BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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 .).

中文翻译：

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帕金森氏病左旋多巴的随机延迟开始试验。

背景技术左旋多巴是帕金森氏病症状的主要治疗方法。确定左旋多巴是否也具有改善疾病的作用，可以为在疾病进程中何时应开始使用该药物的治疗提供指导。方法在一项多中心，双盲，安慰剂对照，延迟开始的试验中，我们随机分配早期帕金森氏病患者接受左旋多巴（每天100毫克，每日3次）和卡比多巴（每天25毫克，每日3次）的联合治疗。 80周（早期开始组）或安慰剂40周，然后左旋多巴与卡比多巴合用40周（延迟开始组）。主要结局是统一帕金森氏病评分量表（UPDRS；从基线到第80周）的平均组间差异。分数范围从0到176，分数越高表示疾病越严重）。次要分析包括通过UPDRS评分测得的症状进展，在第4周至40周之间，以及从早期开始治疗至延缓开始治疗之间的非劣效性，在每周第44至80周之间，非劣质性裕度为每周0.055分。结果共有445例患者被随机分配：早期开始组222例，延迟开始组223例。早期开始组在基线时的UPDRS平均（±SD）得分为28.1±11.4分，延迟开始组为29.3±12.1分。从基线到第80周，UPDRS得分的变化分别为-1.0±13.1点和-2.0±13.0点（差异为1.0点； 95％置信区间[CI]为-1.5至3.5； P = 0.44）；这一发现在第80周时没有明显的组间差异，这表明左旋多巴没有改善疾病的作用。在第4周至第40周之间，以每周UPDRS积分衡量的症状进展率，早期开始组为0.04±0.23，而延迟开始组为0.06±0.34（差异，-0.02； 95％CI ，-0.07至0.03）。第44周和第80周之间的相应比率为0.10±0.25和0.03±0.28（差异为0.07；双面90％CI为0.03至0.10）；在第44周和第80周之间进展率的差异不符合早期接受左旋多巴与延迟接受非劣效性的标准。两组之间运动障碍和左旋多巴相关的运动反应波动率无显着差异。结论在早期帕金森病患者中 在经过80周的评估后，如果使用左旋多巴联合卡比多巴进行治疗，则没有疾病改善效果。（由荷兰卫生研究与发展组织及其他组织资助； LEAP当前对照试验编号，ISRCTN30518857。）。