Background: A run-in phase is often employed prior to randomization in a clinical trial to exclude non-adherent patients, placebo responders, active drug non-responders, or patients who do not tolerate the active drug. This may impact the generalizability of trial results.
Objective: To determine if clinical outcomes differed between randomized controlled trials with run-in phases compared with randomized controlled trials of the same medication without run-in phases.
Design, participants: From 2006 to 2014, the Food and Drug Administration approved 258 new medications. Sitaglitpin, saxagliptin, linagliptin, and alogliptin were among the only drugs with a common mechanism of action that each had multiple clinical trials, some of which had run-in phases and some of which did not. We identified all published randomized controlled trials for these four medications from MEDLINE and EMBASE as well as prior systematic reviews.
Main measures: We extracted key measures of medication efficacy (reduction in hemoglobin A1C) and safety (serious adverse events) from qualifying trials. Study results were pooled for each medication using random effects meta-analysis.
Key results: We identified 106 qualifying trials for DPP4 inhibitors, of which 88 had run-in phases and 18 did not. The average run-in phase duration was 4.0 weeks (range 1-21), and 73% of run-in phases administered placebo rather than active drug. The reduction in hemoglobin A1C compared to baseline was similar for trials with and without run-in phases (0.70%, 95% confidence interval [CI] 0.65-0.75 vs 0.76%, 95% CI 0.69-0.84, p = 0.27). The proportion of patients with serious adverse events was also similar for trials with and without run-in phases (4%, 95% CI: 3-5% vs 3%, 95% CI: 1-4%, p = 0.35).
Conclusion: Trials with run-in phases provided similar estimates for medication efficacy and safety compared to trials without run-in phases. Because run-in phases are costly and time-consuming, these results call their utility into question for clinical trials of short duration.
Keywords: clinical trial; lead-in; run-in; study design.