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更新，标题为“肌酸在HD中的安全性和有效性：协调和统计中心”，是Steven Hersch，M.D.，PhD.来自马萨诸塞州总医院（MGH），标题为“肌酸在亨廷顿氏病中的安全性、耐受性和功效：CREST-E”。本研究的主要目的是调查慢性肌酸一水合物治疗亨廷顿病（HD）的疗效和长期安全性。竞争性更新是必要的，以完成研究，现在是64%的累计。HD是一种显性遗传、致命的神经退行性疾病，目前尚无有效的治疗方法。HD的特征在于突变亨廷顿蛋白的细胞表达，其导致异常的蛋白质/蛋白质相互作用和改变的细胞功能的净效应，包括受损的能量产生， 氧化损伤和改变的转录调节。HD在临床上表现为舞蹈病、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人有症状的HD，另外150，000名健康人有发生HD的遗传风险。患者及其家庭的疾病负担是严重的，并且估计每年给社会带来约20亿美元的经济成本。 临床前和临床数据表明，肌酐可能在HD中发挥疾病调节作用。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发病并减缓病理表型的进展，延长生存期，减少神经病理学并逆转脑ATP缺乏症。在我们最初的对照研究中，肌酸8 g/d每天增加血清和脑肌酸水平，并减少对DNA的氧化损伤的血浆标志物（8 OH 2 'dG），否则在症状性HD中升高3-4倍。我们最近在HD方面的工作表明，肌酸可以减缓脑萎缩，如通过磁共振形态测量法所测量的。 基于上述临床前和临床数据，本研究的主要假设是每日40 g肌酸或最高耐受剂量将减缓与HD相关的功能下降。本提案的具体目的是在一项纵向、随机、双盲、安慰剂对照临床试验中检验这一假设 其设计用于实现84%的功效以检测25%或更大的疾病进展减缓。主要结果是总功能能力的年变化率。为实现这一目标，本多中心、国际研究将入组650例受试者，并随访至少12个月，最长48个月。强有力的理由和缺乏任何治疗药物能够减缓这种毁灭性的神经退行性疾病的进展证明了这项III期临床试验的完成。如果试验结果显示有效性，肌酸的易得和廉价制造不仅会减少疾病的负担，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.