Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Valproic Acid and Levocarnitine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort 1 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 Cohort 2 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 Exclusion Criteria: Cohort 1 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 Cohort 2 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.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Cohort 1a<br>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. | Drug: Valproic Acid and Levocarnitine<br>* VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight<br>* Other names: Carnitor;Drug: Placebo<br> <br> |
| Active Comparator: Cohort 1b<br>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. | Drug: Valproic Acid and Levocarnitine<br>* VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight<br>* Other names: Carnitor;|
| Experimental: Cohort 2<br>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. | Drug: Valproic Acid and Levocarnitine<br>* VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight<br>* Other names: Carnitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Labs | Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function | -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs | 
| Efficacy, Measured Through Motor Function Assessments |  | -4wks, 0, 3 mo, 6 mo, 12 mo | 
| Modified Hammersmith Change From Baseline to 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. | 0 months, 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | The maximum Compound Motor Action Potential (CMAP) is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This is done multiple times, the outcome used is the highest peak, or response observed. | 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) | 
| Max CMAP Amplitude Median | The maximum Compound Motor Action Potential (CMAP) is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This is done multiple times, the outcome used is the highest peak, or response observed. | 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) | The maximum Compound Motor Action Potential (CMAP) area is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This procedure is repeated multiple times. The maximum area is the response that results in the largest area under the response curve. | 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) | 
| Max CMAP Area (Median) | The maximum Compound Motor Action Potential (CMAP) area is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This procedure is repeated multiple times. The maximum area is the response that results in the largest area under the response curve. | 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal Muscular Atrophy (SMA), SMA Type 2, SMA Type 3