Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study
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DOI：
10.1016/s0140-6736(08)60918-6
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发表时间：
2008-06-21
期刊：
影响因子：
168.9
通讯作者：
Filippi, M.
中科院分区：
文献类型：
--
作者：
Comi, G.;Pulizzi, A.;Filippi, M.
一项为期24周的II期临床试验表明：复发缓解型多发性硬化症患者每日服用3mg拉喹莫德耐受性良好，可减少活动性病变的形成。我们评估了每日口服0。3和0。在一项为期36周的双盲、安慰剂对照IIb期研究中，6mg拉喹莫德对mri监测的疾病活动性的影响。方法本研究在9个国家的51个中心进行。纳入标准是入院前一年有一次或多次复发，MRI筛查至少有一次钆增强（GdE）病变。在720名筛选的患者中，306名符合条件的患者入组。年龄在18-50岁之间的患者被随机分配到安慰剂组（n=102），拉喹莫德组(0)。每天3毫克（n=98），或0。每天6毫克（n=106）。脑MRI扫描和临床评估在第4周、基线和每月从第12周至第36周进行。主要结果是GdE病变在第24、28、32和36周的累积数量。主要终点的主要分析是在意向治疗队列上进行的。本研究已在ClinicalTrials.gov注册，注册号NCT00349193。结果：与安慰剂相比，拉喹莫德治疗组疗效显著。每天6mg显示，在最后四次扫描中，每次扫描的基线调整平均累积GdE病变数减少了40.4%(简单平均值为4 - 2 [SD 9.2] vs 2.6 [5-3], p=0。0048);用0处理。每天3mg无显著效果（3-9 [5.5]vs安慰剂，p=0.6740）。两种剂量的拉喹莫德耐受性良好，肝酶有短暂的剂量依赖性增加。有潜在高凝性的患者接受0.6 mg拉喹莫德治疗1个月后出现布-恰利综合征（即血栓性肝静脉流出梗阻）。抗凝治疗后肝酶降至正常，无肝失代偿的临床症状。在复发缓解型多发性硬化症患者中，每天0.6 mg的拉喹莫德可显著降低mri测量的疾病活动性，并且耐受性良好。资助梯瓦制药工业。
Background A 24-week phase II trial has shown that 0 . 3 mg of laquinimod given daily to patients with relapsing-remitting multiple sclerosis was well tolerated and reduced the formation of active lesions. We assessed the effect of oral daily 0 . 3 and 0 . 6 mg laquinimod on MRI-monitored disease activity in a 36-week double-blind, placebo-controlled phase IIb study.Methods The study was done in 51 centres in nine countries. Inclusion criteria were one or more relapses in the year before entry and at least one gadolinium enhancing (GdE) lesion on screening MRI. Of 720 patients screened, 306 eligible patients were enrolled. Patients, aged 18-50 years, were randomly assigned to placebo (n=102), laquinimod 0 . 3 mg a day (n=98), or 0 . 6 mg a day (n=106). Brain MRI scans and clinical assessments were done at week -4, baseline, and monthly from week 12 to week 36. The primary outcome was the cumulative number of GdE lesions at weeks 24, 28, 32, and 36. The principal analysis of the primary endpoint was done on the intention-to-treat cohort. This study is registered with ClinicalTrials.gov, number NCT00349193.Findings Compared with placebo, treatment with laquinimod 0 . 6 mg per day showed a 40.4% reduction of the baseline adjusted mean cumulative number of GdE lesions per scan on the last four scans (simple means 4 - 2 [SD 9.2] vs 2.6 [5-3], p=0 . 0048); treatment with 0 . 3 mg per day showed no significant effects (3-9 [5.5] vs placebo, p=0.6740). Both doses of laquinimod were well tolerated, with some transient and dose-dependent increases in liver enzymes. A case of Budd-Chiari syndrome-ie, a thrombotic venous outflow obstruction of the liver-occurred after 1 month of exposure in a patient with underlying hypercoagulability who received 0.6 mg laquinimod. Anticoagulant treatment resulted in a decline of liver enzymes to normal without any clinical signs of hepatic decompensation.Interpretation In patients with relapsing-remitting multiple sclerosis, 0.6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated.Funding Teva Pharmaceutical Industries.