Determine the Safety and Dose of EN001 in Patients With Charcot-Marie-Tooth Disease (CMT) Type 1A

Study Overview
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Brief Summary
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Open-label, Dose-escalation, Phase 1 Clinical Trial to Determine the Safety and Dose of EN001 in Patients with Charcot-Marie-Tooth disease (CMT) type 1A

Detailed Description
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It is the first in human (FIH), 3+3 design clinical trial to evaluate the safety and tolerability and determine the maximum tolerated dose (MTD) of EN001 (allogeneic umbilical cord-derived mesenchymal stem cells) in the treatment of Charcot-Marie-Tooth disease (CMT) type 1A.

Official Title
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Open-label, Dose-escalation, Phase 1 Clinical Trial to Determine the Safety and Dose of EN001 in Patients With Charcot-Marie-Tooth Disease (CMT) Type 1A

Conditions
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Charcot-Marie-Tooth Disease, Type IA

Intervention / Treatment
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* Drug: EN001
* Drug: EN001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females aged 19 to 75 years old Those diagnosed with CMT type 1A by a genetic test Those whose CMTNS-v2 score is more than 2 and 20 or fewer points, and the severity of the disease is mild to moderate Those who have dorsiflexion muscle weakness Those who can comply with the requirements for clinical trials For women of childbearing potential, those who have a negative urine pregnancy test at screening Those who use a medically acceptable method of contraception until clinical trial visit 7 (short-term follow-up visit, 16 weeks): hormonal contraception, intrauterine device (IUD), intrauterine system (IUS), vasectomy, tubal ligation, or double barrier method using a cervical cap or a diaphragm with a male condom. Those who voluntarily agree to participate in this study and sign an IRB-approved consent form after being informed about the characteristics of this clinical trial prior to all screening tests Exclusion Criteria: Those with other neuromuscular diseases that the investigator judges cannot participate in the clinical trial Patients diagnosed with type 1 or type 2 diabetes Those with a history of stroke or cerebral ischemic attack within 12 months of screening Those with a history of coronary artery diseases such as myocardial infarction or unstable angina within 12 months of screening Those who have undergone orthopedic surgery on the lower extremities (bone and ligament correction, artificial joint insertion, osteotomy, arthroscopic surgery) within 6 months of screening Those who have ankle contractures or have surgery that may affect muscle strength assessment Those who have experience with stem cell therapy or gene therapy before screening Those who have participated in clinical trials for chemical synthetic drugs before screening (except when 5 times the half-life has passed) Patients with uncontrolled hypertension (If the systolic blood pressure is 180 mmHg or higher or the diastolic blood pressure is 110 mmHg or higher) If there is a history of malignant tumors other than basal cell carcinoma or squamous cell carcinoma occurring in the skin within 5 years of screening Those who diagnosed with active pulmonary tuberculosis Immunosuppressed patients who are taking immunosuppressants, chemotherapy, radiation therapy, etc. Mental illness patients Those who are pregnant or lactating Those with significant heart, lung, liver, kidney, hematological, immunological, behavioral disease, or other clinically significant diseases including malignant tumors Those who have a previous or current medical condition that may adversely affect the safety of the subject, make it difficult to complete treatment or affect the evaluation of clinical trial results at the discretion of the investigator Those who do not have the will or ability to comply with clinical trial procedures at the discretion of the investigator

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose group A (Low dose)<br>Participants will receive EN001 intravenously (IV) once on Day 0. | Drug: EN001<br>* EN001 intravenously (IV) in the treatment of Charcot-Marie-Tooth disease (CMT) type 1A Dosage for each group is as follows. Dose group A (Low dose): 5.0x10^5 cells/kg<br>* Other names: EN001 (allogeneic umbilical cord-derived mesenchymal stem cells);|
| Experimental: Dose group B (High dose)<br>Participants will receive EN001 intravenously (IV) once on Day 0. | Drug: EN001<br>* EN001 intravenously (IV) in the treatment of Charcot-Marie-Tooth disease (CMT) type 1A Dosage for each group is as follows. Dose group B (High dose): 2.5x10^6 cells/kg<br>* Other names: EN001 (allogeneic umbilical cord-derived mesenchymal stem cells);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants of any Adverse Events (AEs)/Serious Adverse Events (SAEs) related investigational product | Number of participants with treatment-related AEs/SAEs as assessed by CTCAE v5.0 | Week 16 after treatment | 
| Determination of Dose-limiting toxicity (DLT) levels of EN001 | Among the adverse events occurring for 4 weeks after administration of the investigational product, Grade 3 or higher adverse events according to CTCAE v5.0 | Up to Week 4 after dosing on Day 0 | 
| Determination of Maximum tolerated dose (MTD) levels of EN001 | Among the adverse events occurring for 4 weeks after administration of the investigational product, Grade 3 or higher adverse events according to CTCAE v5.0 Maximum tolerated dose defines the evaluated maximum dose level in which greater than two participants of six participants experience Dose-limiting toxicity (DLT) under the dose level. The dose level where two participants of six participants experience DLT will be the maximum tolerated dose. | Up to Week 4 after dosing on Day 0 | 
| Number of participants with Vital Signs abnormalities | Vital Signs include blood pressure (mmHg), pulse (times/minute), respiratory rate (times/minute), and body temperature (℃) and will be assessed by CTCAE v 5.0 to evaluate safety and tolerability of EN001. The number of participants with at least one potentially clinically significant abnormal vital sign finding were reported as treatment emergent adverse events (TEAEs). | From screening up to Week 16 | 
| Number of participants with clinically significant abnormalities of Physical Examinations | Physical Examinations include general appearance, head, ears/eyes/nose/throat, cardiovascular, respiratory, abdomen, skin, lymph nodes, extremities, musculoskeletal and neurologic and will be assessed by CTCAE v 5.0 to evaluate safety and tolerability of EN001. Number of participants with potentially clinically significant abnormalities in physical examinations were reported as TEAEs. | From screening up to Week 16 | 
| Number of participants with abnormalities of Laboratory Parameters | Laboratory Parameters include hematology, chemistry laboratory tests, urinalysis, coagulation test and plasma viral load test and will be assessed by CTCAE 5.0 to evaluate safety and tolerability of EN001. Number of participants with at least one potentially clinically significant abnormal finding were reported as TEAEs. | From screening up to Week 16 | 
| Number of participants with 12-lead Electrocardiography (ECG) abnormalities | Measured by result of the ECG measurements and findings | From screening to baseline on Day 1 (Predose to end of infusion and 90 min after completion of infusion) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | Occurrence of any adverse reactions, development of new blood clots, tumors, immune responses (like autoimmune reactions) and death, and/or serious adverse events related investigational product will be summarized by actual treatment groups respectively. | From screening to the end of treatment/withdrawal visit (up to approximately 5 years per subject) | 
| Number of participants with abnormalities of Vital Signs, Physical Findings, and Laboratory Parameters | Abnormalities of Vital Signs, Physical Findings, and Laboratory parameters (as described above) will be collected and analyzed, and then assessed by CTCAE 5.0 to evaluate the long-term safety of EN001. | From screening to the end of treatment/withdrawal visit (up to approximately 5 years per subject) | 
| Change from baseline in disease severity CMTNS-v2 score | Disease severity measured by CMTNS-v2 score will be collected and analyzed to evaluate the exploratory efficacy of EN001. | Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) | 
| Change from baseline in gait and balance functions | Gait and balance functions measured by Ten Meter Walking Test(10MWT), Functional Disability Scale (FDS), and Overall Neuropathy Limitation Score (ONLS) leg scale will be collected and analyzed to evaluate the exploratory efficacy of EN001. | Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) | 
| Change from baseline in the degree of muscle damage (%) | The degree of muscle damage measured by lower extremity magnetic resonance imaging (MRI) scan will be collected and analyzed to evaluate the exploratory efficacy of EN001. | Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) | 
| Change from baseline in nerve regeneration potential | Nerve generation potential measured by MNCV, SNCV, CMAP, and SNAP will be collected and analyzed to evaluate the exploratory efficacy of EN001. | Screening and baseline on Day 0 (up to approximately 5 years per subject after Week 4) |