Prospective observational study of FKRP-related limb-girdle muscular dystrophy R9: A GRASP consortium study.

OBJECTIVE: Limb-girdle muscular dystrophy R9 (LGMDR9, formerly known as LGMD2I), caused by variants in the fukutin-related protein (FKRP) gene leads to progressive muscle weakness of the shoulder and pelvic limb-girdles and loss of motor function over time. Clinical management and future trial design are improved by determining which standardized clinical outcome assessments (COA) of function are most appropriate to capture disease presentation and progression, informing endpoint selection and enrollment criteria. The purpose of our study was to evaluate the cross-sectional validity and reliability of clinical outcome assessments in patients with FKRP-related LGMDR9 participating in the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP) natural history study. METHODS: Enrolled patients completed a battery of COA on two consecutive days, including the North Star Assessment for limb girdle-type dystrophies (NSAD), the 100-m timed test (100 m), and the Performance of Upper Limb 2.0 (PUL). RESULTS: A total of 101 patients with FKRP-related LGMDR9 completed COA evaluations. All functional COA were highly and significantly correlated even across constructs, except for the 9-hole peg test. Similarly, all tests demonstrated excellent test-retest reliability across 2-day visits. The NSAD and PUL demonstrate robust psychometrics with good targeting, ordered response thresholds, fit and stability, and limited dependency of items across the scales. CONCLUSIONS: This study has determined the suitability of several functional COA, cross-sectionally, in LGMDR9 to inform future trial design and clinical care

Defining clinical endpoints in limb girdle muscular dystrophy: a GRASP-LGMD study.

BACKGROUND: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. METHODS/DESIGN: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). DISCUSSION: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. TRIAL REGISTRATION: Clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019

Clinical Trial Readiness in Limb Girdle Muscular Dystrophy R1 (LGMDR1): A GRASP Consortium Study

ABSTRACT Objective Identifying functional measures that are both valid and reliable in the limb girdle muscular dystrophy (LGMD) population is critical for quantifying the level of functional impairment related to disease progression in order to establish clinical trial readiness in the context of anticipated therapeutic trials. Methods Through the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP‐LGMD) Consortium, 42 subjects with LGMDR1 were enrolled in a 12‐month natural history study across 11 international sites. Each subject completed a battery of clinical outcome assessments (COA), including the North Star Assessment for Limb Girdle‐Type Dystrophies (NSAD), 10‐m walk/run, and Performance of the Upper Limb (PUL), in addition to several patient‐reported outcome measures (PROM). Results In this baseline cross‐sectional analysis, significant correlations were found between COAs and PROMs, with significant differences in the performance of assessments based on subjects' ambulatory status and genetic variant classification. Interpretation The study has determined that the NSAD and other assessments are valid and reliable measures for quantifying the level of disease impairment in individuals with LGMDR1