A Prospective Longitudinal Observational Study in Myotonic Dystrophy Type One: From Clinical Outcomes to Trial Design
Valeria Sansone1, Carola Ferrari Aggradi1, Andrea Lizio1, Michela Nani1, Jeanne Dekdebrun2, Katy Eichinger2, Cynthia Gagnon3, S Subramony4, Richard Roxburgh5, Johanna Hamel6, Jeffrey Statland7, Karlien Mul8, Baziel van Engelen9, Bakri Elsheikh10, William Arnold11, Chris Turner12, Benedikt Schoser13, Thomas Ragole14, Emma Matthews15, Jacinda Sampson16, Massanori Takahashi17, Matthew Wicklund18, Andrea Swenson19, Chamindra Laverty20, Perry Shieh21, Ericka Greene22, Man Hung23, Ruby Langeslay24, Jennifer Raymond24, Charles Thornton25, Nicholas Johnson24
1The NEMO Clinical Center - Neurorehabilitation Unit, University of Milan, 2University of Rochester, 3Sherbrooke University, 4University of Florida, 5Auckland Hospital, 6University of Rochester, Neurology, 7University of Kansas Medical Center, 8Radboud University, 9Radboud University Nijmegen Medical Centre, 10The Ohio State University Wexner Medical Center, 11University of Missouri, 12University College London, 13Friedrich-Baur Institut, 14University of Colorado Department of Neurology, 15Atkinson-Morley Neuromuscular Centre, 16Stanford University, 17Clinical Neurophysiology, Osaka University, 18UT Health San Antonio, 19University of Iowa Hospitals and Clinics, 20UC San Diego, 21UCLA, 22Methodist Hospital, 23Roseman University, 24Virginia Commonwealth University, 25University of Rochester Medical Center
Objective:
The END-DM1 study is an international prospective longitudinal study involving adult with DM1 to establish biomarkers and clinical endpoints using harmonized protocols and procedures. Here we seek to determine the burden of disease and select endpoints for clinical trials.
Background:
Myotonic dystrophy type 1 (DM1) is among the most variable of diseases, with a wide range of disease burden. Large cohorts are required to assess the variable disease burden to determine appropriate endpoints for clinical trials and to standardize trial site processes.
Design/Methods:
Individuals with DM1 who were older than 18 were enrolled in a 24-month observational study. Measures of cognition, quantitative muscle strength, motor function (e.g., 10 MWT, 6 MWT), myotonia, cardiac arrhythmias, pulmonary function, and quality of life were collected. The medical history and age of onset were collected at baseline. A subset of the cohort had muscle biopsies to assess the degree of RNA mis-splicing.
Results:
700 adults with DM1 were enrolled and the baseline results are presented here. The mean age of the participants was 44 years old, and the mean age of onset was 25. Of the participants, 0.33% were non-ambulatory. Strong associations were identified between measures of muscle strength and motor function, while weak associations were identified with myotonia. The cohort had a wide range of performance on the cogstate, a measure of cognition, with some performing above average. Approximately 1/3 of the cohort had arrhythmias identified on the electrocardiogram.
Conclusions:
The Myotonic Dystrophy Clinical Research Network (DMCRN) proves to be a valid framework to collect clinical and demographic data from a large international cohort of adults with DM1. It allows to compare differences between cohorts and to identify potential fast progressors and most sensitive outcomes that may need to be accounted for in the design of future clinical trials.
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