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Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
This study has been completed.
Sponsors and Collaborators: University of Utah
Families of Spinal Muscular Atrophy
Sigma Tau Pharmaceuticals, Inc.
Abbott
Information provided by: University of Utah
ClinicalTrials.gov Identifier: NCT00227266
  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
 Phase II

Genetics Home Reference related topics: spinal muscular atrophy
MedlinePlus related topics: Spinal Muscular Atrophy
Drug Information available for: Divalproex sodium Valproate Sodium Valproic acid Carnitine
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Crossover Assignment, Efficacy Study
Official Title: Multi-Center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)

Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Safety (including Tolerability), measured through safety labs and parent reports [ Time Frame: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs ] [ Designated as safety issue: Yes ]
  • Efficacy, measured through motor function assessments [ Time Frame: -4wks, 0, 3 mo, 6 mo, 12 mo ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Quantitative assessment of SMN mRNA from blood samples [ Time Frame: -4wks or 0, 3 mo, 6 mo, 12 mo ] [ Designated as safety issue: No ]
  • Peds QL™ assessment: parental version (all), child versions (> 5yrs) [ Time Frame: -4wks, 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • Max CMAP amplitude/area [ Time Frame: -4wks, 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • Ulnar MUNE [ Time Frame: -4 wks, 0, 3 mo, 6 mo, 12 mo ] [ Designated as safety issue: Yes ]
  • Growth and vital sign parameters [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • Nutritional Status [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • DEXA [ Time Frame: 0, 6mo, 12mo ] [ Designated as safety issue: Yes ]
  • Pulmonary Function for pts 5 years+ [ Time Frame: 0, 3mo, 6mo, 12mo ] [ Designated as safety issue: Yes ]

Enrollment: 90
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
Cohort 1a: Placebo Comparator
For six months, Cohort 1 pts are randomized into placebo or treatment. After 6 months, all pts are on treatment. Cohort 2 pts are on open-label treatment throughout
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Cohort 1b: Active Comparator
For six months, Cohort 1 pts are randomized into placebo or treatment. After 6 months, all pts are on treatment. Cohort 2 pts are on open-label treatment throughout.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight
Cohort 2: Experimental
For six months, Cohort 1 pts are randomized into placebo or treatment. After 6 months, all pts are on treatment. Cohort 2 pts are on open-label treatment throughout.
Drug: Valproic Acid and Levocarnitine
VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight

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

Ages Eligible for Study:   2 Years to 17 Years
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: 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
Sigma Tau Pharmaceuticals, Inc.
Abbott
Investigators
Principal Investigator: Kathryn J Swoboda, M.D. University of Utah/Primary Children's Medical Center
  More Information

"Click here for more information about this study"  This link exits the ClinicalTrials.gov site

Publications:
Brahe C, Bertini E. Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med. 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. No abstract available.
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. No abstract available.
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, 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.
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, Rossol 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.
Feldkotter 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.
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.
Bohmer T, Rydning A, Solberg HE. Carnitine levels in human serum in health and disease. Clin Chim Acta. 1974 Nov 20;57(1):55-61. No abstract available.
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. No abstract available.
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. No abstract available.
Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol. 1991 Jan;6(1):7-14. Review.
Scriver C, Beautet A, Sly W, Valle D. The Metabolic Basis of Inherited Disease. New York: McGraw Hill, 1989
Schaub J, Van Hoof F, Vis H. Inborn Errors of Metabolism. New York: Raven Press, 1991
[No authors listed] Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995 Sep;152(3):1107-36. No abstract available.
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Responsible Party: University of Utah ( Kathryn J. Swoboda, M.D., Associate Professor, Pediatric Neurology )
Study ID Numbers: 13698
Study First Received: September 23, 2005
Last Updated: December 23, 2007
ClinicalTrials.gov Identifier: NCT00227266  
Health Authority: United States: Food and Drug Administration

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

Study placed in the following topic categories:
Pathological Conditions, Anatomical
Spinal Cord Diseases
Spinal muscular atrophy
Central Nervous System Diseases
Degenerative motor system disease
Neurodegenerative Diseases
Valproic Acid
Motor neuron disease
Progressive spinal muscular atrophy
 Signs and Symptoms
Neuromuscular Diseases
Muscular Atrophy, Spinal
Neurologic Manifestations
Atrophy
Motor Neuron Disease
Carnitine
Muscular Atrophy

Additional relevant MeSH terms:
Neuromuscular Manifestations
Neurotransmitter Agents
Vitamin B Complex
Tranquilizing Agents
Molecular Mechanisms of Pharmacological Action
Growth Substances
Nervous System Diseases
Physiological Effects of Drugs
Psychotropic Drugs
Central Nervous System Depressants
 Enzyme Inhibitors
Antimanic Agents
Pharmacologic Actions
Vitamins
Therapeutic Uses
GABA Agents
Micronutrients
Central Nervous System Agents
Anticonvulsants

ClinicalTrials.gov processed this record on January 16, 2009



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