Valproate and Levocarnitine in Children With Spinal Muscular Atrophy

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.

Conditions

• Spinal Muscular Atrophy

Interventions

DRUG

Valproate, Levocarnitine

All patients with diagnosis of SMA aged 2-15 years already registered in Myopathy Clinic of AIIMS will be recalled. Information will be sent to all Government Hospitals in Delhi that such a study is currently in progress and all the referrals will also be recruited. These patients and all those newly diagnosed at Myopathy Clinic, AIIMS will be randomized into two groups: Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine) The investigators will be blinded to the code of the medicine. It will be broken only at the end of the study or if there are any significant side effects. So one group will receive Valproate and levocarnitine and other group will receive Placebo and placebo.

DRUG

Placebo

All patients with diagnosis of SMA aged 2-15 years already registered in Myopathy Clinic of AIIMS will be recalled. Information will be sent to all Government Hospitals in Delhi that such a study is currently in progress and all the referrals will also be recruited. These patients and all those newly diagnosed at Myopathy Clinic, AIIMS will be randomized into two groups: Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine) The investigators will be blinded to the code of the medicine. It will be broken only at the end of the study or if there are any significant side effects. So one group will receive Valproate and levocarnitine and other group will receive Placebo and placebo.

Sponsors & Collaborators

• All India Institute of Medical Sciences

  lead OTHER

Principal Investigators

• Gulati Sheffali, MD · All India Institute of Medical Sciences

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

2 Years

Max Age

15 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2013-08-31

Primary Completion

2016-12-31

Completion

2016-12-31

Countries

• India

Study Locations