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 language | English (US) |
|---|---|
| Pages (from-to) | 1716-1728 |
| Number of pages | 13 |
| Journal | Annals of internal medicine |
| Volume | 175 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2022 |
Bibliographical note
Funding Information:This work was supported with funds from the NIAID Division of Intramural Research and from the National Cancer Institute of the NIH under contract no. 75N91019D00024. The analysis used data from ACTT-1 (14), ACTT-2 (16), ACTT-3 (15), and ACTT-4 (17). The ACTT trials were sponsored and primarily funded by the NIAID of the NIH, Bethesda, Maryland. These trials have been funded in part with federal funds from NIAID and the National Cancer Institute of the NIH under contract HHSN261200800001E 75N910D00024, task order number 75N91019F00130/75N91020F00010, and by the Department of Defense, Defense Health Program. These trials have been supported in part by the NIAID of the NIH under award numbers UM1AI148684, UM1AI148576, UM1AI148573, UM1AI148575, UM1AI148452, UM1AI148685, UM1AI148450, and UM1AI148689. These trials have also been funded in part by the governments of Denmark, Japan, Mexico, and Singapore. The trial site in South Korea received funding from the Seoul National University Hospital. Support for the London International Coordinating Centre was also provided by the United Kingdom Medical Research Council (MRC_UU_12023/23).
Funding Information:
Financial Support: This work was supported with funds from the NIAID Division of Intramural Research and from the National Cancer Institute of the NIH under contract no. 75N91019D00024. The analysis used data from ACTT-1 (14), ACTT-2 (16), ACTT-3 (15), and ACTT-4 (17). The ACTT trials were sponsored and primarily funded by the NIAID of the NIH, Bethesda, Maryland. These trials have been funded in part with federal funds from NIAID and the National Cancer Institute of the NIH under contract HHSN261200800001E 75N910D00024, task order number 75N91019F00130/75N91020F00010, and by the Department of Defense, Defense Health Program. These trials have been supported in part by the NIAID of the NIH under award numbers UM1AI148684, UM1AI148576, UM1AI148573, UM1AI148575, UM1AI148452, UM1AI148685, UM1AI148450, and UM1AI148689. These trials have also been funded in part by the governments of Denmark, Japan, Mexico, and Singapore. The trial site in South Korea received funding from the Seoul National University Hospital. Support for the London International Coordinating Centre was also provided by the United Kingdom Medical Research Council (MRC_UU_12023/23).
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