Study of Safety and Dosing Effect on SMN Levels of Valproic Acid (VPA) in Patients With Spinal Muscular Atrophy

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT00374075
• Collaborator: Families of Spinal Muscular Atrophy (Other), Leadiant Biosciences, Inc. (Industry), Abbott (Industry)
• Enrollment: 42
• Location: 1
• Duration (Months): 29
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This is an open label phase I/II clinical trial to assess safety, tolerability and potential effect on SMN mRNA and protein in vivo of a compound in which preliminary evidence supports a potential effect on SMN levels in vitro.

Condition or Disease	Intervention/Treatment	Phase
Spinal Muscular Atrophy	Drug: Valproic Acid	Phase 1

Detailed Description

This is an open label phase I/II trial of valproic acid in 40 SMA subjects > 2 years of age with severe, intermediate, and mild phenotypes. Primary outcome measures includes laboratory and physical examination assessments to monitor effects on liver, hematologic, metabolic and nutritional status. Secondary outcomes includes measures of gross motor function; electrophysiologic measures of denervation; DEXA estimates of body composition, bone mineral density and content; measures of pulmonary function; and quantitative SMN mRNA and protein levels in blood cells. Subjects will need 2-3 baseline visits over a 3 -6 month period prior to enrollment. Follow-up visits will be scheduled at 3, 6 and 12 months on treatment.

Study Design

• Study Type: Interventional
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: In Vivo Study of Safety, Tolerability and Dosing Effect on SMN mRNA and Protein Levels of Valproic Acid in Patients With Spinal Muscular Atrophy
• Study Start Date: Sep 1, 2003
• Study Completion Date: Feb 1, 2006

Outcome Measures

Primary Outcome Measures

1. To assess safety and tolerability of VPA in SMA patients greater than 2 years of age []

Secondary Outcome Measures

1. To look for a potential in vivo effect of VPA on SMN mRNA in patient blood cells at routinely used clinical doses []

2. Measures of gross motor function []

3. Electrophysiologic measures of denervation []

4. DEXA estimates of body composition, bone mineral density and content []

5. Measures of pulmonary function []

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have a diagnosis of SMA, confirmed by genetic testing

• Only patients 2 years of age and older at enrollment will be eligible

Exclusion Criteria:

• Patients taking any medications with known hepatotoxicity, congenital metabolic disorders or on multiple anticonvulsant medications

• Patients taking medications which may interact with VPA

• Patients on ventilatory support for more than 16 hours per day

• Patients currently enrolled in other treatment trials

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Utah/Primary Children's Medical Center	Salt Lake City	Utah	United States	84132

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• "Click here for more information about this study"

Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Bromberg MB, Swoboda KJ. Motor unit number estimation in infants and children with spinal muscular atrophy. Muscle Nerve. 2002 Mar;25(3):445-7.
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• 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.
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• 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.
• 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.
• 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.
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• 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.
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• 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.
• 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.
• 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.
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• 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.
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• Rebouche CJ, Engel AG. Carnitine metabolism and deficiency syndromes. Mayo Clin Proc. 1983 Aug;58(8):533-40. Review.
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• Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995 Sep;152(3):1107-36.
• 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.
• 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.
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• 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.
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• Responsible Party: Kathryn Swoboda, M.D., University of Utah
• ClinicalTrials.gov Identifier: NCT00374075
• Other Study ID Numbers: 11893
• First Posted: Sep 8, 2006
• Last Update Posted: Aug 23, 2016
• Last Verified: Aug 1, 2016

• Keywords provided by Kathryn Swoboda, M.D., University of Utah: Spinal Muscular Atrophy (SMA); Valproic Acid
• Additional relevant MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy; Valproic Acid

Study Results

No Results Posted as of Aug 23, 2016