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

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: Open Label; Primary Purpose: Treatment
Conditions:	Spinal Muscular Atrophy Type II Spinal Muscular Atrophy Type III
Intervention:	Drug: sodium phenylbutyrate

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
The protocol was open for recruitment between January 31, 2007 and September 23, 2008 at neurology clinics affiliated with university hospitals.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
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.

Reporting Groups

	Description
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.

Description

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.

Participant Flow for 2 periods

Period 1: Cohort 1 (500 mg/kg/Day)

	Subjects Enrolled
STARTED	7
COMPLETED	3
NOT COMPLETED	4
Allergic reaction	1
Less than 80% study drug compliance	3

Period 2: Cohort 2 (500 mg/kg/Day)

	Subjects Enrolled
STARTED	2 ^[1]
COMPLETED	1
NOT COMPLETED	1
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.

Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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Reporting Groups

	Description
Subjects Enrolled (Cohort 1, Cohort 2)	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.

Description

Subjects Enrolled (Cohort 1, Cohort 2)

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.

Baseline Measures

	Subjects Enrolled (Cohort 1, Cohort 2)
Overall Participants Analyzed [Units: Participants]	9

Age, Customized [Units: Participants]
24 - 48 months	5
49 -96 months	3
>96 and < 144 months	1

Gender [Units: Participants]
Female	5
Male	4

Region of Enrollment [Units: Participants]
United States	9

Outcome Measures

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1. Primary:

Dose Limiting Toxicities (DLT) [ Time Frame: 29 Days ]

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2. Primary:

Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA) [ Time Frame: Baseline - 12 weeks ]

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3. Primary:

Survival Motor Neuron (SMN) Protein [ Time Frame: Baseline - 12 weeks ]

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4. Secondary:

Drug Safety [ Time Frame: 14 weeks ]

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5. Secondary:

Pharmacokinetic Parameters (Maximum Plasma Concentration) [ Time Frame: 12 weeks ]

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6. Secondary:

Pharmacokinetic Parameters (Time to Maximum Concentration) [ Time Frame: 12 weeks ]

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7. Secondary:

Pharmacokinetic Parameters (Area Under the Plasma Concentration Versus Time Curve (AUC)) [ Time Frame: 12 weeks ]

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8. Secondary:

Overall Study Drug Compliance [ Time Frame: 12 Weeks ]

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Serious Adverse Events

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Other Adverse Events

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Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
The study was closed early due to poor study drug compliance. The sample size is therefore extremely limited.

More Information

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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 agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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
e-mail: renegonin@westat.com

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 )
Study First Received:	February 21, 2007
Results First Received:	January 19, 2010
Last Updated:	August 30, 2010

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