From the Department of Neurology, Amsterdam Neuroscience (C.V.M.V., S.R.S., J.A.B., R.M.A.B.), Clinical Epidemiology, Biostatistics, and Bioinformatics (M.G.W.D.), and the Clinical Research Unit (R.J.H.), Amsterdam UMC, University of Amsterdam, AMC, Amsterdam, the Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behavior, Nijmegen (B.P., B.R.B.), the Department of Neurology, Leiden University Medical Center, Leiden (J.J.H.), the Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen (T.L.), the Department of Neurology, Zuyderland Medical Center, Heerlen (G.T.), and the Department of Neurology, Spaarne Gasthuis, Haarlem (A.G.M.) - all in the Netherlands; the Department of Neurology, University Medical Center Schleswig-Holstein, Kiel, Germany (G.D.); and the Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, University of Toronto, Toronto (A.E.L.).
N Engl J Med. 2019 Jan 24;380(4):315-324. doi: 10.1056/NEJMoa1809983.
Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated.
In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week.
A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups.
Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).
左旋多巴是治疗帕金森病症状的主要药物。确定左旋多巴是否具有疾病修饰作用，可以为何时开始用这种药物治疗提供指导。
在一项多中心、双盲、安慰剂对照、延迟启动试验中，我们将早期帕金森病患者随机分为两组，一组接受左旋多巴（每天 3 次，每次 100mg）联合卡比多巴（每天 3 次，每次 25mg）治疗 80 周（早期开始组），另一组接受安慰剂治疗 40 周，然后接受左旋多巴联合卡比多巴治疗 40 周（延迟开始组）。主要结局是从基线到第 80 周时，统一帕金森病评定量表（UPDRS）总分的组间差异（评分范围为 0 至 176，得分越高表示疾病越严重）。次要分析包括 UPDRS 评分之间的症状进展，以及在第 4 周到第 40 周之间治疗开始时间的非劣效性，非劣效性边界为每周 0.055 分。
共有 445 名患者被随机分配：222 名进入早期开始组，223 名进入延迟开始组。早期开始组的基线 UPDRS 评分平均（±SD）为 28.1±11.4 分，延迟开始组为 29.3±12.1 分。从基线到第 80 周，UPDRS 评分的变化分别为-1.0±13.1 分和-2.0±13.0 分（差异为 1.0 分；95%置信区间[CI]为-1.5 至 3.5；P=0.44）；这一发现表明，在第 80 周时，两组间无显著差异，提示左旋多巴没有疾病修饰作用。在第 4 周到第 40 周之间，以每周 UPDRS 评分表示的症状进展率，早期开始组为 0.04±0.23，延迟开始组为 0.06±0.34（差异为-0.02；95%CI为-0.07 至 0.03）。在第 44 周到第 80 周之间，相应的比率分别为 0.10±0.25 和 0.03±0.28（差异为 0.07；双侧 90%CI 为 0.03 至 0.10）；第 44 周到第 80 周之间的进展率差异不符合早期接受左旋多巴治疗与延迟接受治疗的非劣效性标准。两组之间的运动反应相关运动障碍和左旋多巴相关波动的发生率没有显著差异。
在接受 80 周评估的早期帕金森病患者中，左旋多巴联合卡比多巴治疗没有疾病修饰作用。（由荷兰健康研究与发展组织和其他组织资助；LEAP 现况对照试验编号，ISRCTN30518857）。
