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

Overview

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).

Full Title of Study: “Effects of Intensive Uric Acid Lowering Therapy With RDEA3170 (Verinurad) and Febuxostat in Patients With Albuminuria”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: August 13, 2018

Detailed Description

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.

Interventions

  • Drug: Verinurad 9 mg+Febuxostat 80 mg
    • Capsule administered orally, once daily for 24 weeks
  • Drug: Placebo
    • Capsule administered orally, once daily for 24 weeks

Arms, Groups and Cohorts

  • Experimental: Verinurad 9 mg+Febuxostat 80 mg
    • Capsule administered orally, once daily for 24 weeks
  • Placebo Comparator: Placebo
    • Capsule administered orally, once daily for 24 weeks

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 99 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • AstraZeneca
  • Provider of Information About this Clinical Study
    • Sponsor

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