Wolfe CR, Tomashek KM, Patterson TF, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir Med. 2022 May 23. pii: S2213-2600(22)00088-1. doi: 10.1016/S2213-2600(22)00088-1. (Original study)

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.

Discipline Area Score
Infectious Disease 7 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Respirology/Pulmonology 6 / 7
Intensivist/Critical Care 6 / 7
Comments from MORE raters

Hospital Doctor/Hospitalists rater

As a hospitalist working in ICU, this article and the results are very useful to me. We haven't used baricitinib a lot in our hospital. I can use these results to discuss with the intensivists in my hospital and help reduce steroid use that can cause a lot of adverse effects.

Intensivist/Critical Care rater

A well done RCT but what limits my enthusiasm for this report is that the WHO currently recommends combination baricitinib and dexamethasone in patients with severe COVID. So why do we need a head-to-head trial? Unless there are people who are not following WHO guidance (and using single immune suppressives in severe COVID) or there are resource issues (less likely given dexamethasone is cheap).

Internal Medicine rater

A useful article but unclear how available baricitinib is and when compared to cost (~83$ per pill) of dexamethasone, if cost and availability is valuable when extended to the population level. For the correct institution, this may be a worthwhile option.

Internal Medicine rater

My recollection is that the effectiveness of dexamethasone (vs placebo) was marginal in this non-intubated Covid population. It doesn't look like the side effects led to mortality, so not sure they should be a big focus. Without a difference in mortality and a big difference in cost, hard to make a big plug for changing course.

Respirology/Pulmonology rater

Interesting study showing targeted immune suppression with baricitinib added to remdesivir is as effective as dexamethasone but with fewer side effects.

Respirology/Pulmonology rater

New clinical trial showing similar efficacy with fewer side effects for baricitinib compared with dexamethasone for moderately ill patients with COVID-19.

Respirology/Pulmonology rater

Well done study showing similar efficacy between baricitinib and dexamethasone. Although there is a significant statistical difference in adverse events favoring baricitinib, the article does not inform on how to select one of the therapies for a given patient.
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