A Safety and Tolerability Study of Azilsartan Medoxomil in Participants With Essential Hypertension

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00696384
• Collaborator: (none)
• Enrollment: 418
• Locations: 45
• Arms: 3
• Duration (Months): 22
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the long term safety and tolerability of azilsartan medoxomil, once daily (QD), in participants with Essential Hypertension.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Azilsartan medoxomil; Drug: Azilsartan medoxomil, with or without chlorthalidone and other non-angiotensin II receptor blocker antihypertensive medications.; Drug: Placebo	Phase 3

Detailed Description

Hypertension affects approximately 50 million individuals in the United States. As the population ages, the prevalence of hypertension will continue to increase if broad and effective preventive measures are not implemented. According to the World Health Organization, hypertension is the most common attributable cause of preventable death in developed nations, as uncontrolled hypertension greatly increases the risk of cardiovascular disease, cerebrovascular disease, and renal failure.

A major component of blood pressure regulation is the renin-angiotensin-aldosterone system, a system of hormone-mediated feedback interactions that results in the relaxation or constriction of blood vessels in response to various stimuli. Angiotensin II, a polypeptide hormone, is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme as part of the renin-angiotensin-aldosterone system. AII is the principal pressor agent of the renin-angiotensin-aldosterone system with a myriad of effects on the cardiovascular system and on electrolyte homeostasis. Two receptors for angiotensin II have been identified. Angiotensin II type 1 (AT1) receptors are located predominantly in vascular smooth muscle, where activation by angiotensin II results in vasoconstriction, hypertrophic proliferation, and inflammation. In contrast, stimulation of angiotensin II type 2 (AT2) receptors by angiotensin II results in vasodilation, antiproliferative effects, and other effects that are opposite from those of AT1 receptor stimulation.

Drugs that modulate the renin-angiotensin-aldosterone system are used commonly worldwide for the treatment of hypertension. Of these, some block the synthesis of angiotensin II by inhibiting angiotensin-converting enzyme inhibitors, while others inhibit the action of angiotensin II by binding directly to the AT1 receptor (angiotensin II receptor blockers), thereby allowing blood vessels to dilate, resulting in a reduction in blood pressure. The effects of angiotensin II receptor blockers on other conditions in which the renin-angiotensin-aldosterone system plays a significant role, such as congestive heart failure, post-myocardial infarction management, and diabetic nephropathy, also are being investigated.

Takeda Global Research & Development Center, Inc. is developing TAK-491 (azilsartan medoxomil) to treat mild to moderate essential hypertension. Nonclinical studies have indicated that azilsartan medoxomil is an antagonist of the AT1 receptor subtype.

This study consists of 2 phases. The first phase will be a 26-week, open-label, multicenter phase to evaluate the safety and tolerability of TAK-491 in participants with essential hypertension. Investigators were instructed to manage participants according to a protocol-specified treatment algorithm to achieve target blood pressure. All participants who completed the open-label phase then were randomized into a 6-week double-blind, placebo-controlled (azilsartan medoxomil [maintained at the final dose from the open-label phase] or placebo, in addition to their current other antihypertensive medications including chlorthalidone, as applicable) reversal phase to evaluate maintenance/durability of azilsartan medoxomil -mediated blood pressure reduction, as well as potential rebound following the cessation of azilsartan medoxomil.

Study participation is anticipated to be about 8.5 Months. Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, vital signs including sitting and standing blood pressure and pulse, body height and weight, physical examinations and electrocardiograms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 418 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: An 8-Month Phase 3, Open-Label Study With a Blinded Reversal Phase to Evaluate the Safety and Tolerability of TAK-491 in Subjects With Essential Hypertension
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azilsartan Medoxomil QD-Open Label Phase (Baseline - Week 26)	Drug: Azilsartan medoxomil; All subjects initiated azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, force-titrated to 80 mg, tablets, orally, once daily. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily as needed and other antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after the subject had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up- or down-titrated by 1 dose level per scheduled or unscheduled visit.; Other Names: TAK-491 Edarbi
Experimental: Azilsartan Medoxomil QD - Double-Blind Phase (Week 26-32)	Drug: Azilsartan medoxomil, with or without chlorthalidone and other non-angiotensin II receptor blocker antihypertensive medications.; Azilsartan medoxomil at the final dose received during the open-label phase: (20 mg, 40 mg or 80 mg), tablets, orally, once daily with or without chlorthalidone 25 mg, tablets, orally once daily and other non-ARB antihypertensive medications (if currently taking), for 6 weeks/Week 32.; Other Names: TAK-491 Edarbi
Placebo Comparator: Placebo QD - Double-Blind Phase (Week 26- 32)	Drug: Placebo; Azilsartan medoxomil placebo-matching tablets, orally, once daily with or without chlorthalidone 25 mg or other non-ARB antihypertensive (if currently taking), tablets, orally, once daily for 6 weeks/Week 32.

Outcome Measures

Primary Outcome Measures

1. Change From Double-blind Baseline (Week 26) in Sitting Clinic Diastolic Blood Pressure to Week 32 [Double-blind Baseline (Week 26) and Week 32.]

   The change in sitting clinic diastolic blood pressure measured at final visit or week 32 from Double-blind Baseline/Week 26. Diastolic blood pressure is the arithmetic mean of the 3 trough sitting diastolic blood pressure measurements. Each participant's blood pressure at the Final Visit/Week 26 of the open-label phase represented their Baseline blood pressure for the double-blind reversal phase.

Secondary Outcome Measures

1. Change From Double-blind Baseline (Week 26) in Sitting Clinic Systolic Blood Pressure to Week 32 [Double-blind Baseline (Week 26) and Week 32.]

   The change in sitting clinic systolic blood pressure measured at final visit or week 32 from Double-blind Baseline/Week 26.. Systolic blood pressure is the arithmetic mean of the 3 trough sitting systolic blood pressure measurements. Each participant's blood pressure at the Final Visit/Week 26 of the open-label phase represented their Baseline blood pressure for the double-blind reversal phase.

2. Change From Open Label Baseline (Week 0) in Sitting Clinic Diastolic Blood Pressure to Week 26 [Baseline and Week 26.]

   The change from baseline in sitting clinic diastolic blood pressure measured at final visit or week 26.

3. Change From Open Label Baseline (Week 0) in Sitting Clinic Systolic Blood Pressure to Week 26 [Baseline and Week 26.]

   The change from baseline in sitting clinic systolic blood pressure measured at final visit or week 26.

4. Number of Participants With Adverse Events During the Open-Label Phase [Baseline to Week 26]

   Treatment-emergent adverse events defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after last dose of study drug, or within 30 days after the last dose of study drug for serious adverse event (SAE). A SAE is defined as any untoward medical occurrence that either results in death; is life-threatening; requires hospitalization; results in persistent or significant disability/incapacity; leads to a congenital anomaly/birth defect; or is an important medical event.

5. Number of Participants With Adverse Events in the Double-Blind Baseline Phase [Double-blind Baseline/Week 26 to Week 32]

   Treatment-emergent adverse events defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after last dose of study drug, or within 30 days after the last dose of study drug for SAE. A SAE is defined as any untoward medical occurrence that either results in death; is life-threatening; requires hospitalization; results in persistent or significant disability/incapacity; leads to a congenital anomaly/birth defect; or is an important medical event.

Eligibility Criteria

Criteria

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

Inclusion Criteria

1. Has essential hypertension (diastolic blood pressure ≥ 95mm Hg and ≤ 119 mm Hg. For participants with diabetes or chronic kidney disease diastolic blood pressure must be ≥ 85 mm Hg and ≤ to 109 mm Hg.

2. Female participant is not of childbearing potential (eg, sterilized, postmenopausal).

3. Female participants of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

4. Clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis) are within the reference range for the testing laboratory unless the results are deemed not clinically significant for inclusion into this study by the investigator.

Exclusion Criteria

1. Systolic blood pressure greater than 185 mm Hg.

2. Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:

3. Is hypersensitive to AII receptor blockers.

4. Recent history (within the last 6 months) of myocardial infarction, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, cerebrovascular accident, or transient ischemic attack.

5. History of moderate to severe heart failure or hypertensive encephalopathy.

6. Has clinically significant cardiac conduction defects (eg, third-degree atrioventricular block, sick sinus syndrome).

7. Has secondary hypertension of any etiology.

8. Known or suspected unilateral or bilateral renal artery stenosis.

9. Has severe renal dysfunction or disease (based on calculated creatinine clearance < 30 mL/min/1.73 m2) at Screening.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Huntsville	Alabama	United States
2		Chandler	Arizona	United States
3		Mesa	Arizona	United States
4		Tempe	Arizona	United States
5		Los Gatos	California	United States
6		Sacramento	California	United States
7		Tustin	California	United States
8		Westlake Village	California	United States
9		Colorado Springs	Colorado	United States
10		Wheat Ridge	Colorado	United States
11		Melbourne	Florida	United States
12		Pembroke Pines	Florida	United States
13		Augusta	Georgia	United States
14		South Bend	Indiana	United States
15		Auburn	Maine	United States
16		Marlborough	Massachusetts	United States
17		Chelsea	Michigan	United States
18		St. Louis	Missouri	United States
19		Trenton	New Jersey	United States
20		Rochester	New York	United States
21		Burlington	North Carolina	United States
22		Wilmington	North Carolina	United States
23		Cleveland	Ohio	United States
24		Columbus	Ohio	United States
25		Oklahoma City	Oklahoma	United States
26		Carlisle	Pennsylvania	United States
27		Philadelphia	Pennsylvania	United States
28		Mt. Pleasant	South Carolina	United States
29		San Antonio	Texas	United States
30		Norfolk	Virginia	United States
31		Lakewood	Washington	United States
32		Renton	Washington	United States
33		Madison	Wisconsin	United States
34		Berazategui	Buenos Aires	Argentina
35		Pilar	Buenos Aires	Argentina
36		Cordoba		Argentina
37		Salta		Argentina
38		Leon	Guanajuato	Mexico
39		Guadalajara	Jalisco	Mexico
40		Cuernavaca	Morelos	Mexico
41		Rosario	Santa Fe	Mexico
42		Tampico	Tamaulipas	Mexico
43		Durango		Mexico
44		Mexico DF		Mexico
45		Puebla		Mexico

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: VP Clinical Science Strategy, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT00696384
• Other Study ID Numbers: 01-06-TL-491-016; U1111-1113-9088
• First Posted: Jun 12, 2008
• Last Update Posted: Jan 4, 2012
• Last Verified: Nov 1, 2011

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

Study Results

Participant Flow

Recruitment Details	Participants enrolled at 51 investigative sites in Argentina, Mexico and the United States from 22 June 2007 to 08 May 2009.
Pre-assignment Detail	All participants that completed the open-label phase were randomized into a double-blind reversal phase (to continue with azilsartan medoxomil or to placebo, in addition to any other antihypertensive medications received during the open-label phase).

Arm/Group Title	Azilsartan Medoxomil QD - Open Label Phase	Azilsartan Medoxomil QD - Double-Blind Reversal Phase	Placebo QD - Double-Blind Reversal Phase
Arm/Group Description	All subjects initiated azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, force-titrated to 80 mg, tablets, orally, once daily. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily was added as needed, followed by other non-ARB antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after the subject had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up- or down-titrated by 1 dose level per scheduled or unscheduled visit.	Azilsartan medoxomil at the final dose received during the open-label phase: (20 mg, 40 mg or 80 mg), tablets, orally, once daily with or without chlorthalidone 25 mg, tablets, orally once daily and other non-ARB antihypertensive medications (if currently taking), for 6 weeks.	Azilsartan medoxomil placebo-matching tablets, orally, once daily with or without chlorthalidone 25 mg, orally once daily or other non-ARB antihypertensive (if currently taking), tablets, orally, once daily for 6 weeks.
Period Title: Open Label Phase
STARTED	418	0	0
COMPLETED	299	0	0
NOT COMPLETED	119	0	0
Period Title: Open Label Phase
STARTED	0	148	151
COMPLETED	0	137	145
NOT COMPLETED	0	11	6

Baseline Characteristics

Arm/Group Title	Azilsartan Medoxomil QD - Open Label Phase
Arm/Group Description	Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, titrated to 80 mg, tablets, orally, once daily. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily as needed and other antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after participant had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up or down-titrated by 1 dose level per scheduled or unscheduled visit. Baseline characteristics of this Open Label phase population are described in the table below.
Overall Participants	418
Age, Customized (participants) [Number]
<45 years	89 21.3%
Between 45 and 64 years	287 68.7%
≥ 65 years	42 10%
Age, Customized (percentage of participants) [Number]
<45 years	21.3 5.1%
Between 45 and 64 years	68.7 16.4%
≥ 65 years	10.0 2.4%
Sex/Gender, Customized (participants) [Number]
Female	210 50.2%
Male	208 49.8%

Outcome Measures

1. Primary Outcome

Title	Change From Double-blind Baseline (Week 26) in Sitting Clinic Diastolic Blood Pressure to Week 32
Description	The change in sitting clinic diastolic blood pressure measured at final visit or week 32 from Double-blind Baseline/Week 26. Diastolic blood pressure is the arithmetic mean of the 3 trough sitting diastolic blood pressure measurements. Each participant's blood pressure at the Final Visit/Week 26 of the open-label phase represented their Baseline blood pressure for the double-blind reversal phase.
Time Frame	Double-blind Baseline (Week 26) and Week 32.

Outcome Measure Data

Analysis Population Description

Full analysis set with last observation carried forward.

Arm/Group Title	Azilsartan Medoxomil QD - Double Blind Reversal Phase	Placebo QD - Double Blind Reversal Phase
Arm/Group Description	Azilsartan medoxomil at the final dose received during the open-label phase: (20 mg, 40 mg or 80 mg), tablets, orally, once daily with or without chlorthalidone 25 mg, tablets, orally once daily and other non-ARB antihypertensive medications (if currently taking) as needed for 6 weeks.	Azilsartan medoxomil placebo-matching tablets, orally, once daily with or without chlorthalidone 25 mg or other antihypertensive (if currently taking), tablets, orally, once daily for 6 weeks.
Measure Participants	142	148
Least Squares Mean (Standard Error) [mmHg]	0.14 (0.726)	7.92 (0.712)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azilsartan Medoxomil QD - Double Blind Reversal Phase, Placebo QD - Double Blind Reversal Phase
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Postbaseline P-value was from ANCOVA with terms for treatment (as a factor) and baseline value (as a covariate). Includes participants with both a double-blind baseline and postbaseline value.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.78
	Confidence Interval	(2-Sided) 95%; -9.78 to -5.78
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Double-blind Baseline (Week 26) in Sitting Clinic Systolic Blood Pressure to Week 32
Description	The change in sitting clinic systolic blood pressure measured at final visit or week 32 from Double-blind Baseline/Week 26.. Systolic blood pressure is the arithmetic mean of the 3 trough sitting systolic blood pressure measurements. Each participant's blood pressure at the Final Visit/Week 26 of the open-label phase represented their Baseline blood pressure for the double-blind reversal phase.
Time Frame	Double-blind Baseline (Week 26) and Week 32.

Outcome Measure Data

Analysis Population Description

Full analysis set with last observation carried forward.

Arm/Group Title	Azilsartan Medoxomil QD - Double Blind Reversal Phase	Placebo QD - Double Blind Reversal Phase
Arm/Group Description	Azilsartan medoxomil at the final dose received during the open-label phase: (20 mg, 40 mg or 80 mg), tablets, orally, once daily with or without chlorthalidone 25 mg, tablets, orally once daily and other non-ARB antihypertensive medications (if currently taking) as needed for 6 weeks.	Azilsartan medoxomil placebo-matching tablets, orally, once daily with or without chlorthalidone 25 mg or other antihypertensive (if currently taking), tablets, orally, once daily for 6 weeks.
Measure Participants	142	148
Least Squares Mean (Standard Error) [mmHg]	0.59 (1.121)	12.97 (1.098)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Azilsartan Medoxomil QD - Double Blind Reversal Phase, Placebo QD - Double Blind Reversal Phase
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Postbaseline P-value was from ANCOVA with terms for treatment (as a factor) and baseline value (as a covariate). Includes participants with both a double-blind baseline and postbaseline value.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.38
	Confidence Interval	(2-Sided) 95%; -15.47 to -9.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Open Label Baseline (Week 0) in Sitting Clinic Diastolic Blood Pressure to Week 26
Description	The change from baseline in sitting clinic diastolic blood pressure measured at final visit or week 26.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Safety analysis set with last observation carried forward.

Arm/Group Title	Azilsartan Medoxomil QD - Open Label Phase
Arm/Group Description	All subjects initiated azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, force-titrated to 80 mg, tablets, orally, once daily. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily was added as needed, followed by other non-ARB antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after the subject had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up- or down-titrated by 1 dose level per scheduled or unscheduled visit.
Measure Participants	418
Mean (Standard Deviation) [mmHg]	-15.76 (11.912)

4. Secondary Outcome

Title	Change From Open Label Baseline (Week 0) in Sitting Clinic Systolic Blood Pressure to Week 26
Description	The change from baseline in sitting clinic systolic blood pressure measured at final visit or week 26.
Time Frame	Baseline and Week 26.

Outcome Measure Data

Analysis Population Description

Safety analysis set with last observation carried forward.

Arm/Group Title	Azilsartan Medoxomil QD - Open Label Phase
Arm/Group Description	All subjects initiated azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, force-titrated to 80 mg, tablets, orally, once daily. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily was added as needed, followed by other non-ARB antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after the subject had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up- or down-titrated by 1 dose level per scheduled or unscheduled visit.
Measure Participants	418
Mean (Standard Deviation) [mmHg]	-23.01 (20.657)

5. Secondary Outcome

Title	Number of Participants With Adverse Events During the Open-Label Phase
Description	Treatment-emergent adverse events defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after last dose of study drug, or within 30 days after the last dose of study drug for serious adverse event (SAE). A SAE is defined as any untoward medical occurrence that either results in death; is life-threatening; requires hospitalization; results in persistent or significant disability/incapacity; leads to a congenital anomaly/birth defect; or is an important medical event.
Time Frame	Baseline to Week 26

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azilsartan Medoxomil QD - Open Label Phase
Arm/Group Description	All subjects initiated azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, force-titrated to 80 mg, tablets, orally, once daily. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily was added as needed and other non-ARB antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after the subject had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up- or down-titrated by 1 dose level per scheduled or unscheduled visit.
Measure Participants	418
Serious Adverse Events	8 1.9%
Treatment Emergent Adverse Events	226 54.1%

6. Secondary Outcome

Title	Number of Participants With Adverse Events in the Double-Blind Baseline Phase
Description	Treatment-emergent adverse events defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after last dose of study drug, or within 30 days after the last dose of study drug for SAE. A SAE is defined as any untoward medical occurrence that either results in death; is life-threatening; requires hospitalization; results in persistent or significant disability/incapacity; leads to a congenital anomaly/birth defect; or is an important medical event.
Time Frame	Double-blind Baseline/Week 26 to Week 32

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Azilsartan Medoxomil QD - Double Blind Reversal Phase	Placebo QD - Double Blind Reversal Phase
Arm/Group Description	Azilsartan medoxomil at the final dose received during the open-label phase: (20 mg, 40 mg or 80 mg), tablets, orally, once daily with or without chlorthalidone 25 mg, tablets, orally once daily and other non-ARB antihypertensive medications (if currently taking) as needed for 6 weeks.	Azilsartan medoxomil placebo-matching tablets, orally, once daily with or without chlorthalidone 25 mg or other antihypertensive (if currently taking), tablets, orally, once daily for 6 weeks.
Measure Participants	148	151
Serious Adverse Events	0 0%	1 NaN
Treatment Emergent Adverse Events	42 10%	38 NaN

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious adverse event) after the last dose of double-blind study drug.
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings.
Arm/Group Title	Azilsartan Medoxomil QD - Open Label		Azilsartan Medoxomil QD - Double-Blind Reversal Phase		Placebo QD - Double-Blind Reversal Phase
Arm/Group Description	Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks, titrated to 80 mg, tablets, orally, once daily.. After Week 8, chlorthalidone, 25 mg, tablets, orally, once daily as needed and other antihypertensive medications as needed to achieve target blood pressure (defined as <140/90 mm Hg for participants without diabetes or chronic kidney disease (CKD) and <130/80 mm Hg for participants with diabetes or CKD) for up to 26 weeks. Study medication could have been up-titrated only after the subject had been at the previous dose level for a minimum of 2 weeks. Study medication could only have been up- or down-titrated by 1 dose level per scheduled or unscheduled visit.		Azilsartan medoxomil current dose (20 mg, 40 mg or 80 mg), tablets, orally, once daily with or without chlorthalidone 25 mg, tablets, orally once daily and other antihypertensive medications as needed for 6 weeks.		Azilsartan medoxomil placebo-matching tablets, orally, once daily with or without chlorthalidone 25 mg or other antihypertensive (if currently taking), tablets, orally, once daily for up to 6 weeks.
All Cause Mortality
	Azilsartan Medoxomil QD - Open Label		Azilsartan Medoxomil QD - Double-Blind Reversal Phase		Placebo QD - Double-Blind Reversal Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Azilsartan Medoxomil QD - Open Label		Azilsartan Medoxomil QD - Double-Blind Reversal Phase		Placebo QD - Double-Blind Reversal Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/418 (1.9%)		0/148 (0%)		1/151 (0.7%)
Cardiac disorders
Acute coronary syndrome	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Eye disorders
Diabetic retinopathy	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Eye haemorrhage	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Gastrointestinal disorders
Pancreatitis	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Upper gastrointestinal haemorrhage	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Injury, poisoning and procedural complications
Hip fracture	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Metabolism and nutrition disorders
Dehydration	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Nervous system disorders
Convulsion	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Dizziness	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Vascular disorders
Hypotension	1/418 (0.2%)		0/148 (0%)		0/151 (0%)
Hypertensive crisis	0/418 (0%)		0/148 (0%)		1/151 (0.7%)
Other (Not Including Serious) Adverse Events
	Azilsartan Medoxomil QD - Open Label		Azilsartan Medoxomil QD - Double-Blind Reversal Phase		Placebo QD - Double-Blind Reversal Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/418 (14.4%)		5/148 (3.4%)		8/151 (5.3%)
Nervous system disorders
Headache	30/418 (7.2%)		5/148 (3.4%)		8/151 (5.3%)
Dizziness	36/418 (8.6%)		3/148 (2%)		3/151 (2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

No publication related to study results will be published prior to publication of a multi-center report submitted for publication within 18 months after conclusion or termination of a study at all study sites. Results publications will be submitted to sponsor for review 60 days in advance of publication. Sponsor can require removal of confidential information unrelated to study results. Sponsor can embargo a proposed publication for another 60 days to preserve intellectual property.