Effects of Aliskiren and Amlodipine on the Renin-Angiotensin System (RAS) and Lipid/Carbohydrate Metabolism in Obese Patients With Hypertension

Study Overview
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Brief Summary
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Part 1 determined: aliskiren, amlodipine and angiotensin II concentrations in interstitial fluid of fat and skeletal muscle; aliskiren and angiotensin II concentrations, and renin activity and concentration in fat and skeletal muscle tissues (biopsies); aliskiren, amlodipine and angiotensin II concentrations, and renin activity and concentration in plasma. Part 2 investigated the potential for aliskiren to modulate renin-angiotensin-aldosterone system (RAAS) activity, and lipid/carbohydrate metabolism in adipose and skeletal muscle tissue in obese patients with hypertension in comparison to amlodipine.

Official Title
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Part 1: An Open Label Pilot Study to Determine Interstitial and Tissue Concentrations of Aliskiren and Effects on the Renin- Angiotensin System (RAS) in Fat and Skeletal Muscle of Hypertensive Patients With Abdominal Obesity. Part 2: A Randomized, Double Blind, 12-weeks Parallel Group Study to Compare Effects of Aliskiren 300 mg and Amlodipine 5 mg on the RAS and Lipid/Carbohydrate Metabolism in Fat and Skeletal Muscle of Hypertensive Patients With Abdominal Obesity

Conditions
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Hypertension, Abdominal Obesity

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Amlodipine
* Drug: Placebo of Aliskiren
* Drug: Placebo of amlodipine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: PART 1: Male and female patients 20 to 65 years of age with a diagnosis of hypertension and with abdominal obesity (waist circumference ≥ 102 cm in men and ≥ 88 cm in women) For patients with a history of treated hypertension, mean sitting systolic blood pressure (msSBP)/ mean sitting diastolic blood pressure (msDBP) had to be ≥ 120/80 mmHg and ≤ 160/100 mm Hg. For patients with newly diagnosed, untreated hypertension msSBP/msDBP had to be ≥ 135/85 mmHg and ≤ 160/100 mm Hg Pulse rate 40 - 90 bpm PART 2: Male and female patients 18 to 65 years of age , with a diagnosis of hypertension and with abdominal obesity (waist circumference ≥ 102 cm in men and ≥ 88 cm in women) Systolic and diastolic blood pressure and pulse rate were assessed after the patient had rested for at least five (5) minutes. Vital signs had to be within the following ranges: Patients with history of treated hypertension: msSBP/msDBP ≥ 135/85 mmHg and < 160/100 mmHg at baseline Patients with newly diagnosed, untreated hypertension: msSBP/msDBP ≥ 135/85 mmHg and < 160/100 mmHg at screening and baseline. Exclusion criteria: PART 1 Hypertension Grade 2 (msSBP ≥ 160 mmHg) or Grade 3 (msDBP ≥ 110 mmHg and/or msSBP ≥ 180 mmHg) WHO classification Current treatment with three or more antihypertensive drugs. PART 2 Hypertension Grade 2 (msSBP ≥ 160 and/or msDBP ≥ 100 mmHg). Current treatment with three or more antihypertensive drugs. Other protocol-defined inclusion/exclusion criteria applied

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aliskiren<br>Part 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase (period 1) consisting of treatment with one tablet of placebo to aliskiren once daily (o.d.). This was followed by a 4 week treatment phase (period 2) consisting of treatment with 300 mg aliskiren o.d.. Part 2: Eligible randomized patients in this arm received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks. | Drug: Aliskiren<br>* 300 mg tablet once daily<br>* Other names: SPP100;Drug: Placebo of Aliskiren<br>* Matching placebo of aliskiren 300 mg tablet<br>Drug: Placebo of amlodipine<br>* Matching placebo of amlodipine 5 mg capsule<br>|
| Active Comparator: Amlodipine<br>Part 1: After aliskiren treatment (period 2), each patient was entered into a second washout period (4 weeks) during which blood pressure was required to be ≤ 140/90 mmHg. If blood pressure exceeded 140/90 mmHg on two consecutive days (home monitoring) and was confirmed at the study center, the patient was entered into the amlodipine treatment period (period 3). In period 3, all patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks. Part 2: Eligible patients randomized to part 2 received amlodipine 5 mg o.d. and aliskiren placebo for 12 weeks | Drug: Amlodipine<br>* 5 mg capsule once daily<br>Drug: Placebo of Aliskiren<br>* Matching placebo of aliskiren 300 mg tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Aliskiren Concentrations From Interstitial Fluid (Microdialysis)at the End of Aliskiren Treatment Period | Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method. Interstitial fluid was collected for measurements of drug concentrations on the last day of the aliskiren treatment periods (Day 42). | Day 42 | 
| Part 1: Amlodipine Concentrations From Interstitial Fluid (Microdialysis) at the End of Amlodipine Treatment Period | Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method. Interstitial fluid was collected for measurements of drug concentration on the last day of the amlodipine treatment periods (Day 98). | Day 98 | 
| Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Aliskiren Treatment Period | Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration. | Day 42 | 
| Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Amlodipine Treatment Period | Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration. | Day 98 | 
| Part 1: Aliskiren Concentrations From Tissue at the End of Aliskiren Treatment Period | Biopsies were taken from abdominal adipose and skeletal muscle tissue to determine aliskiren concentration. Tissue biopsy samples for drug concentrations analyses were taken on the last day of the aliskiren treatment periods (Day 42). | Day 42 | 
| Part 1: Angiotensin II Levels From Tissue During Aliskiren Treatment Period | Biopsies were taken from abdominal adipose and skeletal muscle tissue to determine Ang II concentration. | Day 42 | 
| Part 1: Renin Activity and Concentrations From Adipose and Skeletal Tissues During Aliskiren Treatment Period |  | Day 42 | 
| Part 1: Aliskiren Concentrations From Plasma at the End of Aliskiren Treatment Period | Plasma samples were obtained for measurement of aliskiren or amlodipine concentrations. All blood samples were taken by an indwelling cannula inserted in a forearm vein or direct venipuncture. The plasma samples for drug concentrations analyses were taken on the last day of the aliskiren treatment periods (Day 42). | Day 42 | 
| Part 1: Amlodipine Concentrations From Plasma at the End of Amlodipine Treatment Period | Plasma samples were obtained for measurement of aliskiren or amlodipine concentrations. All blood samples were taken by an indwelling cannula inserted in a forearm vein or direct venipuncture. The plasma samples for drug concentrations analyses were taken on the last day of the amlodipine treatment periods (Day 98). | Day 98 | 
| Part 1: Angiotensin II Levels in Plasma During Aliskiren Treatment Period | Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration. | Day 42 | 
| Part 1: Angiotensin II Levels in Plasma During Amlodipine Treatment Period | Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration. | Day 98 | 
| Part 1: Renin Concentrations From Plasma During Aliskiren Treatment Period | Renin concentrations from plasma were measured as: plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration). | Day 42 | 
| Part 1: Renin Concentrations From Plasma During Amlodipine Treatment Period | Renin concentrations from plasma were measured as plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration). | Day 98 | 
| Part 1: Renin Activity From Plasma During Aliskiren Treatment Period | Plasma Renin activity (PRC) was measured by a trapping PRA (tPRA) assay. | Day 42 | 
| Part 1: Renin Activity From Plasma During Amlodipine Treatment Period | Plasma renin activity (PRC) was measured by a trapping PRA (tPRA) assay. | Day 98 | 
| Part 2: Change From Baseline in Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Double Blind Treatment Period | Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration. | Placebo Baseline (Day 14), Active Treatment (Day 98) | 
| Part 2: Change From Baseline in Plasma Angiotensin II Levels During Double Blind Treatment Period | Plasma Ang II was measured prior to and 1 hour after the Insulin modified-frequently sampled intravenous glucose tolerance test (IM-FSIGT) during placebo treatment (Days 14) and active treatment(Day 98). | Placebo Baseline (Day 14), Active Treatment (Day 98) | 
| Part 2: Plasma Renin Activity (PRA) Concentration During Double Blind Treatment Period |  | Day 98 | 
| Part 2: Plasma Renin Concentration (PRC) Levels During Double Blind Treatment Period |  | Day 98 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Microdialysis Metabolic Analytes in Response to Insulin Modified Frequently Sampled Intravenous Glucose Test [IM-FSIGT]for Each Tissue (Adipose or Skeletal Muscle) |  | Day 14 and Day 98 | 
| Part 2: Change From Baseline in Official Blood Pressure |  | Placebo Baseline (Day 14), Active Treatment (Day 98) | 
| Part 2: Renin Activity and Concentration of Aliskiren and Amlodipine in Fat and Skeletal Muscle Interstitial Fluid |  | Placebo Baseline (Day 14), Active Treatment (Day 98) | 
| Part 2: Change From Baseline in Peripheral Insulin Sensitivity in Response to Insulin Modified Frequently Sampled Intravenous Glucose Test [IM-FSIGT]for Each Tissue (Adipose or Skeletal Muscle) |  | Placebo Baseline (Day 14), Active Treatment (Day 98) | 
| Part 2: Change From Baseline in Mitochondrial Mass in Subcutaneous Fat and Skeletal Muscle (Tissue Biopsies) |  | Placebo Baseline (Day 14), Active Treatment (Day 98) | 
| Part 2: Number of Participants With Reported Any Adverse Events, Serious Adverse Events and Death |  | 98 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Aliskiren, Renin-Angiotensin System (RAS), Hypertension, Abdominal obesity