7.98 (±4.4) n=311, control mean 7.16 (±3.2)
n=298.

deterioration, 12.7% higher, RR 1.13, p = 0.74, treatment 20 of

311 (6.4%), control 17 of 298 (5.7%).

risk of no recovery, 24.2% lower, RR 0.76, p = 0.02, treatment

311, control 298, inverted to make RR<1 favor treatment, post-
hoc primary outcome.

risk of no recovery, 64.0% lower, RR 0.36, p = 0.06, treatment 5

of 145 (3.4%), control 10 of 105 (9.5%), NNT 16, day 7, cough.

risk of no recovery, 76.0% lower, RR 0.24, p = 0.38, day 7,

tachypnea.

Rezk, 10/30/2021, prospective, Egypt, peer- risk of death, 80.0% lower, RR 0.20, p = 0.50, treatment 0 of
reviewed, 4 authors, dosage 36mg days 1, 3, 6. 160 (0.0%), control 2 of 160 (1.2%), NNT 80, relative risk is not
0 because of continuity correction due to zero events (with
reciprocal of the contrasting arm).

risk of progression, 55.6% lower, RR 0.44, p = 0.06, treatment 8

of 160 (5.0%), control 18 of 160 (11.2%), NNT 16, 2 weeks,
including deaths.

risk of no recovery, 33.4% lower, RR 0.67, p = 0.27, treatment 14

of 145 (9.7%), control 20 of 138 (14.5%), NNT 21, 4 weeks,
more patients were lost to followup in the control group.

time to viral-, 27.3% lower, relative time 0.73, p = 0.01,

treatment 160, control 160.

Sarojvisut, 12/12/2022, Randomized Controlled risk of ICU admission, 103.8% higher, RR 2.04, p = 0.62,
Trial, Thailand, peer-reviewed, 8 authors, study treatment 2 of 157 (1.3%), control 1 of 160 (0.6%).
period 1 October, 2021 - 31 May, 2022, dosage
400μg/kg days 1-5, trial TCTR20220427005. risk of no improvement, 103.8% higher, RR 2.04, p = 0.62,
treatment 2 of 157 (1.3%), control 1 of 160 (0.6%).

recovery time, 3.8% lower, relative time 0.96, p = 0.63,

treatment 157, control 160.

Shahbaznejad, 1/19/2021, Double Blind risk of death, 197.1% higher, RR 2.97, p = 1.00, treatment 1 of
Randomized Controlled Trial, Iran, peer-reviewed, 8 35 (2.9%), control 0 of 34 (0.0%), continuity correction due to
authors, average treatment delay 6.29 days, dosage zero event (with reciprocal of the contrasting arm), patient died
200μg/kg single dose, trial within 24 hours of admission.
IRCT20111224008507N3.
risk of mechanical ventilation, 94.3% higher, RR 1.94, p = 1.00,
treatment 2 of 35 (5.7%), control 1 of 34 (2.9%).

recovery time, 31.6% lower, relative time 0.68, p = 0.048,

treatment 35, control 34, duration of dsypnea.

recovery time, 19.2% lower, relative time 0.81, p = 0.02,

treatment 35, control 34, duration of all symptoms, primary
outcome.

hospitalization time, 15.5% lower, relative time 0.85, p = 0.02,

treatment 35, control 34.

Shimizu, 12/31/2021, retrospective, Japan, peer- risk of death, 99.9% lower, HR 0.001, p < 0.001, treatment 0 of
reviewed, 11 authors, study period December 2020 39 (0.0%), control 8 of 49 (16.3%), NNT 6.1, adjusted per study,
- May 2021, dosage 200μg/kg days 1, 14. Cox proportional hazard regression.

ventilator free days, 47.9% lower, OR 0.52, p = 0.03, treatment

39, control 49, adjusted per study, inverted to make OR<1 favor
treatment, proportional odds logistic regression, primary
outcome, RR approximated with OR.

ventilation time, 38.5% lower, relative time 0.62, p < 0.001,

treatment 39, control 49.

ICU free days, 42.8% lower, OR 0.57, p = 0.06, treatment 39,

control 49, adjusted per study, inverted to make OR<1 favor
treatment, proportional odds logistic regression, RR
approximated with OR.

ICU time, 37.5% lower, relative time 0.62, p < 0.001, treatment
39, control 49.

GI complications while ventilated, 77.9% lower, RR 0.22, p =

0.03, treatment 39, control 49, adjusted per study, Cox
proportional hazard regression.

Soto, 3/2/2022, retrospective, Peru, peer-reviewed, risk of death, 41.0% higher, HR 1.41, p = 0.001, treatment 280
median age 58.0, 10 authors, study period April of 484 (57.9%), control 374 of 934 (40.0%), adjusted per study,
2020 - August 2020, dosage not specified, multivariable.
excluded in exclusion analyses: substantial
unadjusted confounding by indication likely;
substantial confounding by time possible due to
significant changes in SOC and treatment
propensity near the start of the pandemic.

Soto-Becerra, 10/8/2020, retrospective, database risk of death, 17.1% lower, HR 0.83, p = 0.01, treatment 92 of
analysis, Peru, preprint, median age 59.4, 4 203 (45.3%), control 1,438 of 2,630 (54.7%), NNT 11, IVM vs.
authors, study period 1 April, 2020 - 19 July, 2020, control day 43 (last day available) weighted KM from figure 3,
dosage 200μg/kg single dose, excluded in per the pre-specified rules, the last available day mortality
exclusion analyses: substantial unadjusted results have priority.
confounding by indication likely; includes PCR+
patients that may be asymptomatic for COVID-19 risk of death, 39.0% higher, HR 1.39, p = 0.16, treatment 47 of
but in hospital for other reasons. 203 (23.2%), control 401 of 2,630 (15.2%), adjusted per study,
day 30, Table 2, IVM wHR, primary outcome.
Spoorthi, 11/14/2020, prospective, India, peer- recovery time, 21.1% lower, relative time 0.79, p = 0.03,
reviewed, 2 authors, dosage not specified, this trial treatment 50, control 50.
uses multiple treatments in the treatment arm
(combined with doxycycline) - results of individual hospitalization time, 15.5% lower, relative time 0.84, p = 0.01,
treatments may vary. treatment 50, control 50.

Thairu, 2/25/2022, retrospective, Nigeria, peer- risk of death, 87.9% lower, RR 0.12, p = 0.12, treatment 0 of 21
reviewed, mean age 41.7, 6 authors, study period (0.0%), control 4 of 26 (15.4%), NNT 6.5, relative risk is not 0
April 2021 - November 2021, dosage 200μg/kg because of continuity correction due to zero events (with
days 1-5, excluded in exclusion analyses: reciprocal of the contrasting arm), propensity score matching.
significant confounding by time possible due to
separation of groups in different time periods. risk of death, 93.0% lower, RR 0.07, p = 0.007, treatment 0 of 61
(0.0%), control 4 of 26 (15.4%), NNT 6.5, relative risk is not 0
because of continuity correction due to zero events (with
reciprocal of the contrasting arm), all patients.

time to discharge, 54.6% lower, relative time 0.45, p < 0.001,

treatment 61, control 26, propensity score matching.

risk of no viral clearance, 94.8% lower, RR 0.05, p = 0.001,

treatment 0 of 21 (0.0%), control 10 of 26 (38.5%), NNT 2.6,
relative risk is not 0 because of continuity correction due to zero
events (with reciprocal of the contrasting arm), propensity score
matching, day 21.

risk of no viral clearance, 95.2% lower, RR 0.05, p < 0.001,

treatment 1 of 21 (4.8%), control 26 of 26 (100.0%), NNT 1.1,
propensity score matching, day 14.

risk of no viral clearance, 28.6% lower, RR 0.71, p = 0.005,

treatment 15 of 21 (71.4%), control 26 of 26 (100.0%), NNT 3.5,
propensity score matching, day 5.

Varnaseri, 4/30/2024, Double Blind Randomized risk of mechanical ventilation, 81.8% lower, RR 0.18, p = 0.02,
Controlled Trial, placebo-controlled, Iran, peer- treatment 2 of 55 (3.6%), control 11 of 55 (20.0%), NNT 6.1.
reviewed, 14 authors, study period July 2020 - June
2021, dosage 14mg bid days 1-3. risk of ICU admission, 83.3% lower, RR 0.17, p < 0.001,
treatment 3 of 55 (5.5%), control 18 of 55 (32.7%), NNT 3.7.

hospitalization time, 33.3% lower, relative time 0.67, p < 0.001,

treatment 55, control 55.

recovery time, 28.4% lower, relative time 0.72, p < 0.001,

treatment 55, control 55, all symptoms combined.

recovery time, 25.0% lower, relative time 0.75, p < 0.001,

treatment 55, control 55, dyspnea.

recovery time, 25.0% lower, relative time 0.75, p < 0.001,

treatment 55, control 55, fever.

recovery time, 25.0% lower, relative time 0.75, p < 0.001,

treatment 55, control 55, shivering.

recovery time, 40.0% lower, relative time 0.60, p < 0.001,

treatment 55, control 55, cough.
 recovery time, 37.5% lower, relative time 0.62, p = 0.09,
treatment 55, control 55, sore throat.

recovery time, 25.0% lower, relative time 0.75, p = 0.01,

treatment 55, control 55, nausea.

recovery time, 37.5% lower, relative time 0.62, p = 0.005,

treatment 55, control 55, diarrhea.

recovery time, 40.0% lower, relative time 0.60, p < 0.001,

treatment 55, control 55, myalgia.

Wada, 5/22/2023, Double Blind Randomized risk of progression, 19.0% lower, RR 0.81, p = 0.46, treatment
Controlled Trial, placebo-controlled, Japan, peer- 19 of 106 (17.9%), control 23 of 106 (21.7%), NNT 26, adjusted
reviewed, 26 authors, study period August 2020 - per study, odds ratio converted to relative risk.
October 2021, average treatment delay 6.6 days,
dosage 200μg/kg single dose, trial NCT04703205 risk of progression, 27.1% lower, RR 0.73, p = 0.47, treatment 7
(history). of 28 (25.0%), control 9 of 29 (31.0%), NNT 17, adjusted per
study, odds ratio converted to relative risk, pneumonia for
patients w/o pneumonia at baseline.

risk of oxygen therapy, 14.3% higher, RR 1.14, p = 0.46,

treatment 22 of 106 (20.8%), control 19 of 106 (17.9%),
adjusted per study, odds ratio converted to relative risk.

improvement, 23.5% worse, OR 1.23, p = 0.61, treatment 106,

control 106, adjusted per study, inverted to make OR<1 favor
treatment, RR approximated with OR.

risk of no recovery, 60.0% lower, RR 0.40, p = 0.17, treatment 4

of 107 (3.7%), control 10 of 107 (9.3%), NNT 18, day 15,
dyspnea.

risk of no recovery, 20.0% lower, RR 0.80, p = 1.00, treatment 4

of 107 (3.7%), control 5 of 107 (4.7%), NNT 107, day 15,
headache.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 7 of

107 (6.5%), control 7 of 107 (6.5%), day 15, sore throat.

risk of no recovery, 18.2% lower, RR 0.82, p = 0.81, treatment 9

of 107 (8.4%), control 11 of 107 (10.3%), NNT 53, day 15, nasal
discharge.

risk of no recovery, 3.8% higher, RR 1.04, p = 1.00, treatment 27

of 107 (25.2%), control 26 of 107 (24.3%), day 15, cough.

risk of no recovery, no change, RR 1.00, p = 1.00, treatment 18

of 107 (16.8%), control 18 of 107 (16.8%), day 15, sputum.

risk of no recovery, 20.0% lower, RR 0.80, p = 1.00, treatment 4

of 107 (3.7%), control 5 of 107 (4.7%), NNT 107, day 15,
diarhhea.

risk of no recovery, 66.7% higher, RR 1.67, p = 0.72, treatment 5

of 107 (4.7%), control 3 of 107 (2.8%), day 15, myalgia.
 risk of no recovery, 1000.0% higher, RR 11.00, p = 0.06,
treatment 5 of 107 (4.7%), control 0 of 107 (0.0%), continuity
correction due to zero event (with reciprocal of the contrasting
arm), day 15, arthralgia.

risk of no viral clearance, 4.2% higher, HR 1.04, p = 0.79,

treatment 106, control 106, inverted to make HR<1 favor
treatment, Kaplan–Meier, primary outcome.

Zubair, 1/18/2022, retrospective, Pakistan, peer- risk of death, 9.0% higher, RR 1.09, p = 1.00, treatment 5 of 90
reviewed, 8 authors, study period October 2020 - (5.6%), control 5 of 98 (5.1%), unadjusted.
February 2021, dosage 12mg single dose, excluded
in exclusion analyses: substantial unadjusted hospitalization time, 8.0% higher, relative time 1.08, p = 0.40,
confounding by indication likely; unadjusted results treatment 90, control 98, unadjusted, Table 3, mean number of
with no group details. days.

Prophylaxis.

Effect extraction follows pre-specified rules as detailed above and gives priority to more serious outcomes. Only the
first (most serious) outcome is used in pooled analysis, which may differ from the effect a paper focuses on. Other
outcomes are used in outcome specific analyses.

Alam, 12/15/2020, prospective, Bangladesh, peer- risk of case, 90.6% lower, RR 0.09, p < 0.001, treatment 4 of 58
reviewed, 13 authors, dosage 12mg monthly. (6.9%), control 44 of 60 (73.3%), NNT 1.5.

Behera (B), 2/15/2021, prospective, India, peer- risk of case, 83.0% lower, RR 0.17, p < 0.001, treatment 45 of
reviewed, 14 authors, dosage 300μg/kg days 1, 4. 2,199 (2.0%), control 133 of 1,147 (11.6%), NNT 10, two doses,
primary outcome.

Behera, 11/3/2020, retrospective, India, peer- risk of case, 53.8% lower, RR 0.46, p < 0.001, treatment 41 of
reviewed, 13 authors, dosage 300μg/kg days 1, 4. 117 (35.0%), control 145 of 255 (56.9%), NNT 4.6, adjusted per
study, odds ratio converted to relative risk, model 2 2+ doses
conditional logistic regression.

Bernigaud, 11/28/2020, retrospective, France, peer- risk of death, 99.4% lower, RR 0.006, p = 0.08, treatment 0 of
reviewed, 12 authors, dosage 200μg/kg days 1, 8, 69 (0.0%), control 150 of 3,062 (4.9%), NNT 20, relative risk is
15, 400μg/kg days 1, 8, 15, two different dosages. not 0 because of continuity correction due to zero events (with
reciprocal of the contrasting arm).

risk of case, 55.1% lower, RR 0.45, p = 0.01, treatment 7 of 69

(10.1%), control 692 of 3,062 (22.6%), NNT 8.0.

Carvallo, 11/17/2020, prospective, Argentina, peer- risk of case, 99.9% lower, RR 0.001, p < 0.001, treatment 0 of
reviewed, 4 authors, dosage 12mg weekly, this trial 788 (0.0%), control 237 of 407 (58.2%), NNT 1.7, relative risk is
uses multiple treatments in the treatment arm not 0 because of continuity correction due to zero events (with
(combined with iota-carrageenan) - results of reciprocal of the contrasting arm).
individual treatments may vary, excluded in
exclusion analyses: concern about potential data
issues.

Carvallo (B), 10/19/2020, prospective, Argentina, risk of case, 96.3% lower, RR 0.04, p < 0.001, treatment 0 of
preprint, 1 author, dosage 1mg days 1-14, this trial 131 (0.0%), control 11 of 98 (11.2%), NNT 8.9, relative risk is
uses multiple treatments in the treatment arm not 0 because of continuity correction due to zero events (with
(combined with iota-carrageenan) - results of reciprocal of the contrasting arm).
individual treatments may vary, trial NCT04425850
(history), excluded in exclusion analyses: concern
about potential data issues.

Chahla (B), 1/11/2021, Randomized Controlled risk of moderate/severe case, 95.2% lower, RR 0.05, p = 0.002,
Trial, Argentina, peer-reviewed, 11 authors, study treatment 0 of 117 (0.0%), control 10 of 117 (8.5%), NNT 12,
period 15 October, 2020 - 31 December, 2020, relative risk is not 0 because of continuity correction due to zero
dosage 12mg weekly, this trial uses multiple events (with reciprocal of the contrasting arm), moderate/severe
treatments in the treatment arm (combined with COVID-19.
iota-carrageenan) - results of individual treatments
may vary, trial NCT04701710 (history). risk of case, 84.0% lower, RR 0.16, p = 0.004, treatment 4 of 117
(3.4%), control 25 of 117 (21.4%), NNT 5.6, adjusted per study,
odds ratio converted to relative risk, all cases, primary outcome.

Desort-Henin, 1/5/2023, Double Blind Randomized risk of case with high viral load, 96.0% lower, RR 0.04, p <
Controlled Trial, placebo-controlled, Bulgaria, 0.001, treatment 4 of 200 (2.0%), control 99 of 199 (49.7%),
preprint, 5 authors, study period March 2022 - NNT 2.1.
October 2022, dosage 200μg/kg day 1, 100μg/kg
days 2-28, trial NCT05305560 (history) (SAIVE). risk of case, 71.6% lower, RR 0.28, p < 0.001, treatment 30 of
200 (15.0%), control 105 of 199 (52.8%), NNT 2.6, primary
outcome.

Hellwig, 11/28/2020, retrospective, ecological risk of case, 78.0% lower, RR 0.22, p < 0.02, African countries,
study, multiple countries, peer-reviewed, 2 authors, PCTI vs. no PCT, relative cases per capita.
dosage 200μg/kg, dose varied, typically 150-
200μg/kg, excluded in exclusion analyses: not a
typical trial, analysis of African countries that used
or did not use ivermectin prophylaxis for parasitic
infections.

IVERCOR PREP, 12/20/2020, retrospective, risk of case, 73.4% lower, RR 0.27, p < 0.001, treatment 13 of
Argentina, preprint, 1 author, dosage 12mg weekly, 389 (3.3%), control 61 of 486 (12.6%), NNT 11.
excluded in exclusion analyses: minimal details
provided.

Kerr, 12/11/2021, retrospective, propensity score risk of death, 70.0% lower, RR 0.30, p < 0.001, treatment 25 of
matching, Brazil, peer-reviewed, 9 authors, study 3,034 (0.8%), control 79 of 3,034 (2.6%), NNT 56, adjusted per
period July 2020 - December 2020, dosage study, multivariate linear regression, propensity score matching.
200μg/kg days 1, 2, 16, 17, 0.2mg/kg/day for 2
days every 15 days. risk of hospitalization, 67.0% lower, RR 0.33, p < 0.001,
treatment 44 of 3,034 (1.5%), control 99 of 3,034 (3.3%),
adjusted per study, multivariate linear regression, propensity
score matching.

risk of case, 44.5% lower, RR 0.56, p < 0.001, treatment 4,197 of

113,845 (3.7%), control 3,034 of 45,716 (6.6%), NNT 34.

Mondal, 5/31/2021, retrospective, India, peer- risk of symptomatic case, 87.9% lower, RR 0.12, p = 0.006,
reviewed, 11 authors, dosage not specified. treatment 128, control 1,342, adjusted per study, odds ratio
converted to relative risk, control prevalence approximated with
overall prevalence, multivariable, primary outcome.

Moraes, 4/30/2021, Randomized Controlled Trial, Estimated 400 patient RCT with results unknown and over 3
this trial compares with another treatment - results years late.
may be better when compared to placebo, trial
NCT04384458 (history).
 Morgenstern, 4/16/2021, retrospective, propensity risk of hospitalization, 80.0% lower, RR 0.20, p = 0.50,
score matching, Dominican Republic, peer- treatment 0 of 271 (0.0%), control 2 of 271 (0.7%), NNT 136,
reviewed, 16 authors, dosage 200μg/kg weekly, relative risk is not 0 because of continuity correction due to zero
trial NCT04832945 (history). events (with reciprocal of the contrasting arm), PSM.

risk of case, 74.0% lower, RR 0.26, p = 0.008, treatment 5 of 271

(1.8%), control 18 of 271 (6.6%), NNT 21, adjusted per study,
PSM, multivariate Cox regression, primary outcome.

PREVENT-COVID, 6/24/2023, Double Blind Estimated 412 patient RCT with results unknown and over 2
Randomized Controlled Trial, placebo-controlled, years late.
trial NCT05060666 (history) (PREVENT-COVID).

Samajdar, 11/17/2021, retrospective, India, peer- risk of case, 79.8% lower, RR 0.20, p < 0.001, treatment 12 of
reviewed, 9 authors, study period 1 September, 164 (7.3%), control 29 of 81 (35.8%), NNT 3.5, odds ratio
2020 - 31 December, 2020, dosage not specified, converted to relative risk, physician survey.
excluded in exclusion analyses: minimal details
provided; unadjusted results with no group details; risk of case, 48.6% lower, RR 0.51, p = 0.03, treatment 11 of 109
results may be significantly affected by survey bias. (10.1%), control 39 of 200 (19.5%), NNT 11, odds ratio
converted to relative risk, combined ivermectin or HCQ in
community.

Seet, 4/14/2021, Cluster Randomized Controlled risk of symptomatic case, 49.8% lower, RR 0.50, p < 0.001,
Trial, Singapore, peer-reviewed, 15 authors, study treatment 32 of 617 (5.2%), control 64 of 619 (10.3%), NNT 19.
period 13 May, 2020 - 31 August, 2020, dosage
12mg single dose, 200µg/kg, maximum 12mg, this risk of case, 5.8% lower, RR 0.94, p = 0.61, treatment 398 of 617
trial compares with another treatment - results may (64.5%), control 433 of 619 (70.0%), NNT 18, adjusted per
be better when compared to placebo, trial study, odds ratio converted to relative risk, model 6, primary
NCT04446104 (history). outcome.

Shouman (B), 8/28/2020, Randomized Controlled risk of symptomatic case, 91.3% lower, RR 0.09, p < 0.001,
Trial, Egypt, peer-reviewed, 8 authors, study period treatment 15 of 203 (7.4%), control 59 of 101 (58.4%), NNT 2.0,
1 June, 2020 - 28 July, 2020, dosage 18mg days 1, adjusted per study, inverted to make RR<1 favor treatment,
3, dose varies depending on weight - 40-60kg: multivariate, primary outcome.
15mg, 60-80kg: 18mg, >80kg: 24mg, trial
NCT04422561 (history). risk of severe case, 92.9% lower, RR 0.07, p = 0.002, treatment 1
of 203 (0.5%), control 7 of 101 (6.9%), NNT 16, unadjusted.

Tanioka, 3/26/2021, retrospective, ecological study, risk of death, 88.2% lower, RR 0.12, p = 0.002, relative mean
multiple countries, preprint, 3 authors, dosage mortality per million.
200μg/kg, dose varied, typically 150-200μg/kg,
excluded in exclusion analyses: not a typical trial,
analysis of African countries that used or did not
use ivermectin prophylaxis for parasitic infections.

Supplementary Data

Supplementary Data
Footnotes

a. Viral infection and replication involves attachment, entry, uncoating and release, genome replication and transcription,
translation and protein processing, assembly and budding, and release. Each step can be disrupted by therapeutics.

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