A futility trial of sirolimus in multiple system atrophy

西罗莫司治疗多系统萎缩的无效试验

• 批准号: 9756489
• 负责人: HORACIO KAUFMANN
• 金额: $ 77.71万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756489
• 关键词: Adverse event; Affect; Alzheimer' s Disease; Animal Model; Autophagocytosis; Awareness; Biological Markers; Blood; Brain; Brain imaging; Cell model; Cells; Chronic; Clinical; Clinical Trials; Deposition; Digestion; Disease; Disease Progression; FRAP1 gene; Futility; Goals; Human; Huntington Disease; Impairment; Link; Low Prevalence; Lysosomes; Magnetic Resonance; Measures; Modeling; Multiple System Atrophy; Natural History; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic Deficit; Neurons; Optical Coherence Tomography; Oral; Organelles; Orphan; Outcome; Outcome Measure; Parkinson Disease; Pathway interactions; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Phase; Physiological; Placebos; Plasma; Process; Proteins; Randomized; Retinal; Retinal Degeneration; Sirolimus; Symptoms; System; Therapeutic; Time; United States Food and Drug Administration; alpha synuclein; analog; base; clinical efficacy; combat; cost; design; effective therapy; extracellular vesicles; imaging biomarker; inhibitor/antagonist; interest; macromolecule; misfolded protein; neuroimaging; neuroinflammation; phase 3 study; phase III trial; prospective; retinal imaging; synucleinopathy

PROJECT SUMMARY Our ultimate goal is to develop new treatments for patients with multiple system atrophy (MSA), a rare neurodegenerative disease with no cure caused by the abnormal accumulation of the protein alpha-synuclein (αSyn) in neurons and glia. There are no treatments that can halt or slow the progression of the disease, and patient with MSA die within 8-10 years from symptom onset. Because disease progression in MSA is causally linked to accumulation, aggregation, and spreading of αSyn in the central nervous system (CNS), much effort has gone into devising strategies to combat this process, although, so far, all attempts to identify a treatment have failed. Autophagy is the major cellular digestion process that removes damaged macromolecules, organelles, and misfolded proteins, including αSyn, from cells. In patients with MSA, autophagy is impaired and misfolded αSyn accumulates in neurons and glia, causing neurodegeneration. Sirolimus, a medication that has been approved by the U.S. Food and Drug Administration for chronic treatment in humans for a variety of disorders for almost 20 years ago, is a potent activator of autophagy. Our HYPOTHESIS is that treatment with sirolimus might activate autophagy of αSyn resulting in reduced neurodegeneration and slower progression of the neurological deficits in patients with MSA. Our OBJECTIVE is to perform a single-center, randomized, placebo-controlled, phase II futility clinical trial to determine if sirolimus is of sufficient promise to slow the disease progression of patients with MSA, prior to embarking on a large-scale and costly phase-III study to assess its efficacy. A futility design under the null hypothesis assumes that sirolimus will slow the progression of the disease, whereas the alternative hypothesis assumes no benefit of sirolimus. If the null hypothesis is rejected (i.e., futility of sirolimus to slow progression of MSA), a major phase III study will be discouraged, whereas non-futility will offer strong support for a phase III trial to detect clinical efficacy. The AIMS are: ONE. To determine if sirolimus is of sufficient promise to slow the progression of disease in patients with MSA as measured by patient-reported outcome measures. TWO. To assess the potential effects of sirolimus on retinal and brain imaging biomarkers in patients with MSA. THREE. To explore the effect of sirolimus on CNS-derived blood-based αSyn extracellular vesicles. As far as we are aware, this is the first time sirolimus or analogs will be used clinically with the aim of slowing disease progression in patients with neurodegenerative disorders. Our observations may offer strong support for a phase III trial to confirm the efficacy of sirolimus in MSA. Furthermore, the outcome of our study may potentially have a broad therapeutic benefit for other, more frequent neurodegenerative disorders, such as Parkinson disease.

项目摘要 我们的最终目标是为多系统萎缩（MSA）患者开发新的治疗方法， 一种无法治愈的神经变性疾病，由蛋白质α-突触核蛋白的异常积累引起 （αSyn）在神经元和胶质细胞中。没有治疗方法可以阻止或减缓疾病的进展， MSA患者在症状发作后8-10年内死亡。因为MSA中的疾病进展是因果关系 与αSyn在中枢神经系统（CNS）中的积累、聚集和扩散有关， 已经开始设计对抗这一过程的策略，尽管到目前为止，所有试图确定治疗方法的尝试都是徒劳的。 失败了自噬是主要的细胞消化过程，其去除受损的大分子， 细胞器和错误折叠的蛋白质，包括αSyn。在MSA患者中，自噬受损 错误折叠的αSyn在神经元和胶质细胞中积累，导致神经变性。西罗莫司，一种药物， 已被美国食品和药物管理局批准用于人类的各种慢性治疗。 在近20年前，它是一种自噬的有效激活剂。我们的假设是， 西罗莫司可能激活αSyn的自噬，从而减少神经退行性变和减缓 MSA患者的神经功能缺损。我们的目的是进行一项单中心、随机、 安慰剂对照，II期无效临床试验，以确定西罗莫司是否有足够的希望，以减缓 在进行大规模和昂贵的III期研究之前， 评估其功效。无效假设下的无效设计假设西罗莫司将减缓进展 的疾病，而备择假设假设西罗莫司没有好处。如果零假设被 拒绝（即，西罗莫司对减缓MSA进展无效），将不鼓励进行重大III期研究， 而非无效性将为检测临床疗效的III期试验提供强有力的支持。目标是：一。 为了确定西罗莫司是否有足够的希望减缓MSA患者的疾病进展， 通过患者报告的结局指标进行测量。两个.评估西罗莫司对视网膜病变的潜在影响， 和脑成像生物标志物。三.探讨西罗莫司对CNS源性 血基αSyn细胞外囊泡。据我们所知，这是西罗莫司或类似物首次将 临床上用于减缓神经退行性疾病患者的疾病进展。 我们的观察结果可能为III期试验提供强有力的支持，以确认西罗莫司在MSA中的疗效。 此外，我们的研究结果可能对其他更广泛的治疗益处， 常见的神经退行性疾病，如帕金森病。