An MDA-supported trial of high-dose ascorbic acid (vitamin C) in the type 1A form of Charcot-Marie-Tooth disease (CMT) (CMT1A) did not find a benefit for this treatment, although it appeared safe and was generally well-tolerated. There were no serious adverse events judged to be related to the study drug.
Despite the disappointing results, the trial did have a positive effect on future trials in CMT, say the researchers. It resulted in the development of the necessary infrastructure to coordinate and conduct multicenter trials; helped improve trial design in CMT; and utilized ratings scales designed to measure CMT symptom severity.
The trial was conducted at sites at Wayne State University in Detroit, Johns Hopkins University in Baltimore and the University of Rochester in New York.
MDA grantee Richard A. Lewis, now at Cedars-Sinai Medical Center in Los Angeles and at Wayne State University in Detroit during this trial, with colleagues, published the results June 24, 2013, in JAMA Neurology.
An accompanying editorial, also published June 24 and authored by Pragna Patel at the University of Southern California in Los Angeles and David Pleasure at the University of California, Davis, discusses the study and probes new directions for drug treatment of CMT1A.
The high-dose ascorbic acid trial in CMT1A included 110 participants, ages 13 to 70, with this disorder. They were randomly assigned to receive eight capsules of 500 milligrams each of ascorbic acid per day, or placebo capsules that looked the same as the ascorbic acid capsules.
Four times as many participants were assigned to ascorbic acid as were assigned to the placebo.
Using primarily the CMT Neuropathy Score (CMTNS), a standardized scale to measure the effects of CMT, the investigators compared the scores of 87 participants receiving ascorbic acid, 23 participants receiving placebo capsules, and 72 "natural history" controls — untreated people with CMT1A who were part of an earlier study.
The investigators analyzed changes in the CMTNS and other measures over the course of two years, comparing the two groups in the current study to each other and to a natural history group.
The CMTNS measures motor and sensory function, strength and electrical signals from muscles and nerves. Higher scores reflect more severe disease symptoms. Reductions in a score represent improvement.
The natural history group had worsened, on average, by +1.33 points on the CMTNS over two years. Surprisingly, however, both the placebo group and the ascorbic acid group in the current study did much better on this scale than the natural history group. In fact, both groups improved slightly (showing lower scores than at baseline) after two years, with the placebo group improving a little more (score reduced by -0.92 points) than the ascorbic acid group (score reduced by -0.21 points).
Overproduction of a protein called PMP22, which forms part of the sheath that surrounds nerve fibers, is the biological cause of CMT1A. Therefore, the investigators also measured levels of genetic instructions for PMP22 in skin cells in 69 trial participants — 55 in the ascorbic acid group and 14 in the placebo group. No effects of the treatment were detected.
"Subjects had better outcomes than those reported in natural history studies," the authors of the June 24 publication write, adding that "the concurrent [during this trial] placebo group, though small, had better-than-expected outcomes over a two-year period."
They conclude that it is "unlikely that 4 grams/day ascorbic acid has a clinically meaningful effect upon the course of CMT1A over a two-year period."
The original incentive for the current trial was a 2004 study conducted in France that showed that mice with a disease resembling CMT1A showed improvements in function when given ascorbic acid. The researchers on the mouse study also found evidence that the treatment reduced overproduction of the PMP22 protein.
The promising mouse results led to several trials of ascorbic acid in people with CMT1A, most of them at dosage levels lower than 4 grams per day. None showed clear benefit, but a trial conducted in Australia in 81 CMT1A-affected children showed a low dose of ascorbic acid might have improved function in some of them.
The investigators on the current study note in their publication of the results that the high-dose CMT1A ascorbic acid trial pointed out some potential pitfalls that should be recognized in the design of future trials. They note that:
The investigators also note the important strides made in the ability to conduct multicenter CMT studies as a result of conducting this trial. They note that:
The Rare Diseases Clinical Research Network, funded by the National Institutes of Health, invites families with CMT1A, CMT1B, CMT2A, CMTX, CMT4 or other known or unknown forms of CMT to join an online "contact" registry that asks for information such as your or your child's name, address, date and place of birth, email address and items relevant to your or your child's disorder.
The registry, developed in part with MDA involvement, is designed to help researchers identify and recruit potential participants for future research studies.