Impact of active placebo controls on estimated drug effects in randomised trials

Oral
2023 London
Laursen DR1, Nejstgaard CH1, Bjørkedal E2, Frost AD1, Hansen MR3, Paludan-Müller AS1, Prosenz J4, Werner CP5, Hróbjartsson A1
1Centre for Evidence-Based Medicine Odense (CEBMO) and Cochrane Denmark, Department of Clinical Research, University of Southern Denmark; Open Patient data Explorative Network (OPEN), Odense University Hospital
2Department of Psychology, Faculty of Health Sciences, UiT–The Arctic University of Norway
3Novo Nordisk; Department of Clinical Biochemistry and Pharmacology, Odense University Hospital; Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark
4Department of Internal Medicine 2, University Hospital St. Poelten
5School of Psychology, Faculty of Science, The University of Sydney
Background: Active placebo controls are designed to mimic the nontherapeutic adverse effects of drugs in randomised trials. Active placebos are rarely used but could reduce the risk of bias due to unblinding.

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 active placebo and standard placebo intervention.

Design: A systematic review.

Methods: We searched PubMed, CENTRAL, Embase, and other sources up to October 2020 and included randomised trials directly comparing active placebo versus standard placebo. Our primary inverse-variance, random-effects meta-analysis used standardised mean differences (SMDs) of participant-reported outcomes at earliest post-treatment assessment. An SMD