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