Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

Utah System of Higher Education (USHE)

Status and phase: Completed; Phase 2

Conditions: Spinal Muscular Atrophy

Treatments: Drug: Valproic Acid and Levocarnitine; Drug: Placebo

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00227266

13698

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 94 patients

Sex: All

Ages: 2 to 17 years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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94 participants in 3 patient groups, including a placebo group

Cohort 1a

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Drug: Valproic Acid and Levocarnitine

Cohort 1b

Active Comparator group

Description:

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.

Treatment:

Drug: Valproic Acid and Levocarnitine

Cohort 2

Experimental group

Description:

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.

Treatment:

Drug: Valproic Acid and Levocarnitine