Clinical trial NCT03118739: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hyperuricemia
Albuminuria
Type 2 Diabetes
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2017-04-18
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, double-dummy, placebo-controlled, parallel, independent groups, repeated measures, multi-center study
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Urinary Albumin to Creatinine Ratio (UACR)
timeFrame: From Baseline to 12 Weeks of Treatment
measure: Urinary Albumin to Creatinine Ratio (UACR) Compared to Placebo
timeFrame: From Baseline to 24 Weeks of Treatment
measure: Urinary Albumin to Creatinine Ratio (UACR)
timeFrame: From Baseline to 24 Weeks of Treatment
Secondary outcomes:
measure: sUA
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: eGFR
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: Serum Creatinine
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: Serum Cystatin C
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: Serum High Sensitivity C-reactive Protein
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: Clinical Assessments
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: MRI Variables - LV Mass/End-diastolic Volume
timeFrame: From Baseline to 24 Weeks of Treatment
measure: MRI Variables - Kidney Cortex T2 Star - BOLD MRI
timeFrame: From Baseline to 24 Weeks of Treatment
measure: MRI Variables - LV End-diastolic Volume, LV End-systolic Volume, LV Stroke Volume
timeFrame: From Baseline to 24 Weeks of Treatment
measure: MRI Variables - LV Ejection Fraction, Circumferential Strain, Longitudinal Strain, Radial Strain
timeFrame: From Baseline to 24 Weeks of Treatment
measure: MRI Variables - Diastolic Circumferential Strain Rate, Longitudinal Strain Rate, Radial Strain Rate and Systolic Circumferential Strain Rate, Longitudinal Strain Rate, Radial Strain Rate
timeFrame: From Baseline to 24 Weeks of Treatment
measure: MRI Variables - LV Mass
timeFrame: From Baseline to 24 Weeks of Treatment
Other outcomes:
measure: Flow Mediated Dilatation (Reactive Hyperemia)
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: Urinalysis
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: Clinical Chemistry Values
timeFrame: From Baseline to 12 Weeks and 24 Weeks of Treatment
measure: Baseline eGFR
timeFrame: Baseline
measure: Baseline UACR
timeFrame: Baseline
measure: Baseline Serum Uric Acid (sUA)
timeFrame: Baseline
measure: Baseline Serum Creatinine
timeFrame: Baseline
measure: Baseline Serum Cystatin-C
timeFrame: Baseline
measure: Baseline Serum High-sensitivity C-reactive Protein
timeFrame: Baseline
measure: Baseline MRI Variables - Kidney Cortex T2 Star
timeFrame: Baseline
measure: Baseline MRI Variables - LV End-diastolic Volume
timeFrame: Baseline
measure: Baseline MRI Variables - LV Ejection Fraction
timeFrame: Baseline
measure: Baseline MRI Variables - LV End-systolic Volume
timeFrame: Baseline
measure: Baseline MRI Variables - Circumferential Strain
timeFrame: Baseline
measure: Baseline MRI Variables - Diastolic Circumferential Strain Rate
timeFrame: Baseline
measure: Baseline MRI Variables - Diastolic Longitudinal Strain Rate
timeFrame: Baseline
measure: Baseline MRI Variables - Diastolic Radial Strain Rate
timeFrame: Baseline
measure: Baseline MRI Variables - Longitudinal Strain
timeFrame: Baseline
measure: Baseline MRI Variables - Radial Strain
timeFrame: Baseline
measure: Baseline MRI Variables - Systolic Circumferential Strain Rate
timeFrame: Baseline
measure: Baseline MRI Variables - Systolic Longitudinal Strain Rate
timeFrame: Baseline
measure: Baseline MRI Variables - Systolic Radial Strain Rate
timeFrame: Baseline
measure: Baseline MRI Variables - LV Mass
timeFrame: Baseline
measure: Baseline MRI Variables - LV Mass/End-diastolic Volume
timeFrame: Baseline
measure: Baseline MRI Variables - LV Stroke Volume
timeFrame: Baseline
measure: Baseline Flow Mediated Dilatation (Reactive Hyperemia)
timeFrame: Baseline
Locations:
city: Canyon Country
country: United States
facility: Research Site
state: California
city: Chula Vista
country: United States
facility: Research Site
state: California
city: Corona
country: United States
facility: Research Site
state: California
city: Escondido
country: United States
facility: Research Site
state: California
city: Lakewood
country: United States
facility: Research Site
state: California
city: Lincoln
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Los Angeles
country: United States
facility: Research Site
state: California
city: North Hollywood
country: United States
facility: Research Site
state: California
city: Oceanside
country: United States
facility: Research Site
state: California
city: Orange
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site
state: California
city: Houston
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: Pearland
country: United States
facility: Research Site
state: Texas
city: Sugar Land
country: United States
facility: Research Site
state: Texas
city: Webster
country: United States
facility: Research Site
state: Texas
Study officials:
References:
citation: 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.
citation: 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.