Study to Evaluate Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy

Study Overview
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Brief Summary
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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
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Perform a phase I/II study to evaluate effects of Phenyl Butyrate (PBA) in a cohort of 12 presymptomatic infants. These infants are predicted to have either SMA 1 or 2 given genotype and family history of an older sibling with the respective SMA type. Our goal is twofold: 1) to collect additional safety and pharmacokinetic data in neonates and young infants administered this compound, 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. Data obtained from this aim will guide future trials designed to determine the efficacy of PBA or other butyrate analogs in attenuating disease progression in SMA subjects identified in the presymptomatic period.

Official Title
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Prospective Phase I/II Study to Evaluate Effects of Sodium Phenylbutyrate in Pre-symptomatic Infants With Spinal Muscular Atrophy

Conditions
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Spinal Muscular Atrophy

Intervention / Treatment
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* Drug: Sodium phenylbutyrate (NaPB)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Family history of SMA type I 0-3 months old Confirmation of no more than 3 SMN2 copies | Drug: Sodium phenylbutyrate (NaPB)<br>* 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.<br>|
| Experimental: Cohort 2<br>Family history of SMA type II 0-6 months old Confirmation of no more than 4 SMN2 copies | Drug: Sodium phenylbutyrate (NaPB)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Study Will Assess the Safety, Tolerability and Potential Efficacy of Sodium Phenylbutyrate (NaPB) in Presymptomatic Infants Genetically Confirmed to Have SMA. It Will Also Determine Selected Pharmacokinetic Parameters. | Number of participants with SAE's related to research. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Study Will Determine Potential Benefit of NaPB on Lean Body Mass; Overall Motor Function; Potential Cellular Response to NaPB; and Drug Compliance. |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SMA, Spinal Muscular Atrophy, Sodium Phenylbutyrate