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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01456169
• Collaborator: (none)
• Enrollment: 507
• Locations: 108
• Arms: 3
• Duration (Months): 15
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: Azilsartan medoxomil/placebo; Drug: Azilsartan medoxomil - chlorthalidone	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 507 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: Oct 1, 2011
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Azilsartan medoxomil 40 mg Azilsartan medoxomil 40 mg and placebo to chlorthalidone combination tablets, orally, once daily for up to 8 weeks.	Drug: Azilsartan medoxomil/placebo; Azilsartan medoxomil and placebo to chlorthalidone combination tablets; Other Names: TAK-491 EDARBI
Experimental: Azilsartan medoxomil + chlorthalidone 40/12.5 mg Azilsartan 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks.	Drug: Azilsartan medoxomil - chlorthalidone; Azilsartan medoxomil and chlorthalidone fixed dose combination tablets; Other Names: TAK-491CLD Edarbyclor
Experimental: Azilsartan medoxomil + chlorthalidone 40/25 mg Azilsartan medoxomil 40 mg and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks.	Drug: Azilsartan medoxomil - chlorthalidone; Azilsartan medoxomil and chlorthalidone fixed dose combination tablets; Other Names: TAK-491CLD Edarbyclor

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure [Baseline (of the double-blind treatment period) and Week 8]

   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

1. Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure [Baseline and Week 8]

   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.

2. Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring [Baseline and Week 8, 22-24 hours after dosing]

   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.

3. Change From Baseline to Week 8 in Trough Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring [Baseline and Week 8, 22-24 hours after dosing]

   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.

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

   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.

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

   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.

6. Change From Baseline to Week 8 in the Mean Daytime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [Baseline and Week 8]

   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.

7. Change From Baseline to Week 8 in the Mean Daytime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [Baseline and Week 8]

   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.

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

   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.

9. Change From Baseline to Week 8 in the Mean Nighttime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring [Baseline and Week 8.]

   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.

10. 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 [Baseline and Week 8]

    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.

11. 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 [Baseline and Week 8]

    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.

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

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

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

• ≥140 to ≤160 mm Hg in participants taking 2 antihypertensive medications at Visit

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:

1. 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:

1. 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.

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.

2. 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.

3. The participant is currently treated with more than 2 antihypertensive medications.

4. The participant works a night (third) shift (defined as 11 PM [2300] to 7 AM [0700]).

5. The participant has an upper arm circumference <24 cm or >42 cm.

6. The participant has secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing's syndrome).

7. 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.

8. The participant has clinically significant cardiac conduction defects (e.g., third-degree atrioventricular block, sick sinus syndrome).

9. The participant has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease or hypertrophic cardiomyopathy.

10. 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).

11. Participant has known hemodynamically significant bilateral renal artery stenosis or unilateral disease in a single kidney.

12. 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).

13. The participant has poorly-controlled type 1 or 2 diabetes mellitus (hemoglobin A1c [HbA1c] >8.5%) at Screening.

14. The participant has hypokalemia or hyperkalemia (defined as serum potassium outside of the normal reference range of the central laboratory) at Screening.

15. 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.

1. 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.

2. The participant has a history of hypersensitivity or allergies to angiotensin II receptor blockers (ARB) or thiazide-type diuretics or other sulfonamide-derived compounds.

3. 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.

4. The participant is required to take excluded medications at any point during the study.

5. 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

1. The participant has a clinic SBP >190 mm Hg and DBP >115 mm Hg.

2. The participant is noncompliant (<70% or >130%) with study medication during the placebo run-in period.

3. The participant has a 24-hour mean eligibility ABPM reading of insufficient quality.

Post-single-blind TAK-491 40 mg treatment period

1. The participant has a clinic SBP >180 mm Hg and DBP >110 mm Hg.

2. The participant is noncompliant (<70% or >130%) with study medication during the TAK-491 40 mg single-blind treatment period.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Haskovo		Bulgaria
2		Pazardzhik		Bulgaria
3		Pleven		Bulgaria
4		Plovdiv		Bulgaria
5		Sofia		Bulgaria
6		Varna		Bulgaria
7		Veliko Tarnovo		Bulgaria
8		Paide		Estonia
9		Saku		Estonia
10		Tallinn		Estonia
11		Tartu		Estonia
12		Voru		Estonia
13		Labarthe Sur Leze	Haute Garonne	France
14		Bourg-des-Comptes	Ille et Vilaine	France
15		Tours	Indre et Loire	France
16		Vourey	Isere	France
17		Saint Etienne	Loire	France
18		Orthez	Pyrenees Atlantiques	France
19		Karlsruhe	Baden Wuerttemberg	Germany
20		Bad Woerishofen	Bayern	Germany
21		Nuernberg	Bayern	Germany
22		Frankfurt	Hessen	Germany
23		Stuhr	Niedersachsen	Germany
24		Essen	Nordrhein Westfalen	Germany
25		Kamp-Lintfort	Nordrhein Westfalen	Germany
26		Mainz	Rheinland Pfalz	Germany
27		Dresden	Sachsen	Germany
28		Hamburg		Germany
29		Budapest		Hungary
30		Debrecen		Hungary
31		Gyongyos		Hungary
32		Gyula		Hungary
33		Mosonmagyarovar		Hungary
34		Nyiregyhaza		Hungary
35		Pecs		Hungary
36		Szikszo		Hungary
37		Torrette di Ancona	Ancona	Italy
38		Acquaviva delle Fonti	Bari	Italy
39		Legnago	Verona	Italy
40		Bologna		Italy
41		Brescia		Italy
42		Ferrara		Italy
43		L'Aquila		Italy
44		Milano		Italy
45		Palermo		Italy
46		Pavia		Italy
47		Pisa		Italy
48		Roma		Italy
49		Sassari		Italy
50		Alytus		Lithuania
51		Kaunas		Lithuania
52		Beek		Netherlands
53		Breda		Netherlands
54		Eindhoven		Netherlands
55		Groningen		Netherlands
56		Leiderdorp		Netherlands
57		Maastricht		Netherlands
58		Rotterdam		Netherlands
59		Velp		Netherlands
60		Zoetermeer		Netherlands
61		Zwijndrecht		Netherlands
62		Bydgoszcz		Poland
63		Gdansk		Poland
64		Gdynia		Poland
65		Krakow		Poland
66		Lodz		Poland
67		Lublin		Poland
68		Oswiecim		Poland
69		Parczew		Poland
70		Poznan		Poland
71		Pulway		Poland
72		Rzeszow		Poland
73		Sopot		Poland
74		Torun		Poland
75		Zgierz		Poland
76		Belgrade		Serbia
77		Kragujevac		Serbia
78		Krusevac		Serbia
79		Nis		Serbia
80		Sremska Kamenica		Serbia
81		Zemun		Serbia
82		Bardejov		Slovakia
83		Bratislava		Slovakia
84		Galanta		Slovakia
85		Komarno		Slovakia
86		Kosice		Slovakia
87		Lucenec		Slovakia
88		Martin		Slovakia
89		Nitra		Slovakia
90		Nove Zamky		Slovakia
91		Presov		Slovakia
92		Svidnik		Slovakia
93		Zilina		Slovakia
94		Centelles	Barcelona	Spain
95		Barcelona		Spain
96		Madrid		Spain
97		Malaga		Spain
98		Goteborg		Sweden
99		Lund		Sweden
100		Malmo		Sweden
101		Vallingby		Sweden
102		London	Greater London	United Kingdom
103		Glasgow	Lanarkshire	United Kingdom
104		Blackpool	Lancashire	United Kingdom
105		Northwood	Middlesex	United Kingdom
106		Bath	Somerset	United Kingdom
107		Leamington Spa	Warwickshire	United Kingdom
108		Westbury	Wiltshire	United Kingdom

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01456169
• Other Study ID Numbers: TAK-491CLD_307; 2011-000220-16; U1111-1119-4743; 11-028; NL36272.072.11
• First Posted: Oct 20, 2011
• Last Update Posted: Apr 23, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Takeda: High Blood Pressure; Drug Therapy
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Chlorthalidone; Azilsartan medoxomil

Study Results

Participant Flow

Recruitment Details	A total of 1754 patients were screened at 125 investigative sites in Bulgaria, Estonia, France, Germany, Hungary, Italy, Lithuania, the Netherlands, Poland, Serbia, Slovakia, Spain, Sweden, and the United Kingdom from 31 October 2011 to 24 January 2013.
Pre-assignment Detail	507 participants entered the azilsartan medoxomil 40 mg Single-Blind Monotherapy Treatment Period and 395 participants were eligible to enter the Double-Blind Treatment Period and were randomly assigned to 1 of 3 active treatment arms.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Period Title: Overall Study
STARTED	133	127	135
COMPLETED	123	122	123
NOT COMPLETED	10	5	12

Baseline Characteristics

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg	Total
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.	Total of all reporting groups
Overall Participants	133	127	135	395
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (10.18)	59.2 (10.72)	57.7 (10.46)	58.2 (10.45)
Age, Customized (participants) [Number]
< 45 years	13 9.8%	10 7.9%	12 8.9%	35 8.9%
45 to < 65 years	87 65.4%	79 62.2%	88 65.2%	254 64.3%
≥ 65 years	33 24.8%	38 29.9%	35 25.9%	106 26.8%
Sex: Female, Male (Count of Participants)
Female	46 34.6%	54 42.5%	44 32.6%	144 36.5%
Male	87 65.4%	73 57.5%	91 67.4%	251 63.5%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	1 0.8%	0 0%	1 0.7%	2 0.5%
Asian	0 0%	1 0.8%	0 0%	1 0.3%
Black or African American	1 0.8%	0 0%	0 0%	1 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	1 0.7%	1 0.3%
White	132 99.2%	126 99.2%	134 99.3%	392 99.2%
Multiracial	1 0.8%	0 0%	1 0.7%	2 0.5%
Region of Enrollment (participants) [Number]
Bulgaria	11 8.3%	10 7.9%	11 8.1%	32 8.1%
Estonia	18 13.5%	16 12.6%	18 13.3%	52 13.2%
France	2 1.5%	1 0.8%	2 1.5%	5 1.3%
Germany	29 21.8%	29 22.8%	28 20.7%	86 21.8%
Hungary	10 7.5%	9 7.1%	10 7.4%	29 7.3%
Italy	6 4.5%	4 3.1%	5 3.7%	15 3.8%
Lithuania	5 3.8%	4 3.1%	6 4.4%	15 3.8%
Netherlands	4 3%	6 4.7%	5 3.7%	15 3.8%
Poland	17 12.8%	18 14.2%	17 12.6%	52 13.2%
Serbia	4 3%	3 2.4%	4 3%	11 2.8%
Slovakia	24 18%	24 18.9%	26 19.3%	74 18.7%
Spain	1 0.8%	1 0.8%	1 0.7%	3 0.8%
Sweden	1 0.8%	2 1.6%	1 0.7%	4 1%
United Kingdom	1 0.8%	0 0%	1 0.7%	2 0.5%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	87.59 (15.794)	86.71 (17.037)	87.39 (14.876)	87.24 (15.868)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	171.8 (8.87)	170.6 (9.96)	172.1 (9.74)	171.5 (9.53)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	29.63 (5.066)	29.78 (5.206)	29.52 (4.572)	29.64 (4.937)
Smoking Classification (participants) [Number]
Never smoked	77 57.9%	83 65.4%	77 57%	237 60%
Current smoker	31 23.3%	25 19.7%	30 22.2%	86 21.8%
Ex-smoker	25 18.8%	19 15%	28 20.7%	72 18.2%
Diabetes Status (participants) [Number]
Yes	20 15%	27 21.3%	20 14.8%	67 17%
No	113 85%	100 78.7%	115 85.2%	328 83%
Estimated Glomerular Filtration Rate (eGFR) (mL/min/1.73 m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mL/min/1.73 m^2]	84.8 (16.41)	81.5 (16.25)	82.4 (16.51)	82.9 (16.41)
Baseline eGFR Categories (mL/min/1.73 m^2) (participants) [Number]
30 to < 60 ml/min/1.73 m^2	11 8.3%	10 7.9%	11 8.1%	32 8.1%
60 to < 90 ml/min/1.73 m^2	78 58.6%	85 66.9%	80 59.3%	243 61.5%
≥ 90 ml/min/1.73 m^2	44 33.1%	32 25.2%	44 32.6%	120 30.4%
Trough Clinic Systolic Blood Pressure (SBP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	150.7 (10.69)	149.6 (11.54)	149.8 (10.95)	150.0 (11.04)
Trough Clinic SBP Category (mmHg) (participants) [Number]
<140 mmHg	16 12%	17 13.4%	17 12.6%	50 12.7%
≥140 - <160 mmHg	86 64.7%	87 68.5%	93 68.9%	266 67.3%
≥160 - <180 mmHg	31 23.3%	23 18.1%	25 18.5%	79 20%
≥180 mmHg	0 0%	0 0%	0 0%	0 0%
Trough Clinic Diastolic Blood Pressure (DBP) (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	89.8 (7.76)	87.6 (9.31)	88.8 (7.99)	88.7 (8.39)
Trough Clinic DBP Categories (mmHg) (participants) [Number]
<90 mmHg	68 51.1%	72 56.7%	70 51.9%	210 53.2%
≥90 mmHg	65 48.9%	55 43.3%	65 48.1%	185 46.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 8 in Trough, Sitting, Clinic Systolic Blood Pressure
Description	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.
Time Frame	Baseline (of the double-blind treatment period) and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set, consisting of all randomized participants who received at least 1 dose of double-blind study drug. A participant was included in the analyses only when there was both a baseline value and at least 1 value during the double-blind treatment period. Last observation carried forward (LOCF) was used.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	133	126	135
Baseline	150.7 (0.96)	149.8 (0.98)	149.8 (0.95)
Change from Baseline to Week 8	-6.4 (1.05)	-15.8 (1.08)	-21.1 (1.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azilsartan Medoxomil 40 mg, Azilsartan Medoxomil + Chlorthalidone 40/25 mg
	Comments	The type I error was controlled using a 2-step hierarchical testing procedure. In the first step, the high dose (40/25 mg) of Azilsartan medoxomil + chlorthalidone was compared to Azilsartan medoxomil alone. If the comparison in step 1 was statistically significant at a significance level of 5%, then step 2 was performed by comparing the low dose (40/12.5 mg) and monotherapy at the 5% significance level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with treatment as a fixed effect and baseline trough, sitting, clinic SBP as a covariate.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-14.7
	Confidence Interval	(2-Sided) 95%; -17.6 to -11.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Azilsartan Medoxomil 40 mg, Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	ANCOVA
	Comments	ANCOVA model with treatment as a fixed effect and baseline trough, sitting, clinic SBP as a covariate
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-9.5
	Confidence Interval	(2-Sided) 95%; -12.4 to -6.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Week 8 in Trough, Sitting, Clinic Diastolic Blood Pressure
Description	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set; LOCF was used.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	133	126	135
Baseline	89.8 (0.73)	87.7 (0.75)	88.8 (0.72)
Change from Baseline to Week 8	-3.2 (0.65)	-7.7 (0.67)	-10.3 (0.65)

3. Secondary Outcome

Title	Change From Baseline to Week 8 in Trough Systolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8, 22-24 hours after dosing

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	143.1 (1.55)	140.2 (1.62)	142.0 (1.58)
Change from Baseline to Week 8	-2.5 (1.31)	-14.0 (1.36)	-16.6 (1.32)

4. Secondary Outcome

Title	Change From Baseline to Week 8 in Trough Diastolic Blood Pressure as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8, 22-24 hours after dosing

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	86.4 (1.11)	83.6 (1.16)	86.0 (1.12)
Change from Baseline to Week 8	-2.2 (0.88)	-8.8 (0.92)	-9.4 (0.89)

5. Secondary Outcome

Title	Change From Baseline to Week 8 in the 24-hour Mean Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	138.0 (1.21)	137.0 (1.26)	138.2 (1.22)
Change from Baseline to Week 8	-2.3 (1.02)	-14.7 (1.07)	-18.1 (1.03)

6. Secondary Outcome

Title	Change From Baseline to Week 8 in the 24-hour Mean Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	81.9 (0.89)	80.3 (0.93)	82.5 (0.91)
Change from Baseline to Week 8	-1.6 (0.66)	-8.5 (0.69)	-10.1 (0.67)

7. Secondary Outcome

Title	Change From Baseline to Week 8 in the Mean Daytime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	141.5 (1.24)	141.1 (1.30)	141.9 (1.26)
Change from Baseline to Week 8	-2.4 (1.09)	-15.3 (1.14)	-18.2 (1.11)

8. Secondary Outcome

Title	Change From Baseline to Week 8 in the Mean Daytime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	84.9 (0.96)	83.6 (1.01)	85.7 (0.98)
Change from Baseline to Week 8	-1.7 (0.72)	-8.9 (0.75)	-10.1 (0.73)

9. Secondary Outcome

Title	Change From Baseline to Week 8 in the Mean Nighttime Systolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	127.3 (1.50)	124.2 (1.57)	126.3 (1.52)
Change from Baseline to Week 8	-2.2 (1.18)	-12.7 (1.24)	-17.3 (1.20)

10. Secondary Outcome

Title	Change From Baseline to Week 8 in the Mean Nighttime Diastolic Blood Pressure, as Measured by Ambulatory Blood Pressure Monitoring
Description	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.
Time Frame	Baseline and Week 8.

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	73.2 (0.95)	70.6 (0.99)	72.9 (0.97)
Change from Baseline to Week 8	-1.6 (0.78)	-7.2 (0.82)	-9.8 (0.79)

11. Secondary Outcome

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	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	141.6 (1.30)	141.8 (1.36)	142.3 (1.32)
Change from Baseline to Week 8	-2.3 (1.14)	-15.4 (1.19)	-18.2 (1.16)

12. Secondary Outcome

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	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.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set. Only participants with a Baseline and at least 1 post-baseline value of acceptable quality were included.

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	107	98	104
Baseline	85.2 (1.01)	84.2 (1.05)	86.0 (1.02)
Week 8	-1.6 (0.75)	-8.9 (0.78)	-10.1 (0.76)

13. Secondary Outcome

Title	Percentage of Participants Who Achieve a Target Clinic Systolic Blood Pressure at Week 8
Description	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.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	133	126	135
Number [percentage of participants]	35.3 26.5%	62.7 49.4%	77.8 57.6%

14. Secondary Outcome

Title	Percentage of Participants Who Achieve a Target Clinic Diastolic Blood Pressure at Week 8
Description	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.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	133	126	135
Number [percentage of participants]	60.2 45.3%	81.0 63.8%	85.9 63.6%

15. Secondary Outcome

Title	Percentage of Participants Who Achieve Both Clinic Systolic and Diastolic Blood Pressure Targets at Week 8
Description	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.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Azilsartan Medoxomil 40 mg	Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg	Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo 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.
Measure Participants	133	126	135
Number [percentage of participants]	30.8 23.2%	59.5 46.9%	74.1 54.9%

Adverse Events

Time Frame	For 4 weeks during the monotherapy treatment period and from the first dose of double-blind study drug up to 14 days (or 30 days for a Serious AE) after the last dose of study drug in the 8-week double-blind treatment period.
Adverse Event Reporting Description	The investigator documented any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of relation to study drug.
Arm/Group Title	Monotherapy: Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg		Azilsartan Medoxomil + Chlorthalidone 40/25 mg
Arm/Group Description	Azilsartan medoxomil 40 mg and chlorthalidone placebo combination tablets, orally, once daily for 4 weeks during the Single-Blind Monotherapy Treatment Period. All enrolled participants, including those who were not randomized to double-blind treatment are included in this group.		Azilsartan medoxomil 40 mg and chlorthalidone placebo combination tablets, orally, once daily for up to 8 weeks during the Double-Blind Treatment Period.		Azilsartan 40 mg and chlorthalidone 12.5 mg combination tablets, orally, once daily for up to 8 weeks during the Double-Blind Treatment Period.		Azilsartan medoxomil 40 mg and chlorthalidone 25 mg combination tablets, orally, once daily for up to 8 weeks during the Double-Blind Treatment Period.
All Cause Mortality
	Monotherapy: Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg		Azilsartan Medoxomil + Chlorthalidone 40/25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Monotherapy: Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg		Azilsartan Medoxomil + Chlorthalidone 40/25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/507 (0.6%)		2/133 (1.5%)		0/127 (0%)		0/135 (0%)
Cardiac disorders
Myocardial infarction	0/507 (0%)		1/133 (0.8%)		0/127 (0%)		0/135 (0%)
Acute myocardial infarction	1/507 (0.2%)		0/133 (0%)		0/127 (0%)		0/135 (0%)
Ventricular tachycardia	1/507 (0.2%)		0/133 (0%)		0/127 (0%)		0/135 (0%)
Investigations
Blood pressure increased	1/507 (0.2%)		0/133 (0%)		0/127 (0%)		0/135 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cancer	1/507 (0.2%)		0/133 (0%)		0/127 (0%)		0/135 (0%)
Nervous system disorders
Cerebrovascular accident	1/507 (0.2%)		1/133 (0.8%)		0/127 (0%)		0/135 (0%)
Other (Not Including Serious) Adverse Events
	Monotherapy: Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil 40 mg		Azilsartan Medoxomil + Chlorthalidone 40/12.5 mg		Azilsartan Medoxomil + Chlorthalidone 40/25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/507 (3%)		15/133 (11.3%)		13/127 (10.2%)		26/135 (19.3%)
Infections and infestations
Nasopharyngitis	6/507 (1.2%)		4/133 (3%)		2/127 (1.6%)		4/135 (3%)
Viral infection	0/507 (0%)		4/133 (3%)		0/127 (0%)		0/135 (0%)
Investigations
Blood creatinine increased	2/507 (0.4%)		4/133 (3%)		4/127 (3.1%)		11/135 (8.1%)
Nervous system disorders
Headache	9/507 (1.8%)		2/133 (1.5%)		3/127 (2.4%)		5/135 (3.7%)
Dizziness	3/507 (0.6%)		0/133 (0%)		2/127 (1.6%)		6/135 (4.4%)
Vascular disorders
Hypotension	0/507 (0%)		1/133 (0.8%)		2/127 (1.6%)		4/135 (3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.