Hypertension
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the effect of febuxostat, once daily (QD), compared to placebo on lowering ambulatory 24-hour mean blood pressure of participants with hypertension and hyperuricemia (not associated with gout).
Detailed description
This study is designed to evaluate the effect of febuxostat during 6 weeks of treatment.
Interventions
DRUGFebuxostat
Febuxostat 80 mg, tablets, orally, once daily for up to 6 weeks
DRUGPlacebo
Febuxostat placebo-matching tablets, orally, once daily for up to 6 weeks.
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. The participant has documented hypertension, defined as average clinic systolic blood pressure (SBP) of ≥145 mm Hg and ≤165 mm Hg or average clinic diastolic blood pressure (DBP) of ≥90 mm Hg and ≤105 mm Hg at the Day -21 Screening Visit; the average BP measurement at two of the three Placebo Run-in Visits (Day -14, Day -7 and Day -1) must also meet the above criteria for hypertension. 2. The participant has a serum uric acid (sUA) level ≥7.0 mg/dL not associated with gout, at the Day -21 Screening Visit. 3. The participant has a 24-hour mean ambulatory SBP of ≥130 mm Hg and \< 165 mm Hg at the Baseline (Day 1) Visit. 4. At the initial Screening Visit (Day -21), the maximum number of antihypertensive medications the participant is taking is ≤ 2 (fixed-dose combination medications are considered 2 medications, including diuretics), and the participant has been on a stable dose of this medication for at least1 month prior to start of the initial Screening Visit (Day -21). 5. The participant is male and at least 18 years of age, or a female who is: * Surgically sterilized (hysterectomy, bilateral oophorectomy or tubal ligation), OR * Postmenopausal (defined as at least 1 year since last regular menses with an follicle-stimulating hormone (FSH) \>40 IU/L, or at least 5 years since last regular menses), OR * On hormone replacement therapy and ≥ 55 years of age. 6. 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. 7. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.
Exclusion criteria
1. The participant has received any investigational compound within 30 days, or within 5 half-lives of the compound (whichever is longer) prior to the Screening Visit. 2. The participant has received febuxostat or any urate-lowering therapy (ULT) in a previous clinical study or as a therapeutic agent. 3. The participant has gout, history of gout, or gout flares. 4. The participant has secondary hyperuricemia (HPU) (e.g., due to myeloproliferative disorder, or organ transplant). 5. The participant has known secondary hypertension of any etiology (e.g., renovascular disease, primary hyperaldosteronism, Cushing syndrome). 6. The participant has a history, within the 6 months prior to screening, of myocardial infarction, heart failure, unstable angina, coronary artery bypass graft, or percutaneous coronary intervention. 7. The participant has an irregular cardiac rhythm (e.g., atrial fibrillation, multifocal premature atrial contractions) which leads to difficulty with interpretation of ambulatory blood pressure monitoring (ABPM). 8. The participant has a history of congestive heart failure, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack. 9. The participant has type 1 or poorly controlled type 2 diabetes mellitus (glycosylated hemoglobin \[HbA1c\] \>8.0%) at Screening. 10. The participant has a history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus. 11. The participant has an average clinic SBP \>165 mm Hg or DBP \>105 mm Hg at 1 or more visits during the Placebo Run-in Period. 12. The participant's average clinic SBP or DBP measurement that increases or decreases by \>10 mm Hg between Placebo Run-in visits (Day -14 to Day -7, or Day -7 to Day -1, or Day -14 to Day -1). 13. The participant 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 (e.g., spouse, parent, child, sibling) or may consent under duress. 14. The participant has an alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values greater than 2.0 times the upper limit of normal (ULN). 15. The participant has a significant medical condition and/or conditions that would interfere with the treatment, safety or compliance with the protocol. 16. The participant has a history of alcoholism or illicit drug abuse within 5 years prior to the Screening Visit or is currently consuming \>14 alcoholic drinks per week. 17. The participant has a known hypersensitivity or allergies to febuxostat or any components of the formulations of this compound. 18. The participant is taking or expected to take a medication as described in the excluded medication section. 19. The participant 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 participants with successfully resected basal cell or stage I squamous cell carcinoma of the skin. 20. The participant's estimated glomerular filtration rate (eGFR) is \<30 mL/min/1.73m3, where eGFR is calculated by the Central Laboratory using the Modification of Diet in Renal Disease (MDRD) formula at the Day -21 Screening Visit. 21. The participant is noncompliant (\<80% or \>120%) with study medication during Placebo Run-In Period. 22. The participant has an upper arm circumference less than 24 cm or greater than 42 cm. 23. The participant's work shift includes any hour between 11 PM (2300) to 7 AM (0700). 24. The participant has a baseline 24-hour ABPM reading of insufficient quality (as described in Appendix F of the protocol).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-hour Mean Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Baseline and Week 6 | The change in 24-hour mean SBP measured at final visit or Week 6 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 24-hour Mean Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Baseline and Week 6 | The change in 24-hour mean DBP measured at final visit or Week 6 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. |
| Change From Baseline in Serum Urate Levels at Week 6 | Baseline and Week 6 | — |
Countries
United States
Participant flow
Recruitment details
Participants took part at 29 sites in the United States from 10 January 2012 to 04 August 2014.
Pre-assignment details
Participants with a historical diagnosis of hypertension along with hyperuricemia were enrolled in 1 of 2 treatment groups as follows: Placebo; Febuxostat 80 milligram (mg).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Febuxostat placebo-matching over-encapsulated tablet, orally, once daily for up to 6 weeks. | 60 |
| Febuxostat 80 mg Febuxostat 80 mg, over-encapsulated tablet, orally, once daily for up to 6 week. | 61 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | BP exceeds protocol limits | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Other | 1 | 1 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | Febuxostat 80 mg |
|---|---|---|---|
| Age, Continuous | 55.08 years STANDARD_DEVIATION 10.607 | 53.60 years STANDARD_DEVIATION 10.597 | 52.15 years STANDARD_DEVIATION 10.469 |
| Age, Customized 45 - <65 years | 44 participants | 87 participants | 43 participants |
| Age, Customized Greater than or equal to (>=) 65 years | 8 participants | 12 participants | 4 participants |
| Age, Customized Less than (<) 45 years | 8 participants | 22 participants | 14 participants |
| Alcohol History Current Drinker | 32 participants | 69 participants | 37 participants |
| Alcohol History Ex-Drinker | 2 participants | 6 participants | 4 participants |
| Alcohol History Never Drunk | 26 participants | 46 participants | 20 participants |
| Baseline Medication ARB or ACEi | 26 participants | 54 participants | 28 participants |
| Baseline Medication None | 34 participants | 67 participants | 33 participants |
| Baseline serum uric acid (sUA) >=8.0 mg/dL | 20 participants | 34 participants | 14 participants |
| Baseline serum uric acid (sUA) < 8.0 milligram per deciliter (mg/dL) | 40 participants | 87 participants | 47 participants |
| BMI Category 18.5 - <25 | 3 participants | 6 participants | 3 participants |
| BMI Category 25 - <30 | 18 participants | 35 participants | 17 participants |
| BMI Category >=30 | 39 participants | 80 participants | 41 participants |
| Body Mass Index (BMI) | 31.99 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.133 | 32.78 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.572 | 33.55 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.913 |
| Height | 172.10 centimeter (cm) STANDARD_DEVIATION 8.564 | 172.72 centimeter (cm) STANDARD_DEVIATION 8.878 | 173.33 centimeter (cm) STANDARD_DEVIATION 9.206 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 7 participants | 15 participants | 8 participants |
| Race/Ethnicity, Customized Black or African American | 11 participants | 21 participants | 10 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 9 participants | 23 participants | 14 participants |
| Race/Ethnicity, Customized More than one race | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 51 participants | 98 participants | 47 participants |
| Race/Ethnicity, Customized White | 42 participants | 83 participants | 41 participants |
| Region of Enrollment United States | 60 participants | 121 participants | 61 participants |
| Renal Function Mildly Impaired | 33 participants | 63 participants | 30 participants |
| Renal Function Moderately Impaired | 8 participants | 13 participants | 5 participants |
| Renal Function Normal | 19 participants | 45 participants | 26 participants |
| Sex: Female, Male Female | 12 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Male | 48 Participants | 98 Participants | 50 Participants |
| Smoking History Current smoker | 8 participants | 18 participants | 10 participants |
| Smoking History Ex-smoker | 20 participants | 41 participants | 21 participants |
| Smoking History Never smoked | 32 participants | 62 participants | 30 participants |
| Weight | 95.35 kilogram (kg) STANDARD_DEVIATION 21.199 | 98.14 kilogram (kg) STANDARD_DEVIATION 20.46 | 100.88 kilogram (kg) STANDARD_DEVIATION 19.49 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 60 | 3 / 61 |
| serious Total, serious adverse events | 1 / 60 | 1 / 61 |
Outcome results
Primary
Change From Baseline in 24-hour Mean Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6
The change in 24-hour mean SBP measured at final visit or Week 6 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 6
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication and had a baseline value and at least 1 post-baseline value available, with last observation carried forward.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in 24-hour Mean Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Baseline | 142.3 millimeters of mercury (mmHg) | Standard Error 1.21 |
| Placebo | Change From Baseline in 24-hour Mean Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Change at Week 6 | -3.4 millimeters of mercury (mmHg) | Standard Error 1.31 |
| Febuxostat 80 mg | Change From Baseline in 24-hour Mean Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Baseline | 139.5 millimeters of mercury (mmHg) | Standard Error 1.18 |
| Febuxostat 80 mg | Change From Baseline in 24-hour Mean Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Change at Week 6 | -3.7 millimeters of mercury (mmHg) | Standard Error 1.27 |
Comparison: A total of 120 enrolled participants (60 participants per treatment group) was sufficient to achieve 80 percent (%) power to detect a difference of 6.0 mmHg between the placebo and febuxostat 80 mg treatment groups by a 2 sample t-test of the mean change from Baseline at Week 6 in 24-hour mean ambulatory SBP with a 2-sided significance level of 5%.p-value: 0.88295% CI: [-3.9, 3.4]ANCOVA
Secondary
Change From Baseline in 24-hour Mean Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6
The change in 24-hour mean DBP measured at final visit or Week 6 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 6
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication and had a baseline value and at least 1 post-baseline value available, with last observation carried forward.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in 24-hour Mean Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Baseline | 85.9 mmHg | Standard Error 1.14 |
| Placebo | Change From Baseline in 24-hour Mean Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Change at Week 6 | -2.7 mmHg | Standard Error 0.91 |
| Febuxostat 80 mg | Change From Baseline in 24-hour Mean Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Baseline | 83.0 mmHg | Standard Error 1.11 |
| Febuxostat 80 mg | Change From Baseline in 24-hour Mean Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6 | Change at Week 6 | -2.0 mmHg | Standard Error 0.88 |
Comparison: ANCOVA model with treatment as a factor, and the baseline value and prior use of an ARB or an ACEi as covariates.p-value: 0.61395% CI: [-1.9, 3.2]ANCOVA
Secondary
Change From Baseline in Serum Urate Levels at Week 6
Time frame: Baseline and Week 6
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication and had a baseline value and at least 1 post-baseline value available, with last observation carried forward.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Serum Urate Levels at Week 6 | Baseline | 7.7 mg/dL | Standard Error 0.14 |
| Placebo | Change From Baseline in Serum Urate Levels at Week 6 | Change at Week 6 | 0.1 mg/dL | Standard Error 0.17 |
| Febuxostat 80 mg | Change From Baseline in Serum Urate Levels at Week 6 | Baseline | 7.6 mg/dL | Standard Error 0.14 |
| Febuxostat 80 mg | Change From Baseline in Serum Urate Levels at Week 6 | Change at Week 6 | -3.3 mg/dL | Standard Error 0.17 |
Comparison: ANCOVA model with treatment as a factor, and the baseline value and prior use of an ARB or an ACEi as covariates.p-value: <0.00195% CI: [-3.9, -2.9]ANCOVA