Trial Outcomes & Findings for Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Type I (NCT NCT00439218)

Last Updated: 2010-11-09

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

5 participants

Primary outcome timeframe

29 days

Results posted on

2010-11-09

Participant Flow

The protocol was open for recruitment between January 31, 2007 and April 2, 2009 at neurology clinics affiliated with university hospitals.

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.

Participant milestones

Participant milestones
Measure	Subject Enrollments 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.
Cohort 1 (500 mg/kg/Day) STARTED	4
Cohort 1 (500 mg/kg/Day) COMPLETED	3
Cohort 1 (500 mg/kg/Day) NOT COMPLETED	1
Cohort 2 (500 mg/kg/Day) STARTED	1
Cohort 2 (500 mg/kg/Day) COMPLETED	1
Cohort 2 (500 mg/kg/Day) NOT COMPLETED	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Subject Enrollments 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.
Cohort 1 (500 mg/kg/Day) Less than 80% study drug compliance	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Subject Enrollments (Cohort 1, Cohort 2) n=5 Participants 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.
Age, Customized 7-12 months	2 months n=5 Participants
Age, Customized 13-18 months	3 months n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants
Region of Enrollment United States	5 participants n=5 Participants

PRIMARY outcome

Timeframe: 29 days

Population: The study was closed prematurely due to slow accrual. The MTD could not be determined due to the small number of subjects enrolled.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline - 12 weeks

Population: 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.

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

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline - 12 Weeks

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 14 weeks

Population: 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.

Adverse event (AE) monitoring

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 weeks

Maximum Plasma Concentration (Cmax)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 weeks

Population: 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.

Time to maximum plasma concentration (Tmax)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 weeks

Area under the plasma concentration versus time curve (AUC)

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 12 weeks

Population: A total of 5 participants were enrolled in the study. Four enrolled in Cohort 1.

Subjects receiveing 80% or more of the prescribed doses within each study visit interval were considered compliant.

Outcome measures

Outcome measures
Measure	Subject Enrollments n=5 Participants 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 Study Drug Compliance Cohort 1 (500 mg/kg/day)	3 Participants
Overall Study Drug Compliance Cohort 2 (500 mg/kg/day)	1 Participants

Adverse Events

Subject Enrollments

Serious events: 1 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Subject Enrollments n=5 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Respiration abnormal	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.

Other adverse events

Other adverse events
Measure	Subject Enrollments n=5 participants at risk 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.
Blood and lymphatic system disorders Leukopenia	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Cardiac disorders Tachycardia	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Eye disorders Eye movement disorder	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Eye disorders Ocular hyperaemia	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Gastrointestinal disorders Constipation	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Gastrointestinal disorders Diarrhoea	40.0% 2/5 • Number of events 3 • Data were collected over a 2 year period. 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.
Gastrointestinal disorders Saliva altered	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Gastrointestinal disorders Teething	40.0% 2/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Gastrointestinal disorders Vomiting	20.0% 1/5 • Number of events 2 • Data were collected over a 2 year period. 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.
General disorders Pyrexia	40.0% 2/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Infections and infestations Cellulitis	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Infections and infestations Nasopharyngitis	40.0% 2/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Infections and infestations Otitis Media	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Infections and infestations Varicella	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Injury, poisoning and procedural complications Arthropod bite	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Investigations AST increased	60.0% 3/5 • Number of events 3 • Data were collected over a 2 year period. 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.
Investigations Blood bicarbonate increased	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Investigations Blood chloride increased	40.0% 2/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Investigations Blood urine present	20.0% 1/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Investigations Glucose urine present	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Investigations Haematocrit decreased	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Investigations Haemoglobin decreased	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Investigations Neutrophil count decreased	20.0% 1/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Investigations Platelet count decreased	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Metabolism and nutrition disorders Anorexia	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Musculoskeletal and connective tissue disorders Decreased appetite	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Nervous system disorders Hypertonia	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Nervous system disorders Somnolence	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Psychiatric disorders Initial insomnia	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Respiratory, thoracic and mediastinal disorders Cough	40.0% 2/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Respiratory, thoracic and mediastinal disorders Hypoxia	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	40.0% 2/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Respiratory, thoracic and mediastinal disorders Tonsillar hypertrophy	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Skin and subcutaneous tissue disorders Blister	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Skin and subcutaneous tissue disorders Dry skin	20.0% 1/5 • Number of events 2 • Data were collected over a 2 year period. 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.
Skin and subcutaneous tissue disorders Rash	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Skin and subcutaneous tissue disorders Rash papular	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Skin and subcutaneous tissue disorders Skin irritation	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.
Gastrointestinal disorders Abdominal distension	20.0% 1/5 • Number of events 1 • Data were collected over a 2 year period. 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.

Additional Information

René Gonin, PhD (Math. Stats.)

Westat

Phone: 301-251-1500

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER