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

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

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • COVID-19*
  • Control Groups
  • Humans
  • Pandemics

Associated data

  • ClinicalTrials.gov/NCT04518410