MLB-01-001: Biomarker Development in LGMD2i

Sponsor

ML Bio Solutions, Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04202627

Collaborator

Virginia Commonwealth University (Other)

101

Enrollment

Locations

Anticipated Duration (Months)

9.2

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

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	Intervention/Treatment	Phase
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 :

Dec 1, 2019

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Outcome Measures

Primary Outcome Measures

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
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.
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.
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.
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.
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.
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.
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.

Secondary Outcome Measures

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

Other Outcome Measures

To validate potential biomarkers [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.
To understand the change from baseline in muscle mass using Magnetic Resonance Imaging [Baseline, Month 6, Month 12]
To understand the change from baseline in muscle mass using Magnetic Resonance Imaging

Eligibility Criteria

Criteria

Ages Eligible for Study:

10 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
1	University of California Irvine	Irvine	California	United States	92697
2	University of Colorado Anschutz Medical Campus	Aurora	Colorado	United States	80045
3	University of Florida	Gainesville	Florida	United States	32610
4	University of Iowa	Iowa City	Iowa	United States	52242
5	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
6	Kennedy Krieger Institute	Baltimore	Maryland	United States	21205
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
8	Atrium Health	Charlotte	North Carolina	United States	28207
9	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
10	Virginia Commonwealth University	Richmond	Virginia	United States	23298
11	Copenhagen Neuromuscular Center	Copenhagen		Denmark