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

Chronic Kidney Disease Clinical Trial

— SAPPHIRE  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03990363
• Other study ID #: D5495C00002
• Status: Completed
• Phase: Phase 2
• Start date: July 23, 2019
• Est. completion date: November 22, 2021

Study information

• Verified date: January 2023
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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, 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 861
• Est. completion date: November 22, 2021
• Est. primary completion date: November 22, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

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

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Hyperuricemia
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• 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
• Allopurinol
Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol
• Placebo for Verinurad
Matching Capsule
• Placebo for Allopurinol
Matching tablet

Locations

Country	Name	City	State
Czechia	Research Site	Frydek
Czechia	Research Site	Praha 2
Czechia	Research Site	Praha 6
Czechia	Research Site	Slany
Czechia	Research Site	Trebíc
France	Research Site	Annonay
France	Research Site	Grenoble cedex 9
France	Research Site	Marseille cedex 5
France	Research Site	Paris
France	Research Site	Paris
France	Research Site	Rouen
France	Research Site	Tours
Hungary	Research Site	Baja
Hungary	Research Site	Balatonfured
Hungary	Research Site	Budapest
Hungary	Research Site	Budapest
Hungary	Research Site	Debrecen
Hungary	Research Site	Debrecen
Hungary	Research Site	Hatvan
Hungary	Research Site	Kaposvár
Hungary	Research Site	Nyíregyháza
Hungary	Research Site	Nyíregyháza
Hungary	Research Site	Szeged
Hungary	Research Site	Zalaegerszeg
Israel	Research Site	Afula
Israel	Research Site	Ashdod
Israel	Research Site	Ashkelon
Israel	Research Site	Beer Sheba
Israel	Research Site	Haifa
Israel	Research Site	Haifa
Israel	Research Site	Haifa
Israel	Research Site	Holon
Israel	Research Site	Kfar Sava
Israel	Research Site	Nahariya
Israel	Research Site	Nazareth
Israel	Research Site	Petach-Tikva
Israel	Research Site	Ramat Gan
Israel	Research Site	Rehovot
Israel	Research Site	Safed
Israel	Research Site	Tel-Aviv
Israel	Research Site	Tiberias
Italy	Research Site	Genova
Italy	Research Site	Milano
Italy	Research Site	Parma
Italy	Research Site	Pavia
Italy	Research Site	Verona
Mexico	Research Site	Ciudad Madero
Mexico	Research Site	Estado de Mexico
Mexico	Research Site	Guadalajara
Mexico	Research Site	Mexico
Mexico	Research Site	Mexico
Mexico	Research Site	Tijuana
Mexico	Research Site	Veracruz
Poland	Research Site	Krakow
Poland	Research Site	Lodz
Poland	Research Site	Lublin
Poland	Research Site	Poznan
Poland	Research Site	Rzeszów
Poland	Research Site	Warszawa
Poland	Research Site	Wroclaw
Romania	Research Site	Bucuresti
Romania	Research Site	Bucuresti
Romania	Research Site	Bucuresti
Romania	Research Site	Bucuresti
Romania	Research Site	Deva
Romania	Research Site	Ploiesti
Romania	Research Site	Satu Mare
Romania	Research Site	Timi?oara
Slovakia	Research Site	Bardejov
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Hlohovec
Slovakia	Research Site	Kosice
Slovakia	Research Site	Kralovsky Chlmec
Slovakia	Research Site	Lucenec
Slovakia	Research Site	Puchov
Slovakia	Research Site	Rimavska Sobota
Slovakia	Research Site	Svidnik
South Africa	Research Site	Benoni
South Africa	Research Site	Cape Town
South Africa	Research Site	Cape Town
South Africa	Research Site	Cape Town
South Africa	Research Site	Cape Town
South Africa	Research Site	Durban
South Africa	Research Site	Durban
South Africa	Research Site	George
South Africa	Research Site	Johannesburg
South Africa	Research Site	Johannesburg
South Africa	Research Site	Krugersdorp
South Africa	Research Site	Lenasia
South Africa	Research Site	Paarl
South Africa	Research Site	Stanger
South Africa	Research Site	Tshwane
South Africa	Research Site	Worcester
Spain	Research Site	Alicante
Spain	Research Site	Alicante
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Ciudad Real
Spain	Research Site	Cordoba
Spain	Research Site	Girona
Spain	Research Site	Granada
Spain	Research Site	L'Hospitalet De Llobregat
Spain	Research Site	Málaga
Spain	Research Site	Palma de Mallorca
Spain	Research Site	Puerto De Sagunto
Spain	Research Site	Santander
Spain	Research Site	Sevilla
Spain	Research Site	Valencia
Spain	Research Site	Valencia
United States	Research Site	Alexandria	Virginia
United States	Research Site	Altamonte Springs	Florida
United States	Research Site	Arlington	Texas
United States	Research Site	Asheville	North Carolina
United States	Research Site	Asheville	North Carolina
United States	Research Site	Bakersfield	California
United States	Research Site	Bloomfield	Connecticut
United States	Research Site	Bronx	New York
United States	Research Site	Canyon Country	California
United States	Research Site	Denver	Colorado
United States	Research Site	El Paso	Texas
United States	Research Site	Flint	Michigan
United States	Research Site	Flint	Michigan
United States	Research Site	Hialeah	Florida
United States	Research Site	Houston	Texas
United States	Research Site	Huntsville	Alabama
United States	Research Site	Jacksonville	Florida
United States	Research Site	Jamaica	New York
United States	Research Site	Knoxville	Tennessee
United States	Research Site	Laguna Hills	California
United States	Research Site	Lampasas	Texas
United States	Research Site	Lauderdale Lakes	Florida
United States	Research Site	Lawrenceville	Georgia
United States	Research Site	Lewisville	Texas
United States	Research Site	Long Beach	California
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami Lakes	Florida
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Minneapolis	Minnesota
United States	Research Site	Northridge	California
United States	Research Site	Ocala	Florida
United States	Research Site	Ocoee	Florida
United States	Research Site	Orange	California
United States	Research Site	Orangeburg	South Carolina
United States	Research Site	Paducah	Kentucky
United States	Research Site	Pearland	Texas
United States	Research Site	Pembroke Pines	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Port Charlotte	Florida
United States	Research Site	Rocky Mount	North Carolina
United States	Research Site	Saint Clair Shores	Michigan
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	Takoma Park	Maryland
United States	Research Site	Thousand Oaks	California
United States	Research Site	Vacaville	California
United States	Research Site	Victorville	California
United States	Research Site	Washington	District of Columbia
United States	Research Site	Wauconda	Illinois
United States	Research Site	Wilmington	North Carolina
United States	Research Site	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

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