Advisium, 's Heeren Loo, Amersfoort, the Netherlands.
Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands.
Orphanet J Rare Dis. 2021 Sep 8;16(1):380. doi: 10.1186/s13023-021-02003-z.
Smith-Magenis syndrome (SMS) is a rare genetic neurodevelopmental disorder characterized by intellectual disability and severe behavioural and sleep disturbances. Often, patients with SMS are diagnosed with attention-deficit/hyperactivity disorder (ADHD). However, the effectiveness of methylphenidate (MPH), the first-line pharmacological treatment for ADHD, in patients with SMS is unclear. Our objective is to examine the effectiveness of MPH for ADHD symptoms in individuals with SMS, proposing an alternative trial design as traditional randomized controlled trials are complex in these rare and heterogeneous patient populations.
We will initiate an N-of-1 series of double-blind randomized and placebo-controlled multiple crossover trials in six patients aged ≥ 6 years with a genetically confirmed SMS diagnosis and a multidisciplinary established ADHD diagnosis, according to a power analysis based on a summary measures analysis of the treatment effect. Each N-of-1 trial consists of a baseline period, dose titration phase, three cycles each including randomized intervention, placebo and washout periods, and follow-up. The intervention includes twice daily MPH (doses based on age and body weight). The primary outcome measure will be the subscale hyperactivity/inattention of the Strengths and Difficulties Questionnaire (SDQ), rated daily. Secondary outcome measures are the shortened version of the Emotion Dysregulation Inventory (EDI) reactivity index, Goal Attainment Scaling (GAS), and the personal questionnaire (PQ). Statistical analysis will include a mixed model analysis. All subjects will receive an assessment of their individual treatment effect and data will be aggregated to investigate the effectiveness of MPH for ADHD in SMS at a population level.
This study will provide information on the effectiveness of MPH for ADHD in SMS, incorporating personalized outcome measures. This protocol presents the first properly powered N-of-1 study in a rare genetic neurodevelopmental disorder, providing a much-needed bridge between science and practice to optimize evidence-based and personalized care.
This study is registered in the Netherlands Trial Register (NTR9125).
Smith-Magenis 综合征（SMS）是一种罕见的遗传性神经发育障碍，其特征为智力残疾和严重的行为和睡眠障碍。通常，SMS 患者被诊断为注意力缺陷/多动障碍（ADHD）。然而，对于 SMS 患者，作为 ADHD 一线药物治疗的哌醋甲酯（MPH）的疗效尚不清楚。我们的目的是研究 MPH 对 SMS 患者 ADHD 症状的疗效，并提出一种替代的试验设计，因为在这些罕见和异质的患者群体中，传统的随机对照试验设计较为复杂。
我们将根据基于治疗效果综合评估的功效分析，在 6 名年龄≥6 岁、具有明确的 SMS 遗传诊断和多学科确诊的 ADHD 诊断的患者中启动一项 N-of-1 系列的双盲随机、安慰剂对照、多交叉试验。每个 N-of-1 试验包括基线期、剂量滴定期、三个周期（每个周期包括随机干预、安慰剂和洗脱期）和随访期。干预措施包括每日两次 MPH（根据年龄和体重确定剂量）。主要结局指标为 Strengths and Difficulties Questionnaire（SDQ）多动/注意力不集中分量表，每日评分。次要结局指标包括缩短版的情绪失调量表（EDI）反应指数、目标实现量表（GAS）和个人问卷（PQ）。统计分析将包括混合模型分析。所有患者将接受个体化治疗效果评估，并对数据进行汇总，以研究 MPH 对 SMS 中 ADHD 的疗效。
该研究将提供有关 MPH 对 SMS 中 ADHD 的疗效的信息，纳入个性化的结局指标。该方案首次在罕见的遗传性神经发育障碍中进行了适当功率的 N-of-1 研究，为优化循证和个性化护理提供了科学和实践之间急需的桥梁。
本研究已在荷兰临床试验注册中心（NTR9125）注册。
