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

AbbVie46 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

CoronaVirus Induced Disease-2019 (COVID-19)

Interventions

IbrutinibDRUG

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.

PlaceboDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (9)

Stanford University School of Med /ID# 221954

Stanford, California, United States

Medstar Washington Hospital Center /ID# 221886

Washington D.C., District of Columbia, United States

Duplicate_GW Medical Faculty Associates /ID# 222023

Washington D.C., District of Columbia, United States

Outcomes

Primary Outcomes

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.

Time frame: Through Day 28

Secondary Outcomes

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.

Time frame: 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.

Data from ClinicalTrials.gov

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