Placebo Response Rate in Clinical Trials of Fistulizing Crohn’s Disease: Systematic Review and Meta-analysis
Alexander C. Ford
Clinical Gastroenterology and Hepatology
Articles in Press
Received: July 9, 2014; Received in revised form: August 3, 2014; Accepted: August 28, 2014; Published Online: September 13, 2014
DOI: http://dx.doi.org/10.1016/j.cgh.2014.08.038
Abstract
Abstract
Background
& Aims: It is important to determine the magnitude and identify modifiers of the rate of response to placebo in clinical trials of fistulizing Crohn’s disease (CD), to understand disease progression and calculate sample size. We conducted a systematic review and meta-analysis of rates of response to placebo in trials of patients with fistulizing CD.
Methods
We searched MEDLINE, EMBASE, EMBASE CLASSIC, and the Cochrane central register of controlled trials for randomized controlled trials (RCTs) comparing pharmacologic agents with placebo in adults with fistulizing CD. We identified studies that reported complete fistula closure, partial closure or response. Data were extracted as intention-to-treat analyses, and pooled using a random effects model. Proportions of patients who received placebo and had complete or partial fistula(e) closure were calculated, with 95% confidence intervals (CIs). The effects of trial characteristics on the magnitude of response to placebo were examined.
Results
Thirteen RCTs were eligible for our analysis; these included 579 patients assigned to placebo groups. The pooled rate of response to placebo, among all RCTs, for complete fistula closure was 15.6% (95% CI, 10.9%−20.9%), with significant heterogeneity (I2 = 62.5%; P=.001). The pooled rate of response to placebo for partial fistula closure or response in 9 trials, comprising 423 patients, was 18.3% (95% CI, 14.8%–22.1%). Rates of response to placebo were significantly lower in trials with shorter durations of therapy and shorter intervals to assessment of fistula closure. Neither exposure to the pharmacologic agent during the induction phase of the same (or a related) RCT, nor concomitant medications, had any effect.
Conclusions
In a meta-analysis of rate of response to placebo in patients with fistulizing CD, we found that fistulas closed in almost 1/6 patients given placebo in RCTs of pharmacologic agents. Future research should identify characteristics of patients that predict response to placebo.