Cognitive Function and Electrocardiogram (ECG) During Hypoglycemia and Blockade of the Renin-angiotensin System

Study Overview
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Brief Summary
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Hypothesis: Treating patients with type 1 diabetes with a certain antihypertensive drug preserve cerebral function during hypoglycaemia. Background: Studies have found that certain genetic variations leaves a subject with type 1 diabetes more prone to hypoglycaemia. It it thought to be a decline in cognition during hypoglycaemia that leaves them at risk of severe hypoglycaemia. The idea is tha when you suppress the genetic phenotype with a well known antihypertensive drug an improvement in cognition will occur and this will remove the patients tendency to severe hypoglycaemia. Methods: The investigators want to explore whether the cerebral function is improved during hypoglycaemia in subjects with type 1 diabetes and the above mentioned genetic variation when treated with the antihypertensive drug Candesartan.

Detailed Description
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We will include 25 type 1 diabetic patients from our outpatient clinic. They are already genotyped from another trial. Each patient goes through two cycles with hyperinsulinemic glucose clamp induced hypoglycemia. The study is double blinded, randomised and placebocontrolled so the patients receive both Candesartan and placebo but in different cycles. In each cycle patients will receive either Candesartan or placebo for 7 days. After 8 days patients undergo a hypoglycaemic clamp during which primary and secondary endpoints will be measured. In the hyperinsulinemic hypoglycaemic clamp the patients will undergo an adjustment period towards euglycaemia. A period of approximately 1 hour of euglycemia, an hour of hypoglycemia and a period of recovery towards euglycemia. In each of these glycemic states primary and secondary outcomes will be measured.

Official Title
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Influence of Blockade of the Renin-angiotensin System for Preservation of Cognitive Function, Hormonal Counter-regulatory Response, Symptomatology and Cardiac Repolarisation During Hypoglycaemia in Patients With Type 1 Diabetes

Conditions
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Type 1 Diabetes, Hypoglycemia

Intervention / Treatment
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* Drug: Angiotensin II receptor antagonists (Candesartan)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes Danish spoken and written RAS activity score>7 - diabetes duration > 5 years not pregnant and safe anticonception Signed informed consent. Exclusion Criteria: Treatment with an ACE blocker An ARB og a renin blocker Treatment with other antihypertensive drugs Severe diabetic late complications Renal impairment Pregnancy and breastfeeding Previous reactions to study medication Heart insufficiency (NYHA 3-4)\ Known ischaemic heart disease Epilepsy Alcohol and drug abuse Suspicion of non-compliance, Plasma potassium < 3.5 mmol/l or >5.0 mmol/l.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Candesartan<br> | Drug: Angiotensin II receptor antagonists (Candesartan)<br>* Seven days of treatment with Candesartan 32 mg, capsules.<br>* Other names: Ratacand;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo Capsule matching the active comparator. Given for 7 days once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive function and brain cortical activity assessed by EEG |  | 2 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptoms of hypoglycaemia assessed by Edinburgh Hypoglycaemia Symptom Score questionnaire |  | 2 month | 
| Hormonal counter-regulatory response and substrates |  | 2 month | 
| Blood pressure and pulse |  | 2 month | 
| Cardiac conduction evaluated by a three channel digital Holter Monitor. |  | 2 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Type 1 diabetes, Hypoglycaemia, genetic susceptibility, Renin angiotensin system activity