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Trial registered on ANZCTR


Registration number
ACTRN12618001858280
Ethics application status
Approved
Date submitted
5/11/2018
Date registered
15/11/2018
Date last updated
15/11/2018
Date data sharing statement initially provided
15/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Can Heart attack patients without coronary artery blockages benefit from standard heart attack medical treatment strategies?
Scientific title
Randomized Evaluation of Beta Blocker and Angiotensin Converting Enzyme Inhibitor (ACEI) /Angiotensin Receptor Blocker (ARB) Treatment in MINOCA Patients.
Secondary ID [1] 296391 0
NCT03686696
Secondary ID [2] 296392 0
EudraCT number 2018-000889-11
Universal Trial Number (UTN)
Trial acronym
MINOCA-BAT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myocardial Infarction With Non-obstructive Coronary Arteries 310141 0
Condition category
Condition code
Cardiovascular 308886 308886 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The specific brand of medication to be prescribed will be at the discretion of your cardiologist, but the type of drug will be a beta blocker, Angiotensin Converting Enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB). In Australia, commonly prescribed agents in these drug classes include atenolol, perindopril and candesartan.

The randomisation will be carried out using an online randomization module. Following the screening process, the investigator will discuss the suitability of the participant in the trial with the treating cardiologist. Following the approval from the treating cardiologist, the participant will be approached and consented for the trial. The randomization will be performed in the module using permuted block randomization with 1:1:1:1 ratio, stratified by country.

Group 1: Beta Blocker Alone (oral administration)
- Starting dose (first 2 weeks after the randomisation): Atenolol 25mg daily
- Target dose: Atenolol 50 mg daily

Group 2: ACEI or ARB Alone (oral administration)
- Starting dose (first 2 weeks after the randomisation): Perindopril Arginine 2.5mg daily (or alternatively Perindopril Erbumine 2mg daily) or Candesartan 4mg daily
- Target dose: Perindopril Arginine 10 mg daily (or alternatively Perindopril Erbumine 8 mg daily) or Candesartan 16mg daily

Group 3: Both Beta blocker and ACEI or ARB (oral administration)
- Starting dose (first 2 weeks after the randomisation): Atenolol 25mg daily + Perindopril Arginine 2.5mg daily (or alternative ACEI or
ARB as above)
- Target dose: Atenolol 50mg daily + Perindopril Arginine 10 mg daily (or alternative ACEI or ARB as above)

The suggested target dose escalation is at the treating physician's discretion.

Patients will be encouraged to continue the use of the randomized treatment following
discharge for the total study period (4 years) until contraindications.

Due to the pragmatic nature of this trial, the participant's compliance will be evaluated via follow-up telephone calls by the study coordinator. The study medications will be prescribed by the treating clinician, who will have a thorough understanding of the clinical trial, as part of their routine patient care. Participants will be asked to send their pharmacy receipts for the study drugs to the coordinating centre which will also provide an indication as to medication compliance

Intervention code [1] 312725 0
Treatment: Drugs
Comparator / control treatment
No Intervention: Participants will not be randomised to either beta blockers and/or ACEI/ARB treatments.
Control group
Active

Outcomes
Primary outcome [1] 307859 0
Time to death of any cause, or time to readmission because of AMI, ischemic stroke or heart failure - A Composite of time to all-cause Death and time to re-admission because of acute myocardial infarction, ischemic stroke or heart failure


1) Death (any cause) will be obtained from the hospital/medical or administrative records.
2) Acute myocardial infarction, ischemic stroke, heart failure, unstable angina, atrial fibrillation
will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [1] 307859 0
Time to event from the date of enrollment through study completion, an average of 4 years.
Secondary outcome [1] 353165 0
Time to All-cause death
Death (any cause) will be obtained from the hospital/medical or administrative records.
Timepoint [1] 353165 0
Time to event from the date of enrollment through study completion, an average of 4 years.
Secondary outcome [2] 353752 0
Time to Cardiovascular death

Death (any cause) will be obtained from the hospital/medical or administrative records.
Timepoint [2] 353752 0
Time to event from the date of enrollment through study completion, an average of 4 years.

Secondary outcome [3] 353753 0
Time to readmission because of Acute myocardial infarction

Acute myocardial infarction event will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [3] 353753 0
Time to event from the date of enrollment through study completion, an average of 4 years.
Secondary outcome [4] 353754 0
Time to readmission because of ischemic stroke

Stroke event will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [4] 353754 0
Time to event from the date of enrollment through study completion, an average of 4 years.
Secondary outcome [5] 353755 0
Time to readmission because of heart failure

Heart failure event will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [5] 353755 0
Time to event from the date of enrollment through study completion, an average of 4 years.
Secondary outcome [6] 353756 0
Time to Readmission because of unstable angina

Unstable angina event will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [6] 353756 0
Time to event from the date of enrollment through study completion, an average of 4 years.
Secondary outcome [7] 353757 0
Composite of angina frequency, physical limitation, quality of life and patient satisfaction as scored by the Seattle Angina Questionnaire (SAQ)

The SAQ is a self-administered, disease-specific measure for patients with heart disease. The SAQ quantifies patients’ physical limitations caused by angina, the frequency of and recent changes in their symptoms, their satisfaction with treatment, and the degree to which they perceive their disease to affect their quality of life. Each scale is transformed to a score of 0 to 100, where higher scores indicate better function (eg, less physical limitation, less angina, and better quality of life).

Timepoint [7] 353757 0
1,6, and 12 months post enrollment.
A baseline questionnaire will also be completed at enrolment.
Secondary outcome [8] 353758 0
Angina frequency scored by SAQ.
Timepoint [8] 353758 0
1,6, and 12 months post enrollment.
A baseline questionnaire will also be completed at enrolment.
Secondary outcome [9] 353759 0
Physical limitation scored by SAQ
Timepoint [9] 353759 0
1,6, and 12 months post enrollment.
A baseline questionnaire will also be completed at enrolment.
Secondary outcome [10] 353760 0
Quality of life scored by SAQ
Timepoint [10] 353760 0
1,6, and 12 months post enrollment.
A baseline questionnaire will also be completed at enrolment.
Secondary outcome [11] 353761 0
Patient satisfaction as scored by the SAQ
Timepoint [11] 353761 0
1,6, and 12 months post enrollment.
A baseline questionnaire will also be completed at enrolment.
Secondary outcome [12] 353762 0
Health related quality of life by EQ 5D
EQ-5D is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life that can be used in a wide range of health conditions and treatments.
Timepoint [12] 353762 0
1,6, and 12 months post enrollment.
A baseline questionnaire will also be completed at enrolment.
Secondary outcome [13] 353763 0
Mental health and depression scored by PHQ 9.
The PHQ-9 is a 9-question instrument given to patients in a primary care setting to screen for the presence and severity of depression.
Timepoint [13] 353763 0
1,6, and 12 months post enrollment.
A baseline questionnaire will also be completed at enrolment.
Secondary outcome [14] 353764 0
Assess the prevalence of all-cause mortality

Death (any cause) will be obtained from the hospital/medical or administrative records.
Timepoint [14] 353764 0
12, 24, 36 and 48 months post initial presentation
Secondary outcome [15] 353765 0
Assess the prevalence of Cardiovascular mortality

Death (any cause) will be obtained from the hospital/medical or administrative records.
Timepoint [15] 353765 0
12, 24, 36 and 48 months post initial presentation
Secondary outcome [16] 353766 0
Assess the prevalence of acute myocardial infarction Readmission

The incidence of acute myocardial infarction will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [16] 353766 0
12, 24, 36 and 48 months post initial presentation
Secondary outcome [17] 353767 0
Assess the prevalence of Ischaemic Stroke Admission


The incidence of stroke will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [17] 353767 0
12, 24, 36 and 48 months post initial presentation
Secondary outcome [18] 353768 0
Assess the prevalence of Heart Failure Admission

The incidence of heart failure admission will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [18] 353768 0
12, 24, 36 and 48 months post initial presentation
Secondary outcome [19] 353769 0
Assess the prevalence of Unstable Angina Admission

The incidence of unstable angina will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [19] 353769 0
12, 24, 36 and 48 months post initial presentation
Secondary outcome [20] 353770 0
Time to readmission because of atrial fibrillation.

The incidence of atrial fibrillation admission will be obtained from the hospital/medical records and from patient interviews held via telephone.
Timepoint [20] 353770 0
Time to event from the date of enrollment through study completion, an average of 4 years.

Eligibility
Key inclusion criteria
1. Age equal or greater than 18 years.
2. A clinical diagnosis of MINOCA, including:
a. Acute myocardial infarction – as per the universal myocardial infarction Criteria (Thygesen et al, 2018)
b. Non-obstructive coronary arteries – no lesion equal or greater than 50% in the potential infarct-related artery.
c. No overt non-ischaemic cause for the acute clinical presentation.
3. Left ventricle ejection fraction equal or less than 40% - assessed by echocardiography, MRI or left ventriculography prior to
randomisation.
4. Written informed consent obtained
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Any condition that may influence the patient's ability to comply with study protocol.
2. Pregnancy
3. Previous revascularization (CABG or PCI)
4. Myocarditis Diagnosis (Cardiac MRI proved myocarditis or a strong clinical suspicion
of myocarditis as a cause of the index event)
5. Clinical signs of heart failure
6. Contraindications for ACEI and ARB
7. Contraindications for beta-blockers
8. Prior use of ACE-I, ARB, or beta blockers, which must continue as per treating
physician
9. New indication for beta-blockers or ACEI/ARB other than as secondary prevention as
per treating physician.
10. Participation in a trial evaluating a drug known to interact with beta blockers or
ACEI/ARB

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomization will be performed in the module using permuted block randomization with 1:1:1:1 ratio, stratified by country.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
Phase
Phase 4
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Data collection and management for all countries will be performed through an electronic data capture system (EDC) located at the UCR, Uppsala, Sweden. Presence of inclusion and/or exclusion criteria and randomized treatment/s including generic substance name and planned target dose will be registered in the patient CRFs. Baseline data, data about in-hospital course and at one-year follow-up will be collected from the CADOSA Registry. Data entered into the online randomisation module at the participating CRF will continuously be collected into a complete study database that will comprise the individual CRF for all patients.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
Recruitment hospital [1] 12273 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [2] 12274 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [3] 12275 0
Lyell McEwin Hospital - Elizabeth Vale
Recruitment hospital [4] 12276 0
John Hunter Hospital - New Lambton
Recruitment hospital [5] 12277 0
Gold Coast Hospital - Southport
Recruitment hospital [6] 12278 0
Sunshine Hospital - St Albans
Recruitment postcode(s) [1] 24464 0
5011 - Woodville
Recruitment postcode(s) [2] 24465 0
5000 - Adelaide
Recruitment postcode(s) [3] 24466 0
5112 - Elizabeth Vale
Recruitment postcode(s) [4] 24467 0
2305 - New Lambton
Recruitment postcode(s) [5] 24468 0
4215 - Southport
Recruitment postcode(s) [6] 24469 0
3021 - St Albans
Recruitment outside Australia
Country [1] 20956 0
Sweden
State/province [1] 20956 0
Uppsala

Funding & Sponsors
Funding source category [1] 300996 0
Charities/Societies/Foundations
Name [1] 300996 0
The Hospital Research Foundation
Address [1] 300996 0
60 Woodville Road
Woodville, SA 5011
Country [1] 300996 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Adelaide SA 5005
Country
Australia
Secondary sponsor category [1] 300626 0
None
Name [1] 300626 0
Address [1] 300626 0
Country [1] 300626 0
Other collaborator category [1] 280410 0
University
Name [1] 280410 0
Uppsala university
Address [1] 280410 0
752 36 Uppsala, Sweden
Country [1] 280410 0
Sweden

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301756 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 301756 0
Level 3, Roma Mitchell House
136 North Terrace
Adelaide, South Australia, 5000
Ethics committee country [1] 301756 0
Australia
Date submitted for ethics approval [1] 301756 0
12/03/2018
Approval date [1] 301756 0
14/06/2018
Ethics approval number [1] 301756 0
HREC/18/CALHN/157

Summary
Brief summary
Myocardial infarction with non-obstructive coronary arteries" (MINOCA) occurs in 5-10% of all patients with acute myocardial infarction (AMI). There are neither any randomized clinical trials in MINOCA patients evaluating effects of secondary preventive treatments proven beneficial in patients with classic AMI, nor any treatment guidelines. The primary objective of this multi-national, multi-center pragmatic randomized clinical trial is to determine whether oral beta-blockade compared to no oral beta-blockade, and whether Angiotensin Converting Enzyme Inhibitors (ACEI/ Angiotensin Receptor Blockers (ARB) compared to no ACEI/ARB, reduce the composite endpoint of death of any cause and readmission because of AMI, ischemic stroke or heart failure in patients discharged with MINOCA and with no clinical signs of heart failure and with left ventricular (LV) systolic ejection fraction above or equal to 40%.
Trial website
http://www.ucr.uu.se/swedeheart/forskning-swedeheart/pagaende-r-rct/minoca-bat
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87994 0
Prof John F Beltrame
Address 87994 0
Queen Elizabeth Hospital Campus
Woodville South, SA 5011
Country 87994 0
Australia
Phone 87994 0
+61 88222 6740
Fax 87994 0
+61 8 8222 6042
Email 87994 0
john.beltrame@adelaide.edu.au
Contact person for public queries
Name 87995 0
Dr Sivabaskari Pasupathy
Address 87995 0
Faculty of Health Sciences, Medical Specialities
28 Woodville Road
Woodville South SA 5011
Country 87995 0
Australia
Phone 87995 0
+61 8 8222 8685
Fax 87995 0
+61 8 8222 6042
Email 87995 0
sivabaskari.pasupathy@adelaide.edu.au
Contact person for scientific queries
Name 87996 0
Prof John F Beltrame
Address 87996 0
Queen Elizabeth Hospital Campus
Woodville South, SA 5011
Country 87996 0
Australia
Phone 87996 0
+61 88222 6740
Fax 87996 0
+61 8 8222 6042
Email 87996 0
john.beltrame@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
A limited, de-identified set of data available for researchers outside the primary investigators and will be specified in the data sharing plan.
When will data be available (start and end dates)?
Two years after the publication of the primary results of the study. The endpoint of the availability to be specified by the investigators.
Available to whom?
Researchers outside the primary investigators.
Available for what types of analyses?
The type of analyses must be specified in the data sharing agreement between the providing agency and the requesting researchers.
How or where can data be obtained?
Before data are shared, a data-sharing agreement should be established documenting what data are being shared and how the data can be used. The agreement serves two purposes. First, it protects the agency providing the data, ensuring that the data will not be misused. Second, it prevents miscommunication on the part of the provider of the data and the agency receiving the data by making certain that any questions about data use are discussed. The following items should be covered in the data-sharing agreement:

Period of agreement
The intended use of the data
Constraints on the use of the data
Data confidentiality
Data security
Methods of data-sharing
What supporting documents are/will be available?
Ethical approval
How or where can supporting documents be obtained?
Type [1] 12 0
Ethical approval
Citation [1] 12 0
Link [1] 12 0
Email [1] 12 0
Other [1] 12 0
Summary results
No Results