Ascorbic Acid in Charcot-Marie-Tooth-1A
Ascorbic Acid in Charcot-Marie-Tooth-1A
Lewis RA, McDermott MP, Herrmann DN, et al, for the Muscle Study Group
JAMA Neurol. 2013;70:981-987
At present, no known treatments are effective for neuropathy in Charcot-Marie-Tooth disease type 1A (CMT1A). In a transgenic mouse model of CMT1A, high-dosage ascorbic acid was associated with improvement in neuropathy, suggesting its potential utility for clinical treatment. However, human trials of ascorbic acid at a dose of 1.5 g/day showed that this treatment was ineffective in relieving neuropathy in patients with CMT1A.
The goal of this study was to examine the efficacy of ascorbic acid at 4 g/day in slowing the progression of CMT1A. The trial was designed to determine whether it would be futile to carry out a larger randomized, double-blind, placebo-controlled trial assessing the efficacy of high-dosage (4 g/day) ascorbic acid. Specifically, the futility design aimed to examine whether ascorbic acid could reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period compared with an untreated control group of persons with CMT1A.
At 3 referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and the University of Rochester), the investigators screened 174 persons with CMT1A for study eligibility. Of these, 48 were excluded for failure to meet eligibility criteria and 16 chose not to participate.
In a double-blinded randomization, the remaining 110 participants were allocated 4:1 to receive oral ascorbic acid 4 g/day (69 of 87 completed the study) or matching placebo (16 of 23 completers). The age range of participants was 13-70 years. Adverse effects resulted in study withdrawal in 2 participants in the treatment group and in 1 in the placebo group. The primary endpoint was the change from baseline to year 2 in the CMTNS, which is a validated composite impairment score.
Compared with the natural history, untreated control group, both the ascorbic acid group and the placebo group had a better mean 2-year change in CMTNS (−0.21 for ascorbic acid; −0.92 for placebo; and +1.33 for natural history). Therefore, the investigators could not determine futility (P > .99).
Limitations of this study include the poor choice of a 4:1 allocation of ascorbic acid-treated to placebo control participants based on calculating trial power from historical CMTNS data. In addition, the number of ascorbic acid-treated patients who completed the trial was lower than had originally been calculated to yield sufficient power.
On the basis of the prespecified primary analysis for this trial, high-dosage ascorbic acid could not be declared futile for further study as a treatment for the neuropathy of CMT1A. However, patients receiving high-dose ascorbic acid, as well as those receiving placebo, performed better than natural history over a 2-year period. These findings appear to make it unlikely that a larger trial of 4 g/day ascorbic acid treatment in CMT1A would yield positive efficacy results, or that a 4 g/day dose of ascorbic acid would have a clinically meaningful effect on the course of CMT1A during a 2-year study.
The results of this study also highlight the potential dangers of using historical controls rather than matching placebo controls as the main comparators in a clinical trial.
Abstract
High-Dosage Ascorbic Acid Treatment in Charcot-Marie-Tooth Disease Type 1A: Results of a Randomized, Double-Masked, Controlled Trial
Lewis RA, McDermott MP, Herrmann DN, et al, for the Muscle Study Group
JAMA Neurol. 2013;70:981-987
Study Summary
At present, no known treatments are effective for neuropathy in Charcot-Marie-Tooth disease type 1A (CMT1A). In a transgenic mouse model of CMT1A, high-dosage ascorbic acid was associated with improvement in neuropathy, suggesting its potential utility for clinical treatment. However, human trials of ascorbic acid at a dose of 1.5 g/day showed that this treatment was ineffective in relieving neuropathy in patients with CMT1A.
The goal of this study was to examine the efficacy of ascorbic acid at 4 g/day in slowing the progression of CMT1A. The trial was designed to determine whether it would be futile to carry out a larger randomized, double-blind, placebo-controlled trial assessing the efficacy of high-dosage (4 g/day) ascorbic acid. Specifically, the futility design aimed to examine whether ascorbic acid could reduce worsening on the CMT Neuropathy Score (CMTNS) by at least 50% over a 2-year period compared with an untreated control group of persons with CMT1A.
At 3 referral centers with peripheral nerve clinics (Wayne State University, Johns Hopkins University, and the University of Rochester), the investigators screened 174 persons with CMT1A for study eligibility. Of these, 48 were excluded for failure to meet eligibility criteria and 16 chose not to participate.
In a double-blinded randomization, the remaining 110 participants were allocated 4:1 to receive oral ascorbic acid 4 g/day (69 of 87 completed the study) or matching placebo (16 of 23 completers). The age range of participants was 13-70 years. Adverse effects resulted in study withdrawal in 2 participants in the treatment group and in 1 in the placebo group. The primary endpoint was the change from baseline to year 2 in the CMTNS, which is a validated composite impairment score.
Compared with the natural history, untreated control group, both the ascorbic acid group and the placebo group had a better mean 2-year change in CMTNS (−0.21 for ascorbic acid; −0.92 for placebo; and +1.33 for natural history). Therefore, the investigators could not determine futility (P > .99).
Viewpoint
Limitations of this study include the poor choice of a 4:1 allocation of ascorbic acid-treated to placebo control participants based on calculating trial power from historical CMTNS data. In addition, the number of ascorbic acid-treated patients who completed the trial was lower than had originally been calculated to yield sufficient power.
On the basis of the prespecified primary analysis for this trial, high-dosage ascorbic acid could not be declared futile for further study as a treatment for the neuropathy of CMT1A. However, patients receiving high-dose ascorbic acid, as well as those receiving placebo, performed better than natural history over a 2-year period. These findings appear to make it unlikely that a larger trial of 4 g/day ascorbic acid treatment in CMT1A would yield positive efficacy results, or that a 4 g/day dose of ascorbic acid would have a clinically meaningful effect on the course of CMT1A during a 2-year study.
The results of this study also highlight the potential dangers of using historical controls rather than matching placebo controls as the main comparators in a clinical trial.
Abstract
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