The Effects of Renin Inhibition on Fibrinolytic Balance and Endothelial Function

Study Overview
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Brief Summary
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Aliskiren (also called TekturnaTM) is a new drug for high blood pressure. Aliskiren works by blocking the actions of a substance called renin. Renin is a natural substance in the body that raises blood pressure. Renin is believed to contribute to the production of blood clots by increasing the amount of a substance known as Plasminogen Activator Inhibitor or PAI-1. This study will measure how aliskiren changes the amount of PAI-1 in the blood depending on the time of dosing. The purpose of this study is to find out if it is better to take aliskiren in the morning or at night.

Detailed Description
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Qualifying subjects will be withdrawn from RAAS blockers in a stepwise fashion over one to two weeks. All other blood pressure medications will be continued. If the subject's blood pressure rises above SBP > 170 or DBP > 120 at any time during the study, they will be excluded and the subject will restart their home medication(s). Week Two - Visit 2 - Post-taper visit: will be issued hydrochlorothiazide (25mg po, qd x 18 weeks, open label). All study medications will be taken daily between 7 and 10 AM. PAI-1 blood sample will be drawn. Pre-menopausal women will schedule this visit for when they have began their cycle. Week Four- Visit 3 - If their BP (> 120/60 mmHg), potassium (≤ 5.5 meq/dl) and renal function permit (Cr ≤ 1.5 mg/dl), they will be randomized to aliskiren (150 mg po, qd x 2 weeks) or placebo. If applicable, a urine pregnancy test will be done for child bearing age females. Week Six - Visit 4 - Titration visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check, and basic metabolic panel. If their BP, potassium and renal function permit, the medication will be increased to aliskiren (300 mg po, qd x 4 weeks) or placebo (double dose). If applicable, a urine pregnancy test will be done for child bearing age females. Week Eight - Visit 5 - Post-Titration visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check and basic metabolic panel. If their BP, potassium and renal function permit, they will remain on the current dose of aliskiren. Week 10 - Visit 6 - Study Day 1 - Patients will be admitted to the GCRC as an inpatient. They will be asked to lie supine for 24 hours with the head of their bed no higher than 10 degrees. They will have an interval history and physical. An IV catheter will be placed. After an initial void, they will begin a 24 hour urine creatinine, sodium and aldosterone. They will have a baseline BMP, high sensitivity C-Reactive Protein (hsCRP) and CBC. They will have blood drawn every 3 hours for PAI-1 antigen levels, plasma renin activity, plasma ACE activity, plasma aldosterone levels, plasma cortisol and melatonin. White blood cells will be harvested in PaxGene tubes for future extraction of white blood cell mRNA. They will be on a eucaloric, low sodium diet. At the end of the study day they will remain on their home medications, HCTZ (25mg po, qd), however they will stop their current blinded study medication (aliskiren or placebo). Subjects will have DNA banked from unused blood buffy coats. If applicable, UA pregnancy test will be performed by CRC nurses on admission. Washout Period - The reason for the washout period is four-fold. The washout period insures that drug is completely washed out of the system before initiation of placebo in the arm that received aliskiren first. This will allow the study to observe a placebo effect on blood pressure in the aliskiren first arm, in the event that there is one. It would also insure that that sufficient time has passed between SD1 and SD 2 to see the effect of placebo on hsCRP in the aliskerin first arm. From a safety standpoint, it insures that subjects have more than 8 weeks to recover their blood counts between study days, as a significant amount of blood is drawn on each study day. Fourth, as there is a menstrual variation in Pai-1 levels, it insures that pre-menopausal women participating in the study will be the same phase of their cycle on SD1 and SD2. Week 12 - Visit 7 - Mid-Washout visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check. If their BP permits (<170/120 mmHg) they will remain off study medication. If they are anemic (Hgb < 11) they will be started on iron supplementation. Week 16 - Visit 8 - Post-Washout visit: Subjects will return to the GCRC for an interval history, pill count, blood pressure check, BMP and CBC, if indicated. If BP and renal function permit, the patient will receive their crossover medication (placebo x 2 weeks or aliskiren 150mg po, qd x 2 weeks). If applicable, a urine pregnancy test will be done for child bearing age females. Week 18 - Visit 9 - Titration visit 2: Subjects will return to the GCRC for an interval history, pill count, blood pressure check, and basic metabolic panel, and CBC if indicated. If their BP, potassium and renal function permit, the medication will be increased to aliskiren (300 mg po, qd x 4 weeks) or placebo (double dose). Week 20 - Visit 10 - Post-Titration visit 2: Subjects will return to the GCRC for an interval history, pill count, blood pressure check and basic metabolic pane, and CBC if indicated. If their BP, potassium and renal function permit, they will remain on the current dose of aliskiren. If their Hgb ≥ 11 mg/dl, they will be able to participate in the final study day. Week 22 - Visit 11 - Study Day 2: Patients will be admitted to the GCRC as an inpatient. They will be asked to lie supine for 24 hours with the head of their bed no higher than 10 degrees. They will have an interval history and physical. An IV catheter will be placed. After an initial void, they will begin a 24 hour urine creatinine, sodium and aldosterone. They will have a baseline BMP, hsCRP, and CBC. They will have blood drawn every 3 hours for PAI-1 antigen levels, plasma renin activity, plasma ACE activity, plasma aldosterone levels, plasma cortisol and melatonin. White blood cells will be harvested in PaxGene tubes for future extraction of white blood cell mRNA. They will be on a eucaloric, low sodium diet. At the end of the study day they will remain on their home medications, and resume home medications that were previously stopped for study purposes. If applicable, UA pregnancy test will be performed by CRC nurses on admission.

Official Title
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The Effects of Renin Inhibition on Fibrinolytic Balance and Endothelial Function

Conditions
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High Blood Pressure

Intervention / Treatment
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* Drug: Aliskiren 150 mg
* Drug: Placebo
* Drug: HCTZ
* Drug: Aliskiren 300 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults 18-65 with hypertension Hypertension is defined as a systolic blood pressure at screening of ≥ 140, a diastolic blood pressure of ≥ 90, or a preexisting diagnosis of hypertension taking antihypertensive medication. If the subject is on anti-hypertensive medication, they can be included in the study, independent of the screening blood pressure. Exclusion Criteria: Serum potassium > 5.0 mmol/L (at the visit directly preceding Randomization) History of any cardiovascular event (stroke, TIA, MI, unstable angina, CABG, percutaneous coronary intervention, hospitalization due to HF) during the 3 months prior to Visit 1 or subsequent to enrollment. Malignant Hypertension (at Randomization): any patient with SBP > 170 mmHg or DBP > 120 mmHg Congestive heart failure NYHA class III and IV Unstable serum creatinine Second (II) or third (III) degree heart block without a pacemaker. Concurrent potentially life threatening arrhythmia or other uncontrolled arrhythmia. 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 3 x 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 within the past five years. Any concurrent life threatening condition with a life expectancy less than 2 years. History or evidence of drug or alcohol abuse within 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 hypersensitivity 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 jeopardize the evaluation of efficacy or safety. Persons directly involved in the execution of this protocol. Pregnant or nursing (lactating) women Transmeridian travel in the past 6 months Screening physical and lab findings consistent with the AHA/ADA metabolic syndrome criteria (3 of the following: BP ≥ 130/85 or on antihypertensive medications, waist size > 40 (m) > 35 (f), Fasting Glucose ≥ 100 mg/dl, Triglycerides ≥ 150 mg/dl, HDL <40 mg/dl (m) <50 mg/dl (f)) Smoking

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Diagnostic
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HCTZ plus Aliskiren then HCTZ and Placebo<br>HCTZ 25 mg plus Aliskiren 150mg for 2weeks. Aliskiren is increased to 300mg for 4 week if 150mg was tolerated. Then HCTZ 25 mg po plus Placebo | Drug: Aliskiren 150 mg<br>* Aliskiren 150 mg daily for 2 weeks<br>* Other names: Tekturna;Drug: Placebo<br>* Placebo tablet for Aliskerin<br>Drug: HCTZ<br>* HCTZ 25mg every day for 18 weeks<br>Drug: Aliskiren 300 mg<br>* Aliskiren 300 mg for 4 weeks<br>|
| Experimental: HCTZ and Placebo, then HCTZ and Aliskiren<br>HCTZ 25 mg po plus Placebo. Then HCTZ 25 mg plus Aliskiren 150mg for 2weeks. Aliskiren is increased to 300mg for 4 week if 150mg was tolerated. | Drug: Aliskiren 150 mg<br>* Aliskiren 150 mg daily for 2 weeks<br>* Other names: Tekturna;Drug: Placebo<br>* Placebo tablet for Aliskerin<br>Drug: HCTZ<br>* HCTZ 25mg every day for 18 weeks<br>Drug: Aliskiren 300 mg<br>* Aliskiren 300 mg for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Peak Plasma PAI-1 Level |  | baseline to 18 weeks | 
| Difference in Mean Plasma PAI-1 Level |  | baseline to 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in Mean Plasma Aldosterone Levels |  | baseline to 18 weeks | 
| Difference in Mean Changes in Plasma Renin Activity. |  | baseline to 18 weeks | 
| Difference in Mean Plasma Peak Aldosterone Levels |  | baseline to 18 weeks |