Biomarker Development in LGMD2i (MLB-01-001)

• ClinicalTrials.gov Identifier: NCT04202627
• Recruitment Status: Completed
• First Posted: December 17, 2019
• Last Update Posted: March 29, 2023
• Sponsor: ML Bio Solutions, Inc.
• Collaborator: Virginia Commonwealth University
• Information provided by (Responsible Party): ML Bio Solutions, Inc.

Study Description

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.

Condition or disease
Muscular Dystrophies; Limb Girdle Muscular Dystrophy

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 Design

• Study Type: Observational
• Actual Enrollment: 101 participants
• Observational Model: Cohort
• Time Perspective: Other
• Official Title: Biomarker Development in LGMD2i
• Actual Study Start Date: December 1, 2019
• Actual Primary Completion Date: October 10, 2022
• Actual Study Completion Date: October 10, 2022

Groups and Cohorts

Outcome Measures

Primary Outcome Measures :

1. 10-Meter walk (10 MWT) -mobility [ Time Frame: 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
2. 100-Meter Timed Test (100m) - mobility [ Time Frame: 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.
3. NSAD- Motor performance [ Time Frame: 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.
4. Timed up-and-go (TUG) - mobility [ Time Frame: 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.
5. FVC - Pulmonary function [ Time Frame: 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.
6. Timed 4 stair Climb (4SC) - mobility [ Time Frame: 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.
7. 9 Hole Peg Test (9HPT) - distal upper extremity function [ Time Frame: 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.
8. Performance of Upper Limb (PUL 2.0) - limb function [ Time Frame: 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.
9. Hand Held Dynamometry (HHD) - isometric strength [ Time Frame: 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.

Secondary Outcome Measures :

1. To develop clinical outcome assessments for LGMD2i [ Time Frame: Through study completion at 12 months ]
   To determine the sensitivity of the COAs to longitudinal disease progression

Other Outcome Measures:

1. To validate potential biomarkers [ Time Frame: Baseline, Month 6 ]

   To develop a reliable measure of dystroglycosylation in human skeletal muscle by using fresh tissue biopsy.

   A muscle biopsy will be collected at baseline and 6 months from the right tibialis anterior. The biopsy site will be uniform between investigators. The investigators will utilize a 14-gauge Supercore biopsy instrument to take a total of three aspirations from the same site.

2. To understand the change from baseline in muscle mass using Magnetic Resonance Imaging [ Time Frame: Baseline, Month 6, Month 12 ]
   To understand the change from baseline in muscle mass using Magnetic Resonance Imaging

Biospecimen Retention:   Samples With DNA

Blood and Tissue samples will be taken for biomarker development and retained for future research. No clinical diagnosis will be given to patients.

Eligibility Criteria

• Ages Eligible for Study: 10 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Study participants will be identified through self-selection and direct recruitment options. Participants will be identified from the population of individuals who are followed at the neuromuscular clinics. Participants will also be solicited from the Global FKRP registry.

Criteria

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

Contacts and Locations

Locations

United States, California

University of California Irvine

Irvine, California, United States, 92697

United States, Colorado

University of Colorado Anschutz Medical Campus

Aurora, Colorado, United States, 80045

United States, Florida

University of Florida

Gainesville, Florida, United States, 32610

United States, Iowa

University of Iowa

Iowa City, Iowa, United States, 52242

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Maryland

Kennedy Krieger Institute

Baltimore, Maryland, United States, 21205

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Atrium Health

Charlotte, North Carolina, United States, 28207

United States, Ohio

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

Denmark

Copenhagen Neuromuscular Center

Copenhagen, Denmark

Sponsors and Collaborators

ML Bio Solutions, Inc.

Virginia Commonwealth University

Investigators

• Principal Investigator: Nicholas E Johnson, MD; Virginia Commonwealth University

More Information

• Responsible Party: ML Bio Solutions, Inc.
• ClinicalTrials.gov Identifier: NCT04202627
• Other Study ID Numbers: HM20018755
• First Posted: December 17, 2019
• Last Update Posted: March 29, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by ML Bio Solutions, Inc.:

LGMD; FKRP; Clinical Research; ML Bio Solutions; Limb Girdle Muscular Dystrophy; Limb girdle muscular dystrophy type R9 (LGMD R9); LGMD2i

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn