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CTRI Number  CTRI/2020/06/026228 [Registered on: 29/06/2020] Trial Registered Prospectively
Last Modified On: 03/08/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group Trial 
Public Title of Study   Study in Hospitalized COVID-19 patients with Acalabrutinib along with the Best Supportive Care versus Best Supportive Care 
Scientific Title of Study   A Phase II, 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 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
ACE-ID-201 (D822FC00001) Version 3.0 dated. 28/04/2020  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query
 
Name  Tapankumar M Shah 
Designation  Country Director, Clinical Operations 
Affiliation  AstraZeneca Pharma India Ltd 
Address  Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road.

Bangalore
KARNATAKA
560045
India 
Phone  91-9535104975  
Fax  91-8067748857   
Email  tapankumar.shah@astrazeneca.com  
 
Details of Contact Person
Public Query
 
Name  Tapankumar M Shah 
Designation  Country Director, Clinical Operations 
Affiliation  AstraZeneca Pharma India Ltd 
Address  Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road.


KARNATAKA
560045
India 
Phone  91-9535104975  
Fax  91-8067748857   
Email  tapankumar.shah@astrazeneca.com  
 
Source of Monetary or Material Support  
Acerta Pharma B.V., a Dutch limited liability company, whose registered office is at Kloosterstraat 9, 5349 AB, Oss, The Netherlands, a member of the AstraZeneca group 
 
Primary Sponsor  
Name  Acerta Pharma BV 
Address  Kloosterstraat 9, 5349 AB, Oss, The Netherlands 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
AstraZeneca Pharma India Ltd  Block N1, 12th Floor, Manyata Embassy Business Park Rachenahalli, Outer Ring Road, Bangalore – 560045, India  
 
Countries of Recruitment     Brazil
France
Germany
India
Italy
Japan
Russian Federation
Spain
Sweden
Turkey  
Sites of Study  
No of Sites = 5  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Kartikeya Parmar  B.J. Medical College & Civil Hospital  Department of Medicine Asarwa, PIN -380016
Ahmadabad
GUJARAT 
09924643799
07922685938
drkartik@gmail.com 
Dr Arun Dewan  Max Smart Super Speciality Hospital  A unit of Gujarmal Modi Hospital and Research Centre, Dept. of Critical Care and Medicine, 2. Press Enclave Marg, Mandir Marg Saket, PIN 110017
New Delhi
DELHI 
09810091290
01126510050
dewanarun40@gmail.com 
Dr Anant Ramaswamy  Tata Memorial Hospital  Dept of Medical Oncology Dr. Ernest Borges Road, Parel Mumbai Mumbai City Maharashtra – 400012
Mumbai
MAHARASHTRA 
09833034802

anantr13@gmail.com 
Dr Rohit Kumar  Vardhman Mahavir Medical College and Safdarjung Hospital (VMMC and SJH)   Department of Pulmonology Ansari Nagar East, New Delhi- 110029
New Delhi
DELHI 
08851316190

dr.rohitkumar@mail.com 
Dr KR Raveendra  Victoria Hospital, Bangalore Medical College and Research Institute   Department of Medicine K. R. Road, Fort, PIN 560002
Bangalore
KARNATAKA 
09448134587

drkrraveendra@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 5  
Name of Committee  Approval Status 
Ethics Committee of Bangalore Medical College and Research Institute  Approved 
Institutional Ethics Committee, Vardhaman Mahavir Medical College & Safdarjung Hospital (VMMC and SJH)  Submittted/Under Review 
Max Healthcare Ethics Committee   Approved 
The Institutional Ethics Committee B. J. Medical College & Civil Hospital  Submittted/Under Review 
TMH, Institutional Ethics Committee- I  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  J960||Acute respiratory failure, B972||Coronavirus as the cause of diseases classified elsewhere,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Acalabrutininb (ACP-196)  1:1Assignment Route of Administration: Oral. Duration of therapy: 10 days Frequency:Twice daily (BID) 
Comparator Agent  Best Supportive Care   1:1 Assignment Duration of therapy: 10 days 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent.
2. Men and women ≥18 years of age
3. SARS-CoV-2 confirmed per World Health Organization (WHO) criteria 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

 
 
ExclusionCriteria 
Details  COVID-19 Related Medical Conditions
1. Respiratory failure at the time of screening due to COVID-19 pneumonia.
2. Known medical resuscitation within 14 days of randomization.
3. Any serious medical condition or abnormality of clinical laboratory tests that, in the Investigators judgment, precludes the subjects safe participation in and completion of the study
4. Suspected uncontrolled active bacterial, fungal, viral, or other infection (besides infection with SARSCoV2).
5. 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
6. Not expected to survive 28 days given their pre-existing, uncorrectable medical condition.
7. Pregnant or breast feeding.
8. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin ≥ 3x upper limit of normal (ULN) and/or severe hepatic impairment (Child-Pugh class C).
9. Absolute neutrophil count (ANC) < 500/μL at screening (per local laboratory).
10. Platelet count < 50,000/μL at screening (per local laboratory).
11. 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].
12.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 area allowed to enrol on study.
13.History of chronic hypercarbia, respiratory failure in past 6 months, or use of home oxygen in the setting of severe chronic respiratory disease.
14.Quadriplegia.
15.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.
16.Known active hepatitis B or C infection requiring therapy.

Prior/Concomitant Therapy:

17.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).
18.Requires treatment with proton-pump inhibitors.
19.Received oral antirejection or immunomodulatory drugs.
20.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/enrolment.
21.Subjects at randomization who require inhaled corticosteroids or maintenance doses of more than 7.5 mg of prednisone or equivalent per day.
22.Requires or is receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of acalabrutinib.
23.History of hypersensitivity (ie, allergic response) to active or inactive excipients of acalabrutinib or other Btk inhibitors.
24.Known cytoreductive chemotherapy treatment within 14 days of randomization.
25.Major surgery (as defined by the Investigator) within 4 weeks prior to randomization or still recovering from prior surgery. 
 
Method of Generating Random Sequence   Stratified block randomization 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
The overall objective of the study is to evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19.
For the purpose of this study, 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
(c) Non-invasive positive pressure ventilation or continuous positive airway pressure
(d) Extracorporeal membrane oxygenation
 
Proportion of subjects alive and free of respiratory failure at Day 14  
 
Secondary Outcome  
Outcome  TimePoints 
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19.
Proportion of subjects alive and free of respiratory failure  
at Day 28  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19.
Percent change from baseline in CRP  
Time frame: baseline, Days 3, 5, 7, 10, 14, 28 
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Change from baseline in ferritin  
Time frame: baseline, Days 3, 5, 7, 10, 14, 28 
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Change from baseline in absolute lymphocyte counts  
Time frame: baseline, Days 3, 5, 7, 10, 14, 28 
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
All-cause mortality  
At Day 90  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Proportion of subjects alive and discharged from the ICU  
At Days 14 and 28  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Time from randomization to first occurrence of respiratory failure or death on study
 
Up to 28 days after randomization 
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Number of days alive and free of respiratory failure from randomization  
28 days after randomization 
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Number of days with respiratory failure from randomization  
28 days after randomization  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Number of days hospitalized from randomization  
28 days after randomization  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Number of days in ICU (length of stay) from randomization  
90 days after randomization  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Number of days alive outside of hospital from randomization  
28 days after randomization  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Number of days alive outside of hospital from randomization 
90 days after randomization  
To evaluate the efficacy of adding acalabrutinib to BSC for the treatment of COVID-19
Relative change from baseline in oxygenation index (PaO2/FiO2)  
Day 5 
Safety Objective:
To evaluate the safety of acalabrutinib in subjects with COVID-19 when administered with BSC
 
Entire duration of the trial 
Safety Endpoint/Variable:
Type, frequency, severity, and relationship to study treatment of any TEAEs or abnormalities of Laboratory Tests, SAEs, or AEs leading to discontinuation of Study treatment
 
Entire duration of the trial 
PK objective:
To assess PK of Acalabrutinib and its active metabolite in subjects with COVID-19 when administered with BSC
 
Entire duration of the trial 
PK Endpoint/Variable:

Acalabrutinib, Cmax, tmax, t1/2, AUC 0-time, and its active metabolite, ACP-5862 Cmax, and other PK parameters (e.g. CL/F or Vdss/F) where appropriate
 
Entire duration of the trial 
Exploratory Objectives:
Evaluate changes in inflammatory cytokines/chemokines associated with COVID-19
SARS-CoV-2 and quantitative serology
Pharmacodynamic effects of acalabrutinib
 
Entire duration of the trial 
Exploratory Endpoints/Variables:

Change from baseline in cytokines/chemokines such as INFỾ, TNFα, IL-1β, IL-6, IL-8, IL-10, IL-18, MCP-1, etc
Change from baseline in SARS-CoV-2 levels and serology
Btk occupancy compared to pre-dose
Correlative analysis with treatment effects to determine if any biomarkers can predict response, as well as any relationship to study drug exposure levels
 
Entire duration of the trial 
 
Target Sample Size   Total Sample Size="140"
Sample Size from India="60" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)   29/06/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  15/06/2020 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="0"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)   Open to Recruitment 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   Not yet 
Brief Summary  

This study is multicentre, randomized, open-label, Phase 2 study that will evaluate acalabrutinib plus BSC versus BSC in subjects with COVID-19 who are hospitalized. The purpose of this Phase 2 study is to evaluate the preliminary efficacy and safety of adding acalabrutinib to best supportive care (BSC) for subjects with life-threatening COVID-19 symptoms.

Approximately, 140 patients would be randomized in the study and Subjects will be randomly assigned (1:1) to receive one of the following 2 treatments: Arm 1: Acalabrutinib  BSC (n=70) and Arm 2: BSC alone (n=70)

For the purpose of this study, BSC is per discretion of the Investigator and institutional guidelines (however there are few prohibited or restricted concomitant medications). Subjects will be randomized based on the following stratification factors, which are considered prognostic factors for poor outcome: Age (≥ 65 vs < 65 years); Comorbidities (present vs absent). “Present” is defined as having at least 1 of the following comorbidities: Cardiovascular disease, as defined by either heart failure New York Heart Association class ≥2 or hypertension requiring treatment; Diabetes mellitus requiring treatment; Chronic obstructive pulmonary disease or asthma requiring treatment; Current active solid tumor or hematologic malignancy.

 

Acalabrutinib will be administered for a maximum of 10 days. BSC 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. Subjects who can no longer swallow pills, such as those with nasogastric or enteral feeding tubes utilized for mechanical ventilation, will not be eligible to continue acalabrutinib treatment. Retreatment with acalabrutinib is not allowed.

 

An internal Data Monitoring Committee (iDMC), independent from the Sponsor’s study team, will be established to enable early identification of safety signals in the study, minimize risk to subjects during the study, and make recommendations as to the future conduct of this study in accordance with the iDMC charter. The first safety review will occur approximately 28 days after the first 30 subjects (data cut-off) are randomized into the study. The second safety review will occur approximately 28 days after the first 80 subjects (data cut-off) are randomized into the study

 

The end of study is defined as the last expected visit/contact of the last subject undergoing the study. A subject is considered to have completed the study when he/she has completed his/her last scheduled procedure. All randomized subjects will be followed for survival through 90 (± 7) days after randomization.

All subjects who discontinue the investigational study treatment for any reason other than withdrawal of consent, loss to follow-up, or death will have a safety follow up assessment 28 (± 3) days after the last dose of acalabrutinib. The study may be stopped if, in the judgment of the Sponsor, study subjects are placed at undue risk because of clinically significant findings 
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