Trial record 6 of 42 for: "Spinal muscular atrophy"

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CARNIVAL Type I: Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy (SMA) Type I

This study has been completed.

Sponsor:

Collaborators:

Families of Spinal Muscular Atrophy

Sigma Tau Pharmaceuticals, Inc.

Information provided by (Responsible Party):

Kathryn Swoboda, University of Utah

ClinicalTrials.gov Identifier:

NCT00661453

First received: April 14, 2008

Last updated: November 5, 2012

Last verified: November 2012

History of Changes

Purpose

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.

Condition	Intervention	Phase
Spinal Muscular Atrophy Type I	Drug: Valproic Acid and Levocarnitine	Phase 1 Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Phase I/II Trial of Valproic Acid and Carnitine in Infants With Spinal Muscular Atrophy Type I (CARNI-VAL Type I)

Resource links provided by NLM:

Genetics Home Reference related topics: spinal muscular atrophy spinal muscular atrophy with respiratory distress type 1

MedlinePlus related topics: Spinal Muscular Atrophy

Drug Information available for: Valproic acid Carnitine Levocarnitine Valproate sodium Divalproex sodium

U.S. FDA Resources

Further study details as provided by University of Utah:

Primary Outcome Measures:

Laboratory safety data [ Time Frame: -2 weeks, + 2 weeks, 3 months, 6 months ] [ Designated as safety issue: Yes ]
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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Time to death or ventilator dependence (defined as >16 hours/day) [ Time Frame: monthly ] [ Designated as safety issue: Yes ]
Primary Caregiver Functional Rating Scale for SMA Type I Subjects (PCFRS) [ Time Frame: time 0, and monthly for 12 months ] [ Designated as safety issue: No ]
Functional motor assessments: TIMPSI scores [ Time Frame: -2 weeks, time 0, 3 months, 6 months ] [ Designated as safety issue: No ]
Quantitative SMN mRNA and protein measures [ Time Frame: -2 weeks, time 0 , 3 months, or 6 months ] [ Designated as safety issue: No ]
Maximum Ulnar CMAP amplitude/area and MUNE [ Time Frame: -2 weeks, time 0, 3 months, 6 months ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: Yes ]

Enrollment:	40
Study Start Date:	April 2008
Study Completion Date:	June 2012
Primary Completion Date:	May 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 All patients will receive VPA and carnitine.	Drug: Valproic Acid and Levocarnitine Drug: Valproic Acid and Levocarnitine; syrup; dosage is by weight

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.

Eligibility

Ages Eligible for Study:	up to 12 Months
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00661453

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, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
United States, Ohio
Ohio State University Medical Center, Dept. of Neurology
Columbus, Ohio, United States, 43210
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
Germany
Klinikum der Universität zu Köln
Cologne, Germany, 50924

Sponsors and Collaborators

University of Utah

Families of Spinal Muscular Atrophy

Sigma Tau Pharmaceuticals, Inc.

Investigators

Principal Investigator:	Kathryn Swoboda, M.D.	University of Utah
Study Director:	Sandra P Reyna, M.D.	Families of Spinal Muscular Atrophy

More Information

Additional Information:

Related Info 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.

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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.

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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.

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Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol. 1991 Jan;6(1):7-14. Review.

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[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.

American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002 Aug 15;166(4):518-624. No abstract available.

Responsible Party:	Kathryn Swoboda, Associate Professor, Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah
ClinicalTrials.gov Identifier:	NCT00661453 History of Changes
Other Study ID Numbers:	25409, IND 79276
Study First Received:	April 14, 2008
Last Updated:	November 5, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by University of Utah:

Spinal Muscular Atrophy
SMA
Valproic Acid

Additional relevant MeSH terms:

Spinal Muscular Atrophies of Childhood
Muscular Atrophy
Muscular Atrophy, Spinal
Atrophy
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathological Conditions, Anatomical
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases
Heredodegenerative Disorders, Nervous System

Genetic Diseases, Inborn
Carnitine
Valproic Acid
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Anticonvulsants
Central Nervous System Agents
Therapeutic Uses
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents

ClinicalTrials.gov processed this record on May 19, 2013

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