Hypertension
Conditions
Keywords
Essential Hypertension, Cardiovascular Disease, High Blood Pressure, Drug Therapy
Brief summary
This purpose of this study is to evaluate the long-term safety and tolerability of azilsartan medoxomil in individuals 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. Despite the availability of antihypertensive treatments, hypertension remains inadequately controlled; only about one-third of patients continue to maintain control successfully. Takeda Global Research and Development is developing TAK-491 (azilsartan medoxomil) for the treatment of essential hypertension. This study is being conducted to demonstrate the long-term safety and tolerability of azilsartan medoxomil in individuals with essential hypertension. Study participation is anticipated to be approximately 1 year and 1.5 months, and participants will be required to return to the clinic for 10 study visits.
Interventions
DRUGAzilsartan medoxomil with or without add-on chlorthalidone
Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved.
DRUGAzilsartan medoxomil with or without add-on hydrochlorothiazide
Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diastolic blood pressure greater than or equal to 95 mm Hg and less than or equal to 119 mm Hg. For diabetic subjects and subjects with chronic kidney disease, diastolic blood pressure must be greater than or equal to 85 mm Hg and less than or equal to109 mm Hg). 2. Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating. 3. Clinical laboratory evaluations within the reference range for or deemed not clinically significant by the investigator.
Exclusion criteria
1. Systolic blood pressure greater than 185 mm Hg. 2. Expected to take angiotensin II receptor blockers other than the study drug. 3. Taking more than 2 antihypertensive agents. 4. Hypersensitive to angiotensin II receptor blockers, thiazide-type diuretics or sulfonamide-derived compounds. 5. Recent history of major cardiovascular event. 6. History of moderate to severe heart failure or hypertensive encephalopathy. 7. Clinically significant cardiac conduction defects. 8. Secondary hypertension of any etiology. 9. Known or suspected unilateral or bilateral renal artery stenosis. 10. Severe renal dysfunction or disease. 11. History of drug abuse or a history of alcohol abuse within the past 2 years. 12. Previous history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug.. 13. Uncontrolled diabetes mellitus. 14. Alanine aminotransferase level of greater than 2.5 times the upper limit of normal, active liver disease, or jaundice. 15. Serum potassium level of greater than the upper limit of normal. 16. Currently is participating in another investigational study or has participated in an investigational study within 30 days prior to enrollment. 17. Any other serious disease or condition. 18. Randomized in a previous azilsartan medoxomil study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 1. | 56 weeks. | Treatment-emergent adverse events are 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 the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug. |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 2. | 56 weeks. | Treatment-emergent adverse events are 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 the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | 52 weeks | The change between sitting clinic systolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit. |
| Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | 52 weeks | The change between sitting clinic systolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit. |
| Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | 52 weeks. | The change between sitting clinic diastolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit. |
| Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | 52 weeks. | The change between sitting clinic diastolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit. |
Countries
Chile, Mexico, United States
Participant flow
Recruitment details
Participants enrolled at 39 investigative sites in Chile, Mexico and the United States from 22 June 2007 to 30 April 2010.
Pre-assignment details
Participants with essential hypertension were enrolled in a once-daily (QD) treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Azilsartan Medoxomil Cohort 1: Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved.
Cohort 2: Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved. | 669 |
| Total | 669 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Cohort 1 | Adverse Event | 26 |
| Cohort 1 | Lack of Efficacy | 3 |
| Cohort 1 | Lost to Follow-up | 30 |
| Cohort 1 | Other | 16 |
| Cohort 1 | Protocol Violation | 2 |
| Cohort 1 | Withdrawal by Subject | 25 |
| Cohort 2 | Adverse Event | 24 |
| Cohort 2 | Lack of Efficacy | 4 |
| Cohort 2 | Lost to Follow-up | 38 |
| Cohort 2 | Other | 5 |
| Cohort 2 | Protocol Violation | 5 |
| Cohort 2 | Withdrawal by Subject | 28 |
Baseline characteristics
| Characteristic | Azilsartan Medoxomil |
|---|---|
| Age, Customized <45 years (Cohort 1) | 81 participants |
| Age, Customized <45 years (Cohort 2) | 90 participants |
| Age, Customized ≥65 years (Cohort 1) | 48 participants |
| Age, Customized ≥65 years (Cohort 2) | 24 participants |
| Age, Customized Between 45 and 64 years (Cohort 1) | 233 participants |
| Age, Customized Between 45 and 64 years (Cohort 2) | 193 participants |
| Sex/Gender, Customized Female (Cohort 1) | 173 participants |
| Sex/Gender, Customized Female (Cohort 2) | 144 participants |
| Sex/Gender, Customized Male (Cohort 1) | 189 participants |
| Sex/Gender, Customized Male (Cohort 2) | 163 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 134 / 362 | 106 / 307 |
| serious Total, serious adverse events | 30 / 362 | 22 / 307 |
Outcome results
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 1.
Treatment-emergent adverse events are 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 the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug.
Time frame: 56 weeks.
Population: Full Analysis Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 1. | Number of Participants | 267 participants |
| Cohort 1 | Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 1. | Percentage of Participants | 73.8 participants |
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 2.
Treatment-emergent adverse events are 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 the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug.
Time frame: 56 weeks.
Population: Full Analysis Set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 2. | Percentage of Participants | 78.5 participants |
| Cohort 1 | Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 2. | Number of Participants | 241 participants |
Secondary
Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1.
The change between sitting clinic diastolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time frame: 52 weeks.
Population: Full Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 36 | -19.9 mmHg | Standard Deviation 9.13 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 46 | -19.8 mmHg | Standard Deviation 9.67 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 56 | -18.4 mmHg | Standard Deviation 9.52 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Final Visit | -16.5 mmHg | Standard Deviation 10.23 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 4 | -8.9 mmHg | Standard Deviation 8.73 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 8 | -11.0 mmHg | Standard Deviation 9.97 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 12 | -15.9 mmHg | Standard Deviation 9.12 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 16 | -18.7 mmHg | Standard Deviation 9.06 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1. | Week 26 | -18.6 mmHg | Standard Deviation 9.15 |
Secondary
Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2.
The change between sitting clinic diastolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time frame: 52 weeks.
Population: Full Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 4 | -10.6 mmHg | Standard Deviation 9.23 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 8 | -12.3 mmHg | Standard Deviation 9.05 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 12 | -16.8 mmHg | Standard Deviation 9.48 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 16 | -18.2 mmHg | Standard Deviation 10.28 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 26 | -17.7 mmHg | Standard Deviation 10.95 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 36 | -16.2 mmHg | Standard Deviation 9.08 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 46 | -17.2 mmHg | Standard Deviation 9.57 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Week 56 | -17.9 mmHg | Standard Deviation 10.85 |
| Cohort 1 | Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2. | Final Visit | -16.2 mmHg | Standard Deviation 11.05 |
Secondary
Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1.
The change between sitting clinic systolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time frame: 52 weeks
Population: Full Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 4 | -10.1 mmHg | Standard Deviation 15.21 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 8 | -13.1 mmHg | Standard Deviation 16.72 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 12 | -21.5 mmHg | Standard Deviation 15.8 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 16 | -25.4 mmHg | Standard Deviation 15.09 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 26 | -26.3 mmHg | Standard Deviation 15.97 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 36 | -27.3 mmHg | Standard Deviation 16.63 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 46 | -28.1 mmHg | Standard Deviation 17.21 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Week 56 | -25.2 mmHg | Standard Deviation 18.05 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1. | Final Visit | -22.1 mmHg | Standard Deviation 18.64 |
Secondary
Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2
The change between sitting clinic systolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time frame: 52 weeks
Population: Full Analysis Set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 46 | -23.8 mmHg | Standard Deviation 15.35 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 4 | -14.4 mmHg | Standard Deviation 13.57 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 8 | -17.5 mmHg | Standard Deviation 15.07 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 12 | -23.8 mmHg | Standard Deviation 15.97 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 16 | -26.2 mmHg | Standard Deviation 15.65 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 26 | -24.8 mmHg | Standard Deviation 15.25 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 36 | -22.5 mmHg | Standard Deviation 14.89 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Week 56 | -24.2 mmHg | Standard Deviation 15.96 |
| Cohort 1 | Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2 | Final Visit | -22.7 mmHg | Standard Deviation 17.14 |