Objective

To evaluate the acute efficacy, safety, and tolerability of lisdexamfetamine dimesylate (LDX) vs placebo (PBO) in preschool-aged children with attention-deficit/hyperactivity disorder (ADHD).

Method

This phase 3, double-blind, fixed-dose study randomly assigned children (aged 4-5 years) with ADHD to 6 weeks of LDX (5, 10, 20, 30 mg) or PBO. The prespecified primary (change from baseline at week 6 in ADHD Rating Scale IV, Preschool version, total score [ADHD-RS-IV-PS-TS]) and key secondary (Clinical Global Impression–Improvement [CGI-I] score at week 6) efficacy endpoints were assessed using linear mixed-effects models for repeated measures. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs) and changes in pulse and blood pressure (BP).

Results

The study comprised 199 participants randomly asigned 5:5:5:5:6 to receive 5, 10, 20, 30 mg LDX or PBO, respectively. Least squares (LS) mean (95% CI) treatment difference at week 6 between pooled LDX (10, 20, 30 mg) and PBO was statistically significant for ADHD-RS-IV-PS-TS change (–5.9 [–11.01, –0.78], p = .0242; effect size [ES], –0.43). CGI-I scores improved (ie, 1-2 on CGI-I) in 41.7% for pooled LDX and 24.3% for PBO (p = .0857). The LS mean (95% CI) treatment difference between pooled LDX and PBO for CGI-I score at week 6 was –0.6 (–1.03, –0.16; p = .0074; ES, –0.52). Frequency of TEAEs was 46.6% across all 4 LDX doses vs 42.2% with PBO; the most frequent TEAEs were decreased appetite (13.7% vs 8.9%, respectively) and irritability (9.6% vs 0%). Discontinuations because of TEAEs were 5.5% for all LDX doses and 4.4% for PBO. Mean ± SD pulse/BP changes from baseline at week 6/early termination were numerically greater with LDX vs PBO (pulse beats/min: 2.7 ± 10.79 vs 1.2 ± 9.90; systolic BP, mm Hg: 1.0 ± 7.51 vs 0.3 ± 6.06; diastolic BP, mm Hg: 1.7 ± 5.90 vs 0.0 ± 6.88).

Conclusion

In children aged 4 to 5 years with ADHD, LDX was more efficacious than PBO in reducing symptoms. The observed ES for change in ADHD-RS-IV-PS-TS appears to be smaller in magnitude than has been reported for studies of LDX conducted in older children and adolescents. LDX was generally well tolerated, and no new safety signals were identified.

Clinical trial registration information

Safety and Efficacy Study in Preschool Children Aged 4–5 Years With Attention-Deficit/Hyperactivity Disorder; http://www.clinicaltrials.gov; NCT03260205.

中文翻译：

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Lisdexamfetamine 在注意力缺陷/多动障碍学龄前儿童中的疗效和安全性

客观的

评估 lisdexamfetamine dimesylate (LDX) 与安慰剂 (PBO) 在患有注意力缺陷/多动障碍 (ADHD) 的学龄前儿童中的急性疗效、安全性和耐受性。

方法

该 3 期双盲固定剂量研究将患有 ADHD 的儿童（4-5 岁）随机分配至 6 周的 LDX（5、10、20、30 毫克）或 PBO。预先指定的主要（第 6 周 ADHD 评定量表 IV 的基线变化，学龄前版本，总分 [ADHD-RS-IV-PS-TS]）和关键次要（第 6 周的临床整体印象–改善 [CGI-I] 得分6) 使用重复测量的线性混合效应模型评估疗效终点​​。安全性和耐受性评估包括治疗中出现的不良事件 (TEAE) 以及脉搏和血压 (BP) 的变化。

结果

该研究包括 199 名参与者，他们按照 5:5:5:5:6 的比例随机分配，分别接受 5、10、20、30 毫克 LDX 或 PBO。第 6 周时，合并的 LDX（10、20、30 mg）和 PBO 之间的最小二乘法 (LS) 平均 (95% CI) 治疗差异对于 ADHD-RS-IV-PS-TS 变化具有统计学意义 (–5.9 [–11.01, –0.78]，p  = .0242；效应大小 [ES]，–0.43）。合并 LDX 的 CGI-I 分数提高（即 CGI-I 上的 1-2）为 41.7%，PBO 为 24.3% ( p  = .0857)。第 6 周 CGI-I 评分的合并 LDX 和 PBO 之间的 LS 平均（95% CI）治疗差异为 –0.6（–1.03，–0.16；p = .0074; ES，–0.52）。在所有 4 种 LDX 剂量中，TEAE 的频率为 46.6%，而 PBO 为 42.2%；最常见的 TEAE 是食欲下降（分别为 13.7% 和 8.9%）和烦躁（9.6% 和 0%）。所有 LDX 剂量因 TEAE 而停药的比例为 5.5%，PBO 为 4.4%。LDX 与 PBO 相比，第 6 周/提前终止时基线的平均 ± SD 脉搏/血压变化在数值上更大（脉搏跳动/分钟：2.7 ± 10.79 对比 1.2 ± 9.90；收缩压，mm Hg：1.0 ± 7.51 对比 0.3 ± 6.06；舒张压，毫米汞柱：1.7 ± 5.90 对比 0.0 ± 6.88）。

结论

在 4 至 5 岁的多动症儿童中，LDX 在减轻症状方面比 PBO 更有效。观察到的 ADHD-RS-IV-PS-TS 变化的 ES 似乎比在大龄儿童和青少年中进行的 LDX 研究报告的幅度要小。LDX 通常耐受性良好，并且没有发现新的安全信号。

临床试验注册信息

4-5 岁注意力缺陷/多动障碍学龄前儿童的安全性和有效性研究；http://www.clinicaltrials.gov；NCT03260205。