Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
The George Institute for Global Health, Sydney, New South Wales, Australia.
J Am Soc Nephrol. 2024 May 1;35(5):594-606. doi: 10.1681/ASN.0000000000000326. Epub 2024 Feb 20.
The SAPPHIRE trial was designed to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with allopurinol in patients with CKD. Verinurad 3, 7.5, and 12 mg in combination with allopurinol 300 mg did not reduce albuminuria during 34 weeks treatment compared with allopurinol alone or placebo. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo.
Hyperuricemia is associated with elevated risks of cardiovascular and chronic kidney disease (CKD). Since inhibition of urate transporter 1 has been suggested to be potentially nephroprotective, we performed a phase 2b study to assess albuminuria-lowering effects of the urate transporter 1 inhibitor verinurad combined with the xanthine oxidase inhibitor allopurinol in patients with CKD and hyperuricemia.
In this randomized placebo and active controlled trial, we enrolled participants with serum urate concentrations ≥6.0 mg/dl, eGFR ≥25 ml/min per 1.73 m, and a urinary albumin-creatinine ratio (UACR) 30–5000 mg/g to one of five treatment arms: placebo, placebo+allopurinol 300 mg/day, verinurad 3 mg+allopurinol 300 mg/day, verinurad 7.5 mg+allopurinol 300 mg/day, or verinurad 12 mg+allopurinol 300 mg/day in a 1:1:1:1:1 ratio. The primary end point was the change in UACR from baseline to 34 weeks. Secondary end points were changes from baseline in UACR at week 60 and changes in serum urate and eGFR at weeks 34 and 60.
Between August 2019 and November 2021, 861 adults with CKD (mean age 65 years, 33.0% female, mean eGFR 48 ml/min per 1.73 m, median UACR 217 mg/g) were enrolled. At 34 weeks, the geometric mean percentage change in UACR from baseline did not differ among treatment groups (16.7%, 95% confidence interval [CI], −0.6 to 37.1 in the 3 mg group, 15.0% [95% CI, −1.85 to 34.6] in the 7.5 mg group, 14.0% [95% CI, −3.4 to 34.4] in the 12 mg group versus 9.9% [95% CI, −6.6 to 29.4] in the allopurinol group, and 37.3% [95% CI, 16.6 to 61.8] in the placebo group). UACR and eGFR change from baseline did not differ among treatment groups after 60 weeks. Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. The proportion of patients with adverse events and serious adverse events was balanced among treatment groups.
Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo.
: SAPPHIRE Trial registration number, NCT03990363.
SAPPHIRE 试验旨在评估尿酸转运蛋白 1 抑制剂 verinurad 与别嘌醇联合用于 CKD 患者降低蛋白尿的效果。与别嘌醇单药或安慰剂相比，verinurad 3、7.5 和 12 mg 联合别嘌醇 300 mg 治疗 34 周并未降低蛋白尿。与安慰剂相比，verinurad/别嘌醇联合治疗剂量依赖性地降低了血清尿酸浓度。
高尿酸血症与心血管和慢性肾脏病（CKD）风险升高相关。由于抑制尿酸转运蛋白 1 可能具有肾脏保护作用，我们进行了一项 2b 期研究，以评估尿酸转运蛋白 1 抑制剂 verinurad 与黄嘌呤氧化酶抑制剂别嘌醇联合用于 CKD 和高尿酸血症患者降低蛋白尿的效果。
在这项随机安慰剂和活性对照试验中，我们招募了血清尿酸浓度≥6.0 mg/dl、eGFR≥25 ml/min/1.73 m 和尿白蛋白/肌酐比值（UACR）30-5000 mg/g 的参与者，分为五组治疗之一：安慰剂、安慰剂+别嘌醇 300 mg/天、verinurad 3 mg+别嘌醇 300 mg/天、verinurad 7.5 mg+别嘌醇 300 mg/天或 verinurad 12 mg+别嘌醇 300 mg/天，比例为 1:1:1:1:1。主要终点是从基线到 34 周时 UACR 的变化。次要终点是第 60 周时 UACR 的变化以及第 34 周和第 60 周时血清尿酸和 eGFR 的变化。
2019 年 8 月至 2021 年 11 月，共纳入 861 名 CKD 成年人（平均年龄 65 岁，33.0%为女性，平均 eGFR 48 ml/min/1.73 m，中位数 UACR 217 mg/g）。34 周时，与治疗组相比，UACR 从基线的几何均数百分比变化无差异（3 mg 组为 16.7%[95%CI，-0.6 至 37.1]，7.5 mg 组为 15.0%[95%CI，-1.85 至 34.6]，12 mg 组为 14.0%[95%CI，-3.4 至 34.4]，别嘌醇组为 9.9%[95%CI，-6.6 至 29.4]，安慰剂组为 37.3%[95%CI，16.6 至 61.8]）。60 周后，与治疗组相比，UACR 和 eGFR 从基线的变化无差异。与安慰剂相比，verinurad/别嘌醇联合治疗剂量依赖性地降低了血清尿酸浓度。各组之间不良事件和严重不良事件的比例平衡。
与别嘌醇单药或安慰剂相比，verinurad 联合别嘌醇并未降低 UACR 或 eGFR 下降，但与别嘌醇单药或安慰剂相比，进一步降低了血清尿酸。
SAPPHIRE 试验注册号，NCT03990363。
