Workshop makes preparations for Charcot-Marie-Tooth disease clinical trials

[Guest guest]

Tuesday 15 February 2011

Workshop makes preparations for Charcot-Marie-Tooth disease clinical trials

http://www.muscular-dystrophy.org/research/news/3329

A report has been published which sets out plans to prepare the international

community for future clinical trials for Charcot-Marie-Tooth disease (CMT). The

report is based on the outcomes of a European Neuromuscular Centre (ENMC)

workshop held in the Netherlands in September 2009. Twenty-one expert clinicians

and scientists and two patient representatives from seven European countries,

the USA and Australia attended the workshop.

CMT affects one in 2,500 people and currently no treatment exists besides

physiotherapy and surgery to manage the symptoms. CMT affects the peripheral

nerves which connect the spinal cord to the muscles, joints and skin, carrying

messages in both directions. When these nerves are unable to carry messages

efficiently this leads to weakness and wasting of the muscles below the knees

and often those of the hands. Many people with CMT also have loss of feeling in

the hands and feet. The most common type of CMT - CMT1A - is caused by mutation

of the PMP22 gene but more than 30 other genes have now been identified as

causing other types of CMT.

The development of treatments for CMT is now an exciting and fast moving field

so it is essential that the infrastructure is put in place for clinical trials

to be conducted quickly and efficiently. The workshop discussed five topics to

address this:

Improve current outcome measures

Develop outcome measures for use with children

Review the completed and ongoing vitamin C trials

Design an international patient registry

Review the most promising new therapies

Improve current outcome measures

Outcome measures are ways of testing the benefit of a new potential treatment.

These need to be tested and agreed upon by all clinicians and health

professionals conducting a clinical trial because otherwise it is not possible

to compare results between different clinical trial sites.

The outcome measure currently used is called the CMT neuropathy score - CMTNS.

This is a scale that scores 36 symptoms, signs and measures of the electrical

activity in the nerves (neurophysiology). Several ways to refine and improve the

scoring system were discussed. These changes aim to make the scoring system more

sensitive to small improvements in symptoms. Three of the workshop participants

agreed to incorporate these changes into the scoring system and a plan was put

in place to validate and test it.

Possible new outcome measures were also discussed such as timed walk tests, skin

biopsies, quality of life questionnaires and MRI. Ongoing studies will determine

if these are worth considering for future clinical trials.

Develop outcome measures for use with children

The CMTNS has been shown to work reasonably well for children over 10 years of

age, but is not suitable for younger children. A team of specialists attending

the workshop have been working together on a paediatric CMT scale which measures

symptoms, ankle and foot involvement, hand dexterity and strength, sensation,

balance and motor function in an age appropriate way. This new scoring system

will be tested over the following year.

Review the completed and ongoing vitamin C trials

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.

Clinical trials were then started in various countries including France,

Australia, The Netherlands, the US and (jointly) Italy and the UK. The trials

tested different doses for either one or two years. Most of the trials have

shown little or no improvement in symptoms but there are still some trials

ongoing. After all of the trials are finished 770 people with CMT will have been

enrolled in Vitamin C studies with 450 of them treated with Vitamin C. Analysis

of the results of all the trials once completed will give the final answer as to

if any dose of Vitamin C is effective. These trials have also served as useful

tests for the CMNTS outcome measure, and have resulted in improvements in the

scale as mentioned above.

Design an international patient registry

Patient registries are databases containing information about patients with a

particular condition. This information helps researchers and pharmaceutical

companies plan clinical trials and contact potential trial participants when the

time comes for a trial to start.

Three of the participants at the meeting have been working for some time on

deciding what information should be entered into an international CMT registry.

This minimum dataset was presented, discussed and agreed upon. The registry will

capture all of the information considered crucial for a clinical trial and at

the same time be easily filled in by physicians. Plans were set in place to role

the registry out internationally with the help of TREAT-NMD. The University of

South Florida, USA agreed to host the registry.

Review the most promising new therapies

Finally, the workshop participants discussed the therapies currently being

studied that are most likely to lead to clinical trials in the future. Drugs

called " progesterone antagonists " which prevent the action of the hormone

progesterone were considered to have potential because they have been shown to

be of benefit in animal models of CMT1A. Unfortunately currently available

progesterone antagonists are too toxic to be safely administered to patients but

newer types of these drugs being developed may prove to be safer.

Curcumin, which is found in the spice turmeric, is another promising candidate

for CMT1A and CMT1B. It has been shown to be effective in patients' cells grown

in the laboratory and animal models. Further tests in the laboratory are

ongoing.

To identify new drug candidates for CMT, researchers in the US are screening

hundreds of thousands of potential medications using high-throughput screens.

Read about this type of drug screen in Target Research magazine.

It was agreed that it is very important that future clinical trials for CMT are

well designed and the workshop participants put together a list of criteria to

reach this aim.

Further information and links at link.