Trial Readiness and Endpoint Assessment in LGMD R1

Study Overview
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Brief Summary
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This is a 24-month, observational study of 100 participants with Limb Girdle Muscular Dystrophy type R1, also known as CAPN3.

Detailed Description
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Limb girdle muscular dystrophies (LGMD) are a group of over 30 heterogenous genetic disorders which have in common a pattern of weakness affecting proximal muscles of the shoulders and hips. LGMD type R1 (LGMDR1; also LGMD2A) is due to loss of function of the muscle structural gene calpain 3 (CAPN3) and causes progressive weakness and muscle wasting, which can lead to loss of ambulation or the ability to maintain a job. LGMDR1 is one of the most common LGMDs in the United States and has no FDA approved therapies but is amenable to gene replacement strategies, regenerative medicine approaches, or myostatin based approaches. There have been rapid advances in gene delivery therapies for Duchenne Muscular Dystrophy and for LGMDR4 that have set the stage for targeted therapeutic development for all LGMDs, and LGMDR1 in particular is at a crossroads: the pace of therapeutic development has outstripped the efforts at clinical trial preparedness. There is a need for a more rigorous natural history study to assist in the design of clinical trials; in particular, identifying biomarkers for early phase development and clinical outcome assessments (COAs) for drug approval studies. This study will enroll 100 subjects across participating sites in the GRASP-LGMD Research Consortium. No treatment will be administered as part of this study. A subset of 80 patients will undergo MR scans at selected imaging sites. Study visits will occur at Baseline Day 1, Baseline Day 2, Month 12, and Month 24.

Official Title
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GRASP-01-003: Trial Readiness and Endpoint Assessment in LGMD R1

Conditions
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LGMD2A, Calpain-3 Deficiency Limb Girdle Muscular Dystrophy Type 2A, Limb Girdle Muscular Dystrophy, Limb Girdle Muscular Dystrophy Type R1

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 12-50 at enrollment Clinically affected (defined as weakness on bedside evaluation in a pattern consistent with LGMDR1) Genetic confirmation of LGMDR1 (presence of homozygous or compound heterozygous pathogenic mutations in CAPN3). Must be able to provide written informed consent and be willing and able to comply with all study requirements. Note: Adult participants must be able to provide consent themselves. Legally authorized representatives are not permitted to consent on behalf of adult participants. Exclusion Criteria: Have contraindications to MRI or MRS (e.g., non-MR compatible implanted medical devices or severe claustrophobia) Non-ambulatory as defined by those who are not able to walk 10 meters without assistive devices (ankle foot orthotics excluded) Positive pregnancy test at any timepoint during the trial Have dominantly inherited CAPN3 mutations (LGMDD4) 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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 50 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 |
| --- | --- |
| LGMD Type R1/LGMD2A/CAPN3<br>No intervention will be administered. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Validate the NSAD as a clinical outcome assessment in LGMD R1 | 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 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Validate muscle fat fraction as a biomarker | Quantitative muscle MRI (qMR) of the upper and lower leg muscles will be performed and muscle fat fraction will be measured. | Baseline to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LGMD, Limb Girdle Muscular Dystrophy, LGMD R1, LGMD2A, CAPN3