Abstract
BackgroundIn a randomized crossover trial, each participant is randomized to a sequence of treatments and treatment effect is estimated based on within-individual difference because each participant serves as his/her own control. This feature makes the design and reporting of randomized crossover trials different from that of parallel trials. Our objective was to characterize phase 3 crossover trials with results reported on ClinicalTrials.gov and identify issues and best practices for reporting.MethodsWe searched ClinicalTrials.gov for phase 3 randomized crossover trials that provided results, registered at least one primary outcome, and included at least one link to a results publication in the record by August 6, 2019. Two reviewers independently assessed the eligibility and extracted information from each record into an electronic form developed and maintained in the Systematic Review Data Repository.ResultsOf the 124 crossover trials analyzed, two thirds were a simple “Intervention A then B” or “Intervention B then A” (AB|BA) design. Most trials (78%, 97/124) provided enough information to understand the participant flow throughout the trial. Baseline characteristics were most often reported for all participants as a single group (52%, 65/124). Primary outcomes and adverse events were most commonly reported “per intervention” (85%, 105/124, and 80%, 99/124, respectively).ConclusionsThe registration and reporting of randomized crossover trials must account for the paired nature of the design. Our observations and recommendations informed the development of guidelines for good reporting practices in the registration and reporting of randomized crossover trials.
Highlights
In a randomized crossover trial, each participant is randomized to a sequence of treatments and treatment effect is estimated based on within-individual difference because each participant serves as his/her own control
The randomized crossover design is inappropriate for conditions in which the treatment in an earlier period permanently alters the course of the condition, such that at the entry to the period, the participant characteristics systematically differ from their initial states at the start of the trial [4,5,6]
In the case when the ClinicalTrials.gov registry provided insufficient information to determine if the trial was a randomized crossover trial, we referred to citations provided by trial sponsors or investigators, indexed in the “Publication” section on ClinicalTrials.gov
Summary
In a randomized crossover trial, each participant is randomized to a sequence of treatments and treatment effect is estimated based on within-individual difference because each participant serves as his/her own control. If the effect of treatment A from period 1 persists to period 2, in which a participant is receiving treatment B, the treatment effect observed in the second period will be a combined effect from both treatments yet, attributed only to treatment B Another potential issue in crossover trials is the period effect, which occurs when secular changes are present: For example, a period effect may arise if a condition under study is not stable, such that the effects of treatment are not consistent over time and the true effects of each intervention are confounded by the period in which they are received. The randomized crossover design is inappropriate for conditions in which the treatment in an earlier period permanently alters the course of the condition (e.g., cure the disease), such that at the entry to the period, the participant characteristics systematically differ from their initial states at the start of the trial [4,5,6]
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