Study of Oral Ibrutinib Capsules to Assess Respiratory Failure in Adult Participants With Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Pulmonary Injury

Study Overview
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Brief Summary
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Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Lung failure is the main cause of death related to COVID-19 infection. The main objective of this study was to evaluate if ibrutinib is safe and can reduce respiratory failure in participants with COVID-19 infection.

Detailed Description
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This was a Phase 2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the addition of ibrutinib to supportive care in hospitalized participants who presented with COVID-19- related pulmonary distress requiring supplemental oxygen. Participants were randomized in a 1:1 ratio to receive placebo + supportive care, denoted as SOC or standard-of-care, or ibrutinib 420 mg + SOC, with randomization stratified by prescription for remdesivir. Participants were to be treated with either placebo or ibrutinib in addition to supportive care for up to 28 days unless they met treatment discontinuation criteria and were to be followed for 58 days following start of therapy or until death, whichever occurred first. Treatment could have been stopped at the discretion of the treating physician after 14 days if the participant was clinically stable and had been off supplemental oxygen for > 48 hours.

Official Title
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IbrutiNib in SARS CoV-2 Induced Pulmonary Injury and Respiratory Failure (iNSPIRE)

Conditions
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CoronaVirus Induced Disease-2019 (COVID-19)

Intervention / Treatment
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* Drug: Ibrutinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Requires hospitalization for COVID-19 infection Has Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 infection confirmed by reverse transcription polymerase chain reaction (RT-PCR) test before study entry Requires supplemental oxygen for pulmonary distress related to COVID-19 infection, and has been on supplemental oxygen for no more than 5 days, and on breathing room air have oxygen saturation levels of 94% or less Has radiographic evidence of pulmonary infiltrates Females of childbearing potential (FCBP) must use 1 reliable form of contraception or have complete abstinence from heterosexual intercourse during the following time periods related to this study: while participating in the study; and for at least 1 month after discontinuation of study drug. FCBP must be referred to a qualified provider of contraceptive methods if needed. FCBP must have a negative serum pregnancy test as of screening. Men must agree to use a latex condom during treatment and for up to 3 months after the last dose of ibrutinib during sexual contact with a FCBP. Adequate hematologic, hepatic and renal function as described in the protocol Must be within 10 days of confirmed diagnosis of COVID-19 Exclusion Criteria: Respiratory failure at time of screening as defined per protocol with any of these following therapies: Endotracheal intubation and mechanical ventilation Extracorporeal membrane oxygenation (ECMO) High flow nasal cannula oxygen at flow rates ≥ 30 L/min and fraction of delivered oxygen ≥ 0.5 Non-invasive positive pressure ventilation Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction On a Bruton's tyrosine kinase (BTK)-inhibitor, anti-interleukin 6 (IL6), anti-interleukin 6R (IL6R), or Janus kinase inhibitor (JAKi) Has received rituximab within 180 days from study entry. Known bleeding disorders Major surgery within 4 weeks of study entry Participants in whom surgery is anticipated to be necessary within 72 hours History of stroke or bleeding around or within brain within 6 months prior to enrollment Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV) Currently active, clinically significant cardiovascular disease Asymptomatic arrythmias and or history of ejection fraction < 40% on an echo Participants receiving a strong cytochrome P450 (CYP) 3A4 inhibitor with the exception of those receiving anti-fungal therapy/prophylaxis Chronic liver disease and hepatic impairment meeting Child Pugh class C Female participants who are pregnant, or breastfeeding, or planning to become pregnant while enrolled in this study or within 1 month of last dose of study drug. Male participants who plan to father a child while enrolled in this study or within 3 months after the last dose of study drug. Unwilling or unable to participate in all required study evaluations and procedures Vaccinated with a live, attenuated vaccine within 4 weeks Uncontrolled high blood pressure On therapeutic anticoagulation at baseline Participants with cancer, history of interstitial lung disease, and/or history of malignancies as defined in the protocol Co-enrolled in another interventional trial Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3.0 × ULN, and total bilirubin > 2.0 × ULN International normalized ratio (INR) ≥ 1.5 × ULN attributable to coagulation disorders

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib 420 mg + SOC<br>420 mg ibrutinib administered once daily as three hard gelatin capsules (140 mg each) with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC) | Drug: Ibrutinib<br>* Capsules were to be administered orally with water once daily. For participants who required nasogastric tube (NGT) placement while on study, capsules may have been administered by opening the capsules, mixing with water, and flushing down the NGT.<br>* Other names: Imbruvica;|
| Placebo Comparator: Placebo + SOC<br>Three hard gelatin placebo capsules administered once daily with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC) | Drug: Placebo<br>* Capsules were to be administered orally with water once daily. For participants who required nasogastric tube (NGT) placement while on study, capsules may have been administered by opening the capsules, mixing with water, and flushing down the NGT.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Alive and Without Respiratory Failure Through Day 28 | Respiratory failure is defined as a clinical diagnosis of respiratory failure and initiation of one of the following therapies: endotracheal intubation and mechanical ventilation; OR extracorporeal membrane oxygenation; OR high-flow nasal cannula oxygen delivery (i.e., reinforced nasal cannula delivering heated, humidified oxygen with fraction of delivered oxygen ≥ 0.5 and flow rates of ≥ 30 L/min); OR non-invasive positive pressure ventilation; OR clinical diagnosis of respiratory failure with initiation of none of these measures only when clinical decision-making is driven solely by resource limitation. | Through Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the World Health Organization (WHO)-8 Ordinal Scale From Baseline at Study Day 14 | The WHO-8 is an ordinal scale for clinical improvement with scores ranging from 0 to 8, where a lower score indicates better clinical status. A score of 0 represents uninfected; 1 (ambulatory, no limitation of activities); 2 (ambulatory, limitation of activities); 3 (hospitalized with mild disease, no oxygen therapy); 4 (hospitalized with mild disease, oxygen by mask or nasal prongs); 5 (hospitalized with severe disease, non-invasive ventilation or high-flow oxygen); 6 (hospitalized with severe disease, intubation and mechanical ventilation); 7 (hospitalized with severe disease, ventilation and additional organ support [pressors, renal replacement therapy, extracorporeal membrane oxygenation]); and 8 (death). Negative values indicate improvement from baseline. | At Day 14 | 
| Median Reduction in Days Spent on Supplemental Oxygen | Days spent on supplemental oxygen was set as the date of the participant being off of supplemental oxygen minus the date of initiation of supplemental oxygen + 1 day. If a participant received more than 1 period of supplemental oxygen therapy during the study or switched from supplemental oxygen to a more intensive therapy, then the days spent on supplemental oxygen were to be calculated as the sum of all the periods where the participant was on supplemental oxygen or a more intensive therapy through Day 28. If the date of the first initiation of supplemental oxygen was before Baseline Day 1, then the days spent on supplemental oxygen were to be calculated from Baseline Day 1 to the date of the participant being off the supplemental oxygen. Time on supplemental oxygen was to be imputed to the maximum number of days on study drug (28) for all points following the death of a participant. | Up to Day 28 | 
| All-Cause Mortality at Study Days 7, 14, 21, and 28 | The percentage of participants with mortality from any cause was recorded. | At Study Days 7, 14, 21, and 28 | 
| Percentage of Participants Experiencing Respiratory Failure or Death on Study Days 7, 14, 21, and 28 | Respiratory failure is defined as a clinical diagnosis of respiratory failure and initiation of one of the following therapies: endotracheal intubation and mechanical ventilation; OR extracorporeal membrane oxygenation; OR high-flow nasal cannula oxygen delivery (i.e., reinforced nasal cannula delivering heated, humidified oxygen with fraction of delivered oxygen ≥ 0.5 and flow rates of ≥ 30 L/min), OR non-invasive positive pressure ventilation; OR clinical diagnosis of respiratory failure with initiation of none of these measures only when clinical decision-making is driven solely by resource limitation. | At Study Days 7, 14, 21, and 28 | 
| Mechanical Ventilation-Free Survival | Mechanical ventilation-free survival is defined as the number of days from Baseline Day 1 to the date when a participant initiated mechanical ventilation or died, whichever occurred first, during the 28 days post baseline. If the specified event did not occur by Day 28, participants were to be censored. Specifically, a participant without any post-baseline assessment record was to be censored at Baseline Day 1, a participant who prematurely discontinued from study without a record of death or start of mechanical ventilation was to be censored at the earlier timepoint of the date of study discontinuation or Day 28, an ongoing participant in the study without a record of death or start of mechanical ventilation was to be censored at the earlier timepoint of the date of the last evidence that the participant is not on mechanical ventilation or Day 28. | Up to Day 28 | 
| Days on Mechanical Ventilation | Days spent on mechanical ventilation was defined as the date of the participant being off mechanical ventilation - date of initiation of mechanical ventilation + 1 day. If a participant received more than 1 period of mechanical ventilation during the study or switched from mechanical ventilation to a more intensive therapy, then the days spent on mechanical ventilation were to be calculated as the sum of all the periods where the participant is on mechanical ventilation or a more intensive therapy through Day 28. | Up to Day 28 | 
| Median Duration of Hospitalization | Median duration of hospitalization is defined as the hospitalization discharge date - hospitalization admission date + 1 day. If a participant was hospitalized more than once during the study then the hospitalization time was to be calculated as the sum of all the periods when the participant was hospitalized through Day 28. | Up to Day 28 | 
| Time to Discharge From Hospital | Time to discharge from hospital is defined as the number of days from Baseline Day 1 to the date of the last evidence that a participant is last discharged from hospital, during the 28 days post baseline. If the specified event did not occur by Day 28, participants were censored. Specifically, a participant without any postbaseline assessment record was to be censored at Baseline Day 1, a participant who died was to have time to discharge from hospital censored at Day 28, a participant who prematurely discontinued from study without a record of hospitalization discharge was to be censored at the earlier timepoint of the date of study discontinuation or Day 28, an on-going participant in the study without a record of hospitalization discharge was to be censored at the earlier timepoint of the date of the last evidence that the participant is hospitalized or Day 28. | Up to Day 28 | 
| Partial Pressure of Oxygen in Arterial Blood (PaO2) to Fraction of Inspired Oxygen (FiO2) Ratio | The PaO2/FiO2 ratio is the ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2). A PaO2/FiO2 ratio of 300 to 200 is mild, 200 to 100 moderate, and <100 is severe Adult Respiratory Distress Syndrome (ARDS). | At Study Days 7, 14, 21, and 28 | 
| Oxygenation Index | The oxygenation index is used to assess the intensity of ventilatory support required to maintain oxygenation. An index of 0 to < 25 is predictive of a good outcome; 25 to <40 indicates a chance of death >40%; and an index of 40 to 1000 warrants consideration of extracorporeal membrane oxygenation (ECMO). | At Study Days 7, 14, 21, and 28 | 
| Number of Participants With Adverse Events | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events (TEAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug. | From first dose of study drug until 30 days following last dose of study drug (up to 70 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Imbruvica, Respiratory failure, CoronaVirus Induced Disease-2019, COVID-19, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), Pulmonary Injury, Ibrutinib