Clinical trial NCT00657748: Lithium and Acetate for Canavan Disease
Official title: Evaluation of the Tolerance and Efficiency of a Combined Oral Therapy With Lithium and GTA in Patients With Canavan Disease
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Canavan Disease
Infantile
Deficiency Disease
Aspartoacylase
Leukodystrophy, Spongiform
Keywords: Leukodystrophy
Canavan disease,
Aspartoacylase,
Lithium,
Glyceryl Triacetate
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: European Leukodystrophy Association
First posted: 2008-04-14
Enrollment: 0
Sex: ALL
Minimum age (years): 1
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The aim of this study is to determine whether oral supplementation with lithium and acetate may improve the biological and clinical prognosis in patients with Canavan Disease.

Detailed description: Canavan Disease is an autosomal recessive devastating demyelinating disease caused by a deficiency in Aspartoacylase (ASPA) enzyme. There is no available treatment. ASPA deficiency leads to:- the accumulation of high levels of N-acetylaspartate (NAA), involved in myelin degeneration and epilepsy;- the deficient synthesis of acetate in oligodendrocytes, that could impair CNS myelination.Lithium administration induces a decrease in NAA in the brain of the tremor rats (animal model for CD) and in one patient (JANSON, 2005). On the other hand, administration of acetate could improve myelination in Canavan patients.For this reason, we propose to combine both treatments: Lithium Gluconate and Glyceryl Triacetate (GTA). Eighteen patients, aged 1 to 15 years, will receive oral GTA or Lithium during 4 months, then both treatment in association during 6 months. Patients will be sequentially evaluated up to the end of the treatment and 2 months thereafter for:-tolerance of the therapy (careful monitoring of clinical and biological parameters).- efficacy of the therapy on clinical, biological and radiological parameters. Particularly, we will evaluate using MRI-spectroscopy and CSF samples the decrease in NAA and increase in acetate levels in the brain.

Eligibility criteria: Inclusion Criteria:

* Clinical and biochemical diagnosis of Canavan disease

Exclusion Criteria:

* Renal disease
* Thyroid disease
* Cardiac disease
* Impossibility to perform brain MRI

Primary outcomes:
measure: The primary outcome will be a decrease of the NAA peak (> 20%) or the appearance of an acetate peak at the end of the treatment (10 months), using spectroscopy-MRI.
timeFrame: 10 months
Secondary outcomes:
measure: Secondary outcomes will be assessed at 10 months (end of the treatment): -Improvement of neuromotor performances (GMFM and Mullen scales), spasticity, and neurological severity
timeFrame: 10 months
measure: -Improvement of epilepsy (number of seizures)
timeFrame: 10 months
measure: -Decrease in NAA and increase in acetate contents in fluids (CSF, plasma, urine).
timeFrame: 10 months
Other outcomes:
Locations:
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Patrick Aubourg, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Caroline Sevin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mathew R, Arun P, Madhavarao CN, Moffett JR, Namboodiri MA. Progress toward acetate supplementation therapy for Canavan disease: glyceryl triacetate administration increases acetate, but not N-acetylaspartate, levels in brain. J Pharmacol Exp Ther. 2005 Oct;315(1):297-303. doi: 10.1124/jpet.105.087536. Epub 2005 Jul 7.
citation: Madhavarao CN, Arun P, Moffett JR, Szucs S, Surendran S, Matalon R, Garbern J, Hristova D, Johnson A, Jiang W, Namboodiri MA. Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease. Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5221-6. doi: 10.1073/pnas.0409184102. Epub 2005 Mar 22.
citation: Janson CG, Assadi M, Francis J, Bilaniuk L, Shera D, Leone P. Lithium citrate for Canavan disease. Pediatr Neurol. 2005 Oct;33(4):235-43. doi: 10.1016/j.pediatrneurol.2005.04.015.
citation: Baslow MH, Kitada K, Suckow RF, Hungund BL, Serikawa T. The effects of lithium chloride and other substances on levels of brain N-acetyl-L-aspartic acid in Canavan disease-like rats. Neurochem Res. 2002 May;27(5):403-6. doi: 10.1023/a:1015504031229.