Valproate and Levocarnitine in Children With Spinal Muscular Atrophy

• Status: Unknown status
• Trial end date: 2016-12-01
• Target enrollment: 0
• Participant gender: All

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
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: All India Institute of Medical Sciences, New Delhi
• Treatments: Valproic Acid

Criteria

Inclusion Criteria:

• Children aged 2-15 years having motor weakness, hypotonia and hyporeflexia with onset noticed after 6 months of age.

• Presence of exon7 deletion of SMNT gene. OR Normal/ mildly elevated CPK with electrodiagnostic characteristics suggestive of neurogenic weakness, normal motor and sensory nerve conduction velocities and muscle biopsy showing neurogenic atrophy and /or evidence of reinnervation.

Exclusion Criteria:

1. SMA type I, onset before 6 months of age.

2. Severely ill and unstable patients requiring life support system.

3. Other causes like cerebral palsy, Down syndrome, connective tissue disorders, metabolic disorders.

4. Pre-existing liver damage, bone marrow depression and coagulation disorders.

5. Use of medications or supplements which interfere with valproic acid and carnitine metabolism within 3 months of study enrollment.

6. Current use of either valproate or levocarnitine. If study subject is taking valproate and carnitine then patient must go through a washout period of 12 weeks before enrollment into the study