Kieburtz Karl, Tilley Barbara C, Elm Jordan J, Babcock Debra, Hauser Robert, Ross G Webster, Augustine Alicia H, Augustine Erika U, Aminoff Michael J, Bodis-Wollner Ivan G, Boyd James, Cambi Franca, Chou Kelvin, Christine Chadwick W, Cines Michelle, Dahodwala Nabila, Derwent Lorelei, Dewey Richard B, Hawthorne Katherine, Houghton David J, Kamp Cornelia, Leehey Maureen, Lew Mark F, Liang Grace S Lin, Luo Sheng T, Mari Zoltan, Morgan John C, Parashos Sotirios, Pérez Adriana, Petrovitch Helen, Rajan Suja, Reichwein Sue, Roth Jessie Tatsuno, Schneider Jay S, Shannon Kathleen M, Simon David K, Simuni Tanya, Singer Carlos, Sudarsky Lewis, Tanner Caroline M, Umeh Chizoba C, Williams Karen, Wills Anne-Marie
University of Rochester, Rochester, New York.
University of Texas Health Science Center at Houston.
JAMA. 2015 Feb 10;313(6):584-93. doi: 10.1001/jama.2015.120.
There are no treatments available to slow or prevent the progression of Parkinson disease, despite its global prevalence and significant health care burden. The National Institute of Neurological Disorders and Stroke Exploratory Trials in Parkinson Disease program was established to promote discovery of potential therapies.
To determine whether creatine monohydrate was more effective than placebo in slowing long-term clinical decline in participants with Parkinson disease.
DESIGN, SETTING, AND PATIENTS: The Long-term Study 1, a multicenter, double-blind, parallel-group, placebo-controlled, 1:1 randomized efficacy trial. Participants were recruited from 45 investigative sites in the United States and Canada and included 1741 men and women with early (within 5 years of diagnosis) and treated (receiving dopaminergic therapy) Parkinson disease. Participants were enrolled from March 2007 to May 2010 and followed up until September 2013.
Participants were randomized to placebo or creatine (10 g/d) monohydrate for a minimum of 5 years (maximum follow-up, 8 years).
The primary outcome measure was a difference in clinical decline from baseline to 5-year follow-up, compared between the 2 treatment groups using a global statistical test. Clinical status was defined by 5 outcome measures: Modified Rankin Scale, Symbol Digit Modalities Test, PDQ-39 Summary Index, Schwab and England Activities of Daily Living scale, and ambulatory capacity. All outcomes were coded such that higher scores indicated worse outcomes and were analyzed by a global statistical test. Higher summed ranks (range, 5-4775) indicate worse outcomes.
The trial was terminated early for futility based on results of a planned interim analysis of participants enrolled at least 5 years prior to the date of the analysis (n = 955). The median follow-up time was 4 years. Of the 955 participants, the mean of the summed ranks for placebo was 2360 (95% CI, 2249-2470) and for creatine was 2414 (95% CI, 2304-2524). The global statistical test yielded t1865.8 = -0.75 (2-sided P = .45). There were no detectable differences (P < .01 to partially adjust for multiple comparisons) in adverse and serious adverse events by body system.
Among patients with early and treated Parkinson disease, treatment with creatine monohydrate for at least 5 years, compared with placebo did not improve clinical outcomes. These findings do not support the use of creatine monohydrate in patients with Parkinson disease.
clinicaltrials.gov Identifier: NCT00449865.
尽管帕金森病在全球范围内普遍存在且带来巨大的医疗负担，但目前尚无能够延缓或预防其进展的治疗方法。美国国立神经疾病和中风研究所帕金森病探索性试验项目旨在促进潜在疗法的发现。
确定一水肌酸在减缓帕金森病患者长期临床衰退方面是否比安慰剂更有效。
设计、地点和患者：长期研究1，一项多中心、双盲、平行组、安慰剂对照、1:1随机疗效试验。参与者从美国和加拿大的45个研究地点招募，包括1741名患有早期（诊断后5年内）且接受治疗（接受多巴胺能治疗）的帕金森病男性和女性。参与者于2007年3月至2010年5月入组，并随访至2013年9月。
参与者被随机分配至安慰剂组或一水肌酸组（10克/天），为期至少5年（最长随访8年）。
主要结局指标是从基线到5年随访期间临床衰退的差异，使用整体统计检验在两个治疗组之间进行比较。临床状态由5项结局指标定义：改良Rankin量表、符号数字模态测试、PDQ - 39总结指数、施瓦布和英格兰日常生活活动量表以及步行能力。所有结局指标均进行编码，使得分数越高表明结局越差，并通过整体统计检验进行分析。总和秩次越高（范围为5 - 4775）表明结局越差。
根据对分析日期前至少5年入组的参与者（n = 955）进行的计划中期分析结果，该试验因无效而提前终止。中位随访时间为4年。在955名参与者中，安慰剂组的总和秩次均值为2360（95%CI，2249 - 2470），肌酸组为2414（95%CI，2304 - 2524）。整体统计检验得出t1865.8 = -0.75（双侧P = 0.45）。按身体系统分类的不良事件和严重不良事件没有可检测到的差异（P < 0.01以部分调整多重比较）。
在早期接受治疗的帕金森病患者中，与安慰剂相比，一水肌酸治疗至少5年并未改善临床结局。这些发现不支持在帕金森病患者中使用一水肌酸。
clinicaltrials.gov标识符：NCT00449865。
