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Efficacy and Safety of Extended Release and Immediate Release Febuxostat in Participants With Gout

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ClinicalTrials.gov Identifier: NCT02139046
Recruitment Status : Completed
First Posted : May 15, 2014
Results First Posted : November 3, 2016
Last Update Posted : November 3, 2016
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Gout
Interventions Drug: Febuxostat IR
Drug: Febuxostat XR
Drug: Febuxostat placebo
Drug: Colchicine
Drug: Naproxen
Drug: Lansoprazole
Enrollment 1790
Recruitment Details Participants took part in the study at 217 investigative sites in the United States from 18 April 2014 to 18 November 2015.
Pre-assignment Details Participants with a diagnosis of gout were enrolled equally in 1 of 5 treatment groups: once a day placebo, febuxostat 40 mg extended release (XR), febuxostat 80 mg XR, febuxostat 40 mg immediate release (IR) or febuxostat 80 mg IR.
Arm/Group Title Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Hide Arm/Group Description Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Period Title: Overall Study
Started 358 359 357 358 358
Safety Analysis Set 356 358 355 357 357
Full Analysis Set 357 357 355 357 357
Completed 296 [1] 305 298 290 301
Not Completed 62 54 59 68 57
Reason Not Completed
Pretreatment Event/Adverse Event             9             9             10             13             7
Major Protocol Deviation             9             10             16             12             6
Lost to Follow-up             13             16             16             18             13
Voluntary Withdrawal             20             8             10             15             16
Lack of Efficacy             0             1             2             1             2
Withdrawal due to a Gout Flare             1             1             1             0             1
Other Miscellaneous Reasons             10             9             4             9             12
[1]
Completed=Completed Study Drug
Arm/Group Title Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg Total
Hide Arm/Group Description Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Total of all reporting groups
Overall Number of Baseline Participants 357 357 355 357 357 1783
Hide Baseline Analysis Population Description
Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
54.4  (11.55) 55.5  (11.07) 55.1  (12.68) 54.9  (11.32) 55.4  (11.93) 55.1  (11.71)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
< 45 years 71 58 74 68 61 332
45 to < 65 years 223 225 193 219 222 1082
>= 65 years 63 74 88 70 74 369
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
18 to < 65 years 294 283 267 287 283 1414
65 to < 85 years 60 73 86 69 73 361
>= 85 years 3 1 2 1 1 8
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
Female
41
  11.5%
46
  12.9%
43
  12.1%
42
  11.8%
34
   9.5%
206
  11.6%
Male
316
  88.5%
311
  87.1%
312
  87.9%
315
  88.2%
323
  90.5%
1577
  88.4%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
American Indian or Alaska Native 1 2 0 1 3 7
Asian 23 19 22 23 25 112
Black or African American 94 89 100 98 93 474
Native Hawaiian or Other Pacific Islander 3 5 4 3 5 20
White 231 235 226 230 225 1147
Other: Multi-Racial 5 7 3 2 6 23
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
Hispanic or Latino 53 51 61 49 52 266
Not Hispanic or Latino 304 306 294 308 305 1517
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
357 357 355 357 357 1783
Height   [1] 
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
175.2  (9.95) 174.8  (10.46) 174.4  (10.45) 174.3  (9.42) 175.3  (9.50) 174.8  (9.96)
[1]
Measure Description: Height data is only available for 356, 357, 355, 357 and 357 participants, respectively.
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
106.83  (25.285) 104.65  (24.157) 104.71  (27.995) 102.16  (22.832) 104.64  (23.033) 104.60  (24.745)
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
34.88  (8.276) 34.32  (8.014) 34.29  (8.141) 33.68  (7.477) 34.08  (7.205) 34.25  (7.834)
[1]
Measure Description: BMI data is only available for 356, 357, 355, 357 and 357 participants, respectively.
Smoking History  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
Never Smoked 191 190 185 190 205 961
Current Smoker 58 56 60 65 47 286
Ex-Smoker 108 111 110 102 105 536
Alcohol Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 357 participants 357 participants 355 participants 357 participants 357 participants 1783 participants
Never Drank 81 92 85 68 74 400
Current Drinker 234 204 218 234 232 1122
Ex-Drinker 42 61 52 55 51 261
1.Primary Outcome
Title Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3
Hide Description [Not Specified]
Time Frame Month 3
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication. Participants who discontinued double-blind study drug prior to the Month 3 visit were considered treatment failures, i.e. to have serum urate ≥ 5.0 mg/dL.
Arm/Group Title Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Hide Arm/Group Description:
Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Overall Number of Participants Analyzed 357 357 355 357 357
Measure Type: Number
Unit of Measure: percentage of participants
0.3 15.7 25.9 42.6 50.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Febuxostat XR 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the Cui, Hung, and Wang (CHW) Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 25.6
Confidence Interval (2-Sided) 95%
20.4 to 30.9
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Febuxostat XR 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 49.8
Confidence Interval (2-Sided) 95%
43.9 to 55.8
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Febuxostat IR 40 mg, Febuxostat XR 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 10.2
Confidence Interval (2-Sided) 95%
3.5 to 17.0
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Febuxostat IR 80 mg, Febuxostat XR 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.043
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 7.5
Confidence Interval (2-Sided) 95%
-0.8 to 15.9
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Percentage of Participants With at Least One Gout Flare Requiring Treatment
Hide Description

A participant was considered to have a gout flare if the following criteria were met:

Participant-reported acute particular pain typical of a gout attack that was deemed by participant and/or investigator to require treatment and was treated with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids, Participant experienced at least 3 or more of: 1) Joint swelling, 2) Redness, 3) Tenderness, 4) Pain, Participant experienced at least one or more of: 1) Rapid onset of pain, 2) Decreased range of motion, 3) Joint warmth, 4) Other symptoms similar to a prior gout flare.

Time Frame Baseline to Month 3
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
Arm/Group Title Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Hide Arm/Group Description:
Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Overall Number of Participants Analyzed 357 357 355 357 357
Measure Type: Number
Unit of Measure: percentage of participants
20.7 21.0 22.8 27.2 26.6
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Febuxostat XR 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.503
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 2.1
Confidence Interval (2-Sided) 95%
-4.9 to 9.0
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Febuxostat IR 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.064
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 5.9
Confidence Interval (2-Sided) 95%
-1.2 to 13.0
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Febuxostat IR 40 mg, Febuxostat XR 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.561
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 1.8
Confidence Interval (2-Sided) 95%
-5.1 to 8.7
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Febuxostat IR 80 mg, Febuxostat XR 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.869
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value -0.5
Confidence Interval (2-Sided) 95%
-8.0 to 6.9
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3
Hide Description [Not Specified]
Time Frame Month 3
Hide Outcome Measure Data
Hide Analysis Population Description
FAS included all participants who were randomized and received at least 1 dose of double-blind study medication. Participants who discontinued double-blind study drug prior to the Month 3 visit were considered treatment failures, i.e. to have serum urate ≥ 5.0 mg/dL.
Arm/Group Title Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Hide Arm/Group Description:
Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Overall Number of Participants Analyzed 357 357 355 357 357
Measure Type: Number
Unit of Measure: percentage of participants
0.6 40.3 48.2 57.7 61.1
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Febuxostat XR 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 47.6
Confidence Interval (2-Sided) 95%
41.6 to 53.6
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Febuxostat XR 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 60.5
Confidence Interval (2-Sided) 95%
54.6 to 66.3
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Febuxostat IR 40 mg, Febuxostat XR 40 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.036
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 7.8
Confidence Interval (2-Sided) 95%
-0.5 to 16.1
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Febuxostat IR 80 mg, Febuxostat XR 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.364
Comments To adjust for multiple comparisons, a closed testing strategy was used. Febuxostat XR 40 and 80 mg were tested separately versus placebo and the corresponding febuxostat IR group at a Bonferroni-corrected significance level of 0.025.
Method Z-test
Comments Point estimates, confidence intervals, and p-values are presented using the CHW Z-test which accounts for the interim analysis.
Method of Estimation Estimation Parameter Difference in Proportions
Estimated Value 3.3
Confidence Interval (2-Sided) 95%
-4.9 to 11.6
Estimation Comments [Not Specified]
Time Frame First dose of double-blind study drug to 30 days past last dose of double-blind study drug (Up to 4 Months)
Adverse Event Reporting Description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings reported by the participant or observed by the investigator, irrespective of the relation to study treatment.

Safety Analysis Set included all participants who received at least 1 dose of double-blind study medication.

 
Arm/Group Title Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Hide Arm/Group Description Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject’s eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
All-Cause Mortality
Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   8/356 (2.25%)   12/358 (3.35%)   6/355 (1.69%)   8/357 (2.24%)   8/357 (2.24%) 
Cardiac disorders           
Hypertensive heart disease  1 [1]  0/356 (0.00%)  0/358 (0.00%)  1/355 (0.28%)  0/357 (0.00%)  0/357 (0.00%) 
Cardiac failure congestive  1  0/356 (0.00%)  1/358 (0.28%)  1/355 (0.28%)  0/357 (0.00%)  1/357 (0.28%) 
Acute myocardial infarction  1  0/356 (0.00%)  0/358 (0.00%)  1/355 (0.28%)  0/357 (0.00%)  0/357 (0.00%) 
Atrial fibrillation  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Sinus node dysfunction  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Cardiac arrest  1 [2]  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Cardio-respiratory arrest  1 [3]  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Gastrointestinal disorders           
Pancreatitis  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Pancreatitis acute  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Gastric ulcer haemorrhage  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Abdominal pain  1  2/356 (0.56%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Nausea  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
Vomiting  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
General disorders           
Malaise  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Oedema peripheral  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
Non-cardiac chest pain  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Infections and infestations           
Abdominal abscess  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Amoebiasis  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
Influenza  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
Pneumonia  1  1/356 (0.28%)  1/358 (0.28%)  1/355 (0.28%)  0/357 (0.00%)  0/357 (0.00%) 
Viral infection  1  0/356 (0.00%)  0/358 (0.00%)  1/355 (0.28%)  1/357 (0.28%)  0/357 (0.00%) 
Injury, poisoning and procedural complications           
Lower limb fracture  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
Road traffic accident  1  1/356 (0.28%)  0/358 (0.00%)  1/355 (0.28%)  0/357 (0.00%)  0/357 (0.00%) 
Metabolism and nutrition disorders           
Gout  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Hyperkalaemia  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Dehydration  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Musculoskeletal and connective tissue disorders           
Gouty arthritis  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)           
Tongue neoplasm malignant stage unspecified  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Prostate cancer  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Nervous system disorders           
Basal ganglia stroke  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Ischaemic stroke  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
Hypoglycaemic unconsciousness  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Hemiparesis  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Psychiatric disorders           
Bipolar I disorder  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Renal and urinary disorders           
Acute kidney injury  1  1/356 (0.28%)  1/358 (0.28%)  0/355 (0.00%)  2/357 (0.56%)  0/357 (0.00%) 
Renal failure  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Renal impairment  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Dyspnoea  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  1/357 (0.28%) 
Asthma  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Pleural effusion  1  0/356 (0.00%)  1/358 (0.28%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Pulmonary hypertension  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Acute respiratory failure  1  0/356 (0.00%)  1/358 (0.28%)  1/355 (0.28%)  0/357 (0.00%)  1/357 (0.28%) 
Skin and subcutaneous tissue disorders           
Angioedema  1  0/356 (0.00%)  0/358 (0.00%)  1/355 (0.28%)  0/357 (0.00%)  0/357 (0.00%) 
Dermatitis contact  1  0/356 (0.00%)  0/358 (0.00%)  0/355 (0.00%)  1/357 (0.28%)  0/357 (0.00%) 
Vascular disorders           
Hypertension  1  1/356 (0.28%)  0/358 (0.00%)  0/355 (0.00%)  0/357 (0.00%)  0/357 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
[1]
One treatment-emergent death occurred during treatment with febuxostat XR 40 mg and is not related.
[2]
One treatment-emergent death occurred during treatment with placebo and is not related.
[3]
One treatment-emergent death occurred during treatment with febuxostat IR 80 mg and is related.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Placebo Febuxostat IR 40 mg Febuxostat XR 40 mg Febuxostat IR 80 mg Febuxostat XR 80 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   53/356 (14.89%)   53/358 (14.80%)   45/355 (12.68%)   55/357 (15.41%)   38/357 (10.64%) 
Gastrointestinal disorders           
Diarrhoea  1  13/356 (3.65%)  9/358 (2.51%)  9/355 (2.54%)  21/357 (5.88%)  9/357 (2.52%) 
Infections and infestations           
Nasopharyngitis  1  11/356 (3.09%)  7/358 (1.96%)  7/355 (1.97%)  9/357 (2.52%)  4/357 (1.12%) 
Upper respiratory tract infection  1  4/356 (1.12%)  6/358 (1.68%)  6/355 (1.69%)  5/357 (1.40%)  8/357 (2.24%) 
Investigations           
Alanine aminotransferase increased  1  6/356 (1.69%)  7/358 (1.96%)  8/355 (2.25%)  2/357 (0.56%)  4/357 (1.12%) 
Musculoskeletal and connective tissue disorders           
Arthralgia  1  7/356 (1.97%)  8/358 (2.23%)  5/355 (1.41%)  6/357 (1.68%)  4/357 (1.12%) 
Nervous system disorders           
Headache  1  6/356 (1.69%)  6/358 (1.68%)  8/355 (2.25%)  4/357 (1.12%)  4/357 (1.12%) 
Respiratory, thoracic and mediastinal disorders           
Cough  1  5/356 (1.40%)  9/358 (2.51%)  2/355 (0.56%)  3/357 (0.84%)  1/357 (0.28%) 
Vascular disorders           
Hypertension  1  9/356 (2.53%)  13/358 (3.63%)  6/355 (1.69%)  8/357 (2.24%)  5/357 (1.40%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 18.0
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
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02139046     History of Changes
Other Study ID Numbers: FEB-XR_301
U1111-1152-4040 ( Other Identifier: World Health Organization )
First Submitted: May 13, 2014
First Posted: May 15, 2014
Results First Submitted: September 15, 2016
Results First Posted: November 3, 2016
Last Update Posted: November 3, 2016