Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy

Multi-center Phase II Trial of Valproic Acid and Carnitine in Patients With Spinal Muscular Atrophy (SMA CARNI-VAL Trial)

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.

Study Overview

• Status: Completed
• Conditions: Spinal Muscular Atrophy
• Intervention / Treatment: Drug: Placebo; Drug: Valproic Acid and Levocarnitine

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 Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Hospital Sainte-Justine
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital of Michigan
  • Ohio
    • Columbus, Ohio, United States, 43210-1228
      • Ohio State University
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah/Primary Children's Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-9988
      • University of Wisconsin Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 17 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / 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: Placebo; Drug: Valproic Acid and Levocarnitine; VPA,sprinkle cap; Levocarnitine, syrup; dosage is by weight; Other Names: Depakote; Carnitor; VPA
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; Carnitor; VPA
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; Carnitor; VPA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety Labs	Participants will have labs drawn regularly to maintain appropriate dosing and monitor liver function	-4 wks, 0, 2 wks, 3 mo, 6 mo, 9 mo, 12 mo for safety labs; throughout for AEs
Efficacy, Measured Through Motor Function Assessments		-4wks, 0, 3 mo, 6 mo, 12 mo
Modified Hammersmith Change From Baseline to 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.	0 months, 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative Assessment of SMN mRNA From Blood Samples		-4wks or 0, 3 mo, 6 mo, 12 mo
Peds QL™ Assessment: Parental Version (All), Child Versions (> 5yrs)		-4wks, 0, 3mo, 6mo, 12mo
Max CMAP Amplitude (Mean)	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
Max CMAP Amplitude Median	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
Ulnar MUNE		-4 wks, 0, 3 mo, 6 mo, 12 mo
Growth and Vital Sign Parameters		-4 wks, 0, 3mo, 6mo, 12mo
Nutritional Status		-4 wks, 0, 3mo, 6mo, 12mo
DEXA		0, 6mo, 12mo
Max CMAP Area (Mean)	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)
Max CMAP Area (Median)	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.	1 month prior to official enrollment, beginning of study (0 months), 6 months, 12 months (data point not available)

Collaborators and Investigators

• Sponsor: University of Utah
• Collaborators: Abbott; Leadiant Biosciences, Inc.; Families of Spinal Muscular Atrophy
• Investigators: Principal Investigator: Kathryn J Swoboda, M.D., University of Utah/Primary Children's Medical Center

Publications and helpful links

General Publications

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• 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. doi: 10.1002/ana.20473.
• Crawford TO. From enigmatic to problematic: the new molecular genetics of childhood spinal muscular atrophy. Neurology. 1996 Feb;46(2):335-40. doi: 10.1212/wnl.46.2.335. 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. doi: 10.1038/345823a0.
• 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. doi: 10.1126/science.7910982.
• 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. doi: 10.1093/hmg/8.7.1177.
• 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. doi: 10.1086/513886.
• 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. doi: 10.1093/hmg/9.3.333. Erratum In: Hum Mol Genet. 2007 Nov 1;16(21):2648. Rossol, W [corrected to Rossoll, W].
• 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. doi: 10.1086/338627. 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. doi: 10.1097/00125817-200201000-00004.
• 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. doi: 10.1016/s0092-8674(00)80368-2.
• 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. doi: 10.1073/pnas.171105098.
• 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. doi: 10.1093/hmg/10.24.2841.
• 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. doi: 10.1093/hmg/ddg256. 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. doi: 10.1038/sj.ejhg.5201102.
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• 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. doi: 10.1016/s0022-3476(94)70218-7.
• 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. doi: 10.1006/bbrc.1994.2523.
• 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. doi: 10.2174/1389201033489829.
• Coulter DL. Carnitine deficiency: a possible mechanism for valproate hepatotoxicity. Lancet. 1984 Mar 24;1(8378):689. doi: 10.1016/s0140-6736(84)92209-8. No abstract available.
• Coulter DL. Carnitine, valproate, and toxicity. J Child Neurol. 1991 Jan;6(1):7-14. doi: 10.1177/088307389100600102.
• 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
• Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995 Sep;152(3):1107-36. doi: 10.1164/ajrccm.152.3.7663792. No abstract available.
• 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. doi: 10.1371/journal.pone.0021296. 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):e12140. doi: 10.1371/journal.pone.0012140.

Helpful Links

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Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (ACTUAL): November 1, 2007
• Study Completion (ACTUAL): November 1, 2007

Study Registration Dates

• First Submitted: September 23, 2005
• First Submitted That Met QC Criteria: September 23, 2005
• First Posted (ESTIMATE): September 27, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): September 26, 2011
• Last Update Submitted That Met QC Criteria: September 22, 2011
• Last Verified: September 1, 2011

More Information

Terms related to this study

• Keywords: Spinal Muscular Atrophy (SMA); SMA Type 2; SMA Type 3
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Spinal Cord Diseases; Motor Neuron Disease; Muscular Atrophy; Atrophy; Muscular Atrophy, Spinal; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: 13698