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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03990363
Recruitment Status : Active, not recruiting
First Posted : June 19, 2019
Last Update Posted : August 6, 2021
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Chronic Kidney Disease Drug: Verinurad Drug: Allopurinol Drug: Placebo for Verinurad Drug: Placebo for Allopurinol Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 861 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients With Chronic KIdney Disease and Hyperuricaemia
Actual Study Start Date : July 23, 2019
Estimated Primary Completion Date : November 22, 2021
Estimated Study Completion Date : November 22, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: High Dose
High Dose (mg) (verinurad/allopurinol) Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 12/300
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


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

Experimental: 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
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


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

Experimental: 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.
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


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

Experimental: Allopurinol alone (0/300 mg)
Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose_0/300
Drug: Allopurinol
Study treatments will be titrated in 3 steps: Low dose (100 mg), intermediate (200 mg) and High Dose ( 300 mg) Allopurinol

Placebo Comparator: Placebo (0/0 mg)
Placebo (mg) in 3 steps_0/0
Drug: Placebo for Verinurad
Matching Capsule
Other Name: Placebo

Drug: Placebo for Allopurinol
Matching tablet
Other Name: Placebo




Primary Outcome Measures :
  1. Ratio of urinary albumin to urinary creatinine [ Time Frame: At 6 months ]
    Change from baseline in urinary albumin to creatinine ratio (UACR).


Secondary Outcome Measures :
  1. Estimated glomerular filtration rate (eGFR) [ Time Frame: At 6 months, 12 months. ]
    Change from baseline in estimated glomerular filtration rate

  2. Serum cystatin C [ Time Frame: At 6 months, 12 months. ]
    Change from baseline in cystatin-C.

  3. Serum creatinine [ Time Frame: At 6 months, 12 months. ]
    Change from baseline in creatinine.

  4. Ratio of urinary albumin to urinary creatinine [ Time Frame: At 6 months, 12 months. ]
    Change from baseline in urinary albumin to urinary creatinine ratio (UACR).

  5. Serum uric acid [ Time Frame: At 6 months, 12 months. ]
    Change from baseline in Serum uric acid (sUA)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03990363


Locations
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Sponsors and Collaborators
AstraZeneca
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03990363    
Other Study ID Numbers: D5495C00002
First Posted: June 19, 2019    Key Record Dates
Last Update Posted: August 6, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria:

When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool.

Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access.

For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Chronic Kidney Disease
Additional relevant MeSH terms:
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Kidney Diseases
Renal Insufficiency, Chronic
Hyperuricemia
Urologic Diseases
Renal Insufficiency
Pathologic Processes
Allopurinol
Verinurad
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Physiological Effects of Drugs