Valproate and Levocarnitine in Children With Spinal Muscular Atrophy
- Full Text View
- Tabular View
- No Study Results Posted
- Disclaimer
- How to Read a Study Record
Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Spinal Muscular Atrophy |
Drug: Valproate, Levocarnitine Drug: Placebo |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment |
| Official Title: | Randomized Placebo Controlled Trial of Valproate and Levocarnitine in Children With Spinal Muscular Atrophy Aged 2-15 Years |
- Change in muscle power on a 5 point scale as per the principles of manual muscle testing at 12, 24, 36 and 52 weeks [ Time Frame: Over 52 weeks with assessment at baseline, 12, 24, 36 and 52 weeks ] [ Designated as safety issue: No ]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.
- 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. [ Time Frame: Over 52 weeks starting from baseline folloowed by assessment at 12, 24,36 and 52 weeks ] [ Designated as safety issue: No ]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
- Change in Forced vital capacity (FVC) at 12, 24, 36 and 52 weeks. [ Time Frame: Over 52 weeks with baseline assessment followed by re evaluation at 12, 24, 36 and 52 weeks ] [ Designated as safety issue: No ]Baseline Forced vital capacity (FVC) followed by change in Forced vital capacity (FVC) at 12, 24, 36 and 52 weeks will be measured.
- Prevalence of various side effects of valproate (as mentioned below)in the subjects at 12, 24, 36 and 52 weeks. [ Time Frame: At baseline followed by assessments at 12, 24, 36 and 52 weeks (as and when required) ] [ Designated as safety issue: Yes ]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.
- Prevalence of abnormalities of Hemogram and Liver Function tests in the subjects at 24 and 52 weeks [ Time Frame: At 24 weeks and at 52 weeks ] [ Designated as safety issue: Yes ]Hemogram and Liver Function tests of all recruited patients will be done at 24 and 52 weeks
- Serum Valproate levels at 52 weeks [ Time Frame: At 52 weeks completed ] [ Designated as safety issue: Yes ]Serum Valproate levels of all subjects will be done at 52 weeks
| Estimated Enrollment: | 60 |
| Study Start Date: | September 2012 |
| Estimated Study Completion Date: | September 2014 |
| Estimated Primary Completion Date: | September 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Valproate, levocarnitine
The patients will be randomized into two groups: Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine) |
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. |
|
Placebo Comparator: Placebo
All patients will be randomized into two groups: Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine) |
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. |
Show Detailed Description Eligibility| Ages Eligible for Study: | 2 Years to 15 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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:
- SMA type I, onset before 6 months of age.
- Severely ill and unstable patients requiring life support system.
- Other causes like cerebral palsy, Down syndrome, connective tissue disorders, metabolic disorders.
- Pre-existing liver damage, bone marrow depression and coagulation disorders.
- Use of medications or supplements which interfere with valproic acid and carnitine metabolism within 3 months of study enrollment.
- 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
Contacts and Locations| Contact: Gulati Sheffali, MD | 9868397532 | sheffaligulati@gmail.com |
| India | |
| All India Institute of Medical Sciences | Not yet recruiting |
| New Delhi, Delhi, India, 110029 | |
| Contact: Gulati Sheffali, MD 9868397532 sheffaligulati@gmail.com | |
| Principal Investigator: Gulati Sheffali, MD | |
| Principal Investigator: | Gulati Sheffali, MD | All India Institute of Medical Sciences, New Delhi |
More Information
No publications provided
| Responsible Party: | Sheffali Gulati, Additional Professor, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi |
| ClinicalTrials.gov Identifier: | NCT01671384 History of Changes |
| Other Study ID Numbers: | Valproate and SMA |
| Study First Received: | August 13, 2012 |
| Last Updated: | August 22, 2012 |
| Health Authority: | India: Institutional Review Board |
Keywords provided by All India Institute of Medical Sciences, New Delhi:
|
Valproate levocarnitine SMA physiotherapy placebo |
Additional relevant MeSH terms:
|
Muscular Atrophy Muscular Atrophy, Spinal Atrophy Spinal Cord Diseases Neuromuscular Manifestations Neurologic Manifestations Nervous System Diseases Pathological Conditions, Anatomical Signs and Symptoms Central Nervous System Diseases Motor Neuron Disease Neurodegenerative Diseases Neuromuscular Diseases Carnitine Valproic Acid |
Vitamin B Complex Vitamins Micronutrients Growth Substances Physiological Effects of Drugs Pharmacologic Actions Anticonvulsants Central Nervous System Agents Therapeutic Uses Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action GABA Agents Neurotransmitter Agents Antimanic Agents Tranquilizing Agents |
ClinicalTrials.gov processed this record on May 23, 2013