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Trial record 2 of 2 for:    SAPPHIRE | Asheville, North Carolina, U.S.

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

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ClinicalTrials.gov Identifier: NCT03990363
Recruitment Status : Recruiting
First Posted : June 19, 2019
Last Update Posted : September 26, 2019
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, an inflammatory arthritis caused by deposition of monosodium urate crystals in joints. Gout occurs in patients with serum urate >6.8 mg/dL, which is the solubility limit of monosodium urate. The prevalence of gout increases with higher serum urate. However, the causal relationship between hyperuricaemia / gout and the aforementioned diseases and outcomes remains to be proven.

Verinurad is a novel uric acid transporter 1 (URAT1) inhibitor in Phase 2 development to increase uric acid (UA) excretion and thereby lower sUA levels. Verinurad combined with the xanthine oxidase inhibitor (XOI) febuxostat has been shown to lower UACR in patients with diabetes and albuminuria, and to lower serum uric acid (sUA) by >80% in patients with recurrent gout in Phase 2 studies.

UACR is a measurement of albuminuria, it was chosen because changes in UACR can be detected early in response to treatment, and these changes, if substantial, correlate with progression of CKD, deterioration in estimated glomerular filtration rate (eGFR), and hard outcomes.Therefore, change in UACR is regarded as an appropriate endpoint.

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.

Additional secondary endpoints include changes from baseline in sUA, eGFR, cystatin C, creatinine and N-terminal natriuretic peptide (NT-proBNP). 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.

This study will assess the effects of treatment with verinurad and allopurinol, allopurinol alone, and placebo on UACR at 6 months.

The study will recruit patients with Chronic Kidney Disease and Hyperuricaemia.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 725 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 : July 27, 2020
Estimated Study Completion Date : September 13, 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.

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.

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
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.

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 ]
    urinary albumin to creatinine ratio (UACR).


Secondary Outcome Measures :
  1. Estimated glomerular filtration rate (eGFR) [ Time Frame: At 6 months, at 12 months, and through study completion, an average of 2 years. ]
    Change from baseline in estimated glomerular filtration rate

  2. Serum cystatin C [ Time Frame: At 6 months, at 12 months and through study completion, an average of 2 years. ]
    Change from baseline in cystatin-C.

  3. Serum creatinine [ Time Frame: At 6 months, at 12 months and through study completion, an average of 2 years. ]
    Change from baseline in creatinine.



Information from the National Library of Medicine

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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
  • Male or female adult Patient ≥18 years of age
  • CKD as defined in the Kidney Disease: Improving Global Outcomes guidelines
  • Patients should receive background standard of care treatment for albuminuria and/or Type 2 Diabetes Mellitus (T2DM) and be treated according to locally recognised guidelines. Therapy should have been optimised and stable for ≥4 weeks before study entry and include an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB), unless contraindicated, not tolerated, or in the opinion of the investigator not practically available or suitable.
  • If treated with a sodium-glucose transport protein (SGLT2) inhibitor, the SGLT2 inhibitor dose must have been stable 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 (CKD-EPI formula)
  • Mean UACR between 30 mg/g and 5000 mg/g inclusive.
  • Negative pregnancy test at investigation site for female patients of childbearing potential.
  • Female patients must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception for the study duration 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
  • 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
  • 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


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

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Sponsors and Collaborators
AstraZeneca

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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03990363     History of Changes
Other Study ID Numbers: D5495C00002
First Posted: June 19, 2019    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Individual participant data (IPD) will likely not be shared with external collaborators/researchers as this data is planned to be used only for internal decision-making

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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