Spinal Muscular Atrophy Type IPhase 1/2NPTUNE 02NCT00439218

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

A Phase 1/2 study testing sodium phenylbutyrate in people with Spinal Muscular Atrophy Type I, run by Westat at 5 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy type I; and to determine if the drug has an effect on SMN mRNA and protein levels. Read more about this study

Who is it for?: Ages 2 to 48 months
Conditions the study is for: Spinal Muscular Atrophy Type I
What is being tested?: sodium phenylbutyrate
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 5 participants
Where: 5 sitesUnited States
Study dates: Jan 2008to May 2009
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 2 to 48 months
All sexes
No healthy volunteers
Child

Who may be able to join

Subjects must meet all of the following inclusion criteria within 14 days prior to receiving the first dose of study drug.
Weakness and hypotonia consistent with a clinical diagnosis of spinal muscular atrophy (SMA) type I
Laboratory documentation of homozygous absence of SMN1 exon 7
Older than two months of age, but younger than 48 months of age, at the time of enrollment. If the subject is older than 24 months of age at the time of enrollment, the subject must require ventilatory support for at least 6 hours/day.
Written informed consent of parents/guardian
Weight greater than or equal to 7 kilograms

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Laboratory results drawn within 14 days prior to start of study drug demonstrating: Hemoglobin within normal range at the clinical site; White Blood Cell Count ≥ 3000/mm³; Platelet Count ≥ 75,000/mm³; Lipase and Amylase ≤ 1.5 x upper limit of normal (ULN) in the absence of associated clinical symptoms; AST and ALT ≤2.5x ULN; Bilirubin ≤ 1.5x ULN in the absence of associated clinical symptoms; Sodium ≥ 130 and ≤ 150 mmol/L; Potassium ≥3.0 and ≤ 5.5 mmol/L; Chloride ≤ 110 mmol/L; Calcium ≥ 8.0 mg/dL; Bicarbonate ≥ 16 mmol/L; Glucose ≥ 55 and ≤ 160 mg/dL; BUN ≤ 39 mg/dL; Creatinine ≤ 1.5 x ULN
Subjects who are on ventilators may enroll in the protocol providing they have been on stable ventilator settings for at least the prior two weeks.
Subject is expected to survive for at least 6 months following study entry

Who cannot join

Subjects who meet any of the following criteria will be excluded from participating in the study:
Evidence of renal dysfunction, blood dyscrasia, hepatic insufficiency, symptomatic pancreatitis, cardiac arrhythmia, congenital heart defect, known history of metabolic acidosis, hypertension, significant central nervous system impairment, or neurodegenerative or neuromuscular disease other than SMA.
Any adverse event ≥ Grade 3 at the time of screening based on the protocol toxicity grading table
Any acute co-morbid condition interfering with the well-being of the subject within 7 days of enrollment including bacterial infection, viral infectious process, food poisoning, temperature > 99.0ºF, need for acute treatment or observation due to any other reason, as judged by the investigator.
≥ Grade 2 vomiting;
≥ Grade 2 liver dysfunction/failure (clinical);

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Any abnormality noted on EKG except for asymptomatic sinus arrhythmia
History of allergy/sensitivity to sodium phenylbutyrate
Use of sodium phenylbutyrate within 30 days of study entry
Serious illness requiring systemic treatment and/or hospitalization within 14 days prior to study entry (Subjects are not eligible following serious illness until therapy is complete and the subject is stable, or until the subject is on therapy and stable for at least 14 days.)
Poor respiratory status which is expected to require the initiation of BiPAP during the initial 29 days of drug administration.
Use of medications intended for the treatment of SMA including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatine, carnitine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, haloperidol, agents anticipated to increase or decrease muscle strength or agents with known or presumed histone deacetylase (HDAC) inhibition within 30 days prior to study entry.
Notes: Subjects who use a nebulizer or require an inhaler to receive albuterol will be allowed in the study; however oral use of albuterol is prohibited. Topical use of steroids will be allowed. Oral use of steroids is not allowed at entry, but these may be used as clinically indicated while on study. Event grading will be based on the toxicity-grading table in the protocol.

Trial locations and contacts

5 sites in 1 country.

City, postcode or hospital

5 sites in 1 country

United States5 sites

Children's Hospital, Boston, 300 Longwood Avenue, Fegan 11
Boston, Massachusetts, 02115
University of Texas Southwestern Medical Center at Dallas, Division of Pediatric Neurology, Children's Medical Center of Dallas, Ambulatory Care Pavilion, 2350 Stemmons Freeway, Suite #5074
Dallas, Texas, 75207
Columbia University, 180 Fort Washington Avenue, 5th Floor
New York, New York, 10032
The Children's Hospital of Philadelphia, Clinical Trials Office, A-230, 34th St. and Civic Center Boulevard
Philadelphia, Pennsylvania, 19104-4399
Stanford University Medical Center, 300 Pasteur Drive, Room A343
Stanford, California, 94305-5235

Other trials in United States

About this study

Official title: Phase I/IIa Clinical Trial of Sodium Phenylbutyrate in Pediatric Subjects With Type I Spinal Muscular Atrophy

Read the detailed description

Spinal muscular atrophy (SMA) is a genetic, neuromuscular disorder caused by progressive degeneration of motor neurons in the spinal cord, which results from the loss of survival motor neuron (SMN) protein. The disorder is characterized by weakness and wasting of the voluntary muscles and is a leading cause of hereditary infant death. Sodium phenylbutyrate-a drug used to treat urea cycle disorders-may increase the amount of SMN protein in the body and consequently may decrease the severity of SMA. However, this has not yet been proven.

In this multicenter trial, physicians will evaluate multiple dosage levels of sodium phenylbutyrate to determine the maximum tolerated dose (MTD), or the highest dose that can be safely given to children with SMA type I. The initial dosage tested will be 500 mg/kg/day. Depending upon tolerability, subsequent groups may receive dosages of 675, 900, or 1200 mg/kg/day. Blood levels of SMN mRNA and protein will also be measured to determine whether sodium phenylbutyrate can increase the amount of these two biomarkers in the blood. Up to 24 children will be enrolled in the study, and will be on sodium phenylbutyrate for 12 weeks. The MTD will be determined based on safety data from Day 0 through the Day 29 visit. Participants will continue to be monitored for safety and SMN mRNA and protein levels through the 12 week study drug administration period.

Potential participants will be screened by having their complete medical and treatment histories recorded, as well as undergoing a physical examination, laboratory tests, and an electrocardiogram (EKG). Parents of eligible participants will receive a supply of sodium phenylbutyrate and instructions on how to administer the drug. Participants will return to the clinic on days 8, 22, 29, and at weeks 8 and 12 of the study to update their medical and treatment histories, have a physical exam, and have blood and urine collected for laboratory testing. A follow-up clinic visit will occur approximately 14 days after the last dose of sodium phenylbutyrate is given. During this visit participants will update their complete medical and treatment histories and have a physical examination. Duration of the study is about 14 weeks.

Information from this study, which is part of the NINDS Pilot Therapeutics Network (NPTUNE), may be used for future studies to determine if sodium phenylbutyrate is effective for treating SMA, and if the drug has an effect on SMA symptoms.

Conditions: Spinal Muscular Atrophy Type I
Being tested: sodium phenylbutyrate
Keywords: spinal muscular atrophy type I, SMA type I, spinal muscular atrophy, SMA, sodium phenylbutyrate, motor neuron disease, neuromuscular, survival motor neuron, SMN, dose escalation
Medical subject headings: Spinal Muscular Atrophies of Childhood, Muscular Atrophy, Spinal, Motor Neuron Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

sodium phenylbutyrateDrug
500 mg/kg/day, depending upon tolerability subsequent dosages may increase to 675, 900, or 1200 mg/kg/day to identify maximum tolerated dose (MTD) and then an additional 6 participants will enroll at the MTD.

Study groups in NCT00439218
Study group	Role	What they receive
Subject Enrollments	Experimental	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 dosage of the next cohort 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. Receives: Drug: sodium phenylbutyrate

What is being measured

The primary outcome is the main question the study is designed to answer.

Dose Limiting Toxicities (DLT)
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.
Measured: 29 days
Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA)
The change of level in blood SMN mRNA from baseline to assess time course and dose response.
Measured: Baseline - 12 weeks
Survival Motor Neuron (SMN) Protein
The change of level in blood SMN protein from baseline to assess time course and dose response.
Measured: Baseline - 12 Weeks

Secondary outcomes (5)

Drug Safety
Adverse event (AE) monitoring
Measured: 14 weeks
Pharmacokinetic Parameters (Maximum Plasma Concentration)
Maximum Plasma Concentration (Cmax)
Measured: 12 weeks
Pharmacokinetic Parameters (Time to Maximum Plasma Concentration)
Time to maximum plasma concentration (Tmax)
Measured: 12 weeks
Pharmacokinetic Parameters (Area Under the Plasma Concentration Versus Time Curve (AUC))
Area under the plasma concentration versus time curve (AUC)
Measured: 12 weeks
Overall Study Drug Compliance
Subjects receiveing 80% or more of the prescribed doses within each study visit interval were considered compliant.
Measured: 12 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jan 2008May 2009

First posted23 Feb 2007 (estimated)
Study startJan 2008
Primary completionMay 2009
Study completionMay 2009

Why it stopped: Extremely slow enrollment

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Spinal Muscular Atrophy Type IStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 5 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00439218
Sponsor's protocol ID: N01NS42361_NPTUNE02
Other IDs: HHSN265200423611C, N01NS42361
Acronym: NPTUNE 02
Status last verified: May 2009
First submitted: 22 Feb 2007
Last updated: 9 Nov 2010
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

RecruitingObservational study
A Study of Risdiplam in Participants With Type I and Type II Spinal Muscle Atrophy (SMA)
Spinal Muscle Atrophy
Not yet recruitingEarly Phase 1
SPX-01 Gene Therapy in Pediatric Patients With Spinal Muscular Atrophy Type 1 (RISE)
Spinal Muscular Atrophy (SMA)
RecruitingObservational study
Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
Rare Disorders, Undiagnosed Disorders
RecruitingPhase 1/2
A Phase I/II Clinical Study to Evaluate SKG0201 Injection in Subjects With Spinal Muscular Atrophy Type I
Spinal Muscular Atrophy 1
Active, not recruitingPhase 3
Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
Spinal Muscular Atrophy Type I, Spinal Muscular Atrophy Type II

All Spinal Muscular Atrophy Type I trials

Study at a glance

From the registry record, last updated by the sponsor on 9 Nov 2010. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Phase I/IIa Clinical Trial of Sodium Phenylbutyrate in Pediatric Subjects With Type I Spinal Muscular Atrophy
ClinicalTrials.gov ID: NCT00439218
Acronym / sponsor ID: NPTUNE 02 / N01NS42361_NPTUNE02
Conditions: Spinal Muscular Atrophy Type I
Keywords: spinal muscular atrophy type I, SMA type I, spinal muscular atrophy, SMA, sodium phenylbutyrate, motor neuron disease, neuromuscular, survival motor neuron
Phase: Phase 1/2
Study type: Interventional
Recruitment status: TerminatedReason stopped: Extremely slow enrollment
Enrolment: 5 participants (actual)
Lead sponsor: WestatUniversity, hospital or other
Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
Study start: Jan 2008
Primary completion: May 2009 (actual)
Study completion: May 2009 (actual)
First posted: 23 Feb 2007 (estimated)
Results: Posted 20 Jul 2010

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 1

Arm	Type	Receives
Subject Enrollments	Experimental	Drug: sodium phenylbutyrateCohorts 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 dosage of the next cohort 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.

Who may qualify

Ages: 2 to 48 months
Sex: All
Healthy volunteers: Not accepted
Age groups: Child

Key inclusion criteria (9 listed)

Subjects must meet all of the following inclusion criteria within 14 days prior to receiving the first dose of study drug.
Weakness and hypotonia consistent with a clinical diagnosis of spinal muscular atrophy (SMA) type I
Laboratory documentation of homozygous absence of SMN1 exon 7
Older than two months of age, but younger than 48 months of age, at the time of enrollment. If the subject is older than 24 months of age at the time of enrollment, the subject must require ventilatory support for at least 6 hours/day.
Written informed consent of parents/guardian

Key exclusion criteria (13 listed)

Subjects who meet any of the following criteria will be excluded from participating in the study:
Evidence of renal dysfunction, blood dyscrasia, hepatic insufficiency, symptomatic pancreatitis, cardiac arrhythmia, congenital heart defect, known history of metabolic acidosis, hypertension, significant central nervous system impairment, or neurodegenerative or neuromuscular disease other than SMA.
Any adverse event ≥ Grade 3 at the time of screening based on the protocol toxicity grading table
Any acute co-morbid condition interfering with the well-being of the subject within 7 days of enrollment including bacterial infection, viral infectious process, food poisoning, temperature > 99.0ºF, need for acute treatment or observation due to any other reason, as judged by the investigator.
≥ Grade 2 vomiting;

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
sodium phenylbutyrate500 mg/kg/day, depending upon tolerability subsequent dosages may increase to 675, 900, or 1200 mg/kg/day to identify maximum tolerated dose (MTD) and then an additional 6 participants will enroll at the MTD.	Drug	Subject Enrollments

Primary outcome

Dose Limiting Toxicities (DLT)
Time frame: 29 days
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.
Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA)
Time frame: Baseline - 12 weeks
The change of level in blood SMN mRNA from baseline to assess time course and dose response.
Survival Motor Neuron (SMN) Protein
Time frame: Baseline - 12 Weeks
The change of level in blood SMN protein from baseline to assess time course and dose response.

5 secondary outcomes

Drug Safety
Time frame: 14 weeks
Pharmacokinetic Parameters (Maximum Plasma Concentration)
Time frame: 12 weeks
Pharmacokinetic Parameters (Time to Maximum Plasma Concentration)
Time frame: 12 weeks
Pharmacokinetic Parameters (Area Under the Plasma Concentration Versus Time Curve (AUC))
Time frame: 12 weeks
Overall Study Drug Compliance
Time frame: 12 weeks

Results and safety

Results posted to the registry on 20 Jul 2010, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Subject Enrollments	4	3

Primary outcome: Dose Limiting Toxicities (DLT)

Time frame: 29 days. Number. Unit: DLT(s)

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

Primary outcome: Survival Motor Neuron (SMN) Messenger Ribonucleic Acid (mRNA)

Time frame: Baseline - 12 weeks. Mean (Standard Error). Unit: Cycle Threshold (Ct)

Population analysed: 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.

Primary outcome: Survival Motor Neuron (SMN) Protein

Time frame: Baseline - 12 Weeks. Mean (Standard Deviation). Unit: SMN/beta tubulin

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: Data were collected over a 2 year period.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Subject Enrollments	1 of 5 (20%)	5 of 5 (100%)	Not reported

Limitations and caveats (from the sponsor): This study was closed early due to slow accrual. The sample size is therefore extremely limited.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Nov 2010.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.

Related trials for Spinal Muscular Atrophy Type I

RecruitingObservational study
A Study of Risdiplam in Participants With Type I and Type II Spinal Muscle Atrophy (SMA)
Spinal Muscle Atrophy
Not yet recruitingEarly Phase 1
SPX-01 Gene Therapy in Pediatric Patients With Spinal Muscular Atrophy Type 1 (RISE)
Spinal Muscular Atrophy (SMA)
RecruitingObservational study
Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
Rare Disorders, Undiagnosed Disorders
RecruitingPhase 1/2
A Phase I/II Clinical Study to Evaluate SKG0201 Injection in Subjects With Spinal Muscular Atrophy Type I
Spinal Muscular Atrophy 1
Active, not recruitingPhase 3
Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi
Spinal Muscular Atrophy Type I, Spinal Muscular Atrophy Type II

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

René Gonin, PhD principal investigator

Mathematical Statistician, Westat

Peter R Gilbert, ScM study director

The National Institute of Neurological Disorders and Stroke

5 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing sodium phenylbutyrate in people with Spinal Muscular Atrophy Type I, run by Westat at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 9 Nov 2010. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Jul 2010). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Dose Limiting Toxicities (DLT) (time frame: 29 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00439218.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Nov 2010.