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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00413049

Enrollment

698

Registered

2006-12-19

Start date

2007-01-31

Completion date

2007-11-30

Last updated

2011-04-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Hypertension

Keywords

Hypertension, valsartan, amlodipine, high blood pressure

Brief summary

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

Interventions

DRUGValsartan/amlodipine 80/5 mg

1 valsartan/amlodipine 80/5 mg tablet and 1 placebo capsule matching amlodipine 5 mg to be taken with water at approximately 8:00 a.m. once daily, except on the morning of every scheduled study visit, when study drug was taken after the completion of all other study procedures.

DRUGAmlodipine 5 mg

1 amlodipine 5 mg capsule and 1 placebo tablet matching valsartan/amlodipine 80/5 mg to be taken with water at approximately 8:00 a.m. once daily, except on the morning of every scheduled study visit, when study drug was taken after the completion of all other study procedures.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 85 Years

Healthy volunteers

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).

Design outcomes

Primary

Measure	Time frame	Description
Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8)	Baseline to end of study (Week 8)	Blood pressure (BP) was measured with a calibrated aneroid or mercury sphygmomanometer. The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position for five minutes, systolic/diastolic BP was measured 3 times at 1-2-minute intervals. The mean of the 3 measurements was calculated. A negative change score indicates lowered BP.

Secondary

Measure	Time frame	Description
Change in Mean Sitting Systolic Blood Pressure (msSBP) From Baseline to End of Study (Week 8)	Baseline to end of study (Week 8)	Blood pressure (BP) was measured with a calibrated aneroid or mercury sphygmomanometer. The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position for five minutes, systolic/diastolic BP was measured 3 times at 1-2-minute intervals. The mean of the 3 measurements was calculated. A negative change score indicates lowered BP.
Percentage of Patients Achieving a Diastolic Response at the End of the Study (Week 8)	Baseline to end of study (Week 8)	A patient achieved a diastolic response if their msDBP \< 90 mmHg at Week 8 or they had a ≥ 10 mmHg decrease in msDBP compared to baseline at the end of the study (Week 8). Blood pressure (BP) was measured with a calibrated aneroid or mercury sphygmomanometer. The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position for five minutes, systolic/diastolic BP was measured 3 times at 1-2-minute intervals. The mean of the 3 measurements was calculated.
Percentage of Patients Achieving Diastolic Control at the End of the Study (Week 8)	Baseline to end of study (Week 8)	A patient achieved diastolic control if their msDBP \< 90 mmHg at the end of the study (Week 8). Blood pressure (BP) was measured with a calibrated aneroid or mercury sphygmomanometer. The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position for five minutes, systolic/diastolic BP was measured 3 times at 1-2-minute intervals. The mean of the 3 measurements was calculated.
Percentage of Patients Achieving Overall Control at the End of the Study (Week 8)	Baseline to end of study (Week 8)	A patient achieved overall control if the msSBP/msDBP \< 140/90 mmHg at the end of the study (Week 8). Blood pressure (BP) was measured with a calibrated aneroid or mercury sphygmomanometer. The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position for five minutes, systolic/diastolic BP was measured 3 times at 1-2-minute intervals. The mean of the 3 measurements was calculated.
Change in 24-hour Mean Ambulatory Diastolic and Systolic BP From Baseline at the End of the Study (Week 8)	Baseline to end of study (Week 8)	Two 24 hour ambulatory blood pressure monitoring (ABPM) evaluations were performed, one at baseline prior to randomization and one at Week 8 (end of study), in a subset of the intent-to-treat population of patients. For each evaluation, the ABPM device was attached to the non-dominant arm of the patient. A correlation was made between the ABPM device readings and measurements taken with a mercury sphygmomanometer and stethoscope. Following the correlation procedure, BP was measured at study specified intervals. A negative change score indicates lowered BP.

Countries

China

Participant flow

Pre-assignment details

Two patients in the valsartan/amlodipine group were excluded from the intent-to-treat population used for the efficacy analyses for having no post-baseline efficacy assessment.

Participants by arm

Arm	Count
Valsartan/Amlodipine 80/5 mg 1 valsartan/amlodipine 80/5 mg tablet and 1 placebo capsule matching amlodipine 5 mg to be taken with water at approximately 8:00 a.m. once daily, except on the morning of every scheduled study visit, when study drug was taken after the completion of all other study procedures.	347
Amlodipine 5 mg 1 amlodipine 5 mg capsule and 1 placebo tablet matching valsartan/amlodipine 80/5 mg to be taken with water at approximately 8:00 a.m. once daily, except on the morning of every scheduled study visit, when study drug was taken after the completion of all other study procedures.	349
Total	696

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Abnormal laboratory value(s)	1	0
Overall Study	Adverse Event	10	8
Overall Study	Lack of Efficacy	1	0
Overall Study	Lost to Follow-up	2	3
Overall Study	Protocol Violation	3	1
Overall Study	Subject no longer requires study drug	0	1
Overall Study	Withdrawal by Subject	7	5

Baseline characteristics

Characteristic	Valsartan/Amlodipine 80/5 mg	Amlodipine 5 mg	Total
Age Continuous	53.4 years STANDARD_DEVIATION 9.7	54.2 years STANDARD_DEVIATION 9.1	53.8 years STANDARD_DEVIATION 9.4
Sex: Female, Male Female	134 Participants	109 Participants	243 Participants
Sex: Female, Male Male	213 Participants	240 Participants	453 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 349	0 / 349
serious Total, serious adverse events	4 / 349	2 / 349

Outcome results

Primary

Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Baseline to End of Study (Week 8)

Blood pressure (BP) was measured with a calibrated aneroid or mercury sphygmomanometer. The arm in which the highest sitting diastolic BP was found at study entry was used for all subsequent readings. At each visit, after the patient was in a sitting position for five minutes, systolic/diastolic BP was measured 3 times at 1-2-minute intervals. The mean of the 3 measurements was calculated. A negative change score indicates lowered BP.