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

• Published in: JAMA neurology Vol. 70; no. 8; p. 981
• Main Authors: Lewis, Richard A, McDermott, Michael P, Herrmann, David N, Hoke, Ahmet, Clawson, Lora L, Siskind, Carly, Feely, Shawna M E, Miller, Lindsey J, Barohn, Richard J, Smith, Patricia, Luebbe, Elizabeth, Wu, Xingyao, Shy, Michael E
• Format: Journal Article
• Language: English
• Published: United States 01.08.2013
• Subjects: 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
• ISSN: 2168-6157
• DOI: 10.1001/jamaneurol.2013.3178

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. 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). 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. clinicaltrials.gov Identifier: NCT00484510.