Biomarker Development in LGMD2i

Study Overview
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Brief Summary
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The overall goal of this natural history study is to define the key LGMD2i phenotypes as measured by standard clinical outcome assessments (COAs), and to validate a muscle biomarker for LGMD2i to support therapeutic development.

Detailed Description
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Limb Girdle Muscular Dystrophy (LGMD) 2i is an autosomal recessive form of LGMD that is due to missense mutations in the Fukutin-related protein (FKRP) gene. Patients develop progressive proximal muscle weakness that leads to loss of ambulation. Patients will also commonly develop a cardiomyopathy and respiratory compromise. There are promising new therapies that have been developed and as a result therapeutic trials are approaching. The rationale for this study is to define appropriate COAs for LGMD2i, which will facilitate therapeutic development and ensure properly powered clinical trials. In addition, measurement of dystroglycan in muscles represents a potential muscle biomarker that could be used in early phase clinical trials as a measure of target engagement. The clinical utility of changes in dystroglycan has not been validated in human samples.

Official Title
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Biomarker Development in LGMD2i

Conditions
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Muscular Dystrophies, Limb Girdle Muscular Dystrophy

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 10-65 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 FKRP (LGMD2i) Willing and able to give informed consent and follow all procedures and requirements Exclusion Criteria: 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 A 10-meter walk time of <4 seconds

Ages Eligible for Study
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Minimum Age: 10 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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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 10-Meter walk (10 MWT) -mobility | The 10 MWT will be used to determine the ambulatory Cohort for of all subjects. For the purposes of this study, the definitions for ambulation are as follows: Cohort A: completes the 10 MWT unaided in ≥ 4 to ≤ 12 seconds Cohort B: completes the walk unaided in > 12 seconds or is non-ambulatory | Through study completion at 12 months | 
| 100-Meter Timed Test (100m) - mobility | The 100m timed test is designed to capture maximal ambulatory capacity. The participant will be asked to complete 4 full laps around 2 cones set 25 meters apart as quickly and as safely as possible, including running if able. This will not be assessed in participants with a 10-meter walk time greater than 12 seconds. | Through study completion at 12 months | 
| NSAD- Motor performance | 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. | Through study completion at 12 months | 
| Timed up-and-go (TUG) - mobility | The TUG is an assessment used to evaluate functional ambulation, balance, and fall risk. The fastest time to rise from a chair, walk 3 meters, and return to sitting independently without an assistive device will be recorded. This will not be assessed in Cohort B participants. | Through study completion at 12 months | 
| FVC - Pulmonary function | The total amount of air exhaled during the forced expiratory volume test (Forced vital capacity - FVC) will be assessed in a sitting position only. | Through study completion at 12 months | 
| Timed 4 stair Climb (4SC) - mobility | The 4SC quantifies the time required for the participant to ascend 4 standard steps. This will not be assessed in participants with a 10 meter walk time greater than 12 seconds. | Through study completion at 12 months | 
| 9 Hole Peg Test (9HPT) - distal upper extremity function | The 9HPT is a quantitative measure of distal upper extremity function. It measures the time required for patients to place 9 pegs in the 9 holes on the board and then remove them as quickly as possible. | Through study completion at 12 months | 
| Performance of Upper Limb (PUL 2.0) - limb function | The PUL is a tool designed for assessing upper limb function in persons with neuromuscular disorders. It was developed as a conceptual framework reflecting the progression of weakness and natural history of functional decline in Duchenne muscular dystrophy (DMD). There are 22 scored items; a score of 42 indicates the highest level of independent function and 0 the lowest. | Through study completion at 12 months | 
| Hand Held Dynamometry (HHD) - isometric strength | HHD using the MicroFET2 myometer will be utilized to capture isometric strength in target muscle groups. Maximum strength in kilograms will be reported for each muscle group provided a continuous scale variable for analysis. | Through study completion at 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To develop clinical outcome assessments for LGMD2i | To determine the sensitivity of the COAs to longitudinal disease progression | Through study completion at 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LGMD, FKRP, Clinical Research, ML Bio Solutions, Limb Girdle Muscular Dystrophy, Limb girdle muscular dystrophy type R9 (LGMD R9), LGMD2i