Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.

Autor:	Wolfe CR; Duke University, Durham, NC, USA., Tomashek KM; The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Patterson TF; University of Texas Health San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio, TX, USA., Gomez CA; University of Utah, Salt Lake City, UT, USA., Marconi VC; Emory University, Atlanta, GA, USA., Jain MK; University of Texas Southwestern and Parkland Health and Hospital System, Dallas, TX, USA., Yang OO; University of California, Los Angeles, CA, USA., Paules CI; Pennsylvania State Health Milton S Hershey Medical Center, Hershey, PA, USA., Palacios GMR; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico., Grossberg R; Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA., Harkins MS; University of New Mexico Health Sciences Center, Albuquerque, NM, USA., Mularski RA; Kaiser Permanente Northwest, Portland, OR, USA., Erdmann N; University of Alabama at Birmingham, Birmingham, AL, USA., Sandkovsky U; Baylor University Medical Center, Dallas, TX, USA., Almasri E; University of California, San Francisco, CA, USA., Pineda JR; Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico., Dretler AW; Infectious Disease Specialists of Atlanta and Emory Decatur Hospital, Decatur, GA, USA., de Castilla DL; Evergreen Health Medical Center, Kirkland, WA, USA., Branche AR; University of Rochester Medical Center, Rochester, NY, USA., Park PK; University of Michigan, Ann Arbor, MI, USA., Mehta AK; Emory University, Atlanta, GA, USA., Short WR; The University of Pennsylvania, Philadelphia, PA, USA., McLellan SLF; The University of Texas Medical Branch, Galveston, TX, USA., Kline S; The University of Minnesota Medical School, Minneapolis, MN, USA., Iovine NM; University of Florida Health, Shands Hospital, Gainesville, FL, USA., El Sahly HM; Baylor College of Medicine, Houston, TX, USA., Doernberg SB; University of California, San Francisco, CA, USA., Oh MD; Seoul National University Hospital, Seoul, South Korea., Huprikar N; Walter Reed National Military Medical Center, Bethesda, MD, USA., Hohmann E; Massachusetts General Hospital, Boston, MA, USA., Kelley CF; Grady Memorial Hospital, Atlanta, GA, USA., Holodniy M; VA Palo Alto Health Care System, Palo Alto, CA, USA., Kim ES; Seoul National University Bundang Hospital, Seongnam, South Korea., Sweeney DA; University of California, San Diego, La Jolla, CA, USA., Finberg RW; University of Massachusetts Medical School, Worcester, MA, USA., Grimes KA; Houston Methodist Hospital, Houston, TX, USA., Maves RC; Naval Medical Center, San Diego, CA, USA., Ko ER; Duke University, Durham, NC, USA., Engemann JJ; Duke University, Durham, NC, USA., Taylor BS; University of Texas Health San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio, TX, USA., Ponce PO; University of Texas Health San Antonio, University Health, and the South Texas Veterans Health Care System, San Antonio, TX, USA., Larson L; University of Nebraska Medical Center, Omaha, NE, USA., Melendez DP; University of Utah, Salt Lake City, UT, USA., Seibert AM; University of Utah, Salt Lake City, UT, USA., Rouphael NG; Emory University, Atlanta, GA, USA., Strebe J; University of Texas Southwestern and Parkland Health and Hospital System, Dallas, TX, USA., Clark JL; University of California, Los Angeles, CA, USA., Julian KG; Pennsylvania State Health Milton S Hershey Medical Center, Hershey, PA, USA., de Leon AP; Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico., Cardoso A; Eli Lilly, Indianapolis, IN, USA., de Bono S; Eli Lilly, Indianapolis, IN, USA., Atmar RL; Baylor College of Medicine, Houston, TX, USA., Ganesan A; Walter Reed National Military Medical Center, Bethesda, MD, USA., Ferreira JL; The Emmes Company, LLC, Rockville, MD, USA., Green M; The Emmes Company, LLC, Rockville, MD, USA., Makowski M; The Emmes Company, LLC, Rockville, MD, USA., Bonnett T; Clinical Monitoring Research Program Directorate, Frederick National Laboratory, Frederick, MD, USA., Beresnev T; The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Ghazaryan V; The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Dempsey W; The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Nayak SU; The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Dodd LE; The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Beigel JH; The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Kalil AC; University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: akalil@unmc.edu.
Jazyk:	angličtina
Zdroj:	The Lancet. Respiratory medicine [Lancet Respir Med] 2022 Sep; Vol. 10 (9), pp. 888-899. Date of Electronic Publication: 2022 May 23.
DOI:	10.1016/S2213-2600(22)00088-1
Abstrakt:	Background: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. Methods: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. Findings: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). Interpretation: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. Funding: National Institute of Allergy and Infectious Diseases. Competing Interests: Declaration of interests We declare no competing interests. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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