A Double-Blind, Randomized, Parallel-Group Study to Compare the Efficacy and Safety of TAK-491 With Ramipril in Subjects With Essential Hypertension
Overview
- Phase
- Phase 3
- Intervention
- Azilsartan medoxomil
- Conditions
- Hypertension
- Sponsor
- Takeda
- Enrollment
- 885
- Primary Endpoint
- Change From Baseline in Mean Trough Clinic Sitting Systolic Blood Pressure.
- Status
- Completed
- Last Updated
- 13 years ago
Overview
Brief Summary
The purpose of this study is to determine the efficacy and safety of azilsartan medoxomil, once daily (QD), compared to ramipril for treating Essential Hypertension.
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 (azilsartan medoxomil) 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 azilsartan medoxomil and ramipril for the treatment of hypertension. Participants 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Essential hypertension (sitting systolic blood pressure between 150 and 180 mm Hg, inclusive).
- •A female participant 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 -
- •If the participant is on amlodipine prior to screening, the participant 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.
- •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.
Arms & Interventions
Azilsartan Medoxomil 40 mg QD
Intervention: Azilsartan medoxomil
Azilsartan Medoxomil 80 mg QD
Intervention: Azilsartan medoxomil
Ramipril 10 mg QD
Intervention: Ramipril
Outcomes
Primary Outcomes
Change From Baseline in Mean Trough Clinic Sitting Systolic Blood Pressure.
Time Frame: Baseline and Week 24.
The change in mean trough clinic sitting systolic blood pressure measured at final visit or week 24 relative to baseline. Systolic blood pressure is the arithmetic mean of the 3 trough sitting systolic blood pressure measurements.
Secondary Outcomes
- Change From Baseline in Mean Trough Clinic Sitting Diastolic Blood Pressure(Baseline and Week 24.)
- Change From Baseline in 24-hour Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)
- Change From Baseline in 24-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)
- Change From Baseline in the 12-hour Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring(Baseline and Week 24.)
- Change From Baseline in the 12-hour Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring(Baseline and Week 24.)
- Change From Baseline in Daytime (6am to 10 pm) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)
- Change From Baseline in Daytime (6am to 10 pm) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)
- Change From Baseline in the Nighttime (12 am to 6 am) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)
- Change From Baseline in the Nighttime (12 am to 6 am) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)
- Change From Baseline in the Trough (22-24-hr) Mean Systolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)
- Change From Baseline in the Trough (22-24-hr) Mean Diastolic Blood Pressure Measured by Ambulatory Blood Pressure Monitoring.(Baseline and Week 24.)