Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 94
- 试验地点
- 6
- 主要终点
- Safety Labs
研究概览
简要总结
This is a multi-center trial to assess safety and efficacy of a combined regimen of oral valproic acid (VPA) and carnitine in patients with Spinal Muscular Atrophy (SMA) 2 to 17 years of age. Cohort 1 is a double-blind placebo-controlled randomized intention to treat protocol for SMA "sitters" 2 - 8 years of age. Cohort 2 is an open label protocol for SMA "standers and walkers" 3 - 17 years of age to explore responsiveness of efficacy outcomes. Outcome measures will include blood chemistries, functional testing, pulmonary function testing, electrophysiological evaluations, PedsQL quality of life assessment, quantitative assessments of survival motor neuron (SMN) mRNA from blood samples, growth and vital sign parameters. Six centers will enroll a total of 90 patients.
详细描述
This is a multi-center phase II trial of a combined regimen of oral valproic acid (VPA) and carnitine in patients with Spinal Muscular Atrophy (SMA) 2 to 17 years of age. Cohort 1 is a double-blind placebo-controlled randomized intention to treat protocol for SMA "sitters" 2 - 8 years of age. Subjects will undergo two baseline assessments over 4 to 6 week period, then will be randomized to treatment or placebo for the next six months. All subjects will then be placed on active treatment for the subsequent six month period. Cohort 2 is an open label protocol for SMA "standers and walkers" 3 - 17 years of age to explore responsiveness of efficacy outcomes. Subjects will undergo two baseline assessments over a four to six week period, followed by one year active treatment with VPA and carnitine. Outcome measures are performed every 3 to 6 months, and include blood chemistries, functional testing, pulmonary function testing, electrophysiological evaluations, PedsQL quality of life assessment, quantitative assessments of survival motor neuron (SMN) mRNA from blood samples, growth and vital sign parameters. Six centers will enroll a total of 90 patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 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 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed genetic diagnosis of 5q SMA
- •SMA 2 or non-ambulatory SMA 3: all subjects must be able to sit independently for at least 3 seconds without support
- •Age 2 to 8 years at time of enrollment
- •Confirmed genetic diagnosis of 5q SMA
- •SMA subjects (SMA types 2 or 3) who can stand independently without braces or other support for up to 2 seconds, or walk independently
- •Age 3 to 17 years at time of study enrollment
排除标准
- •Need for BiPAP support > 12 hours per day
- •Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
- •Inability to meet study visit requirements or cooperate reliably with functional testing
- •Coexisting medical conditions that contraindicate travel, testing or study medications
- •Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
- •Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must go through a washout period of 12 weeks before enrollment into the study
- •Body Mass Index > 90th % for age
- •Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
- •Inability to meet study visit requirements or cooperate with functional testing
- •Transaminases, amylase or lipase > 3.0 x normal values, WBC < 3.0 or neutropenia < 1.0, platelets < 100 K, or hematocrit < 30 persisting over a 30 day period.
- •Coexisting medical conditions that contraindicate travel, testing or study medications
- •Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
- •Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must be go through a washout period of 12 weeks before enrollment in the study.
- •Body Mass Index > 90th % for age
- •Pregnant women/girls, or those intending to try to become pregnant during the course of the study.
研究组 & 干预措施
Cohort 1a
Patients in Cohort 1a - Placebo Comparator, will be on a placebo for 6 months and then will switch to the active treatment. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor or equivalent placebo in the liquid form.
干预措施: Valproic Acid and Levocarnitine (Drug)
Cohort 1a
Patients in Cohort 1a - Placebo Comparator, will be on a placebo for 6 months and then will switch to the active treatment. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor or equivalent placebo in the liquid form.
干预措施: Placebo (Drug)
Cohort 1b
Cohort 1b - Active Comparator will be on treatment throughout the study. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor in the liquid form.
干预措施: Valproic Acid and Levocarnitine (Drug)
Cohort 2
Cohort 2 pts are on open-label treatment throughout. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor or equivalent placebo in the liquid form.
干预措施: Valproic Acid and Levocarnitine (Drug)
结局指标
主要结局
Safety Labs
时间窗: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs
Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function
Efficacy, Measured Through Motor Function Assessments
时间窗: -4wks, 0, 3 mo, 6 mo, 12 mo
Modified Hammersmith Change From Baseline to 6 Months
时间窗: 0 months, 6 months
Comparison of Modified Hammersmith Change from baseline to 6 months. Scores range from 0 to 40. A higher score indicates a better outcome. This scale is used to assess gross motor abilities of non-ambulant children with SMA in multiple research trials as well as in clinical settings.
次要结局
- Quantitative Assessment of SMN mRNA From Blood Samples(-4wks or 0, 3 mo, 6 mo, 12 mo)
- Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)(-4wks, 0, 3mo, 6mo, 12mo)
- Max CMAP Amplitude (Mean)(1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available))
- Max CMAP Amplitude Median(1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available))
- Ulnar MUNE(-4 wks, 0, 3 mo, 6 mo, 12 mo)
- Growth and Vital Sign Parameters(-4 wks, 0, 3mo, 6mo, 12mo)
- Nutritional Status(-4 wks, 0, 3mo, 6mo, 12mo)
- DEXA(0, 6mo, 12mo)
- Max CMAP Area (Mean)(1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available))
- Max CMAP Area (Median)(1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available))