Clinical trial NCT00227266: Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
Official title: Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Spinal Muscular Atrophy
Keywords: Spinal Muscular Atrophy (SMA)
SMA Type 2
SMA Type 3
Lead sponsor: University of Utah
Sponsor class: OTHER
Collaborators: name: Families of Spinal Muscular Atrophy
name: Leadiant Biosciences, Inc.
name: Abbott
First posted: 2005-09-27
Enrollment: 94
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety Labs
timeFrame: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs
measure: Efficacy, Measured Through Motor Function Assessments
timeFrame: -4wks, 0, 3 mo, 6 mo, 12 mo
measure: Modified Hammersmith Change From Baseline to 6 Months
timeFrame: 0 months, 6 months
Secondary outcomes:
measure: Quantitative Assessment of SMN mRNA From Blood Samples
timeFrame: -4wks or 0, 3 mo, 6 mo, 12 mo
measure: Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)
timeFrame: -4wks, 0, 3mo, 6mo, 12mo
measure: Max CMAP Amplitude (Mean)
timeFrame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
measure: Max CMAP Amplitude Median
timeFrame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
measure: Ulnar MUNE
timeFrame: -4 wks, 0, 3 mo, 6 mo, 12 mo
measure: Growth and Vital Sign Parameters
timeFrame: -4 wks, 0, 3mo, 6mo, 12mo
measure: Nutritional Status
timeFrame: -4 wks, 0, 3mo, 6mo, 12mo
measure: DEXA
timeFrame: 0, 6mo, 12mo
measure: Max CMAP Area (Mean)
timeFrame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
measure: Max CMAP Area (Median)
timeFrame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Salt Lake City
country: United States
facility: University of Utah/Primary Children's Medical Center
state: Utah
city: Madison
country: United States
facility: University of Wisconsin Children's Hospital
state: Wisconsin
city: Montreal
country: Canada
facility: Hospital Sainte-Justine
state: Quebec
Study officials:
affiliation: University of Utah/Primary Children's Medical Center
name: Kathryn J Swoboda, M.D.
role: PRINCIPAL_INVESTIGATOR
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