Effect of Febuxostat on Blood Pressure

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01496469
• Collaborator: (none)
• Enrollment: 121
• Locations: 46
• Arms: 2
• Duration (Months): 30
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Febuxostat; Drug: Placebo	Phase 2

Detailed Description

This study is designed to evaluate the effect of febuxostat during 6 weeks of treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Double-Blind, Placebo-Controlled Study to Assess the Effect of Febuxostat 80 mg Once Daily Compared to Placebo on Ambulatory Blood Pressure in Subjects With Hyperuricemia and Hypertension
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Febuxostat 80 mg QD Febuxostat 80 mg, tablets, orally, once daily for up to 6 weeks.	Drug: Febuxostat; Febuxostat 80 mg, tablets, orally, once daily for up to 6 weeks; Other Names: TMX-67 Uloric
Placebo Comparator: Placebo QD Febuxostat placebo-matching tablets, orally, once daily for up to 6 weeks.	Drug: Placebo; Febuxostat placebo-matching tablets, orally, once daily for up to 6 weeks.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. Change From Baseline in Serum Urate Levels at Week 6 [Baseline and Week 6]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

1. 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.

2. 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).

1. 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.

2. The participant has an alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values greater than 2.0 times the upper limit of normal (ULN).

3. The participant has a significant medical condition and/or conditions that would interfere with the treatment, safety or compliance with the protocol.

4. 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.

5. The participant has a known hypersensitivity or allergies to febuxostat or any components of the formulations of this compound.

6. The participant is taking or expected to take a medication as described in the excluded medication section.

7. 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.

8. 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.

9. The participant is noncompliant (<80% or >120%) with study medication during Placebo Run-In Period.

10. The participant has an upper arm circumference less than 24 cm or greater than 42 cm.

11. The participant's work shift includes any hour between 11 PM (2300) to 7 AM (0700).

12. The participant has a baseline 24-hour ABPM reading of insufficient quality (as described in Appendix F of the protocol).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Foley	Alabama	United States
2		Buena Park	California	United States
3		Carmichael	California	United States
4		Fresno	California	United States
5		Irvine	California	United States
6		Lomita	California	United States
7		Paramount	California	United States
8		Sacramento	California	United States
9		San Diego	California	United States
10		Wildomar	California	United States
11		Milford	Connecticut	United States
12		Fort Lauderdale	Florida	United States
13		Miami	Florida	United States
14		Tallahassee	Florida	United States
15		Tampa	Florida	United States
16		Dunwoody	Georgia	United States
17		Roswell	Georgia	United States
18		Suwanee	Georgia	United States
19		Avon	Indiana	United States
20		Indianapolis	Indiana	United States
21		Lexington	Kentucky	United States
22		Biddeford	Maine	United States
23		Saint Peters	Missouri	United States
24		St. Louis	Missouri	United States
25		St. Peters	Missouri	United States
26		Henderson	Nevada	United States
27		Las Vegas	Nevada	United States
28		Albuquerque	New Mexico	United States
29		Glens Falls	New York	United States
30		Greensboro	North Carolina	United States
31		Salisbury	North Carolina	United States
32		Shelby	North Carolina	United States
33		Fargo	North Dakota	United States
34		Cincinnati	Ohio	United States
35		Columbus	Ohio	United States
36		Lyndhurst	Ohio	United States
37		Oklahoma City	Oklahoma	United States
38		Portland	Oregon	United States
39		Tipton	Pennsylvania	United States
40		Carrollton	Texas	United States
41		Dallas	Texas	United States
42		San Antonio	Texas	United States
43		Burke	Virginia	United States
44		Manassas	Virginia	United States
45		Port Orchard	Washington	United States
46		Madison	Wisconsin	United States

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Uloric Package Insert

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01496469
• Other Study ID Numbers: TMX-67_206; U1111-1124-4638
• First Posted: Dec 21, 2011
• Last Update Posted: Aug 31, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Hypertension; Febuxostat

Study Results

Participant Flow

Recruitment Details	Participants took part at 29 sites in the United States from 10 January 2012 to 04 August 2014.
Pre-assignment Detail	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).

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching over-encapsulated tablet, orally, once daily for up to 6 weeks.	Febuxostat 80 mg, over-encapsulated tablet, orally, once daily for up to 6 week.
Period Title: Overall Study
STARTED	60	61
COMPLETED	50	53
NOT COMPLETED	10	8

Baseline Characteristics

Arm/Group Title	Placebo	Febuxostat 80 mg	Total
Arm/Group Description	Febuxostat placebo-matching over-encapsulated tablet, orally, once daily for up to 6 weeks.	Febuxostat 80 mg, over-encapsulated tablet, orally, once daily for up to 6 week.	Total of all reporting groups
Overall Participants	60	61	121
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.08 (10.607)	52.15 (10.469)	53.60 (10.597)
Age, Customized (participants) [Number]
Less than (<) 45 years	8 13.3%	14 23%	22 18.2%
45 - <65 years	44 73.3%	43 70.5%	87 71.9%
Greater than or equal to (>=) 65 years	8 13.3%	4 6.6%	12 9.9%
Sex: Female, Male (Count of Participants)
Female	12 20%	11 18%	23 19%
Male	48 80%	50 82%	98 81%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	1 1.6%	1 0.8%
Asian	7 11.7%	8 13.1%	15 12.4%
Black or African American	11 18.3%	10 16.4%	21 17.4%
White	42 70%	41 67.2%	83 68.6%
More than one race	0 0%	1 1.6%	1 0.8%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	9 15%	14 23%	23 19%
Not Hispanic or Latino	51 85%	47 77%	98 81%
Region of Enrollment (participants) [Number]
United States	60 100%	61 100%	121 100%
Height (centimeter (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeter (cm)]	172.10 (8.564)	173.33 (9.206)	172.72 (8.878)
Weight (kilogram (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram (kg)]	95.35 (21.199)	100.88 (19.490)	98.14 (20.460)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	31.99 (5.133)	33.55 (5.913)	32.78 (5.572)
BMI Category (participants) [Number]
18.5 - <25	3 5%	3 4.9%	6 5%
25 - <30	18 30%	17 27.9%	35 28.9%
>=30	39 65%	41 67.2%	80 66.1%
Smoking History (participants) [Number]
Never smoked	32 53.3%	30 49.2%	62 51.2%
Current smoker	8 13.3%	10 16.4%	18 14.9%
Ex-smoker	20 33.3%	21 34.4%	41 33.9%
Alcohol History (participants) [Number]
Never Drunk	26 43.3%	20 32.8%	46 38%
Current Drinker	32 53.3%	37 60.7%	69 57%
Ex-Drinker	2 3.3%	4 6.6%	6 5%
Renal Function (participants) [Number]
Moderately Impaired	8 13.3%	5 8.2%	13 10.7%
Mildly Impaired	33 55%	30 49.2%	63 52.1%
Normal	19 31.7%	26 42.6%	45 37.2%
Baseline serum uric acid (sUA) (participants) [Number]
< 8.0 milligram per deciliter (mg/dL)	40 66.7%	47 77%	87 71.9%
>=8.0 mg/dL	20 33.3%	14 23%	34 28.1%
Baseline Medication (participants) [Number]
ARB or ACEi	26 43.3%	28 45.9%	54 44.6%
None	34 56.7%	33 54.1%	67 55.4%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in 24-hour Mean Systolic Blood Pressure (SBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching over-encapsulated tablet, orally, once daily for up to 6 weeks.	Febuxostat 80 mg, over-encapsulated tablet, orally, once daily for up to 6 week.
Measure Participants	53	56
Baseline	142.3 (1.21)	139.5 (1.18)
Change at Week 6	-3.4 (1.31)	-3.7 (1.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 80 mg
	Comments	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%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.882
	Comments	Analysis of covariance (ANCOVA) model with treatment as a factor, and the baseline value and prior use of an ARB or an ACEi as covariates.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -3.9 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in 24-hour Mean Diastolic Blood Pressure (DBP) Measured by Ambulatory Blood Pressure Monitoring at Week 6
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching over-encapsulated tablet, orally, once daily for up to 6 weeks.	Febuxostat 80 mg, over-encapsulated tablet, orally, once daily for up to 6 week.
Measure Participants	53	56
Baseline	85.9 (1.14)	83.0 (1.11)
Change at Week 6	-2.7 (0.91)	-2.0 (0.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 80 mg
	Comments	ANCOVA model with treatment as a factor, and the baseline value and prior use of an ARB or an ACEi as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.613
	Comments	Tested at 5% significance level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.6
	Confidence Interval	(2-Sided) 95%; -1.9 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Serum Urate Levels at Week 6
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching over-encapsulated tablet, orally, once daily for up to 6 weeks.	Febuxostat 80 mg, over-encapsulated tablet, orally, once daily for up to 6 week.
Measure Participants	52	51
Baseline	7.7 (0.14)	7.6 (0.14)
Change at Week 6	0.1 (0.17)	-3.3 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 80 mg
	Comments	ANCOVA model with treatment as a factor, and the baseline value and prior use of an ARB or an ACEi as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Tested at 5% significance level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -3.9 to -2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent AEs are defined as any AEs, regardless of relationship to study drug, which occurs on or after the first double-blind dose date and up to 30 days after the last dose date of the 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. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo		Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching over-encapsulated tablet, orally, once daily for up to 6 weeks.		Febuxostat 80 mg, over-encapsulated tablet, orally, once daily for up to 6 week.
All Cause Mortality
	Placebo		Febuxostat 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Febuxostat 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/60 (1.7%)		1/61 (1.6%)
Cardiac disorders
Coronary artery insufficiency	0/60 (0%)		1/61 (1.6%)
Investigations
Blood pressure increased	1/60 (1.7%)		0/61 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Febuxostat 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/60 (1.7%)		3/61 (4.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/60 (1.7%)		3/61 (4.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.