Trial Outcomes & Findings for Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Types II or III (NCT NCT00439569)

Last Updated: 2010-09-08

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

9 participants

Primary outcome timeframe

29 Days

Results posted on

2010-09-08

Participant Flow

The protocol was open for recruitment between January 31, 2007 and September 23, 2008 at neurology clinics affiliated with university hospitals.

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.

Participant milestones

Participant milestones
Measure	Subjects Enrolled 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.
Cohort 1 (500 mg/kg/Day) STARTED	7
Cohort 1 (500 mg/kg/Day) COMPLETED	3
Cohort 1 (500 mg/kg/Day) NOT COMPLETED	4
Cohort 2 (500 mg/kg/Day) STARTED	2
Cohort 2 (500 mg/kg/Day) COMPLETED	1
Cohort 2 (500 mg/kg/Day) NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Subjects Enrolled 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.
Cohort 1 (500 mg/kg/Day) Allergic reaction	1
Cohort 1 (500 mg/kg/Day) Less than 80% study drug compliance	3
Cohort 2 (500 mg/kg/Day) Less than 80% study drug compliance	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Subjects Enrolled (Cohort 1, Cohort 2) n=9 Participants 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.
Age, Customized 24 - 48 months	5 Participants n=5 Participants
Age, Customized 49 -96 months	3 Participants n=5 Participants
Age, Customized >96 and < 144 months	1 Participants n=5 Participants
Sex: Female, Male Female	5 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants
Region of Enrollment United States	9 participants n=5 Participants

PRIMARY outcome

Timeframe: 29 Days

Population: 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).

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline - 12 weeks

Timeframe: 12 Weeks

Population: Four of the nine subjects enrolled were less than 80% compliant. The study was closed prematurely due to poor compliance with study drug administration.

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

Outcome measures

Outcome data not reported

Adverse Events

Cohorts 1 & 2 (500 mg/kg/Day)

Serious events: 1 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cohorts 1 & 2 (500 mg/kg/Day) n=9 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Atelectasis	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	Cohorts 1 & 2 (500 mg/kg/Day) n=9 participants at risk 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.
Gastrointestinal disorders Abdominal pain	22.2% 2/9 • Number of events 2 • Data were collected over a 17 month 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	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Aspartate aminotransferase increased	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 alkaline phosphatase increased	22.2% 2/9 • Number of events 2 • Data were collected over a 17 month 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 decreased	22.2% 2/9 • Number of events 2 • Data were collected over a 17 month 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	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 glucose increased	22.2% 2/9 • Number of events 2 • Data were collected over a 17 month 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 Chapped lips	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	22.2% 2/9 • Number of events 2 • Data were collected over a 17 month 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.
Immune system disorders Drug hypersensitivity	11.1% 1/9 • Number of events 3 • Data were collected over a 17 month 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 Fatigue	22.2% 2/9 • Number of events 4 • Data were collected over a 17 month 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 Flatulence	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	22.2% 2/9 • Number of events 2 • Data were collected over a 17 month 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 Headache	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Hyperhidrosis	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Hyperkalaemia	11.1% 1/9 • Number of events 2 • Data were collected over a 17 month 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 Increased appetite	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Infantile spitting up	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Nasal congestion	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Nausea	11.1% 1/9 • Number of events 3 • Data were collected over a 17 month 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	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Pleuritic pain	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Productive cough	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	33.3% 3/9 • Number of events 3 • Data were collected over a 17 month 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	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Skin laceration	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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 Tremor	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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.
Renal and urinary disorders Urine odour abnormal	11.1% 1/9 • Number of events 1 • Data were collected over a 17 month 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	55.6% 5/9 • Number of events 5 • Data were collected over a 17 month 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 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.
Publication restrictions are in place

Restriction type: OTHER