Trial Readiness and Endpoint Assessment in LGMD R1

Limb Girdle Muscular Dystrophy Clinical Trial

— GRASP-01-003  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05618080
• Other study ID #: HM20025359
• Secondary ID: Limb-Girdle Musc
• Status: Recruiting
• Start date: January 31, 2024
• Est. completion date: August 5, 2028

Study information

• Verified date: May 2024
• Source: Virginia Commonwealth University
• Contact: Jennifer Raymond
• Phone: 804-828-6318
• Email: jennifer.raymond[@]vcuhealth.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: August 5, 2028
• Est. primary completion date: May 5, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Limb Girdle Muscular Dystrophy
• Muscular Dystrophies

Locations

Country	Name	City	State
Netherlands	Leiden University Medical Center	Leiden
United Kingdom	Newcastle University	Newcastle Upon Tyne
United States	University of Colorado Anschutz Medical Campus	Aurora	Colorado
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Florida	Gainesville	Florida
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of Minnesota, Department of Neurology	Minneapolis	Minnesota
United States	University of California, Irvine	Orange	California
United States	Virginia Commonwealth University	Richmond	Virginia
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	The Community Health Clinic, Inc.	Shipshewana	Indiana

Sponsors (12)

Lead Sponsor	Collaborator
Virginia Commonwealth University	Amsterdam/Leiden University Medical Center, Community Health Clinic, Nationwide Children's Hospital, Newcastle University, University of California, Irvine, University of Colorado, Denver, University of Florida, University of Iowa, University of Kansas, University of Minnesota, Washington University School of Medicine

Countries where clinical trial is conducted

United States,  Netherlands,  United Kingdom, 

References & Publications (23)

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Batra A, Lott DJ, Willcocks R, Forbes SC, Triplett W, Dastgir J, Yun P, Reghan Foley A, Bonnemann CG, Vandenborne K, Walter GA. Lower Extremity Muscle Involvement in the Intermediate and Bethlem Myopathy Forms of COL6-Related Dystrophy and Duchenne Muscular Dystrophy: A Cross-Sectional Study. J Neuromuscul Dis. 2020;7(4):407-417. doi: 10.3233/JND-190457. — View Citation

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Comi GP, Niks EH, Cinnante CM, Kan HE, Vandenborne K, Willcocks RJ, Velardo D, Ripolone M, van Benthem JJ, van de Velde NM, Nava S, Ambrosoli L, Cazzaniga S, Bettica PU. Characterization of patients with Becker muscular dystrophy by histology, magnetic resonance imaging, function, and strength assessments. Muscle Nerve. 2022 Mar;65(3):326-333. doi: 10.1002/mus.27475. Epub 2021 Dec 30. — View Citation

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Feng X, Luo S, Li J, Yue D, Xi J, Zhu W, Gao X, Guan X, Lu J, Liang Z, Zhao C. Fatty infiltration evaluation and selective pattern characterization of lower limbs in limb-girdle muscular dystrophy type 2A by muscle magnetic resonance imaging. Muscle Nerve. 2018 Oct;58(4):536-541. doi: 10.1002/mus.26169. Epub 2018 Sep 3. — View Citation

Fischer D, Walter MC, Kesper K, Petersen JA, Aurino S, Nigro V, Kubisch C, Meindl T, Lochmuller H, Wilhelm K, Urbach H, Schroder R. Diagnostic value of muscle MRI in differentiating LGMD2I from other LGMDs. J Neurol. 2005 May;252(5):538-47. doi: 10.1007/s00415-005-0684-4. Epub 2005 Feb 23. — View Citation

Hung M, Baumhauer JF, Brodsky JW, Cheng C, Ellis SJ, Franklin JD, Hon SD, Ishikawa SN, Latt LD, Phisitkul P, Saltzman CL, SooHoo NF, Hunt KJ; Orthopaedic Foot & Ankle Outcomes Research (OFAR) of the American Orthopaedic Foot & Ankle Society (AOFAS). Psychometric Comparison of the PROMIS Physical Function CAT With the FAAM and FFI for Measuring Patient-Reported Outcomes. Foot Ankle Int. 2014 Jun;35(6):592-599. doi: 10.1177/1071100714528492. — View Citation

Hung M, Clegg DO, Greene T, Saltzman CL. Evaluation of the PROMIS physical function item bank in orthopaedic patients. J Orthop Res. 2011 Jun;29(6):947-53. doi: 10.1002/jor.21308. Epub 2011 Mar 15. — View Citation

Hung M, Voss MW, Bounsanga J, Gu Y, Granger EK, Tashjian RZ. Psychometrics of the Patient-Reported Outcomes Measurement Information System Physical Function instrument administered by computerized adaptive testing and the Disabilities of Arm, Shoulder and Hand in the orthopedic elbow patient population. J Shoulder Elbow Surg. 2018 Mar;27(3):515-522. doi: 10.1016/j.jse.2017.10.015. Epub 2018 Jan 9. — View Citation

Jaka O, Azpitarte M, Paisan-Ruiz C, Zulaika M, Casas-Fraile L, Sanz R, Trevisiol N, Levy N, Bartoli M, Krahn M, Lopez de Munain A, Saenz A. Entire CAPN3 gene deletion in a patient with limb-girdle muscular dystrophy type 2A. Muscle Nerve. 2014 Sep;50(3):448-53. doi: 10.1002/mus.24263. Epub 2014 Aug 5. — View Citation

Khadka J, Pesudovs K, McAlinden C, Vogel M, Kernt M, Hirneiss C. Reengineering the glaucoma quality of life-15 questionnaire with rasch analysis. Invest Ophthalmol Vis Sci. 2011 Sep 1;52(9):6971-7. doi: 10.1167/iovs.11-7423. — View Citation

Mercuri E, Bushby K, Ricci E, Birchall D, Pane M, Kinali M, Allsop J, Nigro V, Saenz A, Nascimbeni A, Fulizio L, Angelini C, Muntoni F. Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures. Neuromuscul Disord. 2005 Feb;15(2):164-71. doi: 10.1016/j.nmd.2004.10.008. Epub 2004 Nov 26. — View Citation

Moore SA, Shilling CJ, Westra S, Wall C, Wicklund MP, Stolle C, Brown CA, Michele DE, Piccolo F, Winder TL, Stence A, Barresi R, King N, King W, Florence J, Campbell KP, Fenichel GM, Stedman HH, Kissel JT, Griggs RC, Pandya S, Mathews KD, Pestronk A, Serrano C, Darvish D, Mendell JR. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol. 2006 Oct;65(10):995-1003. doi: 10.1097/01.jnen.0000235854.77716.6c. — View Citation

Nallamilli BRR, Chakravorty S, Kesari A, Tanner A, Ankala A, Schneider T, da Silva C, Beadling R, Alexander JJ, Askree SH, Whitt Z, Bean L, Collins C, Khadilkar S, Gaitonde P, Dastur R, Wicklund M, Mozaffar T, Harms M, Rufibach L, Mittal P, Hegde M. Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients. Ann Clin Transl Neurol. 2018 Dec 1;5(12):1574-1587. doi: 10.1002/acn3.649. eCollection 2018 Dec. — View Citation

Reyngoudt H, Marty B, Boisserie JM, Le Louer J, Koumako C, Baudin PY, Wong B, Stojkovic T, Behin A, Gidaro T, Allenbach Y, Benveniste O, Servais L, Carlier PG. Global versus individual muscle segmentation to assess quantitative MRI-based fat fraction changes in neuromuscular diseases. Eur Radiol. 2021 Jun;31(6):4264-4276. doi: 10.1007/s00330-020-07487-0. Epub 2020 Nov 21. — View Citation

van de Velde NM, Hooijmans MT, Sardjoe Mishre ASD, Keene KR, Koeks Z, Veeger TTJ, Alleman I, van Zwet EW, Beenakker JM, Verschuuren JJGM, Kan HE, Niks EH. Selection Approach to Identify the Optimal Biomarker Using Quantitative Muscle MRI and Functional Assessments in Becker Muscular Dystrophy. Neurology. 2021 Aug 3;97(5):e513-e522. doi: 10.1212/WNL.0000000000012233. Epub 2021 Jun 23. — View Citation

Willcocks RJ, Arpan IA, Forbes SC, Lott DJ, Senesac CR, Senesac E, Deol J, Triplett WT, Baligand C, Daniels MJ, Sweeney HL, Walter GA, Vandenborne K. Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: effects of age and disease progression. Neuromuscul Disord. 2014 May;24(5):393-401. doi: 10.1016/j.nmd.2013.12.012. Epub 2014 Jan 11. — View Citation

Willcocks RJ, Rooney WD, Triplett WT, Forbes SC, Lott DJ, Senesac CR, Daniels MJ, Wang DJ, Harrington AT, Tennekoon GI, Russman BS, Finanger EL, Byrne BJ, Finkel RS, Walter GA, Sweeney HL, Vandenborne K. Multicenter prospective longitudinal study of magnetic resonance biomarkers in a large duchenne muscular dystrophy cohort. Ann Neurol. 2016 Apr;79(4):535-47. doi: 10.1002/ana.24599. Epub 2016 Feb 19. — View Citation

Willis TA, Hollingsworth KG, Coombs A, Sveen ML, Andersen S, Stojkovic T, Eagle M, Mayhew A, de Sousa PL, Dewar L, Morrow JM, Sinclair CD, Thornton JS, Bushby K, Lochmuller H, Hanna MG, Hogrel JY, Carlier PG, Vissing J, Straub V. Quantitative magnetic resonance imaging in limb-girdle muscular dystrophy 2I: a multinational cross-sectional study. PLoS One. 2014 Feb 28;9(2):e90377. doi: 10.1371/journal.pone.0090377. eCollection 2014. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in mobility (100-meter walk)	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.	Baseline to 24 months
Other	Change in Forced vital capacity (FVC)	Volume of air forcefully exhaled will be measured using Spirometry performed in sitting and supine positions using standardized equipment	Baseline to 24 months
Other	Change in Forced expiratory volume (FEV1)	Volume of air forcefully exhaled in one second will be measured using Spirometry performed in a sitting position using standardized equipment	Baseline to 24 months
Other	Change in upper limb function characteristics (PUL)	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.	Baseline to 24 months
Other	Change in Timed Up-And-Go (TUG)	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.	Baseline to 24 months
Other	Change in 4 Stair Climb	Time to ascend 4 steps as quickly and safely as possible, using handrails if needed, will be assessed.	Baseline to 24 months
Other	Change in Handheld Dynamometry and Pinch Grip	Maximum hand, pinch, and grip strength will be assessed using a myometer. The participant will be asked to squeeze a handheld tool.	Baseline to 24 months
Other	Change in self-reported social, mental, and physical health (PROMIS-57)	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.	Baseline to 24 months
Other	Change in activity limitations (ACTLIVLIM)	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.	Baseline to 24 months
Other	Change in overall health (Domain Delta)	Domain Delta Questionnaire is a patient reported measure that assesses overall health over the previous 12 months.	Baseline to 24 months
Other	Change in overall health-related quality of life (LGMD-HI)	The LGMD Health Index is a disease-specific, patient reported measure that assesses overall health-related quality of life in LGMD.	Baseline to 24 months
Primary	Validate the NSAD as a clinical outcome assessment in LGMD R1	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.	Baseline to 24 months
Secondary	Validate muscle fat fraction as a biomarker	Quantitative muscle MRI (qMR) of the upper and lower leg muscles will be performed and muscle fat fraction will be measured.	Baseline to 12 months