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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Hypertension With Metabolic Syndrome

Intervention / Treatment
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* Drug: Amlodipine
* Drug: Aliskiren
* Drug: Ramipril


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aliskiren / ramipril / amlodipine<br>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<br>* 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.<br>Drug: Aliskiren<br>* 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.<br>Drug: Ramipril<br>* 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.<br>|
| Experimental: Aliskiren / amlodipine<br>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<br>* 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.<br>Drug: Aliskiren<br>* 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.<br>|
| Active Comparator: Ramipril / amlodipine<br>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<br>* 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.<br>Drug: Ramipril<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine) | 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. | Baseline to Week 12 | 
| Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine | 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. | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine | 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. | Baseline to Week 12 | 
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine | 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. | Baseline to Week 12 | 
| Percentage of Patients Who Achieved Normalized Blood Pressure at End of Study | Normalized was defined as a msSBP < 140 mmHg and/or a msDBP < 90 mmHg. | Week 12 | 
| Change in HOMA-IR From Baseline to End of Study | Homeostasis model assessment-insulin resistance (HOMA-IR) was defined as (fasting insulin [μU/mL] x fasting glucose [mmol/L]) / 22.5. | Baseline to Week 12 | 
| Change in HOMA-β From Baseline to End of Study | Homeostasis model assessment-β (HOMA-β) was defined as fasting insulin (μU/mL) x 20 / (fasting glucose (mmol/L) - 3.5). | Baseline to Week 12 | 
| Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Ramipril/Amlodipine vs Ramipril/Amlodipine |  | Baseline to Week 12 | 
| Change in HbA1c (Glycated Hemoglobin) From Baseline to End of Study - Aliskiren/Amlodipine vs Ramipril/Amlodipine) |  | Baseline to Week 12 | 
| Percentage of Patients Who Developed Diabetes at End of Study | A patient had diabetes if fasting plasma glucose > 7 mmol/L. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Metabolic Syndrome, Dual combination therapy, Triple combination therapy, Aliskiren, Direct Renin inhibitor