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Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.
Wolfe, Cameron R; Tomashek, Kay M; Patterson, Thomas F; Gomez, Carlos A; Marconi, Vincent C; Jain, Mamta K; Yang, Otto O; Paules, Catharine I; Palacios, Guillermo M Ruiz; Grossberg, Robert; Harkins, Michelle S; Mularski, Richard A; Erdmann, Nathaniel; Sandkovsky, Uriel; Almasri, Eyad; Pineda, Justino Regalado; Dretler, Alexandra W; de Castilla, Diego Lopez; Branche, Angela R; Park, Pauline K; Mehta, Aneesh K; Short, William R; McLellan, Susan L F; Kline, Susan; Iovine, Nicole M; El Sahly, Hana M; Doernberg, Sarah B; Oh, Myoung-Don; Huprikar, Nikhil; Hohmann, Elizabeth; Kelley, Colleen F; Holodniy, Mark; Kim, Eu Suk; Sweeney, Daniel A; Finberg, Robert W; Grimes, Kevin A; Maves, Ryan C; Ko, Emily R; Engemann, John J; Taylor, Barbara S; Ponce, Philip O; Larson, LuAnn; Melendez, Dante Paolo; Seibert, Allan M; Rouphael, Nadine G; Strebe, Joslyn; Clark, Jesse L; Julian, Kathleen G; de Leon, Alfredo Ponce; Cardoso, Anabela.
  • 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.
Lancet Respir Med ; 2022 May 23.
Article in English | MEDLINE | ID: covidwho-1864689
ABSTRACT

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 (11) 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.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Controlled clinical trial / Randomized controlled trials Topics: Vaccines Language: English Year: 2022 Document Type: Article Affiliation country: S2213-2600(22)00088-1

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Controlled clinical trial / Randomized controlled trials Topics: Vaccines Language: English Year: 2022 Document Type: Article Affiliation country: S2213-2600(22)00088-1