A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled Study of Verinurad and Allopurinol in Patients With Chronic KIdney Disease and Hyperuricaemia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- AstraZeneca
- 入组人数
- 861
- 试验地点
- 1
- 主要终点
- Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM)
研究概览
简要总结
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.
详细描述
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%..
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 130 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
High Dose
High Dose (mg) (verinurad/allopurinol) Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 12/300
干预措施: Verinurad (Drug)
High Dose
High Dose (mg) (verinurad/allopurinol) Step 1 - titration_ 3/100 Step 2 - titration_ 7.5/200 Step 3 - target dose_ 12/300
干预措施: Allopurinol (Drug)
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
干预措施: Verinurad (Drug)
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
干预措施: Allopurinol (Drug)
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.
干预措施: Verinurad (Drug)
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.
干预措施: Allopurinol (Drug)
Allopurinol alone (0/300 mg)
Step 1 - titration_0/100 Step 2 - titration_0/200 Step 3 - target dose_0/300
干预措施: Allopurinol (Drug)
Placebo (0/0 mg)
Placebo (mg) in 3 steps_0/0
干预措施: Placebo for Verinurad (Drug)
Placebo (0/0 mg)
Placebo (mg) in 3 steps_0/0
干预措施: Placebo for Allopurinol (Drug)
结局指标
主要结局
Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 6 Months (Visit 8), Repeated Measures Mixed Model (MMRM)
时间窗: 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.
次要结局
- Serum Uric Acid (sUA) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM)(Baseline to 12 months (Visit 10); analysis at 12 months (Visit 10))
- Urinary Albumin to Creatinine Ratio (uACR) (mg/g) Change From Baseline at 12 Months (Visit 10), Repeated Measures Mixed Model (MMRM)(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)(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 6 Months (V8), Repeated Measures Mixed Model (MMRM)(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 to 12 months (Visit 10))
- S-creatinine (mg/dL) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)(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 to 12 months (Visit 10))
- P-cystatin C (mg/L) Change From Baseline at 6 Months (V8), Repeated Measures Mixed Model (MMRM)(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 to 12 months (Visit 10))