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

Phase 4

Completed

• Conditions: Coronary Artery Disease
• Interventions: Drug: Febuxostat; Drug: Febuxostat placebo

• Registration Number: NCT01763996
• Lead Sponsor: Takeda

Brief Summary

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

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 Timeline

• Study First Submitted: 2013-01-07
• Study First Submitted QC: 2013-01-07
• Study First Posted: 2013-01-09
• Study Start: 2013-05
• Primary Completion: 2015-03
• Study Completion: 2015-04
• Status Verified: 2016-03
• Results First Submitted: 2016-03-10
• Results First Submitted QC: 2016-03-10
• Last Update Submitted: 2016-03-10
• Results First Posted: 2016-04-13
• Last Update Posted: 2016-04-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

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:

   1. ≥50 % stenosis of ≥1 major coronary artery confirmed by angiography; OR
   2. Documented prior myocardial infarction (MI) by enzymes/electrocardiogram (ECG) changes; OR
   3. Documented prior exercise or pharmacologic stress/echo myocardial imaging study positive for ischemia.

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

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

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

8. 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.

9. 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.

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

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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:

    1. New York Heart Association Class III or IV heart failure.
    2. Acute coronary syndrome or a coronary revascularization procedure within 2 months of Screening.
    3. Wolff-Parkinson-White syndrome.
    4. Pacemaker or implantable cardioverter defibrillator.
    5. Arrhythmias (ie, supraventricular tachycardia (SVT), atrial fibrillation/flutter, or ventricular tachycardia (VT) during Screening).

11. 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.

12. 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).

13. Has unstable angina that:

    1. Occurs when the patient is at rest.
    2. Is prolonged, usually greater than 20 minutes.
    3. Occurs with increasing in intensity, duration, and/or frequency.
    4. Responds poorly to nitroglycerin (ie, does not go away after three doses of nitroglycerin or returns after the nitroglycerin helped at first).

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

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

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

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

18. Has hypertrophic cardiomyopathy.

19. 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.

20. 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.

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

22. 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.

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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence 1: Febuxostat 80 mg + Placebo	Febuxostat 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.
Sequence 2: Placebo + Febuxostat 80 mg	Febuxostat placebo	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.
Sequence 1: Febuxostat 80 mg + Placebo	Febuxostat	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.
Sequence 2: Placebo + Febuxostat 80 mg	Febuxostat	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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
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.
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.