Ibrutinib for Hospitalized Adults With Severe Coronavirus Disease 2019 Infection: Results of the Randomized, Double-Blind, Placebo-Controlled iNSPIRE Study

Coutre et al., Open Forum Infectious Diseases, doi:10.1093/ofid/ofac104, iNSPIRE, NCT04375397, Mar 2022

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RCT 46 hospitalized patients with severe COVID-19 showing no significant differences with ibrutinib treatment.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments1. Only expensive, high-profit treatments were approved. Low-cost treatments were excluded, reducing the probability of treatment—especially early—due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments.

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risk of death, 9.1% higher, RR 1.09, p = 1.00, treatment 1 of 22 (4.5%), control 1 of 24 (4.2%), day 58.

risk of death, 209.1% higher, RR 3.09, p = 0.48, treatment 1 of 22 (4.5%), control 0 of 24 (0.0%), continuity correction due to zero event (with reciprocal of the contrasting arm), day 28.

risk of no hospital discharge, 9.1% higher, RR 1.09, p = 1.00, treatment 1 of 22 (4.5%), control 1 of 24 (4.2%), day 58.

risk of progression, 34.5% lower, RR 0.65, p = 0.70, treatment 3 of 22 (13.6%), control 5 of 24 (20.8%), NNT 14, mortality or respiratory failure, day 28.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. c19early.org, c19early.org/soc/usa.html.c19early.org/soc/usa.html.

Coutre et al., 24 Mar 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, median age 51.5, 12 authors, study period 6 June, 2020 - 8 June, 2021, trial NCT04375397 (history) (iNSPIRE). Contact: steven_treon@dfci.harvard.edu.

This Paper Ibrutinib All

Ibrutinib for Hospitalized Adults With Severe Coronavirus Disease 2019 Infection: Results of the Randomized, Double-Blind, Placebo-Controlled iNSPIRE Study

Steven E Coutre, Christopher Barnett, Olayemi Osiyemi, Daanish Hoda, Moti Ramgopal, Alexander C Fort, Roula Qaqish, Yiran Hu, Joi Ninomoto, Negar N Alami, Lori Styles, MD Steven P Treon

Open Forum Infectious Diseases, doi:10.1093/ofid/ofac104

Background. Few therapies are approved for hospitalized patients with severe coronavirus disease 2019 . Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, may mitigate COVID-19-induced lung damage by reducing inflammatory cytokines. The multicenter, randomized, double-blind phase 2 iNSPIRE study evaluated ibrutinib for prevention of respiratory failure in hospitalized patients with severe COVID-19. Methods. Adult patients with severe COVID-19 requiring hospitalization and supplemental oxygen but without respiratory failure were randomized 1:1 (stratified by remdesivir prescription) to ibrutinib 420 mg or placebo once daily for up to 28 days plus standard of care (SOC), including remdesivir and/or dexamethasone. Results. Forty-six patients were randomized to ibrutinib plus SOC (n = 22) or placebo plus SOC (n = 24). The primary endpoint (proportion of patients alive and without respiratory failure through day 28) was not met, with no statistically significant difference adjusting for remdesivir prescription (86% with ibrutinib plus SOC vs 79% with placebo plus SOC; adjusted difference, 5.8% [80% confidence interval, -9.2% to 20.4%]; P = .599). Secondary endpoints also showed no statistically significant improvement with ibrutinib plus SOC. Median treatment duration was 14 days for ibrutinib and placebo. Adverse events were similar with ibrutinib plus SOC vs placebo plus SOC (overall: 55% vs 50%; serious: 18% vs 13%) and were consistent with the known safety profile of ibrutinib. Conclusions. Addition of ibrutinib to SOC did not improve the proportion of patients alive and without respiratory failure through day 28 in hospitalized patients with severe COVID-19. Ibrutinib had a manageable safety profile, with similar safety to placebo. Clinical Trials Registration. NCT04375397.

Supplementary Data Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader,

References

Beigel, Tomashek, Dodd, Mehta, Remdesivir for the treatment of COVID-19-final report, N Engl J Med

Florence, Krupa, Booshehri, Davis, Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza-induced acute lung injury, Am J Physiol Lung Cell Mol Physiol

Greil, Tedeschi, Moreno, Anz, Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study, Ann Hematol

Horby, Lim, Emberson, Mafham, Dexamethasone in hospitalized patients with COVID-19, N Engl J Med

Huang, Wang, Li, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet

Marconi, Ramanan, De Bono, Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial, Lancet Respir Med

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Wu, Mcgoogan, Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention, JAMA

DOI record: { "DOI": "10.1093/ofid/ofac104", "ISSN": [ "2328-8957" ], "URL": "http://dx.doi.org/10.1093/ofid/ofac104", "abstract": "Abstract\n \n Background\n Few therapies are approved for hospitalized patients with severe coronavirus disease 2019 (COVID-19). Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, may mitigate COVID-19–induced lung damage by reducing inflammatory cytokines. The multicenter, randomized, double-blind phase 2 iNSPIRE study evaluated ibrutinib for prevention of respiratory failure in hospitalized patients with severe COVID-19.\n \n \n Methods\n Adult patients with severe COVID-19 requiring hospitalization and supplemental oxygen but without respiratory failure were randomized 1:1 (stratified by remdesivir prescription) to ibrutinib 420 mg or placebo once daily for up to 28 days plus standard of care (SOC), including remdesivir and/or dexamethasone.\n \n \n Results\n Forty-six patients were randomized to ibrutinib plus SOC (n = 22) or placebo plus SOC (n = 24). The primary endpoint (proportion of patients alive and without respiratory failure through day 28) was not met, with no statistically significant difference adjusting for remdesivir prescription (86% with ibrutinib plus SOC vs 79% with placebo plus SOC; adjusted difference, 5.8% [80% confidence interval, –9.2% to 20.4%]; P = .599). Secondary endpoints also showed no statistically significant improvement with ibrutinib plus SOC. Median treatment duration was 14 days for ibrutinib and placebo. Adverse events were similar with ibrutinib plus SOC vs placebo plus SOC (overall: 55% vs 50%; serious: 18% vs 13%) and were consistent with the known safety profile of ibrutinib.\n \n \n Conclusions\n Addition of ibrutinib to SOC did not improve the proportion of patients alive and without respiratory failure through day 28 in hospitalized patients with severe COVID-19. 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