None listed
Conditions
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.
Interventions
Eplerenone 50mg orally once daily for 12 weeks
Proof-of-concept, non-randomized, open-label study.
Sponsors
Pfizer Australia and New Zealand
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to 50 Years
Healthy volunteers
Yes
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.
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.
Outcome results
None listed