Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial

Gail E. Potter*, Tyler Bonnett, Kevin Rubenstein, David A. Lindholm, Rekha R. Rapaka, Sarah B. Doernberg, David C. Lye, Richard A. Mularski, Noreen A. Hynes, Susan Kline, Catharine I. Paules, Cameron R. Wolfe, Maria G. Frank, Nadine G. Rouphael, Gregory A. Deye, Daniel A. Sweeney, Rhonda E. Colombo, Richard T. Davey, Aneesh K. Mehta, Jennifer A. WhitakerJose G. Castro, Alpesh N. Amin, Christopher J. Colombo, Corri B. Levine, Mamta K. Jain, Ryan C. Maves, Vincent C. Marconi, Robert Grossberg, Sameh Hozayen, Timothy H. Burgess, Robert L. Atmar, Anuradha Ganesan, Carlos A. Gomez, Constance A. Benson, Diego Lopez de Castilla, Neera Ahuja, Sarah L. George, Seema U. Nayak, Stuart H. Cohen, Tahaniyat Lalani, William R. Short, Nathaniel Erdmann, Kay M. Tomashek, Pablo Tebas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Background: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear. Objective: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial). Design: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]) Setting: 94 hospitals in 10 countries (86% U.S. participants). Participants: Adults hospitalized with COVID-19. Intervention: SOC. Measurements: 28-day mortality and recovery. Results: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages. Limitation: Unmeasured confounding. Conclusion: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.

Original languageEnglish
Pages (from-to)1716-1728
Number of pages13
JournalAnnals of Internal Medicine
Volume175
Issue number12
DOIs
StatePublished - Dec 2022
Externally publishedYes

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