Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy

Bruno Scherrer, Julien Guiraud, Giovanni Addolorato, Henri Jean Aubin, Andrea de Bejczy, Amine Benyamina, Wim van den Brink, Fabio Caputo, Maurice Dematteis, Anna E. Goudriaan, Antoni Gual, Falk Kiefer, Lorenzo Leggio, Otto Michael Lesch, Icro Maremmani, David J. Nutt, François Paille, Pascal Perney, Roch Poulnais, Quentin RaffaillacJürgen Rehm, Benjamin Rolland, Nicolas Simon, Bo Söderpalm, Wolfgang H. Sommer, Henriette Walter, Rainer Spanagel

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1722-1734
Number of pages13
JournalAlcoholism: Clinical and Experimental Research
Volume45
Issue number9
DOIs
Publication statusPublished - Sep 2021

Keywords

  • alcohol dependence
  • alcohol use disorder
  • placebo response
  • predictor
  • randomized controlled trials

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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