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Ascorbic Acid Treatment in CMT1A Trial (AATIC) (AATIC)

Primary Purpose

Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies

Status
Completed
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
Placebo
ascorbic acid
Sponsored by
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Charcot-Marie-Tooth Disease focused on measuring Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies, Ascorbic Acid, Vitamin C

Eligibility Criteria

12 Years - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Department of Neurology Academic Medical Center University of Amsterdam

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

1

2

Arm Description

Ascorbic acid

Placebo

Outcomes

Primary Outcome Measures

Change in motor nerve conduction velocity of the median nerve after 1 year

Secondary Outcome Measures

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

Full Information

First Posted
January 3, 2006
Last Updated
July 2, 2008
Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
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1. Study Identification

Unique Protocol Identification Number
NCT00271635
Brief Title
Ascorbic Acid Treatment in CMT1A Trial (AATIC)
Acronym
AATIC
Official Title
Phase 2 Study of Ascorbic Acid Treatment in Charcot-Marie-Tooth Type 1A
Study Type
Interventional

2. Study Status

Record Verification Date
July 2008
Overall Recruitment Status
Completed
Study Start Date
January 2006 (undefined)
Primary Completion Date
July 2007 (Actual)
Study Completion Date
July 2007 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies
Keywords
Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies, Ascorbic Acid, Vitamin C

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Arm Description
Ascorbic acid
Arm Title
2
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo 4 capsules b.i.d. during 1 year
Intervention Type
Drug
Intervention Name(s)
ascorbic acid
Other Intervention Name(s)
Vitamin C
Intervention Description
Ascorbic acid 1000 mg (4 capsules of 250 mg) b.i.d. during 1 year
Primary Outcome Measure Information:
Title
Change in motor nerve conduction velocity of the median nerve after 1 year
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Change in minimal F response latency of the median nerve after 1 year
Time Frame
1 year
Title
Changes in compound muscle action potential amplitude and area after 1 year
Time Frame
1 year
Title
Change in motor unit number estimation of the abductor pollicis brevis muscle after 1 year
Time Frame
1 year
Title
Changes in handgrip strength, strength of armflexors, foot dorsiflexors, knee extensors and hip flexors after 1 year
Time Frame
1 year
Title
Change in overall disability sum score after 1 year
Time Frame
1 year
Title
Change in AMC Linear Disability Scale score after 1 year
Time Frame
1 year
Title
Evaluation of serum ascorbic acid concentrations during 1 year
Time Frame
1 year
Title
Evaluation of side effects during 1 year
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
C. Verhamme, MD
Organizational Affiliation
Department of Neurology, Academic Medical Center, University of Amsterdam
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
M. Vermeulen, MD, PhD
Organizational Affiliation
Department of Neurology, Academic Medical Center, University of Amsterdam
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
F. Baas, MD, PhD
Organizational Affiliation
Department of Neurology, Academic Medical Center, University of Amsterdam
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
R. de Haan, MD, PhD
Organizational Affiliation
Department of Neurology, Academic Medical Center, University of Amsterdam
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
M. de Visser, MD, PhD
Organizational Affiliation
Department of Neurology, Academic Medical Center, University of Amsterdam
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
I. N van Schaik, MD, PhD
Organizational Affiliation
Department of Neurology, Academic Medical Center, University of Amsterdam
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Neurology Academic Medical Center University of Amsterdam
City
Amsterdam
State/Province
P.O.Box 22660
ZIP/Postal Code
1100 DD
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
15034573
Citation
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. doi: 10.1038/nm1023. Epub 2004 Mar 21.
Results Reference
background
PubMed Identifier
15645349
Citation
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. doi: 10.1007/s00415-004-0578-x.
Results Reference
background
PubMed Identifier
19909499
Citation
Verhamme C, de Haan RJ, Vermeulen M, Baas F, de Visser M, van Schaik IN. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial. BMC Med. 2009 Nov 12;7:70. doi: 10.1186/1741-7015-7-70.
Results Reference
derived

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Ascorbic Acid Treatment in CMT1A Trial (AATIC)

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