Spinal Muscular Atrophy Type I
Conditions
Keywords
Spinal Muscular Atrophy, SMA, Valproic Acid
Brief summary
This is a multi-center trial to test safety and evaluate early treatment intervention with valproic acid and carnitine in moderating SMA symptoms of Type I infants.
Detailed description
Spinal muscular atrophy (SMA) is a genetic disorder that results in severe muscle weakness. It is one of the most common conditions causing muscle weakness in children. Patients with SMA most often develop weakness as babies or young children. Most people with SMA gradually lose muscle strength and abilities over time. Babies with the severe infantile form of SMA, SMA type I, usually lose abilities and strength quickly over a few weeks or months. Valproic acid (VPA) is a medicine that has been used for many years to treat patients with epilepsy. Recent research suggests that VPA may be able to upregulate expression of a backup copy of the SMN gene in SMA patient cell lines. In addition, some preliminary data suggests it may prolong survival in animal models of SMA. Because VPA can deplete carnitine in children with SMA Type I, carnitine is added to help prevent possible toxicity. In this multi-center trial, we will evaluate the effects of VPA/carnitine on infants with SMA type I. A variety of outcome measures, including assessment of safety, will be performed at each study visit to follow the course of the disease. The protocol includes two baseline visits over a period of two weeks, two clinical assessments on medication at 3 and 6 months, and then 6 months additional followup via telephone. Total duration of the study will be approximately 12 months.
Interventions
Drug: Valproic Acid and Levocarnitine; syrup; dosage is by weight
Sponsors
Families of Spinal Muscular Atrophy
Leadiant Biosciences, Inc.
University of Utah
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Weeks to 12 Months
Healthy volunteers
No
Inclusion criteria
* Laboratory documentation of SMN mutation/deletion consistent with a genetic diagnosis of SMA * Clinical diagnosis of SMA type I * Age 2 weeks to 12 months * Written informed consent of parents/guardian
Exclusion criteria
* Any clinical or laboratory evidence of hepatic or pancreatic insufficiency. * Laboratory results drawn within 14 days prior to start of study drug demonstrating: Liver transaminases (AST, ALT), lipase, amylase: \> 1.5 x ULN White Blood Cell Count: \< 3 Neutropenia: \<1 Platelet: \<100K Hematocrit: \<30, persisting over a 30-day period * Serious illness requiring systemic treatment and/or hospitalization within two weeks prior to study entry. * Use of medications or supplements within 30 days of study enrollment that interfere with VPA or carnitine metabolism; that increase the potential risks of VPA or carnitine; or that are hypothesized to have a beneficial effect in SMA animal models or human neuromuscular disorders, including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatinine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, or agents anticipated to increase or decrease muscle strength or agents with presumed histone deacetylase (HDAC) inhibition. * Infants who have participated in a treatment trial for SMA within 30 days of study entry or who will become enrollees in any other treatment trial during the course of this study. * Unwillingness to travel for study assessments. * Coexisting medical conditions that contradict use of VPA/carnitine or travel to and from study site.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Laboratory Safety Data | -2 weeks, + 2 weeks, 3 months, 6 months |
| Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures) | -2 weeks, time 0, 3 months, 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Functional Motor Assessments: TIMPSI Scores | -2 weeks, time 0, 3 months, 6 months |
| Quantitative SMN mRNA and Protein Measures | -2 weeks, time 0 , 3 months, or 6 months |
| Time to Death or Ventilator Dependence (Defined as >16 Hours/Day) | monthly |
| Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content | -2 weeks or time 0, 3 months, 6 months |
| Maximum Ulnar CMAP Amplitude/Area and MUNE | -2 weeks, time 0, 3 months, 6 months |
| Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS) | time 0, and monthly for 12 months |
Countries
Canada, Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SMA Type 1 All patients will receive VPA and carnitine.
Valproic Acid and Levocarnitine: Drug: Valproic Acid and Levocarnitine; syrup; dosage is by weight | 38 |
| Total | 38 |
Baseline characteristics
| Characteristic | SMA Type 1 |
|---|---|
| Age, Continuous | 5.52 months STANDARD_DEVIATION 2.72 |
| Region of Enrollment Canada | 2 participants |
| Region of Enrollment Germany | 2 participants |
| Region of Enrollment United States | 34 participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 36 / 38 |
| serious Total, serious adverse events | 29 / 38 |
Outcome results
Primary
Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures)
Time frame: -2 weeks, time 0, 3 months, 6 months
Population: 20 participants have baseline values, only 12 have 3 and 6 month values
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SMA Type 1 | Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures) | Lean Mass Baseline | 4317.15 g | Standard Deviation 1334.48 |
| SMA Type 1 | Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures) | Lean Mass 3 months | 4993.92 g | Standard Deviation 1676.13 |
| SMA Type 1 | Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures) | Lean Mass 6 months | 5133.83 g | Standard Deviation 2122.99 |
| SMA Type 1 | Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures) | Fat Mass Baseline | 3011.37 g | Standard Deviation 1467.83 |
| SMA Type 1 | Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures) | Fat Mass 3 months | 3618.25 g | Standard Deviation 1343.25 |
| SMA Type 1 | Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures) | Fat Mass 6 months | 4316.08 g | Standard Deviation 1857.16 |
Primary
Laboratory Safety Data
Time frame: -2 weeks, + 2 weeks, 3 months, 6 months
Secondary
Functional Motor Assessments: TIMPSI Scores
Time frame: -2 weeks, time 0, 3 months, 6 months
Secondary
Maximum Ulnar CMAP Amplitude/Area and MUNE
Time frame: -2 weeks, time 0, 3 months, 6 months
Secondary
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS)
Time frame: time 0, and monthly for 12 months
Secondary
Quantitative SMN mRNA and Protein Measures
Time frame: -2 weeks, time 0 , 3 months, or 6 months
Secondary
Time to Death or Ventilator Dependence (Defined as >16 Hours/Day)
Time frame: monthly
Secondary
Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content
Time frame: -2 weeks or time 0, 3 months, 6 months