Valproate and Levocarnitine in Children With Spinal Muscular Atrophy

NCT01671384 | Unknown Phase 3 DMC

• 1 other identifier: Valproate and SMA
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

Valproate; levocarnitine; SMA; physiotherapy; placebo

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (1)

• 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.

  Over 52 weeks starting from baseline folloowed by assessment at 12, 24,36 and 52 weeks

Other Outcomes (4)

• Change in Forced vital capacity (FVC) at 12, 24, 36 and 52 weeks.

  Over 52 weeks with baseline assessment followed by re evaluation at 12, 24, 36 and 52 weeks

• Prevalence of various side effects of valproate (as mentioned below)in the subjects at 12, 24, 36 and 52 weeks.

  At baseline followed by assessments at 12, 24, 36 and 52 weeks (as and when required)

• Prevalence of abnormalities of Hemogram and Liver Function tests in the subjects at 24 and 52 weeks

  At 24 weeks and at 52 weeks

Study Arms (2)

Valproate, levocarnitine

ACTIVE COMPARATOR

The patients will be randomized into two groups: Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine)

Drug: Valproate, Levocarnitine

Placebo

PLACEBO COMPARATOR

All patients will be randomized into two groups: Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine)

Drug: Placebo

Interventions

Valproate, Levocarnitine DRUG

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.

Also known as: Valprol and carnisure

Valproate, levocarnitine

Placebo DRUG

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.

Also known as: Sugar based syrup

Placebo

Eligibility Criteria

• Age: 2 Years - 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• All India Institute of Medical Sciences: lead

Study Sites (1)

All India Institute of Medical Sciences

New Delhi, National Capital Territory of Delhi, 110029, India

RECRUITING

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Interventions

Valproic Acid; Carnitine

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines

Study Officials

• Gulati Sheffali, MD

  All India Institute of Medical Sciences

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gulati Sheffali, MD

CONTACT

9868397532; sheffaligulati@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Additional Professor, Department of Pediatrics

Study Record Dates

• First Submitted: August 13, 2012
• First Posted: August 23, 2012
• Study Start: August 1, 2013
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: January 1, 2016

Record last verified: 2015-12

Locations

IN (1)