Hypertension
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to compare the antihypertensive effect of azilsartan medoxomil versus placebo in Korean adults with essential hypertension.
Detailed description
The drug being tested in this study is called azilsartan medoxomil. Azilsartan medoxomil is being tested to treat Korean adults with hypertension. This study will look at changes in blood pressure in people who take azilsartan medoxomil. The study will enroll approximately 325 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): * Azilsartan medoxomil 40 mg * Azilsartan medoxomil 80 mg * Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient. All participants will be asked to take two tablets at the same time each day throughout the study. This multi-centre trial will be conducted in Korea. The overall time to participate in this study is 12 weeks. Participants will make 7 visits to the clinic, and will be contacted by telephone 7 days after last dose of study drug for a follow-up assessment.
Interventions
Azilsartan medoxomil tablets
Azilsartan medoxomil placebo-matching tablets
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. 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. 3. Is treated with antihypertensive therapy and has a post-washout mean sitting clinic systolic blood pressure (SBP) ≥150 and ≤180 mm Hg on Day 1; or the patient has not received antihypertensive treatment within 28 days prior to Screening and has a mean sitting clinic SBP ≥150 and ≤180 mm Hg at the Screening Visit and on Day 1. 4. Is male or female aged ≥19 years. 5. 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 last study drug dose. 6. Is willing to discontinue current antihypertensive medications on Day -21. If on amlodipine or chlorthalidone prior to Screening, the participant is willing to discontinue this medication on Day -28.
Exclusion criteria
1. Has received any investigational compound within 30 days prior to the first dose of study medication. 2. Has received TAK-491 in a previous clinical study or as a therapeutic agent. 3. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 4. Has sitting trough clinic diastolic blood pressure (DBP) greater than 114 mm Hg at Day 1 (after placebo run-in). 5. Has a history of hypersensitivity to TAK-491 (azilsartan medoxomil), any of its excipients, or other angiotensin-converting enzyme (ARBs). 6. Has a history of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack. 7. Has clinically significant cardiac conduction defects (e.g., 3rd degree atrioventricular block, left bundle branch block, sick sinus syndrome, atrial fibrillation, or flutter). 8. Has hemodynamically significant left ventricular outflow obstruction due to aortic valvular disease and hypertrophic obstructive cardiomyopathy (HOCM). 9. Has secondary hypertension of any etiology (e.g., renovascular disease, pheochromocytoma, Cushing syndrome). 10. Is noncompliant (less than 70% or greater than 130%) with study medication during placebo run-in period. 11. Has severe renal dysfunction or disease (confirmed by calculated creatinine clearance \<30 mL/min/1.73m\^2) at Screening. 12. Has known or suspected unilateral or bilateral renal artery stenosis. 13. Has a history of drug or alcohol abuse within the past 2 years. 14. Has a history of cancer that has not been in remission for at least 5 years prior to the first dose of study drug. (This criterion does not apply to those patients with basal cell or stage I squamous cell carcinoma of the skin.) 15. Has type 1 or poorly controlled type 2 diabetes mellitus (hemoglobin A1c \[HbA1c\]\>8.0%) at Screening. 16. Has an alanine aminotransferase (ALT) level greater than 2.5 times the upper limit of normal, active liver disease, or jaundice at Screening. 17. Has hyperkalemia (defined as serum potassium greater than the upper limit of normal per the central laboratory) at Screening. 18. Has any other serious disease or condition at screening or randomization that would compromise participant safety, might affect life expectancy, or make it difficult to successfully manage and follow the participant according to the protocol. 19. Is required to take excluded medications. 20. If female, is pregnant or lactating or intending to become pregnant before, during, or within 30 days after participating in this study; or intending to donate ova during such time period.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 6 in Trough Clinic Sitting Systolic Blood Pressure (SBP) | Baseline and Week 6 | The change in trough clinic sitting systolic blood pressure measured at week 6 relative to baseline. The trough is the average of the non-missing values of 3 serial trough sitting systolic blood pressure measurements. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 6 blood pressure was measured approximately 24 hours after the previous day's dose. An analysis of covariance (ANCOVA) model, with treatment group as a fixed effect and Baseline sitting clinic systolic blood pressure as a covariate was used for analysis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved a Clinic SBP Response at Week 6 | Baseline and Week 6 | SBP response is defined as clinic SBP \<140 mmHg and/or reduction of ≥20 mmHg from Baseline. SBP is the arithmetic mean of 3 serial systolic blood pressure measurements. |
| Percentage of Participants Who Achieved Both a Clinic DBP and SBP Response at Week 6 | Baseline and Week 6 | Percentage of participants who achieved both a clinic DBP and SBP response measured at week 6 defined as clinic DBP \<90 mmHg and/or reduction of ≥10 mmHg from Baseline AND clinic SBP \<140 mmHg and/or reduction of ≥20 mmHg from Baseline. DBP and SBP are based on the arithmetic mean of 3 serial blood pressure measurements. |
| Change From Baseline to Week 6 in Trough Clinic Sitting Diastolic Blood Pressure (DBP) | Baseline and Week 6 | The change in trough clinic sitting diastolic blood pressure measured at week 6 relative to baseline. The trough is the average of the non-missing values of 3 serial trough sitting diastolic blood pressure measurements. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 6 blood pressure was measured approximately 24 hours after the previous day's dose. An analysis of covariance (ANCOVA) model, with treatment group as a fixed effect and Baseline sitting clinic diastolic blood pressure as a covariate was used for analysis. |
| Percentage of Participants Who Achieved a Clinic DBP Response at Week 6 | Baseline and Week 6 | Clinic DBP response is defined as clinic DBP \<90 mmHg and/or reduction of ≥10 mmHg from Baseline. DBP is the arithmetic mean of 3 serial diastolic blood pressure measurements. |
Countries
South Korea
Participant flow
Recruitment details
Participants took part in the study at 29 investigative sites in Korea from 12 July 2014 to 03 February 2016.
Pre-assignment details
Participants with a diagnosis of essential hypertension were randomized at a ratio of 2:2:1 into 1 of 3 treatment groups, once a day azilsartan medoxomil 40 mg, 80 mg or placebo. One participant in the 80 mg group was randomized twice, counted once in the randomized set, and is excluded from the Full Analysis Set and Safety Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Azilsartan medoxomil placebo-matching tablets, orally, once daily for 6 weeks. | 65 |
| Azilsartan Medoxomil 40 mg Azilsartan medoxomil 40 mg, tablets, orally, once daily for 6 weeks. | 132 |
| Azilsartan Medoxomil 80 mg Azilsartan medoxomil 80 mg, tablets, orally, once daily for 6 weeks. | 130 |
| Total | 327 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 3 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Major Protocol Deviation | 1 | 1 | 0 |
| Overall Study | Pretreatment Event/Adverse Event | 1 | 3 | 2 |
| Overall Study | Reason Not Specified | 0 | 2 | 1 |
| Overall Study | Voluntary Withdrawal | 3 | 3 | 8 |
Baseline characteristics
| Characteristic | Placebo | Total | Azilsartan Medoxomil 80 mg | Azilsartan Medoxomil 40 mg |
|---|---|---|---|---|
| Age, Continuous Overall Study | 58.8 years STANDARD_DEVIATION 10.21 | 59.0 years STANDARD_DEVIATION 10.97 | 58.3 years STANDARD_DEVIATION 11.57 | 59.8 years STANDARD_DEVIATION 10.75 |
| Body Mass Index (BMI) | 25.64 kg/m^2 STANDARD_DEVIATION 2.653 | 25.74 kg/m^2 STANDARD_DEVIATION 3.237 | 25.50 kg/m^2 STANDARD_DEVIATION 3.46 | 26.02 kg/m^2 STANDARD_DEVIATION 3.272 |
| Diabetes Status No | 61 participants | 289 participants | 117 participants | 111 participants |
| Diabetes Status Yes | 4 participants | 38 participants | 13 participants | 21 participants |
| Estimated Glomerular Filtration Rate(eGFR) | 85.72 mL/min/1.73m^2 STANDARD_DEVIATION 14.798 | 87.59 mL/min/1.73m^2 STANDARD_DEVIATION 17.74 | 88.68 mL/min/1.73m^2 STANDARD_DEVIATION 18.443 | 87.44 mL/min/1.73m^2 STANDARD_DEVIATION 18.393 |
| Female Reproductive Status Of Childbearing Potential | 3 participants | 18 participants | 10 participants | 5 participants |
| Female Reproductive Status Postmenopausal | 9 participants | 61 participants | 24 participants | 28 participants |
| Female Reproductive Status Surgically Sterile | 2 participants | 9 participants | 3 participants | 4 participants |
| Gender Female | 14 Participants | 88 Participants | 37 Participants | 37 Participants |
| Gender Male | 51 Participants | 239 Participants | 93 Participants | 95 Participants |
| Height | 166.1 cm STANDARD_DEVIATION 8.43 | 165.4 cm STANDARD_DEVIATION 8.53 | 165.6 cm STANDARD_DEVIATION 8 | 164.8 cm STANDARD_DEVIATION 9.09 |
| Race/Ethnicity, Customized Asian | 65 participants | 327 participants | 130 participants | 132 participants |
| Region of Enrollment Korea, Republic Of | 65 participants | 327 participants | 130 participants | 132 participants |
| Smoking Classification Current smoker | 12 participants | 60 participants | 26 participants | 22 participants |
| Smoking Classification Ex-smoker | 24 participants | 102 participants | 39 participants | 39 participants |
| Smoking Classification Never smoked | 29 participants | 165 participants | 65 participants | 71 participants |
| Weight | 70.85 kg STANDARD_DEVIATION 9.892 | 70.69 kg STANDARD_DEVIATION 12.291 | 70.32 kg STANDARD_DEVIATION 13.07 | 70.97 kg STANDARD_DEVIATION 12.636 |
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 | 7 / 65 | 8 / 132 | 14 / 130 |
| serious Total, serious adverse events | 0 / 65 | 0 / 132 | 2 / 130 |
Outcome results
Primary
Change From Baseline to Week 6 in Trough Clinic Sitting Systolic Blood Pressure (SBP)
The change in trough clinic sitting systolic blood pressure measured at week 6 relative to baseline. The trough is the average of the non-missing values of 3 serial trough sitting systolic blood pressure measurements. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 6 blood pressure was measured approximately 24 hours after the previous day's dose. An analysis of covariance (ANCOVA) model, with treatment group as a fixed effect and Baseline sitting clinic systolic blood pressure as a covariate was used for analysis.
Time frame: Baseline and Week 6
Population: Participants from the Full Analysis Set (FAS), including all randomized participants, who received at least 1 dose of double-blind study drug, with both a Baseline value and at least 1 post-baseline value, who were randomized only once. Missing values were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in Trough Clinic Sitting Systolic Blood Pressure (SBP) | -8.776 mmHg | Standard Error 2.0039 |
| Azilsartan Medoxomil 40 mg | Change From Baseline to Week 6 in Trough Clinic Sitting Systolic Blood Pressure (SBP) | -22.093 mmHg | Standard Error 1.4117 |
| Azilsartan Medoxomil 80 mg | Change From Baseline to Week 6 in Trough Clinic Sitting Systolic Blood Pressure (SBP) | -23.731 mmHg | Standard Error 1.4017 |
p-value: <0.00195% CI: [-18.138, -8.497]ANCOVA
p-value: <0.00195% CI: [-19.77, -10.141]ANCOVA
Secondary
Change From Baseline to Week 6 in Trough Clinic Sitting Diastolic Blood Pressure (DBP)
The change in trough clinic sitting diastolic blood pressure measured at week 6 relative to baseline. The trough is the average of the non-missing values of 3 serial trough sitting diastolic blood pressure measurements. Blood pressure was measured using a validated, automated device after the participant had been sitting for at least 5 minutes. Week 6 blood pressure was measured approximately 24 hours after the previous day's dose. An analysis of covariance (ANCOVA) model, with treatment group as a fixed effect and Baseline sitting clinic diastolic blood pressure as a covariate was used for analysis.
Time frame: Baseline and Week 6
Population: Participants from the FAS, including all randomized participants, who received at least 1 dose of double-blind study drug, with both a Baseline value and at least 1 post-baseline value, who were randomized only once. Missing values were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 6 in Trough Clinic Sitting Diastolic Blood Pressure (DBP) | -2.6 mmHg | Standard Deviation 8.6 |
| Azilsartan Medoxomil 40 mg | Change From Baseline to Week 6 in Trough Clinic Sitting Diastolic Blood Pressure (DBP) | -10.7 mmHg | Standard Deviation 10.12 |
| Azilsartan Medoxomil 80 mg | Change From Baseline to Week 6 in Trough Clinic Sitting Diastolic Blood Pressure (DBP) | -11.6 mmHg | Standard Deviation 10.12 |
Secondary
Percentage of Participants Who Achieved a Clinic DBP Response at Week 6
Clinic DBP response is defined as clinic DBP \<90 mmHg and/or reduction of ≥10 mmHg from Baseline. DBP is the arithmetic mean of 3 serial diastolic blood pressure measurements.
Time frame: Baseline and Week 6
Population: Participants from the FAS, including all randomized participants, who received at least 1 dose of double-blind study drug, with both a Baseline value and at least 1 post-baseline value, who were randomized only once. Missing values were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieved a Clinic DBP Response at Week 6 | 42.9 percentage of participants |
| Azilsartan Medoxomil 40 mg | Percentage of Participants Who Achieved a Clinic DBP Response at Week 6 | 83.5 percentage of participants |
| Azilsartan Medoxomil 80 mg | Percentage of Participants Who Achieved a Clinic DBP Response at Week 6 | 85.3 percentage of participants |
Secondary
Percentage of Participants Who Achieved a Clinic SBP Response at Week 6
SBP response is defined as clinic SBP \<140 mmHg and/or reduction of ≥20 mmHg from Baseline. SBP is the arithmetic mean of 3 serial systolic blood pressure measurements.
Time frame: Baseline and Week 6
Population: Participants from the FAS, including all randomized participants, who received at least 1 dose of double-blind study drug, with both a Baseline value and at least 1 post-baseline value, who were randomized only once. Missing values were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieved a Clinic SBP Response at Week 6 | 38.1 percentage of participants |
| Azilsartan Medoxomil 40 mg | Percentage of Participants Who Achieved a Clinic SBP Response at Week 6 | 63.0 percentage of participants |
| Azilsartan Medoxomil 80 mg | Percentage of Participants Who Achieved a Clinic SBP Response at Week 6 | 65.9 percentage of participants |
Secondary
Percentage of Participants Who Achieved Both a Clinic DBP and SBP Response at Week 6
Percentage of participants who achieved both a clinic DBP and SBP response measured at week 6 defined as clinic DBP \<90 mmHg and/or reduction of ≥10 mmHg from Baseline AND clinic SBP \<140 mmHg and/or reduction of ≥20 mmHg from Baseline. DBP and SBP are based on the arithmetic mean of 3 serial blood pressure measurements.
Time frame: Baseline and Week 6
Population: Participants from the FAS, including all randomized participants, who received at least 1 dose of double-blind study drug, with both a Baseline value and at least 1 post-baseline value, who were randomized only once. Missing values were imputed using last observation carried forward (LOCF).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Who Achieved Both a Clinic DBP and SBP Response at Week 6 | 25.4 percentage of participants |
| Azilsartan Medoxomil 40 mg | Percentage of Participants Who Achieved Both a Clinic DBP and SBP Response at Week 6 | 62.2 percentage of participants |
| Azilsartan Medoxomil 80 mg | Percentage of Participants Who Achieved Both a Clinic DBP and SBP Response at Week 6 | 65.9 percentage of participants |