So far, there are no specific therapies for Charcot–Marie–Tooth (CMT) disease. A Cochrane review1 of treatment for CMT showed that trials of exercise, orthosis, creatine, and ganglioside injections were too small to identify moderate benefit or harm, although a small trial with neurotrophin-3 showed possible benefit in CMT type 1A (CMT1A). Several trials have recently been undertaken after the finding that ascorbic acid is effective in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), an animal model of human CMT1A. 2 Treated animals, aged 2–4 months, showed remyelination on nerve biopsy and improved locomotor function compared with untreated controls. Three phase 2 trials3–5 of patients with CMT1A investigated the effect of ascorbic acid over 1 year and reported negative results. Two of the trials had motor conduction nerve velocity as the primary outcome, 3, 4 and in one trial the CMT neuropathy score (CMTNS) was used. 5 In this issue of The Lancet Neurology, Davide Pareyson and colleagues6 report data for an Anglo-Italian collaborative study. The investigators should be commended for their well performed randomised, placebo-controlled, doubleblind trial assessing efficacy and tolerability of ascorbic acid treatment over 2 years in patients with CMT1A recruited from eight Italian centres and one UK centre, with CMTNS as a primary outcome. 7 138 patients received 1· 5 g ascorbic acid per day and 133 received placebo, on the basis of a power calculation that used a predicted change of the CMTNS of 1· 4 points over 2 years. 8 The investigators reported that ascorbic acid did not have a significant effect on either the primary outcome or the secondary outcome measures. 6 No safety issues arose. An equal number of patients discontinued treatment with either ascorbic acid or placebo, mainly because of gastrointestinal side-effects. Pareyson and colleagues discuss the possible explanations for their findings and consider an insufficient dose of ascorbic acid unlikely, for pharmacokinetic reasons. However, in the French trial5 the investigators reported a trend towards an effect of ascorbic acid in the group receiving 3 g per day, 5 and the results of a US trial (NCT00484510) with 4 g ascorbic acid per day are awaited. Pareyson and colleagues suggest that they might have missed a small effect of ascorbic acid because of the unexpectedly slow progression of the disease—0· 5 CMTNS points (95% CI 0· 0–1· 0) over 2 years. However, this disease course is similar to that reported in a prospective study undertaken by our group, showing a deterioration of 1· 5 points (95% CI 0· 5–2· 4) over 5 years in adult patients. 9

Clinical trials are only as credible as their outcomes. 10 The selection of outcomes that are relevant to patients is crucial to the design of randomised controlled trials: proof-of-concept phase 2 trials might need outcome measures at the impairment level, whereas functional outcome measures are more appropriate in phase 3 trials. Although there was a consensus that CMTNS would be the appropriate outcome measure for CMT1A trials, 11 the question is whether this score is clinically relevant. CMTNS is a composite impairment score based on history, neurological examination, and