Efficacy and Safety of Valsartan and Amlodipine in Patients With Essential Hypertension

Conditions

Essential Hypertension

Keywords

Hypertension, Valsartan, Amlodipine, high blood pressure

Brief summary

The purpose of this study is to evaluate the safety and efficacy of fixed combination of valsartan (40 mg and 80 mg) and amlodipine (2.5 mg and 5 mg), valsartan and amlodipine alone, and placebo in reducing blood pressure. The study will investigate the dose response relationship for the combinations, monotherapies, and placebo.

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Interventions

DRUGValsartan + amlodipine 40/2.5 mg

Valsartan + amlodipine 40/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily

DRUGValsartan + amlodipine 40/5 mg

Valsartan + amlodipine 40/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily

DRUGValsartan + amlodipine 80/2.5 mg

Valsartan + amlodipine 80/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily

DRUGValsartan + amlodipine 80/5 mg

Valsartan + amlodipine 80/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily

DRUGValsartan 40 mg

Valsartan 40 mg tablet plus 3 tablet and 2 capsule placebos taken once daily

DRUGValsartan 80 mg

Valsartan 80 mg tablet plus 3 tablet and 2 capsule placebos taken once daily

DRUGAmlodipine 2.5 mg

Amlodipine 2.5 mg capsule plus 4 tablet and 1 capsule placebos taken once daily

DRUGAmlodipine 5 mg

Amlodipine 5 mg capsule plus 4 tablet and 1 capsule placebos taken once daily

DRUGPlacebo

4 tablet and 2 capsule placebos taken once daily

Study design

Allocation

RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

20 Years to 80 Years

Healthy volunteers

No

Inclusion criteria

* Patients with essential hypertension measured by electronic hemodynamometer. - - Patients must satisfy the following criteria. 1. MSDBP \<110 mmHg and MSSBP \<180 mmHg at Visit 1 2. MSDBP ≥ 90 mmHg and \< 110 mmHg and MSSBP \< 180 mmHg at Visit 2 3. MSDBP ≥ 95 mmHg and \< 110 mmHg and MSSBP \< 180 mmHg at Visit 3 4. The absolute difference in MSDBP between Visit 2 and 3 is ≤ 10 mmHg * Male or female outpatients. * Aged =\> 20 and =\< 80 years (at the time of signing informed consent). * Patients who have written informed consent to participate in this study.

Exclusion criteria

* Pregnant women, nursing (lactating) mothers, women suspected of being pregnant, or women who wish to be pregnant during the study, women of child-bearing potential. * Patients with secondary hypertension or suspected of having secondary hypertension. * Patients with a history of malignant hypertension. * Patients with an inability to completely discontinue all prior antihypertensive medications safely for a period of 12 weeks as required by the protocol. * Patients with or with a history of any of the following diseases or signs: Cardiac disease, renal disease, cerebrovascular disorder * Patients with a clinically significant allergy (asthma on pharmacotherapy, multi-drug allergy, or drug-induced or food-induced anaphylactic reactions). * Patients hypersensitive to AII receptor antagonists, calcium channel blockers or dihydropyridine derivatives. * Known moderate or malignant retinopathy. * Patients with or with a history of pancreatitis. Patients with pancreatic injury, or evidence of impaired pancreatic function/injury within 12 months of Visit 1. * Patients with any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug. * Patients with volume depletion based on the investigator's or subinvestigator's clinical judgment using vital signs, skin turgor, moistness of mucous membrane and laboratory values. * Patients who are found to have low Na and K (Na \<130 mEq/L, K \<3.3mEq/L) or high in these parameters (Na ≥ 152 mEq/L, K ≥ 5.2 mEq/L) by laboratory tests at Visit 1. * Patients with type I diabetes mellitus on treatment with insulin, or patients with type II diabetes with poor glucose control defined as a glycosylated hemoglobin (HbA1c) \> 8.0% at Visit 1. * Patients with or with a history of malignant tumors including leukemia and lymphoma, treated or untreated, within the past 5 years of Visit 1 whether or not there is evidence of local recurrence or metastases (except for localized basal cell carcinoma of the skin). * Patients with any severe, life-threatening disease within the past 5 years. Patients with a history of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. * Any surgical or medical condition, which in the opinion of the investigator or subinvestigator, place the patient at higher risk from his/her participation in the study, or are likely to prevent the patient from complying with the requirement of the study or completing the trial period. * Patients who have with or with a history of drug or alcohol abuse within the last 2 years of Visit 1. Patients who have received other investigational product within 12 weeks of Visit 1. * Any chronic inflammatory condition needing chronic anti-inflammatory drug therapy. * Persons directly involved in the execution of this study. * Patients who are considered unlikely to comply with the requirements specified in the protocol by the investigator or subinvestigator.

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)	At study entry, blood pressure was measured in both arms using a standard method described in the protocol. The arm with the higher diastolic BP reading was used for the measurements at all subsequent visits. Blood pressure in the sitting position was measured after resting in a seated position for at least 5 minutes. The measurement was repeated a total of 3 times at intervals of 1 to 2 minutes. A negative number indicates lowered blood pressure.

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)	At study entry, blood pressure was measured in both arms using a standard method described in the protocol. The arm with the higher diastolic BP reading was used for the measurements at all subsequent visits. Blood pressure in the sitting position was measured after resting in a seated position for at least 5 minutes. The measurement was repeated a total of 3 times at intervals of 1 to 2 minutes. A negative number indicates lowered blood pressure.
Percentage of Patients Achieving MSDBP < 90 mmHg or a => 10 mm Hg Decrease Compared to Baseline at the End of the Study (Week 8)	Baseline to end of study (Week 8)	At study entry, blood pressure was measured in both arms using a standard method described in the protocol. The arm with the higher diastolic BP reading was used for the measurements at all subsequent visits. Blood pressure in the sitting position was measured after resting in a seated position for at least 5 minutes. The measurement was repeated a total of 3 times at intervals of 1 to 2 minutes. A negative number indicates lowered blood pressure.
Percentage of Patients Achieving MSDBP < 90mmHg at the End of the Study (Week 8)	Baseline to end of study (Week 8)	At study entry, blood pressure was measured in both arms using a standard method described in the protocol. The arm with the higher diastolic BP reading was used for the measurements at all subsequent visits. Blood pressure in the sitting position was measured after resting in a seated position for at least 5 minutes. The measurement was repeated a total of 3 times at intervals of 1 to 2 minutes. A negative number indicates lowered blood pressure.
Percentage of Patients Achieving MSDBP < 90 mm Hg and MSSBP < 140 mm Hg at the End of the Study (Week 8)	Baseline to end of study (Week 8)	At study entry, blood pressure was measured in both arms using a standard method described in the protocol. The arm with the higher diastolic BP reading was used for the measurements at all subsequent visits. Blood pressure in the sitting position was measured after resting in a seated position for at least 5 minutes. The measurement was repeated a total of 3 times at intervals of 1 to 2 minutes. A negative number indicates lowered blood pressure.

Countries

Japan

Participant flow

Participants by arm

Arm	Count
Valsartan + Amlodipine 40/2.5 mg Valsartan + amlodipine 40/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily	159
Valsartan + Amlodipine 40/5 mg Valsartan + amlodipine 40/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily	167
Valsartan + Amlodipine 80/2.5 mg Valsartan + amlodipine 80/2.5 mg tablet plus 3 tablet and 2 capsule placebos taken once daily	160
Valsartan + Amlodipine 80/5 mg Valsartan + amlodipine 80/5mg tablet plus 3 tablet and 2 capsule placebos taken once daily	162
Valsartan 40 mg Valsartan 40 mg tablet plus 3 tablet and 2 capsule placebos taken once daily	169
Valsartan 80 mg Valsartan 80 mg tablet plus 3 tablet and 2 capsule placebos taken once daily	163
Amlodipine 2.5 mg Amlodipine 2.5 mg capsule plus 4 tablet and 1 capsule placebos taken once daily	161
Amlodipine 5 mg Amlodipine 5 mg capsule plus 4 tablet and 1 capsule placebos taken once daily	161
Placebo 4 tablet and 2 capsule placebos taken once daily	166
Total	1,468

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008
Overall Study	Adverse Event	2	2	0	1	4	6	2	3	8
Overall Study	Lack of Efficacy	0	0	0	0	1	3	3	0	5
Overall Study	Lost to Follow-up	0	1	0	0	1	0	0	0	0
Overall Study	Protocol Violation	1	0	1	0	0	0	0	5	3
Overall Study	Withdrawal by Subject	2	0	2	1	4	0	2	2	2

Baseline characteristics

Characteristic	Valsartan + Amlodipine 40/2.5 mg	Valsartan + Amlodipine 40/5 mg	Valsartan + Amlodipine 80/2.5 mg	Valsartan + Amlodipine 80/5 mg	Valsartan 40 mg	Valsartan 80 mg	Amlodipine 2.5 mg	Amlodipine 5 mg	Placebo	Total
Age Continuous	53.9 years STANDARD_DEVIATION 10.34	52.8 years STANDARD_DEVIATION 10.7	52.8 years STANDARD_DEVIATION 10.76	54.1 years STANDARD_DEVIATION 9.75	52.9 years STANDARD_DEVIATION 10.08	52.6 years STANDARD_DEVIATION 11.29	53.2 years STANDARD_DEVIATION 10.83	54.4 years STANDARD_DEVIATION 10.67	51.5 years STANDARD_DEVIATION 10.58	53.1 years STANDARD_DEVIATION 10.57
Sex: Female, Male Female	46 Participants	49 Participants	40 Participants	39 Participants	38 Participants	49 Participants	49 Participants	40 Participants	55 Participants	405 Participants
Sex: Female, Male Male	113 Participants	118 Participants	120 Participants	123 Participants	131 Participants	114 Participants	112 Participants	121 Participants	111 Participants	1063 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	17 / 166	23 / 169	19 / 163	12 / 161	17 / 159	9 / 160	12 / 161	20 / 167	14 / 162
serious Total, serious adverse events	2 / 166	0 / 169	0 / 163	1 / 161	0 / 159	1 / 160	0 / 161	1 / 167	0 / 162

Outcome results

Primary

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

At study entry, blood pressure was measured in both arms using a standard method described in the protocol. The arm with the higher diastolic BP reading was used for the measurements at all subsequent visits. Blood pressure in the sitting position was measured after resting in a seated position for at least 5 minutes. The measurement was repeated a total of 3 times at intervals of 1 to 2 minutes. A negative number indicates lowered blood pressure.

Time frame: Baseline to end of study (Week 8)