Evaluating the Effect of Aliskiren Versus HCTZ on Coronary Flow Reserve in Hypertensive Type II Diabetics

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of Tekturna (aliskiren), in combination with an ACE and calcium channel blocker in hypertensive patients diagnosed with Type II diabetes.

Detailed Description
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This study focuses on diabetic patients who are already on any blood pressure-lowering medication (excluding Tekturna) in addition to either an ACE inhibitor or an ARB (angiotensin receptor blocker) and still have a blood pressure greater than 130/80 mm Hg. The purpose of the study is to compare the effects of two different blood pressure treatment regimens, each containing three medications, on heart function in diabetics with uncontrolled hypertension. The two treatments are 1) lisinopril (an ACE inhibitor that works by reducing blood pressure) plus amlodipine (a calcium channel blocker that reduces blood pressure) plus aliskiren (a renin inhibitor, which also reduces blood pressure), or 2) lisinopril plus amlodipine plus hydrochlorothiazide (a diuretic, or water pill). Participants will have their coronary flow reserve - which is a measure of coronary vessel function, a predictor of future cardiovascular events - and a number of cardiovascular biomarkers in blood and urine at baseline and after 6 months of treatment. In this manner hydrochlorothiazide will be compared with aliskiren, which researchers think will have a better effect on heart artery blood flow.

Official Title
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A Prospective, Randomized, Open-label Clinical Trial to Evaluate the Effect of Tekturna (Aliskiren), Angiotensin Inhibitors, Diuretics, and Calcium Channel Blockers on Coronary Flow Reserve in Patients With Type II Diabetes and Hypertension

Conditions
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Hypertension, Diabetes Type 2

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Hydrochlorothiazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-85 Diagnosed with Type II Diabetes and Hypertension Taking either ACE or ARB in addition to any other antihypertensive medication excluding aliskiren Blood Pressure >130/80 Exclusion Criteria: Serum Potassium >5.2 mmol/L History of any cardiovascular event (stroke, TIA, unstable angina, CABG, percutaneous coronary intervention, hospitalization due to HF) during the 3 months prior to Visit 1. History of MI Documented ejection fraction of <50% Hypertension (at Screening): any patient with msSBP ≥ 180 mmHg or msDBP ≥ 110 mmHg Congestive Heart Failure NYHA class III and IV Concomitant treatment with two (2) or more renin-angiotensin-aldosterone system blocking agents, e.g. ACE inhibitor, ARB or aldosterone-antagonist. Unstable serum creatinine Second (II) or third (III) degree heart block without a pacemaker Concurrent potentially life threatening arrythmia or other uncontrolled arrythmia Clinically significant valvular heart disease Known renal artery stenosis Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of the study drugs including, but not limited to, any of the following: History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection (patients with previous bariatric surgery>6 months prior to Visit 1 are allowed to participate). Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase. Evidence of hepatic disease as determined by any one of the following: SGPT value exceeding 3x Upper Limit of Normal (ULN) at Visit 1, a history of hepatic encephalopathy, a history of cirrhosis, esophageal varices, or a history of portocaval shunt. History of malignancy other than basal cell skin cancer that is likely to reduce the subject's life span to less than 2 years. Any concurrent life threatening condition with a life expectancy less than 2 years History or evidence of drug or alcohol abuse with the last 12 months Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study. History of hypersensitively to any of the study drugs or to medications belonging to the same therapeutic class as the study drugs as well as known or suspected contraindications to the study drugs History of noncompliance to medical regimens or unwillingness to comply with the study protocol Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer Any condition that in the opinion of the investigator would jeopardized the evaluation of efficacy or safety Persons directly involved in the execution of this protocol Pregnant or nursing (lactating) women Women of Child Bearing Potential unless post menopausal for at least one year, surgically sterile or using effective methods of contraception as defined by local Health Authorities.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aliskiren<br>Aliskiren will be prescribed at 150mg po per day. If the subjects blood pressure is not controlled by week 5 the dose will be increased to 300mg po per day. Patients will be assigned to the treatment arm containing aliskiren. The prescribed drugs will include: Lisinopril 40mg + amlo 5mg + aliskiren 150-300mg | Drug: Aliskiren<br>* Aliskiren will be prescribed at 150mg po per day. If the subjects blood pressure is not controlled by week 5 the dose will be increased to 300mg po per day. All subjects will be prescribed lisinopril 40mg and amlodipine 5mg po daily.<br>* Other names: Tekturna;|
| Active Comparator: Hydrochlorothiazide<br>HCTZ will be prescribed at 12.5 po per day. If the subjects blood pressure is not controlled by week 5 the dose will be increased to 25mg po per day. Patients will be assigned to the treatment arm containing HCTZ. The prescribed drugs will include: Lisinopril 40mg + amlo 5mg + HCTZ 12.5-25mg | Drug: Hydrochlorothiazide<br>* Hydrochlorothiazide will be prescribed at 12.5 po per day. If the subjects blood pressure is not controlled by week 5 the dose will be increased to 25mg po per day. All subjects will be prescribed lisinopril 40mg and amlodipine 5mg po daily<br>* Other names: HCTZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is to assess the effect of a multimodal drug therapy regimen including the renin inhibitor Tekturna (aliskiren), an ACE inhibitor, and a calcium channel blocker on coronary flow reserve (CFR) in hypertensive Type II diabetics. | CFR will be assessed by a PET-based imaging technique. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary measures include evaluation of serum and urine biomarkers related to endothelial function, the renin-angiotensin system, oxidative stress, and inflammation. | Biomarkers include asymmetric dimethylarginine, B-type natriuretic peptide, plasma renin activity, high-sensitivity C-reactive protein, adiponectin, aldosterone, angiotensinogen, and hemoglobin A1c. | 6 months |