Purpose / Objectives

Primary Outcome

Proportion of subjects alive and free of respiratory failure at Day 14.

For the purpose of this study, respiratory failure is defined based on resource utilization of any of the following modalities:
o Endotracheal intubation and mechanical ventilation
o Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates >20 L/min with fraction of delivered oxygen ≥0.5)
o Noninvasive positive pressure ventilation or continuous positive airway pressure
o Extracorporeal membrane oxygenation

Secondary Outcomes

• Proportion of subjects alive and free of respiratory failure (defined above) at Day 28
• Percent change from baseline in C-reactive protein (CRP; time frame: baseline, Days 3, 5, 7, 10, 14, 28)
• Change from baseline in ferritin (time frame: baseline, Days 3, 5, 7, 10, 14, 28)
• Change from baseline in absolute lymphocyte counts (time frame: baseline, Days 3, 5, 7, 10, 14, 28)
• All-cause mortality at Day 90
• Proportion of subjects alive and discharged from the intensive care unit (ICU) at Days 14 and 28
• Time from randomization to first occurrence of respiratory failure or death on study (up to 28 days after randomization) due to any cause
• Number of days alive and free of respiratory failure from randomization to 28 days after randomization

Diagnosis

• COVID-19 infection

severe acute respiratory syndrome coronavirus 2 positive

Target population

Age

18-130

Inclusion criteria

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent or have a legal representative provide consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).
• Men and women ≥18 years of age at the time of signing the Informed Consent Form (ICF).
• SARS-CoV-2 confirmed per World Health Organization (WHO) criteria (including positive nucleic acid test of any specimen [eg, respiratory, blood, urine, stool, or other bodily fluid]) within 4 days of randomization.
• COVID-19 pneumonia (documented radiographically) requiring hospitalization and oxygen saturation <94% on room air or requires supplemental oxygen.
• Able to swallow pills.
• Willing to follow contraception guidelines

Exclusion criteria

COVID-19 Related Medical Conditions

• Respiratory failure at the time of screening (see Section 3 for definition of respiratory failure) due to COVID-19 pneumonia.
• Known medical resuscitation within 14 days of randomization.
• Any serious medical condition or abnormality of clinical laboratory tests that, in the Investigator's judgment, precludes the subject’s safe participation in and completion of the study.
• Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection with SARSCoV2).
• In the opinion of the Investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatments.

Medical Conditions

• Not expected to survive 28 days given their preexisting, uncorrectable medical condition, for example, subjects with, or suspected to have, the following conditions: multiorgan failure, poorly controlled neoplasms; endstage cardiac disease; cardiac arrest requiring cardiopulmonary resuscitation or with pulseless electrical activity or asystole within past 30 days; endstage lung disease; endstage liver disease; or human immunodeficiency virus/acquired immunodeficiency syndrome with known endstage process.
• Pregnant or breast feeding.
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin ≥ 3x upper limit of normal (ULN) and/or severe hepatic impairment (Child-Pugh class C; see Appendix G) detected within 24 hours at screening (per local laboratory).
• Absolute neutrophil count (ANC) < 500/μL at screening (per local laboratory).
• Platelet count < 50,000/μL at screening (per local laboratory).
• Estimated creatinine clearance of <30 mL/min calculated using the Cockcroft-Gault formula [(140age) × mass (kg)/(72 × creatinine mg/dL) multiply by 0.85 if female].
• Uncontrolled or untreated symptomatic arrhythmias, myocardial infarction within the last 6 weeks, or congestive heart failure (NYHA Grade 3 or 4).
  Exception: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll on study.
• History of chronic hypercarbia, respiratory failure in past 6 months, or use of home oxygen in the setting of severe chronic respiratory disease.
• Quadriplegia.
• History of primary immunodeficiency, tuberculosis, progressive multifocal leukoencephalopathy (PML), aspergillus or other invasive mold/fungal infection, or received organ or bone marrow transplantation within 6 months of randomization.
• Known active hepatitis B or C infection requiring therapy.

Prior/Concomitant Therapy

• Treatment with a strong cytochrome P450 (CYP)3A inhibitor (within 14 days before first dose of study drug) or inducer (within 7 days before first dose of study drug).
• Requires treatment with proton-pump inhibitors (PPIs; eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving PPIs who switch to H2-receptor antagonists or antacids are eligible for enrollment in this study.
• Received oral antirejection or immunomodulatory drugs (eg, anti-cytokines, Btk inhibitors, JAK inhibitors, PI3K inhibitors) within 30 days before randomization.
• Active participation in other drug clinical trials or received treatment with an investigational drug within 5 half-lives or 30 days (whichever is longer) of randomization/enrollment.
  Exception: Subjects may receive COVID-specific antiviral drugs (eg, remdesivir, hydroxychloroquine).
• Subjects at randomization who require inhaled corticosteroids or maintenance doses of more than 7.5 mg of prednisone or equivalent per day.
• Requires or is receiving anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon) within 7 days of first dose of acalabrutinib.
• History of hypersensitivity (ie, allergic response) to active or inactive excipients of acalabrutinib or other Btk inhibitors.
• Known cytoreductive chemotherapy treatment within 14 days of randomization.
• Major surgery (as defined by the Investigator) within 4 weeks prior to randomization or still recovering from prior surgery.

Study design

• Phase II
• Multicenter
• Prospective
• Two-arm
• Open Label
• Randomized

Intervention

Acalabrutinib 100 mg twice per day will be administered for a maximum of 10 days (treatment beyond 10 days is not permitted). Best supportive care will be administered across all arms per Investigator’s discretion and institutional guidelines. Subjects who have respiratory failure before completing the maximum treatment period will be permitted to continue treatment with acalabrutinib for the maximum treatment period, according to the Investigator’s clinical judgment.

Miscellaneous

Randomization 1:1

Documents (password protected)

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Responsibilities in overall study

Sponsor

Acerta Pharma