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

This study has been terminated.
(Early termination resulted from interim analysis of the ALTITUDE trial)
Sponsor:
Information provided by (Responsible Party):
Novartis
ClinicalTrials.gov Identifier:
NCT00498433
First received: July 8, 2007
Last updated: October 23, 2013
Last verified: October 2013
  Purpose

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.


Condition Intervention Phase
Hypertension
Abdominal Obesity
Drug: Aliskiren
Drug: Amlodipine
Drug: Placebo of Aliskiren
Drug: Placebo of amlodipine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Part 1: Aliskiren Concentrations From Interstitial Fluid (Microdialysis)at the End of Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    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).

  • Part 1: Amlodipine Concentrations From Interstitial Fluid (Microdialysis) at the End of Amlodipine Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]
    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).

  • Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

  • Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Amlodipine Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]
    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

  • Part 1: Aliskiren Concentrations From Tissue at the End of Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    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).

  • Part 1: Angiotensin II Levels From Tissue During Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Biopsies were taken from abdominal adipose and skeletal muscle tissue to determine Ang II concentration.

  • Part 1: Renin Activity and Concentrations From Adipose and Skeletal Tissues During Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
  • Part 1: Aliskiren Concentrations From Plasma at the End of Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    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).

  • Part 1: Amlodipine Concentrations From Plasma at the End of Amlodipine Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]
    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).

  • Part 1: Angiotensin II Levels in Plasma During Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

  • Part 1: Angiotensin II Levels in Plasma During Amlodipine Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]
    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

  • Part 1: Renin Concentrations From Plasma During Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Renin concentrations from plasma were measured as: plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration).

  • Part 1: Renin Concentrations From Plasma During Amlodipine Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]
    Renin concentrations from plasma were measured as plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration).

  • Part 1: Renin Activity From Plasma During Aliskiren Treatment Period [ Time Frame: Day 42 ] [ Designated as safety issue: No ]
    Plasma Renin activity (PRC) was measured by a trapping PRA (tPRA) assay.

  • Part 1: Renin Activity From Plasma During Amlodipine Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]
    Plasma renin activity (PRC) was measured by a trapping PRA (tPRA) assay.

  • Part 2: Change From Baseline in Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Double Blind Treatment Period [ Time Frame: Placebo Baseline (Day 14), Active Treatment (Day 98) ] [ Designated as safety issue: No ]
    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

  • Part 2: Change From Baseline in Plasma Angiotensin II Levels During Double Blind Treatment Period [ Time Frame: Placebo Baseline (Day 14), Active Treatment (Day 98) ] [ Designated as safety issue: No ]
    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).

  • Part 2: Plasma Renin Activity (PRA) Concentration During Double Blind Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]
  • Part 2: Plasma Renin Concentration (PRC) Levels During Double Blind Treatment Period [ Time Frame: Day 98 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Part 2: Microdialysis Metabolic Analytes in Response to Insulin Modified Frequently Sampled Intravenous Glucose Test [IM-FSIGT]for Each Tissue (Adipose or Skeletal Muscle) [ Time Frame: Day 14 and Day 98 ] [ Designated as safety issue: No ]
  • Part 2: Change From Baseline in Official Blood Pressure [ Time Frame: Placebo Baseline (Day 14), Active Treatment (Day 98) ] [ Designated as safety issue: No ]
  • Part 2: Renin Activity and Concentration of Aliskiren and Amlodipine in Fat and Skeletal Muscle Interstitial Fluid [ Time Frame: Placebo Baseline (Day 14), Active Treatment (Day 98) ] [ Designated as safety issue: No ]
  • 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) [ Time Frame: Placebo Baseline (Day 14), Active Treatment (Day 98) ] [ Designated as safety issue: No ]
  • Part 2: Change From Baseline in Mitochondrial Mass in Subcutaneous Fat and Skeletal Muscle (Tissue Biopsies) [ Time Frame: Placebo Baseline (Day 14), Active Treatment (Day 98) ] [ Designated as safety issue: No ]
  • Part 2: Number of Participants With Reported Any Adverse Events, Serious Adverse Events and Death [ Time Frame: 98 days ] [ Designated as safety issue: Yes ]

Enrollment: 46
Study Start Date: June 2007
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Aliskiren

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
300 mg tablet once daily
Other Name: SPP100
Drug: Placebo of Aliskiren
Matching placebo of aliskiren 300 mg tablet
Drug: Placebo of amlodipine
Matching placebo of amlodipine 5 mg capsule
Active Comparator: Amlodipine

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
5 mg capsule once daily
Drug: Placebo of Aliskiren
Matching placebo of aliskiren 300 mg tablet

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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:

    1. Patients with history of treated hypertension: msSBP/msDBP ≥ 135/85 mmHg and < 160/100 mmHg at baseline
    2. 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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00498433

Locations
Germany
Novartis Investigative Site
Berlin-Buch, Germany, 13125
Novartis Investigative Site
Hannover, Germany, 30159
Sponsors and Collaborators
Novartis
Investigators
Principal Investigator: Novartis Investigative site
  More Information

No publications provided

Responsible Party: Novartis
ClinicalTrials.gov Identifier: NCT00498433     History of Changes
Other Study ID Numbers: CSPP100A2238
Study First Received: July 8, 2007
Results First Received: March 21, 2013
Last Updated: October 23, 2013
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Novartis:
Aliskiren
Renin-Angiotensin System (RAS)
Hypertension
Abdominal obesity

Additional relevant MeSH terms:
Hypertension
Obesity
Obesity, Abdominal
Vascular Diseases
Cardiovascular Diseases
Overnutrition
Nutrition Disorders
Overweight
Body Weight
Signs and Symptoms
Amlodipine
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents

ClinicalTrials.gov processed this record on August 20, 2014