Abstract
SummaryBackgroundAscorbic 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.MethodsAdult 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 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL).FindingsWe 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.InterpretationAscorbic 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.FundingTelethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK.
Highlights
Charcot–Marie–Tooth disease (CMT), a disease for which no drug treatments are available, is the most common inherited neuromuscular disorder, and is characterised clinically by distal wasting, weakness, and sensory loss
In the main analysis of the primary outcome with missing data imputed, mean CMT neuropathy score (CMTNS) changed from 14·7 (SD 4·8) at baseline to 14·9 (5·4) at 24 months in the ascorbic acid group, and from 13·9 (4·2) to 14·2 (4·4) in the placebo group
Mean change in CMTNS from baseline to 24 months 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, with a mean betweengroup difference of 0·0
Summary
Charcot–Marie–Tooth disease (CMT), a disease for which no drug treatments are available, is the most common inherited neuromuscular disorder, and is characterised clinically by distal wasting, weakness, and sensory loss. The main subtype is type 1A (CMT1A), representing about half of all CMT cases. CMT1A is associated with an autosomal dominant duplication of the peripheral myelin protein 22 gene (PMP22), causing peripheral nerve demyelination and secondary axonal loss.. Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing PMP22, an animal model of human CMT1A, compared with untreated mice.. Ascorbic acid promotes myelination in vitro and possibly decreases PMP22 expression.. Evidence of efficacy of ascorbic acid in the animal model prompted initiation of randomised controlled trials to test the efficacy of ascorbic acid in patients with CMT1A Ascorbic acid promotes myelination in vitro and possibly decreases PMP22 expression. Evidence of efficacy of ascorbic acid in the animal model prompted initiation of randomised controlled trials to test the efficacy of ascorbic acid in patients with CMT1A
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