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Spinal Muscular AtrophyPhase 2NCT00227266

Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

A Phase 2 study testing Valproic Acid and Levocarnitine in people with Spinal Muscular Atrophy, run by University of Utah at 6 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This is a multi-center trial to assess safety and efficacy of a combined regimen of oral valproic acid (VPA) and carnitine in patients with Spinal Muscular Atrophy (SMA) 2 to 17 years of age. Cohort 1 is a double-blind placebo-controlled randomized intention to treat protocol for SMA "sitters" 2 - 8 years of age. Read more about this study

Who is it for?
Ages 2 to 17 years
Conditions the study is for
Spinal Muscular Atrophy
What is being tested?
Valproic Acid and Levocarnitine
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
94 participants
Where
6 sitesin 2 countries
Study dates
Sep 2005to Nov 2007
Phase
Phase 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 17 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • Cohort 1
  • Confirmed genetic diagnosis of 5q SMA
  • SMA 2 or non-ambulatory SMA 3: all subjects must be able to sit independently for at least 3 seconds without support
  • Age 2 to 8 years at time of enrollment
  • Cohort 2
  • Confirmed genetic diagnosis of 5q SMA
  • SMA subjects (SMA types 2 or 3) who can stand independently without braces or other support for up to 2 seconds, or walk independently
  • Age 3 to 17 years at time of study enrollment

Who cannot join

  • Cohort 1
  • Need for BiPAP support > 12 hours per day
  • Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
  • Inability to meet study visit requirements or cooperate reliably with functional testing
  • Coexisting medical conditions that contraindicate travel, testing or study medications
  • Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
Show all 17Show fewer
  • Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must go through a washout period of 12 weeks before enrollment into the study
  • Body Mass Index > 90th % for age
  • Cohort 2
  • Spinal rod or fixation for scoliosis or anticipated need within six months of enrollment
  • Inability to meet study visit requirements or cooperate with functional testing
  • Transaminases, amylase or lipase > 3.0 x normal values, WBC < 3.0 or neutropenia < 1.0, platelets < 100 K, or hematocrit < 30 persisting over a 30 day period.
  • Coexisting medical conditions that contraindicate travel, testing or study medications
  • Use of medications or supplements which interfere with valproic acid or carnitine metabolism within 3 months of study enrollment.
  • Current use of either VPA or carnitine. If study subject is taking VPA or carnitine then patient must be go through a washout period of 12 weeks before enrollment in the study.
  • Body Mass Index > 90th % for age
  • Pregnant women/girls, or those intending to try to become pregnant during the course of the study.

Trial locations and contacts

6 sites in 2 countries.

6 sites in 2 countries

United States5 sites

  • Johns Hopkins University

    Baltimore, Maryland, 21287

  • Ohio State University

    Columbus, Ohio, 43210-1228

  • Children's Hospital of Michigan

    Detroit, Michigan, 48201

  • University of Wisconsin Children's Hospital

    Madison, Wisconsin, 53792-9988

  • University of Utah/Primary Children's Medical Center

    Salt Lake City, Utah, 84132

Other trials in United States

Canada1 site

  • Hospital Sainte-Justine

    Montreal, Quebec, H3T 1C5

Other trials in Canada

About this study

Official title: Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)

This is a multi-center trial to assess safety and efficacy of a combined regimen of oral valproic acid (VPA) and carnitine in patients with Spinal Muscular Atrophy (SMA) 2 to 17 years of age. Cohort 1 is a double-blind placebo-controlled randomized intention to treat protocol for SMA "sitters" 2 - 8 years of age. Cohort 2 is an open label protocol for SMA "standers and walkers" 3 - 17 years of age to explore responsiveness of efficacy outcomes. Outcome measures will include blood chemistries, functional testing, pulmonary function testing, electrophysiological evaluations, PedsQL quality of life assessment, quantitative assessments of survival motor neuron (SMN) mRNA from blood samples, growth and vital sign parameters. Six centers will enroll a total of 90 patients.

Read the detailed description

This is a multi-center phase II trial of a combined regimen of oral valproic acid (VPA) and carnitine in patients with Spinal Muscular Atrophy (SMA) 2 to 17 years of age. Cohort 1 is a double-blind placebo-controlled randomized intention to treat protocol for SMA "sitters" 2 - 8 years of age. Subjects will undergo two baseline assessments over 4 to 6 week period, then will be randomized to treatment or placebo for the next six months. All subjects will then be placed on active treatment for the subsequent six month period. Cohort 2 is an open label protocol for SMA "standers and walkers" 3 - 17 years of age to explore responsiveness of efficacy outcomes. Subjects will undergo two baseline assessments over a four to six week period, followed by one year active treatment with VPA and carnitine. Outcome measures are performed every 3 to 6 months, and include blood chemistries, functional testing, pulmonary function testing, electrophysiological evaluations, PedsQL quality of life assessment, quantitative assessments of survival motor neuron (SMN) mRNA from blood samples, growth and vital sign parameters. Six centers will enroll a total of 90 patients.

Being tested
Valproic Acid and Levocarnitine, Placebo
Keywords
Spinal Muscular Atrophy (SMA), SMA Type 2, SMA Type 3
Medical subject headings
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

    Also called Depakote, VPA, Carnitor

    VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight

  • PlaceboDrug

Study groups in NCT00227266
Study groupRoleWhat they receive
Cohort 1aPlacebo comparatorPatients in Cohort 1a - Placebo Comparator, will be on a placebo for 6 months and then will switch to the active treatment. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor or equivalent placebo in the liquid form.
Receives: Drug: Valproic Acid and Levocarnitine; Drug: Placebo
Cohort 1bActive comparatorCohort 1b - Active Comparator will be on treatment throughout the study. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor in the liquid form.
Receives: Drug: Valproic Acid and Levocarnitine
Cohort 2ExperimentalCohort 2 pts are on open-label treatment throughout. Dosage of the VPA will start at 10-20 mg/kg/day divided into two or tree doses. The dose will be adjusted to achieve a therapeutic trough level of 50-120 micrograms/ml. VPA will be given in the form of 125 mg sprinkle capsules. Dosage for Carnitor will be 50 mg/kg/day with a maximum dose of 10000 mg/day divided into two doses. Carnitor elixir comes as 500 mg/5 ml. All subjects will be given Carnitor or equivalent placebo in the liquid form.
Receives: Drug: Valproic Acid and Levocarnitine

What is being measured

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

  1. Safety Labs

    Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function

    Measured: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs

  2. Efficacy, Measured Through Motor Function Assessments

    Measured: -4wks, 0, 3 mo, 6 mo, 12 mo

  3. Modified Hammersmith Change From Baseline to 6 Months

    Comparison of Modified Hammersmith Change from baseline to 6 months. Scores range from 0 to 40. A higher score indicates a better outcome. This scale is used to assess gross motor abilities of non-ambulant children with SMA in multiple research trials as well as in clinical settings.

    Measured: 0 months, 6 months

Secondary outcomes (10)

  1. Quantitative Assessment of SMN mRNA From Blood Samples

    Measured: -4wks or 0, 3 mo, 6 mo, 12 mo

  2. Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)

    Measured: -4wks, 0, 3mo, 6mo, 12mo

  3. Max CMAP Amplitude (Mean)

    The maximum Compound Motor Action Potential (CMAP) is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This is done multiple times, the outcome used is the highest peak, or response observed.

    Measured: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

  4. Max CMAP Amplitude Median

    The maximum Compound Motor Action Potential (CMAP) is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This is done multiple times, the outcome used is the highest peak, or response observed.

    Measured: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

  5. Ulnar MUNE

    Measured: -4 wks, 0, 3 mo, 6 mo, 12 mo

  6. Growth and Vital Sign Parameters

    Measured: -4 wks, 0, 3mo, 6mo, 12mo

  7. Nutritional Status

    Measured: -4 wks, 0, 3mo, 6mo, 12mo

  8. DEXA

    Measured: 0, 6mo, 12mo

  9. Max CMAP Area (Mean)

    The maximum Compound Motor Action Potential (CMAP) area is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This procedure is repeated multiple times. The maximum area is the response that results in the largest area under the response curve.

    Measured: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

  10. Max CMAP Area (Median)

    The maximum Compound Motor Action Potential (CMAP) area is a measurement obtained through EMG testing that is associated with disease progression. In this study, we measure the maximum CMAP by stimulating one nerve in the hand and measuring the response of the muscle. This procedure is repeated multiple times. The maximum area is the response that results in the largest area under the response curve.

    Measured: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

Timeline

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

  1. First posted27 Sep 2005 (estimated)
  2. Study startSep 2005
  3. Primary completionNov 2007
  4. Study completionNov 2007

Resources

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
94 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00227266
Sponsor's protocol ID
13698
Status last verified
Sep 2011
First submitted
23 Sep 2005
Last updated
19 Mar 2025
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 8912176

  • Roberts 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 4245389

  • Pearn 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 745211

  • Czeizel 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 2614795

  • Emery 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 1822774

  • Merlini 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 1483045

  • Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26;1(8174):919-22. doi: 10.1016/s0140-6736(80)90847-8.

    PubMed 6103267

  • Bromberg 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 11870724

  • Swoboda 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 15852397

  • Crawford 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 8614490

  • Gilliam 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 1972783

  • Melki 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 7910982

  • Monani 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 10369862

  • Campbell 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 9245983

  • Lefebvre 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

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Valproic Acid and Levocarnitine in people with Spinal Muscular Atrophy, run by University of Utah at 6 sites in 2 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 8 inclusion and 17 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 19 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States, Canada. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

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 3 May 2011). 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?

Safety Labs (time frame: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs). 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 NCT00227266, which also lists 44 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 19 Mar 2025.

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