Meta-Analysis: Placebo Response and Its Determinants in Functional Dyspepsia

Abstract

INTRODUCTION: Placebo response rates are relatively higher in clinical trials of disorders of brain-gut interaction. However, placebo response in functional dyspepsia (FD) has not been well described. Minimizing placebo response is important in drug development. We therefore conducted a meta-analysis to determine placebo response in trials for FD and to identify factors affecting placebo response rates. METHODS: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched to identify double-blinded randomized controlled trials (RCTs) comparing medication with placebo in patients with FD. Both symptom improvement and complete relief were considered as separate primary endpoints in the analysis. Proportions of placebo patients experiencing any symptom improvement or complete relief were calculated. Dropouts after randomization for any reason were assumed to represent treatment failure for data extraction and analysis. Placebo response was pooled by a random-effects model, and effects of trial characteristics on the magnitude of placebo response were evaluated. RESULTS: In 58 eligible placebo-controlled RCTs of FD from 52 selected citations, 6,732 of 17,890 participants in all trials received placebo. Pooled placebo response rates for symptom improvement and complete relief were 44.3% and 15.6%, respectively. The placebo response rate was lower when improvements were assessed for ≥8 weeks. Trials assessing complete symptom relief showed lower placebo response rates even in trials for <8 weeks. DISCUSSION: Our systematic review and meta-analysis showed that pooled placebo response rates in double-blinded RCTs of FD depended on efficacy criteria. Trials assessing complete symptom relief showed stable low placebo response rates in short-term trials.

Placebo response in pharmacological trials in patients with functional dyspepsia—A systematic review and meta‐analysis

“…This meta‐analysis was prompted by the fact that only very limited data are available regarding the pooled placebo response rate and its possible moderators in pharmacological trials in FD. The pooled placebo response rates in this meta‐analysis were in line with the pooled placebo response rate in another recent meta‐analysis 15 . However, approximately half of the included articles in that meta‐analysis had a non‐pharmacological active therapy and varying dosage forms, what probably led to more heterogeneity in their results with larger confidence intervals.…”

“…The previously identified predictors of the placebo response rate, that is, an association of a higher BMI, 16,17 a nonsmoking status, 16 low symptom severity at baseline, 16 symptom progression during run-in, 16 and a longer study period 15 with a higher placebo response, were not completely in line with the results of this metaanalysis. The effect of smoking status and symptom progression during run-in could not be evaluated, because of incomplete reporting of these factors in the individual trials.…”

“…The pooled placebo response rates in this meta-analysis were in line with the pooled placebo response rate in another recent meta-analysis. 15 However, approximately half of the included articles in that meta-analysis had a F I G U R E 2 Forest plot of the proportion of placebo responders with the symptom responder definition (9 trials with this endpoint). It is noteworthy that there was considerable heterogeneity across trials regarding responder definitions.…”

Placebo effects in functional dyspepsia: Causes and implications for clinical trials

“…These findings are consistent with a previous meta-analysis of 58 functional dyspepsia clinical trials 4 in which an average 44% placebo response was reported for symptom improvement and 15.6% for complete symptomatic relief. Similar rates have also been found in irritable bowel syndrome where a 2010 meta-analysis of 73 clinical trials reported a 37.5% placebo response rate for symptomatic improvement, 5 while Ballou 6 and colleagues reported a 29% placebo response rate in chronic constipation when abdominal pain was the endpoint and Nee 7 and colleagues reported pooled placebo response rate from 13% to 26% depending on which endpoint was considered.…”

Factors Associated With Placebo Treatment Response in Functional Dyspepsia Clinical Trials

“…An impediment to evaluating therapies is the high rate of placebo response, estimated in a recent meta-analysis to be 44% meeting response criteria and 15% when complete relief was the end point (5). Because a treatment effect for an intervention is estimated as the difference between the change/response observed among individuals receiving an experimental therapy and that observed among individuals receiving a placebo (6), a high placebo response can lead to low estimates of treatment effect size even if the treatment is itself associated with a strong and consistent reduction in symptoms.…”