A Ph2 Randomized, Placebo-controlled, Multiple Dose Study to Determine the Safety, Pharmacokinetics and Efficacy of Oral Ifetroban in Subjects with Duchenne Musculary Dystrophy IND136895 (10/10/2018)

项目摘要/摘要 Duchenne肌营养不良症(DMD)是一种罕见的致命疾病，每3500人中约有1人患病 所有种族和文化的男性生育都无法治愈。DMD会导致行动不便，呼吸衰竭， 心肌病(CM)和过早死亡。肌萎缩侧索硬化症现在是DMD的主要死亡原因。有限 DMD患者的行走通常掩盖了心力衰竭的典型症状，从而导致了不受控制的CM疾病 进步。如果没有积极的DMD筛查，CM的首发症状可能是不可逆转的心脏 心力衰竭或心脏猝死。我们的团队和其他人已经显示出血栓素前列腺素的激活 位于血小板、免疫细胞、平滑肌和心肌细胞上的受体(TPR)参与了 对心脏有害的影响。此外，TPR用强效和选择性的TPR拮抗剂ifetroban， 在多种DMD CM动物模型中，预防心脏纤维化，改善心功能和死亡率。 异前列腺素(IP)激活TPR，在DMD时升高。它们不仅是最可靠的标志 评估氧化应激，IP是血管功能障碍的介体。它们使炎症永久化 氧化损伤的反应，这可能在DMD CM的发病机制中起关键作用。我们的总体目标是 确定伊非曲班的安全性和有效性，以支持其批准用于治疗DMD CM，这是一种罕见的 没有当前治疗方法的情况，因此直接服务于孤儿产品开发公司的 任务。拟议的临床研究旨在确定口服的安全性、药代动力学和疗效。 伊非曲班在DMD-CM患者中的应用除了量化的心脏和呼吸结果外， 口服伊非罗班对肌肉力量、日常活动和生活质量的可测量影响将在#年进行调查 DMD患者。这项随机、安慰剂对照的多中心2期试验旨在测试 TPR信号促进心脏炎症和IP过量产生导致DMD的假说 从而使导致心脏纤维化和血管功能障碍的炎症反应永久化。 目的1将确定口服tpr拮抗剂ifetroban治疗DMD的安全性和有效性。 厘米。在年内最大的DMD中心拥有DMD和心脏影像专业知识的儿科心脏病专家网络 该国将加快这种罕见疾病的招生速度。同样的成像设备和标准化 心脏成像方案将用于比较不同中心的心脏成像数据。目标2将决定 阻断TPR对蛋白表达和CMR结构的影响。样本和成像将是 用于确定TPR阻断对骨骼肌和CM疾病进展的影响。成功 这项第二阶段试验的完成将有助于支持批准ifetroban用于治疗DMD CM。学习 结果将为设计关键阶段3研究提供必要的信息，使其具有最大的 对减少DMD患者死亡和残疾的影响。

PROJECT SUMMARY/ABSTRACT Duchenne muscular dystrophy (DMD) is a rare and fatal disease affecting approximately 1 in every 3,500 live male births across all races and cultures with no cure. DMD results in loss of ambulation, respiratory failure, cardiomyopathy (CM), and premature death. CM is now the leading cause of death in DMD. Limited ambulation in DMD patients often masks typical symptoms of heart failure, allowing unchecked CM disease progression. Without aggressive screening in DMD, the first manifestation of CM can be irreversible heart failure or sudden cardiac death. Our group and others have shown activation of the thromboxane prostanoid receptor (TPr) located on platelets, immune cells, smooth muscle and cardiomyocytes contributes to deleterious effects in the heart. Further, TPr blockade with the potent and selective TPr antagonist, ifetroban, prevents cardiac fibrosis, improves cardiac function and mortality in multiple animal models of DMD CM. Isoprostanes (IP) activate the TPr and are elevated in DMD. Not only are they the most reliable marker for assessing oxidative stress, IP are mediators of vascular dysfunction. They perpetuate the inflammatory response to oxidant injury, which may play a key role in DMD CM pathogenesis. Our overall goal is to determine the safety and efficacy of ifetroban to support its approval for the treatment of DMD CM, a rare condition where no current therapy exists thereby directly serving the Orphan Products Development’s mission. The proposed clinical study aims to determine the safety, pharmacokinetics and efficacy of oral ifetroban in patients with DMD CM. In addition to quantitative cardiac and respiratory outcomes, the measurable effect of oral ifetroban on muscle strength, daily activity and quality-of-life will be investigated in DMD patients. This randomized, placebo-controlled, multicenter phase 2 trial is designed to test the central hypothesis that TPr signaling promotes cardiac inflammation and drives IP overproduction contributing to DMD CM, thereby perpetuating the inflammatory response which leads to cardiac fibrosis and vascular dysfunction. Aim 1 will determine the safety and efficacy of ifetroban, an oral TPr antagonist, as treatment for DMD CM. A network of pediatric cardiologists with DMD and cardiac imaging expertise at the largest DMD centers in the country will expedite enrollment for this rare disease. The same imaging equipment and standardized cardiac imaging protocol will be used to compare cardiac imaging data across centers. Aim 2 will determine the effect of TPr blockade on protein expression and CMR structures. Specimens and imaging will be used to determine the effects of TPr blockade on skeletal muscle and CM disease progression. Successful completion of this phase 2 trial will help support the approval of ifetroban for treatment of DMD CM. Study outcomes will provide the necessary information for design of the pivotal phase 3 study to have the greatest impact on reducing death and disability in patients with DMD.