Trial to Investigate the Effect of Dapagliflozin on Ischemia Reperfusion Induced Endothelial Dysfunction

Study Overview
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Brief Summary
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The aim of the study is to investigate the effect of dapagliflozin or placebo on acetylcholine (Ach)- or nitroglycerin (GTN)-induced vasodilation of the forearm resistance vasculature, as determined by FBF measurement before and 10 minutes after 20 minutes of forearm ischemia.

Detailed Description
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The aim is to test the effect of dapagliflozin or placebo on ACh-induced vasodilatation of the forearm resistance vasculature as assessed by FBF measurement before and 10 min after a 20 min forearm ischemia as well as after a 14 day treatment period. The area under the dose-effect curve (AUC) of different ACh doses will be calculated and compared between treatment groups (dapagliflozin vs. placebo) and different time points (pre-ischemia vs. post-ischemia). FBF measurements will be made in response to increasing intra-arterial doses of ACh (25, 50, 100 nmol/min) to assess endothelial function or GTN (4, 8, 16 nmol/min) to test vascular smooth muscle vasodilator function.

Official Title
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A Randomized, Double - Blind, Placebo - Controlled Trial to Investigate the Effect of Dapagliflozin on Ischemia Reperfusion Induced Endothelial Dysfunction of the Forearm Vasculature in Healthy Male Subjects

Conditions
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Reperfusion Injury, Vascular Complications

Intervention / Treatment
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* Drug: Dapagliflozin 10mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subjects; 18 - 40 years of age Body mass index between 18 and 27 kg/m2 Written informed consent Normal findings in medical history Non-smoking Exclusion Criteria: Regular intake of any medication including OTC drugs and herbals within 2 weeks before IMP administration History of occlusive vascular diseases History of vascular anomalies History of coagulation disorders History of diabetes mellitus (Type 1&2) or pre-diabetes (i.e. HbA1c ≥ 5,7 %) History of kidney disease History of ketoacidosis Impaired liver function (AST, ALT, gGT, bilirubin >3 x ULN) Impaired renal function (serum creatinine > 1.3 mg/dl) Any other relevant deviation from the normal range in clinical chemistry, haematology or urine analysis HIV-1/2-Ab, HbsAg or HCV-Ab positive serology Systolic blood pressure above 145 mmHg, diastolic blood pressure above 95 mmHg Known allergy against any test agent under study and/or lactose intolerance Regular daily consumption of more than on litre of xanthine-containing beverages or more than 40g alcohol Participation in another clinical trial during the preceding 3 weeks

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomized, placebo-controlled, double-blind, parallel group, phase 1 trial. Subjects in study group A will receive a daily oral dose of 10 mg dapagliflozin for 14 days (until study day 15) Subjects in study group B will receive a 14 day treatment with placebo-dapagliflozin.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin<br>14 day orally treatment with dapagliflozin | Drug: Dapagliflozin 10mg<br>* Daily orally administration of 10mg dapagliflozin<br>* Other names: Forxiga 10mg Tabletten;|
| Placebo Comparator: Dapagliflozin-placebo<br>14 day orally treatment with dapagliflozin - placebo | Drug: Placebo<br>* Daily orally administration of 10mg dapagliflozin-placebo<br>* Other names: Placebo tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acetylcholine - Area under the curve forearm blood flow measurement | effect of dapagliflozin after a two weeks period of regular intake on forearm blood flow (FBF) reactivity in response to the vasodilators acetylcholine (ACh; endothelium-dependent agonist) or nitroglycerin (GTN; endothelium-independent vasodilator) | 14 days | 
| Acetylcholine - Area under the curve forearm blood flow measurement | acute effect of dapagliflozin on forearm blood flow (FBF) reactivity in response to the vasodilators acetylcholine (ACh; endothelium-dependent agonist) or nitroglycerin (GTN; endothelium-independent vasodilator) 10 min before (baseline) and after 20 min forearm ischemia, respectively. | 30 min | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dapagliflozin, forearm blood flow measurement, reperfusion injury, vascular function