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

• Sponsor: Novartis (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00498433
• Collaborator: (none)
• Enrollment: 46
• Locations: 2
• Arms: 2
• Duration (Months): 57
• Patients Per Site: 23
• Patients Per Site Per Month: 0.4

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertension; Abdominal Obesity	Drug: Aliskiren; Drug: Amlodipine; Drug: Placebo of Aliskiren; Drug: Placebo of amlodipine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, 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
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
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 Names: 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

Outcome Measures

Primary Outcome Measures

1. Part 1: Aliskiren Concentrations From Interstitial Fluid (Microdialysis)at the End of Aliskiren Treatment Period [Day 42]

   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).

2. Part 1: Amlodipine Concentrations From Interstitial Fluid (Microdialysis) at the End of Amlodipine Treatment Period [Day 98]

   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).

3. Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Aliskiren Treatment Period [Day 42]

   Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

4. Part 1: Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Amlodipine Treatment Period [Day 98]

   Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

5. Part 1: Aliskiren Concentrations From Tissue at the End of Aliskiren Treatment Period [Day 42]

   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).

6. Part 1: Angiotensin II Levels From Tissue During Aliskiren Treatment Period [Day 42]

   Biopsies were taken from abdominal adipose and skeletal muscle tissue to determine Ang II concentration.

7. Part 1: Renin Activity and Concentrations From Adipose and Skeletal Tissues During Aliskiren Treatment Period [Day 42]

8. Part 1: Aliskiren Concentrations From Plasma at the End of Aliskiren Treatment Period [Day 42]

   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).

9. Part 1: Amlodipine Concentrations From Plasma at the End of Amlodipine Treatment Period [Day 98]

   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).

10. Part 1: Angiotensin II Levels in Plasma During Aliskiren Treatment Period [Day 42]

    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

11. Part 1: Angiotensin II Levels in Plasma During Amlodipine Treatment Period [Day 98]

    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

12. Part 1: Renin Concentrations From Plasma During Aliskiren Treatment Period [Day 42]

    Renin concentrations from plasma were measured as: plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration).

13. Part 1: Renin Concentrations From Plasma During Amlodipine Treatment Period [Day 98]

    Renin concentrations from plasma were measured as plasma renin concentration (PRC), prorenin concentration and total renin concentration (renin + prorenin concentration).

14. Part 1: Renin Activity From Plasma During Aliskiren Treatment Period [Day 42]

    Plasma Renin activity (PRC) was measured by a trapping PRA (tPRA) assay.

15. Part 1: Renin Activity From Plasma During Amlodipine Treatment Period [Day 98]

    Plasma renin activity (PRC) was measured by a trapping PRA (tPRA) assay.

16. Part 2: Change From Baseline in Angiotensin II Levels in Interstitial Fluid of Fat and Skeletal Muscle (Microdialysis) During Double Blind Treatment Period [Placebo Baseline (Day 14), Active Treatment (Day 98)]

    Interstitial fluid was obtained from subcutaneous adipose and skeletal muscle tissues by microdialysis using the zero-flow method to determine Ang II concentration.

17. Part 2: Change From Baseline in Plasma Angiotensin II Levels During Double Blind Treatment Period [Placebo Baseline (Day 14), Active Treatment (Day 98)]

    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).

18. Part 2: Plasma Renin Activity (PRA) Concentration During Double Blind Treatment Period [Day 98]

19. Part 2: Plasma Renin Concentration (PRC) Levels During Double Blind Treatment Period [Day 98]

Secondary Outcome Measures

1. Part 2: Microdialysis Metabolic Analytes in Response to Insulin Modified Frequently Sampled Intravenous Glucose Test [IM-FSIGT]for Each Tissue (Adipose or Skeletal Muscle) [Day 14 and Day 98]

2. Part 2: Change From Baseline in Official Blood Pressure [Placebo Baseline (Day 14), Active Treatment (Day 98)]

3. Part 2: Renin Activity and Concentration of Aliskiren and Amlodipine in Fat and Skeletal Muscle Interstitial Fluid [Placebo Baseline (Day 14), Active Treatment (Day 98)]

4. 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) [Placebo Baseline (Day 14), Active Treatment (Day 98)]

5. Part 2: Change From Baseline in Mitochondrial Mass in Subcutaneous Fat and Skeletal Muscle (Tissue Biopsies) [Placebo Baseline (Day 14), Active Treatment (Day 98)]

6. Part 2: Number of Participants With Reported Any Adverse Events, Serious Adverse Events and Death [98 days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Berlin-Buch		Germany	13125
2	Novartis Investigative Site	Hannover		Germany	30159

Sponsors and Collaborators

• Novartis

Investigators

• Principal Investigator: Novartis, Investigative site

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis
• ClinicalTrials.gov Identifier: NCT00498433
• Other Study ID Numbers: CSPP100A2238
• First Posted: Jul 10, 2007
• Last Update Posted: Sep 10, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Novartis: Aliskiren; Renin-Angiotensin System (RAS); Hypertension; Abdominal obesity
• Additional relevant MeSH terms: Hypertension; Obesity; Obesity, Abdominal; Amlodipine

Study Results

Participant Flow

Pre-assignment Detail	Total 46 patients entered into the study; 10 patients in part 1 received study drug. 36 patients enrolled into part 2 and and 16 patients received study drug.

Arm/Group Title	Placebo	Aliskiren	Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 2, Period 1: After confirming study eligibility based on inclusion and exclusion criteria, patients underwent a two week single-blind placebo run-in phase.	Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks. Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Period Title: Part 1, Period 1:Placebo Run-in(2 Weeks)
STARTED	10	0	0
COMPLETED	10	0	0
NOT COMPLETED	0	0	0
Period Title: Part 1, Period 1:Placebo Run-in(2 Weeks)
STARTED	0	10	0
COMPLETED	0	10	0
NOT COMPLETED	0	0	0
Period Title: Part 1, Period 1:Placebo Run-in(2 Weeks)
STARTED	0	0	10
COMPLETED	0	0	10
NOT COMPLETED	0	0	0
Period Title: Part 1, Period 1:Placebo Run-in(2 Weeks)
STARTED	36	0	0
COMPLETED	16	0	0
NOT COMPLETED	20	0	0
Period Title: Part 1, Period 1:Placebo Run-in(2 Weeks)
STARTED	0	8	8
COMPLETED	0	8	8
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine	Part 2, Double Blind Period: Aliskiren	Part 2, Double Blind: Amlodipine	Total
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.	Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks	Total of all reporting groups
Overall Participants	10	8	8	26
Age (years) [Mean (Standard Deviation) ]
Part 1, Open Label	46 (7.5)	NA (NA)	NA (NA)	46 (7.5)
Part 2, Double blind	NA (NA)	46.0 (10.92)	49.4 (10.53)	47.7 (10.17)
Sex: Female, Male (Count of Participants)
Female	2 20%	2 25%	2 25%	6 23.1%
Male	8 80%	6 75%	6 75%	20 76.9%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacokinetics (PK)/ pharmacodynamics (PD) data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Adipose tissue	2.38 (2.11)
Skeletal muscle	7.05 (4.24)

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Zero flow concentrations from microdialysates could not be derived by linear regression because of missing data due to inadequate sample volumes.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	0

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

4. Secondary Outcome

Title	Part 2: Change From Baseline in Official Blood Pressure
Time Frame	Placebo Baseline (Day 14), Active Treatment (Day 98)

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

5. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Due to technical limitations, zero flow concentrations could not be derived for Ang II.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	0

7. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Due to technical limitations, zero flow concentrations could not be derived for Ang II.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	0

8. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacokinetics data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	9
Adipose tissue (n=6)	29.05 (16.71)
Skeletal muscle (n=9)	107.32 (68.64)

9. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

More than 50% of the biopsy samples over all time points were either below lower limit of quantification (LLOQ) or not received.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	0

10. Primary Outcome

Title	Part 1: Renin Activity and Concentrations From Adipose and Skeletal Tissues During Aliskiren Treatment Period
Time Frame	Day 42

Outcome Measure Data

Analysis Population Description

Renin activity and concentration from adipose tissue and skeletal muscles were all below lower limitation of quantification (LLOQ) at all time points.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	0

11. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacokinetics data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Mean (Standard Deviation) [ng/mL]	8.38 (4.41)

12. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacokinetics data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Mean (Standard Deviation) [ng/mL]	7.78 (3.61)

13. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacodynamic data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Geometric Mean (95% Confidence Interval) [fmol/mL]	0.534

14. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacodynamic data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Geometric Mean (95% Confidence Interval) [fmol/mL]	2.20

15. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacodynamic data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Plasma Renin Concentration	22.29
Total Renin Concentration	89.9
Prorenin Concentration	62.1

16. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacodynamic data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Plasma Renin Concentration	7.36
Total Renin Concentration	66.3
Prorenin Concentration	57.9

17. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacodynamic data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Geometric Mean (95% Confidence Interval) [ng/nl/h]	0.145

18. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients who received at least one dose of study drug and had at least one post-baseline assessment of pharmacodynamic data were included in the data analysis.

Arm/Group Title	Part 1: Placebo/Aliskiren/Amlodipine
Arm/Group Description	Part 1, Period 1: After a 1-2 weeks initial washout period, all eligible patients underwent a two week placebo run-in phase. Part 1 , Period 2: All eligible patients received 4 week treatment of 300 mg aliskiren o.d.. Part 1, Period 3: All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.
Measure Participants	10
Geometric Mean (95% Confidence Interval) [ng/nl/h]	0.670

19. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

20. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

21. Primary Outcome

Title	Part 2: Plasma Renin Activity (PRA) Concentration During Double Blind Treatment Period
Time Frame	Day 98

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients of this arm received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients of this arm received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

22. Primary Outcome

Title	Part 2: Plasma Renin Concentration (PRC) Levels During Double Blind Treatment Period
Time Frame	Day 98

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

23. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

24. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

Total 40 completed subjects needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.

Arm/Group Title	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Double Blind Period: Eligible randomized patients received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind Period: Eligible randomized patients received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	0	0

25. Secondary Outcome

Title	Part 2: Number of Participants With Reported Any Adverse Events, Serious Adverse Events and Death
Time Frame	98 days

Outcome Measure Data

Analysis Population Description

The safety population consisted of all patients who received at least one dose of study drug with at least one post-baseline safety assessment. Patients were analyzed according to treatment received.

Arm/Group Title	Placebo run-in	Aliskiren	Amlodipine
Arm/Group Description	Part 2, Period 1, Placebo run-in phase: After confirming study eligibility based on inclusion and exclusion criteria, patients will undergo a two week single-blind placebo run-in phase.	Part 2, Double Blind Period: Eligible randomized patients of this arm received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks	Part 2, Double Blind: Eligible randomized patients of this arm received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
Measure Participants	36	8	8
Adverse event	9 90%	2 25%	3 37.5%
Serious Adverse Event	1 10%	0 0%	0 0%
Death	0 0%	0 0%	0 0%

Adverse Events

Adverse Event Reporting Description	The Safety Population consisted of all patients that received at least one dose of study drug with at least one post-baseline safety assessment. In Part 1 of the study, no events were reported in period 1 when patients received placebo.
Arm/Group Title	Part 1: Aliskiren		Part 1: Amlodipine		Part 2: Placebo run-in Period		Part 2: Aliskiren		Part 2: Amlodipine
Arm/Group Description	All eligible patients received 4 week treatment of 300 mg aliskiren o.d..		All patients received 5 mg amlodipine o.d.. The length of the amlodipine period varied from 4 to 7 weeks.		After confirming study eligibility based on inclusion and exclusion criteria, patients will undergo a two week single-blind placebo run-in phase.		Eligible randomized patients of this arm received aliskiren 300 mg tablet o.d. and amlodipine placebo capsule o.d. for 12 weeks		Double Blind Period: Eligible randomized patients of this arm received amlodipine 5 mg o.d. and aliskiren placebo o.d. for 12 weeks
All Cause Mortality
	Part 1: Aliskiren		Part 1: Amlodipine		Part 2: Placebo run-in Period		Part 2: Aliskiren		Part 2: Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1: Aliskiren		Part 1: Amlodipine		Part 2: Placebo run-in Period		Part 2: Aliskiren		Part 2: Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		0/10 (0%)		1/36 (2.8%)		0/8 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
MUSCLE HAEMORRHAGE	1/10 (10%)		0/10 (0%)		0/36 (0%)		0/8 (0%)		0/8 (0%)
Vascular disorders
HYPERTENSIVE CRISIS	0/10 (0%)		0/10 (0%)		1/36 (2.8%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: Aliskiren		Part 1: Amlodipine		Part 2: Placebo run-in Period		Part 2: Aliskiren		Part 2: Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/10 (60%)		3/10 (30%)		1/36 (2.8%)		2/8 (25%)		3/8 (37.5%)
Gastrointestinal disorders
DIARRHOEA	0/10 (0%)		1/10 (10%)		0/36 (0%)		0/8 (0%)		1/8 (12.5%)
DRY MOUTH	0/10 (0%)		0/10 (0%)		0/36 (0%)		1/8 (12.5%)		0/8 (0%)
General disorders
IRRITABILITY	0/10 (0%)		0/10 (0%)		0/36 (0%)		1/8 (12.5%)		0/8 (0%)
Infections and infestations
NASOPHARYNGITIS	2/10 (20%)		2/10 (20%)		0/36 (0%)		0/8 (0%)		0/8 (0%)
RHINITIS	1/10 (10%)		0/10 (0%)		0/36 (0%)		0/8 (0%)		0/8 (0%)
Injury, poisoning and procedural complications
CONTUSION	0/10 (0%)		0/10 (0%)		0/36 (0%)		0/8 (0%)		1/8 (12.5%)
MUSCLE STRAIN	1/10 (10%)		0/10 (0%)		0/36 (0%)		0/8 (0%)		0/8 (0%)
POST PROCEDURAL HAEMATOMA	1/10 (10%)		0/10 (0%)		0/36 (0%)		0/8 (0%)		0/8 (0%)
Investigations
WEIGHT INCREASED	0/10 (0%)		0/10 (0%)		0/36 (0%)		1/8 (12.5%)		0/8 (0%)
Nervous system disorders
HEADACHE	1/10 (10%)		0/10 (0%)		1/36 (2.8%)		1/8 (12.5%)		0/8 (0%)
PARAESTHESIA	0/10 (0%)		0/10 (0%)		0/36 (0%)		1/8 (12.5%)		0/8 (0%)
Psychiatric disorders
INSOMNIA	0/10 (0%)		0/10 (0%)		0/36 (0%)		1/8 (12.5%)		0/8 (0%)
Renal and urinary disorders
DYSURIA	0/10 (0%)		0/10 (0%)		0/36 (0%)		0/8 (0%)		1/8 (12.5%)
Reproductive system and breast disorders
ERECTILE DYSFUNCTION	0/10 (0%)		0/10 (0%)		0/36 (0%)		1/8 (12.5%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
COUGH	2/10 (20%)		1/10 (10%)		0/36 (0%)		0/8 (0%)		0/8 (0%)
Skin and subcutaneous tissue disorders
PSORIASIS	0/10 (0%)		0/10 (0%)		0/36 (0%)		0/8 (0%)		1/8 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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 or disclosure of trial results in their entirety.