Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial
Lamotrigine for neuroprotection in secondary progressive multiple sclerosis: a randomised, double-blind, placebo-controlled, parallel-group trial
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DOI：
10.1016/s1474-4422(10)70131-9
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发表时间：
2010-07-01
期刊：
影响因子：
48
通讯作者：
Miller, David H.
中科院分区：
文献类型：
--
作者：
Kapoor, Raju;Furby, Julian;Miller, David H.
部分阻断电压门控钠通道在炎症性脱髓鞘疾病的实验模型中具有神经保护作用。在这个第2阶段的试验，我们的目的是评估是否钠通道阻滞剂拉莫三嗪也是继发性进行性多发性sclerosis.Methods患者继发性进行性多发性硬化症谁参加了国家医院神经病学和神经外科或皇家免费医院，伦敦，英国，有资格列入本双盲，平行组试验。患者通过网站按最小化随机分配接受拉莫三嗪（目标剂量400 mg/天）或安慰剂治疗2年。治疗医生、评估医生和患者均对治疗分配设盲。主要结局是24个月内部分（中央）脑体积的变化率。所有随机分配的患者均纳入主要分析。该试验注册于ClinicalTrials.gov，NCT 00257855。结果120例患者被随机分配到治疗组（87例女性和33例男性）：61例拉莫三嗪组和59例安慰剂组。对108例患者进行了主要终点分析：拉莫三嗪组52例，安慰剂组56例。拉莫三嗪组每年部分（中央）脑容量的平均变化为-3.18 mL（SD -1.25），安慰剂组为-2.48 mL（-0.97）（差异-0.71 mL，95% CI -2.56至1.15; p=0.40）。然而，在一项探索性建模分析中，拉莫三嗪治疗似乎与第一年比安慰剂更大的部分（中央）脑容量损失相关（p=0.04），治疗停止后容量部分增加（p=0.04）。拉莫三嗪治疗减少了定时25英尺步行的恶化（p=0.02），但不影响其他次要临床结局指标。皮疹和剂量相关的步态和平衡恶化的患者在拉莫三嗪组比安慰剂group.Interpretation拉莫三嗪对继发性进展型多发性硬化症患者的脑容量的影响没有显着差异，从安慰剂超过24个月，但拉莫三嗪似乎会导致早期容量损失，逆转部分停止治疗。未来的多发性硬化症神经保护试验应包括研究中枢神经系统不同部分的复杂早期体积变化，与神经退行性变无关的作用，以及针对早期和更多炎症性疾病。
Background Partial blockade of voltage-gated sodium channels is neuroprotective in experimental models of inflammatory demyelinating disease. In this phase 2 trial, we aimed to assess whether the sodium-channel blocker lamotrigine is also neuroprotective in patients with secondary progressive multiple sclerosis.Methods Patients with secondary progressive multiple sclerosis who attended the National Hospital for Neurology and Neurosurgery or the Royal Free Hospital, London, UK, were eligible for inclusion in this double-blind, parallel-group trial. Patients were randomly assigned via a website by minimisation to receive lamotrigine (target dose 400 mg/day) or placebo for 2 years. Treating physicians, evaluating physicians, and patients were masked to treatment allocation. The primary outcome was the rate of change of partial (central) cerebral volume over 24 months. All patients who were randomly assigned were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT00257855.Findings 120 patients were randomly assigned to treatment (87 women and 33 men): 61 to lamotrigine and 59 to placebo. 108 patients were analysed for the primary endpoint: 52 in the lamotrigine group and 56 in the placebo group. The mean change in partial (central) cerebral volume per year was -3.18 mL (SD -1.25) in the lamotrigine group and -2.48 mL (-0.97) in the placebo group (difference -0.71 mL, 95% CI -2.56 to 1.15; p=0.40). However, in an exploratory modelling analysis, lamotrigine treatment seemed to be associated with greater partial (central) cerebral volume loss than was placebo in the first year (p=0.04), and volume increased partially after treatment stopped (p=0.04). Lamotrigine treatment reduced the deterioration of the timed 25-foot walk (p=0.02) but did not affect other secondary clinical outcome measures. Rash and dose-related deterioration of gait and balance were experienced more by patients in the lamotrigine group than the placebo group.Interpretation The effect of lamotrigine on cerebral volume of patients with secondary progressive multiple sclerosis did not differ from that of placebo over 24 months, but lamotrigine seemed to cause early volume loss that reversed partially on discontinuation of treatment. Future trials of neuroprotection in multiple sclerosis should include investigation of complex early volume changes in different compartments of the CNS, effects unrelated to neurodegeneration, and targeting of earlier and more inflammatory disease.