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

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ClinicalTrials.gov Identifier: NCT01763996
Recruitment Status : Completed
First Posted : January 9, 2013
Results First Posted : April 13, 2016
Last Update Posted : April 13, 2016
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Coronary Artery Disease
Interventions Drug: Febuxostat
Drug: Febuxostat placebo
Enrollment 30
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 Details 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
Hide 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 2
Started 15 15
Completed 15 14
Not Completed 0 1
Reason Not Completed
Adverse Event             0             1
Arm/Group Title All Participants
Hide Arm/Group Description All participants who were randomized and received study drug (febuxostat 80 mg and placebo) during the study.
Overall Number of Baseline Participants 30
Hide Baseline Analysis Population Description
All participants
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 30 participants
59  (7.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 30 participants
Female
3
  10.0%
Male
27
  90.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 30 participants
African-American 5
White 25
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 30 participants
30
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 30 participants
176  (7.7)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 30 participants
87.8  (16)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 30 participants
28.3  (4.12)
Left Ventricular Ejection Fraction  
Mean (Standard Deviation)
Unit of measure:  Percent
Number Analyzed 30 participants
56.8  (9.24)
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 29 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mL/min
8.8
(0.40 to 17.28)
10.7
(2.23 to 19.11)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
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
Estimation Comments [Not Specified]
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 29 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mm^2
0.45
(-0.177 to 1.074)
0.03
(-0.595 to 0.656)
3.Secondary Outcome
Title Change in Coronary Flow Velocity From Rest to IHG Exercise at the End of the Administration of Febuxostat and Placebo
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 29 29
Least Squares Mean (95% Confidence Interval)
Unit of Measure: cm/second
1.6
(-0.10 to 3.40)
2.2
(0.43 to 3.93)
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 11 15
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mL/min
17.0
(-6.00 to 39.98)
13.0
(-2.53 to 28.43)
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 11 15
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mm^2
3.35
(1.449 to 5.244)
2.86
(1.582 to 4.138)
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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 11 15
Least Squares Mean (95% Confidence Interval)
Unit of Measure: cm/second
-0.95
(-4.120 to 2.213)
-0.66
(-2.792 to 1.472)
7.Secondary Outcome
Title Change in Time to Onset of ≥1 mm ST-Segment Depression During Exercise Treadmill Test (ETT)
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 4 2
Mean (Standard Deviation)
Unit of Measure: seconds
514  (252) 316  (122)
8.Secondary Outcome
Title Change in Maximum ST-segment Depression During Exercise Treadmill Test
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 4 2
Mean (Standard Deviation)
Unit of Measure: 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
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 30 28
Measure Type: Number
Unit of Measure: percentage of participants
0.0 3.6
10.Secondary Outcome
Title Time to Onset of Angina During Exercise Treadmill Test at the End of the Administration of Febuxostat and Placebo
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 0 1
Mean (Standard Deviation)
Unit of Measure: seconds
330 [1]   (NA)
[1]
Standard deviation cannot be calculated for 1 participant.
11.Secondary Outcome
Title Exercise Duration
Hide 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)
Hide Outcome Measure Data
Hide 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
Hide 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.
Overall Number of Participants Analyzed 30 28
Least Squares Mean (95% Confidence Interval)
Unit of Measure: seconds
702
(682.1 to 721.6)
722
(700.5 to 742.9)
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
Hide 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 (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Febuxostat 80 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   0/30 (0.00%)   0/30 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Febuxostat 80 mg
Affected / at Risk (%) Affected / at Risk (%)
Total   7/30 (23.33%)   6/30 (20.00%) 
Cardiac disorders     
Ventricular extrasystoles  1  1/30 (3.33%)  2/30 (6.67%) 
General disorders     
Fatigue  1  2/30 (6.67%)  0/30 (0.00%) 
Infections and infestations     
Common cold  1  3/30 (10.00%)  1/30 (3.33%) 
Musculoskeletal and connective tissue disorders     
Musculoskeletal discomfort  1  1/30 (3.33%)  2/30 (6.67%) 
Nervous system disorders     
Headache  1  1/30 (3.33%)  2/30 (6.67%) 
Skin and subcutaneous tissue disorders     
Dermatitis contact  1  2/30 (6.67%)  0/30 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director, Clinical Science
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01763996     History of Changes
Other Study ID Numbers: CCR-FEB-002
U1111-1136-2270 ( Registry Identifier: WHO )
First Submitted: January 7, 2013
First Posted: January 9, 2013
Results First Submitted: March 10, 2016
Results First Posted: April 13, 2016
Last Update Posted: April 13, 2016