Phase 1, Febuxostat XR Relative Bioavailability Study

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02504320
• Collaborator: (none)
• Enrollment: 78
• Location: 1
• Arms: 4
• Duration (Months): 2
• Patients Per Site Per Month: 38.9

Study Details

Study Description

Brief Summary

This study will assess the relative bioavailability, safety and tolerability following administration of 80 mg single oral doses of 4 febuxostat extended release (XR) formulations.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Drug: Febuxostat XR 80 mg Capsule F1; Drug: Febuxostat XR 80 mg Capsule F2; Drug: Febuxostat XR 80 mg Capsule F3; Drug: Febuxostat XR 80 mg Capsule F4	Phase 1

Detailed Description

The drug being tested is this study is febuxostat XR. Four different formulations of febuxostat XR are being tested to see how the drug moves through the body. This study will look at safety and side effects in people who take febuxostat XR.

This cross-over study will enroll approximately 78 patients. Participants will be randomly assigned to 1of 4 sequences which will determine the order of the 4 treatments received:

• Febuxostat XR 80 mg capsule Formulation 1

• Febuxostat XR 80 mg capsule Formulation 2

• Febuxostat XR 80 mg capsule Formulation 3

• Febuxostat XR 80 mg capsule Formulation 4

Participants will take 1 dose on Day 1 with a washout period between each period.

This single-center trial will be conducted in the United States. The overall time to participate in this study is up to 80 days. Participants will make multiple visits to the clinic including a period of confinement, and will be contacted by telephone 30 days after last dose of study drug for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 78 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Phase 1, Randomized, Open-Label, Single-Dose, 4-Way Crossover Study to Assess the Relative Bioavailability of Four 80 mg Febuxostat XR Formulations
• Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Sequence ABDC Febuxostat XR 80 mg capsule Formulation 1 (F1), orally, once on Day 1 of Period 1 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 2 (F2), orally, once on Day 1 of Period 2 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 4 (F4), orally, once on Day 1 of Period 3 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 3 (F3), orally, once on Day 1 of Period 4 (C).	Drug: Febuxostat XR 80 mg Capsule F1; Febuxostat extended-release (XR) capsules formulation 1; Drug: Febuxostat XR 80 mg Capsule F2; Febuxostat XR capsules formulation 2; Drug: Febuxostat XR 80 mg Capsule F3; Febuxostat XR capsules formulation 3; Drug: Febuxostat XR 80 mg Capsule F4; Febuxostat XR capsules formulation 4
Experimental: Treatment Sequence DACB Febuxostat XR 80 mg capsule F4, orally, once on Day 1 of Period 1 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1 orally, once on Day 1 of Period 2 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F3, orally, once on Day 1 of Period 3 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 4 (B).	Drug: Febuxostat XR 80 mg Capsule F1; Febuxostat extended-release (XR) capsules formulation 1; Drug: Febuxostat XR 80 mg Capsule F2; Febuxostat XR capsules formulation 2; Drug: Febuxostat XR 80 mg Capsule F3; Febuxostat XR capsules formulation 3; Drug: Febuxostat XR 80 mg Capsule F4; Febuxostat XR capsules formulation 4
Experimental: Treatment Sequence CDBA Febuxostat XR 80 mg capsule F3, orally, once on Day 1 of Period 1 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F4 orally, once on Day 1 of Period 2 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 3 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1, orally, once on Day 1 of Period 4 (A).	Drug: Febuxostat XR 80 mg Capsule F1; Febuxostat extended-release (XR) capsules formulation 1; Drug: Febuxostat XR 80 mg Capsule F2; Febuxostat XR capsules formulation 2; Drug: Febuxostat XR 80 mg Capsule F3; Febuxostat XR capsules formulation 3; Drug: Febuxostat XR 80 mg Capsule F4; Febuxostat XR capsules formulation 4
Experimental: Treatment Sequence BCAD Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 1 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F3 orally, once on Day 1 of Period 2 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1, orally, once on Day 1 of Period 3 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F4, orally, once on Day 1 of Period 4 (D).	Drug: Febuxostat XR 80 mg Capsule F1; Febuxostat extended-release (XR) capsules formulation 1; Drug: Febuxostat XR 80 mg Capsule F2; Febuxostat XR capsules formulation 2; Drug: Febuxostat XR 80 mg Capsule F3; Febuxostat XR capsules formulation 3; Drug: Febuxostat XR 80 mg Capsule F4; Febuxostat XR capsules formulation 4

Outcome Measures

Primary Outcome Measures

1. Mean Cmax: Maximum Observed Plasma Concentration for Febuxostat [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

   Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.

2. Mean AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Febuxostat [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

   AUCt is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration.

3. Mean AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Febuxostat [Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose]

   AUC∞ is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures including requesting that a participant fast for any laboratory evaluations.

3. Is a healthy male or female and aged 18 to 55 years, inclusive, at the time of informed consent and first study medication dose.

4. Weighs at least 50.0 kg and has a body mass index (BMI) from 18.0 to 30.0 kg/m2, inclusive at Screening.

5. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 30 days after the last dose.

6. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent,

7. Is willing to refrain from strenuous exercise from Day -1 of Period 1 until Study Exit (Day 3 of Period 4).

8. Has estimated glomerular filtration rate (eGFR) ≥90 mL/min at Screening and Check-in (Day -1 of Period 1).

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to the first dose of study medication.

2. Has received febuxostat in a previous clinical study or as a therapeutic agent.

3. Is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in the conduct of this study.

4. Has uncontrolled, clinically significant (CS) disease or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results.

5. Has a known hypersensitivity to any component of the formulation of XO inhibitors, xanthine compounds, caffeine, or any component of the formulation of febuxostat capsules.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Austin	Texas	United States	78744

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02504320
• Other Study ID Numbers: Febuxostat XR-1011; U1111-1168-1117
• First Posted: Jul 21, 2015
• Last Update Posted: Jan 19, 2017
• Last Verified: Nov 1, 2016

• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Febuxostat

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 1 investigative site in the United States from 29 June 2015 to 01 October 2015.
Pre-assignment Detail	Healthy participants were enrolled equally in 1 of 4 sequences which determined order of treatment: Regimen A (Febuxostat extended release [XR] 80 mg capsule [cap] Formulation [F] 1), B (Febuxostat XR 80 mg cap F2), C (Febuxostat XR 80 mg cap F3) and D (Febuxostat XR 80 mg cap F4). Each regimen is separated by a 7-day washout period.

Arm/Group Title	Treatment Sequence ABDC	Treatment Sequence DACB	Treatment Sequence CDBA	Treatment Sequence BCAD
Arm/Group Description	Febuxostat XR 80 mg capsule Formulation 1 (F1), orally, once on Day 1 of Period 1 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 2 (F2), orally, once on Day 1 of Period 2 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 4 (F4), orally, once on Day 1 of Period 3 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 3 (F3), orally, once on Day 1 of Period 4 (C).	Febuxostat XR 80 mg capsule F4, orally, once on Day 1 of Period 1 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1 orally, once on Day 1 of Period 2 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F3, orally, once on Day 1 of Period 3 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 4 (B).	Febuxostat XR 80 mg capsule F3, orally, once on Day 1 of Period 1 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F4 orally, once on Day 1 of Period 2 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 3 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1, orally, once on Day 1 of Period 4 (A).	Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 1 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F3 orally, once on Day 1 of Period 2 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1, orally, once on Day 1 of Period 3 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F4, orally, once on Day 1 of Period 4 (D).
Period Title: Treatment Period 1
STARTED	19	19	20	20
COMPLETED	19	19	19	20
NOT COMPLETED	0	0	1	0
Period Title: Treatment Period 1
STARTED	19	19	19	20
COMPLETED	19	18	19	20
NOT COMPLETED	0	1	0	0
Period Title: Treatment Period 1
STARTED	19	18	19	20
COMPLETED	19	18	18	19
NOT COMPLETED	0	0	1	1
Period Title: Treatment Period 1
STARTED	19	18	18	19
COMPLETED	19	18	18	19
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Treatment Sequence ABDC	Treatment Sequence DACB	Treatment Sequence CDBA	Treatment Sequence BCAD	Total
Arm/Group Description	Febuxostat XR 80 mg capsule Formulation 1 (F1), orally, once on Day 1 of Period 1 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 2 (F2), orally, once on Day 1 of Period 2 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 4 (F4), orally, once on Day 1 of Period 3 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule Formulation 3 (F3), orally, once on Day 1 of Period 4 (C).	Febuxostat XR 80 mg capsule F4, orally, once on Day 1 of Period 1 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1 orally, once on Day 1 of Period 2 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F3, orally, once on Day 1 of Period 3 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 4 (B).	Febuxostat XR 80 mg capsule F3, orally, once on Day 1 of Period 1 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F4 orally, once on Day 1 of Period 2 (D), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 3 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1, orally, once on Day 1 of Period 4 (A).	Febuxostat XR 80 mg capsule F2, orally, once on Day 1 of Period 1 (B), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F3 orally, once on Day 1 of Period 2 (C), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F1, orally, once on Day 1 of Period 3 (A), followed by at least a 7-day washout period, followed by Febuxostat XR 80 mg capsule F4, orally, once on Day 1 of Period 4 (D).	Total of all reporting groups
Overall Participants	19	19	20	20	78
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.7 (7.56)	30.7 (6.51)	34.0 (8.87)	31.2 (7.78)	31.9 (7.70)
Gender (Count of Participants)
Female	10 52.6%	10 52.6%	9 45%	14 70%	43 55.1%
Male	9 47.4%	9 47.4%	11 55%	6 30%	35 44.9%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	11 57.9%	7 36.8%	9 45%	10 50%	37 47.4%
Not Hispanic or Latino	8 42.1%	12 63.2%	11 55%	10 50%	41 52.6%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	0 0%	0 0%	1 5%	1 1.3%
Black or African American	4 21.1%	7 36.8%	6 30%	6 30%	23 29.5%
White	15 78.9%	11 57.9%	14 70%	13 65%	53 67.9%
Multiracial	0 0%	1 5.3%	0 0%	0 0%	1 1.3%
Region of Enrollment (Count of Participants)
United States	19 100%	19 100%	20 100%	20 100%	78 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	167.6 (10.13)	171.1 (11.75)	167.5 (9.70)	165.7 (6.67)	167.9 (9.71)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	72.98 (12.685)	79.05 (11.846)	71.22 (12.350)	69.72 (11.015)	73.17 (12.273)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.84 (2.663)	26.98 (2.722)	25.29 (3.168)	25.28 (2.802)	25.83 (2.878)
Smoking Classification (Count of Participants)
Has Never Smoked	13 68.4%	14 73.7%	13 65%	18 90%	58 74.4%
Is a Current Smoker	0 0%	0 0%	0 0%	0 0%	0 0%
Is an Ex-smoker	6 31.6%	5 26.3%	7 35%	2 10%	20 25.6%
Alcohol Classification (Count of Participants)
Has Never Drunk	4 21.1%	6 31.6%	6 30%	7 35%	23 29.5%
Is a Current Drinker	8 42.1%	9 47.4%	6 30%	4 20%	27 34.6%
Is an Ex-drinker	7 36.8%	4 21.1%	8 40%	9 45%	28 35.9%
Xanthine/Caffeine Consumption (Count of Participants)
Yes	12 63.2%	13 68.4%	12 60%	14 70%	51 65.4%
No	7 36.8%	6 31.6%	8 40%	6 30%	27 34.6%
Female Reproductive Status (Count of Participants)
Not Applicable (Participant is Male)	9 47.4%	9 47.4%	11 55%	6 30%	35 44.9%
Female of Childbearing Potential	7 36.8%	9 47.4%	8 40%	12 60%	36 46.2%
Surgically Sterile	2 10.5%	1 5.3%	0 0%	2 10%	5 6.4%
Postmenopausal	1 5.3%	0 0%	1 5%	0 0%	2 2.6%
Estimated Glomerular Filtration Rate (eGFR) (mL/min) [Mean (Standard Deviation) ]
Screening (n=19, 19, 19, 20)	111.42 (11.815)	112.84 (11.987)	108.05 (11.664)	114.00 (13.377)	111.61 (12.211)
Check-in (n=19, 19, 20, 20)	115.53 (12.294)	115.26 (12.229)	112.00 (10.964)	116.55 (12.845)	114.82 (11.987)

Outcome Measures

1. Primary Outcome

Title	Mean Cmax: Maximum Observed Plasma Concentration for Febuxostat
Description	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants with valid parameters for Regimen D and at least one of the test regimen were included in the analyses for this outcome measure. Here, number of participants analyzed is the participants who were evaluable for this outcome measure.

Arm/Group Title	Regimen A: Febuxostat XR 80 mg Formulation 1	Regimen B: Febuxostat XR 80 mg Formulation 2	Regimen C: Febuxostat XR 80 mg Formulation 3	Regimen D: Febuxostat XR 80 mg Formulation 4
Arm/Group Description	Febuxostat XR 80 mg capsule formulation 1 (F1), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 2 (F2), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 3 (F3), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 4 (F4), orally, once on Day 1 of periods 1, 2, 3 or 4.
Measure Participants	76	74	77	76
Mean (Standard Deviation) [ng/mL]	2027.1184 (1278.28368)	1442.2267 (991.94583)	1730.2468 (1013.56204)	1809.3158 (1170.53245)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A: Febuxostat XR 80 mg Formulation 1, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen A) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	1.0848
	Confidence Interval	(2-Sided) 90%; 0.9528 to 1.2350
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen B: Febuxostat XR 80 mg Formulation 2, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen B) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.7709
	Confidence Interval	(2-Sided) 90%; 0.6767 to 0.8782
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Regimen C: Febuxostat XR 80 mg Formulation 3, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen C) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.9389
	Confidence Interval	(2-Sided) 90%; 0.8246 to 1.0689
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

2. Primary Outcome

Title	Mean AUCt: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Febuxostat
Description	AUCt is a measure of total plasma exposure to the drug from time 0 to time of the last quantifiable concentration.
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants with valid parameters for Regimen D and at least one of the test regimen were included in the analyses for this outcome measure. Here, number of participants analyzed is the participants who were evaluable for this outcome measure.

Arm/Group Title	Regimen A: Febuxostat XR 80 mg Formulation 1	Regimen B: Febuxostat XR 80 mg Formulation 2	Regimen C: Febuxostat XR 80 mg Formulation 3	Regimen D: Febuxostat XR 80 mg Formulation 4
Arm/Group Description	Febuxostat XR 80 mg capsule formulation 1 (F1), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 2 (F2), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 3 (F3), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 4 (F4), orally, once on Day 1 of periods 1, 2, 3 or 4.
Measure Participants	76	75	77	76
Mean (Standard Deviation) [ng*hr/mL]	9395.6014 (3961.55203)	7971.0624 (3291.36390)	8652.7080 (3673.91666)	8817.3600 (3429.94880)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A: Febuxostat XR 80 mg Formulation 1, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen A) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	1.0435
	Confidence Interval	(2-Sided) 90%; 0.9840 to 1.1066
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen B: Febuxostat XR 80 mg Formulation 2, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen B) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.8777
	Confidence Interval	(2-Sided) 90%; 0.8274 to 0.9311
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Regimen C: Febuxostat XR 80 mg Formulation 3, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen A) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.9540
	Confidence Interval	(2-Sided) 90%; 0.8996 to 1.0117
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

3. Primary Outcome

Title	Mean AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Febuxostat
Description	AUC∞ is a measure of total plasma exposure to the drug from time zero extrapolated to infinity.
Time Frame	Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose

Outcome Measure Data

Analysis Population Description

Participants with valid parameters for Regimen D and at least one of the test regimen were included in the analyses for this outcome measure. Here, number of participants analyzed is the participants who were evaluable for this outcome measure.

Arm/Group Title	Regimen A: Febuxostat XR 80 mg Formulation 1	Regimen B: Febuxostat XR 80 mg Formulation 2	Regimen C: Febuxostat XR 80 mg Formulation 3	Regimen D: Febuxostat XR 80 mg Formulation 4
Arm/Group Description	Febuxostat XR 80 mg capsule formulation 1 (F1), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 2 (F2), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 3 (F3), orally, once on Day 1 of periods 1, 2, 3 or 4.	Febuxostat XR 80 mg capsule formulation 4 (F4), orally, once on Day 1 of periods 1, 2, 3 or 4.
Measure Participants	69	62	69	69
Mean (Standard Deviation) [ng*hr/mL]	9368.0744 (3944.01280)	8278.6143 (3205.31556)	8938.8765 (3746.60153)	9102.3700 (3430.45699)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Regimen A: Febuxostat XR 80 mg Formulation 1, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen A) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	1.0283
	Confidence Interval	(2-Sided) 90%; 0.9691 to 1.0911
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Regimen B: Febuxostat XR 80 mg Formulation 2, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen B) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimate
	Estimated Value	0.9056
	Confidence Interval	(2-Sided) 90%; 0.8516 to 0.9630
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Regimen C: Febuxostat XR 80 mg Formulation 3, Regimen D: Febuxostat XR 80 mg Formulation 4
	Comments	Relative bioavailability of a single dose of Febuxostat XR 80 mg in test (Regimen C) and reference (Regimen D).
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Bioequivalence of Febuxostat formulation 1, 2, and 3 to Febuxostat formulation 4 was declared if the 90% confidence intervals for the ratios of central values were within the pre-specified interval of 0.80 to 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Point Estimates
	Estimated Value	0.9463
	Confidence Interval	(2-Sided) 90%; 0.8909 to 1.0051
	Parameter Dispersion	Type: Value:
	Estimation Comments	Point estimate and 90% CI were obtained from the exponentiated results of analysis of the natural log (ln)-transformed parameters was performed with regimen, sequence, period, and participants nested within sequence as fixed effects.

Adverse Events

Time Frame	From the first administration of study drug on Day 1 of Period 1 up to 30 days after the last dose of study drug or Early termination visit (approximately up to 95 days)
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. Safety Set included all participants who received at least 1 dose of study drug.
Arm/Group Title	Regimen A: Febuxostat XR 80 mg Formulation 1		Regimen B: Febuxostat XR 80 mg Formulation 2		Regimen C: Febuxostat XR 80 mg Formulation 3		Regimen D: Febuxostat XR 80 mg Formulation 4
Arm/Group Description	Febuxostat XR 80 mg capsule formulation 1 (F1), orally, once on Day 1 of periods 1, 2, 3 or 4.		Febuxostat XR 80 mg capsule formulation 2 (F2), orally, once on Day 1 of periods 1, 2, 3 or 4.		Febuxostat XR 80 mg capsule formulation 3 (F3), orally, once on Day 1 of periods 1, 2, 3 or 4.		Febuxostat XR 80 mg capsule formulation 4 (F4), orally, once on Day 1 of periods 1, 2, 3 or 4.
All Cause Mortality
	Regimen A: Febuxostat XR 80 mg Formulation 1		Regimen B: Febuxostat XR 80 mg Formulation 2		Regimen C: Febuxostat XR 80 mg Formulation 3		Regimen D: Febuxostat XR 80 mg Formulation 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Regimen A: Febuxostat XR 80 mg Formulation 1		Regimen B: Febuxostat XR 80 mg Formulation 2		Regimen C: Febuxostat XR 80 mg Formulation 3		Regimen D: Febuxostat XR 80 mg Formulation 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Investigations
Blood creatine phosphokinase increased	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Other (Not Including Serious) Adverse Events
	Regimen A: Febuxostat XR 80 mg Formulation 1		Regimen B: Febuxostat XR 80 mg Formulation 2		Regimen C: Febuxostat XR 80 mg Formulation 3		Regimen D: Febuxostat XR 80 mg Formulation 4
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/76 (7.9%)		9/76 (11.8%)		7/77 (9.1%)		7/76 (9.2%)
Gastrointestinal disorders
Diarrhoea	0/76 (0%)		0/76 (0%)		2/77 (2.6%)		0/76 (0%)
Nausea	1/76 (1.3%)		0/76 (0%)		0/77 (0%)		1/76 (1.3%)
Vomiting	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Infections and infestations
Nasopharyngitis	0/76 (0%)		2/76 (2.6%)		0/77 (0%)		0/76 (0%)
Bacterial vaginosis	1/76 (1.3%)		0/76 (0%)		0/77 (0%)		0/76 (0%)
Oral herpes	0/76 (0%)		0/76 (0%)		0/77 (0%)		1/76 (1.3%)
Trichomoniasis	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Injury, poisoning and procedural complications
Contusion	0/76 (0%)		0/76 (0%)		0/77 (0%)		1/76 (1.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/76 (1.3%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Myalgia	1/76 (1.3%)		0/76 (0%)		0/77 (0%)		0/76 (0%)
Nervous system disorders
Headache	1/76 (1.3%)		2/76 (2.6%)		1/77 (1.3%)		3/76 (3.9%)
Syncope	1/76 (1.3%)		0/76 (0%)		1/77 (1.3%)		0/76 (0%)
Dizziness	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Presyncope	0/76 (0%)		0/76 (0%)		1/77 (1.3%)		0/76 (0%)
Psychiatric disorders
Libido decreased	0/76 (0%)		0/76 (0%)		1/77 (1.3%)		0/76 (0%)
Reproductive system and breast disorders
Dysmenorrhoea	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Vaginal discharge	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Skin and subcutaneous tissue disorders
Dry skin	0/76 (0%)		1/76 (1.3%)		0/77 (0%)		0/76 (0%)
Papule	0/76 (0%)		0/76 (0%)		0/77 (0%)		1/76 (1.3%)
Pruritus	0/76 (0%)		0/76 (0%)		1/77 (1.3%)		0/76 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Research Organization shall not publish any articles or papers nor make any presentations, nor assist any other person in publishing any articles or papers or in making any presentations relating or referring to the Study or any results, data or insights from or any data, information or materials obtained or generated in the performance of its obligations without the prior written consent of Takeda, which consent may be granted or withheld in Takeda's sole discretion.