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Comparison of Aliskiren and Amlodipine on Insulin Resistance and Endothelial Dysfunction in Patients With Hypertension and Metabolic Syndrome

Primary Purpose

High Blood Pressure, Metabolic Syndrome, Insulin Resistance

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Aliskiren
Amlodipine
Placebo Aliskiren
Placebo Amlodipine
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for High Blood Pressure focused on measuring High Blood pressure, Hypertension, metabolic syndrome, insulin resistance, endothelial dysfunction, pre-diabetic, amlodipine,, aliskiren,, IGT,, IFG,, MBF

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

  • Male or female adults aged 18 to 55 years, inclusive.
  • Sitting diastolic blood pressure ≥80 mm Hg and/or sitting systolic blood pressure ≥ 130 at screening.
  • Metabolic Syndrome as defined by the Adult Treatment Panel (ATP) III criteria.

  • Hypertension (defined above) and impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) plus one or more out of the remaining 3 criteria to satisfy entry into the study. IGT and IFG will be classified according to American Diabetes Association (ADA) guidelines:

    • IFG: Fasting plasma glucose of 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l)
    • IGT: Two-hour plasma glucose of 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l)
  • Abnormal Positron Emission Tomography (PET) results at baseline. (Myocardial Blood Flow (MBF) of less than or equal to 35%.)
  • Abnormal euglycemic clamp results at baseline. (Glucose infusion rate (GINF) of less than or equal to 4.2 mg/kg/min.)
  • Body mass index (BMI) of less than 40.

Exclusion criteria:

  • Smokers (use of tobacco products in the recent past)
  • Cardiovascular abnormalities including myocardial infarction, angina pectoris, hypertensive encephalopathy, stroke, transient ischemic attack, valvular heart disease, ventricular arrhythmia, A-V block, atrial fibrillation or cardiac revascularization/angioplasty in the past 12 months.
  • Symptoms or clinical evidence of congestive heart failure or known left ventricular ejection fraction < 40%.
  • Supine Blood pressure ≥ 160 mmHg systolic or ≥110 mmHg diastolic.
  • Clinically significant echocardiogram (ECG) abnormalities, including history of a prolonged QT-interval syndrome.
  • Significant autonomic dysfunction.
  • Severe bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated).
  • Clinically significant drug allergy, atopic allergy (asthma, urticaria, eczematous dermatitis).
  • Pregnant or breastfeeding females. Pre-menopausal females who are not practicing a non-hormonal method of birth control.
  • African Americans will not be eligible for this study.

Other protocol-defined inclusion/exclusion criteria may apply.

Sites / Locations

  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Aliskiren 300 mg

Amlodipine 5 mg

Arm Description

Eligible participants received oral Aliskiren 300 mg + Placebo Amlodipine once daily for 12 weeks. Study medication was taken with 200 mL of water in the morning. Breakfast was eaten 1 hour after taking study medication. Study medication was swallowed whole, and not chewed.

Eligible participants received oral Amlodipine 5 mg + Placebo Aliskiren once daily for 12 weeks. Study medication was taken with 200 mL of water in the morning. Breakfast was eaten 1 hour after taking study medication. Study medication was swallowed whole, and not chewed.

Outcomes

Primary Outcome Measures

Mean Change in Endothelial Function as Measured by Myocardial Blood Flow (MBF) From Baseline and After 12 Weeks of Treatment
MBF is measured by Positron Emission Tomography (PET) first at rest, then 45 minutes later, during cold pressor testing (CPT). The patient is placed in the PET scanner and injected with N-13 ammonia as a tracer. PET images are taken to assess myocardial blood flow at rest. After 40 minutes, the patient immerses one hand in ice water and PET images are taken to assess myocardial blood flow at sympathetic activation. Change from baseline data is analyzed by an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor.

Secondary Outcome Measures

Mean Change in Insulin Sensitivity as Measured by Glucose Infusion Rate (Last 30 Minutes) From Baseline and After 12 Weeks of Treatment.
Insulin sensitivity is measured by the hyperglycemic euglycemic clamp procedure where a supine patient has 2 IV lines inserted for sampling blood. Regular human insulin (60mU/m^2 surface area/min) is infused for 120 minutes. Dextrose (20% w/v) is infused to maintain glycemia at < 100 mg/dL and is adjusted based on plasma glucose levels obtained every 5 minutes. Blood for glucose and insulin is taken at specified time intervals. Change from baseline data is analyzed by analysis of variance model including treatment and week as fixed factors, and subject (nested in treatment) as a random factor.
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment
Insulin Concentration is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor.
Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment
C-peptide level is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor.
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment
Arterial Compliance is determined by Pulse Wave Analysis measured by a detector placed at the carotid artery while taking ECG and tonometry at the same time. Procedure is repeated for the femoral artery. Pulse Wave data are calculated by dividing distance between 2 arteries by the difference between the rise delay of the distal pulse wave and the R wave of the QRS complex and the rise delay of the proximal pulse wave to the QRS complex. Data analysis used an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor.

Full Information

First Posted
December 28, 2006
Last Updated
September 22, 2011
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00417170
Brief Title
Comparison of Aliskiren and Amlodipine on Insulin Resistance and Endothelial Dysfunction in Patients With Hypertension and Metabolic Syndrome
Official Title
A Double-blind, Double Dummy, Randomized Parallel Design Trial to Study the Effects of 12 Weeks of Treatment With 300mg Aliskiren vs. 5mg Amlodipine on Insulin Resistance and Endothelial Dysfunction in Hypertensive Patients With Metabolic Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
September 2011
Overall Recruitment Status
Completed
Study Start Date
October 2007 (undefined)
Primary Completion Date
July 2010 (Actual)
Study Completion Date
July 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study was to determine the effects of Aliskiren on insulin resistance (IR) and endothelial dysfunction (ED) in patients with high blood pressure and metabolic syndrome. The efficacy of Aliskiren was compared to Amlodipine.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
High Blood Pressure, Metabolic Syndrome, Insulin Resistance, Endothelial Dysfunction
Keywords
High Blood pressure, Hypertension, metabolic syndrome, insulin resistance, endothelial dysfunction, pre-diabetic, amlodipine,, aliskiren,, IGT,, IFG,, MBF

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Aliskiren 300 mg
Arm Type
Experimental
Arm Description
Eligible participants received oral Aliskiren 300 mg + Placebo Amlodipine once daily for 12 weeks. Study medication was taken with 200 mL of water in the morning. Breakfast was eaten 1 hour after taking study medication. Study medication was swallowed whole, and not chewed.
Arm Title
Amlodipine 5 mg
Arm Type
Active Comparator
Arm Description
Eligible participants received oral Amlodipine 5 mg + Placebo Aliskiren once daily for 12 weeks. Study medication was taken with 200 mL of water in the morning. Breakfast was eaten 1 hour after taking study medication. Study medication was swallowed whole, and not chewed.
Intervention Type
Drug
Intervention Name(s)
Aliskiren
Intervention Description
Aliskiren 300 mg tablets taken orally once daily
Intervention Type
Drug
Intervention Name(s)
Amlodipine
Intervention Description
Amlodipine 5 mg capsule taken orally once daily
Intervention Type
Drug
Intervention Name(s)
Placebo Aliskiren
Intervention Description
Placebo Aliskiren taken orally once daily.
Intervention Type
Drug
Intervention Name(s)
Placebo Amlodipine
Intervention Description
Placebo Amlodipine taken orally once daily
Primary Outcome Measure Information:
Title
Mean Change in Endothelial Function as Measured by Myocardial Blood Flow (MBF) From Baseline and After 12 Weeks of Treatment
Description
MBF is measured by Positron Emission Tomography (PET) first at rest, then 45 minutes later, during cold pressor testing (CPT). The patient is placed in the PET scanner and injected with N-13 ammonia as a tracer. PET images are taken to assess myocardial blood flow at rest. After 40 minutes, the patient immerses one hand in ice water and PET images are taken to assess myocardial blood flow at sympathetic activation. Change from baseline data is analyzed by an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor.
Time Frame
At baseline and after 12 weeks of treatment
Secondary Outcome Measure Information:
Title
Mean Change in Insulin Sensitivity as Measured by Glucose Infusion Rate (Last 30 Minutes) From Baseline and After 12 Weeks of Treatment.
Description
Insulin sensitivity is measured by the hyperglycemic euglycemic clamp procedure where a supine patient has 2 IV lines inserted for sampling blood. Regular human insulin (60mU/m^2 surface area/min) is infused for 120 minutes. Dextrose (20% w/v) is infused to maintain glycemia at < 100 mg/dL and is adjusted based on plasma glucose levels obtained every 5 minutes. Blood for glucose and insulin is taken at specified time intervals. Change from baseline data is analyzed by analysis of variance model including treatment and week as fixed factors, and subject (nested in treatment) as a random factor.
Time Frame
At baseline and after 12 weeks of treatment
Title
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment
Description
Insulin Concentration is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor.
Time Frame
At baseline and after 12 weeks of treatment
Title
Mean Change From Baseline in Inflammatory Marker ( C-peptide) as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment [Time Frame: At Baseline and After 12 Weeks of Treatment
Description
C-peptide level is determined by the Oral Glucose Tolerance Test (OGTT) which begins after a 10 hour overnight fast. Blood samples are taken at baseline and after an oral 75 gram dose of glucose. Additional samples of blood are taken to measure glucose and insulin levels at 30, 60, 120 and 180 minutes post glucose intake. Changes from pre-glucose intake values are analyzed by an analysis of variance (ANOVA) model including treatment, visit and post-dose time points ( 30, 60, 120 and 180 minutes) as fixed factors and subject (nested in treatment) as a random factor.
Time Frame
Baseline and after 12 weeks of treatment
Title
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment
Description
Arterial Compliance is determined by Pulse Wave Analysis measured by a detector placed at the carotid artery while taking ECG and tonometry at the same time. Procedure is repeated for the femoral artery. Pulse Wave data are calculated by dividing distance between 2 arteries by the difference between the rise delay of the distal pulse wave and the R wave of the QRS complex and the rise delay of the proximal pulse wave to the QRS complex. Data analysis used an analysis of variance (ANOVA) model including treatment and week as fixed factors and subject (nested in treatment) as a random factor.
Time Frame
At baseline and after 12 weeks of treatment

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: Male or female adults aged 18 to 55 years, inclusive. Sitting diastolic blood pressure ≥80 mm Hg and/or sitting systolic blood pressure ≥ 130 at screening. Metabolic Syndrome as defined by the Adult Treatment Panel (ATP) III criteria. Hypertension (defined above) and impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) plus one or more out of the remaining 3 criteria to satisfy entry into the study. IGT and IFG will be classified according to American Diabetes Association (ADA) guidelines: IFG: Fasting plasma glucose of 100 mg/dl (5.6 mmol/l) to 125 mg/dl (6.9 mmol/l) IGT: Two-hour plasma glucose of 140 mg/dl (7.8 mmol/l) to 199 mg/dl (11.0 mmol/l) Abnormal Positron Emission Tomography (PET) results at baseline. (Myocardial Blood Flow (MBF) of less than or equal to 35%.) Abnormal euglycemic clamp results at baseline. (Glucose infusion rate (GINF) of less than or equal to 4.2 mg/kg/min.) Body mass index (BMI) of less than 40. Exclusion criteria: Smokers (use of tobacco products in the recent past) Cardiovascular abnormalities including myocardial infarction, angina pectoris, hypertensive encephalopathy, stroke, transient ischemic attack, valvular heart disease, ventricular arrhythmia, A-V block, atrial fibrillation or cardiac revascularization/angioplasty in the past 12 months. Symptoms or clinical evidence of congestive heart failure or known left ventricular ejection fraction < 40%. Supine Blood pressure ≥ 160 mmHg systolic or ≥110 mmHg diastolic. Clinically significant echocardiogram (ECG) abnormalities, including history of a prolonged QT-interval syndrome. Significant autonomic dysfunction. Severe bronchospastic disease (including asthma and chronic obstructive pulmonary disease, treated or not treated). Clinically significant drug allergy, atopic allergy (asthma, urticaria, eczematous dermatitis). Pregnant or breastfeeding females. Pre-menopausal females who are not practicing a non-hormonal method of birth control. African Americans will not be eligible for this study. Other protocol-defined inclusion/exclusion criteria may apply.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Santa Monica
State/Province
California
ZIP/Postal Code
90404
Country
United States

12. IPD Sharing Statement

Learn more about this trial

Comparison of Aliskiren and Amlodipine on Insulin Resistance and Endothelial Dysfunction in Patients With Hypertension and Metabolic Syndrome

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