Example

“2. Rescue Medication

For weeks 0-3, topical mometasone furoate 0.1% cream or ointment (30 g/week) will be permitted with participants preferably using ointment.
Participants will be instructed to apply the topical mometasone furoate to blisters/lesions as required (not to areas of unaffected skin). If the
participant is allergic to mometasone furoate or the hospital pharmacy does not stock it, then an alternative topical steroid may be prescribed but this
must be in the potent class. In addition, participants will be advised that they can apply a light moisturiser to blisters/lesions at any time during the
study.

For weeks 3-6, use of mometasone furoate (or other topical corticosteroids) is strongly discouraged to prevent potential systemic effects. Accidental
use of mometasone furoate or other potent topical steroid during this period will be classified as a protocol deviation.

After week 6, potent topical corticosteroids (up to 30 g/week) may be used to treat symptoms and localised disease if they would have normally been
used as part of normal clinical care by the physician in charge of that patient. This must be recorded on the trial treatment log.

However, those patients who are on a dose reducing regime for oral steroids, 30 g/week of a “potent” topical steroid will be allowed.

3. Prohibited Concomitant Medications

The administration of live virus vaccines is not permitted for all participants during weeks 0-6 as the investigator is blinded to treatment allocation,
and must therefore warn all participants to refrain for [sic] having a live virus vaccine. However, after week 6, once the investigator knows which
medication the participant is on, only those taking prednisolone will not be allowed live virus vaccines.

Participants should continue to take medications for other conditions as normal. However, if it is anticipated that the participant will need a live virus
vaccine during the intervention phase, they will be ineligible for entry into the study.”50

Explanation

In a controlled trial, a key goal is to have comparable study groups that differ only by the intervention being evaluated, so that any difference in outcomes can be
attributed to effects of the study intervention. Cointervention bias can arise when the study groups receive different concomitant care or interventions (in addition
to the assigned trial interventions) that may affect trial outcomes.162 To promote comparability of study groups, the protocol should list the relevant concomitant
care and interventions that are allowed (including rescue interventions), as well as any that are prohibited.

Outcomes

Item 12: Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from
baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of
chosen efficacy and harm outcomes is strongly recommended
Example

“1. Primary Outcome Measures

Difference between the two treatment arms in the proportion of participants classed as treatment success at 6 weeks. Treatment success is
defined as 3 or less significant blisters present on examination at 6 weeks. Significant blisters are defined as intact blisters containing fluid which
are at least 5 mm in diameter. However, if the participant has popped a blister, or the blister is at a site that makes it susceptible to bursting such as
the sole of the foot, it can be considered part of the blister count, providing there is a flexible (but not dry) roof present over a moist base. Mucosal
blisters will be excluded from the count.

A survey of the UK DCTN [Dermatology Clinical Trials Network] membership showed that a point estimate of 25% inferiority in effectiveness would be
acceptable assuming a gain in the safety profile of at least 10%.

This measure of success was selected as it was considered to be more clinically relevant than a continuous measure of blister count. It would be less
clinically relevant to perform an absolute blister count and report a percentage reduction. Instead, to state that treatment is considered a success if
remission is achieved (ie the presence of three or less blisters on physical examination at 6 weeks) more closely reflects clinical practice. In addition, it
is far less burdensome on investigators than including a full blister count, which would mean counting in the region of 50-60 blisters in many cases.
This outcome measure will be performed as a single blind assessment.

Difference between the two treatment arms in the proportion of participants reporting grade 3, 4 and 5 (mortality) adverse events which are
possibly, probably or definitely related to BP [bullous pemphigoid] medication in the 52 weeks following randomisation. A modified version of The
Common Terminology Criteria for Adverse Events (CTCAE v3.0) will be used to grade adverse events. At each study visit, participants will be
questioned about adverse events they have experienced since the last study visit (using a standard list of known side effects of the two study
drugs).

2. Secondary Outcome Measures

For the secondary and tertiary endpoints a participant will be classed as a treatment success if they have 3 or less significant blisters present on
examination and have not had their treatment modified (changed or dose increased) on account of a poor response.

Difference in the proportion of participants who are classed as a treatment success at 6 weeks.
Difference in the proportion of participants in each treatment arm who are classed as treatment success at 6 weeks and are alive at 52 weeks. This
measure will provide a good overall comparison of the two treatment arms.”50

Explanation

The trial outcomes are fundamental to study design and interpretation of results. For a given intervention, an outcome can generally reflect efficacy (beneficial
effect) or harm (adverse effect). The outcomes of main interest are designated as primary outcomes, which usually appear in the objectives (Item 7) and sample
size calculation (Item 14). The remaining outcomes constitute secondary or other outcomes.

For each outcome, the trial protocol should define four components: the specific measurement variable, which corresponds to the data collected directly from trial
participants (eg, Beck Depression Inventory score, all cause mortality); the participant-level analysis metric, which corresponds to the format of the outcome data
that will be used from each trial participant for analysis (eg, change from baseline, final value, time to event); the method of aggregation, which refers to the
summary measure format for each study group (eg, mean, proportion with score > 2); and the specific measurement time point of interest for analysis.163

It is also important to explain the rationale for the choice of trial outcomes. An ideal outcome is valid, reproducible, relevant to the target population (eg, patients),
and responsive to changes in the health condition being studied.67 The use of a continuous versus dichotomous method of aggregation can affect study power and
estimates of treatment effect,164 165 and subjective outcomes are more prone to bias from inadequate blinding (ascertainment bias) and allocation concealment
(selection bias) than objective outcomes.166 167 Although composite outcomes increase event rates and statistical power, their relevance and interpretation can
be unclear if the individual component outcomes vary greatly in event rates, importance to patients, or amount of missing data.168 169 170 171

The number of primary outcomes should be as small as possible. Although up to 38% of trials define multiple primary outcomes,4 35 163 this practice can
introduce problems with multiplicity, selective reporting, and interpretation when there are inconsistent results across outcomes. Problems also arise when trial
protocols do not designate any primary outcomes, as seen in half (28/59) of protocols for a sample of trials published from 2002-2008,12 and in 25% of
randomised trial protocols that received ethics approval in Denmark in 1994-95.4 Furthermore, major discrepancies in the primary outcomes designated in
protocols/registries/regulatory submissions versus final trial publications are common; favour the reporting of statistically significant primary outcomes over
non-significant ones; and are often not acknowledged in final publications.172 173 174 175 176 Such bias can only be identified and deterred if trial outcomes are
clearly defined beforehand in the protocol and if protocol information is made public.177

Where possible, the development and adoption of a common set of key trial outcomes within a specialty can help to deter selective reporting of outcomes and to
facilitate comparisons and pooling of results across trials in a meta-analysis.178 179 180 The COMET (Core Outcome Measures in Effectiveness Trials) Initiative
aims to facilitate the development and application of such standardised sets of core outcomes for clinical trials of specific conditions (www.comet-