Efficacy and Safety of TAK-491 and Chlorthalidone in Subjects With Moderate to Severe Hypertension

Condition(s) targeted: Essential Hypertension

Intervention: TAK-491 and chlorthalidone (Drug); TAK-491 and hydrochlorothiazide (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Takeda Global Research & Development Center, Inc.

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

Overall contact:
Takeda Study Registration Call Center, Phone: 800-778-2860, Email: medicalinformation@tpna.com

The purpose of this study is to compare the antihypertensive effect of chlorthalidone vs hydrochlorothiazide when each is used with TAK-491 in subjects with moderate to severe essential hypertension.

Official title: A Phase 3, Double-Blind, Randomized, Efficacy and Safety Study of the TAK 491 Plus Chlorthalidone Fixed-Dose Combination Compared With TAK-491 and Hydrochlorothiazide Coadministration Therapy in Subjects With Moderate to Severe Essential Hypertension

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

Primary outcome: Change from Baseline in trough, sitting, Clinic Systolic Blood Pressure

Secondary outcome:

Change from Baseline in trough, sitting, Clinic Diastolic Blood Pressure

Change from Baseline in mean trough Systolic Blood Pressure and Diastolic Blood Pressure (22 to 24 hours after dosing) per ambulatory blood pressure monitoring.

Change from Baseline in 24-hour mean Systolic Blood Pressure and Diastolic Blood Pressure per ambulatory blood pressure monitoring.

Change from Baseline in the mean daytime (6 AM to 10 PM) Systolic Blood Pressure and Diastolic Blood Pressure per ambulatory blood pressure monitoring.

Change from baseline in the mean nighttime (12 AM to 6 AM) systolic blood pressure and diastolic blood pressure per ambulatory blood pressure monitoring.

Change from baseline in the mean Systolic Blood Pressure and Diastolic Blood Pressure at 0 to 12 hours after dosing per ambulatory blood pressure monitoring.

Trough-to-Peak Ratio as determined by ambulatory blood pressure monitoring.

Proportion of subjects who reached their target Systolic Blood Pressure, Diastolic Blood Pressure, and Systolic Blood Pressure/Diastolic Blood Pressure

Detailed description: According to the World Health Organization, hypertension is the most common attributable cause of preventable death in developed nations, as uncontrolled hypertension greatly increases the risk of cardiovascular disease, cerebrovascular disease, and renal failure. Despite the availability of antihypertensive agents, hypertension remains inadequately controlled; only about one-third of patients continue to maintain control successfully.

Although most antihypertensive agents are effective at the appropriate dose, the majority have side effects that limit their use. As a class, angiotensin II receptor blockers generally are considered more tolerable than other classes of antihypertensive agents. TAK-491 is an angiotensin II receptor blocker being evaluated by Takeda to treat essential hypertension.

Treatments for essential hypertension commonly include use of a thiazide-type diuretic, either alone or as part of combination treatment. Although chlorthalidone was commonly prescribed in the past, its use has widely been replaced with hydrochlorothiazide, presumably due to a lack of available combination products containing chlorthalidone, the assumption that hydrochlorothiazide and chlorthalidone have similar antihypertensive effects and cardiovascular benefits, and the perception that chlorthalidone use is associated with a greater frequency of hypokalemia. However, the frequency of hypokalemia with chlorthalidone use is relatively low in the dose range of 12. 5 to 25 mg and these doses have been shown to be associated with potent blood pressure reduction. Several long-term outcomes trials have shown that blood pressure reductions associated with chlorthalidone treatment reduce risk of cardiovascular morbidity and mortality.

Most hypertensive patients require two or more agents to achieve target blood pressure and diuretics are commonly used in combination with other antihypertensive agents. This trial is designed to compare chlorthalidone and hydrochlorothiazide when coadministered with TAK-491.

Subjects in this study will receive either chlorthalidone or hydrochlorothiazide in combination with TAK-491. Total commitment time for this study is about 13 weeks. Subjects will be required to wear a blood pressure monitor for three 24 hours periods during the study.

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 - 1 or the subject is treatment naïve 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 from Screening through 30 days after the last administered study drug dose.

- Has clinical laboratory test results (clinical chemistry, hematology, and complete

urinalysis) 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 on Day -21 or Day -28

if the subject is on amlodipine or chlorthalidone.

Exclusion Criteria:

- Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg on Day -1.

- Has a baseline 24-hour ambulatory blood pressure monitoring reading of insufficient

quality.

- Works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]).

- Has an upper arm circumference less than 24 cm or greater than 42 cm.

- Is noncompliant (less than 70% or greater than 130%) with study medication during the

placebo run-in period.

- 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, atrial fibrillation, or atrial flutter).

- Has hemodynamically significant left ventricular outflow obstruction due to aortic

valvular disease.

- Has severe renal dysfunction or disease [based on estimated glomerular filtration rate

less than 30 mL/min/1. 73m2 at Screening].

- 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. (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%) at Screening.

- Has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal

reference range of the central laboratory).

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

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

- 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 the subject according to the protocol.

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

diuretics or other sulfonamide-derived compounds.

- Has been randomized in a previous TAK-491 study.

- Is currently participating in another investigational study or has participated in an

investigational study within 30 days prior to Randomization.

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

- Is required to take or intends to continue taking any disallowed medication, any

prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

- Antihypertensive agents, including those used for treatment of other conditions,

such as benign prostatic hyperplasia (a-blockers) or edema (diuretics).

- Insulin.

- Other agents that alter blood pressure, including:

- Tricyclic antidepressants.

- Monoamine oxidase inhibitors.

- Central nervous system stimulants.

- Amphetamines or their derivatives.

- Dopamine agonists.

- Atypical antipsychotic agents.

- Opiates

- Muscle relaxants.

- Trazodone.

- Lithium.

- Phosphodiesterase type 5 inhibitors.

- Diet medications.

- Nitrates.

- Chronically used common cold medications with pseudoephedrine or

nonsteroidal anti-inflammatory drugs, including aspirin more than 325 mg/day or cyclooxygenase-2 inhibitors.

- Systemic use of corticosteroids.

- Thiazolidinediones.

- Medications for treatment of insomnia are limited to no more than once a week on

average and are prohibited on ambulatory blood pressure monitoring days.

Takeda Study Registration Call Center, Phone: 800-778-2860, Email: medicalinformation@tpna.com

Gilbert, Arizona, United States; Recruiting

Sierra Vista, Arizona, United States; Recruiting

San Diego, California, United States; Not yet recruiting

Wheat Ridge, Colorado, United States; Not yet recruiting

Adventura, Florida, United States; Not yet recruiting

Brooksville, Florida, United States; Recruiting

Crystal River, Florida, United States; Not yet recruiting

DeLand, Florida, United States; Not yet recruiting

Doral, Florida, United States; Recruiting

Miami, Florida, United States; Not yet recruiting

Naranja, Florida, United States; Not yet recruiting

Tampa, Florida, United States; Not yet recruiting

Sarasota, Florida, United States; Not yet recruiting

West Palm Beach, Florida, United States; Not yet recruiting

Winter Haven, Florida, United States; Not yet recruiting

Atlanta, Georgia, United States; Not yet recruiting

Stockbridge, Georgia, United States; Not yet recruiting

Suwanee, Georgia, United States; Recruiting

Valparaiso, Indiana, United States; Recruiting

Crestview Hills, Kentucky, United States; Recruiting

St. Louis, Missouri, United States; Not yet recruiting

St. Peters, Missouri, United States; Recruiting

Cincinnati, Ohio, United States; Recruiting

Kettering, Ohio, United States; Not yet recruiting

Lansdale, Pennsylvania, United States; Recruiting

Goose Creek, South Carolina, United States; Recruiting

Bryan, Texas, United States; Recruiting

San Antonio, Texas, United States; Recruiting

Ettrick, Virginia, United States; Not yet recruiting

Madison, Wisconsin, United States; Recruiting

Starting date: January 2009
Ending date: May 2010
Last updated: February 9, 2009