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Original Investigation | Clinical Trial

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

Richard A. Lewis, MD1,6; Michael P. McDermott, PhD2,3; David N. Herrmann, MD3; Ahmet Hoke, MD, PhD4; Lora L. Clawson, MSN, CRNP4; Carly Siskind, MS1,7; Shawna M. E. Feely, MS1,8; Lindsey J. Miller, MS1; Richard J. Barohn, MD5; Patricia Smith, BS3; Elizabeth Luebbe, MS3; Xingyao Wu, MD, PhD1,8; Michael E. Shy, MD1,8; Muscle Study Group
[+] Author Affiliations
1Department of Neurology, Wayne State University, Detroit, Michigan
2Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York
3Department of Neurology, University of Rochester, Rochester, New York
4Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland
5Department of Neurology, University of Kansas, Kansas City
6currently with the Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California
7currently with the Department of Neurology, Stanford University, Palo Alto, California
8currently with the Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City
JAMA Neurol. 2013;70(8):981-987. doi:10.1001/jamaneurol.2013.3178.
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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

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Figure 1.
Flow of Subjects Through the Trial
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Figure 2.
Changes in the Charcot-Marie-Tooth Neuropathy Score (CMTNS) Over the 2-Year Study

Adjusted mean changes in the CMTNS over 2 years are shown for the ascorbic acid group and placebo group. These are compared with the mean change at 2 years expected from published natural history19 and observed mean changes in the placebo groups in the French trial10 and the Italian/UK trial.11 Bars indicate 1 SEM. Larger (positive) changes indicate greater worsening.

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Figure 3.
Adjusted Mean Changes in Ascorbic Acid Levels Over the 2-Year Study

Mean changes in serum ascorbic acid levels are shown for subjects receiving 4-g/d ascorbic acid and those receiving placebo. Bars indicate 1 SEM. Group differences in mean levels were statistically significant (P < .002) at all times. To convert ascorbic acid to micromoles per liter, multiply by 56.78.

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