Efficacy and safety of baricitinib in patients with COVID-19 infection: Results from the randomised, double-blind, placebo-controlled, parallel-group COV-BARRIER phase 3 trial

Marconi, Vincent C.; Ramanan, Athimalaipet V; Bono, Stephanie de; Kartman, Cynthia E; Krishnan, Venkatesh; Liao, Ran; Piruzeli, Maria Lucia B; Goldman, Jason D.; Alatorre-Alexander, Jorge; Pellegrini, Rita de Cassia; Estrada, Vicente; Som, Mousumi; Cardoso, Anabela; Chakladar, Sujatro; Crowe, Brenda; Reis, Paulo; Zhang, Xin; Adams, David H.; Ely, E. Wesley

doi:10.1101/2021.04.30.21255934

Cited by 35 publications

(38 citation statements)

References 24 publications

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“…The JAK inhibitors baricitinib and tofacitinib have largely shown benefit for patients who are not receiving mechanical ventilation but who require high levels of oxygen support 4 and in conjunction with glucocorticoid use. 5 While IL-6ra require intravenous administration, JAK inhibitors are given orally, are usually less costly than IL-6ra, and may be more widely available globally. How these drugs compare head to head is not known, and combination treatment with IL-6ra and JAK inhibition is not recommended pending data from ongoing studies.…”

Section: Related Articlementioning

confidence: 99%

“…Effective treatments for COVID-19 continue to evolve; antiinflammatory agents, such as dexamethasone, 3 JAK inhibitors, [4][5][6] antiviral drugs including remdesivir, 7 and now at least 1 combination of monoclonal antibodies, 8 have been associated with improved time to recovery and a mortality benefit in certain groups of patients hospitalized for COVID-19. Also, among noncritically ill patients hospitalized with elevated D-dimer levels, therapeutic anticoagulation with heparin decreased COVID-19 disease progression.…”

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confidence: 99%

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IL-6 Receptor Antagonist Therapy for Patients Hospitalized for COVID-19

Matthay

Luetkemeyer

2021

JAMA

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Although substantial progress has been made in the treatment and prevention of COVID-19, more effective treatments for patients with COVID-19 who require hospitalization are still needed. One promising immunomodulatory strategy is inhibition of interleukin 6 (IL-6), based on the hypothesis that SARS-CoV-2 creates injury to the lung and other organs in part through activation of cytokine and downstream proinflammatory networks. While several clinical trials have investigated the effect of IL-6 receptor antagonists (IL-6ra) in patients with COVID-19, the results have not been consistent, with some trials reporting benefit and others no benefit. In this issue of JAMA, investigators from the World Health Organization Rapid Evidence Appraisal for COVID Therapies (REACT) Working Group have provided a muchneeded meta-analysis of 27 randomized trials of IL-6ra that included 10 930 patients with COVID-19 who were treated between October 2020 and January 2021. 1 The primary results indicate that all-cause mortality was reduced in patients hospitalized for COVID-19 and treated with IL-6ra compared with those treated with placebo or usual care. By day 28 after randomization, 1407 deaths occurred among 6449 patients randomized to receive IL-6 antagonists and 1158 deaths occurred among 4481 patients randomized to usual care or placebo (summary odds ratio [OR], 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). Importantly, a significant mortality benefit was only found when IL-6ra were coadministered with glucocorticoids (summary OR for the association of IL-6 antagonist treatment with 28-day allcause mortality, 0.78 with concomitant glucocorticoid administration vs 1.09 without glucocorticoid administration). The benefits of IL-6ra were most evident among patients who received respiratory support with oxygen by nasal cannula, face mask, high-flow nasal oxygen (OR for death, 0.81 [95% CI, 0.67-0.98]), or noninvasive ventilation (OR, 0.83 [95% CI, 0.72-0.96]) vs those who required invasive mechanical ventilation (IMV) (OR, 0.95 [95% CI, 0.78-1.16]). Furthermore, there was not a clear benefit associated with IL-6ra use for reducing 90-day mortality or the duration of IMV among patients who already required mechanical ventilation at the time of randomization.The beneficial outcomes associated with IL-6ra therapy did not differ according to patient age, sex, race and ethnicity, use of cardiovascular support defined by the need for vasopressors, or the level of C-reactive protein. Also, there was no evidence for an increase in the risk of secondary infections associated with IL-6ra at 28 days, although ascertainment of infectious adverse events varied and was quite limited in some trials (eTable 3 in Supplement 1). 1 In terms of the specific pharmacologic agents,

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Section: Related Articlementioning

confidence: 99%

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confidence: 99%

IL-6 Receptor Antagonist Therapy for Patients Hospitalized for COVID-19

Matthay

Luetkemeyer

2021

JAMA

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“…Between 65 studies were full-text articles which were assessed for their eligibility, and 37 articles were excluded due to discouraging results (still recruiting or withdrawn subjects), seven articles had no control or comparison group, five articles did not bring up the criteria of the outcome of interest, two articles were not in English. This meta-analysis involved 14 studies [24][25][26][27][28][29][30][31][32][33][34][35][36][37] which included a total of 4,363 coronavirus disease 2019 patients (Figure 1). Out of 14 research, three research were double-blind randomized clinical trials, one research was a single-blind randomized clinical trial, two research were non-randomized clinical trials, five were prospective cohort research, and three were retrospective cohort research.…”

Section: Study Selection and Characteristicsmentioning

confidence: 99%

“…Retrospective cohort 67 ± 14 Kalil AC et al [30] . Marconi VC et al [31] . Maslennikov R et al [32] .…”

Section: (B) 191mentioning

confidence: 99%

Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis

Limen

Sedono

Sugiarto

et al. 2021

Expert Review of Anti-infective Therapy

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Background: Currently, JAK-inhibitors are repurposed for therapy of Covid-19 because of their ability in restraining immune response, yet the corroboration regarding their advantage is still unclear. This study sought to analyze the efficacy of JAK-inhibitors to ameliorate the outcomes of Covid-19 sufferer. Research design and methods: Using specific keywords, we comprehensively go through the potential articles on ClinicalTrials.gov, Europe PMC, and PubMed sources until June 2 nd , 2021. All published studies on JAK-inhibitors and Covid-19 were collected. Results: There were 14 studies with 4,363 Covid-19 patients contained in the meta-analysis. Based on our data, we suggested that JAK-inhibitors corresponded with increased recovery rate (RR 1.17; 95%CI: 1.01-1.36, p= 0.040, I 2 = 91%, random-effect modeling); shortened time to recovery (mean difference −0.96; 95%CI: −1.15, −0.77, p< 0.00001, I 2 = 28%, random-effect modeling); reduction of clinical deterioration risk (RR 0.66; 95%CI: 0.48-0.89, p= 0.008, I 2 = 57%, random-effect modeling); and reduction of Covid-19 mortality (RR 0.52; 95%CI: 0.36-0.76, p= 0.0006, I 2 = 33%, random-effect modeling).Conclusions: This study propose that JAK-inhibitors perhaps provide advantageous effects on Covid-19 outcomes. JAK-inhibitors may be given during 1-2 weeks of disease to optimize its beneficial effects in halting the exaggerated immune response.

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“…In addition, a Phase III placebo controlled clinical study of baricitinib in 1,525 hospitalized adults with COVID-19 receiving SOC have demonstrated that "treatment with baricitinib in addition to SOC (predominantly dexamethasone) significantly reduced mortality with a similar safety profile between groups of hospitalized COVID-19 participants." On the other hand, reduction in disease progression did not achieve statistical significance in this study (72). Accordingly, on November 19, 2020, FDA issued an Emergency Use Authorization (EUA) for the emergency use of baricitinib (Olumiant), in combination with remdesivir (Veklury), for the treatment of severe COVID-19 patient.…”

Section: Discussionmentioning

confidence: 54%

The Binary Model of Chronic Diseases Applied to COVID-19

Elkoshi

2021

Front. Immunol.

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A binary model for the classification of chronic diseases has formerly been proposed. The model classifies chronic diseases as “high Treg” or “low Treg” diseases according to the extent of regulatory T cells (Treg) activity (frequency or function) observed. The present paper applies this model to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The model correctly predicts the efficacy or inefficacy of several immune-modulating drugs in the treatment of severe coronavirus disease 2019 (COVID-19) disease. It also correctly predicts the class of pathogens mostly associated with SARS-CoV-2 infection. The clinical implications are the following: (a) any search for new immune-modulating drugs for the treatment of COVID-19 should exclude candidates that do not induce “high Treg” immune reaction or those that do not spare CD8+ T cells; (b) immune-modulating drugs, which are effective against SARS-CoV-2, may not be effective against any variant of the virus that does not induce “low Treg” reaction; (c) any immune-modulating drug, which is effective in treating COVID-19, will also alleviate most coinfections; and (d) severe COVID-19 patients should avoid contact with carriers of “low Treg” pathogens.

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Efficacy and safety of baricitinib in patients with COVID-19 infection: Results from the randomised, double-blind, placebo-controlled, parallel-group COV-BARRIER phase 3 trial

Cited by 35 publications

References 24 publications

IL-6 Receptor Antagonist Therapy for Patients Hospitalized for COVID-19

IL-6 Receptor Antagonist Therapy for Patients Hospitalized for COVID-19

Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis

The Binary Model of Chronic Diseases Applied to COVID-19

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