Back to resultsValproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
Primary Purpose
Spinal Muscular Atrophy
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Valproic Acid and Levocarnitine
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Spinal Muscular Atrophy focused on measuring Spinal Muscular Atrophy (SMA), SMA Type 2, SMA Type 3
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.
Sites / Locations
- Johns Hopkins University
- Children's Hospital of Michigan
- Ohio State University
- University of Utah/Primary Children's Medical Center
- University of Wisconsin Children's Hospital
- Hospital Sainte-Justine
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Placebo Comparator
Active Comparator
Experimental
Arm Label
Cohort 1a
Cohort 1b
Cohort 2
Arm 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.
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.
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.
Outcomes
Primary Outcome Measures
Safety Labs
Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function
Efficacy, Measured Through Motor Function Assessments
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.
Secondary Outcome Measures
Quantitative Assessment of SMN mRNA From Blood Samples
Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)
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.
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.
Ulnar MUNE
Growth and Vital Sign Parameters
Nutritional Status
DEXA
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.
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.
Full Information
NCT ID
NCT00227266
First Posted
September 23, 2005
Last Updated
September 22, 2011
Sponsor
University of Utah
Collaborators
Families of Spinal Muscular Atrophy, Leadiant Biosciences, Inc., Abbott
1. Study Identification
Unique Protocol Identification Number
NCT00227266
Brief Title
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
2. Study Status
Record Verification Date
September 2011
Overall Recruitment Status
Completed
Study Start Date
September 2005 (undefined)
Primary Completion Date
November 2007 (Actual)
Study Completion Date
November 2007 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Utah
Collaborators
Families of Spinal Muscular Atrophy, Leadiant Biosciences, Inc., Abbott
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Spinal Muscular Atrophy
Keywords
Spinal Muscular Atrophy (SMA), SMA Type 2, SMA Type 3
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
94 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1a
Arm Type
Placebo Comparator
Arm 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.
Arm Title
Cohort 1b
Arm Type
Active Comparator
Arm 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.
Arm Title
Cohort 2
Arm Type
Experimental
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Valproic Acid and Levocarnitine
Other Intervention Name(s)
Depakote, VPA, Carnitor
Intervention Description
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Safety Labs
Description
Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function
Time Frame
-4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs
Title
Efficacy, Measured Through Motor Function Assessments
Time Frame
-4wks, 0, 3 mo, 6 mo, 12 mo
Title
Modified Hammersmith Change From Baseline to 6 Months
Description
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.
Time Frame
0 months, 6 months
Secondary Outcome Measure Information:
Title
Quantitative Assessment of SMN mRNA From Blood Samples
Time Frame
-4wks or 0, 3 mo, 6 mo, 12 mo
Title
Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)
Time Frame
-4wks, 0, 3mo, 6mo, 12mo
Title
Max CMAP Amplitude (Mean)
Description
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.
Time Frame
1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
Title
Max CMAP Amplitude Median
Description
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.
Time Frame
1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
Title
Ulnar MUNE
Time Frame
-4 wks, 0, 3 mo, 6 mo, 12 mo
Title
Growth and Vital Sign Parameters
Time Frame
-4 wks, 0, 3mo, 6mo, 12mo
Title
Nutritional Status
Time Frame
-4 wks, 0, 3mo, 6mo, 12mo
Title
DEXA
Time Frame
0, 6mo, 12mo
Title
Max CMAP Area (Mean)
Description
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.
Time Frame
1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
Title
Max CMAP Area (Median)
Description
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.
Time Frame
1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kathryn J Swoboda, M.D.
Organizational Affiliation
University of Utah/Primary Children's Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Children's Hospital of Michigan
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48201
Country
United States
Facility Name
Ohio State University
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210-1228
Country
United States
Facility Name
University of Utah/Primary Children's Medical Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
University of Wisconsin Children's Hospital
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792-9988
Country
United States
Facility Name
Hospital Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
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Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
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