Spinal Muscular Atrophy
Conditions
Keywords
Spinal Muscular Atrophy, SMA, Sodium Phenylbutyrate
Brief summary
In this single-center trial, we will evaluate the effects of NaPB on presymptomatic Spinal Muscular Atrophy (SMA) type I (cohort 1)and presymptomatic SMA type II (cohort 2) infants. A variety of outcome measures will be performed at each study visit to follow the course of the disease. Total duration of the study for type I infants will be 18 months, for type II infants, 24 months.
Detailed description
Perform a phase I/II study to evaluate effects of sodium phenylbutyrate (NaPB) in a cohort of presymptomatic infants, predicted to develop either SMA type 1 or SMA type 2 given genotype and family history of an older sibling with the respective SMA type. Primary outcomes: 1) to collect additional safety and pharmacokinetic data in neonates and young infants administered NaPB within the dosing guidelines already in use for urea cycle disorder therapy, and 2) to determine possible benefit of early treatment intervention with regard to status of denervation and functional motor status at specific time points for which we have matched natural history data to perform a comparison between cohorts and between each cohort and participants from our natural history database matched for age, SMN2 dosage and gender.
Interventions
DRUGSodium phenylbutyrate
Sodium phenylbutyrate is dispensed as a powder, 450-600 mg/kg/day, divided into four doses. For cohort 1, treatment and monitoring continues for 18 months. For cohort 2, treatment and monitoring continues for 24 months.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Utah
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Days to 6 Months
Healthy volunteers
No
Inclusion criteria
* Laboratory documentation of homozygous absence of SMN1 exon 7. * Confirmation of no more than 3 SMN2 copies for cohort 1; no more than 4 copies for cohort 2. * Family history of affected sibling with SMA type I for cohort 1 and SMA type II for cohort 2. * Age ≤ 3 months, cohort 1; Age ≤ 6 months, cohort 2. * Written informed consent of parents/guardian. * Laboratory results demonstrating normal values for age.
Exclusion criteria
-Evidence of hepatic insufficiency, renal insufficiency, edema with sodium retention, known seizure disorder, urea cycle disorder, cardiac arrhythmia, congenital heart defect, hypertension, significant central nervous system (CNS) impairment, or neurodegenerative or neuromuscular disease other than SMA. History of allergy/sensitivity to sodium phenylbutyrate (NaPB). * Use of NaPB within 30 days of study entry. * Serious illness requiring hospitalization ≤ 14 days prior to study entry. * Use of medications intended for the treatment of SMA including riluzole, valproic acid, hydroxyurea, oral use of albuterol, NaPB, butyrate derivatives, creatine, 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 within 30 days prior to study entry. * Unwillingness to travel for study assessments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Sodium Phenylbutyrate in Neonates and Infants With SMA | 24 months | The number of participants able to achieve specific developmental milestones, such as sitting unsupported or walking independently, during the study period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Family history of SMA type I 0-3 months old Confirmation of no more than 3 SMN2 copies
Sodium phenylbutyrate (NaPB): The powder form of the drug will be dispensed. The target NaPB dosing is 450-600 mg/kg/day, divided into four doses. For cohort 1, we propose to continue treatment for 18 months. For cohort 2, we propose to continue treatment for 24 months. | 6 |
| Cohort 2 Family history of SMA type II 0-6 months old Confirmation of no more than 4 SMN2 copies
Sodium phenylbutyrate (NaPB): The powder form of the drug will be dispensed. The target NaPB dosing is 450-600 mg/kg/day, divided into four doses. For cohort 1, we propose to continue treatment for 18 months. For cohort 2, we propose to continue treatment for 24 months. | 8 |
| Total | 14 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 8 Participants | 14 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 8 / 8 |
| serious Total, serious adverse events | 6 / 6 | 7 / 8 |
Outcome results
Primary
Safety and Tolerability of Sodium Phenylbutyrate in Neonates and Infants With SMA
The number of participants able to achieve specific developmental milestones, such as sitting unsupported or walking independently, during the study period.
Time frame: 24 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 | Safety and Tolerability of Sodium Phenylbutyrate in Neonates and Infants With SMA | Able to sit unsupported | 1 Participants |
| Cohort 1 | Safety and Tolerability of Sodium Phenylbutyrate in Neonates and Infants With SMA | Able to walk independently | 0 Participants |
| Cohort 2 | Safety and Tolerability of Sodium Phenylbutyrate in Neonates and Infants With SMA | Able to sit unsupported | 8 Participants |
| Cohort 2 | Safety and Tolerability of Sodium Phenylbutyrate in Neonates and Infants With SMA | Able to walk independently | 1 Participants |