Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.
Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis.
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DOI：
10.1056/nejmoa1803583
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发表时间：
2018-08-30
期刊：
影响因子：
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通讯作者：
NN102/SPRINT-MS Trial Investigators
中科院分区：
文献类型：
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作者：
Fox RJ;Coffey CS;Conwit R;Cudkowicz ME;Gleason T;Goodman A;Klawiter EC;Matsuda K;McGovern M;Naismith RT;Ashokkumar A;Barnes J;Ecklund D;Klingner E;Koepp M;Long JD;Natarajan S;Thornell B;Yankey J;Bermel RA;Debbins JP;Huang X;Jagodnik P;Lowe MJ;Nakamura K;Narayanan S;Sakaie KE;Thoomukuntla B;Zhou X;Krieger S;Alvarez E;Apperson M;Bashir K;Cohen BA;Coyle PK;Delgado S;Dewitt LD;Flores A;Giesser BS;Goldman MD;Jubelt B;Lava N;Lynch SG;Moses H;Ontaneda D;Perumal JS;Racke M;Repovic P;Riley CS;Severson C;Shinnar S;Suski V;Weinstock-Guttman B;Yadav V;Zabeti A;NN102/SPRINT-MS Trial Investigators
进行性多发性硬化症的治疗方法有限。异丁司特抑制几种环核苷酸磷酸二酯酶、巨噬细胞迁移抑制因子和Toll样受体4，并可穿过血脑屏障，对进展性多发性硬化症具有潜在的有益作用。我们招募了原发性或继发性进展型多发性硬化症患者参加一项口服异丁司特（每日≤100 mg）或安慰剂治疗96周的2期随机试验。主要疗效终点是脑萎缩率，通过脑实质分数（脑大小相对于脑外表面轮廓的体积）测量。主要的次要终点包括扩散张量成像中锥体束的变化，正常脑组织的磁化传递率，视网膜神经纤维层的厚度和皮质萎缩，所有这些都是多发性硬化症组织损伤的指标。在255名接受随机分组的患者中，129名被分配到异丁司特组，126名被分配到安慰剂组。异丁司特组和安慰剂组分别有53%和52%的患者出现原发性疾病进展，其他患者出现继发性疾病进展。异丁司特组脑实质分数的变化率为每年-0.0010，安慰剂组为每年-0.0019（差异为0.0009; 95%置信区间为0.00004 ~ 0.0017; P = 0.04），这表明在96周的时间内，异丁司特组的脑组织损失减少约2.5 ml。异丁司特的不良反应包括胃肠道症状、头痛和抑郁。在一项涉及进行性多发性硬化症患者的2期试验中，异丁司特与脑萎缩的进展比安慰剂慢，但与胃肠道副作用、头痛和抑郁的发生率较高相关。
There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis. We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis. Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was −0.0010 per year with ibudilast and −0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P = 0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression. In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression.