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

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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:
Information provided by (Responsible Party):
AstraZeneca

Study Description
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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).

Condition or disease Intervention/treatment Phase
Hyperuricemia Albuminuria Type 2 Diabetes Drug: Verinurad 9 mg+Febuxostat 80 mg Drug: Placebo Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
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
Official Title: Effects of Intensive Uric Acid Lowering Therapy With RDEA3170 (Verinurad) and Febuxostat in Patients With Albuminuria
Actual Study Start Date : May 18, 2017
Actual Primary Completion Date : August 13, 2018
Actual Study Completion Date : August 13, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Febuxostat

Arms and Interventions
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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 Name: 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


Outcome Measures
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Primary Outcome Measures :
  1. 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

  2. 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

  3. 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 Outcome Measures :
  1. sUA [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
    LS Mean Percentage Change (95% CI) from Baseline in sUA

  2. eGFR [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
    LS Mean Percentage Change (95% CI) from Baseline in eGFR

  3. 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

  4. 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

  5. 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

  6. Clinical Assessments [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
    Change from Baseline in Diastolic and Systolic Blood Pressure

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. 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)

  12. 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)


Other Outcome Measures:
  1. 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.


  2. Urinalysis [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
    Changes in Urinalysis (CFB = Change from Baseline)

  3. Clinical Chemistry Values [ Time Frame: From Baseline to 12 Weeks and 24 Weeks of Treatment ]
    Changes in Clinical Chemistry Values (CFB = Change for Baseline)

  4. Baseline eGFR [ Time Frame: Baseline ]
  5. Baseline UACR [ Time Frame: Baseline ]
  6. Baseline Serum Uric Acid (sUA) [ Time Frame: Baseline ]
  7. Baseline Serum Creatinine [ Time Frame: Baseline ]
  8. Baseline Serum Cystatin-C [ Time Frame: Baseline ]
  9. Baseline Serum High-sensitivity C-reactive Protein [ Time Frame: Baseline ]
  10. Baseline MRI Variables - Kidney Cortex T2 Star [ Time Frame: Baseline ]
  11. Baseline MRI Variables - LV End-diastolic Volume [ Time Frame: Baseline ]
  12. Baseline MRI Variables - LV Ejection Fraction [ Time Frame: Baseline ]
  13. Baseline MRI Variables - LV End-systolic Volume [ Time Frame: Baseline ]
  14. Baseline MRI Variables - Circumferential Strain [ Time Frame: Baseline ]
  15. Baseline MRI Variables - Diastolic Circumferential Strain Rate [ Time Frame: Baseline ]
  16. Baseline MRI Variables - Diastolic Longitudinal Strain Rate [ Time Frame: Baseline ]
  17. Baseline MRI Variables - Diastolic Radial Strain Rate [ Time Frame: Baseline ]
  18. Baseline MRI Variables - Longitudinal Strain [ Time Frame: Baseline ]
  19. Baseline MRI Variables - Radial Strain [ Time Frame: Baseline ]
  20. Baseline MRI Variables - Systolic Circumferential Strain Rate [ Time Frame: Baseline ]
  21. Baseline MRI Variables - Systolic Longitudinal Strain Rate [ Time Frame: Baseline ]
  22. Baseline MRI Variables - Systolic Radial Strain Rate [ Time Frame: Baseline ]
  23. Baseline MRI Variables - LV Mass [ Time Frame: Baseline ]
  24. Baseline MRI Variables - LV Mass/End-diastolic Volume [ Time Frame: Baseline ]
  25. Baseline MRI Variables - LV Stroke Volume [ Time Frame: Baseline ]
  26. 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.



Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03118739


Locations
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United States, California
Research Site
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
United States, Texas
Research Site
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
Sponsors and Collaborators
AstraZeneca
  Study Documents (Full-Text)

Documents provided by AstraZeneca:
Study Protocol and Statistical Analysis Plan  [PDF] September 13, 2018

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03118739    
Other Study ID Numbers: D5495C00007
First Posted: April 18, 2017    Key Record Dates
Results First Posted: January 10, 2020
Last Update Posted: January 10, 2020
Last Verified: December 2019
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Albuminuria
Hyperuricemia
Pathologic Processes
Proteinuria
Urination Disorders
Urologic Diseases
 Urological Manifestations
Febuxostat
Verinurad
Gout Suppressants
Antirheumatic Agents