Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12623000661673
Ethics application status
Approved
Date submitted
17/04/2023
Date registered
19/06/2023
Date last updated
19/06/2023
Date data sharing statement initially provided
19/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Can Semaglutide or empagliflozin stabilise coronary atherosclerosis in people with type 2 diabetes after acute coronary syndrome
Scientific title
The "Can Semaglutide or eMpAgliflozin Stabilise coronary atHerosclerosis after Acute Coronary Syndrome (SMASH-ACS)” study in people with type 2 diabetes
Secondary ID [1] 309468 0
2022-CP-Heart-010-8310
Universal Trial Number (UTN)
U1111-1287-6009
Trial acronym
SMASH-ACS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes 329731 0
Coronary atherosclerosis 329732 0
Condition category
Condition code
Cardiovascular 326629 326629 0 0
Coronary heart disease
Metabolic and Endocrine 326630 326630 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a prospective, randomised, open, blinded end-point (PROBE)-designed trial.

Semaglutide (a glucagon-like peptide-1 receptor agonist (GLP-1 RA) will be self-administered subcutaneously by the patient (starting at 0.25mg/week, uptitrated on a monthly basis based on patient tolerance and at the direction of a physician, up to 1.0 mg/week as tolerated) in an open label manner.

Participants will undergo a baseline CT coronary angiogram (CTCA), continue on the treatment for 12 months, and then undergo a repeat CTCA.

Adherence will be assessed by patient report at 1, 2, 3, 6, 9, and 12 months.
Intervention code [1] 325894 0
Treatment: Drugs
Comparator / control treatment
The comparator will be empagliflozin (a sodium-glucose co-transporter-2 (SGLT2) inhibitor), at a starting dose of 10mg daily, which can be uptitrated to 25mg daily at 3 months at clinician discretion, in an open label manner.

Participants will undergo a baseline CT coronary angiogram (CTCA), continue on the treatment for 12 months, and then undergo a repeat CTCA.

Adherence will be assessed by patient report at 1, 2, 3, 6, 9, and 12 months.
Control group
Active

Outcomes
Primary outcome [1] 334497 0
Progression rates of low attenuation plaque under influence of GLP-1 RA as compared to SGLT2 inhibition as assessed by CT coronary angiography
Timepoint [1] 334497 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [1] 420874 0
Change in total non-calcified plaque volume as assessed by CT coronary angiography
Timepoint [1] 420874 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [2] 420886 0
Change in HbA1c from baseline as assessed by serum HbA1c measurement
Timepoint [2] 420886 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [3] 420887 0
Change in renal function as assessed by serum creatinine from baseline
Timepoint [3] 420887 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [4] 420888 0
Change in weight as assessed by a digital scale
Timepoint [4] 420888 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [5] 420889 0
Change in blood pressure from baseline as measured by non-invasive blood pressure measurements obtained using a manual sphygmomanometer
Timepoint [5] 420889 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [6] 420890 0
Change in high sensitivity C-reactive protein from baseline using serum high sensitivity C-reactive protein
Timepoint [6] 420890 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [7] 420891 0
Change in lipid profile composition from baseline using serum lipid profile (total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride measurements)
Timepoint [7] 420891 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [8] 420892 0
Assess change in quality of life from baseline as assessed by the SF36v2 questionnaire
Timepoint [8] 420892 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [9] 420893 0
Assess change in diabetic distress compared with baseline as assessed using a composite of the Diabetes Distress Screening Scale and PHQ-9 questionnaires
Timepoint [9] 420893 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [10] 420894 0
Evaluate changes in coronary artery shear stress as evaluated by CTCA from baseline
Timepoint [10] 420894 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [11] 420895 0
Evaluate autophagy at baseline and after 12 months of study drug administration assessed using peripheral blood mononuclear cells with an ELISA-based assay
Timepoint [11] 420895 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [12] 422549 0
Calcified coronary plaque volume as assessed. by CTCA
Timepoint [12] 422549 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [13] 422550 0
Percent coronary atheroma volume as assessed. by CTCA
Timepoint [13] 422550 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [14] 422551 0
Maximum lumen stenosis as assessed. by CTCA
Timepoint [14] 422551 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [15] 422552 0
Leaman score as assessed. by CTCA
Timepoint [15] 422552 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [16] 422553 0
Pericoronary adipose tissue attenuation as assessed. by CTCA
Timepoint [16] 422553 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [17] 422554 0
Epicardial fat volume as assessed by CTCA
Timepoint [17] 422554 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [18] 422555 0
Assess change in gastro-intestinal autonomic function from baseline as assessed by the PAGI-SYM questionnaire
Timepoint [18] 422555 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [19] 422556 0
Assess change in genitourinary autonomic function from baseline as assessed by International Index of Erectile Function (IIEF) questionnaire
Timepoint [19] 422556 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [20] 422557 0
Assess change in mental well being from baseline as assessed using a self-developed questionnaire
Timepoint [20] 422557 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [21] 422558 0
Assess change in non-cardiac pain as assessed by the self-developed questionnaires
Timepoint [21] 422558 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [22] 422872 0
Assess change in quality of life from baseline as assessed by the AQoL 8D questionnaire
Timepoint [22] 422872 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [23] 422873 0
Change in renal function as assessed by eGFR from baseline
Timepoint [23] 422873 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [24] 422993 0
Epicardial fat density as assessed by CTCA
Timepoint [24] 422993 0
Baseline and 12 months post-commencement of treatment
Secondary outcome [25] 422994 0
Assess change in gastro-intestinal autonomic function from baseline as assessed by the diabetes bowel symptom survey questionnaire
Timepoint [25] 422994 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [26] 422995 0
Assess change in genitourinary autonomic function from baseline as assessed by the International Prostate Symptom Score (IPSS) score
Timepoint [26] 422995 0
Baseline, 6 months and 12 months post-commencement of treatment
Secondary outcome [27] 422996 0
Assess change in genitourinary autonomic function from baseline as assessed by the ICIQ-IU short form questionnaire
Timepoint [27] 422996 0
Baseline, 6 months and 12 months post-commencement of treatment

Eligibility
Key inclusion criteria
- Hospitalisation with an acute coronary syndrome (as defined by the 2020 European Society of Cardiology (ESC) Guidelines for the Management of Acute Coronary Syndromes), where participant has undergone invasive coronary angiography and is left with residual atherosclerotic stenoses in one or more coronary arteries of at least 20% severity that will be left for medical management with no intention to revascularise by stenting or bypass grafting in the next 12 months
- Previous or new (in hospital) diagnosis of type 2 diabetes
- No contraindication to glucagon-like peptide-1 receptor agonists (GLP-1 RA) or sodium glucose co-transporter-2 (SGLT2) inhibitor usage (see key exclusion criteria)
- Eligible to use either GLP-1 RA or SGLT2 inhibitor as per PBS criteria (in summary, patients must have type 2 diabetes, and be on treatment with metformin and/or sulfonylurea as tolerated, and have a HbA1c >7%)
- Willing to use injectable medication
- Willingness to be on birth control for women of childbearing age or established post-menopausal
- Participants are required to have undergone screening, enrolment, baseline imaging and randomisation and drug initiation within 30 days of their index admission for their acute coronary syndrome
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Contraindication to GLP-1 RA use, including history of pancreatitis (acute or chronic), and established retinopathy
- Contraindication to SGLT2 inhibitor use, including recurrent genitourinary infections, and history of ketoacidosis
- Known history of a clinically significant gastric emptying abnormality, such as severe gastroparesis or gastric outlet obstruction, or being planned for bariatric surgery within the next 12 months
- Left ventricular ejection fraction <=35% or New York Heart Association (NYHA) class IV heart failure
- A personal or family history of medullary thyroid carcinoma, or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN2)
- Known type 1 diabetes
- Prior/known intolerance of GLP-1 receptor agonists or SGLT2 inhibitors
- Concurrent DPP4 use or use within the 2 weeks prior to randomisation occurring
- Dialysis or estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2
- Previous or planned coronary artery bypass grafting
- Pregnant women or women planning pregnancy in the following 12 months
- Life expectancy <1year
- Contraindications to CT coronary angiography
- Concurrent enrolment in another placebo-controlled trial or within 30 days of finishing another trial
- Enrolment and participation in another trial involving ionising radiation in the last 12 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)
Allocation concealment will occur, with central randomisation performed by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis
An intention-to-treat analysis will be the primary analysis. For the primary outcome, the change in low attenuation plaque (LAP) volume will be compared between the treatment groups using a linear regression model, adjusting for the baseline measurement and the stratification variables. Secondary outcomes will be analysed similarly using linear regression models for continuous outcomes and logistic regression models for binary outcomes.

Per protocol analysis will be performed on those with treatment compliance >80% as a sensitivity analysis. P-values of <0.05 will be considered statistically significant.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
17/07/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
132
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 313665 0
Charities/Societies/Foundations
Name [1] 313665 0
The Hospital Research Foundation
Country [1] 313665 0
Australia
Primary sponsor type
Other Collaborative groups
Name
South Australian Health and Medical Research Institute
Address
North Terrace, Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 315467 0
None
Name [1] 315467 0
Address [1] 315467 0
Country [1] 315467 0
Other collaborator category [1] 282632 0
Hospital
Name [1] 282632 0
Royal Adelaide Hospital
Address [1] 282632 0
Port Road, Adelaide SA 5000
Country [1] 282632 0
Australia
Other collaborator category [2] 282633 0
Hospital
Name [2] 282633 0
Flinders Medical Centre
Address [2] 282633 0
Flinders Drive, Bedford Park SA 5042
Country [2] 282633 0
Australia
Other collaborator category [3] 282634 0
Hospital
Name [3] 282634 0
The Queen Elizabeth Hospital
Address [3] 282634 0
28 Woodville Rd, Woodville South SA 5011
Country [3] 282634 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312830 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 312830 0
CALHN Research Services, Central Adelaide Local Health Network Inc., SA Health
Level 3, Roma Mitchell Building, 136 North Terrace, Adelaide, SA 5000
Ethics committee country [1] 312830 0
Australia
Date submitted for ethics approval [1] 312830 0
11/04/2023
Approval date [1] 312830 0
31/05/2023
Ethics approval number [1] 312830 0
2023/HRE00023

Summary
Brief summary
Type 2 diabetes mellitus (T2DM) is a chronic disease, the prevalence of which is rapidly growing world-wide. As a result of historical concerns of the safety of available glucose-lowering therapies, cardiovascular outcome trials (CVOTs) were mandated by the Food and Drug Administration (FDA) in 2008 to ensure that new anti-diabetic therapies coming onto the market were safe from a cardiovascular perspective. Out of the recently studied drug classes, GLP-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors have both shown to provide cardiovascular benefits, not just safety/non-inferiority compared to the more traditional glucose-lowering agents they have been compared to. Both are currently recommended in guidelines for use in patients with a cardiac history, however, it is not clear whether one would confer a greater benefit than the other in patients who have recently had an acute coronary syndrome (ACS), nor whether they can slow plaque progression, as a possible mechanism of their cardiovascular benefit. Given patients in Australia can only access one therapy at a time on the PBS, any information regarding their direct comparison in this patient population would be useful.

This will be a prospective, randomised, open, blinded end-point (PROBE)-designed trial that will evaluate the effect of semaglutide and empagliflozin on coronary plaque, as assessed by computer tomography coronary angiography (CTCA) at baseline and following 12 months of treatment with either semaglutide or empagliflozin in participants with diabetes and known coronary artery disease who have presented with an acute coronary syndrome.

We hypothesise that participants prescribed semaglutide will have a slower progression in coronary plaque development as compared with participants on empagliflozin.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 126070 0
A/Prof Peter Psaltis
Address 126070 0
South Australian Health and Medical Research Institute
Port Rd
Adelaide SA 5000
Country 126070 0
Australia
Phone 126070 0
+61 8 8128 4710
Fax 126070 0
Email 126070 0
peter.psaltis@sahmri.com
Contact person for public queries
Name 126071 0
Dr Jessica Marathe
Address 126071 0
Royal Adelaide Hospital
Port Rd
Adelaide SA 5000
Country 126071 0
Australia
Phone 126071 0
+61 8 7074 6182
Fax 126071 0
Email 126071 0
jessica.marathe@sa.gov.au
Contact person for scientific queries
Name 126072 0
Dr Jessica Marathe
Address 126072 0
Royal Adelaide Hospital
Port Rd
Adelaide SA 5000
Country 126072 0
Australia
Phone 126072 0
+61 8 7074 6182
Fax 126072 0
Email 126072 0
jessica.marathe@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



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.