Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Type I
Information source: Westat
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Spinal Muscular Atrophy Type I
Intervention: sodium phenylbutyrate (Drug)
Phase: Phase 1/Phase 2
Status: Terminated
Sponsored by: Westat Official(s) and/or principal investigator(s): René Gonin, PhD, Principal Investigator, Affiliation: Mathematical Statistician, Westat Peter R Gilbert, ScM, Study Director, Affiliation: The National Institute of Neurological Disorders and Stroke
Summary
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.
Clinical Details
Official title: Phase I/IIa Clinical Trial of Sodium Phenylbutyrate in Pediatric Subjects With Type I Spinal Muscular Atrophy
Study design: Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Dose Limiting Toxicities (DLT)Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) Survival Motor Neuron (SMN) Protein
Secondary outcome: Drug SafetyPharmacokinetic Parameters (Maximum Plasma Concentration) Pharmacokinetic Parameters (Time to Maximum Plasma Concentration) Pharmacokinetic Parameters (Area Under the Plasma Concentration Versus Time Curve (AUC)) Overall Study Drug Compliance
Detailed description:
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.
Eligibility
Minimum age: 2 Months.
Maximum age: 48 Months.
Gender(s): Both.
Criteria:
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 I
- Laboratory documentation of homozygous absence of SMN1 exon 7
- Older than two months of age, but younger than 48 months of age, at the time of
enrollment. If the subject is older than 24 months of age at the time of enrollment,
the subject must require ventilatory support for at least 6 hours/day.
- Written informed consent of parents/guardian
- Weight greater than or equal to 7 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. 5x 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
- Subjects who are on ventilators may enroll in the protocol providing they have been
on stable ventilator settings for at least the prior two weeks.
- 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.)
- Poor respiratory status which is expected to require the initiation of BiPAP during
the initial 29 days of drug administration.
- 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.
Locations and Contacts
Stanford University Medical Center, 300 Pasteur Drive, Room A343, Stanford, California 94305-5235, United States
Children's Hospital, Boston, 300 Longwood Avenue, Fegan 11, Boston, Massachusetts 02115, United States
Columbia University, 180 Fort Washington Avenue, 5th Floor, New York, New York 10032, United States
The Children's Hospital of Philadelphia, Clinical Trials Office, A-230, 34th St. and Civic Center Boulevard, Philadelphia, Pennsylvania 19104-4399, United States
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 75207, United States
Additional Information
Starting date: January 2008
Last updated: October 27, 2010
|