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

Authors

• 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.

APA Citation

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.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/938

Department

Medicine