Safety, Tolerability, and Efficacy of Once Daily Amlodipine/Valsartan 5/80 as Compared to Amlodipine/Valsartan 5/40 or to Amlodipine 5 mg Monotherapy in Patients 65 Years of Age and Older With Essential Hypertension

Study Overview
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Brief Summary
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To characterize the safety, tolerability, and efficacy profile of amlodipine/valsartan 5/80 mg as compared to amlodipine/valsartan 5/40 mg (with optional titration to 5/80 mg) and amlodipine 5 mg monotherapy in elderly patients (≥ 65 years of age) with essential hypertension. All three regimens are expected to be well tolerated.

Official Title
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A Multicenter, Double-blind, Randomized, Parallel-group Study to Evaluate the Safety, Tolerability, and Efficacy of Once Daily Amlodipine/Valsartan 5/80 mg as Compared to Amlodipine/Valsartan 5/40 mg or to Amlodipine 5 mg Once Daily in Elderly Patients With Essential Hypertension Not Adequately Controlled After Four Weeks on Amlodipine 5 mg Once Daily

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Amlodipine 5 mg
* Drug: Valsartan 80 mg
* Drug: Valsartan 40 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Provide written informed consent before any assessment was performed. Male or female at least 65 years of age. Diagnosed as having hypertension: At Visit 1/Screening, treatment naïve patients had to have a mean seated SBP ≥ 155 mmHg and < 180 mmHg; patients undergoing washout from their previous antihypertension medication had to have a mean seated SBP <180 mmHg. At Visit 2/Single-blind run-in entry, all patients had to have a mean seated SBP ≥ 155 mmHg and < 180 mmHg. At Visit 3/Core double-blind treatment period entry, all patients had to have a mean seated SBP ≥ 145 mmHg and < 180 mmHg. Ability to communicate and comply with all study requirements including measuring their blood pressure at home, daily as instructed, using the home blood pressure monitor provided by the Sponsor. Female patients had to be post-menopausal for at least one year. Exclusion criteria Severe hypertension (mean seated SBP ≥ 180 mmHg and/or a mean seated DBP ≥ 110 mmHg). History of secondary hypertension (including primary aldosteronism, renovascular hypertension, pheochromocytoma, etc.). Use of three or more antihypertensive drugs. Dual fixed dose combination therapy was considered as two antihypertensive drugs. Administration of any agent indicated for the treatment of hypertension after Visit 1, with the permitted exception of those antihypertensive medications requiring tapering down (e.g. beta-blocker and/or clonidine) commencing with Visit 1. Known moderate or malignant retinopathy. Moderate was defined as retinal signs of hemorrhage, microaneurysm, cotton-wool spot, hard exudates, or a combination thereof; malignant defined as signs of moderate retinopathy plus swelling of the optic disk. Known or suspected contraindications, including history of allergy or hypersensitivity to angiotensin receptor blockers (ARB), calcium channel blockers (CCB), or to drugs with similar chemical structures. History of cerebrovascular accident, thrombotic stroke, or transient ischemic attack. Significant history of coronary artery disease (CAD) such as any history of myocardial infarction (MI), angina pectoris, and all types of revascularization procedures. History of or diagnosis of congestive heart failure Grade II-IV according to the New York Heart Association (NYHA) classification. Clinically significant valvular heart disease. All patients with Type 1 diabetes mellitus and those patients with Type 2 diabetes mellitus who, in the opinion of the investigator, were not well controlled. Patients who needed oral anti-diabetic medication to adequately control their Type 2 diabetes had to be on a stable dose of oral anti-diabetic medication for at least 4 weeks prior to Visit 1. Concomitant potentially life threatening arrhythmia or symptomatic arrhythmia. Second or third degree heart block with or without a pacemaker. Significant hepatic disease, as demonstrated by any one of the following: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values greater than two times the upper limit of normal at Visit 1, a history of hepatic encephalopathy, a history of esophageal varices, or a history of a portocaval shunt. Evidence of renal impairment as determined by any one of the following: glomerular filtration rate (GFR) < 50 ml/min/1.73m2 as measured by the Modification of Diet in Renal Disease (MDRD) formula at Visit 1, a history of dialysis, or a history of nephrotic syndrome. History of clinically significant allergies including asthma and/or multiple drug allergies. Any surgical or medical condition with the potential to significantly alter the absorption, distribution, metabolism, or excretion of any drug including but not limited to any of the following: history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, bowel resection, gastric bypass, gastric stapling, or gastric banding, currently active or inactive inflammatory bowel syndrome within 12 months prior to Visit 1, currently active gastritis, ulcers, or gastrointestinal/rectal bleeding, or urinary tract obstruction regarded as clinically meaningful by the investigator. Any condition, not identified in the protocol, that, in the opinion of the investigator or the Novartis monitor, placed the patient at higher risk from his/her participation in the study, or was likely to prevent the patient from complying with the requirement of the study or completing the trial period. History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there was evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Any chronic inflammatory condition needing chronic anti-inflammatory therapy. History of drug or alcohol abuse within the last 2 years. Use of investigational drugs at the time of enrollment, or within 30 days prior to Visit 1 (Week 8). Inability to communicate and comply with all study requirements including the unwillingness or inability to provide informed consent. Persons directly involved in the execution of this protocol. History of non-compliance to medical regimens, or patients unwilling to comply with the study protocol. Any severe, life-threatening disease within the past five years.

Ages Eligible for Study
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Minimum Age: 65 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: Amlodipine/Valsartan 5/80 mg<br>1 capsule amlodipine 5 mg, 1 capsule valsartan 80 mg once daily | Drug: Amlodipine 5 mg<br>* 1 capsule amlodipine 5 mg orally once daily<br>Drug: Valsartan 80 mg<br>* 1 capsule valsartan 80 mg orally once daily<br>|
| Active Comparator: Amlodipine/Valsartan 5/40 mg<br>1 capsule amlodipine 5 mg, 1 capsule valsartan 40 mg once daily | Drug: Amlodipine 5 mg<br>* 1 capsule amlodipine 5 mg orally once daily<br>Drug: Valsartan 40 mg<br>* 1 capsule valsartan 40 mg orally once daily<br>|
| Active Comparator: Amlodipine 5 mg<br>1 capsule amlodipine 5 mg, 1 capsule placebo to match valsartan once daily | Drug: Amlodipine 5 mg<br>* 1 capsule amlodipine 5 mg orally once daily<br>Drug: Placebo<br>* 1 capsule placebo to match valsartan orally once daily<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 (Week 8) | At study entry, blood pressure (BP) was measured in both arms with an automatic BP monitor. The arm with the higher systolic BP reading was used for all measurements throughout the study. At each study visit, 3 separate sitting BPs were obtained 23-26 hours post-dose with at least 2 minutes between measurements and with the cuff fully deflated. Mean BP was automatically calculated from the 3 readings. A negative change from baseline indicates lowered BP. | Baseline to end of study (Week 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8) | At study entry, blood pressure (BP) was measured in both arms with an automatic BP monitor. The arm with the higher systolic BP reading was used for all measurements throughout the study. At each study visit, 3 separate sitting BPs were obtained 23-26 hours post-dose with at least 2 minutes between measurements and with the cuff fully deflated. Mean BP was automatically calculated from the 3 readings. A negative change from baseline indicates lowered BP. | Baseline to end of study (Week 8) | 
| Percentage of Patients Achieving a Systolic Blood Pressure Response at Week 8 | A systolic blood pressure response was defined as a msSBP < 140 mmHg or ≥ 15 mmHg reduction from baseline at the end of the study (Week 8). At study entry, blood pressure (BP) was measured in both arms with an automatic BP monitor. The arm with the higher systolic BP reading was used for all measurements throughout the study. At each study visit, 3 separate sitting BPs were obtained 23-26 hours post-dose with at least 2 minutes between measurements and with the cuff fully deflated. Mean BP was automatically calculated from the 3 readings. | Baseline to end of study (Week 8) | 
| Percentage of Patients Achieving Systolic Blood Pressure Control at the End of the Study (Week 8) | Systolic blood pressure control was defined as a msSBP < 140 mmHg at the end of the study (Week 8). At study entry, blood pressure (BP) was measured in both arms with an automatic BP monitor. The arm with the higher systolic BP reading was used for all measurements throughout the study. At each study visit, 3 separate sitting BPs were obtained 23-26 hours post-dose with at least 2 minutes between measurements and with the cuff fully deflated. Mean BP was automatically calculated from the 3 readings. | End of study (Week 8) | 
| Percentage of Patients Achieving Overall Blood Pressure Control at the End of the Study (Week 8) | Overall blood pressure control was defined as a msSBP < 140 mmHg and msDBP < 90 mmHg at the end of the study (Week 8). At study entry, blood pressure (BP) was measured in both arms with an automatic BP monitor. The arm with the higher systolic BP reading was used for all measurements throughout the study. At each study visit, 3 separate sitting BPs were obtained 23-26 hours post-dose with at least 2 minutes between measurements and with the cuff fully deflated. Mean BP was automatically calculated from the 3 readings. | End of study (Week 8) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood pressure, hypertension, elderly