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

ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)730-739
Number of pages10
JournalAmerican journal of respiratory and critical care medicine
Volume206
Issue number6
DOIs
StatePublished - Sep 15 2022

Bibliographical note

Funding Information:
Supported by the U.S. Operation Warp Speed Program; the National Institute of Allergy and Infectious Diseases and Leidos Biomedical Research for the INSIGHT NETWORK; the National Heart, Lung, and Blood Institute; the Research Triangle Institute for the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network; the Cardiothoracic Surgical Trials Network (CTSN); the Office of Research & Development, U.S. Department of Veterans Affairs; grants from the Government of Denmark, National Research Foundation no. 126; Australian Government, National Health and Medical Research Council; and the Government of the United Kingdom, Medical Research Council grant MRC_UU_12023/ 23; and National Institutes of Health agreement 1OT2HL156812-01. Trial medications were donated by Eli Lilly (LY-CoV555; bamlanivimab), Vir/ GlaxoSmithKline (VIR-7831; sotrovimab), Brii Biosciences (BRII-196/198), and Gilead Sciences (remdesivir). The views and conclusions contained in this document are those of the authors and should not be interpreted as representing official policies, either expressed or implied, of the NIH or Department of Veterans Affairs. A.L.G., S.P., and A.G.B., receive funding in support of their salary from the Medical Research Council, United Kingdom (grant MC_UU_00004/03 and MC_UU_00004/04).

Publisher Copyright:
Copyright © 2022 by the American Thoracic Society.

Keywords

  • COVID-19
  • monoclonal antibodies
  • outcomes assessment
  • SARS-CoV-2
  • Aftercare
  • Humans
  • Patient Discharge
  • Treatment Outcome
  • Aged
  • Antibodies, Monoclonal

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Journal Article
  • Research Support, N.I.H., Extramural

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