Ascorbic acid in Charcot–Marie–Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial

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 () and EudraCT 2006-000032-27 ().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.

Safety and Efficacy of Intravenous Ultra-high Dose Methylcobalamin Treatment for Peripheral Neuropathy: A Phase I/II Open Label Clinical Trial

“…For CMT disease, ascorbic acid, progesterone and HDAC6 inhibitors have been shown to be beneficial in animal models (20)(21)(22)(23) but not in clinical trials (21,(24)(25)(26). Such specific treatments according to the pathophysiology of each neuropathy are necessary.…”

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

“…For instance, PMP22 overexpression in rodent models can be reduced by high-dose ascorbic acid (18); however, in clinical trials, ascorbic acid did not reduce the level of PMP22 mRNA in skin biopsies from treated CMT1A patients (19)(20)(21). Progesterone antagonists and GABA B agonists have also been shown to reduce PMP22 mRNA expression (22,23), but their potential is hampered by diverse effects on the gene-regulation program of Schwann cells and possibly other cell types, which may complicate a chronic treatment of an inherited disease.…”

Proximal nerve magnetization transfer MRI relates to disability in Charcot-Marie-Tooth diseases

“…10 These techniques are typically limited to the study of distal nerves, which are often severely damaged and, therefore, unavailable for these tests. Due in part to this limitation, recent CMT1A clinical trials 12,13 noted difficulty in detecting disease progression when using CMTNS as an outcome measure. In addition, quality of life assessments have shown little sensitivity to disease progression.…”