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


Tracking Information

Start Date  ICMJEMarch 2009
Estimated Primary Completion DateMay 2010   (final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE 
 (submitted: August 24, 2009)		Change from baseline to Week 8 in trough, systolic blood pressure as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Original Primary Outcome Measures  ICMJE 
 (submitted: February 18, 2009)		Change from baseline to Week 8 in trough, systolic blood pressure as measured by ABPM. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
Change HistoryComplete list of historical versions of study NCT00847626 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE 
 (submitted: August 24, 2009)
  • Change from baseline to Week 8 in trough, sitting, clinic systolic blood pressure. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in trough, sitting, clinic diastolic blood pressure. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean trough diastolic blood pressure (22 to 24 hours after dosing), as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the 24-hour mean systolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the 24-hour mean diastolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean daytime (6 AM to 10 PM) systolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean daytime (6 AM to 10 PM) diastolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean nighttime (12 AM to 6 AM) systolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean nighttime (12 AM to 6 AM) diastolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean systolic blood pressure at 0 to 12 hours after dosing, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean diastolic blood pressure at 0 to 12 hours after dosing, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Proportion of responders at Week 8, as defined by clinic systolic blood pressure <140 mm Hg and/or a reduction of ≥20 mm Hg from baseline. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Proportion of responders at Week 8, as defined by clinic diastolic blood pressure <90 mm Hg and/or a reduction of ≥10 mm Hg from baseline. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
  • Proportion of responders at Week 8, as defined by clinic systolic blood pressure <140 mm Hg and/or a reduction of ≥20 mm Hg from baseline AND clinic diastolic blood pressure <90 mm Hg and/or a reduction of ≥10 mm Hg from baseline. [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Original Secondary Outcome Measures  ICMJE 
 (submitted: February 18, 2009)
  • Change from baseline to Week 8 in trough, sitting, clinic systolic blood pressure. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in trough, sitting, clinic diastolic blood pressure. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean trough diastolic blood pressure (22 to 24 hours after dosing), as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the 24-hour mean systolic blood pressure and diastolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean daytime (6 AM to 10 PM) systolic blood pressure and diastolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean nighttime (12 AM to 6 AM) systolic blood pressure and diastolic blood pressure, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Change from Baseline to Week 8 in the mean systolic blood pressure and diastolic blood pressure at 0 to 12 hours after dosing, as measured by Ambulatory Blood Pressure Monitoring. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Proportion of responders at Week 8, as defined by clinic systolic blood pressure <140 mm Hg and/or a reduction of ≥20 mm Hg from baseline. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Proportion of responders at Week 8, as defined by clinic diastolic blood pressure <90 mm Hg and/or a reduction of ≥10 mm Hg from baseline. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]
  • Proportion of responders at Week 8, as defined by clinic systolic blood pressure <140 mm Hg and/or a reduction of ≥20 mm Hg from baseline AND clinic diastolic blood pressure <90 mm Hg and/or a reduction of ≥10 mm Hg from baseline. [ Time Frame: 8 Weeks ] [ Designated as safety issue: No ]

Descriptive Information

Brief Title  ICMJEEfficacy and Safety of TAK-491 Combined With Chlorthalidone in Subjects With Moderate to Severe Hypertension
Official Title  ICMJEA Phase 3, Double-Blind, Randomized, Factorial, Efficacy and Safety Study of TAK 491 Plus Chlorthalidone Fixed-Dose Combination in Subjects With Moderate to Severe Hypertension
Brief Summary

The purpose of this study is to determine the efficacy and safety of TAK-491 combined with chlorthalidone in subjects with moderate to severe hypertension.

Detailed Description

According to the World Health Organization (WHO), 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. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. 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 that is 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.

This study is designed to compare the antihypertensive effect and the safety and tolerability of the TAK-491 plus chlorthalidone fixed-dose combination product (TAK 491CLD FDC) with TAK 491 monotherapy and chlorthalidone monotherapy during 8 weeks of treatment.

Subjects participating in this study will be randomized to receive one of 11 possible dosing combinations of TAK-491, chlorthalidone and placebo over an 8 week period. The total duration of the study will be approximately 13 weeks. Subjects will make 12 visits to the clinic. Each subject will also be contacted by telephone 14 days after last dose of study drug for a follow-up assessment.

Study PhasePhase III
Study Type  ICMJEInterventional
Study Design  ICMJETreatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Factorial Assignment, Safety/Efficacy Study
Condition  ICMJEHypertension
Intervention  ICMJE
  • Drug: TAK-491 and chlorthalidone
    TAK-491 20 mg, tablets, orally, once daily and chlorthalidone 12.5 mg, tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: TAK-491 and chlorthalidone
    TAK-491 20 mg, tablets, orally, once daily and chlorthalidone 25 mg, tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: TAK-491 and chlorthalidone
    TAK-491 40 mg, tablets, orally, once daily and chlorthalidone 12.5 mg, tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: TAK-491 and chlorthalidone
    TAK-491 40 mg, tablets, orally, once daily and chlorthalidone 25 mg, tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: TAK-491 and chlorthalidone
    TAK-491 80 mg, tablets, orally, once daily and chlorthalidone 12.5 mg, tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: TAK-491 and chlorthalidone
    TAK-491 80 mg, tablets, orally, once daily and chlorthalidone 25 mg, tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: Chlorthalidone
    TAK-491 placebo-matching tablets, orally, once daily and chlorthalidone 12.5 mg, tablets, orally, once daily for up to 8 weeks
  • Drug: Chlorthalidone
    TAK-491 placebo-matching tablets, orally, once daily and chlorthalidone 25 mg, tablets, orally, once daily for up to 8 weeks
  • Drug: TAK-491
    TAK-491 20 mg, tablets, orally, once daily and chlorthalidone placebo-matching tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: TAK-491
    TAK-491 40 mg, tablets, orally, once daily and chlorthalidone placebo-matching tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
  • Drug: TAK-491
    TAK-491 80 mg, tablets, orally, once daily and chlorthalidone placebo-matching tablets, orally, once daily for up to 8 weeks
    Other Name: azilsartan medoxomil
Study Arms / Comparison Groups
  • 1: Experimental
    Intervention: Drug: TAK-491 and chlorthalidone
  • 2: Experimental
    Intervention: Drug: TAK-491 and chlorthalidone
  • 3: Experimental
    Intervention: Drug: TAK-491 and chlorthalidone
  • 4: Experimental
    Intervention: Drug: TAK-491 and chlorthalidone
  • 5: Experimental
    Intervention: Drug: TAK-491 and chlorthalidone
  • 6: Experimental
    Intervention: Drug: TAK-491 and chlorthalidone
  • 7: Active Comparator
    Intervention: Drug: Chlorthalidone
  • 8: Active Comparator
    Intervention: Drug: Chlorthalidone
  • 9: Experimental
    Intervention: Drug: TAK-491
  • 10: Experimental
    Intervention: Drug: TAK-491
  • 11: Experimental
    Intervention: Drug: TAK-491

Recruitment Information

Estimated Enrollment  ICMJE1650
Estimated Completion DateJuly 2010
Estimated Primary Completion DateMay 2010   (final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 the day prior to randomization, or the subject has not received antihypertensive treatment within 28 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 the day prior to randomization.
  • 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 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 on Day -21 or on Day -28 if on amlodipine or chlorthalidone.

Exclusion Criteria:

  • Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg on the day prior to randomization.
  • Has a baseline 24-hour ambulatory blood pressure measurement reading of insufficient quality.
  • Has 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.
  • Has is noncompliant with study medication during the placebo run-in period.
  • Has secondary hypertension of any etiology.
  • Has recent history 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.
  • 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 type 2 diabetes mellitus at Screening.
  • Has hypokalemia or hyperkalemia.
  • 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 Has according to the protocol.
  • Has known hypersensitivity to angiotensin II receptor blockers, 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 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 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 the evaluation of the study medication, including:

    • Antihypertensive agents, including benign prostatic hyperplasia (alpha-blockers) or edema (diuretics).
    • Tricyclic antidepressants.
    • Monoamine oxidase inhibitors.
    • Central nervous system stimulants.
    • Amphetamines or their derivatives.
    • Dopamine agonists.
    • Atypical antipsychotic agents.
    • Trazodone.
    • Lithium.
    • Diet medications.
    • Nitrates.
    • Chronically used common cold medications with pseudoephedrine or nonsteroidal anti-inflammatory drugs, including aspirin greater than 325 mg/day or cyclooxygenase-2 inhibitors.
    • Systemic use of corticosteroids.
    • Thiazolidinediones.
GenderBoth
Ages18 Years and older
Accepts Healthy VolunteersNo
Contacts  ICMJE
Contact: Takeda Study Registration Call Center800-778-2860medicalinformation@tpna.com
Location Countries  ICMJEUnited States,   Russian Federation

Administrative Information

NCT ID  ICMJENCT00847626
Responsible PartySr. VP, Clinical Science, Takeda Global Research & Development Center, Inc.
Study ID Numbers  ICMJETAK-491CLD_302, 2008-004218-28
Study Sponsor  ICMJETakeda Global Research & Development Center, Inc.
Collaborators  ICMJE 
Investigators  ICMJE
Study Director:Executive Medical DirectorTakeda Global Research & Development Center, Inc.
Information Provided ByTakeda Global Research & Development Center, Inc.