Audit of the TREAT-NMD global DMD and SMA registries: new insights into data collection methods

Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249 1

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Institute of Myology, Paris, France; Consultants for Research in imaging and Spectroscopy, Tournai, Belgium Recent years have seen tremendous progress towards the development of quantitative NMR-based outcome measures to monitor NMD. Methods based on the chemical shift difference between water and fat protons (such as 3ptDIXON or IDEAL) are currently the reference approaches to quantitatively assess fat infiltration in muscle tissues. T1 values are also strongly affected when healthy muscle is chronically replaced by fat. This is often used for diagnostic purposes by grading T1 weighted images with the MercuryLamminen scale. With the development of fast NMR sequences, quantitative T1 imaging is now possible within short acquisition times. The goal of this study was to evaluate the ability of fast T1 mapping to monitor the degree of fat infiltration within skeletal muscle tissues in patients suffering from NMD. NMR imaging was performed on the thighs of 30 healthy volunteers and 30 patients suffering from Becker muscular dystrophy (BMD). The T1 mapping sequence consisted in the acquisition of a 1000 radial spokes FLASH echo train following magnetization inversion. The following parameters were used: TE/TR = 2.75/5.08 ms, resolution = 1.8x1.8mm2, 5 slices, Tacq = 50s. Fat fractions were also quantified using a standard 3D GRE acquisition (spatial resolution = 1x1x5mm3, Tacq = 1 min36s) and the 3pt-Dixon approach. T1 values were significantly lower in the skeletal muscles of BMD patients compared to healthy volunteers (864 ± 320 ms VS 1149 ± 38 ms, p < 0.01), while fat fraction were significantly higher in patients (33 ± 32 % VS 5 ± 3%, p < 0.01). T1 values negatively correlated with fat fractions (R = -0.98, p < 0.01). A few FF maps reconstructed from the standard 3pt-Dixon presented the classical water/fat swapping artifact while T1 maps were usable for all subjects. The short acquisition time of 10 seconds per slice provides to this T1 approach the ability to perform dynamic acquisitions or ultrafast imaging on the pediatric population while being highly sensitive to FF variations. http://dx.doi.org/10.1016/j.nmd.2017.06.128

P.99 Reliability of DTI-based muscle-volumetry as compared to conventional T1-based manual segmentation R. Rehmann, L. Schlaffke, R. Kley, M. Vorgerd, M. Tegenthoff University hospital Bergmannsheil Bochum, Bochum, Germany The purpose of this study is to compare two methods of muscle segmentation to assess muscle volumes in human calf muscles. In this prospective cross-sectional study, we evaluated lower leg muscles of 18 healthy volunteers (9 females, mean age 27.6 ± 3.8 years) using muscle diffusion tensor imaging (DTI) and tractography. MRI was performed using a 3T MRI (Achieva 3T X, Philips medical Systems) and a 16 channel Philips Torso XL coil. The lower legs were separated into two FOV to improve shimming. For every FOV a sequence of T1w, T2w and diffusion weighted imaging were acquired. Post procession was done with Mathematica 11 and ExploreDTI (running under Matlab). 3D fiber tractography and DTI analysis were performed for each whole muscle structure. Conventional volumetry based on T1w images was manually performed using 3D Slicer software. Correlation analysis between manual segmented volumes and DTI-based tractvolumes were performed as well as Cronbachs alpha analysis to assess reliability of outcome values. The tract-based volumetry showed a significantly positive correlation (p < 0.05) with conventional T1w based volumetry in every lower leg muscle (for both left and right legs). Internal consistency of both methods was found to be significant (Cronbachs alpha 0.656 – 0.908). Absolut volumes of DTI based volumetry show overall higher muscle volumes than the conventional T1w based volumetry. We could show that muscle DTI information can not only be used to assess microstructural muscle properties and DTI parameters, but can also be used to segment calf muscles and to estimate individual muscle volumes. This could be important for longitudinal evaluations or group comparisons of different muscle diseases with DTI. Muscle volume can provide additional disease specific information besides the diffusion specific information and can

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be acquired in the same sequence. The differences in absolute muscle volumes are most likely due to partial volume effects caused by different voxel size of T1w images and DTI-images. http://dx.doi.org/10.1016/j.nmd.2017.06.129

P.100 Auto calculation of muscle impairment ratio utilizing Mercuri grades from CT and MR images of muscle T. Nakayama 1, A. Ishiyama 2, T. Murakami 3, E. Kimura 2, S. Kuru 4 1 Yokohama Rosai Hospital, Kanagawa, Japan; 2 National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Japan; 3 NHO Higashisaitama Hospital, Hasuda, Japan; 4 NHO Suzuka Hospital, Suzuka, Japan Mercuri grading of muscle images of patients with muscular dystrophy is well appreciated and useful for evaluating progression of muscular dystrophies, but it has not been automated until now. Limited number of experts of muscle imaging are confident of Mercuri grading of muscle images, because it is opinionand skill-based. We developed a method to calculate Mercuri grade automatically for widely utilized. We used CT and MR images of thigh and calf muscles taken from the Japanese image database of patients with limb-girdle dystrophy. Firstly, we calculated muscle impairment ratio based on CT images, which was then converted to Mercuri grade ratio. Secondly, we applied the method to T1-weighted MR images. Finally, the radiation absorption dose in muscle and chest CTs in Yokohama Rosai Hospital was analyzed. There is a very close correlation between our automatically calculated Mercuri grades using CT and T1-weighted MR images and visually determined Mercuri grades. The radiation absorption doses in total dose length product in muscle CT (128.8 mGy-cm) were and lower than those (326 mGy-cm) in chest CTs. We have developed a new method using absolute CT values of CT images, and researchers can automatically calculate muscle impairment ratio and Mercuri grade using both CT and T1-weighted MR images. We recommend the use of this automated grading for greater accuracy. In addition, the radiation doses of selected body scan slice segments in muscle CT are lower than those in chest CT. http://dx.doi.org/10.1016/j.nmd.2017.06.130

PSYCHO-SOCIAL ASPECTS P.101 Audit of the TREAT-NMD global DMD and SMA registries: new insights into data collection methods R. Leary 1, A. Oyewole 1, N. Goemans 2, H. Dawkins 3, C. Campbell 4 1 John Walton Muscular Dystrophy Research Centre, Newcastle upon Tyne, UK; 2 Neuromuscular Reference Centre, Leuven, Belgium; 3 Office of Population Health Genomics, Perth, Australia; 4 Children’s Hospital-London Health Sciences Centre and at the University of Western Ontario, London, Canada The global TREAT-NMD Alliance facilitates translational research and accelerates the development of therapies for patients with neuromuscular diseases (NMD). Key tools in this effort are the TREAT-NMD Duchene muscular dystrophy (DMD) and spinal muscular atrophy (SMA) global registries which collect data at multiple national sites, from over 40 countries across Europe, North America, Asia, Australasia and South America. Data are collected with clinical trial readiness in mind, information from genetically confirmed patients such as ambulation status; respiratory function and steroid use are collected. gThe TREAT-NMD DMD and SMA registries have been used for etiological research, clinical trial studies (including patient recruitment), and health policy decisionmaking. To assure data quality, all registries collect a core dataset which is updated on annually, however the “federated” approach of the global registries means heterogeneity exists. In order to evaluate the systems implemented by registries to capture data elements, a questionnaire was developed by the

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Abstracts 2017 / Neuromuscular Disorders 27 (2017) S96–S249

TREAT-NMD global database oversight committee. A total of 59 registries from 35 countries completed the survey (72% response rate). Nearly half are run by academic institutions, followed by medical organisations (37%) and patient organisations (36%). The majority of TREAT-NMD registries are clinician entered; in contrast, patient reported registries made up only 12%. The results showed that 49% of registries were utilising a Microsoft (Access/Excel) database systems, which is likely indicative of the affordable nature of this IT solution. This global audit has improved our understanding of the landscape of rare NMD registries. Irrespective of country and size of registry, similar limitations (financial, technical and logistical) were identified. This study identified key outcomes that will help facilitate changes to contribute to the sustainability and usefulness of TREAT-NMD global registries. http://dx.doi.org/10.1016/j.nmd.2017.06.131

P.102 Registry of congenital neuromuscular disorders in Japan: establishment and implementation A. Ishiyama 1, E. Kimura 2, H. Nakamura 2, H. Komaki 1, M. Sasaki 1, I. Nishino 3 1 National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Japan; 2 Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan; 3 National Institute of Neuroscience, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan Congenital neuromuscular disorders are rare, making clinical studies and recruitment of patients for clinical trials difficult. To facilitate research, we established a Japanese registry of congenital neuromuscular disorders. The registry included patients with congenital neuromuscular disorder whose clinical presentation was consistent with the known pathology, genetic diagnosis, or clinical diagnosis. Patients with dystrophinopathy, myotonic dystrophy, Fukuyama-type congenital muscular dystrophy, or spinal muscular atrophy were excluded because separate registries are available for these disorders. Patients to be included in this registry should have undergone genetic diagnosis and at least one muscular pathological examination. However, patients with only a clinical diagnosis were also included in the registry. To assure the accuracy of diagnosis prior to registration, patients were stratified into 3 levels: 1) diagnostic category A (definitive diagnosis based on neuromuscular pathological examination after muscle biopsy and/or identification of the responsible gene by genetic analysis, without any discrepancy from the known clinical course); 2) category B (no discrepancy from the known clinical symptoms or test findings but failure to identify the cause with muscle biopsy or genetic analysis); and 3) category C (patients who had not undergone diagnostic or genetic analysis based on muscle biopsy, but were clinically diagnosed by experts as not contradicting the known clinical symptoms or test findings of the disease). The registry was established in September 2016. To date, 13 patients have been registered, including 3 with muscular dystrophy, 7 with congenital myopathy, 1 with congenital myasthenia, and 2 with myofibrillar myopathy. This registry should stimulate research on congenital neuromuscular disorders. An important task of this registry will be rapid dissemination of data/materials on clinical trials, treatment, and education. http://dx.doi.org/10.1016/j.nmd.2017.06.132

P.103 Utilization of corticosteroids in DuchenneConnect registry participants L. Cowen 1, M. Mancini 1, A. Lucas 2, A. Martin 2, J. Lavigne 2, J. Donovan 1 1 Catabasis Pharmaceuticals, Cambridge, USA; 2 Parent Project Muscular Dystrophy, Hackensack, USA DuchenneConnect, established by PPMD in 2007, is the largest US-based patient-report registry for Duchenne muscular dystrophy. Patient registries assist in clinical development by understanding current practice, providing insight for protocol feasibility and improving protocol design, while also

connecting patients with actively recruiting trials. To understand the landscape of corticosteroid (CS) use in the US, we performed an analysis of the DuchenneConnect database for CS use in males from the US under 35 who were identified as diagnosed with Duchenne. Data were from 2007–2016 and included 1690 responses from 1595 unique individuals, 83% of whom were age 18 or less. Registry responses for boys under age 10 reported treatment with CS began on average at age 5. Use of CS was maximal at age 8 with 84% of boys on CS, 2% no longer on CS, and 14% never on CS. From age 10 to 19, CS use gradually declined with approximately 50% on CS by late teens. Overall, use of deflazacort (54%) was more common than prednisone/prednisolone (46%). The primary reason for discontinuation of CS was either “problems with side effects” (65%) or “not enough benefit” (28%). The average dose of prednisone/ prednisolone and deflazacort were reported to be similar at 0.7 mg/kg. The average dose of prednisone/prednisolone and deflazacort dose appeared to decline as age increased. Over the last ten years, there appears to be a trend toward increased CS use over age 18. Of those who “rarely or never walk”, 47% were currently on CS, while 28% were previously on CS and 25% had never been on CS. Despite consensus recommendations, a considerable fraction of patients registered with DuchenneConnect were not on CS. Side effects appear to be a significant consideration in decision making. These data reinforce the need for additional treatment options for those affected by Duchenne. http://dx.doi.org/10.1016/j.nmd.2017.06.133

P.104 Data analysis of dystrophinopathy national registry in Japan E. Kimura, M. Mori-Yoshimura, H. Nakamura, H. Komaki, I. Nishino, S. Takeda National Center of Neurology and Psychiatry, Kodaira, Japan The rare disease registry has been recognized as an important tool of clinical research, as the TREAT-NMD global dystrophinopathy patient registry, harmonized with over 30 national registries, has accelerated the international clinical development. Remudy was established in 2009 to run the Japanese national dystrophinopathy registry in collaboration with neuromuscular experts, patient advocacy groups, and the TREAT-NMD. To present current status and data analysis of Japanese dystrophinopathy national registry and discuss its utility for clinical research. Following the charter for TREAT-NMD patient database/registry, remudy took patient-reported system, genetic and clinical curators, and information committee to judge enquiry from third parties. We analyzed and presented clinical and genetic data, and the age of loss of ambulation and death. By February 2016, total registrants were 1,607: 1,485 completed and 122 during process. Clinical classifications were DMD: 1,158, IMD: 36, BMD: 291, and, in addition, female dystrophinopathy: 8. Remudy contributed to feasibility studies and trial recruitments with TREAT-NMD or domestic groups. We presented analysis of loss of ambulation by severity classification, age, and steroid treatment, and the association between major gene mutations and loss of ambulation by the end of October, 2016. In addition, there were 59 death cases, average age was 26.2 ± 9.7. Our results provided useful information for the clinical practice and research. In spite of the results that, by age of DMD every 10 years, the age of loss of ambulation in the 2000s was delayed compared to before, bias due to the delay in updating the information could influence the result. It might be a limitation of the patient self-reported registry. The national dystrophinopathy registry could still demonstrate its utility in clinical research and care standardization. http://dx.doi.org/10.1016/j.nmd.2017.06.134

P.105 DMD Genetic registry in Russia. D. Vlodavets 1, D. Reshetov 2, S. Artemieva 1, I. Shulyakova 1, O. Shidlovskaya 1, A. Monakhova 1, F. Vitrensky 1, D. Kazakov 1, E. Litvinova 1, E. Belousova 1