Efficacy and Safety Study of TAK-491 Compared to Ramipril for Treating Essential Hypertension - Full Text View

Sponsored by:	Takeda Global Research & Development Centre (Europe) Ltd.
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00760214

Purpose

The purpose of this study is to determine the efficacy and safety of TAK-491 compared to Ramipril for treating Essential Hypertension.

Condition	Intervention	Phase
Essential Hypertension	Drug: TAK-491 Drug: Ramipril	Phase III

MedlinePlus related topics: High Blood Pressure

Drug Information available for: Ramipril

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study
Official Title:	A Double-Blind, Randomized, Parallel-Group Study to Compare the Efficacy and Safety of TAK-491 With Ramipril in Subjects With Essential Hypertension

Further study details as provided by Takeda Global Research & Development Center, Inc.:

Primary Outcome Measures:

Change from Baseline in the sitting trough clinic systolic blood pressure. [ Time Frame: Week 24 or Final Visit ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change from Baseline in the sitting trough clinic diastolic blood pressure. [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in the systolic and diastolic blood pressure using ambulatory blood pressure monitoring measurements (24-hour mean, daytime [6 AM to 10 PM] mean and night-time [12 AM to 6 AM] mean). [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Change from Baseline in the systolic and diastolic blood pressure via ambulatory blood pressure monitoring measurements (blood pressure mean at 0 to 12 hours after dosing, and trough mean at 22 to 24 hours after dosing, peak effect and trough-to-peak ra [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20 and 24 or Final Visit. ] [ Designated as safety issue: No ]
Comparison of safety endpoints (adverse events and vital signs) of TAK-491 with Ramipril. [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Comparison of safety endpoints (electrocardiograms) of TAK-491 with Ramipril. [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]
Comparison of safety endpoints (safety laboratory tests) of TAK-491 with Ramipril. [ Time Frame: Weeks: 2, 4, 8, 12, 16, 20 and 24 or Final Visit. ] [ Designated as safety issue: Yes ]

Enrollment:	1227
Study Start Date:	January 2008
Estimated Study Completion Date:	April 2009
Estimated Primary Completion Date:	April 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental	Drug: TAK-491 TAK-491 20 mg tablet, orally, once daily for two weeks; then increased to 40 mg tablet, orally, once daily for up to 22 weeks.
2: Experimental	Drug: TAK-491 TAK-491 20 mg tablet, orally, once daily for two weeks; then increased to 80 mg tablet, orally, once daily for up to 22 weeks.
3: Active Comparator	Drug: Ramipril Ramipril 2.5 mg tablet, orally, once daily for two weeks; then increased to 10 mg tablet, orally, once daily for up to 22 weeks.

Detailed Description:

A major component of blood pressure regulation is the renin-angiotensin-aldosterone system, a system of hormone-mediated feedback interactions that results in the relaxation or constriction of blood vessels in response to various stimuli. Angiotensin II, a polypeptide hormone, is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme as part of the renin-angiotensin-aldosterone system. Angiotensin II is the principal pressor agent of the renin-angiotensin-aldosterone system with a myriad of effects on the cardiovascular system and on electrolyte homeostasis. Two receptors for angiotensin II have been identified. Angiotensin II type 1 receptors are located predominantly in vascular smooth muscle, where activation by angiotensin II results in vasoconstriction, hypertrophic proliferation, and inflammation. In contrast, stimulation of angiotensin II type 2 receptors by angiotensin II results in vasodilatation, antiproliferative effects that are opposite from those of angiotensin II type 1 receptor stimulation.

Drugs that modulate the renin-angiotensin-aldosterone system are used commonly worldwide for the treatment of hypertension. Of these, some block the synthesis of angiotensin II by inhibiting angiotensin-converting enzymes, while others inhibit the action of angiotensin II by binding directly to the angiotensin II type 1 receptor (called angiotensin II receptor blockers), thereby causing vasodilatation of blood vessels, resulting in a reduction in blood pressure. The effects of angiotensin II receptor blockers on other conditions in which the renin-angiotensin-aldosterone system plays a significant role, such as congestive heart failure, postmyocardial infarction management and diabetic nephropathy have also been investigated.

Although antihypertensive agents are effective at the appropriate dose, the majority have side effects that limit their use. Angiotensin-converting enzyme inhibitors are commonly associated with cough and more rarely with angioedema. Beta-blockers are associated with fatigue and erectile dysfunction, calcium antagonists with peripheral edema and diuretics with metabolic complications. As a class, angiotensin II receptor blockers generally are considered more tolerable than other classes of hypertensive agents, although there is still a need for compounds with improved tolerability and efficacy for the treatment of hypertension.

TAK-491 is an angiotensin II receptor blocker with high affinity for, and selective antagonistic activity at, the angiotensin II type 1 receptor, and is being developed for clinical use as an antihypertensive agent.

Ramipril is an angiotensin-converting enzyme inhibitor widely prescribed in Europe and Asia for the treatment of mild to moderate essential hypertension.

This study is designed to compare the efficacy and safety/tolerability of TAK-491 and Ramipril for the treatment of hypertension.

Subjects participating in this study will be seen twice during the first month, then once a month for five months. Participants will also be required to fast for 8 hours prior to each visit to the study center. Total duration of study participation is 24-weeks, plus a safety follow up phone call after the study has ended.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Has essential hypertension.
A female subject of childbearing potential who is sexually active agrees to use adequate contraception from screening throughout the duration of the study, and cannot be pregnant.
Has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory at Screening or the results are deemed not clinically significant for inclusion into this study by the investigator.
Is willing to discontinue current antihypertensive medications at Screening Day -21. If the subject is on amlodipine prior to screening, the subject is willing to discontinue this medication at Screening Day -28.

Exclusion Criteria:

Has an systolic blood pressure greater than 180 mmHg or diastolic blood pressure greater than 114 mmHg at Randomization.
Is taking or expected to take an excluded medication including antihypertensive agents, insulin or other agents that alter blood pressure, including:
- Tricyclic antidepressants.
- Monoamine oxidase inhibitors.
- Lithium.
- Phosphodiesterase type 5 inhibitors.
- Diet medications.
- Amphetamines or their derivatives.
- Chronically used (defined as more than 3 doses per week) common cold medications or nonsteroidal anti-inflammatory, including aspirin greater than 300 mg/day or cyclooxygenase-2 inhibitors.
- Systemic use of corticosteroids (topical or inhaled is acceptable).
- Thiazolidinediones
- Herbal medications
Is hypersensitive to angiotensin II receptor blockers and/or angiotensin-converting enzyme inhibitors.
Has a recent history within the last 6 months of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
Has clinically significant cardiac conduction defects (eg, third-degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation or flutter).
Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).
Is noncompliant (less than 70% or greater than 130%) with study medication during placebo run-in period.
Has severe renal dysfunction or disease (based on calculated creatinine clearance less than 30 mL/min/1.73 m² at Screening).
Has known or suspected unilateral or bilateral renal artery stenosis.
Has a history of drug or alcohol abuse within the past 2 years.
Has a previous history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. (This criterion does not apply to those subjects with basal cell or stage I squamous cell carcinoma of the skin).
Has type 1 or poorly controlled type 2 diabetes mellitus (hemoglobin A1c greater than 8.0%) or is taking insulin.
Has hyperkalemia as defined by the central laboratory normal reference range at Screening.
Has an upper arm circumference less than 24 cm or greater than 42 cm.
Works night (third) shift (defined as 11 PM to 7 AM).
Has an alanine aminotransferase level at Screening of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
Is currently participating in another investigational study or has participated in an investigational study within 30 days prior to Screening.
Has any other serious disease or condition at Screening or Randomization that would compromise subject safety, might affect life expectancy, or make it difficult to successfully manage and follow the subject according to the protocol.
Has been randomized in a previous TAK-491 study.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00760214

Show 71 Study Locations

Sponsors and Collaborators

Takeda Global Research & Development Centre (Europe) Ltd.

Investigators

Study Director:

Medical Director

Takeda Global Research & Development Center (Europe), Ltd.

More Information

Responsible Party:	Takeda Global Research & Development Centre (Europe), Ltd.. ( VP Clinical Science )
Study ID Numbers:	01-06-TL-491-020, 2007-002583-10
Study First Received:	September 24, 2008
Last Updated:	December 18, 2008
ClinicalTrials.gov Identifier:	NCT00760214
Health Authority:	Bulgaria: Bulgarian Drug Agency; Estonia: The State Agency of Medicine; Finland: National Agency for Medicines; Germany: Federal Institute for Drugs and Medical Devices; Netherlands: The Central Committee on Research Involving Human Subjects (CCMO); Russia: Ministry of Health and Social Development of the Russian Federation; Slovakia: State Institute for Drug Control; Ukraine: State Pharmacological Center - Ministry of Health; Sweden: Läkemedelsverket Kliniska prövningar; Serbia: Medicines and Medical Devices Agency of Serbia; Poland: Central Register of Therapeutic Products, Medical Products and Biocides

Keywords provided by Takeda Global Research & Development Center, Inc.:

Essential Hypertension
Hypertension
Drug Therapy

Blood Pressure, High
Vascular Disease
Cardiovascular Disease

Study placed in the following topic categories:

Vascular Diseases
Essential hypertension
Ramipril
Hypertension

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Therapeutic Uses
Angiotensin-Converting Enzyme Inhibitors
Enzyme Inhibitors
Cardiovascular Diseases

Cardiovascular Agents
Antihypertensive Agents
Pharmacologic Actions
Protease Inhibitors

ClinicalTrials.gov processed this record on January 14, 2009