The Influence of Febuxostat on Coronary Artery Endothelial Dysfunction in Participants With Chronic Stable Angina

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01763996
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arms: 2
• Duration (Months): 23
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the effect of febuxostat on coronary artery flow in patients with coronary artery disease.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Febuxostat; Drug: Febuxostat placebo	Phase 4

Detailed Description

The drug being tested in this study is called febuxostat. Febuxostat is being tested to treat people who have angina. This study will look at the heart and blood flow of people who take febuxostat.

The study will enroll approximately 30 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups (or sequences)-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need):

• Sequence 1: 6 weeks febuxostat followed by 6 weeks of placebo.

• Sequence 2: 6 week placebo followed by 6 weeks of febuxostat

All participants will be asked to take one capsule at the same time each day throughout the study. All participants will be asked to record any time they have angina symptoms during the study.

This single-center trial will be conducted in the United States. The overall time to participate in this study is 16 weeks. Participants will make 7 visits to the clinic including a final visit 4 weeks after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: The Influence of Febuxostat on Coronary Artery Endothelial Dysfunction in Subjects With Chronic Stable Angina: A Phase 4 Randomized, Placebo-Controlled, Double-Blind, Cross-Over Study
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sequence 1: Febuxostat 80 mg + Placebo Febuxostat 80 mg, capsules, orally, once daily for 6 weeks in Period 1, followed by febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 2.	Drug: Febuxostat; Febuxostat capsules; Drug: Febuxostat placebo; Febuxostat placebo-matching capsules
Experimental: Sequence 2: Placebo + Febuxostat 80 mg Febuxostat placebo-matching capsules, orally, once daily for 6 weeks in Period 1, followed by febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 2.	Drug: Febuxostat; Febuxostat capsules; Drug: Febuxostat placebo; Febuxostat placebo-matching capsules

Outcome Measures

Primary Outcome Measures

1. Change in Coronary Artery Flow From Rest to Isometric Handgrip (IHG) Exercise at the End of the Administration of Febuxostat and Placebo [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Coronary artery flow was measured using magnetic resonance imaging (MRI) at rest and during sustained isometric (static) handgrip exercises. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.

Secondary Outcome Measures

1. Change in Coronary Artery Cross-Sectional Area From Rest to IHG Exercise at the End of the Administration of Febuxostat and Placebo [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Coronary artery cross-sectional area was measured by MRI at rest and during sustained isometric (static) handgrip exercise. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.

2. Change in Coronary Flow Velocity From Rest to IHG Exercise at the End of the Administration of Febuxostat and Placebo [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Coronary flow velocity was measured by MRI at rest and during sustained isometric (static) handgrip exercise. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.

3. Change in Coronary Artery Flow Following the Administration of Sublingual Nitroglycerin at the End of the Administration of Febuxostat and Placebo [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Coronary artery flow was measured by MRI before and following administration of nitroglycerin under the tongue. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.

4. Change in Coronary Artery Cross Sectional Area Following the Administration of Sublingual Nitroglycerin at the End of the Administration of Febuxostat and Placebo [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Coronary artery cross sectional area was measured by MRI before and following administration of nitroglycerin under the tongue. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.

5. Change in Coronary Flow Velocity Following the Administration of Sublingual Nitroglycerin at the End of the Administration of Febuxostat and Placebo [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Coronary flow velocity was measured by MRI before and following administration of nitroglycerin under the tongue. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.

6. Change in Time to Onset of ≥1 mm ST-Segment Depression During Exercise Treadmill Test (ETT) [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Time in seconds to ischemic ECG changes during ETT. Continuous electrocardiography (ECG) was performed during an exercise treadmill test (modified Bruce protocol) to assess the onset of ST-segment depression after administration of febuxostat or placebo for 6 weeks in participants with a normal ST segment at randomization. . Data at the end of each treatment period was combined for the febuxostat and the placebo arms.

7. Change in Maximum ST-segment Depression During Exercise Treadmill Test [Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)]

   Continuous ECG was performed during an exercise treadmill test (modified Bruce protocol) to assess the maximum ST-segment depression after 6 weeks of febuxostat or placebo treatment in participants with a normal ST segment at randomization. A negative change from Baseline indicates improvement. Data at the end of each treatment period was combined for the febuxostat and the placebo arms.

8. Percentage of Participants Stopping Exercise Treadmill Test Due to Angina at the End of the Administration of Febuxostat and Placebo [At the end of each 6 week treatment period (Week 6 and Week 12)]

   An exercise treadmill test (modified Bruce protocol) was performed. Data at the end of each treatment period was combined for the febuxostat and the placebo arms.

9. Time to Onset of Angina During Exercise Treadmill Test at the End of the Administration of Febuxostat and Placebo [At the end of each 6 week treatment period (Week 6 and Week 12)]

   Time in seconds to ischemic chest pain/ angina during ETT. Data at the end of each period was combined for the febuxostat and the placebo arms

10. Exercise Duration [At the end of each 6 week treatment period (Week 6 and Week 12)]

    Exercise duration is the exercise time in seconds during ETT. Data at the end of each period was combined for the febuxostat and the placebo arms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts 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 signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.

3. Has a serum urate ≥4.0 mg/dL.

4. Has a history of coronary artery disease, defined as:

5. ≥50 % stenosis of ≥1 major coronary artery confirmed by angiography; OR

6. Documented prior myocardial infarction (MI) by enzymes/electrocardiogram (ECG) changes; OR

7. Documented prior exercise or pharmacologic stress/echo myocardial imaging study positive for ischemia.

8. Has estimated glomerular filtration rate (eGFR) ≥30 mL/min by Modification of Diet in Renal Disease (MDRD) at the screening visit.

9. Has a change in coronary artery flow from rest to isometric handgrip exercise of less than + 10 mL/min.

10. Is male or female and aged 18 to 85 years, inclusive.

11. A female of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.

12. Is on stable (30 days prior to Screening Day-21) medication doses prescribed for any underlying medical condition (ie, hypertension, angina) and is expected to remain on stable doses throughout the study duration.

13. Is able to take nitroglycerin for anginal symptoms during study procedures.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to Screening.

2. Has received allopurinol or febuxostat in a previous clinical study or as a therapeutic agent with-in 6 months of randomization.

3. Has gout or secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant) or has experienced a gout flare.

4. Has a history of xanthinuria.

5. Has known contraindication to magnetic resonance imaging (MRI) scanning

6. 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.

7. Has a history of hypersensitivity or allergies to febuxostat or nitroglycerin.

8. Has hemoglobin <10 g/L at Screening.

9. Has a history or clinical manifestations of a significant medical condition that might affect his/her ability to complete the study.

10. Has any of the following during Screening:

11. New York Heart Association Class III or IV heart failure.

12. Acute coronary syndrome or a coronary revascularization procedure within 2 months of Screening.

13. Wolff-Parkinson-White syndrome.

14. Pacemaker or implantable cardioverter defibrillator.

15. Arrhythmias (ie, supraventricular tachycardia (SVT), atrial fibrillation/flutter, or ventricular tachycardia (VT) during Screening).

16. Has a recent history (within the last 2 months prior to Screening) of acute coronary syndrome or a coronary revascularization procedure, MI, heart failure, coronary artery bypass graft, percutaneous coronary intervention, hypertensive encephalopathy, cerebrovascular accident, or transient ischemic attack.

17. Has a contraindication for using nitrates (severe anemia, increased intracranial pressure, and those with a known sensitivity or hypersensitivity to nitroglycerin or its ingredients, or other nitrates or nitrites; concomitant use either regularly and/or intermittently, with phosphodiesterase type 5 (PDE5) inhibitors).

18. Has unstable angina that:

19. Occurs when the patient is at rest.

20. Is prolonged, usually greater than 20 minutes.

21. Occurs with increasing in intensity, duration, and/or frequency.

22. Responds poorly to nitroglycerin (ie, does not go away after three doses of nitroglycerin or returns after the nitroglycerin helped at first).

23. Is unable to exercise sufficiently to complete exercise treadmill test (ETT) due to leg claudication, arthritis, deconditioning, or associated pulmonary disease.

24. Has severe or critical valvular disease documented by echocardiogram, or congenital heart disease.

25. The subject has left ventricular ejection fraction (LVEF) less than 35%, as documented by echocardiogram, left ventriculogram, or gated blood pool scan..

26. The subject has clinically significant cardiac conduction defects (ie, second- or third-degree atrioventricular block, or sick sinus syndrome) at Screening

27. Has hypertrophic cardiomyopathy.

28. Has an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level of greater than 2.0 times the upper limit of normal, has active liver disease, or jaundice.

29. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to the Screening Visit.

30. Is required or expected to require excluded medications including digoxin or digoxin-containing compounds.

31. If female, is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.

32. Has participated in another clinical trial within the past 30 days.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Baltimore	Maryland	United States

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01763996
• Other Study ID Numbers: CCR-FEB-002; U1111-1136-2270
• First Posted: Jan 9, 2013
• Last Update Posted: Apr 13, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Coronary Artery Disease; Angina, Stable; Febuxostat

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at one investigative site in the United States from 29 May 2013 (first participant signed the formed consent form) to 14 April 2015.
Pre-assignment Detail	Participants with a diagnosis of chronic stable angina were enrolled in one of 2 sequence cross-over arms: (1) febuxostat 80 mg for 6 weeks then placebo for 6 weeks, or (2) placebo for 6 weeks then febuxostat 80 mg for 6 weeks.

Arm/Group Title	Sequence 1: Febuxostat 80 mg + Placebo	Sequence 2: Placebo + Febuxostat 80 mg
Arm/Group Description	Febuxostat 80 mg, capsules, orally, once daily for 6 weeks in Period 1, followed by febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 2.	Febuxostat placebo-matching capsules, orally, once daily for 6 weeks in Period 1, followed by febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 2.
Period Title: Treatment Period 1
STARTED	15	15
COMPLETED	15	15
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	15	15
COMPLETED	15	14
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	All participants who were randomized and received study drug (febuxostat 80 mg and placebo) during the study.
Overall Participants	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59 (7.7)
Sex: Female, Male (Count of Participants)
Female	3 10%
Male	27 90%
Race/Ethnicity, Customized (participants) [Number]
African-American	5 16.7%
White	25 83.3%
Region of Enrollment (participants) [Number]
United States	30 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	176 (7.7)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	87.8 (16)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	28.3 (4.12)
Left Ventricular Ejection Fraction (percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent]	56.8 (9.24)

Outcome Measures

1. Primary Outcome

Title	Change in Coronary Artery Flow From Rest to Isometric Handgrip (IHG) Exercise at the End of the Administration of Febuxostat and Placebo
Description	Coronary artery flow was measured using magnetic resonance imaging (MRI) at rest and during sustained isometric (static) handgrip exercises. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	29	29
Least Squares Mean (95% Confidence Interval) [mL/min]	8.8	10.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.756
	Comments	0.05 level of significance
	Method	ANOVA
	Comments	Analysis of variance (ANOVA) model that includes sequence, period, and treatment as fixed factors and subjects within sequence as a random factor.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -10.10 to 13.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Coronary Artery Cross-Sectional Area From Rest to IHG Exercise at the End of the Administration of Febuxostat and Placebo
Description	Coronary artery cross-sectional area was measured by MRI at rest and during sustained isometric (static) handgrip exercise. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	29	29
Least Squares Mean (95% Confidence Interval) [mm^2]	0.45	0.03

3. Secondary Outcome

Title	Change in Coronary Flow Velocity From Rest to IHG Exercise at the End of the Administration of Febuxostat and Placebo
Description	Coronary flow velocity was measured by MRI at rest and during sustained isometric (static) handgrip exercise. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	29	29
Least Squares Mean (95% Confidence Interval) [cm/second]	1.6	2.2

4. Secondary Outcome

Title	Change in Coronary Artery Flow Following the Administration of Sublingual Nitroglycerin at the End of the Administration of Febuxostat and Placebo
Description	Coronary artery flow was measured by MRI before and following administration of nitroglycerin under the tongue. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, who used nitroglycerin.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	11	15
Least Squares Mean (95% Confidence Interval) [mL/min]	17.0	13.0

5. Secondary Outcome

Title	Change in Coronary Artery Cross Sectional Area Following the Administration of Sublingual Nitroglycerin at the End of the Administration of Febuxostat and Placebo
Description	Coronary artery cross sectional area was measured by MRI before and following administration of nitroglycerin under the tongue. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, who used nitroglycerin.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	11	15
Least Squares Mean (95% Confidence Interval) [mm^2]	3.35	2.86

6. Secondary Outcome

Title	Change in Coronary Flow Velocity Following the Administration of Sublingual Nitroglycerin at the End of the Administration of Febuxostat and Placebo
Description	Coronary flow velocity was measured by MRI before and following administration of nitroglycerin under the tongue. Data at the end of each treatment period was combined for the febuxostat and the placebo arms. A positive change from Baseline indicates improvement.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, who used nitroglycerin.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	11	15
Least Squares Mean (95% Confidence Interval) [cm/second]	-0.95	-0.66

7. Secondary Outcome

Title	Change in Time to Onset of ≥1 mm ST-Segment Depression During Exercise Treadmill Test (ETT)
Description	Time in seconds to ischemic ECG changes during ETT. Continuous electrocardiography (ECG) was performed during an exercise treadmill test (modified Bruce protocol) to assess the onset of ST-segment depression after administration of febuxostat or placebo for 6 weeks in participants with a normal ST segment at randomization. . Data at the end of each treatment period was combined for the febuxostat and the placebo arms.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with ischemic ECG changes.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	4	2
Mean (Standard Deviation) [seconds]	514 (252)	316 (122)

8. Secondary Outcome

Title	Change in Maximum ST-segment Depression During Exercise Treadmill Test
Description	Continuous ECG was performed during an exercise treadmill test (modified Bruce protocol) to assess the maximum ST-segment depression after 6 weeks of febuxostat or placebo treatment in participants with a normal ST segment at randomization. A negative change from Baseline indicates improvement. Data at the end of each treatment period was combined for the febuxostat and the placebo arms.
Time Frame	Baseline and at the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with ST segment change.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	4	2
Mean (Standard Deviation) [mm]	1.3 (0.5)	1.5 (0.7)

9. Secondary Outcome

Title	Percentage of Participants Stopping Exercise Treadmill Test Due to Angina at the End of the Administration of Febuxostat and Placebo
Description	An exercise treadmill test (modified Bruce protocol) was performed. Data at the end of each treatment period was combined for the febuxostat and the placebo arms.
Time Frame	At the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	30	28
Number [percentage of participants]	0.0 0%	3.6 NaN

10. Secondary Outcome

Title	Time to Onset of Angina During Exercise Treadmill Test at the End of the Administration of Febuxostat and Placebo
Description	Time in seconds to ischemic chest pain/ angina during ETT. Data at the end of each period was combined for the febuxostat and the placebo arms
Time Frame	At the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with ischemic chest pain.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	0	1
Mean (Standard Deviation) [seconds]	330 (NA)

11. Secondary Outcome

Title	Exercise Duration
Description	Exercise duration is the exercise time in seconds during ETT. Data at the end of each period was combined for the febuxostat and the placebo arms.
Time Frame	At the end of each 6 week treatment period (Week 6 and Week 12)

Outcome Measure Data

Analysis Population Description

Participants from the Full Analysis Set, all randomized participants who received at least one dose of study drug, with data available.

Arm/Group Title	Placebo	Febuxostat 80 mg
Arm/Group Description	Febuxostat placebo-matching capsules, orally, once daily for up to 6 weeks in Period 1 or 2.	Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
Measure Participants	30	28
Least Squares Mean (95% Confidence Interval) [seconds]	702	722

Adverse Events

Time Frame	First dose of study drug to up to 30 days after the last dose of study drug (Up to 16 Weeks)
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 capsules, orally, once daily for up to 6 weeks in Period 1 or 2.		Febuxostat 80 mg, capsules, orally, once daily for up to 6 weeks in Period 1 or 2.
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	0/30 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Febuxostat 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/30 (23.3%)		6/30 (20%)
Cardiac disorders
Ventricular extrasystoles	1/30 (3.3%)		2/30 (6.7%)
General disorders
Fatigue	2/30 (6.7%)		0/30 (0%)
Infections and infestations
Common cold	3/30 (10%)		1/30 (3.3%)
Musculoskeletal and connective tissue disorders
Musculoskeletal discomfort	1/30 (3.3%)		2/30 (6.7%)
Nervous system disorders
Headache	1/30 (3.3%)		2/30 (6.7%)
Skin and subcutaneous tissue disorders
Dermatitis contact	2/30 (6.7%)		0/30 (0%)

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.