Spinal Muscular Atrophy Type IPhase 1/2NCT00661453
CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I
A Phase 1/2 study testing Valproic Acid and Levocarnitine in people with Spinal Muscular Atrophy Type I, run by University of Utah at 8 sites in 3 countries.
Trial summary
This is a multi-center trial to test safety and evaluate early treatment intervention with valproic acid and carnitine in moderating SMA symptoms of Type I infants. Read more about this study
- Who is it for?
- Ages 2 weeks to 12 months
- Conditions the study is for
- Spinal Muscular Atrophy Type I
- What is being tested?
- Valproic Acid and Levocarnitine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- 8 sitesin 3 countries
- Study dates
- Apr 2008to Jun 2012
- 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 weeks to 12 months
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Laboratory documentation of SMN mutation/deletion consistent with a genetic diagnosis of SMA
- Clinical diagnosis of SMA type I
- Age 2 weeks to 12 months
- Written informed consent of parents/guardian
Who cannot join
- Any clinical or laboratory evidence of hepatic or pancreatic insufficiency.
- Laboratory results drawn within 14 days prior to start of study drug demonstrating:
- Liver transaminases (AST, ALT), lipase, amylase: > 1.5 x ULN White Blood Cell Count: < 3 Neutropenia: <1 Platelet: <100K Hematocrit: <30, persisting over a 30-day period
- Serious illness requiring systemic treatment and/or hospitalization within two weeks prior to study entry.
- Use of medications or supplements within 30 days of study enrollment that interfere with VPA or carnitine metabolism; that increase the potential risks of VPA or carnitine; or that are hypothesized to have a beneficial effect in SMA animal models or human neuromuscular disorders, including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatinine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, or agents anticipated to increase or decrease muscle strength or agents with presumed histone deacetylase (HDAC) inhibition.
- Infants who have participated in a treatment trial for SMA within 30 days of study entry or who will become enrollees in any other treatment trial during the course of this study.
- Unwillingness to travel for study assessments.
- Coexisting medical conditions that contradict use of VPA/carnitine or travel to and from study site.
Trial locations and contacts
8 sites in 3 countries.
8 sites in 3 countries
United States6 sites
Johns Hopkins University
Baltimore, Maryland, 21287
Ohio State University Medical Center, Dept. of Neurology
Columbus, Ohio, 43210
Children's Hospital of Michigan
Detroit, Michigan, 48201
Duke University Medical Center
Durham, North Carolina, 27710
University of Wisconsin Children's Hospital
Madison, Wisconsin, 53792-9988
University of Utah/Primary Children's Medical Center
Salt Lake City, Utah, 84132
About this study
Official title: Phase I/II Trial of Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy Type I (CARNI-VAL Type I)
This is a multi-center trial to test safety and evaluate early treatment intervention with valproic acid and carnitine in moderating SMA symptoms of Type I infants.
Read the detailed description
Spinal muscular atrophy (SMA) is a genetic disorder that results in severe muscle weakness. It is one of the most common conditions causing muscle weakness in children. Patients with SMA most often develop weakness as babies or young children. Most people with SMA gradually lose muscle strength and abilities over time. Babies with the severe infantile form of SMA, SMA type I, usually lose abilities and strength quickly over a few weeks or months.
Valproic acid (VPA) is a medicine that has been used for many years to treat patients with epilepsy. Recent research suggests that VPA may be able to upregulate expression of a backup copy of the SMN gene in SMA patient cell lines. In addition, some preliminary data suggests it may prolong survival in animal models of SMA. Because VPA can deplete carnitine in children with SMA Type I, carnitine is added to help prevent possible toxicity.
In this multi-center trial, we will evaluate the effects of VPA/carnitine on infants with SMA type I. A variety of outcome measures, including assessment of safety, will be performed at each study visit to follow the course of the disease. The protocol includes two baseline visits over a period of two weeks, two clinical assessments on medication at 3 and 6 months, and then 6 months additional followup via telephone. Total duration of the study will be approximately 12 months.
- Conditions
- Spinal Muscular Atrophy Type I
- Being tested
- Valproic Acid and Levocarnitine
- Keywords
- Spinal Muscular Atrophy, SMA, Valproic Acid
- Medical subject headings
- Spinal Muscular Atrophies of Childhood, Muscular Atrophy, Spinal
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Valproic Acid and LevocarnitineDrug
Drug: Valproic Acid and Levocarnitine; syrup; dosage is by weight
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | All patients will receive VPA and carnitine. Receives: Drug: Valproic Acid and Levocarnitine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Laboratory Safety Data
Measured: -2 weeks, + 2 weeks, 3 months, 6 months
Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures)
Measured: -2 weeks, time 0, 3 months, 6 months
Secondary outcomes (6)
Time to Death or Ventilator Dependence (Defined as >16 Hours/Day)
Measured: monthly
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS)
Measured: time 0, and monthly for 12 months
Functional Motor Assessments: TIMPSI Scores
Measured: -2 weeks, time 0, 3 months, 6 months
Quantitative SMN mRNA and Protein Measures
Measured: -2 weeks, time 0 , 3 months, or 6 months
Maximum Ulnar CMAP Amplitude/Area and MUNE
Measured: -2 weeks, time 0, 3 months, 6 months
Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content
Measured: -2 weeks or time 0, 3 months, 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2008 (estimated)
- Study startApr 2008
- Primary completionMay 2012
- Study completionJun 2012
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.
- Publications (42)Papers the sponsor has linked to this study.
- Other trials for Spinal Muscular Atrophy Type IStudies of the same condition, open and under way.
- More trials run by University of UtahThe sponsor's other registered studies.
- 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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Utah
- Sponsor type
- University, hospital or other
- Collaborators
- Families of Spinal Muscular Atrophy, Leadiant Biosciences, Inc.
- Responsible party
- Principal investigator, Kathryn Swoboda, University of Utah
- Investigators
- Kathryn Swoboda, M.D., Principal investigator, University of UtahSandra P Reyna, M.D., Study director, Families of Spinal Muscular Atrophy
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00661453
- Sponsor's protocol ID
- 25409
- Other IDs
- IND 79276
- Status last verified
- Jun 2015
- First submitted
- 14 Apr 2008
- Last updated
- 15 Jun 2015
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Brahe C, Bertini E. Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med (Berl). 1996 Oct;74(10):555-62. doi: 10.1007/s001090050059.
PubMed 8912176Roberts DF, Chavez J, Court SD. The genetic component in child mortality. Arch Dis Child. 1970 Feb;45(239):33-8. doi: 10.1136/adc.45.239.33.
PubMed 4245389Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978 Dec;15(6):409-13. doi: 10.1136/jmg.15.6.409.
PubMed 745211Czeizel A, Hamula J. A hungarian study on Werdnig-Hoffmann disease. J Med Genet. 1989 Dec;26(12):761-3. doi: 10.1136/jmg.26.12.761.
PubMed 2614795Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1(1):19-29. doi: 10.1016/0960-8966(91)90039-u.
PubMed 1822774Merlini L, Stagni SB, Marri E, Granata C. Epidemiology of neuromuscular disorders in the under-20 population in Bologna Province, Italy. Neuromuscul Disord. 1992;2(3):197-200. doi: 10.1016/0960-8966(92)90006-r.
PubMed 1483045Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26;1(8174):919-22. doi: 10.1016/s0140-6736(80)90847-8.
PubMed 6103267Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002 Mar;25(3):445-7. doi: 10.1002/mus.10050.
PubMed 11870724Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP, Bromberg MB. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.
PubMed 15852397Crawford TO. From enigmatic to problematic: the new molecular genetics of childhood spinal muscular atrophy. Neurology. 1996 Feb;46(2):335-40. doi: 10.1212/wnl.46.2.335. No abstract available.
PubMed 8614490Gilliam TC, Brzustowicz LM, Castilla LH, Lehner T, Penchaszadeh GK, Daniels RJ, Byth BC, Knowles J, Hislop JE, Shapira Y, et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature. 1990 Jun 28;345(6278):823-5. doi: 10.1038/345823a0.
PubMed 1972783Melki J, Lefebvre S, Burglen L, Burlet P, Clermont O, Millasseau P, Reboullet S, Benichou B, Zeviani M, Le Paslier D, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science. 1994 Jun 3;264(5164):1474-7. doi: 10.1126/science.7910982.
PubMed 7910982Monani UR, Lorson CL, Parsons DW, Prior TW, Androphy EJ, Burghes AH, McPherson JD. A single nucleotide difference that alters splicing patterns distinguishes the SMA gene SMN1 from the copy gene SMN2. Hum Mol Genet. 1999 Jul;8(7):1177-83. doi: 10.1093/hmg/8.7.1177.
PubMed 10369862Campbell L, Potter A, Ignatius J, Dubowitz V, Davies K. Genomic variation and gene conversion in spinal muscular atrophy: implications for disease process and clinical phenotype. Am J Hum Genet. 1997 Jul;61(1):40-50. doi: 10.1086/513886.
PubMed 9245983Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munnich A, Dreyfuss G, Melki J. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997 Jul;16(3):265-9. doi: 10.1038/ng0797-265.
PubMed 9207792
Study at a glance
From the registry record, last updated by the sponsor on 15 Jun 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I/II Trial of Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy Type I (CARNI-VAL Type I)
- ClinicalTrials.gov ID
- NCT00661453
- Acronym / sponsor ID
- 25409
- Conditions
- Spinal Muscular Atrophy Type I
- Keywords
- Spinal Muscular Atrophy, SMA, Valproic Acid
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- University of UtahUniversity, hospital or other
- Collaborators
- Families of Spinal Muscular Atrophy, Leadiant Biosciences, Inc.
- Study start
- Apr 2008
- Primary completion
- May 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 18 Apr 2008 (estimated)
- Results
- Posted 15 Jun 2015
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a multi-center trial to test safety and evaluate early treatment intervention with valproic acid and carnitine in moderating SMA symptoms of Type I infants.
Detailed description
Spinal muscular atrophy (SMA) is a genetic disorder that results in severe muscle weakness. It is one of the most common conditions causing muscle weakness in children. Patients with SMA most often develop weakness as babies or young children. Most people with SMA gradually lose muscle strength and abilities over time. Babies with the severe infantile form of SMA, SMA type I, usually lose abilities and strength quickly over a few weeks or months.
Valproic acid (VPA) is a medicine that has been used for many years to treat patients with epilepsy. Recent research suggests that VPA may be able to upregulate expression of a backup copy of the SMN gene in SMA patient cell lines. In addition, some preliminary data suggests it may prolong survival in animal models of SMA. Because VPA can deplete carnitine in children with SMA Type I, carnitine is added to help prevent possible toxicity.
In this multi-center trial, we will evaluate the effects of VPA/carnitine on infants with SMA type I. A variety of outcome measures, including assessment of safety, will be performed at each study visit to follow the course of the disease. The protocol includes two baseline visits over a period of two weeks, two clinical assessments on medication at 3 and 6 months, and then 6 months additional followup via telephone. Total duration of the study will be approximately 12 months.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Valproic Acid and LevocarnitineAll patients will receive VPA and carnitine. |
Who may qualify
- Ages
- 2 weeks to 12 months
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (4 listed)
- Laboratory documentation of SMN mutation/deletion consistent with a genetic diagnosis of SMA
- Clinical diagnosis of SMA type I
- Age 2 weeks to 12 months
- Written informed consent of parents/guardian
Key exclusion criteria (8 listed)
- Any clinical or laboratory evidence of hepatic or pancreatic insufficiency.
- Laboratory results drawn within 14 days prior to start of study drug demonstrating:
- Liver transaminases (AST, ALT), lipase, amylase: > 1.5 x ULN White Blood Cell Count: < 3 Neutropenia: <1 Platelet: <100K Hematocrit: <30, persisting over a 30-day period
- Serious illness requiring systemic treatment and/or hospitalization within two weeks prior to study entry.
- Use of medications or supplements within 30 days of study enrollment that interfere with VPA or carnitine metabolism; that increase the potential risks of VPA or carnitine; or that are hypothesized to have a beneficial effect in SMA animal models or human neuromuscular disorders, including riluzole, valproic acid, hydroxyurea, oral use of albuterol, sodium phenylbutyrate, butyrate derivatives, creatinine, growth hormone, anabolic steroids, probenecid, oral or parenteral use of corticosteroids at entry, or agents anticipated to increase or decrease muscle strength or agents with presumed histone deacetylase (HDAC) inhibition.
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 |
|---|---|---|
| Valproic Acid and LevocarnitineDrug: Valproic Acid and Levocarnitine; syrup; dosage is by weight | Drug | 1 |
Primary outcome
Laboratory Safety Data
Time frame: -2 weeks, + 2 weeks, 3 months, 6 months
Anthropometric Measures of Nutritional Status (Body Mass Index [BMI] Z-scores, Weight for Length Ratios, Lean/Fat Mass Via DEXA, Growth Parameters, and Triceps Skinfold Measures)
Time frame: -2 weeks, time 0, 3 months, 6 months
6 secondary outcomes
Time to Death or Ventilator Dependence (Defined as >16 Hours/Day)
Time frame: monthly
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS)
Time frame: time 0, and monthly for 12 months
Functional Motor Assessments: TIMPSI Scores
Time frame: -2 weeks, time 0, 3 months, 6 months
Quantitative SMN mRNA and Protein Measures
Time frame: -2 weeks, time 0 , 3 months, or 6 months
Maximum Ulnar CMAP Amplitude/Area and MUNE
Time frame: -2 weeks, time 0, 3 months, 6 months
Whole Body DEXA Scanning for Lean Body Mass and Total Bone Mineral Density/ Content
Time frame: -2 weeks or time 0, 3 months, 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jun 2015.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 8912176Brahe C, Bertini E. Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med (Berl). 1996 Oct;74(10):555-62. doi: 10.1007/s001090050059.
- Background: PubMed 4245389Roberts DF, Chavez J, Court SD. The genetic component in child mortality. Arch Dis Child. 1970 Feb;45(239):33-8. doi: 10.1136/adc.45.239.33.
- Background: PubMed 745211Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978 Dec;15(6):409-13. doi: 10.1136/jmg.15.6.409.
- Background: PubMed 2614795Czeizel A, Hamula J. A hungarian study on Werdnig-Hoffmann disease. J Med Genet. 1989 Dec;26(12):761-3. doi: 10.1136/jmg.26.12.761.
- Background: PubMed 1822774Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1(1):19-29. doi: 10.1016/0960-8966(91)90039-u.
- Background: PubMed 1483045Merlini L, Stagni SB, Marri E, Granata C. Epidemiology of neuromuscular disorders in the under-20 population in Bologna Province, Italy. Neuromuscul Disord. 1992;2(3):197-200. doi: 10.1016/0960-8966(92)90006-r.
- Background: PubMed 6103267Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26;1(8174):919-22. doi: 10.1016/s0140-6736(80)90847-8.
- Background: PubMed 11870724Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002 Mar;25(3):445-7. doi: 10.1002/mus.10050.
- Background: PubMed 15852397Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, Reyna SP, Bromberg MB. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005 May;57(5):704-12. doi: 10.1002/ana.20473.
- Background: PubMed 8614490Crawford TO. From enigmatic to problematic: the new molecular genetics of childhood spinal muscular atrophy. Neurology. 1996 Feb;46(2):335-40. doi: 10.1212/wnl.46.2.335. No abstract available.
- Background: PubMed 1972783Gilliam TC, Brzustowicz LM, Castilla LH, Lehner T, Penchaszadeh GK, Daniels RJ, Byth BC, Knowles J, Hislop JE, Shapira Y, et al. Genetic homogeneity between acute and chronic forms of spinal muscular atrophy. Nature. 1990 Jun 28;345(6278):823-5. doi: 10.1038/345823a0.
- Background: PubMed 7910982Melki J, Lefebvre S, Burglen L, Burlet P, Clermont O, Millasseau P, Reboullet S, Benichou B, Zeviani M, Le Paslier D, et al. De novo and inherited deletions of the 5q13 region in spinal muscular atrophies. Science. 1994 Jun 3;264(5164):1474-7. doi: 10.1126/science.7910982.
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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.
Kathryn Swoboda, M.D. principal investigator
University of Utah
Sandra P Reyna, M.D. study director
Families of Spinal Muscular Atrophy
8 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Valproic Acid and Levocarnitine in people with Spinal Muscular Atrophy Type I, run by University of Utah at 8 sites in 3 countries.
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 4 inclusion and 8 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: finished, as of the sponsor's last update on 15 Jun 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Canada, Germany. 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 15 Jun 2015). 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?
Laboratory Safety Data (time frame: -2 weeks, + 2 weeks, 3 months, 6 months). The study lists 2 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 NCT00661453, which also lists 42 linked publications.
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 15 Jun 2015.