Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19.

Phase 2

Completed

Conditions: COVID-19

Interventions: Drug: Acalabrutinib

Registration Number: NCT04346199

Lead Sponsor: AstraZeneca

Brief Summary: CALAVI will investigate the safety, efficacy and pharmacokinetics of acalabrutinib together with Best Supportive Care in the treatment of COVID-19.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 177

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
Confirmed infection with SARS-CoV-2 confirmed per World Health Organization (WHO) criteria (including positive RT-PCR 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

Respiratory failure at time of screening due to COVID-19
Known medical resuscitation within 14 days of randomization
Pregnant or breast feeding
Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection with SARS-CoV-2)
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin ≥ 3x upper limit of normal (ULN) and/or severe hepatic impairment detected within 24 hours at screening (per local lab)
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
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, anticytokines, Btk inhibitors, JAK inhibitors, PI3K inhibitors) within 30 days before randomization on study

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1	Acalabrutinib	Acalabrutinib+ Best Supportive Care

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Alive and Free of Respiratory Failure at Day 14	At Day 14	Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) 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) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events and Serious Adverse Events	Screening to 28 (+3) days after last dose of acalabrutinib (for acalabrutinib + BSC participants) or to 38 (+3) days after randomization (for BSC alone participants)
Percentage of Participants Alive and Free of Respiratory Failure at Day 28	At Day 28	Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Percent Change From Baseline in C-reactive Protein.	Days 3, 5, 7, 10, 14, 28	Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Percent Change From Baseline in Ferritin	Days 3, 5, 7, 10, 14, 28	Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Overall Survival	From randomization until 90 days after randomization. Safety Issue:	Median overall survival, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
Percent Change From Baseline in Oxygenation Index	Days 3, 5, 7, 10, 14, 28	Baseline is defined as the result obtained on the date of randomization. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Percentage of Participants Alive and Discharged From ICU	At Day 14 and at Day 28
Number of Days in ICU	From randomization to 90 days after randomization.	For this summary, the ICU stay must be considered clinically indicated to count as a day in ICU. For participants who die (due to any cause) prior to Day 90, days from death to Day 90 are counted as days in ICU.
Number of Days Alive Outside of Hospital	From randomization to 90 days after randomization.
Percent Change From Baseline in Absolute Lymphocyte Count	Days 3, 5, 7, 10, 14, 28	Baseline is defined as the result obtained on the date of randomization. If no result was obtained on the date of randomization, the last result prior to the date of randomization is used. Percent change from baseline at Day X is calculated by multiplying the following result by 100%: (Day X value - Baseline value)/Baseline value. The mean of this result for all analyzed patients is taken to get the mean percent change from baseline.
Number of Days Alive and Free of Respiratory Failure	From randomization to 28 days after randomization.	Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) Oxygen delivered by highflow nasal cannula (heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates \>20 L/min with fraction of delivered oxygen ≥0.5) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause	From randomization to 28 days after randomization.	Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
Number of Days With Respiratory Failure	From randomization to 28 days after randomization.	Respiratory failure, is defined based on resource utilization of any of the following modalities: a) Endotracheal intubation and mechanical ventilation b) 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) c) Non-invasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days with respiratory failure. For participants in hospital and experiencing respiratory failure at the time they withdraw from the study, days from last known status to Day 28 are counted as days with respiratory failure.
Number of Days Hospitalized	From randomization to 28 days after randomization.	For this summary, the hospitalization must be considered clinically indicated to count as a day hospitalized. For participants who die (due to any cause) prior to Day 28, days from death to Day 28 are counted as days hospitalized. For participants in hospital at the time they withdraw from the study, days from last known status to Day 28 are counted as days hospitalized.
Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale	From randomization to 28 days after randomization.	9-point category ordinal scale: 0. \* Uninfected, no clinical or virological evidence of infection 1. Ambulatory, no limitation of activities 2. Ambulatory, limitation of activities 3. Hospitalized - mild disease, no oxygen therapy 4. Hospitalized - mild disease, oxygen by mask or nasal prongs 5. Hospitalized - severe disease, non-invasive ventilation or high flow oxygen 6. Hospitalised - severe disease, intubation and mechanical ventilation 7. Hospitalized - severe disease, ventilation and additional organ support, such as pressors, renal replacement therapy, extracorporeal membrane oxygenation 8. Death Median time to first occurrence of respiratory failure or death, calculated using the Kaplan-Meier technique. Confidence interval for median overall survival (days) is derived based on Brookmeyer-Crowley method with log-log transformation.
Pharmacokinetics of Acalabrutinib	Day 3 and Day 7	Summary of plasma concentrations (ng/mL) of acalabrutinib
Pharmacokinetics of ACP-5862	Day 3 and Day 7	Summary of plasma concentrations (ng/mL) of ACP-5862