.A larger trial with longer-term follow-up would more precisely assess the relative benefits and risks of selonsertib in this setting. Background Selonsertib is an apoptosis signal–regulating kinase 1 inhibitor that reduces inflammation, fibrosis, and apoptosis. The MOSAIC study evaluated whether selonsertib attenuated kidney function decline in patients with diabetic kidney disease. Methods We conducted a phase 2b study in adults with type 2 diabetes and eGFR 20 to <60 ml/min per 1.73 m2 with urine albumin-creatinine ratio 150–5000 mg/g on maximum tolerated dose of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. To account for an acute selonsertib-related decrease in serum creatinine–based eGFR (eGFRcr), patients entered a 4-week selonsertib run-in period to establish treatment-specific baseline eGFRcr. Patients were randomized 1:1 to selonsertib 18 mg or matching placebo once daily. We followed all participants up until the last randomized participant completed 48 weeks of follow-up. The primary efficacy outcome was the difference in eGFRcr slopes from treatment-specific baselines to week 84, evaluated at a prespecified two-sided P = 0.30. We also evaluated kidney clinical events (eGFRcr ≥40% decline from pre–run-in baseline, kidney failure, or death due to kidney disease) and adverse events. Results In total, 310 patients were randomized (selonsertib n=154, placebo n=156; 68% male, mean age 65 years, mean baseline eGFRcr 35 ml/min per 1.73 m2). Mean difference between selonsertib and placebo eGFRcr slopes at week 84 was 1.20 ml/min per 1.73 m2 per year (95% confidence interval, −0.41 to 2.81; P = 0.14). Kidney clinical events occurred in 17% (26/154) of patients randomized to selonsertib and 12% (19/156) of those randomized to placebo (difference 4.7%; 95% confidence interval, −6.3% to 15.9%). The most common investigator-reported adverse event was AKI (selonsertib 11.0/100 and placebo 5.9/100 patient-years). Conclusions Selonsertib attenuated the decline in eGFRcr over up to 84 weeks; however, it resulted in a numerically higher number of patients reaching a kidney clinical event and a numerically higher rate of investigator-reported AKI. Clinical Trial registry name and registration number: Study to Evaluate the Efficacy and Safety of Selonsertib in Participants With Moderate to Advanced Diabetic Kidney Disease (MOSAIC), NCT04026165....

中文翻译：

---

糖尿病肾病患者的 Selonsertib：一项 2b 期随机主动磨合临床试验


.在这种情况下，一项具有长期随访的更大规模试验将更准确地评估 selonsertib 的相对益处和风险。背景 Selonsertib 是一种细胞凋亡信号调节激酶 1 抑制剂，可减少炎症、纤维化和细胞凋亡。MOSAIC 研究评估了 selonsertib 是否减轻了糖尿病肾病患者的肾功能下降。方法 我们在 2 型糖尿病成人中进行了一项 2b 期研究，eGFR 为 20 至 <60 ml/min/1.73 m2，尿白蛋白-肌酐比值为 150-5000 mg/g血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂的最大耐受剂量。为了解释血清肌酐基 eGFR （eGFRcr） 的急性 selonsertib 相关降低，患者进入了为期 4 周的 selonsertib 磨合期，以建立治疗特异性基线 eGFRcr。患者以 1：1 的比例随机分配至 selonsertib 18 mg 或匹配的安慰剂组，每日一次。我们跟踪了所有参与者，直到最后一名随机受试者完成 48 周的随访。主要疗效结果是 eGFRcr 斜率从治疗特异性基线到第 84 周的差异，在预先指定的双侧 P = 0.30 下评估。我们还评估了肾脏临床事件 （eGFRcr ≥ 较磨合前基线下降 40%、肾衰竭或因肾脏疾病死亡）和不良事件。结果 总共有 310 名患者被随机分组 （selonsertib n=154，安慰剂 n=156;68% 为男性，平均年龄 65 岁，平均基线 eGFRcr 为 35 ml/min/1.73 m2）。第 84 周时 selonsertib 和安慰剂 eGFRcr 斜率的平均差为每年每 1.73 m2 1.20 ml/min（95% 置信区间，-0.41 至 2.81;P = 0.14）。 17% （26/154） 随机分配至 selonsertib 的患者和 12% （19/156） 随机分配至安慰剂组的患者发生肾脏临床事件 （差异 4.7%;95% 置信区间，-6.3% 至 15.9%）。研究者报告的最常见不良事件是 AKI （selonsertib 11.0/100 和安慰剂 5.9/100 患者年）。结论 Selonsertib 在长达 84 周内减轻了 eGFRcr 的下降;然而，它导致发生肾脏临床事件的患者数量增加，研究者报告的 AKI 发生率在数量上更高。临床试验注册名称和注册号：评估 Selonsertib 在中度至晚期糖尿病肾病 （MOSAIC） 参与者中的疗效和安全性的研究 NCT04026165....