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

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

Official Title
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A Phase 2, Open Label, Randomized Study of the Efficacy and Safety of Acalabrutinib With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Acalabrutinib


Participation Criteria
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Eligibility Criteria
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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 criteria (including positive RT-PCR nucleic acid test) 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 the time of screening due to COVID-19 pneumonia that impedes the ability to swallow pills, or in the opinion of the treating physician, the subject is likely to require mechanical ventilation within the immediate 24 hours and therefore unable to swallow pills. 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), and/or aspartate aminotransferase (AST) and/or bilirubin ≥ 3x upper limit of normal (ULN) and/or severe hepatic impairment detected during the screening period (per local lab) Exception: AST and/or ALT ≤5 × ULN if considered due to underlying COVID-19 disease, but cannot be associated with concurrent elevated bilirubin (≤2 × ULN). 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 7 days before first dose of study drug) or inducer (within 14 days before first dose of study drug).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Study will consist of two arms Arm 1 is acalabrutinib + best supportive care or Arm 2 is best supportive care alone
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Acalabrutinib+ Best Supportive Care | Drug: Acalabrutinib<br>* Acalabrutinib administered orally<br>|
| No Intervention: Arm 2<br>Best Supportive Care | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation | At Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Alive and Free of Respiratory Failure 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 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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation | At Day 14 | 
| Percent Change From Baseline in C-reactive Protein. | 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. | Days 3, 5, 7, 10, 14, 28 | 
| Percent Change From Baseline in Ferritin | 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. | Days 3, 5, 7, 10, 14, 28 | 
| Percent Change From Baseline in Absolute Lymphocyte Count | 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. | Days 3, 5, 7, 10, 14, 28 | 
| Overall Survival | 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. | From randomization until 90 days after randomization. | 
| Percentage of Participants Alive and Discharged From ICU |  | At Day 14 and at Day 28 | 
| Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause | 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. | From randomization to 28 days after randomization. | 
| Number of Days Alive and Free of Respiratory Failure | 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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation | From randomization to 28 days after randomization. | 
| Number of Days With Respiratory Failure | 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) Noninvasive 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. | From randomization to 28 days after randomization. | 
| Number of Days Hospitalized | 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. | From randomization to 28 days after randomization. | 
| Number of Days in ICU | 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. | From randomization to 90 days after randomization. | 
| Number of Days Alive Outside of Hospital |  | From randomization to 28 days after randomization. | 
| Number of Days Alive Outside of Hospital |  | From randomization to 90 days after randomization. | 
| Percent Change From Baseline in Oxygenation Index | 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. | Days 3, 5, 7, 10, 14, 28 | 
| Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale | 9-point category ordinal scale: 0. * Uninfected, no clinical or virological evidence of infection Ambulatory, no limitation of activities Ambulatory, limitation of activities Hospitalized - mild disease, no oxygen therapy Hospitalized - mild disease, oxygen by mask or nasal prongs Hospitalized - severe disease, non-invasive ventilation or high flow oxygen Hospitalised - severe disease, intubation and mechanical ventilation Hospitalized - severe disease, ventilation and additional organ support, such as pressors, renal replacement therapy, extracorporeal membrane oxygenation 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. | From randomization to 28 days after randomization. | 
| Pharmacokinetics of Acalabrutinib | Summary of plasma concentrations (ng/mL) of acalabrutinib | Day 3 and Day 7 | 
| Pharmacokinetics of ACP-5862 | Summary of plasma concentrations (ng/mL) of ACP-5862 | Day 3 and Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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2019 novel coronavirus disease, Acalabrutinib, Btk inhibitor