Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; The George Institute for Global Health, Sydney, Australia.
Late Stage Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA.
Kidney Int. 2024 Oct;106(4):723-735. doi: 10.1016/j.kint.2024.06.007. Epub 2024 Jul 4.
Glomerular filtration rate (GFR) decline is used as surrogate endpoint for kidney failure. Interventions that reduce chronic kidney disease (CKD) progression often exert acute GFR reductions which differ from their long-term benefits and complicate the estimation of long-term benefit. Here, we assessed the utility of two alternative trial designs (wash-out design and active run-in randomized withdrawal design) that attempt to exclude the impact of acute effects. Post-hoc analyses of two clinical trials that characterized the effect of an intervention with acute reductions in GFR were conducted. The two trials included a wash-out period (EMPA-REG Outcome testing empagliflozin vs placebo) or an active run-in period with a randomized withdrawal (SONAR testing atrasentan vs placebo). We compared the drug effect on GFR decline calculated from the first on-treatment visit to the end of treatment (chronic slope in a standard randomized trial design) with GFR change calculated from randomization to end of wash out, or GFR change from treatment-specific baseline GFR values (GFR at start-of-run-in for placebo and end-of-run-in for atrasentan) until end-of-treatment. The effect of empagliflozin versus placebo on chronic GFR slope was 1.72 (95% confidence interval 1.49-1.94) mL/min/1.73 m/year, similar to total GFR decline from baseline to the end of wash-out period using a linear mixed model 1.64 (1.44-1.85) mL/min/1.73 m/year). The effect of atrasentan versus placebo on chronic GFR slope was 0.72 (0.32-1.11) mL/min/1.73 m/year, similar to total slope from a single slope model when estimated from treatment specific baseline GFR values 0.77 (0.39-1.14) mL/min/1.73 m/year). Statistical power of the two designs outperformed the standard randomized design. Thus, wash-out and active-run-in randomized-withdrawal trial designs are appropriate models to compute treatment effects on GFR decline.
肾小球滤过率（GFR）下降被用作肾衰竭的替代终点。降低慢性肾脏病（CKD）进展的干预措施通常会导致急性 GFR 下降，这与它们的长期益处不同，并使长期益处的估计复杂化。在这里，我们评估了两种替代试验设计（洗脱设计和主动入组随机撤药设计）的效用，这些设计试图排除急性效应的影响。对两项描述干预措施对 GFR 急性下降影响的临床试验进行了事后分析。这两项试验包括洗脱期（EMPA-REG 结局试验恩格列净与安慰剂对照）或主动入组期伴随机撤药（SONAR 试验阿曲生坦与安慰剂对照）。我们比较了从第一次治疗访视到治疗结束时（标准随机试验设计中的慢性斜率）计算的药物对 GFR 下降的影响，与从随机化到洗脱结束时计算的 GFR 变化，或从特定治疗的基线 GFR 值（安慰剂的入组时 GFR 和阿曲生坦的入组结束时 GFR）到治疗结束时计算的 GFR 变化。与安慰剂相比，恩格列净对慢性 GFR 斜率的影响为 1.72（95%置信区间 1.49-1.94）mL/min/1.73 m/年，与线性混合模型从基线到洗脱结束时的总 GFR 下降相似 1.64（1.44-1.85）mL/min/1.73 m/年）。与安慰剂相比，阿曲生坦对慢性 GFR 斜率的影响为 0.72（0.32-1.11）mL/min/1.73 m/年，与从特定治疗基线 GFR 值估计的单个斜率模型的总斜率相似 0.77（0.39-1.14）mL/min/1.73 m/年）。两种设计的统计效能均优于标准随机设计。因此，洗脱和主动入组随机撤药试验设计是计算 GFR 下降治疗效果的合适模型。
