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

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients With Chronic KIdney Disease and Hyperuricaemia

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Drug: Verinurad
* Drug: Allopurinol
* Drug: Placebo for Verinurad
* Drug: Placebo for Allopurinol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose<br>High Dose (mg) (verinurad/allopurinol) Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 12/300 | Drug: Verinurad<br>* Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9<br>Drug: Allopurinol<br>* Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol<br>|
| Experimental: Intermediate Dose<br>Intermediate Dose (mg) verinurad/allopurinol Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 7.5/300 | Drug: Verinurad<br>* Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9<br>Drug: Allopurinol<br>* Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol<br>|
| Experimental: Low Dose<br>Low Dose (mg) verinurad/allopurinol Step 1 - titration_3/100 Step 2 - titration_3/200 Step 3 - target dose_3/300. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at Visit 9. | Drug: Verinurad<br>* Study treatments will be titrated in 3 steps for target low dose (3 mg), intermediate dose ( 7.5 mg) and High Dose (12 mg) Verinurad. As per Protocol Version 5.0, Patients from 3 mg dose will be switched to 24 mg at visit 9<br>Drug: Allopurinol<br>* Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol<br>|
| Experimental: Allopurinol alone (0/300 mg)<br>Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose_0/300 | Drug: Allopurinol<br>* Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol<br>|
| Placebo Comparator: Placebo (0/0 mg)<br>Placebo (mg) in 3 steps_0/0 | Drug: Placebo for Verinurad<br>* Matching Capsule<br>* Other names: Placebo;Drug: Placebo for Allopurinol<br>* Matching tablet<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | Analyses of change from baseline in uACR at 6 months (Visit 8) focused on: High dose vs Placebo High dose and Inter. dose combined vs Allopurinol alone Inter. dose vs Placebo Low dose vs Placebo High dose vs Allopurinol Inter. dose vs Allopurinol Low dose vs Allopurinol Allopurinol vs Placebo For High dose and Inter. dose combined the 2 categories merged forming 1 new temporary category. | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM) | Change from baseline in uACR at 12 months (Visit 10) for comparison of Switch dose protocol version 5.0 (PA5) versus double-capsule Placebo. The statistical model applied was an MMRM, which was basically the same as the one applied in the primary analysis but adjusted for a 12 month horizon and adapted to the double-capsule regimen from Visit 9 on. | Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10) | 
| Serum Uric Acid (sUA) (mg/dL) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) | Change from baseline in sUA at 6 months (Visit 8), there were 7 comparisons requested for each endpoint, namely: High dose vs Placebo Inter. dose vs Placebo Low dose vs Placebo High dose vs Allopurinol Inter. dose vs Allopurinol Low dose vs Allopurinol Allopurinol vs Placebo. | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | 
| Serum Uric Acid (sUA) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM) | Change from baseline in sUA at 12 months (Visit 10) for comparison of Switch dose protocol version 5.0 (PA5) versus double-capsule Placebo. | Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10) | 
| Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | Change from baseline in eGFR at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: High dose vs Placebo Inter. dose vs Placebo Low dose vs Placebo High dose vs Allopurinol Inter. dose vs Allopurinol Low dose vs Allopurinol Allopurinol vs Placebo. | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | 
| Estimated Glomerular Filtration Rate (eGFR) (mL/Min/1.73 m²) Change From Baseline at 12 Months (Visit 10) | Change from baseline in eGFR at 12 months (Visit 10) for the following treatments: High Dose Inter. Dose Low Dose (a) Switch Dose protocol version 5.0 (PA5) (b) Allopurinol Placebo Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg. | Change from baseline to 12 months (Visit 10) | 
| S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | Change from baseline in S-creatinine at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: High dose vs Placebo Inter. dose vs Placebo Low dose vs Placebo High dose vs Allopurinol Inter. dose vs Allopurinol Low dose vs Allopurinol Allopurinol vs Placebo. | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | 
| S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10) | Change from baseline in S-creatinine at 12 months (Visit 10) for the following treatments: High Dose Inter. Dose Low Dose (a) Switch Dose protocol version 5.0 (PA5) (b) Allopurinol Placebo Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg. | Change from baseline to 12 months (Visit 10) | 
| P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM) | Change from baseline in P-cystatin C at 6 months (Visit 8), there were 7 comparisons requested for this endpoint, namely: High dose vs Placebo Inter. dose vs Placebo Low dose vs Placebo High dose vs Allopurinol Inter. dose vs Allopurinol Low dose vs Allopurinol Allopurinol vs Placebo. | Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8) | 
| P-cystatin C (mg/L) Change From Baseline at 12 Months (Visit 10) | Change from baseline in S-creatinine at 12 months (Visit 10) for the following treatments: High Dose Inter. Dose Low Dose (a) Switch Dose protocol version 5.0 (PA5) (b) Allopurinol Placebo Subjects that switched from Verinurad 3 mg to Verinurad 24 mg at Visit 9 are not included in this group for Visit 10. Contains all subjects randomized to the low dose group that later switched to Verinurad 24 mg plus Allopurinol 300 mg. | Change from baseline to 12 months (Visit 10) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Kidney Disease