Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis

Abstract

Background: We aimed to evaluate the use of baricitinib, a Janus kinase (JAK) 1-2 inhibitor, for the treatment of patients admitted to hospital with COVID-19.

Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple possible treatments in patients hospitalised with COVID-19 in the UK. Eligible and consenting patients were randomly allocated (1:1) to either usual standard of care alone (usual care group) or usual care plus baricitinib 4 mg once daily by mouth for 10 days or until discharge if sooner (baricitinib group). The primary outcome was 28-day mortality assessed in the intention-to-treat population. A meta-analysis was done, which included the results from the RECOVERY trial and all previous randomised controlled trials of baricitinib or other JAK inhibitor in patients hospitalised with COVID-19. The RECOVERY trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936) and is ongoing.

Findings: Between Feb 2 and Dec 29, 2021, from 10 852 enrolled, 8156 patients were randomly allocated to receive usual care plus baricitinib versus usual care alone. At randomisation, 95% of patients were receiving corticosteroids and 23% were receiving tocilizumab (with planned use within the next 24 h recorded for a further 9%). Overall, 514 (12%) of 4148 patients allocated to baricitinib versus 546 (14%) of 4008 patients allocated to usual care died within 28 days (age-adjusted rate ratio 0·87; 95% CI 0·77-0·99; p=0·028). This 13% proportional reduction in mortality was somewhat smaller than that seen in a meta-analysis of eight previous trials of a JAK inhibitor (involving 3732 patients and 425 deaths), in which allocation to a JAK inhibitor was associated with a 43% proportional reduction in mortality (rate ratio 0·57; 95% CI 0·45-0·72). Including the results from RECOVERY in an updated meta-analysis of all nine completed trials (involving 11 888 randomly assigned patients and 1485 deaths) allocation to baricitinib or another JAK inhibitor was associated with a 20% proportional reduction in mortality (rate ratio 0·80; 95% CI 0·72-0·89; p<0·0001). In RECOVERY, there was no significant excess in death or infection due to non-COVID-19 causes and no significant excess of thrombosis, or other safety outcomes.

Interpretation: In patients hospitalised with COVID-19, baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.

Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Figure 1

Trial profile Baricitinib unavailable and baricitinib considered unsuitable are not mutually exclusive. *Number recruited overall during period that adult participants could be recruited into the baricitinib comparison.

Figure 2

Effect of allocation to baricitinib on 28-day mortality

Figure 3

Effect of allocation to baricitinib on 28-day mortality by baseline characteristics Subgroup-specific rate ratio estimates are represented by squares (with areas of the squares proportional to the amount of statistical information) and the lines through them correspond to the 95% CIs. The days since onset and use of corticosteroids subgroups exclude those with missing data, but these patients are included in the overall summary diamond.

Figure 4

Meta-analysis of mortality in randomised controlled trials of a JAK inhibitor in patients hospitalised with COVID-19 JAK=Janus kinase. O–E=observed–expected. Var=variance. RR=mortality rate ratio. Details of the individual studies, including the use of placebo or other treatments in the control group are shown in the appendix (p 62). *For RECOVERY, the O–E and and its variance are calculated from the age-adjusted log RR and its standard error. For the other trials, the O–E statistics and their variances are calculated from 2 × 2 tables. Rate ratio is calculated by taking ln rate ratio to be (O–E)/V with normal variance 1/V, where V=Var (O–E). Subtotals or totals of (O–E) and of V yield inverse-variance weighted averages of the ln rate ratio values. †These trials assessed a JAK inhibitor other than baricitinib. If the meta-analysis was restricted to RECOVERY plus the three other trials of baricitinib, the RR would be 0·81 (95% CI 0·73–0·91). ‡For balance, controls in the n:1 studies count n times in the control totals and subtotals, but only count once when calculating their O–E or V values.