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

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.

• Authors: 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, Muscle Study Group
• Journal: JAMA neurology (JAMA Neurol) Vol. 70 Issue 8 Pg. 981-7 (Aug 2013) ISSN: 2168-6157 [Electronic] United States
• PMID: 23797954 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Ascorbic Acid

Topics

• Adolescent
• Adult
• Aged
• Animals
• Antioxidants (administration & dosage, adverse effects, pharmacology)
• Ascorbic Acid (administration & dosage, adverse effects, pharmacology)
• Charcot-Marie-Tooth Disease (diagnosis, drug therapy, 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