Table_1_Delayed-Release Dimethyl Fumarate Safety and Efficacy in Pediatric Patients With Relapsing-Remitting Multiple Sclerosis.docx

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5–5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS.
Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13–17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR).
Results: Twenty participants [median (range) age, 17 (14–18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16–24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0–6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction (n = 20; 95% confidence interval: 66.8–92.8; p < 0.0001) vs. the year before DMF initiation.
Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment.

背景：儿童多发性硬化（Pediatric multiple sclerosis, MS）较为罕见，仅1.5%~5%的多发性硬化病例在18岁前被确诊，且针对儿童多发性硬化的疾病修正治疗（disease-modifying therapies, DMTs）相关数据较为有限。CONNECTED研究评估了口服多发性硬化疾病修正治疗药物——缓释富马酸二甲酯（delayed-release dimethyl fumarate, DMF）用于儿童多发性硬化患者的长期安全性与有效性。
方法：CONNECTED研究是针对FOCUS研究的96周延长期队列；FOCUS是一项纳入13~17岁患者的24周Ⅱ期临床试验，受试者均接受每日两次、每次240mg的DMF治疗。研究终点包括：主要终点为不良事件（adverse events, AEs）、严重不良事件的发生率，以及因不良事件导致的DMF停药率；次要终点则为磁共振成像下的T2高信号病灶发生率，以及年复发率（annualized relapse rate, ARR）。
结果：共有20名完成FOCUS研究的受试者[年龄中位数（范围）：17（14~18）岁；女性占比65%]入组CONNECTED研究，其中17名（85%）完成了该延长期研究。18名受试者（90%）报告了不良事件，最常见的不良事件为潮红（25%）。无受试者出现与淋巴细胞计数降低相关的感染或发热症状。3名受试者共发生4起严重不良事件，无一例导致DMF停药。在第16~24周期间，17名受试者中有12名（71%）未出现新发病灶或新发/增大的T2病灶；2名（12%）出现1个病灶；另有1名受试者分别出现2个、3个及5个以上病灶[中位数（范围）：0（0~6）]。在整个120周的治疗周期中，年复发率为0.2，较DMF启动前一年相对降低84.5%（n=20；95%置信区间：66.8~92.8；p<0.0001）。
结论：CONNECTED研究中观察到的长期安全性与有效性数据与成人人群一致，提示儿童及青少年多发性硬化患者或可从DMF治疗中获益。