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

• ClinicalTrials.gov Identifier: NCT00699192
• Recruitment Status: Completed
• First Posted: June 17, 2008
• Results First Posted: June 6, 2011
• Last Update Posted: June 6, 2011
• Sponsor: Novartis Pharmaceuticals
• Information provided by: Novartis

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypertension	Drug: Amlodipine 5 mg; Drug: Valsartan 80 mg; Drug: Valsartan 40 mg; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 965 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 2008
• Actual Primary Completion Date: May 2009
• Actual Study Completion Date: May 2009

Arms and Interventions

Arm	Intervention/treatment
Experimental: Amlodipine/Valsartan 5/80 mg; 1 capsule amlodipine 5 mg, 1 capsule valsartan 80 mg once daily	Drug: Amlodipine 5 mg; 1 capsule amlodipine 5 mg orally once daily; Drug: Valsartan 80 mg; 1 capsule valsartan 80 mg orally once daily
Active Comparator: Amlodipine/Valsartan 5/40 mg; 1 capsule amlodipine 5 mg, 1 capsule valsartan 40 mg once daily	Drug: Amlodipine 5 mg; 1 capsule amlodipine 5 mg orally once daily; Drug: Valsartan 40 mg; 1 capsule valsartan 40 mg orally once daily
Active Comparator: Amlodipine 5 mg; 1 capsule amlodipine 5 mg, 1 capsule placebo to match valsartan once daily	Drug: Amlodipine 5 mg; 1 capsule amlodipine 5 mg orally once daily; Drug: Placebo; 1 capsule placebo to match valsartan orally once daily

Outcome Measures

Primary Outcome Measures :

1. Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8) [ Time Frame: 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.

Secondary Outcome Measures :

1. Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8) [ Time Frame: 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.
2. Percentage of Patients Achieving a Systolic Blood Pressure Response at Week 8 [ Time Frame: Baseline to end of study (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.
3. Percentage of Patients Achieving Systolic Blood Pressure Control at the End of the Study (Week 8) [ Time Frame: End of 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.
4. Percentage of Patients Achieving Overall Blood Pressure Control at the End of the Study (Week 8) [ Time Frame: End of 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.

Eligibility Criteria

• Ages Eligible for Study: 65 Years and older (Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Czech Republic

Novartis Investigative site

Brno, Czech Republic

Investigative site Czech Republic

Chrudim, Czech Republic

Investigative sites Czech Repbulic

Hodonin, Czech Republic

Investigative site Czech Repbulic

Jicin, Czech Republic

Sites in Czech Republic

Nachod, Czech Republic

Investigative sites Czech Republic

Praha, Czech Republic

Finland

Investigative site Finland

Helsinki, Finland

Investigative site Finland

Joensuu, Finland

Investigative site Finland

Kerava, Finland

Investigative site Finland

Tampere, Finland

France

Investigative site France

Paris, France

Germany

Investigative site Germany

Berlin, Germany

Hungary

Investigative site Hungary

Budapest, Hungary

Italy

Investigative site Italy

Rome, Italy

Poland

Investigative site Poland

Warsaw, Poland

Slovakia

Investigative site Slovakia

Bratislava, Slovakia

Spain

Investigative site Spain

Valencia, Spain

Sweden

Investigative site Sweden

Malmo, Sweden

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: External Affairs, Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00699192 History of Changes
• Other Study ID Numbers: CVAA489A2318
• First Posted: June 17, 2008
• Results First Posted: June 6, 2011
• Last Update Posted: June 6, 2011
• Last Verified: May 2011

Keywords provided by Novartis:

Blood pressure; hypertension; elderly

Additional relevant MeSH terms:

Hypertension; Essential Hypertension; Vascular Diseases; Cardiovascular Diseases; Amlodipine; Valsartan; Amlodipine, Valsartan Drug Combination; Antihypertensive Agents; Calcium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Vasodilator Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists