Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial.
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.


RESULTS
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 -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.


CONCLUSIONS
12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached.
Discipline of Paediatrics and Child Health, Faculty of Medicine, University of Sydney, and Institute for Neuromuscular Research, Children's Hospital at Westmead, Sydney, NSW, Australia. Joshuab2@chw.edu.au
Joshua
J
Burns
Robert A
RA
Ouvrier
Eppie M
EM
Yiu
Pathma D
PD
Joseph
Andrew J
AJ
Kornberg
Michael C
MC
Fahey
Monique M
MM
Ryan
D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D012189:Retrospective Studies; D016896:Treatment Outcome
D000975:Antioxidants; D001205:Ascorbic Acid