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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]

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

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Cardiovascular

Other cardiovascular diseases

Eye

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]

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]

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]

Assessed at baseline and at 12 weeks after intervention commencement.

Primary outcome [2]

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]

Assessed at baseline and at 12 weeks after intervention commencement.

Primary outcome [3]

Change in central macula thickness (CMT) as measured by Optical Coherence Tomography (OCT).

Timepoint [3]

Assessed at baseline and at 12 weeks after intervention commencement.

Secondary outcome [1]

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]

Assessed at baseline and at 12 weeks after intervention commencement.

Secondary outcome [2]

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]

Assessed at baseline and at 12 weeks after intervention commencement.

Secondary outcome [3]

Impact on the individual's quality of life as assessed by questionnaires - Quality of Life (QOL) and Pittsburgh Sleep Quality Index.

Timepoint [3]

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]

Royal North Shore Hospital - St Leonards

Recruitment postcode(s) [1]

2065 - Royal North Shore Hospital

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Northern Sydney Local Health District

Address [1]

Royal North Shore Hospital
Reserve Road, St Leonards,
NSW 2065

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Not yet submitted

Ethics committee name [1]

Northern Sydney Local Health District Human Research Ethics Committee

Ethics committee address [1]

Research Office, 
Level 13, Kolling Building, 
Royal North Shore Hospital, 
Pacific Highway, St. Leonards, NSW 2065

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

30/11/2013

Approval date [1]

Ethics approval number [1]

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

Dr Anastasia Susie Mihailidou

Address

Level 13 Kolling Building
Royal North Shore Hospital
Pacific Highway
St Leonards, NSW 2065

Country

Australia

Phone

+61 2 9926 4956

Fax

+61 2 9926 4044

Email

[email protected]

Contact person for public queries

Name

Anastasia Susie Mihailidou

Address

Level 13 Kolling Building
Royal North Shore Hospital
Pacific Highway
St Leonards, NSW 2065

Country

Australia

Phone

+61 2 9926 4956

Fax

+61 2 9926 4044

Email

[email protected]

Contact person for scientific queries

Name

Anastasia Susie Mihailidou

Address

Level 13 Kolling Building
Royal North Shore Hospital
Pacific Highway
St Leonards, NSW 2065

Country

Australia

Phone

+61 2 9926 4956

Fax

+61 2 9926 4044

Email

[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

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.