Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation
Performance of GFR Slope as a Surrogate End Point for Kidney Disease Progression in Clinical Trials: A Statistical Simulation
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DOI：
10.1681/asn.2019010009
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发表时间：
2019-09-01
影响因子：
13.6
通讯作者：
Inker, Lesley A.
中科院分区：
文献类型：
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作者：
Greene, Tom;Ying, Jian;Inker, Lesley A.
CKD治疗的随机试验传统上使用CKD进展晚期的临床事件作为终点。这需要昂贵的研究，大样本量和长期随访。替代终点，如GFR斜率可能会加快新疗法的评估，使较小的研究与较短的follow-up.Methods我们使用了统计模拟，以确定试验的情况下，GFR斜率提供了增加的统计权力相比，血清肌酐或肾功能衰竭的临床终点加倍。我们根据47个随机治疗比较的数据模拟GFR轨迹。我们评估了所需的样本量足够的统计功率的基础上GFR斜率计算从基线和3个月follow-up.Results在大多数情况下，治疗没有急性效应，GFR斜率分析提供了类似的或改善的统计功率相比，临床终点，往往允许调查人员缩短随访至少一半，同时减少样本量。当患者的GFR较高时，GFR斜率的幂优势增加。然而，随机化后几个月内的急性治疗效果可能会增加基于GFR斜率的治疗错误结论的风险。在研究设计和分析，以避免这种错误的conclusion.Conclusions护理使用GFR斜率可以大大增加统计功率相比，临床终点，特别是当基线GFR是高的，没有急性效应。基于GFR的最佳终点取决于多种因素，包括GFR下降率、治疗效果类型和研究设计。
Background Randomized trials of CKD treatments traditionally use clinical events late in CKD progression as end points. This requires costly studies with large sample sizes and long follow-up. Surrogate end points like GFR slope may speed up the evaluation of new therapies by enabling smaller studies with shorter follow-up.Methods We used statistical simulations to identify trial situations where GFR slope provides increased statistical power compared with the clinical end point of doubling of serum creatinine or kidney failure. We simulated GFR trajectories based on data from 47 randomized treatment comparisons. We evaluated the sample size required for adequate statistical power based on GFR slopes calculated from baseline and from 3 months follow-up.Results In most scenarios where the treatment has no acute effect, analyses of GFR slope provided similar or improved statistical power compared with the clinical end point, often allowing investigators to shorten follow-up by at least half while simultaneously reducing sample size. When patients' GFRs are higher, the power advantages of GFR slope increase. However, acute treatment effects within several months of randomization can increase the risk of false conclusions about therapies based on GFR slope. Care is needed in study design and analysis to avoid such false conclusions.Conclusions Use of GFR slope can substantially increase statistical power compared with the clinical end point, particularly when baseline GFR is high and there is no acute effect. The optimum GFR-based end point depends on multiple factors including the rate of GFR decline, type of treatment effect and study design.