Charcot-Marie-Tooth DiseasePhase 2AATICNCT00271635
Ascorbic Acid Treatment in CMT1A Trial (AATIC)
A Phase 2 study testing ascorbic acid in people with Charcot-Marie-Tooth Disease and Hereditary Motor and Sensory Neuropathies, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
Trial 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. Read more about this study
- Who is it for?
- Ages 12 to 25 years
- Conditions the study is for
- Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies
- What is being tested?
- ascorbic acid
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 13 participants
- Where
- 1 siteNetherlands
- Study dates
- Jan 2006to Jul 2007
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- DNA-proven CMT1A patients
- Age 12-25 years
- CMT 1A patients with symptomatology defined as muscle weakness in at least foot dorsiflexion
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Department of Neurology Academic Medical Center University of Amsterdam
Amsterdam, P.O.Box 22660, 1100 DD
About this study
Official title: Phase 2 Study of Ascorbic Acid Treatment in Charcot-Marie-Tooth Type 1A
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.
Read the 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.
- Being tested
- Placebo, ascorbic acid
- Keywords
- Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies, Ascorbic Acid, Vitamin C
- Medical subject headings
- Charcot-Marie-Tooth Disease, Hereditary Sensory and Motor Neuropathy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Placebo 4 capsules b.i.d. during 1 year
ascorbic acidDrug
Also called Vitamin C
Ascorbic acid 1000 mg (4 capsules of 250 mg) b.i.d. during 1 year
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Ascorbic acid Receives: Drug: ascorbic acid |
| 2 | Placebo comparator | Placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in motor nerve conduction velocity of the median nerve after 1 year
Measured: 1 year
Secondary outcomes (8)
Change in minimal F response latency of the median nerve after 1 year
Measured: 1 year
Changes in compound muscle action potential amplitude and area after 1 year
Measured: 1 year
Change in motor unit number estimation of the abductor pollicis brevis muscle after 1 year
Measured: 1 year
Changes in handgrip strength, strength of armflexors, foot dorsiflexors, knee extensors and hip flexors after 1 year
Measured: 1 year
Change in overall disability sum score after 1 year
Measured: 1 year
Change in AMC Linear Disability Scale score after 1 year
Measured: 1 year
Evaluation of serum ascorbic acid concentrations during 1 year
Measured: 1 year
Evaluation of side effects during 1 year
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jan 2006 (estimated)
- Study startJan 2006
- Primary completionJul 2007
- Study completionJul 2007
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Charcot-Marie-Tooth DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
- Sponsor type
- University, hospital or other
- Investigators
- C. Verhamme, MD, Principal investigator, Department of Neurology, Academic Medical Center, University of AmsterdamM. Vermeulen, MD, PhD, Principal investigator, Department of Neurology, Academic Medical Center, University of AmsterdamF. Baas, MD, PhD, Principal investigator, Department of Neurology, Academic Medical Center, University of AmsterdamR. de Haan, MD, PhD, Principal investigator, Department of Neurology, Academic Medical Center, University of AmsterdamM. de Visser, MD, PhD, Principal investigator, Department of Neurology, Academic Medical Center, University of AmsterdamI. N van Schaik, MD, PhD, Principal investigator, Department of Neurology, Academic Medical Center, University of Amsterdam
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00271635
- Sponsor's protocol ID
- 04/320
- Acronym
- AATIC
- Status last verified
- Jul 2008
- First submitted
- 3 Jan 2006
- Last updated
- 4 Jul 2008
- Results posted
- No
- Data monitoring committee
- Yes
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. doi: 10.1038/nm1023. Epub 2004 Mar 21.
PubMed 15034573Verhamme 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.
PubMed 15645349Verhamme 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.
PubMed 19909499
Study at a glance
From the registry record, last updated by the sponsor on 4 Jul 2008. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2 Study of Ascorbic Acid Treatment in Charcot-Marie-Tooth Type 1A
- ClinicalTrials.gov ID
- NCT00271635
- Acronym / sponsor ID
- AATIC / 04/320
- Keywords
- Charcot-Marie-Tooth Disease, Hereditary Motor and Sensory Neuropathies, Ascorbic Acid, Vitamin C
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)University, hospital or other
- Study start
- Jan 2006
- Primary completion
- Jul 2007 (actual)
- Study completion
- Jul 2007 (actual)
- First posted
- 4 Jan 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: ascorbic acidAscorbic acid |
| 2 | Placebo comparator | Drug: PlaceboPlacebo |
Who may qualify
- Ages
- 12 to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (3 listed)
- DNA-proven CMT1A patients
- Age 12-25 years
- CMT 1A patients with symptomatology defined as muscle weakness in at least foot dorsiflexion
Key exclusion criteria (16 listed)
- 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
- Regular use of vitamin C
- Clinical or echographic signs of nephrolithiasis
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboPlacebo 4 capsules b.i.d. during 1 year | Drug | 2 |
| ascorbic acidAlso: Vitamin CAscorbic acid 1000 mg (4 capsules of 250 mg) b.i.d. during 1 year | Drug | 1 |
Primary outcome
Change in motor nerve conduction velocity of the median nerve after 1 year
Time frame: 1 year
8 secondary outcomes
Change in minimal F response latency of the median nerve after 1 year
Time frame: 1 year
Changes in compound muscle action potential amplitude and area after 1 year
Time frame: 1 year
Change in motor unit number estimation of the abductor pollicis brevis muscle after 1 year
Time frame: 1 year
Changes in handgrip strength, strength of armflexors, foot dorsiflexors, knee extensors and hip flexors after 1 year
Time frame: 1 year
Change in overall disability sum score after 1 year
Time frame: 1 year
Change in AMC Linear Disability Scale score after 1 year
Time frame: 1 year
Evaluation of serum ascorbic acid concentrations during 1 year
Time frame: 1 year
Evaluation of side effects during 1 year
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jul 2008.
- Background: PubMed 15034573Passage 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.
- Background: PubMed 15645349Verhamme 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.
- Derived from this study: PubMed 19909499Verhamme 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
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
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing ascorbic acid in people with Charcot-Marie-Tooth Disease and Hereditary Motor and Sensory Neuropathies, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 Jul 2008. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in motor nerve conduction velocity of the median nerve after 1 year (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00271635, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jul 2008.