ARTICLE OPEN ACCESS Assessment of disease progression in dysferlinopathy A 1-year cohort study Ursula Moore, MBBchir, Marni Jacobs, PhD, Meredith K. James, PT, Anna G. Mayhew, PT, PhD, Roberto Fernandez-Torron, MD, Correspondence Jia Feng, MSc, Avital Cnaan, PhD, Michelle Eagle, PT, PhD, Karen Bettinson, MSc, Laura E. Rufibach, PhD, Robert Muni Lofra, PT, Prof. Straub Andrew M. Blamire, PhD, Pierre G. Carlier, MD, PhD, Plavi Mittal, PhD, Linda Pax Lowes, PT, PhD, Lindsay Alfano, DPT, volker.straub@ Kristy Rose, PT, PhD, Tina Duong, MPT, Katherine M. Berry, PT, Elena Montiel-Morillo, PT, Irene Pedrosa-Hernández, PT, newcastle.ac.uk Scott Holsten, PT, Mohammed Sanjak, PT, PhD, Ai Ashida, DPT, Chikako Sakamoto, PT, Takayuki Tateishi, PT, Hiroyuki Yajima, PT, Aurélie Canal, PT, Gwenn Ollivier, PT, Valerie Decostre, PhD, Juan Bosco Mendez, MD, Nieves Sánchez-Aguilera Praxedes, PT, Simone Thiele, PT, Catherine Siener, PT, MHS, Jeanine Shierbecker, PT, Julaine M. Florence, PT, MHS, DPT, Bruno Vandevelde, Brittney DeWolf, PT, DPT, PCS, Meghan Hutchence, BSc, PT, Richard Gee, MPT, Juliana Prügel, PT, Elke Maron, PT, Heather Hilsden, BA, Hanns Lochmüller, MD, Ulrike Grieben, MD, Simone Spuler, MD, Carolina Tesi Rocha, MD, John W. Day, MD, Kristi J. Jones, MD, PhD, Diana X. Bharucha-Goebel, MD, Emmanuelle Salort-Campana, MD, Matthew Harms, MD, Alan Pestronk, MD, Sabine Krause, MD, PhD, Olivia Schreiber-Katz, MD, Maggie C. Walter, MD, MA, Carmen Paradas, MD, PhD, Jean-Yves Hogrel, PhD, Tanya Stojkovic, MD, Shin’ichi Takeda, MD, PhD, Madoka Mori-Yoshimura, MD, PhD, Elena Bravver, MD, Susan Sparks, MD, Jordi Dı́az-Manera, MD, PhD, Luca Bello, MD, PhD, Claudio Semplicini, MD, PhD, Elena Pegoraro, MD, PhD, Jerry R. Mendell, MD, Kate Bushby, MD, and Volker Straub, MD, for the Jain COS Consortium ® Neurology 2019;92:e461-e474. doi:10.1212/WNL.0000000000006858 Abstract Objective To assess the ability of functional measures to detect disease progression in dysferlinopathy over 6 months and 1 year. Methods One hundred ninety-three patients with dysferlinopathy were recruited to the Jain Foundation’s International Clinical Outcome Study for Dysferlinopathy. Baseline, 6-month, and 1-year assessments included adapted North Star Ambulatory Assessment (a-NSAA), Motor Function Measure (MFM-20), timed function tests, 6-minute walk test (6MWT), Brooke scale, Jebsen test, manual muscle testing, and hand-held dynamometry. Patients also completed the ACTIVLIM questionnaire. Change in each measure over 6 months and 1 year was calculated and compared between disease severity (ambulant [mild, moderate, or severe based on a-NSAA score] or nonambulant [unable to complete a 10-meter walk]) and clinical diagnosis. Results The functional a-NSAA test was the most sensitive to deterioration for ambulant patients overall. The a-NSAA score was the most sensitive test in the mild and moderate groups, while the 6MWT was most sensitive in the severe group. The 10-meter walk test was the only test showing significant change across all ambulant severity groups. In non- ambulant patients, the MFM domain 3, wrist flexion strength, and pinch grip were most sensitive. Progression rates did not differ by clinical diagnosis. Power calculations determined that 46 moderately affected patients are required to determine clinical effectiveness for a hypothetical 1-year clinical trial based on the a-NSAA as a clinical endpoint. Conclusion Certain functional outcome measures can detect changes over 6 months and 1 year in dysferlinopathy and potentially be useful in monitoring progression in clinical trials. ClinicalTrials.gov identifier: NCT01676077. From the John Walton Muscular Dystrophy Research Centre (U.M., M.K.J., A.G.M., R.F.-T., M.E., K.B., R.M.L., H.H., H.L., K.B., V.S.), Newcastle University and Newcastle Hospitals NHS Foundation Trust, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Central Parkway, Newcastle Upon Tyne, UK; Center for Translational Science (M.J., J.F., A. Cnaan), Division of Biostatistics and Study Methodology, Cooperative International Neuromuscular Research Group (T.D., B.D.), and Department of Neurology (D.X.B.-G.), Children’s National Health System; Pediatrics, Epidemiology and Biostatistics (M.J., A. Cnaan), George Washington University, Washington, DC; Neuromuscular Area (R.F.-T.), Biodonostia Health Research Institute, Neurology Service, Donostia University Hospital, Donostia-San Sebastian, Spain; Jain Foundation (L.E.R., P.M.), Seattle, WA; Magnetic Resonance Centre (A.M.B.), Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK; AIM & CEA NMR Laboratory (P.G.C.), Institute of Myology, Pitié-Salpêtrière University Hospital, 47-83, Paris, France; Research Institute at Nationwide Children’s Hospital (L.P.L., L.A., K.M.B., J.R.M.), The Ohio State University, Columbus; Institute for Neuroscience and Muscle Research (K.R., M. Hutchence, K.J.J.), Children’s Hospital at Westmead, University of Sydney, Australia; Lucile Salter Packard Children’s Hospital at Stanford (T.D.), 24349, Neurology, Palo Alto, CA; Physical Medicine and Rehabilitation (E.M.-M., I.P.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Neuroscience Institute (S.H., M.S., E.B., S. Sparks), Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, NC; Department of Physical Rehabilitation (A.A., C. Sakamoto, T.T., H.Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Institut de Myologie (A. Canal, G.O., V.D., J.-Y.H., T.S.), AP-HP, GH Pitié-Salpêtrière, Paris, France; Neurorehabilitation Unit (J.B.M.), Rehabilitation Hospital Universitario Virgen del Rocı́o Sevilla; Neurophysiotherapy Department (N.S.-A.P.), Hospital Universitario Virgen del Rocı́o, Seville, Spain; Friedrich-Baur-Institute (S. Thiele, S.K., O.S.-K. M.C.W.), Department of Neurology, Ludwig-Maximilians-University of Munich, Germany; Department of Neurology (C. Siener, J.S., J.M.F., M. Harms, A.P.), Washington University School of Medicine, St. Louis, MO; Centre de Reference des Maladies Neuromusculaires PACA Réunion Rhone Alpes (B.V., E.S.-C.), Hopital de la Timone, Aix-Marseille Université, France; ELAN-PHYSIO (J.P., E.M.), Praxis für Physiotherapie Maron; Charite Muscle Research Unit (U.G., S. Spuler), Experimental and Clinical Research Center, a joint cooperation of the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany; Department of Neurology and Neurological Sciences (C.T.R., J.W.D.), Stanford University School of Medicine, CA; NIH (D.X.B.-G.), Bethesda, MD; Neuromuscular Unit (C.P.), Department of Neurology, Hospital U. Virgen del Rocı́o/Instituto de Biomedicina de Sevilla, Spain; Department of Neurology (S. Takeda, M.M.-Y.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; Centro de Investigación Biomédica en Red en Enfermedades Raras (J.D.-M.); Neuromuscular Disorders Unit (J.D.-M.), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; and Department of Neuroscience (L.B., C. Semplicini, E.P.), University of Padova, Italy. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Jain COS Consortium coinvestigators are listed in the Appendix at the end of the article. The Article Processing Charge was funded by the Jain Foundation. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. e461 Glossary a-NSAA = adapted North Star Ambulatory Assessment; COS = Jain Clinical Outcome Study in Dysferlinopathy; HHD = hand- held dynamometry; LGMD2B = limb girdle muscular dystrophy 2B; MFM = Motor Function Measure; MMT = manual muscle testing; 6MWT = 6-minute walk test; SRM = standardized response mean. Dysferlinopathy is a rare, recessively inherited muscular dys- Standard protocol approvals, registrations, trophy caused by mutations in the DYSF1–4 gene. Potential and patient consents therapies are in development, and some of them have entered The study was initially approved by the following: NRES human clinical trials (NCT02579239, NCT01863004, Committee North East—Newcastle & North Tyneside on NCT02710500). As the development of newly licensed and February 2, 2012 (reference 211/NE/0360/R&D 5918). The emerging treatments for Duchenne muscular dystrophy5,6 study was also approved by ethics review boards in each and spinal muscular atrophy type 17 has shown, proving ef- country. All patients provided written informed consent. The ficacy and satisfying regulators can be difficult in slowly pro- trial was registered at ClinicalTrials.gov (NCT01676077). gressive and varied conditions.8 Functional outcome measures Appropriate powering of a clinical trial requires understanding Clinical assessments were standardized through trainings at of disease progression and responsiveness of various outcome investigator meetings, and all evaluations were performed by measures over time.9 Selection of outcome measures for clinical trained clinicians. Assessments included the adapted North trials in dysferlinopathy is particularly challenging. Dysferlin- Star Ambulatory Assessment (a-NSAA),4 MFM-20, timed opathy is characterized by a range of ages at onset and patterns function tests (timed rise from floor, 10-m walk/run, 4-stair of weakness and severity,4,10 variable rate of progression,4 climb and descend, Timed Up and Go, and the 6-minute walk modifying factors that are not clearly elucidated,10–13 and no test [6MWT]), Brooke Upper Extremity Scale, Jebsen Hand appropriate measures for monitoring progression. While some Function Test, manual muscle testing (MMT), and hand-held measures such as the Motor Function Measure (MFM) have dynamometry (HHD). No assessments have been specifically been shown to be reliable in dysferlinopathy,14 the variability of validated in a dysferlin-specific population. These assessments progression makes it difficult to demonstrate responsiveness in were chosen because of their widespread suitability for limb small cohorts. girdle muscular dystrophy. The MFM-20 was selected over the MFM-32 to reduce patient fatigue and duplication. All The Jain Clinical Outcome Study in Dysferlinopathy (COS) assessments were attempted for ambulant patients. Non- aims to address these difficulties by characterizing the clinical, ambulant patients did not complete the a-NSAA or biochemical, and radiologic parameters of 209 patients with ambulation-based timed function tests. dysferlinopathy over 3 years. Muscle strength was assessed with an 11-point scale for This article summarizes findings from a planned interim MMT.4 The best of 3 attempts for HHD was used for analysis. analysis of baseline, 6-month, and year 1 data to determine whether disease progression is detectable and which measures Functional ability was assessed with qualitative scales and are most able to detect this progress. We propose a power timed tests. Total scores were calculated for the a-NSAA15 in calculation using the most sensitive measures to determine ambulant patients, and the MFM-20 and the Brooke scale a potential clinical trial cohort required to demonstrate sig- were calculated in all patients. The MFM-20 was also analyzed nificant functional change. on the basis of its 3 components: D1 (standing and transfers), D2 (axial and proximal), and D3 (distal). Any patient with an incomplete score was excluded from analysis for that test. To Methods account for patients who became nonambulant or unable to complete timed function tests due to disease progression, The COS study timed test values were converted to velocity measures (either The COS study is an international collaborative study of meter per second or task per second), with a 0-m/s velocity patients with a genetic and/or protein assay–confirmed di- assigned for the first instance a patient was unable to complete agnosis of dysferlinopathy.4 Screening, baseline, 6-month, and the test. 1-year visits took place between October 2012 and March 2016. One hundred ninety-seven of the original 209 recruited Patient perception of progression patients completed a baseline visit. Of the original 209 The ACTIVLIM questionnaire, a Rasch-built patient- patients, 7 did not meet inclusion criteria, and 5 chose not to reported outcome measure,16 was used to capture patient- continue past the screening visit (figure 1). Full inclusion and reported functional ability. The total score, out of a maximum exclusion criteria, the study protocol, and patient de- of 36, was compared between visits. A higher score indicates mographics have been described previously.4 greater functional ability. e462 Neurology | Volume 92, Number 5 | January 29, 2019 Neurology.org/N Figure 1 Flowchart of patient numbers at each visit Number of patients who completed each assessment (baseline, 6 months, and 12 months) and how many of them were used for each analysis window. Statistical analysis and SDs of the functional measure that demonstrated most Statistical analysis was completed with SAS 9.3 (SAS Institute change over time. For this analysis, the a-NSAA was used, Inc, Cary, NC). Mean and median change scores were cal- which limited estimates to ambulant patients only. Sample culated for each test between baseline and 6 months, 6 sizes needed to evaluate a variety of expected drug effects were months and year 1, and baseline and year 1. Data from some calculated for reference, including halting of disease pro- visits were excluded if the visit occurred ±2 months outside gression (i.e., assuming mean progression estimates from the the scheduled appointment date. A majority of functional current sample among untreated and no progression among outcome measures were not normally distributed; thus, treated patients), reflective of potential protein-restoring ge- comparisons between baseline and follow-up time points netic therapies. An α level of 0.05, 80% power, and a treated- were conducted with the Wilcoxon signed rank-sum test and to-untreated ratio of 1:1 were assumed. For comparison with standardized response mean (SRM).17 A comparison was a widely used measure in muscular dystrophy, sample sizes made between the performance of patients with the most were also calculated on the basis of the 6MWT. common clinical diagnoses of limb girdle muscular dystrophy 2B (LGMD2B) and Miyoshi myopathy with Kruskal-Wallis Data availability statement test with Steel-Dwass-Critchlow-Fligner correction for mul- Deidentified cohort level data can be requested. All protocol tiple comparisons.18 assessments are in the public domain apart from the a-NSAA, which can be requested from the steering group (publication Nonambulant patients (unable to walk 10 meters with usual in draft). The statistical plan is detailed above. All data for this orthotics and walking aids) were compared to 3 categories of natural history study will be stored for at least 5 years after the ambulant patients: ambulation affected severely, moderately, end of the study. Data can be requested by all interested or mildly. Using patients’ a-NSAA scores at baseline, we de- stakeholders for clinical research and trial planning. Data fined ambulant severity categories based on a clinical im- requests are reviewed by the Jain COS Steering Committee, pression of disease severity and binomial distribution of who can be contacted via the corresponding author. a-NSAA scores, with cut points of 0 to 10 (severe disease severity), 11 to 40 (moderate disease severity), and 41+ (mild disease severity). The lower cut point was based on the end of Results the first a-NSAA peak, and the high cut point was placed at the Of the initial 197 eligible enrolled patients, 3 patients with- start of the second peak, with the wide spread in between drew after baseline, and 1 withdrew after 6 months. This is representing a plateau between peaks. Significance was de- summarized in figure 1. Patients included in this analysis were fined as p ≤ 0.05. Results are expressed as median change between 11 and 86 years of age at baseline and were at all (range) and p value. stages of disease progression, from asymptomatic hyper- CKemia to nonambulant. Power analyses to support a hypothetical future clinical trial were conducted to estimate the sample size required to detect Functional outcome measures significant statistical differences in progression over the course Functional outcome measure results are summarized in tables of 1 year with PASS 14 software. Because change scores were 1 and 2, figure 2, and table e-1 (available from Dryad, doi.org/ normally distributed, calculations used mean change scores 10.5061/dryad.tp08m60). Some of the assessments, by their Neurology.org/N Neurology | Volume 92, Number 5 | January 29, 2019 e463 e464 Neurology | Volume 92, Number 5 | January 29, 2019 Table 1 Change in scores of functional tests from baseline to 6 months, 6 months to 1 year, and baseline to 1 year for the a-NSAA, MFM, Jebsen, Brooke, patient-reported ACTIVLIM, and 6-minute walk tests Change in score, baseline–6 mo Change in score, 6 mo–1 y Change in score, baseline–1 y Baseline median Median Outcome measure score n Median (range) p Value n Median (range) p Value n (range) p Value SRM Total North Star scorea 19 130 −1.00 (−19.0 to 19.0) <0.0001a 119 0.00 (−14.0 to 5.00) 0.025a 117 −2.00 (−16.0 to 7.00) <0.0001b 0.61 Total MFM scorea 45 161 −1.00 (−17.0 to 7.00) <0.0001a 148 −0.50 (−11.0 to 11.0) 0.0226a 149 −1.00 (−13.0 to 6.00) <0.0001b 0.44 MFM D1 score a 10 166 0.00 (−7.00 to 4.00) 0.0007 a 152 0.00 (−7.00 to 6.00) 0.0033 a 151 −1.00 (−8.00 to 6.00) <0.0001 b 0.4 MFM D2 scorec 23 166 0.00 (−12.0 to 5.00) 0.0004c 154 0.00 (−6.00 to 10.0) 0.7945 157 0.00 (−8.00 to 5.00) 0.0171b 0.19 MFM D3 scoreb 11 174 0.00 (−3.00 to 2.00) 0.0655 158 0.00 (−3.00 to 3.00) 0.1431 160 0.00 (−6.00 to 2.00) 0.0011b 0.26 b b Brooke Upper Extremity Scale 1 181 0.00 (−2.00 to 5.00) 0.2025 164 0.00 (−5.00 to 2.00) 0.477 164 0.00 (−2.00 to 2.00) 0.0334 0.18 a a a b ACTIVLIM total score 26 180 0.00 (−9.00 to 8.00) 0.0042 165 0.00 (−9.00 to 10.0) 0.0026 164 −1.00 (−8.00 to 6.00) <0.0001 0.46 Jebsen writing time taken, s 12.7 180 0.10 (−17.3 to 14.9) 0.5794 165 0.10 (−11.3 to 30.5) 0.56 162 −0.15 (−14.4 to 28.1) 0.7109 0.11 6-min walk distance, meters/min c 331 124 −4.00 (−95.0 to 123) 0.2041 112 −7.00 (−110 to 51.0) 0.0003 c 113 −13.0 (−123 to 142) <0.0001 b 0.37 Abbreviations: a-NSAA = adapted North Star Ambulatory Assessment; MFM = Motor Function Measure; SLM = standardized response mean. p Values were calculated with the Wilcoxon signed-rank method. The SRM is a measure of effect size reported for change over 1 year. a Consistent significant change over 6 months. b Change over 1 year. c Change over one 6-month period but not both 6-month periods. Neurology.org/N Neurology.org/N Table 2 Change scores for MMT with a possible range of scores of 0 to 10 and HHM measured with a dynamometer Median score Change in score, baseline–6 mo Change in score, 6 mo–1 year Change in score, baseline–1 y at baseline, median (range) n Median (range) p Value n Median (range) p Value n Median (range) p Value SRM MMT shoulder flexion 7 (1–10) 184 0.00 (−3.00 to 3.00) 0.9973 169 0.00 (−3.00 to 3.00) 0.0577 166 0.00 (−4.00 to 3.00) 0.1979 0.20 MMT shoulder abductiona 7 (1–10) 184 0.00 (−6.00 to 5.00) 0.2465 169 0.00 (−4.00 to 4.00) 0.1172 166 0.00 (−4.00 to 3.00) 0.011a 0.11 b b a HHM elbow flexion biceps, lb 16.60 (1.00–65.00) 177 −0.70 (−24.5 to 10.80) 0.0012 159 −0.20 (−28.7 to 16.90) 0.9424 156 −0.60 (−30.6 to 15.10) 0.0026 0.23 b b a MMT elbow flexion biceps 8 (1–10) 184 0.00 (−4.00 to 4.00) 0.0322 169 0.00 (−4.00 to 4.00) 0.1412 166 0.00 (−4.00 to 4.00) 0.0016 0.13 HHM elbow flexion brachioradialis, lb 16.40 (0.00–56.60) 175 −0.30 (−29.1 to 17.80) 0.1451 159 −0.10 (−20.4 to 14.40) 0.5082 156 −0.45 (−32.9 to 15.20) 0.0616 0.07 MMT elbow flexion brachioradialis 8 (1–10) 184 0.00 (−5.00 to 3.00) 0.7979 169 0.00 (−4.00 to 4.00) 0.1109 166 0.00 (−5.00 to 3.00) 0.1388 0.24 a a MMT elbow extension 8.00 (2–10) 176 0.00 (−5.00 to 4.00) 0.1263 161 0.00 (−3.00 to 5.00) 0.9587 160 0.00 (−5.00 to 4.00) 0.0472 0.03 MMT wrist flexiona 9 (2–10) 184 0.00 (−7.00 to 5.00) 0.0647 169 0.00 (−8.00 to 6.00) 0.3377 166 0.00 (−4.00 to 3.00) 0.0024a 0.15 HHM wrist flexion, lb 15.80 (0.00–46.10) 176 0.00 (−18.1 to 15.10) 0.721 161 −0.20 (−22.4 to 17.30) 0.4597 158 −0.15 (−28.3 to 15.30) 0.8098 0.04 HHM wrist extension, lb 20.40 (3.10–50.30) 178 −0.15 (−16.3 to 20.30) 0.5521 163 0.00 (−25.0 to 15.40) 0.9028 160 −0.55 (−26.9 to 17.60) 0.162 0.23 MMT wrist extension 9 (3–10) 184 0.00 (−3.00 to 4.00) 0.4453 169 0.00 (−3.00 to 4.00) 0.5773 166 0.00 (−3.00 to 3.00) 0.3273 0.16 HHM grip, lbb 60.00 (0.00–260.0) 172 −1.00 (−173 to 103.1) 0.1287 160 −1.00 (−83.0 to 94.40) 0.0058b 152 −2.00 (−186 to 94.90) 0.0004a 0.01 HHM pinch grip, lb b 24.80 (0.00–97.00) 171 0.00 (−42.0 to 39.00) 0.2784 158 −1.00 (−35.0 to 22.00) <0.0001 b 150 −1.00 (−34.0 to 40.00) 0.0019 a 0.20 a a Neurology | Volume 92, Number 5 | January 29, 2019 MMT hip flexion 6 (0–10) 176 0.00 (−7.00 to 4.00) 0.3953 160 0.00 (−4.00 to 7.00) 0.1663 160 0.00 (−5.00 to 4.00) 0.0093 0.18 MMT hip extension 3 (0–10) 173 0.00 (−4.00 to 5.00) 0.5764 156 0.00 (−4.00 to 5.00) 0.9785 155 0.00 (−7.00 to 4.00) 0.6247 0.04 MMT hip abduction 6 (1–10) 175 0.00 (−5.00 to 7.00) 0.2452 156 0.00 (−5.00 to 5.00) 0.5303 156 0.00 (−7.00 to 7.00) 0.5382 0.26 HHM hip abduction, lb 20.50 (2.10–71.80) 161 0.10 (−37.4 to 34.30) 0.4108 148 0.10 (−33.3 to 22.70) 0.6222 149 0.10 (−36.5 to 26.10) 0.49 0.21 MMT hip adductionb 2 (0–10) 175 0.00 (−5.00 to 5.00) 0.0732 156 0.00 (−4.00 to 4.00) 0.0052b 156 0.00 (−5.00 to 5.00) 0.0009a 0.16 HHM hip adduction, lba 11.65 (0.00–49.60) 147 −0.10 (−25.2 to 21.30) 0.5118 133 −0.40 (−22.4 to 15.30) 0.0838 138 −1.15 (−28.4 to 17.20) 0.0168a b b MMT knee flexion 4 (0–10) 173 0.00 (−5.00 to 4.00) 0.0256 155 0.00 (−3.00 to 4.00) 0.6457 155 0.00 (−5.00 to 3.00) 0.014a 0.26 HHM knee flexion, lb b 9.60 (0.00–65.70) 141 −0.70 (−19.0 to 15.90) 0.007 b 127 −0.40 (−34.1 to 14.80) 0.1201 127 −1.20 (−44.5 to 20.00) <0.0001 a 0.20 MMT knee extension 3 (0–10) 182 0.00 (−3.00 to 4.00) 0.5574 167 0.00 (−4.00 to 5.00) 0.2943 164 0.00 (−5.00 to 5.00) 0.5064 0.12 b b a HHM knee extension, lb 11.80 (0.00–95.30) 154 −0.55 (−35.2 to 22.60) 0.0007 139 −0.20 (−39.5 to 41.10) 0.3253 138 −0.80 (−37.7 to 19.70) 0.0052 0.05 a a MMT ankle dorsiflexion 4 (0–10) 180 0.00 (−7.00 to 6.00) 0.1944 165 0.00 (−6.00 to 7.00) 0.1841 164 0.00 (−5.00 to 6.00) 0.0295 0.24 HHM ankle dorsiflexion, lbb 11.30 (0.00–55.90) 140 −0.75 (−29.5 to 22.70) 0.0018b 118 0.00 (−28.8 to 30.00) 0.7194 118 −0.50 (−40.5 to 25.90) 0.0537 0.23 Continued e465 nature, are suitable only for ambulant patients. In addition, SRM When the same muscle groups are tested by both methods, they are grouped together to aid interpretation. p Values were calculated with the Wilcoxon signed-rank method. No MMT or HHM assessments changed consistently 0.23 0.23 0.04 0.17 0.16 0.21 some patients did not complete all assessments because of equipment or individual patient factors such as recent injury 0.0193a 0.0174a p Value 0.1945 0.6789 a 0.013a 0.002 and were excluded from analysis of that assessment. The number of patients who completed each assessment is listed. Change in score, baseline–1 y −0.70 (−33.9 to 30.20) −1.15 (−39.6 to 22.60) 0.00 (−10.0 to 8.00) The a-NSAA, MFM-20 (total and subdomain D1), the Timed 0.00 (−6.00 to 5.00) 0.00 (−4.00 to 5.00) 0.00 (−6.00 to 3.00) Up and Go, and timed 10-meter walk showed significant Median (range) change in median score over both 6-month periods and 1 year (table 1 and figure 2); no MMT or HHD values changed consistently over both 6-month windows (table 2). The MFM D2, some MMT and HHD, velocity to rise from 137 123 153 124 164 164 floor, climb 4 stairs, descend 4 stairs, and the 6MWT showed over both 6-month periods. The SRM, a measure of effect size, is reported for change over 1 year. MMT and HHM assessments all showed low responsiveness to change. n significant change over only one 6-month window and over 1 0.0003b p Value 0.2234 0.8154 year (tables 1 and 2 and figure 2). 0.212 0.229 0.242 Table 2 Change scores for MMT with a possible range of scores of 0 to 10 and HHM measured with a dynamometer (continued) The MFM D3, some MMT and HHD, and the Brooke scale Change in score, 6 mo–1 year −0.50 (−28.6 to 32.90) −0.30 (−34.5 to 22.10) showed change in median score at 1 year but did not change 0.00 (−6.00 to 8.00) 0.00 (−5.00 to 6.00) 0.00 (−5.00 to 4.00) 0.00 (−5.00 to 4.00) over either 6-month windows (tables 1 and 2). Median (range) The timed test demonstrating the greatest change in velocity was the 10-meter walk, changing −0.1 m/s (range −1.24 to 0.55 m/s) from a baseline median velocity of 1.11 m/s (range 0.00–4.55 m/s). The velocity of all timed tests at year 1 139 127 154 127 165 164 slowed by almost 10% of baseline velocity for that task n (figure 2). p Value b 0.2528 0.0138 0.6828 0.8232 0.273 Abbreviations: HHM = hand-held myometry; MMT = manual muscle testing; SRM = standardized response mean. 0.21 The Jebsen Hand Function Test and remaining MMT and Change in score, baseline–6 mo HHD tests showed no change over 1 year. −0.40 (−34.2 to 23.70) −0.75 (−25.6 to 29.00) 0.00 (−10.0 to 7.00) 0.00 (−6.00 to 7.00) 0.00 (−7.00 to 6.00) 0.00 (−6.00 to 4.00) The tests most responsive to change for the whole cohort, as Median (range) calculated by the SRM, were NSAA (SRM 0.61), 10-meter walk/run velocity (0.56), ACTIVLIM (0.46), rise from floor velocity (0.44), and MFM total score (0.44). When assessed by severity subgroup, for ambulant patients, 157 140 173 144 180 179 n the a-NSAA was the most sensitive test in the mildly (SRM 0.44) and moderately (SRM 0.89) affected groups, while the 12.60 (0.00–81.00) 12.20 (0.00–57.90) Change over a single 6-month period but not both 6-month periods. median (range) 6MWT was most sensitive in the severely affected ambulant Median score at baseline, group (SRM 0.9). The 10-meter walk was the only test showing significant change in all ambulant subgroups. For 3 (0–10) 3 (0–10) 7 (0–10) 5 (0–10) nonambulant patients, the most sensitive test was the MMT for wrist flexion (SRM 0.69), while the most sensitive com- bined measure was the distal domain of the MFM (SRM HHM ankle plantar flexors (knee straight), lb b HHM ankle plantar flexors (knee flexed), lb MMT ankle plantarflexion (knee straight)a 0.46). Table e-1 (available from Dryad doi.org/10.5061/ MMT ankle plantarflexion (knee flexed)a dryad.tp08m60) shows SRM values for all assessments by severity subgroup. Change in functional test scores (MFM and a-NSAA) did not differ between the 2 most common clinical diagnoses of LGMD2B and Miyoshi myopathy (table 3). MMT ankle eversionb MMT ankle inversion Change over 1 year. Patient perception of progression Responses recorded by the ACTIVLIM questionnaire sup- ported the deterioration in function, with the ACTIVLIM score decreasing statistically significantly over both 6 and 12 months (table 1). b a e466 Neurology | Volume 92, Number 5 | January 29, 2019 Neurology.org/N Figure 2 Change in timed tests over 6 months and 1 year Boxplots showing range, interquartile range (IQR), and median values of time taken to perform timed tests. Paired com- parisons of calculated velocity (1/time in seconds) were used to determine signifi- cant vs insignificant change in order to in- clude those unable to complete the test. These are displayed as time taken to com- plete each task (rather than velocity) to aid visual interpretation. Comparisons of baseline and year 1, baseline and 6 months, and 6 months and 1 year are shown. The numbers differ depending on the number of patients completing each test at both visits. Blue shows significant change (p < 0.05) over 1 year; red shows if change is seen over both 6-month periods; and green shows change in only the green 6-month window. Some patients were very slow, and those taking >25 seconds to complete a test are not displayed but are included in median and IQR calculations. Estimated sample size for trials group at baseline, who showed the greatest changes in Estimated clinical trial sample size is highly dependent on the a-NSAA scores over 1 year, would reduce the total sample size expected treatment effect; the smaller the effect size, the larger to 176 for a 50% reduction in progression and 46 to detect the sample required (table 4). For example, with the inclusion a halt in progression. A treatment that is anticipated to im- of ambulant patients of all disease severities, a total of 328 prove muscle function, producing a greater effect size than patients (164 in both the treatment and placebo groups) simply halting progression, would require even fewer patients. would be needed to detect a 50% reduction in disease pro- gression (i.e., half the deterioration seen in the current sam- The 6MWT would require 216 ambulant patients to detect ple) over 1 year compared to 90 patients (45 in each group) a halting of progression. However, as reflected by the high needed to detect halting in progression. The a-NSAA was SRM in the severe-ambulant population, if trials were limited chosen for its capability to detect change as demonstrated by to the severe-ambulant subgroup of patients, 42 patients the highest overall SRM in the current analysis. Limiting would be needed to detect a halting in progression with the a clinical trial to a subset of patients in the moderate severity 6MWT. Neurology.org/N Neurology | Volume 92, Number 5 | January 29, 2019 e467 Table 3 Scores in LGMD2B and Miyoshi myopathy Kruskal- Wallis test of difference between LGMD2B Miyoshi myopathy groups Median Median p Outcome n (range) p Value SRM n (range) Value SRM p Value Total North Star score 67 −2.00 (−14.0 to 5.00) <0.0001 0.69 35 −2.00 (−16.0 to 7.00) 0.0015 0.50 0.8663 Total MFM Score 84 −1.00 (−13.0 to 6.00) <0.0001 0.46 48 −1.00 (−10.0 to 6.00) 0.0131 0.38 0.87 MFM D1 score 85 −1.00 (−6.00 to 6.00) 0.0006 0.36 49 0.00 (−8.00 to 3.00) 0.0042 0.42 0.8898 MFM D2 score 91 0.00 (−8.00 to 4.00) 0.0201 0.25 49 0.00 (−4.00 to 5.00) 0.4588 0.08 0.8873 MFM D3 score 92 0.00 (−3.00 to 2.00) 0.0026 0.32 51 0.00 (−6.00 to 2.00) 0.2350 0.19 0.6595 MMT shoulder abduction 97 0.00 (−4.00 to 3.00) 0.0530 0.21 51 0.00 (−2.00 to 2.00) 0.2754 0.18 0.9883 MMT shoulder flexion 97 0.00 (−3.00 to 2.00) 0.2873 0.12 51 0.00 (−2.00 to 3.00) 0.8111 0.02 0.8958 MMT elbow flexion biceps 97 0.00 (−4.00 to 4.00) 0.1284 0.16 51 0.00 (−3.00 to 3.00) 0.0505 0.25 0.9713 MMT elbow flexion 97 0.00 (−5.00 to 3.00) 0.3926 0.11 51 0.00 (−3.00 to 3.00) 0.7598 0.03 0.9249 brachioradialis MMT wrist extension 97 0.00 (−3.00 to 3.00) 0.9115 0.01 51 0.00 (−2.00 to 2.00) 0.6209 0.09 0.8412 MMT wrist flexion 97 0.00 (−4.00 to 3.00) 0.0750 0.19 51 0.00 (−4.00 to 3.00) 0.0444 0.28 0.9326 MMT knee extension 96 0.00 (−3.00 to 4.00) 0.9472 0.04 51 0.00 (−3.00 to 5.00) 0.5997 0.06 0.9994 MMT ankle dorsiflexion 96 0.00 (−5.00 to 4.00) 0.0536 0.20 51 0.00 (−3.00 to 6.00) 0.1403 0.14 0.9966 MMT ankle inversion 96 0.00 (−4.00 to 4.00) 0.8853 0.01 51 0.00 (−4.00 to 5.00) 0.7866 0.04 0.9927 MMT ankle eversion 96 0.00 (−5.00 to 3.00) 0.0701 0.22 51 0.00 (−6.00 to 3.00) 0.1469 0.22 0.9941 MMT ankle plantarflexion 78 0.00 (−5.00 to 8.00) 0.6160 0.02 44 0.00 (−10.0 to 7.00) 0.0062 0.36 0.0455 (knee straight)a MMT ankle plantarflexion 86 0.00 (−6.00 to 5.00) 0.2716 0.11 50 0.00 (−2.00 to 5.00) 0.0876 0.17 0.6968 (knee flexed) MMT hip extension 88 0.00 (−5.00 to 4.00) 0.2450 0.12 50 0.00 (−7.00 to 2.00) 0.4626 0.37 0.423 MMT knee flexion 89 0.00 (−5.00 to 3.00) 0.3173 0.14 50 0.00 (−3.00 to 2.00) 0.0147 0.20 0.3917 MMT hip Abduction 89 0.00 (−7.00 to 7.00) 0.2638 0.12 50 0.00 (−4.00 to 6.00) 0.5599 0.10 0.4836 MMT hip Adduction 89 0.00 (−5.00 to 3.00) 0.0025 0.32 50 0.00 (−5.00 to 5.00) 0.6168 0.06 0.2017 MMT hip flexion 92 0.00 (−5.00 to 2.00) 0.1230 0.19 51 0.00 (−3.00 to 4.00) 0.1110 0.20 0.8431 MMT elbow extension 92 0.00 (−5.00 to 4.00) 0.0653 0.20 51 0.00 (−3.00 to 4.00) 0.8632 0.02 0.6868 HHM elbow flexion biceps, lb 91 −0.30 (−17.6 to 11.00) 0.0904 0.24 48 −0.85 (−23.6 to 15.10) 0.0498 0.23 0.7967 HHM elbow flexion 91 −0.60 (−20.5 to 8.20) 0.2003 0.19 48 0.20 (−21.0 to 15.20) 0.5768 0.09 0.9248 brachioradialis, lb HHM wrist extension, lba 93 −1.40 (−17.4 to 14.60) 0.0173 0.21 50 1.40 (−15.5 to 17.60) 0.0798 0.15 0.0187 HHM wrist flexion, lb 93 −0.10 (−16.6 to 15.30) 0.8544 0.03 48 0.60 (−10.4 to 7.60) 0.5540 0.05 0.8952 HHM grip, lb 93 −1.00 (−186 to 87.10) 0.0085 0.27 42 −2.00 (−85.0 to 62.90) 0.1015 0.25 0.9728 HHM pinch grip, lb 93 −1.00 (−31.0 to 40.00) 0.0175 0.19 42 0.00 (−27.0 to 16.00) 0.2026 0.28 0.9623 HHM knee extension, lb 81 −0.10 (−30.3 to 15.50) 0.2259 0.17 42 −1.10 (−36.6 to 19.70) 0.0215 0.24 0.5599 HHM knee flexion, lb 73 −1.00 (−11.6 to 16.60) 0.0276 0.14 39 −1.00 (−13.5 to 20.00) 0.0011 0.21 0.6533 HHM hip abduction, lb 86 −0.10 (−14.7 to 19.20) 0.8929 0.08 48 0.90 (−36.5 to 26.10) 0.0948 0.11 0.3955 Continued e468 Neurology | Volume 92, Number 5 | January 29, 2019 Neurology.org/N Table 3 Scores in LGMD2B and Miyoshi myopathy (continued) Kruskal- Wallis test of difference between LGMD2B Miyoshi myopathy groups Median Median p Outcome n (range) p Value SRM n (range) Value SRM p Value HHM hip adduction, lb 82 −1.00 (−20.8 to 13.40) 0.1396 0.16 41 −1.10 (−15.5 to 17.20) 0.2555 0.07 0.9905 HHM ankle dorsiflexion, lb 68 −0.65 (−18.5 to 17.00) 0.0833 0.15 35 0.00 (−22.2 to 25.90) 0.8751 0.01 0.5334 HHM ankle plantar flexors (knee 71 −1.00 (−23.0 to 20.90) 0.0331 0.24 37 −1.20 (−10.7 to 16.10) 0.1155 0.11 0.9482 flexed), lb HHM ankle plantar flexors (knee 71 −1.00 (−27.0 to 17.30) 0.1283 0.18 36 −0.45 (−30.6 to 14.40) 0.9234 0.08 0.69 straight), lb Brooke Upper Extremity Scale 97 0.00 (−1.00 to 2.00) 0.0301 0.21 51 0.00 (−1.00 to 1.00) 0.3877 0.17 0.9764 ACTIVLIM total score 95 −1.00 (−8.00 to 4.00) <0.0001 0.51 51 −1.00 (−8.00 to 6.00) 0.0520 0.28 0.8076 Jebsen writing time taken, s 95 −0.20 (−14.4 to 28.10) 0.6479 0.15 49 0.50 (−10.5 to 6.40) 0.5693 0.04 0.9795 6-min walk test total distance, 65 −8.00 (−123 to 71.00) 0.0137 0.33 34 −15.50 (−108 to 142.0) 0.0607 0.24 0.9881 meters/min Abbreviations: HHM = hand-held myometry; LGMD2B = limb girdle muscular dystrophy type 2B; MFM = Motor Function Measure; MMT = manual muscle testing; SRM = standardized response mean. This table shows the change scores over 1 year for patients with a diagnosis of LGMD2B or Miyoshi myopathy. Change scores were compared between groups with the Kruskal-Wallis test and Steel-Dwass-Critchlow-Fligner control for multiple comparisons. The SRM is a measure of effect size demonstrated by each test, shown for each diagnostic group. Overall functional scores of the MFM and adapted North Star Ambulatory Assessment did not differ between diagnostic subgroups. a Only 2 muscle groups (ankle plantar flexion and wrist extension) showed a difference between these 2 groups. Discussion ambulation. However, this is unlikely to be used in clinical trials, particularly because this subgroup of patients is small This analysis supports the use of specified physical and patient- (37 severe-ambulant patients in this study), thus reducing the reported outcome measures in the assessment of dysferlinop- number of patients available to appropriately power a study. athy by demonstrating clinically detectable deterioration in muscle strength and function and self-reported deterioration Trials in rare diseases are often forced to rely on small cohort over 6 months and 1 year in a large cohort of patients. sizes. Here, we show that while variation in physical progression can be high in dysferlinopathy, sensitive outcome measures can Defining a set of disease specific tests is useful in coordinating be identified (a-NSAA, 10-meter walk, etc.), particularly in further research and patient follow-up and developing clinical ambulant patients. We confirm that a moderate disease severity trial outcome measures. The most sensitive assessments for group based on the a-NSAA could be identified, making it monitoring progression in dysferlinopathy that were identified possible to power a clinical trial with a reasonably sized sample. in this study are the a-NSAA, MFM-20, timed 10-meter walk, The actual number needed would depend on the expected and Timed Up and Go; they demonstrated consistent change treatment effect over 1 year. Numbers needed for a trial could over both 6 months and 1 year with a relatively high SRM. be further reduced by using this longitudinal natural history Other tests such as the Brooke and some MMT assessments sample as a control group for future clinical studies.19 In addi- showed change over 1 year but not 6 months, suggesting that tion, longer evaluation times and identification of more sensitive they are less sensitive scales. This was also true for D3 (distal scoring systems could further reduce the number of participants function) of the MFM, consistent with other published cross- needed for effective clinical trials. Future work aiming to assess sectional data on its poor suitability for this population.14 Some the cohort by modeling methods will look at progression based tests such as the 6MWT and MFM D2 domain changed over on a variety of disease and environmental factors to attempt to one 6-month window but not the other. This poor repeatability determine whether any subgroups exist with differing rates of of demonstrable change makes these measures less reliable in progression. Any particularly fast-progressing group would be assessing the dysferlinopathy patient cohort as a whole. very good candidates for potential trials in terms of both patient benefit and reduced sample size requirement. The 6MWT showed the highest SRM for the severely affected ambulant patients, perhaps capturing a large deterioration in Increasing the sensitivity and utility of functional scoring the walking pace of some of these weak patients as they lose systems across the disease spectrum requires the creation of Neurology.org/N Neurology | Volume 92, Number 5 | January 29, 2019 e469 Table 4 Sample size estimates for a placebo-controlled clinical trial Target treatment effect, n 50% Reduction in 75% Reduction in Halting of 20% 50% Target study population progression progression progression Improvement Improvement All ambulant patients 328 148 90 62 42 Moderate patients only (baseline 176 80 46 34 22 a-NSAA score 11–40) Abbreviation: a-NSAA = adapted North Star Ambulatory Assessment. Sample size estimates for a placebo-controlled clinical trial are based on projected mean change in a-NSAA score for variable treatment effects over 1 year. The numbers represent the total sample size based on equally sized treatment and control groups. Calculations are based on an observed decrease in NSAA score in untreated patients of 2.4 overall and 3.8 among moderate patients, the expected control effect. Estimated change in a-NSAA score among treatment groups over 1 year is therefore as follows: 50% reduction, decrease of 1.2 (all) and 1.9 (moderate) in a-NSAA score; 75% reduction, decrease of 0.6 (all) and 0.9 (moderate) in a-NSAA score; halting of progression, no change in a-NSAA score; 20% improvement, increase of 0.5 (all) and 0.7 (moderate) in a-NSAA score; and 50% improvement, increase of 1.2 (all) and 1.9 (moderate) in a-NSAA score. a disease-specific scale. We are working to streamline the patients, there is a low responsiveness and high variability of a-NSAA and MFM-20 to remove redundant and less sensitive MMT and HHD results because measures of specific muscle items and to combine elements of each scale using a Rasch change. Other measures of strength, longer time scales, and analysis20 to create a linearizable, dysferlin-specific score. This MRI may be needed to monitor effects of local treatments. modified scale, called the North Star Assessment for Dysfer- linopathy, will be validated with the 2- and 3-year COS visits In all tests, a small number of individuals of all ages and disease and will be assessed with Rasch analysis to determine whether severities improved their time or qualitative functional score the new scale is capable of measuring change over a wider over 1 year. While in some this may reflect a true improvement proportion of the patient population over time. in function, we would not expect an improvement in un- derlying pathology. Therefore, it is likely that some of this Characterizing which individual muscles demonstrate most improvement can be attributed to potentially confounding rapid deterioration in dysferlinopathy is useful for both factors. With functional scales, improvement may be due to monitoring progression and targeting potential therapeutics, a learning effect22; that is, patients become more practiced at some of which involve local intramuscular injections.21 These certain tests, although we attempted to mitigate this by having results over 1 year show some sensitivity to change of a few all patients perform a full assessment at screening. Some distal muscle groups in nonambulant patients, in whom intertester variation in scoring is also possible because, although functional scores are less useful. However, in ambulant all were trained by the same provider, different physiotherapists conducted consecutive patient visits at some sites. However, we anticipate this effect to be small because the functional Table 5 Intraclass correlation coefficient between assessments used have previously demonstrated high inter- screening and baseline assessments for tester reliability in other diseases,23–25 and intraclass correlation functional tests carried out at a maximum of 90 comparison of baseline and screening results (table 5) shows days apart consistency of scoring, particularly for the a-NSAA (intraclass Test Intraclass correlation n Multiple correlation 0.99), on which much of this analysis is based. Finally, this may simply reflect environmental, physiologic, or NSAA 0.99 132 119 individual factors such as motivation or fatigue, which can cause MFM total score 0.99 170 150 natural fluctuations in performance on functional tests22 on the background of more slowly progressing pathology. If trends in Time to stand 0.85 91 77 scores are maintained in future visits, suggesting a true sub- Time to walk/run 10 m 0.99 127 114 group of static or even functionally improving patients, this will Timed Up and Go 0.84 112 104 be revisited to assess for potential disease modifiers. Time to climb 4 steps 0.93 109 101 The ACTIVLIM is a rating scale with documented high Time to descend 4 steps 0.53 108 101 sensitivity in many neuromuscular conditions.16,26 We have 6-min walk distance 0.97 129 121 shown that this holds true for the dysferlinopathy population, who show changes in score across all levels of function. A very ACTIVLIM 0.97 174 167 small number of patients reported an improvement in the Abbreviations: MFM = Motor Function Measure; NSAA = North Star Ambu- ability to perform tasks of daily living. These patients had latory Assessment. undertaken lifestyle changes, including weight loss, dietary A high intraclass correlation demonstrates consistency between screening and baseline assessments. change, and participation in physiotherapy. Future work will explore and capture patient access to physiotherapy, e470 Neurology | Volume 92, Number 5 | January 29, 2019 Neurology.org/N participation in exercise, and the use of aids and adaptations in Avital Cnaan: design or conceptualization of the study, the home and workplace. These findings suggest that the drafting or revising the manuscript for intellectual content. ACTIVLIM is a reliable patient-reported outcome measure in Karen Bettinson: major role in the acquisition of data, drafting dysferlinopathy that is a valuable complementary tool for or revising the manuscript for intellectual content. Laura clinical trials at any stage of the disease. Rufibach: design or conceptualization of the study, drafting or revising the manuscript for intellectual content. Robert Muni There are several limitations of this study. The first is the Lofra, Andrew M. Blamire, and Pierre G. Carlier: design or relatively short period of time over which change was ex- conceptualization of the study, major role in the acquisition of amined; this will be addressed in future analysis of this data, drafting or revising the manuscript for intellectual con- 3-year study. Second, the use of ordinal, rather than con- tent. Plavi Mittal: design or conceptualization of the study, tinuous, functional scales presented challenges in data drafting or revising the manuscript for intellectual content. analysis, necessitating the use of medians, making intuitive Michelle Eagle: design or conceptualization of the study, interpretation more difficult. However, these scales also major role in the acquisition of data, drafting or revising the have benefits because a single point change on a functional manuscript for intellectual content. Linda Lowes, Lindsay change necessarily represents a clinically, rather than sim- Alfano, Kristy Rose, Tina Duong, Katherine Berry, Elena ply statistically, noticeable change. Future work will explore Montiel-Morillo, Irene Pedrosa-Hernández, Scott E. Holsten, the potential to linearize these Rasch-based measures, Mohammed Sanjak, Ai Ashida, Chikako Sakamoto, Tatyuki allowing us to keep the benefits of these scales while pro- Tateishi, Hiroyuki Yajima, Aurélie Canal, Gwenn Olliver, viding the opportunity to subject them to more rigorous Valerie Decostre, Bosco Mendez, Nieves Sánchez-Aguilera parametric statistics. Práxedes, Simone Thiele, Catherine Siener, Jeannine Sheier- becker, Julaine Florence, Bruno Vandevelde, Brittney DeW- Although function is measured, the importance attributed by olf, Meghan Harman, Richard Gee, Juliane Prugel, Elke patients to the loss of ability to perform 1 particular action Maron, and Heather Hilsden: major role in the acquisition of over another is not measured here. To clarify the clinical data, drafting or revising the manuscript for intellectual con- significance of the statistically significant changes demon- tent. Hanns Lochmüller: design or conceptualization of the strated here, further correlations are needed between these study, drafting or revising the manuscript for intellectual functional and patient-reported measures, as well as consid- content. Ulrike Grieben, Simone Spuler, Carolina Tesi Rocha, eration of patient valuation of the importance of the loss of John W. Day, Kristi J. Jones, Diana X. Bharucha-Goebel, individual functions. Emmanuelle Salort-Campana, Matthew Harms, Alan Pes- tronk, Sabine Krause, Olivia Schreiber-Katz, Maggie C. Wal- Our current assessment of arm function is limited in the ter, Carmen Paradas, Jean-Yves Hogrel, Tanya Stojkovic, scales currently used in this study. Further work is required Shin’ich Takeda, Madoka Mori-Yoshimura, Elena Bravver, to develop or determine suitable measures for upper limb Susan Sparks, Jordi Dı́az-Manera, Luca Bello, Claudio Sem- function. plicini, Elena Pegoraro, Jerry R. Mendell, and Kate Bushby: design or conceptualization of the study, major role in the This study demonstrates significant population-level change acquisition of data, drafting or revising the manuscript for over 6 months and 1 year in several functional and patient- intellectual content. Volker Straub: design or conceptualiza- reported measures. We anticipate that the planned combi- tion of the study, major role in the acquisition of data, drafting nation of the most sensitive elements of the a-NSAA and or revising the manuscript for intellectual content, overall MFM to create a dysferlin-specific score will produce an im- responsibility for the content of this paper. For Study Group: portant measure that will become the basis for assessment of the Jain Consortium: All members of the Jain Consortium are progression in dysferlinopathy regardless of ambulatory sta- listed in the Appendix. All members of the study group played tus. This measure combined with MRI data and further pa- a role in acquisition of data. tient subgroup analysis will add to the pathophysiologic understanding and trial readiness of the dysferlinopathy Acknowledgment population and may further reduce the cohort size required to This study has been possible only thanks to the international power potential clinical trials. collaboration of several specialized centers promoted by the Jain Foundation. The Jain COS Consortium thanks the study Author contributions participants and their families for their invaluable contribu- Ursula Moore: analysis or interpretation of the data, statistical tions and acknowledges the ongoing support that the Jain analysis, drafting or revising the manuscript for intellectual Foundation provides in the development, management, and content. Marni Jacobs: statistical analysis. Meredith James, analysis of this study. The Jain Foundation, based in Seattle, analysis or interpretation of the data, drafting or revising the WA, is focused entirely on LGMD2B/dysferlinopathy/ manuscript for intellectual content. Anna Mayhew and Rob- Miyoshi myopathy. The foundation does not solicit funding erto Fernandez Torron: analysis or interpretation of the data, from patients but instead funds research and clinical studies drafting or revising the manuscript for intellectual content. Jia worldwide with the goal of finding treatments for dysferlin- Feng: analysis or interpretation of the data, statistical analysis. opathy. Please visit jain-foundation.org for more information Neurology.org/N Neurology | Volume 92, Number 5 | January 29, 2019 e471 about the foundation. If you are a patient with dysferlinopathy, MRC Centre for Neuromuscular Diseases (grant MR/ please consider enrolling in their interactive dysferlinopathy K000608/1). registry, which seeks to build a strong, engaged, and supportive community (patients@jain-foundation.org). Disclosure The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures. Study funding The estimated US $4 million needed to fund this study is Publication history being provided by the Jain Foundation. The John Walton Received by Neurology May 4, 2018. Accepted in final form October 1, Centre Muscular Dystrophy Research Centre is part of the 2018. Appendix 1 Coinvestigators: The Jain COS Consortium Coinvestigator Affiliation and role in study Adrienne Arrieta, MS Children’s National Medical Center, Washington, DC; data management and training Esther Hwang Jain Foundation, Seattle, WA; recruitment, development of assessment form Elaine Lee, PhD Jain Foundation, Seattle, WA; recruitment, development of assessment forms Isabel Illa, MD Hospital de la Santa Creu i Sant Pau/CIBERER, Barcelona, Spain; site investigator Eduard Gallardo, MD Hospital de la Santa Creu i Sant Pau/CIBERER, Barcelona, Spain; site investigator Izaskun Belmonte Jimeno, PT Servei de Medicina F ı́sica i Rehabilitació, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; site investigator Jaume Llauger Rossello Radiology Department, Universitat Autònoma de Barcelona, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; radiologist Bruce Harwick Department of Radiology, CMC Mercy Charlotte, Carolinas Healthcare System Neurosciences Institute, Charlotte, NC; NMR technologist Jackie Sykes, RN, BSN Carolinas HealthCare System, Charlotte, NC; study coordinator Brent Yetter, MS Nationwide Children’s Hospital, Columbus, OH; study coordinator Mark Smith, MS, DABMP, Department of Radiology, Nationwide Children’s Hospital, Columbus, OH; site investigator RT (MR) Bernard Lapeyssonie, PT Neuromuscular and ALS Center, La Timone Hospital, Aix-Marseille Université, Marseille, France; site investigator David Bendahan, PhD Centre de Résonance, MagnétiqueBiologique et Médicale, UMR CNRS 7339, Marseille, France; Aix-Marseille Université, Marseille, France; site investigator Yann Le Fur, PhD Aix-Marseille Université, Marseille, France; site investigator Attarian Shahram, MD, PhD Neuromuscular and ALS Center, La Timone Hospital, Aix-Marseille Université, Marseille, France; site investigator Testot-Ferry Albane, CRA Neuromuscular and ALS Center, La Timone Hospital, Aix-Marseille Université, Marseille, France; study coordinator Eva M. Coppenrath, MD Department of Clinical Radiology, Ludwig-Maximilians-University Munich, Germany; site investigator Elizabeth Harris, MD John Walton Muscular Dystrophy Research Centre, Newcastle Upon Tyne, UK; clinical investigator Michela Guglieri, MD John Walton Muscular Dystrophy Research Centre, Newcastle Upon Tyne, UK; clinical investigator Teresinha Evangelista, MD The John Walton Muscular Dystrophy Research Centre, Newcastle Upon Tyne, UK; clinical investigator Alex Murphy, MD The John Walton Muscular Dystrophy Research Centre, Newcastle Upon Tyne, UK; clinical investigator Dionne Moat The John Walton Muscular Dystrophy Research Centre, Newcastle Upon Tyne, UK; clinical investigator Tim Hodgson, MClinRES Magnetic Resonance Centre, Institute for Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK; site investigator Dorothy Wallace, BSc Magnetic Resonance Centre, Institute for Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK; site investigator Louise Ward, DCR Magnetic Resonance Centre, Institute for Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK; site investigator Debra Galley Magnetic Resonance Centre, Newcastle University, Newcastle Upon Tyne, UK; radiology assistant Chiara Calore University of Padova, Padova, Italy, site investigator Roberto Stramare, MD Radiology Unit, Department of Medicine, University of Padova, Padova, Italy; site investigator Continued e472 Neurology | Volume 92, Number 5 | January 29, 2019 Neurology.org/N Appendix 1 (continued) Coinvestigator Affiliation and role in study Alessandro Rampado, MRT Radiology Unit, Department of Medicine, University of Padova, Padova, Italy; site investigator Teresa Gidaro Institut de Myologie, Paris, France; site investigator Suna Turk, MSc AIM & CEA NMR Laboratory, Institute of Myology, Pitié-Salpêtrière University Hospital, 47-83, Paris, France; site investigator Laurent Servais Institut de Myologie, Paris, France; site investigator Cyrille Theis Institut de Myologie, Paris, France; site investigator Oumar Diabaté Institut de Myologie, Paris, France; study coordinator Linda Schimmoeller Washington University, St. Louis, MO; study coordinator Glenn Foster, RTR (MR) Center for Clinical Imaging Research CCIR, Washington University, St. Louis, MO; site investigator Pilar Carbonell, MD Hospital U. Virgen del Rocı́o/Instituto de Biomedicina de Sevilla, Seville, Spain; site investigator Macarena Cabrera, MD Hospital U. Virgen del Rocı́o/Instituto de Biomedicina de Sevilla, Seville, Spain; site investigator Yolanda Morgado, MD Hospital U. Virgen de Valme/Instituto de Biomedicina de Sevilla, Seville, Spain; site investigator Susana Rico Gala, MD Department of Radiology, Hospital U. Virgen de Valme, Seville, Spain; site investigator Jennifer Perez Stanford University School of Medicine, Stanford, CA; study coordinator Anne Marie Sawyer, FSMRT Lucas Centre for Imaging, Stanford University School of Medicine, Stanford, CA; site investigator Nigel F. Clarke, MD Institute for Neuroscience and Muscle Research, Sydney, Australia; site investigator Sarah Sandaradura, MD Institute for Neuroscience and Muscle Research, Sydney, Australia; site investigator Roula Ghaoui, MD Institute for Neuroscience and Muscle Research, Sydney, Australia; site investigator Kayla Cornett, Ex Phys Institute for Neuroscience and Muscle Research, Sydney, Australia; site investigator Claire Miller, PT Institute for Neuroscience and Muscle Research, Sydney, Australia; site investigator Sheryl Foster, MHlthSc Department of Radiology, Westmead Hospital; Faculty of Health Sciences, University of Sydney, Australia; site investigator Anthony Peduto, MBBS Department of Radiology, Westmead Hospital; Faculty of Health Sciences, University of Sydney, Australia; site investigator Noriko Sato, MD, PhD Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; site investigator Takeshi Tamaru, MRT Department of Radiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan; site investigator Yoko Kobayashi, MD National Center of Neurology and Psychiatry, Tokyo, Japan; site investigator Ai Ashida, PT National Center of Neurology and Psychiatry, Tokyo, Japan; site investigator Takahiro Nakayama, MD, PhD Yokohama Rosai Hospital, Yokohama, Japan; study advisor Kazuhiko Segawa, MD, National Center of Neurology and Psychiatry, Tokyo, Japan; site investigator PhD Sachiko Ohtaguro National Center of Neurology and Psychiatry, Tokyo, Japan; study assistant Harumasa Nakamura, MD National Center of Neurology and Psychiatry, Tokyo, Japan; study advisor Maki Ohhata National Center of Neurology and Psychiatry, Tokyo, Japan; study coordinator En Kimura, MD, PhD National Center of Neurology and Psychiatry, Tokyo, Japan; study advisor Makiko Endo National Center of Neurology and Psychiatry, Tokyo, Japan; study coordinator Nora Brody, PT, DPT Children’s National Health System, Washington, DC: site investigator Meganne E. Leach, MSN, Children’s National Health System, Washington, DC: site investigator APRN Allyn Toles Children’s National Health System, Washington, DC: study coordinator Stanley T. Fricke, PhD Department of Diagnostic Imaging and Radiology, Children’s National Health System, Washington, DC; site investigator Hansel J. Otero, MD Department of Diagnostic Imaging and Radiology, Children’s National Health System, Washington DC; site investigator Neurology.org/N Neurology | Volume 92, Number 5 | January 29, 2019 e473 References 16. Batcho CS, Van den Bergh PY, Van Damme P, Roy AJ, Thonnard JL, Penta M. How robust is ACTIVLIM for the follow-up of activity limitations in patients with neu- 1. Bushby K, Straub V. One gene, one or many diseases? Simplifying dysferlinopathy. romuscular diseases? Neuromuscul Disord 2016;26:211–220. Neurology 2010;75:298–299. 17. Husted JA, Cook RJ, Farewell VT, Gladman DD. Methods for assessing responsiveness: 2. Nguyen K, Bassez G, Bernard R, et al. 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