Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD

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 (FSHD-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 320 subjects.

• FSHD-specific functional rating scale (Diagnostic test), also known as FSHD-COM: The FSHD-COM is composed of disease-relevant functional tasks such as leg function; shoulder and arm function; trunk function, hand function, and balance.
• Electrical Impedance Myography (Device), also known as EIM: 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.

Primary outcomes

• FSHD composite (FSHD-COM) [24 Months]: The FSHD composite (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.
• Electrical Impedance Myography (EIM) [24 Months]: EIM is administered using an investigational device manufactured by Skulpt, Inc (Boston, MA) that non-invasively measures the impedance of skeletal muscle over a frequency range between 1 kHz and 10 MHz (Figure 2). The impedance is measured at each frequency by applying low-intensity electrical current (<1 mA) via surface electrodes and measuring the resulting voltage signals using a second set of surface electrodes, converting them into 2 impedance parameters, the resistance and the reactance.

Secondary outcomes

• Motor Function Measure (MFM) Domain 1 [24 Months]: The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.
• Facial Function [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.
• Reachable Workspace (RWS) [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.
• Manual Muscle Testing (MMT) [24 Months]: Strength testing will be performed using manual muscle testing (MMT) using a hand held force dynamometer.
• Force Vital Capacity (FVC) [24 Months]: The researchers will obtain bedside spirometry including forced vital capacity and forced expiratory volume in 1 second.
• Maximum Inspiratory Pressure (MIP) and Maximum Expiratory Pressure (MEP) [24 Months]: The researchers will obtain maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) using bedside spirometry.
• Whole body and regional lean muscle mass (LMM) [24 Months]: Whole body and regional lean muscle mass (LMM) will be measured via Dual Energy X-Ray Absorptiometry (DEXA).
• Severity Scores [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.
• FSHD-Health Index (FSHD-HI) [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.
• Patient-Reported Outcomes Measurement Information System-57 (PROMIS57) [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.
• The Upper Extremity Functional Index [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.
• The Facial Disability Index (FDI) [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.
• Fall assessment [Total between Month 3 and Month 6 Visit]: Fall assessment will be completed weekly for 3 months after the month 3 visit.
• Domain Delta Anchor [24 Months]: Participants will be asked to complete a self-assessment "domain-delta" questionnaire at 3, 12, 18 and 24-month visits. The purpose of the "domain-delta" questionnaire is to determine each patient's perceived change in their health-related quality-of-life in the last 6-months. This questionnaire will inquire about total health as well as health related to 14 subdomains self-identified as important by patients during development of the FSHD Health Index. Participants indicate their perceived change by answering if an area "is a lot worse", "is a little worse", "there has been no change", "it is a little better", or "it is a lot better" for each subdomain.
• Quantitative myometry (QMA) [24 Months]: Force will be measured on digital myometer, in KG-force.
• Muscle Biopsy [24 Months]: Will be performed on 30 subjects at European and United Kingdom sites only. Participants will undergo one needle muscle biopsy of one lower extremity muscle (Vastus Lateralis (VL), Tibialis Anterior (TA), Medial Gastrocnemius (MG), or Lateral Gastrocnemius (LG)) at any study visit. For each biopsy, approximately three muscle tissue samples will be collected, two samples will be individually flash frozen in liquid nitrogen while the third sample will be put into media for myoblast cell cultures.
• Blood biomarkers [24-Months]: DNA and RNA will be collected at Baseline and 3-month visits. Plasma and serum samples will be collected at every visit (Baseline, 3, 12, 18, and 24-months).

Sex: All, ages: 18 Years to 75 Years

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

• Results publication: 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. PMID 31506080

• Jeffrey Statland, MD, Principal investigator, University of Kansas Medical Center
• Rabi Tawil, MD, Principal investigator, University of Rochester

NIH grants: U01NS101944