Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12611000495921
Ethics application status
Approved
Date submitted
10/05/2011
Date registered
11/05/2011
Date last updated
15/05/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
Multi-Parametric Cardiovascular Magnetic Resonance Assessment of Hypertrophic Cardiomyopathy - Therapeutic Metformin sub-study
Scientific title
Multi-Parametric Cardiovascular Magnetic Resonance Assessment of Hypertrophic Cardiomyopathy - Therapeutic Metformin sub-study
Secondary ID [1] 262143 0
None
Universal Trial Number (UTN)
U1111-1121-2660
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertrophic Cardiomopathy 265821 0
Condition category
Condition code
Cardiovascular 265975 265975 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
From the main study criteria (ACTRN12611000479909), patients with reduced PCR/ATP ratio of < 1.7 will be eligible to participate in the therapeutic metformin sub-study. They will have a baseline 10ml blood sample before having 12 weeks treatment of either metformin 1g orally 3 x daily or placebo orally 3 x daily before crossing over to the other treatment after a 4 week drug wash-out period. At the end of each 12 week treatment phase they will have another 10ml blood sample, cardiac magnetic resonance imaging with gadolinium contrast (0.025mmol/kg body weight), cardiac magnetic resonance spectroscopy with adenosine intravenously (140mcg/kg/min) for 3-6 mins and echocardiography.
Intervention code [1] 264556 0
Treatment: Drugs
Comparator / control treatment
40 patients will take part in the therapeutic metformin sub-study. In a double-blind randomised control trial manner, they will either receive metformin tablets 1g 3 x daily or placebo tablets 3 x daily for 12 weeks, and be crossed over to the other treatment arm after a 4 week drug wash-out period. Placebo is packed with microcrystalline cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 266721 0
Phosphocreatine (PCr)/Adenosinetriphosphate (ATP) ratio. Method: Cardiac magnetic resonance spectroscopy will be used to measure cardiac high energy phosphate metabolism in-vivo. The novel SLOOP method (spatial localisation with optimum pointspread function) allows accurate measurement of absolute concentrations of high-energy phosphates.
Timepoint [1] 266721 0
28 weeks
Secondary outcome [1] 276246 0
AMPK activity as measured by peripheral blood test
Timepoint [1] 276246 0
28 weeks
Secondary outcome [2] 276247 0
Absolute concentration of high-energy phosphates as measured by cardiac magnetic spectroscopy.
Timepoint [2] 276247 0
28 weeks
Secondary outcome [3] 276248 0
LV diastolic function as measured by cardiac magnetic resonance imaging and doppler echocardiography
Timepoint [3] 276248 0
28 weeks
Secondary outcome [4] 276249 0
Regional function as measured by cardiac magnetic resonance imaging
Timepoint [4] 276249 0
28 weeks
Secondary outcome [5] 276250 0
LV systolic function as measured by cardiac magnetic resonance imaging
Timepoint [5] 276250 0
28 weeks

Eligibility
Key inclusion criteria
Hypertrophic cardiomyopathy patients aged between 18 and 75; phenotype positive (established by echocardiography or cardiac magnetic resonance scan); genotype positive for cardiac myosin binding protein-C gene mutations or cardiac beta-myosin heavy chain gene mutations; patients with reduced baseline PCR/ATP ratio of <1.7
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Impaired LV systolic function (EF <50%) as detected on echocardiography or cardiac magnetic resonance scan; history of diabetes mellitus, calculated GFR <30mls/hr; significant derranged liver function defined as liver enzymes of 3 x ULN; current therapy with metformin or amiodarone; absolute contraindication of having MRI scan.

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)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 2
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/07/2011
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
120
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)

Funding & Sponsors
Funding source category [1] 265036 0
Charities/Societies/Foundations
Name [1] 265036 0
National Heart Foundation
Country [1] 265036 0
Australia
Primary sponsor type
Individual
Name
Professor Joseph Selvanayagam
Address
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
BEDFORD PARK SA 5042
Country
Australia
Secondary sponsor category [1] 264134 0
Individual
Name [1] 264134 0
Professor John Horowitz
Address [1] 264134 0
Department of Cardiology
The Queen Elizabeth Hospital
Woodville South, Adelaide
South Australia 5011
Country [1] 264134 0
Australia
Secondary sponsor category [2] 264135 0
Individual
Name [2] 264135 0
Professor Christopher Semsarian
Address [2] 264135 0
Molecular Cardiology, Centenary Institute
Royal Prince Alfred Hospital
Missenden Rd
Camperdown, NSW 2050
Country [2] 264135 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 267029 0
Flinders Clinical Research Ethics Committee
Ethics committee address [1] 267029 0
Flinders Medical Centre
Flinders Drive
BEDFORD PARK
South Australia 5042
Ethics committee country [1] 267029 0
Australia
Date submitted for ethics approval [1] 267029 0
09/09/2010
Approval date [1] 267029 0
17/12/2010
Ethics approval number [1] 267029 0
36910

Summary
Brief summary
HCM is the most common cardiovascular genetic disorder and can cause significant morbidity and mortality, including the most serious complications of heart failure and sudden death. At present, there are no proven pharmacological therapies that either prevent or cause regression of clinical features. This is largely due to a lack of knowledge in our understanding of the molecular and functional consequences of the disease-causing gene mutations leading to the clinical disease. The proposed study will aim to test whether cardiac energetic compromise is a central pathophysiological mechanism in HCM. We will investigate potentially beneficial treatments based on our hypothesis, by trialling the use of metformin in an HCM group. If the results from this ‘proof of concept study’ are confirmatory, it could pave the way for larger multi-centre randomised studies (with longer duration of treatment) with either metformin or facilitators of fatty acid oxidation such as ranolazine. If realised, these treatments could prevent the vicious cycle of cardiac hypertrophy and myocardial dysfunction seen in hypertrophic cardiomyopathy, leading to improved morbidity and mortality.
These investigations will establish early phenotype changes in HCM patients and provide insights into potential therapeutic interventions for a condition that currently has little therapeutic evidence base. This therapeutic sub-study is linked to the main study ACTRN12611000479909.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 32594 0
Address 32594 0
Country 32594 0
Phone 32594 0
Fax 32594 0
Email 32594 0
Contact person for public queries
Name 15841 0
Christine Edwards
Address 15841 0
Flinders Clinical Research
Level 3A
Mark Oliphant Building
Laffer Drive
BEDFORD PARK SA 5042
Country 15841 0
Australia
Phone 15841 0
+61 8 8204 5656
Fax 15841 0
+61 8 8204 7047
Email 15841 0
christine.edwards2@health.sa.gov.au
Contact person for scientific queries
Name 6769 0
Professor Joseph Selvanayagam
Address 6769 0
Department of Cardiovascular Medicine
Flinders Medical Centre
1 Flinders Drive
BEDFORD PARK SA 5042
Country 6769 0
Australia
Phone 6769 0
+61 8 8404 2195
Fax 6769 0
Email 6769 0
joseph.selvanayagam@health.sa.gov.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
No additional documents have been identified.