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

• ClinicalTrials.gov Identifier: NCT04380688
• Recruitment Status: Completed
• First Posted: May 8, 2020
• Results First Posted: September 13, 2021
• Last Update Posted: September 13, 2021
• Sponsor: AstraZeneca
• Collaborator: Acerta Pharma BV
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Acalabrutinib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 62 participants
• 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
• 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
• Actual Study Start Date: June 13, 2020
• Actual Primary Completion Date: November 16, 2020
• Actual Study Completion Date: November 16, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1; Acalabrutinib+ Best Supportive Care	Drug: Acalabrutinib; Acalabrutinib administered orally
No Intervention: Arm 2; Best Supportive Care

Outcome Measures

Primary Outcome Measures :

1. 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) ]
2. 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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation

Secondary Outcome Measures :

1. 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 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
2. 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.

3. 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.

4. 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.

5. Overall Survival [ Time Frame: From randomization until 90 days after randomization. ]
   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.
6. Percentage of Participants Alive and Discharged From ICU [ Time Frame: At Day 14 and at Day 28 ]
7. 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.
8. 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) Noninvasive positive pressure ventilation or continuous positive airway pressure d) Extracorporeal membrane oxygenation
9. 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 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.
10. 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.

11. 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.

12. Number of Days Alive Outside of Hospital [ Time Frame: From randomization to 28 days after randomization. ]
13. Number of Days Alive Outside of Hospital [ Time Frame: From randomization to 90 days after randomization. ]
14. 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.

15. 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.

16. Pharmacokinetics of Acalabrutinib [ Time Frame: Day 3 and Day 7 ]
    Summary of plasma concentrations (ng/mL) of acalabrutinib
17. Pharmacokinetics of ACP-5862 [ Time Frame: Day 3 and Day 7 ]
    Summary of plasma concentrations (ng/mL) of ACP-5862

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 130 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 criteria (including positive RT-PCR nucleic acid test)
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 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.
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), 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).
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 7 days before first dose of study drug) or inducer (within 14 days before first dose of study drug).

Contacts and Locations

Locations

United States, Alabama

Research Site

Anniston, Alabama, United States, 36207

Research Site

Mobile, Alabama, United States, 36604

United States, California

Research Site

Escondido, California, United States, 92029

Research Site

Fullerton, California, United States, 92835

Research Site

Glendale, California, United States, 91206

Research Site

Newport Beach, California, United States, 92663

United States, Connecticut

Research Site

New Haven, Connecticut, United States, 06519

United States, District of Columbia

Research Site

Washington, District of Columbia, United States, 20010

United States, Florida

Research Site

Fort Lauderdale, Florida, United States, 33308

Research Site

Jacksonville, Florida, United States, 32207

Research Site

Jacksonville, Florida, United States, 32209

Research Site

Loxahatchee Groves, Florida, United States, 33470

United States, Indiana

Research Site

Fort Wayne, Indiana, United States, 46804

United States, Kentucky

Research Site

Louisville, Kentucky, United States, 40207

United States, Maryland

Research Site

Annapolis, Maryland, United States, 21401

Research Site

Baltimore, Maryland, United States, 21287

Research Site

Bethesda, Maryland, United States, 20889

Research Site

Bethesda, Maryland, United States, 20892-1374

Research Site

Silver Spring, Maryland, United States, 20910

United States, New Jersey

Research Site

Hackensack, New Jersey, United States, 07601

United States, New York

Research Site

Albany, New York, United States, 12208

Research Site

Bronx, New York, United States, 10467

Research Site

Buffalo, New York, United States, 14263

Research Site

New York, New York, United States, 10029

United States, Pennsylvania

Research Site

Philadelphia, Pennsylvania, United States, 19140

United States, Tennessee

Research Site

Nashville, Tennessee, United States, 38120

United States, Texas

Research Site

Houston, Texas, United States, 77030

Research Site

Houston, Texas, United States, 77090

Research Site

Tyler, Texas, United States, 75701

United States, Virginia

Research Site

Richmond, Virginia, United States, 23298

United States, Washington

Research Site

Renton, Washington, United States, 98055

Sponsors and Collaborators

AstraZeneca

Acerta Pharma BV

  Study Documents (Full-Text)

Documents provided by AstraZeneca:

Study Protocol  [PDF] July 24, 2020

Statistical Analysis Plan  [PDF] October 1, 2020

More Information

Additional Information:

Redacted CSP 

Related Info 

CSR Synopsis 

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04380688
• Other Study ID Numbers: D822FC00003
• First Posted: May 8, 2020
• Results First Posted: September 13, 2021
• Last Update Posted: September 13, 2021
• Last Verified: September 2021

Individual Participant Data (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; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)
• 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 deidentified 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:

2019 novel coronavirus disease; Acalabrutinib; Btk inhibitor

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Acalabrutinib; Antineoplastic Agents