Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial.
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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, de Bono Stephanie, Atmar Robert L, Ganesan Anuradha, Ferreira Jennifer L, Green Michelle, Makowski Mat, Bonnett Tyler, Beresnev Tatiana, Ghazaryan Varduhi, Dempsey Walla, Nayak Seema U, Dodd Lori E, Beigel John H, Kalil Andre C, ACTT-4 Study Group
Аннотация
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.