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Trial Readiness and Endpoint Assessment in LGMD R1 (GRASP-01-003)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT05618080
Recruitment Status : Not yet recruiting
First Posted : November 16, 2022
Last Update Posted : June 1, 2023
University of California, Irvine
University of Kansas
University of Colorado, Denver
Nationwide Children's Hospital
Washington University School of Medicine
University of Iowa
University of Florida
University of Minnesota
Information provided by (Responsible Party):
Virginia Commonwealth University

Brief Summary:
This is a 24-month, observational study of 100 participants with Limb Girdle Muscular Dystrophy type R1, also known as CAPN3.

Condition or disease
Calpain-3 Deficiency Limb Girdle Muscular Dystrophy Type 2A Limb Girdle Muscular Dystrophy Limb Girdle Muscular Dystrophy Type R1 LGMD2A

Detailed Description:

Limb girdle muscular dystrophies (LGMD) are a group of over 30 heterogenous genetic disorders which have in common a pattern of weakness affecting proximal muscles of the shoulders and hips. LGMD type R1 (LGMDR1; also LGMD2A) is due to loss of function of the muscle structural gene calpain 3 (CAPN3) and causes progressive weakness and muscle wasting, which can lead to loss of ambulation or the ability to maintain a job. LGMDR1 is one of the most common LGMDs in the United States and has no FDA approved therapies but is amenable to gene replacement strategies, regenerative medicine approaches, or myostatin based approaches. There have been rapid advances in gene delivery therapies for Duchenne Muscular Dystrophy and for LGMDR4 that have set the stage for targeted therapeutic development for all LGMDs, and LGMDR1 in particular is at a crossroads: the pace of therapeutic development has outstripped the efforts at clinical trial preparedness.

There is a need for a more rigorous natural history study to assist in the design of clinical trials; in particular, identifying biomarkers for early phase development and clinical outcome assessments (COAs) for drug approval studies.

This study will enroll 100 subjects across participating sites in the GRASP-LGMD Research Consortium. No treatment will be administered as part of this study. A subset of 80 patients will undergo MR scans at selected imaging sites. Study visits will occur at Baseline Day 1, Baseline Day 2, Month 12, and Month 24.

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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: GRASP-01-003: Trial Readiness and Endpoint Assessment in LGMD R1
Estimated Study Start Date : September 5, 2023
Estimated Primary Completion Date : March 5, 2028
Estimated Study Completion Date : June 5, 2028

No intervention will be administered.

Primary Outcome Measures :
  1. Validate the NSAD as a clinical outcome assessment in LGMD R1 [ Time Frame: Baseline to 24 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.

Secondary Outcome Measures :
  1. Validate muscle fat fraction as a biomarker [ Time Frame: Baseline to 12 months ]
    Quantitative muscle MRI (qMR) of the upper and lower leg muscles will be performed and muscle fat fraction will be measured.

Other Outcome Measures:
  1. Change in mobility (100-meter walk) [ Time Frame: Baseline to 24 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.

  2. Change in Forced vital capacity (FVC) [ Time Frame: Baseline to 24 months ]
    Volume of air forcefully exhaled will be measured using Spirometry performed in sitting and supine positions using standardized equipment

  3. Change in Forced expiratory volume (FEV1) [ Time Frame: Baseline to 24 months ]
    Volume of air forcefully exhaled in one second will be measured using Spirometry performed in a sitting position using standardized equipment

  4. Change in upper limb function characteristics (PUL) [ Time Frame: Baseline to 24 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.

  5. Change in Timed Up-And-Go (TUG) [ Time Frame: Baseline to 24 months ]
    Time to stand from a chair, walk 3 meters, and return to seated will be recorded. The test will be repeated three times at applicable visits.

  6. Change in 4 Stair Climb [ Time Frame: Baseline to 24 months ]
    Time to ascend 4 steps as quickly and safely as possible, using handrails if needed, will be assessed.

  7. Change in Handheld Dynamometry and Pinch Grip [ Time Frame: Baseline to 24 months ]
    Maximum hand, pinch, and grip strength will be assessed using a myometer. The participant will be asked to squeeze a handheld tool.

  8. Change in self-reported social, mental, and physical health (PROMIS-57) [ Time Frame: Baseline to 24 months ]

    PROMIS is a set of patient-reported measures developed by the NIH. The social health set of questions 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.

    The mental health set 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.

    The physical health set 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.

  9. Change in activity limitations (ACTLIVLIM) [ Time Frame: Baseline to 24 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.

  10. Change in overall health (Domain Delta) [ Time Frame: Baseline to 24 months ]
    Domain Delta Questionnaire is a patient reported measure that assesses overall health over the previous 12 months.

  11. Change in overall health-related quality of life (LGMD-HI) [ Time Frame: Baseline to 24 months ]
    The LGMD Health Index is a disease-specific, patient reported measure that assesses overall health-related quality of life in LGMD.

Biospecimen Retention:   Samples With DNA
Blood samples will be taken for biomarker development and retained for future research. No clinical diagnosis will be given to patients.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   12 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The study population includes ambulatory individuals aged 12-50 at enrollment who are clinically affected by and have genetic confirmation of LGMDR1.

Inclusion Criteria:

  • Age between 12-50 at enrollment
  • Clinically affected (defined as weakness on bedside evaluation in a pattern consistent with LGMDR1)
  • Genetic confirmation of LGMDR1 (presence of homozygous or compound heterozygous pathogenic mutations in CAPN3).

Exclusion Criteria:

  • Have contraindications to MRI or MRS (e.g., non-MR compatible implanted medical devices or severe claustrophobia)
  • Non-ambulatory as defined by those who are not able to walk 10 meters without assistive devices (AFOs excluded)
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05618080

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Contact: Jennifer Raymond 804-828-6318 jennifer.raymond@vcuhealth.org
Contact: Ruby Langeslay ruby.langeslay@vcuhealth.org

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United States, Virginia
Virginia Commonwealth University
Richmond, Virginia, United States, 23298
Contact: Ruby Langeslay       ruby.langeslay@vcuhealth.org   
Contact: Abel Bulti       abel.bulti@vcuhealth.org   
Principal Investigator: Nicholas Johnson, MD         
Sponsors and Collaborators
Virginia Commonwealth University
University of California, Irvine
University of Kansas
University of Colorado, Denver
Nationwide Children's Hospital
Washington University School of Medicine
University of Iowa
University of Florida
University of Minnesota
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Principal Investigator: Nicholas Johnson, MD Virginia Commonwealth University

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Responsible Party: Virginia Commonwealth University
ClinicalTrials.gov Identifier: NCT05618080    
Other Study ID Numbers: HM20025359
GRASP-LGMDR1 ( Other Identifier: Virginia Commonwealth University )
GRASP-R1 ( Other Identifier: Virginia Commonwealth University )
First Posted: November 16, 2022    Key Record Dates
Last Update Posted: June 1, 2023
Last Verified: May 2023
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Virginia Commonwealth University:
Limb Girdle Muscular Dystrophy
Additional relevant MeSH terms:
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Muscular Dystrophies
Muscular Dystrophies, Limb-Girdle
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn