Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial.
Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial.
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DOI：
10.1016/s1474-4422(11)70025-4
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发表时间：
2011-04
期刊：
影响因子：
48
通讯作者：
Solari, Alessandro
中科院分区：
文献类型：
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作者：
Pareyson, Davide;Reilly, Mary M.;Schenone, Angelo;Fabrizi, Gian Maria;Cavallaro, Tiziana;Santoro, Lucia;Vita, Giuseppe;Quattrone, Aldo;Padua, Luca;Gemignani, Franco;Visioli, Francesco;Laura, Matilde;Radice, Davide;Calabrese, Daniela;Hughes, Richard A. C.;Solari, Alessandro
抗坏血酸降低了过度表达外周髓鞘蛋白22（PMP 22）的转基因小鼠神经病变的严重程度，这是一种与PMP 22复制相关的Charcot-Marie-Tooth病1A型（CMT 1A）模型。然而，在三项为期一年的试验中，抗坏血酸对人类没有任何益处。我们进行了一项为期2年的多中心试验，以测试抗坏血酸在CMT 1A患者中的疗效和耐受性。从意大利和英国的9个中心招募了症状性CMT 1A成人患者（年龄18-70岁），并随机分配（1：1比例）接受1.5 g/天口服抗坏血酸或匹配的安慰剂治疗24个月。通过区组随机化计算机生成随机化序列，按中心和疾病严重程度分层，通过电话将患者分配至治疗组。主要结局是24个月时CMT神经病变评分（CMTNS）的变化。次要结果为计时10米步行试验、九孔桩试验、总体神经病变限制量表、远端最大自主等长收缩、疼痛和疲劳视觉模拟量表、36项简短问卷和电生理测量。患者、治疗医生和评估结局指标的医生对治疗分配设盲。对所有接受至少一剂研究药物的随机化患者进行主要结局分析。本研究已注册，编号为ISRCTN 61074476（）和EudraCT 2006-000032-27（）。我们招募并随机分配了277名患者，其中6名（4名分配接受抗坏血酸）在接受治疗前撤回同意书; 138名接受抗坏血酸治疗，133名接受安慰剂治疗，符合分析条件。治疗耐受性良好：271名患者中的241名（每组89%）完成了研究; 20名患者（9名接受抗坏血酸治疗）因不良事件退出。在缺失数据插补的情况下，抗坏血酸组基线时的平均CMTNS为14.7（SD 4.8），安慰剂组为13.9（4.2）。抗坏血酸组CMTNS平均恶化为0.2（SD 2.8，95%CI − 0.3至0.7），安慰剂组为0.2（2.7，− 0.2至0.7）（平均差异0.0，95%CI − 0.6至0.7; p= 0.93）。在24个月时，我们记录到两组的次要结局无差异。20名患者发生了21起严重不良事件，其中抗坏血酸组8起，安慰剂组13起。2年后，与安慰剂相比，补充抗坏血酸对神经病变没有显著影响，这表明没有证据支持在CMT 1A成人中使用抗坏血酸治疗。Telethon-UILDM和AIFA（意大利药品管理局）为CMT-TRIAAL，肌营养不良症运动为CMT-TRAUK。
Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), a model of Charcot–Marie–Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A. Adult patients (aged 18–70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 () and EudraCT 2006-000032-27 (). We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI −0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, −0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI −0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group. Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A. Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK.