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

Sponsor:	Takeda Global Research & Development Center, Inc.
Information provided by:	Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier:	NCT00818883

Purpose

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.

Condition	Intervention	Phase
Essential Hypertension	Drug: TAK-491 and chlorthalidone Drug: TAK-491 and hydrochlorothiazide	Phase III

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

Resource links provided by NLM:

MedlinePlus related topics: High Blood Pressure

Drug Information available for: Hydrochlorothiazide Chlorthalidone

U.S. FDA Resources

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

Primary Outcome Measures:

Change from Baseline in trough, sitting, Clinic Systolic Blood Pressure [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change from Baseline in trough, sitting, Clinic Diastolic Blood Pressure [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from Baseline in mean trough Systolic Blood Pressure (22 to 24 hours after dosing) per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from Baseline in mean trough Diastolic Blood Pressure (22 to 24 hours after dosing) per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from Baseline in 24-hour mean Systolic Blood Pressure per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from Baseline in 24-hour mean Diastolic Blood Pressure per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from Baseline in the mean daytime (6 AM to 10 PM) Systolic Blood Pressure per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from Baseline in the mean daytime (6 AM to 10 PM) Diastolic Blood Pressure per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from baseline in the mean nighttime (12 AM to 6 AM) Systolic Blood Pressure per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from baseline in the mean nighttime (12 AM to 6 AM) Diastolic Blood Pressure per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from baseline in the mean Systolic Blood Pressure at 0 to 12 hours after dosing per ambulatory blood pressure monitoring [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Change from baseline in the mean Diastolic Blood Pressure at 0 to 12 hours after dosing per ambulatory blood pressure monitoring. [ Time Frame: Weeks 6 and 10 ] [ Designated as safety issue: No ]
Proportion of subjects who reached their trough, sitting, clinic Systolic and Diastolic blood pressure targets, defined as <140/90 mm Hg without diabetes or chronic kidney disease or <130/80 mm Hg with diabetes or chronic kidney disease [ Time Frame: Weeks 2, 4, 6, 8 and 10 ] [ Designated as safety issue: No ]
Proportion of subjects who reached their trough, sitting, clinic Systolic blood pressure targets, defined as <140 mm Hg for subjects without diabetes or chronic kidney disease or <130 mm Hg for subjects with diabetes or chronic kidney disease [ Time Frame: Weeks 2, 4, 6, 8 and 10 ] [ Designated as safety issue: No ]
Proportion of subjects who reached their trough, sitting, clinic Diastolic blood pressure targets, defined as <90 mm Hg for subjects without diabetes or chronic kidney disease or <80 mm Hg for subjects with diabetes or chronic kidney disease [ Time Frame: Weeks 2, 4, 6, 8 and 10 ] [ Designated as safety issue: No ]

Enrollment:	609
Study Start Date:	February 2009
Study Completion Date:	November 2009
Primary Completion Date:	November 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental	Drug: TAK-491 and chlorthalidone TAK-491 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily and hydrochlorothiazide placebo-matching capsules, orally, once daily for up to 10 weeks. For subjects who do not achieve target blood pressure by Week 6, the dose of chlorthalidone will be increased for the remaining 4 weeks of treatment.
2: Experimental	Drug: TAK-491 and hydrochlorothiazide TAK-491 40 mg, tablets, orally, once daily and hydrochlorothiazide 12.5 mg, capsules, orally, once daily for up to 10 weeks. For subjects who do not achieve target blood pressure by Week 6, the dose of hydrochlorothiazide will be increased for the remaining 4 weeks of treatment.

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.

Eligibility

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

Criteria

Inclusion Criteria:

Is treated with antihypertensive therapy and has a post-washout mean sitting clinic SBP greater than or equal to 160 and less than or equal to 190 mm Hg on Day -1; or the subject has not received antihypertensive treatment within 28 days prior to Screening and has a mean sitting clinic SBP 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 poorly-controlled type 1 or type 2 diabetes mellitus 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.
Currently participating in another investigational study or is receiving 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 an excluded medication, including:
- Antihypertensive agents, including those used for treatment of other conditions, such as benign prostatic hyperplasia (α-blockers) or edema (diuretics).
- Other agents that alter Blood Pressure including:
  - Tricyclic antidepressants.
  - Monoamine oxidase (MAO) inhibitors.
  - Central nervous system stimulants.
  - Amphetamines or their derivatives.
  - Dopamine agonists.
  - Atypical antipsychotic agents.
  - Trazodone.
  - Lithium.
  - Diet medications (except orlistat).
  - Nitrates.
  - Chronically used (defined as more than 3 doses per week) common cold medications with pseudoephedrine or phenylephrine, or nonsteroidal anti-inflammatory drugs (or NSAIDs), including aspirin >325 mg/day or cyclooxygenase-2 (COX-2) inhibitors.
  - Systemic use of corticosteroids (topical or inhaled is acceptable).
  - Thiazolidinediones.
- Prescription 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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00818883

Show 53 Study Locations

Sponsors and Collaborators

Takeda Global Research & Development Center, Inc.

Investigators

Study Director:

Executive Medical Director

Takeda Global Research & Development Center, Inc.

More Information

No publications provided

Responsible Party:	Takeda Global Research & Development Center, Inc. ( Sr. VP, Clinical Science )
Study ID Numbers:	TAK-491CLD_306, U1111-1112-7119
Study First Received:	January 7, 2009
Last Updated:	December 2, 2009
ClinicalTrials.gov Identifier:	NCT00818883 History of Changes
Health Authority:	United States: Food and Drug Administration; Russia: Ministry of Health and Social Development of the Russian Federation

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

Essential Hypertension
Hypertensive
Blood Pressure, High

Vascular Disease
Cardiovascular Disease
Drug Therapy

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Sodium Chloride Symporter Inhibitors
Diuretics
Vascular Diseases
Cardiovascular Agents
Antihypertensive Agents
Hydrochlorothiazide

Pharmacologic Actions
Membrane Transport Modulators
Natriuretic Agents
Chlorthalidone
Therapeutic Uses
Cardiovascular Diseases
Hypertension

ClinicalTrials.gov processed this record on February 08, 2010