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

NCT00439218 | Terminated Phase 1 Results DMC

• 3 other identifiers: N01NS42361_NPTUNE02HHSN265200423611CN01NS42361
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 5

Brief 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.

Conditions

Spinal Muscular Atrophy Type I

Keywords

spinal muscular atrophy type I; SMA type I; spinal muscular atrophy; SMA; sodium phenylbutyrate; motor neuron disease; neuromuscular; survival motor neuron; SMN; dose escalation

Outcome Measures

Primary Outcomes (3)

• Dose Limiting Toxicities (DLT)

  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.

  29 days

• Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA)

  The change of level in blood SMN mRNA from baseline to assess time course and dose response.

  Baseline - 12 weeks

• Survival Motor Neuron (SMN) Protein

  The change of level in blood SMN protein from baseline to assess time course and dose response.

  Baseline - 12 Weeks

Secondary Outcomes (5)

• Drug Safety

  14 weeks

• Pharmacokinetic Parameters (Maximum Plasma Concentration)

  12 weeks

• Pharmacokinetic Parameters (Time to Maximum Plasma Concentration)

  12 weeks

• Pharmacokinetic Parameters (Area Under the Plasma Concentration Versus Time Curve (AUC))

  12 weeks

• Overall Study Drug Compliance

  12 weeks

Study Arms (1)

Subject Enrollments

EXPERIMENTAL

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

Interventions

sodium phenylbutyrate DRUG

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.

Subject Enrollments

Eligibility Criteria

• Age: 2 Months - 48 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Westat: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator

Study Sites (5)

Stanford University Medical Center, 300 Pasteur Drive, Room A343

Stanford, California, 94305-5235, United States

Location

Children's Hospital, Boston, 300 Longwood Avenue, Fegan 11

Boston, Massachusetts, 02115, United States

Location

Columbia University, 180 Fort Washington Avenue, 5th Floor

New York, New York, 10032, United States

Location

The Children's Hospital of Philadelphia, Clinical Trials Office, A-230, 34th St. and Civic Center Boulevard

Philadelphia, Pennsylvania, 19104-4399, United States

Location

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

Location

MeSH Terms

Conditions

Spinal Muscular Atrophies of Childhood; Muscular Atrophy, Spinal; Motor Neuron Disease

Interventions

4-phenylbutyric acid

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

This study was closed early due to slow accrual. The sample size is therefore extremely limited.

Results Point of Contact

• Title: René Gonin, PhD (Math. Stats.)
• Organization: Westat

renegonin@westat.com

301-251-1500

Study Officials

• René Gonin, PhD

  Mathematical Statistician, Westat

  PRINCIPAL INVESTIGATOR

• Peter R Gilbert, ScM

  The National Institute of Neurological Disorders and Stroke

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: February 22, 2007
• First Posted: February 23, 2007
• Study Start: January 1, 2008
• Primary Completion: May 1, 2009
• Study Completion: May 1, 2009
• Last Updated: November 9, 2010
• Results First Posted: July 20, 2010

Record last verified: 2009-05

Locations

US (5)