Efficacy of Aliskiren Compared to Ramipril in the Treatment of Moderate Systolic Hypertensive Patients

Study Overview
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Brief Summary
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This prospective multicenter, double blind study will evaluate the efficacy and safety of aliskiren versus ramipril in patients with moderate systolic essential hypertension.

Official Title
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Efficacy of Aliskiren Compared to Ramipril in the Treatment of Moderate Systolic Hypertensive Patients

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Ramipril
* Drug: Matching placebo to Aliskiren
* Drug: Matching placebo to Ramipril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients > 18 years Male or female patients. Female patients must have been either post-menopausal for one year, surgically sterile, or using effective contraceptive methods Patients with essential hypertension, previously treated with an antihypertensive single-drug therapy, either uncontrolled or intolerant. BP thresholds at visit 1: For patients previously treated and uncontrolled: 140≤ office SBP<180 mmHg For patients previously treated, controlled but intolerant: office SBP≥130 mmHg BP thresholds at visit 2 (for all patients): 160≤office SBP<180 mmHg AND 155≤home SBP<175 mmHg (3-day period of home blood pressure monitoring just before randomization) Exclusion Criteria: Women of child-bearing potential not using any effective methods of contraception Severe hypertension (office BP ≥ 180/110 mmHg) Impossibility to stop abruptly previous antihypertensive treatments at visit 1 Patients previously untreated or patients treated with two or three antihypertensive medications History or evidence of a secondary form of hypertension History of hypersensitivity to ACEi or renin inhibitors History of heart failure, stroke or coronary heart disease Serum potassium ≥ 5.2 mmol/l Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Active Comparator: Ramipril<br>In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Ramipril 5 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to Ramipril 10 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal): At visit 4, part of patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4). | Drug: Ramipril<br>* Ramipril 5 mg was given in capsule form.<br>Drug: Matching placebo to Aliskiren<br>* The tablet of matching placebo to aliskiren 150 mg for period I and III. In period II, matching placebo to Aliskiren was given to Ramipril active treatment arm.<br>|
| Experimental: Aliskiren<br>In period I (washout and single-blind): from visit 1 to visit 2, 2 weeks placebo run-in. In period II (double-blind treatment, randomized): Aliskiren 150 mg for 4 weeks (visit 2 - visit 3). At visit 3, medications had to be titrated to aliskiren 300 mg only if BP remained ≥ 140/90 mmHg. Double blind treatment had to be continued for another 4-week period until visit 4. In period III (double-blind withdrawal ): At visit 4, part of the patients received the active treatment for 1 day. The study ended at visit 5 (48 hours later than visit 4). | Drug: Aliskiren<br>* 150 mg Aliskiren as film-coated tablet<br>Drug: Matching placebo to Ramipril<br>* The placebo capsule to ramipril 5 mg for period I and III. In period II, matching placebo to Ramipril was given to Aliskiren active treatment arm.<br>|
| Placebo Comparator: Placebo to Ramipril<br>In period III (double-blind withdrawal ): At visit 4, part of patients from Ramipril arm received placebo to Ramipril for 1 day. The study ended at visit 5 (48 hours later than visit 4). | Drug: Matching placebo to Ramipril<br>* The placebo capsule to ramipril 5 mg for period I and III. In period II, matching placebo to Ramipril was given to Aliskiren active treatment arm.<br>|
| Placebo Comparator: Placebo to Aliskiren<br>In period III (double-blind withdrawal ): At visit 4, part of the patients from Aliskiren arm received placebo to Aliskiren for 1 day. The study ended at visit 5 (48 hours later than visit 4). | Drug: Matching placebo to Aliskiren<br>* The tablet of matching placebo to aliskiren 150 mg for period I and III. In period II, matching placebo to Aliskiren was given to Ramipril active treatment arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of covariance included treatment factor and baseline mean sitting SBP as covariable. | Baseline to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of variance included treatment factor and baseline value of mean sitting DBP as covariable. | Baseline to 8 weeks | 
| Percentage of Patients With Controlled Blood Pressure | The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. Controlled blood pressure (BP) is defined as mean office systolic BP/ diastolic BP < 140/90 mmHg. | At 4 and 8 weeks | 
| Number of the Participants With More Than 55 mmHg Difference Between the Mean SBP Measured at the Morning Surge and the Mean Minimal SBP Measured During the Night | Ambulatory blood pressure measurement (ABPM) over 24 hours was performed for all patients on the day before visit 4, the device attached to the ambulatory blood pressure non-dominant arm of the patient. The BP morning surge was defined as the average of the measurements taken during the first 2 hours after waking the patient. The minimal night blood pressure was defined as the average of the two lowest BP measures (the lowest hourly average) recorded during night time. | After 8 weeks | 
| Change in msSBP and msDBP From Visit 2 (Baseline) to Visit 3 (at 4 Weeks) | The arm in which the highest sitting systolic blood pressure (SBP) was found at study entry was used for all subsequent readings. At each study visit, after leaving the patient to rest 5 minutes in a sitting position, the blood pressure (BP) was measured three times with an oscillometric device. The measurements were performed at 1-2 minute intervals. The mean BP was calculated from the 3 readings. The analysis of covariance included treatment factor and baseline mean sitting SBP and mean sitting DBP as covariables. | Baseline to 4 weeks | 
| Difference Between the Maximal and the Minimal Mean-hour SPB Measured Between 1 and 8 am at Week 8 | Ambulatory blood pressure measurement (ABPM) over 24 hours was performed for all patients on the eve of visit 4 (week 8), the device attached to the ambulatory blood pressure non-dominant arm of the patient. The difference between mean-hour maximum SBP mean-hour minimum SBP between 1 am and 8 am was measured. | At week 8 | 
| Change in Mean Sitting DBP and SBP in Specified Sub-groups From Visit 2 (Baseline) to Visit 4 (at 8 Weeks) | The sub-groups were: Riser = patients with >= 55 mmHg difference between the mean SPB measured at the morning surge and the mean minimal SBP measured during the night. The Non-risers in whom the difference is <55 mmHg. Patients called dippers in whom there was a decrease in average nocturnal SBP ≥ 10% compared with average daytime SBP, in contrast to patients non-dippers  in whom this difference was <10%. | Baseline to 8 weeks | 
| Change in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) From Last Active Dose Taken to After a One-day Missed-dose | The change in blood pressure was measured between visit 4 (end of the period of double-blind active treatment which was at week 8) and visit 5 (48 hours after the last active dose taken) in the group of patients who received aliskiren or placebo and those who received ramipril or placebo. The analysis of covariance included treatment factor and baseline mean sitting SBP and mean sitting DBP as covariables. | From 8 weeks to 48 hours after week 8 | 
| Number Patients Reported With Adverse Events (AEs), Serious Adverse Events (SAE) and Death (Period II and Period III) | Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. | 8 weeks + 1 day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Moderate systolic hypertension - adults - aliskiren -ramipril