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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03990363
Other study ID # D5495C00002
Secondary ID
Status Completed
Phase Phase 2
First received
Last updated
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
Health authority
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. ยท 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

Study Design


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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