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Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy
This study has been completed.
Study NCT00227266   Information provided by University of Utah

First Received on September 23, 2005.   Last Updated on September 22, 2011   History of Changes
Results First Received: March 19, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Crossover Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Spinal Muscular Atrophy
Interventions: Drug: Valproic Acid and Levocarnitine
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subject's were recruited during the periods of September 2005 to September 2006 across the United States.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Cohort 1a Sitters Placebo Then 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.
Cohort 1b Sitters 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 in the liquid form.
Cohort 2 Standers and Walkers - 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 in the liquid form.

Participant Flow:   Overall Study
    Cohort 1a Sitters Placebo Then Treatment     Cohort 1b Sitters Treatment     Cohort 2 Standers and Walkers - Treatment  
STARTED     31     30     33  
COMPLETED     30     30     29  
NOT COMPLETED     1     0     4  
Withdrawal by Subject                 0                 0                 1  
Protocol Violation                 1                 0                 1  
Excessive weight gain                 0                 0                 2  



  Baseline Characteristics
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Reporting Groups
  Description
Cohort 1a Sitters Placebo Then 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.
Cohort 1b Sitters 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 in the liquid form.
Cohort 2 Standers and Walkers - 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 in the liquid form.

Baseline Measures
    Cohort 1a Sitters Placebo Then Treatment     Cohort 1b Sitters Treatment     Cohort 2 Standers and Walkers - Treatment     Total  
Number of Participants  
[units: participants]
 		  31     30     33     94  
Age  
[units: participants]
 		       
<=18 years     31     30     33     94  
Between 18 and 65 years     0     0     0     0  
>=65 years     0     0     0     0  
Age  
[units: years]
Mean ± Standard Deviation 		  4.4  ± 1.9     4.3  ± 2.1     7.3  ± 3.7     5.4  ± 3.0  
Gender  
[units: participants]
 		       
Female     11     17     11     39  
Male     20     13     22     55  
Ethnicity (NIH/OMB)  
[units: Participants]
 		       
Hispanic or Latino     2     1     0     3  
Not Hispanic or Latino     29     27     30     86  
Unknown or Not Reported     0     2     3     5  
Race (NIH/OMB)  
[units: Participants]
 		       
American Indian or Alaska Native     0     0     0     0  
Asian     1     2     1     4  
Native Hawaiian or Other Pacific Islander     0     0     0     0  
Black or African American     1     0     0     1  
White     26     25     29     80  
More than one race     0     0     0     0  
Unknown or Not Reported     3     3     3     9  
Region of Enrollment  
[units: participants]
 		       
United States     25     26     29     80  
Canada     6     4     4     14  



  Outcome Measures
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1.  Primary:   Modified Hammersmith Change From Baseline to 6 Months   [ Time Frame: 0 months, 6 months ]
  Show Outcome Measure 1

2.  Secondary:   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) ]
  Show Outcome Measure 2

3.  Secondary:   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) ]
  Show Outcome Measure 3

4.  Secondary:   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) ]
  Show Outcome Measure 4

5.  Secondary:   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) ]
  Show Outcome Measure 5

6.  Post-Hoc:   Modified Hammersmith Extend Baseline   [ Time Frame: 1 month prior to enrollment, at enrollment (0 months) ]
  Show Outcome Measure 6

7.  Primary:   Safety Labs   [ Time Frame: -4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   Yes

8.  Primary:   Efficacy, Measured Through Motor Function Assessments   [ Time Frame: -4wks, 0, 3 mo, 6 mo, 12 mo ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   Yes

9.  Secondary:   Quantitative Assessment of SMN mRNA From Blood Samples   [ Time Frame: -4wks or 0, 3 mo, 6 mo, 12 mo ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   No

10.  Secondary:   Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)   [ Time Frame: -4wks, 0, 3mo, 6mo, 12mo ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   Yes

11.  Secondary:   Ulnar MUNE   [ Time Frame: -4 wks, 0, 3 mo, 6 mo, 12 mo ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   Yes

12.  Secondary:   Growth and Vital Sign Parameters   [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   Yes

13.  Secondary:   Nutritional Status   [ Time Frame: -4 wks, 0, 3mo, 6mo, 12mo ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   Yes

14.  Secondary:   DEXA   [ Time Frame: 0, 6mo, 12mo ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   Yes


  Serious Adverse Events
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  Other Adverse Events
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.  


Results Point of Contact:  
Name/Title: Sandra Reyna, M.D.
Organization: University of Utah
phone: 801-581-3551
e-mail: sreyna@genetics.utah.edu


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.
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.

Publications automatically indexed to this study:
Kissel JT, Scott CB, Reyna SP, Crawford TO, Simard LR, Krosschell KJ, Acsadi G, Elsheik B, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson S, Maczulski JA, Bromberg MB, Chan GM, Swoboda KJ; Project Cure Spinal Muscular Atrophy Investigators' Network. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS One. 2011;6(7):e21296. Epub 2011 Jul 6.
Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, Krosschell KJ, Acsadi G, Elsheik B, Schroth MK, D'Anjou G, LaSalle B, Prior TW, Sorenson SL, Maczulski JA, Bromberg MB, Chan GM, Kissel JT; Project Cure Spinal Muscular Atrophy Investigators Network. SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010 Aug 19;5(8)


Responsible Party: Kathryn Swoboda, University of Utah
ClinicalTrials.gov Identifier: NCT00227266     History of Changes
Other Study ID Numbers: 13698
Study First Received: September 23, 2005
Results First Received: March 19, 2010
Last Updated: September 22, 2011
Health Authority: United States: Food and Drug Administration





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