CMT 1A: Results of Vitamin C trial in the UK

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First clinical trial of Ascorbic Acid (Vit. C) for Charcot-Marie-Tooth disease

http://www.muscular-dystrophy.org/research/grants/completed_grants/2713_first_cl\

inical_trial_for_charcot-marie-tooth_disease

Project Leader: Dr Reilly

Location: MRC Centre for Neuromuscular Diseases, Department of Molecular

Neuroscience, UCL Institute of Neurology

Condition: Charcot-Marie-Tooth disease 1A

Duration: 3 years, completed August 2009

Total Project Cost: £201,601

Official Title: Randomised double blind placebo controlled trial of long-term

ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A.

Dr Reilly and colleagues organised this first clinical trial for

Charcot-Marie-Tooth disease type 1A (CMT1A) to determine if vitamin C could slow

the progression of the condition. Unfortunately the trial showed that while the

high doses of vitamin C were safe, it did not improve the symptoms nor did it

slow the progression of CMT1A on objective tests. The trial did however gather

important information on the progression of CMT1A and gained experience in

conducting clinical trials for this condition that will be valuable for future

CMT1A clinical trials.

What were the researchers aiming to do?

In 2004, researchers discovered that when they gave vitamin C to a mouse model

of CMT1A, there was an improvement in the symptoms the mice were displaying.

These mice also performed better in a series of muscle function tests than

untreated mice. Since vitamin C is already freely available there was concern

that some people with CMT1A were taking high doses of vitamin C, having read

about this study, without there being clear evidence of a similar effect in

humans. It was, therefore, decided that a trial should be set up to test if

vitamin C did indeed have a similar effect in humans and whether it was safe for

this group of individuals to be taking high dose vitamin C.

Dr Reilly and her colleagues in Italy set up this trial to test the safety and

efficacy of vitamin C in CMT1A. The trial was a randomized, double-blind,

placebo-controlled trial. This means that participants were randomly assigned to

receive either vitamin C or a placebo (an inactive substance that looks and

tastes just like vitamin C) and neither the doctors nor the participants knew

who was getting what. As this was the first trial for CMT it was very important

to think carefully about what to measure in order to correctly establish if

there was a difference between the people treated with Vitamin C and those who

got the placebo - these are called outcome measures. Prior to the trial

starting, a European Neuromuscular Centre funded workshop was organised to

determine the best outcome measures. The workshop was attended by an

international group of clinicians and importantly also included two patient

representatives.

Following the workshop it was decided to run the trial in the UK and Italy with

the aim of recruiting 272 participants. The participants, aged between 18 and 70

years of age, would get three doses of either Vitamin C (1.5 g in total per day)

or the placebo every day for 2 years. They were followed up every 6 months and

measurements such as muscle strength, changes in feeling, walking speed and

levels of pain and fatigue assessed. 50 participants were to be recruited in the

UK arm of the study, run by Dr Reilly.

What did their research show?

Of the original 50 participants, 38 completed the trial. The 12 who did not

complete the trial dropped out for a variety of reasons including adverse

events, pregnancy, admissions for surgery, withdrawal of consent and failure to

attend follow-up appointments.

Unfortunately the trial showed that while the high doses of vitamin C were safe,

it did not improve the symptoms nor did it slow the progression of CMT1A on

objective tests. Although this is a negative result, it was still important to

carry out the trial to prove one way or the other whether vitamin C would have

an effect. Researchers will be able to use this information and move onto

exploring other avenues for possible therapy.

One important result of this trial has been the validation of the outcome

measures for CMT. The fact that this has been a long term trial (2 years) has

also allowed Dr Reilly and her colleagues to gather detailed information about

how this condition progresses and changes over time. This valuable information

will help with the planning of future clinical trials for CMT.

How will the outcomes of the research benefit patients?

This trial has shown that vitamin C does not improve the symptoms or slow the

progression of CMT1A. As many people were taking high doses of vitamin C having

heard about the animal study, it was important to determine if this might indeed

prove to be an effective treatment or whether people were unnecessarily taking

this substance.

The work done in this trial also will help to inform and improve future trials

for CMT.

Background Information

CMT is the most prevalent inherited neuromuscular condition affecting around

23,000 people in the UK. CMT1A is the commonest form of CMT and is caused by the

presence of an extra copy of a gene that carries the instructions for a protein

called peripheral myelin protein 22 (PMP-22). PMP-22 has an important role in

the formation and maintenance of myelin. Myelin is the layer wrapped around the

axon of nerve cells and it is important for the conduction of electrical signals

down the nerve. It is thought that having an extra copy of the PMP-22 gene may

impair the function of the myelin and thus affecting how well the nerves are

able to conduct the electrical signals.

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