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Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Types II or III (NPTUNE01)

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ClinicalTrials.gov Identifier: NCT00439569
Recruitment Status : Terminated (Due to poor compliance with study drug administration.)
First Posted : February 23, 2007
Results First Posted : February 12, 2010
Last Update Posted : September 8, 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
Conditions Spinal Muscular Atrophy Type II
Spinal Muscular Atrophy Type III
Intervention Drug: sodium phenylbutyrate
Enrollment 9
Recruitment Details The protocol was open for recruitment between January 31, 2007 and September 23, 2008 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 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 Subjects Enrolled
Hide Arm/Group Description Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1. Two new subjects were then enrolled in Cohort 2.
Period Title: Cohort 1 (500 mg/kg/Day)
Started 7
Completed 3
Not Completed 4
Reason Not Completed
Allergic reaction             1
Less than 80% study drug compliance             3
Period Title: Cohort 2 (500 mg/kg/Day)
Started 2 [1]
Completed 1
Not Completed 1
Reason Not Completed
Less than 80% study drug compliance             1
[1]
2 new subjects in Cohort 2 were enrolled into the study after Cohort 1 completed the study.
Arm/Group Title Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
Overall Number of Baseline Participants 9
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 9 participants
24 - 48 months 5
49 -96 months 3
>96 and < 144 months 1
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants
Female
5
  55.6%
Male
4
  44.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 9 participants
9
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(AE),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;abnormality of Na, K, Cl, Ca, HCO3, glucose, BUN or creatinine.
Time Frame 29 Days
Hide Outcome Measure Data
Hide Analysis Population Description
The study was closed prematurely due to poor compliance with study drug administration. The MTD could not be determined as it was less than the lowest dosage studied (500 mg/kg/day).
Arm/Group Title Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
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 poor compliance with study drug administration. These data have not yet been analyzed. Their interpretability will be limited because of the small number of specimens collected.
Arm/Group Title Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
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 poor compliance with study drug administration. These data have not yet been analyzed. Their interpretability will be limited because of the small number of specimens collected.
Arm/Group Title Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
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 poor compliance with study drug administration. 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 study monitoring committee (SMC).
Arm/Group Title Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
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 Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
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 Concentration)
Hide Description Time to Maximum Concentration (Tmax)
Time Frame 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
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 Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
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 receiving 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
Four of the nine subjects enrolled were less than 80% compliant. The study was closed prematurely due to poor compliance with study drug administration.
Arm/Group Title Subjects Enrolled (Cohort 1, Cohort 2)
Hide Arm/Group Description:
Cohorts of 3 subjects were to be enrolled sequentially in escalating dosage levels. The first 3 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 subjects (4 not completed), more than 3 subjects were enrolled in Cohort 1.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Data were collected over a 17 month 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 Cohorts 1 & 2 (500 mg/kg/Day)
Hide Arm/Group Description Cohort 1 was assigned a dosage of 500 mg/kg/day. One subject was replaced due to an allergic reaction and four subjects due to less than 80 percent study drug compliance. Due to these replacements, more than 3 subjects were enrolled in the first cohort. Cohort 2 was assigned a dosage of 500 mg/kg/day by the MCRM and approved by the SMC due to dose-limiting toxicities experienced in Cohort 1. For the purpose of reporting adverse events, these two cohorts were combined for a total of 9 enrolled subjects.
All-Cause Mortality
Cohorts 1 & 2 (500 mg/kg/Day)
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Cohorts 1 & 2 (500 mg/kg/Day)
Affected / at Risk (%) # Events
Total   1/9 (11.11%)    
Respiratory, thoracic and mediastinal disorders   
Atelectasis  1  1/9 (11.11%)  1
Indicates events were collected by 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%
Cohorts 1 & 2 (500 mg/kg/Day)
Affected / at Risk (%) # Events
Total   9/9 (100.00%)    
Gastrointestinal disorders   
Abdominal pain * 1  2/9 (22.22%)  2
Chapped lips * 1  1/9 (11.11%)  1
Diarrhoea * 1  2/9 (22.22%)  2
Flatulence * 1  1/9 (11.11%)  1
Infantile spitting up * 1  1/9 (11.11%)  1
Nausea  1  1/9 (11.11%)  3
Vomiting  1  5/9 (55.56%)  5
General disorders   
Fatigue * 1  2/9 (22.22%)  4
Pyrexia * 1  3/9 (33.33%)  3
Immune system disorders   
Drug hypersensitivity * 1  1/9 (11.11%)  3
Infections and infestations   
Otitis media * 1  1/9 (11.11%)  1
Injury, poisoning and procedural complications   
Arthropod bite * 1  1/9 (11.11%)  1
Skin laceration * 1  1/9 (11.11%)  1
Investigations   
Aspartate aminotransferase increased * 1  1/9 (11.11%)  1
Blood alkaline phosphatase increased * 1  2/9 (22.22%)  2
Blood bicarbonate decreased * 1  2/9 (22.22%)  2
Blood chloride increased * 1  1/9 (11.11%)  1
Blood glucose increased * 1  2/9 (22.22%)  2
Haemoglobin decreased * 1  2/9 (22.22%)  2
Metabolism and nutrition disorders   
Anorexia * 1  1/9 (11.11%)  1
Hyperkalaemia * 1  1/9 (11.11%)  2
Increased appetite * 1  1/9 (11.11%)  1
Nervous system disorders   
Headache * 1  1/9 (11.11%)  1
Somnolence * 1  1/9 (11.11%)  1
Tremor * 1  1/9 (11.11%)  1
Renal and urinary disorders   
Urine odour abnormal * 1  1/9 (11.11%)  1
Respiratory, thoracic and mediastinal disorders   
Cough * 1  1/9 (11.11%)  1
Nasal congestion * 1  1/9 (11.11%)  1
Pleuritic pain * 1  1/9 (11.11%)  1
Productive cough * 1  1/9 (11.11%)  1
Skin and subcutaneous tissue disorders   
Hyperhidrosis * 1  1/9 (11.11%)  1
Skin irritation * 1  1/9 (11.11%)  1
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (8.1)
The study was closed early due to poor study drug compliance. 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.
The Publication Policy for the National Institute of Neurological Disorders and Stroke (NINDS) Pilot Therapeutic Trials Network (NPTUNE) outlines procedures for the development and review of concept sheets, abstracts, publications,presentations. 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
Name/Title: René Gonin, PhD (Math. Stats.)
Organization: Westat
Phone: 301-251-1500
Responsible Party: René Gonin, PhD (Math. Stats.), Senior Biostatistician and NPTUNE Principal Investigator, Westat
ClinicalTrials.gov Identifier: NCT00439569     History of Changes
Other Study ID Numbers: N01NS42361_NPTUNE01
HHSN265200423611C ( Other Grant/Funding Number: NIH Contract )
First Submitted: February 21, 2007
First Posted: February 23, 2007
Results First Submitted: January 19, 2010
Results First Posted: February 12, 2010
Last Update Posted: September 8, 2010