Efficacy and Safety of Azilsartan Medoxomil and Chlorthalidone Compared to Olmesartan Medoxomil and Hydrochlorothiazide in Participants With Moderate to Severe Hypertension.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT01033071
First received: December 14, 2009
Last updated: January 4, 2012
Last verified: January 2012
  Purpose

The purpose of this study is to compare the antihypertensive effect of azilsartan medoxomil plus chlorthalidone, once daily (QD), to olmesartan medoxomil plus hydrochlorothiazide in participants with moderate to severe hypertension.


Condition Intervention Phase
Essential Hypertension
Drug: Azilsartan medoxomil and chlorthalidone
Drug: Olmesartan medoxomil and hydrochlorothiazide
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3b, Double-Blind, Randomized, 12-Week Efficacy and Safety Study Comparing the TAK-491 Plus Chlorthalidone Fixed-Dose Combination vs Olmesartan Medoxomil-Hydrochlorothiazide in Subjects With Moderate to Severe Hypertension

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in sitting trough clinic systolic blood pressure measured at week 12 or final visit relative to baseline. Trough blood pressure is the average of the non-missing values of the 3 serial trough sitting systolic blood pressure measurements.


Secondary Outcome Measures:
  • Change From Baseline in Trough, Sitting, Clinic Systolic Blood Pressure. [ Time Frame: Baseline, Week 4 and Week 8. ] [ Designated as safety issue: No ]
    The change in sitting trough clinic systolic blood pressure measured at each week indicated relative to baseline. Trough blood pressure is the average of the non-missing values of the 3 serial trough sitting systolic blood pressure measurements.

  • Change From Baseline in Trough, Sitting, Clinic Diastolic Blood Pressure. [ Time Frame: Baseline, Week 4, Week 8 and Week 12. ] [ Designated as safety issue: No ]
    The change in sitting trough clinic diastolic blood pressure measured at each week indicated relative to baseline. Trough blood pressure is the average (arithmetic mean) of the non-missing values of the 3 serial trough sitting systolic blood pressure measurements.

  • Change From Baseline in Mean Trough Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in trough systolic blood pressure measured at week 12 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Trough is the average of all measurements recorded from 22 to 24 hours after dosing.

  • Change From Baseline in Mean Trough Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in trough diastolic blood pressure measured at week 12 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Trough is the average of all measurements recorded from 22 to 24 hours after dosing.

  • Change From Baseline in 24-hour Mean Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in 24-hour mean systolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing.

  • Change From Baseline in 24-hour Mean Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in 24-hour mean diastolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 24-hour mean is the average of all measurements recorded for 24 hours after dosing.

  • Change From Baseline in Mean Daytime (6 AM to 10 PM) Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in daytime (6am to 10pm) mean systolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 AM (inclusive) and 10 PM (exclusive).

  • Change From Baseline in Mean Daytime (6 AM to 10 PM) Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in daytime (6am to 10pm) mean diastolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Daytime mean is the average of all measurements recorded between the hours of 6 AM (inclusive) and 10 PM (exclusive).

  • Change From Baseline in Mean Nighttime (12 AM to 6 AM) Systolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in the mean nighttime (12am to 6am) systolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Mean nighttime is the average (arithmetic mean) of measurements recorded between the hours of 12 AM (inclusive) and 6 AM (exclusive).

  • Change From Baseline in Mean Nighttime (12 AM to 6 AM) Diastolic Blood Pressure by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in the mean nighttime (12am to 6am) diastolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Mean nighttime is the average (arithmetic mean) of measurements recorded between the hours of 12 AM (inclusive) and 6 AM (exclusive).

  • Change From Baseline in the Mean Systolic Blood Pressure at 0 to 12 Hours After Dosing by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in the mean 12 hour systolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The mean consists of the average (arithmetic mean) of measurements.

  • Change From Baseline in the Mean Diastolic Blood Pressure at 0 to 12 Hours After Dosing by Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change in the mean 12 hour diastolic blood pressure measured at week 12 or final visit relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The mean consists of the average (arithmetic mean) of measurements.

  • Change From Baseline in the Mean Systolic Blood Pressure During Each Hour of the 24-hour Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change from baseline for each hour interval of the 24-hour ambulatory blood pressure monitoring measured at week 12 or final visit. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The mean consists of the average (arithmetic mean) of measurements collected at each hour.

  • Change From Baseline in the Mean Diastolic Blood Pressure During Each Hour of the 24-hour Ambulatory Blood Pressure Monitoring. [ Time Frame: Baseline and Week 12. ] [ Designated as safety issue: No ]
    The change from baseline for each hour interval of the 24-hour ambulatory blood pressure monitoring measured at week 12 or final visit. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The mean consists of the average (arithmetic mean) of measurements collected at each hour.

  • Percentage of Participants Who Reached Target Clinic Systolic Blood Pressure of <140 mm Hg and/or Reduction of ≥20 mm Hg From Baseline. [ Time Frame: Baseline, Week 4, Week 8 and Week 12. ] [ Designated as safety issue: No ]
    Percentage of participants who achieve a clinic systolic blood pressure response measured at each week indicated, defined as less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg. Systolic blood pressure is the arithmetic mean of the non-missing values of the 3serial trough sitting systolic blood pressure measurements.

  • Percentage of Participants Who Reached Target Clinic Diastolic Blood Pressure of <90 mm Hg and/or Reduction of ≥10 mm Hg From Baseline. [ Time Frame: Baseline, Week 4, Week 8 and Week 12. ] [ Designated as safety issue: No ]
    Percentage of participants who achieve a clinic diastolic blood pressure response measured at each week indicated, defined as less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg. Diastolic blood pressure is the arithmetic mean of the non-missing values of the 3 serial trough sitting diastolic blood pressure measurements.

  • Percent of Participants Who Reached Target Clinic Systolic Blood Pressure of <140 mm Hg and/or Reduction of ≥20 mm Hg From Baseline and Target Clinic Diastolic Blood Pressure of <90 mm Hg and/or Reduction of ≥10 mm Hg From Baseline. [ Time Frame: Baseline, Week 4, Week 8 and Week 12. ] [ Designated as safety issue: No ]
    Percentage of participants who achieve both a clinic diastolic and systolic blood pressure response measured at each week indicated, defined as less than 90 mm Hg and/or reduction from baseline of greater than or equal to 10 mm Hg AND less than 140 mm Hg and/or reduction from baseline of greater than or equal to 20 mm Hg. Diastolic and systolic blood pressure is based on the arithmetic mean of the non-missing values of the 3 serial trough sitting blood pressure measurements.


Enrollment: 1071
Study Start Date: January 2010
Study Completion Date: November 2010
Primary Completion Date: October 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Azilsartan Medoxomil 20-40mg/Chlorthalidone 12.5-25mg QD Drug: Azilsartan medoxomil and chlorthalidone

Azilsartan medoxomil 20 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily and olmesartan and hydrochlorothiazide placebo-matching tablets, orally, once daily for up to 4 weeks.

Participants will be force titrated at Week 4 to azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for the next 4 weeks.

Participants will then be force titrated at Week 8 to azilsartan medoxomil 40 mg and chlorthalidone 25 mg combination tablets, orally, once daily for the next 4 weeks.

Other Names:
  • azilsartan medoxomil plus chlorthalidone
  • TAK-491CLD
Experimental: Azilsartan Medoxomil 40-80mg/Chlorthalidone 12.5-25mg QD Drug: Azilsartan medoxomil and chlorthalidone

Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily and olmesartan and hydrochlorothiazide placebo-matching tablets, orally, once daily for up to 4 weeks.

Participants will be force titrated at Week 4 to azilsartan medoxomil 80 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for the next 4 weeks.

Participants will then be force titrated at Week 8 to azilsartan medoxomil 80 mg and chlorthalidone 25 mg combination tablets, orally, once daily for the next 4 weeks.

Other Names:
  • azilsartan medoxomil plus chlorthalidone
  • TAK-491CLD
Active Comparator: Olmesartan Medoxomil 20-40mg/Hydrochlorothiazide 12.5-25mg QD Drug: Olmesartan medoxomil and hydrochlorothiazide

Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablets, orally, once daily and azilsartan medoxomil and chlorthalidone placebo-matching tablets, orally, once daily for up to 4 weeks.

Participants will be force titrated at Week 4 to olmesartan medoxomil 40 mg and hydrochlorothiazide 12.5 mg combination tablets, orally, once daily for the next 4 weeks.

Participants will then be force titrated at Week 8 to olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg combination tablets, orally, once daily for the next 4 weeks.

Other Name: Benicar HCT®

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. 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.

Treatment algorithms for essential hypertension commonly include 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 medoxomil) is an angiotensin II receptor blocker developed by Takeda to treat participants with essential hypertension.

This study will compare the safety and tolerability of azilsartan medoxomil plus chlorthalidone (TAK-491CLD) fixed-dose combination to olmesartan medoxomil plus hydrochlorothiazide fixed-dose combination.

  Eligibility

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

Inclusion Criteria:

  1. Has a mean sitting clinic systolic blood pressure greater than or equal to 160 and less than or equal to 190 mm Hg.
  2. 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.
  3. 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.
  4. Is willing to discontinue current antihypertensive medications on Day -21 or Day -28 if the participant is on amlodipine or chlorthalidone.

Exclusion Criteria:

  1. Has a mean sitting clinic diastolic blood pressure greater than 119 mm Hg on Day -1.
  2. Has a baseline 24-hour ambulatory blood pressure monitoring reading of insufficient quality.
  3. Works a night (third) shift.
  4. Has an upper arm circumference less than 24 cm or greater than 42 cm.
  5. Has secondary hypertension of any etiology.
  6. Has a recent history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.
  7. Has clinically significant cardiac conduction defects.
  8. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
  9. Has severe renal dysfunction or disease.
  10. Has known or suspected unilateral or bilateral renal artery stenosis.
  11. Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug.
  12. Has poorly-controlled diabetes mellitus at Screening.
  13. Has hypokalemia or hyperkalemia.
  14. Has an alanine aminotransferase or aspartate aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice.
  15. 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 participant according to the protocol.
  16. Has known hypersensitivity to angiotensin II receptor blockers or thiazide-type diuretics or other sulfonamide-derived compounds.
  17. Has a history of drug abuse or a history of alcohol abuse within the past 2 years.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01033071

  Show 94 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: Sr VP Clinical Science Takeda
  More Information

Additional Information:
No publications provided by Takeda

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01033071     History of Changes
Other Study ID Numbers: TAK-491CLD_303, U1111-1112-4298
Study First Received: December 14, 2009
Results First Received: January 4, 2012
Last Updated: January 4, 2012
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Takeda:
Hypertensive
Blood Pressure, High
Cardiovascular disease
Vascular Disease
Drug Therapy

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Chlorthalidone
Hydrochlorothiazide
Olmesartan medoxomil
Olmesartan
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists

ClinicalTrials.gov processed this record on July 20, 2014