Biomarker Development in LGMD2i (MLB-01-001)

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.

Study Overview

• Status: Completed
• Conditions: 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 Type: Observational
• Enrollment (Actual): 101

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark
    • Copenhagen neuromuscular center
• United States
  • California
    • Irvine, California, United States, 92697
      • University of California Irvine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Anschutz Medical Campus
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Atrium Health
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To validate potential biomarkers	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.	Baseline, Month 6
To understand the change from baseline in muscle mass using Magnetic Resonance Imaging	To understand the change from baseline in muscle mass using Magnetic Resonance Imaging	Baseline, Month 6, Month 12

Collaborators and Investigators

• Sponsor: ML Bio Solutions, Inc.
• Collaborators: Virginia Commonwealth University
• Investigators: Principal Investigator: Nicholas E Johnson, MD, Virginia Commonwealth University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2019
• Primary Completion (Actual): October 10, 2022
• Study Completion (Actual): October 10, 2022

Study Registration Dates

• First Submitted: December 11, 2019
• First Submitted That Met QC Criteria: December 16, 2019
• First Posted (Actual): December 17, 2019

Study Record Updates

• Last Update Posted (Actual): March 29, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Clinical Research; LGMD; FKRP; ML Bio Solutions; Limb Girdle Muscular Dystrophy; Limb girdle muscular dystrophy type R9 (LGMD R9); LGMD2i
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle
• Other Study ID Numbers: HM20018755

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No