Ascorbic acid for CMT 1A in children: a randomised, double-blind, placebo-contr

[Guest guest]

Lancet Neurology, Early Online Publication, 7 May

http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(09)70108-5/fullte\

xt

Editors' note: Although Charcot-Marie-Tooth disease type 1a (CMT1A) is the most

common inherited neuropathy, no drugs are approved to treat the disorder.

Ascorbic acid (vitamin C) has been suggested as a potential treatment on the

basis of promising results in preclinical studies, and this randomised

controlled trial tested whether high-dose ascorbic acid could be beneficial in

children with CMT1A. After 1 year there was no significant benefit in the

primary outcome of median nerve conduction when ascorbic acid was compared with

placebo, although in post-hoc observations the investigators noted that the five

children who had the largest increases in median nerve conduction velocity were

all in the ascorbic acid group.

Ascorbic acid for Charcot—Marie—Tooth disease type 1A in children: a randomised,

double-blind, placebo-controlled, safety and efficacy trial

Original Text Burns PhD a , A Ouvrier MD a, Eppie M Yiu MBBS b,

Pathma D ph MPharm c, J Kornberg MBBS b, C Fahey PhD d,

M MMed b

Summary

Background

Charcot—Marie—Tooth disease type 1A (CMT1A) is the most common inherited nerve

disorder. CMT1A is characterised by peripheral nerve demyelination, weakness,

and impaired motor function and is caused by the duplication of PMP22, the gene

that encodes peripheral myelin protein 22. High-dose ascorbic acid has been

shown to have remyelinating potential and to correct the phenotype of a

transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the

efficacy and safety of ascorbic acid supplementation in children with CMT1A.

Methods

This 12-month, randomised, double-blind, placebo-controlled trial undertaken

between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid

(about 30 mg/kg/day) in 81 children with CMT1A (2—16 years). Randomisation was

done on a 1:1 ratio by a computer-generated algorithm. All investigators and

participants were blinded to treatment allocation with the exception of the

trial pharmacist. The primary efficacy outcome was median nerve motor conduction

velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength,

motor function, walking ability, and quality of life. Compliance was measured by

plasma ascorbic acid concentration, pill count, and medication diary entries.

Analysis was by intention to treat. This trial is registered with the Australian

New Zealand Clinical Trials Registry, number 12606000481572.

Findings

81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or

placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid

group had a small, non-significant increase in median nerve motor conduction

velocity compared with the placebo group (adjusted mean difference 1·7 m/s, 95%

CI & #8722;0·1 to 3·4; p=0·06). There was no measurable effect of ascorbic acid

on neurophysiological, strength, function, or quality of life outcomes. Two

children in the ascorbic acid group and four children in the placebo group

reported gastrointestinal symptoms. There were no serious adverse events.

Interpretation

12 months of treatment with high-dose ascorbic acid was safe and well tolerated

but none of the expected efficacy endpoints were reached.

Funding

University of Sydney Research and Development Scheme; National Health and

Medical Research Council of Australia; N Kirby Foundation; New South Wales

Podiatrists Registration Board; Australian Podiatry Education and Research

Foundation; Charcot—Marie—Tooth Association of Australia.