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Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04439006
Recruitment Status : Not yet recruiting
First Posted : June 19, 2020
Last Update Posted : August 4, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Janssen Scientific Affairs, LLC
Information provided by (Responsible Party):
Jennifer Woyach, Ohio State University Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE June 17, 2020
First Posted Date  ICMJE June 19, 2020
Last Update Posted Date August 4, 2020
Estimated Study Start Date  ICMJE August 15, 2020
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 31, 2020)
  • 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.
  • Death [ Time Frame: During hospitalization for COVID-19 infection or within 30 days of registration ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 18, 2020)
  • Proportion of patients who require artificial ventilation [ 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.
  • Death [ Time Frame: During hospitalization for COVID-19 infection or within 30 days of registration ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 18, 2020)
  • 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.
  • 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.
  • Time in intensive care unit (ICU) [ Time Frame: Up to 14 days ]
  • Time to ICU admission [ Time Frame: Up to 14 days ]
  • Number of days requiring supplemental oxygen [ Time Frame: Up to 14 days ]
  • Total days of mechanical ventilation [ Time Frame: Up to 14 days ]
  • Time to mechanical ventilation [ Time Frame: Up to 14 days ]
  • Shock and need for pressure support [ Time Frame: Up to 14 days ]
  • Incidence of any infection (viral, fungal, bacterial) [ Time Frame: Up to 14 days ]
  • Time to clinical resolution [ Time Frame: Up to 14 days ]
  • Incidence of grade 3 or higher adverse events [ Time Frame: Up to 12 months ]
    Adverse events will be summarized by grade, type, and attribution (regardless of attribution and treatment-related) for each arm.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ibrutinib for the Treatment of COVID-19 in Patients Requiring Hospitalization
Official Title  ICMJE Randomized Double-Blind Phase 2 Trial of Ibrutinib Versus Standard Treatment for COVID-19 Illness Requiring Hospitalization With Safety Lead-In
Brief Summary This phase Ib/II trial studies the side effects and best dose of ibrutinib and how well it works in treating patients with COVID-19 requiring hospitalization. Ibrutinib may help improve COVID-19 symptoms by lessening the inflammatory response in the lungs, while preserving overall immune function. This may reduce the need to be on a ventilator to help with breathing.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Aplastic Anemia
  • Hematopoietic and Lymphoid Cell Neoplasm
  • Malignant Solid Neoplasm
  • Monoclonal B-Cell Lymphocytosis
  • Monoclonal Gammopathy of Undetermined Significance
  • Myelodysplastic Syndrome
  • Symptomatic COVID-19 Infection Laboratory-Confirmed
Intervention  ICMJE
  • Other: Best Practice
    Receive usual care
    Other Names:
    • standard of care
    • standard therapy
  • Drug: Ibrutinib
    Given PO
    Other Names:
    • BTK Inhibitor PCI-32765
    • CRA-032765
    • Imbruvica
    • PCI-32765
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Ibrutinib
  • Active Comparator: Arm B (usual care)
    Patients receive usual care.
    Intervention: Other: Best Practice
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: June 18, 2020)
72
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

  • Active uncontrolled systemic bacterial or fungal infection
  • Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon)
  • Currently receiving BTK inhibitor therapy
  • Actively receiving anti-cancer therapy. All anti-cancer therapy must be stopped at the time of screening
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ohio State Comprehensive Cancer Center 1-800-293-5066 OSUCCCClinicaltrials@osumc.edu
Contact: Kaitlyn Dvorak 614-688-9493 Kaitlyn.Dvorak@osumc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04439006
Other Study ID Numbers  ICMJE OSU-20135
NCI-2020-03341 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA016058 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jennifer Woyach, Ohio State University Comprehensive Cancer Center
Study Sponsor  ICMJE Jennifer Woyach
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Janssen Scientific Affairs, LLC
Investigators  ICMJE
Principal Investigator: Jennifer A Woyach, MD Ohio State University Comprehensive Cancer Center
PRS Account Ohio State University Comprehensive Cancer Center
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP