Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

• Sponsor: University of Utah (Other)
• Overall Status: Completed
• CT.gov ID: NCT00227266
• Collaborator: Families of Spinal Muscular Atrophy (Other), Leadiant Biosciences, Inc. (Industry), Abbott (Industry)
• Enrollment: 94
• Locations: 6
• Arms: 3
• Duration (Months): 26
• Patients Per Site: 15.7
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Spinal Muscular Atrophy	Drug: Valproic Acid and Levocarnitine; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 94 participants
• 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)
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Nov 1, 2007
• Actual Study Completion Date: Nov 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. Safety Labs [-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

2. Efficacy, Measured Through Motor Function Assessments [-4wks, 0, 3 mo, 6 mo, 12 mo]

3. Modified Hammersmith Change From Baseline to 6 Months [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

1. Quantitative Assessment of SMN mRNA From Blood Samples [-4wks or 0, 3 mo, 6 mo, 12 mo]

2. Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs) [-4wks, 0, 3mo, 6mo, 12mo]

3. Max CMAP Amplitude (Mean) [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.

4. Max CMAP Amplitude Median [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.

5. Ulnar MUNE [-4 wks, 0, 3 mo, 6 mo, 12 mo]

6. Growth and Vital Sign Parameters [-4 wks, 0, 3mo, 6mo, 12mo]

7. Nutritional Status [-4 wks, 0, 3mo, 6mo, 12mo]

8. DEXA [0, 6mo, 12mo]

9. Max CMAP Area (Mean) [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.

10. Max CMAP Area (Median) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	Johns Hopkins University	Baltimore	Maryland	United States	21287
2	Children's Hospital of Michigan	Detroit	Michigan	United States	48201
3	Ohio State University	Columbus	Ohio	United States	43210-1228
4	University of Utah/Primary Children's Medical Center	Salt Lake City	Utah	United States	84132
5	University of Wisconsin Children's Hospital	Madison	Wisconsin	United States	53792-9988
6	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

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.
• 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.
• 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.
• 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.
• Christiansen RZ, Bremer J. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim Biophys Acta. 1976 Nov 2;448(4):562-77.
• 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.
• Crawford TO. From enigmatic to problematic: the new molecular genetics of childhood spinal muscular atrophy. Neurology. 1996 Feb;46(2):335-40. Review.
• 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.
• Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit--when supplementation is necessary? Curr Pharm Biotechnol. 2003 Jun;4(3):211-9. Review.
• 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.
• 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.
• 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.
• Lindstedt S, Lindstedt G. Distribution and Excretion of Carnitine in the Rat. Acta. Chem. Scand. 1961;15:701-702
• 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.
• 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.
• 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.
• 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].
• Pearn J. Classification of spinal muscular atrophies. Lancet. 1980 Apr 26;1(8174):919-22.
• Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978 Dec;15(6):409-13.
• 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.
• Roberts DF, Chavez J, Court SD. The genetic component in child mortality. Arch Dis Child. 1970 Feb;45(239):33-8.
• Schaub J, Van Hoof F, Vis H. Inborn Errors of Metabolism. New York: Raven Press, 1991
• Scriver C, Beautet A, Sly W, Valle D. The Metabolic Basis of Inherited Disease. New York: McGraw Hill, 1989
• 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.
• 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.
• 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.
• Van Wouwe JP. Carnitine deficiency during valproic acid treatment. Int J Vitam Nutr Res. 1995;65(3):211-4.

• Responsible Party: Kathryn Swoboda, Associate Professor, Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah
• ClinicalTrials.gov Identifier: NCT00227266
• Other Study ID Numbers: 13698
• First Posted: Sep 27, 2005
• Last Update Posted: Sep 26, 2011
• Last Verified: Sep 1, 2011

• Keywords provided by Kathryn Swoboda, Associate Professor, Neurology and Pediatrics Director, Pediatric Motor Disorders Research Program, University of Utah: Spinal Muscular Atrophy (SMA); SMA Type 2; SMA Type 3
• Additional relevant MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy; Valproic Acid

Study Results

Participant Flow

Recruitment Details	Subject's were recruited during the periods of September 2005 to September 2006 across the United States.

Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment	Cohort 1b Sitters Treatment	Cohort 2 Standers and Walkers - Treatment
Arm/Group Description	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.	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.	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.
Period Title: Overall Study
STARTED	31	30	33
COMPLETED	30	30	29
NOT COMPLETED	1	0	4

Baseline Characteristics

Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment	Cohort 1b Sitters Treatment	Cohort 2 Standers and Walkers - Treatment	Total
Arm/Group Description	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.	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.	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.	Total of all reporting groups
Overall Participants	31	30	33	94
Age (Count of Participants)
<=18 years	31 100%	30 100%	33 100%	94 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.4 (1.9)	4.3 (2.1)	7.3 (3.7)	5.4 (3.0)
Sex: Female, Male (Count of Participants)
Female	11 35.5%	17 56.7%	11 33.3%	39 41.5%
Male	20 64.5%	13 43.3%	22 66.7%	55 58.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 6.5%	1 3.3%	0 0%	3 3.2%
Not Hispanic or Latino	29 93.5%	27 90%	30 90.9%	86 91.5%
Unknown or Not Reported	0 0%	2 6.7%	3 9.1%	5 5.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 3.2%	2 6.7%	1 3%	4 4.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 3.2%	0 0%	0 0%	1 1.1%
White	26 83.9%	25 83.3%	29 87.9%	80 85.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	3 9.7%	3 10%	3 9.1%	9 9.6%
Region of Enrollment (participants) [Number]
United States	25 80.6%	26 86.7%	29 87.9%	80 85.1%
Canada	6 19.4%	4 13.3%	4 12.1%	14 14.9%

Outcome Measures

1. Primary Outcome

Title	Safety Labs
Description	Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function
Time Frame	-4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

2. Primary Outcome

Title	Efficacy, Measured Through Motor Function Assessments
Time Frame	-4wks, 0, 3 mo, 6 mo, 12 mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Quantitative Assessment of SMN mRNA From Blood Samples
Time Frame	-4wks or 0, 3 mo, 6 mo, 12 mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)
Time Frame	-4wks, 0, 3mo, 6mo, 12mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Max CMAP Amplitude (Mean)
Description	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.
Time Frame	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment	Cohort 1b Sitters Treatment	Cohort 2 Standers and Walkers - Treatment
Arm/Group Description	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.	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.	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.
Measure Participants	23	21	24
Baseline	2.28 (1.55)	2.93 (1.56)	5.52 (2.56)
6 months	2.32 (1.75)	2.37 (1.82)	6.56 (2.99)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment	Cohort 1b Sitters Treatment	Cohort 2 Standers and Walkers - Treatment
Arm/Group Description	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.	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.	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.
Measure Participants	23	21	24
Baseline	1.91	2.2	5.3
6 months	1.44	1.8	5.85

7. Secondary Outcome

Title	Ulnar MUNE
Time Frame	-4 wks, 0, 3 mo, 6 mo, 12 mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Growth and Vital Sign Parameters
Time Frame	-4 wks, 0, 3mo, 6mo, 12mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Nutritional Status
Time Frame	-4 wks, 0, 3mo, 6mo, 12mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Post-Hoc Outcome

Title	Modified Hammersmith Extend Baseline
Description	Baseline Modified Hammersmith Extend testing. The baseline test is the score they receive during their screening visits. This scale ranges from 0 to 56. A higher score indicates a better outcome. This scale is used to assess gross motor abilities of children with SMA in multiple research trials as well as in clinical settings.
Time Frame	1 month prior to enrollment, at enrollment (0 months)

Outcome Measure Data

Analysis Population Description

Analysis was determined per protocol

Arm/Group Title	Cohort 2 Experimental
Arm/Group Description	Patients in cohort 2 (SMA "standers and walkers") will receive VPA + Carnitine treatment for the entire 12 month time period.
Measure Participants	33
Modified Hammersmith Extend at S1 (-4 weeks)	47.0
Modified Hammersmith Extend at S2 (0 weeks)	48.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cohort 1a Sitters Placebo Then Treatment
	Comments	MHFMS-Extend was not normally distributed at p=0.048. Test-retest reliability of MHFMS-Extend measurements from the first (S1) to the second (S2) screening visit was analyzed using Spearman's correlation.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Spearman's correlation
	Comments
Method of Estimation	Estimation Parameter	Spearman's correlation
	Estimated Value	0.93
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	Modified Hammersmith Change From Baseline to 6 Months
Description	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.
Time Frame	0 months, 6 months

Outcome Measure Data

Analysis Population Description

Analysis only pertains to cohort 1a and 1b.

Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment	Cohort 1b Sitters Treatment
Arm/Group Description
Measure Participants	31	30
Baseline visit (0 weeks)	20.0 (9.3)	16.6 (8.7)
6 Month visit (V2)	20.6 (8.1)	16.8 (7.9)
Change from Baseline	0.6 (3.98)	0.2 (2.88)

12. Secondary Outcome

Title	DEXA
Time Frame	0, 6mo, 12mo

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Max CMAP Area (Mean)
Description	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.
Time Frame	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment	Cohort 1b Sitters Treatment	Cohort 2 Standers and Walkers - Treatment
Arm/Group Description	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.	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.	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.
Measure Participants	23	21	24
Baseline	5.46 (5.03)	5.45 (4.23)	14.85 (7.68)
6 months	5.28 (4.49)	5.26 (4.65)	16.26 (7.13)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment	Cohort 1b Sitters Treatment	Cohort 2 Standers and Walkers - Treatment
Arm/Group Description	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.	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.	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.
Measure Participants	23	21	24
Baseline	3.6	4.6	13.65
6 months	3.74	3.4	16.85

Adverse Events

Time Frame	Phase 1 Serious Adverse Events (time period during which placebo (1a) and treatment (1b)were randomly treated): 6 months. And Phase 1 and 2 Adverse Events: 12 months
Arm/Group Title	Cohort 1a Sitters Placebo Then Treatment		Cohort 1b Sitters Treatment		Cohort 2 Standers and Walkers - Treatment
Arm/Group Description	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.		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.		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.
All Cause Mortality
	Cohort 1a Sitters Placebo Then Treatment		Cohort 1b Sitters Treatment		Cohort 2 Standers and Walkers - Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1a Sitters Placebo Then Treatment		Cohort 1b Sitters Treatment		Cohort 2 Standers and Walkers - Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/31 (3.2%)		4/30 (13.3%)		4/33 (12.1%)
Gastrointestinal disorders
Diarrhea	0/31 (0%)		0/30 (0%)		2/33 (6.1%)
Vomiting	0/31 (0%)		1/30 (3.3%)		1/33 (3%)
General disorders
General Disorder	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Infections and infestations
Pneumonitis	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Upper respiratory infection	1/31 (3.2%)		0/30 (0%)		1/33 (3%)
Metabolism and nutrition disorders
Dehydration	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Pneumonia	0/31 (0%)		2/30 (6.7%)		1/33 (3%)
Tachyponea	0/31 (0%)		1/30 (3.3%)		1/33 (3%)
Skin and subcutaneous tissue disorders
Skin Rash	0/31 (0%)		0/30 (0%)		1/33 (3%)
Other (Not Including Serious) Adverse Events
	Cohort 1a Sitters Placebo Then Treatment		Cohort 1b Sitters Treatment		Cohort 2 Standers and Walkers - Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/31 (58.1%)		23/30 (76.7%)		28/33 (84.8%)
Ear and labyrinth disorders
Otorrhoea	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Gastrointestinal disorders
Abdominal Pain Upper	2/31 (6.5%)		3/30 (10%)		7/33 (21.2%)
Constipation	1/31 (3.2%)		0/30 (0%)		1/33 (3%)
Diarrhea	0/31 (0%)		2/30 (6.7%)		1/33 (3%)
Dry Mouth	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Gastroesophagheal Reflux Disease	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Nausea	2/31 (6.5%)		4/30 (13.3%)		2/33 (6.1%)
Vomiting	6/31 (19.4%)		12/30 (40%)		6/33 (18.2%)
General disorders
Fatigue	2/31 (6.5%)		0/30 (0%)		1/33 (3%)
Pyrexia	4/31 (12.9%)		5/30 (16.7%)		7/33 (21.2%)
Immune system disorders
Dermatitis Allergic	3/31 (9.7%)		2/30 (6.7%)		1/33 (3%)
Hypersensitivity	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Multiple Allergies	0/31 (0%)		2/30 (6.7%)		5/33 (15.2%)
Infections and infestations
Bronchitis	0/31 (0%)		1/30 (3.3%)		1/33 (3%)
Croup	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Ear Infection	2/31 (6.5%)		3/30 (10%)		4/33 (12.1%)
Nasopharyngitis	3/31 (9.7%)		3/30 (10%)		0/33 (0%)
Pneumonitis	1/31 (3.2%)		1/30 (3.3%)		0/33 (0%)
Sinusitis	1/31 (3.2%)		1/30 (3.3%)		2/33 (6.1%)
Tinea Infection	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Upper Respiratory Infection	2/31 (6.5%)		1/30 (3.3%)		0/33 (0%)
Urinary Tract Infection	0/31 (0%)		3/30 (10%)		0/33 (0%)
Injury, poisoning and procedural complications
Join Sprain	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Investigations
Oxygen Saturation Decreased	0/31 (0%)		0/30 (0%)		1/33 (3%)
Weight Incresed	4/31 (12.9%)		3/30 (10%)		0/33 (0%)
Metabolism and nutrition disorders
Decreased Appetite	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Dehydration	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Increased Appetite	2/31 (6.5%)		0/30 (0%)		0/33 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Femur Fracture	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Foot Fracture	0/31 (0%)		0/30 (0%)		2/33 (6.1%)
Forearm Fracture	0/31 (0%)		0/30 (0%)		1/33 (3%)
Hand Fracture	0/31 (0%)		0/30 (0%)		1/33 (3%)
Joint Pain	1/31 (3.2%)		1/30 (3.3%)		1/33 (3%)
Muscle Cramp	0/31 (0%)		0/30 (0%)		1/33 (3%)
Pain in Extremity	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Patella Fracture	0/31 (0%)		0/30 (0%)		0/33 (0%)
Nervous system disorders
Agitation	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Headache	1/31 (3.2%)		2/30 (6.7%)		0/33 (0%)
Impulsive Behaviour	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Irritability	2/31 (6.5%)		1/30 (3.3%)		0/33 (0%)
Lethargy	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Tremor	2/31 (6.5%)		0/30 (0%)		0/33 (0%)
Psychiatric disorders
Emotional Disorder of Childhood	2/31 (6.5%)		0/30 (0%)		0/33 (0%)
Renal and urinary disorders
Incontinence	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Increased Urination Frequency	1/31 (3.2%)		0/30 (0%)		0/33 (0%)
Respiratory, thoracic and mediastinal disorders
Chocking Sensation	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Cough	2/31 (6.5%)		7/30 (23.3%)		4/33 (12.1%)
Dyspnea	2/31 (6.5%)		0/30 (0%)		0/33 (0%)
Nasal Congestion	2/31 (6.5%)		1/30 (3.3%)		2/33 (6.1%)
Pharyngeal Pain	1/31 (3.2%)		0/30 (0%)		1/33 (3%)
Pharyngeal Pain	0/31 (0%)		0/30 (0%)		0/33 (0%)
Pneumonia	2/31 (6.5%)		6/30 (20%)		2/33 (6.1%)
Rhinorrhoea	0/31 (0%)		0/30 (0%)		1/33 (3%)
Tachypnoea	0/31 (0%)		1/30 (3.3%)		0/33 (0%)
Skin and subcutaneous tissue disorders
Rash Papular	1/31 (3.2%)		1/30 (3.3%)		0/33 (0%)

Limitations/Caveats

[Not Specified]

More Information

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.