- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04439006
Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
Randomized Double-Blind Phase 2 Trial of Ibrutinib Versus Standard Treatment for COVID-19 Illness Requiring Hospitalization With Safety Lead-In
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the feasibility and tolerability of administering ibrutinib in COVID-19 infected patients and determining the recommended phase 2 dose (RP2D). (Phase Ib) II. To determine whether ibrutinib administration (Arm A) in cancer patients can diminish the need for artificial ventilation (mechanical ventilation, bilevel positive airway pressure [BiPAP] or extracorporeal membrane oxygenation [ECMO]) or death due to COVID-19 as compared to untreated control population receiving standard therapy (antiviral, chloroquine, hydroxychloroquine, cytokine blocking peptides or small molecules) (Arm B). (Phase II)
SECONDARY OBJECTIVES:
I. To determine the time to defervescence (oral temperature < 100.5 degrees Fahrenheit [F] for a 48 hour time period) among patients treated with ibrutinib (Arm A) versus control population receiving standard (Arm B) therapy.
II. To determine time to clinical resolution of need for supplemental oxygen (i.e. maintenance of oxygen saturation of 93% or greater on room air with ambulation).
III. To determine rate of intensive care unit (ICU) admission and length of ICU admission for patients treated with ibrutinib (Arm A) versus control population receiving standard therapy (Arm B).
IV. To determine rate of shock requiring vasopressor support for patients treated with ibrutinib (Arm A) versus control population receiving standard therapy (Arm B).
V. To determine the rate of secondary infection (bacterial, fungal, viral) for patients treated with ibrutinib (Arm A) versus control population receiving standard therapy (Arm B).
VI. To determine the time to hospital discharge for patients treated with ibrutinib (Arm A) versus control population receiving standard therapy (Arm B).
VII. To determine time to hospital discharge and rate of death for patients who cross over to ibrutinib (Arm A) from standard therapy (Arm B).
VIII. To determine grade 3 or higher toxicity observed in patients treated with ibrutinib (Arm A) versus control population receiving standard therapy (Arm B).
IX. To determine time to mechanical ventilation, the number of days of mechanical ventilation per patient and total observed in patients treated with ibrutinib (Arm A) versus control population receiving standard therapy (Arm B).
EXPLORATORY OBJECTIVES:
I. To examine the impact of baseline clinical features (e.g. type of cancer, active therapy), duration of symptoms prior to admission and laboratory features (e.g. T cell count) on outcome for patients treated on this therapeutic study.
II. To determine the proportion of patients with viral clearance at end of ibrutinib therapy, time of hospital discharge and follow up thereafter among patients treated with ibrutinib (Arm A) versus control (Arm B) treatment.
III. To determine the time and proportion of patients who develop immunoglobulin (Ig)M and IgG levels toward SARS-coronavirus (CoV)-2 treated with ibrutinib (Arm A) versus control treatment (Arm B).
IV. To examine immune cell subsets for absolute number, activation, exhaustion markers, and presence of maturation arrest (natural killer [NK] cells) at baseline and over time among patients treated with ibrutinib (Arm A) versus control (Arm B) treatment.
V. To examine T-cell repertoire over time among patients treated with ibrutinib (Arm A) versus control (Arm B) treatment.
VI. To determine the influence of epigenetic age, clonal hematopoiesis, and monoclonal B cell lymphocytosis (MBL) on treatment outcome.
VII. To determine serial change in inflammatory markers as CRP, ferritin, D-dimer and cytokines including IL6, IL1B, and TNF-alpha serum levels over time among patients treated with ibrutinib (Arm A) versus control (Arm B) treatment.
OUTLINE: This is a phase Ib, dose-escalation study followed by a phase II study.
The first 12 patients will all receive ibrutinib. In the randomized part, patients are randomized to 1 of 2 arms.
ARM A: Patients receive ibrutinib orally (PO) once daily (QD) on days 1-7. Treatment repeats every 7 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who remain hospitalized or are re-admitted after 2 cycles may receive an additional 2 cycles per physician's discretion.
ARM B: Patients receive usual care. Patients who meet the requirement of mechanical ventilation may cross-over to Arm A.
After completion of study treatment, patients are followed up for up to 12 months.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Ohio
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Columbus, Ohio, United States, 43210
- Ohio State University Comprehensive Cancer Center
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- History or active diagnosis of cancer (solid or hematologic) or precursor of cancer (monoclonal gammopathy of undetermined significance [MGUS]), monoclonal B lymphocytosis (MBL), aplastic anemia or myelodysplastic syndrome) that is associated with immune suppression
- Hospitalization for confirmed polymerase chain reaction (PCR) positive COVID-19 infection
- Patients with evidence of pulmonary involvement who meet any of the followings; presence of infiltrates on chest X-ray or computed tomography (CT) scan or need for supplemental oxygen < 8 L nasal cannula or pulse oximetry < 94% on room air
- Creatinine clearance >= 25 ml/min by Cockcroft-Gault equation
- Total bilirubin =< 1.5 x upper limit of normal (ULN) unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x ULN
- Absolute neutrophil count (ANC) >= 1000/mm^3 independent of growth factor support
- Platelets >= 50,000/mm^3
- Ability to swallow capsules
- Ability to provide informed consent indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study
- Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug
- Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study
Exclusion Criteria:
- New-onset malignancy requiring urgent initiation of systemic chemotherapy
- Active uncontrolled systemic bacterial or fungal or other viral infection
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon)
- Currently receiving BTK inhibitor therapy
- Actively receiving anti-cancer therapy (other than hormonal therapies). All anti-cancer therapy (except hormonal therapies) must be stopped at the time of screening; can be resumed as soon as ibrutinib is discontinued. Significantly T cell suppressive chemotherapy (defined as requiring PJP prophylaxis per standard guidelines) is not allowed for 3 months prior to enrollment.
- Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional classification requirement for mechanical ventilation at screening
- Known bleeding disorders (e.g., Von Willebrand's disease, platelet storage pool disorders, or hemophilia)
- Stroke or intracranial hemorrhage within 6 months of screening
- Major surgery or non-healing wound within 4 weeks of enrollment
- Concomitant administration of prohibited medications
- Known history of human immunodeficiency virus (HIV), or active hepatitis B or C infection
- Disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption (malabsorption syndrome, resection of the small bowel, poorly controlled inflammatory bowel disease, etc.)
- Requires chronic treatment with strong CYP3A inhibitors
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Arm A (ibrutinib)
Patients receive ibrutinib PO QD on days 1-7.
Treatment repeats every 7 days for 2 cycles in the absence of disease progression or unacceptable toxicity.
Patients who remain hospitalized or are re-admitted after 2 cycles may receive an additional 2 cycles per physician's discretion.
|
Given PO
Other Names:
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Active Comparator: Arm B (usual care)
Patients receive usual care.
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Receive usual care
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Proportion of patients with diminished respiratory failure and death
Time Frame: During hospitalization for COVID-19 infection or within 30 days of registration
|
Associations between baseline characteristics and the primary endpoint will be evaluated with logistic regression, adjusting for arm.
These analyses will be largely descriptive, as a result of a limited sample size.
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During hospitalization for COVID-19 infection or within 30 days of registration
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Death
Time Frame: During hospitalization for COVID-19 infection or within 30 days of registration
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During hospitalization for COVID-19 infection or within 30 days of registration
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time from study initiation to 48 hours fever-free
Time Frame: Up to 14 days
|
Fever-free will be assessed by a temperature of < 100.5 degrees Fahrenheit orally.
Will be estimated for each arm using the method of Kaplan-Meier.
Medians estimates and/or estimates at specific time points will be provided with 95% confidence intervals.
|
Up to 14 days
|
Duration of hospitalization
Time Frame: Up to 14 days
|
Will be estimated for each arm using the method of Kaplan-Meier.
Medians estimates and/or estimates at specific time points will be provided with 95% confidence intervals.
|
Up to 14 days
|
Time in intensive care unit (ICU)
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Time to ICU admission
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Number of days requiring supplemental oxygen
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Total days of mechanical ventilation
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Time to mechanical ventilation
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Shock and need for pressure support
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Incidence of any infection (viral, fungal, bacterial)
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Time to clinical resolution
Time Frame: Up to 14 days
|
Up to 14 days
|
|
Incidence of grade 3 or higher adverse events
Time Frame: Up to 12 months
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Adverse events will be summarized by grade, type, and attribution (regardless of attribution and treatment-related) for each arm.
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Up to 12 months
|
At the end of therapy (day 14)
Time Frame: Up to 14 days
|
The proportion of patients with viral clearance at the time of hospital discharge will be estimated with 95% confidence intervals for each arm.
|
Up to 14 days
|
Time to viral clearance
Time Frame: Up to 12 months
|
Will be estimated for each arm using the method of Kaplan-Meier.
Medians estimates and/or estimates at specific time points will be provided with 95% confidence intervals.
|
Up to 12 months
|
Survival
Time Frame: Up to12 months
|
Patients will be followed for up to 12 months or until death or withdrawal of study consent for further follow-up.
Following hospitalization, study visits will be telephone or video encounters.
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Up to12 months
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Jennifer A Woyach, MD, Ohio State University Comprehensive Cancer Center
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Coronavirus Infections
- Coronaviridae Infections
- Nidovirales Infections
- RNA Virus Infections
- Virus Diseases
- Infections
- Respiratory Tract Infections
- Respiratory Tract Diseases
- Immune System Diseases
- Immunoproliferative Disorders
- Pneumonia, Viral
- Pneumonia
- Lung Diseases
- Bone Marrow Diseases
- Hematologic Diseases
- Blood Protein Disorders
- Occupational Diseases
- Anemia
- Leukocyte Disorders
- Bone Marrow Failure Disorders
- Hypergammaglobulinemia
- Leukocytosis
- Neoplasms
- COVID-19
- Myelodysplastic Syndromes
- Anemia, Aplastic
- Paraproteinemias
- Monoclonal Gammopathy of Undetermined Significance
- Laboratory Infection
- Lymphocytosis
Other Study ID Numbers
- OSU-20135
- NCI-2020-03341 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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