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

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

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.

Study Overview

• Status: Completed
• Conditions: Charcot-Marie-Tooth Disease

Detailed Description

The study is a prospective observational pilot study involving two investigational sites:

1. Department of Neurology, Arhus University Hospital
2. 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

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Denmark
  • Jutland
    • Aarhus, Jutland, Denmark, 8200
      • Aarhus University Hospital
• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Eligible CMT patients will be invited to participate at the respective study sites. Age matched healthy volunteers will be recruited through advertisement at the respective study sites

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
CMT Patients; Individuals with Charcot-Marie-Tooth Disease Types 1 and 2.
Healthy Controls; Healthy age-matched volunteers

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CMTES2 Score	This test measures CMT disease severity. Total score is calculated as the sum of the 7 sub-scores with a maximum of score of 28	This test is performed at baseline in individuals with CMT disease
Adverse Events	Number of adverse events by severity	At baseline for healthy controls and from baseline until final visit at day 42 for CMT patients
Tolerability of test procedures	The tolerability score assessed on a 0-9 rating scale (0=no discomfort to 9=worst possible discomfort)	Performed for each test at each visit (baseline, day 14, 28 and 42)
Association between NMJ function and clinical function in CMT patients	Correlation	Baseline

Collaborators and Investigators

• Sponsor: NMD Pharma A/S
• Collaborators: Aarhus University Hospital; Ohio State University
• Investigators: Principal Investigator: Henning Andersen, MD, PhD, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 7, 2021
• Primary Completion (ACTUAL): March 3, 2022
• Study Completion (ACTUAL): March 3, 2022

Study Registration Dates

• First Submitted: July 7, 2021
• First Submitted That Met QC Criteria: July 19, 2021
• First Posted (ACTUAL): July 28, 2021

Study Record Updates

• Last Update Posted (ACTUAL): March 7, 2022
• Last Update Submitted That Met QC Criteria: March 4, 2022
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Neuromuscular Disease; Repetitive Nerve Stimulation; Neuromuscular Junction Transmission; Single Fiber EMG
• Additional Relevant MeSH Terms: Nervous System Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Neuromuscular Diseases; Stomatognathic Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Tooth Diseases; Nerve Compression Syndromes; Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy
• Other Study ID Numbers: CMT Observational

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No