Spinal Muscular Atrophy Clinical Trial
Official title:
Randomized Placebo Controlled Trial of Valproate and Levocarnitine in Children With Spinal Muscular Atrophy Aged 2-15 Years
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.
Status | Recruiting |
Enrollment | 60 |
Est. completion date | December 2016 |
Est. primary completion date | December 2016 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 2 Years to 15 Years |
Eligibility |
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 |
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
India | All India Institute of Medical Sciences | New Delhi | Delhi |
Lead Sponsor | Collaborator |
---|---|
All India Institute of Medical Sciences, New Delhi |
India,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Change in Forced vital capacity (FVC) at 12, 24, 36 and 52 weeks. | Baseline Forced vital capacity (FVC) followed by change in Forced vital capacity (FVC) at 12, 24, 36 and 52 weeks will be measured. | Over 52 weeks with baseline assessment followed by re evaluation at 12, 24, 36 and 52 weeks | No |
Other | Prevalence of various side effects of valproate (as mentioned below)in the subjects at 12, 24, 36 and 52 weeks. | All patients will be assessed for side effect profile of valproate (dyspepsia, weight gain, dysphoria, fatigue, dizziness, drowsiness, hair loss, headaches, nausea, sedation and tremors) at 12, 24, 36 and 52 weeks. | At baseline followed by assessments at 12, 24, 36 and 52 weeks (as and when required) | Yes |
Other | Prevalence of abnormalities of Hemogram and Liver Function tests in the subjects at 24 and 52 weeks | Hemogram and Liver Function tests of all recruited patients will be done at 24 and 52 weeks | At 24 weeks and at 52 weeks | Yes |
Other | Serum Valproate levels at 52 weeks | Serum Valproate levels of all subjects will be done at 52 weeks | At 52 weeks completed | Yes |
Primary | Change in muscle power on a 5 point scale as per the principles of manual muscle testing at 12, 24, 36 and 52 weeks | Baseline assessment will include a detailed muscle charting on a 5 point scale as per the principles of manual muscle testing by a child physiotherapist.Patients will be clinically re-evaluated at 12, 24, 36 and 52 weeks by a detailed muscle charting on a 5 point scale as per the principles of manual muscle testing by a child physiotherapist. | Over 52 weeks with assessment at baseline, 12, 24, 36 and 52 weeks | No |
Secondary | a) Change in functional measure using modified Hammersmith Functional Motor Scale (MHFMS) score at 12, 24, 36 and 52 weeks 12, 24, 36 and 52 weeks. | Baseline functional status will be assessed using modified Hammersmith Functional Motor Scale (MHFMS) score. Change in functional measure using modified Hammersmith Functional Motor Scale (MHFMS) score will be measured at 12, 24, 36 and 52 weeks | Over 52 weeks starting from baseline folloowed by assessment at 12, 24,36 and 52 weeks | No |
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