Evaluating primary endpoints for COVID-19 therapeutic trials to assess recovery

• Main Authors: 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 Edward, 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., Ginde, Adit A.
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Medicine; COVID-19; Outcomes Assessment
• Online Access: https://hdl.handle.net/10356/164556
• Institution: Nanyang Technological University

Rationale: Uncertainty regarding the natural history of coronavirus disease (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 patients with COVID-19. 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 TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU 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 postdischarge events captured by the TICO approach. Conclusions: Among patients hospitalized with COVID-19, 20% had clinically significant postdischarge events within 90 days after randomization in patients who would be considered "recovered" using the hospital discharge approach. Using the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should use follow-up times up to 90 days to assess clinical recovery more accurately.