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

NCT00498433 | Terminated Phase 2 Results DMC

• 1 other identifier: CSPP100A2238
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 2

Brief Summary

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.

Conditions

Hypertension; Abdominal Obesity

Keywords

Aliskiren; Renin-Angiotensin System (RAS); Hypertension; Abdominal obesity

Outcome Measures

Primary Outcomes (19)

• 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 Outcomes (6)

• 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)

Study Arms (2)

Aliskiren

EXPERIMENTAL

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; Drug: Placebo of Aliskiren; Drug: Placebo of amlodipine

Amlodipine

ACTIVE COMPARATOR

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; Drug: Placebo of Aliskiren

Interventions

Aliskiren DRUG

300 mg tablet once daily

Also known as: SPP100

Aliskiren

Amlodipine DRUG

5 mg capsule once daily

Amlodipine

Placebo of Aliskiren DRUG

Matching placebo of aliskiren 300 mg tablet

Aliskiren; Amlodipine

Placebo of amlodipine DRUG

Matching placebo of amlodipine 5 mg capsule

Aliskiren

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis: lead

Study Sites (2)

Novartis Investigative Site

Buch, 13125, Germany

Location

Novartis Investigative Site

Hanover, 30159, Germany

Location

MeSH Terms

Conditions

Hypertension; Obesity, Abdominal

Interventions

aliskiren; Amlodipine

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Obesity; Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis

  Investigative site

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 8, 2007
• First Posted: July 10, 2007
• Study Start: June 1, 2007
• Primary Completion: March 1, 2012
• Study Completion: March 1, 2012
• Last Updated: September 10, 2014
• Results First Posted: October 24, 2013

Record last verified: 2014-09

Locations

DE (2)