Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: A meta-regression analysis to develop an enrichment strategy.
alcohol dependence
alcohol use disorder
placebo response
predictor
randomized controlled trials
Journal
Alcoholism, clinical and experimental research
ISSN: 1530-0277
Titre abrégé: Alcohol Clin Exp Res
Pays: England
ID NLM: 7707242
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
03
06
2021
received:
08
03
2021
accepted:
09
07
2021
pubmed:
22
8
2021
medline:
19
2
2022
entrez:
21
8
2021
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 34418121
doi: 10.1111/acer.14670
pmc: PMC9291112
doi:
Types de publication
Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1722-1734Informations de copyright
© 2021 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.
Références
Addict Biol. 2018 Jul;23(4):969-986
pubmed: 30043457
Eur Neuropsychopharmacol. 2016 Dec;26(12):1941-1949
pubmed: 27842940
Alcohol. 2012 Mar;46(2):121-31
pubmed: 21925828
Lancet Psychiatry. 2017 Jun;4(6):469-476
pubmed: 28456501
Br J Psychiatry. 1997 Jul;171:73-7
pubmed: 9328500
Arch Gen Psychiatry. 1997 Aug;54(8):737-42
pubmed: 9283509
Eur Neuropsychopharmacol. 2015 Aug;25(8):1167-77
pubmed: 26048580
Arch Gen Psychiatry. 2003 Jan;60(1):92-9
pubmed: 12511176
Addiction. 2008 Dec;103(12):2035-44
pubmed: 18855810
J Psychopharmacol. 2014 Aug;28(8):733-44
pubmed: 24671340
Addiction. 2010 May;105(5):817-43
pubmed: 20331573
Alcohol Clin Exp Res. 2015 Nov;39(11):2189-99
pubmed: 26414337
Braz J Psychiatry. 2003 Sep;25(3):156-9
pubmed: 12975689
J Stud Alcohol Drugs. 2014 May;75(3):438-46
pubmed: 24766756
Int J Psychiatry Med. 2011;42(3):227-66
pubmed: 22439295
Eur Addict Res. 2015;21(1):6-18
pubmed: 25342593
Alcohol Clin Exp Res. 2011 Mar;35(3):523-31
pubmed: 21143249
Sci Adv. 2019 Sep 25;5(9):eaax4043
pubmed: 31579824
Cochrane Database Syst Rev. 2019 Oct 3;10:ED000142
pubmed: 31643080
Alcohol Clin Exp Res. 2013 Dec;37(12):2128-37
pubmed: 23889231
Eur Neuropsychopharmacol. 2013 Feb;23(2):89-97
pubmed: 22920734
Control Clin Trials. 1998 Apr;19(2):178-87
pubmed: 9551282
Addict Biol. 2020 Mar;25(2):e12866
pubmed: 31859437
Handb Exp Pharmacol. 2014;225:273-90
pubmed: 25304537
Dialogues Clin Neurosci. 2002 Mar;4(1):105-13
pubmed: 22034204
Alcohol Alcohol. 2000 Mar-Apr;35(2):176-87
pubmed: 10787394
J Clin Psychopharmacol. 2005 Aug;25(4):349-57
pubmed: 16012278
N Engl J Med. 2020 Feb 6;382(6):554-561
pubmed: 32023375
JAMA. 2014 May 14;311(18):1889-900
pubmed: 24825644
J Consult Clin Psychol. 2013 Feb;81(1):13-22
pubmed: 23231573
Eur Neuropsychopharmacol. 2013 Nov;23(11):1432-42
pubmed: 23562264
Alcohol Clin Exp Res. 2021 Sep;45(9):1722-1734
pubmed: 34418121
Am J Psychiatry. 1999 Nov;156(11):1758-64
pubmed: 10553740
Addict Biol. 2018 Jul;23(4):961-968
pubmed: 30043407
Addict Biol. 2012 May;17(3):513-27
pubmed: 22458728
Alcohol Alcohol. 2013 Sep-Oct;48(5):570-8
pubmed: 23873853