Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD)

Study Overview
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Brief Summary
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Limb Girdle Muscular Dystrophy comprise a group of disorders made up of over 30 mutations which share a common phenotype of progressive weakness of the shoulder and hip girdle muscles. While the individual genetic mutations are rare, as a cohort, LGMDs are one of the four most common muscular dystrophies. The overall goal of project 1 is to define the key phenotypes as measured by standard clinical outcome assessments (COAs) for limb girdle muscular dystrophies (LGMD) to hasten therapeutic development.

Detailed Description
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The genetic heterogeneity has been a barrier to broad natural history efforts, with prior investigations often limited to single gene mutations. Much attention is paid to the variability within individual mutations (e.g. distal presentations), as opposed to defining the best strategy for measuring change in overall LGMD disease burden. This presents a major dilemma for LGMD rare disease research: how to balance diverse genes leading to overlapping phenotypes, versus variants in the same gene leading to divergent phenotypes. What is clear, is as a group, LGMDs are chronic and progressive leading to significant lifetime morbidity and represent a large unmet clinical need. Recent developments in the investigator's genetic understanding of LGMD and molecular approaches to therapy have led to proposed gene replacement therapies for at least three of the LGMD mutations. Several of these gene replacement therapies are currently in pre-clinical/phase 1 testing, leading to an urgent need for natural history data. In addition, non-specific therapies which target muscle mass or function are being tested in other muscular dystrophies and may prove beneficial for LGMD.

Official Title
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GRASP-LGMD: Defining Clinical Endpoints in LGMD

Conditions
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Limb Girdle Muscular Dystrophy, Muscular Dystrophies

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - Arm 1: Age between 4-65 at enrollment Clinically affected (defined as weakness on bedside evaluation in either a limb-girdle pattern, or in a distal extremity) A genetically or functionally confirmed mutation in ANO5, CAPN3, DYSF, DNAJB6 or SGCA-G. Willing and able to give informed consent and follow all study procedures and requirements Inclusion Criteria - Arm 2: Age between 4-65 at enrollment Clinically affected (defined as weakness on bedside evaluation in either a limb-girdle pattern, or in a distal extremity) a genetically confirmed mutation in SGCA-G Willing and able to give informed consent and follow all study procedures and requirements Exclusion Criteria - Arm 1: Any other illness that would interfere with the ability to undergo safe testing or would interfere with interpretation of the results in the opinion of the site investigator. History of a bleeding disorder, platelet count <50,000, current use of an anticoagulant. Positive pregnancy test at time any timepoint during the trial. Exclusion Criteria - Arm 2: Any other illness that would interfere with the ability to undergo safe testing or would interfere with interpretation of the results in the opinion of the site investigator. History of a bleeding disorder, platelet count <50,000, current use of an anticoagulant Positive pregnancy test at time any timepoint during the trial.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CAPN3 (LGMD2A)<br>Clinical Assessments, Biomarkers | |
| DYSF (LGMD2B)<br>Clinical Assessments, Biomarkers | |
| ANO5 (LGMD2L)<br>Clinical Assessments, Biomarkers | |
| DNAJB6 (LGMD1D)<br>Clinical Assessments, Biomarkers | |
| Sarcoglycan (LGMD2D) (LGMD2E) (LGMD2C) (LGMD2F)<br>Clinical assessments | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mobility | Mobility will be measured using the 100 Meter Timed Test (100m) in which the participant is asked to complete 2 laps around 2 cones set 25 meters apart as quickly as safely possible, running if able, and the time in seconds is recorded. | Baseline to 12 months | 
| Change in motor performance | The North Star Assessment for Dysferlinopathy (NSAD) is a functional scale specifically designed to measure motor performance in individuals with LGMD. It consists of 29 items that are considered clinically relevant items from the North Star Ambulatory Assessment and the Motor Function Measure 20 with a maximum score of 54 and higher scores indicate higher functional abilities. | Baseline to 12 months | 
| Change in upper limb function characteristics | The Performance of Upper Limb 2.0 (PUL) scale measures the progression of weakness and natural history of functional decline in Duchenne muscular dystrophy. There are 22 scored items; a score of 42 indicates the highest level of independent function and 0 the lowest. | Baseline to 12 months | 
| Change in workspace volume | Workspace volume (WSV) will be measured using ACTIVE, an interactive video game which will calculate the combination of upper extremity and trunk strength and function in cubic meters. | Baseline to 12 months | 
| Change in Forced vital capacity (FVC) | Volume of air forcefully exhaled will be measured using Spirometry performed in a sitting position using standardized equipment | Baseline to 12 months | 
| Changes in Forced expiratory volume (FEV1) | Volume of air forcefully exhaled in one second will be measured using Spirometry performed in a sitting position using standardized equipment | Baseline to 12 months | 
| Change in activity limitations | ACTIVLIM is a patient-reported measure of activity limitations for individuals with upper and/or lower limb impairments, which measures the ability to perform daily activities. | Baseline to 12 months | 
| Change in upper extremity disability | The Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH) questionnaire measures levels of disability in an individual's upper extremity. | Baseline to 12 months | 
| Change in self-reported physical health | PROMIS Physical Health is part of a set of patient-reported measures developed by a National Institute of Health that evaluates general physical health by assessing fatigue, pain intensity, pain interference, physical function, sleep disturbance, dyspnea, gastrointestinal symptoms, itch, pain behavior, pain quality, sexual function, and sleep related impairment. | Baseline to 12 months | 
| Change in self-reported mental health | PROMIS Mental Health is part of a set of patient-reported measures developed by a National Institute of Health that evaluates general mental health by assessing anxiety, depression, alcohol use, anger, cognitive function, life satisfaction, meaning and purpose, positive affect, psychosocial illness impact, self-efficacy for managing chronic conditions, smoking, and substance use | Baseline to 12 months | 
| Change in self-reported social health | PROMIS Social Health is part of a set of patient-reported measures developed by a National Institute of Health that evaluates general social health by assessing ability to participate in social roles and activities, companionship, satisfaction with social roles and activities, social isolation, and social support. | Baseline to 12 months | 
| Change in whole body health | The Quality of Life in Genetic Neuromuscular Disease Questionnaire was developed to measure whole-body health impact in neuromuscular diseases. | Baseline to 12 months | 
| Change in overall health | Domain Delta Questionnaire is a patient reported measure that assesses overall health over the previous 12 months. | Baseline to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SGCA, SGCB, SGCD, SGCG, LGMD, Limb Girdle Muscular Dystrophy, CAPN3, ANO5, DYSF, DNAJB6, Sarcoglycan