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Trial registered on ANZCTR


Registration number
ACTRN12613001355763
Ethics application status
Not yet submitted
Date submitted
8/12/2013
Date registered
11/12/2013
Date last updated
11/12/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Blockade of Aldosterone Receptors as promising treatment for Type-1 Diabetes
Scientific title
Delaying or preventing the complications of Type-1 diabetes by adding the selective mineralocorticoid receptor antagonist eplerenone to standard medication for patients with Type-1 Diabetes.
Secondary ID [1] 283722 0
Nil Known
Universal Trial Number (UTN)
U1111-1151-1682
Trial acronym
BART-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 1 diabetes 290688 0
Condition category
Condition code
Metabolic and Endocrine 291057 291057 0 0
Diabetes
Cardiovascular 291058 291058 0 0
Other cardiovascular diseases
Eye 291059 291059 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Eplerenone 50mg orally once daily for 12 weeks

Proof-of-concept, non-randomized, open-label study.
Intervention code [1] 288417 0
Treatment: Drugs
Comparator / control treatment
Only the patients with Type 1 diabetes will receive eplerenone.

There is a control group of healthy participants who will not receive Eplerenone are included to determine the features of healthy heart function and blood pressure in healthy individuals to compare the areas of the heart that are not working properly in Type 1 diabetic individuals and identify novel biomarkers.
Control group
Active

Outcomes
Primary outcome [1] 291048 0
Change in composite outcome of ambulatory blood pressure, resting blood pressure, heart rate, pulse wave velocity and cardiac function and structure: left ventricular indices such as mass, mass index, ejection fraction, diastolic function, left atrial size and right ventricular function at 12 weeks after intervention commencement.
Timepoint [1] 291048 0
Assessed at baseline and at 12 weeks after intervention commencement.
Primary outcome [2] 291050 0
Change in haemostatic functions:
-reduction in prothrombotic and haemostatic/inflammatory factors such as von Willebrand Factor (vWF) antigen, platelet/granulocyte aggregates, thromboxane B2, whole blood aggregometry, fibrinogen, CRP, IL6, Factor VIII:c, Overall Haemostatic Potential (OHP) and cortisol at 12 weeks after intervention commencement.
Timepoint [2] 291050 0
Assessed at baseline and at 12 weeks after intervention commencement.
Primary outcome [3] 291051 0
Change in central macula thickness (CMT) as measured by Optical Coherence Tomography (OCT).
Timepoint [3] 291051 0
Assessed at baseline and at 12 weeks after intervention commencement.
Secondary outcome [1] 305890 0
Changes in metabolic variables: including glycaemic control, determined by glycosylated HbA1c, fasting plasma glucose, fasting insulin, number of patients taking insulin compared to baseline, insulin dose and other medications at 12 weeks after intervention commencement.
Timepoint [1] 305890 0
Assessed at baseline and at 12 weeks after intervention commencement.
Secondary outcome [2] 305891 0
Idenitification of disease biomarkers such as microRNA, fibrosis and oxidative stress biomarkers by collecting plasma from both the healthy volunteer group (control) and comparing microRNA, protein markers of fibrosis and oxidative stress between the 2 groups.
Timepoint [2] 305891 0
Assessed at baseline and at 12 weeks after intervention commencement.
Secondary outcome [3] 305892 0
Impact on the individual's quality of life as assessed by questionnaires - Quality of Life (QOL) and Pittsburgh Sleep Quality Index.
Timepoint [3] 305892 0
Assessed at baseline and at 12 weeks after intervention commencement.

Eligibility
Key inclusion criteria
1. Confirmed diagnosis of Type 1 diabetes for at least 10 years prior to informed consent;
2. Male and female participants must have optimal dose, or maximally tolerated dose of standard diabetes medication including ACE inhibitors/ARBs and diuretics (documented) such that minimal or no dose changes of other medications are required;
3. HbA1c greater than or equal to 7.0% and less than or equal to 9% at Visit 1 before entering the treatment period;
4. Mild non-proliferative retinopathy at Visit 1;
5. Participants must have ability to swallow pills.
6. Signed and dated written informed consent by date of Visit 1 in accordance with Good Clinical Practice (GCP) and local legislation.


Group 2: Control Group of healthy participants
Inclusion criteria:
- must not have been diagnosed with diabetes (type 1 or 2);
- have stable metabolic control (BP, lipids, blood sugar levels);
- Age 18-50 years;
- signed and dated written informed consent in accordance with Good Clinical Practice (GCP) and local legislation.
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Serum potassium level greater than 5.0 mmol/l;
2. Indication of renal dysfunction defined by serum creatinine greater than 220 µmol/L;
3. Indication of impaired renal function, defined as estimated glomerular filtration rate (eGFR) less than 45 ml/min/1.73m2;
4. Participants who have known allergy to aldosterone receptor antagonists or are currently taking an aldosterone receptor antagonist;
5. Participants enrolled in other trials or participation in the follow-up period of another trial;
6. Participants who have a contra-indication to cardiac MRI, including administration of gadolinium-based IV contrast;
7. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined during Visit 1;
8. Participants with significant vascular disease, stroke or TIA within 3 months prior to informed consent; co-existing cardiac disease including nonsinus rhythm, left bundle branch block, history of established epicardial CAD, previous revascularisation or previous myocardial infarction and severe hypertension greater than 180/110;
9. Participants with suboptimal echocardiographic image quality or ischaemia.
10. Known contraindications to eplerenone according to the local label;
11. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years;
12. Known blood dyscrasias or any disorders causing hemolysis or unstable red blood cell count (e.g. malaria, babesiosis, haemolytic anemia) due to the short lifespan of the RBC and its impact on HbA1c;
13.Current treatment with systemic steroids (orally taken or parenteral) at time of informed consent or change in dosage of thyroid hormones within 6 weeks prior to informed consent or any other uncontrolled endocrine disorder except T1D;
14. Premenopausal women (last menstruation =1 year prior to informed consent) who:
- are nursing or pregnant or
- are of childbearing potential and are not practicing an acceptable method of birth control, or do not plan to continue using this method throughout the trial and do not agree to submit to periodic pregnancy testing during participation in the trial. Acceptable methods of birth control include tubal ligation, transdermal patch, intra uterine devices/systems (IUDs/IUSs), oral, implantable or injectable contraceptives, complete sexual abstinence (if acceptable by local health authorities), double barrier method and vasectomised partner
15. Alcohol or drug abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to trial procedures or trial drug intake, in the judgment of the investigators.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Open-Label study, allocation is not concealed.

Patients with Type 1 diabetes who meet the eligibility criteria for the study will be identified from the RNSH Diabetes Clinic Registry and contacted by phone by one of the research team who will explain the study and answer questions. A copy of the Participant Information Sheet will be provided to participants to read and discuss with family and friends. Patients will attend the Diabetic Clinic where the informed consent form will be collected.

Participants in the control group will be recruited by advertisement (newspaper or noticeboards) and will only have the initial measurements.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Open label, non-randomised trial
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
There will be 2 groups – Participants with Type 1 diabetes for at least 10 years who will receive eplerenone. The second group is the Control Group, who do not receive eplerenone but are included to determine the features of healthy heart function and blood pressure in healthy individuals to compare the areas of the heart that are not working properly in Type 1 diabetic individuals and identify novel biomarkers.
Phase
Phase 4
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Currently there are no studies that have examined the impact of eplerenone on the hemodynamic, haemostatic and inflammatory factors and cardiac imaging measures we will be assessing in patients with type 1 diabetes.

Our pilot study will provide us with the magnitude of the treatment effect on each of these measures.

Intention-to-treat analysis for the various variables at completion of treatment compared to baseline.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/01/2014
Actual
Date of last participant enrolment
Anticipated
9/12/2014
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
40
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 1840 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 7626 0
2065 - Royal North Shore Hospital

Funding & Sponsors
Funding source category [1] 288403 0
Hospital
Name [1] 288403 0
Northern Sydney Local Health District
Country [1] 288403 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Pfizer Australia and New Zealand
Address
38-42 Wharf Road, West Ryde, NSW 2114
Country
Australia
Secondary sponsor category [1] 287103 0
None
Name [1] 287103 0
Address [1] 287103 0
Country [1] 287103 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 290282 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 290282 0
Research Office,
Level 13, Kolling Building,
Royal North Shore Hospital,
Pacific Highway, St. Leonards, NSW 2065
Ethics committee country [1] 290282 0
Australia
Date submitted for ethics approval [1] 290282 0
30/11/2013
Approval date [1] 290282 0
Ethics approval number [1] 290282 0

Summary
Brief summary
Type 1 diabetes (T1D) incidence is rising globally at a rate of 3–5% per year with patients having increased susceptibility to macrovascular complications and diabetic retinopathy a major microvascular complication of diabetes. Cardiovascular disease is the major cause of disability and death, with diabetic retinopathy the leading cause of blindness and significant burden to the individual and society. Current treatments target elevated blood glucose, high blood lipids and blood pressure, however diabetic patients continue to have 2- to 4-fold greater risk of a heart attack (MI), hence the optimum treatment for minimising this complication during diabetes has not yet been established, and additional treatment strategies are urgently needed.

Hormones of the renin-angiotensin-system (RAS) are key mediators of adverse complications in diabetes, with blockade of this system by medications known as angiotensin converting
enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are routinely used as therapy for diabetes; although there are mixed reports for their efficacy in diabetic retinopathy. We propose this variability is due to the action of aldosterone, another steroid hormone in the renin-angiotensin-aldosterone system (RAAS). Aldosterone exerts adverse actions via activation of mineralocorticoid receptors (MR), often referred to as “aldosterone receptors”. Our hypothesis is that adding a medication known as “aldosterone receptor” antagonist to standard treatment for T1D will delay or prevent
progression of complications of diabetes. Although this medication is used treat patients with heart failure and MI,
there are no clinical trials investigating this medication in T1D.

The design is open label, 9 week duration, proof-of-concept
study to assess the efficacy of the selective "aldosterone receptor" antagonist, eplerenone in T1D. Twenty patients with T1D will be recruited from the Diabetes clinic. They will have baseline measures within the first week and then receive eplerenone for 12 weeks in addition to standard treatment. The same measures are repeated in each patient at the end of the treatment period; hence the proof-of-concept is baseline versus treatment for each person. The patients will return 7 days after completing the study for routine clinical visit. A separate group of 20 age matched, healthy volunteers will be recruited for comparing the same measures to establish prognostic markers.

Our specific objectives are:
1. Prevent and arrest the complications of diabetes on cardiac structure and function, including platelet activation and reactivity and endothelial dysfunction;
2. Prevent progression to diabetic retinopathy;
3. Improve metabolic control;
4. Provide prognostic and predictive biomarkers for clinical
management.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 44834 0
Dr Anastasia Susie Mihailidou
Address 44834 0
Level 13 Kolling Building
Royal North Shore Hospital
Pacific Highway
St Leonards, NSW 2065
Country 44834 0
Australia
Phone 44834 0
+61 2 9926 4956
Fax 44834 0
+61 2 9926 4044
Email 44834 0
[email protected]
Contact person for public queries
Name 44835 0
Anastasia Susie Mihailidou
Address 44835 0
Level 13 Kolling Building
Royal North Shore Hospital
Pacific Highway
St Leonards, NSW 2065
Country 44835 0
Australia
Phone 44835 0
+61 2 9926 4956
Fax 44835 0
+61 2 9926 4044
Email 44835 0
[email protected]
Contact person for scientific queries
Name 44836 0
Anastasia Susie Mihailidou
Address 44836 0
Level 13 Kolling Building
Royal North Shore Hospital
Pacific Highway
St Leonards, NSW 2065
Country 44836 0
Australia
Phone 44836 0
+61 2 9926 4956
Fax 44836 0
+61 2 9926 4044
Email 44836 0
[email protected]

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

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No documents have been uploaded by study researchers.

Documents added automatically
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