Back to resultsEffects of Aliskiren and Amlodipine on the Renin-Angiotensin System (RAS) and Lipid/Carbohydrate Metabolism in Obese Patients With Hypertension
Primary Purpose
Hypertension, Abdominal Obesity
Status
Terminated
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Aliskiren
Amlodipine
Placebo of Aliskiren
Placebo of amlodipine
Sponsored by
About this trial
This is an interventional treatment trial for Hypertension focused on measuring Aliskiren, Renin-Angiotensin System (RAS), Hypertension, Abdominal obesity
Eligibility 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:
- 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
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Aliskiren
Amlodipine
Arm Description
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.
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
Outcomes
Primary Outcome Measures
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).
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).
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.
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.
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).
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.
Part 1: Renin Activity and Concentrations From Adipose and Skeletal Tissues During Aliskiren Treatment Period
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).
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).
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.
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.
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).
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).
Part 1: Renin Activity From Plasma During Aliskiren Treatment Period
Plasma Renin activity (PRC) was measured by a trapping PRA (tPRA) assay.
Part 1: Renin Activity From Plasma During Amlodipine Treatment Period
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
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
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
Part 2: Plasma Renin Concentration (PRC) Levels During Double Blind Treatment Period
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)
Part 2: Change From Baseline in Official Blood Pressure
Part 2: Renin Activity and Concentration of Aliskiren and Amlodipine in Fat and Skeletal Muscle Interstitial Fluid
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)
Part 2: Change From Baseline in Mitochondrial Mass in Subcutaneous Fat and Skeletal Muscle (Tissue Biopsies)
Part 2: Number of Participants With Reported Any Adverse Events, Serious Adverse Events and Death
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00498433
Brief Title
Effects of Aliskiren and Amlodipine on the Renin-Angiotensin System (RAS) and Lipid/Carbohydrate Metabolism in Obese Patients With Hypertension
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
Study Type
Interventional
2. Study Status
Record Verification Date
September 2014
Overall Recruitment Status
Terminated
Why Stopped
Early termination resulted from interim analysis of the ALTITUDE trial
Study Start Date
June 2007 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
March 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension, Abdominal Obesity
Keywords
Aliskiren, Renin-Angiotensin System (RAS), Hypertension, Abdominal obesity
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
46 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Aliskiren
Arm Type
Experimental
Arm Description
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.
Arm Title
Amlodipine
Arm Type
Active Comparator
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Aliskiren
Other Intervention Name(s)
SPP100
Intervention Description
300 mg tablet once daily
Intervention Type
Drug
Intervention Name(s)
Amlodipine
Intervention Description
5 mg capsule once daily
Intervention Type
Drug
Intervention Name(s)
Placebo of Aliskiren
Intervention Description
Matching placebo of aliskiren 300 mg tablet
Intervention Type
Drug
Intervention Name(s)
Placebo of amlodipine
Intervention Description
Matching placebo of amlodipine 5 mg capsule
Primary Outcome Measure Information:
Title
Part 1: Aliskiren Concentrations From Interstitial Fluid (Microdialysis)at the End of Aliskiren Treatment Period
Description
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).
Time Frame
Day 42
Title
Part 1: Amlodipine Concentrations From Interstitial Fluid (Microdialysis) at the End of Amlodipine Treatment Period
Description
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).
Time Frame
Day 98
Title
Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Aliskiren Treatment Period
Description
Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.
Time Frame
Day 42
Title
Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Amlodipine Treatment Period
Description
Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.
Time Frame
Day 98
Title
Part 1: Aliskiren Concentrations From Tissue at the End of Aliskiren Treatment Period
Description
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).
Time Frame
Day 42
Title
Part 1: Angiotensin II Levels From Tissue During Aliskiren Treatment Period
Description
Biopsies were taken from abdominal adipose and skeletal muscle tissue to determine Ang II concentration.
Time Frame
Day 42
Title
Part 1: Renin Activity and Concentrations From Adipose and Skeletal Tissues During Aliskiren Treatment Period
Time Frame
Day 42
Title
Part 1: Aliskiren Concentrations From Plasma at the End of Aliskiren Treatment Period
Description
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).
Time Frame
Day 42
Title
Part 1: Amlodipine Concentrations From Plasma at the End of Amlodipine Treatment Period
Description
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).
Time Frame
Day 98
Title
Part 1: Angiotensin II Levels in Plasma During Aliskiren Treatment Period
Description
Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.
Time Frame
Day 42
Title
Part 1: Angiotensin II Levels in Plasma During Amlodipine Treatment Period
Description
Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.
Time Frame
Day 98
Title
Part 1: Renin Concentrations From Plasma During Aliskiren Treatment Period
Description
Renin concentrations from plasma were measured as: plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration).
Time Frame
Day 42
Title
Part 1: Renin Concentrations From Plasma During Amlodipine Treatment Period
Description
Renin concentrations from plasma were measured as plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration).
Time Frame
Day 98
Title
Part 1: Renin Activity From Plasma During Aliskiren Treatment Period
Description
Plasma Renin activity (PRC) was measured by a trapping PRA (tPRA) assay.
Time Frame
Day 42
Title
Part 1: Renin Activity From Plasma During Amlodipine Treatment Period
Description
Plasma renin activity (PRC) was measured by a trapping PRA (tPRA) assay.
Time Frame
Day 98
Title
Part 2: Change From Baseline in Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Double Blind Treatment Period
Description
Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.
Time Frame
Placebo Baseline (Day 14), Active Treatment (Day 98)
Title
Part 2: Change From Baseline in Plasma Angiotensin II Levels During Double Blind Treatment Period
Description
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).
Time Frame
Placebo Baseline (Day 14), Active Treatment (Day 98)
Title
Part 2: Plasma Renin Activity (PRA) Concentration During Double Blind Treatment Period
Time Frame
Day 98
Title
Part 2: Plasma Renin Concentration (PRC) Levels During Double Blind Treatment Period
Time Frame
Day 98
Secondary Outcome Measure Information:
Title
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
Title
Part 2: Change From Baseline in Official Blood Pressure
Time Frame
Placebo Baseline (Day 14), Active Treatment (Day 98)
Title
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)
Title
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)
Title
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)
Title
Part 2: Number of Participants With Reported Any Adverse Events, Serious Adverse Events and Death
Time Frame
98 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility 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:
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis
Organizational Affiliation
Investigative site
Official's Role
Principal Investigator
Facility Information:
Facility Name
Novartis Investigative Site
City
Berlin-Buch
ZIP/Postal Code
13125
Country
Germany
Facility Name
Novartis Investigative Site
City
Hannover
ZIP/Postal Code
30159
Country
Germany
12. IPD Sharing Statement
Learn more about this trial
Effects of Aliskiren and Amlodipine on the Renin-Angiotensin System (RAS) and Lipid/Carbohydrate Metabolism in Obese Patients With Hypertension
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