Aliskiren and Valsartan vs Valsartan Alone in Patients With Stage II Systolic Hypertension and Type II Diabetes Mellitus

Study Overview
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Brief Summary
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The purpose of the study was to evaluate the blood pressure (BP)-lowering efficacy of the combination of aliskiren and valsartan, as initial therapy, compared to valsartan monotherapy in Type II Diabetic patients with Stage II hypertension.

Detailed Description
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When protocol Amendment 2 was released, there were patients who had already been randomized into the study. These patients were included in the trial prior to making changes to the eligibility criteria. Thus, the study contains 2 distinct cohorts. Cohort 1 contains those patients who had already been randomized, and had been deemed eligible based on the original inclusion/exclusion criteria, prior to Amendment 2. No new patients were randomized to Cohort 1. Cohort 2 contains patients who were randomized, having been found eligible based on the revised inclusion/exclusion criteria, after Amendment 2. Differences in the inclusion and exclusion criteria are indicated below.

Official Title
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An 8 Week Randomized, Double-Blind, Parallel Group, Multi-Center, Active Controlled Study to Evaluate the Antihypertensive Efficacy and Safety of Aliskiren Administered in Combination With Valsartan Versus Valsartan Alone in Patients With Stage 2 Systolic Hypertension and Type 2 Diabetes Mellitus

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Aliskiren
* Drug: Valsartan
* Drug: Placebo for Aliskiren
* Drug: Placebo for Valsartan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who are eligible and able to participate in the study, and who give written informed consent before any assessment is performed. Men or women 18 years and older. Patients with Type 2 diabetes mellitus with an HbA1c ≤ 9 % at visit 1 and on a stable anti-diabetic regimen not including insulin or stable diet and exercise for at least 4 weeks prior to visit 1. Cohort 1: Patients with Stage 2 systolic hypertension, defined as having a MSSBP ≥160 mmHg and <200 mmHg at Visit 5 (randomization). Patients who have been newly diagnosed with hypertension or who have not received antihypertensive medication for at least 4 weeks (28 days) prior to Visit 1 must have MSSBP ≥ 160 mmHg and < 200 mmHg at Visit 1, otherwise, they will be considered screen failures. Patients receiving antihypertensive medication must have a MSSBP of ≥150 mmHg and <200 mmHg at Study Visit 1, otherwise they will be considered screen failures. Cohort 2: Patients must also have had a mean 8-hour daytime ambulatory systolic blood pressure (ASBP) ≥140 mmHg AND mean 8-hour daytime ambulatory diastolic blood pressure (ADBP) ≥90 mmHg at Visit 5 (randomization). Hypertensive patients with MSSBP ≥150 mmHg and but <200 mmHg AND MSDBP ≥95 but <120 mmHg at Visit 5 (randomization). Patients who had been newly diagnosed with hypertension or who had not received antihypertensive medication for at least 4 weeks (28 days) prior to Visit 1 must have had MSSBP ≥150 mmHg but <200 mmHg and MSDBP ≥95 but <120 mmHg at Visit 1, otherwise, they were considered screen failures. Exclusion Criteria: Office blood pressure measured by cuff (MSSBP ≥200 mmHg or MSDBP ≥120 mmHg). History or evidence of secondary hypertension of any etiology. Refractory hypertension, defined as having uncontrolled BP (≥140/90 mmHg) while receiving 3 antihypertensive medications at the maximum approved dose of each drug, one of which must be a diuretic. Patients treated with more than 3 antihypertensive medications (each component of a combination drug counts individually). Type 2 diabetes mellitus currently requiring insulin treatment. modification of diet in renal disease (MDRD) estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 Serum sodium less than lower limit of normal, serum potassium < 3.5 mEq/L or ≥ 5.3 mEq/L at Visit 1. Known Keith-Wagener grade III or IV hypertensive retinopathy. Cohort 1: - Patients with known diabetic retinopathy (eg, having a history of laser therapy for diabetic retinopathy) or diabetic neuropathy (eg, receiving medication for diabetic neuropathy). Cohort 2: - Patients with known diabetic retinopathy or diabetic neuropathy and/or having a history of treatment for either. Other protocol-defined inclusion/exclusion criteria applied.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination Therapy: Aliskiren + Valsartan<br>To adequately blind the study, patients were required to take a total of 4 tablets/capsules a day (2 tablets and 2 capsules of study drug per day)for 8 weeks. 1 tablet of Aliskiren 150 mg + 1 tablet of placebo Aliskiren 150 mg + 1 capsule of Valsartan 160 mg + 1 capsule of placebo Valsartan 160 mg daily for 2 weeks. Forced titrated to: 2 tablets of Aliskiren 150 mg + 2 capsules of Valsartan 160 mg daily for 6 weeks | Drug: Aliskiren<br>* Aliskiren 150 mg tablet<br>Drug: Valsartan<br>* Valsartan 160 mg capsules<br>Drug: Placebo for Aliskiren<br>* Placebo for Aliskiren 150 mg tablets<br>Drug: Placebo for Valsartan<br>* Placebo for Valsartan 160 mg capsules<br>|
| Active Comparator: Monotherapy: Valsartan<br>To adequately blind the study, patients were required to take a total of 4 tablets/capsules a day (2 tablets and 2 capsules of study drug per day) for 8 weeks. 1 capsule of Valsartan 160 mg + 1 capsule of placebo Valsartan 160 mg + 2 tablets of placebo Aliskiren 150 mg daily for 2 weeks. Forced titrated to: 2 capsules of Valsartan 160 mg + 2 tablets of placebo Aliskiren 150 mg daily for 6 weeks. | Drug: Valsartan<br>* Valsartan 160 mg capsules<br>Drug: Placebo for Aliskiren<br>* Placebo for Aliskiren 150 mg tablets<br>Drug: Placebo for Valsartan<br>* Placebo for Valsartan 160 mg capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean 24-hour Ambulatory Systolic Blood Pressure (MASBP) at Week 8 | The 24-hour ambulatory systolic blood pressure was evaluated at baseline (Week 0) and post-baseline visits. The mean hourly systolic blood pressure was calculated at post-dosing hours 1-24 for each patient. The MASBP for each patient was calculated by averaging the patient's available hourly means for post-dosing hours 1-24. | baseline, week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) | Sitting blood pressure was measured at trough (24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the arm in which the highest sitting diastolic blood pressure was found was the arm used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for five minutes, systolic and diastolic blood pressures were measured 3 times using the standard mercury sphygmomanometer. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting office blood pressure for that visit. | Baseline, week 8 | 
| Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (MADBP) at Week 8 | The 24-hour ambulatory diastolic blood pressure was evaluated at baseline (Week 0) and post-baseline visits. The mean hourly diastolic blood pressure was calculated at post-dosing hours 1-24 for each patient. The MADBP for each patient was calculated by averaging the patient's available hourly means for post-dosing hours 1-24. | baseline, week 8 | 
| Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (MAPP) at Week 8 | The 24-hour ambulatory pulse pressure was evaluated at baseline (Week 0) and post-baseline visits. | baseline, week 8 | 
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) | Sitting blood pressure was measured at trough (24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the arm in which the highest sitting diastolic blood pressure was found was the arm used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for five minutes, systolic and diastolic blood pressures were measured 3 times using the standard mercury sphygmomanometer. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting office blood pressure for that visit. | Baseline, week 8 | 
| Change From Baseline in Mean Sitting Pulse Pressure (MSPP) at Week 8 | At each visit, the pulse rate was measured for 30 seconds just prior to the first sitting blood pressure measurement. | baseline, week 8 | 
| Percentage of Patients Achieving Blood Pressure Control | Blood pressure control was defined as MSSBP/MSDBP <140/90 mmHg. Percentage of patients achieving of blood pressure control at the corresponding visit was reported | 8 weeks | 
| Percentage of Responders | Responders were defined as patients with MSSBP <130 mmHg or a reduction from baseline in MSSBP of >20 mmHg.Percentage of responders achieving a response at the corresponding visit was reported. | Baseline, Week 8 | 
| Change From Baseline in Plasma Renin Activity (PRA) at Week 8 |  | Baseline, week 8 | 
| Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 |  | Baseline, week 8 | 
| Change From Baseline in Plasma Aldosterone at Week 8 |  | Baseline, week 8 | 
| Number of Patients With Adverse Events, Serious Adverse Events and Death | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Type II Diabetes, Aliskiren, Valsartan,, Systolic blood pressure, Diastolic blood pressure,, Stage II, Combination