Toward Functional Outcome Measures for Clinical Trials in DM1

Published on Sat, 09/24/2016

The Problem of Clinical Outcome Measures in DM1

Despite much work being done to develop knowledge, clinical development tools, and relationships to de-risk the entire therapeutic development pipeline for DM1, the status of clinical trial outcome measures has remained a substantive hurdle. The intersection of the slow progression of most aspects of DM with the need for timely go/no decision-making on safety and efficacy of candidate therapeutics highlights the difficulties in arriving at a pragmatic battery of outcome measures. Moreover, the heterogeneity of presentation and progression of DM1 means that outcome measure development and validation can be driven only by sufficiently powered natural history studies using optimized operating procedures across multiple clinical sites.

Progress Toward DM1 Outcome Measures

Dr. Aura Cecilia Jimenez-Moreno (Newcastle University) and colleagues, working within the international Outcome Measures for Myotonic Dystrophy (OMMYD) group, have published a large cohort, cross-sectional and longitudinal analysis of a battery of tests aimed at identifying functional outcome measures for DM1 (Jimenez-Moreno et al., 2019). Measures included in the study were 6-minute walk test, 30-second sit and stand test, timed 10-minute walk test, timed 10-minute walk/run test, and 9-hole peg test, following specified operating procedures.

The OMMYD study was initiated with cross-sectional analysis of the five outcome measures in a cohort of 213 subjects recruited at two sites (University College London and Newcastle University; 98 subjects then were followed longitudinally at the NU site). The battery of tests selected here appears feasible for use in interventional clinical trials as 96% of the participants completed all outcome measures in a single test session. Both body mass index and disease severity associate with functional measures. Gender differences in outcome measure performance were a bit complex, with their relationship to established phenotypic variations in DM1 by gender (Dogan et al., 2016) unclear. Intra-session reliability analysis showed that two trials of each of the functional tests were sufficient to provide reliable/valid scores. Average scores of most functional tests significantly correlated with subject quantitative muscle strength, SARA score, and results of PROMs (MDHI and DM1-ActivC).

Longitudinal analysis of the Newcastle cohort involved a second follow-up at 12 months. This cohort included both adult- and late-onset phenotypic DM1. Except for the 9-hole peg test, all the functional tests and SARA showed significant changes from the first evaluation—changes were similar in both phenotypic groups.

Limitations and Path Forward

This study did not, however, report out on study subject perception of the meaningfulness of the functional changes in outcome measures (i.e., potential changes in burden of disease) detected across the 12-month longitudinal study period. This information will be vital to how regulatory agencies view the impact of a candidate therapeutic. The authors also note that use of independent evaluations on two successive days would have provided important data on instrument validity and measurement error. Assessment of inter-rater variations also was not determined. Finally, it was suggested that larger cohorts will be needed to account for differences in subgroups identifiable within the study cohort.

Overall, the OMMYD report makes many valuable specific recommendations for subsequent natural history studies geared toward assessing and validating clinical outcome measures for interventional trials in DM1. Continued efforts by OMMYD, the U.S.-based Myotonic Dystrophy Clinical Research Network, and other teams, particularly coordination among these efforts, may be essential to establish a validated protocol that is both feasible and sufficient for decision-making in clinical trials.


Analysis of the functional capacity outcome measures for myotonic dystrophy.
Jimenez-Moreno AC, Nikolenko N, Kierkegaard M, Blain AP, Newman J, Massey C, Moat D, Sodhi J, Atalaia A, Gorman GS, Turner C, Lochmüller H.
Ann Clin Transl Neurol. 2019 Aug;6(8):1487-1497. doi: 10.1002/acn3.50845. Epub 2019 Jul 22.

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.
Dogan C, De Antonio M, Hamroun D, Varet H, Fabbro M, Rougier F, Amarof K, Arne Bes MC, Bedat-Millet AL, Behin A, Bellance R, Bouhour F, Boutte C, Boyer F, Campana-Salort E, Chapon F, Cintas P, Desnuelle C, Deschamps R, Drouin-Garraud V, Ferrer X, Gervais-Bernard H, Ghorab K, Laforet P, Magot A, Magy L, Menard D, Minot MC, Nadaj-Pakleza A, Pellieux S, Pereon Y, Preudhomme M, Pouget J, Sacconi S, Sole G, Stojkovich T, Tiffreau V, Urtizberea A, Vial C, Zagnoli F, Caranhac G, Bourlier C, Riviere G, Geille A, Gherardi RK, Eymard B, Puymirat J, Katsahian S, Bassez G.
PLoS One. 2016 Feb 5;11(2):e0148264. doi: 10.1371/journal.pone.0148264. eCollection 2016.