Hypertension
Conditions
Keywords
Essential Hypertension, Cardiovascular Disease, High Blood Pressure, Drug Therapy
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.
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.
Interventions
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.
DRUGAzilsartan 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.
DRUGPlacebo
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.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Argentina, Mexico, United States
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 details
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).
Participants by arm
| Arm | Count |
|---|---|
| Azilsartan Medoxomil QD - Open Label Phase 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. | 418 |
| Total | 418 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Double Blind Phase | Adverse Event | 0 | 2 | 2 |
| Double Blind Phase | Lack of Efficacy | 0 | 1 | 0 |
| Double Blind Phase | Lost to Follow-up | 0 | 2 | 1 |
| Double Blind Phase | Physician Decision | 0 | 2 | 0 |
| Double Blind Phase | Withdrawal by Subject | 0 | 4 | 3 |
| Open Label Phase | Adverse Event | 27 | 0 | 0 |
| Open Label Phase | Lack of Efficacy | 3 | 0 | 0 |
| Open Label Phase | Lost to Follow-up | 24 | 0 | 0 |
| Open Label Phase | Other | 6 | 0 | 0 |
| Open Label Phase | Physician Decision | 4 | 0 | 0 |
| Open Label Phase | Protocol Violation | 18 | 0 | 0 |
| Open Label Phase | Withdrawal by Subject | 37 | 0 | 0 |
Baseline characteristics
| Characteristic | Azilsartan Medoxomil QD - Open Label Phase |
|---|---|
| Age, Customized <45 years | 21.3 percentage of participants |
| Age, Customized ≥ 65 years | 42 participants |
| Age, Customized Between 45 and 64 years | 287 participants |
| Sex/Gender, Customized Female | 210 participants |
| Sex/Gender, Customized Male | 208 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 60 / 418 | 5 / 148 | 8 / 151 |
| serious Total, serious adverse events | 8 / 418 | 0 / 148 | 1 / 151 |
Outcome results
Primary
Change From Double-blind Baseline (Week 26) in Sitting Clinic Diastolic Blood Pressure to 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.
Time frame: Double-blind Baseline (Week 26) and Week 32.
Population: Full analysis set with last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Change From Double-blind Baseline (Week 26) in Sitting Clinic Diastolic Blood Pressure to Week 32 | 0.14 mmHg | Standard Error 0.726 |
| Placebo QD - Double Blind Reversal Phase | Change From Double-blind Baseline (Week 26) in Sitting Clinic Diastolic Blood Pressure to Week 32 | 7.92 mmHg | Standard Error 0.712 |
p-value: <0.00195% CI: [-9.78, -5.78]ANCOVA
Secondary
Change From Double-blind Baseline (Week 26) in Sitting Clinic Systolic Blood Pressure to 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.
Time frame: Double-blind Baseline (Week 26) and Week 32.
Population: Full analysis set with last observation carried forward.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Change From Double-blind Baseline (Week 26) in Sitting Clinic Systolic Blood Pressure to Week 32 | 0.59 mmHg | Standard Error 1.121 |
| Placebo QD - Double Blind Reversal Phase | Change From Double-blind Baseline (Week 26) in Sitting Clinic Systolic Blood Pressure to Week 32 | 12.97 mmHg | Standard Error 1.098 |
p-value: <0.00195% CI: [-15.47, -9.29]ANCOVA
Secondary
Change From Open Label Baseline (Week 0) in Sitting Clinic Diastolic Blood Pressure to Week 26
The change from baseline in sitting clinic diastolic blood pressure measured at final visit or week 26.
Time frame: Baseline and Week 26.
Population: Safety analysis set with last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Change From Open Label Baseline (Week 0) in Sitting Clinic Diastolic Blood Pressure to Week 26 | -15.76 mmHg | Standard Deviation 11.912 |
Secondary
Change From Open Label Baseline (Week 0) in Sitting Clinic Systolic Blood Pressure to Week 26
The change from baseline in sitting clinic systolic blood pressure measured at final visit or week 26.
Time frame: Baseline and Week 26.
Population: Safety analysis set with last observation carried forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Change From Open Label Baseline (Week 0) in Sitting Clinic Systolic Blood Pressure to Week 26 | -23.01 mmHg | Standard Deviation 20.657 |
Secondary
Number of Participants With Adverse Events During the Open-Label Phase
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Number of Participants With Adverse Events During the Open-Label Phase | Serious Adverse Events | 8 participants |
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Number of Participants With Adverse Events During the Open-Label Phase | Treatment Emergent Adverse Events | 226 participants |
Secondary
Number of Participants With Adverse Events in the Double-Blind Baseline Phase
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Number of Participants With Adverse Events in the Double-Blind Baseline Phase | Serious Adverse Events | 0 participants |
| Azilsartan Medoxomil QD - Double Blind Reversal Phase | Number of Participants With Adverse Events in the Double-Blind Baseline Phase | Treatment Emergent Adverse Events | 42 participants |
| Placebo QD - Double Blind Reversal Phase | Number of Participants With Adverse Events in the Double-Blind Baseline Phase | Serious Adverse Events | 1 participants |
| Placebo QD - Double Blind Reversal Phase | Number of Participants With Adverse Events in the Double-Blind Baseline Phase | Treatment Emergent Adverse Events | 38 participants |