芬戈莫德对复发缓解型多发性硬化患者脑弥散性组织损伤的影响。
Effect of fingolimod on diffuse brain tissue damage in relapsing-remitting multiple sclerosis patients.
机构信息
Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
Novartis Pharma AG, Basel, Switzerland.
出版信息
Mult Scler Relat Disord. 2016 May;7:98-101. doi: 10.1016/j.msard.2016.03.017. Epub 2016 Mar 31.
BACKGROUND
Multiple sclerosis (MS) affects all areas of the brain resulting in both focal and diffuse damage. In Phase 3 clinical trials, fingolimod showed significant reductions in both focal lesions and rate of brain volume loss (BVL) in patients with relapsing-remitting MS.
OBJECTIVE
To investigate if the effects of fingolimod 0.5mg on BVL are mediated exclusively through its effects on focal damage or if fingolimod also acts independently in reducing diffuse damage.
METHODS
This was a pooled post-hoc analysis of patients from two Phase 3 studies (FREEDOMS [N=1272] and FREEDOMS II [N=1083]), with no evidence of focal disease activity as defined by absence of gadolinium-enhancing lesions at baseline and new active lesions and clinical relapses at follow-up. The percent brain volume change (PBVC), as a measure of diffuse tissue damage, was assessed at Month (M) 12 and M24 by using the Structural Image Evaluation using Normalization of Atrophy (SIENA) method. A regression analysis was performed in the pooled intent-to-treat (ITT) population to quantify the treatment effect of fingolimod on BVL vs. placebo (PBO) in the overall population (unadjusted model), and whether this effect is sustained after adjusting for new active lesions and on-study relapses (adjusted model).
RESULTS
Of 1088 patients, 638 (PBO, n=127; fingolimod, n=511) at M12 and 450 patients (PBO, n=68; fingolimod, n=382) at M24 showed no focal activity. Fingolimod significantly reduced PBVC by 65.5% over 12M (fingolimod vs. PBO: -0.16 vs. -0.45; p=0.001) and by 48.2% over 24M (-0.42 vs. -0.81; p=0.004). An absolute difference in PBVC of -0.27% (p<0.001) in favor of fingolimod vs. PBO over 24M was still evident in the pooled ITT population, after adjusting for active lesions and on-study relapses. The regression model suggests that 54% (-0.27%/-0.51%) of effects of fingolimod on PBVC are independent of its effects on visible focal damage.
CONCLUSIONS
The effect of fingolimod on diffuse damage is partly independent of its treatment effect on focal damage, suggesting that both inflammatory and neurodegenerative components of MS are affected.
背景
多发性硬化症（MS）影响大脑的各个区域，导致局灶性和弥漫性损伤。在 3 期临床试验中，芬戈莫德显示出在复发缓解型 MS 患者中，局灶性病变和脑容量损失（BVL）的发生率均显著降低。
目的
研究 fingolimod 0.5mg 对 BVL 的影响是否完全通过其对局灶性损伤的作用介导，或者 fingolimod 是否也独立地降低弥漫性损伤。
方法
这是一项来自两项 3 期研究（FREEDOMS [N=1272]和 FREEDOMS II [N=1083]）的患者的事后 pooled 分析，基线时无局灶性疾病活动的证据，定义为无钆增强病变，且随访时无新发活动性病变和临床复发。通过使用结构图像评估正常化萎缩（SIENA）方法，在第 12 个月（M）和第 24 个月（M）评估脑容量变化百分比（PBVC），作为弥漫性组织损伤的衡量标准。在 pooled 意向治疗（ITT）人群中进行回归分析，以量化 fingolimod 对 BVL 与安慰剂（PBO）的治疗效果（总体人群中未调整模型），以及在调整新发活动性病变和研究期间复发后，这种效果是否持续（调整模型）。
结果
在 1088 例患者中，638 例（PBO，n=127；fingolimod，n=511）在 M12 时和 450 例患者（PBO，n=68；fingolimod，n=382）在 M24 时显示无局灶性活性。fingolimod 在 12 个月时显著降低 PBVC 65.5%（fingolimod 与 PBO：-0.16 与-0.45；p=0.001），在 24 个月时降低 48.2%（-0.42 与-0.81；p=0.004）。在调整活动性病变和研究期间复发后，pooled ITT 人群中，fingolimod 与 PBO 相比，24 个月时 PBVC 的绝对差异为-0.27%（p<0.001）仍然明显。回归模型表明，fingolimod 对 PBVC 的影响有 54%（-0.27%/-0.51%）独立于其对可见局灶性损伤的影响。
结论
fingolimod 对弥漫性损伤的影响部分独立于其对局灶性损伤的治疗作用，这表明 MS 的炎症和神经退行性成分均受到影响。
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