The Effect of Aliskiren on Endothelial Function in Pre-Diabetes and Diabetes

Study Overview
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Brief Summary
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The purpose of this research is to study and determine the effects of Aliskiren on blood vessels and blood flow. The primary hypothesis is that Aliskiren will increase endothelial function by 30% or more in comparison to the placebo group.

Official Title
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The Effect of Aliskiren on Endothelial Function in Pre-Diabetes and Diabetes

Conditions
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Diabetes Type 2

Intervention / Treatment
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* Drug: Placebo
* Drug: Aliskiren


Participation Criteria
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Eligibility Criteria
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Group 1. Subjects At Risk of Developing Type 2 Diabetes INCLUSION CRITERIA Ages of 21-80 years Subjects at risk of developing type 2 Diabetes Mellitus (First degree relatives history of type 2 Diabetes Mellitus, History of gestational Diabetes, Known impaired glucose tolerance, Impaired fasting plasma glucose 100-126 mg/dl at the time of enrollment) EXCLUSION CRITERIA Treatment with Aliskiren (Tekturna) Smokers (use of tobacco products in the previous 3 months) Active or Uncontrolled Cardiovascular Disease Myocardial infarction, or angina within 12 months of study participation Arrhythmia (uncontrolled, highly symptomatic, requiring treatment or life-threatening) CHF (Class III and IV symptoms of heart failure on less than ordinary exertion or at rest) Stroke or Transient Ischemic Attack (TIA) within 12 months of study participation Uncontrolled Hypertension (SBP >180 mmHg or DBP >105 mmHg; 2 abnormal readings during visit) History of previous hypotensive episodes Liver Disease (AST, ALT, Alk Phos levels > 2x UNL) Renal Disease (creatinine > 1.7 mg/dL for women and >2.0 mg/dL for men and/or estimated GFR <30 mL/min, history of dialysis, nephrotic syndrome and known renovascular hypertension) at the time of enrollment Hyperkalemia (serum potassium >5.0 meq/L) Severe Dyslipidemia (TG > 600 mg/dL or Cholesterol >350 mg/dL) Any Other Serious Chronic Disease Requiring Active Treatment Females of Childbearing Potential Not Using an Effective Form of Birth Control as Determined by co-investigators Pregnancy Taking Any of the Following Medications: Systemic (not inhaled) Glucocorticoids Antineoplastic Agents Cyclosporine, Ketoconazole, Furosemide, Warfarin Bronchodilators (aminophyline, inhaled beta agonists) on a regular basis Patient is known to have a history of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result in the past History of drug or alcohol abuse within the 12months prior to dosing or evidence of such abuse as indicated by laboratory assays conducted during screening or baseline evaluations Group 2. Type 2 Diabetic Patients INCLUSION CRITERIA Ages of 21-80 years Type 2 Diabetes Mellitus stable and not expected to change during the study period EXCLUSION CRITERIA Treatment with Aliskiren (Tekturna) Smokers (use of tobacco products in the previous 3 months) Active or Uncontrolled Cardiovascular Disease Myocardial infarction, or angina within 12 months of study participation Arrhythmia (uncontrolled, highly symptomatic, requiring treatment or life-threatening) CHF (Class III and IV symptoms of heart failure on less than ordinary exertion or at rest) Stroke or Transient Ischemic Attack (TIA) within 12 months of study participation Uncontrolled Hypertension (SBP >180 mmHg or DBP >105 mmHg; 2 abnormal readings during visit) History of previous hypotensive episodes Liver Disease (AST, ALT, Alk Phos levels > 2x UNL) Renal Disease (creatinine > 1.7 mg/dL for women and >2.0 mg/dL for men and/or estimated GFR <30 mL/min, history of dialysis, nephrotic syndrome and known renovascular hypertension) at the time of enrollment Hyperkalemia (serum potassium >5.0 meq/L) Severe Dyslipidemia (TG > 600 mg/dL or Cholesterol >350 mg/dL) Any Other Serious Chronic Disease Requiring Active Treatment Females of Childbearing Potential Not Using an Effective Form of Birth Control as Determined by co-investigators Pregnancy Taking Any of the Following Medications: Systemic (not inhaled) Glucocorticoids Antineoplastic Agents Cyclosporine, Ketoconazole, Furosemide, Warfarin Bronchodilators (aminophyline, inhaled beta agonists) on a regular basis Patient is known to have a history of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) and/or positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result in the past History of drug or alcohol abuse within the 12months prior to dosing or evidence of such abuse as indicated by laboratory assays conducted during screening or baseline evaluations Severe proliferative retinopathy that renders the subject legally blinded Previous diagnosis of severe gastroparesis diabeticorum due to autonomic neuropathy that has necessitated hospital admission Presence of non-healing foot ulceration due to severe peripheral diabetic neuropathy Documented diabetic nephropathy manifested as macro-albuminuria, (2 of 3 urine specimens collected within a 3-6 month period with urine albumin>300 ug/mg creatinine

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* 0mg tablet, taken orally for 12 weeks daily<br>|
| Experimental: Aliskiren<br> | Drug: Aliskiren<br>* 150mg tablet, taken orally for 12 weeks daily<br>* Other names: Trade name: Tekturna;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Flow Mediated Vasodilation | Using ultrasound, percent change in brachial artery diameter is measured in response to an increase in shear stress from a tightened blood pressure cuff, which causes endothelium-dependent dilatation. | Baseline | 
| Flow Mediated Vasodilation | Using ultrasound, percent change in brachial artery diameter is measured in response to an increase in shear stress from a tightened blood pressure cuff, which causes endothelium-dependent dilatation. | 12 Weeks post-randomization | 
| Nitroglycerin Induced Dilation | Using ultrasound, images are taken pre- and post-vasodilation of the brachial artery induced with a 0.4mg tablet of NTG. | Baseline | 
| Nitroglycerine Induced Vasodilation | Using ultrasound, images are taken pre- and post-vasodilation of the brachial artery induced with a 0.4mg tablet of NTG. | 12 Weeks post-randomization | 
| Skin Blood Flow Before and After Iontophoresis With Acetylcholine and Sodium Nitroprusside | Laser doppler imaging is used to measure microcirculatory changes pre- and post-iontophoresis of acetylcholine and sodium nitroprusside. | Baseline | 
| Skin Blood Flow Before and After Iontophoresis With Acetylcholine and Sodium Nitroprusside | Laser doppler imaging is used to measure microcirculatory changes pre- and post-iontophoresis of acetylcholine (Ach) and sodium nitroprusside (NaNP). | 12 Weeks post-randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Biochemical Markers of Endothelial Function, sICAM-1, ng/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Biochemical Markers of Endothelial Function, sVCAM-1, ng/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Biochemical Markers of Endothelial Function, t-PAI, pg/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Biochemical Markers of Endothelial Function, C-reactive Protein, μg/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Biochemical Markers of Endothelial Function, E-Selectin, ng/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, Osteoprotegerin, pg/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, Osteopontin, ng/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, G-CSF, pg/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, GM-CSF pg/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, IL-8, pg/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, MCP-1 pg/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, MDC ng/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, sCD-40L ng/mL |  | 12 Weeks post-randomization | 
| Absolute Change in Inflammatory Cytokines and Growth Factors, TNFα, pg/mL |  | 12 Weeks post-randomization |