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).

Assessment of the Efficacy and Safety of Baricitinib Treatment in COVID-19 Patients: a real-world study

“…This reduction in mortality aligns with the observed mortality reduction in less severely ill patients in the primary COV-BARRIER study population [24]. While a more recent randomized, double-blind phase 3 trial examined the e cacy and safety of BAR among hospitalized patients with severe or critical COVID-19 infection, the trial was prematurely terminated, rendering it underpowered to reach a de nitive conclusion [15]. However, there is currently no de nitive evidence regarding the effectiveness of BAR in complex scenarios such as severe or critical illness in China, where numerous variants of COVID-19 are prevalent and spreading extensively.…”

“…Baricitinib (BAR), an oral selective Janus kinase 1/2 inhibitor, is approved for patients with autoimmune diseases owing to its recognized anti-in ammatory properties, such as rheumatoid arthritis [12], atopic dermatitis [13], and alopecia areata [14]. BAR has been demonstrated to inhibit the release of multiple cytokines, including IL-6 and interferon-gamma [12], and to disrupt the binding of SARS-CoV-2 to the angiotensin-converting enzyme 2 receptor [15]. Several observational cohort studies have indicated that BAR reduces mortality and the risk of progression to invasive mechanical ventilation in hospitalized patients with COVID-19 infection.…”

“…The collective randomized evidence available to date indicates that JAK inhibitors, primarily BAR, decrease mortality in patients hospitalized for COVID-19 by approximately one-fth [18]. However, in a clinical trial investigating the e cacy and safety of BAR in treating severe or critical COVID-19, the trial was prematurely halted due to insu cient external evidence and being underpowered to conclusively determine any potential survival bene t of BAR in severe/critical COVID-19 cases [15]. In China, the safety and e cacy of BAR in patients with Omicron infection remain unclear, warranting further investigation through additional trials and real-world studies.…”

Adjuvante Behandlung bei COVID-19 und Sepsis − was haben wir gelernt?

“…Not all patients are candidates for immunotherapy. Even in the case of COVID-19 following the successful trials of anakinra [ 13 , 14 ], tocilizumab [ 22 ] and baricitinib [ 23 ], several subsequent trials failed to disclose similar benefits [ 9 , 24 ]. Does this mean that immunotherapy does not really work?…”

Successful salvage of a severe COVID-19 patient previously with lung cancer and radiation pneumonitis by mesenchymal stem cells: a case report and literature review

“…On the other hand, baricitinib and tocilizumab, two widely used inflammatory factor inhibitors, also improve the survival of patients with severe or critical COVID-19. However, approximately 18.0% of patients treated with baricitinib and 24% of patients treated with tocilizumab did not respond to these drugs, among whom 56.0% and 46.7%, respectively, progressed to death ( 11 , 12 ). Thus, the therapy that possesses the ability of inflammatory modulation and tissue repair might be the ideal choice for those who do not respond to frontline treatment.…”