SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy

John T Kissel, Charles B Scott, Sandra P Reyna, Thomas O Crawford, Louise R Simard, Kristin J Krosschell, Gyula Acsadi, Bakri Elsheik, Mary K Schroth, Guy D'Anjou, Bernard LaSalle, Thomas W Prior, Susan Sorenson, Jo Anne Maczulski, Mark B Bromberg, Gary M Chan, Kathryn J Swoboda, Project Cure Spinal Muscular Atrophy Investigators' Network, John T Kissel, Charles B Scott, Sandra P Reyna, Thomas O Crawford, Louise R Simard, Kristin J Krosschell, Gyula Acsadi, Bakri Elsheik, Mary K Schroth, Guy D'Anjou, Bernard LaSalle, Thomas W Prior, Susan Sorenson, Jo Anne Maczulski, Mark B Bromberg, Gary M Chan, Kathryn J Swoboda, Project Cure Spinal Muscular Atrophy Investigators' Network

Abstract

Background: Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children.

Methods: This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores.

Results: Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful.

Conclusions: This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Inclusion/exclusion criteria for study enrollment.
Figure 1. Inclusion/exclusion criteria for study enrollment.
Figure 2. Consort flow sheet.
Figure 2. Consort flow sheet.
Figure 3. Box Plots of baseline values…
Figure 3. Box Plots of baseline values for Fine Motor Module, Gross Motor Module, and Timed Tests of Function.
The Values on the ordinate refer to seconds for the timed tests, and absolute scores for the motor modules. Δ indicates mean; – indicates median.
Figure 4. Box plot of baseline myometry…
Figure 4. Box plot of baseline myometry data (column 1) and change from baseline (CFB) at 6 months (column 2) and 12 months (column 3).
LE = lower extremity; TE = total myometry; UE = upper extremity. Δ indicates mean; – indicates median.

References

    1. Brahe C, Bertini E. Spinal muscular atrophies: recent insights and impact on molecular diagnosis. J Mol Med. 2006;74:555–562.
    1. Roberts DF, Chavez J, Court SD. The genetic component in child mortality. Arch Dis Child. 1970;45(239):33–38.
    1. Pearn J. Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy. J Med Genet. 1978;15(6):409–413.
    1. Czeizel A, Hamula J. A Hungarian study on Werdnig-Hoffmann disease. J Med Genet. 1989;26:761–763.
    1. Emery AE. Population frequencies of inherited neuromuscular diseases–a world survey. Neuromuscul Disord. 1991;1(1):19–29.
    1. Merlini L, Stagni SB, Marri E, Granata C. Epidemiology of neuromuscular disorders in the under-20 population in Bologna Province, Italy. Neuromuscul Disord. 1992;2:197–200.
    1. Lefebvre S, Burgien L, Reboullet S, Clermont O, Burlet P, et al. Identification and Characterization of a Spinal Muscular Atrophy-determining Gene. Cell. 1995;80:155–165.
    1. Wirth B, Herz M, Wetter A, Moskau S, Hahnen E, et al. Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutation in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling. Am J Hum Genet. 1999;64:1340–1356.
    1. Wan L, Battle DJ, Yong J, Gubitz AK, Kolb SJ, et al. The survival of motor neurons protein determines the capacity for snRNP assembly: biochemical deficiency in spinal muscular atrophy. Mol Cell Biol. 1995;25:5543–5551.
    1. Lorson CL, Hahnen E, Androphy EJ, Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci USA. 1998;96:6307–6311.
    1. Burghes AHM, Beatty CE. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nature Reviews Neuroscience. 2009;10:597–609.
    1. 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;70(2):358–368.
    1. Mailman MD, Heinz JW, Papp AC, Snyder PJ, Sedra MS, et al. Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2. Genet Med. 2002;4:20–26.
    1. Swoboda KJ, Prior TW, Scott CB, McNaught TP, Wride MC, et al. Natural history of denervation in SMA: relation to age, SMN2 copy number, and function. Ann Neurol. 2005;57:704–712.
    1. Wirth B, Brichta L, Schrank B, Lochmüller H, Blick S, et al. Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number. Hum Genet. 2006;119:422–428.
    1. Prior TW, Swoboda KJ, Scott HD, Hejmanowski AQ. Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2. Am J Med Genet A. 2004;130:307–310.
    1. Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, et al. Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet. 1997;1997; 16:265–269.
    1. Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Gen. 2009;85:408–413.
    1. Oprea GE, Krober S, McWhorter ML, Rossoll W, Muller S, et al. Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science. 2008;320:524–527.
    1. Leng Y, Chuang DM. Endogenous α-synuclein is induced by valproic acid through histone deacetylase inhibition and participates in neuroprotection against glutamate-induced excitotoxicity. J Neurosci. 2006;26(28):7502–7512.
    1. van Bergeijk J, Haastert K, Grothe C, Claus P. Valproic acid promotes neurite outgrowth in PC12 cells independent from regulation of the survival of motoneuron protein. Chem Biol Drug Des. 2006;67:244–247.
    1. Sugai F, Yamamoto Y, Miyaguchi K, Zhou Z, Sumi H, et al. Benefit of valproic acid in suppressing disease progression of ALS model mice. Eur J Neurosci. 2004;20:3179–3183.
    1. Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, et al. Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy. Hum Mol Genet. 2003;12:2481–2489.
    1. Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, et al. Valproic acid increases SMN levels in spinal muscular atrophy patient cells. Ann Neurol. 2003;54:647–654.
    1. Brichta L, Holker I, Haug K, Klockgether T, Wirth B. In vivo activation of SMN in spinal muscular atrophy carriers and patients treated with valproate. Ann Neurol. 2006;59:970–975.
    1. Kernochan LE, Russo ML, Woodling NS, Huynh TN, Avila AM, et al. The role of histone acetylation in SMN gene expression. Hum Mol Genet. 2005;14:1171–1182.
    1. Tsai LK, Tsai MS, Lin TB, Hwu WL, Li H. Establishing a standardized therapeutic testing protocol for spinal muscular atrophy. Neurobiol Dis. 2006;24:286–295.
    1. Tsai LK, Tsai MS, Ting CH, Li H. Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice. J Mol Med. 2008;86:1243–1254.
    1. Weihl CC, Connolly AM, Pestronk A. Valproate may improve strength and function in patients with type III/IV spinal muscular atrophy. Neurology. 2006;67:500–501.
    1. Tsai LK, Yang CC, Hwu WL, Li H. Valproic acid treatment in six patients with spinal muscular atrophy. Eur J Neurol. 2007;14:e8–e9.
    1. Swoboda KJ, Scott CB, Reyna SP, Prior T, Chan G, et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS ONE. 2009;4(5):e5268. Epub 2009 May 14.
    1. Swoboda KJ, Scott CB, Crawford TO, Simard LR, Reyna SP, et al. SMA CARNI-VAL Trial part 1: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS One. 2010 (In Press)
    1. Krosschell KJ, Maczulski JA, Crawford TO, Scott C, Swoboda KJ. A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy. Neuromuscul Disord. 2006;16(7):417–26.
    1. Varni JW, Limbers C, Burwinkle TM. Literature review: health-related quality of life measurement in pediatric oncology: hearing the voices of the children. J Ped Psychol. 2007:1–13.
    1. Beenakker EA, van der Hoeven JH, Fock JM, Maurits NM. Reference values of maximum isometric muscle force obtained in 270 children aged 4–16 years by hand-held dynamometry. Neuromuscul Disord. 2001;11(5):441–446.
    1. Merlini L, Mazzone ES, Solari A, Morandi L. Reliability of hand-held dynamometry in spinal muscular atrophy. Muscle Nerve. 2002;26(1):64–70.
    1. Sloan C. Review of the reliability and validity of myometry with children. Phys Occup Ther Pediatr. 2002;22(2):79–93.
    1. Sproule DM, Montes J, Montgomery M, Battista V, Koenigsberger d, et al. Increased fat mass and high incidence of overweitht despite low body mass index in patients with spinal muscular atrophy. Neuromuscul Disord. 2009;19(6):391–396.
    1. Sroule DM, Montes, Dunaway S, Montgomery M, Battista V, et al. Adiposity is increased among high-functioning, non-ambulatory patients with spinal muscular atrophy. Neuromuscul Disord. 2010;20(7):448–452.

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