Clinical trial NCT01456169: A Study to Evaluate the Effectiveness and Safety of a Fixed Dose Combination of Azilsartan Medoxomil and Chlorthalidone in Patients With High Blood Pressure Who do Not Achieve Target Blood Pressure Following Treatment With Azilsartan Medoxomil Alone
Official title: A Phase-3 Randomized, Double-Blind, Efficacy and Safety Study Evaluating the Fixed Dose Combinations of TAK-491 Plus Chlorthalidone (40/12.5 mg and 40/25 mg) in Subjects With Grades 2 or 3 Essential Hypertension, Who Do Not Achieve Target Blood Pressure Following Treatment With TAK-491 40 mg Monotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Essential Hypertension
Keywords: High Blood Pressure
Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-10-20
Enrollment: 507
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 the efficacy and safety of the fixed dose combinations of azilsartan medoxomil plus chlorthalidone (40/12.5 and 40/25 mg), once daily, in participants with grades 2 or 3 essential hypertension who do not reach target blood pressure following treatment with 40 mg azilsartan medoxomil monotherapy after 4 weeks.

Detailed description: Eligible participants completed a 2-week single-blind run-in period (Days -42 to -29) prior to a Single-Blind Monotherapy Treatment Period (Day -28 to Day -1) where they received azilsartan medoxomil 40 mg. After the Single-Blind Monotherapy Treatment Period, those participants who achieved target blood pressure discontinued treatment and resumed standard of care management at the discretion of their treating physician, while those participants who did not achieve target blood pressure (defined as clinic systolic blood pressure ≥140 mmHg) were randomly assigned to 1 of 3 active treatment arms: azilsartan medoxomil 40 mg plus placebo, azilsartan medoxomil plus chlorthalidone 40/12.5 mg, or azilsartan medoxomil plus chlorthalidone 40/25 mg.

Eligibility criteria: Inclusion Criteria:

At Screening

1. The participant has grade 2-3 essential hypertension which is not adequately controlled, as defined by mean, trough, sitting, clinic systolic blood pressure (SBP):

   * ≥160 to ≤180 mm Hg in participants who have not received any antihypertensive medication in the 14 days prior to Visit 1.
   * ≥150 to ≤170 mm Hg in participants taking 1 antihypertensive medication at Visit 1.
   * ≥140 to ≤160 mm Hg in participants taking 2 antihypertensive medications at Visit 1.
2. The participant has clinical laboratory test results (clinical chemistry, hematology, and complete urinalysis) within the reference range for the testing laboratory or the investigator does not consider the results to be clinically relevant for precluding entry in to the study in this hypertensive population.
3. The participant is willing to discontinue current antihypertensive medications.
4. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
5. 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.
6. Male or female adult, at least 18 years of age.
7. A female 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. NOTE: Women NOT of childbearing potential are defined as those who have been surgically sterilized (hysterectomy, bilateral oophorectomy, tubal ligation \[performed more than one 1 year prior to Screening\]) or who are postmenopausal (defined as at least 1 year since last regular menses).

   Post-placebo run-in:
8. The participant must have a post-placebo run-in, 24-hour mean SBP by ambulatory blood pressure monitoring (ABPM) of 140-175 mm Hg inclusive, and a clinic SBP measurement of 160 to 190 mm Hg inclusive (determined by the mean of 3 sitting, trough, measurements on Day -29) to qualify for entry in to the 4 week single-blind TAK-491 40 mg monotherapy treatment period.

   Post-4 week, single-blind TAK-491 40 mg monotherapy treatment:
9. The participant does not achieve target blood pressure (defined as clinic SBP ≥140 mm Hg as determined by the mean of 3 sitting, trough, measurements) following 4 weeks single-blind treatment with TAK-491 40 mg monotherapy at Day -1, prior to randomization to double-blind treatment.

Exclusion Criteria:

At Screening

1. The participant has clinic diastolic blood pressure (DBP) \>110 mm Hg.
2. The participant's 3 SBP measurements differ by more than 15 mm Hg (confirmed by a second set of three measurements).
3. The participant has received any investigational compound within 30 days prior to Screening or is currently participating in another investigational study. NOTE: Participants participating in observational studies (per local definition) may enter Screening provided that the last intervention or invasive procedure was \>30 days prior to Visit 1.
4. The participant has been randomized/enrolled in a previous TAK-491 or TAK-491CLD study. NOTE: This criterion does not apply to participants who entered screening or placebo run-in in another TAK-491 or TAK-491CLD study but were not randomized/enrolled.
5. The participant is a study site employee or is in a dependent relationship with a study site employee who is involved in conduct of this study (e.g., spouse, parent, child, sibling) or may consent under duress.
6. The participant is currently treated with more than 2 antihypertensive medications.
7. The participant works a night (third) shift (defined as 11 PM \[2300\] to 7 AM \[0700\]).
8. The participant has an upper arm circumference \<24 cm or \>42 cm.
9. The participant has secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing's syndrome).
10. The participant has any history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, persistent or permanent atrial fibrillation or transient ischemic attack.
11. The participant has clinically significant cardiac conduction defects (e.g., third-degree atrioventricular block, sick sinus syndrome).
12. The participant has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease or hypertrophic cardiomyopathy.
13. The participant has severe renal dysfunction or disease \[based on estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73m\^2 at screening\], prior renal transplantation or nephrotic syndrome (defined as a urinary albumin/creatinine ratio \>2000 mg/g at Screening).
14. Participant has known hemodynamically significant bilateral renal artery stenosis or unilateral disease in a single kidney.
15. The participant has a history of cancer that has not been in remission for at least 5 years prior to the first dose of single-blind TAK-491 monotherapy study drug. (This criterion does not apply to those participants with basal cell or Stage 1 squamous cell carcinoma of the skin).
16. The participant has poorly-controlled type 1 or 2 diabetes mellitus (hemoglobin A1c \[HbA1c\] \>8.5%) at Screening.
17. The participant has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory) at Screening.
18. The participant has an alanine aminotransferase or aspartate aminotransferase level \>2.5 times the upper limit of normal, active liver disease, or jaundice at Screening.
19. The participant 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.
20. The participant has a history of hypersensitivity or allergies to angiotensin II receptor blockers (ARB) or thiazide-type diuretics or other sulfonamide-derived compounds.
21. The participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse per local guidelines within the past 2 years.
22. The participant is required to take excluded medications at any point during the study.
23. If female, the participant is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

    Post-placebo run-in period
24. The participant has a clinic SBP \>190 mm Hg and DBP \>115 mm Hg.
25. The participant is noncompliant (\<70% or \>130%) with study medication during the placebo run-in period.
26. The participant has a 24-hour mean eligibility ABPM reading of insufficient quality.

    Post-single-blind TAK-491 40 mg treatment period
27. The participant has a clinic SBP \>180 mm Hg and DBP \>110 mm Hg.
28. The participant is noncompliant (\<70% or \>130%) with study medication during the TAK-491 40 mg single-blind treatment period.

Primary outcomes:
measure: Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure
timeFrame: Baseline (of the double-blind treatment period) and Week 8
Secondary outcomes:
measure: Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8, 22-24 hours after dosing
measure: Change From Baseline to Week 8 in Trough Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8, 22-24 hours after dosing
measure: Change From Baseline to Week 8 in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Mean Daytime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Mean Daytime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Mean Nighttime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Mean Nighttime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8.
measure: Change From Baseline to Week 8 in the Mean Systolic Blood Pressure 0 to 12 Hours After Dosing, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Change From Baseline to Week 8 in the Mean Diastolic Blood Pressure 0 to 12 Hours After Dosing, as Measured by Ambulatory Blood Pressure Monitoring
timeFrame: Baseline and Week 8
measure: Percentage of Participants Who Achieve a Target Clinic Systolic Blood Pressure at Week 8
timeFrame: Week 8
measure: Percentage of Participants Who Achieve a Target Clinic Diastolic Blood Pressure at Week 8
timeFrame: Week 8
measure: Percentage of Participants Who Achieve Both Clinic Systolic and Diastolic Blood Pressure Targets at Week 8
timeFrame: Week 8
Other outcomes:
Locations:
city: Haskovo
country: Bulgaria
city: Pazardzhik
country: Bulgaria
city: Pleven
country: Bulgaria
city: Plovdiv
country: Bulgaria
city: Sofia
country: Bulgaria
city: Varna
country: Bulgaria
city: Veliko Tarnovo
country: Bulgaria
city: Paide
country: Estonia
city: Saku
country: Estonia
city: Tallinn
country: Estonia
city: Tartu
country: Estonia
city: Voru
country: Estonia
city: Labarthe Sur Leze
country: France
state: Haute Garonne
city: Bourg-des-Comptes
country: France
state: Ille et Vilaine
city: Tours
country: France
state: Indre et Loire
city: Vourey
country: France
state: Isere
city: Saint Etienne
country: France
state: Loire
city: Orthez
country: France
state: Pyrenees Atlantiques
city: Karlsruhe
country: Germany
state: Baden Wuerttemberg
city: Bad Woerishofen
country: Germany
state: Bayern
city: Nuernberg
country: Germany
state: Bayern
city: Frankfurt
country: Germany
state: Hessen
city: Stuhr
country: Germany
state: Niedersachsen
city: Essen
country: Germany
state: Nordrhein Westfalen
city: Kamp-Lintfort
country: Germany
state: Nordrhein Westfalen
city: Mainz
country: Germany
state: Rheinland Pfalz
city: Dresden
country: Germany
state: Sachsen
city: Hamburg
country: Germany
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Gyongyos
country: Hungary
city: Gyula
country: Hungary
city: Mosonmagyarovar
country: Hungary
city: Nyiregyhaza
country: Hungary
city: Pecs
country: Hungary
city: Szikszo
country: Hungary
city: Torrette di Ancona
country: Italy
state: Ancona
city: Acquaviva delle Fonti
country: Italy
state: Bari
city: Legnago
country: Italy
state: Verona
city: Bologna
country: Italy
city: Brescia
country: Italy
city: Ferrara
country: Italy
city: L'Aquila
country: Italy
city: Milano
country: Italy
city: Palermo
country: Italy
city: Pavia
country: Italy
city: Pisa
country: Italy
city: Roma
country: Italy
city: Sassari
country: Italy
city: Alytus
country: Lithuania
city: Kaunas
country: Lithuania
city: Beek
country: Netherlands
city: Breda
country: Netherlands
city: Eindhoven
country: Netherlands
city: Groningen
country: Netherlands
city: Leiderdorp
country: Netherlands
city: Maastricht
country: Netherlands
city: Rotterdam
country: Netherlands
city: Velp
country: Netherlands
city: Zoetermeer
country: Netherlands
city: Zwijndrecht
country: Netherlands
city: Bydgoszcz
country: Poland
city: Gdansk
country: Poland
city: Gdynia
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Lublin
country: Poland
city: Oswiecim
country: Poland
city: Parczew
country: Poland
city: Poznan
country: Poland
city: Pulway
country: Poland
city: Rzeszow
country: Poland
city: Sopot
country: Poland
city: Torun
country: Poland
city: Zgierz
country: Poland
city: Belgrade
country: Serbia
city: Kragujevac
country: Serbia
city: Krusevac
country: Serbia
city: Nis
country: Serbia
city: Sremska Kamenica
country: Serbia
city: Zemun
country: Serbia
city: Bardejov
country: Slovakia
city: Bratislava
country: Slovakia
city: Galanta
country: Slovakia
city: Komarno
country: Slovakia
city: Kosice
country: Slovakia
city: Lucenec
country: Slovakia
city: Martin
country: Slovakia
city: Nitra
country: Slovakia
city: Nove Zamky
country: Slovakia
city: Presov
country: Slovakia
city: Svidnik
country: Slovakia
city: Zilina
country: Slovakia
city: Centelles
country: Spain
state: Barcelona
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Malaga
country: Spain
city: Goteborg
country: Sweden
city: Lund
country: Sweden
city: Malmo
country: Sweden
city: Vallingby
country: Sweden
city: London
country: United Kingdom
state: Greater London
city: Glasgow
country: United Kingdom
state: Lanarkshire
city: Blackpool
country: United Kingdom
state: Lancashire
city: Northwood
country: United Kingdom
state: Middlesex
city: Bath
country: United Kingdom
state: Somerset
city: Leamington Spa
country: United Kingdom
state: Warwickshire
city: Westbury
country: United Kingdom
state: Wiltshire
Study officials:
affiliation: Takeda
name: Medical Director, Clinical Science
role: STUDY_DIRECTOR
References: