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

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

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).

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Albuminuria; Hyperuricemia
• Intervention / Treatment: Drug: Verinurad 9 mg+Febuxostat 80 mg; Drug: Placebo

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
• Enrollment (Actual): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Canyon Country, California, United States, 91351
      • Research Site
    • Chula Vista, California, United States, 91911
      • Research Site
    • Corona, California, United States, 92882
      • Research Site
    • Escondido, California, United States, 92025
      • Research Site
    • Lakewood, California, United States, 90805
      • Research Site
    • Lincoln, California, United States, 95648
      • Research Site
    • Los Angeles, California, United States, 90017
      • Research Site
    • Los Angeles, California, United States, 90022
      • Research Site
    • Los Angeles, California, United States, 90036
      • Research Site
    • North Hollywood, California, United States, 91606
      • Research Site
    • Oceanside, California, United States, 92056-4510
      • Research Site
    • Orange, California, United States, 92868
      • Research Site
    • Sacramento, California, United States, 95821
      • Research Site
  • Texas
    • Houston, Texas, United States, 77058
      • Research Site
    • Houston, Texas, United States, 77070
      • Research Site
    • Pearland, Texas, United States, 77584
      • Research Site
    • Sugar Land, Texas, United States, 77478
      • Research Site
    • Webster, Texas, United States, 77598
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow Mediated Dilatation (Reactive Hyperemia)	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.	From Baseline to 12 Weeks and 24 Weeks of Treatment
Urinalysis	Changes in Urinalysis (CFB = Change from Baseline)	From Baseline to 12 Weeks and 24 Weeks of Treatment
Clinical Chemistry Values	Changes in Clinical Chemistry Values (CFB = Change for Baseline)	From Baseline to 12 Weeks and 24 Weeks of Treatment
Baseline eGFR		Baseline
Baseline UACR		Baseline
Baseline Serum Uric Acid (sUA)		Baseline
Baseline Serum Creatinine		Baseline
Baseline Serum Cystatin-C		Baseline
Baseline Serum High-sensitivity C-reactive Protein		Baseline
Baseline MRI Variables - Kidney Cortex T2 Star		Baseline
Baseline MRI Variables - LV End-diastolic Volume		Baseline
Baseline MRI Variables - LV Ejection Fraction		Baseline
Baseline MRI Variables - LV End-systolic Volume		Baseline
Baseline MRI Variables - Circumferential Strain		Baseline
Baseline MRI Variables - Diastolic Circumferential Strain Rate		Baseline
Baseline MRI Variables - Diastolic Longitudinal Strain Rate		Baseline
Baseline MRI Variables - Diastolic Radial Strain Rate		Baseline
Baseline MRI Variables - Longitudinal Strain		Baseline
Baseline MRI Variables - Radial Strain		Baseline
Baseline MRI Variables - Systolic Circumferential Strain Rate		Baseline
Baseline MRI Variables - Systolic Longitudinal Strain Rate		Baseline
Baseline MRI Variables - Systolic Radial Strain Rate		Baseline
Baseline MRI Variables - LV Mass		Baseline
Baseline MRI Variables - LV Mass/End-diastolic Volume		Baseline
Baseline MRI Variables - LV Stroke Volume		Baseline
Baseline Flow Mediated Dilatation (Reactive Hyperemia)	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.	Baseline

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• Heerspink HJL, Stack AG, Terkeltaub R, Greene TA, Inker LA, Bjursell M, Perl S, Rikte T, Erlandsson F, Perkovic V. Rationale, design, demographics and baseline characteristics of the randomized, controlled, Phase 2b SAPPHIRE study of verinurad plus allopurinol in patients with chronic kidney disease and hyperuricaemia. Nephrol Dial Transplant. 2022 Jul 26;37(8):1461-1471. doi: 10.1093/ndt/gfab237.
• 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. 2021 Apr;77(4):481-489. doi: 10.1053/j.ajkd.2020.09.009. Epub 2020 Oct 29.

Helpful Links

• Redacted Protocol
• redacted SAP

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2017
• Primary Completion (Actual): August 13, 2018
• Study Completion (Actual): August 13, 2018

Study Registration Dates

• First Submitted: April 12, 2017
• First Submitted That Met QC Criteria: April 13, 2017
• First Posted (Actual): April 18, 2017

Study Record Updates

• Last Update Posted (Actual): January 10, 2020
• Last Update Submitted That Met QC Criteria: December 18, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Urological Manifestations; Urination Disorders; Proteinuria; Albuminuria; Hyperuricemia; Antirheumatic Agents; Gout Suppressants; Febuxostat; Verinurad
• Other Study ID Numbers: D5495C00007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No