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.
To determine whether 4-g/d AA improves the neuropathy of subjects with CMT1A.
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.
Three referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins
University, and University of Rochester).
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.
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.
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
clinicaltrials.gov Identifier: NCT00484510