• 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 Whitaker, Jose 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, and Pablo Tebas.
• Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland (G.E.P.).
• Ann. Intern. Med. 2022 Dec 1; 175 (12): 171617271716-1727.

BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT 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]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough 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.LimitationUnmeasured confounding.ConclusionChanges 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.Primary Funding SourceNational Institute of Allergy and Infectious Diseases.

21 keywords...

hide…