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

NCT ID: NCT03990363

Last Updated: 2023-03-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 861 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-07-23
• Study Completion Date: 2021-11-22

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.

Conditions

Chronic Kidney Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

High Dose

High Dose (mg) (verinurad/allopurinol) Step 1 - titration\_ 3/100 Step 2 - titration\_ 7.5/200 Step 3 - target dose\_ 12/300

Group Type: EXPERIMENTAL

Verinurad

Intervention Type: DRUG

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

Allopurinol

Intervention Type: DRUG

Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol

Intermediate Dose

Intermediate Dose (mg) verinurad/allopurinol Step 1 - titration\_ 3/100 Step 2 - titration\_ 7.5/200 Step 3 - target dose\_ 7.5/300

Group Type: EXPERIMENTAL

Verinurad

Intervention Type: DRUG

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

Allopurinol

Intervention Type: DRUG

Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol

Low Dose

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.

Group Type: EXPERIMENTAL

Verinurad

Intervention Type: DRUG

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

Allopurinol

Intervention Type: DRUG

Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol

Allopurinol alone (0/300 mg)

Step 1 - titration\_0/100 Step 2 - titration\_0/200 Step 3 - target dose\_0/300

Group Type: EXPERIMENTAL

Allopurinol

Intervention Type: DRUG

Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol

Placebo (0/0 mg)

Placebo (mg) in 3 steps\_0/0

Group Type: PLACEBO_COMPARATOR

Placebo for Verinurad

Intervention Type: DRUG

Matching Capsule

Placebo for Allopurinol

Intervention Type: DRUG

Matching tablet

Interventions

Verinurad

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

Intervention Type: DRUG

Allopurinol

Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol

Intervention Type: DRUG

Placebo for Verinurad

Matching Capsule

Intervention Type: DRUG

Placebo for Allopurinol

Matching tablet

Intervention Type: DRUG

Other Intervention Names

Placebo; Placebo

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Research Site

Huntsville, Alabama, United States

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Bakersfield, California, United States

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Canyon Country, California, United States

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Laguna Hills, California, United States

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Long Beach, California, United States

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Northridge, California, United States

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Orange, California, United States

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Thousand Oaks, California, United States

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Vacaville, California, United States

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Victorville, California, United States

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Denver, Colorado, United States

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Bloomfield, Connecticut, United States

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Washington D.C., District of Columbia, United States

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Altamonte Springs, Florida, United States

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Hialeah, Florida, United States

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Jacksonville, Florida, United States

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Lauderdale Lakes, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami, Florida, United States

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Miami Lakes, Florida, United States

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Ocala, Florida, United States

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Ocoee, Florida, United States

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Pembroke Pines, Florida, United States

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Port Charlotte, Florida, United States

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Lawrenceville, Georgia, United States

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Wauconda, Illinois, United States

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Paducah, Kentucky, United States

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Takoma Park, Maryland, United States

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Flint, Michigan, United States

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Flint, Michigan, United States

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Saint Clair Shores, Michigan, United States

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Minneapolis, Minnesota, United States

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Jamaica, New York, United States

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The Bronx, New York, United States

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Asheville, North Carolina, United States

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Asheville, North Carolina, United States

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Rocky Mount, North Carolina, United States

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Wilmington, North Carolina, United States

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Winston-Salem, North Carolina, United States

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Philadelphia, Pennsylvania, United States

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Orangeburg, South Carolina, United States

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Knoxville, Tennessee, United States

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Arlington, Texas, United States

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El Paso, Texas, United States

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Houston, Texas, United States

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Lampasas, Texas, United States

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Lewisville, Texas, United States

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Pearland, Texas, United States

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San Antonio, Texas, United States

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San Antonio, Texas, United States

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San Antonio, Texas, United States

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Alexandria, Virginia, United States

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Milwaukee, Wisconsin, United States

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Frýdek-Místek, , Czechia

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Prague, , Czechia

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Prague, , Czechia

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Slaný, , Czechia

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Třebíč, , Czechia

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Annonay, , France

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Grenoble, , France

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Marseille, , France

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Paris, , France

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Paris, , France

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Rouen, , France

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Tours, , France

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Baja, , Hungary

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Balatonfüred, , Hungary

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Budapest, , Hungary

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Budapest, , Hungary

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Debrecen, , Hungary

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Debrecen, , Hungary

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Hatvan, , Hungary

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Kaposvár, , Hungary

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Nyíregyháza, , Hungary

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Nyíregyháza, , Hungary

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Szeged, , Hungary

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Zalaegerszeg, , Hungary

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Afula, , Israel

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Ashdod, , Israel

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Ashkelon, , Israel

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Beersheba, , Israel

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Haifa, , Israel

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Haifa, , Israel

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Haifa, , Israel

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Holon, , Israel

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Kfar Saba, , Israel

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Nahariya, , Israel

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Nazareth, , Israel

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Petah Tikva, , Israel

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Ramat Gan, , Israel

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Rehovot, , Israel

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Safed, , Israel

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Tel Aviv, , Israel

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Tiberias, , Israel

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Genova, , Italy

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Milan, , Italy

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Parma, , Italy

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Pavia, , Italy

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Verona, , Italy

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Ciudad Madero, , Mexico

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Estado de México, , Mexico

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Guadalajara, , Mexico

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México, , Mexico

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México, , Mexico

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Tijuana, , Mexico

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Veracruz, , Mexico

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Krakow, , Poland

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Lodz, , Poland

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Lublin, , Poland

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Poznan, , Poland

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Rzeszów, , Poland

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Warsaw, , Poland

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Wroclaw, , Poland

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Bucharest, , Romania

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Bucharest, , Romania

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Bucharest, , Romania

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Bucharest, , Romania

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Deva, , Romania

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Ploieşti, , Romania

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Satu Mare, , Romania

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Timișoara, , Romania

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Bardejov, , Slovakia

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Bratislava, , Slovakia

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Hlohovec, , Slovakia

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Košice, , Slovakia

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Kráľovský Chlmec, , Slovakia

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Lučenec, , Slovakia

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Púchov, , Slovakia

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Rimavská Sobota, , Slovakia

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Svidník, , Slovakia

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Benoni, , South Africa

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Cape Town, , South Africa

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Cape Town, , South Africa

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Cape Town, , South Africa

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Cape Town, , South Africa

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Durban, , South Africa

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Durban, , South Africa

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George, , South Africa

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Johannesburg, , South Africa

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Johannesburg, , South Africa

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Krugersdorp, , South Africa

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KwaDukuza, , South Africa

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Lenasia, , South Africa

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Paarl, , South Africa

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Pretoria, , South Africa

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Worcester, , South Africa

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Alicante, , Spain

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Alicante, , Spain

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Barcelona, , Spain

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Barcelona, , Spain

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Barcelona, , Spain

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Barcelona, , Spain

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Ciudad Real, , Spain

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Córdoba, , Spain

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Girona, , Spain

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Granada, , Spain

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L'Hospitalet de Llobregat, , Spain

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Málaga, , Spain

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Palma de Mallorca, , Spain

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Port de Sagunt, , Spain

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Santander, , Spain

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Seville, , Spain

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Valencia, , Spain

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Valencia, , Spain

Countries

United States; Czechia; France; Hungary; Israel; Italy; Mexico; Poland; Romania; Slovakia; South Africa; Spain

References

Heerspink HJL, Stack AG, Terkeltaub R, Jongs N, Inker LA, Bjursell M, Maklad N, Perl S, Eklund O, Rikte T, Sjostrom CD, Perkovic V; SAPPHIRE Investigators. Combination Treatment with Verinurad and Allopurinol in CKD: A Randomized Placebo and Active Controlled Trial. J Am Soc Nephrol. 2024 May 1;35(5):594-606. doi: 10.1681/ASN.0000000000000326. Epub 2024 Feb 20.

Reference Type: DERIVED

PMID: 38564654 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34383954 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://filehosting-v2.pharmacm.com/api/Attachment/Download?tenantId=80217111&parentIdentifier=D5495C00002&attachmentIdentifier=40101669-5639-49e4-88e0-31ed4e294c1d&fileName=d5495c00002StudySynopsisRedacted.pdf&versionIdentifier=

CSR

Other Identifiers

D5495C00002

Identifier Type: -

Identifier Source: org_study_id