Safety and Tolerability of Azilsartan Medoxomil Plus Chlorthalidone Compared to Olmesartan Medoxomil Plus Hydrochlorothiazide in Participants With Essential Hypertension

Condition(s) targeted: Essential Hypertension

Intervention: Azilsartan medoxomil and chlorthalidone (Drug); Olmesartan medoxomil and hydrochlorothiazide (Drug)

Phase: Phase 3

Status: Completed

Sponsored by: Takeda

Official(s) and/or principal investigator(s):
Executive Medical Director, Clinical Science, Study Director, Affiliation: Takeda

The purpose of this study is to compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone, once daily (QD), versus olmesartan medoxomil-hydrochlorothiazide in adults with essential hypertension.

Official title: A Phase 3, Open-Label, Randomized, Long-Term Comparison of the Safety and Tolerability of the TAK-491 Plus Chlorthalidone Fixed-Dose Combination vs. Olmesartan Medoxomil-Hydrochlorothiazide Fixed-Dose Combination in Subjects With Essential Hypertension

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Percentage of Participants With at Least 1 Adverse Event

Secondary outcome: Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN)

Detailed description: High Blood Pressure (Hypertension) is the most common cause of preventable death in developed nations. Uncontrolled hypertension greatly increases the risk of heart disease, brain disease, and kidney failure. As the population ages, the incidence of hypertension will continue to increase if effective preventive measures are not implemented. Despite the availability of antihypertensive agents, hypertension is not adequately controlled; only about one in three patients successfully keep blood pressure normal. Treatment for high blood pressure includes thiazides or thiazide-like diuretics, either alone or as part of combination treatment. Chlorthalidone is a commercially available, orally administered thiazide-type diuretic agent. TAK-491 (azilsartan) is an angiotensin II receptor blocker being evaluated by Takeda to treat patients with high blood pressure (essential hypertension). This study will compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone (TAK-491CLD) fixed-dose combination to olmesartan medoxomil-hydrochlorothiazide fixed-dose combination. Initially patients will undergo a Screening Visit to confirm that they are eligible to participate in the study. All participants will receive the study drug for up to 52 weeks. The dose of the study drug may be gradually increased throughout the study so that a target blood pressure value can be reached for each participant. Throughout the treatment period of the study, participants will be required to visit the research site for 11 visits. At these study visits participants will be required to undergo certain study procedures including physical examinations, vital sign measurements (blood pressure, heart rate, weight and height), electrocardiograms (monitoring of the heart), and blood and urine samples taken for clinical laboratory tests.

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

Criteria:

Inclusion Criteria:

- Is treated with antihypertensive therapy and has a post-washout mean sitting clinic

systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg on Day, or has not received antihypertensive treatment within 14 days prior to Screening and has a mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg at the Screening Visit and on Day 1.

- Females of childbearing potential who are sexually active agree to routinely use

adequate contraception, and can neither be pregnant nor lactating from before study participation to Screening to 30 days after the last study drug dose.

- Has clinical laboratory test results within the reference range for the testing

laboratory or the investigator does not consider the results to be clinically significant.

- Is willing to discontinue current antihypertensive medications up to 3 weeks before

enrollment. Exclusion Criteria:

- Has a mean clinic diastolic blood pressure (sitting, trough) greater than 119 mm Hg

on Day 1.

- Has secondary hypertension of any etiology (eg, renovascular disease,

pheochromocytoma, Cushing's syndrome).

- 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 (ie, third-degree

atrioventricular block, sick sinus syndrome).

- Has hemodynamically significant left ventricular outflow obstruction due to aortic

valvular disease.

- Has severe renal dysfunction or disease.

- Has known or suspected unilateral or bilateral renal artery stenosis.

- Has a history of cancer that has not been in remission for at least 5 years prior to

the first dose of study drug.

- Has poorly-controlled type 1 or 2 diabetes mellitus at Screening.

- Has hypokalemia or hyperkalemia at Screening.

- Has an alanine aminotransferase or aspartate aminotransferase level of greater than

2. 5 times the upper limit of normal, active liver disease, or jaundice at Screening.

- Has any other known serious disease or condition that would compromise safety, might

affect life expectancy, or make it difficult to successfully manage and follow according to the protocol.

- Has known hypersensitivity to angiotensin II receptor blockers or thiazide-type

diuretics or other sulfonamide-derived compounds.

- Has been randomized/enrolled in a previous azilsartan or azilsartan medoxomil plus

chlorthalidone study.

- Currently is participating in another investigational study or has received any

investigational compound within 30 days prior to Screening.

- Has a history of drug abuse or a history of alcohol abuse within the past 2 years.

- Is taking or expected to take any excluded medication, including:

- Antihypertensive medications must be discontinued completely by Day -14, except

antihypertensive medications used in the open-label treatment period in accordance with the titration-to-target blood pressure titration.

- Angiotensin II receptor blockers or thiazide-type diuretics other than study

medication.

- Over-the-counter products not permitted by investigator.

Groningen, Netherlands

Karlsruhe, Baden-Wurttemberg, Germany

Avon, England, United Kingdom

Bolton, England, United Kingdom

Chorley, England, United Kingdom

Inverness, England, United Kingdom

Liverpool, England, United Kingdom

Surrey, England, United Kingdom

Warwickshire, England, United Kingdom

Bydgoszcz, Kuyavian-Pomeranian, Poland

Skierniewice, L0dz, Poland

Zgierz, L0dz, Poland

Hannover, Lower Saxony, Germany

Breda, North Brabant, Netherlands

Eindhoven, North Brabant, Netherlands

Amsterdam, North Holland, Netherlands

Gdansk, Pomeranian, Poland

Gdynia, Pomeranian, Poland

Sopot, Pomeranian, Poland

Velp, Rheden, Netherlands

Kiel-Kronshagen, Schleswig-Holstein, Germany

Mikolow, Silesian, Poland

Leiderdorp, South Holland, Netherlands

Zoetermeer, South Holland, Netherlands

Graz, Styria, Austria

Rotterdam, Zuid-Holland, Netherlands

EDARBYCLOR Package Insert

FDA Safety Alerts and Recalls

Starting date: October 2009
Last updated: October 15, 2012