Item 12: Primary, secondary, and other outcomes, including the specific measurement variable (e.g., systolic blood pressure), analysis metric (e.g., change from baseline, final value, time to event), method of aggregation (e.g., 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 [United Kingdom 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 (i.e. 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 (e.g., 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 (e.g., change from baseline, final value, time to event); the method of aggregation, which refers to the summary measure format for each study group (e.g., 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 (e.g., 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.168-171
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.172-176 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.178-180 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 (http://www.comet-initiative.org). Trial investigators are encouraged to ascertain whether there is a core outcome set relevant to their trial and, if so, to include those outcomes in their trial. Existence of a common set of outcomes does not preclude inclusion of additional relevant outcomes for a given trial.
| 11d: Concomitant care | 13: Participant timeline |
