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Randomized controlled trials are an important tool within the “research pillar” of outbreak response. Rapid identification of interventions that reduce disease transmission, morbidity and mortality will aid disease control, yet a multitude of unknowns exist when planning a trial during a novel infectious disease outbreak. Uncertainties arise from an imperfect understanding about illness, limited data about proposed medical countermeasures, complexities in measuring relevant patient outcomes, unpredictable case numbers, rapidly evolving supportive care, and disease evolution (e.g., new variants). Further, outbreaks can quickly cause an overloaded medical system with limited resources for research and heightened pressure to find cures quickly. The COVID-19 pandemic highlighted all these issues and more.
The Adaptive COVID-19 Treatment Trial (ACTT) opened within three weeks of planning initiation and was the first randomized controlled trial to commence outside of China. Rapid timelines meant making decisions to move the study forward in the absence of full information, hence the trial included flexibility to adapt to evolving information. Critical decisions included study endpoints, how many agents to include, and when to drop/add study agents. I will review how these decisions were repeatedly addressed throughout the implementation of the ACTT trials.