Impact of active placebo controls on estimated drug effects in randomised trials: a systematic review of trials with both active placebo and standard placebo.

Autor:	Laursen DR; Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.; Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark., Nejstgaard CH; Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.; Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark., Bjørkedal E; Department of Psychology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway., Frost AD; Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.; Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark., Hansen MR; Novo Nordisk, Søborg, Denmark.; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark.; Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark., Paludan-Müller AS; Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.; Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark., Prosenz J; Department of Internal Medicine 2, University Hospital St. Poelten, St. Poelten, Austria., Werner CP; School of Psychology, Faculty of Science, The University of Sydney, Sydney, Australia., Hróbjartsson A; Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.; Open Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark.
Jazyk:	angličtina
Zdroj:	The Cochrane database of systematic reviews [Cochrane Database Syst Rev] 2023 Mar 06; Vol. 3. Cochrane AN: MR000055. Date of Electronic Publication: 2023 Mar 06.
DOI:	10.1002/14651858.MR000055.pub2
Abstrakt:	Background: An estimated 60% of pharmacological randomised trials use placebo control interventions to blind (i.e. mask) participants. However, standard placebos do not control for perceptible non-therapeutic effects (i.e. side effects) of the experimental drug, which may unblind participants. Trials rarely use active placebo controls, which contain pharmacological compounds designed to mimic the non-therapeutic experimental drug effects in order to reduce the risk of unblinding. A relevant improvement in the estimated effects of active placebo compared with standard placebo would imply that trials with standard placebo may overestimate experimental drug effects. Objectives: We aimed to estimate the difference in drug effects when an experimental drug is compared with an active placebo versus a standard placebo control intervention, and to explore causes for heterogeneity. In the context of a randomised trial, this difference in drug effects can be estimated by directly comparing the effect difference between the active placebo and standard placebo intervention. Search Methods: We searched PubMed, CENTRAL, Embase, two other databases, and two trial registries up to October 2020. We also searched reference lists and citations and contacted trial authors. Selection Criteria: We included randomised trials that compared an active placebo versus a standard placebo intervention. We considered trials both with and without a matching experimental drug arm. Data Collection and Analysis: We extracted data, assessed risk of bias, scored active placebos for adequacy and risk of unintended therapeutic effect, and categorised active placebos as unpleasant, neutral, or pleasant. We requested individual participant data from the authors of four cross-over trials published after 1990 and one unpublished trial registered after 1990. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of active versus standard placebo for participant-reported outcomes at earliest post-treatment assessment. A negative SMD favoured the active placebo. We stratified analyses by trial type (clinical or preclinical) and supplemented with sensitivity and subgroup analyses and meta-regression. In secondary analyses, we investigated observer-reported outcomes, harms, attrition, and co-intervention outcomes. Main Results: We included 21 trials (1462 participants). We obtained individual participant data from four trials. Our primary analysis of participant-reported outcomes at earliest post-treatment assessment resulted in a pooled SMD of -0.08 (95% confidence interval (CI) -0.20 to 0.04; I 2 = 31%; 14 trials), with no clear difference between clinical and preclinical trials. Individual participant data contributed 43% of the weight of this analysis. Two of seven sensitivity analyses found more pronounced and statistically significant differences; for example, in the five trials with low overall risk of bias, the pooled SMD was -0.24 (95% CI -0.34 to -0.13). The pooled SMD of observer-reported outcomes was similar to the primary analysis. The pooled odds ratio (OR) for harms was 3.08 (95% CI 1.56 to 6.07), and for attrition, 1.22 (95% CI 0.74 to 2.03). Co-intervention data were limited. Meta-regression found no statistically significant association with adequacy of the active placebo or risk of unintended therapeutic effect. Authors' Conclusions: We did not find a statistically significant difference between active and standard placebo control interventions in our primary analysis, but the result was imprecise and the CI compatible with a difference ranging from important to irrelevant. Furthermore, the result was not robust, because two sensitivity analyses produced a more pronounced and statistically significant difference. We suggest that trialists and users of information from trials carefully consider the type of placebo control intervention in trials with high risk of unblinding, such as those with pronounced non-therapeutic effects and participant-reported outcomes. (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)
Databáze:	MEDLINE
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