A multicenter, randomized, placebo -controlled, double-blind phase 3 trial with open -arm comparison indicates safety and ef fi cacy of nephroprotective therapy with ramipril in children with Alport ? s syndrome see commentary
A multicenter, randomized, placebo -controlled, double-blind phase 3 trial with open -arm comparison indicates safety and ef fi cacy of nephroprotective therapy with ramipril in children with Alport ? s syndrome see commentary
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DOI：
10.1016/j.kint.2019.12.015
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发表时间：
2020-06-01
影响因子：
19.6
通讯作者：
Friede, Tim
中科院分区：
文献类型：
--
作者：
Gross, Oliver;Toenshoff, Burkhard;Friede, Tim
患有Alport综合征的儿童在生命早期发生肾衰竭。由于预先肾保护治疗的安全性和有效性尚不确定，我们在14个德国研究中心进行了一项随机、安慰剂对照、双盲试验，对接受雷米普利治疗的儿童患者进行了3至6年加6个月的随访，以确定这些参数。预先治疗的儿童和那些父母拒绝随机化的儿童成为开放式对照组，与未治疗儿童的前瞻性真实世界数据进行比较。共同主要终点为安全性（药物不良反应）和疗效（至疾病进展时间）。在66名症状轻微的儿童中，22名被随机分组，44名参加了开放组比较。雷米普利治疗未显示出安全性问题（雷米普利治疗总患者年为216.4;不良事件率比1.00; 95%置信区间0.66-1.53）。尽管没有显著性，我们的结果谨慎地表明雷米普利治疗是有效的：在随机分组中，雷米普利使疾病进展的风险降低了近一半（风险比0.51（0.12-2.20）），减少了白蛋白尿进展的斜率和肾小球滤过率的下降。在校正分析中，疗效指征得到了接受开放标签治疗的参与者与未接受治疗的儿童相比的前瞻性数据的支持，其中雷米普利似乎再次将进展减少了近一半（0.53（0.22-1.29））。通过贝叶斯证据合成将这些结果纳入随机化数据，得到风险比更精确的估计值为0.52（0.19-1.39）。因此，我们的研究显示了早期开始治疗的安全性，并支持了延缓肾衰竭多年的希望，强调了先发制人治疗的价值。因此，儿童和年轻人肾小球性血尿的筛查计划可以受益于Alport相关基因变异的基因检测。
Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12–2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.