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

• ClinicalTrials.gov Identifier: NCT03118739
• Recruitment Status: Completed
• First Posted: April 18, 2017
• Results First Posted: January 10, 2020
• Last Update Posted: January 10, 2020
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: April 12, 2017
• First Posted Date: April 18, 2017
• Results First Submitted Date: July 15, 2019
• Results First Posted Date: January 10, 2020
• Last Update Posted Date: January 10, 2020
• Actual Study Start Date: May 18, 2017
• Actual Primary Completion Date: August 13, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 18, 2019)

• 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

Original Primary Outcome Measures (submitted: April 13, 2017)

Urinary Albumin to Creatinine Ratio (UACR) after 12 weeks [ Time Frame: From Baseline to 12 Weeks of Treatment ]

To assess the effects of intensive uric acid lowering therapy with RDEA3170 and febuxostat on albuminuria

Current Secondary Outcome Measures (submitted: December 18, 2019)

• 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)

Original Secondary Outcome Measures (submitted: April 13, 2017)

• Estimated glomerular filtration rate (eGFR), Cystatin C, creatinine [ Time Frame: From baseline up to 24 weeks of treatment ]
  To assess the effects of intensive uric acid lowering therapy with RDEA3170 and febuxostat on kidney function.
• Serum uric acid [ Time Frame: From baseline up to 24 weeks of treatment ]
  To assess the metabolic effects of intensive uric acid lowering therapy with RDEA3170 and febuxostat
• Left ventricular cardiac strain,function and mass, kidney oxygenation [ Time Frame: From baseline up to 24 weeks of treatment ]
  To assess the structural and functional effects of intensive uric acid lowering therapy with RDEA3170 and febuxostat on the heart and kidney using magnetic resonance imaging
• High sensitivity C-reactive protein and Troponin I [ Time Frame: From baseline up to 24 weeks of treatment ]
  To assess the effects of intensive uric acid lowering therapy with RDEA3170 and febuxostat on biomarkers and parameters related to inflammation, and cardiac health
• Blood pressure (systolic and diastolic) [ Time Frame: From baseline up to 24 weeks of treatment ]
  To assess the effects of intensive uric acid lowering therapy with RDEA3170 and febuxostat on cardiovascular parameters
• RDEA3170 plasma concentration at trough [ Time Frame: From baseline up to 24 weeks of treatment ]
  To assess plasma exposure of RDEA3170 in this patient population

Current Other Pre-specified Outcome Measures (submitted: December 18, 2019)

• Flow Mediated Dilatation (Reactive Hyperemia) [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
  LS Mean Change (95% CI) from Baseline in Flow Mediated Dilatation. The flow mediated dilatation metric is obtained using a device from Cordex, and a proprietary algorithm. This metric represents the volume difference between a baseline arterial compliance curve and hyperemia arterial compliance curve in the positive transmural pressure region. This metric has a direct relationship to a subject's cardiovascular condition. Output range is 0-150. A higher score is indicative of a better flow mediated dilatation.
• Urinalysis [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
  Changes in Urinalysis (CFB = Change from Baseline)
• Clinical Chemistry Values [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
  Changes in Clinical Chemistry Values (CFB = Change for Baseline)
• Baseline eGFR [ Time Frame: Baseline ]
• Baseline UACR [ Time Frame: Baseline ]
• Baseline Serum Uric Acid (sUA) [ Time Frame: Baseline ]
• Baseline Serum Creatinine [ Time Frame: Baseline ]
• Baseline Serum Cystatin-C [ Time Frame: Baseline ]
• Baseline Serum High-sensitivity C-reactive Protein [ Time Frame: Baseline ]
• Baseline MRI Variables - Kidney Cortex T2 Star [ Time Frame: Baseline ]
• Baseline MRI Variables - LV End-diastolic Volume [ Time Frame: Baseline ]
• Baseline MRI Variables - LV Ejection Fraction [ Time Frame: Baseline ]
• Baseline MRI Variables - LV End-systolic Volume [ Time Frame: Baseline ]
• Baseline MRI Variables - Circumferential Strain [ Time Frame: Baseline ]
• Baseline MRI Variables - Diastolic Circumferential Strain Rate [ Time Frame: Baseline ]
• Baseline MRI Variables - Diastolic Longitudinal Strain Rate [ Time Frame: Baseline ]
• Baseline MRI Variables - Diastolic Radial Strain Rate [ Time Frame: Baseline ]
• Baseline MRI Variables - Longitudinal Strain [ Time Frame: Baseline ]
• Baseline MRI Variables - Radial Strain [ Time Frame: Baseline ]
• Baseline MRI Variables - Systolic Circumferential Strain Rate [ Time Frame: Baseline ]
• Baseline MRI Variables - Systolic Longitudinal Strain Rate [ Time Frame: Baseline ]
• Baseline MRI Variables - Systolic Radial Strain Rate [ Time Frame: Baseline ]
• Baseline MRI Variables - LV Mass [ Time Frame: Baseline ]
• Baseline MRI Variables - LV Mass/End-diastolic Volume [ Time Frame: Baseline ]
• Baseline MRI Variables - LV Stroke Volume [ Time Frame: Baseline ]
• Baseline Flow Mediated Dilatation (Reactive Hyperemia) [ Time Frame: Baseline ]
  Baseline in Flow Mediated Dilatation. The flow mediated dilatation metric is obtained using a device from Cordex, and a proprietary algorithm. This metric represents the volume difference between a baseline arterial compliance curve and hyperemia arterial compliance curve in the positive transmural pressure region. This metric has a direct relationship to a subject's cardiovascular condition. Output range is 0-150. A higher score is indicative of a better flow mediated dilatation.

Original Other Pre-specified Outcome Measures (submitted: April 13, 2017)

Rates of adverse events and serious adverse events. Changes in vital signs, physical examinations, and electrocardiograms. Changes in clinical laboratory parameters, including assessment of creatinine, cystatin C, and blood urea nitrogen [ Time Frame: From signing of the infromed consent form until 4 weeks after the last dose ]

To assess the safety and tolerability of intensive uric acid lowering therapy with RDEA3170 and febuxostat

Descriptive Information

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

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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Randomized, double-blind, double-dummy, placebo-controlled, parallel, independent groups, repeated measures, multi-center study

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

Verinurad capsules/matching placebo capsules and febuxostat/matching placebo capsules with randomization code printed on each label

Primary Purpose: Treatment

Condition

• Hyperuricemia
• Albuminuria
• Type 2 Diabetes

Intervention

• Drug: Verinurad 9 mg+Febuxostat 80 mg
  Capsule administered orally, once daily for 24 weeks
  Other Name: Verinurad (RDEA3170), Febuxostat(Uloric)
• Drug: Placebo
  Capsule administered orally, once daily for 24 weeks

Study Arms

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

• Publications *: Stack AG, Dronamraju N, Parkinson J, Johansson S, Johnsson E, Erlandsson F, Terkeltaub R. Effect of Intensive Urate Lowering With Combined Verinurad and Febuxostat on Albuminuria in Patients With Type 2 Diabetes: A Randomized Trial. Am J Kidney Dis. 2020 Oct 29. pii: S0272-6386(20)31072-6. doi: 10.1053/j.ajkd.2020.09.009. [Epub ahead of print]

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 13, 2017): 60
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 13, 2018
• Actual Primary Completion Date: August 13, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03118739
• Other Study ID Numbers: D5495C00007
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Individual participant data (IPD) will likely not be shared with external collaborators/researchers as this data is planned to be used only for internal decision-making

• Responsible Party: AstraZeneca
• Study Sponsor: AstraZeneca
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: December 2019