Intensive Uric Acid Lowering With Verinurad and Febuxostat in Patients With Albuminuria

Study Overview
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Brief Summary
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The purpose of this clinical research study is to evaluate signals of potential clinical benefit of the combination of Verinurad and Febuxostat in lowering concentrations of circulating uric acid and thus improving kidney or cardiovascular status of patients with hyperuricemia, albuminuria, and Type 2 diabetes (T2DM).

Detailed Description
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Evidence shows independent associations between elevated serum uric acid (sUA) and the risk of hypertension, myocardial infarction (MI), chronic kidney disease (CKD), T2DM, heart failure (HF), and metabolic syndrome, including obesity. Gout is associated with an increased risk of all-cause death, as well as cardiovascular death. The causal relationship between elevated sUA, gout, and these disease outcomes remains to be proven. Verinurad (RDEA3170), is a novel Urate Transporter 1 (URAT1) inhibitor in Phase II development. Verinurad combined with the xanthine oxidase (XO) inhibitor febuxostat has been shown to lower sUA in patients with recurrent gout in Phase II studies by >80%. The extensive lowering of sUA delivered by the combination presents a unique opportunity to explore whether intensive urate lowering therapy can improve kidney and/or cardiac health. This study will assess if intensive serum urate lowering therapy, more potent than ever explored before in the chronic out-patient setting, can improve chronic kidney or cardiac function in the study population. In order to maximize the scientific value of the study and minimize the risk for systemic biases a parallel group, double blind, randomized design will be utilized. The study will recruit patients with hyperuricemia and presenting with albuminuria. Hyperuricemic patients are expected to benefit more from urate lowering, and albuminuria at baseline is required, as the primary objective of the study will be to assess changes in albuminuria. Patients are also required to be diagnosed with T2DM. Patients with T2DM frequently exhibit changes in cardiac function detectable using magnetic resonance imaging (MRI) that represents an early, pre-symptomatic state of HF. By limiting recruitment to patients with T2DM and by performing MRI at baseline and 6 months of therapy, the study will deliver insights into whether or not intensive urate lowering therapy can positively affect not only chronic kidney disease, but also cardiac disease.

Official Title
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Effects of Intensive Uric Acid Lowering Therapy With RDEA3170 (Verinurad) and Febuxostat in Patients With Albuminuria

Conditions
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Hyperuricemia, Albuminuria, Type 2 Diabetes

Intervention / Treatment
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* Drug: Verinurad 9 mg+Febuxostat 80 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Serum Uric Acid ≥6.0 mg/dL eGFR ≥30 mL/min/1.73 m2 UACR between 30 mg/g and 3500 mg/g inclusive Diagnosed with T2DM Exclusion Criteria: Treated with any drug for hyperuricemia in the 6 months preceding randomization.Drugs for hyperuricemia include all XO inhibitors (allopurinol, febuxostat and topiroxostat) and URAT1 inhibitors (lesinurad, verinurad, probenecid, and benzbromarone) Prior history of gout, unless prophylaxis therapy isn't required Patients who are pregnant, lactating, or planning to become pregnant Patients unsuitable or unable to undergo MRI assessment

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: Parallel Assignment
Interventional Model Description: Randomized, double-blind, double-dummy, placebo-controlled, parallel, independent groups, repeated measures, multi-center study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Verinurad 9 mg+Febuxostat 80 mg<br>Capsule administered orally, once daily for 24 weeks | Drug: Verinurad 9 mg+Febuxostat 80 mg<br>* Capsule administered orally, once daily for 24 weeks<br>* Other names: Verinurad (RDEA3170), Febuxostat(Uloric);|
| Placebo Comparator: Placebo<br>Capsule administered orally, once daily for 24 weeks | Drug: Placebo<br>* Capsule administered orally, once daily for 24 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary Albumin to Creatinine Ratio (UACR) | LS Mean Percentage Change (95% CI) from Baseline in UACR | From Baseline to 12 Weeks of Treatment | 
| Urinary Albumin to Creatinine Ratio (UACR) Compared to Placebo | LS Mean Percentage Change (90% CI) from Baseline in UACR Compared to Placebo | From Baseline to 24 Weeks of Treatment | 
| Urinary Albumin to Creatinine Ratio (UACR) | LS Mean Percentage Change (95% CI) from Baseline in UACR | From Baseline to 24 Weeks of Treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| sUA | LS Mean Percentage Change (95% CI) from Baseline in sUA | From Baseline to 12 Weeks and 24 Weeks of Treatment | 
| eGFR | LS Mean Percentage Change (95% CI) from Baseline in eGFR | From Baseline to 12 Weeks and 24 Weeks of Treatment | 
| Serum Creatinine | LS Mean Percentage Change (95% CI) from Baseline in Serum Creatinine | From Baseline to 12 Weeks and 24 Weeks of Treatment | 
| Serum Cystatin C | LS Mean Percentage Change (95% CI) from Baseline in Serum Cystatin C | From Baseline to 12 Weeks and 24 Weeks of Treatment | 
| Serum High Sensitivity C-reactive Protein | LS Mean Percentage Change (95% CI) from Baseline in Serum High Sensitivity C-reactive Protein | From Baseline to 12 Weeks and 24 Weeks of Treatment | 
| Clinical Assessments | Change from Baseline in Diastolic and Systolic Blood Pressure | From Baseline to 12 Weeks and 24 Weeks of Treatment | 
| MRI Variables - LV Mass/End-diastolic Volume | Change from Baseline in MRI Variables at Week 24 (CFB = Change from Baseline) | From Baseline to 24 Weeks of Treatment | 
| MRI Variables - Kidney Cortex T2 Star - BOLD MRI | Change from Baseline in MRI Variables at Week 24 (CFB = Change from Baseline) | From Baseline to 24 Weeks of Treatment | 
| MRI Variables - LV End-diastolic Volume, LV End-systolic Volume, LV Stroke Volume | Change from Baseline in MRI Variables at Week 24 (CFB = Change from Baseline) | From Baseline to 24 Weeks of Treatment | 
| MRI Variables - LV Ejection Fraction, Circumferential Strain, Longitudinal Strain, Radial Strain | Change from baseline in MRI Variables at Week 24 (CFB = Change from Baseline) | From Baseline to 24 Weeks of Treatment | 
| MRI Variables - Diastolic Circumferential Strain Rate, Longitudinal Strain Rate, Radial Strain Rate and Systolic Circumferential Strain Rate, Longitudinal Strain Rate, Radial Strain Rate | Change from Baseline in MRI Variables at Week 24 (CFB = Change from Baseline) | From Baseline to 24 Weeks of Treatment | 
| MRI Variables - LV Mass | Change from Baseline in MRI Variables at Week 24 (CFB = Change from Baseline) | From Baseline to 24 Weeks of Treatment |