Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: A phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study
Efficacy and tolerability of lisdexamfetamine dimesylate (NRP-104) in children with attention-deficit/hyperactivity disorder: A phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study
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DOI：
10.1016/s0149-2918(07)80083-x
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发表时间：
2007-03-01
影响因子：
3.2
通讯作者：
Findling, Robert L.
中科院分区：
文献类型：
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作者：
Biederman, Joseph;Krishnan, Suma;Findling, Robert L.
背景：二甲磺酸利右苯丙胺（LDX）是一种无治疗活性的苯丙胺前药。它的开发目标是提供一个延长的持续时间的效果是一致的一整天，减少滥用的可能性，过量的毒性，和药物篡改。在摄入后，通过限速水解作用逐渐释放具有生物活性的d-苯丙胺分子。目的：本研究的目的是评估LDX的疗效和耐受性在学龄儿童注意力缺陷/多动障碍（ADHD）在社区治疗，并描述LDX的作用时间与安慰剂相比。方法：这第三阶段，多中心，随机，双盲，强制剂量，平行组研究在美国的40个中心进行。6 - 12岁ADHD男女儿童随机接受LDX 30、50或70 mg强制剂量滴定或安慰剂，PO QD，持续4周。使用ADHD评定量表第四版（ADHD-RS-IV）、Conners父母评定量表（CPRS）和临床总体印象改善量表评估疗效。结果：在290名随机患者中（201名男孩，89名女孩;平均[SD]年龄，9 [1.8]岁），230名完成了试验（LDX 30 mg，n = 56; LDX 50 mg，n = 60; LDX 70 mg，n = 60;安慰剂，n = 54）。研究中止的最常见原因（n = 60）是缺乏疗效（LDX 30 mg，1%; LDX 50 mg，0%; LDX 70 mg，1%;安慰剂，17%）和不良事件（AE）（LDX 30 mg，9%; LDX 50 mg，5%; LDX 70 mg，14%;安慰剂，1%）。与安慰剂相比，所有剂量的LDX均观察到ADHD-RS-IV评分显著改善（所有，P < 0.001），全天所有LDX剂量与安慰剂相比CPRS评分显著改善（所有，所有比较P < 0.001）。在治疗的第一周观察到疗效，并且在一天中观察到改善，直至下午6点。在接受LDX治疗的患者中，最常报告的AE是典型的安非他明产品：食欲下降（活性药物治疗组为39%，安慰剂组为4%），失眠（19% vs 3%），上腹痛（12% vs 6%），头痛（12% vs 10%），易怒（10% vs 0%），呕吐（9% vs 4%），体重减轻（9% vs 1%）和恶心（6%对3%）;大多数为轻度至中度，发生在第一周。在这个患有ADHD的儿童人群中，每天一次用剂量为30至70 mg的前药LDX治疗似乎是有效的，并且具有与目前市售的缓释兴奋剂相似的耐受性特征。(Clin Ther. 2007;29：450-463）版权所有（c）2007 Excerpta Medica，Inc.
Background: Lisdexamfetamine dimesylate (LDX) is a therapeutically inactive amphetamine prodrug. It was developed with the goal of providing an extended duration of effect that is consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering. Following ingestion, the pharmacologically active d-amphetamine molecule is gradually released by rate-limited hydrolysis. Objectives: The aims of this study were to assess the efficacy and tolerability of LDX in school-aged children with attention-deficit/hyperactivity disorder (ADHD) treated in the community, and to characterize the duration of action of LDX compared with placebo.Methods: This Phase III, multicenter, randomized, double-blind, forced-dose, parallel-group study was conducted at 40 centers across the United States. Male and female children aged 6 to 12 years with ADHD were randomly assigned to receive LDX 30, 50, or 70 mg with forced-dose titration, or placebo, PO QD for 4 weeks. Efficacy was assessed using the ADHD Rating Scale Version IV (ADHD-RS-IV), the Conners' Parent Rating Scale (CPRS), and the Clinical Global Impression of Improvement scale. Tolerability was assessed throughout the study.Results: Of the 290 randomized patients (201 boys, 89 girls; mean [SD] age, 9 [1.8] years), 230 completed the trial (LDX 30 mg, n = 56; LDX 50 mg, n = 60; LDX 70 mg, n = 60; and placebo, n = 54). The most common reasons for study discontinuation (n = 60) were lack of efficacy (LDX 30 mg, 1%; LDX 50 mg, 0%; LDX 70 mg, 1%; and placebo, 17%) and adverse events (AEs) (LDX 30 mg, 9%; LDX 50 mg, 5%; LDX 70 mg, 14%; and placebo, 1%). Significant improvements in ADHD-RS-IV scores were seen with all doses of LDX compared with placebo (all, P < 0.001), and in CPRS scores with all LDX doses versus placebo throughout the day (all, P < 0.001 for all comparisons). Efficacy was observed by the first week of treatment, and improvements were observed throughout the day up to similar to 6 PM. The most frequently reported AEs among patients receiving LDX were typical of amphetamine products: decreased appetite (39% with active treatment vs 4% with placebo), insomnia (19% vs 3%), upper abdominal pain (12% vs 6%), headache (12% vs 10%), irritability (10% vs 0%), vomiting (9% vs 4%), weight decrease (9% vs 1%), and nausea (6% vs 3%); most were mild to moderate and occurred in the first week.Conclusion: In this population of children with ADHD, treatment once daily with the prodrug LDX at doses of 30 to 70 mg appeared to be effective and had a tolerability profile similar to those of currently marketed extended-release stimulants. (Clin Ther. 2007;29:450-463) Copyright (c) 2007 Excerpta Medica, Inc.