CLINICAL PILOT TRIAL OF CREATINE IN AMYOTROPHIC LATERAL SCLEROSIS (ALS)

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目的：肌萎缩侧索硬化症(ALS)是一种进行性、退行性的随意运动系统疾病，导致全身肌肉无力、吞咽困难、构音障碍，并最终导致呼吸衰竭。已有假说认为ALS可能参与了氧化自由基损伤和线粒体能量代谢受损，进而导致兴奋性细胞死亡。肌酸是一种改善线粒体功能的试剂，已被证明在ALS和亨廷顿病的动物模型中具有神经保护作用。该项目的目标是确定肌酸是否延缓了ALS患者的疾病进展。这项建议的具体目的是：(1)确定肌酸治疗是否导致肌肉力量的急剧增加，以及长期治疗是否能维持这种效果；(2)确定肌酸的长期治疗是否会将肌萎缩侧索硬化症患者的运动和肺功能的进行性恶化速度减缓35%；以及(3)确定在肌萎缩侧索硬化症患者中先服用负荷量的肌酸，然后再进行慢性治疗是否安全。研究计划和方法：这是一项2期、双盲、安慰剂对照、随机、多中心的肌酸在200名ALS受试者中的安全性和有效性研究。每个中心将招募大约20名患者。患者将随机接受肌酸治疗(10克/天，5天，然后5克/天，研究持续时间)与安慰剂治疗。患者将在前3周每周进行一次评估，在3个月内每月进行一次评估，然后每两个月进行一次评估，直到研究完成。然后，患者将被允许参与一项开放标签研究，直到研究的盲目部分的数据可以分析为止。主要的结果衡量指标是疾病进展率的变化，通过八个手臂肌肉组(双侧肩和肘屈伸)的最大自愿等长收缩(MVIC)力量来衡量。次要终点包括用力肺活量下降率(FVC，预测百分比)、手动肌肉力量、握力、ALS功能评定量表(ALSFRS-R)和SF-12(生活质量量表)的变化、肌酸的安全性和耐受性以及生存。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the voluntary motor system resulting in generalized muscle weakness, dysphagia, dysarthria, and eventual respiratory failure. It has been hypothesized that in ALS there may be involvement of oxidative free radical damage and impaired mitochondrial energy metabolism that could in turn lead to excitotoxic cell death. Creatine, an agent that improves mitochondrial function, has been shown to be neuroprotective in animal models of ALS and Huntington's disease. The objective of this project is to determine whether creatine slows disease progression in patients with ALS. The specific aims of this proposal are to: (1) Determine whether treatment with creatine results in an acute increase in muscle strength and whether that effect is sustained with chronic therapy; (2) Determine whether chronic treatment with creatine will slow by 35% the progressive deterioration of motor and pulmonary function in patients with ALS; and (3) Determine whether administration of loading doses of creatine followed by chronic treatment is safe in patients with ALS. RESEARCH PLAN AND METHODS: This is a phase 2, double-blind, placebo-controlled, randomized, multi-center safety and efficacy study of creatine in 200 subjects with ALS. Each center will recruit approximately 20 patients. Patients will be randomized to receive treatment with creatine (10 grams/d for 5 days followed by 5 grams/d for duration of study) vs. placebo. The patients will be evaluated weekly for the first 3 weeks, monthly for 3 months, and then bimonthly until the completion of the study. Patients will then be offered participation in an open-label study until the data from the blinded portion of the study can be analyzed. The primary outcome measure is change in disease progression rate as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups (bilateral shoulder and elbow flexion and extension). Secondary endpoints include the rate of decline of forced vital capacity (FVC, percent predicted), manual muscle strength, grip strength, the change in the ALS functional rating scale (ALSFRS-R) and the SF-12 (quality of life instrument), the safety and tolerability of creatine, and survival.