High-dosage Ascorbic Acid Treatment in Charcot-Marie-Tooth Disease Type 1A: Results of a Randomized, Double-Masked, Controlled Trial

JAMA Neurol. 2013 Aug;70(8):981-7. doi: 10.1001/jamaneurol.2013.3178.

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.

Trial registration: clinicaltrials.gov Identifier: NCT00484510.

Publication types

  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antioxidants / administration & dosage
  • Antioxidants / adverse effects
  • Antioxidants / pharmacology*
  • Ascorbic Acid / administration & dosage
  • Ascorbic Acid / adverse effects
  • Ascorbic Acid / pharmacology*
  • Charcot-Marie-Tooth Disease / diagnosis
  • Charcot-Marie-Tooth Disease / drug therapy*
  • Charcot-Marie-Tooth Disease / pathology
  • Disease Models, Animal
  • Disease Progression
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Medical Futility*
  • Mice
  • Middle Aged
  • Severity of Illness Index
  • Time Factors
  • Young Adult

Substances

  • Antioxidants
  • Ascorbic Acid

Associated data

  • ClinicalTrials.gov/NCT00484510