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Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Type I (NPTUNE 02)

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ClinicalTrials.gov Identifier: NCT00439218
Recruitment Status : Terminated (Extremely slow enrollment)
First Posted : February 23, 2007
Results First Posted : July 20, 2010
Last Update Posted : November 9, 2010
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by:
Westat

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Spinal Muscular Atrophy Type I
Intervention Drug: sodium phenylbutyrate
Enrollment 5
Recruitment Details The protocol was open for recruitment between January 31, 2007 and April 2, 2009 at neurology clinics affiliated with university hospitals.
Pre-assignment Details Pre-specified dosage levels of sodium phenylbutyrate(NaPB) were calculated using the modified Fibonacci rule yielding the dosage levels of 500, 675, 900 and 1200 mg /kg/day. The selection of 500 mg/kg/day as the initial dosage was based on the recommended dosage of 450 -600 mg/kg/day for the approved indication for urea cycle disorders in children.
Arm/Group Title Subject Enrollments
Hide Arm/Group Description 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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Period Title: Cohort 1 (500 mg/kg/Day)
Started 4
Completed 3 [1]
Not Completed 1
Reason Not Completed
Less than 80% study drug compliance             1
[1]
3 subjects completed the study in Cohort 1. Cohort 2 was then opened for new enrollments.
Period Title: Cohort 2 (500 mg/kg/Day)
Started 1 [1]
Completed 1
Not Completed 0
[1]
One new subject was enrolled into the study after Cohort 1 completed the study.
Arm/Group Title Subject Enrollments (Cohort 1, Cohort 2)
Hide Arm/Group Description 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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Baseline Participants 5
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Months
Number Analyzed 5 participants
7-12 months 2
13-18 months 3
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 5 participants
Female
1
  20.0%
Male
4
  80.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 5 participants
5
1.Primary Outcome
Title Dose Limiting Toxicities (DLT)
Hide Description 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.
Time Frame 29 days
Hide Outcome Measure Data
Hide Analysis Population Description
The study was closed prematurely due to slow accrual. The MTD could not be determined due to the small number of subjects enrolled.
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
2.Primary Outcome
Title Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA)
Hide Description The change of level in blood SMN mRNA from baseline to assess time course and dose response.
Time Frame Baseline - 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study was closed prematurely due to slow accrual. These data are exploratory and have not yet been analyzed. Their interpretability will be limited because of the small number of specimens collected.
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
3.Primary Outcome
Title Survival Motor Neuron (SMN) Protein
Hide Description The change of level in blood SMN protein from baseline to assess time course and dose response.
Time Frame Baseline - 12 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study was closed prematurely due to slow accrual. These data are exploratory and have not yet been analyzed. Their interpretability will be limited because of the small number of specimens collected.
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
4.Secondary Outcome
Title Drug Safety
Hide Description Adverse event (AE) monitoring
Time Frame 14 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study was closed prematurely due to slow accrual. These data have not yet been analyzed. Their interpretability will be limited because of the small number of subjects enrolled. There were no safety concerns reported by the SMC.
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
5.Secondary Outcome
Title Pharmacokinetic Parameters (Maximum Plasma Concentration)
Hide Description Maximum Plasma Concentration (Cmax)
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Pharmacokinetic Parameters (Time to Maximum Plasma Concentration)
Hide Description Time to maximum plasma concentration (Tmax)
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study was closed prematurely due to slow accrual. These data have not yet been analyzed. Their interpretability will be limited because of the small number of specimens collected.
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
7.Secondary Outcome
Title Pharmacokinetic Parameters (Area Under the Plasma Concentration Versus Time Curve (AUC))
Hide Description Area under the plasma concentration versus time curve (AUC)
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
8.Secondary Outcome
Title Overall Study Drug Compliance
Hide Description Subjects receiveing 80% or more of the prescribed doses within each study visit interval were considered compliant.
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
A total of 5 participants were enrolled in the study. Four enrolled in Cohort 1.
Arm/Group Title Subject Enrollments
Hide Arm/Group Description:
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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
Overall Number of Participants Analyzed 5
Measure Type: Number
Unit of Measure: Participants
Cohort 1 (500 mg/kg/day) 3
Cohort 2 (500 mg/kg/day) 1
Time Frame Data were collected over a 2 year period.
Adverse Event Reporting Description Data were collected at scheduled clinic and telephone study visits via medical history, physical examinations, laboratory tests, EKG, and other tests as necessary. In addition, adverse events were reported to site investigators by subjects' parents in between visits, as needed.
 
Arm/Group Title Subject Enrollments
Hide Arm/Group Description 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 next cohort's dosage 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. Due to the replacement of a subject (1 not completed), more than 3 subjects were enrolled in cohort 1. One new subject was enrolled in Cohort 2.
All-Cause Mortality
Subject Enrollments
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Subject Enrollments
Affected / at Risk (%) # Events
Total   1/5 (20.00%)    
Respiratory, thoracic and mediastinal disorders   
Respiration abnormal * 1  1/5 (20.00%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (8.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Subject Enrollments
Affected / at Risk (%) # Events
Total   5/5 (100.00%)    
Blood and lymphatic system disorders   
Leukopenia * 1  1/5 (20.00%)  1
Cardiac disorders   
Tachycardia * 1  1/5 (20.00%)  1
Eye disorders   
Eye movement disorder * 1  1/5 (20.00%)  1
Ocular hyperaemia * 1  1/5 (20.00%)  1
Gastrointestinal disorders   
Constipation * 1  1/5 (20.00%)  1
Diarrhoea * 1  2/5 (40.00%)  3
Saliva altered * 1  1/5 (20.00%)  1
Teething * 1  2/5 (40.00%)  2
Vomiting * 1  1/5 (20.00%)  2
Abdominal distension * 1  1/5 (20.00%)  1
General disorders   
Pyrexia * 1  2/5 (40.00%)  2
Infections and infestations   
Cellulitis * 1  1/5 (20.00%)  1
Nasopharyngitis * 1  2/5 (40.00%)  2
Otitis Media * 1  1/5 (20.00%)  1
Varicella * 1  1/5 (20.00%)  1
Injury, poisoning and procedural complications   
Arthropod bite * 1  1/5 (20.00%)  1
Investigations   
AST increased * 1  3/5 (60.00%)  3
Blood bicarbonate increased * 1  1/5 (20.00%)  1
Blood chloride increased * 1  2/5 (40.00%)  2
Blood urine present * 1  1/5 (20.00%)  2
Glucose urine present * 1  1/5 (20.00%)  1
Haematocrit decreased * 1  1/5 (20.00%)  1
Haemoglobin decreased * 1  1/5 (20.00%)  1
Neutrophil count decreased * 1  1/5 (20.00%)  2
Platelet count decreased * 1  1/5 (20.00%)  1
Metabolism and nutrition disorders   
Anorexia * 1  1/5 (20.00%)  1
Musculoskeletal and connective tissue disorders   
Decreased appetite * 1  1/5 (20.00%)  1
Nervous system disorders   
Hypertonia * 1  1/5 (20.00%)  1
Somnolence * 1  1/5 (20.00%)  1
Psychiatric disorders   
Initial insomnia * 1  1/5 (20.00%)  1
Respiratory, thoracic and mediastinal disorders   
Cough * 1  2/5 (40.00%)  2
Hypoxia * 1  1/5 (20.00%)  1
Pharyngolaryngeal pain * 1  1/5 (20.00%)  1
Rhinorrhoea * 1  2/5 (40.00%)  2
Tonsillar hypertrophy * 1  1/5 (20.00%)  1
Skin and subcutaneous tissue disorders   
Blister * 1  1/5 (20.00%)  1
Dry skin * 1  1/5 (20.00%)  2
Rash * 1  1/5 (20.00%)  1
Rash papular * 1  1/5 (20.00%)  1
Skin irritation * 1  1/5 (20.00%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (8.1)
This study was closed early due to slow accrual. The sample size is therefore extremely limited.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Investigators must submit an application to the NPTUNE Publications Committee for the use of data. A Writing Committee, appointed by the Publications Committee, is responsible for initiating, coordinating, and approving publications and presentations.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: René Gonin, PhD (Math. Stats.)
Organization: Westat
Phone: 301-251-1500
EMail: renegonin@westat.com
Layout table for additonal information
Responsible Party: René Gonin, PhD (Math. Stats.), Senior Biostatistician and NPTUNE Principal Investigator, Westat
ClinicalTrials.gov Identifier: NCT00439218     History of Changes
Other Study ID Numbers: N01NS42361_NPTUNE02
HHSN265200423611C ( Other Grant/Funding Number: NIH Contract )
First Submitted: February 22, 2007
First Posted: February 23, 2007
Results First Submitted: April 16, 2010
Results First Posted: July 20, 2010
Last Update Posted: November 9, 2010