Clinical trial NCT01309828: Long-Term Safety of Azilsartan Medoxomil and Chlorthalidone Compared to Olmesartan Medoxomil and Hydrochlorothiazide in Participants With Hypertension and Kidney Disease
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Safety
Keywords: Renal Insufficiency
Kidney Diseases
Hypertension
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-03-07
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Primary outcomes:
measure: Number of Participants With at Least 1 Adverse Event (AE)
timeFrame: 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).
Secondary outcomes:
measure: Percentage of Participants at Final Visit Who Achieve Target Systolic Blood Pressure <130 mm Hg
timeFrame: Week 52
measure: Percentage of Participants at Final Visit Who Achieved Target Diastolic Blood Pressure <80 mm Hg
timeFrame: Week 52
measure: Percentage of Participants at Final Visit Who Achieved Both a Clinic Systolic and Diastolic Blood Pressure Response
timeFrame: Week 52
Other outcomes:
Locations:
city: Kazanlak
country: Bulgaria
city: Pleven
country: Bulgaria
city: Sevlievo
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Mannheim
country: Germany
state: Baden Wuerttemberg
city: Nurnberg
country: Germany
state: Bayern
city: Nürnberg
country: Germany
state: Bayern
city: Frankfurt
country: Germany
state: Hessen
city: Offenbach
country: Germany
state: Hessen
city: Rodgau Dudenhofen
country: Germany
state: Hessen
city: Essen
country: Germany
state: Nordrhein Westfalen
city: Goch
country: Germany
state: Nordrhein Westfalen
city: Wuppertal
country: Germany
state: Nordrhein Westfalen
city: Berlin
country: Germany
city: Hamburg
country: Germany
city: Daugavpils
country: Latvia
city: Kuldiga
country: Latvia
city: Limbazi
country: Latvia
city: Riga
country: Latvia
city: Tukums
country: Latvia
city: Ventspils
country: Latvia
city: Alytus
country: Lithuania
city: Kaunas
country: Lithuania
city: Klaipeda
country: Lithuania
city: Siauliai
country: Lithuania
city: Vilnius
country: Lithuania
city: Amsterdam
country: Netherlands
city: Groningen
country: Netherlands
city: Maastricht
country: Netherlands
city: Venlo
country: Netherlands
city: Grodzisk Mazowiecki
country: Poland
city: Lodz
country: Poland
city: Torun
country: Poland
city: Warszawa
country: Poland
city: Warszaw
country: Poland
city: Zgierz
country: Poland
city: Banska Bystrica
country: Slovakia
city: Bardejov
country: Slovakia
city: Bratislava
country: Slovakia
city: Komarno
country: Slovakia
city: Kosice
country: Slovakia
city: Martin
country: Slovakia
city: Nitra
country: Slovakia
city: Ruzomberok
country: Slovakia
city: Svidnik
country: Slovakia
city: Donetsk
country: Ukraine
city: Ivano-Frankivsk
country: Ukraine
city: Kharkiv
country: Ukraine
city: Kiev
country: Ukraine
city: Kyiv
country: Ukraine
city: Lutsk
country: Ukraine
city: Lviv
country: Ukraine
city: Vinnitsya
country: Ukraine
city: Vinnytsya
country: Ukraine
Study officials:
affiliation: Takeda
name: Medical Director, Clinical Science
role: STUDY_DIRECTOR
References:
citation: Bakris GL, Zhao L, Kupfer S, Juhasz A, Hisada M, Lloyd E, Oparil S. Long-term efficacy and tolerability of azilsartan medoxomil/chlorthalidone vs olmesartan medoxomil/hydrochlorothiazide in chronic kidney disease. J Clin Hypertens (Greenwich). 2018 Apr;20(4):694-702. doi: 10.1111/jch.13230. Epub 2018 Mar 4.