Open access Protocol

BMJ Open: first published as 10.1136/bmjopen-2024-085272 on 13 May 2024. Downloaded from [Link] on November 23, 2024 by guest. Protected by copyright.
Low-­dose naltrexone for post-­COVID
fatigue syndrome: a study protocol for a
double-­blind, randomised trial in
British Columbia
Hiten Naik ‍ ‍,1,2 Erin Cooke ‍ ‍,3 Travis Boulter,4,5 Roger Dyer,3
Jeffrey N Bone ‍ ‍,3 Melody Tsai,4,5 Jaymie Cristobal,4,5 R Jane McKay,1
Xiaowei Song,6,7 Luis Nacul4,5,8,9

To cite: Naik H, Cooke E, ABSTRACT

Boulter T, et al. Low-­dose Introduction A significant proportion of individuals
STRENGTHS AND LIMITATIONS OF THIS STUDY
naltrexone for post-­COVID suffering from post COVID-­19 condition (PCC, also ⇒ The trial will be decentralised and will recruit par-
fatigue syndrome: a study ticipants from throughout the geographically large
known as long COVID) can present with persistent,
protocol for a double-­blind, and ethnically diverse Canadian province of British
randomised trial in British
disabling fatigue similar to myalgic encephalomyelitis/
chronic fatigue syndrome (ME/CFS) and post-­viral fatigue Columbia (BC); this will permit the inclusion of pa-
Columbia. BMJ Open
2024;14:e085272. doi:10.1136/ syndromes. There remains no clear pharmacological tients from communities that do not typically have
bmjopen-2024-085272 therapy for patients with this subtype of PCC, which can access to investigational treatments and patients
be referred to as post-­COVID fatigue syndrome (PCFS). A who may be too symptomatic to attend in-­person
► Prepublication history assessments.
low dose of the opioid antagonist naltrexone (ie, low-­dose
and additional supplemental ⇒ In addition to evaluating fatigue severity as the pri-
material for this paper are
naltrexone (LDN)) has emerged as an off-­label treatment
for treating fatigue and other symptoms in PCC. However, mary outcome, the study will capture several sec-
available online. To view these
files, please visit the journal only small, non-­controlled studies have assessed LDN in ondary outcome measures known to be important
online ([Link] PCC, so randomised trials are urgently required. to post COVID-­19 condition patients, including pain,
bmjopen-2024-085272). Methods and analysis A prospective, randomised, overall symptom burden, health-­related quality of
double-­blind, parallel arm, placebo-­controlled phase II life and activity levels (as measured by step count).
HN and EC contributed equally. trial will be performed to assess the efficacy of LDN for ⇒ The study does not have a restriction on how long
improving fatigue in PCFS. The trial will be decentralised a participant may have had their symptoms since
Received 10 February 2024 COVID-­19; this may limit the treatment effect if low-­
Accepted 18 April 2024 and open to eligible individuals throughout the Canadian
province of British Columbia (BC). Participants will be dose naltrexone efficacy is greater earlier in the dis-
recruited through the province-­wide Post-­COVID-­19 ease course.
Interdisciplinary Clinical Care Network (PC-­ICCN) ⇒ As in-­person evaluation is optional, this limits the
and research volunteer platform (REACH BC). Eligible ability to assess potentially important objective out-
participants will be 19–69 years old, have had a confirmed comes in some participants.
or physician-­suspected SARS-­CoV-­2 infection at least 3
months prior and meet clinical criteria for PCFS adapted
from the Institute of Medicine ME/CFS criteria. Individuals Columbia/Children’s and Women’s Health Centre of British
who are taking opioid medications, have a history of ME/ Columbia Research Ethics Board. On completion, findings
will be disseminated to patients, caregivers and clinicians
CFS prior to COVID-­19 or history of significant liver disease
through engagement activities within existing PCC and
will be excluded. Participants will be randomised to an
ME/CFS networks. Results will be published in academic
LDN intervention arm (n=80) or placebo arm (n=80).
journals and presented at conferences.
Participants in each arm will be prescribed identical
Trial registration number NCT05430152.
capsules starting at 1 mg daily and follow a prespecified
schedule for up-­titration to 4.5 mg daily or the maximum
© Author(s) (or their tolerated dose. The trial will be conducted over 16 weeks, INTRODUCTION
employer(s)) 2024. Re-­use with assessments at baseline, 6, 12 and 16 weeks. The Background and rationale
permitted under CC BY-­NC. No primary outcome will be fatigue severity at 16 weeks
commercial re-­use. See rights Approximately 15–20% of adults with a
evaluated by the Fatigue Severity Scale. Secondary
and permissions. Published by confirmed or suspected SARS-­CoV-­2 infection
BMJ.
outcomes will include pain Visual Analogue Scale score,
overall symptom severity as measured by the Patient
experience long-­term symptoms lasting over 3
For numbered affiliations see
Phenotyping Questionnaire Short Form, 7-­day step count months.1–4 The presence of new or persistent
end of article. symptoms following acute COVID-­19 disease
and health-­related quality of life measured by the EuroQol
Correspondence to 5-­Dimension questionnaire. is now referred to as post COVID-­19 condi-
Dr Hiten Naik; Ethics and dissemination The trial has been authorised tion (PCC) or ‘long COVID’.5–11 Among the
​hiten.​naik@u​ bc.​ca by Health Canada and approved by The University of British hundreds of symptoms reported by people

Naik H, et al. BMJ Open 2024;14:e085272. doi:10.1136/bmjopen-2024-085272 1

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with PCC, fatigue is one of the most common and may all touted LDN as a potential PCC treatment, citing the
have the greatest impact on functioning.5 12–20 Given anecdotal experiences of people with PCC and physi-
that millions of individuals may be currently affected by cians.69–76 However, published evidence for LDN in the
PCC worldwide, it has become a priority to investigate post-­COVID-­19 context remains limited. In a single-­centre
the potential treatments in randomised controlled trials study, 52 patients treated with LDN had, on average,
(RCTs).5 21 22 overall improvement in activities of daily living, energy
However, it has been challenging to identify candidate levels, pain, concentration and sleep disturbance.40 In a
treatments for PCC as it is a heterogeneous illness, and retrospective study, 37 of 59 (62.7%) patients treated with
the underlying pathobiology is poorly understood. It is LDN reported improvement in at least one symptom.77
suspected that different groups of people with PCC may RCTs are required to determine whether LDN is an
have distinct underlying disease processes, such that the effective treatment for post-­COVID-­19 symptoms. Since
ideal pharmacological therapy may not be the same for there is no widely accepted pharmacological treatment
all.5 21 Increasingly, studies have suggested that PCC may for PCFS, the ideal comparator group is a placebo.
not represent a single disease but rather a collection of Accordingly, we have designed a double-­blinded placebo-­
different conditions or subtypes.15 23 24 controlled trial of daily LDN versus placebo for the treat-
For example, clinical experience and patient-­centred ment of fatigue severity in PCFS.
studies have indicated that a proportion of people with
PCC present with a symptom profile indistinguish- Objectives
able from myalgic encephalomyelitis/chronic fatigue Study objectives are outlined in table 1. The primary
syndrome (ME/CFS).25–30 ME/CFS is characterised by objective is to determine whether LDN can reduce
persistent disabling fatigue accompanied by other symp- fatigue severity associated with PCFS, as measured by the
toms including non-­restorative sleep and post-­exertional Fatigue Severity Scale (FSS). The secondary objectives
malaise.31–33 While the precise pathogenesis of ME/ are to determine whether it can reduce pain, reduce
CFS also remains unresolved, it usually follows acute symptom severity, improve health-­related quality of life
infections.34 When provoked by a viral infection, ME/ (HRQOL) and increase activity levels. We have developed
CFS is often referred to as a post-­viral fatigue syndrome additional exploratory objectives that examine other
(PVFS).34–37 It is believed that some PCC patients have patient-­
reported outcome measures (PROMs), labora-
developed a PVFS from SARS-­CoV-­2, and we will refer to tory outcomes and physical measurements.
this subset of PCC patients as having ‘post-­COVID fatigue
syndrome’ (PCFS).35–38 Trial design
A low dose of the medication naltrexone is a potential The development of this trial protocol followed the
treatment for PCFS.39 40 Naltrexone is an opiate antag- Standard Protocol Items: Recommendations for Inter-
onist that is approved for treatment for alcohol and ventional Trials (SPIRIT) guidelines.78 This trial is
opiate use disorders.41 For these indications, it is typically designed as a randomised, controlled, double-­blind
prescribed at 25–50 mg.42 At lower doses (≤5 mg), it has prospective trial with two parallel groups and a primary
been used off-­label for chronic pain, multiple sclerosis, end point of fatigue severity at 16 weeks. The inter-
Crohn’s disease, recurrent depression, fibromyalgia (FM) vention group will receive LDN capsules dosed at 1.0
and ME/CFS.43–57 Although evidence supporting the mg to 4.5 mg daily and the control group will receive
use of low-­dose naltrexone (LDN) in ME/CFS has been placebo capsules. Randomisation will be stratified by
limited to case series and chart reviews,46 54 it has been sex and performed as permuted block randomisation
investigated in clinical trials for related conditions such with a 1:1 allocation. The trial will be conducted in
as FM.50 51 54 57 In these and other studies, LDN has been British Columbia (BC), Canada.
shown to be safe with a limited side-­effect profile.49 51–53 57
Based on its hypothesised mechanism of action, it is
plausible that LDN could be efficacious for ME/CFS and METHODS AND ANALYSIS
PCFS. LDN increases circulation of the endogenously Study setting
produced opiate-­ like molecule beta-­ endorphin, which The trial will involve a collaboration between BC’s
is reduced in ME/CFS.58 59 Furthermore, LDN has been Post-­COVID-­ 19 Interdisciplinary Clinical Care
found to antagonise toll-­like receptors on neuroglia and Network (PC-­ ICCN) and the Complex Chronic
peripheral blood mononuclear cells, resulting in reduced Diseases Program (CCDP) at BC Children’s and
production of inflammatory cytokines such as inter- Women’s Hospital and Health Centre (C&W) located
leukin-­6 (IL-­6) and tumour necrosis factor (TNF).60–63 in Vancouver. The PC-­ICCN was founded as a learning
Increased IL-­6 and TNF signalling have been implicated health system for post-­COVID-­19 care and research in
in PCC,64 and studies have implicated increased neuroin- BC.79–82 The network previously comprised of five phys-
flammation in ME/CFS and PCC pathogenesis.5 65–68 ical Post-­COVID Recovery Clinics (PCRCs) but has now
There is ongoing public interest in investigating LDN consolidated to a single virtual programme. Adults
for PCC. Media outlets including Rolling Stone, National throughout BC may be referred to this programme
Geographic, Reuters and The New York Times Magazine have by their primary care provider (PCP) if they have had

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Table 1 Summary of study objectives and associated outcomes
Primary objective Primary outcome
To determine if LDN, administered at 1–4.5 mg/day to individuals with FSS score at 16 weeks.
PCFS, reduces fatigue severity.

Secondary objectives Secondary outcomes

To determine if LDN, administered at 1–4.5 mg/day to Reduces pain. Pain VAS score at 16 weeks.
individuals with PCFS: Improves severity of symptoms PQSymp-­12 score at 16 weeks.
associated with PCFS.
Increases activity levels. Average number of steps over 7 days at
16 weeks.
Improves self-­reported quality of life. EQ-­5D-­5L health utility score at 16
weeks.

Exploratory objectives Exploratory outcomes

To determine if LDN, administered Reduces inflammatory marker values in IL-­6, IFNγ and CRP values at 16 weeks.
at 1–4.5 mg/day to individuals with peripheral blood. Cytokine profile values using Human Cytokine
PCFS: Proinflammatory Focused 15-­plex Discovery Assay Array at
16 weeks.
Improves disease severity associated CK level at 16 weeks.
with PCFS.124
Improves rT3 as an indirect marker of rT3 in conjunction with TSH, free T3 and free T4 at 16
disease severity.125 weeks.
Improves AM blood cortisol and improves AM blood cortisol level at 16 weeks.
ACTH. ACTH level at 16 weeks.
Reduces fatigue VAS score. Fatigue VAS score at 16 weeks.
Improves sleep. SQ-­2 at 16 weeks.
Sleep VAS score at 16 weeks.
Improves depression symptoms. PHQ-­9 score at 16 weeks.
Improves anxiety symptoms. GAD-­7 score at 16 weeks.
Improves self-­reported health. Self-­reported health VAS score at 16 weeks.
Improves functional status. Post-­COVID-­19 Functional Status Scale at 16 weeks.
Reduces prevalence markers of POTS or Prevalence of POTS or postural hypotension symptoms
postural hypotension.* based on serial blood pressure and heart rate
measurements at 16 weeks.
Improves clinical endurance/strength Hand grip strength at 16 weeks.126
parameters in subjects with PCFS.* Sit and stand test results at 16 weeks.

*Optional in-­person visits.

ACTH, adrenocorticotropic hormone; CK, creatine kinase; CRP, C reactive protein; EQ-­5D-­5L, EuroQol 5 Dimension 5-­level; FSS, Fatigue Severity
Scale; GAD-­7, General Anxiety Disorder-­7; IFN, interferon; IL-­6, interleukin-­6; LDN, low-­dose naltrexone; PCFS, post-­COVID fatigue syndrome;
PHQ-­9, Patient Health Questionnaire-­9; POTS, postural orthostatic tachycardia syndrome; PQSymp-­12, Patient Phenotyping Questionnaire Short
Form-­12; rT3, reverse triiodothyronine; SQ-­2, Sleep Questionnaire-­2; T3, triiodothyronine; T4, thyroxine; TSH, thyroid stimulating hormone; VAS,
Visual Analogue Scale.

COVID-­19 and meet the criteria for PCC. The CCDP is a SARS-­CoV-­2 infection and meet the criteria we have
an interdisciplinary programme that supports patients developed for PCFS. These criteria are adapted from the
with ME/CFS and related conditions.83 Institute of Medicine (IOM) ME/CFS standard clinical
Eligible participants will be recruited from criteria,33 but with a duration of symptoms of 3 months
throughout BC. Participants will have virtual or rather than 6 months to be consistent with PCC defini-
in-­person study visits, may have their study product tions (box 1).11 Diagnosis for eligibility purposes will be
and pedometer delivered to them, complete question- determined from clinical assessment by a study physician
naires electronically and have blood tests done at their and supported by laboratory data and responses to the
local laboratories. The collection of exploratory data
screening and baseline questionnaires. If there is clin-
during in-­person visits will be optional.
ical uncertainty regarding the diagnosis, the case will be
Eligibility criteria discussed with a second physician. Participants who do
Inclusion and exclusion criteria are listed in table 2. To not have a documented positive PCR test will be eligible
be included, participants must be aged 19–69 years, have if they are determined by a physician through medical
significant fatigue and related symptoms that started after history to have had a positive rapid antigen test (RAT)

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Table 2 Inclusion and exclusion criteria
Inclusion criteria Exclusion criteria
1. Male and female patients aged 19 to less than 70 years. 1. Pregnant, planning to become pregnant or breast feeding.
2. Case of SARS-­CoV-­2 over 3 months previously, confirmed 2. Use of opioid medications within last 15 days, as reported
by a positive test result or clinical confirmation by a by the patient or during the trial.
physician. 3. A positive urine test for opioids (only for the first 16
3. Meet the clinical diagnostic criteria for PCFS (box 1). participants; see below).
4. Agree to maintain any other regular medications at current 4. History of alcohol, opioid or other substance misuse.
doses for the duration of the trial (except for essential need 5. Participation in another interventional clinical trial in the last
of new medication or dose change, as prescribed by a 30 days or planned during the trial period.
physician). 6. Confirmed ME/CFS or FM existing prior to SARS-­CoV-­2
5. Agree to use effective contraception for the trial duration, infection.
as appropriate (if female). 7. Allergy to naltrexone or medication components.
6. The participant resides within the delivery area for the drug 8. Acute hepatitis, liver failure or severe kidney failure.
as determined by FedEx Clinical Trial Services. 9. Current or recent use of naltrexone within 30 days.
FM, fibromyalgia; ME/CFS, myalgic encephalomyelitis/chronic fatigue syndrome; PCFS, post-­COVID-­19 fatigue syndrome.

or compatible symptoms. Individuals will be excluded if (Flocel 101).85 Placebo capsules will look identical to
they have a history of ME/CFS prior to SARS-­CoV-­2 infec- the compounded LDN capsules and filled with the same
tion, have significant liver disease, have taken naltrexone diluent and food colouring. We will complete batch
within 30 days or have taken opioids within 15 days. testing of the LDN and placebo compounds (online
supplemental appendix 1).
Interventions The dose-­ titration schedule from 1 mg to 4.5 mg is
Eligible participants will be randomised at a ratio of 1:1 outlined in table 3. The drug will be dispensed to partic-
(n=80 each) into either an active treatment group with ipants by certified courier, temperature-­controlled ship-
LDN or a placebo. The treatment duration is 16 weeks. ping, in-­person pick-­up or delivered by staff. Participants
The LDN and placebo will be compounded by Macdon- will be able to adjust treatment doses by reverting to the
ald’s Prescriptions Labs (Vancouver, BC) and dispensed previous well-­tolerated dose if they experience persistent
at the C&W Pharmacy where the blinding will occur. but minor side effects following any increase in dose. If a
Macdonald’s Prescriptions Labs will compound the participant has reverted to a previous dose, that dosage
required doses of LDN from Naltrexone Hydrochlo- will be maintained for the remainder of the study period.
ride USP supplied by MEDISCA in empty gelatin CONI-­ Changes in doses will be documented by the participant
SNAP capsules.84 The compounded LDN capsules will by completing a daily dosing diary, completed for the first
be filled with CELLULOSE, NF/EP (Microcrystalline) 4 weeks and 7 days after any change in dose.
By allowing participants to reduce doses if experi-
encing any potential side effects, we expect low rates
Box 1 Study diagnostic criteria of post-­COVID fatigue
syndrome
Table 3 Product supply timeline and titration schedule
Diagnosis requires that the patient have the following three symptoms
after a SARS-­CoV-­2 infection: Week(s) Supply Dose Capsules
⇒ A substantial reduction or impairment in the ability to engage in 1 First 1 mg/day 1 mg capsule
pre-­illness levels of activity (occupational, educational, social or 2 First 2 mg/day Two 1 mg capsule
personal life) that:
⇒ lasts for more than 3 months. 3 First 3 mg/day Three 1 mg capsules
⇒ is accompanied by fatigue that is: 4–6 First 4.5 mg/day Three 1 mg capsules,
⇒ often profound, plus one 1.5 mg capsule
⇒ of new onset (not life-­long), 7–16 Second 4.5 mg/day* One 4.5 mg capsule*
⇒ not the result of ongoing or unusual excessive exertion,
⇒ not substantially alleviated by rest. There will be two dispensing time points when participants will be
⇒ Post-­exertional malaise. supplied with the study product. The first supply will be for weeks
1–6 and the second supply will be for weeks 7–16 of the study. For
⇒ Unrefreshing sleep.
the first supply, participants will receive 1 mg and 1.5 mg capsules
At least one of the two manifestations must be present:
of the study product (low-­dose naltrexone or placebo). They will
⇒ Cognitive impairment. be asked to up-­titrate the dosage as tolerated and keep a diary
⇒ Orthostatic intolerance. of their dosage. In the second dispensing period, they will be
AND supplied with capsules of their maximum tolerated dose.
Absence of other diseases or conditions that explain symptoms, based *Or maximum tolerated dosage (ie, one 1 mg capsule, one 2 mg
on differential diagnosis. capsule or one 3 mg capsule).

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of medication use interruption. In addition to diaries, There will be several exploratory outcomes (online
participants may also have visits or contact with the study supplemental table S1), including PROMs (fatigue VAS,
team where adherence can be discussed. Furthermore, sleep, depression symptoms, anxiety symptoms, self-­
there are treatment compliance questions asked with reported health and functional status), laboratory based
each series of questionnaires. The participants will be (inflammatory markers, CK, thyroid profile, AM cortisol
asked to return the unused study drug, empty containers and ACTH level) and based on physical measurements
and study drug diary sheet(s). (grip strength, sit and stand test, and orthostatic changes
Participants will be asked to maintain any other regular in vitals). Physical measurements will be limited to partic-
medications at their current doses for the duration of the ipants who choose to attend in-­person visits.
trial unless there is an essential need for a new medication
or dose change. Participants can withdraw from the study MRI study
at any time without giving reasons. Withdrawal criteria As a sub-­study of the RCT, 25 participants of each study
arm are planned to have brain MRI scans at baseline
are described in online supplemental box S1.
prior to the intervention/placebo and at 16 weeks. A
multimodal functional and spectroscopy (fMRI/MRS)
Outcome measures protocol piloted in an ME/CFS study (REB# H20-­01804,
The primary outcome measure is fatigue severity, as unpublished) will be employed (online supplemental
measured by the FSS. The FSS is a 9-­item PROM scored figure S1). MRI findings will be linked to the primary and
from 9 (least fatigue) to 63 (most fatigue).86 A score of >36 other outcome measures.
is consistent with clinically significant fatigue.87 88 The FSS
has been validated in multiple diseases and has been used Participant timeline
in randomised trials for ME/CFS.87 89–91 The FSS received The participant timeline is detailed in figure 1 and table 4.
the highest level of recommendation of any subjective
fatigue measure for ME/CFS by the National Institute Sample size
of Neurological Disorders and Stroke Common Data The sample size was calculated based on the primary
Elements (NINDS CDE) Project and was a recommended hypothesis of reduction in fatigue severity with treatment.
measure by the Post-­COVID-­19 Core Outcome Set (PC-­ To detect a 4.7-­point difference (effect size (d)=0.5) in
COS) initiative.17 18 92–95 We have previously investigated the Fatigue Severity Scale (FSS) (9–63) between arms,
the FSS in patients with PCC in BC and demonstrated we estimate a sample size of 64 participants per arm
that the instrument has strong acceptability, internal assuming 80% power, 5% significance and a pooled SD
consistency and construct validity in this population.17 of 9.4 (estimated from the CCDP Data Registry).83 To
Secondary PROMs will include pain severity as account for possible loss to follow-­up of 20%, we estimate
measured by the pain Visual Analogue Scale (VAS); total a final sample size of 80 per arm, for a total target sample
symptom score on the Patient Phenotyping Question- size of 160 participants. We chose this method for sample
naire Short Form (PQSymp-­12) and HRQOL captured size estimation (as opposed to the use of a minimal clini-
by the EQ-­5D-­5L instrument. Pain is a common symptom cally important difference (MCID)) because we believed
this to be a realistic treatment effect and there were no
in PCC, and studies have suggested that LDN may be an
published MCID values available for the FSS in ME/CFS
effective analgesic.5 16 43 49 52 53 55 The pain VAS is a single-­
or PCC.103 104 In a sensitivity analysis, we calculated sample
item tool that has been shown to have strong psycho-
size using a published MCID for systemic lupus erythema-
metric properties among patients with chronic pain.96
tosus and this yielded a similar estimate (online supple-
The PQSymp-­12 is a 12-­item questionnaire that covers
mental appendix 2).105
seven clusters of symptoms derived from the Canadian
Consensus Criteria for ME/CFS; it has been recom- Recruitment and screening
mended as a core assessment measure for ME/CFS by the New PC-­ ICCN patients will be contacted regarding
European Network on ME/CFS (EUROMENE)97 and is study participation, and the PC-­ICCN directory will
included in the UK ME/CFS biobank.98 The EQ-­5D-­5L be used to identify other candidate PCC patients to
is a generic HRQOL instrument that was recommended contact. Additionally, the trial will be accessible to
by PC-­COS.95 By applying Canadian preference weights, individuals through REACH BC, a provincial online
responses to the EQ-­5D will be used to derive a health platform that facilitates connections between research
utility (HU) score from 0 (dead) to 1 (perfect health).99 studies and participants. All potential participants will
An additional secondary outcome is the average step be asked to complete an online pre-­screening ques-
count. We will ask participants to wear a pedometer and tionnaire, and those potentially eligible will meet with
document daily step counts for 7 days prior to starting the research staff to provide consent. Consented partic-
study drug and again in week 16. All participants will use ipants will complete baseline questionnaires and be
the same brand and type of pedometer (OZO Fitness CS1 assessed by a physician to confirm eligibility. Baseline
Easy Walk Pedometer). Step counts have been used previ- laboratory studies for all participants will be done
ously in randomised trials to measure a change in activity prior to initiation of the study drug and abnormal
levels among patients with ME/CFS.91 100–102 results will be reviewed by a study physician.

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Figure 1 Flowchart of initial study procedures. This flowchart outlines the process for study recruitment, eligibility assessment
and baseline assessments. A full study timeline is outlined in table 4. BC, British Columbia; LDN, low-­dose naltrexone; PCC,
post-­COVID-­19 condition; PC-­ICCN, Post-­COVID-­19 Interdisciplinary Clinical Care Network; SAQ, Short Answer Questionnaire.

Allocation Pharmacy. After confirmation of eligibility, research

Participants will be randomised into either the LDN staff will randomise participants by REDCap, which
treatment group or the placebo at a ratio of 1:1 will provide the randomisation code. CWH Pharmacy
(n=80 each), as per a computer-­generated randomis- staff will then dispense the study drug based on the
ation schedule stratified by sex and using permuted randomisation allocation sequence.
blocks varying between two, four and six partici-
pants. A statistician who is not part of the study team Blinding
will generate a randomisation sequence and corre- All participants will be blinded to their treatment
sponding randomisation codes. The randomisation regimen. The placebo and intervention capsules will
codes will be used to maintain the blinding and will be appear identical, and the C&W Pharmacy will distribute
uploaded to REDCap. The randomisation sequence the study drug to study staff in identical containers.
will be provided to the unblinded CWH Research Participants, their healthcare providers and all study staff

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Table 4 Participant timeline and schedule of study procedures
Screening
Timepoint and baseline Week 1 Weeks 4–5 Week 6 Week 12 Week 16
ENROLMENT:
 Eligibility screening by research staff and study X
physician
 Informed consent X
 Allocation X
INTERVENTIONS:
 Study drug (LDN or placebo) X X X X X X
 Study drug diary (daily for first 4 weeks and for X X X
7 days after any change in dose)
VISITS:
 Adverse effects check X X X* X* X
*
 Monitor study drug use X X X* X X
ASSESSMENTS:
 Questionnaires† X X X X
 Laboratory investigations X X
 Pedometer (number of steps per day) X X
 Hand grip (muscle strength)‡ X X
 Blood pressure and heart rate‡ X X
 Sit and stand test‡ X X
This table outlines the schedule of study procedures. See figure 1 for timeline of recruitment, eligibility screening and baseline assessments.
*Occurs as part of questionnaires if optional visit does not occur.
†Short answer questionnaire for demographic and clinical information is done at baseline only.
‡Only for those agreeing to have in-­person visits.
LDN, low dose naltrexone.

including research assistants, coordinators, statisticians, additional sample testing related to this protocol that may
trial physicians and investigators will be blind to alloca- be identified from the results of this study.
tion. Unblinding will only occur when knowledge of the
actual treatment is essential for further management Monitoring and oversight
of the patient or investigation of serious adverse events A Trial Steering Committee (TSC) will be formed with
(SAEs). If unblinding is deemed necessary by the DSMB patient partners, investigators and other research team
or investigator, the C&W Pharmacy will be contacted for members. Additionally, we have formed a Data Safety
release of treatment allocation. and Monitoring Board (DSMB) that is comprised of peer
researchers with expertise in clinical trials and ethics and
Data collection and management independent from the study team. Lastly, an independent
We will use the secure REDCap platform for the storage study monitor from the CWH Quality Assurance Office
of study data.106 107 Participants will complete question- has been hired to verify participant rights and well-­being,
naires electronically, with the links provided to the partic- data collection and compliance with regulatory require-
ipant via email. Data from other sources will be entered ments. Roles of the TSC, DSMB and study monitor are
manually and will include study physician assessments, outlined in online supplemental box 2.
laboratory results, dose diary information, step counts,
physical assessment measures and adverse events (AEs). Statistical methods
REDCap field validation tools will be used where possible Primary and secondary outcomes will be analysed by
to optimise data accuracy (eg, dates that are out of range intention-­to-­treat. The primary outcome (FSS score at 16
and data that are missing). No new data will be collected weeks) will be analysed using a linear mixed effects model
from participants who withdraw, except for reason for adjusting for baseline level, sex (stratification factor) and
withdrawal and details regarding AEs and SAEs. other relevant prognostic factors identified a priori. The
model will include interaction between treatment arm
Biological specimens and time, treatment arm and baseline level and include
Leftover plasma will be stored at −80°C at the BC Chil- all post-­randomisation timepoints at which the FSS is
dren’s Hospital Biobank for up to 10 years to allow for captured. To assess the FSS at 16 weeks, we will calculate

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an estimated marginal mean difference between arms Patient and public involvement
with a corresponding 95% CI, with statistical significance Patient partners will be included as part of the TSC.
set at 0.05. Similar contrasts at each interim time point
will be provided. Effect modification by baseline FSS Trial dates
level will be demonstrated graphically. Participants who This trial started recruitment in January 2024 and aims to
are lost to follow-­up will be compared descriptively with complete follow-­up by the end of 2024.
those who remain in the trial. If selection bias occurs,
we will consider inverse probability weights for censored
individuals. ETHICS AND DISSEMINATION
For secondary and exploratory outcomes, question- Research ethics approval
naire, laboratory and physical measure data will be anal- This study was approved by the UBC/C&W harmonised
ysed similarly with generalised linear models, adjusting REB (#H21-­02254); any protocol modifications will be
for baseline level and other relevant prognostic factors reported to the REB.
and using link function based on the variable type from Consent or assent
questionnaires (eg, logit for binary outcomes). Research staff will have interested participants consent
Effect modification by baseline factors will be consid- via the secure REDCap electronic consent platform.
ered by the inclusion of interaction terms with treat- Participants will receive information regarding the trial
ment arm in the above models. Possible effect modifiers electronically and will have the opportunity to discuss
include baseline fatigue severity, sex, gender, age, severity the trial specifics and meet with a research team member
of and time of acute SARS-­CoV-­2 infection, pre-­existing (virtually or in person) before deciding on participation.
co-­
morbidities, COVID-­ 19 vaccination, final dose and The consent form is provided in online supplemental
side effects. The significance of effect modification will appendix 4.
be based on the likelihood ratio test comparing models
with and without the interaction term. Access to data
Dose-­ response analyses will involve a comparison of The study principal investigator, co-­investigators, clinical
various dosing levels as a covariate versus control in the research coordinator, research assistants and statistician
primary linear model. Secondary analysis will look only will have access to the collected data.
at dose comparisons within the intervention arm. Dose
will be included in these models as a non-­linear effect via Dissemination policy
restricted cubic splines. We will follow the Consolidated Standards of Reporting
We will conduct a per-­ protocol analysis to assess Trials (CONSORT) guidelines for reporting the results
the expected effect of adhering to the trial protocol of parallel arm trials.109 We will submit manuscripts to
using G-­methods, which allow for adjustment for post-­ peer review journals, give presentations at conferences,
randomisation confounding.108 and media releases will be organised. We will leverage our
All analyses of primary and secondary outcomes will be connections with PCC and ME/CFS networks to share
pre-­specified in detail in a Statistical Analysis Plan and our findings with patients, their caregivers, PCPs and
signed off on by all investigators prior to data analysis. other care providers.

Harms DISCUSSION
Protocols to address particular AEs and SAEs are This report described the protocol for a 16-­week, phase
described in online supplemental appendix 3. We will II RCT to investigate the efficacy of LDN for treating
implement REDCap alerts for AEs noted through the fatigue severity in patients with PCFS, an illness we have
questionnaires. Additionally, participants will be asked defined as ME/CFS symptoms persisting at least 3 months
if they have had any AEs at each study visit. All AEs following SARS-­CoV-­2 infection.
will be assessed by a study physician. All SAEs will be Our study will build on prior and ongoing evaluations
reported to the DSMB. SAEs will be reported to the of LDN. In our review of studies listed on ​ClinicalTrials.​
Research Ethics Board (REB) and Health Canada (HC) gov, we identified one upcoming trial (NCT05946551)
as per local regulations. For mild AEs, the patient may which also investigates LDN in PCC. However, this trial
be reassured to continue taking the medication as per is smaller (expected n=36) and focused on feasibility
protocol. Previous studies and our clinical experience outcomes. There are no trials listed that investigate LDN
have suggested that LDN is generally well tolerated, in ME/CFS.
and mild AEs will often ease with treatment continua- A positive outcome in our trial would inspire greater
tion.40 48 49 51–53 confidence in LDN as a treatment for the millions of
patients with PCFS symptoms and could prompt larger,
Inspections and auditing multi-­institutional phase III studies. Unlike other candi-
The trial will be subject to inspections or audits by HC, date PCC treatments such as Paxlovid, stellate ganglion
REB and the Canadian Institutes for Health Research. blockade and hyperbaric oxygen,110–116 LDN is widely

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available, relatively inexpensive and generally safe. A the study ID and personal information will be saved
negative outcome in this trial would also be a valuable separately.
contribution to the literature and would directly impact
clinician decisions regarding prescribing LDN. The Author affiliations
1
results of this trial may inform guidelines for PCC. Department of Medicine, The University of British Columbia, Vancouver, British
Columbia, Canada
The trial has limitations. It is limited to English 2
Post-­COVID-­19 Interdisciplinary Clinical Care Network, Vancouver, British Columbia,
speakers and is based in a single province. We do not Canada
have a restriction on how long a participant may have had 3
BC Children’s Hospital Research Institute, Vancouver, British Columbia, Canada
4
their symptoms since COVID-­19. This may limit the treat- 5
Women's Health Research Institute, Vancouver, British Columbia, Canada
ment effect if LDN efficacy is greater earlier in the disease Complex Chronic Diseases Program, BC Women's Hospital and Health Centre,
Vancouver, British Columbia, Canada
course. The decentralised nature of the trial also limits 6
Fraser Health Authority, Surrey, British Columbia, Canada
the number of objective outcomes that can be collected 7
Department of Biomedical Physiology and Kinesiology, Simon Fraser University,
from all participants. Burnaby, British Columbia, Canada
8
However, our decentralised strategy for this trial has Department of Family Practice, The University of British Columbia, Vancouver,
several advantages. First, it will allow individuals who British Columbia, Canada
9
London School of Hygiene and Tropical Medicine, London, UK
live outside Vancouver to participate, including those
in communities who may not have access to off-­label X Hiten Naik @ADS-1906-2022
or investigational treatments.14 Second, it will permit
Acknowledgements The authors thank Dr Adeera Levin, Alia Izquierdo and Esther
the inclusion of more symptomatic individuals. Some Khor for their support of this study.
individuals with PCFS have reported symptom exac-
Contributors Study conception: LN. Study design and protocol development: HN,
erbation from even minimal cognitive and physical EC, TB, JNB, RJM, XS, LN. Statistical analysis: JNB. Administrative support: EC, TB,
exertion,117 and remote participation may prevent MT, JC. Supervision: RJM, XS, LN. Batch testing of study products: RD. Drafting of
flare-­ups experienced from in-­person visits. Third, it manuscript: HN, EC. Critical review of manuscript and reviewed and approved the
will encourage participation from patients who may final version of the manuscript: all authors. LN takes responsibility for the overall
content as guarantor.
be reluctant to attend in person given the risks of
Funding This study is funded by the Canadian Institutes for Health Research
COVID-­19 re-­infection. Lastly, it will expedite study
(grant reference number: 177749). The Post-­COVID-­19 Interdisciplinary Clinical
completion by broadening the pool of eligible appli- Care Network (PC-­ICCN) receives research funding from the British Columbia
cants and reducing logistical barriers associated with Ministry of Health (grant reference number: N/A) and St. Paul’s Foundation (grant
in-­person recruitment and enrolment. reference number: 1866667). HN is supported by The University of British Columbia
Clinician Investigator Program (grant reference number: N/A) and a CAN-­TAP-­
This trial has other strengths. By using the provincial
TALENT & Michael Smith Health Research BC Post Doctoral Fellowship (grant
PC-­ICCN and REACH BC directories, we will be able reference number: N/A). LN is supported by the BC Women’s Health Foundation
to efficiently identify and contact hundreds of poten- (grant reference number: N/A) and the BCCDC Foundation for Public Health (grant
tial participants by email. Our focus specifically on reference number: N/A).
individuals with the ME/CFS phenotype distinguishes Competing interests HN is a member of the Canadian Guidelines for Post-­
this trial from others for PCC and increases the like- COVID-­19 Condition Guideline Team for Pharmacologic and Nonpharmacologic
Clinical Interventions. The other authors have no competing interests to declare.
lihood that participants will have a similar underlying
pathophysiology. Lastly, our trial includes multiple Patient and public involvement Patients and/or the public were involved in the
design, or conduct, or reporting, or dissemination plans of this research. Refer to
secondary and exploratory outcome measures that the Methods section for further details.
may be valuable for further hypothesis generation.
Patient consent for publication Not applicable.
This is one of the first trials in Canada investigating
Provenance and peer review Not commissioned; peer reviewed for ethical and
a pharmacological treatment for PCC and will have a
funding approval prior to submission.
direct impact on how this illness is treated. We hope
Supplemental material This content has been supplied by the author(s). It has
that it will also promote engagement, good faith and not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
optimism among the PCC community—a group that peer-­reviewed. Any opinions or recommendations discussed are solely those
has experienced stigma and has expressed frustration of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
regarding the paucity of interventional studies for responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
their illness.21 118–122 Furthermore, the trial has implica- of the translations (including but not limited to local regulations, clinical guidelines,
tions beyond COVID-­19; we expect that the results will terminology, drug names and drug dosages), and is not responsible for any error
have applicability to ME/CFS and other post-­infection and/or omissions arising from translation and adaptation or otherwise.
fatigue syndromes, including those that could emerge Open access This is an open access article distributed in accordance with the
from future pandemics.123 Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work is
Confidentiality properly cited, appropriate credit is given, any changes made indicated, and the use
Following UBC REB guidelines, all study-­related infor- is non-­commercial. See: [Link]
mation will be stored in locked facilities at C&W,
ORCID iDs
and all electronic material stored on secure network Hiten Naik [Link]
drives or servers. Participants will be allocated study Erin Cooke [Link]
identification (ID) numbers and a master file linking Jeffrey N Bone [Link]

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