Introduction
There have been some anomalously high placebo rates in recent clinical trials for inflammatory bowel diseases (IBD). Thus, we conducted an umbrella review to summarize the best available evidence for factors which influence placebo rates to help inform trial design.
Aims & Methods
A systematic search was conducted on October 29, 2025 in MEDLINE, Embase, and the Cochrane CDSR to identify systematic reviews with meta-analysis focused on factors associated with placebo response and remission rates in placebo-controlled RCTs in IBD. Outcomes were clinical, endoscopic and histological response and remission for induction and maintenance phases. For each outcome, placebo rates, predictors of placebo outcomes and their effect estimates were extracted.
Results
Eighteen reviews between 2004-2025 were eligible. Pooled placebo rates and significant predictors of placebo outcomes varied widely across reviews. Some factors reflecting higher baseline disease activity were consistently associated with lower placebo rates. We identified predictors related to outcome measure: definition of outcomes, but also timing of measurement (earlier timepoint in induction yielding lower placebo rates) and with central endoscopy reading (consistently associated with lower placebo rates). Placebo rates increased with treatment route in the following order: oral, topical, subcutaneous and intravenous. Some consistent factors were related to trial design and location: longer maintenance phases, asymmetrical randomization, studies conducted outside of North America or with fewer sites consistently having higher placebo rates. The Table contains a summary of findings.
Table: factors associated with changes in response and remission rates on placebo in clinical trials in inflammatory bowel diseases.
Cells colored in blue indicate factors associated with a lower placebo effect. Cells colored in green indicate factors associated with a higher placebo effect.
Area concerned
| Factors evaluated
| Influence on placebo
|
|---|
Population characteristics at baseline
| Disease severity, biologic exposure, Mayo endoscopic subscore, albumin, CRP (CD), extensive disease (UC), disease activity scores, age at diagnosis
| Markers of higher severy associated with lower placebo rates
|
Endpoint
| Subjective endpoints
| Higher number of factors influencing placebo
|
Definition of clinical response (CDAI decrease by ≥ 100 vs. ≥ 70-points from baseline)
| Lower placebo rates
|
Earlier outcome measure in induction
| Lower placebo rates
|
Central reading
| Lower placebo rates
|
| Design | Short duration of induction, longer duration of maintenance
| Lower placebo rates
|
Asymmetrical randomization (clinical remission, CD)
| Higher placebo rates
|
| Location | Northern America
| Lower placebo rates
|
Higher number of centers
| Lower placebo rates
|
Conclusion
We identified several factors which consistently influence placebo rates across multiple clinical trials. Implementation of these into trial design may lower placebo rates.
Disclosure
Marianne Hupé: consulting/advisory board/lecture fees from Takeda, Pfizer, Johnson&Johnson, Lilly. Speaker fees from Abbvie, Pfizer, Lilly.
Yuhong Yuan declares no conflict of interest.
Vipul Jairath: Consulting/advisory board fees from AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly,
Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus,
Reistone Biopharma, Roche, Sandoz, Second Genome,Takeda, Teva, Topivert, Ventyx, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire,
Takeda, Fresenius Kabi.
