Charcot-Marie-Tooth Disease, Type IA Clinical Trial
Official title:
Muscle MRI in Charcot Mary Tooth Disease: a Prospective Cohort Study
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
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.
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