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Ascorbic Acid Treatment in CMT1A Trial (AATIC)

This study is not yet open for patient recruitment.

Verified by Academisch Medisch Centrum - Universiteit van Amsterdam

(AMC-UvA) January 2006

Sponsored by: Academisch Medisch Centrum - Universiteit van Amsterdam

(AMC-UvA)

Information provided by: Academisch Medisch Centrum - Universiteit

van Amsterdam (AMC-UvA)

ClinicalTrials.gov Identifier: NCT00271635

Purpose

Charcot-Marie-Tooth type IA (CMT1A) is the most prevalent hereditary

peripheral neuropathy. Demyelination of peripheral nerves is the

hallmark of CMT1A. Ascorbic acid has been shown to have a favorable

influence on myelination in in vitro studies and in a mouse model for

CMT1A. We will study the efficacy and safety of ascorbic acid

treatment in young patients with CMT1A.

Condition Intervention Phase

Charcot-Marie-Tooth Disease

Hereditary Motor and Sensory Neuropathies

Drug: Ascorbic Acid

Phase II

MedlinePlus related topics: Charcot-Marie-Tooth Disease;

Degenerative Nerve Diseases; Genetic Disorders; Head and Brain

Malformations; Peripheral Nerve Disorders

Genetics Home Reference related topics: Charcot-Marie-Tooth disease

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Placebo Control,

Parallel Assignment, Safety/Efficacy Study

Official Title: Phase 2 Study of Ascorbic Acid Treatment in Charcot-

Marie-Tooth Type 1A

Further study details as provided by Academisch Medisch Centrum -

Universiteit van Amsterdam (AMC-UvA):

Primary Outcomes: Change in motor nerve conduction velocity of the

median nerve after 1 year

Secondary Outcomes: Change in minimal F response latency of the

median nerve after 1 year; Changes in compound muscle action

potential amplitude and area after 1 year; Change in motor unit

number estimation of the abductor pollicis brevis muscle after 1

year; Changes in handgrip strength, strength of armflexors, foot

dorsiflexors, knee extensors and hip flexors after 1 year; Change in

overall disability sum score after 1 year; Change in AMC Linear

Disability Scale score after 1 year; Evaluation of serum ascorbic

acid concentrations during 1 year; Evaluation of side effects during

1 year

Expected Total Enrollment: 12

Study start: January 2006; Expected completion: November 2007

Last follow-up: February 2007; Data entry closure: August 2007

Charcot-Marie-Tooth type 1A (CMT1A), or hereditary motor and sensory

neuropathy type Ia (HMSN Ia), is an autosomal dominant disease, most

often caused by a 1.5 Mb duplication of chromosome 17, giving rise to

three copies of the peripheral myelin protein 22 gene (PMP22).

Mutations in this gene rarely cause CMT1A. It is a primarily

demyelinating neuropathy, as has been shown in nerve conduction

studies and in histopathological investigations. The conduction

velocities of peripheral nerves are already slowed at the age of five

years. Longitudinal data show that these conduction velocities do not

change during life, indicating that the degree of demyelination is

rather constant during life.

CMT1A is characterized clinically by distal muscle weakness and

wasting, legs more than arms, impaired distal sensation, and reduced

or absent reflexes. Moreover, foot and hand deformities are often

encountered. In childhood, disease progression has been shown. In

adults, there are indications for disease progression, but properly

conducted longitudinal studies are awaited. Cross-sectional studies

show that disease severity in adults is variable: a group of CMT1A

patients is asymptomatic (5-10%), whereas other patients are

wheelchair dependent (5-10%), still most have the classical CMT

phenotype. Therapy is symptomatic and aims at maintaining functional

possibilities and learning compensation mechanisms. There is no

medication available that stabilizes or improves the clinical signs

and symptoms.

Ascorbic acid is needed in in vitro studies for proper myelination of

axons (in cultures containing serum). Recently, in a mouse model for

CMT1A it has been shown that ascorbic acid improves the CMT1A

phenotype. Mice (2-4 months old) treated with ascorbic acid once a

week during three months showed an increase in the percentage of

myelinating nerve fibers and showed better results in locomotor

tests.

In this phase 2 study we will study the efficacy and safety of

ascorbic acid in young patients with CMT1A. We will investigate

whether ascorbic acid induces remyelination by measuring the nerve

conduction of a peripheral nerve during a one year study period.

CMT1A patients aged 12 years or older may cooperate sufficiently in

nerve conduction studies. We include young patients, as clinical

signs and symptoms especially develop relatively early in life. These

signs and symptoms are due to axonal dysfunction, secondary to the

demyelination. This is why we will investigate additionally whether

there is an effect of ascorbic acid treatment on axonal function,

strength and disabilities.

Eligibility

Ages Eligible for Study: 12 Years - 25 Years, Genders Eligible

for Study: Both Criteria

Inclusion Criteria:

DNA-proven CMT1A patients

Age 12-25 years

CMT 1A patients with symptomatology defined as muscle weakness in at

least foot dorsiflexion

Exclusion Criteria:

Due to possible influence on severity of the neuropathy:

Known other disease that may cause a neuropathy, that may decrease

mobility, or that may lead to severe disability or death in a short

time

Medication that may cause a neuropathy

Chronic alcohol abuse

Due to study medication (ascorbic acid):

Regular use of vitamin C

Clinical or echographic signs of nephrolithiasis

Reduced glomerular filtration rate

Iron overload

No regular dental control at the dentist

Pregnancy or active pregnancy wish for women

Due to study design and primary outcome:

Not signing the informed consent

Psychiatric co-morbidity which may influence compliance

Not being comfortable during nerve conduction studies of the median

nerve

A too small CMAP amplitude of the abductor pollicis brevis muscle for

a proper determination of the nerve conduction velocity of the median

nerve

Location and Contact Information

Please refer to this study by ClinicalTrials.gov identifier

NCT00271635

Camiel Verhamme, MD +31-20-56663842 c.verhamme@...

Ivo N van Schaik, MD, PhD +31-20-56663842

i.n.vanschaik@...

Netherlands, P.O.Box 22660

Department of Neurology Academic Medical Center University of

Amsterdam, Amsterdam, P.O.Box 22660, 1100 DD, Netherlands

C. Verhamme, MD +31-20-5663856 c.verhamme@...

Study chairs or principal investigators

C. Verhamme, MD, Principal Investigator, Department of Neurology,

Academic Medical Center, University of Amsterdam

M. Vermeulen, MD, PhD, Principal Investigator, Department of

Neurology, Academic Medical Center, University of Amsterdam

F. Baas, MD, PhD, Principal Investigator, Department of Neurology,

Academic Medical Center, University of Amsterdam

R. de Haan, MD, PhD, Principal Investigator, Department of

Neurology, Academic Medical Center, University of Amsterdam

M. de Visser, MD, PhD, Principal Investigator, Department of

Neurology, Academic Medical Center, University of Amsterdam

I. N van Schaik, MD, PhD, Principal Investigator, Department of

Neurology, Academic Medical Center, University of Amsterdam

More Information

Publications

Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J,

Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontes M. Ascorbic acid

treatment corrects the phenotype of a mouse model of Charcot-Marie-

Tooth disease. Nat Med. 2004 Apr;10(4):396-401. Epub 2004 Mar 21.

Verhamme C, van Schaik IN, Koelman JH, de Haan RJ, Vermeulen M, de

Visser M. Clinical disease severity and axonal dysfunction in

hereditary motor and sensory neuropathy Ia. J Neurol. 2004 Dec;251

(12):1491-7.

Study ID Numbers: 04/320

Last Updated: January 3, 2006

Record first received: January 3, 2006

ClinicalTrials.gov Identifier: NCT00271635

Health Authority: Netherlands: The Central Committee on Research

Involving Human Subjects (CCMO)

ClinicalTrials.gov processed this record on 2006-01-11