Improving clinical trial design for Duchenne muscular dystrophy.
Improving clinical trial design for Duchenne muscular dystrophy.
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DOI：
10.1186/s12883-015-0408-z
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发表时间：
2015-08-26
期刊：
影响因子：
2.6
通讯作者：
Sabatelli P
中科院分区：
文献类型：
--
作者：
Merlini L;Sabatelli P
目前，最有希望的治疗杜氏肌营养不良症（DMD）的方法是外显子跳跃和停止密码子读取，这两种策略旨在恢复肌营养不良蛋白的表达。drisapersen是一种设计用于诱导51外显子跳跃的药物，其3期临床试验未能显示出主要结果指标（6分钟步行测试）的显着改善。在这里，我们回顾了在设计这些新疗法的临床试验时应该考虑的一些关键点。首先，年轻患者比老年患者有更多的功能能力和更多的肌肉纤维可以保存，因此是更好的试验对象，旨在证明新疗法的成功。其次，将使用皮质类固醇的患者同时纳入治疗组和安慰剂组是值得关注的，因为皮质类固醇的积极作用可能掩盖正在测试的治疗的效果。此外，这些疗法的合理预期是减缓疾病进展，而不是改善。因此，适当的临床终点是从地板站立、爬楼梯和行走能力的延长，而不是肌肉力量或功能的增加。因此，检测新的肌营养不良蛋白的时间框架（在几个月内发生）和证明疾病进展减缓的能力（需要数年）明显不同。最后，如果需要失明数年才能证明疾病进展的减缓，那么安慰剂对照试验是很难管理的。因此，新疗法的加速/有条件批准应基于替代生化结果：证明新生肌营养不良蛋白的产生及其对肌纤维功能恢复的有益作用。这些数据表明，DMD患者的临床试验必须适应该疾病的特定特征，以证明新疗法的预期积极效果。
Currently, the most promising therapies for Duchenne muscular dystrophy (DMD) are exon skipping and stop codon read-through, two strategies aimed at restoring the expression of dystrophin. A phase 3 clinical trial with drisapersen, a drug designed to induce exon 51-skipping, has failed to show significant improvement of the primary outcome measure, the six-minute walk test. Here, we review some key points that should be considered when designing clinical trials for these new therapies. First, younger patients have more functional abilities and more muscle fibers to preserve than older patients and therefore are better subjects for trials designed to demonstrate the success of new treatments. Second, the inclusion of patients on corticosteroids both in the treatment and placebo groups is of concern because the positive effect of corticosteroids might mask the effect of the treatment being tested. Additionally, the reasonable expectation from these therapies is the slowing of disease progression rather than improvement. Therefore, the appropriate clinical endpoints are the prolongation of the ability to stand from the floor, climb stairs, and walk, not an increase in muscle strength or function. Hence, the time frames for the detection of new dystrophin, which occurs within months, and the ability to demonstrate a slowing of disease progression, which requires years, are strikingly different. Finally, placebo-controlled trials are difficult to manage if years of blindness are required to demonstrate a slowing of disease progression. Thus, accelerated/conditional approval for new therapies should be based on surrogate biochemical outcomes: the demonstration of de novo dystrophin production and of its beneficial effect on the functional recovery of muscle fiber. These data suggest that clinical trials for DMD patients must be adapted to the particular characteristics of the disease in order to demonstrate the expected positive effect of new treatments.