Evaluating Primary Endpoints for COVID-19 Therapeutic Trials to Assess Recovery

David J. Douin, University of Colorado Denver Department of Anesthesiology, 156151, Aurora, Colorado, United States.
Lianne Siegel, University of Minnesota School of Public Health, 43353, Biostatistics, Minneapolis, Minnesota, United States.
Greg Grandits, University of Minnesota School of Public Health, 43353, Minneapolis, Minnesota, United States.
Andrew Phillips, University College London, 4919, Infection and Population Health, London, London, United Kingdom of Great Britain and Northern Ireland.
Neil R. Aggarwal, University of Colorado Denver School of Medicine, 12225, Medicine, Aurora, Colorado, United States.
Jason Baker, Hennepin Healthcare System Inc, 5532, Minneapolis, Minnesota, United States.
Samuel M. Brown, Intermountain Medical Center, Center for Humanizing Critical Care, Murray, Utah, United States.
Christina C. Chang, University of New South Wales, 7800, The Kirby Institute, Sydney, New South Wales, Australia.
Anna L. Goodman, London School of Hygiene & Tropical Medicine, 4906, MRC Clinical Trials Unit, London, London, United Kingdom of Great Britain and Northern Ireland.
Birgit Grund, University of Minnesota School of Public Health, 43353, School of Statistics, Minneapolis, Minnesota, United States.
Elizabeth S. Higgs, National Institute of Allergy and Infectious Diseases, 35037, Bethesda, Maryland, United States.
Catherine L. Hough, Oregon Health & Science University, 6684, Portland, Oregon, United States.
Daniel D. Murray, Rigshospitalet, 53146, CHIP Center of Excellence for Health, Immunity and Infections and Department of Infectious Diseases, Kobenhavn, Denmark.
Roger Paredes, Hospital Germans Trias i Pujol, 16514, Badalona, Catalunya, Spain.
Mahesh Parmar, University College London, 4919, The Medical Research Council Clinical Trials Unit, London, London, United Kingdom of Great Britain and Northern Ireland.
Sarah Pett, University College London, 4919, Medical Research Council Clinical Trails Unit, London, London, United Kingdom of Great Britain and Northern Ireland.
Mark N. Polizzotto, University of New South Wales, 7800, John Curtin School of Medical Research, The Australian National University and the Kirby Institute, Sydney, New South Wales, Australia.
Uriel Sandkovsky, Baylor University Medical Center at Dallas, 22683, Infectious Diseases, Dallas, Texas, United States.
Wesley H. Self, Vanderbilt University Medical Center, 12328, Department of Emergency Medicine, Nashville, Tennessee, United States.
Barnaby E. Young, National Centre for Infectious Diseases, 534956, Singapore, Singapore.
Abdel G. Babiker, University College London, 4919, The Medical Research Council Clinical Trials Unit, London, London, United Kingdom of Great Britain and Northern Ireland.
Victoria J. Davey, Department of Veterans Affairs, Office of Research and Development, Washington, DC, United States.
Virginia Kan, VA Medical Center and George Washington University, Washington DC, United States.
Annetine C. Gelijns, Icahn School of Medicine at Mountsinai, Population Health Science and Policy, New York, New York, United States.
Gail Matthews, University of New South Wales, 7800, The Kirby Institute, Sydney, New South Wales, Australia.
B Taylor Thompson, Massachusetts General Hospital, Harvard School of Medicine,, 5Division of Pulmonary and Critical Care Medicine, Department of Medicine, Boston, Massachusetts, United States.
H Clifford Lane, National Institute of Allergy and Infectious Diseases, 35037, Bethesda, Maryland, United States.
James D. Neaton, University of Minnesota School of Public Health, 43353, Biostatistics, Minneapolis, Minnesota, United States.
Jens D. Lundgren, Rigshospitalet and Copenhagen University Hospital, CHIP, Department of Infectious Diseases and Rheumatology, Copenhagen, Denmark.
Adit A. Ginde, University of Colorado Denver School of Medicine, 12225, Department of Emergency Medicine, Aurora, Colorado, United States; adit.ginde@cuanschutz.edu.

Document Type

Journal Article

Publication Date

5-17-2022

Journal

American journal of respiratory and critical care medicine

DOI

10.1164/rccm.202112-2836OC

Keywords

COVID-19; Monoclonal Antibodies; Outcomes Assessment

Abstract

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.

Department

Medicine

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