SPINAL MUSCULAR ATROPHY FUNCTIONAL COMPOSITE SCORE: A FUNCTIONAL MEASURE IN SPINAL MUSCULAR ATROPHY JACQUELINE MONTES, PT, EdD,1,2‡ ALLAN M. GLANZMAN, PT, DPT,3‡ ELENA S. MAZZONE, PT,4‡ WILLIAM B. MARTENS, BA,5 SALLY DUNAWAY, PT, DPT,1 AMY PASTERNAK, PT, DPT,6 SUSAN O RILEY, PT, DPT,6 JANET QUIGLEY, PT, DPT,6 SHREE PANDYA, MS, PT,5 DARRYL C DE VIVO, MD,1 PETRA KAUFMANN, MD, MSc,1 CLAUDIA A. CHIRIBOGA, MD, MPH,1 RICHARD S. FINKEL, MD,7 GIHAN I. TENNEKOON, MBBS,8 BASIL T. DARRAS, MD,6 MARIKA PANE, MD,4 EUGENIO MERCURI, MD, PhD,4 and MICHAEL P. MCDERMOTT, PhD,5,9 for the Pediatric Neuromuscular Clinical Research Network, Muscle Study Group, SMA Europe 1

Department of Neurology, Columbia University Medical Center, 180 Ft. Washington Avenue, Fifth Floor, New York, New York 10032, USA 2 Department of Rehabilitation and Regenerative Medicine, Columbia University Medical Center, New York, New York, USA 3 Department of Physical Therapy, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA 4 Department of Paediatric Neurology, Catholic University, Rome, Italy 5 Department of Neurology, University of Rochester, Rochester, New York, USA 6 Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA 7 Division of Neurology, Nemours Children’s Hospital, Orlando, Florida, USA 8 Division of Neurology, Children’s Hospital of Philadelphia and Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 9 Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA Accepted 25 March 2015 ABSTRACT: Introduction: With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). Methods: Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale—Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. Results: The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. Conclusions: This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients. Muscle Nerve 52: 942–947, 2015

Spinal muscular atrophy (SMA) is an autosomal recessive disease with an estimated birth incidence of 1:6,000 to 1:11,000.1,2 The phenotypic presentation of disease includes weakness, contractures, and functional limitations ranging from severe in infancy to a presentation later in childhood or adulthood that is more slowly progressive, with Abbreviations: 6MWT, 6-minute walk test; HMFSE, Hammersmith Functional Motor Scale—Expanded; SMA, spinal muscular atrophy; SMA-FC, Spinal Muscular Atrophy—Functional Composite; ULM, Upper Limb Module Key words: clinical trial; composite score; motor function; outcome measure; SMA; spinal muscular atrophy This study was funded by the Spinal Muscular Atrophy Foundation and SMA Europe The first 3 authors (J.M., A.M.G., and E.S.M.) contributed equally to this study. Correspondence to: J. Montes; e-mail: [email protected] C 2015 Wiley Periodicals, Inc. V

Published online 3 April 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mus.24670

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periods of stability that can span many years. SMA is characterized by a permissive effect of the SMN2 gene when the SMN1 gene has sustained a diseasecausing mutation. The broad clinical presentation reflects the variable copynumber and functionality of the SMN2 gene.3 Functional scales representing various aspects of motor performance have been used frequently as outcome measures in SMA clinical trials and to aid in the description of the natural history of SMA patients.4–6 Some of these scales have been proposed as primary outcome measures for clinical trials, because they reflect important functional skills and have been validated both by their sensitivity to decline over time and by correlation with other markers of disease in cross-sectional studies.7–14 In other pediatric neuromuscular disorders, composite measures that include evaluation of motor and sensory function and strength have been developed.15,16 In SMA, disease-specific assessments have been developed to evaluate motor function in individuals who achieve the ability to sit unsupported but never walk (type 2) and in those who walk without support (type 3). However, the phenotypic spectrum of SMA types 2 and 3 is continuous. Type 2 patients can lose the ability to sit and type 3 patients can lose the ability to walk. Motor function scales have been expanded to address these transitions and evaluate sitters and walkers on the same scale17; however, there may be a lack of sensitivity at the extreme ends of the scales. The range of function in SMA is broad. The weakest type 2 patients have lost the ability to sit unsupported and present with only minimal hand function, whereas, on the other end of the phenotypic MUSCLE & NERVE

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spectrum, the stronger and less affected type 3 patients present with limited endurance and difficulty navigating stairs and rising from the floor. To assess skills relevant to weaker children, an upper limb assessment was developed to specifically address upper extremity function.13 In addition, in the last few years, there has been increasing evidence in several neuromuscular disorders that the 6-minute walk test (6MWT) provides reliable information on endurance and gait that is complementary to the activities assessed with functional scales.14,18–20 Because SMA is a rare disorder, inclusion of the broadest range of phenotypes in clinical trials facilitates recruitment. Alternatively, some clinical trials may target a more homogeneous subset of SMA patients to minimize variability among participants. Inclusion of a heterogeneous population requires an outcome measure that quantifies the entire range of motor function to accommodate a broad phenotypic population and captures change at the extremes of function. Typically, a gross motor function assessment is used as the primary assessment, and upper limb and walking assessments are included as separate modules in appropriate patients. Because it is difficult to predict which aspect of motor function is most amenable to treatment, inclusion of all aspects of motor function is critical. A composite score that includes the broadest spectrum of clinically meaningful activities could amplify the aggregate strengths of each assessment. However, if aspects of motor function that are not amenable to treatment are included in the composite score, there is a risk of reduced sensitivity and clarity of interpretation. A composite score is going to be most helpful if all or most aspects of motor function are amenable to treatment. We have chosen 3 instruments that have been designed to measure various components of motor skill with the goal of combining them to provide an assessment that covers the multidimensional spectrum of skills in patients with SMA types 2 and 3. We hypothesize that a composite score of global function based on these instruments will discriminate among SMA patients ranging broadly from the weakest type 2 patient to the strongest type 3 patient. Such a score may allow detection of clinically meaningful change over a wider phenotypic range in clinical trials of promising therapeutic interventions. METHODS Participants.

Data from 3 sources were used in this investigation: 2 prospective, ongoing natural history studies (Pediatric Neuromuscular Clinical Research Network and Rome); and baseline data SMA Functional Composite Score

from a clinical trial (ISIS 396443-CS2 Study). Training was performed independently for all 3 research consortia. Clinical evaluators from all groups used the same procedure manuals and were trained annually at in-person meetings. At these meetings, interrater reliability was established, and clinical evaluators were considered eligible to perform the assessments. One hundred twenty-six participants (55 females and 71 males) with type 2 or type 3 SMA having complete data on the Hammersmith Functional Motor Scale—Expanded (HFMSE), the Upper Limb Module (ULM), and the 6MWT were included.13,14,17 In the natural history studies, data were obtained from the first visit at which all 3 evaluations were available. Sixty-seven participants had type 2 SMA, and 59 had type 3 SMA, with 47 able to walk independently at the time of evaluation. All participants were evaluated using the HFMSE, and all ambulatory participants were administered the 6MWT. Twenty-seven ambulatory participants were tested on the ULM, and all achieved the maximum score of 18; therefore, for the purposes of analysis, participants who were non-ambulatory were given a score of 0 on the 6MWT total distance, and all ambulatory participants were given a score of 18 on the ULM. Assessments. Hammersmith Functional Motor Scale—Expanded. The HFMSE is a 33-item scale designed for use in SMA types 2 and 3. It is associated with minimal patient burden, requires only standard equipment, and is completed in 72,400 specimens. Eur J Hum Genet 2012;20:27–32. Lefebvre S, B€ urglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 1995;80:155–165. Kaufmann P, McDermott MP, Darras BT, Finkel RS, Sproule DM, Kang PB, et al. Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology 2012;79:1889–1897. Pane M, Staccioli S, Messina S, D’Amico A, Pallicioni M, Mazzone ES, et al. Daily salbutamol in young patients with SMA type II. Neuromuscul Disord 2008;18:536–540. Kissel JT, Elsheikh B, King WM, Freimer M, Scott CB, Kolb SJ, et al. SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy. Muscle Nerve 2014;49:187–192. Main M, Kairon H, Mercuri E, Muntoni F. The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation. Eur J Paediatr Neurol 2003;7:155–159. Glanzman AM, Mazzone E, Main M, Pellicioni M, Wood J, Swoboda KJ, et al. The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND): test development and reliability. Neuromuscul Disord 2010;20:155–161. Glanzman AM, O’Hagen JM, McDermott MP, Martens WB, Flickinger J, Riley S, et al. Validation of the Expanded Hammersmith Functional Motor Scale in spinal muscular atrophy type II and III. J Child Neurol 2011;26:1499–1507. Nelson L, Owens H, Hynan LS, Iannaccone ST. The gross motor function measure is a valid and sensitive outcome measure for spinal muscular atrophy. Neuromuscul Disord 2006;16:374–380. Krosschell KJ, Maczulski JA, Crawford TO, Scott C, Swoboda KJ. A modified Hammersmith functional motor scale for use in multicenter research on spinal muscular atrophy. Neuromuscul Disord 2006;16:417–426. Vuillerot C, Payan C, Girardot F, Fermanian J, Iwaz J, B erard C, et al. Responsiveness of the motor function measure in neuromuscular diseases. Arch Phys Med Rehabil 2012;93:2251–2256. Mazzone E, Bianco F, Martinelli D, Glanzman AM, Messina S, De Sanctis R, et al. Assessing upper limb function in nonambulant SMA patients: development of a new module. Neuromuscul Disord 2011; 21:406–412. Montes J, McDermott MP, Martens WB, Dunaway S, Glanzman AM, Riley S, et al. Six-Minute Walk Test demonstrates motor fatigue in spinal muscular atrophy. Neurology 2010;74:833–838. Burns TM, Conaway M, Sanders DB, Composite MG, Group M-QS. The MG Composite: a valid and reliable outcome measure for myasthenia gravis. Neurology 2010;74:1434–1440. Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology 2005;64:1209–1214. O’Hagen JM, Glanzman AM, McDermott MP, Ryan PA, Flickinger J, Quigley J, et al. An expanded version of the Hammersmith Functional Motor Scale for SMA II and III patients. Neuromuscul Disord 2007;17:693–697. Montes J, Dunaway S, Montgomery MJ, Sproule D, Kaufmann P, De Vivo DC, et al. Fatigue leads to gait changes in spinal muscular atrophy. Muscle Nerve 2011;43:485–488. Mazzone ES, Pane M, Sormani MP, Scalise R, Berardinelli A, Messina S, et al. 24 month longitudinal data in ambulant boys with Duchenne muscular dystrophy. PLoS One 2013;8:e52512. McDonald CM, Henricson EK, Abresch RT, Florence JM, Eagle M, Gappmaier E, et al. The 6-minute walk test and other clinical endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve 2013;48:357–368. Solway S, Brooks D, Lacasse Y, Thomas S. A qualitative systematic overview of the measurement properties of functional walk tests used in the cardiorespiratory domain. Chest 2001;119:256– 270. ATS Statement. Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–117. Montes J, Blumenschine M, Dunaway S, Alters S, Engelstat K, Rao AK, et al. Weakness and fatigue in diverse neuromuscular diseases. J Child Neurol 2013;28:1277–1283. Mazzone E, Bianco F, Main M, van den Hauwe M, Ash M, de Vries R, et al. Six minute walk test in type III spinal muscular atrophy: a 12-month longitudinal study. Neuromuscul Disord 2013;23:624– 628. Geiger R, Strasak A, Treml B, H€ ogler W, St€ uben K, Strasak A, et al. Six-minute walk test in children and adolescents. J Pediatr 2007;150: 395–399. Gibbons WJ, Fruchter N, Sloan S, Levy RD. Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years. J Cardiopulm Rehabil 2001;21:87–93.

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27. Cano SJ, Mayhew A, Glanzman AM, Krosschell KJ, Swoboda KJ, Main M, et al. Rasch analysis of clinical outcome measures in spinal muscular atrophy. Muscle Nerve 2014;49:422–430. 28. Mazzone ES, Mayhew A, Main M, Montes J, Ramsey D, Scoto M, et al. Old measures and new analysis in non ambulant SMA patients. Neuromuscul Disord 2014;24:905. 29. Sarepta Therapeutics I. 2013. Available at: http://investorrelations.sarepta.com/phoenix.zhtml?c564231&p5irol-newsArticle&ID51875187/.

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30. Lewis RA, McDermott MP, Herrmann DN, Hoke A, Clawson LL, Siskind C, et al. High-dosage ascorbic acid treatment in CharcotMarie-Tooth disease type 1A: results of a randomized, doublemasked, controlled trial. JAMA Neurol 2013;70:981–987. 31. Mayhew A, Mazzone ES, Eagle M, Duong T, Ash M, Decostre V, et al. Development of the Performance of the Upper Limb Module for Duchenne muscular dystrophy. Dev Med Child Neurol 2013;55:1038– 1055.

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Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy.

With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal mu...
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