Creatine Safety and Efficacy in HD: Coordination and Statistical Center

肌酸在 HD 中的安全性和有效性：协调和统计中心

基本信息

批准号：
8851522
负责人：
GIOVANNI SCHIFITTO
金额：
$ 92.64万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851522
关键词：
Activities of Daily Living Address Affect Animal Model Biometry Brain Buffers Case Report Form Cell physiology Cells Cerebrum Cessation of life Chorea Chronic Clinical Clinical Data Clinical Trials Clinical Trials Data Monitoring Committees Companions Computational Biology Consent Forms Consultations Controlled Clinical Trials Controlled Study Creatine Cytosol DNA Data Databases Disclosure Disease Disease Progression Doctor of Medicine Doctor of Philosophy Dose Double-Blind Method Dystonia Electronics Emergency treatment Enrollment Environment Event Family Futility General Hospitals Generations Genetic Risk Goals HDAC1 gene Health Human Human Resources Huntington Disease Impaired cognition Inherited Injury International Knock-in Mouse Label Link Magnetic Resonance Maintenance Manuals Massachusetts Measures Medical center Mitochondria Modeling Modification Monitor National Center for Complementary and Alternative Medicine Neurodegenerative Disorders Online Systems Orphan Oxidative Stress Pathologic Patients Peripheral Personality Pharmaceutical Preparations Phase Phase III Clinical Trials Phenotype Phosphocreatine Placebo Control Plasma Play Preparation Procedures Production Protocols documentation Randomized Reporting Research Design Research Infrastructure Research Subjects Resolution Role Safety Sampling Secure Serious Adverse Event Serum Site Societies Source Standardization Supplementation Suspension substance Suspensions System Testing Therapeutic Therapeutic Agents Tissues Training Transcriptional Regulation Transgenic Organisms United States United States National Institutes of Health Universities Withdrawal Work base burden of illness cerebral atrophy clinically significant cost data management design dietary supplements dosage double-blind placebo controlled trial effective therapy electronic data follow-up functional decline human Huntingtin protein meetings morphometry mutant neurogenetics neuropathology operation oxidative damage performance site pre-clinical premature primary outcome protein protein interaction relational database statistical center

项目摘要

DESCRIPTION (provided by applicant): This application is a competing renewal, entitled "Creatine Safety and Efficacy in HD: Coordination and Statistical Center", and is a companion application to that of Steven Hersch, M.D., PhD. from Massachusetts General Hospital (MGH), entitled "Creatine Safety, Tolerability and Efficacy in Huntington's Disease: CREST- E". The primary aim of the study is to investigate the efficacy and long-term safety of chronic creatine monohydrate treatment in Huntington's disease (HD). The competitive renewal is necessary to complete the study that is now 64% accrued. HD is a dominantly inherited, fatal, neurodegenerative disorder for which there is no effective treatment. HD is characterized by the cellular expression of the mutant huntingtin protein, which leads to aberrant protein/protein interactions and a net effect of altered cellular functioning including impaired energy production, oxidative damage, and altered transcriptional regulation. HD manifests clinically with chorea, dystonia, personality changes, and cognitive impairment leading to the loss of independence and eventually death. Approximately 30,000 people in the United States have symptomatic HD, and an additional 150,000 healthy people are at genetic risk of developing HD. The disease burden to patients and their family is severe and is combined with an estimated economical cost to society of about two billion dollars per year. Preclinical and clinical data suggest that creatne may play a disease modifying role in HD. In HD transgenic and knock-in mice, creatine delays the onset and slows the progression of the pathologic phenotype in a dose dependent manner, extends survival, reduces neuropathology and reverses cerebral ATP deficiency. In our initial controlled study, creatine 8 g/d daily increased serum and brain levels of creatine and reduced a plasma marker of oxidative injury to DNA (8OH2'dG) that is otherwise elevated 3-4 fold in symptomatic HD. Our most recent work in HD suggests that creatine may slow brain atrophy, as measured by magnetic resonance morphometry. Based on the above preclinical and clinical data, the primary hypothesis of the study is that 40 grams daily of creatine or highest tolerated dose will slow the functional decline associated with HD. The specific aim of this proposal is to test this hypothesis in a longitudinal, randomized, double-blind, placebo-controlled clinical trial that is designed to achieve 84% power to detect a 25% or greater slowing of disease progression. The primary outcome is the annualized rate of change in total functional capacity. To achieve this goal, 650 subjects will be enrolled in this multicenter, international study and followed for a minimum of 12 months and a maximum of 48 months. The strong rationale and the lack of any therapeutic agent able to slow the progression of this devastating neurodegenerative disease justify the completion of this phase III clinical trial. Should the resuls of the trial show efficacy, the readily available and inexpensive manufacturing of creatine will no only decrease the burden of the disease but do so at very low cost.

描述（由申请人提供）：本申请是一项竞争性更新，题为“HD 中的肌酸安全性和功效：协调和统计中心”，并且是 Steven Hersch 医学博士、博士申请的配套申请。来自马萨诸塞州总医院 (MGH) 的研究，题为“肌酸在亨廷顿病中的安全性、耐受性和功效：CREST-E”。该研究的主要目的是调查慢性一水肌酸治疗亨廷顿病（HD）的疗效和长期安全性。竞争性更新对于完成目前已完成 64% 的研究是必要的。 HD 是一种显性遗传的、致命的神经退行性疾病，目前尚无有效的治疗方法。 HD 的特征是突变亨廷顿蛋白的细胞表达，这会导致异常的蛋白质/蛋白质相互作用以及细胞功能改变的净效应，包括能量产生受损、氧化损伤和转录调控改变。 HD 临床表现为舞蹈症、肌张力障碍、人格改变和认知障碍，导致丧失独立性并最终死亡。在美国大约有 30,000 人患有有症状的 HD，另外 150,000 名健康人有患 HD 的遗传风险。患者及其家人的疾病负担十分严重，估计每年给社会造成约 20 亿美元的经济损失。临床前和临床数据表明肌酸可能在 HD 中发挥疾病缓解作用。在 HD 转基因和基因敲入小鼠中，肌酸以剂量依赖性方式延迟病理表型的发病并减缓其进展，延长生存期，减少神经病理学并逆转脑 ATP 缺乏。在我们最初的对照研究中，每天 8 g/d 肌酸可增加血清和脑部的肌酸水平，并降低 DNA 氧化损伤的血浆标志物 (8OH2'dG)，而该标志物在有症状的 HD 中会升高 3-4 倍。我们最近在 HD 方面的研究表明，根据磁共振形态测量法测量，肌酸可以减缓脑萎缩。基于上述临床前和临床数据，该研究的主要假设是每天 40 克肌酸或最高耐受剂量将减缓与 HD 相关的功能衰退。该提案的具体目的是在纵向、随机、双盲、安慰剂对照临床试验中检验这一假设旨在实现 84% 的功效来检测 25% 或更大的疾病进展减缓。主要结果是总功能能力的年化变化率。为了实现这一目标，650 名受试者将参加这项多中心、国际研究，并进行最短 12 个月、最长 48 个月的随访。强有力的理由以及缺乏任何能够减缓这种破坏性神经退行性疾病进展的治疗药物证明了完成这项 III 期临床试验的合理性。如果试验结果显示疗效，那么容易获得且廉价的肌酸生产不仅会减轻疾病负担，而且成本非常低。