Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD

• ClinicalTrials.gov Identifier: NCT03458832
• Recruitment Status: Active, not recruiting
• First Posted: March 8, 2018
• Last Update Posted: October 5, 2021
• Sponsor: University of Kansas Medical Center
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): University of Kansas Medical Center

Study Description

Brief Summary:

The primary cause of facioscapulohumeral muscular dystrophy (FSHD), a common adult-onset dystrophy, was recently discovered identifying targets for therapy. As multiple drug companies pursue treatments for FSHD, there is an urgent need to define the clinical trial strategies which will hasten drug development, including creating disease-relevant outcome measures and optimizing inclusion criteria. This proposal will develop two new outcome measures and optimize eligibility criteria by testing 160 patients in 7 sites over a period of 24 months.

Condition or disease	Intervention/treatment
Facioscapulohumeral Muscular Dystrophy	Diagnostic Test: FSHD-specific functional rating scale; Device: Electrical Impedance Myography

Detailed Description:

The overall aim of this study is to hasten drug development for facioscapulohumeral muscular dystrophy (FSHD). Recent breakthroughs in FSHD research have identified the primary disease mechanism as the aberrant expression of a normally silenced gene, DUX4, resulting in a toxic gain-of-function. This disease mechanism is particularly amenable to knock-down of DUX4 using epigenetic strategies or RNA therapies, as well as to other interventions targeting the downstream effects of DUX4 expression. There are many drug companies actively working towards disease-targeted therapies, and two clinical trials either under way now, or planned to start in early Fall 2016. However, meetings with industry, advocacy groups, and FSHD researchers have identified several gaps in the clinical trial arsenal, and clinical trial planning as a major goal for the community. Consequently, there is an urgent need to establish the tools necessary for the conduct of currently planned and expected therapeutic trials in FSHD.

To this end, the researchers propose to develop two novel clinical outcome assessments (COA), a composite functional outcome measure (FSH-COM) and skeletal muscle biomarker, electrical impedance myography (EIM). In addition there is broad consensus a better understanding of the relationship of genetic and demographic features to disease progression will be necessary for enumerating eligibility criteria.

The specific aims are to: 1. Determine the multi-site validity of the COAs, 2. Compare the responsiveness of new COAs to other FSHD outcomes and determine the minimal clinically meaningful changes, and 3. establish FSHD cohort characteristics useful for determining clinical trial eligibility criteria. To achieve these aims, the researchers are conducting a multicenter, prospective, 24 months study of 160 subjects.

Study Design

• Study Type: Observational
• Estimated Enrollment: 160 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD
• Actual Study Start Date: March 5, 2018
• Estimated Primary Completion Date: March 2023
• Estimated Study Completion Date: March 2023

Groups and Cohorts

Group/Cohort

Intervention/treatment

FSHD-COM; All participants will be asked to undergo FSHD-specific functional rating scale tests and procedures and Electrical Impedance Myography.

Diagnostic Test: FSHD-specific functional rating scale; The FSHD-COM is composed of disease-relevant functional tasks such as leg function; shoulder and arm function; trunk function, hand function, and balance.; Other Name: FSHD-COM; Device: Electrical Impedance Myography; EIM is a non-invasive, painless, and fast technique for obtaining information on how a patient's muscle structure is changing. EIM uses a small electrical current to measure the health of the underlying muscle. The patient will be asked to lie down and a trained clinical evaluator will perform testing on 16 total muscles (8 on each side) on your arms and legs.; Other Name: EIM

Outcome Measures

Primary Outcome Measures :

1. Validate FSHD-COM as COA [ Time Frame: 24 Months ]
   The FSHD-COM is an 18-item evaluator-administered instrument comprised of individually validated functional motor tasks. The body regions represented match areas of importance identified by patients and include: leg function; shoulder and arm function; trunk function, hand function; and balance. Each item is scored on a 0-4 scale, with 0 representing unaffected/normal performance, and the divisions based on healthy population normative values, or the relative degree of ability to perform the functional task. The total scale has 72 points, with larger weight given to the two most frequently patient-cited areas of functional motor concern - leg function and shoulder and arm function.
2. Validate EIM as COA [ Time Frame: 24 Months ]

Secondary Outcome Measures :

1. Motor Function Measure (MFM) Domain 1 [ Time Frame: 24 Months ]
   The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.
2. Facial Function [ Time Frame: 24 Months ]
   The Iowa Oral Performance Instrument (IOPI) is a means to quantify lip, tongue, and buccal strength using a validated tool with published ranges for normative data for lingual measurements.
3. Reachable Workspace [ Time Frame: 24 Months ]
   Subjects are seated in front of a 3D camera and asked to perform a standardized upper extremity movement protocol under the supervision of a study clinical evaluator.
4. Manual Muscle Testing [ Time Frame: 24 Months ]
   Strength testing will be performed using manual muscle testing (MMT) using a hand held force dynamometer.
5. Respiratory Function [ Time Frame: 24 Months ]
   The researchers will obtain forced vital capacity and forced expiratory volume in 1 second using bedside spirometry.
6. Whole body and regional lean muscle mass (LMM) [ Time Frame: 24 Months ]
   Whole body and regional lean muscle mass (LMM) will be measured via Dual Energy X-Ray Absorptiometry (DEXA).
7. Severity Scores [ Time Frame: 24 Months ]
   A limited physical exam and strength testing will be used to derive two FSHD clinical severity scores. These severity scores both rank weakness in the face, shoulders, arms, distal, and proximal lower extremities on either a 10 or 15 point scale.
8. FSHD-Health Inventory (HI) [ Time Frame: 24 Months ]
   The HI is a 15 domain questionnaire designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. 116 questions are combined into a total score, the score is transformed onto a percentage scale, with 100 representing maximal disability, and lower scores representing decreasing disability.
9. Patient-Reported Outcomes Measurement Information System-57 (PROMIS57) [ Time Frame: 24 Months ]
   The PROMIS57 is an instrument developed by the NIH which generates scores for physical function, and the impact of physical limitations on daily life. 57 questions are summed into a total score, which is transformed into a normalized t-score with 50 representing normal, and lower scores representing increasing disability.
10. The Upper Extremity Functional Index [ Time Frame: 24 Months ]
    This index measures upper extremity dysfunction. 20 questions are combined into a total score, the score is transformed into a normalized score with 80 representing normal, and lower scores representing increasing disability.
11. The Facial Disability Index (FDI) [ Time Frame: 24 Months ]
    The FDI is a short 5 item questionnaire. The five questions are summed into total score which transformed onto a percentage scale, with 100 representing normal, and lower scores representing increasing disability.
12. Fall assessment [ Time Frame: Total between Month 3 and Month 6 Visit ]
    Fall assessment will be completed weekly for 3 months after the month 3 visit.
13. Quantitative myometry [ Time Frame: 24 Months ]
    Force will be measured on digital myometer, in KG-force.

Biospecimen Retention:   Samples With DNA

Each subject will have approximately 15 mL of blood collected at baseline and month 3 for genetic testing. The month 3 sample will be stored for use as a back-up for any lost samples, or for use in future studies.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Participants with FSHD that are seen in the researchers clinic.

Criteria

Inclusion Criteria:

• Patients with genetically confirmed FSHD1 or clinical diagnosis of FSHD with characteristic findings on exam and an affected parent or offspring
• Patients with symptomatic limb weakness
• Patients must be able to walk 30 feet without the support of another person or assistance (canes, walking sticks, and braces allowed; no walker).
• If taking over the counter supplements, willing to remain consistent with supplement regimen throughout the course of the study

Exclusion Criteria:

• Patients with cardiac or respiratory dysfunction (deemed clinically unstable, or would interfere with safe testing, in the opinion of the Investigator)
• Patients with orthopedic conditions that preclude safe testing of muscle function
• Patients that regularly use available muscle anabolic/catabolic agents such as corticosteroids, oral testosterone or derivatives, or oral beta agonists
• Patients that have used an experimental drug in an FSHD clinical trial within the past 30 days
• Patients that are pregnant

Contacts and Locations

Locations

United States, California

University of California Los Angeles

Los Angeles, California, United States, 90095

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Maryland

Kennedy Krieger Institute

Baltimore, Maryland, United States, 21205

United States, New York

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, Ohio

The Ohio State University

Columbus, Ohio, United States, 43210

United States, Utah

University of Utah

Salt Lake City, Utah, United States, 84132

United States, Virginia

Virginia Commonwealth University

Richmond, Virginia, United States, 23298

United States, Washington

University of Washington

Seattle, Washington, United States, 98195

Sponsors and Collaborators

University of Kansas Medical Center

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Jeffrey Statland, MD; University of Kansas Medical Center
• Principal Investigator: Rabi Tawil, MD; University of Rochester

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

LoRusso S, Johnson NE, McDermott MP, Eichinger K, Butterfield RJ, Carraro E, Higgs K, Lewis L, Mul K, Sacconi S, Sansone VA, Shieh P, van Engelen B, Wagner K, Wang L, Statland JM, Tawil R; ReSolve Investigators and the FSHD CTRN18. Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study. BMC Neurol. 2019 Sep 10;19(1):224. doi: 10.1186/s12883-019-1452-x.

• Responsible Party: University of Kansas Medical Center
• ClinicalTrials.gov Identifier: NCT03458832
• Other Study ID Numbers: STUDY00140842; U01NS101944 ( U.S. NIH Grant/Contract )
• First Posted: March 8, 2018
• Last Update Posted: October 5, 2021
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Kansas Medical Center:

muscular dystrophy.; FSHD

Additional relevant MeSH terms:

Muscular Dystrophies; Muscular Dystrophy, Facioscapulohumeral; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, Inborn