Placebo Rates in Crohn’s Disease Randomized Clinical Trials: An Individual Patient Data Meta-Analysis

Abstract

Background & Aims

Understanding placebo rates is critical for efficient clinical trial design. We assessed placebo rates and associated factors using individual patient data from Crohn’s disease trials.

Methods

We conducted a meta-analysis of phase 2/3 placebo-controlled trials evaluating advanced therapies in moderate to severe Crohn’s disease (2010–2021). Deidentified individual patient data were obtained through Vivli Inc and the Yale University Open Data Access Project. Primary outcomes were clinical response and remission. Pooled placebo rates and 95% confidence intervals (CIs) were estimated using 1- and 2-stage meta-analytic approaches. Regression analyses identified patient-level factors associated with placebo rates.

Results

Analysis of individual patient data from 8 induction (n = 1147) and 4 maintenance (n = 524) trials showed overall placebo clinical response and remission rates for induction were 27% (95% CI, 23%–32%) and 10% (95% CI, 8%–14%), respectively, and 32% (95% CI, 23%–42%) and 22% (95% CI, 14%–33%) for maintenance, respectively. Among biologic (bio)-naïve patients, placebo response and remission rates during induction were 29% (95% CI, 24%–35%) and 11% (95% CI, 8%–15%) respectively, and 26% (95% CI, 20%–33%) and 10% (95% CI, 8%–14%) for biologic (bio)-exposed patients, respectively. During maintenance, biologic-naïve response and remission rates were 41% (95% CI, 34%–48%) and 32% (95% CI, 24%–40%), respectively, and 29% (95% CI, 24%–34%) and 16% (95% CI, 13%–21%) for bio-exposed, respectively. Higher baseline C-reactive protein concentration predicted lower placebo rates, whereas higher baseline albumin levels and body mass index increased the odds of placebo outcomes. Increased baseline Crohn’s Disease Activity Index and 2-item patient-reported outcome scores predicted higher response rates in induction, lower response rates in maintenance, and lower remission rates in induction and maintenance.

Conclusions

Patient- and trial-level characteristics influence placebo rates in Crohn’s disease trials. Careful implementation of eligibility criteria, outcome definitions, and patient stratification may reduce placebo rates.