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Randomized Controlled Trial
. 2013 Aug;70(8):981-7.
doi: 10.1001/jamaneurol.2013.3178.

High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial

Richard A Lewis  1 , 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; Muscle Study Group
Collaborators, Affiliations
Randomized Controlled Trial

High-dosage ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A: results of a randomized, double-masked, controlled trial

Richard A Lewis et al. JAMA Neurol. 2013 Aug.

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr. Lewis has consulted for Baxter, CSL Behring, AxelaCare, Novartis, and Bristol-Myers Squibb. Dr. Shy has received grant support from the National Institute of Neurological Disorders and Stroke, Muscular Dystrophy Association, and Charcot-Marie-Tooth Association.

Figures

Figure 1
Figure 1
Flow of subjects through the trial.
Figure 2
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 history and observed mean changes in the placebo groups in the French trial and the Italian/UK trial. Bars indicate 1 SEM. Larger (positive) changes indicate greater worsening.
Figure 3
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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References

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