Overview

Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Type I

Status:
Terminated
Trial end date:
2009-05-01
Target enrollment:
0
Participant gender:
All
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.
Phase:
Phase 1/Phase 2
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Westat
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Treatments:
4-phenylbutyric acid
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.