Official Title: “A Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-491 When Co-Administered With Chlorthalidone in Subjects With Essential Hypertension”

The purpose of this study is to evaluate the efficacy and safety of TAK-491 co-administered with chlorthalidone in treating individuals with essential hypertension, compared to treatment with chlorthalidone alone.

Study Type: Interventional

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

Study Primary Completion Date: March 2009

Hypertension affects approximately 50 million individuals in the United States. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. 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 treatments, hypertension remains inadequately controlled; only about one-third of patients continue to maintain control successfully.

TAK-491 is an angiotensin II receptor blocker that was shown to be a orally active antihypertensive agent with a prolonged duration of activity and good safety tolerability in a recent clinical study. Based on other recent studies with both TAK-491 and TAK-536, the expected therapeutic dose range of TAK-491 is 20 to 80 mg QD. Chlorthalidone is a thiazide-like diuretic that reduces blood pressure by decreasing intravascular volume through urinary salt and water excretion. By combining this action with TAK-491, a greater reduction in blood pressure is expected than with either agent alone. For subjects requiring combination therapy, TAK-491 plus chlorthalidone offers a novel combination that may provide a more potent and safe combination for blood pressure reduction.

This study is being conducted to determine whether administration of TAK-491 in combination with chlorthalidone to subjects with uncontrolled hypertension is more effective in reducing blood pressure than chlorthalidone alone. This study is also being conducted to evaluate the safety and tolerability of TAK-491 combined with chlorthalidone.

Individuals who want to participate in this study will be required to provide written informed consent. Study participation is anticipated to be about 10 Weeks. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, vital signs including sitting and standing blood pressure and pulse, body height and weight, physical examinations, electrocardiogram. Outside of the study center, participants will be required to wear an ambulatory blood pressure monitoring device at 24 hour intervals.

Intervention(s) in this Clinical Trial

• Drug: TAK-491 and chlorthalidone
  • TAK-491 40 mg, tablets, orally, once daily; TAK-491 80 mg placebo-matching tablets, orally, once daily; and chlorthalidone 25 mg, tablets, orally, once daily for up to 6 weeks.
• Drug: TAK-491 and chlorthalidone
  • TAK-491 80 mg, tablets, orally, once daily; TAK-491 40 mg placebo-matching tablets, orally, once daily and chlorthalidone 25 mg, tablets, orally, once daily for up to 6 weeks.
• Drug: Chlorthalidone
  • Chlorthalidone 25 mg, tablets, orally, once daily; TAK-491 80 mg placebo-matching tablets, orally, once daily and TAK-491 40 mg placebo-matching tablets, orally, once daily for up to 6 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Experimental: 2
• Active Comparator: 3

Primary Measures

• Change from baseline to Week 6 in the 24-hour mean systolic blood pressure by ambulatory blood pressure monitor.
  • Time Frame: Week 6
    Safety Issue?: No

Secondary Measures

• Change from baseline to Week 6 in trough clinic sitting systolic blood pressure.
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline to Week 6 in the 24-hour mean diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline to Week 6 in trough clinic sitting diastolic blood pressure.
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for daytime mean (6am to 10pm) systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for daytime mean (6am to 10pm) diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for nighttime mean (12am to 6am) systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for nighttime mean (12am to 6am) diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for 0-12-hr mean systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for 0-12-hr mean diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for trough mean (22-24-hr) systolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Change from baseline for trough mean (22-24-hr) diastolic blood pressure by ambulatory blood pressure monitor
  • Time Frame: Week 6
    Safety Issue?: No
• Proportion of subjects who achieve a Clinic Diastolic Blood Pressure Response, defined as less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg
  • Time Frame: Week 6
    Safety Issue?: No
• Proportion of subjects who achieve a Clinic Systolic Blood Pressure Response, defined as less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg
  • Time Frame: Week 6
    Safety Issue?: No
• Proportion of subjects who achieve both a clinic Diastolic and Systolic Blood Pressure Response
  • Time Frame: Week 6
    Safety Issue?: No

Inclusion Criteria

• Has essential hypertension (defined as sitting trough clinic systolic blood pressure between 160 and 190 mm Hg inclusive at Day minus 1 and 24-hour mean systolic blood pressure greater than or equal to 140 mm Hg and ≤ 180 mm Hg at Day 1).
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
• Has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or results that are deemed not clinically significant for inclusion into this study by the investigator.
• Willing to discontinue current antihypertensive medications at the Screening Day minus 21 visit. If the subject is on amlodipine prior to screening, the subject is willing to discontinue this medication at Screening Day minus 28.

Exclusion Criteria

• Has sitting trough clinic diastolic blood pressure greater than 119 mmHg at Day minus 1.
• Has a baseline 24 hour ambulatory blood pressure monitor reading of insufficient quality.
• Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:
• Antihypertensive agents except those used at the time of screening visit, which must be discontinued during the washout/run-in period and for the remainder of the study.
• Amlodipine should be discontinued at Screening Day -28; all other antihypertensive agents should be discontinued at Screening Day -21
• Insulin.
• Other agents that alter blood pressure, including:
• tricyclic antidepressants
• monoamine oxidase inhibitors
• lithium
• Phosphodiesterase type 5
• diet medications
• amphetamines or their derivatives
• chronically used (defined as more than 3 doses per week) common cold medications or non-steroidal anti-inflammatory drugs, including aspirin greater than 325 mg per day or cyclooxygenase-2 inhibitors
• Thiazolidinediones
• Atypical antipsychotic agents.
• Hypersensitive to AII receptor blockers, thiazide-type diuretics, or other sulfonamide-derived compounds.
• 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.
• Clinically significant cardiac conduction defects (for example, 3rd degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation).
• Hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
• The subject has secondary hypertension of any etiology.
• Non-compliant (less than 70% or greater than 130%) with study medication
• during the placebo run- in period.
• Severe renal dysfunction or disease (based on calculated creatinine clearance less than 30 mL/min/1.73 m2) at Screening.
• Known or suspected unilateral or bilateral renal artery stenosis.
• History of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic drinks per day) within the past 2 years.
• 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 1 squamous cell carcinoma of the skin.)
• Type 1 or poorly controlled type 2 diabetes mellitus (glycosylated hemoglobin greater than 8.0%).
• Hypo- or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory).
• Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
• Upper arm circumference less than 24 cm or greater than 42 cm.
• Works night (3rd) shift (defined as 11PM [2300] to 7AM [0700]).
• Currently is participating in another investigational study or has participated in an investigational study within 30 days prior to randomization.
• Study site employee, or is an immediate family member ( ie, spouse, parent, child, sibling) of a study site employee who is involved in conduct of this study.
• 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.
• Randomized in a previous TAK-491 study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Takeda Global Research & Development Center, Inc.

Overall Clinical Trial Officials and Contacts

Executive Medical Director Clinical Science Study Director Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00591773

Study ID Number: 01-05-TL-491-009

ClinicalTrials.gov Identifier: NCT00591773

Health Authority: United States: Food and Drug Administration