St Luke's Medical Center, Center for Neurological Disorders, Milwaukee, WI 53215, USA.
Lancet Neurol. 2011 Jun;10(6):520-9. doi: 10.1016/S1474-4422(11)70099-0. Epub 2011 May 13.
In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod.
Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834.
1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p<0.0001 for T2 lesions at both doses; p=0.002 for T1 at 0.5 mg; p=0.011 for T1 at 1.25 mg), and the pattern of adverse events shifted towards that typical for fingolimod. Over 24 months, in continuous fingolimod groups compared with the group that switched from interferon beta-1a to fingolimod, we recorded lower ARRs (0.18 [95% CI 0.14-0.22] for 0.5 mg; 0.20 [0.16-0.25] for 1.25 mg; 0.33 [0.27-0.39] for the switch group; p<0.0001 for both comparisons), fewer new or newly enlarged T2 lesions (p=0.035 for 0.5 mg, p=0.068 for 1.25 mg), and fewer patients with Gd-enhancing T1 lesions (p=0.001 for 0.5 mg fingolimod vs switch group; p=0.002 for 1.25 mg fingolimod vs switch group). There was no benefit on disability progression.
Switching from interferon beta-1a to fingolimod led to enhanced efficacy with no unexpected safety concerns. Compared with patients switched from interferon beta-1a to fingolimod, continuous treatment with fingolimod for 2 years provides a sustained treatment effect with improved clinical and MRI outcomes.
Novartis Pharma AG.
在一项针对复发缓解型多发性硬化症（RRMS）患者的 12 个月 3 期研究中，与干扰素β-1a 相比，特立氟胺在复发率和 MRI 结果方面显示出更大的疗效。我们的扩展研究有两个目的：比较转换患者的第 2 年与第 1 年，以评估从干扰素β-1a 转换为特立氟胺的效果，以及比较原始随机分组的治疗组以评估延迟特立氟胺治疗开始的效果。
在核心研究中随机分配接受 0.5mg 或 1.25mg 每日口服特立氟胺的患者在扩展研究中继续接受相同的治疗；最初接受 30μg 每周肌内注射干扰素β-1a 的患者被随机（1:1）重新分配接受 0.5mg 或 1.25mg 特立氟胺。扩展研究中最初分配的特立氟胺初始随机分组和剂量对患者和研究者均保持盲态。与核心研究一样，重新随机分组以 6 个为一组进行，按地点分层。我们的疗效终点是年复发率（ARR）、残疾进展和 MRI 结果。我们的组内分析基于进入扩展研究的意向治疗和安全性人群。我们的组间分析基于核心研究的意向治疗和安全性人群。本研究在 ClinicalTrials.gov 注册，编号为 NCT00340834。
1027 名患者进入我们的扩展研究并接受了研究药物，882 名患者完成了 24 个月的治疗。接受连续特立氟胺治疗的患者在 ARR 方面持续受益（0.5mg 特立氟胺[ n =356]，0.12[95%CI 0.08-0.17]在 0-12 个月与 13-24 个月；1.25mg 特立氟胺[ n =330]，0.15[95%CI 0.10-0.21]与 0.11[0.08-0.16]；然而，在最初接受干扰素β-1a 的患者中，与前 12 个月相比，转换为特立氟胺后 ARR 降低（干扰素β-1a 至 0.5mg 特立氟胺[ n =167]，0.31[95%CI 0.22-0.43]在 0-12 个月与 13-24 个月，p =0.049；干扰素β-1a 至 1.25mg 特立氟胺[ n =174]，0.29[95%CI 0.20-0.40]与 0.18[95%CI 0.12-0.27]，p =0.024）。与前 12 个月的干扰素β-1a 治疗相比，转换为特立氟胺后新的或新扩大的 T2 和钆增强 T1 病变的数量显著减少（两种剂量的 T2 病变均<0.0001；0.5mg 的 T1 病变，p =0.002；1.25mg 的 T1 病变，p =0.011），不良事件的模式转向特立氟胺的典型模式。与从干扰素β-1a 转换为特立氟胺的患者相比，在连续特立氟胺组中，我们记录到较低的 ARR（0.5mg 特立氟胺的 0.18[95%CI 0.14-0.22]；1.25mg 特立氟胺的 0.20[95%CI 0.16-0.25]；转换组的 0.33[95%CI 0.27-0.39]；两者比较均<0.0001），新的或新扩大的 T2 病变较少（0.5mg 的 p =0.035，1.25mg 的 p =0.068），钆增强 T1 病变的患者较少（0.5mg 特立氟胺与转换组相比，p =0.001；1.25mg 特立氟胺与转换组相比，p =0.002）。残疾进展无获益。
从干扰素β-1a 转换为特立氟胺可增强疗效，无意外安全问题。与从干扰素β-1a 转换为特立氟胺的患者相比，连续使用特立氟胺治疗 2 年可提供持续的治疗效果，并改善临床和 MRI 结果。
诺华制药公司。
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