Background

Therapeutic options for children with multiple sclerosis are scarce. Teriflunomide is approved in more than 80 countries for the treatment of adults with relapsing multiple sclerosis. The TERIKIDS study examined the safety and efficacy of teriflunomide in children with relapsing multiple sclerosis.

Methods

The TERIKIDS trial was a multicentre, phase 3, double-blind, parallel-group, randomised, placebo-controlled study conducted at 57 clinical centres in 22 countries in Asia, Europe, the Middle East, North Africa, and North America. The trial enrolled patients aged 10–17 years, diagnosed with relapsing multiple sclerosis and with at least one relapse in the year preceding screening or at least two relapses in the 2 years preceding screening. Patients were randomly assigned (2:1) to oral teriflunomide (dosage equivalent to 14 mg in adults) or matching placebo, using an interactive web and voice response system, for up to 96 weeks. Personnel in all sites and all patients were masked to study treatment in the double-blind period. Early entry into a subsequent 96-week open-label extension phase was possible before the end of the double-blind period for patients with confirmed clinical relapse or high MRI activity (at least five new or enlarged T2 lesions at week 24, followed by at least nine new or enlarged T2 lesions at week 36, or at least five new or enlarged T2 lesions at weeks 36 and 48, or at weeks 48 and 72). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period. Key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Efficacy endpoints were analysed in the intention-to-treat population, and safety was assessed in all patients randomly assigned to treatment and exposed to the double-blind study medication. This study is registered with ClinicalTrials.gov (trial number NCT02201108) and is closed to recruitment, but an additional optional open-label extension is ongoing.

Findings

Between July 24, 2014, and the date of last patient visit on Oct 25, 2019, 185 patients were screened for eligibility, 166 (90%) were enrolled, and 109 were randomly assigned teriflunomide and 57 were randomly assigned placebo. 102 (94%) of 109 and 53 (93%) of 57 completed the double-blind period. Switch to the ongoing open-label extension because of high MRI activity was more frequent than anticipated in the placebo group (14 [13%] of 109 patients in the teriflunomide group vs 15 [26%] of 57 in the placebo group), decreasing the power of the study. After 96 weeks, there was no difference in time to first confirmed clinical relapse with teriflunomide compared with placebo (hazard ratio 0·66, 95% CI 0·39–1·11; p=0·29). Teriflunomide reduced the number of new or enlarged T2 lesions versus placebo by 55% (relative risk 0·45, 95% CI 0·29–0·71; p=0·00061), and the number of gadolinium-enhancing lesions by 75% (relative risk 0·25, 0·13–0·51; p<0·0001). Adverse events occurred in 96 (88%) patients in the teriflunomide group and 47 (82%) patients in the placebo group; serious adverse events occurred in 12 (11%) patients in the teriflunomide group and 6 (11%) patients in the placebo group. Nasopharyngitis, upper-respiratory-tract infection, alopecia, paraesthesia, abdominal pain, and increased blood creatine phosphokinase were more frequent with teriflunomide than with placebo. During the double-blind phase, four patients in the teriflunomide group had pancreatic adverse events (two with acute pancreatitis and two with pancreatic enzyme elevation), of which three events led to treatment discontinuation.

Interpretation

No significant difference in time to first confirmed clinical relapse was found, possibly because more patients than expected switched from the double-blind to the open-label treatment period because of high MRI activity. Key secondary imaging analyses and a prespecified sensitivity analysis of probability of relapse or high MRI activity suggest that teriflunomide might have beneficial effects in children with relapsing multiple sclerosis by reducing the risk of focal inflammatory activity.

Funding

Sanofi.

中文翻译：

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特立氟胺治疗儿童多发性硬化症 (TERIKIDS) 的安全性和有效性：一项多中心、双盲、3 期、随机、安慰剂对照试验

背景

多发性硬化症儿童的治疗选择很少。特立氟胺在 80 多个国家被批准用于治疗成人复发性多发性硬化症。TERIKIDS 研究检查了特立氟胺在儿童复发性多发性硬化症中的安全性和有效性。

方法

TERIKIDS 试验是一项多中心、3 期、双盲、平行组、随机、安慰剂对照研究，在亚洲、欧洲、中东、北非和北美的 22 个国家的 57 个临床中心进行。该试验招募了 10-17 岁的患者，被诊断患有复发性多发性硬化症，并且在筛查前一年至少复发一次或在筛查前 2 年内至少复发两次。患者被随机分配（2:1）口服特立氟胺（剂量相当于成人 14 毫克）或匹配安慰剂，使用交互式网络和语音响应系统，长达 96 周。所有地点的人员和所有患者都被蒙面以研究双盲期间的治疗。对于已确认临床复发或高 MRI 活动的患者（第 24 周时至少有 5 个新的或扩大的 T2 病灶，随后在第 36 周时至少有 9 个新的或扩大的 T2 病灶，或在第 36 周和第 48 周或第 48 周和第 72 周时至少有五个新的或扩大的 T2 病灶）。主要终点是到双盲期结束时首次确认临床复发的时间。关键的次要成像终点是新的或扩大的 T2 病灶的数量和每次 MRI 扫描的钆增强病灶的数量。在意向治疗人群中分析了疗效终点，并在所有随机分配接受治疗并接受双盲研究药物治疗的患者中评估了安全性。

发现

从 2014 年 7 月 24 日到最后一次患者就诊日期为 2019 年 10 月 25 日，对 185 名患者进行了合格筛查，其中 166 名（90%）患者入组，109 名随机分配特立氟胺，57 名随机分配安慰剂。109 人中的 102 人（94%）和 57 人中的 53 人（93%）完成了双盲期。由于高 MRI 活动性而改用正在进行的开放标签扩展比安慰剂组的预期更频繁（特立氟胺组 109 名患者中的 14 [13%] vs安慰剂组 57 人中有 15 人 [26%]），降低了研究的功效。96 周后，与安慰剂相比，特立氟胺首次确认临床复发的时间没有差异（风险比 0·66，95% CI 0·39–1·11；p=0·29）。与安慰剂相比，特立氟胺将新的或扩大的 T2 病灶数量减少了 55%（相对风险 0·45，95% CI 0·29–0·71；p=0·00061），钆增强病灶的数量减少了 75 %（相对风险 0·25、0·13–0·51；p<0·0001）。特立氟胺组 96 例 (88%) 患者和安慰剂组 47 例 (82%) 患者发生了不良事件；特立氟胺组 12 例（11%）患者和安慰剂组 6 例（11%）患者发生严重不良事件。鼻咽炎、上呼吸道感染、脱发、感觉异常、腹痛、特立氟胺组的血肌酸磷酸激酶升高比安慰剂组更常见。在双盲阶段，特立氟胺组4例患者出现胰腺不良事件（2例急性胰腺炎，2例胰酶升高），其中3例导致治疗中断。

解释

首次确认临床复发的时间没有显着差异，这可能是由于高 MRI 活动性，从双盲转为开放标签治疗期的患者多于预期。关键的二次成像分析和预先指定的复发概率或高 MRI 活动的敏感性分析表明，teriflunomide 可能通过降低局灶性炎症活动的风险对患有复发性多发性硬化症的儿童产生有益的影响。

资金

赛诺菲。