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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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Quantifying Uric Acid Excretion With RDEA3170, Febuxostat and Dapagliflozin

Conditions
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Asymptomatic Hyperuricemia

Intervention / Treatment
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* Drug: Verinurad
* Drug: Febuxostat
* Drug: Dapagliflozin
* Other: Dapagliflozin matched placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 65 years old Asymptomatic hyperuricemia (sUA > 6.0 mg/dL) Body mass index between 18 and 35 kg/m2 inclusive and weight at least 50 kg and no more than 150 kg Females must be non-pregnant, as well as post-menopausal or willing to use an acceptable method of contraception during the study. Exclusion Criteria: 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 eGFR* < 45 mL/minute/1.73 m2 at Screening. Type 2 diabetes mellitus with HbA1c >8%. History of diabetic ketoacidosis, hyperosmolar non-ketotic coma, gout, or alcohol or drug abuse. Ongoing treatment with an SGLT2-inhibitor, a URAT1-inhibitor, and/or a xanthine oxidase inhibitor. Positive test for hepatitis B, hepatitis C or HIV. Use of any medications in the 2 weeks preceding first administration of study drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Randomized patients will receive orally once daily fixed dose of the following drugs: verinurad + febuxostat + dapagliflozin; | Drug: Verinurad<br>* 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<br>* Other names: RDEA3170;Drug: Febuxostat<br>* 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<br>* Other names: ULORIC;Drug: Dapagliflozin<br>* 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<br>* Other names: FARXIGA;|
| Experimental: Treatment B<br>Randomized patients will receive orally once daily fixed dose of the following drugs: verinurad + febuxostat + dapagliflozin matched placebo | Drug: Verinurad<br>* 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<br>* Other names: RDEA3170;Drug: Febuxostat<br>* 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<br>* Other names: ULORIC;Other: Dapagliflozin matched placebo<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Peak Urinary Excretion of Uric Acid (UA) on Day 7 | 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. | On Day -1 and Day 7 of each treatment period | 
| Change From Baseline in Plasma Concentration (Cmax) on Day 7 | Cmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin | 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) | 
| Change From Baseline in Area Under Plasma Concentration Time Curve From Time Zero to the Time of Last Measurable Concentration (AUClast) on Day 7 | AUClast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin | 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) | 
| Change From Baseline in Area Under Plasma Concentration Time Curve Over a Dosing Interval (24 Hours) (AUCτ) on Day 7 | AUCτ assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Urinary Excretion of Serum UA (sUA) on 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. | At Day -1 and Day 7 | 
| Change From Baseline in Time to Reach Maximum Observed Concentration (Tmax) on Day 7 | tmax assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin | 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) | 
| Change From Baseline in Time of Last Measurable Concentration (Tlast) on Day 7 | tlast assessment for Verinurad, M1, and M8 following daily oral administration of verinurad and febuxostat with and without dapagliflozin | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gout, Uric acid, Hyperuricemia, Asymptomatic gout, Febuxostat, Dapagliflozin, Uric acid transporter 1 (URAT1) Inhibitor, Xanthine Oxidase Inhibitor, Sodium-glucose cotransporter 2 (SGLT2) Inhibitor