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

ACTT-4 Study Group

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)888-899
Number of pages12
JournalThe Lancet Respiratory Medicine
Volume10
Issue number9
DOIs
StatePublished - Sep 2022

Bibliographical note

Funding Information:
The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the Uniformed Services University of the Health Sciences, the Henry M Jackson Foundation for the Advancement of Military Medicine, the Departments of the Army, Navy, or Air Force, the Department of Defense, or the Department of Veterans Affairs, nor does any mention of trade names, commercial products, or organisations imply endorsement by the US Government. Gilead Sciences provided remdesivir for use in this trial but did not provide any financial support. Eli Lilly provided baricitinib for use in this trial but did not provide any financial support. Employees of Gilead Sciences and Eli Lilly participated in discussions about protocol development and in weekly protocol team calls. The National Institute of Allergy and Infectious Diseases (NIAID) ultimately made all decisions regarding trial design and implementation. The trial was sponsored and primarily funded by the NIAID, National Institutes of Health (NIH; Bethesda, MD, USA). This trial has been funded in part with federal funds from the NIAID and the National Cancer Institute, NIH, under contract HHSN261200800001E 75N91019D00024, task order number 75N91020F00010; in part by the NIAID under award numbers UM1AI148684, UM1AI148576, UM1AI148575, UM1AI148685, UM1AI148450, and UM1AI148689; and in part by the US Department of Defense, Defense Health Program. This trial has also been funded in part by the governments of Japan, Mexico, and Singapore for the trial sites in those countries; and the trial sites in South Korea received funding from the Seoul National University Hospital and Seoul National University Bundang Hospital (grant number 02-2020-001). We thank the members of the ACTT-4 Study Team for their many contributions in conducting the trial.

Funding Information:
The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, the Uniformed Services University of the Health Sciences, the Henry M Jackson Foundation for the Advancement of Military Medicine, the Departments of the Army, Navy, or Air Force, the Department of Defense, or the Department of Veterans Affairs, nor does any mention of trade names, commercial products, or organisations imply endorsement by the US Government. Gilead Sciences provided remdesivir for use in this trial but did not provide any financial support. Eli Lilly provided baricitinib for use in this trial but did not provide any financial support. Employees of Gilead Sciences and Eli Lilly participated in discussions about protocol development and in weekly protocol team calls. The National Institute of Allergy and Infectious Diseases (NIAID) ultimately made all decisions regarding trial design and implementation. The trial was sponsored and primarily funded by the NIAID, National Institutes of Health (NIH; Bethesda, MD, USA). This trial has been funded in part with federal funds from the NIAID and the National Cancer Institute, NIH, under contract HHSN261200800001E 75N91019D00024, task order number 75N91020F00010; in part by the NIAID under award numbers UM1AI148684, UM1AI148576, UM1AI148575, UM1AI148685, UM1AI148450, and UM1AI148689; and in part by the US Department of Defense, Defense Health Program. This trial has also been funded in part by the governments of Japan, Mexico, and Singapore for the trial sites in those countries; and the trial sites in South Korea received funding from the Seoul National University Hospital and Seoul National University Bundang Hospital (grant number 02-2020-001). We thank the members of the ACTT-4 Study Team for their many contributions in conducting the trial.

Publisher Copyright:
© 2022 Elsevier Ltd

PubMed: MeSH publication types

  • Journal Article
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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