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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

Primary Purpose

Essential Hypertension

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Azilsartan medoxomil/placebo

Azilsartan medoxomil - chlorthalidone

About this trial

This is an interventional treatment trial for Essential Hypertension focused on measuring High Blood Pressure, Drug Therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

At Screening

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.
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.
The participant is willing to discontinue current antihypertensive medications.
In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
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.
Male or female adult, at least 18 years of age.
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:
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:
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

The participant has clinic diastolic blood pressure (DBP) >110 mm Hg.
The participant's 3 SBP measurements differ by more than 15 mm Hg (confirmed by a second set of three measurements).
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.
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.
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.
The participant is currently treated with more than 2 antihypertensive medications.
The participant works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]).
The participant has an upper arm circumference <24 cm or >42 cm.
The participant has secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing's syndrome).
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.
The participant has clinically significant cardiac conduction defects (e.g., third-degree atrioventricular block, sick sinus syndrome).
The participant has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease or hypertrophic cardiomyopathy.
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).
Participant has known hemodynamically significant bilateral renal artery stenosis or unilateral disease in a single kidney.
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).
The participant has poorly-controlled type 1 or 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8.5%) at Screening.
The participant has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory) at Screening.
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.
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.
The participant has a history of hypersensitivity or allergies to angiotensin II receptor blockers (ARB) or thiazide-type diuretics or other sulfonamide-derived compounds.
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.
The participant is required to take excluded medications at any point during the study.
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
The participant has a clinic SBP >190 mm Hg and DBP >115 mm Hg.
The participant is noncompliant (<70% or >130%) with study medication during the placebo run-in period.
The participant has a 24-hour mean eligibility ABPM reading of insufficient quality.
Post-single-blind TAK-491 40 mg treatment period
The participant has a clinic SBP >180 mm Hg and DBP >110 mm Hg.
The participant is noncompliant (<70% or >130%) with study medication during the TAK-491 40 mg single-blind treatment period.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Azilsartan medoxomil 40 mg

Azilsartan medoxomil + chlorthalidone 40/12.5 mg

Azilsartan medoxomil + chlorthalidone 40/25 mg

Arm Description

Azilsartan medoxomil 40 mg and placebo to chlorthalidone combination tablets, orally, once daily for up to 8 weeks.

Azilsartan 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks.

Azilsartan medoxomil 40 mg and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks.

Outcomes

Primary Outcome Measures

Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure

The change between trough systolic blood pressure measured at final visit or Week 8 relative to baseline. Systolic blood pressure is the arithmetic mean of the 3 trough sitting systolic blood pressure measurements.

Secondary Outcome Measures

Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure

The change between trough diastolic blood pressure measured at final visit or week 8 relative to baseline Diastolic blood pressure is the arithmetic mean of the 3 trough sitting diastolic blood pressure measurements.

Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring

The change in trough systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing.

Change From Baseline to Week 8 in Trough Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring

The change in trough diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The trough is the average of all measurements recorded from 22 to 24 hours after dosing.

Change From Baseline to Week 8 in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

The change in 24-hour mean systolic blood pressure measured at final visit or week 8 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 to Week 8 in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

The change in 24-hour mean diastolic blood pressure measured at final visit or week 8 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 to Week 8 in the Mean Daytime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

The change in daytime (6 am to 10 pm) mean systolic blood pressure measured at final visit or week 8 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 and 10 pm.

Change From Baseline to Week 8 in the Mean Daytime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

The change in daytime (6 am to 10 pm) mean diastolic blood pressure measured at final visit or week 8 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 and 10 pm.

Change From Baseline to Week 8 in the Mean Nighttime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

The change in nighttime (12 am to 6 am) mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am.

Change From Baseline to Week 8 in the Mean Nighttime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

The change in nighttime (12 am to 6 am) mean diastolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. Nighttime mean is the average of all measurements recorded between the hours of 12 am and 6 am.

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

The change in the 12-hour mean systolic blood pressure measured at final visit or week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded in the first 12 hours after dosing.

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

The change in the 12-hour mean diastolic blood pressure measured at final visit or Week 8 relative to baseline. Ambulatory blood pressure monitoring measures blood pressure at regular intervals throughout the day and night. The 12-hour mean is the average of all measurements recorded in the first 12 hours after dosing.

Percentage of Participants Who Achieve a Target Clinic Systolic Blood Pressure at Week 8

Percentage of participants who achieve a target clinic systolic blood pressure measured at final visit or week 8, defined as less than 140 mm Hg (or less than 130 mm Hg for participants with diabetes or chronic kidney disease). Systolic blood pressure is the arithmetic mean of the 3 trough sitting Systolic blood pressure measurements.

Percentage of Participants Who Achieve a Target Clinic Diastolic Blood Pressure at Week 8

Percentage of participants who achieve a target clinic diastolic blood pressure measured at final visit or week 8, defined as less than 90 mm Hg (or less than 80 mm Hg for participants with diabetes or chronic kidney disease). Diastolic blood pressure is based on the arithmetic mean of the 3 trough sitting diastolic blood pressure measurements.

Percentage of Participants Who Achieve Both Clinic Systolic and Diastolic Blood Pressure Targets at Week 8

Percentage of participants who achieve both clinic systolic and diastolic blood pressure targets at Week 8, defined as less than 140 mm Hg (or less than 130 mm Hg for participants with diabetes or chronic kidney disease) for systolic AND less than 90 mm Hg (or less than 80 mm Hg for participants with diabetes or chronic kidney disease) for diastolic blood pressure.

Full Information

NCT ID

NCT01456169

First Posted

October 18, 2011

Last Updated

March 21, 2014

Sponsor

Takeda

1. Study Identification

Unique Protocol Identification Number

NCT01456169

Brief Title

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

2. Study Status

Record Verification Date

March 2014

Overall Recruitment Status

Completed

Study Start Date

October 2011 (undefined)

Primary Completion Date

December 2012 (Actual)

Study Completion Date

January 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Takeda

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Essential Hypertension

Keywords

High Blood Pressure, Drug Therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

507 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Azilsartan medoxomil 40 mg

Arm Type

Active Comparator

Arm Description

Azilsartan medoxomil 40 mg and placebo to chlorthalidone combination tablets, orally, once daily for up to 8 weeks.

Arm Title

Azilsartan medoxomil + chlorthalidone 40/12.5 mg

Arm Type

Experimental

Arm Description

Azilsartan 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks.

Arm Title

Azilsartan medoxomil + chlorthalidone 40/25 mg

Arm Type

Experimental

Arm Description

Azilsartan medoxomil 40 mg and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks.

Intervention Type

Drug

Intervention Name(s)

Azilsartan medoxomil/placebo

Other Intervention Name(s)

TAK-491, EDARBI

Intervention Description

Azilsartan medoxomil and placebo to chlorthalidone combination tablets

Intervention Type

Drug

Intervention Name(s)

Azilsartan medoxomil - chlorthalidone

Other Intervention Name(s)

TAK-491CLD, Edarbyclor

Intervention Description

Azilsartan medoxomil and chlorthalidone fixed dose combination tablets

Primary Outcome Measure Information:

Title

Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure

Description

Time Frame

Baseline (of the double-blind treatment period) and Week 8

Secondary Outcome Measure Information:

Title

Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure

Description

Time Frame

Baseline and Week 8

Title

Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8, 22-24 hours after dosing

Title

Change From Baseline to Week 8 in Trough Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8, 22-24 hours after dosing

Title

Change From Baseline to Week 8 in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8

Title

Change From Baseline to Week 8 in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8

Title

Change From Baseline to Week 8 in the Mean Daytime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8

Title

Change From Baseline to Week 8 in the Mean Daytime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8

Title

Change From Baseline to Week 8 in the Mean Nighttime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8

Title

Change From Baseline to Week 8 in the Mean Nighttime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring

Description

Time Frame

Baseline and Week 8.

Title

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

Description

Time Frame

Baseline and Week 8

Title

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

Description

Time Frame

Baseline and Week 8

Title

Percentage of Participants Who Achieve a Target Clinic Systolic Blood Pressure at Week 8

Description

Time Frame

Week 8

Title

Percentage of Participants Who Achieve a Target Clinic Diastolic Blood Pressure at Week 8

Description

Time Frame

Week 8

Title

Percentage of Participants Who Achieve Both Clinic Systolic and Diastolic Blood Pressure Targets at Week 8

Description

Time Frame

Week 8

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: At Screening 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. 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. The participant is willing to discontinue current antihypertensive medications. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 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. Male or female adult, at least 18 years of age. 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: 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: 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 The participant has clinic diastolic blood pressure (DBP) >110 mm Hg. The participant's 3 SBP measurements differ by more than 15 mm Hg (confirmed by a second set of three measurements). 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. 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. 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. The participant is currently treated with more than 2 antihypertensive medications. The participant works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]). The participant has an upper arm circumference <24 cm or >42 cm. The participant has secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing's syndrome). 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. The participant has clinically significant cardiac conduction defects (e.g., third-degree atrioventricular block, sick sinus syndrome). The participant has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease or hypertrophic cardiomyopathy. 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). Participant has known hemodynamically significant bilateral renal artery stenosis or unilateral disease in a single kidney. 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). The participant has poorly-controlled type 1 or 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8.5%) at Screening. The participant has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory) at Screening. 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. 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. The participant has a history of hypersensitivity or allergies to angiotensin II receptor blockers (ARB) or thiazide-type diuretics or other sulfonamide-derived compounds. 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. The participant is required to take excluded medications at any point during the study. 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 The participant has a clinic SBP >190 mm Hg and DBP >115 mm Hg. The participant is noncompliant (<70% or >130%) with study medication during the placebo run-in period. The participant has a 24-hour mean eligibility ABPM reading of insufficient quality. Post-single-blind TAK-491 40 mg treatment period The participant has a clinic SBP >180 mm Hg and DBP >110 mm Hg. The participant is noncompliant (<70% or >130%) with study medication during the TAK-491 40 mg single-blind treatment period.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director, Clinical Science

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

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

State/Province

Haute Garonne

Country

France

City

Bourg-des-Comptes

State/Province

Ille et Vilaine

Country

France

City

Tours

State/Province

Indre et Loire

Country

France

City

Vourey

State/Province

Isere

Country

France

City

Saint Etienne

State/Province

Loire

Country

France

City

Orthez

State/Province

Pyrenees Atlantiques

Country

France

City

Karlsruhe

State/Province

Baden Wuerttemberg

Country

Germany

City

Bad Woerishofen

State/Province

Bayern

Country

Germany

City

Nuernberg

State/Province

Bayern

Country

Germany

City

Frankfurt

State/Province

Hessen

Country

Germany

City

Stuhr

State/Province

Niedersachsen

Country

Germany

City

Essen

State/Province

Nordrhein Westfalen

Country

Germany

City

Kamp-Lintfort

State/Province

Nordrhein Westfalen

Country

Germany

City

Mainz

State/Province

Rheinland Pfalz

Country

Germany

City

Dresden

State/Province

Sachsen

Country

Germany

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

State/Province

Ancona

Country

Italy

City

Acquaviva delle Fonti

State/Province

Bari

Country

Italy

City

Legnago

State/Province

Verona

Country

Italy

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

State/Province

Barcelona

Country

Spain

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

State/Province

Greater London

Country

United Kingdom

City

Glasgow

State/Province

Lanarkshire

Country

United Kingdom

City

Blackpool

State/Province

Lancashire

Country

United Kingdom

City

Northwood

State/Province

Middlesex

Country

United Kingdom

City

Bath

State/Province

Somerset

Country

United Kingdom

City

Leamington Spa

State/Province

Warwickshire

Country

United Kingdom

City

Westbury

State/Province

Wiltshire

Country

United Kingdom

12. IPD Sharing Statement

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