Observational Study

. 2022 Dec;175(12):1716-1727.

doi: 10.7326/M22-2116. Epub 2022 Nov 29.

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 Potter¹, Tyler Bonnett², Kevin Rubenstein², David A Lindholm³, Rekha R Rapaka⁴, Sarah B Doernberg⁵, David C Lye⁶, Richard A Mularski⁷, Noreen A Hynes⁸, Susan Kline⁹, Catharine I Paules¹⁰, Cameron R Wolfe¹¹, Maria G Frank¹², Nadine G Rouphael¹³, Gregory A Deye¹⁴, Daniel A Sweeney¹⁵, Rhonda E Colombo¹⁶, Richard T Davey Jr¹⁷, Aneesh K Mehta¹⁸, Jennifer A Whitaker¹⁹, Jose G Castro²⁰, Alpesh N Amin²¹, Christopher J Colombo²², Corri B Levine²³, Mamta K Jain²⁴, Ryan C Maves²⁵, Vincent C Marconi²⁶, Robert Grossberg²⁷, Sameh Hozayen²⁸, Timothy H Burgess²⁹, Robert L Atmar³⁰, Anuradha Ganesan³¹, Carlos A Gomez³², Constance A Benson³³, Diego Lopez de Castilla³⁴, Neera Ahuja³⁵, Sarah L George³⁶, Seema U Nayak¹⁴, Stuart H Cohen³⁷, Tahaniyat Lalani³⁸, William R Short³⁹, Nathaniel Erdmann⁴⁰, Kay M Tomashek¹⁴, Pablo Tebas⁴¹

Affiliations

¹ Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland (G.E.P.).
² Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland (T.B., K.R.).
³ Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and Brooke Army Medical Center, Joint Base San Antonio-Fort Sam Houston, Texas (D.A.L.).
⁴ University of Maryland Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland (R.R.R.).
⁵ Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, San Francisco, California (S.B.D.).
⁶ National Centre for Infectious Diseases, Tan Tock Seng Hospital, Yong Loo Lin School of Medicine, and Lee Kong Chian School of Medicine, Singapore (D.C.L.).
⁷ Department of Pulmonary and Critical Care Medicine, Northwest Permanente PC, and Kaiser Permanente Northwest Center for Health Research, Portland, Oregon (R.A.M.).
⁸ Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (N.A.H.).
⁹ Department of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota Medical School, Minneapolis, Minnesota (S.K.).
¹⁰ Division of Infectious Diseases, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania (C.I.P.).
¹¹ Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina (C.R.W.).
¹² Department of Medicine, Denver Health Hospital Authority, Denver, Colorado, and University of Colorado School of Medicine, Aurora, Colorado (M.G.F.).
¹³ Hope Clinic, Emory Vaccine Center, Infectious Diseases Division, Atlanta, Georgia (N.G.R.).
¹⁴ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (G.A.D., S.U.N., K.M.T.).
¹⁵ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, San Diego, California (D.A.S.).
¹⁶ Madigan Army Medical Center, Tacoma, Washington, Infectious Diseases Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland (R.E.C.).
¹⁷ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (R.T.D.).
¹⁸ Division of Infectious Diseases, Emory University School of Medicine, and National Emerging Special Pathogens Training and Education Center, Atlanta, Georgia (A.K.M.).
¹⁹ Departments of Molecular Virology and Microbiology and Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas (J.A.W.).
²⁰ Division of Infectious Diseases, University of Miami, Miami, Florida (J.G.C.).
²¹ Department of Medicine, University of California, Irvine, Irvine, California (A.N.A.).
²² Madigan Army Medical Center, Tacoma, Washington, and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (C.J.C.).
²³ Department of Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch, Galveston, Texas (C.B.L.).
²⁴ Department of Internal Medicine, Division of Infectious Disease and Geographic Medicine, UT Southwestern Medical Center, and Parkland Health & Hospital System, Dallas, Texas (M.K.J.).
²⁵ Wake Forest University School of Medicine, Winston-Salem, North Carolina, and Infectious Diseases Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland (R.C.M.).
²⁶ Emory University School of Medicine, Rollins School of Public Health, and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia (V.C.M.).
²⁷ Department of Medicine, Division of Infectious Diseases, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York (R.G.).
²⁸ Department of Medicine, Division of Hospital Medicine, University of Minnesota, Minneapolis, Minnesota (S.H.).
²⁹ Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland (T.H.B.).
³⁰ Department of Medicine, Baylor College of Medicine, Houston, Texas (R.L.A.).
³¹ Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and Walter Reed National Military Medical Center, Bethesda, Maryland (A.G.).
³² Department of Internal Medicine, Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, Nebraska (C.A.G.).
³³ Division of Infectious Diseases and Global Public Health, University of California San Diego, San Diego, California (C.A.B.).
³⁴ Division of Infectious Diseases, Evergreen Health Medical Center, Kirkland, Washington (D.L.).
³⁵ Department of Internal Medicine, Stanford University Medical Center, Palo Alto, California (N.A.).
³⁶ Saint Louis University and St. Louis VA Medical Center, Saint Louis, Missouri (S.L.G.).
³⁷ Division of Infectious Diseases, University of California, Davis, Sacramento, California (S.H.C.).
³⁸ Naval Medical Center Portsmouth, Portsmouth, Virginia, Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland (T.L.).
³⁹ Department of Medicine, Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania (W.R.S.).
⁴⁰ Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (N.E.).
⁴¹ Division of Infectious Diseases/Clinical Trials Unit, University of Pennsylvania, Philadelphia, Pennsylvania (P.T.).

PMID: 36442063
PMCID: PMC9709721
DOI: 10.7326/M22-2116

Observational Study

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 et al. Ann Intern Med. 2022 Dec.

. 2022 Dec;175(12):1716-1727.

doi: 10.7326/M22-2116. Epub 2022 Nov 29.

Authors

Affiliations

¹ Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland (G.E.P.).
² Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, Maryland (T.B., K.R.).
³ Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and Brooke Army Medical Center, Joint Base San Antonio-Fort Sam Houston, Texas (D.A.L.).
⁴ University of Maryland Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland (R.R.R.).
⁵ Department of Medicine, Division of Infectious Diseases, University of California, San Francisco, San Francisco, California (S.B.D.).
⁶ National Centre for Infectious Diseases, Tan Tock Seng Hospital, Yong Loo Lin School of Medicine, and Lee Kong Chian School of Medicine, Singapore (D.C.L.).
⁷ Department of Pulmonary and Critical Care Medicine, Northwest Permanente PC, and Kaiser Permanente Northwest Center for Health Research, Portland, Oregon (R.A.M.).
⁸ Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland (N.A.H.).
⁹ Department of Medicine, Division of Infectious Diseases and International Medicine, University of Minnesota Medical School, Minneapolis, Minnesota (S.K.).
¹⁰ Division of Infectious Diseases, Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania (C.I.P.).
¹¹ Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina (C.R.W.).
¹² Department of Medicine, Denver Health Hospital Authority, Denver, Colorado, and University of Colorado School of Medicine, Aurora, Colorado (M.G.F.).
¹³ Hope Clinic, Emory Vaccine Center, Infectious Diseases Division, Atlanta, Georgia (N.G.R.).
¹⁴ Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (G.A.D., S.U.N., K.M.T.).
¹⁵ Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, San Diego, California (D.A.S.).
¹⁶ Madigan Army Medical Center, Tacoma, Washington, Infectious Diseases Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland (R.E.C.).
¹⁷ National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (R.T.D.).
¹⁸ Division of Infectious Diseases, Emory University School of Medicine, and National Emerging Special Pathogens Training and Education Center, Atlanta, Georgia (A.K.M.).
¹⁹ Departments of Molecular Virology and Microbiology and Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas (J.A.W.).
²⁰ Division of Infectious Diseases, University of Miami, Miami, Florida (J.G.C.).
²¹ Department of Medicine, University of California, Irvine, Irvine, California (A.N.A.).
²² Madigan Army Medical Center, Tacoma, Washington, and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland (C.J.C.).
²³ Department of Internal Medicine, Division of Infectious Disease, University of Texas Medical Branch, Galveston, Texas (C.B.L.).
²⁴ Department of Internal Medicine, Division of Infectious Disease and Geographic Medicine, UT Southwestern Medical Center, and Parkland Health & Hospital System, Dallas, Texas (M.K.J.).
²⁵ Wake Forest University School of Medicine, Winston-Salem, North Carolina, and Infectious Diseases Clinical Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland (R.C.M.).
²⁶ Emory University School of Medicine, Rollins School of Public Health, and Atlanta Veterans Affairs Medical Center, Atlanta, Georgia (V.C.M.).
²⁷ Department of Medicine, Division of Infectious Diseases, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York (R.G.).
²⁸ Department of Medicine, Division of Hospital Medicine, University of Minnesota, Minneapolis, Minnesota (S.H.).
²⁹ Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland (T.H.B.).
³⁰ Department of Medicine, Baylor College of Medicine, Houston, Texas (R.L.A.).
³¹ Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., and Walter Reed National Military Medical Center, Bethesda, Maryland (A.G.).
³² Department of Internal Medicine, Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, Nebraska (C.A.G.).
³³ Division of Infectious Diseases and Global Public Health, University of California San Diego, San Diego, California (C.A.B.).
³⁴ Division of Infectious Diseases, Evergreen Health Medical Center, Kirkland, Washington (D.L.).
³⁵ Department of Internal Medicine, Stanford University Medical Center, Palo Alto, California (N.A.).
³⁶ Saint Louis University and St. Louis VA Medical Center, Saint Louis, Missouri (S.L.G.).
³⁷ Division of Infectious Diseases, University of California, Davis, Sacramento, California (S.H.C.).
³⁸ Naval Medical Center Portsmouth, Portsmouth, Virginia, Infectious Disease Clinical Research Program, Department of Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, and The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, Maryland (T.L.).
³⁹ Department of Medicine, Division of Infectious Diseases, University of Pennsylvania, Philadelphia, Pennsylvania (W.R.S.).
⁴⁰ Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama (N.E.).
⁴¹ Division of Infectious Diseases/Clinical Trials Unit, University of Pennsylvania, Philadelphia, Pennsylvania (P.T.).

PMID: 36442063
PMCID: PMC9709721
DOI: 10.7326/M22-2116

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.

Primary funding source: National Institute of Allergy and Infectious Diseases.

PubMed Disclaimer

Conflict of interest statement

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-2116.

Figures

**Visual Abstract.. Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults.**
The standard of care (SOC) for COVID-19 evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear. In this post hoc analysis of a series of phase 3 trials that evaluated COVID-19 therapeutics from February 2020 through May 2021, the authors sought to evaluate whether recovery and mortality improved as the SOC evolved.

**Figure 1.. U.S. hospitalization rates (8) and treatment milestones (A) and time trends of concomitant medication use (B) in ACTT-1, ACTT-2, and ACTT-3.**
Treatment groups and periods of enrollment (*dark colors*) and follow-up after the last enrolled participant (*light colors*) are shown at the top of the figure. The colors of the bars correspond to the treatment groups. Treatment recommendations are from the National Institutes of Health COVID-19 Treatment Guidelines Panel (2). ACTT = Adaptive COVID-19 Treatment Trial; Bari = baricitinib; CQ = chloroquine; DEX = dexamethasone; EAP = Expanded Access Program; EUA = emergency use authorization; FDA = U.S. Food and Drug Administration; HCQ = hydroxychloroquine; RDV = remdesivir.

**Figure 2.. Oxygen delivery system/OS by day and phase (ACTT-1, ACTT-2, and ACTT-3) for enrolled remdesivir recipients.**
Panel A shows weekly enrollments by baseline oxygen delivery system, which corresponds to the OS of disease severity for hospitalized patients. Panel B shows proportions rather than counts to facilitate comparison of OS distributions between stages. Panels A and B show baseline distributions, whereas panel C includes all observations for each participant from enrollment until day 28 or discharge. ACTT = Adaptive COVID-19 Treatment Trial; ECMO = extracorporeal membrane oxygenation; NIPPV = noninvasive positive pressure ventilation; OS = ordinal score.

**Figure 3.. Propensity score–weighted and unweighted survival curves for recovery and mortality in ACTT-1 and ACTT-2.**
Note that the y-axis scale differs between panels. ACTT = Adaptive COVID-19 Treatment Trial; HR = hazard ratio.

**Figure 4.. Propensity score–weighted and unweighted survival curves for recovery and mortality for the comparison between ACTT-2 and ACTT-3.**
This analysis excludes patients with chronic liver disease and a baseline ordinal score of 7, as these were exclusion criteria for ACTT-3. Note that the y-axis scale differs between panels. ACTT = Adaptive COVID-19 Treatment Trial; HR = hazard ratio.

See this image and copyright information in PMC

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Medical