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Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta‐regression analysis to develop an enrichment strategy
Author(s) -
Scherrer Bruno,
Guiraud Julien,
Addolorato Giovanni,
Aubin HenriJean,
Bejczy Andrea,
Benyamina Amine,
Brink Wim,
Caputo Fabio,
Dematteis Maurice,
Goudriaan Anna E.,
Gual Antoni,
Kiefer Falk,
Leggio Lorenzo,
Lesch OttoMichael,
Maremmani Icro,
Nutt David J.,
Paille François,
Perney Pascal,
Poulnais Roch,
Raffaillac Quentin,
Rehm Jürgen,
Rolland Benjamin,
Simon Nicolas,
Söderpalm Bo,
Sommer Wolfgang H.,
Walter Henriette,
Spanagel Rainer
Publication year - 2021
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14670
Subject(s) - placebo , abstinence , interquartile range , medicine , population , randomized controlled trial , meta analysis , severity of illness , psychiatry , alternative medicine , environmental health , pathology
Background There is considerable unexplained variability in alcohol abstinence rates (AR) in the placebo groups of randomized controlled trials (RCTs) for alcohol dependence (AD). This is of particular interest because placebo responses correlate negatively with treatment effect size. Recent evidence suggests that the placebo response is lower in very heavy drinkers who show no “spontaneous improvement” prior to treatment initiation (high‐severity population) than in a mild‐severity population and in studies with longer treatment duration. We systematically investigated the relationship between population severity, treatment duration, and the placebo response in AR to inform a strategy aimed at reducing the placebo response and thereby increasing assay sensitivity in RCTs for AD. Methods We conducted a systematic literature review on placebo‐controlled RCTs for AD.We assigned retained RCTs to high‐ or mild‐severity groups of studies based on baseline drinking risk levels and abstinence duration before treatment initiation. We tested the effects of population severity and treatment duration on the placebo response in AR using meta‐regression analysis. Results Among the 19 retained RCTs (comprising 1996 placebo‐treated patients), 11 trials were high‐severity and 8 were mild‐severity RCTs. The between‐study variability in AR was lower in the high‐severity than in the mild‐severity studies (interquartile range: 7.4% vs. 20.9%). The AR in placebo groups was dependent on population severity ( p = 0.004) and treatment duration ( p = 0.017) and was lower in the high‐severity studies (16.8% at 3 months) than the mild‐severity studies (36.7% at 3 months). Conclusions Pharmacological RCTs for AD should select high‐severity patients to decrease the magnitude and variability in the placebo effect and and improve the efficiency of drug development efforts for AD.