Spinal Muscular Atrophy Type IIPhase 1/2NPTUNE01NCT00439569
Clinical Trial of Sodium Phenylbutyrate in Children With Spinal Muscular Atrophy Types II or III
A Phase 1/2 study testing sodium phenylbutyrate in people with Spinal Muscular Atrophy Type II and Spinal Muscular Atrophy Type III, run by Westat at 5 sites in United States.
Trial summary
The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy types II or III; 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 11 years
- Conditions the study is for
- Spinal Muscular Atrophy Type II, Spinal Muscular Atrophy Type III
- What is being tested?
- sodium phenylbutyrate
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 5 sitesUnited States
- Study dates
- Jan 2008to Aug 2008
- 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 11 years
- 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 II or III
- Laboratory documentation of homozygous absence of SMN1 exon 7
- Type III subjects who are unable to get up from the floor unaided. "Unaided" is defined as not using a device or obtaining assistance from another person.
- 2 years of age or older, but younger than 12 years of age, at the time of enrollment
- Written informed consent of parents/guardian
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- Weight greater than or equal to 10 kilograms
- 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 ≤ 2.5 x 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
- 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.)
- 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.
5 sites in 1 country
United States5 sites
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
Washington University Medical School, Washington University, 660 S. Euclid Avenue, Box 8111
St Louis, Missouri, 63110
Stanford University Medical Center, 300 Pasteur Drive, Room A343
Stanford, California, 94305-5235
About this study
Official title: Phase I/IIa Clinical Trial of Sodium Phenylbutyrate in Pediatric Subjects With Type II/III Spinal Muscular Atrophy
The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy types II or III; and to determine if the drug has an effect on SMN mRNA and protein levels.
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 types II or III. 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.
- Being tested
- sodium phenylbutyrate
- Keywords
- spinal muscular atrophy type II/III, SMA type II/III, 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 group | Role | What they receive |
|---|---|---|
| Single Arm | 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) calculation 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(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.
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 Concentration)
Time to Maximum 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 receiving 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.
- First posted23 Feb 2007 (estimated)
- Study startJan 2008
- Primary completionAug 2008
- Study completionAug 2008
Why it stopped: Due to poor compliance with study drug administration.
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 IIStudies 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
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Westat
- Sponsor type
- University, hospital or other
- Investigators
- René Gonin, PhD, Principal investigator, Mathematical Statistician, WestatPeter R. Gilbert, ScM, Study director, National Institute of Neurological Disorders and Stroke, Program Director
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00439569
- Sponsor's protocol ID
- N01NS42361_NPTUNE01
- Other IDs
- HHSN265200423611C, N01NS42361
- Acronym
- NPTUNE01
- Status last verified
- Aug 2009
- First submitted
- 21 Feb 2007
- Last updated
- 8 Sep 2010
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 8 Sep 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 II/III Spinal Muscular Atrophy
- ClinicalTrials.gov ID
- NCT00439569
- Acronym / sponsor ID
- NPTUNE01 / N01NS42361_NPTUNE01
- Keywords
- spinal muscular atrophy type II/III, SMA type II/III, spinal muscular atrophy, SMA, sodium phenylbutyrate, motor neuron disease, neuromuscular, survival motor neuron
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to poor compliance with study drug administration.
- Enrolment
- 9 participants (actual)
- Lead sponsor
- WestatUniversity, hospital or other
- Collaborators
- National Institute of Neurological Disorders and Stroke (NINDS)
- Study start
- Jan 2008
- Primary completion
- Aug 2008 (actual)
- Study completion
- Aug 2008 (actual)
- First posted
- 23 Feb 2007 (estimated)
- Results
- Posted 12 Feb 2010
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to identify the maximum tolerated dosage of sodium phenylbutyrate in children with spinal muscular atrophy types II or III; and to determine if the drug has an effect on SMN mRNA and protein levels.
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 types II or III. 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Arm | 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) calculation 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 11 years
- 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 II or III
- Laboratory documentation of homozygous absence of SMN1 exon 7
- Type III subjects who are unable to get up from the floor unaided. "Unaided" is defined as not using a device or obtaining assistance from another person.
- 2 years of age or older, but younger than 12 years of age, at the time of enrollment
Key exclusion criteria (12 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 | Single Arm |
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(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.
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 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
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Sep 2010.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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
National Institute of Neurological Disorders and Stroke, Program Director
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 II and Spinal Muscular Atrophy Type III, 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 12 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 8 Sep 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 12 Feb 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?
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 8 Sep 2010.