Pre-randomization run-in periods in randomized controlled trials of chronic diseases: a methodological study.

Abstract: Objective To systematically review the epidemiology of pre-randomization run-in periods in randomized controlled trials (RCTs) of chronic diseases. Study Design and Setting Meta-epidemiologic study of all RCTs from the four highest impact medical journals from 2011 to 2016. Eligible trials included parallel RCTs that evaluated pharmacologic therapies in adults with chronic diseases with a minimum follow-up of 24 weeks. Results Of 262 eligible manuscripts, 48 (18.3%), representing 42 unique RCTs, included run-in periods. Run-in periods were most common in cardiovascular disease and diabetes trials. Of the 42 RCTs, in 22 patients received the experimental therapy, 15 placebo, 4 both (either sequentially or in combination) and one did not report the run-in period drug. The median run-in period duration was 28 days (Q1:Q3 14:66 days). Reasons for including a run-in period included ensuring eligibility criteria were met (18, 42.9%), excluding participants with non-adherence (18, 42.9%) and intolerances to therapy (15, 35.7%), and to standardize therapy prior to randomization (8, 19.0%). The median run-in completion rate was 77.4% (Q1:Q3 62.2:87.8%). Conclusions Run-in periods are uncommon in RCTs of chronic drug treatments and when used, their reporting is heterogeneous. Further research to improve the design, use and reporting of run-in periods is necessary.