Ascorbic Acid Treatment in CMT1A Trial (AATIC) - Full Text View

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: Placebo Drug: ascorbic acid	Phase II

Genetics Home Reference related topics: Charcot-Marie-Tooth disease familial encephalopathy with neuroserpin inclusion bodies hereditary neuropathy with liability to pressure palsies

MedlinePlus related topics: Charcot-Marie-Tooth Disease Tooth Disorders

Drug Information available for: Ascorbic acid

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), 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 Outcome Measures:

Change in motor nerve conduction velocity of the median nerve after 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change in minimal F response latency of the median nerve after 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Changes in compound muscle action potential amplitude and area after 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Change in motor unit number estimation of the abductor pollicis brevis muscle after 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Changes in handgrip strength, strength of armflexors, foot dorsiflexors, knee extensors and hip flexors after 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Change in overall disability sum score after 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Change in AMC Linear Disability Scale score after 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Evaluation of serum ascorbic acid concentrations during 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Evaluation of side effects during 1 year [ Time Frame: 1 year ] [ Designated as safety issue: No ]

Enrollment:	13
Study Start Date:	January 2006
Study Completion Date:	July 2007
Primary Completion Date:	July 2007 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Ascorbic acid	Drug: ascorbic acid Ascorbic acid 1000 mg (4 capsules of 250 mg) b.i.d. during 1 year
2: Placebo Comparator Placebo	Drug: Placebo Placebo 4 capsules b.i.d. during 1 year

Detailed Description:

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 to 25 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00271635

Locations

Netherlands, P.O.Box 22660
Department of Neurology Academic Medical Center University of Amsterdam
Amsterdam, P.O.Box 22660, Netherlands, 1100 DD

Sponsors and Collaborators

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Investigators

Principal Investigator:	C. Verhamme, MD	Department of Neurology, Academic Medical Center, University of Amsterdam
Principal Investigator:	M. Vermeulen, MD, PhD	Department of Neurology, Academic Medical Center, University of Amsterdam
Principal Investigator:	F. Baas, MD, PhD	Department of Neurology, Academic Medical Center, University of Amsterdam
Principal Investigator:	R. de Haan, MD, PhD	Department of Neurology, Academic Medical Center, University of Amsterdam
Principal Investigator:	M. de Visser, MD, PhD	Department of Neurology, Academic Medical Center, University of Amsterdam
Principal Investigator:	I. N van Schaik, MD, PhD	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.

Responsible Party:	Academic Medical Center, university of Amsterdam ( C. Verhamme, MD )
Study ID Numbers:	04/320
Study First Received:	January 3, 2006
Last Updated:	July 2, 2008
ClinicalTrials.gov Identifier:	NCT00271635
Health Authority:	Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Charcot-Marie-Tooth Disease
Hereditary Motor and Sensory Neuropathies
Ascorbic Acid
Vitamin C

Study placed in the following topic categories:

Tooth Diseases
Nervous System Malformations
Roussy Levy hereditary areflexic dystasia
Charcot-Marie-Tooth Disease
Polyneuropathies
Neurodegenerative Diseases
Nerve Compression Syndromes
Tomaculous neuropathy
Heredodegenerative Disorders, Nervous System

Neuromuscular Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Hereditary Motor and Sensory Neuropathies
Stomatognathic Diseases
Congenital Abnormalities
Ascorbic Acid
Charcot Marie Tooth disease
Charcot-Marie-Tooth disease, Type 1A

Additional relevant MeSH terms:

Antioxidants
Molecular Mechanisms of Pharmacological Action
Growth Substances
Vitamins
Physiological Effects of Drugs

Nervous System Diseases
Micronutrients
Protective Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009