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. 2023 Aug 31;228(Suppl 2):S92-S100.
doi: 10.1093/infdis/jiad209.

Pooling Different Placebos as a Control Group in a Randomized Platform Trial: Benefits and Challenges From Experience in the ACTIV-2 COVID-19 Trial

Carlee B Moser  1 , Kara W Chew  2 , Justin Ritz  1 , Matthew Newell  3 , Arzhang Cyrus Javan  4 , Joseph J Eron  3 , Eric S Daar  5 , David A Wohl  3 , Judith S Currier  2 , Davey M Smith  6 , Michael D Hughes  7 ; ACTIV-2/A5401 Study Team
Collaborators, Affiliations

Pooling Different Placebos as a Control Group in a Randomized Platform Trial: Benefits and Challenges From Experience in the ACTIV-2 COVID-19 Trial

Carlee B Moser et al. J Infect Dis. .

Abstract

Adaptive platform trials were implemented during the coronavirus disease 2019 (COVID-19) pandemic to rapidly evaluate therapeutics, including the placebo-controlled phase 2/3 ACTIV-2 trial, which studied 7 investigational agents with diverse routes of administration. For each agent, safety and efficacy outcomes were compared to a pooled placebo control group, which included participants who received a placebo for that agent or for other agents in concurrent evaluation. A 2-step randomization framework was implemented to facilitate this. Over the study duration, the pooled placebo design achieved a reduction in sample size of 6% versus a trial involving distinct placebo control groups for evaluating each agent. However, a 26% reduction was achieved during the period when multiple agents were in parallel phase 2 evaluation. We discuss some of the complexities implementing the pooled placebo design versus a design involving nonoverlapping control groups, with the aim of informing the design of future platform trials. Clinical Trials Registration. NCT04518410.

Keywords: COVID-19; adaptive platform trials; pooled placebo; randomization.

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Conflict of interest statement

Potential conflicts of interest. C. B. M. participated on a data safety monitoring board for the BONE STAR study. K. W. C. has received research funding to the institution from Merck Sharp & Dohme; and is a consultant for Pardes Biosciences. E. S. D. receives consulting fees from Gilead Sciences, Merck, and GSK/ViiV; and research support through the institution from Gilead Sciences and GSK/ViiV. D. A. W. has received funding to the institution to support research and honoraria for advisory boards and consulting from Gilead Sciences. J. S. C. has consulted for Merck and Company. J. J. E. is an ad hoc consultant to GSK/VIR; and data monitoring committee chair for Adagio phase 3 studies. D. M. S. has consulted for Evidera, Fluxergy, Kiadis, Linear Therapies, Matrix BioMed, Arena Pharmaceuticals, VxBiosciences, Model Medicines, Bayer Pharmaceuticals, Signant Health, and Brio Clinical. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Illustrative example of randomization scheme for a stratum of participants eligible for 3 agents, A, B, and C.
Figure 2.
Figure 2.
Enrollment timelines for placebo-controlled evaluation of agents in ACTIV-2. Dashed arrow perimeters indicate agents for which phase 2 enrollment was terminated early for administrative reasons. Enrollment shown is for placebo-controlled phase 2 evaluation for all agents and placebo-controlled phase 3 evaluation of A/R (the only agent that underwent placebo-controlled phase 3 evaluation in ACTIV-2). Abbreviations: A/R, amubarvimab/romlusevimab; Bam, bamlanivimab; IM, intramuscular injection; IV, intravenous infusion; Ph, phase; T/C, tixagevimab/cilgavimab.
Figure 3.
Figure 3.
Enrollment over time for the placebo-controlled evaluation of agents in ACTIV-2. Abbreviations: A/R-Ph2, amubarvimab/romlusevimab phase 2; A/R-Ph3, amubarvimab/romlusevimab phase 3; Bam-700 mg, bamlanivimab 700 mg; Bam-7000 mg, bamlanivimab 7000 mg; BMS, BMS-986414 + BMS-986413; SAB-185-high, SAB-185 high dose; SAB-185-low, SAB-185 low dose; T/C IV, tixagevimab/cilgavimab by intravenous infusion; T/C-IM, tixagevimab/cilgavimab by intramuscular injection.
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