Division of Nephrology, Tufts Medical Center, Boston, MA.
Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Am J Kidney Dis. 2021 Sep;78(3):340-349.e1. doi: 10.1053/j.ajkd.2021.03.007. Epub 2021 Mar 26.
RATIONALE & OBJECTIVE: An early change in proteinuria is considered a reasonably likely surrogate end point in immunoglobulin A nephropathy (IgAN) and can be used as a basis for accelerated approval of therapies, with verification in a postmarketing confirmatory trial. Glomerular filtration rate (GFR) slope is a recently validated surrogate end point for chronic kidney disease progression and may be considered as the end point used for verification. We undertook a meta-analysis of clinical trials in IgAN to compare treatment effects on change in proteinuria versus change in estimated GFR (eGFR) slope.
Individual patient-level meta-analysis.
SETTING & STUDY POPULATIONS: Individual data of 1,037 patients from 12 randomized trials.
Randomized trials of IgAN with proteinuria measurements at baseline and 6 (range, 2.5-14) months and at least a further 1 year of follow-up for the clinical outcome.
For each trial, we estimated the treatment effects on proteinuria and on the eGFR slope, computed as the total slope starting at baseline or the chronic slope starting 3 months after randomization. We used a Bayesian mixed-effects analysis to relate the treatment effects on proteinuria to effects on GFR slope across these studies and developed a prediction model for the treatment effect on the GFR slope based on the effect on proteinuria.
Across all studies, treatment effects on proteinuria accurately predicted treatment effects on the total slope at 3 years (median R = 0.88; 95% Bayesian credible interval [BCI], 0.06-1) and on the chronic slope (R = 0.98; 95% BCI, 0.29-1). For future trials, an observed treatment effect of approximately 30% reduction in proteinuria would confer probabilities of at least 90% for nonzero treatment benefits on the total and chronic slopes of eGFR. We obtained similar results for proteinuria at 9 and 12 months and total slope at 2 years.
Study population restricted to 12 trials of small sample size, leading to wide BCIs. There was heterogeneity among trials with respect to study design and interventions.
These results provide new evidence supporting that early reduction in proteinuria can be used as a surrogate end point for studies of chronic kidney disease progression in IgAN.
蛋白尿的早期变化被认为是免疫球蛋白 A 肾病（IgAN）中相当可能的替代终点，可以作为加速批准治疗的基础，并在上市后确证性试验中进行验证。肾小球滤过率（GFR）斜率是最近验证的慢性肾脏病进展替代终点，也可考虑作为验证的终点。我们对 IgAN 的临床试验进行了荟萃分析，比较了治疗对蛋白尿变化与估计 GFR（eGFR）斜率变化的影响。
个体患者水平的荟萃分析。
来自 12 项随机试验的 1037 名患者的个体数据。
基线和 6（范围 2.5-14）个月时有蛋白尿测量值，并至少有 1 年以上临床结局随访的 IgAN 随机试验。
对于每个试验，我们估计了治疗对蛋白尿和 eGFR 斜率的影响，将其计算为从基线开始的总斜率或随机分组后 3 个月开始的慢性斜率。我们使用贝叶斯混合效应分析来比较这些研究中治疗对蛋白尿的影响与对 GFR 斜率的影响，并基于对蛋白尿的影响建立了一个 GFR 斜率治疗效果的预测模型。
在所有研究中，治疗对蛋白尿的影响准确预测了 3 年时总斜率（中位数 R=0.88；95%贝叶斯可信区间 [BCI]，0.06-1）和慢性斜率（R=0.98；95%BCI，0.29-1）的治疗效果。对于未来的试验，蛋白尿减少约 30%的观察到的治疗效果将使总斜率和慢性斜率的 eGFR 治疗效果具有至少 90%的非零治疗获益的概率。我们在蛋白尿 9 个月和 12 个月以及总斜率 2 年时获得了类似的结果。
研究人群仅限于样本量较小的 12 项试验，导致 BCI 较宽。试验之间在研究设计和干预措施方面存在异质性。
这些结果为蛋白尿早期减少可作为 IgAN 慢性肾脏病进展研究的替代终点提供了新的证据支持。
