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Meta-Analysis
. 2023 Mar 6;3(3):MR000055.
doi: 10.1002/14651858.MR000055.pub2.

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

David Rt Laursen  1   2 , Camilla Hansen Nejstgaard  1   2 , Espen Bjørkedal  3 , Anders Dreyer Frost  1   2 , Morten Rix Hansen  4   5   6 , Asger S Paludan-Müller  1   2 , Julian Prosenz  7 , Christoph Patrick Werner  8 , Asbjørn Hróbjartsson  1   2
Affiliations
Meta-Analysis

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

David Rt Laursen et al. Cochrane Database Syst Rev. .

Abstract

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; I2 = 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.

Trial registration: ClinicalTrials.gov NCT02194088 NCT02629146 NCT02283281.

PubMed Disclaimer

Conflict of interest statement

MRH has received grants from Pfizer, paid to his employer, outside the submitted work, has received speaking fees from Novartis outside the submitted work, and owns stocks in Novo Nordisk. During the editorial process, MRH changed employment from Odense University Hospital and University of Southern Denmark to Novo Nordisk on 1 February 2022; this was after submission of the first review draft and response to peer review comments, but before the copy editing. All three affiliations are therefore listed.

JP, EB and CPW are co‐authors of three of the included studies and were not involved in the study inclusion, data extraction, and risk of bias assessment of any studies.

The remaining authors (DRTL, CHN, ADF, ASP, AH) declare no financial or non‐financial conflicts of interest.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Funnel plot of Comparison 1. Patient‐reported outcomes at earliest post‐treatment assessment; Outcome 1.1. Main analysis.
1.1
1.1. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 1: Main analysis
1.2
1.2. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 2: Sensitivity analysis – excluding dichotomous data
1.3
1.3. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 3: Sensitivity analysis – adding nearly eligible trials
1.4
1.4. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 4: Sensitivity analysis – low risk of bias
1.5
1.5. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 5: Sensitivity analysis – fixed‐effect model
1.6
1.6. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 6: Sensitivity analysis – adding observer‐reported outcomes
1.7
1.7. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 7: Sensitivity analysis – preferring change scores
1.8
1.8. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 8: Sensitivity analysis – adjusting trials with individual participant data for baseline
1.9
1.9. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 9: Subgroup analysis – trial design
1.10
1.10. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 10: Subgroup analysis – experimental arm or no experimental arm
1.11
1.11. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 11: Subgroup analysis – active placebo effects
1.12
1.12. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 12: Subgroup analysis – publication status
1.13
1.13. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 13: Data for main analysis – continuous data
1.14
1.14. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 14: Data for main analysis – dichotomous data
1.15
1.15. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 15: Data for main analysis – continuous crossover data
1.16
1.16. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 16: Data for sensitivity analysis – preferring change scores – continuous data
1.17
1.17. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 17: Data for sensitivity analysis – adding nearly eligible studies – continuous data
1.18
1.18. Analysis
Comparison 1: Participant‐reported outcomes at earliest post‐treatment assessment, Outcome 18: Data for sensitivity analysis – adding nearly eligible studies – dichotomous data
2.1
2.1. Analysis
Comparison 2: Patient‐reported outcomes at latest follow‐up, Outcome 1: Main analysis
2.2
2.2. Analysis
Comparison 2: Patient‐reported outcomes at latest follow‐up, Outcome 2: Data for main analysis – continuous data
3.1
3.1. Analysis
Comparison 3: Observer‐reported outcomes at earliest post‐treatment assessment, Outcome 1: Main analysis
3.2
3.2. Analysis
Comparison 3: Observer‐reported outcomes at earliest post‐treatment assessment, Outcome 2: Data for main analysis – continuous data
3.3
3.3. Analysis
Comparison 3: Observer‐reported outcomes at earliest post‐treatment assessment, Outcome 3: Data for main analysis – dichotomous data
3.4
3.4. Analysis
Comparison 3: Observer‐reported outcomes at earliest post‐treatment assessment, Outcome 4: Data for main analysis – continuous cross‐over data
4.1
4.1. Analysis
Comparison 4: Observer‐reported outcomes at latest follow‐up, Outcome 1: Main analysis
4.2
4.2. Analysis
Comparison 4: Observer‐reported outcomes at latest follow‐up, Outcome 2: For main analysis – continuous data
5.1
5.1. Analysis
Comparison 5: Harms, Outcome 1: Main analysis
5.2
5.2. Analysis
Comparison 5: Harms, Outcome 2: Subgroup analysis – predictable effects versus other harms
5.3
5.3. Analysis
Comparison 5: Harms, Outcome 3: For main analysis – dichotomous data
5.4
5.4. Analysis
Comparison 5: Harms, Outcome 4: For main analysis – continuous data
6.1
6.1. Analysis
Comparison 6: Attrition, Outcome 1: Main analysis
7.1
7.1. Analysis
Comparison 7: Co‐interventions, dichotomous, Outcome 1: Main analysis
8.1
8.1. Analysis
Comparison 8: Co‐interventions, continuous, Outcome 1: Main analysis
See this image and copyright information in PMC

Update of

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Abse 1956 {published data only}
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