Meta-Analysis: The Placebo Response in Modern Treatments for Cholestatic Pruritus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND/AIMS: Cholestatic pruritus is a debilitating symptom with substantial placebo responses. We aimed to quantify this response and identify trial-level moderators in randomized controlled trials of contemporary therapies. METHODS: We performed a systematic review and meta-analysis of placebo-controlled trials evaluating ileal bile acid transporter inhibitors or PPAR agonists (searched through March 2026, with a supplementary search on 11 July 2026). Primary outcomes included the standardized mean change (SMC) of pruritus intensity, placebo response rate and mean difference (MD) in Numerical Rating Scale (NRS) and Worst-Itch NRS (WI-NRS) scores. Secondary outcomes included PBC-40 and 5-D Itch scores. We used random-effects models with Hartung-Knapp adjustment and meta-regression. RESULTS: Thirteen trials (n = 548) were analysed. Across placebo groups, pruritus intensity decreased significantly from baseline during follow-up periods of up to 52 weeks. The pooled SMC was -0.49 (95% CI, -0.72 to -0.27) overall, and -0.57 (95% CI, -0.81 to -0.33) for moderate-to-severe pruritus. Pooled response rates were 30.0% (overall) and 27.4% (moderate-to-severe). In moderate-to-severe patients, NRS showed a significant mean reduction of -1.62, whereas the WI-NRS change (-0.65) was not statistically significant. Significant reductions occurred in the PBC-40 itch domain (-2.02) and overall score (-9.13), while 5-D Itch changes were non-significant. None of the evaluated moderators were statistically significant. CONCLUSIONS: The magnitude of placebo-associated improvement differed across outcome instruments and may affect estimates and interpretation of treatment effects in cholestatic-pruritus trials. These findings may inform endpoint selection and assumptions used in future trial design. TRIAL REGISTRATION: PROSPERO registration number: CRD420261385974.