Saida Takahiko, Itoyama Yasuto, Kikuchi Seiji, Hao Qi, Kurosawa Takayoshi, Ueda Kengo, Auberson Lixin Zhang, Tsumiyama Isao, Nagato Kazuo, Kira Jun-Ichi
Institute of Multiple Sclerosis Therapeutics, Nishinokyo-Kasugacho 16-44-409, Nakakyo-ku, Kyoto, 604-8453, Japan.
Kyoto Min-Iren-Central Hospital, Kyoto, Japan.
BMC Neurol. 2017 Jan 28;17(1):17. doi: 10.1186/s12883-017-0794-5.
The low level of disease activity and manageable safety profile seen with fingolimod versus placebo in a 6-month, phase 2, randomized controlled trial in Japanese patients with relapsing multiple sclerosis (MS; ClinicalTrials.gov Identifier NCT00537082) were maintained in the initial 6-month observational study extension. Here, we report long-term safety and efficacy results of the 3-year follow-up to the phase 2 study extension.
The 6-month core study was completed by 147 patients, of whom 143 entered the extension and took at least one dose of fingolimod. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg (n = 23) or 0.5 mg (n = 27). During the extension, the patients taking fingolimod 1.25 mg (n = 46) were switched to open-label fingolimod 0.5 mg, and those originally randomized to fingolimod 0.5 mg (n = 47) continued with open-label fingolimod 0.5 mg.
Continuous fingolimod treatment was associated with a sustained low level of MRI and relapse activity for the duration of the extension phase; 75-100% (range across all assessment time points up to end of study) of patients remained free of Gd-enhanced T1 lesions, 88-100% remained free of new/newly enlarged T2 lesions, and 45-62% remained relapse-free. In patients who switched to the active treatment, a 79.5% decrease in annualized relapse rate (ARR; from 1.131 before switch to 0.232 6-months after switch) was observed in the first 6 months of the extension phase and thereafter remained low until the end of study (0.16-0.31 across all assessment time points after switch up to end of study). The mean number of Gd-enhanced T1 and new/newly enlarged T2 lesions decreased up to month 9 and thereafter remained low until the end of study (0.0-0.1 and 0.0-0.3, respectively, across all assessment time points after switch up to end of study). Fingolimod was generally well-tolerated and the safety profile was consistent with the core and 6-month extension. Serious adverse events were reported in 13.3% of patients during the extension study, with the range in the continuous fingolimod and placebo-fingolimod switch groups (3.7-21.7%) being similar to that reported in the core study for the placebo and fingolimod groups (5.3-20.4%).
Continuous fingolimod treatment over 36 months was associated with maintained efficacy and a manageable safety profile with no new safety signals. These results indicate that fingolimod provides long-term treatment benefit for Japanese patients with relapsing MS.
ClinicalTrials.gov NCT00670449 (April 28, 2008).
在一项针对日本复发型多发性硬化症（MS）患者的为期6个月的2期随机对照试验中（ClinicalTrials.gov标识符NCT00537082），与安慰剂相比，芬戈莫德显示出低疾病活动水平和可控的安全性，在最初的6个月观察性研究延长期内得以维持。在此，我们报告2期研究延长期3年随访的长期安全性和疗效结果。
147例患者完成了6个月的核心研究，其中143例进入延长期并至少服用一剂芬戈莫德。那些最初随机分配到安慰剂组的患者被重新随机分配到1.25毫克芬戈莫德组（n = 23）或0.5毫克芬戈莫德组（n = 27）。在延长期内，服用1.25毫克芬戈莫德的患者（n = 46）转为开放标签的0.5毫克芬戈莫德，而最初随机分配到0.5毫克芬戈莫德组的患者（n = 47）继续服用开放标签的0.5毫克芬戈莫德。
在延长期内，持续使用芬戈莫德治疗与MRI和复发活动的持续低水平相关；在研究结束前的所有评估时间点范围内，75 - 100%的患者没有钆增强T1病变，88 - 100%的患者没有新的/新增大的T2病变，45 - 62%的患者没有复发。在转为活性治疗的患者中，观察到延长期的前6个月年化复发率（ARR）下降了79.5%（从转换前的1.131降至转换后6个月的0.232），此后直至研究结束一直保持在低水平（转换后至研究结束的所有评估时间点为0.16 - 0.31）。钆增强T1和新的/新增大的T2病变的平均数量在第9个月前下降，此后直至研究结束一直保持在低水平（转换后至研究结束的所有评估时间点分别为0.0 - 0.1和0.0 - 0.3）。芬戈莫德总体耐受性良好，安全性与核心研究及6个月延长期一致。在延长期研究中，13.3%的患者报告了严重不良事件，持续使用芬戈莫德组和安慰剂 - 芬戈莫德转换组的发生率范围（3.7 - 21.7%）与核心研究中安慰剂组和芬戈莫德组报告的发生率范围（5.3 - 20.4%）相似。
36个月持续使用芬戈莫德治疗与疗效维持和可控的安全性相关，没有新的安全信号。这些结果表明，芬戈莫德为日本复发型MS患者提供了长期治疗益处。
ClinicalTrials.gov NCT00670449（2008年4月28日）
