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Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00227266
First Posted: September 27, 2005
Last Update Posted: September 26, 2011
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Families of Spinal Muscular Atrophy
Leadiant Biosciences, Inc.
Abbott
Information provided by (Responsible Party):
Kathryn Swoboda, University of Utah
  Purpose
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.

Condition Intervention Phase
Spinal Muscular Atrophy Drug: Valproic Acid and Levocarnitine Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)

Resource links provided by NLM:


Further study details as provided by Kathryn Swoboda, University of Utah:

Primary Outcome Measures:
  • Safety Labs [ Time Frame: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs ]
    Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function

  • Efficacy, Measured Through Motor Function Assessments [ Time Frame: -4wks, 0, 3 mo, 6 mo, 12 mo ]
  • Modified Hammersmith Change From Baseline to 6 Months [ Time Frame: 0 months, 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.


Secondary Outcome Measures:
  • Quantitative Assessment of SMN mRNA From Blood Samples [ Time Frame: -4wks or 0, 3 mo, 6 mo, 12 mo ]
  • Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs) [ Time Frame: -4wks, 0, 3mo, 6mo, 12mo ]
  • Max CMAP Amplitude (Mean) [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ]
    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.

  • Max CMAP Amplitude Median [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ]
    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.

  • Ulnar MUNE [ Time Frame: -4 wks, 0, 3 mo, 6 mo, 12 mo ]
  • Growth and Vital Sign Parameters [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
  • Nutritional Status [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
  • DEXA [ Time Frame: 0, 6mo, 12mo ]
  • Max CMAP Area (Mean) [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ]
    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.

  • Max CMAP Area (Median) [ Time Frame: 1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available) ]
    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.


Enrollment: 94
Study Start Date: September 2005
Study Completion Date: November 2007
Primary Completion Date: November 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Cohort 1a
Patients 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.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Other Names:
  • Depakote
  • VPA
  • Carnitor
Drug: Placebo
Active Comparator: Cohort 1b
Cohort 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.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Other Names:
  • Depakote
  • VPA
  • Carnitor
Experimental: Cohort 2
Cohort 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.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Other Names:
  • Depakote
  • VPA
  • Carnitor

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.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   2 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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.
  • 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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00227266


Locations
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Michigan
Children's Hospital of Michigan
Detroit, Michigan, United States, 48201
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210-1228
United States, Utah
University of Utah/Primary Children's Medical Center
Salt Lake City, Utah, United States, 84132
United States, Wisconsin
University of Wisconsin Children's Hospital
Madison, Wisconsin, United States, 53792-9988
Canada, Quebec
Hospital Sainte-Justine
Montreal, Quebec, Canada, H3T 1C5
Sponsors and Collaborators
University of Utah
Families of Spinal Muscular Atrophy
Leadiant Biosciences, Inc.
Abbott
Investigators
Principal Investigator: Kathryn J Swoboda, M.D. University of Utah/Primary Children's Medical Center
  More Information

Additional Information:
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. Review.
Roberts DF, Chavez J, Court SD. The genetic component in child mortality. Arch Dis Child. 1970 Feb;45(239):33-8.
Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978 Dec;15(6):409-13.
Czeizel A, Hamula J. A hungarian study on Werdnig-Hoffmann disease. J Med Genet. 1989 Dec;26(12):761-3.
Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1(1):19-29. Review.
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.
Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26;1(8174):919-22.
Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002 Mar;25(3):445-7.
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.
Crawford TO. From enigmatic to problematic: the new molecular genetics of childhood spinal muscular atrophy. Neurology. 1996 Feb;46(2):335-40. Review.
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.
Melki J, Lefebvre S, Burglen L, Burlet P, Clermont O, Millasseau P, Reboullet S, Bénichou 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.
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.
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.
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.
Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S, Schrank B, Rossoll W, Prior TW, Morris GE, Burghes AH. The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(-/-) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet. 2000 Feb 12;9(3):333-9. Erratum in: Hum Mol Genet. 2007 Nov 1;16(21):2648. Rossol, W [corrected to Rossoll, W].
Feldkötter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet. 2002 Feb;70(2):358-68. Epub 2001 Dec 21.
Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, Wirth B, Burghes AH, Prior TW. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002 Jan-Feb;4(1):20-6. doi: 10.1097/00125817-200201000-00004.
Fischer U, Liu Q, Dreyfuss G. The SMN-SIP1 complex has an essential role in spliceosomal snRNP biogenesis. Cell. 1997 Sep 19;90(6):1023-9.
Chang JG, Hsieh-Li HM, Jong YJ, Wang NM, Tsai CH, Li H. Treatment of spinal muscular atrophy by sodium butyrate. Proc Natl Acad Sci U S A. 2001 Aug 14;98(17):9808-13.
Andreassi C, Jarecki J, Zhou J, Coovert DD, Monani UR, Chen X, Whitney M, Pollok B, Zhang M, Androphy E, Burghes AH. Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients. Hum Mol Genet. 2001 Nov 15;10(24):2841-9.
Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet. 2003 Oct 1;12(19):2481-9. Epub 2003 Jul 29.
Andreassi C, Angelozzi C, Tiziano FD, Vitali T, De Vincenzi E, Boninsegna A, Villanova M, Bertini E, Pini A, Neri G, Brahe C. Phenylbutyrate increases SMN expression in vitro: relevance for treatment of spinal muscular atrophy. Eur J Hum Genet. 2004 Jan;12(1):59-65.
Böhmer T, Rydning A, Solberg HE. Carnitine levels in human serum in health and disease. Clin Chim Acta. 1974 Nov 20;57(1):55-61.
Brooks H, Goldberg L, Holland R, Klein M, Sanzari N, DeFelice S. Carnitine-induced effects on cardiac and peripheral hemodynamics. J Clin Pharmacol. 1977 Oct;17(10 Pt 1):561-8.
Christiansen RZ, Bremer J. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim Biophys Acta. 1976 Nov 2;448(4):562-77.
Lindstedt S, Lindstedt G. Distribution and Excretion of Carnitine in the Rat. Acta. Chem. Scand. 1961;15:701-702
Rebouche CJ, Engel AG. Carnitine metabolism and deficiency syndromes. Mayo Clin Proc. 1983 Aug;58(8):533-40. Review.
Rebouche CJ, Paulson DJ. Carnitine metabolism and function in humans. Annu Rev Nutr. 1986;6:41-66. Review.
Igarashi N, Sato T, Kyouya S. Secondary carnitine deficiency in handicapped patients receiving valproic acid and/or elemental diet. Acta Paediatr Jpn. 1990 Apr;32(2):139-45.
Thurston JH, Hauhart RE. Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice: possible clinical significance. Pediatr Res. 1992 Apr;31(4 Pt 1):419-23.
Tein I, DiMauro S, Xie ZW, De Vivo DC. Valproic acid impairs carnitine uptake in cultured human skin fibroblasts. An in vitro model for the pathogenesis of valproic acid-associated carnitine deficiency. Pediatr Res. 1993 Sep;34(3):281-7.
Melegh B, Pap M, Morava E, Molnar D, Dani M, Kurucz J. Carnitine-dependent changes of metabolic fuel consumption during long-term treatment with valproic acid. J Pediatr. 1994 Aug;125(2):317-21.
Tein I, Xie ZW. Reversal of valproic acid-associated impairment of carnitine uptake in cultured human skin fibroblasts. Biochem Biophys Res Commun. 1994 Oct 28;204(2):753-8.
Van Wouwe JP. Carnitine deficiency during valproic acid treatment. Int J Vitam Nutr Res. 1995;65(3):211-4.
Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit--when supplementation is necessary? Curr Pharm Biotechnol. 2003 Jun;4(3):211-9. Review.
Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet. 1984 Mar 24;1(8378):689.
Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol. 1991 Jan;6(1):7-14. Review.
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Kathryn Swoboda, Associate Professor, Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah
ClinicalTrials.gov Identifier: NCT00227266     History of Changes
Other Study ID Numbers: 13698
First Submitted: September 23, 2005
First Posted: September 27, 2005
Results First Submitted: March 19, 2010
Results First Posted: May 3, 2011
Last Update Posted: September 26, 2011
Last Verified: September 2011

Keywords provided by Kathryn Swoboda, University of Utah:
Spinal Muscular Atrophy (SMA)
SMA Type 2
SMA Type 3

Additional relevant MeSH terms:
Atrophy
Muscular Atrophy
Muscular Atrophy, Spinal
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs


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