Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial

Abstract

Background: Baricitinib has shown efficacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifically on severe/critical COVID, including vaccinated participants.

Methods: Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures.

Results: Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modified intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49-69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 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]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (- 3.2% [- 9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a significant interaction between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated participants were on average 11 years older, with more comorbidities.

Conclusion: This clinical trial was prematurely stopped for external evidence and therefore underpowered to conclude on a potential survival benefit of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these findings warrant further investigation in other trials and real-world studies. Trial registration Bari-SolidAct is registered at NCT04891133 (registered May 18, 2021) and EUClinicalTrials.eu ( 2022-500385-99-00 ).

Keywords: Baricitinib; COVID-19; Safety; Vaccination.

Conflict of interest statement

MT has been member of scientific advisory board for Lilly. JRA has received advisory fees from 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 other authors have nothing to declare.

© 2023. The Author(s).

Figures

Fig. 1

Study Flowchart

Fig. 2

Kaplan–Meier plot of the probability of death within 60 days (measured at day 61 after inclusion), using the modified Intention to Treat population (mITT), consisting of all randomised participants who received at least one dose of study drug; A All observations regardless of study intervention discontinuation and/or receipt of rescue therapy; B Sensitivity analysis with participants censored at date of rescue therapy or date of discontinuation