Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000282482
Ethics application status
Approved
Date submitted
24/05/2024
Date registered
11/04/2025
Date last updated
11/04/2025
Date data sharing statement initially provided
11/04/2025
Type of registration
Retrospectively registered

Titles & IDs
Public title
EMERALD: An assessment of feasibility of treating coronary microvascular dysfunction with SGLT2 inhibitors
Scientific title
EMERALD: A NovEl Machine LEaRning Assessment of Coronary Microvascular Function using CTCA and Angiography, and Evaluating the Effects of EmpagLiflozin on Coronary Microvascular Dysfunction in Adults with Angina
Secondary ID [1] 312207 0
Nil known
Universal Trial Number (UTN)
Trial acronym
EMERALD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Coronary microvascular dysfunction 333886 0
Coronary artery disease 333887 0
Inflammation 333888 0
Condition category
Condition code
Cardiovascular 330561 330561 0 0
Coronary heart disease
Cardiovascular 330562 330562 0 0
Diseases of the vasculature and circulation including the lymphatic system
Inflammatory and Immune System 330563 330563 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
"Empagliflozin 10 mg tablet consumed oral once daily for a total of six months" vs. "Standard of care". Patients will be randomised in a 1:1 fashion. For the purpose of this study, standard of care is maximally tolerated angiotensin-converting-enzyme (ACE) inhibition (any agent within the class), aspirin, beta-blockade, or calcium channel blockade in line with the European Society of Cardiology's (ESC) 2024 statement on Chronic Coronary Syndromes. The individual medications prescribed by treating clinicians will be recorded.

After their clinically-indicated invasive coronary angiogram and has shown evidence of microvascular disease, all patients who provide informed consent will undergo a symptom questionnaire, CT-coronary angiogram, and serology at the time of enrolment to the trial and once again at the exit of the trial (i.e. 6 months). There are no interim bloods or scans required. Some patients at the time of recruitment will have had some of this work-up already completed, and anything within 28 days will be considered sufficiently recent.

The recorded angiographic videos or 'cinegraphs' will be securely and confidentially analysed using a research software to validate potential non-invasive methods of assessing microvascular disease. This is performed via the QAngio XA 3D software (Medis, The Netherlands). It uses a limited machine learning algorithm to perform frame-by-frame counting of contrast with known constants (e.g. coronary flow and velocity) to identify the presence and grade severity of CMD. The exact algorithm is proprietary, and the algorithm was crafted by Medis using serial analyses of company datasets. No patient details leave the local, secured computer ensuring it remains confidential. The researchers will perform a simultaneous, manual frame count for accuracy and validity.

Study participation will also involve two cardiac CT scans, known as CT-coronary angiograms or ‘CTCA’. The first will be conducted from one to twenty-eight days after the angiogram, and again on completion of the study. The results and calculations derived from these CT scans will be compared to the results of the invasive procedures to determine whether there is a relationship between these measurements. The anatomical results of the CTs are not being directly compared to the anatomical results of the angiogram.

At the time of study recruitment, we will also take a small sample of blood (20 mL). This will be used to measure baseline biochemical characteristics, including those considered ‘standard of care’ as well as some markers for the purpose of the research study. The blood tests are targeted and will investigate inflammation, cholesterol, and diabetic status. These will be repeated at exit of the study.

A person’s cultural or linguistic background should not be a barrier to participating in research, and we hope to include participants from a wide range of cultures. However, we must ensure they fully understand what is involved with participation and have the capacity to consent. In the case a potential participant’s English level is such that there is doubt of capacity or comprehension of the written patient informed consent form document, we will err on the side of caution and not offer participation given concerns that consent may be invalid. An interpreter may be used to assist in discussing interest in participating.

Due to the exposure to radiation and the use of a medication not currently recommended in pregnancy or breastfeeding, we will not be recruiting people who are planning on becoming pregnant or breastfeeding across the study period. We also ask that if you do become pregnant, you notify the trial team as soon as possible.

There are three additional research assessments we ask of our participants:

1) Cardiac CT imaging: Computer tomography (CT) scans are special X-ray scans that produce highly detailed, cross-sectional pictures of the body. A cardiac CT examines the heart, its arteries, and its function. The CT machine looks like a large doughnut with a narrow table in the middle. The table moves through the large circular hole in the centre of the scanner. It requires the use of iodinated contrast which allows your organs and blood vessels to be seen more clearly. This requires the insertion of a needle (IV cannula) into a vein in your arm. You will have to take a medication called glyceryl trinitrate (GTN) prior to your scan. This increases the diameter of your blood vessels, making them easier to assess. Your heart rate will be assessed prior to the scan. You may be given a type of medication called a beta blocker to slow down your heart rate to about 60 beats per minute.

2) Blood tests: Blood will be taken by a peripheral vein for assessment of standard, clinically-indicated parameters (full blood examination, urea, electrolytes and creatinine, liver function tests, coagulation studies) as well as important research markers (full lipid profile, glycosylated haemoglobin, high sensitivity C-reactive protein, tumour necrosis factor a, Rho-kinase, and interleukin-1).

3) Patient Questionnaires: Two will be completed with you. The Seattle Angina Questionnaire (SAQ) is a self-reported, twelve question survey to assess the impact chest pain is having on a person’s daily living. The EQ-5D-5L is a two-page survey to objectively characterise a person’s current quality of life across five domains – mobility, self-care, usual activities, pain or discomfort, and anxiety or depression.

Participation is required for the complete assessment upon recruitment as described above, with a single follow-up required by participants at six months. At this stage, the invasive coronary angiogram, CTCA, blood tests, and questionnaires will be repeated.
Intervention code [1] 328653 0
Treatment: Drugs
Comparator / control treatment
Standard of care for coronary artery microvascular dysfunction (aspirin, statin, ACE inhibitor) will be initiated and titrated by the patient's primary GP or Cardiologist in according with the ESC 2024 guideline for chronic coronary syndromes. This allows flexibility in the dosing and as such medication regimen is part of the recorded data on recruitment and trial exit.
Control group
Active

Outcomes
Primary outcome [1] 338341 0
Coronary microvascular resistance
Timepoint [1] 338341 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [1] 435483 0
Inflammation
Timepoint [1] 435483 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [2] 435484 0
Quality of life
Timepoint [2] 435484 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [3] 435485 0
Quantitative angina symptom burden
Timepoint [3] 435485 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [4] 435486 0
Presence of anaemia
Timepoint [4] 435486 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [5] 435487 0
Presence of previous macrovascular atherosclerotic disease (composite of stroke, transient ischaemic attack, or clinically relevant peripheral arterial disease)
Timepoint [5] 435487 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [6] 444000 0
Presence of dyslipidaemia (binary presence or absence of excessive total cholesterolaemia, hypertriglyceridaemia, or low-density lipoprotein)
Timepoint [6] 444000 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [7] 444001 0
Presence of diabetes (inclusive of type 1, type 2, iatrogenic, or latent autoimmune diabetes of adulthood)
Timepoint [7] 444001 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [8] 444002 0
Presence of elevated body mass index
Timepoint [8] 444002 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [9] 444003 0
Presence of first-hand exposure to tobacco smoking
Timepoint [9] 444003 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [10] 444004 0
Presence of diagnosed obstructive sleep apnoea
Timepoint [10] 444004 0
Baseline and at six months of treatment (i.e. end of study)
Secondary outcome [11] 444005 0
Renal function
Timepoint [11] 444005 0
Baseline and at six months of treatment (i.e. end of study)

Eligibility
Key inclusion criteria
1. Patients aged 18 years and over, AND;
2. Patients undergoing a clinically-indicated invasive coronary angiogram, AND;
3. Patients with symptoms of angina.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. A non-coronary indication for invasive coronary angiography, OR;
2. Significant renal impairment, defined as an eGFR < 30 mL/min/1.73 m2, OR;
3. Obstructive disease on angiography, defined as a stenotic lesion > 50% lesion by diameter or a fractional flow reserve (FFR) of < 0.80, OR;
4. Inability to provide written, informed consent due to altered conscious state, cognitive impairment, or a culturally or linguistically diverse background.
5. Pregnancy of people who are actively breastfeeding.
6. Use of regular Sodium/GLucose coTransporter-2 (SGLT2) inhibition within ninety days.

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)
Web-based randomisation system.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The analysis plan is based on an intention-to-treat principle in line with CONSORT (Consolidated Standards of Reporting Trails) guidelines. It focuses on estimation of treatment effect differences with 95% confidence intervals (CI) and p-values. Continuous outcomes will be analysed using linear regression with adjustment for baseline levels where these are available. Standard transformations will be applied to non-normally distributed variables to achieve approximate normality prior to analysis. Logistic regression method will be applied for binary variables. Machine learning (ML) models to predict IMR will be compared with logistic regression statistical model. The accuracy of QMR will be assessed by Pearson/Spearman’s correlation and receiver operating characteristic (ROC) analysis. The quantitative or 'delta' numerical changes in Seattle Angina Questionnaire (SAQ), Quality of Life (QOL) metrics, and IMR between empagliflozin and control will be compared by t-test or Mann-Whitney test as appropriate. These have been expressed in supplemetary documentation as the Greek symbol for delta followed by the relevant parameter, e.g. 'delta-IMR'.

The project needs thirty-five (35) patients per group to detect a difference of 10% in the change in IMR between the empagliflozin group and control (standard deviation/SD = 3, alpha = 0.05, power = 80%).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
17/03/2025
Date of last participant enrolment
Anticipated
1/08/2026
Actual
Date of last data collection
Anticipated
31/12/2026
Actual
Sample size
Target
70
Accrual to date
2
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,WA,VIC
Recruitment hospital [1] 26574 0
Victorian Heart Hospital - Clayton
Recruitment hospital [2] 26575 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [3] 26576 0
Gosford Hospital - Gosford
Recruitment hospital [4] 26577 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 26578 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 26579 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 42618 0
3168 - Clayton
Recruitment postcode(s) [2] 42619 0
5011 - Woodville
Recruitment postcode(s) [3] 42620 0
2250 - Gosford
Recruitment postcode(s) [4] 42621 0
2139 - Concord
Recruitment postcode(s) [5] 42622 0
5000 - Adelaide
Recruitment postcode(s) [6] 42623 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 316583 0
Hospital
Name [1] 316583 0
Victorian Heart Hospital, Monash Health
Country [1] 316583 0
Australia
Funding source category [2] 318215 0
Hospital
Name [2] 318215 0
Royal Adelaide Hospital
Country [2] 318215 0
Australia
Funding source category [3] 318216 0
Hospital
Name [3] 318216 0
Gosford Hospital, NSW Health
Country [3] 318216 0
Australia
Funding source category [4] 318217 0
Hospital
Name [4] 318217 0
Royal Perth Hospital
Country [4] 318217 0
Australia
Funding source category [5] 318218 0
Hospital
Name [5] 318218 0
The Queen Elizabeth II Hospital, Adelaide
Country [5] 318218 0
Australia
Funding source category [6] 318219 0
Hospital
Name [6] 318219 0
Concord Repatriation General Hospital, NSW Health
Country [6] 318219 0
Australia
Primary sponsor type
University
Name
Monash University
Address
Country
Australia
Secondary sponsor category [1] 318763 0
Charities/Societies/Foundations
Name [1] 318763 0
Heart Foundation
Address [1] 318763 0
Country [1] 318763 0
Australia
Secondary sponsor category [2] 320604 0
Government body
Name [2] 320604 0
National Health and Medical Research Council
Address [2] 320604 0
Country [2] 320604 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315371 0
Monash Health Human Research Ethics Committee A
Ethics committee address [1] 315371 0
Ethics committee country [1] 315371 0
Australia
Date submitted for ethics approval [1] 315371 0
20/03/2024
Approval date [1] 315371 0
18/09/2024
Ethics approval number [1] 315371 0
RES-24-0000-215A

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 134490 0
A/Prof Dennis Wong
Address 134490 0
Victorian Heart Hospital, 631 Blackburn Road Clayton VIC 3168
Country 134490 0
Australia
Phone 134490 0
+61 3 7511 1680
Fax 134490 0
Email 134490 0
[email protected]
Contact person for public queries
Name 134491 0
Dennis Wong
Address 134491 0
Victorian Heart Hospital, 631 Blackburn Road Clayton VIC 3168
Country 134491 0
Australia
Phone 134491 0
+61 3 7511 1680
Fax 134491 0
Email 134491 0
[email protected]
Contact person for scientific queries
Name 134492 0
Dennis Wong
Address 134492 0
Victorian Heart Hospital, 631 Blackburn Road Clayton VIC 3168
Country 134492 0
Australia
Phone 134492 0
+61 3 7511 1680
Fax 134492 0
Email 134492 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No IPD sharing reason/comment: IPD will be kept confidential and only shared via secure transfer methods amongst principal investigators to protect participant confidentiality and privacy.



What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23781Informed consent form    Master PICF v1.3 2024.10.17 - EMERALD PICF - Master v1.3.pdf
23782Study protocol    Protocol 1.3 2024.09.09 - EMERALD Protocol v1.3.pdf
23783Study protocol    Participant flow chart 2024.05.24 - EMERALD PICF Flow Chart.pdf
23784Other https://www.nps.org.au/assets/medicines/bc1e9b89-964b-4683-b044-a53300ffaebd.pdf  Trial medication CMI Jardiance Consumer Medication Information.pdf
23785Ethical approval    HREC Approval 2024.10.08 - RES-24-0000-215A HREC Review Only Approval Letter.pdf
24502Ethical approval    Ethics Ammendment - SSA Approval 2024.11.13 - Monash Health EMERALD RES-24-0000-215A - SSA Authorisation Letter.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.