Comparison of Aliskiren and Amlodipine on Insulin Resista... | NCT00417170

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Aliskiren 300 mg	Experimental	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.	Drug: Aliskiren Drug: Placebo Amlodipine
Amlodipine 5 mg	Active Comparator	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.	Drug: Amlodipine Drug: Placebo Aliskiren

Name	Type	Description	Arm Group Labels	Other Names
Aliskiren	Drug	Aliskiren 300 mg tablets taken orally once daily	Aliskiren 300 mg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	At baseline and after 12 weeks of treatment

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

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.

Name	Affiliation	Role
Novartis Pharmaceuticals	Novartis Pharmaceuticals	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Novartis Investigative Site		Santa Monica	California	90404	United States

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Aliskiren 300 mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.
FG001	Amlodipine 5 mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

ID	Title	Description
BG000	Aliskiren 300 mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.
BG001	Amlodipine 5 mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00023 BG00125 BG00248

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

The Pharmacodynamic (PD) analysis set includes all participants with available PD data and no major protocol deviation with impact on PD data. Participants with observations at both baseline and endpoint were included in the analysis.

Posted

Least Squares Mean

Standard Error

mL/g/min

At baseline and after 12 weeks of treatment

ID	Title	Description
OG000	Aliskiren 300 mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.
OG001	Amlodipine 5 mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.

Units	Counts
Participants	OG00021 OG00123

Title

Denominators

Categories

Title	Measurements
	OG0000.06± 0.39 OG0010.12± 0.39

Secondary

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.

Posted

Least Squares Mean

Standard Error

mg/kg/min

At baseline and after 12 weeks of treatment

ID	Title	Description
OG000	Aliskiren 300 mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.
OG001	Amlodipine 5 mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.

Secondary

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.

The Pharmacodynamic (PD) analysis set included all participants with available PD data and no major protocol deviation with impact on PD data. During different time points, participants with observations at that time point were included in the analysis.

Posted

Least Squares Mean

Standard Error

mU/L

At baseline and after 12 weeks of treatment

ID	Title	Description
OG000	Aliskiren 300 mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.
OG001	Amlodipine 5 mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.

Secondary

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.

The PD analysis set included all subjects with available PD data and no major protocol deviations with impact on PD data. During different time points, participants with observations at that time point were included in the analysis.

Posted

Least Squares Mean

Standard Error

ng/mL

Baseline and after 12 weeks of treatment

ID	Title	Description
OG000	Aliskiren 300 mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.
OG001	Amlodipine 5 mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.

Secondary

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.

Posted

Least Squares Mean

Standard Error

mmHg

At baseline and after 12 weeks of treatment

ID	Title	Description
OG000	Aliskiren 300 mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.
OG001	Amlodipine 5 mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Aliskiren 300mg	Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.			0	23	2	23
EG001	Amlodipine 5mg	Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.			0	25	6	25

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
OEDEMA PERIPHERAL	General disorders	MedDRA	Systematic Assessment	EG0000 affected23 at risk EG0012 affected25 at risk
UPPER RESPIRATORY TRACT INFECTION	Infections and infestations	MedDRA	Systematic Assessment	EG0002 affected23 at risk EG0011 affected25 at risk
GLUCOSE TOLERANCE INCREASED	Investigations	MedDRA	Systematic Assessment	EG0000 affected23 at risk EG0012 affected25 at risk
MUSCLE SPASMS	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected23 at risk EG0012 affected25 at risk

ID	Term
D006973	Hypertension
D024821	Metabolic Syndrome
D007333	Insulin Resistance
D018149	Glucose Intolerance

ID	Term
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D006946	Hyperinsulinism
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D006943	Hyperglycemia

ID	Term
D004095	Dihydropyridines
D011725	Pyridines
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds