Kröpelin Tobias F, de Zeeuw Dick, Andress Dennis L, Bijlsma Maarten J, Persson Frederik, Parving Hans-Henrik, Heerspink Hiddo J Lambers
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands;
AbbVie Laboratories, Chicago, Illinois;
Clin J Am Soc Nephrol. 2015 Mar 6;10(3):410-6. doi: 10.2215/CJN.07780814. Epub 2015 Jan 7.
Albuminuria change is often used to assess drug efficacy in intervention trials in nephrology. The change is often calculated using a variable number of urine samples collected at baseline and end of treatment. Yet more albuminuria measurements usually occur. Because albuminuria shows a large day-to-day variability, this study assessed to what extent the average and the precision of the antialbuminuric drug effect varies with the number of urine collections at each visit and the number of follow-up visits.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study used data from three randomized intervention trials (Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy, Selective Vitamin D Receptor Activation for Albuminuria Lowering, and Residual Albuminuria Lowering with Endothelin Antagonist Atrasentan) including patients with type 2 diabetes and macroalbuminuria. Albuminuria-lowering drug effects were estimated from one, two, or three urine collections at consecutive days before each study visit and reported as albuminuria change from baseline to end of treatment or the change over time considering an average of all follow-up albuminuria measurements.
Increasing the number of urine collections for an albuminuria measurement at baseline and end of treatment or using all study visits during follow-up did not alter the average drug effect. The precision of the drug effect increased (decreased SEM) when the number of study visits and the number of urine collections per visit were increased. Using all albuminuria measurements at all study visits led to a 4- to 6-fold reduction in sample size to detect a 30% albuminuria-lowering treatment effect with 80% power compared with using baseline and end-of-treatment albuminuria measurements alone.
Increasing the number of urine collections per study visit and the number of visits over time does not change the average drug effect estimate but markedly increases the precision, thereby enhancing statistical power. Thus, clinical trial designs in diabetic nephropathy using albuminuria as an end point can be significantly improved, leading to smaller sample sizes and less complex trials.
在肾脏病干预试验中，蛋白尿变化常被用于评估药物疗效。该变化通常根据基线期和治疗结束时收集的数量不等的尿液样本计算得出。然而，通常会进行更多次的蛋白尿测量。由于蛋白尿呈现出较大的每日变异性，本研究评估了抗蛋白尿药物效应的平均值和精密度在每次访视时尿液采集次数以及随访访视次数的情况下会在多大程度上有所不同。
设计、地点、参与者及测量方法：本研究使用了三项随机干预试验（阿利吉仑联合氯沙坦治疗2型糖尿病肾病、选择性维生素D受体激活剂降低蛋白尿、内皮素拮抗剂阿曲生坦降低残余蛋白尿）的数据，这些试验纳入了2型糖尿病和大量蛋白尿患者。在每次研究访视前连续几天采集一、二或三次尿液样本，以此估算降低蛋白尿的药物效应，并将其报告为从基线期到治疗结束时的蛋白尿变化，或者考虑所有随访蛋白尿测量值的平均值得出的随时间的变化。
在基线期和治疗结束时增加蛋白尿测量的尿液采集次数，或者在随访期间使用所有研究访视的数据，均未改变药物效应的平均值。当研究访视次数和每次访视的尿液采集次数增加时，药物效应的精密度提高（标准误降低）。与仅使用基线期和治疗结束时的蛋白尿测量值相比，使用所有研究访视的所有蛋白尿测量值可使检测出降低30%蛋白尿治疗效应且检验效能为80%所需的样本量减少4至6倍。
增加每次研究访视的尿液采集次数以及随时间推移的访视次数，并不会改变药物效应的平均估计值，但会显著提高精密度，从而增强统计效能。因此，以蛋白尿作为终点的糖尿病肾病临床试验设计可得到显著改进，从而使样本量更小且试验更简单。
