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Trial registered on ANZCTR

Registration number

ACTRN12609000789268

Ethics application status

Approved

Date submitted

23/06/2009

Date registered

10/09/2009

Date last updated

7/03/2013

Type of registration

Retrospectively registered

Titles & IDs

Public title

Non-invasive cardiac imaging in the detection and assessment of subclinical diabetic heart disease

Scientific title

Non-invasive cardiac imaging in the detection and assessment of subclinical diabetic heart disease in type 2 diabetes mellitus patients - outcome of antifibrotic therapy with spironolactone

Secondary ID [1]

No secondary ID

Universal Trial Number (UTN)

Trial acronym

No acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Diabetic cardiomyopathy

Condition category

Condition code

Cardiovascular

Other cardiovascular diseases

Metabolic and Endocrine

Diabetes

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Subjects (n=225) will be screened for evidence of diabetic heart disease. Subjects with either will then be matched to patients with diabetes but without these findings.
Patients with subclinical dysfunction will be randomized to spironolactone 1x25 mg tablet orally per day for 6 months (as an anti-fibrotic drug) or 1x placebo tablet orally per day for 6 months (lactose based tablet). Randomization will be stratified by evidence of diastolic dysfunction on tissue Doppler imaging echocardiographic parameters. After 6 months, patients will be free to take additional therapy for glycemic control. In order to check for adverse events and compliance with treatment, subjects will receive follow-up phone calls and electrolyte monitoring with blood tests at 4 week intervals.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Subjects in the spironolactone arm will be compared with matched subjects in the placebo arm.

Control group

Placebo

Outcomes

Primary outcome [1]

Improvement in early diastolic tissue velocity on tissue Doppler imaging echocardiography following anti-fibrotic therapy with spironolactone

Timepoint [1]

Patients will be screened with exhocardiography pre and post a 6 month intervention with spironolactone

Secondary outcome [1]

Improvement in collagen biomarkers following anti-fibrotic therapy with spironolactone

Timepoint [1]

Biomarkers will be measured pre and post a 6 month intervention with spironolactone

Secondary outcome [2]

Improvement in deformation parameters on tissue Doppler imaging echocardiography following anti-fibrotic therapy with spironolactone

Timepoint [2]

Patients will be screened with echocardiography pre and post a 6 month intervention with spironolactone

Secondary outcome [3]

Improvement in diastolic functional class (on echocardiographic criteria) following anti-fibrotic therapy with spironolactone

Timepoint [3]

Patients will be screened with echocardiography pre and post a 6 month intervention with spironolactone

Secondary outcome [4]

Improvement of myocardial fibrosis on contrast enhanced magnetic resonance imaging (MRI) following anti-fibrotic therapy with spironolactone

Timepoint [4]

Patients will be screened with magnetic resonance imaging (MRI) pre and post a 6 month intervention with spironolactone

Secondary outcome [5]

Improvement in exercise capacity following anti-fibrotic therapy with spironolactone

Timepoint [5]

Patients will be screened with treadmill exercise testing and maximal oxygen uptake pre and post a 6 month intervention with spironolactone

Eligibility

Key inclusion criteria

Type 2 diabetes mellitus

Minimum age

40 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

Cardiac disease
Pregnancy or breast feeding
Psychiatric illness precluding compliance
Atrial Fibrillation (AF)
Other serious medical illness including renal impairment

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)

After suitability is confirmed by data entry, the database will generate an enrolment number and randomization statement via a central randomisation computer program with randomisation arm concealed from both the study investigators and the study subject.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation sequence is generated by random number generation.

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

16/02/2009

Actual

16/02/2009

Date of last participant enrolment

Anticipated

31/12/2010

Actual

10/01/2011

Date of last data collection

Anticipated

Actual

Sample size

Target

225

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National health and Medical Research Council (NHMRC)

Address [1]

National Health and Medical Research Council
National Institute of Clinical Studies
GPO Box 4530
Melbourne Vic 3001

Country [1]

Australia

Primary sponsor type

University

Name

The University of Queensland

Address

Southern Medical School
Princess Alexandra Hospital
Level 4 Building 1
199 Ipswich Rd
Woolloongabba
QLD 4102

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Princess Alexandra Hospital Ethics Committee

Ethics committee address [1]

Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba 
QLD 4102

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

05/06/2007

Ethics approval number [1]

2007/85

Summary

Brief summary

This project aims to establish the prevalence of subclinical diabetic heart disease, its relationship to myocardial fibrosis on imaging and biochemical parameters and its response to antifibrotic therapy with spironolactone.
MATERIALS & METHODS
Patient Selection
The patient cohort will compromise apparently healthy patients with type 2 diabetes mellitus (T2DM) and suboptimal control (glycosylated haemoglobin [HbA1c] > 7%) recruited from the hospital clinics and the community. Subjects with known macrovascular or microvascular complications of type two diabetes mellitus (T2DM), hypertensive, valvular or coronary disease or other significant co-morbidities such as arrhythmias, malignancy, psychiatric or renal disease will be excluded. Pregnant and breast feeding women will also be excluded.
Study design
225 patients will be recruited and undergo initial screening with echocardiography and cardiac magnetic resonance imaging for evidence of diabetic heart disease. Based on past studies at our research centre, it is predicted that approximately one third of these participants will have evidence of subclinical myocardial dysfunction. Previous work with spironolactone and hypertensive heart disease in our group has shown a significant impact on myocardial properties in patient numbers of less than 30, so a proportionate reduction should be detectable from this study group even allowing for a 30% drop-out. There are no previous studies investigating myocardial fibrosis in type 2 diabetes mellitus (T2DM) with cardiac magnetic resonance imaging on which this study can be powered.  
Baseline measures on all subjects will include: body mass index, hip and waist circumference and resting haemodynamic parameters. Fasting blood samples will be collected to assess haematological parameters, renal and hepatic function, lipid profile, glucose, insulin, glycosylated haemoglobin (HbA1c) and brain natriuretic peptide (BNP) concentrations. Urine collection for albumin to creatinine ratio for detection of diabetic nephropathy will also be performed. Additional plasma, serum and urine will be stored for subsequent investigation of collagen biomarkers as surrogate measures of myocardial fibrosis.
All study subjects will undergo a baseline transthoracic echocardiogram to assess for evidence of systolic or diastolic dysfunction using standard echocardiographic parameters. Tissue Doppler imaging (TDI)including tissue velocity, strain and strain rate will be employed to detect further subclinical abnormalities. All subjects will then undergo a standard treadmill exercise stress test before being reimaged at peak heart rate for evidence of inducible wall motion abnormalities (indicative of ischaemic heart disease) and with tissue Doppler imaging (TDI) for subtle myocardial dysfunction which is not otherwise apparent at rest. Those with inducible wall motion abnormalities will be excluded based on their likelihood to have ischaemic heart disease. Appropriate clinical follow-up will be arranged.
Patients who are found to have evidence of subclinical myocardial dysfunction and a proportion of matched controls from the original patient group will then be further investigated with cardiac magnetic resonance imaging for evidence of underlying myocardial fibrosis. Patients with subclinical dysfunction will also be randomised to anti-fibrotic therapy with spironolactone (25 mg orally per day) or placebo for 6 months with the aim of reducing the extent and progression of myocardial collagen deposition. Throughout the intervention period, patients will receive 4 weekly follow-up to monitor for adverse events and compliance. Post-intervention, anthropometric measurements, biochemical markers and imaging with resting and exercise echocardiograms and cardiac magnetic resonance imaging will be repeated. 
PROJECTED OUTCOMES
This work aims to highlight the importance of early detection and treatment of subclinical diabetic heart disease, which, if left unaddressed, may result in an epidemic of symptomatic diabetic heart disease in the future. We also hypothesize that anti-fibrotic therapy will have a favourable effect on myocardial function and exercise capacity.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Christine Jellis

Address

School of Medicine
The University of Queensland
Princess Alexandra Hospital
199 Ipswich Rd
Woolloongabba
4102, Qld

Country

Australia

Phone

+61 32405813

Fax

c.jellis@uq.edu.au

Contact person for public queries

Name

Christine Jellis

Address

Southern School of Medicine
University of Queensland
Princess Alexandra Hospital
Level 4 Building 1
199 Ipswich Rd
Woolloongabba
QLD 4102

Country

Australia

Phone

+61 7 3240 5813

Fax

+61 7 3240 5399

c.jellis@uq.edu.au

Contact person for scientific queries

Name

Christine Jellis

Address

Southern School of Medicine
University of Queensland
Princess Alexandra Hospital
Level 4 Building 1
199 Ipswich Rd
Woolloongabba
QLD 4102

Country

Australia

Phone

+61 7 3240 5813

Fax

+61 7 3240 5399

c.jellis@uq.edu.au

No information has been provided regarding IPD availability

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

Source	Title	Year of Publication	DOI
Dimensions AI	Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions	2023	https://doi.org/10.1038/s41420-023-01553-4

N.B. These documents automatically identified may not have been verified by the study sponsor.

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