Clinical trial NCT05618080: LGMD R1 Natural History Study
Official title: GRASP-01-003: Trial Readiness and Endpoint Assessment in LGMD R1
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Calpain-3 Deficiency Limb Girdle Muscular Dystrophy Type 2A
Limb Girdle Muscular Dystrophy
Limb Girdle Muscular Dystrophy Type R1
LGMD2A
Keywords: LGMD
Limb Girdle Muscular Dystrophy
LGMD R1
LGMD2A
CAPN3
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: Nationwide Children's Hospital
name: Washington University School of Medicine
name: University of Iowa
name: University of Florida
name: University of Minnesota
name: Newcastle University
name: University of Kansas Medical Center
name: University of Colorado, Denver
name: Indiana CHC (Community Health Clinic)
name: University of California, Irvine
First posted: 2022-11-16
Enrollment: 100
Sex: ALL
Minimum age (years): 12
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: OTHER
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.

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

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.

Eligibility criteria: Inclusion Criteria:

1. Age between 12-50 at enrollment
2. Clinically affected (defined as weakness on bedside evaluation in a pattern consistent with LGMDR1)
3. Genetic confirmation of LGMDR1 (presence of homozygous or compound heterozygous pathogenic mutations in CAPN3).
4. Must be able to provide written informed consent and be willing and able to comply with all study requirements. Note: Adult participants must be able to provide consent themselves. Legally authorized representatives are not permitted to consent on behalf of adult participants.

Exclusion Criteria:

1. Have contraindications to MRI or MRS (e.g., non-MR compatible implanted medical devices or severe claustrophobia)
2. Non-ambulatory as defined by those who are not able to walk 10 meters without assistive devices (ankle foot orthotics excluded)
3. Positive pregnancy test at any timepoint during the trial
4. Have dominantly inherited CAPN3 mutations (LGMDD4)
5. 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.

Primary outcomes:
measure: Validate the NSAD as a clinical outcome assessment in LGMD R1
timeFrame: Baseline to 24 months
Secondary outcomes:
measure: Validate muscle fat fraction as a biomarker
timeFrame: Baseline to 12 months
Other outcomes:
measure: Change in mobility (100-meter walk)
timeFrame: Baseline to 24 months
measure: Change in Forced vital capacity (FVC)
timeFrame: Baseline to 24 months
measure: Change in Forced expiratory volume (FEV1)
timeFrame: Baseline to 24 months
measure: Change in upper limb function characteristics (PUL)
timeFrame: Baseline to 24 months
measure: Change in Timed Up-And-Go (TUG)
timeFrame: Baseline to 24 months
measure: Change in 4 Stair Climb
timeFrame: Baseline to 24 months
measure: Change in Handheld Dynamometry and Pinch Grip
timeFrame: Baseline to 24 months
measure: Change in self-reported social, mental, and physical health (PROMIS-57)
timeFrame: Baseline to 24 months
measure: Change in activity limitations (ACTLIVLIM)
timeFrame: Baseline to 24 months
measure: Change in overall health (Domain Delta)
timeFrame: Baseline to 24 months
measure: Change in overall health-related quality of life (LGMD-HI)
timeFrame: Baseline to 24 months
Locations:
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Aurora
country: United States
facility: University of Colorado Anschutz Medical Campus
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Shipshewana
country: United States
facility: The Community Health Clinic, Inc.
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Minneapolis
country: United States
facility: University of Minnesota, Department of Neurology
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Newcastle Upon Tyne
country: United Kingdom
facility: Newcastle University
Study officials:
affiliation: Virginia Commonwealth University
name: Nicholas Johnson, MD
role: PRINCIPAL_INVESTIGATOR
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