IbrutiNib in SARS CoV-2 Induced Pulmonary Injury and Respiratory Failure (iNSPIRE)
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Sponsor
- Enrollment
- 46
- Locations
- 9
- Primary Endpoint
- Percentage of Participants Alive and Without Respiratory Failure Through Day 28
Study Overview
Brief Summary
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
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.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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
Arms & Interventions
Ibrutinib 420 mg + SOC
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)
Intervention: Ibrutinib (Drug)
Placebo + SOC
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)
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Percentage of Participants Alive and Without Respiratory Failure Through Day 28
Time Frame: 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.
Secondary Outcomes
- Median Reduction in Days Spent on Supplemental Oxygen(Up to Day 28)
- All-Cause Mortality at Study Days 7, 14, 21, and 28(At Study Days 7, 14, 21, and 28)
- Change in the World Health Organization (WHO)-8 Ordinal Scale From Baseline at Study Day 14(At Day 14)
- Median Duration of Hospitalization(Up to Day 28)
- Number of Participants With Adverse Events(From first dose of study drug until 30 days following last dose of study drug (up to 70 days))
- Time to Discharge From Hospital(Up to Day 28)
- Partial Pressure of Oxygen in Arterial Blood (PaO2) to Fraction of Inspired Oxygen (FiO2) Ratio(At Study Days 7, 14, 21, and 28)
- Days on Mechanical Ventilation(Up to Day 28)
- Oxygenation Index(At Study Days 7, 14, 21, and 28)
- Percentage of Participants Experiencing Respiratory Failure or Death on Study Days 7, 14, 21, and 28(At Study Days 7, 14, 21, and 28)
- Mechanical Ventilation-Free Survival(Up to Day 28)