Spinal Muscular Atrophy
Conditions
Keywords
Spinal Muscular Atrophy (SMA), SMA Type 2, SMA Type 3
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.
Interventions
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
DRUGPlacebo
Sponsors
Families of Spinal Muscular Atrophy
Leadiant Biosciences, Inc.
Abbott
University of Utah
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modified Hammersmith Change From Baseline to 6 Months | 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. |
| Safety Labs | -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 | -4wks, 0, 3 mo, 6 mo, 12 mo | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Max CMAP Amplitude Median | 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) | 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 | -4 wks, 0, 3 mo, 6 mo, 12 mo | — |
| Growth and Vital Sign Parameters | -4 wks, 0, 3mo, 6mo, 12mo | — |
| Quantitative Assessment of SMN mRNA From Blood Samples | -4wks or 0, 3 mo, 6 mo, 12 mo | — |
| 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) | 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) | 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) | 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. |
| Nutritional Status | -4 wks, 0, 3mo, 6mo, 12mo | — |
| 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) | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
Subject's were recruited during the periods of September 2005 to September 2006 across the United States.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1a Sitters Placebo Then 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. | 31 |
| Cohort 1b Sitters 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 in the liquid form. | 30 |
| Cohort 2 Standers and Walkers - 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 in the liquid form. | 33 |
| Total | 94 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Excessive weight gain | 0 | 0 | 2 |
| Overall Study | Protocol Violation | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 1a Sitters Placebo Then Treatment | Cohort 1b Sitters Treatment | Cohort 2 Standers and Walkers - Treatment | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 31 Participants | 30 Participants | 33 Participants | 94 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 4.4 years STANDARD_DEVIATION 1.9 | 4.3 years STANDARD_DEVIATION 2.1 | 7.3 years STANDARD_DEVIATION 3.7 | 5.4 years STANDARD_DEVIATION 3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 27 Participants | 30 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) White | 26 Participants | 25 Participants | 29 Participants | 80 Participants |
| Region of Enrollment Canada | 6 participants | 4 participants | 4 participants | 14 participants |
| Region of Enrollment United States | 25 participants | 26 participants | 29 participants | 80 participants |
| Sex: Female, Male Female | 11 Participants | 17 Participants | 11 Participants | 39 Participants |
| Sex: Female, Male Male | 20 Participants | 13 Participants | 22 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 31 | 23 / 30 | 28 / 33 |
| serious Total, serious adverse events | 1 / 31 | 4 / 30 | 4 / 33 |
Outcome results
Primary
Efficacy, Measured Through Motor Function Assessments
Time frame: -4wks, 0, 3 mo, 6 mo, 12 mo
Primary
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.
Time frame: 0 months, 6 months
Population: Analysis only pertains to cohort 1a and 1b.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a Sitters Placebo Then Treatment | Modified Hammersmith Change From Baseline to 6 Months | Baseline visit (0 weeks) | 20.0 Score | Standard Deviation 9.3 |
| Cohort 1a Sitters Placebo Then Treatment | Modified Hammersmith Change From Baseline to 6 Months | 6 Month visit (V2) | 20.6 Score | Standard Deviation 8.1 |
| Cohort 1a Sitters Placebo Then Treatment | Modified Hammersmith Change From Baseline to 6 Months | Change from Baseline | 0.6 Score | Standard Deviation 3.98 |
| Cohort 1b Sitters Treatment | Modified Hammersmith Change From Baseline to 6 Months | Baseline visit (0 weeks) | 16.6 Score | Standard Deviation 8.7 |
| Cohort 1b Sitters Treatment | Modified Hammersmith Change From Baseline to 6 Months | 6 Month visit (V2) | 16.8 Score | Standard Deviation 7.9 |
| Cohort 1b Sitters Treatment | Modified Hammersmith Change From Baseline to 6 Months | Change from Baseline | 0.2 Score | Standard Deviation 2.88 |
Primary
Safety Labs
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
Secondary
DEXA
Time frame: 0, 6mo, 12mo
Secondary
Growth and Vital Sign Parameters
Time frame: -4 wks, 0, 3mo, 6mo, 12mo
Secondary
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.
Time frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Amplitude (Mean) | Baseline | 2.28 mV | Standard Deviation 1.55 |
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Amplitude (Mean) | 6 months | 2.32 mV | Standard Deviation 1.75 |
| Cohort 1b Sitters Treatment | Max CMAP Amplitude (Mean) | Baseline | 2.93 mV | Standard Deviation 1.56 |
| Cohort 1b Sitters Treatment | Max CMAP Amplitude (Mean) | 6 months | 2.37 mV | Standard Deviation 1.82 |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Amplitude (Mean) | Baseline | 5.52 mV | Standard Deviation 2.56 |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Amplitude (Mean) | 6 months | 6.56 mV | Standard Deviation 2.99 |
Secondary
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.
Time frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Amplitude Median | Baseline | 1.91 mV |
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Amplitude Median | 6 months | 1.44 mV |
| Cohort 1b Sitters Treatment | Max CMAP Amplitude Median | Baseline | 2.2 mV |
| Cohort 1b Sitters Treatment | Max CMAP Amplitude Median | 6 months | 1.8 mV |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Amplitude Median | Baseline | 5.3 mV |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Amplitude Median | 6 months | 5.85 mV |
Secondary
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.
Time frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Area (Mean) | Baseline | 5.46 mVms | Standard Deviation 5.03 |
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Area (Mean) | 6 months | 5.28 mVms | Standard Deviation 4.49 |
| Cohort 1b Sitters Treatment | Max CMAP Area (Mean) | Baseline | 5.45 mVms | Standard Deviation 4.23 |
| Cohort 1b Sitters Treatment | Max CMAP Area (Mean) | 6 months | 5.26 mVms | Standard Deviation 4.65 |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Area (Mean) | Baseline | 14.85 mVms | Standard Deviation 7.68 |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Area (Mean) | 6 months | 16.26 mVms | Standard Deviation 7.13 |
Secondary
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.
Time frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Area (Median) | Baseline | 3.6 mVms |
| Cohort 1a Sitters Placebo Then Treatment | Max CMAP Area (Median) | 6 months | 3.74 mVms |
| Cohort 1b Sitters Treatment | Max CMAP Area (Median) | Baseline | 4.6 mVms |
| Cohort 1b Sitters Treatment | Max CMAP Area (Median) | 6 months | 3.4 mVms |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Area (Median) | Baseline | 13.65 mVms |
| Cohort 2 Standers and Walkers - Treatment | Max CMAP Area (Median) | 6 months | 16.85 mVms |
Secondary
Nutritional Status
Time frame: -4 wks, 0, 3mo, 6mo, 12mo
Secondary
Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)
Time frame: -4wks, 0, 3mo, 6mo, 12mo
Secondary
Quantitative Assessment of SMN mRNA From Blood Samples
Time frame: -4wks or 0, 3 mo, 6 mo, 12 mo
Secondary
Ulnar MUNE
Time frame: -4 wks, 0, 3 mo, 6 mo, 12 mo
Post Hoc
Modified Hammersmith Extend Baseline
Baseline Modified Hammersmith Extend testing. The baseline test is the score they receive during their screening visits. This scale ranges from 0 to 56. A higher score indicates a better outcome. This scale is used to assess gross motor abilities of children with SMA in multiple research trials as well as in clinical settings.
Time frame: 1 month prior to enrollment, at enrollment (0 months)
Population: Analysis was determined per protocol
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1a Sitters Placebo Then Treatment | Modified Hammersmith Extend Baseline | Modified Hammersmith Extend at S1 (-4 weeks) | 47.0 Score |
| Cohort 1a Sitters Placebo Then Treatment | Modified Hammersmith Extend Baseline | Modified Hammersmith Extend at S2 (0 weeks) | 48.3 Score |
Comparison: MHFMS-Extend was not normally distributed at p=0.048. Test-retest reliability of MHFMS-Extend measurements from the first (S1) to the second (S2) screening visit was analyzed using Spearman's correlation.p-value: <0.001Spearman's correlation