Efficacy and Safety of Baricitinib for the Treatment of Hospitalized Adults with Severe or Critical COVID-19 (Bari-SolidAct): A Randomised, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Trial

Abstract

Background: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in mixed populations of hospitalised participants with COVID-19. Bari-SolidAct is the first trial in the investigator-initiated, adaptive platform trial EU-SolidAct, and is a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in hospitalised patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in hospitalised adults with severe or critical COVID-19.

Methods: The study was conducted in 39 clinical sites (hospital wards and intensive care units) across 10 European countries. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection and severe or critical illness were randomly assigned in combination with standard of care (1:1) to baricitinib (4 mg) or matching placebo once daily for up to 14 days The primary end point was all-cause mortality within 60 days, and patients were remotely followed up to day 90 for safety and patient related outcome measures. The efficacy and safety analyses were completed in all randomised participants receiving at least one treatment dose of study drug (modified intention to treat population). The trial was stopped for immunocompetent participants before reaching the planned sample size of 1,900 due to external evidence from the Recovery trial indicating survival benefit of baricitinib in the trial population. The Bari-SolidAct trial is registered with ClinicalTrials.gov, NCT04891133.

Findings: Between 3 rd June 2021 and 7 th March 2022, 299 patients were screened, 284 randomised, and 275 participants received study drugs (139 baricitinib and 136 placebo). There were 21 deaths in each group, with a proportion of death at day 60 of 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI -0·1% [-8·3 to 8·0]). There were no differences between the study groups with regard to changes in viral load, lymphocyte count, neutrophil count, lactate dehydrogenase, D-Dimer, CRP, procalcitonin or ferritin levels. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. There were 54 serious adverse events in 32 participants (23%) in the baricitinib group and 60 in 34 participants (25%) in the placebo group. In a post-hoc analysis, there was a significant interaction between vaccination status and treatment allocation on serious adverse events (interaction p-value = 0.003), with an increased occurrence of respiratory complications and severe infections in vaccinated participants treated with baricitinib.

Interpretation: We found no difference in participants treated with baricitinib for the primary mortality endpoint at day 60. There was a potential interaction between vaccination status and treatment allocation on mortality and occurrence of serious adverse events, although our findings are not conclusive. Real-world data and subgroup analyses according to vaccination status and disease severity in larger trials, are warranted to assess the precise risk/benefit ratio of baricitinib in vaccinated patients with severe/critical COVID-19. 

Trial Registration: EU-SolidAct/Bari-SolidAct is registered at www.clinicaltrials.gov (NCT04891133) and euclinicaltrials.eu (EU CTIS number 2022-500385-99-00).

Funding: European Commission.

Declaration of Interest: MT has been member of scientific advisory board for Lilly. MT has been member of scientific advisory board for Lilly. JP reports lecture fees from Gilead; support for attending meetings from Gilead, Eumedica, Merck Sharp & Dohme, outside the submitted work. ARH reports personal fee from Pfizer (2021) for lectures outside the submitted work. MH(it) has received funding for other trials on COVID-19 from the Federal Belgian Center for Knowledge and the joint Université Libre de Bruxelles-Fonds Erasme-COVID-19 projects (2020-21), personal fees from Gilead (2020) and Pfizer (2021) for editing and lectures outside the submitted work, and travel/congress grants from Pfizer (2020, 2021), and Gilead (2022). MJ reports consulting or speakers fees from Baxter, Gilead, CLS Behring, AM-Pharma, Novartis, Fresenius and grant support from Fresenius, Baxter, outside the submitted work. JAP reports fees for lectures and advisory boards from MSD, Pfizer, Astra-Zeneca, Jansen, Gilead, AOP Orphan Pharmaceuticals, Cepheid MB reports an unrestricted grant for Moderna (2022) outside the submitted work. MB reports an unrestricted grant for Moderna (2022) outside the submitted work. KL reports personal fees from Gilead, MSD, Janssen and ViiV Healthcare for advisory boards and lectures outside of the submitted work. JM reports personal fees from Pfizer (2017) for lectures outside the submitted work and travel fees from Pfizer (2022) and Menarini (2021). JCR reports a grant from Hamilton medical (2019-2020) outside the submitted work FLJ reports Helse Sør-Øst grant for developing COVID-19 serology (2020-2021) and Grant from CEPI to monitor responses in patients (2021-2023) DC reports an HIV grant from Janssen (2019-2020), personal fees from Gilead (2020) and Pfizer (2022) for lectures outside the submitted work. All ther authors have nothing to declare.

Ethical Approval: The trial was conducted in accordance with ICH E6 (R2) Good Clinical Practice and the ethical principles of the Declaration of Helsinki. Informed consent by the study participant or legally authorised representative was given prior to inclusion in the study. This is an international trial conducted in several European countries, with approval from ethics committees and national competent authority in each country, and in some countries also regional and site specific ethics approvals. The trial was initially submitted through the volunteer harmonized procedure (VHP) in the CTFG system, with first ethical approvals in France and Norway, followed by approval in all other countries in the trial. The trial has been transferred to CTIS and is now accepted under the Clinical Trial Regulation (CTR), euclinicaltrials.eu (EU CTIS number 2022-500385-99-00). EU-SolidAct/Bari-SolidAct is also registered at www.clinicaltrials.gov (NCT04891133).

Keywords: COVID-19, immunomodulator, safety, baricitinib, JAK inhibitor