Valproate and Levocarnitine in Children With Spinal Muscular Atrophy

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by All India Institute of Medical Sciences, New Delhi
Sponsor:
Information provided by (Responsible Party):
Sheffali Gulati, All India Institute of Medical Sciences, New Delhi
ClinicalTrials.gov Identifier:
NCT01671384
First received: August 13, 2012
Last updated: November 4, 2013
Last verified: November 2013
  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

Resource links provided by NLM:


Further study details as provided by All India Institute of Medical Sciences, New Delhi:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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


Other Outcome Measures:
  • 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: August 2013
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
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01671384

Contacts
Contact: Gulati Sheffali, MD 9868397532 sheffaligulati@gmail.com

Locations
India
All India Institute of Medical Sciences Recruiting
New Delhi, Delhi, India, 110029
Contact: Gulati Sheffali, MD    9868397532    sheffaligulati@gmail.com   
Principal Investigator: Gulati Sheffali, MD         
Sponsors and Collaborators
All India Institute of Medical Sciences, New Delhi
Investigators
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: November 4, 2013
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:
Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases
Valproic Acid
Carnitine
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Vitamin B Complex
Vitamins

ClinicalTrials.gov processed this record on October 19, 2014