Sirolimus TSC Epilepsy Prevention Study (STEPS) IND#145820 11/8/2019

总结/摘要 癫痫是非常普遍和高度难治性目前可用的药物治疗的硬化症 TSC综合征是一种遗传性疾病，影响1：6000的活产婴儿。TSC中的药物难治性癫痫与 终生智力残疾和神经发育缺陷依维莫司和西罗莫司，药理学 雷帕霉素复合物1（mTORC 1）的机制靶点抑制剂，已成功地重新用于 治疗TSC的可能临床表现，包括局灶性癫痫。然而，很少有患者会癫痫发作- mTORC 1抑制剂治疗后，60%的TSC患者仍需要有效的 治疗TSC的小鼠模型和人类临床试验表明用mTORC 1抑制剂进行早期治疗， 在癫痫发作之前，可能是一种更有效的治疗癫痫和癫痫的策略- 在诊断为TSC的患者中存在神经发育相关缺陷。本研究提出了一个阶段 IIb多中心、随机、双盲、安慰剂对照西罗莫司临床试验，以检验这一假设。 临床试验的主要目的是（1）证明西罗莫司预防或延迟婴儿癫痫发作 0-12月龄TSC;（2）证明西罗莫司在婴儿中安全且耐受良好 0-12个月大的TSC。试验的其他（次要）目的是：（1）证明早期 西罗莫司治疗可改善发育迟缓、语言障碍、适应技能和自闭症风险;（2） 评估EEG和MRI生物标志物用于测量脑中mTORC 1抑制的效用;以及（3）验证 西罗莫司在TSC婴儿中的精确剂量。

SUMMARY/ABSTRACT Epilepsy is very prevalent and highly refractory to currently available medical treatments in Tuberous Sclerosis Complex (TSC), a genetic disorder affecting 1:6000 live births. Medically-refractory epilepsy in TSC is associated with lifelong intellectual disability and neurodevelopmental deficits. Everolimus and sirolimus, pharmacological inhibitors of the mechanistic target of rapamycin complex 1 (mTORC1), have been successfully repurposed to treat may clinical manifestations of TSC, including focal-onset epilepsy. However, few patients become seizure- free following treatment with mTORC1 inhibitors and 60% of patients with TSC are still in need of effective treatment. Mouse models of TSC and human clinical trials indicate early treatment with mTORC1 inhibitors, before the onset of seizures, may be a more effective treatment strategy against epilepsy and epilepsy- associated deficits in neurodevelopment in patients diagnosed with TSC. The current study proposes a Phase IIb multicenter, randomized, double-blind, placebo-controlled clinical trial with sirolimus to test this hypothesis. The primary aims of the clinical trial are (1) to demonstrate that sirolimus prevents or delays seizures in infants with TSC that are 0-12 months of age; and (2) to demonstrate that sirolimus is safe and well-tolerated in infants with TSC that are 0-12 months of age. Additional (secondary) aims of the trial are: (1) to demonstrate that early sirolimus treatment improves developmental delay, language impairment, adaptive skills, and autism risk; (2) to assess the utility of EEG and MRI biomarkers for measuring mTORC1 inhibition in the brain; and (3) to validate precision dosing of sirolimus in infants with TSC.