Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD) (GRASP-01-001)

• ClinicalTrials.gov Identifier: NCT03981289
• Recruitment Status: Recruiting
• First Posted: June 10, 2019
• Last Update Posted: May 1, 2024
• Sponsor: Virginia Commonwealth University
• Collaborators: Newcastle University; University of California, Irvine; University of Kansas; University of Colorado Anschutz Medical Center; Nationwide Children's Hospital; Washington University School of Medicine; University of Iowa; Hugo W. Moser Research Institute at Kennedy Krieger, Inc.; University of Minnesota
• Information provided by (Responsible Party): Virginia Commonwealth University

Tracking Information

• First Submitted Date: June 3, 2019
• First Posted Date: June 10, 2019
• Last Update Posted Date: May 1, 2024
• Actual Study Start Date: June 14, 2019
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 7, 2019)

• Change in mobility [ Time Frame: Baseline to 12 months ]
  Mobility will be measured using the 100 Meter Timed Test (100m) in which the participant is asked to complete 2 laps around 2 cones set 25 meters apart as quickly as safely possible, running if able, and the time in seconds is recorded.
• Change in motor performance [ Time Frame: Baseline to 12 months ]
  The 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.
• Change in upper limb function characteristics [ Time Frame: Baseline to 12 months ]
  The Performance of Upper Limb 2.0 (PUL) scale measures the progression of weakness and natural history of functional decline in Duchenne muscular dystrophy. There are 22 scored items; a score of 42 indicates the highest level of independent function and 0 the lowest.
• Change in workspace volume [ Time Frame: Baseline to 12 months ]
  Workspace volume (WSV) will be measured using ACTIVE, an interactive video game which will calculate the combination of upper extremity and trunk strength and function in cubic meters.
• Change in Forced vital capacity (FVC) [ Time Frame: Baseline to 12 months ]
  Volume of air forcefully exhaled will be measured using Spirometry performed in a sitting position using standardized equipment
• Changes in Forced expiratory volume (FEV1) [ Time Frame: Baseline to 12 months ]
  Volume of air forcefully exhaled in one second will be measured using Spirometry performed in a sitting position using standardized equipment
• Change in activity limitations [ Time Frame: Baseline to 12 months ]
  ACTIVLIM is a patient-reported measure of activity limitations for individuals with upper and/or lower limb impairments, which measures the ability to perform daily activities.
• Change in upper extremity disability [ Time Frame: Baseline to 12 months ]
  The Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH) questionnaire measures levels of disability in an individual's upper extremity.
• Change in self-reported physical health [ Time Frame: Baseline to 12 months ]
  PROMIS Physical Health is part of a set of patient-reported measures developed by a National Institute of Health that evaluates general physical health by assessing fatigue, pain intensity, pain interference, physical function, sleep disturbance, dyspnea, gastrointestinal symptoms, itch, pain behavior, pain quality, sexual function, and sleep related impairment.
• Change in self-reported mental health [ Time Frame: Baseline to 12 months ]
  PROMIS Mental Health is part of a set of patient-reported measures developed by a National Institute of Health that evaluates general mental health by assessing anxiety, depression, alcohol use, anger, cognitive function, life satisfaction, meaning and purpose, positive affect, psychosocial illness impact, self-efficacy for managing chronic conditions, smoking, and substance use
• Change in self-reported social health [ Time Frame: Baseline to 12 months ]
  PROMIS Social Health is part of a set of patient-reported measures developed by a National Institute of Health that evaluates general social health by assessing ability to participate in social roles and activities, companionship, satisfaction with social roles and activities, social isolation, and social support.
• Change in whole body health [ Time Frame: Baseline to 12 months ]
  The Quality of Life in Genetic Neuromuscular Disease Questionnaire was developed to measure whole-body health impact in neuromuscular diseases.
• Change in overall health [ Time Frame: Baseline to 12 months ]
  Domain Delta Questionnaire is a patient reported measure that assesses overall health over the previous 12 months.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy (LGMD)
• Official Title: GRASP-LGMD: Defining Clinical Endpoints in LGMD
• Brief Summary: Limb Girdle Muscular Dystrophy comprise a group of disorders made up of over 30 mutations which share a common phenotype of progressive weakness of the shoulder and hip girdle muscles. While the individual genetic mutations are rare, as a cohort, LGMDs are one of the four most common muscular dystrophies. The overall goal of project 1 is to define the key phenotypes as measured by standard clinical outcome assessments (COAs) for limb girdle muscular dystrophies (LGMD) to hasten therapeutic development.

Detailed Description

The genetic heterogeneity has been a barrier to broad natural history efforts, with prior investigations often limited to single gene mutations. Much attention is paid to the variability within individual mutations (e.g. distal presentations), as opposed to defining the best strategy for measuring change in overall LGMD disease burden. This presents a major dilemma for LGMD rare disease research: how to balance diverse genes leading to overlapping phenotypes, versus variants in the same gene leading to divergent phenotypes. What is clear, is as a group, LGMDs are chronic and progressive leading to significant lifetime morbidity and represent a large unmet clinical need.

Recent developments in the investigator's genetic understanding of LGMD and molecular approaches to therapy have led to proposed gene replacement therapies for at least three of the LGMD mutations. Several of these gene replacement therapies are currently in pre-clinical/phase 1 testing, leading to an urgent need for natural history data. In addition, non-specific therapies which target muscle mass or function are being tested in other muscular dystrophies and may prove beneficial for LGMD.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Other
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: GRASP-LGMD covers a broad geographical distribution and we expect the race and ethnicity to match that of the United States. However, past experience in both the clinical and research LGMD populations shows that some minority subgroups are under-represented in research studies. To assist with recruitment of persons from diverse backgrounds we will utilize the Community and Special Populations Engagement Personnel supported through the CTSA networks to reach out to under-represented communities through a variety of local techniques which could include direct outreach, advertising with local advocacy groups, organizations, or newsletters, and local advertising using a variety of media which could include Social Media (e.g. Facebook, Twitter), radio, and newspapers.

Condition

• Limb Girdle Muscular Dystrophy
• Muscular Dystrophies

• Intervention: Not Provided

Study Groups/Cohorts

• CAPN3 (LGMD2A)
  Clinical Assessments, Biomarkers
• DYSF (LGMD2B)
  Clinical Assessments, Biomarkers
• ANO5 (LGMD2L)
  Clinical Assessments, Biomarkers
• DNAJB6 (LGMD1D)
  Clinical Assessments, Biomarkers
• Sarcoglycan (LGMD2D) (LGMD2E) (LGMD2C) (LGMD2F)
  Clinical assessments

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 7, 2019): 80
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: June 30, 2025
• Estimated Primary Completion Date: June 30, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria - Arm 1:

• Age between 4-65 at enrollment
• Clinically affected (defined as weakness on bedside evaluation in either a limb-girdle pattern, or in a distal extremity)
• A genetically or functionally confirmed mutation in ANO5, CAPN3, DYSF, DNAJB6 or SGCA-G.
• Willing and able to give informed consent and follow all study procedures and requirements

Inclusion Criteria - Arm 2:

• Age between 4-65 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 SGCA-G
• Willing and able to give informed consent and follow all study procedures and requirements

Exclusion Criteria - Arm 1:

• 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 at time any timepoint during the trial.

Exclusion Criteria - Arm 2:

• 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 at time any timepoint during the trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Ruby Langeslay; 804-828-8481; Ruby.Langeslay@vcuhealth.org

Contact: Jennifer Raymond; 804-828-6318; Jennifer.Raymond@vcuhealth.org

• Listed Location Countries: United Kingdom, United States

Administrative Information

• NCT Number: NCT03981289
• Other Study ID Numbers: HM20018721; GRASP-LGMD ( Other Identifier: Virginia Commonwealth University )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: Aggregated and deidentified data will be shared with qualified investigators upon majority approval of the LGMD investigators

• Current Responsible Party: Virginia Commonwealth University
• Original Responsible Party: Same as current
• Current Study Sponsor: Virginia Commonwealth University
• Original Study Sponsor: Same as current

Collaborators

• Newcastle University
• University of California, Irvine
• University of Kansas
• University of Colorado Anschutz Medical Center
• Nationwide Children's Hospital
• Washington University School of Medicine
• University of Iowa
• Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
• University of Minnesota

Investigators

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

• PRS Account: Virginia Commonwealth University
• Verification Date: April 2024