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

Condition(s) targeted: Essential Hypertension

Intervention: TAK-491 (Drug); TAK-491 (Drug); Ramipril (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Takeda Global Research & Development Centre (Europe) Ltd.

Official(s) and/or principal investigator(s):
Medical Director, Study Director, Affiliation: Takeda Global Research & Development Center (Europe), Ltd.

Overall contact:
Study Manager, Phone: +0207 759 5000, Ext: 5116

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

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

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Parallel Assignment, Safety/Efficacy Study

Primary outcome: Change from Baseline in the sitting trough clinic systolic blood pressure.

Secondary outcome:

Change from Baseline in the sitting trough clinic diastolic blood pressure.

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).

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

Comparison of safety endpoints (adverse events and vital signs) of TAK-491 with Ramipril.

Comparison of safety endpoints (electrocardiograms) of TAK-491 with Ramipril.

Comparison of safety endpoints (safety laboratory tests) of TAK-491 with Ramipril.

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Study Manager, Phone: +0207 759 5000, Ext: 5116

Pleven, Bulgaria; Recruiting

Plovdiv, Bulgaria; Recruiting

Rouse, Bulgaria; Recruiting

Sofia, Bulgaria; Recruiting

Varna, Bulgaria; Recruiting

Paide, Estonia; Recruiting

Tallinn, Estonia; Recruiting

Tartu, Estonia; Recruiting

Viljandi, Estonia; Recruiting

Joensuu, Finland; Recruiting

Mikkeli, Finland; Recruiting

Tampere, Finland; Recruiting

Turku, Finland; Recruiting

Augsburg, Germany; Recruiting

Bad Krozingen, Germany; Recruiting

Bad Segeberg, Germany; Recruiting

Berlin, Germany; Recruiting

Dortmund, Germany; Recruiting

Dresden, Germany; Recruiting

Essen, Germany; Recruiting

Frankfurt, Germany; Recruiting

Goch, Germany; Recruiting

Grossheirath, Germany; Recruiting

Hamburg, Germany; Recruiting

Karlsruhe, Germany; Recruiting

Koeln, Germany; Recruiting

Kuenzing, Germany; Recruiting

Leipzig, Germany; Recruiting

Luebeck, Germany; Recruiting

Mannheim, Germany; Recruiting

Muenchen, Germany; Recruiting

Nuernberg, Germany; Recruiting

Deurne, Netherlands; Recruiting

Ewijk, Netherlands; Recruiting

Geleen, Netherlands; Recruiting

Lichtenvoorde, Netherlands; Recruiting

Oude Pekela, Netherlands; Recruiting

Rijswijk, Netherlands; Recruiting

Roelofarendsveen, Netherlands; Recruiting

Rotterdam, Netherlands; Recruiting

Wildervank, Netherlands; Recruiting

Chrzanow, Poland; Recruiting

Gdansk, Poland; Recruiting

Gniewkowo, Poland; Recruiting

Kamieniec Zabkowicki, Poland; Recruiting

Katowice, Poland; Recruiting

Lodz, Poland; Recruiting

Olawa, Poland; Recruiting

Plock, Poland; Recruiting

Poznan, Poland; Recruiting

Skierniewice, Poland; Recruiting

Tarnow, Poland; Recruiting

Moscow, Russian Federation; Recruiting

Perm, Russian Federation; Recruiting

St Petersburg, Russian Federation; Recruiting

Belgrade, Serbia; Recruiting

Nis, Serbia; Recruiting

Niska Banja, Serbia; Recruiting

Zemun, Serbia; Recruiting

Bratislava, Slovakia; Recruiting

Galanta, Slovakia; Recruiting

Levice, Slovakia; Recruiting

Lucenec, Slovakia; Recruiting

Rimavska Sobota, Slovakia; Recruiting

Trencin, Slovakia; Recruiting

Boden, Sweden; Recruiting

Göteborg, Sweden; Recruiting

Lund, Sweden; Recruiting

Malmö, Sweden; Recruiting

Örebro, Sweden; Recruiting

Skene, Sweden; Recruiting

Dnipropetrovsk, Ukraine; Not yet recruiting

Lutsk, Ukraine; Not yet recruiting

Zaporizhzhya, Ukraine; Not yet recruiting

Uzhgorod, Ukraine; Not yet recruiting

Kharkiv, Ukraine; Not yet recruiting

Kyiv, Ukraine; Not yet recruiting

Starting date: January 2008
Ending date: July 2009
Last updated: September 25, 2008