Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Types II or III (NPTUNE01)

• Dose Limiting Toxicities (DLT) [ Time Frame: 29 Days ] [ Designated as safety issue: Yes ]
  Number of DLTs to determine the maximum tolerated dosage. A DLT is defined as any Grade (GR)3 or higher adverse event(AE),GR 1 or higher cardiac arrhythmia;GR 2 or higher vomiting;GR 2 or higher liver dysfunction/failure (clinical);GR 2 elevation of amylase or lipase accompanied by clinical symptoms of pancreatitis.The following GR 2 events are classified as DLTs if evaluated to be clinically significant by the principal investigator or medical safety monitor:decrease of hemoglobin, WBCs, platelets; elevation of AST, ALT,bilirubin;abnormality of Na, K, Cl, Ca, HCO3, glucose, BUN or creatinine.
• Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) [ Time Frame: Baseline - 12 weeks ] [ Designated as safety issue: No ]
  The change of level in blood SMN mRNA from baseline to assess time course and dose response.
• Survival Motor Neuron (SMN) Protein [ Time Frame: Baseline - 12 weeks ] [ Designated as safety issue: No ]
  The change of level in blood SMN protein from baseline to assess time course and dose response.

• Drug Safety [ Time Frame: 14 weeks ] [ Designated as safety issue: Yes ]
  Adverse event(AE)monitoring
• Pharmacokinetic Parameters (Maximum Plasma Concentration) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Maximum Plasma Concentration (Cmax)
• Pharmacokinetic Parameters (Time to Maximum Concentration) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Time to Maximum Concentration (Tmax)
• Pharmacokinetic Parameters (Area Under the Plasma Concentration Versus Time Curve (AUC)) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  Area Under the Plasma Concentration versus Time curve (AUC)
• Overall Study Drug Compliance [ Time Frame: 12 Weeks ] [ Designated as safety issue: No ]
  Subjects receiving 80% or more of the prescribed doses within each study visit interval were considered compliant.

The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy types II or III; and to determine if the drug has an effect on SMN mRNA and protein levels.

Spinal muscular atrophy (SMA) is a genetic, neuromuscular disorder caused by progressive degeneration of motor neurons in the spinal cord, which results from the loss of survival motor neuron (SMN) protein. The disorder is characterized by weakness and wasting of the voluntary muscles and is a leading cause of hereditary infant death. Sodium phenylbutyrate--a drug used to treat urea cycle disorders--may increase the amount of SMN protein in the body and consequently may decrease the severity of SMA. However, this has not yet been proven.

In this multicenter trial, physicians will evaluate multiple dosage levels of sodium phenylbutyrate to determine the maximum tolerated dose (MTD), or the highest dose that can be safely given to children with SMA types II or III. The initial dosage tested will be 500 mg/kg/day. Depending upon tolerability, subsequent groups may receive dosages of 675, 900, or 1200 mg/kg/day. Blood levels of SMN mRNA and protein will also be measured to determine whether sodium phenylbutyrate can increase the amount of these two biomarkers in the blood. Up to 24 children will be enrolled in the study and will be on sodium phenylbutyrate for 12 weeks. The MTD will be determined based on safety data from Day 0 through the Day 29 visit. Participants will continue to be monitored for safety and SMN mRNA and protein levels through the 12 week study drug administration period.

Potential participants will be screened by having their complete medical and treatment histories recorded, as well as undergoing a physical examination, laboratory tests, and an electrocardiogram (EKG). Parents of eligible participants will receive a supply of sodium phenylbutyrate and instructions on how to administer the drug. Participants will return to the clinic on days 8, 22, 29, and at weeks 8 and 12 of the study to update their medical and treatment histories, have a physical exam, and have blood and urine collected for laboratory testing. A follow-up clinic visit will occur approximately 14 days after the last dose of sodium phenylbutyrate is given. During this visit participants will update their complete medical and treatment histories and have a physical examination. Duration of the study is about 14 weeks.

Information from this study, which is part of the NINDS Pilot Therapeutics Network (NPTUNE), may be used for future studies to determine if sodium phenylbutyrate is effective for treating SMA, and if the drug has an effect on SMA symptoms.

• Spinal Muscular Atrophy Type II
• Spinal Muscular Atrophy Type III

Inclusion Criteria:

Subjects must meet all of the following inclusion criteria within 14 days prior to receiving the first dose of study drug.

• Weakness and hypotonia consistent with a clinical diagnosis of spinal muscular atrophy (SMA) type II or III
• Laboratory documentation of homozygous absence of SMN1 exon 7
• Type III subjects who are unable to get up from the floor unaided. "Unaided" is defined as not using a device or obtaining assistance from another person.
• 2 years of age or older, but younger than 12 years of age, at the time of enrollment
• Written informed consent of parents/guardian
• Weight greater than or equal to 10 kilograms
• Laboratory results drawn within 14 days prior to start of study drug demonstrating: Hemoglobin within normal range at the clinical site; White Blood Cell Count ≥ 3000/mm³; Platelet Count ≥ 75,000/mm³; Lipase and Amylase ≤ 1.5 x upper limit of normal (ULN) in the absence of associated clinical symptoms; AST and ALT ≤ 2.5 x ULN; Bilirubin ≤ 1.5x ULN in the absence of associated clinical symptoms; Sodium ≥ 130 and ≤ 150 mmol/L; Potassium ≥3.0 and ≤ 5.5 mmol/L; Chloride ≤ 110 mmol/L; Calcium ≥ 8.0 mg/dL; Bicarbonate ≥ 16 mmol/L; Glucose ≥ 55 and ≤ 160 mg/dL; BUN ≤ 39 mg/dL; Creatinine ≤ 1.5 x ULN
• Subject is expected to survive for at least 6 months following study entry.

Exclusion Criteria:

Subjects who meet any of the following criteria will be excluded from participating in the study:

• Evidence of renal dysfunction, blood dyscrasia, hepatic insufficiency, symptomatic pancreatitis, cardiac arrhythmia, congenital heart defect, known history of metabolic acidosis, hypertension, significant central nervous system impairment, or neurodegenerative or neuromuscular disease other than SMA.
• Any adverse event ≥ Grade 3 at the time of screening based on the protocol toxicity grading table
• Any acute co-morbid condition interfering with the well-being of the subject within 7 days of enrollment including bacterial infection, viral infectious process, food poisoning, temperature > 99.0ºF, need for acute treatment or observation due to any other reason, as judged by the investigator
• ≥ Grade 2 vomiting;
• ≥ Grade 2 liver dysfunction/failure (clinical);
• Any abnormality noted on EKG except for asymptomatic sinus arrhythmia
• History of allergy/sensitivity to sodium phenylbutyrate
• Use of sodium phenylbutyrate within 30 days of study entry
• Serious illness requiring systemic treatment and/or hospitalization within 14 days prior to study entry (Subjects are not eligible following serious illness until therapy is complete and the subject is stable, or until the subject is on therapy and stable for at least 14 days.)
• Use of medications intended for the treatment of SMA including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, haloperidol, agents anticipated to increase or decrease muscle strength or agents with known or presumed histone deacetylase (HDAC) inhibition within 30 days prior to study entry

Notes: Subjects who use a nebulizer or require an inhaler to receive albuterol will be allowed in the study; however oral use of albuterol is prohibited. Topical use of steroids will be allowed. Oral use of steroids is not allowed at entry, but these may be used as clinically indicated while on study. Event grading will be based on the toxicity-grading table in the protocol.