Clinical trial NCT03990363: A Study of Verinurad and Allopurinol in Patients With Chronic Kidney Disease and Hyperuricaemia
Official title: A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients With Chronic KIdney Disease and Hyperuricaemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Kidney Disease
Keywords: Chronic Kidney Disease
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2019-06-19
Enrollment: 861
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this clinical research study is to establish the dose of verinurad combined with allopurinol 300 mg once daily that will elicit the desired response; ie, reduction in urinary albumin to creatinine ratio (UACR) at 6 months.

Detailed description: Evidence shows independent associations between hyperuricaemia and the risk of hypertension, myocardial infarction, chronic kidney disease (CKD), type 2 diabetes, heart failure, and metabolic syndrome, including obesity Furthermore, gout, an inflammatory arthritis caused by deposition of monosodium urate crystals in joints, is associated with an increased risk of all-cause death, as well as cardiovascular (CV) death.

Hyperuricaemia is a prerequisite for development of gout, thus linking high levels of sUA to gout and to poor outcomes. However, the causal relationship between hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven.

Uric acid transporter 1 (URAT1) is responsible for reabsorption of uric acid (UA in the proximal tubule. Inhibition of URAT1 results in increased urinary excretion of UA.

Verinurad (RDEA3170) is a novel URAT1 inhibitor in Phase 2 development for chronic kidney disease and heart failure.

Verinurad combined with the xanthine oxidase (XO)inhibitor (XOI) febuxostat or allopurinol has been shown to lower sUA in patients with recurrent gout in Phase 2 studies by up to 80%..

The primary objective of this study is to assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months.

In this study, change in UACR at 6 months of treatment is the primary endpoint for the efficacy evaluation of treatment with the combination of verinurad and allopurinol vs. placebo.

A key secondary objective is evaluation of verinurad plus allopurinol on the reduction in UACR at 12 months.

Further, standard safety parameters such as adverse event (AEs), serious adverse event (SAEs), and laboratory evaluations will be employed to assess the safety profile of the study drugs.

Verinurad, allopurinol and oxypurinol plasma concentrations over time will also be measured.

The study will recruit patients with Chronic Kidney Disease and Hyperuricaemia.

Eligibility criteria: Inclusion Criteria:

* The subject has given written informed consent prior to any mandatory study specific procedures, sampling, and analyses, and is able to understand and comply with all study procedures
* Adult Patient ≥18 years of age with CKD for \>3 months.
* Patients with background standard of care treatment for albuminuria and/or T2DM and treated according to locally recognised guidelines. Therapy optimised and stable for ≥4 weeks before study entry and including an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, unless justified.
* If treated with a sodium-glucose transport protein (SGLT2) inhibitor, stable dose for ≥4 weeks before randomisation.
* Meeting screening criteria for sUA and eGFR (Visit 2): sUA ≥6.0 mg/dL. ∙ eGFR ≥25 mL/min/1.73 m2 Chronic Kidney Disease Epidemiology Collaboration
* UACR between 30 mg/g and 5000 mg/g.
* Female patients: Negative pregnancy test for childbearing potential. 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception during the study and 4 weeks after the last dose of study treatment.

Exclusion Criteria:

* Autosomal dominant or autosomal recessive polycystic kidney disease, lupus nephritis or anti-neutrophil cytoplasmic antibody associated vasculitis (granulomatosis with polyangiitis \[Wegener's granulomatosis\], microscopic polyangiitis, or eosinophilic granulomatosis with polyangiitis \[Churg-Strauss syndrome\]).
* History of renal transplantation
* Known carrier of the Human Leukocyte Antigen-B \*58:01 allele.
* Patients diagnosed with tumor lysis syndrome or Lesch-Nyhan syndrome
* Patients who in the opinion of investigator are unable to perform the patients' tasks associated with the protocol or Presence of any condition which, places the patient at undue risk or potentially jeopardises the quality of the data to be generated
* History of stroke, myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft in the past 6 months
* Uncontrolled hypertension presenting with systolic blood pressure \>180 mm Hg and/or diastolic blood pressure \>100 mm Hg
* Diagnosed with heart failure and New York Heart Association Functional Classification Class IV at the time of randomisation
* QT interval corrected by the Fridericia formula \>470 msec; patients diagnosed with long QT syndrome; patients with a family history of long QT syndrome.
* Subjects with severe hepatic impairment, as judged by the investigator, of Child-Pugh Class C (decompensated cirrhosis), or with major cirrhosis complications (eg, hepatorenal syndrome)
* Receiving cytotoxic or immunosuppressive therapy or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment
* Treated with any drug for hyperuricaemia in the 6 months preceding randomisation.
* Dose of ACEi, ARBs, fenofibrate, guaifenesin, or SGLT2 inhibitors changed within 4 weeks of randomisation or further dose titration expected after randomization

Primary outcomes:
measure: Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM)
timeFrame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
Secondary outcomes:
measure: Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM)
timeFrame: Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10)
measure: Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM)
timeFrame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
measure: Serum Uric Acid (sUA) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM)
timeFrame: Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10)
measure: Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)
timeFrame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
measure: Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10)
timeFrame: Change from baseline to 12 months (Visit 10)
measure: S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)
timeFrame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
measure: S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10)
timeFrame: Change from baseline to 12 months (Visit 10)
measure: P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)
timeFrame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
measure: P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10)
timeFrame: Change from baseline to 12 months (Visit 10)
Other outcomes:
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city: Barcelona
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city: Ciudad Real
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city: Cordoba
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city: Girona
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city: L'Hospitalet De Llobregat
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city: Málaga
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city: Palma de Mallorca
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city: Santander
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city: Sevilla
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city: Valencia
country: Spain
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city: Valencia
country: Spain
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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.