Nicholas Anthony P, Borgohain Rupam, Chaná Pedro, Surmann Erwin, Thompson Emily L, Bauer Lars, Whitesides John, Elmer Lawrence W
Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Neurology, Nizam's Institute of Medical Sciences, Andhra Pradesh, India.
J Parkinsons Dis. 2014;4(3):361-73. doi: 10.3233/JPD-130320.
Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established.
This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h.
Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'.
409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age.
The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.
先前针对左旋多巴治疗控制不佳的晚期帕金森病（PD）患者开展的Ⅲ期研究表明，使用最高达16 mg/24 h的罗替戈汀透皮系统可显著减少“关”期时间。然而，最小有效剂量尚未确定。
这项国际、随机、双盲、安慰剂对照研究（SP921；NCT00522379）调查了最高达8 mg/24 h的罗替戈汀剂量反应。
晚期特发性PD患者（稳定剂量左旋多巴治疗下每日“关”期时间≥2.5小时）按1:1:1:1:1随机分组，分别接受2、4、6或8 mg/24 h的罗替戈汀或安慰剂治疗，治疗4周并维持12周。主要疗效变量为从基线至维持期末“关”期绝对时间的变化。
514例随机分组患者中有409例（80%）完成维持期治疗。安慰剂组平均（±标准差）基线每日“关”期时间（小时/天）为6.4（±2.5），罗替戈汀2 - 8 mg/24 h组为6.4（±2.6）。与安慰剂相比，8 mg/24 h的罗替戈汀是显著减少“关”期时间的最小剂量。罗替戈汀8 mg/24 h组每日“关”期时间自基线的最小二乘均值（±标准误）绝对变化为-2.4（±0.28），安慰剂组为-1.5（±0.26）；8 mg/24 h组与安慰剂组相比，“关”期时间的绝对变化为-0.85小时/天（95%置信区间-1.59，-0.11；p = 0.024）。存在明显的剂量依赖性趋势。罗替戈汀8 mg/24 h组报告的不良事件（AE）发生率高于安慰剂组的包括用药部位反应、恶心、口干和运动障碍；即使在≥75岁的患者中，失眠、嗜睡、体位性低血压、意识模糊状态或幻觉也未加重。
减少绝对“关”期时间的罗替戈汀最小统计学显著有效剂量为8 mg/24 h。不良事件谱与先前研究相似。
