Chronic Kidney DiseasePhase 2SAPPHIRENCT03990363
A Study of Verinurad and Allopurinol in Patients With Chronic Kidney Disease and Hyperuricaemia
A Phase 2 study testing Verinurad and Allopurinol in people with Chronic Kidney Disease, run by AstraZeneca at 165 sites in 12 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 130 years
- Conditions the study is for
- Chronic Kidney Disease
- What is being tested?
- Verinurad and Allopurinol
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 861 participants
- Where
- 165 sitesin 12 countries
- Study dates
- 23 Jul 2019to 22 Nov 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 130 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
165 sites in 12 countries.
165 sites in 12 countries
United States54 sites
Research Site
Alexandria, Virginia, 22304
Research Site
Altamonte Springs, Florida, 32701
Research Site
Arlington, Texas, 76015
Research Site
Asheville, North Carolina, 28801
Research Site
Asheville, North Carolina, 28803
Research Site
Bakersfield, California, 93309
Research Site
Bloomfield, Connecticut, 06002
Research Site
Canyon Country, California, 91351
Research Site
Denver, Colorado, 80230
Research Site
El Paso, Texas, 79935
Research Site
Flint, Michigan, 48504
Research Site
Flint, Michigan, 48532
Research Site
Hialeah, Florida, 33012
Research Site
Houston, Texas, 77004
Research Site
Huntsville, Alabama, 35805
Research Site
Jacksonville, Florida, 32204
Research Site
Jamaica, New York, 11432
Research Site
Knoxville, Tennessee, 37923
Research Site
Laguna Hills, California, 92653
Research Site
Lampasas, Texas, 76550
Research Site
Lauderdale Lakes, Florida, 33313
Research Site
Lawrenceville, Georgia, 30046
Research Site
Lewisville, Texas, 75057
Research Site
Long Beach, California, 90807
Research Site
Miami, Florida, 33015
Research Site
Miami, Florida, 33126-2956
Research Site
Miami, Florida, 33165
Research Site
Miami Lakes, Florida, 33014
Research Site
Milwaukee, Wisconsin, 53226
Research Site
Minneapolis, Minnesota, 55404
Research Site
Northridge, California, 91324
Research Site
Ocala, Florida, 34471
Research Site
Ocoee, Florida, 34761
Research Site
Orange, California, 92868
Research Site
Orangeburg, South Carolina, 29118
Research Site
Paducah, Kentucky, 42003
Research Site
Pearland, Texas, 77584
Research Site
Pembroke Pines, Florida, 33026
Research Site
Philadelphia, Pennsylvania, 19107
Research Site
Port Charlotte, Florida, 33952
Research Site
Rocky Mount, North Carolina, 27804
Research Site
Saint Clair Shores, Michigan, 48081
Research Site
San Antonio, Texas, 78212
Research Site
San Antonio, Texas, 78231
Research Site
San Antonio, Texas, 78258
Research Site
Takoma Park, Maryland, 20912
Research Site
The Bronx, New York, 10461
Research Site
Thousand Oaks, California, 91360
Research Site
Vacaville, California, 95687
Research Site
Victorville, California, 92395
Research Site
Washington D.C., District of Columbia, 20037
Research Site
Wauconda, Illinois, 60084
Research Site
Wilmington, North Carolina, 28401
Research Site
Winston-Salem, North Carolina, 27103
Spain18 sites
Research Site
Alicante, 03010
Research Site
Alicante, 03550
Research Site
Barcelona, 08003
Research Site
Barcelona, 08023
Research Site
Barcelona, 08035
Research Site
Barcelona, 08036
Research Site
Ciudad Real, 13005
Research Site
Córdoba, 14004
Research Site
Girona, 17007
Research Site
Granada, 18012
Research Site
L'Hospitalet de Llobregat, 08907
Research Site
Málaga, 29011
Research Site
Palma de Mallorca, 7120
Research Site
Port de Sagunt, 46520
Research Site
Santander, 39010
Research Site
Seville, 41071
Research Site
Valencia, 46014
Research Site
Valencia, 46017
Israel17 sites
Research Site
Afula, 1834111
Research Site
Ashdod, 77000
Research Site
Ashkelon, 78278
Research Site
Beersheba, 8410101
Research Site
Haifa, 3109601
Research Site
Haifa, 34362
Research Site
Haifa, 35152
Research Site
Holon, 58100
Research Site
Kfar Saba, 44281
Research Site
Nahariya, 22100
Research Site
Nazareth, 16100
Research Site
Petah Tikva, 49100
Research Site
Ramat Gan, 52621
Research Site
Rehovot, 7642001
Research Site
Safed, 13100
Research Site
Tel Aviv, 61480
Research Site
Tiberias, 15208
South Africa16 sites
Research Site
Benoni, 1501
Research Site
Cape Town, 1730
Research Site
Cape Town, 7505
Research Site
Cape Town, 7570
Research Site
Cape Town, 7925
Research Site
Durban, 4001
Research Site
Durban, 4092
Research Site
George, 6530
Research Site
Johannesburg, 2001
Research Site
Johannesburg, 2132
Research Site
Krugersdorp, 1739
Research Site
KwaDukuza, 4450
Research Site
Lenasia, 1827
Research Site
Paarl, 7647
Research Site
Pretoria, 0084
Research Site
Worcester, 6850
Hungary12 sites
Research Site
Baja, 6500
Research Site
Balatonfüred, 8230
Research Site
Budapest, 1033
Research Site
Budapest, 1036
Research Site
Debrecen, 4025
Research Site
Debrecen, 4032
Research Site
Hatvan, 3000
Research Site
Kaposvár, 7400
Research Site
Nyíregyháza, 4400
Research Site
Nyíregyháza, 4405
Research Site
Szeged, 6725
Research Site
Zalaegerszeg, 8900
Slovakia9 sites
Research Site
Bardejov, 085 01
Research Site
Bratislava, 85101
Research Site
Hlohovec, 920 01
Research Site
Košice
Research Site
Kráľovský Chlmec, 077 01
Research Site
Lučenec, 984 01
Research Site
Púchov, 2001
Research Site
Rimavská Sobota, 979 01
Research Site
Svidník, 08901
Romania8 sites
Research Site
Bucharest, 010192
Research Site
Bucharest, 010825
Research Site
Bucharest, 050538
Research Site
Bucharest, 40172
Research Site
Deva, 330084
Research Site
Ploieşti, 100342
Research Site
Satu Mare, 440055
Research Site
Timișoara, 300456
France7 sites
Research Site
Annonay, 07103
Research Site
Grenoble, 38043
Research Site
Marseille, 13385
Research Site
Paris, 75018
Research Site
Paris, 75970
Research Site
Rouen, 76031
Research Site
Tours, 37000
Mexico7 sites
Research Site
Ciudad Madero, 89440
Research Site
Estado de México, 54800
Research Site
Guadalajara, 44650
Research Site
México, 03100
Research Site
México, 06700
Research Site
Tijuana, 22500
Research Site
Veracruz, 91910
Poland7 sites
Research Site
Krakow, 31-559
Research Site
Lodz, 90-302
Research Site
Lublin, 20-538
Research Site
Poznan, 61-655
Research Site
Rzeszów, 35-055
Research Site
Warsaw, 00-465
Research Site
Wroclaw, 50-127
Czechia5 sites
Research Site
Frýdek-Místek, 738 01
Research Site
Prague, 128 08
Research Site
Prague, 160 00
Research Site
Slaný, 274 01
Research Site
Třebíč, 674 01
Italy5 sites
Research Site
Genova, 16132
Research Site
Milan, 20132
Research Site
Parma, 43126
Research Site
Pavia, 27100
Research Site
Verona, 37124
About this study
Official title: A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients With Chronic KIdney Disease and Hyperuricaemia
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.
Read the 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
- Being tested
- Verinurad, Allopurinol, Placebo for Verinurad, Placebo for Allopurinol
- Keywords
- Chronic Kidney Disease
- Medical subject headings
- Renal Insufficiency, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VerinuradDrug
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
AllopurinolDrug
Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol
Placebo for VerinuradDrug
Also called Placebo
Matching Capsule
Placebo for AllopurinolDrug
Also called Placebo
Matching tablet
| Study group | Role | What they receive |
|---|---|---|
| High Dose | Experimental | High Dose (mg) (verinurad/allopurinol) Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 12/300 Receives: Drug: Verinurad; Drug: Allopurinol |
| Intermediate Dose | Experimental | Intermediate Dose (mg) verinurad/allopurinol Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 7.5/300 Receives: Drug: Verinurad; Drug: Allopurinol |
| Low Dose | Experimental | 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. Receives: Drug: Verinurad; Drug: Allopurinol |
| Allopurinol alone (0/300 mg) | Experimental | Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose_0/300 Receives: Drug: Allopurinol |
| Placebo (0/0 mg) | Placebo comparator | Placebo (mg) in 3 steps_0/0 Receives: Drug: Placebo for Verinurad; Drug: Placebo for Allopurinol |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
Secondary outcomes (9)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Change from baseline to 12 months (Visit 10)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Jun 2019
- Study start23 Jul 2019
- Primary completion22 Nov 2021
- Study completion22 Nov 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Chronic Kidney DiseaseStudies of the same condition, open and under way.
- More trials run by AstraZenecaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 861 participants (actual)
Sponsor and investigators
- Lead sponsor
- AstraZeneca
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03990363
- Sponsor's protocol ID
- D5495C00002
- Acronym
- SAPPHIRE
- Status last verified
- Jan 2023
- First submitted
- 30 May 2019
- Last updated
- 2 Mar 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Publications
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.
PubMed 38564654Heerspink 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.
PubMed 34383954
Study at a glance
From the registry record, last updated by the sponsor on 2 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients With Chronic KIdney Disease and Hyperuricaemia
- ClinicalTrials.gov ID
- NCT03990363
- Acronym / sponsor ID
- SAPPHIRE / D5495C00002
- Conditions
- Chronic Kidney Disease
- Keywords
- Chronic Kidney Disease
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 861 participants (actual)
- Lead sponsor
- AstraZenecaIndustry (pharma, biotech, devices)
- Study start
- 23 Jul 2019 (actual)
- Primary completion
- 22 Nov 2021 (actual)
- Study completion
- 22 Nov 2021 (actual)
- First posted
- 19 Jun 2019 (actual)
- Results
- Posted 2 Mar 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| High Dose | Experimental | Drug: Verinurad, Drug: AllopurinolHigh Dose (mg) (verinurad/allopurinol) Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 12/300 |
| Intermediate Dose | Experimental | Drug: Verinurad, Drug: AllopurinolIntermediate Dose (mg) verinurad/allopurinol Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 7.5/300 |
| Low Dose | Experimental | Drug: Verinurad, Drug: AllopurinolLow 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. |
| Allopurinol alone (0/300 mg) | Experimental | Drug: AllopurinolStep 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose_0/300 |
| Placebo (0/0 mg) | Placebo comparator | Drug: Placebo for Verinurad, Drug: Placebo for AllopurinolPlacebo (mg) in 3 steps_0/0 |
Who may qualify
- Ages
- 18 to 130 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VerinuradStudy 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 | Drug | High Dose, Intermediate Dose, Low Dose |
| AllopurinolStudy treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol | Drug | Allopurinol alone (0/300 mg), High Dose, Intermediate Dose, Low Dose |
| Placebo for VerinuradAlso: PlaceboMatching Capsule | Drug | Placebo (0/0 mg) |
| Placebo for AllopurinolAlso: PlaceboMatching tablet | Drug | Placebo (0/0 mg) |
Primary outcome
Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM)
Time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
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.
9 secondary outcomes
Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: Change from baseline to 12 months (Visit 10)
S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)
Time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)
S-creatinine (mg/dL) Change From Baseline at 12 Months (Visit 10)
Time frame: 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)
Time frame: 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)
Time frame: Change from baseline to 12 months (Visit 10)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Mar 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38564654Heerspink 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.
- Derived from this study: PubMed 34383954Heerspink 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.
- CSRLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
165 sites in 12 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Verinurad and Allopurinol in people with Chronic Kidney Disease, run by AstraZeneca at 165 sites in 12 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 165 sites in United States, Spain, Israel, South Africa, Hungary and 7 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Mar 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM) (time frame: Baseline to 9 months (Visit 9); analysis at 6 months (Visit 8)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03990363, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Mar 2023.