key: cord-0742320-tnej4mxd
authors: Coutre, Steven E; Barnett, Christopher; Osiyemi, Olayemi; Hoda, Daanish; Ramgopal, Moti; Fort, Alexander C; Qaqish, Roula; Hu, Yiran; Ninomoto, Joi; Alami, Negar N; Styles, Lori; Treon, Steven P
title: Ibrutinib for Hospitalized Adults with Severe COVID-19 Infection: Results of the Randomized, Double-Blind, Placebo-Controlled iNSPIRE Study
date: 2022-03-24
journal: Open Forum Infect Dis
DOI: 10.1093/ofid/ofac104
sha: efdf8dddd5c706953e361a6539345d27472d8d95
doc_id: 742320
cord_uid: tnej4mxd

BACKGROUND: Few therapies are approved for hospitalized patients with severe coronavirus disease 2019 (COVID-19). Ibrutinib, a once-daily Bruton’s 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% CI, –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 versus 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.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1] . Severe occurs in approximately 20% of cases, with respiratory failure being the leading cause of death [1, 2] . The etiology of pulmonary injury and respiratory failure associated with COVID-19 involves an exaggerated cytokine response resembling macrophage activation syndrome [3] . Elevated inflammatory cytokines have been reported in hospitalized patients with COVID-19, with even higher levels reported in patients requiring intensive care [1, 4] .

Ibrutinib is a once-daily Bruton's tyrosine kinase inhibitor approved in the United States for various B-cell malignancies and for chronic graft-versus-host disease but uncertainty remains regarding the benefit of continued ibrutinib treatment in patients who develop COVID-19. Ibrutinib decreased inflammatory cytokines and prevented lung injury and death in a mouse influenza model [5] . In the phase 3 iLLUMINATE study, ibrutinib suppressed obinutuzumab-induced increases in multiple inflammatory cytokines associated with infusion-related reactions [6] . In a case series of six patients with COVID-19 receiving ibrutinib for Waldenström macroglobulinemia, no dyspnea or hypoxia was observed in five patients on full-dose ibrutinib (420 mg/day), whereas one patient on reduced-dose ibrutinib (140 mg/day) experienced progressive dyspnea and hypoxia requiring hospitalization that improved rapidly after increasing the ibrutinib dose to 420 mg/day [7] . These findings suggest that ibrutinib may mitigate the hyperinflammatory state associated with COVID-19-induced lung damage. We conducted the phase 2 iNSPIRE study to A c c e p t e d M a n u s c r i p t 6 evaluate the efficacy and safety of ibrutinib for prevention of respiratory failure in hospitalized patients with severe COVID-19.

iNSPIRE (ClinicalTrials.gov: NCT04375397) was a multicenter, randomized, doubleblind, placebo-controlled phase 2 study conducted at seven hospitals in the United Table 1 Patients were randomized 1:1 (stratified by remdesivir prescription) to receive oral ibrutinib 420 mg once daily or placebo plus standard of care (SOC); for patients unable to take oral medications, capsule contents could be mixed with water and administered via feeding tube (Supplementary Methods). Treatment continued for up A c c e p t e d M a n u s c r i p t 7 to 28 days in the absence of unacceptable toxicity or intercurrent illness. Treatment could be stopped after 14 days if the patient was clinically stable and off supplemental oxygen for >48 hours at the discretion of the treating physician.

Patients were followed for 58 days after start of therapy or until death, whichever occurred first.

The primary endpoint was the proportion of patients alive and without respiratory failure (as defined above) through study day 28. Secondary endpoints included change in World Health Organization (WHO) 8-point ordinal scale [8] (Supplementary Table 2 ) from baseline to day 14; duration of supplemental oxygen;

all-cause mortality rate by days 7, 14, 21, and 28; respiratory failure or death rate by days 7, 14, 21, and 28; mechanical ventilation-free survival; duration of mechanical ventilation; duration of hospitalization; time to discharge; and safety and tolerability.

A sample size of 46 patients would provide ≥80% power to detect a between-group response rate difference of 30% for the primary endpoint at a two-sided alpha of .2.

For binary endpoints, between-group differences in proportions of patients were analyzed using the Miettinen-Nurminen method adjusting for the stratification factor of remdesivir prescription. For time-to-event endpoints, distribution of time to the specified event was estimated using the Kaplan-Meier method. Efficacy and safety were assessed in all randomized patients who received ≥1 dose of study treatment.

A c c e p t e d M a n u s c r i p t 8

The study was conducted in accordance with International Conference on Harmonisation guidelines for Good Clinical Practice and principles of the Declaration of Helsinki. The protocol was approved by institutional review boards or independent ethics committees of all participating institutions. All patients provided written informed consent.

Forty-six patients were enrolled and received ibrutinib plus SOC (n = 22) or placebo plus SOC (n = 24). Study treatment was discontinued before day 28 in 18 (82%) patients in the ibrutinib plus SOC arm and 18 (75%) in the placebo plus SOC arm; most patients who discontinued treatment did so due to being clinically stable and off supplemental oxygen for >48 hours on day 14 (7 [32%] and 12 [50%], respectively), Baseline characteristics were generally balanced between arms (Table 1 ). In the ibrutinib plus SOC and placebo plus SOC arms, 11 (50%) patients and 13 (54%) patients, respectively, were Hispanic/Latino, and four (18%) and four (17%) were Black/African American. There were no major differences between the ibrutinib plus SOC and placebo plus SOC arms in the prevalence of comorbid conditions associated with risk for severe COVID-19 ( Thirteen (59%) patients in the ibrutinib plus SOC arm and 16 (67%) in the placebo plus SOC arm had a prescription for remdesivir at randomization. During the study period, 15 (68%) patients in the ibrutinib plus SOC arm and 18 (75%) in the placebo plus SOC arm received concomitant remdesivir, and 13 (59%) and 16 (67%), respectively, received concomitant dexamethasone. No patients received concomitant tocilizumab during the study period.

The proportion of patients alive and without respiratory failure through day 28, adjusting for remdesivir prescription, was not statistically significant (86% [19/22] with ibrutinib plus SOC and 79% [19/24] with placebo plus SOC; adjusted difference, 5.8%; 80% CI, -9.2 to 20.4; P = .599) ( Figure 1A ). In patients with remdesivir prescription at randomization, the proportion alive and without respiratory failure through day 28 was 77% (10/13) with ibrutinib plus SOC and 75% (12/16) with placebo plus SOC (difference, 1.9%; 80% CI, -19.5 to 22.3; P = .906); in patients without remdesivir prescription, corresponding proportions were 100% (9/9) and 88% (7/8), respectively (difference, 12.5%; 80% CI, -4.8 to 34.7; P = .289) ( Figure 1A ).

Differences in risk of respiratory failure or death were observed among some subgroups ( Figure 1B) . Table 3 ).

Overall, AEs occurred in 12 (55%) patients with ibrutinib plus SOC and 12 (50%) with placebo plus SOC. The most frequent AEs (>2 patients overall) were elevated alanine aminotransferase, anemia, acute respiratory failure, hypertension, elevated aspartate aminotransferase, nausea, and sepsis ( Table 2 ). All hypertension events in the ibrutinib plus SOC arm were grade 1 and considered unrelated to study treatment as assessed by investigators. Serious AEs occurred in four (18%) patients with ibrutinib plus SOC and three (13%) with placebo plus SOC ( Table 2 ). One patient on the ibrutinib plus SOC arm died of acute respiratory failure due to COVID-19 pneumonia (unrelated to study treatment) on day 21; one patient on the placebo plus SOC arm died of COVID-19 pneumonia (unrelated to study treatment) on day 43. Overall, AEs leading to discontinuation of study treatment occurred in 10 (22%) patients, including six patients (27%) in the ibrutinib plus SOC arm and four patients (17%) in the placebo plus SOC arm. The only AE leading to discontinuation in two or more patients overall was acute respiratory failure, which was reported by one patient in each arm (Supplementary Table 4 ).

The primary endpoint of proportion of patients alive and without respiratory failure through day 28 was not met, with no statistically significant difference observed between ibrutinib plus SOC and placebo plus SOC. Small sample size precluded detection of statistically significant differences in outcomes and the possibility of a 

Ibrutinib had a manageable safety profile but did not improve the proportion of patients alive and without respiratory failure through day 28 versus placebo in this population of hospitalized patients with severe COVID-19 also receiving supportive standard of care.

A c c e p t e d M a n u s c r i p t 13 Financial Support: This study was supported by Pharmacyclics LLC, an AbbVie Company.

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Characteristics of and important lessons from the

COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease

Characterization of the inflammatory response to severe COVID-19 illness

Inhibiting Bruton's tyrosine kinase rescues mice from lethal influenza-induced acute lung injury

Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusionrelated reactions in patients with CLL: analysis from the iLLUMINATE study

The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients

World Health Organization: WHO R&D blueprint: novel coronavirus: COVID-19 therapeutic trial synopsis

We thank the patients who participated in the study, as well as the investigators and clinical research staff from the study centers. iNSPIRE was sponsored by Pharmacyclics LLC, an AbbVie Company. Medical writing support was provided by Melanie Sweetlove, MSc, and funded by Pharmacyclics LLC, an AbbVie Company.Author Contributions: Drs. Coutre, Qaqish, Styles, and Treon designed the study. Drs.Coutre, Barnett, Osiyemi, Hoda, Ramgopal, Fort, and Treon collected data. Drs. Hu, Ninomoto, Alami, and Styles performed data analysis. All authors contributed to interpretation of the data and to editing, revising, and finalizing the article before submission.All authors approved the final article and are accountable for all aspects of the work.Potential Conflicts of Interest: Dr. Coutre reports honoraria from AbbVie, Janssen, and

A c c e p t e d M a n u s c r i p t 18 A c c e p t e d M a n u s c r i p t 21 Figure 1