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Trial registered on ANZCTR


Registration number
ACTRN12620001256965p
Ethics application status
Submitted, not yet approved
Date submitted
8/10/2020
Date registered
24/11/2020
Date last updated
24/11/2020
Date data sharing statement initially provided
24/11/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Chronic Myocardial Injury-Evaluating The Possible Role Of Sodium Glucose Co-Transporter 2 Inhibition (CHIRON)
Scientific title
Chronic Myocardial Injury-Evaluating The Possible Role Of SGLT-2 Inhibition. A phase II multicentre double blind randomised parallel group comparison of 10mg dapagliflozin versus placebo over 6 months in chronic myocardial injury
Secondary ID [1] 301730 0
Nil known
Universal Trial Number (UTN)
U1111-1258-5955
Trial acronym
CHIRON
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Myocardial Injury 318188 0
Condition category
Condition code
Cardiovascular 316200 316200 0 0
Coronary heart disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This a double-blind randomised controlled study of a sodium-glucose co-transporter 2 (SGLT2) inhibitor called Dapagliflozin in patients with chronic myocardial injury.
Those enrolled in this study and randomly allocated to the intervention arm will be required to take 10mg of Dapagliflozin orally daily (in the morning) for a total duration of 6 months.

The study aims to enrol 120 participants in total, with the aim of enrolling 90 of these eligible participants in to a sub study. All eligible participants will be offered the opportunity to participant in the sub-study entailing an additional imaging protocol for assessment of outcomes, i.e. Cardiac MRI, until the sub-study number is reached. Cardiac MRIs will be taken pre-enrolment and 6 months post enrolment and the investigation is expected to take approximately 45 minutes. All imaging sessions will be supervised by a cardiologist recognised by the Conjoint Committee for Certification in Cardiac MRI.
Intervention code [1] 318031 0
Treatment: Drugs
Comparator / control treatment
Those enrolled in this study who are randomly allocated to the control arm will be required to take 10mg of matching placebo orally daily (in the morning) for a total duration of 6 months.

Matching placebo will consist of inactive ingredients (with the exception of crospovidone) as the study drug and will be capsuled and coated identically to the study drug.
Control group
Placebo

Outcomes
Primary outcome [1] 324383 0
Change in high sensitivity troponin T (hs-cTnT) concentration by 6-months.

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought.
Timepoint [1] 324383 0
Baseline and 6 months
Secondary outcome [1] 384503 0
Change in NT-proBNP concentration by 6 months.

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought.
Timepoint [1] 384503 0
Baseline and 6 months
Secondary outcome [2] 384504 0
Change in echocardiographic parameters by 6 months.
Specifically: left ventricular volume and function, diastology, global longitudinal strain, myocardial work, left atrial volume and function.

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought.
Timepoint [2] 384504 0
Baseline and 6 months
Secondary outcome [3] 384509 0
Sub-study only: Change in CMR parameters by 6 months:
Specifically: extracellular volume (ECV), blood oxygen level dependent signal intensity (BOLD SI%), end systolic volume index (ESVi), left ventricular ejection fraction (LVEF), end diastolic volume index (EDVi), left ventricular (LV) mass, feature tracking CMR.

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought.
Timepoint [3] 384509 0
Baseline and 6 months
Secondary outcome [4] 384517 0
Change in fasting glucose and insulin levels.

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought.
Timepoint [4] 384517 0
Baseline and 6 months
Secondary outcome [5] 384520 0
Health-related Quality of Life: EuroQol 5D 5 level Quality of Life questionnaire (EQ-5D)

This data will be obtained through telephone, email, mail-out or similar follow up.
Timepoint [5] 384520 0
Baseline, 30 days, 3 months and 6 months
Secondary outcome [6] 384521 0
Kansas City Cardiomyopathy Questionnaire (KCCQ)

This data will be obtained through telephone, email, mail-out or similar follow up.
Timepoint [6] 384521 0
Baseline, 30 days, 3 months and 6 months
Secondary outcome [7] 388679 0
Cardiovascular death

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought. All event documents will be blinded and independently adjudicated by clinical experts in accordance with event definitions.
Timepoint [7] 388679 0
6 months post baseline
Secondary outcome [8] 388680 0
Type 1 myocardial infarction

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought. All event documents will be blinded and independently adjudicated by clinical experts in accordance with event definitions.
Timepoint [8] 388680 0
6 months post baseline
Secondary outcome [9] 388681 0
Rehospitalisation for heart failure,

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought. All event documents will be blinded and independently adjudicated by clinical experts in accordance with event definitions.
Timepoint [9] 388681 0
6 months post baseline
Secondary outcome [10] 388682 0
Cardiac arrhythmia.

All data for in-hospital care will be obtained by data linkage of public and private hospital admissions and care through electronic medical records systems. Where required, paper medical records will be sought. All event documents will be blinded and independently adjudicated by clinical experts in accordance with event definitions.
Timepoint [10] 388682 0
6 months post baseline

Eligibility
Key inclusion criteria
Patients will be considered eligible if they meet all of the following:
1. Chronic elevation of defined as a troponin T velocity of <3ng/L/hour assessed with at least 3 troponin values measued, with at least 2 of these being 4 hours apart, AND with at least 1 of these values >14ng/L, within the first 24 hours of initial presentation;
2. Age of 18 years or older;
3. Willing to give informed consent
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be considered ineligible if they meet any of the following:
1. Troponin T: Maximal in hospital troponin level >100ng/L within the first 24 hours of initial presentation or acute myocardial injury, defined as a rise and/or fall in troponin T with a velocity of >3ng/L/hr;
2. Recent coronary revascularization (PCI and CABG) within the last 6 months
3. Active heart failure with clinical symptoms of dyspnoea or extra-vascular volume overload and a NT-proBNP level >500ng/L;
4. Treated diabetes, defined as receiving any long-term/chronic oral or parenteral pharmacotherapies for the treatment of established diabetes;
5. Renal impairment with a documented eGFR of <45ml/min/1.73m2;
6. Documented HBA1C level >7% in the previous 3 months;
7. Presentation with documented ST segment elevation on ECG representing either ST-segment elevation MI or pericarditis;
8. Documented pulmonary embolus or aortic dissection;
9. History of bladder cancer or history of radiation therapy to the lower abdomen or pelvis at any time;
10. Recurrent genital infections;
11. Pregnancy or breast-feeding (female), planning to donate sperm (male) or trying to conceive within the next 6 months (males and females);
12. History of allergy to SGLT2 inhibitors or similar drug
13. Concurrent participation in another randomized clinical trial;
14. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
15. Previous enrolment or randomisation in the present study
16. Currently taking an SGLT2 inhibitor or previous treatment with SGLT2 inhibitor in the last 6 months

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)
Randomisation schedule generated by and only available to nominated individual not involved in study conduct. Randomisation will occur centrally via an electronic database.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Analysis plan and populations: The primary analysis population will include all randomised patients who have received at least 30 days blinded therapy (dapagliflozin or placebo) cumulatively over the 6 months following randomization.

General Analysis Approach: The primary analysis will compare the mean change in hs-cTnT levels between index hospitalization and 6-months follow-up for patients randomised to dapagliflozin and placebo using non-parametic regression adjusting for differences in baseline covariates expected given the small sample size. Secondary biomarker and cardiac imaging end points will be compared in similar manner and will be considered exploratory and therefore no adjustment of the significance level for multiple testing will be undertaken. The 6-month freedom from cardiovascular mortality, recurrent heart failure readmission will be assessed by survival analysis. A p value of <0.05 will be considered statistically significant. A full statsitical analysis plan will be developed and finalized before data-base lock.

All sub analyses conducted will be aligned with the key objectives of this project and thus considered ethically approved within the scope of the study.

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,SA
Recruitment hospital [1] 17042 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 17043 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 17044 0
Liverpool Hospital - Liverpool
Recruitment hospital [4] 17045 0
Bankstown-Lidcombe Hospital - Bankstown
Recruitment hospital [5] 17046 0
Campbelltown Hospital - Campbelltown
Recruitment postcode(s) [1] 30712 0
5000 - Adelaide
Recruitment postcode(s) [2] 30713 0
5042 - Bedford Park
Recruitment postcode(s) [3] 30714 0
2170 - Liverpool
Recruitment postcode(s) [4] 30715 0
2200 - Bankstown
Recruitment postcode(s) [5] 30716 0
2560 - Campbelltown

Funding & Sponsors
Funding source category [1] 306168 0
Commercial sector/Industry
Name [1] 306168 0
AstraZeneca Pty.Ltd.
Address [1] 306168 0
AstraZeneca Australia, Head Office
66 Talavera Road
Macquarie Park NSW 2113
Country [1] 306168 0
Australia
Primary sponsor type
University
Name
Flinders University of South Australia
Address
Flinders University
1 Flinders Drive
Bedford Park SA 5042

Country
Australia
Secondary sponsor category [1] 306638 0
None
Name [1] 306638 0
Address [1] 306638 0
Country [1] 306638 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 306381 0
The Southern Adelaide Clincal Human Research Ethics Committee
Ethics committee address [1] 306381 0
Flinders Medical Centre, 1 Flinders Drive,Bedford Park, South Australia-5042
Ethics committee country [1] 306381 0
Australia
Date submitted for ethics approval [1] 306381 0
26/10/2020
Approval date [1] 306381 0
Ethics approval number [1] 306381 0

Summary
Brief summary
While a significant volume of research and resources are devoted to the diagnosis and management of myocardial infarction, chronic myocardial injury represents a far greater proportion of patients with high-sensitivity troponin T threshold above the upper reference limit of >14ng/L. In South Australia almost a third of patients presenting to emergency services have elevated troponin levels, of which approximately 40% are eventually diagnosed with chronic myocardial injury and are associated with greater rates of late cardiovascular deaths and events. Despite the overwhelming burden of chronic cardiac injury, currently no evidence-based recommendations exist for the management of these patients. SGLT-2 inhibitors such as dapagliflozin have shown to reduce heart failure related rehospitalisations and cardiovascular-related mortality among both patients with established diabetes and heart failure as well as patients with heart failure in the absence of diabetes, representing an exciting opportunity to improve the outcomes of patients with cardio-metabolic disease. This study will evaluate the impact of dapagliflozin on the cardiac biomarkers of myocardial injury among patients with chronic cardiac injury.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103686 0
Prof Derek Chew
Address 103686 0
Flinders Medical Centre
GPO Box 2100, Adelaide 5001, South Australia

Country 103686 0
Australia
Phone 103686 0
+61 08 8404 2001
Fax 103686 0
Email 103686 0
derek.chew@flinders.edu.au
Contact person for public queries
Name 103687 0
Ms Kristina Lambrakis
Address 103687 0
College of Medicine & Public Health, Flinders University
Flinders Medical Centre
Cardiology, Level 6, Rm 6R347
1 Flinders Drive
Bedford Park SA 5042
Country 103687 0
Australia
Phone 103687 0
+61 08 8204 5836
Fax 103687 0
Email 103687 0
Kristina.Lambrakis@flinders.edu.au
Contact person for scientific queries
Name 103688 0
Ms Kristina Lambrakis
Address 103688 0
College of Medicine & Public Health, Flinders University
Flinders Medical Centre
Cardiology, Level 6, Rm 6R347
1 Flinders Drive
Bedford Park SA 5042
Country 103688 0
Australia
Phone 103688 0
+61 08 8204 5836
Fax 103688 0
Email 103688 0
Kristina.Lambrakis@flinders.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data may contain individual participant information that will not be readily de-identifiable. IPD sharing will be considered at a later stage.
What supporting documents are/will be available?
No other documents available
Summary results
No Results