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

• ClinicalTrials.gov Identifier: NCT04346199
• Recruitment Status: Completed
• First Posted: April 15, 2020
• Results First Posted: September 13, 2021
• Last Update Posted: September 17, 2021
• Sponsor: AstraZeneca
• Collaborator: Acerta Pharma BV
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: April 9, 2020
• First Posted Date: April 15, 2020
• Results First Submitted Date: September 8, 2021
• Results First Posted Date: September 13, 2021
• Last Update Posted Date: September 17, 2021
• Actual Study Start Date: June 12, 2020
• Actual Primary Completion Date: November 17, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 8, 2021)

Percentage of Participants Alive and Free of Respiratory Failure at Day 14 [ Time Frame: 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

Original Primary Outcome Measures (submitted: April 14, 2020)

Treatment failure rate [ Time Frame: Approximately 30 days ]

Treatment failure rate, where treatment failure is defined as use of assisted ventilation or death.

Current Secondary Outcome Measures (submitted: September 8, 2021)

• Number of Participants With Adverse Events and Serious Adverse Events [ Time Frame: 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 [ Time Frame: 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. [ Time Frame: 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 [ Time Frame: 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 Absolute Lymphocyte Count [ Time Frame: 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 [ Time Frame: 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.
• Percentage of Participants Alive and Discharged From ICU [ Time Frame: At Day 14 and at Day 28 ]
• Time From Randomization to First Occurrence of Respiratory Failure or Death on Study Due to Any Cause [ Time Frame: 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 Alive and Free of Respiratory Failure [ Time Frame: 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
• Number of Days With Respiratory Failure [ Time Frame: 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 [ Time Frame: 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.
• Number of Days in ICU [ Time Frame: 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 [ Time Frame: From randomization to 28 days after randomization. ]
• Number of Days Alive Outside of Hospital [ Time Frame: From randomization to 90 days after randomization. ]
• Percent Change From Baseline in Oxygenation Index [ Time Frame: 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.
• Time From Randomization to Clinical Improvement of at Least 2 Points on a 9-point Category Ordinal Scale [ Time Frame: 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 [ Time Frame: Day 3 and Day 7 ]
  Summary of plasma concentrations (ng/mL) of acalabrutinib
• Pharmacokinetics of ACP-5862 [ Time Frame: Day 3 and Day 7 ]
  Summary of plasma concentrations (ng/mL) of ACP-5862

Original Secondary Outcome Measures (submitted: April 14, 2020)

• Number of days alive free of assisted ventilation [ Time Frame: Approximately 30 days ]
• Number of days with assisted ventilator use [ Time Frame: Approximately 30 days ]
• Number of days hospitalized [ Time Frame: Approximately 30 days ]
• Number of days in ICU [ Time Frame: Approximately 30 days ]
• Number of days alive outside of hospital [ Time Frame: Approximately 30 days ]
• Number of days alive outside of hospital [ Time Frame: Approximately 90 days ]
• Occurrence of Adverse Events and Serious Adverse Events [ Time Frame: Approximately 30 days ]
• Pharmacokinetics of acalabrutinib and its active metabolite ACP-5862 (Cmax) [ Time Frame: Approximately 30 days ]
  Peak Plasma Concentration (Cmax)
• Pharmacokinetics of acalabrutinib and its active metabolite ACP-5862 (Tmax) [ Time Frame: Approximately 30 days ]
  Time to Maximum Concentration (Tmax)
• Pharmacokinetics of acalabrutinib and its active metabolite ACP-5862 (AUC) [ Time Frame: Approximately 30 days ]
  Area under the plasma concentration versus time curve (AUC)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Acalabrutinib Study With Best Supportive Care Versus Best Supportive Care in Subjects Hospitalized With COVID-19.
• Official Title: 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Treatment

• Condition: COVID-19

Intervention

Drug: Acalabrutinib

Acalabrutinib- administered orally

Study Arms

• Experimental: Arm 1
  Acalabrutinib+ Best Supportive Care
  Intervention: Drug: Acalabrutinib
• No Intervention: Arm 2
  Best Supportive Care

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 1, 2021): 177
• Original Estimated Enrollment (submitted: April 14, 2020): 428
• Actual Study Completion Date: November 17, 2020
• Actual Primary Completion Date: November 17, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. 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)
2. Men and women ≥18 years of age at the time of signing the informed consent form
3. 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
4. COVID-19 pneumonia (documented radiographically) requiring hospitalization and oxygen saturation <94% on room air or requires supplemental oxygen
5. Able to swallow pills
6. Willing to follow contraception guidelines

Exclusion Criteria:

1. Respiratory failure at time of screening due to COVID-19
2. Known medical resuscitation within 14 days of randomization
3. Pregnant or breast feeding
4. Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection with SARS-CoV-2)
5. 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)
6. 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
7. 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).
8. 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
9. Received oral antirejection or immunomodulatory drugs (eg, anticytokines, Btk inhibitors, JAK inhibitors, PI3K inhibitors) within 30 days before randomization on study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, Chile, France, Germany, India, Italy, Japan, Mexico, Peru, Poland, Russian Federation, South Africa, Turkey
• Removed Location Countries: Spain

Administrative Information

• NCT Number: NCT04346199
• Other Study ID Numbers: D822FC00001
• 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

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Same as current
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Acerta Pharma BV
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: September 2021