Biomarker Development in LGMD2i

Completed

• Conditions: Limb Girdle Muscular Dystrophy; Muscular Dystrophies

• Registration Number: NCT04202627
• Lead Sponsor: ML Bio Solutions, Inc.

Brief Summary

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

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.

Study Timeline

• Study Start: 2019-12-01
• Study First Submitted: 2019-12-11
• Study First Submitted QC: 2019-12-16
• Study First Posted: 2019-12-17
• Primary Completion: 2022-10-10
• Study Completion: 2022-10-10
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-28
• Last Update Posted: 2023-03-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 101

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

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
10-Meter walk (10 MWT) -mobility	Through study completion at 12 months	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
FVC - Pulmonary function	Through study completion at 12 months	The total amount of air exhaled during the forced expiratory volume test (Forced vital capacity - FVC) will be assessed in a sitting position only.
Hand Held Dynamometry (HHD) - isometric strength	Through study completion at 12 months	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.
100-Meter Timed Test (100m) - mobility	Through study completion at 12 months	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.
9 Hole Peg Test (9HPT) - distal upper extremity function	Through study completion at 12 months	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.
NSAD- Motor performance	Through study completion at 12 months	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.
Timed up-and-go (TUG) - mobility	Through study completion at 12 months	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.
Performance of Upper Limb (PUL 2.0) - limb function	Through study completion at 12 months	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.
Timed 4 stair Climb (4SC) - mobility	Through study completion at 12 months	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.

Secondary Outcome Measures

Name	Time	Method
To develop clinical outcome assessments for LGMD2i	Through study completion at 12 months	To determine the sensitivity of the COAs to longitudinal disease progression

Trial Locations

Locations (11)

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

Atrium Health; 🇺🇸 Charlotte, North Carolina, United States

Copenhagen Neuromuscular Center; 🇩🇰 Copenhagen, Denmark

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

University of California Irvine; 🇺🇸 Irvine, California, United States

University of Colorado Anschutz Medical Campus; 🇺🇸 Aurora, Colorado, United States

Kennedy Krieger Institute; 🇺🇸 Baltimore, Maryland, United States

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States

Virginia Commonwealth University; 🇺🇸 Richmond, Virginia, United States

University of Kansas Medical Center; 🇺🇸 Kansas City, Kansas, United States