ALTO: Efficacy and Safety of Aliskiren/Ramipril/Amlodipine Compared With Ramipril/Amlodipine and Aliskiren/Amlodipine in Patients With Metabolic Syndrome

• Sponsor: Novartis (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00542269
• Collaborator: (none)
• Enrollment: 178
• Location: 1
• Arms: 3
• Duration (Months): 16
• Patients Per Site Per Month: 11.1

Study Details

Study Description

Brief Summary

This proof of concept study is designed to evaluate the efficacy and safety of the combination therapy of aliskiren and ramipril as add-on to amlodipine in the treatment of patients with essential hypertension and metabolic syndrome who do not respond adequately to amlodipine monotherapy.

Condition or Disease	Intervention/Treatment	Phase
Hypertension With Metabolic Syndrome	Drug: Amlodipine; Drug: Aliskiren; Drug: Ramipril	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 178 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Twelve Week, Randomized, Double-blind, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of the Combination of Aliskiren/Ramipril/Amlodipine (300/10/5-10 mg) Compared to the Combinations of Ramipril/Amlodipine (10/5-10 mg) and Aliskiren/Amlodipine (300/5-10 mg) in Patients With Essential Hypertension and Metabolic Syndrome Not Adequately Responsive to Amlodipine 5-10 mg
• Study Start Date: Mar 1, 2008
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aliskiren / ramipril / amlodipine 6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	Drug: Amlodipine; amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.; Drug: Aliskiren; aliskiren 150-300 mg tablets. Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.; Drug: Ramipril; ramipril 5-10 mg capsules. Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Experimental: Aliskiren / amlodipine 6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	Drug: Amlodipine; amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.; Drug: Aliskiren; aliskiren 150-300 mg tablets. Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Active Comparator: Ramipril / amlodipine 6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	Drug: Amlodipine; amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.; Drug: Ramipril; ramipril 5-10 mg capsules. Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.

Outcome Measures

Primary Outcome Measures

1. Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine) [Baseline to Week 12]

   Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msSBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.

2. Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine [Baseline to Week 12]

   Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msSBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.

Secondary Outcome Measures

1. Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine [Baseline to Week 12]

   Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msDBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.

2. Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine [Baseline to Week 12]

   Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msDBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.

3. Percentage of Patients Who Achieved Normalized Blood Pressure at End of Study [Week 12]

   Normalized was defined as a msSBP < 140 mmHg and/or a msDBP < 90 mmHg.

4. Change in HOMA-IR From Baseline to End of Study [Baseline to Week 12]

   Homeostasis model assessment-insulin resistance (HOMA-IR) was defined as (fasting insulin [μU/mL] x fasting glucose [mmol/L]) / 22.5.

5. Change in HOMA-β From Baseline to End of Study [Baseline to Week 12]

   Homeostasis model assessment-β (HOMA-β) was defined as fasting insulin (μU/mL) x 20 / (fasting glucose (mmol/L) - 3.5).

6. Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine [Baseline to Week 12]

7. Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine) [Baseline to Week 12]

8. Percentage of Patients Who Developed Diabetes at End of Study [Week 12]

   A patient had diabetes if fasting plasma glucose > 7 mmol/L.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Outpatients 18-75 years of age.

• Male or female patients are eligible.

• Patients with a diagnosis of hypertension:

• Newly diagnosed patients or patients who have not been treated for hypertension within the 4 weeks prior to Visit 1 must have a mean sitting systolic blood pressure (MSSBP)

150 mmHg and < 180 mmHg at Visit 1.

• Patients treated with antihypertensive monotherapy must have a MSSBP ≥ 140 mmHg and <180 mmHg at Visit 1.

• Patients taking amlodipine monotherapy MSSBP > 140 mmHg and < 180 mmHg at visit 1.

• All patients must have a MSSBP ≥ 140 mmHg and < 180 mmHg at Visit 3, the end of the amlodipine run-in period.

• Metabolic syndrome.

• Patients who are eligible and able to participate in the study, and who consent to do so after the purpose and nature of the investigation has been clearly explained to them (written inform consent form).

Exclusion Criteria:

• Severe hypertension (office cuff MSDBP ≥ 115 mmHg and/or MSSBP ≥ 180 mmHg).

• History or evidence of a secondary form of hypertension.

• History of hypertensive encephalopathy or cerebrovascular accident, transient ischemic cerebral attack (TIA), myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention (PCI).

• Serum sodium < 135 mmol/L at Visit 1 if confirmed on repeat sample.

• Serum potassium < 3.5 mmol/L or ≥ 5.3 mmol/L at Visit 1, if confirmed on repeat sample.

• Type 1 diabetes mellitus.

• Type 2 diabetes if oral hypoglycaemic therapy changed (dose change or medication change) in previous 3 months.

• Pregnant or nursing (lactating) women.

Other protocol-defined inclusion/exclusion criteria applied to the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Addenbrookes Hospital	Cambridge		United Kingdom

Sponsors and Collaborators

• Novartis

Investigators

• Study Chair: Novartis, Novartis Great Britian

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00542269
• Other Study ID Numbers: CSPP100AGB01
• First Posted: Oct 11, 2007
• Last Update Posted: May 24, 2011
• Last Verified: Apr 1, 2011

• Keywords provided by , ,: Hypertension; Metabolic Syndrome; Dual combination therapy; Triple combination therapy; Aliskiren; Direct Renin inhibitor
• Additional relevant MeSH terms: Hypertension; Metabolic Syndrome; Syndrome; Amlodipine; Ramipril

Study Results

Participant Flow

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Aliskiren /Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Period Title: Overall Study
STARTED	61	60	57
COMPLETED	48	54	51
NOT COMPLETED	13	6	6

Baseline Characteristics

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Aliskiren /Amlodipine	Ramipril / Amlodipine	Total
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	Total of all reporting groups
Overall Participants	61	60	57	178
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.3 (8.90)	58.3 (8.95)	59.1 (8.86)	59.6 (8.95)
Age, Customized (participants) [Number]
< 65 years	37 60.7%	47 78.3%	42 73.7%	126 70.8%
≥ 65 years	24 39.3%	13 21.7%	15 26.3%	52 29.2%
Sex: Female, Male (Count of Participants)
Female	17 27.9%	18 30%	19 33.3%	54 30.3%
Male	44 72.1%	42 70%	38 66.7%	124 69.7%

Outcome Measures

1. Primary Outcome

Title	Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine)
Description	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msSBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	61	57
Least Squares Mean (Standard Error) [mmHg]	-12.8 (1.56)	-10.9 (1.59)

2. Primary Outcome

Title	Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine
Description	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msSBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	60	57
Least Squares Mean (Standard Error) [mmHg]	-12.4 (1.36)	-10.0 (1.39)

3. Secondary Outcome

Title	Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine
Description	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msDBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	61	57
Least Squares Mean (Standard Error) [mmHg]	-6.0 (0.94)	-4.1 (0.96)

4. Secondary Outcome

Title	Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine
Description	Automated blood pressure determinations were made with the Omron HEM-705CP blood pressure monitor at trough (24 hours ± 3 hours post-dose) and recorded at all study visits following detailed directions specified in the study protocol. Three readings were made and msDBP was calculated as the average of the 3 readings. In the event of aberrant readings, ie, the lowest reading was ≥ 10 mmHg systolic or ≥ 5 mmHg diastolic lower than the highest of the 3 readings, 3 additional readings were obtained. A negative change indicates improvement.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	60	57
Least Squares Mean (Standard Error) [mmHg]	-5.8 (0.98)	-4.5 (1.00)

5. Secondary Outcome

Title	Percentage of Patients Who Achieved Normalized Blood Pressure at End of Study
Description	Normalized was defined as a msSBP < 140 mmHg and/or a msDBP < 90 mmHg.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Aliskiren /Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	61	60	57
Number [Percentage of patients]	45.90	43.33	42.11

6. Secondary Outcome

Title	Change in HOMA-IR From Baseline to End of Study
Description	Homeostasis model assessment-insulin resistance (HOMA-IR) was defined as (fasting insulin [μU/mL] x fasting glucose [mmol/L]) / 22.5.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Aliskiren /Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	45	44	45
Mean (Standard Deviation) [mmol/L]	0.98 (2.292)	0.87 (5.883)	0.60 (6.186)

7. Secondary Outcome

Title	Change in HOMA-β From Baseline to End of Study
Description	Homeostasis model assessment-β (HOMA-β) was defined as fasting insulin (μU/mL) x 20 / (fasting glucose (mmol/L) - 3.5).
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Aliskiren /Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	45	44	45
Mean (Standard Deviation) [mmol/L]	2.71 (152.108)	0.87 (5.883)	0.60 (6.186)

8. Secondary Outcome

Title	Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	57	54
Least Squares Mean (Standard Error) [mmol/mol]	0.1 (0.05)	0.1 (0.05)

9. Secondary Outcome

Title	Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine)
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population. All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the variable.

Arm/Group Title	Aliskiren / Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	58	54
Least Squares Mean (Standard Error) [mmol/mol]	0.1 (0.06)	0.1 (0.06)

10. Secondary Outcome

Title	Percentage of Patients Who Developed Diabetes at End of Study
Description	A patient had diabetes if fasting plasma glucose > 7 mmol/L.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All patients that received at least 1 dose of study drug and had baseline and at least 1 post-baseline assessment of the primary efficacy variable.

Arm/Group Title	Aliskiren / Ramipril / Amlodipine	Aliskiren /Amlodipine	Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.	6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
Measure Participants	61	60	57
Number [Percentage of patients]	1.9	4.1	2.1

Adverse Events

Arm/Group Title	Aliskiren / Ramipril / Amlodipine		Aliskiren /Amlodipine		Ramipril / Amlodipine
Arm/Group Description	6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.		6 weeks treatment with aliskiren 150 mg tablets, ramipril 5 mg placebo capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg tablets, ramipril 10 mg placebo capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.		6 weeks treatment with aliskiren 150 mg placebo tablets, ramipril 5 mg capsules, and amlodipine 5-10 mg tablets followed by an additional 6 weeks treatment with aliskiren 300 mg placebo tablets, ramipril 10 mg capsules, and amlodipine 5-10 mg tablets. Patients received amlodipine 5 mg (or 10 mg if they were receiving 10 mg prior to study start). Each dose was to be taken orally with water once daily at approximately 8:00 A.M. with or without food, except on the morning of an office/clinic visit, when the study drug was to be taken at the site after the visit procedures had been completed.
All Cause Mortality
	Aliskiren / Ramipril / Amlodipine		Aliskiren /Amlodipine		Ramipril / Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Aliskiren / Ramipril / Amlodipine		Aliskiren /Amlodipine		Ramipril / Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/61 (4.9%)		1/60 (1.7%)		3/57 (5.3%)
Cardiac disorders
Myocardial infarction	1/61 (1.6%)		0/60 (0%)		0/57 (0%)
Immune system disorders
Latex allergy	0/61 (0%)		1/60 (1.7%)		0/57 (0%)
Infections and infestations
Eczema infected	0/61 (0%)		1/60 (1.7%)		0/57 (0%)
Investigations
Glucose tolerance test abnormal	0/61 (0%)		0/60 (0%)		1/57 (1.8%)
Metabolism and nutrition disorders
Diabetes mellitus	2/61 (3.3%)		0/60 (0%)		2/57 (3.5%)
Other (Not Including Serious) Adverse Events
	Aliskiren / Ramipril / Amlodipine		Aliskiren /Amlodipine		Ramipril / Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/61 (44.3%)		24/60 (40%)		26/57 (45.6%)
Gastrointestinal disorders
Dyspepsia	2/61 (3.3%)		3/60 (5%)		0/57 (0%)
General disorders
Oedema peripheral	17/61 (27.9%)		14/60 (23.3%)		16/57 (28.1%)
Infections and infestations
Lower respiratory tract infection	3/61 (4.9%)		0/60 (0%)		3/57 (5.3%)
Urinary tract infection	0/61 (0%)		1/60 (1.7%)		3/57 (5.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/61 (3.3%)		3/60 (5%)		2/57 (3.5%)
Nervous system disorders
Dizziness	5/61 (8.2%)		2/60 (3.3%)		2/57 (3.5%)
Headache	2/61 (3.3%)		3/60 (5%)		2/57 (3.5%)
Respiratory, thoracic and mediastinal disorders
Cough	4/61 (6.6%)		2/60 (3.3%)		1/57 (1.8%)

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.