High-dosage ascorbic acid treatment in charcot-marie-tooth disease type 1A results of a randomized, double-masked, controlled trial

Richard A. Lewis, Michael P. McDermott, David N. Herrmann, Ahmet Hoke, Lora L. Clawson, Carly Siskind, Shawna M.E. Feely, Lindsey J. Miller, Richard J. Barohn, Patricia Smith, Elizabeth Luebbe, Xingyao Wu, Michael E. Shy

Research output: Contribution to journalArticle

Abstract

IMPORTANCE No current medications improve neuropathy in subjects with Charcot-Marie-Tooth disease type 1A (CMT1A). Ascorbic acid (AA) treatment improved the neuropathy of a transgenic mouse model of CMT1A and is a potential therapy. A lower dosage (1.5 g/d) did not cause improvement in humans. It is unknown whether a higher dosage would prove more effective. OBJECTIVE To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A. DESIGN A futility design to determine whether AA was unable to reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period relative to a natural history control group. SETTING Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and University of Rochester). PARTICIPANTS One hundred seventy-four subjects with CMT1A were assessed for eligibility; 48 did not meet eligibility criteria and 16 declined to participate. The remaining 110 subjects, aged 13 to 70 years, were randomly assigned in a double-masked fashion with 4:1 allocation to oral AA (87 subjects) or matching placebo (23 subjects). Sixty-nine subjects from the treatment group and 16 from the placebo group completed the study. Two subjects from the treatment group and 1 from the placebo group withdrew because of adverse effects. INTERVENTIONS Oral AA (4 g/d) or matching placebo. MAIN OUTCOMES AND MEASURES Change from baseline to year 2 in the CMTNS, a validated composite impairment score for CMT. RESULTS The mean 2-year change in the CMTNS was -0.21 for the AA group and -0.92 for the placebo group, both better than natural history (+1.33). This was well below 50% reduction of CMTNS worsening from natural history, so futility could not be declared (P > .99). CONCLUSIONS AND RELEVANCE Both treated patients and those receiving placebo performed better than natural history. It seems unlikely that our results support undertaking a larger trial of 4-g/d AA treatment in subjects with CMT1A.

Original languageEnglish (US)
Pages (from-to)981-987
Number of pages7
JournalJAMA Neurology
Volume70
Issue number8
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Clinical Neurology

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    Lewis, R. A., McDermott, M. P., Herrmann, D. N., Hoke, A., Clawson, L. L., Siskind, C., Feely, S. M. E., Miller, L. J., Barohn, R. J., Smith, P., Luebbe, E., Wu, X., & Shy, M. E. (2013). High-dosage ascorbic acid treatment in charcot-marie-tooth disease type 1A results of a randomized, double-masked, controlled trial. JAMA Neurology, 70(8), 981-987. https://doi.org/10.1001/jamaneurol.2013.3178