Long-Term Safety of Azilsartan Medoxomil and Chlorthalidone Compared to Olmesartan Medoxomil and Hydrochlorothiazide in Participants With Hypertension and Kidney Disease

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT01309828
First received: March 4, 2011
Last updated: September 28, 2013
Last verified: September 2013
  Purpose

The purpose of this study is to evaluate long term safety and tolerability of azilsartan medoxomil and chlorthalidone, once daily (QD), compared with olmesartan medoxomil and hydrochlorothiazide in hypertensive participants with moderate renal impairment.


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

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Open-Label, Phase 3 Study to Compare Long-Term Safety and Tolerability of the TAK-491 and Chlorthalidone Fixed-Dose Combination Versus Olmesartan Medoxomil and Hydrochlorothiazide Fixed-Dose Combination in Hypertensive Subjects With Moderate Renal Impairment

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Number of Participants With at Least 1 Adverse Event (AE) [ Time Frame: From the first dose of open-label study drug until 14 days (or 30 days for a serious adverse event) after the last dose of open- label study drug (up to 56 weeks). ] [ Designated as safety issue: Yes ]
    An AE is any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have a causal relationship with this treatment. A serious AE is defined as any untoward medical occurrence that resulted in death, was life threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, led to a congenital anomaly/birth defect or was an important medical event that may have required intervention to prevent any of items above.


Secondary Outcome Measures:
  • Percentage of Participants at Final Visit Who Achieve Target Systolic Blood Pressure <130 mm Hg [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
    Systolic blood pressure is the arithmetic mean of the 3 serial sitting systolic blood pressure measurements. Percentage of participants who achieve a sitting clinic systolic blood pressure response defined as less than 130 mm Hg at Week 52.

  • Percentage of Participants at Final Visit Who Achieved Target Diastolic Blood Pressure <80 mm Hg [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
    Diastolic blood pressure is the arithmetic mean of the 3 serial sitting diastolic blood pressure measurements. Percentage of participants at Week 52 who achieved a sitting clinic diastolic blood pressure response, defined as less than 80 mm Hg.

  • Percentage of Participants at Final Visit Who Achieved Both a Clinic Systolic and Diastolic Blood Pressure Response [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
    Systolic/diastolic blood pressure is the arithmetic mean of the 3 serial sitting systolic/diastolic blood pressure measurements. Percentage of participants who achieved both a sitting clinic systolic and diastolic blood pressure response, defined as systolic blood pressure less than 130 mm Hg and diastolic blood pressure less than 80 mm Hg at Week 52.


Enrollment: 153
Study Start Date: March 2011
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Azilsartan Medoxomil + Chlorthalidone
United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets, titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks.
Drug: Azilsartan medoxomil and chlorthalidone
Fixed-dose combination tablets.
Other Name: TAK-491CLD
Active Comparator: Olmesartan Medoxomil + Hydrochlorothiazide
United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks.
Drug: Olmesartan medoxomil and hydrochlorothiazide
Fixed-dose combination tablets.
Other Names:
  • Olmesartan medoxomil
  • Hydrochlorothiazide
  • Benicar hydrochlorothiazide
  • Olmetec Plus

Detailed Description:

A major component of blood pressure regulation is the renin-angiotensin-aldosterone system (RAAS). Drugs that modulate the RAAS are used commonly worldwide for the treatment of hypertension. TAK-491 (azilsartan medoxomil) is a prodrug of TAK-536 (azilsartan), an angiotensin II receptor blocker (ARB). Azilsartan medoxomil is being evaluated by Takeda to treat participants with essential hypertension.

Chlorthalidone is an orally administered thiazide-like diuretic agent, and long-term outcomes trials show blood pressure reductions associated with chlorthalidone treatment reduce risk of cardiovascular morbidity and mortality.

Hypertensive patients with moderate renal impairment are a relatively more severe and resistant hypertension population, and may benefit from effective fixed-dose combination treatments such as an ARB plus a diuretic for blood pressure control.

Participants will be randomized to receive azilsartan medoxomil and chlorthalidone or olmesartan medoxomil and hydrochlorothiazide for up to 52 weeks to evaluate long term safety of azilsartan medoxomil and chlorthalidone. A titration-to-target blood pressure approach will be used to guide the titration of study medication in this trial.

  Eligibility

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

Inclusion Criteria:

  1. Is treated with 2 or 3 antihypertensive medications and on stable therapy, defined as ≥6 weeks on medication, and has a mean sitting clinic systolic blood pressure ≥135 and ≤160 mm Hg at the Screening Visit and on Day 1.
  2. Has an estimated glomerular filtration rate (eGFR) in the range of ≥30 to <60 mL/min/1.73 m^2 (Stage 3 chronic kidney disease) at the Screening Visit.
  3. Is a man or woman and aged 18 years or older.
  4. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of the informed consent through 30 days after the last study drug dose.
  5. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
  6. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
  7. Has clinical laboratory test results (clinical chemistry, hematology, and complete urinalysis) that the investigator does not consider to be clinically significant in this moderate renal impaired population.
  8. Is willing to discontinue the current antihypertensive medications 2 days prior to randomization.

Exclusion Criteria:

  1. Has received any investigational compound within 30 days prior to Screening or is currently participating in another investigational study.
  2. Has been randomized/enrolled in a previous TAK-491 or TAK-491CLD study. NOTE: This criterion does not apply to participants who began participation in another TAK-491 or TAK-491CLD study but were not randomized/enrolled, nor does it apply to participants who participated in observational studies that lacked an intervention or invasive procedure.
  3. Is receiving a combination of olmesartan and hydrochlorothiazide at the Screening Visit.
  4. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
  5. Has a mean clinic diastolic (sitting, trough) >110 mm Hg on Day 1.
  6. Has secondary hypertension of any etiology (eg, renovascular disease, pheochromocytoma, Cushing's syndrome).
  7. 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.
  8. Has clinically significant cardiac conduction defects (ie, third-degree atrioventricular block, sick sinus syndrome).
  9. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease.
  10. Has severe renal dysfunction or disease (based on eGFR <30 mL/min/1.73m^2 at Screening) prior renal transplantation or nephrotic syndrome (defined as a urinary albumin/creatinine ratio >2000 mg/g at Screening).
  11. Has known or suspected unilateral or bilateral renal artery stenosis.
  12. 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 participants with basal cell or stage I squamous cell carcinoma of the skin.)
  13. Has poorly-controlled type 1 or 2 diabetes mellitus (glycosylated hemoglobin A [HbA1c] >8.5%) at Screening.
  14. Has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory).
  15. Has an alanine aminotransferase or aspartate aminotransferase level of >2.5 times the upper limit of normal, active liver disease, or jaundice.
  16. 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.
  17. has a history of hypersensitivity or allergies to ARBs or thiazide-type diuretics or other sulfonamide-derived compounds.
  18. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within the past 2 years.
  19. Is required to take excluded medications.
  20. If female, is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.
  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: NCT01309828

  Show 55 Study Locations
Sponsors and Collaborators
Takeda
Investigators
Study Director: Medical Director, Clinical Science Takeda
  More Information

Additional Information:
No publications provided

Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01309828     History of Changes
Other Study ID Numbers: TAK-491CLD_309, 2010-023098-21, U1111-1119-5131, NL35552.072.11
Study First Received: March 4, 2011
Results First Received: September 28, 2013
Last Updated: September 28, 2013
Health Authority: Bulgaria: Ministry of Health
Germany: Federal Institute for Drugs and Medical Devices
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Latvia: State Agency of Medicines
Lithuania: State Medicine Control Agency - Ministry of Health
Poland: Ministry of Health
Slovakia: State Institute for Drug Control
Ukraine: Ministry of Health
United States: Food and Drug Administration

Keywords provided by Takeda:
Renal Insufficiency
Kidney Diseases
Hypertension
Drug Therapy

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

ClinicalTrials.gov processed this record on October 23, 2014