Clinical trial NCT04375397: 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
Official title: IbrutiNib in SARS CoV-2 Induced Pulmonary Injury and Respiratory Failure (iNSPIRE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: CoronaVirus Induced Disease-2019 (COVID-19)
Keywords: CoronaVirus Induced Disease-2019
COVID-19
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)
Pulmonary Injury
Ibrutinib
Imbruvica
Respiratory failure
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development LLC; Pharmacyclics LLC (An AbbVie Company)
First posted: 2020-05-05
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants Alive and Without Respiratory Failure Through Day 28
timeFrame: Through Day 28
Secondary outcomes:
measure: Change in the World Health Organization (WHO)-8 Ordinal Scale From Baseline at Study Day 14
timeFrame: At Day 14
measure: Median Reduction in Days Spent on Supplemental Oxygen
timeFrame: Up to Day 28
measure: All-Cause Mortality at Study Days 7, 14, 21, and 28
timeFrame: At Study Days 7, 14, 21, and 28
measure: Percentage of Participants Experiencing Respiratory Failure or Death on Study Days 7, 14, 21, and 28
timeFrame: At Study Days 7, 14, 21, and 28
measure: Mechanical Ventilation-Free Survival
timeFrame: Up to Day 28
measure: Days on Mechanical Ventilation
timeFrame: Up to Day 28
measure: Median Duration of Hospitalization
timeFrame: Up to Day 28
measure: Time to Discharge From Hospital
timeFrame: Up to Day 28
measure: Partial Pressure of Oxygen in Arterial Blood (PaO2) to Fraction of Inspired Oxygen (FiO2) Ratio
timeFrame: At Study Days 7, 14, 21, and 28
measure: Oxygenation Index
timeFrame: At Study Days 7, 14, 21, and 28
measure: Number of Participants With Adverse Events
timeFrame: From first dose of study drug until 30 days following last dose of study drug (up to 70 days)
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University School of Med /ID# 221954
state: California
city: Washington
country: United States
facility: Medstar Washington Hospital Center /ID# 221886
state: District of Columbia
city: Washington
country: United States
facility: Duplicate_GW Medical Faculty Associates /ID# 222023
state: District of Columbia
city: Fort Pierce
country: United States
facility: Midway Immunology and Research /ID# 222004
state: Florida
city: Miami
country: United States
facility: University of Miami /ID# 223227
state: Florida
city: West Palm Beach
country: United States
facility: Triple O Research Institute /ID# 222944
state: Florida
city: Boston
country: United States
facility: Brigham & Women's Hospital /ID# 221847
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center /ID# 222994
state: Massachusetts
city: Salt Lake City
country: United States
facility: Intermountain Healthcare /ID# 221955
state: Utah
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: Coutre SE, Barnett C, Osiyemi O, Hoda D, Ramgopal M, Fort AC, Qaqish R, Hu Y, Ninomoto J, Alami NN, Styles L, Treon SP. Ibrutinib for Hospitalized Adults With Severe Coronavirus Disease 2019 Infection: Results of the Randomized, Double-Blind, Placebo-Controlled iNSPIRE Study. Open Forum Infect Dis. 2022 Mar 24;9(5):ofac104. doi: 10.1093/ofid/ofac104. eCollection 2022 May.