Baricitinib versus Dexamethasone for Adults Hospitalised with COVID-19 (ACTT-4): a Randomised, Double-blind, Double Placebo-controlled Trial
2022 Sep
Journal Article
Authors:
Wolfe, C.R.;
Tomashek, K.M.;
Patterson, T.F.;
Gomez, C.A.;
Marconi, V.C.;
Jain, M.K.;
Yang, O.O.;
Paules, C.I.;
Palacios, G.M.Ruiz;
Grossberg, R.;
Harkins, M.S.;
Mularski, R.A.;
Erdmann, N.;
Sandkovsky, U.;
Almasri, E.;
Pineda, J.Regalado;
Dretler, A.W.;
de Castilla, D.Lopez;
Branche, A.R.;
Park, P.K.;
Mehta, A.K.;
Short, W.R.;
McLellan, S.L.F.;
Kline, S.;
Iovine, N.M.;
Sahly, H.M.El;
Doernberg, S.B.;
Oh, M.D.;
Huprikar, N.;
Hohmann, E.;
Kelley, C.F.;
Holodniy, M.;
Kim, E.Suk;
Sweeney, D.A.;
Finberg, R.W.;
Grimes, K.A.;
Maves, R.C.;
Ko, E.R.;
Engemann, J.J.;
Taylor, B.S.;
Ponce, P.O.;
Larson, L.A.;
Melendez, D.Paolo;
Seibert, A.M.;
Rouphael, N.G.;
Strebe, J.;
Clark, J.L.;
Julian, K.G.;
de Leon, A.Ponce;
Cardoso, A.;
de Bono, S.;
Atmar, R.L.;
Ganesan, A.;
Ferreira, J.L.;
Green, M.;
Makowski, M.;
Bonnett, T.;
Beresnev, T.;
Ghazaryan, V.;
Dempsey, W.;
Nayak, S.U.;
Dodd, L.E.;
Beigel, J.H.;
Kalil, A.C.
Secondary:
Lancet Respir Med
Volume:
10
Pagination:
888-899
Issue:
9
PMID:
35617986
URL:
https://pubmed.ncbi.nlm.nih.gov/35617986/
DOI:
10.1016/S2213-2600(22)00088-1
Keywords:
Adolescent; Adult; Azetidines; COVID-19 Drug Treatment; Dexamethasone; Double-Blind Method; Female; Humans; Male; Middle Aged; Oxygen; Purines; Pyrazoles; SARS-CoV-2; Sulfonamides; Treatment Outcome
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.
