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）：此申请是一种竞争续约，标题为“ HD：协调和统计中心的肌酸安全性和功效”，是对史蒂文·赫奇（Steven Hersch）的同伴申请。来自马萨诸塞州综合医院（MGH），题为“亨廷顿氏病的肌酸安全性，耐受性和功效：Crest- e”。该研究的主要目的是研究慢性肌酸一水合物治疗在亨廷顿氏病（HD）中的疗效和长期安全性。竞争性更新对于完成目前64％的研究是必要的。 HD是一种主要遗传，致命的，神经退行性疾病，没有有效的治疗方法。 HD的特征是突变亨廷汀蛋白的细胞表达，这会导致异常的蛋白/蛋白质相互作用，并且细胞功能改变的净作用，包括能量产生受损，氧化损伤和转录调节改变。 HD在临床上表现出唱片，肌张力障碍，人格变化和认知障碍，导致失去独立并最终死亡。在美国，大约有30,000人患有症状性高清，另外15万名健康的人有发展高清的遗传风险。对患者及其家人的疾病负担很严重，并且与每年约20亿美元的社会经济成本相结合。临床前和临床数据表明，Creatne可能在HD中起着疾病的作用。在HD转基因和敲门小鼠中，肌酸以剂量依赖性方式延迟了发作并减慢病理表型的进展，扩展生存率，减少神经病理学并逆转大脑ATP缺乏症。在我们最初的对照研究中，肌酸每天8 g/d每天增加肌酸的血清和大脑水平，并降低了DNA（8OH2'DG）氧化损伤的等离子体标记，否则在症状HD中升高了3-4倍。我们最近在HD中的工作表明，肌酸可能会减慢脑萎缩，这是通过磁共振形态测定的。基于上述临床前和临床数据，该研究的主要假设是每天有40克肌酸或最高耐受剂量会减慢与HD相关的功能下降。该提案的具体目的是在纵向，随机，双盲，安慰剂对照的临床试验中检验该假设旨在实现84％的能力来检测疾病进展减慢25％或更高的能力。主要结果是总功能能力的年度变化率。为了实现这一目标，将参加这项多中心，国际研究的650名受试者，然后至少12个月，最多48个月。强大的理由和缺乏能够减慢这种毁灭性神经退行性疾病进展的任何治疗剂证明了该III期临床试验的完成是合理的。如果试验的重新调查显示出疗效，那么肌酸的易用和廉价制造不仅会减轻疾病的负担，而且要以非常低的成本进行。