t compared with allopurinol alone or placebo.Verinurad/allopurinol combination dose-dependently reduced serum urate concentrations compared with placebo. Background 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. Methods 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 m2, 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. Results 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 m2, 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. Conclusions Verinurad in combination with allopurinol did not decrease UACR or eGFR decline, but further reduced serum urate compared with allopurinol alone or placebo. Clinical Trial registry name and registration number: SAPPHIRE Trial registration number, NCT03990363....

中文翻译：

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Verinurad 和别嘌呤醇联合治疗 CKD：随机安慰剂和主动对照试验

与单独的别嘌呤醇或安慰剂相比。与安慰剂相比，Verinurad/别嘌呤醇组合剂量依赖性地降低血清尿酸盐浓度。背景 高尿酸血症与心血管和慢性肾病（CKD）风险升高相关。由于抑制尿酸转运蛋白 1 被认为具有潜在的肾保护作用，因此我们进行了一项 2b 期研究，以评估尿酸转运蛋白 1 抑制剂 verinurad 联合黄嘌呤氧化酶抑制剂别嘌呤醇对 CKD 和高尿酸血症患者降低白蛋白尿的作用。方法 在这项随机安慰剂和主动对照试验中，我们招募了血清尿酸浓度≥6.0 mg/dl、eGFR ≥25 ml/min/1.73 m2、尿白蛋白肌酐比值 (UACR) 30-5000 mg/g 的参与者。五个治疗组之一：安慰剂、安慰剂+别嘌呤醇 300 毫克/天、verinurad 3 毫克+别嘌呤醇 300 毫克/天、verinurad 7.5 毫克+别嘌呤醇 300 毫克/天，或 verinurad 12 毫克+别嘌呤醇 300 毫克/天，剂量为 1： 1:1:1:1 比例。主要终点是 UACR 从基线到 34 周的变化。次要终点是第 60 周时 UACR 相对于基线的变化以及第 34 周和第 60 周时血清尿酸盐和 eGFR 的变化。 结果 2019 年 8 月至 2021 年 11 月期间，861 名 CKD 成人（平均年龄 65 岁，33.0% 女性，平均 eGFR 48） ml/min 每 1.73 m2，中位 UACR 217 mg/g）被纳入。 34周时，UACR相对于基线的几何平均百分比变化在治疗组之间没有差异（3 mg组为16.7%，95%置信区间[CI]，-0.6至37.1，15.0%[95% CI，-1.85] 7.5 mg 组为 14.0% [95% CI, -3.4 至 34.4]，12 mg 组为 9.9% [95% CI, -6.6 至 29.4]，别嘌呤醇组为 37.3% [95%] CI，16.6 至 61.8]（安慰剂组）。 60 周后，治疗组之间 UACR 和 eGFR 相对于基线的变化没有差异。与安慰剂相比，Verinurad/别嘌呤醇组合剂量依赖性地降低血清尿酸盐浓度。治疗组之间发生不良事件和严重不良事件的患者比例是平衡的。结论 与单独使用别嘌呤醇或安慰剂相比，Verinurad 联合别嘌呤醇并未降低 UACR 或 eGFR 下降，但进一步降低血清尿酸。临床试验注册名称和注册号：SAPPHIRE 试验注册号，NCT03990363....