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

• 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: Takeda
• 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

Participant Flow

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
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

Baseline Characteristics

Arm/Group Title		Placebo	Febuxostat IR 40 mg	Febuxostat XR 40 mg	Febuxostat IR 80 mg	Febuxostat XR 80 mg	Total
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
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

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3
Description	[Not Specified]
Time Frame	Month 3

Outcome Measure Data

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
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

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]

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]

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]

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
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

Outcome Measure Data

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
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

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]

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]

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]

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
Description	[Not Specified]
Time Frame	Month 3

Outcome Measure Data

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
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

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]

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]

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]

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]

Adverse Events

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
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	--/--	--/--	--/--	--/--	--/--
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.
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

Limitations and Caveats

[Not Specified]

More Information

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

• Name/Title: Medical Director
• Organization: Takeda
• Phone: +1-877-825-3327
• EMail: trialdisclosures@takeda.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Saag KG, Becker MA, Whelton A, Hunt B, Castillo M, Kisfalvi K, Gunawardhana L. Efficacy and Safety of Febuxostat Extended and Immediate Release in Patients With Gout and Renal Impairment: A Phase III Placebo-Controlled Study. Arthritis Rheumatol. 2019 Jan;71(1):143-153. doi: 10.1002/art.40685.

• 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