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

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.

Automated summary

During the COVID-19 pandemic, adaptive platform trials were used to quickly assess therapeutics, such as the ACTIV-2 trial, which evaluated 7 investigational agents with different administration routes. The trial compared safety and efficacy outcomes of each agent to a pooled placebo control group. The implementation of a pooled placebo design resulted in a 6% reduction in sample size compared to a trial with separate placebo control groups, and a 26% reduction during the phase 2 evaluation of multiple agents. This study discusses the complexities and provides insights for the design of future platform trials.