Efficacy/Safety of Valsartan Plus Amlodipine and Amlodipine Alone in Patients With Hypertension

A Multi-national, Multicenter, Double-blind, Double-dummy, Randomized, Active-controlled, Parallel Study Comparing the Efficacy and Safety of Valsartan/Amlodipine 80/5 mg to Amlodipine 5 mg Alone Once Daily in Patients With Mild to Moderate Essential Hypertension Not Adequately Controlled With Amlodipine 5 mg Monotherapy

This study will evaluate the safety and efficacy of the fixed combination of valsartan/amlodipine in adult patients with mild to moderate hypertension

Inclusion criteria

• Male or female outpatients ≥ 18 years and < 86 years
• Patients with essential hypertension measured by calibrated mercury sphygmomanometer (preferred) or an aneroid device if a mercury sphygmomanometer was not available.
• At Visit 1, patients not treated with antihypertensive medications had to have a MSDBP of ≥ 95 mmHg and < 110 mmHg; those patients treated with antihypertensive medication had to have a MSDBP of < 110 mmHg.
• At Visit 2, patients must have a MSDBP of ≥ 95 mmHg but < 110 mmHg.
• At Visit 3, patients must have a MSDBP of ≥ 90 mmHg and < 110 mmHg.
• Patients who were eligible and able to participate in the study, and who consented to do so after the purpose and nature of the investigation had been clearly explained to them (written informed consent).

Exclusion criteria

• Severe hypertension (MSDBP ≥ 110 mmHg and/or MSSBP ≥ 180 mmHg).
• In cases where the patient was on more than one antihypertensive drug whether in fixed or free combination, the investigator considered the efficacy and strength of each active ingredient in order to determine if the patient could be safely removed from their antihypertensive treatment.
• 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.
• Administration of any agent indicated for the treatment of hypertension after Visit 1 with the exception of those agents that required tapering down.
• Inability to discontinue all prior antihypertensive medications safely for a maximum period of up to 28 days prior to Visit 2, as required by the protocol.
• History of hypertensive encephalopathy, cerebrovascular accident or transient ischemic attack, myocardial infarction or all types of revascularization.
• Malignant hypertension.
• All patients with Type 1 diabetes mellitus and those patients with Type 2 diabetes mellitus who were not well controlled based on the investigator's clinical judgment. Patients being treated for diabetes mellitus had to have satisfactory metabolic control. Type 2 diabetic patients taking oral anti-diabetic medication had to be on a stable dose for at least 4 weeks prior to Visit 1.
• Pregnant or nursing (lactating) women, where pregnancy was defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/ml).
• Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precluded intercourse with a male partner and women whose partners had been sterilized by vasectomy or other means, UNLESS they met the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) levels > 40 mIU/m or 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy OR were using one or more of the following acceptable methods of contraception: surgical sterilization (e.g., bilateral tubal ligation, vasectomy), and double-barrier methods (any double combination of: intra-uterine device [IUD], male or female condom with spermicidal gel, diaphragm, sponge, cervical cap). Acceptable methods of contraception included total abstinence at the discretion of the investigator in cases where the age, career, lifestyle, or sexual orientation of the patient ensured compliance. Reliable contraception had to be maintained throughout the study and for 7 days after study drug discontinuation. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal were not acceptable methods of contraception. Hormonal contraceptive use was disallowed.
• History of heart failure Grade II-IV according to the New York Heart Association (NYHA) classification.
• Second or third degree heart block with or without a pacemaker.
• Concomitant potentially life threatening arrhythmia or symptomatic arrhythmia.
• Angina pectoris of any type, including unstable angina pectoris.
• Clinically significant valvular heart disease.
• Evidence of a secondary form of hypertension, including but not limited to any of the following: coarctation of the aorta, hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing disease, pheochromocytoma, polycystic kidney disease.
• Known moderate or malignant retinopathy, defined as: moderate (retinal signs of hemorrhage, microaneurysm, cotton-wool spot, hard exudates, or a combination thereof) or malignancy (signs of moderate retinopathy plus swelling of the optic disk).
• Evidence of hepatic disease as determined 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 anyone of the following: serum creatinine > 1.5 times the upper limit of normal 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 active 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 surgical or medical condition, which in the opinion of the investigator or the Novartis monitor, placed the patient at higher risk from his/her participation in the study, or were likely to prevent the patient from complying with the requirement of the study or completing the trial period.
• Volume depletion based on the investigator's clinical judgment using vital signs, skin turgor, moistness of mucous membranes, and laboratory values.
• Any chronic inflammatory condition requiring chronic anti-inflammatory therapy.
• 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.
• History of drug of alcohol abuse within the last 2 years.
• Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever was longer.
• 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 unwillingness to comply with the study protocol.
• Currently taking prohibited concomitant medications(s) listed and inability/unwillingness to discontinue them for the entire study period.
• Any severe, life-threatening disease within the past five years.
• Arm circumference > 42 cm for patients participating in ambulatory blood pressure monitoring (ABPM).