Randomized Placebo Controlled Trial of Valproate and Levocarnitine in Children With Spinal Muscular Atrophy Aged 2-15 Years
试验速览
- 阶段
- 3 期
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Change in muscle power on a 5 point scale as per the principles of manual muscle testing at 12, 24, 36 and 52 weeks
研究概览
简要总结
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.
详细描述
Spinal muscular atrophy is an autosomal recessive disease of varying severity that destroys motor neurons, resulting in atrophy and weakness of the voluntary muscles. Around 95% of the cases demonstrate a homozygous deletion/mutation involving exon 7 in SMN1 (survival motor neuron 1), resulting in the biochemical deficiency of the SMN protein.
Although the pathogenesis of the spinal muscular atrophy remains speculative, several hypotheses include defective inhibition of apoptosis, glutamate excitotoxicity and lack of a neurotrophic factor(s) in nerve or muscle.
Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, directly increases SMN expression in SMA patient-derived cell lines in vitro. It has also been demonstrated to have neuroprotective properties on glutamate induced excitotoxicity via up-regulation of alphasynuclein and increases neurite outgrowth in vitro.
The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1). The SMN2 gene, a nearly identical copy of SMN1, has been detected as a promising target for SMA therapy. Transcriptional SMN2 activation or modulation of its splicing pattern to increase FL-SMN levels is believed to be clinically beneficial and therefore a crucial challenge in SMA research. Drugs such as valproic acid, phenylbutyrate, and sodium butyrate that mainly act as histone deacetylase inhibitors can mediate both: they stimulate the SMN2 gene transcription and/or restore the splicing pattern, thereby elevating the levels of FL-SMN2 protein.
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Years 至 15 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Valproate, levocarnitine
The patients will be randomized into two groups:
Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine)
干预措施: Valproate, Levocarnitine (Drug)
Placebo
All patients will be randomized into two groups:
Group I (Physiotherapy + Placebos) Group II (Physiotherapy + Valproate and Levocarnitine)
干预措施: Placebo (Drug)
结局指标
主要结局
Change in muscle power on a 5 point scale as per the principles of manual muscle testing at 12, 24, 36 and 52 weeks
时间窗: Over 52 weeks with assessment at baseline, 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.
次要结局
- 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)
研究者
Sheffali Gulati
Additional Professor, Department of Pediatrics
All India Institute of Medical Sciences, New Delhi