Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.
Curr Opin Nephrol Hypertens. 2020 Nov;29(6):581-590. doi: 10.1097/MNH.0000000000000647.
There is a paucity of therapies for chronic kidney disease (CKD), in part because of the slow nature of the disease which poses challenges in selection of endpoints in randomized controlled trials (RCT). There is increasing evidence for the use of glomerular filtration rate (GFR)-based endpoints either as percentage decline using time-to-event analyses, or as difference in slope between treatment arms. We reviewed the rationale for using surrogate endpoints and optimal methods for their evaluation prior to their use and evidence for GFR-based endpoints and particularly GFR slope as validated surrogate endpoints and considerations for their use in RCTs.
In an individual patient meta-analysis of 47 studies (60 620 participants), treatment effects on the clinical endpoint were accurately predicted from treatment effects on 3-year total slope [median R = 0.97 (95% Bayesian confidence interval (BCI), 0.78-1.00] and on the chronic slope [R = 0.96 (95% BCI, 0.63-1.00)]. In a simulation study, GFR slope substantially reduced the required sample size and duration of follow-up compared to the clinical endpoint given high baseline GFR and absence of acute treatment effect. In the presence of acute effect, results were more complicated.
GFR decline is accepted, and GFR slope is being considered, by regulatory authorities as a validated surrogate endpoint for CKD RCTs.
慢性肾脏病（CKD）的治疗方法有限，部分原因是该病进展缓慢，这给随机对照试验（RCT）的终点选择带来了挑战。越来越多的证据表明，使用肾小球滤过率（GFR）为基础的终点，无论是使用时间事件分析的百分比下降，还是治疗组之间斜率的差异，都具有合理性。我们综述了在使用替代终点之前评估其合理性和最佳方法的理由，以及 GFR 为基础的终点，特别是 GFR 斜率作为验证替代终点的证据，以及在 RCT 中使用它们的考虑因素。
在 47 项研究（60620 名参与者）的个体患者荟萃分析中，治疗对临床终点的影响可以从治疗对 3 年总斜率（中位数 R = 0.97（95%贝叶斯置信区间（BCI），0.78-1.00）和慢性斜率（R = 0.96（95%BCI，0.63-1.00））的影响中准确预测。在一项模拟研究中，与临床终点相比，GFR 斜率大大减少了所需的样本量和随访时间，前提是基线 GFR 较高且无急性治疗效果。在存在急性效应的情况下，结果更为复杂。
监管机构接受 GFR 下降，并将 GFR 斜率视为 CKD RCT 的验证替代终点。
