Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery
American journal of respiratory and critical care medicine
COVID-19; Monoclonal Antibodies; Outcomes Assessment
RATIONALE: Uncertainty regarding the natural history of coronavirus disease 2019 (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized COVID-19 patients. OBJECTIVES: Evaluate 90-day clinical course of patients hospitalized with COVID-19 comparing three distinct definitions of recovery. METHODS: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1) the hospital discharge approach 2) the Therapeutics for Inpatients with COVID-19 (TICO) trials "sustained recovery" approach, and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-intensive care unit setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. MEASUREMENTS AND MAIN RESULTS: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age 68 vs. 59 years; p<0.001) and more had a comorbidity (84% vs. 70%; p<0.001). Of 170 discordant participants, 106 (62%) had post-discharge events captured by the TICO approach. CONCLUSIONS: Among patients hospitalized with COVID-19, 20% had clinically significant post-discharge events within 90 days after randomization, in patients that would be considered "recovered" using the hospital discharge approach. Employing the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should employ follow-up times up to 90 days to assess clinical recovery more accurately.
Douin, David J.; Siegel, Lianne; Grandits, Greg; Phillips, Andrew; Aggarwal, Neil R.; Baker, Jason; Brown, Samuel M.; Chang, Christina C.; Goodman, Anna L.; Grund, Birgit; Higgs, Elizabeth S.; Hough, Catherine L.; Murray, Daniel D.; Paredes, Roger; Parmar, Mahesh; Pett, Sarah; Polizzotto, Mark N.; Sandkovsky, Uriel; Self, Wesley H.; Young, Barnaby E.; Babiker, Abdel G.; Davey, Victoria J.; Kan, Virginia; Gelijns, Annetine C.; Matthews, Gail; Thompson, B Taylor; Lane, H Clifford; Neaton, James D.; Lundgren, Jens D.; and Ginde, Adit A., "Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery" (2022). GW Authored Works. Paper 938.