A Study to Assess the Effect of Intensive Uric Acid (UA) Lowering Therapy With RDEA3170, Febuxostat, Dapagliflozin on Urinary Excretion of UA

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03316131
• Collaborator: Contract Research Organization: USA (Other), PAREXEL Early Phase Clinical Unit Baltimore (Other), PAREXEL Early Phase Clinical Unit-Los Angeles (Other), Clinical Laboratory: USA (Other), Harbor Hospital Laboratory (Other), GenX Laboratories Inc. (Other), Analytical Laboratory (Pharmacokinetic Sample Analysis): USA (Other), Covance Bioanalytical Services, LLC (Other)
• Enrollment: 36
• Locations: 2
• Arms: 2
• Actual Duration (Months): 8.8
• Patients Per Site: 18
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

This is a randomized, placebo controlled, double-blind, 2-way crossover study conducted on asymptomatic hyperuricemic patients. The core study consists of screening period, 2 treatment periods (verinurad + febuxostat + dapagliflozin/placebo) and follow-up visit

Condition or Disease	Intervention/Treatment	Phase
Asymptomatic Hyperuricemia	Drug: Verinurad; Drug: Febuxostat; Drug: Dapagliflozin; Other: Dapagliflozin matched placebo	Phase 2

Detailed Description

This is a randomized, placebo controlled, double-blind, 2-way crossover study to assess the effect of intensive UA lowering therapy with verinurad (RDEA3170), febuxostat, and dapagliflozin on urinary excretion of UA, in asymptomatic hyperuricemic patients. Thirty-six asymptomatic hyperuricemic patients aged 18 to 65 years (inclusive) will be enrolled into this study at 2 study centers. Twenty-four patients have been enrolled and completed the study to date. Due to inadequate urine sampling, 12 additional patients were included to ensure an adequate sample size (at least 20 evaluable patients) to evaluate the effects of intensive UA lowering with verinurad, febuxostat and dapagliflozin on urinary excretion of UA. With 24 completers available during the interim analysis, this will provide for a total sample size of 36 evaluable patients.

Before any study specific assessments are performed, potential patients must provide informed consent. Each patient will undergo the below mentioned visits:

• A Screening period of maximum 28 days;

• Two treatment periods during which patients will be resident in the Clinical Unit from Day -2 to Day 1 and from Day 6 to Day 8; and

• A Follow-up Visit within 14 to 28 days after the first administration of Investigational Medicinal Product (IMP) in Treatment Period 2.

On Day -2 of Treatment period 1, patient will be randomized (1:1) to 1 of 2 treatment sequences (AB or BA). Each randomized patient will receive orally once daily fixed dose of the below mentioned 2 treatments for 7 consecutive days (1 treatment per treatment period).

• Treatment A: Verinurad + febuxostat + dapagliflozin

• Treatment B: Verinurad + febuxostat + placebo For each treatment period, baseline measurements will be performed. On Day 1, after all dosing and all assessments have been performed, patients will receive instruction to administer the IMP at home once daily in the morning from Day 2 to Day 6 and the IMP will be dispensed for home dosing. Patients will return to the Clinical Unit on Day 6 and will be residential in the Clinical Unit from Day 6 to Day 8.

Treatment Period 1 and Treatment Period 2 will be separated by a washout period of 7 to 21 days.

Patients will return to the Clinical Unit for a Follow-up Visit, 14 to 28 days after Day 1 of Treatment Period 2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Masking Description: The pharmacokineticist will remain blinded during the study conduct, unless otherwise required based on study findings. The pharmacokineticist will be unblinded to perform the final PK analyses after all patients have completed the study, final bioanalytical results are available and all required study data are considered clean. This may occur before database lock.
• Primary Purpose: Treatment
• Official Title: Quantifying Uric Acid Excretion With RDEA3170, Febuxostat and Dapagliflozin
• Actual Study Start Date: Oct 25, 2017
• Actual Primary Completion Date: Jul 19, 2018
• Actual Study Completion Date: Jul 19, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment A Randomized patients will receive orally once daily fixed dose of the following drugs: verinurad + febuxostat + dapagliflozin;	Drug: Verinurad; Randomized patients will receive orally once daily fixed dose of verinurad in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo; Other Names: RDEA3170 ; Drug: Febuxostat; Randomized patients will receive orally once daily fixed dose of febuxostat in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo; Other Names: ULORIC ; Drug: Dapagliflozin; Randomized patients will receive orally once daily fixed dose of dapagliflozin in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo; Other Names: FARXIGA
Experimental: Treatment B Randomized patients will receive orally once daily fixed dose of the following drugs: verinurad + febuxostat + dapagliflozin matched placebo	Drug: Verinurad; Randomized patients will receive orally once daily fixed dose of verinurad in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo; Other Names: RDEA3170 ; Drug: Febuxostat; Randomized patients will receive orally once daily fixed dose of febuxostat in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo; Other Names: ULORIC ; Other: Dapagliflozin matched placebo; Randomized patients will receive orally once daily fixed dose of dapagliflozin matched placebo in 2 treatment sequences AB or BA for 7 consecutive days. Treatment A: verinurad + febuxostat + dapagliflozin; Treatment B: verinurad + febuxostat + placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7 [On Day -1 and Day 7 of each treatment period]

   Change from baseline in peak UA excretion during the first 8 hours on Day 7 of treatment to assess the effects of intensive UA lowering therapy with verinurad, febuxostat and dapagliflozin. Urine sample was collected in hourly intervals, and the highest amount of UA excreted in any interval was designated as peak UA excretion for each patient and treatment period.

2. Change From Baseline in Plasma Concentration (Cmax) on Day 7 [On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)]

   Cmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin

3. Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 [On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)]

   AUClast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin

4. Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 [On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)]

   AUCτ assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin

Secondary Outcome Measures

1. Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7 [At Day -1 and Day 7]

   Change from baseline in sUA to assess the intensive UA lowering effect of RDEA3170, febuxostat and dapagliflozin by evaluating the sUA levels after 7 days of treatment.

2. Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 [On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)]

   tmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin

3. Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 [On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)]

   tlast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 18 to 65 years old

2. Asymptomatic hyperuricemia (sUA > 6.0 mg/dL)

3. Body mass index between 18 and 35 kg/m2 inclusive and weight at least 50 kg and no more than 150 kg

4. Females must be non-pregnant, as well as post-menopausal or willing to use an acceptable method of contraception during the study.

Exclusion Criteria:

1. History of any clinically significant disease or disorder putting the patient at risk during the study, or influencing study results or ability to participate in the study

2. eGFR* < 45 mL/minute/1.73 m2 at Screening.

3. Type 2 diabetes mellitus with HbA1c >8%.

4. History of diabetic ketoacidosis, hyperosmolar non-ketotic coma, gout, or alcohol or drug abuse.

5. Ongoing treatment with an SGLT2-inhibitor, a URAT1-inhibitor, and/or a xanthine oxidase inhibitor.

6. Positive test for hepatitis B, hepatitis C or HIV.

7. Use of any medications in the 2 weeks preceding first administration of study drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Glendale	California	United States	91206
2	Research Site	Baltimore	Maryland	United States	21225

Sponsors and Collaborators

• AstraZeneca
• Contract Research Organization: USA
• PAREXEL Early Phase Clinical Unit Baltimore
• PAREXEL Early Phase Clinical Unit-Los Angeles
• Clinical Laboratory: USA
• Harbor Hospital Laboratory
• GenX Laboratories Inc.
• Analytical Laboratory (Pharmacokinetic Sample Analysis): USA
• Covance Bioanalytical Services, LLC

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 16, 2018
• Study Protocol - May 10, 2018

More Information

Additional Information:

• Related Info
• Related Info

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT03316131
• Other Study ID Numbers: D5495C00001
• First Posted: Oct 20, 2017
• Last Update Posted: Aug 28, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Gout; Uric acid; Hyperuricemia; Asymptomatic gout; Febuxostat; Dapagliflozin; Uric acid transporter 1 (URAT1) Inhibitor; Xanthine Oxidase Inhibitor; Sodium-glucose cotransporter 2 (SGLT2) Inhibitor
• Additional relevant MeSH terms: Hyperuricemia; Dapagliflozin; Febuxostat; Verinurad

Study Results

Participant Flow

Recruitment Details	The trial was conducted at two study centres: Baltimore and Los Angeles. The date of the first subject visit was 25 Oct 2017 and the date of the last subject last visit was 19 Jul 2018. A total of 36 adults asymptomatic hyperuricemic patients were included into this study.
Pre-assignment Detail	Patients who provided informed consent underwent screening procedures within the 28 days. Patients returned to the Clinical Unit on Day -2 of Treatment Period 1 and were randomized (1:1) to two treatment sequences ( treatment AB or BA).

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Period Title: Treatment Period 1
STARTED	18	18
COMPLETED	18	18
NOT COMPLETED	0	0
Period Title: Treatment Period 1
STARTED	18	18
COMPLETED	17	18
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	All Subjects
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin/placebo. Each patient randomized to treatment A in period 1 received Treatment B in period 2 and each patient randomized to treatment B in period 1 received Treatment A in period 2
Overall Participants	36
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.3 (12.01)
Sex: Female, Male (Count of Participants)
Female	1 2.8%
Male	35 97.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 5.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	17 47.2%
White	14 38.9%
More than one race	3 8.3%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7
Description	Change from baseline in peak UA excretion during the first 8 hours on Day 7 of treatment to assess the effects of intensive UA lowering therapy with verinurad, febuxostat and dapagliflozin. Urine sample was collected in hourly intervals, and the highest amount of UA excreted in any interval was designated as peak UA excretion for each patient and treatment period.
Time Frame	On Day -1 and Day 7 of each treatment period

Outcome Measure Data

Analysis Population Description

Protocol Analysis Set

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Measure Participants	36	36
Least Squares Mean (95% Confidence Interval) [milligrams (mg)]	-12.87	-13.15

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.28
	Confidence Interval	(2-Sided) 95%; -8.67 to 9.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in Plasma Concentration (Cmax) on Day 7
Description	Cmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
Time Frame	On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Measure Participants	36	36
Verinurad	17.52 (45.87)	15.26 (52.48)
M1	25.28 (41.55)	25.61 (57.24)
M8	18.45 (35.45)	18.42 (44.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for Verinurad
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 90%; 1.03 to 1.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for M1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 90%; 0.88 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for M8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 90%; 0.91 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7
Description	AUClast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
Time Frame	On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Measure Participants	36	36
Verinurad	149.1 (37.79)	141.0 (44.90)
M1	212.7 (42.74)	221.3 (49.13)
M8	174.2 (34.57)	176.5 (36.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for Verinurad
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 90%; 1.00 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for M1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 90%; 0.90 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for M8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 90%; 0.94 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Urinary Excretion of Serum UA (sUA) on Day 7
Description	Change from baseline in sUA to assess the intensive UA lowering effect of RDEA3170, febuxostat and dapagliflozin by evaluating the sUA levels after 7 days of treatment.
Time Frame	At Day -1 and Day 7

Outcome Measure Data

Analysis Population Description

Pharmacodynamic Analysis Set

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Measure Participants	36	36
Least Squares Mean (95% Confidence Interval) [umol/L]	-327.161	-264.851

5. Secondary Outcome

Title	Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7
Description	tmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
Time Frame	On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Measure Participants	36	36
Verinurad	4.00	4.00
M1	4.00	4.00
M8	4.00	4.00

6. Secondary Outcome

Title	Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7
Description	tlast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
Time Frame	On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Measure Participants	36	36
Verinurad	24.00	24.00
M1	24.00	24.00
M8	24.00	24.00

7. Primary Outcome

Title	Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7
Description	AUCτ assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin
Time Frame	On Treatment Period 1 and 2: Day 7 (Pre-dose and 15 minutes, 30 minutes, 1 hour, 1.5, 2, 3, 4, 8, 12 and 24 hours post-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set

Arm/Group Title	Treatment Sequence A+B	Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
Measure Participants	36	36
Verinurad	149.0 (37.84)	140.9 (44.90)
M1	212.6 (42.78)	221.1 (49.13)
M8	174.1 (34.59)	176.3 (36.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for Verinurad
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 90%; 1.00 to 1.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for M1
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.96
	Confidence Interval	() 90%; 0.90 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Treatment Sequence A+B, Treatment Sequence B+A
	Comments	Treatment A/Treatment B, for M8
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 90%; 0.94 to 1.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were collected from the start of randomization throughout the treatment period up to and including the Follow-up Visit. Serious adverse events were recorded from the time of informed consent.
Adverse Event Reporting Description	From screening (Day -28) to follow-up (Day 23)
Arm/Group Title	Treatment Sequence A+B		Treatment Sequence B+A
Arm/Group Description	Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + 10 mg dapagliflozin (Treatment A). Each patient randomized to treatment A in period 1 received Treatment B in period 2 as this is 2-way crossover study		Each patient received orally once daily dose of 9 mg verinurad + 80 mg febuxostat + placebo (Treatment B). Each patient randomized to treatment B in period 1 received Treatment A in period 2 as this is 2-way crossover study
All Cause Mortality
	Treatment Sequence A+B		Treatment Sequence B+A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/36 (0%)
Serious Adverse Events
	Treatment Sequence A+B		Treatment Sequence B+A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Sequence A+B		Treatment Sequence B+A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/35 (20%)		5/36 (13.9%)
Gastrointestinal disorders
Diarrhoea	1/35 (2.9%)		1/36 (2.8%)
Flatulence	1/35 (2.9%)		1/36 (2.8%)
Nausea	0/35 (0%)		1/36 (2.8%)
General disorders
Catheter Site Pain	0/35 (0%)		1/36 (2.8%)
Influenza Like Illness	1/35 (2.9%)		0/36 (0%)
Vessel Puncture Site Haematoma	1/35 (2.9%)		1/36 (2.8%)
Infections and infestations
Upper Respiratory Tract Infection	0/35 (0%)		1/36 (2.8%)
Injury, poisoning and procedural complications
Eyelid Injury	1/35 (2.9%)		0/36 (0%)
Skin Abrasion	0/35 (0%)		1/36 (2.8%)
Nervous system disorders
Headache	1/35 (2.9%)		1/36 (2.8%)
Psychiatric disorders
Insomnia	1/35 (2.9%)		0/36 (0%)
Skin and subcutaneous tissue disorders
Dry Skin	0/35 (0%)		1/36 (2.8%)

Limitations/Caveats

The initial plan was to recruit 24 patients, but due to difficulties in determining the peak urinary uric acid excretion in 11 patients, it was decided to include 12 additional patients to ensure adequate sample size.

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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.