Creatine Safety and Efficacy in HD: Coordination and Statistical Center

描述(由申请人提供)：本申请是一项竞争性续展申请，题为“肌酸在HD中的安全性和有效性：协调和统计中心”，是Steven Hersch，医学博士，博士的配套申请。来自马萨诸塞州综合医院(MGH)，题为“亨廷顿病的肌酸安全性、耐受性和有效性：CREST-E”。这项研究的主要目的是研究慢性一水肌酸治疗亨廷顿病(HD)的有效性和长期安全性。竞争更新是完成现在%应得的学习所必需的。HD是一种遗传性、致命性、神经退行性疾病，目前还没有有效的治疗方法。HD的特点是突变的亨廷顿蛋白在细胞内表达，导致蛋白质/蛋白质相互作用异常，以及包括能量产生受损在内的细胞功能改变的净效应， 氧化损伤，并改变转录调控。HD的临床表现为舞蹈症、肌张力障碍、人格改变和导致丧失独立性并最终死亡的认知障碍。在美国，大约有30,000人患有症状性HD，另外150,000名健康的人面临患HD的遗传风险。疾病给患者及其家人带来了沉重的负担，估计每年给社会造成的经济损失约为20亿美元。临床前和临床资料提示肌酸可能在HD中起到改善疾病的作用。在HD转基因和敲入小鼠中，肌酸以剂量依赖的方式延缓病理表型的发病和进展，延长生存时间，减轻神经病理，逆转脑内ATP缺乏。在我们最初的对照研究中，肌酸每天8g/d增加了血清和大脑的肌酸水平，并降低了DNA氧化损伤的血浆标记物(8OH2‘DG)，否则在有症状的HD患者中该标记物会升高3-4倍。我们最近在HD上的工作表明，根据磁共振形态计量学的测量，肌酸可以减缓脑萎缩。基于上述临床前和临床数据，这项研究的主要假设是，每天40克肌酸或最高耐受量将减缓与HD相关的功能衰退。这项建议的具体目的是在一项纵向、随机、双盲、安慰剂对照的临床试验中检验这一假设。 这是为了达到84%的能力来检测25%或更多的疾病进展放缓。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的国际研究，并进行至少12个月和最多48个月的跟踪调查。强大的理论基础和缺乏任何能够减缓这种毁灭性神经退行性疾病进展的治疗剂，证明完成这一第三阶段临床试验是合理的。如果试验结果显示有效，随时可以获得的廉价肌酸制造不仅将减轻疾病的负担，而且成本非常低。

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.