Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Type I (NPTUNE 02)
The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy type I; and to determine if the drug has an effect on SMN mRNA and protein levels.
Spinal Muscular Atrophy Type I
Drug: sodium phenylbutyrate
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase I/IIa Clinical Trial of Sodium Phenylbutyrate in Pediatric Subjects With Type I Spinal Muscular Atrophy|
- 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, 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; abnormlity of Na, K, Cl, CA, HCO3, glucose, BUN, 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 Plasma Concentration) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]Time to maximum plasma 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 receiveing 80% or more of the prescribed doses within each study visit interval were considered compliant.
|Study Start Date:||January 2008|
|Study Completion Date:||May 2009|
|Primary Completion Date:||May 2009 (Final data collection date for primary outcome measure)|
Experimental: Subject Enrollments
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first three subjects enrolled at 500 mg/kg/day for the duration of the study drug period. The dosage of the next cohort was determined by the Modified Continual Re-assessment Method (MCRM) approach and approval of the Study Monitoring Committee (SMC). The MCRM calculation could indicate that additional subjects should be enrolled at the same dosage or a higher dosage.
Drug: sodium phenylbutyrate
500 mg/kg/day, depending upon tolerability subsequent dosages may increase to 675, 900, or 1200 mg/kg/day to identify maximum tolerated dose (MTD) and then an additional 6 participants will enroll at the MTD.
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 type I. 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.
|United States, California|
|Stanford University Medical Center, 300 Pasteur Drive, Room A343|
|Stanford, California, United States, 94305-5235|
|United States, Massachusetts|
|Children's Hospital, Boston, 300 Longwood Avenue, Fegan 11|
|Boston, Massachusetts, United States, 02115|
|United States, New York|
|Columbia University, 180 Fort Washington Avenue, 5th Floor|
|New York, New York, United States, 10032|
|United States, Pennsylvania|
|The Children's Hospital of Philadelphia, Clinical Trials Office, A-230, 34th St. and Civic Center Boulevard|
|Philadelphia, Pennsylvania, United States, 19104-4399|
|United States, Texas|
|University of Texas Southwestern Medical Center at Dallas, Division of Pediatric Neurology, Children's Medical Center of Dallas, Ambulatory Care Pavilion, 2350 Stemmons Freeway, Suite #5074|
|Dallas, Texas, United States, 75207|
|Principal Investigator:||René Gonin, PhD||Mathematical Statistician, Westat|
|Study Director:||Peter R Gilbert, ScM||The National Institute of Neurological Disorders and Stroke|