A Study of Verinurad and Allopurinol in Patients With Chronic Kidney Disease and Hyperuricaemia

  • STATUS
    Recruiting
  • End date
    Sep 13, 2021
  • participants needed
    725
  • sponsor
    AstraZeneca
Updated on 1 July 2020
Investigator
AstraZeneca Clinical Study Information Center
Primary Contact
Research Site (4.2 mi away) Contact
+225 other location
diabetes
ace inhibitor
angiotensin
nephropathy
angiotensin converting enzyme

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.

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, an inflammatory arthritis caused by deposition of monosodium urate crystals in joints. Gout occurs in patients with serum urate >6.8 mg/dL, which is the solubility limit of monosodium urate. The prevalence of gout increases with higher serum urate. However, the causal relationship between hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven.

Verinurad is a novel uric acid transporter 1 (URAT1) inhibitor in Phase 2 development to increase uric acid (UA) excretion and thereby lower sUA levels. Verinurad combined with the xanthine oxidase inhibitor (XOI) febuxostat has been shown to lower UACR in patients with diabetes and albuminuria, and to lower serum uric acid (sUA) by >80% in patients with recurrent gout in Phase 2 studies.

UACR is a measurement of albuminuria, it was chosen because changes in UACR can be detected early in response to treatment, and these changes, if substantial, correlate with progression of CKD, deterioration in estimated glomerular filtration rate (eGFR), and hard outcomes.Therefore, change in UACR is regarded as an appropriate endpoint.

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.

Additional secondary endpoints include changes from baseline in sUA, eGFR, cystatin C, creatinine and N-terminal natriuretic peptide (NT-proBNP). 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.

This study will assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months.

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

Details
Treatment Allopurinol, Verinurad, Placebo for Verinurad, Placebo for Allopurinol
Clinical Study IdentifierNCT03990363
SponsorAstraZeneca
Last Modified on1 July 2020

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Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 18 yrs and 130 yrs?
Gender: Male or Female
Do you have any of these conditions: Chronic renal failure or chronic renal insufficiency?
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
Male or female adult Patient 18 years of age
CKD as defined in the Kidney Disease: Improving Global Outcomes guidelines
Patients should receive background standard of care treatment for albuminuria and/or Type 2 Diabetes Mellitus (T2DM) and be treated according to locally recognised guidelines. Therapy should have been optimised and stable for 4 weeks before study entry and include an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), unless contraindicated, not tolerated, or in the opinion of the investigator not practically available or suitable
If treated with a sodium-glucose transport protein (SGLT2) inhibitor, the SGLT2 inhibitor dose must have been stable 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 (CKD-EPI formula)
Mean UACR between 30 mg/g and 5000 mg/g inclusive
Negative pregnancy test at investigation site for female patients of childbearing potential
Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception for the study duration 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
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
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
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