Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls

Study Overview
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Brief Summary
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The primary aim of this study is to discover whether patients with CMT type 1 and 2 have neuromuscular junction transmission deficits. The secondary aim is to collect information of different clinical and electrophysiological test procedures to perform possible future clinical trials in CMT patients.

Detailed Description
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The study is a prospective observational pilot study involving two investigational sites: Department of Neurology, Arhus University Hospital Department of Neurology, Ohio State University A total of 20 patients with Charcot-Marie-Tooth (CMT) disease and 10 healthy age-matched controls will be included with each site including 10 CMT patients and 5 Healthy Controls. CMT patients will undergo electrophysiological (repetitive nerve stimulation and single fiber EMG analyses) and functional (different tests of muscle strength, fatigability, dexterity, and balance) testing on 4 separate occasions. Healthy controls will undergo electrophysiological testing at baseline only. To assess whether patients with CMT have deficits in NMJ transmission, results from repetitive nerve stimulation and single fiber EMG analyses in CMT patients will be compared to those obtained in healthy controls at baseline. To inform future clinical trials, results relability and tolerability estimates obtained from sequential electrophysiological and functional tests will be calculated

Official Title
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An Open Observational Study of Clinical and Electrophysiological Outcomes in Male and Female Patients With CMT Type 1 & 2, and Aged-matched Healthy Controls

Conditions
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Charcot-Marie-Tooth Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for CMT Patients Age ≥ 18 years Diagnosis of CMT confirmed by: Clinical presentation and electro diagnostics or genetics Physical Features (all must apply): 1) Ambulation for at least 10 meters, without a brace 2) Left and right ankle plantar flexion Medical Research Council (MRC) grade 2 to 5, inclusive 3) Left and right ankle dorsiflexion MRC manual muscle testing (MMT) grade 2 to 4+, inclusive. Ability to adhere to the study visit schedule/procedures, and to understand and comply with protocol requirements Stable concomitant medications for 2 months prior to enrolment Signed written informed consent Exclusion Criteria for CMT Patients Severe deformity or ankle contracture that would sufficiently limit passive range of motion to affect assessment of dorsiflexion strength Ulceration that would interfere with functional ability Recent major surgery Significant change in physical activity or exercise (e.g., significant increase or decrease in intensity or frequency) within 8 weeks before Study Day 1 or inability to maintain the baseline level of physical activity throughout the study Any disability or condition that would prevent completion of the study tasks Moderate to severe Neuropathic or inflammatory/musculoskeletal pain that would interfere with performance of the tests A diagnosis of a primary NMJ disorder such as myasthenia gravis, Lambert Eaton Myasthenic Syndrome or congenital myasthenic disorder Inclusion Criteria for Healthy Volunteers Healthy male or female volunteers Age ≥18 years Able to give written informed consent Exclusion Criteria for Healthy Volunteers Pregnant Requiring prescription medicines likely to interfere with electromyography (EMG) recordings Presence of current or previous medical condition which might interfere with participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| CMT Patients<br>Individuals with Charcot-Marie-Tooth Disease Types 1 and 2. | |
| Healthy Controls<br>Healthy age-matched volunteers | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Repetitive Nerve Stimulation - difference between CMT patients and healthy controls | Percentage decrement of CMAP for the trapezius | Baseline | 
| Repetitive Nerve Stimulation - difference between CMT patients and healthy controls | Percentage decrement of CMAP for abductor pollicis brevis | Baseline | 
| Single Fiber Electro Myography (sfEMG) - difference between CMT patients and healthy controls | Percentage blocking | Baseline | 
| Single Fiber Electro Myography (sfEMG) - difference between CMT patients and healthy controls | Jitter | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Isometric Dynamometry - test reliability in patients with CMT | This test will be used to evaluate maximum isometric strength | The test is performed at baseline and day 14, 28 and 42. | 
| Manual Muscle Testing - test reliability in patients with CMT | This test is a physical examination of muscle strength. 15 muscle groups/motions will be tested. 13 of these are tested bilaterally. A total score between (0-280) is calculated | The test is performed at baseline and day 14, 28 and 42. | 
| 9 Hole Peg Test - test reliability in patients with CMT | This is a test of finger dexterity | The test is performed at baseline and day 14, 28 and 42. | 
| 6-Spot Step Test - test reliability in patients with CMT | This test is a quantitative measure of lower extremity function | The test is performed at baseline and day 14, 28 and 42. | 
| 10-Meter Walk/run Test - test reliability in patients with CMT | This test measures how fast the participant can walk/run 10 meters. | The test is performed at baseline and day 14, 28 and 42. | 
| Timed Up and Go - test reliability in patients with CMT | This test measures how fast the participant can stand from a chair, walk 3 meters, turn around, return, and sit in the chair at a comfortable and safe pace | The test is performed at baseline and day 14, 28 and 42. | 
| Berg Balance Scale - test reliability in patients with CMT | The test measures balance during different functional tasks. A total score is calculated as the sum of the individual scores for each item, with maximum value 56, with a lower score meaning worse balance | The test is performed at baseline and day 14, 28 and 42. | 
| 6 Minute Walk Test - test reliability in patients with CMT | This test measures how far a person can walk in six minutes | The test is performed at baseline and day 14, 28 and 42. | 
| Single Fiber Electro Myography (sfEMG) - test reliability in patients with CMT | Percantage blocking | The test is performed at baseline and day 14, 28 and 42. | 
| Single Fiber Electro Myography (sfEMG) - test reliability in patients with CMT | Jitter | The test is performed at baseline and day 14, 28 and 42. | 
| Repetitive Nerve Stimulation - test reliability in patients with CMT | Percentage decrement of CMAP for Trapezius | The test is performed at baseline and day 14, 28 and 42. | 
| Repetitive Nerve Stimulation - test reliability in patients with CMT | Percentage decrement of CMAP for abductor pollicis brevis | The test is performed at baseline and day 14, 28 and 42. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuromuscular Junction Transmission, Repetitive Nerve Stimulation, Neuromuscular Disease, Single Fiber EMG