Trial Outcomes & Findings for Comparison of Aliskiren and Amlodipine on Insulin Resistance and Endothelial Dysfunction in Patients With Hypertension and Metabolic Syndrome (NCT NCT00417170)

NCT ID: NCT00417170

Last Updated: 2011-09-26

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 48 participants
• Primary outcome timeframe: At baseline and after 12 weeks of treatment
• Results posted on: 2011-09-26

Participant Flow

Screening for eligibility took place up to 6 weeks prior to study start. Participants stopped taking all medications during the 6 week screening period and washed out of all medications, including antihypertensive medication prior to randomization and start of study dosing.

Participant milestones

Measure	Aliskiren 300 mg Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
Overall Study STARTED	23	25
Overall Study Pharmacodynamics Population	21	23
Overall Study COMPLETED	21	22
Overall Study NOT COMPLETED	2	3

Reasons for withdrawal

Measure	Aliskiren 300 mg Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
Overall Study Adverse Event	1	1
Overall Study Withdrawal by Subject	1	1
Overall Study Lost to Follow-up	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Aliskiren 300 mg n=23 Participants Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg n=25 Participants Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.	Total n=48 Participants Total of all reporting groups
Age Continuous	45.0 years STANDARD_DEVIATION 11.3 • n=5 Participants	44.1 years STANDARD_DEVIATION 5.3 • n=7 Participants	44.5 years STANDARD_DEVIATION 8.6 • n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	8 Participants n=7 Participants	24 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	17 Participants n=7 Participants	24 Participants n=5 Participants

PRIMARY outcome

Timeframe: At baseline and after 12 weeks of treatment

Population: 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.

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.

Outcome measures

Measure	Aliskiren 300 mg n=21 Participants Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg n=23 Participants Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
Mean Change in Endothelial Function as Measured by Myocardial Blood Flow (MBF) From Baseline and After 12 Weeks of Treatment	0.06 mL/g/min Standard Error 0.39	0.12 mL/g/min Standard Error 0.39

SECONDARY outcome

Timeframe: At baseline and after 12 weeks of treatment

Population: 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.

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.

Outcome measures

Measure	Aliskiren 300 mg n=21 Participants Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg n=22 Participants Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
Mean Change in Insulin Sensitivity as Measured by Glucose Infusion Rate (Last 30 Minutes) From Baseline and After 12 Weeks of Treatment.	0.23 mg/kg/min Standard Error 0.379	0.55 mg/kg/min Standard Error 0.371

SECONDARY outcome

Timeframe: At baseline and after 12 weeks of treatment

Population: 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.

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.

Outcome measures

Measure	Aliskiren 300 mg n=21 Participants Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg n=23 Participants Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment 0 minutes (n=21, 23)	3.54 mU/L Standard Error 14.666	-3.08 mU/L Standard Error 14.014
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment 30 minutes (n=17, 21)	31.26 mU/L Standard Error 15.748	-15.46 mU/L Standard Error 14.436
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment 60 minutes (n=19, 22)	16.71 mU/L Standard Error 15.169	-27.87 mU/L Standard Error 14.231
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment 120 minutes (n=17, 19)	33.27 mU/L Standard Error 15.745	-52.67 mU/L Standard Error 14.930
Mean Change in Insulin Concentration as Measured During Oral Glucose Tolerance Test (OGTT) From Baseline and After 12 Weeks of Treatment 180 minutes (n=19, 22)	22.96 mU/L Standard Error 15.144	-43.58 mU/L Standard Error 14.231

SECONDARY outcome

Timeframe: Baseline and after 12 weeks of treatment

Population: 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.

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.

Outcome measures

Measure	Aliskiren 300 mg n=21 Participants Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg n=23 Participants Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
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 0 minutes ( n = 21, 23)	0.302 ng/mL Standard Error 0.3891	-0.215 ng/mL Standard Error 0.3718
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 30 minutes ( n= 20, 22)	0.862 ng/mL Standard Error 0.3987	-0.888 ng/mL Standard Error 0.3802

SECONDARY outcome

Timeframe: At baseline and after 12 weeks of treatment

Population: 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.

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.

Outcome measures

Measure	Aliskiren 300 mg n=20 Participants Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5 mg n=21 Participants Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment Central Systolic Blood Pressure	-17.7 mmHg Standard Error 2.22	-11.1 mmHg Standard Error 2.19
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment Central Mean Pressure	-1.39 mmHg Standard Error 0.158	-0.85 mmHg Standard Error 0.156
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment Central Diastolic Blood Pressure	-11.0 mmHg Standard Error 1.38	-6.3 mmHg Standard Error 1.36
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment Systolic Blood Pressure (Peripheral)	-16.2 mmHg Standard Error 2.15	-10.0 mmHg Standard Error 2.12
Mean Change in Arterial Compliance as Measured by Pulse Wave Analysis From Baseline and After 12 Weeks of Treatment Diastolic Blood Pressure (Peripheral)	-10.6 mmHg Standard Error 1.34	-6.0 mmHg Standard Error 1.32

Adverse Events

Aliskiren 300mg

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Amlodipine 5mg

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Aliskiren 300mg n=23 participants at risk Aliskiren 300 mg + Placebo Amlodipine orally once daily for 12 weeks.	Amlodipine 5mg n=25 participants at risk Amlodipine 5 mg + Placebo Aliskiren orally once daily for 12 weeks.
General disorders OEDEMA PERIPHERAL	0.00% 0/23	8.0% 2/25
Infections and infestations UPPER RESPIRATORY TRACT INFECTION	8.7% 2/23	4.0% 1/25
Investigations GLUCOSE TOLERANCE INCREASED	0.00% 0/23	8.0% 2/25
Musculoskeletal and connective tissue disorders MUSCLE SPASMS	0.00% 0/23	8.0% 2/25

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Results disclosure agreements

• Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
• Publication restrictions are in place

Restriction type: OTHER