Valproate and Levocarnitine in Children With Spinal Muscular Atrophy
Status:
Unknown status
Trial end date:
2016-12-01
Target enrollment:
Participant gender:
Summary
Spinal muscular atrophy (SMA), an autosomal recessive disorder, is characterized by muscle
weakness due to degeneration of anterior horn cells in the spinal cord and brain stem nuclei.
It has a variable incidence of 1 in 6700 to 1 in 25000 live births and prevalence of 0.12 to
25 per 10,000 populations in different geographic areas and genetic constitution. A
homozygous deletion/mutation involving exon 7 in SMN1 (survival motor neuron 1) is present in
around 95% of the cases, resulting in the biochemical deficiency of the SMN protein. A
genomic duplication at the same locus produces nearly identical SMN2 (survival motor neuron
2) that differs from SMN1 by a nucleotide substitution that promotes exon 7 exclusion thus
giving rise to only a fraction of the full length protein. Phenotypic variation in SMA
correlates with the number of SMN2 gene copies and the level of SMN protein in cells.
Several hypotheses including defective inhibition of apoptosis, glutamate excitotoxicity and
lack of a neurotrophic factor(s) in nerve or muscle have been speculated in the pathogenesis
of SMA.
Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, directly increases SMN
expression in SMA patient-derived cell lines in vitro. Till date 3 open label trials and 1
placebo controlled RCT of VPA in human subjects have been published, all indicating a
possible benefit in strength and/or motor function. Till date there is no effective therapy
for SMA. Therapy is mainly supportive and palliative which can prolong lifespan and prevent
complications to some extent without actually curing the disease.
Children with SMA may have a reduced capacity to synthesis carnitine consequent to
significantly diminished skeletal muscle mass. VPA independently inhibits carnitine transport
and its metabolites deplete carnitine levels by binding to them. So along with valproate
these patients should be supplemented with carnitine.
With this background the investigators have planned a double blind randomized placebo
controlled trial of Valproate and levocarnitine in 60 children (30 each in intervention and
control arm) with Spinal Muscular Atrophy aged 2-15 years over a 2 year period with one
baseline and four follow up visits. The study will be conducted in the Department of
Pediatrics, AIIMS at the Myopathy clinic.
Phase:
Phase 3
Details
Lead Sponsor:
All India Institute of Medical Sciences, New Delhi