| 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 |
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Type of Study
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Drug |
| Study Design |
Randomized, Parallel Group Trial |
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Public Title of Study
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Study in Hospitalized COVID-19 patients with Acalabrutinib along with the Best Supportive Care versus Best Supportive Care |
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Scientific Title of Study
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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 |
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Secondary IDs if Any
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| Secondary ID |
Identifier |
| ACE-ID-201 (D822FC00001) Version 3.0 dated. 28/04/2020 |
Protocol Number |
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Details of Principal Investigator or overall Trial Coordinator (multi-center study)
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| Name |
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| Designation |
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| Affiliation |
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| Address |
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| Phone |
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| Fax |
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| Email |
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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 |
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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 |
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Source of Monetary or Material Support
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| 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 |
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Primary Sponsor
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| Name |
Acerta Pharma BV |
| Address |
Kloosterstraat 9, 5349 AB, Oss, The Netherlands |
| Type of Sponsor |
Pharmaceutical industry-Global |
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Details of Secondary Sponsor
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| Name |
Address |
| AstraZeneca Pharma India Ltd |
Block N1, 12th Floor, Manyata Embassy Business Park
Rachenahalli, Outer Ring Road, Bangalore – 560045, India
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Countries of Recruitment
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Brazil
France
Germany
India
Italy
Japan
Russian Federation
Spain
Sweden
Turkey |
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Sites of Study
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| 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 |
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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 |
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Regulatory Clearance Status from DCGI
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Health Condition / Problems Studied
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| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: J960||Acute respiratory failure, (2) ICD-10 Condition: B972||Coronavirus as the cause of diseases classified elsewhere, |
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Intervention / Comparator Agent
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| 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 |
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Inclusion Criteria
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| 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
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| 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. |
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Method of Generating Random Sequence
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Stratified block randomization |
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Method of Concealment
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Centralized |
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Blinding/Masking
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Open Label |
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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
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Proportion of subjects alive and free of respiratory failure at Day 14 |
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Secondary Outcome
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| 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
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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
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Entire duration of the trial |
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Target Sample Size
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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" |
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Phase of Trial
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Phase 2 |
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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 |
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Estimated Duration of Trial
|
Years="0"
Months="6"
Days="0" |
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Recruitment Status of Trial (Global)
|
Open to Recruitment |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
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Publication Details
|
Not yet |
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Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
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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 |