Muscle MRI in Charcot Mary Tooth Disease: a Prospective Cohort Study

October 3, 2018 updated by: University College, London
This cohort study (participants with CMT and control participants) has two parts (Part 1: CMT1A cohort; Part2: CMT1B, CMT2A and CMTX1 cohort) and is proposed to take place over 3 years across three sites. Participants with CMT aged 5-60 for potential enrolment in the trial will be identified through the existing inherited neuropathy clinics at each site and control participants will be identified among the unaffected relatives and carers of the participants with CMT. If they show interest in participating, they will be given the relevant Patient Information Sheets, Written Consent forms and/or Assent forms. Half of the participants will be recruited at the UK sites (NHNN and GOSH) and the other half at the US collaborating site. Each participant will be invited to two separate research visits (12 months apart) for which travel expenses (return journey) will be reimbursed. Each research visit is expected to last approximately 3 hours and during it, relevant detailed clinical data will be collected (CMTPedS for participants with CMT aged 5-20, CMTESv2-R for participants with CMT over the age of 10, CMT-HI for participants with CMT over the age of 16) and the participant will also undergo an MRI scan (up to 45 minutes) of the lower limbs (feet and calves or calves and thighs). Two separate neuromuscular MRI protocols with specific sequences will be used for the scans of foot and calf muscles and scans of calf and thigh muscles. Blood samples for plasma NEFL levels will be optional at both research visits for the participants at the UK trial sites; plasma NEFL levels will be processed according to our previously published protocol

Study Overview

Detailed Description

In this proposed study we will use magnetic resonance imaging (MRI) of skeletal muscle to better delineate the natural history of intramuscular fat accumulation in Charcot Marie Tooth disease (CMT ) and investigate the use of muscle MRI and plasma neurofilament light chain (NEFL) levels as outcome measures in children and adults with specific subtypes of CMT (CMT1A, CMT1B, CMT2A and CMTX1).

We will ascertain the value of MRI-determined fat accumulation in foot, calf and thigh muscles as an independent outcome measure, by analysing its correlation with validated clinical measures [CMT Paediatric Score (CMTPedS) and/or CMT Examination Score version 2 - Rasch (CMTESv2-R)] and sensitivity to change over time compared to matched controls. We will also ascertain the utility of plasma NEFL levels as an independent outcome measure and a potential predictive biomarker of muscle fat accumulation over 12 months.

Following this trial, easily implemented outcome measures will be immediately available for clinical trials seeking to evaluate novel therapies in CMT and data from this trial will also be available to establish sample size for future clinical trials.

This study (participants with CMT and control participants) has two parts (Part 1: CMT1A cohort; Part2: CMT1B, CMT2A and CMTX1 cohort) and is proposed to take place over 3 years across three sites. Participants with CMT aged 5-60 for potential enrolment in the trial will be identified through the existing inherited neuropathy clinics at each site and control participants will be identified among the unaffected relatives and carers of the participants with CMT.

Approximately half of the participants will be recruited at the UK sites (NHNN and GOSH) and the other half at the US collaborating centre (University of IOWA). Each research visit is expected to last approximately 3 hours and during it, relevant detailed clinical data will be collected (CMTPedS for participants with CMT aged 5-20, CMTESv2-R for participants with CMT over the age of 10, CMT-HI for participants with CMT over the age of 16) and the participant will also undergo an MRI scan (up to 45 minutes) of the lower limbs (feet and calves or calves and thighs). Two separate neuromuscular MRI protocols with specific sequences will be used for the scans of foot and calf muscles and scans of calf and thigh muscles. Blood samples for plasma NEFL levels will be optional at both research visits for the participants at the UK trial sites; plasma NEFL levels will be processed according to our previously published protocol.

The primary objective is to define the responsiveness of MRI-determined fat accumulation in foot and calf muscles (in children/young adults aged 5-20 with CMT1A) or calf and thigh muscles (in adults aged 16-60 with CMT1B, CMT2A and CMTX1) over 12 months.

The secondary objectives are a) to assess the validity of MRI-determined muscle fat accumulation as a biomarker by correlating it with validated clinical scores (CMTPedS and/or CMTESv2-R), b) investigate the responsiveness of plasma NEFL in patients with CMT compared to matched controls over 12 months, and c) to investigate the utility of multi-level T2-weighted STIR (short T1 inversion recovery) and plasma NEFL levels as potential predictive biomarkers of muscle fat accumulation over the subsequent 12 months.

Study Type

Observational

Enrollment (Anticipated)

130

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • London, United Kingdom, WC1n3BG
        • Recruiting
        • Queen Square Centre for Neuromuscular Diseases

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years to 58 years (Child, Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Probability Sample

Study Population

Patients aged 5-20 with genetically proven CMT1A, patients aged 16-60 with genetically proven CMT1B and CMT2A and male patients aged 16-60 with genetically proven CMTX1

Description

Inclusion Criteria:

Inclusion Criteria for participants with CMT

Part 1 inclusion criteria:

  1. Participants aged 5-20 years with genetically proven CMT1A or with a clinical diagnosis of CMT1A (including neurophysiology) and a genetically confirmed diagnosis of CMT1A in patient or a 1st degree relative.
  2. Participants must be able to undergo an MRI scan without sedation and complete the CMTESv2-R and/or CMTPedS scores as appropriate.
  3. Female participants of childbearing potential who are sexually active must agree to use an effective method of contraception from the time consent is signed until the final research visit.
  4. Female participants of childbearing potential must have a negative urinary pregnancy test prior to every MRI scan. Participants are considered not of childbearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
  5. Participants and/or their parent(s)/guardian are willing and able to provide written informed consent and/or appropriate assent. Participants must have a good understanding of English language, in order to be able to do this.

Part 2 inclusion criteria:

  1. Participants aged 16-60 years with genetically proven CMT1B, CMT2A or CMTX1 or with a clinical diagnosis of one of the above three (including neurophysiology) and a genetically confirmed diagnosis in a 1st degree relative.
  2. Participants with CMTX1 must be male.
  3. Participants must be able to undergo an MRI scan without sedation and complete the CMTESv2-R score.
  4. Female participants of childbearing potential who are sexually active must agree to use an effective method of contraception from the time consent is signed until the final research visit.
  5. Female participants of childbearing potential must have a negative urinary pregnancy test prior to every MRI scan. Participants are considered not of childbearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
  6. Participants are willing and able to provide written informed consent. Participants must have a good understanding of English language, in order to be able to do this.

Inclusion criteria for control participants

  1. Participants are aged 5-60 years.
  2. Participants must be able to undergo an MRI scan without sedation.
  3. Female participants of childbearing potential who are sexually active must agree to use an effective method of contraception from the time consent is signed until the final research visit.
  4. Female participants of childbearing potential must have a negative urinary pregnancy test prior to every MRI scan. Participants are considered not of childbearing potential if they are surgically sterile (i.e. they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal.
  5. Participants and/or their parent(s)/guardian are willing and able to provide written informed consent and/or appropriate assent. Participants must have a good understanding of English language, in order to be able to do this.

Exclusion Criteria:

Exclusion criteria for participants with CMT

  1. Participants have undergone foot surgery in the 6 months prior to trial enrollment or are due to undergo foot surgery during the 12 months of the trial.
  2. Participants have another medical condition which precludes them from having an MRI scan or completing the CMTESv2-R or the CMTPedS scores as appropriate.
  3. Participants with known diagnosis of another neuromuscular disease.
  4. Females who are planning pregnancy or breastfeeding

Exclusion criteria for control participants

  1. Participants with known diagnosis of another neuromuscular disease.
  2. A risk of developing a neuromuscular condition if the control participant is a relative of a participating patient with CMT.
  3. Females who are planning pregnancy or breastfeeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Participants with CMT
Participants with CMT1A, CMT1B, CMT2A or CMTX1
Control participants

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
MRI Change in fat accumulation in CMT1A
Time Frame: 12 months
Part 1: Statistically significant (p<0.05) change of MRI-determined fat accumulation in foot and calf muscles in children/young adults with CMT1A over 12 months compared to matched controls.
12 months
MRI Change in fat accumulation in CMT1B; CMT2A and CMTX1
Time Frame: 12 months
Part 2: Statistically significant (p<0.05) change of MRI-determined fat accumulation in calf and thigh muscles in adults with CMT1B and CMT2A and male adults with CMTX1 over 12 months compared to matched controls.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
MRI changes validation - CMTPedS
Time Frame: 12 months
Validating the change in MRI-determined fat accumulation in foot and calf muscles in children/young adults with CMT1A over 12 months by correlating it with the CMTPedS (all children) and the CMTESv2-R (children aged >10).
12 months
MRI changes validation - CMTESv2-R
Time Frame: 12 months
Validating the change in MRI-determined fat accumulation in calf and thigh muscles in adults with CMT1B, CMT2A and CMTX1 over 12 months by correlating it with the CMTESv2-R
12 months
NEFL plasma responsiveness
Time Frame: 12 months
Defining the responsiveness of plasma NEFL in patients with CMT compared to matched controls over 12 months.
12 months
NEFL plasma (biomarker)
Time Frame: 12 months
Establishing the utility of plasma NEFL levels as a predictive biomarker of intramuscular fat accumulation over the subsequent 12 months in children/young adults with CMT1A.
12 months
Multi-level T2-weighted STIR and plasma NEFL levels (biomarker)
Time Frame: 12 months
Establishing the utility of multi-level T2-weighted STIR and plasma NEFL levels as predictive biomarkers of intramuscular fat accumulation over the subsequent 12 months in adults with CMT1B, CMT2A and CMTX1
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 11, 2018

Primary Completion (Anticipated)

July 1, 2021

Study Completion (Anticipated)

October 1, 2021

Study Registration Dates

First Submitted

May 14, 2018

First Submitted That Met QC Criteria

June 7, 2018

First Posted (Actual)

June 8, 2018

Study Record Updates

Last Update Posted (Actual)

October 4, 2018

Last Update Submitted That Met QC Criteria

October 3, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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