A Prospective Natural History and Outcome Measure Discovery Study of Charcot-Marie-Tooth Disease, Type 4J
Conditions: Peripheral Neuropathy, Neuro-Degenerative Disease, Neuromuscular Diseases
Sponsor: Elpida Therapeutics SPC

Natural History Study CMT4J                                                                                                       Protocol Number: TBD 
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Clinical Study Protocol 
 
 
Title 
A Prospective Natural History and Outcome Measure 
Discovery Study of Charcot-Marie-Tooth Disease, Type 4J 
Study Sponsor 
Elpida Therapeutics SPC 
12643 Rancho Bernardo Rd 
San Diego, CA 92127 
Sponsor Contact 
Terry Pirovolakis 
CEO & Founder 
Ph: (416) 625-1933; terry@elpidatx.com 
Lead Principal Investigator 
Susan T. Iannaccone, MD 
Professor, Pediatric Neurology, University of Texas 
Southwestern Medical Center 
Ph: (214) 456-5220; susan.iannaccone@utsouthwestern.edu 
Protocol Version and Date 
Version 1 (6-July2023) 
 
 
 
 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, potential 
investigators, consultants, study staff, and applicable independent Ethics Committees and/or 
Institutional Review Boards. The contents of this document shall not be disclosed to others 
without written authorization from Elpida Therapeutics (or authorized designees) unless it is 
necessary to obtain informed consent from potential study participants. 

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SIGNATURE PAGE/STATEMENT OF COMPLIANCE 
 
 
 
 
Title: 
A Prospective Natural History and Outcome Measure Discovery Study 
of Charcot-Marie-Tooth Disease, Type 4J  
 
Protocol No: 
 
TBD 
 
 
 
 
 
Elpida Therapeutics ______________________________ 
 
________________ 
 
 
 
 Terry Pirovolakis 
 
 
 
 
Date 
 
 
  
CEO & Founder 
 
 
The trial will be conducted in accordance with the International Conference on Harmonisation (ICH) 
E6 and the Code of Federal Regulations on the Protection of Human Subjects (45 CFR Part 46). Except 
where necessary to eliminate an immediate hazard(s) to the trial subjects, the Principal Investigator will 
assure that no deviation from, or changes to the protocol will take place without prior agreement from 
the sponsor and documented approval from the Institutional Review Board (IRB) and/or Independent 
Ethics Committee (IEC). All personnel involved in the conduct of this study have completed Human 
Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments. 
 
 
Principal Investigator: _________________________ 
 
_______________ 
 
 
 
      
Signature 
 
 
 
Date 
 
 
Name: ________________________ 
(Print) 
 
 
 

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TABLE OF CONTENTS: 
SIGNATURE PAGE/STATEMENT OF COMPLIANCE ...................................................2 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................. 5 
CLINICAL PROTOCOL SYNOPSIS .................................................................................. 6 
1 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE .......................................................................................................................... 9 
1.1 
Introduction and Purpose .........................................................................................9 
1.2 
Background and Rationale .......................................................................................9 
1.3 
Concise Summary of Project ...................................................................................9 
2 
OBJECTIVES ............................................................................................................... 10 
2.1 
Study Objectives ....................................................................................................10 
3 
STUDY ELIGIBILITY, ENROLLMENT AND CONSENTING ............................ 10 
3.1 
Target and Study Population .................................................................................10 
3.2 
Subject Inclusion Criteria ......................................................................................10 
3.3 
Recruitment Methods ............................................................................................11 
3.4 
Consenting Process and Review of Genetic Diagnosis .........................................11 
3.5 
Withdrawal from the Study ...................................................................................12 
 
Reasons for Withdrawal or Termination ...............................................................12 
 
Handling of Subject Withdrawals or Termination ................................................12 
4 
STUDY PROCEDURES AND SCHEDULE .............................................................. 12 
4.1 
Medical Information ..............................................................................................13 
4.2 
Outcome Measures ................................................................................................13 
4.3 
Procedures .............................................................................................................15 
4.4 
Skin Biopsy (Optional) ..........................................................................................16 
4.5 
Subject Withdrawal ...............................................................................................16 
4.6 
Unscheduled Visit(s) .............................................................................................16 
5 
POTENTIAL RISKS .................................................................................................... 16 
6 
SUBJECT SAFETY AND DATA MONITORING ................................................... 20 
7 
PROCEDURES TO MAINTAIN CONFIDENTIALITY ......................................... 20 
8 
POTENTIAL BENEFITS ............................................................................................ 20 
9 
PROTOCOL DEVIATIONS ....................................................................................... 21 
10 SAFETY ......................................................................................................................... 21 
10.1 
Definition of Adverse Event ..................................................................................21 
10.2 
Definition of Serious Adverse Event (SAE)..........................................................21 

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10.3 
Collecting, Recording, and Managing Adverse Events .........................................22 
 
Identifying Adverse Events ...................................................................................22 
 
Recording AE/SAEs ..............................................................................................22 
 
Managing Adverse Events .....................................................................................22 
 
Grading Criteria .....................................................................................................23 
 
Definition of Attribution ........................................................................................23 
 
SAE Reporting Criteria and Procedures ................................................................24 
11 STATISTICAL CONSIDERATIONS ........................................................................ 24 
11.1 
Data Management ..................................................................................................25 
12 ETHICAL CONSIDERATIONS (AND INFORMED CONSENT) ......................... 25 
12.1 
Ethical Standard .....................................................................................................25 
12.2 
Institutional Review Board ....................................................................................25 
APPENDIX 1:  SCHEDULE OF EVENTS ........................................................................ 26 
13 REFERENCES .............................................................................................................. 28 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
ADL 
 
Activities of Daily Living 
AE 
 
adverse event 
ALT 
 
alanine transaminase 
AST 
 
aspartate transaminase 
BUN 
 
blood urea nitrogen 
BUN/Cr 
BUN/creatine ratio 
CBC 
 
complete blood count 
CIDP  
chronic inflammatory demyelinating polyneuropathy 
CMT 
 
Charcot-Marie-Tooth disease 
CMT1A 
Charcot-Marie-Tooth disease, type 1A 
CMT4J  
Charcot-Marie-Tooth disease, type 4J 
CMT-FOM 
CMT Functional Outcome Measure 
CMTHI 
CMT Health Index 
CMTNSv2 
CMT Neuropathy Score, second version 
CMTPedS 
CMT Pediatric Scale 
CRF 
 
case report form 
CRP 
 
c-reactive protein 
CTCAE 
common terminology criteria for adverse events 
DSMB  
Data and Safety Monitoring Board 
EDB 
 
extensor digitorum brevis muscle 
EOS 
 
end of study 
ESR 
 
erythrocyte sedimentation rate 
FEF 
 
forced expiratory flow 
FEV 
 
forced expiratory volume 
FF 
 
fat fraction 
FIG4 
 
Factor-induced Gene 4 
FVC 
 
forced vital capacity 
GCP 
 
Good Clinical Practice 
GGT 
 
gamma-glutamyl transferase 
IRB 
 
Institutional Review Board 
MFF 
 
muscle fat fraction 
MRI 
 
magnetic resonance imaging 
NCS 
 
nerve conduction study 
ONLS  
Overall Neuropathy Limitation Scale 
pCMT-QOL 
pediatric CMT quality of life 
PEDI  
Pediatric Evaluation of Disability Inventory 
PEDICAT 
PEDI Computer Adaptive Test 
PedsQL 
Pediatric Quality of Life Inventory 
PFT 
 
pulmonary function test 
PRO 
 
patient-reported outcome 
PT/INR  
prothrombin time test and international normalized ratio 
PTT 
 
partial thromboplastin time test 
SAE 
 
serious adverse event 
TA 
 
tibialis anterior muscle 
TUG 
 
Timed Up & Go 
 
 
 

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CLINICAL PROTOCOL SYNOPSIS 
Study Title 
A Prospective Natural History and Outcome Measure Discovery Study of 
Charcot-Marie-Tooth Disease, Type 4J 
Sponsor 
Elpida Therapeutics SPC 
Trial Phase 
Observational 
Study Population 
Subjects with a genetically confirmed diagnosis of CMT4J will be included. 
Investigational Site 
4 US sites 
• 
University of Texas Southwestern Medical Center /Children’s Health 
• 
University of Iowa 
• 
NIH (National Institute of Neurological Disorders and Stroke) 
• 
Stanford School of Medicine 
Study Objectives 
 
 
• 
To gain a better understanding of the course of illness 
• 
To collect data about genotype-phenotype correlations to allow for better 
prediction of disease progression based on genetic information 
• 
To investigate and follow at long term different outcome measurements 
(e.g., motor, quality of life, radiologic and electrophysiological) 
• 
To expedite research and access to new therapies for rare conditions like 
CMT4J 
Study Design 
A multicenter, longitudinal, prospective observational natural history study of 
subjects with a molecular confirmed diagnosis of CMT4J 
Eligibility Criteria 
Inclusion Criteria: 
1. Male or female, all ages 
2. A molecularly-confirmed diagnosis of CMT4J (confirmed by a CLIA 
certified, CE-marked, or equivalent lab): Genomic DNA mutation 
analysis demonstrating 1) bi-allelic pathogenic and/or likely 
pathogenic variants (by ACMG criteria) in the FIG4 gene, or 2) bi-
allelic variants with one pathogenic and/or likely pathogenic variant 
in trans with a variant of uncertain significance if laboratory evidence 
and expert consensus exits in support of loss of FIG4 function exists. 
3. Informed consent from patients 18 years or older who are able to 
provide consent and from caregivers; parent(s)/guardian(s) providing 
consent for subjects younger than 18 years at Screening and patients 
older than 18 years unable to provide informed consent 
4. Informed assent of patients younger than 18 years at Screening who 
are able to provide assent 
5. Able and willing to comply with the study protocol, including travel 
to Study Center, procedures, measurements and visits 
 
Exclusion Criteria:  
1. Any known genetic abnormality, including chromosomal aberrations 
that confound the clinical phenotype  
2. Current participation in an interventional or therapeutic study  
3. Receiving an investigational drug within 90 days of the Baseline Visit 

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4. Prior or current treatment with gene or stem cell therapy 
5. Any other diseases which may significantly interfere with the 
assessment of CMT4J 
6. Have any other conditions, which, in the opinion of the Investigator 
or Sponsor would make the subject unsuitable for inclusion or could 
interfere with the subject participating in or completing the study 
Study Duration 
Subject visits will occur every 12 months + 4 weeks for up to 2 years for the 
initial period with extension of up to 60 months if feasible. No investigational 
product will be used during the study. 
Assessments 
Clinical Assessments: 
• 
Electrophysiology 
• 
Nerve Conduction Studies (NCS)  
• 
Pulmonary Function Tests (PFTs) 
• 
Scoliosis series X-ray 
• 
Magnetic Resonance Imaging  
1. Thigh and calf muscle without contrast 
2. Brain without contrast 
 
Neuropsychological Assessments: 
• 
Vineland Adaptive Behavior Score, 3rd edition 
• 
Bayley Scales of Infant and Toddler Development-III 
• 
Wechsler Abbreviated Scale of Intelligence Second Edition / Wechsler 
Preschool & Primary Scale of Intelligence Fourth Edition (WASI-II / 
WPPSI-IV) 
• 
Stanford-Binet V (SB5) 
 
Physical Therapy Assessments: 
• 
PEDICAT 
• 
CMTPedS for subjects 5 to 17 years of age 
• 
CMTInfS (< 4 years old) 
• 
CMTNSv2 for subjects >18 years of age 
• 
CMT-FOM for subjects > 18 years of age 
• 
Timed Up and Go Test (TUG)  
 
Questionnaires:  
• 
PedsQL (2-18 years) 
• 
ONLS (18 years and older) 
• 
pCMT-QOL PRO (8-18 years)  
• 
pCMT-QOL parent proxy (8-18 years) 
• 
pCMT-QOL parent proxy (0-7 years) 
• 
CMT Health Index (CMTHI) for >18 years of age 
 

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Exploratory Assessments: 
• 
Blood collection for exploratory biomarker 
• 
Wearable devices 
• 
Optional skin biopsy 
STATISTICAL 
CONSIDERATIONS 
The sample size of 20 subjects is expected to provide sufficient insights into 
the natural history of individuals with CMT4J, a rare disease, to provide 
exploratory and descriptive results and guide the design of future studies of 
CMT4J. No formal sample size estimation was performed for this study. 
Parametric and non-parametric tests will be used to analyze possible 
associations between clinical, radiographic, and laboratory data. The tests will 
be selected based on the question being asked of the database. This database 
will be used to analyze multiple medical issues among subjects with confirmed 
CMT4J. 
 

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1 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
1.1 
Introduction and Purpose 
Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies, affecting 1 in 
1,214 (1) to 2,500 (2). CMT can affect both females and males of all ethnicities. 
 
CMT is classified according to the type of nerve damage (demyelinating vs. axonal) and its type of 
inheritance (autosomal recessive, dominant or X-linked). Mutations in more than 80 genes cause CMT. 
Most of the CMT neuropathies are demyelinating, especially CMT1A which comprises 60 to 65% of 
cases. 
 
CMT4J is a rare autosomal recessive, peripheral motor demyelinating neuropathy caused by biallelic 
pathogenic variants in the FIG4 gene. CMT4J is characterized by childhood onset gait abnormalities 
and balance difficulties, that rapidly progress to muscle weakness and muscle atrophy during the teen 
or adult years. Onset can be acute or sub-acute, mimicking an acquired neuropathy and often 
misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP), or a subacute 
presentation of Guillain-Barre Syndrome. Involvement can be asymmetric and can affect distal as well 
as proximal musculature. Although sensory symptoms are minimal, examination may reveal decreased 
response to touch, pin prick, or vibration distally. Bulbar and cranial nerve functions are often spared; 
intellect is often normal. 
 
This study is designed to investigate the clinical characteristics and natural history of CMT4J. We aim 
to follow subjects with a molecularly confirmed diagnosis of CMT4J longitudinally to collect 
standardized clinical data to evaluate epidemiological characteristics, clinical course, and to identify 
potential outcome measures which may be used in future clinical trials. Clinical data collection will 
include medical history and physical exam, hematology and biochemical analyses, calf muscle imaging, 
nerve conduction studies, pulmonary function testing and neuropsychological assessments. 
 
The study will be conducted in accordance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
1.2 
Background and Rationale 
 
There is no causative treatment available for CMT, but therapeutic clinical trials for the most common 
types of CMT, like CMT1A, are ongoing. Most recently, animal models have demonstrated the 
possibility of treating some types of CMT, like CMT4J, with gene transfer therapy through viral 
vectors. To be able to understand the condition over time and evaluate these therapies at long term, 
natural history studies are indispensable. This study investigates the natural history of CMT4J.  
 
1.3 
Concise Summary of Project 
 
This is a multicenter, longitudinal, prospective observational natural history study of subjects with a 
molecularly confirmed diagnosis of CMT4J. We plan to enroll 20 subjects of any age into a uniform 
protocol for follow-up and evaluations. We will obtain demographic and medical history information. 
Natural history data will be collected prospectively on an annual basis and may include 
physical/neurological exams, standard laboratory tests, CMT outcome and disability measures, 
neuropsychological tests, nerve conduction studies (NCS), and imaging studies (muscle MRI). 
Pulmonary function test (PFT) and scoliosis series x-ray Subject visits will occur every 12 months 

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+ 4 weeks for up to 2 years. Subjects who terminate from the study prior to Visit 3 will undergo an early 
termination/end of study visit (EOS) if possible. The early termination/end of study visit is comprised 
of the Visit 3 assessments. If needed, the Investigator may conduct unscheduled visits with Sponsor’s 
approval. No investigational product will be used during the study. 
 
Since CMT4J is a rare disease, there is a high likelihood that both national and international families 
may be interested in study participation.  
 
 
OBJECTIVES 
 
1.4 
Study Objectives 
• 
To gain a better understanding of the CMT4J disease course and phenotypic 
spectrum. 
• 
To explore CMT4J genotype-phenotype correlations to allow for better prediction of 
disease progression based on genetic information. 
• 
To evaluate candidate clinical trial outcome measures related to motor function, 
quality of life, radiology, and electrophysiology. To expedite research and access to 
new therapies for rare conditions like CMT4J. 
2 
STUDY ELIGIBILITY, ENROLLMENT AND CONSENTING 
 
2.1 
Target and Study Population 
Subjects with a prior diagnosis of CMT4J will be included. CMT4J diagnosis will be made by both 
clinical manifestations and a confirmed genetic confirmation. Examples of clinical manifestations 
consistent with CMT4J, include but are not limited to, childhood onset gait abnormalities, poor balance, 
and accelerated, most commonly asymmetric, limb weakness and muscle atrophy, involving distal and 
proximal musculature. 
 
2.2 
Subject Inclusion Criteria 
 
Inclusion Criteria: 
1. Male or female, all ages 
2. A molecularly-confirmed diagnosis of CMT4J (confirmed by a CLIA certified, CE-marked, 
or equivalent lab): Genomic DNA mutation analysis demonstrating 1) bi-allelic pathogenic 
and/or likely pathogenic variants (by ACMG criteria) in the FIG4 gene, or 2) bi-allelic 
variants with one pathogenic and/or likely pathogenic variant in trans with a variant of 
uncertain significance if laboratory evidence and expert consensus exits in support of loss of 
FIG4 function exists. 
3. Informed consent from patients 18 years or older who are able to provide consent and from 
caregivers; parent(s)/guardian(s) providing consent for subjects younger than 18 years at 
Screening and patients older than 18 years unable to provide informed consent 
4. Informed assent of patients younger than 18 years at Screening who are able to provide assent 

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5. Able and willing to comply with the study protocol, including travel to Study Center, 
procedures, measurements and visits 
 
Exclusion Criteria:  
1. Any known genetic abnormality, including chromosomal aberrations that confound the 
clinical phenotype  
2. Current participation in an interventional or therapeutic study  
3. Receiving an investigational drug within 90 days of the Baseline Visit 
4. Prior or current treatment with gene or stem cell therapy 
5. Any other diseases which may significantly interfere with the assessment of CMT4J 
6. Have any other conditions, which, in the opinion of the Investigator or Sponsor would make 
the subject unsuitable for inclusion or could interfere with the subject participating in or 
completing the study 
 
2.3 
Recruitment Methods 
 
We plan to enroll up to 20 subjects into the study. The gender, race, and ethnic distribution of the 
accrued study population may not be representative of the general population but is expected to reflect 
those affected with the disease under study. Patients who currently seek medical care at a study site 
may be approached to participate in the study. For those patients who are followed at a study site, their 
treating physician will inform the patient and/or family of the study. Should the patient/family be 
amenable to learning more about the study, then a member of the research staff will speak with them 
about study participation. The patient/family will be given ample time to review the consent form and 
ask questions. The patient may enroll into the study at any time during their care. 
 
Participants will be recruited through clinician or self-referral. The study will be posted at 
clinicaltrials.gov to aid recruitment. An IRB-approved study advertisement will also be made available 
to patient and professional organizations such as Cure CMT4J and the Inherited Neuropathies 
Consortium, respectively. The approved advertisement may be posted on patient organization 
websites/social media accounts and may also be made available at scientific/medical/patient 
conferences. 
  
Participant selection will be equitable considering the rarity of CMT4J. All ages within the specified 
range, races, and both sexes will be accepted. There will be no restriction based on geographic location. 
The study team will enhance retention by sending email reminders to participants prior to scheduled 
visits and will be available to answer any study-related questions between visits. 
 
If a patient/family contacts the study personnel, they will send a consent form to the patient/family and 
answer their questions accordingly. If the patient/family is interested in establishing care at a study site, 
the study staff will connect them with the proper department. 
 
2.4 
Consenting Process and Review of Genetic Diagnosis 
 
Documentation of genetic confirmation will be reviewed by the Investigator prior to any on-site visits 
being arranged, in order to confirm eligibility. Each site will follow their IRB guidelines on consent 
processes for obtaining genetic test results prior to on-site patient visits. 
 
The Sponsor is using a vendor to manage travel planning and expenses for the site and subjects. The 
vendor will act as a third-party working with both the site and subject to book travel (including flights, 
hotels, ground transportation, etc.) The vendor will bill the Sponsor directly for subject travel costs, 

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and any travel expenses incurred by the subject (e.g., meals, tolls, parking fees, etc.) will be reimbursed 
to the subject. Only the travel expenses of the subject and up to two caregivers will be covered. The 
Investigator must confirm eligibility of the subject prior to any travel or on-site visits being arranged. 
The subject will be asked to sign a vendor-specific data use consent prior to any travel arrangements. 
Once a potential subject expresses interest in study participation and chooses to travel to the site, the 
study staff will connect the subject to the vendor coordinator to sign the vendor data use consent and 
proceed with travel arrangements. This may be done prior to the subject signing the study’s informed 
consent document. 
 
Informed consent will be obtained from all subjects with sufficient capacity or from legal 
guardians/representatives of subjects with insufficient capacity to consent. Written or verbal assent will 
be obtained in accordance with Institutional Review Board (IRB) guidelines. Dissent from all subjects 
will be respected. 
 
2.5 
Withdrawal from the Study 
 
Reasons for Withdrawal or Termination 
Participation in the study is strictly voluntary. Subjects have the right to withdraw from the study at any 
time and for any reason, without penalty. Site Principal Investigators and/or designees may, at her/their 
discretion, withdraw a subject from continuing in the study if it is in the subject’s best interest, or if the 
subject is not willing or able to comply with the study requirements. The reason for withdrawal will be 
documented. 
 
Handling of Subject Withdrawals or Termination 
Every effort will be made to undertake protocol-specified safety follow-up procedures to capture 
protocol specified assessments. An investigator may discontinue or withdraw a participant from the 
study for the following reasons: 
• 
Significant non-compliance  
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Subject has completed the study follow-up period 
• 
Death 
• 
Screening Failure 
 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
discontinuation/withdrawal Case Report Form (CRF). 
 
A participant will be considered lost to follow-up if a follow up visit is missed and the participant is 
unable to be contacted by the study site staff following at least three attempts (where possible, three 
telephone calls and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). 
 
3 
STUDY PROCEDURES AND SCHEDULE 
 
The frequency of the following assessments will be according to the schedule of study procedures in 
Appendix 1. Not all the following assessments need to be performed at every visit, only those that the 
subject is able to perform.  

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1. 4.1 Medical Information 
 
Medical History: Medical history of participating subjects will be recorded in order to obtain the 
following data: basic demographic information (sex, ethnicity), past medical history, birth history, 
surgical history, developmental history, medications and family history. We will also collect time of 
symptoms onset (e.g., motor, language, etc.) and progression, age at diagnosis and genetic results. 
 
Physical and Neurological Examination: At each visit, a physical exam will be recorded including but 
not limited to evaluation of the ears, nose, throat, heart, lungs, abdomen, back, and extremities, motor 
and sensory, and vital signs which will include blood pressure (measured in one arm or, if necessary, 
one leg, after the subject has been seated for approximately 5 minutes), pulse, temperature, height, 
weight, and head circumference. 
 
A detailed neurological examination including but not limited to evaluation of cranial nerves, muscle 
tone, muscle strength, sensation, gait, coordination and deep tendon reflex testing will also be 
performed. Handheld dynamometry will also be performed during clinic visits in muscles of the upper 
and lower extremities. The examination is anticipated to take approximately 30 minutes. 
 
3.1 
Outcome Measures 
CMT Pediatric Scale (CMTPedS): The CMTPedS is a clinical tool used to supplement a neurological 
examination and capture functionally relevant limitations caused by CMT in the pediatric population. 
It is intended to have broad application in natural history studies and clinical trials of rehabilitative 
(e.g., orthoses, stretching, strengthening), pharmacological (e.g., curcumin, anti-progesterone) and 
surgical (e.g., foot and hand tendon transfer, arthrodesis, hip dysplasia) interventions (3). This scale 
will be used for subjects aged 5 to 17 years 11 months (less than 18 years). 
 
CMT Infant Scale (CMTInfS): The CMTInfS is a validated clinical tool and requires 20 min to 
administer and is a reliable and sensitive 15-item functional outcome measure for early onset CMT and 
related neuropathies. The CMTInfS can be implemented in natural history studies to understand the 
rate of progression at the earliest stages of disease in preparation for therapeutic trials of early 
interventions. The CMTPedS involves some difficult items that require advanced levels of 
comprehension, so high variability is seen in children <4 years of age. Therefore, for children aged 3 
years, the CMTInfS may be more sensitive to disease severity and clinical impression. 
 
CMT Neuropathy Score, second version (CMTNSv2): The CMTNSv2 is a validated clinical outcome 
measure developed for use in clinical trials to monitor disease impairment, severity and progression in 
affected CMT subjects (4). This scale will be used for subjects 18 years of age or older. 
 
CMT Functional Outcome Measure (CMT-FOM): The CMT-FOM is a performance-based outcome 
assessment which measures limitations in functional abilities in adults with CMT1A (5). It was based 
on the validated CMTPedS and further developed using review of the literature, patient interviews and 
a survey of 407 adults with CMT, and subjects 18 years of age or older. 
 
CMT Health Index (CMTHI): The CMTHI is a disease-specific, patient reported outcome measure 
designed to capture the disease burden of inherited neuropathies, in the context of a clinical trial (6). 
This scale will be used for subjects 18 years of age or older. 
 
Vineland Adaptive Behavior Scale, 3rd Edition: The caregiver interview form will be used to evaluate 
communication, socialization, and daily living skills of subjects to assess their overall adaptive 

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functioning. The items in the Vineland Adaptive Behavior Scale requires the caregiver to be familiar 
with the subject’s day-to-day functioning in areas of communication, socializing, and daily living skills. 
As such, for subjects who reside independently, the rater who administers the assessment should 
determine if the caregiver, if he/she is available during the visit, has sufficient knowledge of the 
subject’s day-to-day functioning to be able to complete the interview. If the caregiver is not familiar 
with the subject’s day-to-day functioning skills, then the assessment should not be completed. The 
motor subdomain will be administered to those up to age 9 years. This assessment is an interview of 
the caregiver by a qualified rater (8). The semi-structured interviews will be recorded in a standardized 
manner. 
 
Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III): The comprehensive tool 
has 5 developmental domains, of which we will utilize 4: Cognitive Scale, which assesses attention to 
familiar and unfamiliar objects, looking for a fallen object, and pretend play, Language Scale, which 
focuses on recognition of objects and people, following directions, and naming objects and pictures, 
Motor Scale, which assesses gross and fine motor skills such as grasping, sitting, stacking blocks, and 
climbing stairs, and Social-Emotional Scale, which measures a child's ability to engage with others 
socially, self-calm and takes part in age-appropriate play. We will not make use of the Adaptive 
Behavior Scale to avoid duplication of the same information. Raw scores of successfully completed 
items are converted to scale scores and to composite scores. These scores are used to determine the 
child's performance compared with norms taken from typically developing children of their age (in 
months). The Bayley-III will be performed through 42 months of age. 
 
Wechsler Abbreviated Scale of Intelligence Second Edition / Wechsler Preschool & Primary Scale of 
Intelligence Fourth Edition (WASI-II / WPPSI-IV): A test of intellectual functioning comprised of 
verbal and visual reasoning subtests as well as tasks of working memory and processing speed. 
 
Stanford-Binet Fifth Edition (SB5): The Stanford-Binet test V is an examination meant to gauge 
intelligence through five factors of cognitive ability. These five factors include fluid reasoning, 
knowledge, quantitative reasoning, visual-spatial processing and working memory. Both verbal and 
nonverbal responses are measured. Each of the five factors is given a weight and the combined score is 
often reduced to a ratio known commonly as the intelligence quotient, or IQ. For children ages 2 to 5, 
use the early SB5. 
 
Timed Up & Go Test (TUG): The Timed Up and Go Test (TUG) is a measure of mobility. Patients are 
asked to sit in a regular chair and upon command rise from the chair, walk at their normal pace to a line 
on the floor 10 feet (3 meters) away from the chair, return to the chair and sit down again. The time 
required by the patient to complete the assessment is measured and recorded. The TUG should be 
performed in triplicate at each visit and the best performance will be used for analyses. The TUG is 
administered by a Physician, a Physical Therapist, or designee familiar with the test. Every attempt 
should be made that the same assessor is administering the TUG in a given patient throughout the study. 
TUG will be administered to ambulatory patients in this Study. 
 
Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDICAT): PEDI, originally 
published in 1992 by Haley et al. and revised as a computer adaptive test (CAT) – the PEDI-CAT, is a 
parent/clinician functional test that measures abilities in 4 content domains: daily activities, mobility, 
social/cognitive, responsibility. It will be completed by the caregiver with support from a qualified 
study center staff, for subjects younger than 20 years of age (9).  
 
Pediatric Quality of Life Inventory (PedsQL)-Family Impact Module: Measures parent self-reported 
physical, emotional, social, and cognitive functioning, communication, and worry (10). The Module 

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also measures parent-reported family daily activities and family relationships. This assessment will be 
used in subjects between 2 and18 years of age. 
 
Overall Neuropathy Limitation Scale (ONLS): The scale was derived by modifying the Overall 
Disability Sum Score (ODSS) slightly to avoid the ceiling effect. Its inter-rater reliability was found to 
be high, as was its correlation with the ODSS (11). It is used to assess the limitations of subjects with 
immune-mediated peripheral neuropathies. It focuses on upper and lower limb functions and consists 
of a checklist for interviewing subjects. This scale will be used in subjects 18 years of age or older. 
 
Pediatric CMT-specific Quality of Life Patient-reported Outcome Measure (pCMT-QOL PRO) and 
parent proxy (pCMT-QOL parent proxy): Measures patient-reported physical (symptoms, function, 
social activities) and social (feelings, cognition, and social skills) domains specific for children with 
CMT (12). This scale will be used in subjects 8 to 18 years of age. 
 
Pediatric CMT-specific Quality of Life Parent-proxy Outcome Measure (pCMT-QOL [0 to 7 years 
parent-proxy]): Measure parent-reported physical (symptoms, function, social activities) and social 
(feelings, cognition, and social skills) domains specific for children with CMT (13). This scale will be 
used in subjects 7 years of age or younger. 
 
3.2 
Procedures 
 
Magnetic Resonance Imaging (MRI): An MRI scan (without contrast) of the bilateral thigh and calf 
muscles will be performed to characterize the pattern of muscle involvement and evaluate the muscle 
fat fraction (MFF). Three-point Dixon MRI of leg muscles will be performed to generate fat fraction 
(FF) maps as described in the detailed CMT47 Imaging protocol. All MR imaging will be supervised 
by an attending pediatric neuroradiologist to ensure acquisition of complete, high-quality scans. MR 
imaging will be acquired at baseline and at multiple time points. The data will be transferred to a central 
site for quality control and analysis. 
 
Nerve Conduction Study (NCS): NCS is an electrophysiological test to evaluate the sensory and motor 
responses in the upper and lower extremities. The specific measurements include distal latency, 
amplitude and conduction velocity. Serial measurements can show progression of the disease, as in 
axonal and demyelinating conditions. Ideally, NCS will be performed on the left arm and left leg. The 
same limbs will be assessed at every visit. The following nerves will be studied: median motor, radial 
sensory and peroneal motor response at the extensor digitorum brevis (EDB) and the tibialis anterior 
(TA). 
 
Pulmonary Function Test, sitting and lying (PFT): The primary purpose of pulmonary function testing 
is to identify the severity and progression of pulmonary impairment. The specific measurements are 
lung volumes (Forced Vital Capacity-FVC, Forced Expiratory Volume-FEV and Forced Expiratory 
Flow-FEF) and maximal respiratory pressures (inspiratory and expiratory). PFTs will be performed in 
subjects older than 5 years of age based on the evaluator’s assessment of subject’s compliance and/or 
ability to follow instructions. The evaluator should complete the seated PFT prior to the supine PFT.  
 
Scoliosis Series X-ray: The scoliosis X-ray includes the thoracic spine (upper back) and the lumbar 
spine (lower back). The scoliosis X-ray will not be completed on subjects older than 17 years of age.  
 
Pregnancy Test- (individuals of childbearing potential only) Urine pregnancy test for females of child-
bearing potential (Subject has experienced onset of menses and is not postmenopausal) will be 
collected. Results of urine pregnancy test must be reviewed and confirmed to be negative prior to 

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proceeding with any assessments involving radiation. If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test. If the subject’s urine or serum pregnancy test is positive, 
assessments involving radiation should not be performed. 
 
3.3 
Skin Biopsy (Optional)  
 An optional skin sample will be taken for exploratory research purposes. If the participant consents, 
the neurologist will take a small skin sample via punch biopsy (approximately 3-4mm). Lidocaine 
cream will may be applied 30 mins prior to the area to be biopsied to anesthetize the skin. The skin 
sample will be sent to specialized laboratory for fibroblast culturing and subsequently the participants 
fibroblasts will be stored for future use. 
 
3.4 
Subject Withdrawal 
Subjects may be withdrawn from the study for any of the following reasons: 
• 
Withdrawal of the informed consent 
• 
Lost to follow-up 
• 
Withdrawal at the investigator’s discretion 
Subjects should be withdrawn at any time if the investigator concludes that it would be in the subjects’ 
best interest for any reason. Subjects may voluntarily withdraw from the study for any reason at any 
time. They may be considered withdrawn if they state an intention to withdraw, or fail to return for 
visits, or become lost to follow up for any other reason. Protocol deviations should not lead to subject 
withdrawal unless they indicate a significant risk to the subject’s safety. If premature subject 
withdrawal occurs for any reason, the investigator must determine the primary reason for a subject’s 
premature withdrawal from the study and record this information on the case report form (CRF). For 
subjects who are lost to follow-up (i.e., those subjects whose status is unclear because they fail to appear 
for study visits without stating an intention to withdraw), the investigator should show due diligence 
by documenting in the source documents steps taken to contact the subject, e.g., dates of telephone 
calls, registered letters, etc. In the case of death, a subject will be considered withdrawn.  
 
Subjects who terminate from the study prior to Visit 3, if they agree, will undergo an early 
termination/end of study visit if possible. The early termination/end of study visit is comprised of the 
Visit 3 assessments. Subjects can voluntarily withdraw from participation in this research study at any 
time. They may also request that their information be removed and destroyed from the study and that 
their data not be used in the analysis, evaluation or publication of this research study. That request 
would need to be in a written format, directed and submitted to the Principal Investigator. 
 
3.5 
Unscheduled Visit(s) 
Subjects who experience any serious adverse effects (per21cFR312.32) or severe adverse events 
(CTCA>grade3) or experience another event of concern to the site Principal Investigator can be 
scheduled for an additional visit for further evaluation. If an unscheduled visit occurs, a member of the 
clinical study team (PI, sub-investigator, nurse coordinator, or clinical nurse) will evaluate the subject 
to determine the cause of the visit and provide care as needed. All procedures and/or sample collections 
should be documented within in unscheduled visit CRF. 
4 
POTENTIAL RISKS 
Medical History and Record Review: There may be psychological distress associated with providing 
medical and family history. Frequent breaks or even cessation of the interview may be taken to reduce 

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risk of distress. There is a risk of potential loss of confidentiality and personal health information. Every 
effort will be made to keep the subject’s information confidential; however, this cannot be guaranteed.  
 
Physical and Neurological Examination: There is a small risk of mild pain or discomfort from 
positioning, activities, equipment, and procedures for the neurologic examination.  
 
Neuropsychological Tests and Quality of Life Measures: These tests do not involve any medical 
procedures and have no inherent risks. However, subjects may experience mild frustration or 
nervousness due to cognitively challenging tasks. Subjects and parents may experience mild levels of 
psychological discomfort when completing rating forms on topics including school performance, mood, 
and quality of life.  
 
NCS: Electrical stimulation may cause muscle contraction that may be uncomfortable. Also, there may 
be mild muscle soreness after muscle testing. This may last for one to two days. Subjects may 
experience some slight discomfort from having to lay or sit still during the procedure.  
 
MRI: Subjects are at risk for injury from the MRI magnet if they have pacemakers or other implanted 
electrical devices, brain stimulators, some types of dental implants, aneurysm clips, metallic prostheses, 
permanent eyeliners, implanted delivery pump, or shrapnel fragments. Welders and metal workers are 
also at risk for injury because of possible small metal fragments in the eye of which they may be 
unaware. Individuals will be screened for these conditions and implants before having any scan, and if 
they have any, they will not receive an MRI scan (or per the clinical judgement of a certified radiologist 
and radiology staff, may have a modified MRI that is deemed safe). In addition, all magnetic objects 
must be removed before entering the MRI scan room. We do not plan to administer gadolinium contrast 
as part of this imaging protocol.  
 
Subjects with fear of confined spaces may become anxious during an MRI. Those with back problems 
or significant contractures may have pain or discomfort from lying in the scanner. The noise from the 
scanner is loud enough to damage hearing. Everyone having an MRI scan will be fitted with hearing 
protection. There are no known long-term risks of MRI scans.  
 
X-Ray: This is a relatively painless and safe study. Subjects are exposed to a minimal amount of 
radiation during the scoliosis series X-ray to create detailed images of the spine.  
 
Pulmonary Function Tests: There are no known risks. Subjects may feel tired after the procedure due 
to the respiratory effort.  
 
Physical therapy assessments: The outcome measures (CMTPedS and CMTNSv2) carry a very small 
risk of mild pain, fatigue or discomfort from positioning, activities and equipment.  
 
Blood collection: Subjects may experience minor pain and bruising during routine phlebotomy. All 
proper precautions will be taken, and only qualified individuals will perform blood draws. 
 
Loss of confidentiality: There is a risk that confidentiality may be breached during the study. These 
risks are mitigated by anonymizing data and using secure servers and databases. If there is a 
confidentiality or data breach, the subject will be informed as soon as it is discovered.  
 
Unforeseen risks: A previously unknown problem could result from participation in this observational 
study. It is not possible to estimate the chance of such problems or how serious problems could be. 
 

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Procedures and Risks 
Description 
Risk 
Mitigation 
measures 
Neurology Clinic Visit 
Vital signs, 
anthropometrics, history 
of present illness and 
interim information will 
be obtained. 
Physical examination 
including general, 
neurological exam 
(including MMT) and 
hand-held dynamometry 
Discomfort or 
psychological stress.  
Subjects 
allowed to take 
breaks. 
CMT Specific Scales 
- 
CMTPedS for 
subjects 5-17 
years of age 
- 
CMTInfS < 4 
years of age 
- 
CMTNSv2 for 
subjects >18 
years of age 
- 
CMT-FOM for 
subjects > 18 
years of age 
- 
CMT Health 
Index (CMTHI) 
for >18 years of 
age 
Validated clinical 
outcome measures to 
monitor progression of 
sensorimotor function, 
disease-burden and 
quality of life in CMT 
subjects  
No known risks.  
May experience mild 
frustration or fatigue 
with challenging tasks.  
May experience mild 
psychological 
discomfort when 
completing rating 
forms on topics 
including school 
performance, mood, 
and quality of life. 
Subjects 
allowed to take 
breaks. 
Electrophysiology 
Nerve Conduction 
Studies (NCS) 
Evaluates sensory and 
motor responses in the 
upper and lower 
extremities including 
distal latency, amplitude 
and conduction velocity. 
Risk of discomfort 
with muscle 
contraction from 
stimulation.  
Mild muscle soreness 
and fatigue.  
Discomfort from 
staying still during the 
procedure. 
Procedure 
expectations 
will be 
communicated 
with the 
subjects and 
time will be 
given between 
stimulations. 
Magnetic Resonance 
Imaging of the thigh and 
calf muscle without 
contrast 
 
 
 
Brain MRI without 
contrast 
MRI scan of the thigh and 
calf muscle to 
characterize the structural 
abnormalities in CMT4J. 
 
 
 
MRI scan of the brain. 
Risk for injury from 
the MRI magnet if 
present: pacemakers or 
other implanted 
electrical devices, 
brain stimulators, some 
dental implants, 
aneurysm clips, 
metallic prostheses, 
permanent eyeliners, 
implanted delivery 
pump, magnetic 
devices (such as 
Individuals are 
screened to 
ensure MRI 
safety 
procedures are 
met before a 
scan 
Hearing 
protection for 
risk of hearing 
damage 

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magnetic spine 
growing rods) or 
shrapnel fragments.  
Risk of discomfort 
from laying on hard 
surface or anxiety if 
fear of confined spaces 
or loud noises 
 
Neuropsychological and 
Physical therapy 
Assessments 
A series of performance-
based activities to assess 
psychomotor functioning 
and quality of life. This 
includes: 
• 
Vineland 
Adaptive 
Behavioral Scale 
• 
PEDICAT 
• 
PedsQL 
• 
ONLS 
• 
pCMT-QOL 
• 
Bayley-III,  
• 
WASI-II, 
WPPSI-IV 
• 
Stanford-Binet 
test V 
• 
TUG 
Discomfort or 
psychological stress 
and tiredness.  
Subjects 
allowed to take 
breaks. 
Pulmonary Function 
Tests (PFTs) 
PFTs to identify severity 
and progression of 
pulmonary dysfunction. 
Lung volume 
measurements: Forced 
Vital Capacity-FVC, 
Forced Expiratory 
Volume-FEV, and Forced 
Expiratory Flow-FEF. 
Pressure Measurements: 
maximal inspiratory and 
expiratory. 
No known risks. May 
feel tired after the 
procedure. 
Subjects 
allowed to take 
breaks. 
 
Scoliosis series X-ray 
Scoliosis series X-ray 
includes the thoracic 
spine (upper back) and 
the lumbar spine (lower 
back) to identify areas of 
spine curvature. 
Exposure to minimal 
amount of radiation. 
Adherence to 
the minimum 
exposure to 
radiation as 
permittable. 
Blood collection 
Exploratory blood draw 
Minor pain and 
bruising 
Adherence to 
maximum blood 
volumes 
permitted in 

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pediatric 
subjects 
Skin biopsy (optional) 
Small punch biopsy for 
future exploratory use 
Exposure to lidocaine 
cream and a small 
irritation to the skin for 
the punch biopsy 
Only trained 
individuals can 
perform a skin 
biopsy 
 
5 
SUBJECT SAFETY AND DATA MONITORING 
This study will not involve an investigational drug and does not require a DSMB. 
Clinical data collected will be entered into a 21CFR11-compliant database by each study site. CRFs 
will be associated with each scheduled visit and all protocol-related research assessments. 
 
As part of the consent process, subjects will be informed that their de-identified data will be shared 
with various third parties, including Regulatory Authorities, IRBs or other academic researchers and 
collaborating biotechnology companies without future consent requests. Future use of data and samples, 
including sharing with third parties (e.g., regulatory authorities), will be governed by each site’s local 
informed consent form. 
6 
PROCEDURES TO MAINTAIN CONFIDENTIALITY 
Subjects enrolled in the natural history study will be given a unique identifier that includes the project 
(disease), a site number that corresponds to the site, and a sequentially assigned subject number (ex: 
CMT4J-001-001). 
 
Collaboration with other institutions and/or researchers may occur. In this case, all subject information 
shared with collaborators will be de-identified. Identifiable information may be shared with other 
studies if approved by the IRB or other regulatory body. 
 
Study records are confidential, and they will be kept in a secure environment and protected to the full 
extent of the law. 
 
The study monitor, representatives of the Institutional Review Board (IRB), and/or regulatory agencies 
may inspect all documents and records required to be maintained by the site Principal Investigators, 
including but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study sites will permit access to such records. 
  
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
  
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within an electronic data capture system which is 21 CFR11 compliant. 
The electronic case report form will not include the participant’s contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification 
number. 
7 
POTENTIAL BENEFITS 
Participation in this research study may not provide a direct benefit to participants. This study may 
expand our knowledge about the genotype range and phenotypic expression of CMT4J. It will also 

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yield information about other system involvement and the frequency of this in the CMT4J/FIG4 
population. The long-term objective is to be able to provide information about natural history and 
outcome measure validity, which is essential for future therapeutic clinical trials. 
8 
PROTOCOL DEVIATIONS 
A major protocol deviation is a deviation that may adversely affect the rights, safety or well-being of 
the subjects and/or the quality and integrity of data or may affect the subject’s willingness to have 
consented in the study. “May” in this paragraph refers to a “reasonable possibility” of having such an 
effect; it does not require that such an effect has unequivocally occurred. 
 
Major protocol deviations include but are not limited to: enrolment of ineligible subjects, factors that 
may confound measurement or interpretation of key outcome measures (e.g., a final study endpoint or 
several smaller “during study” outcome measures), safety or efficacy assessments not performed, or a 
pattern or frequency of “minor” deviations that together meet criteria described herein for a major 
deviation. 
 
A minor protocol deviation is a deviation that is unlikely to adversely affect the rights, safety or well-
being of the subjects and/or the compromise the quality and integrity of data or affect the subject’s 
willingness to participate in the study. An example of a minor protocol deviation would be a missed 
laboratory test or a missed study visit. 
9 
SAFETY 
9.1 
Definition of Adverse Event 
 
An AE is any untoward medical occurrence in a subject after administration of an investigational 
vaccine and that does not necessarily have a causal relationship with the investigational vaccine. As 
this study is an observational study with no investigational product, any medical condition or diagnosis 
that is present at the time before the subject is consented will be recorded as Medical History. Any new 
or worsening of any chronic medical condition that is expected in the course of the disease occurring 
after consent will not be reported as an AE but recorded as ongoing medical history. Any significant 
event that emerges as a result of participation in this study, that is not a symptom or condition related 
to the natural course of the disease, will be reported as an adverse event.  
 
9.2 
Definition of Serious Adverse Event (SAE) 
A SAE is any AE that results in any of the following outcomes: 
1. Death. A death that occurs or that comes to the attention of the investigator. 
2. A life-threatening event. A life-threatening event is any adverse experience that, in the 
view of the investigator, places the study subject at immediate risk of death from the 
reaction as it occurred. (Note: This does not refer to an event that could hypothetically 
have caused death had it been more severe). 
3. An inpatient hospitalization or prolongation of existing hospitalization. Hospitalization is 
defined as an inpatient admission, regardless of length of stay. 
4. Persistent or significant disability/incapacity. 
5. Congenital anomaly/birth defect. 
6. An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based on appropriate medical judgment, 
it may jeopardize the subject and may require medical or surgical intervention to prevent 

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one of the outcomes listed above. (Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization.) 
 
Regardless of the relationship of the AE to the study, the event will be reported to the sponsor as an 
SAE if it meets any of the above definitions. 
Events not considered to be serious adverse events are hospitalizations for: 
• 
A procedure for protocol/disease-related investigations. However, hospitalization or 
prolonged hospitalization for a complication of such procedures remains a reportable 
serious adverse event. 
• 
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an adverse event. 
• 
A procedure that is planned (i.e., planned prior to the starting of treatment on study); 
must be documented in the source document and the eCRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable serious adverse event. 
• 
An elective treatment of or an elective procedure for a pre-existing medical condition that 
does not worsen. 
• 
Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria above. 
 
9.3 
Collecting, Recording, and Managing Adverse Events 
 
 
Identifying Adverse Events 
 
Any AE that occurs from the moment the subject has signed the consent form until the end of the study 
visit or the final assessment at the time of dropout or discontinuation from the study visit will be 
recorded and is reportable. 
 
Adverse events may be discovered through any of these methods: 
• 
Observing the subject, 
• 
Questioning the subject or caregiver with standardized questions/procedures, 
• 
Receiving an unsolicited complaint from the subject or caregiver, 
• 
An abnormal value or result for a clinical laboratory evaluation. 
 
 
Recording AE/SAEs 
 
Throughout the study all identified AEs (serious and non-serious) will be recorded on all appropriate 
source documents and AE or SAE CRF regardless of their severity or relation to the study. SAEs will 
include a narrative of the event signed and dated by the principal investigator. 
 
A complete description of all AEs will include event description, investigator assessment of severity, 
relationship to study procedures, diagnosis, date started/stopped, outcome, and treatment required. A 
change in the severity of the AE will also be documented. 
 
 
Managing Adverse Events 
 

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The site investigator must apply his or her clinical judgment as to whether an AE is of sufficient severity 
to require that the subject immediately be withdrawn from the study. The investigator must institute 
any necessary medical therapy to protect a subject from any immediate dangers. 
 
An AE will be followed until any of the following takes place: a) it is resolved, b) subject is stable, or 
c) a minimum of 30 days after subject is discontinued from the study, whichever comes first. 
 
Adverse events assessed as related to study procedure and serious adverse events will be followed for 
as long as necessary to adequately evaluate the subject’s safety, or until the event stabilizes, is otherwise 
explained, death occurs, or the subject is lost to follow up. If resolved, a resolution date should be 
provided. 
 
 
Grading Criteria 
 
Assessment should include the intensity (severity) of the AE, whether clinical or laboratory, and the 
relationship to study procedure(s). 
 
The severity of AEs experienced by study subjects will be graded according to the criteria set forth in 
the National Cancer Institute’s Common Terminology Criteria for Adverse Events Version (version 5.0 
2017-11-27) unless otherwise indicated. This document (referred to herein as the NCI-CTCAE manual) 
provides a common language to describe levels of severity, to analyze and interpret data, and to 
articulate the clinical significance of all AEs. These criteria have been reviewed by the study 
investigators and the sponsor and have been determined appropriate for this study population. 
 
All AEs whether or not listed in the NCI-CTCAE will be graded on a scale from 1 to 5 according to the 
following standards in the NCI-CTCAE manual (A semi-colon indicates ‘or’ within the description of 
the grade.): 
• 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age- 
appropriate instrumental Activities of Daily Living (ADL). 
• 
Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• 
Grade 4 = Life-threatening consequences; or urgent intervention indicated. 
• 
Grade 5 = Death. 
 
For additional information and a printable version of the NCI-CTCAE manual, NCI-CTCAE website: 
http://ctep.cancer.gov/reporting/ctc.html will be consulted). 
 
 
Definition of Attribution 
 
The attribution of an AE to the study will be determined by the site investigator. The site investigator 
will record the determination of attribution on the appropriate AE or SAE CRF.  
 
Relationship of an AE or SAE is to be determined by the investigator based on the following 
definitions: 
 

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Descriptor 
Definition (guidelines) 
UNRELATED CATEGORY 
Unrelated 
The AE is clearly not related to the study or to disease progression. 
The AE is completely related to an etiology other than the study 
procedures (the alternative etiology must be documented in the 
study subject’s medical record) or disease progression. 
Unlikely 
The AE is doubtfully related to the study or to disease progression 
and likely to be related to factors other than study procedures. 
RELATED CATEGORIES 
Possible 
The AE may be related to a study procedure or to disease 
progression. There is an association between the event and the 
study procedures and there is a plausible mechanism for the event 
to be related to the study procedures; there may be also an 
alternative etiology, such as characteristics of the subject’s clinical 
status and/or underlying disease. 
Probable 
The AE is likely related to a study procedure or to disease 
progression. There is (1) an association between the event and the 
study procedures, (2) a plausible mechanism for the event to be 
related to the study procedures, and (3) the event could not be 
reasonably explained by known characteristics of the subject’s 
clinical status and/or an alternative etiology is not apparent. 
Definite 
The AE is clearly related to a study procedure or to disease 
progression. There is (1) an association between the event and the 
study procedures, (2) a plausible mechanism for the event to be 
related to the related to the study procedure, and (3) causes other 
than the study procedures have been ruled out and/or the event re-
appeared on re-exposure to the study procedure. 
 
 
SAE Reporting Criteria and Procedures 
 
The following process for reporting a SAE ensures compliance with the ICH guidelines. When an 
investigator identifies a SAE, he or she must notify the sponsors within 24 hours of discovering the 
event. In addition, the investigator must ensure that these events are entered in the electronic data 
capture platform.  
 
All serious adverse events will be reported through completion of the adverse event eCRF. The 
Investigator will be responsible for reporting serious adverse events to the central IRB and local IRB 
(per local IRB policy)  
 
10 STATISTICAL CONSIDERATIONS 
 
Sample Size and Power Calculations: The sample size of approximately 20 subjects is expected to 
provide sufficient insights into the natural history of individuals with CMT4J to provide exploratory 
and descriptive results and guide the design of future studies of CMT4J. No formal sample size 
estimation was performed for this study. Parametric and non-parametric tests will be used to analyze 
possible associations between clinical, radiographic, and laboratory data. The tests will be selected 
based on the question being asked of the database. This database will be used to analyze multiple 

Natural History Study CMT4J                                                                                                       Protocol Number: TBD 
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medical issues among subjects with confirmed CMT4J. All analysis will be considered exploratory in 
nature.  
 
10.1 Data Management 
Quality control audits of all key safety, laboratory, and clinical data in the database will be made after 
data entry has been completed. Coexistent medical conditions, AEs and other medical events will be 
coded using MedDRA dictionary. Concomitant medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). When the database has been declared to be complete and 
accurate, the database will be locked. Any changes to the database after that time can only be made by 
joint written agreement of the study team. 
11 ETHICAL CONSIDERATIONS (AND INFORMED CONSENT) 
11.1 Ethical Standard 
The Investigator will ensure that this study is conducted in full conformity with the principles set forth 
in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research of the US National Commission for the Protection of Human Subjects of Biomedical and 
Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal 
Regulations 25691 (1997). 
11.2 Institutional Review Board 
The local institution must provide for the review and approval of this protocol and the associated 
informed consent documents by an appropriate ethics review committee or IRB. Any amendments to 
the protocol or consent materials must also be approved before they are placed into use unless it is in 
the best interest of the subjects’ safety to implement changes prior to approval. In both the US and in 
other countries, only institutions holding a current U. S. Federal-Wide Assurance issued by the Office 
for Human Research Protections (OHRP) may participate.  
Prior to enrollment of subjects into this clinical study, the protocol and the informed consent form(s) 
(ICF) will be reviewed and approved by the appropriate IRB. Any amendments to the protocol or 
consent materials will also be reviewed and approved by the appropriate IRB. The responsible official 
for the IRB will sign the IRB letter of approval of the protocol prior to the start of this clinical study. If 
amendments to the protocol are required, the amendments will be submitted to the IRB; an IRB letter 
of approval of the amendment must be obtained prior to implementing the amendment. 

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APPENDIX 1:  
SCHEDULE OF EVENTS 
Study Day 
Screening 
Baseline 
Month 12 
Month 24 
Windows 
 
(+ 4 wks) 
(+ 4 wks) 
(+ 4 wks) 
Informed Consent 
X 
 
 
 
Medical Information 
 
X 
X 
X 
Demographics 
 
 
 
 
Medical History 
 
X 
X 
X 
Family History 
 
X 
 
 
CMT4J Diagnosis and History  
 
X 
 
 
Clinical Procedures 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
Vital Signsa 
 
X 
X 
X 
Height and Weight 
 
X 
X 
X 
Physical Examb 
 
X 
X 
X 
Neurological Examc 
 
X 
X 
X 
Urine Pregnancy (for female 
subjects)d 
 
X 
X 
X 
Blood Collection for Future 
Exploratory Analysise 
 
 
X 
X 
X 
Skin biopsy (optional, any visit, 
only once) 
 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
Concomitant Medications 
 
X 
X 
X 
CMT Scales* 
 
 
 
 
CMTPedSf 
X 
X 
X 
X 
CMTInfSg 
X 
X 
X 
X 
CMTNSv2h 
X 
X 
X 
X 
CMT-FOMh 
X 
X 
X 
X 
CMT Health Index (CMTHI)h 
X 
X 
X 
X 
Clinical Studies 
 
 
 
 
Thigh and Calf MRI without 
contrast 
 
X 
X 
X 
Brain MRI without contrast 
 
X 
X 
X 
Nerve Conduction Study (NCS)i 
 
X 
X 
X 
Pulmonary Function Test (PFT)j 
 
X 
X 
X 
Scoliosis Series X-rayk 
 
X 
X 
X 
Neuropsychological and Physical 
Therapy Assessments 
 
 
 
 
Vineland Adaptive Behavior Scale 
 
X 
X 
X 
PEDICATl 
 
X 
X 
X 
Bailey III 
 
X 
X 
X 
WASI-II or WPPSI-IV 
 
X 
X 
X 
Stanford Binet – V 
 
X 
X 
X 
Timed up and go (TUG) 
 
X 
X 
X 
Wearable devices 
X 
X 
X 
X 
Questionnaires 
 
 
 
 
PedsQLm 
 
X 
X 
X 
Overall Neuropathy Limitation 
Scale (ONLS) (18 years and older) 
 
X 
X 
X 
pCMT-QOL PRO (8 to 18 years) 
 
X 
X 
X 
pCMT-QOL (8 to 18 years parent-
proxy) 
 
X 
X 
X 
pCMT-QOL (0 to 7 years parent-
proxy) 
 
X 
X 
X 

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a Temperature, pulse, blood pressure measured in one arm or leg after the patient has been seated for ~ 5 minutes. 
b Exam of heart, lungs, abdomen, back, and extremities; height and weight; head circumference  
c Includes evaluation of cranial nerves, muscle tone, muscle strength, sensation, gait, coordination and deep tendon reflex testing, handheld dynamometry 
d Urine pregnancy test for females of child-bearing potential. Results of urine pregnancy test must be reviewed and confirmed to be negative prior to 
proceeding with any assessments involving radiation. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test. If the subject’s 
urine or serum pregnancy test is positive, assessments involving radiation should not be performed. 
e With subject consent, blood and blood products may be stored long-term for exploratory purpose; these samples will be maintained for up to 10 years 
f Subjects aged 5 to 17 years 11 months (less than 18 years) 
     g Subject < 4 years of age 
h Subjects aged 18 years and older 
i Ideally, performed on the left arm and leg, the same limbs will be assessed at each visit 
j Subjects older than 5 years of age based on the physiotherapist’s assessment of subject’s compliance and/or ability to follow instructions 
k Thoracic and lumbar spine 
l Subjects < 20 years 
m Subjects 2 to 18 years 
*Video capture will be used for some parts of the CMT scales. 

Natural History Study CMT4J                                                                                                       Protocol Number: TBD 
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12 REFERENCES 
1. Braathen G, Sand J, Lobato A, Høyer H, Russell M. Genetic epidemiology of Charcot-Marie-
Tooth in the general population. Eur J Neurol. 2011;18(1):39–48. 
2. Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet.1974;6(2): 
98-118. 
3. Burns J, Ouvrier R, Estilow T, Shy R, Laura M, Pallant JF, Lek M, Muntoni F, Reilly MM, 
Pareyson D, Acsadi G, Shy ME, Finkel RS. Validation of the Charcot-Marie-Tooth disease 
pediatric scale as an outcome measure of disability. Ann Neurol. 2012;71(5):642-652. 
4. Murphy SM, Herrmann DN, McDermott MP, Scherer SS, Shy ME, Reilly MM, Pareyson D. 
Reliability of the CMT neuropathy score (second version) in Charcot-Marie-Tooth disease. J 
Peripher Nerv Syst. 2011;16(3):191-198. 
5. Eichinger K, Burns J, Cornett K, Bacon C, Shepherd M, Mountain J, Sowden J, Shy R, Shy 
ME, Herrmann DN. The Charcot- Marie- Tooth Functional Outcome Measure (CMT-FOM). 
Neurology. 2018;91(15):e1381-e1384. 
6. Johnson NE, Heatwole C, Creigh P, McDermott MP, Dilek N, Hung M, Bounsanga J, Tang 
W, Shy ME, Herrmann DN. The Charcot-Marie-Tooth Health Index: Evaluation of a Patient 
Reported Outcome. Ann Neurol. 2018;84(2):225-233. 
7. Morrow JM, Evans MRB, Grider T, Sinclair CDJ, Thedens D, Shah S, Yousry TA, Hanna 
MG, Nopoulos P, Thornton JS, Shy ME, Reilly MM. Validation of MRC Centre MRI calf 
muscle fat fraction protocol as an outcome measure in CMT1A. Neurology 
2018;91(12):1125-1129. 
8. Sparrow SS, Cichetti DV, Balla DA, Doll E A. (2005). Vineland Adaptive Behavior Scales, 
second edition manual. Bloomington, MN: PsychCorp. 
9. Haley SM, Coster WJ, Dumas HM, Fragala-Pinkham MA, Ni PS, Kramer J, Feng T, Kao 
YC, Moed R, Ludlow LH. Accuracy and precision of the Pediatric Evaluation of Disability 
Inventory computer adaptive tests (PEDI-CAT). Dev Med Child Neurol. 2011;53(12):1100-
1106. 
10. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of 
life inventory. Med Care. 1999;37(2):126-139. 
11. Graham RC and Hughes RAC. A modified peripheral neuropathy scale: the Overall 
Neuropathy Limitations Scale. J Neurol Neurosurg Psychiatry. 2006;77(8):973-976. 
12. Ramchandren S, Wu TT, Finkel RS, Siskind CE, Feely SME, Burns J, Reilly MM, Estilow T, 
Shy ME, Childhood CMT Study Group. Development and validation of the pediatric 
Charcot-Marie-Tooth disease quality of life outcome measure. Ann Neurol. 2021;89(2):369-
379. 
13. Wu TT, Finkel SR, Siskind CE, Feely SM, Burns J, Reilly MM, Muntoni F, Milev E, Estilow 
T, Shy ME, Ramchandren S, Childhood CMT Study Group of the Interited Neuropathy 
Consortium. Validation of the parenty-proxy version of the pediatric Charcot-Marie-Tooth 
disease quality of life instrument for children aged 0-7 years. J Peripher Nerv Syst. 2023;May 
11. doi:10.1111/jns.12557.