A Phase 1b/2a Clinical Trial to Evaluate the Safety and Efficacy of EN001 in Patients With Charcot-Marie-Tooth Disease Type 1A(CMT1A) (Phase 1b: Open-label, Dose-escalation, Single-center; Phase 2a: Randomized, Double-blind, Placebo-controlled, Multicenter)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 27
- 试验地点
- 4
- 主要终点
- Dose limiting toxicity (DLT) and adverse drug reactions related to discontinuation of investigational product administration
研究概览
简要总结
A Phase 1b/2a Clinical Trial to Evaluate the Safety and Efficacy of EN001 in Patients with Charcot-Marie-Tooth Disease type 1A(CMT1A) (Phase 1b: Open-label, Dose-escalation, Single-center; Phase 2a: Randomized, Double-blind, Placebo-controlled, Multicenter)
详细描述
This clinical trial consists of two stages (Phase 1b and Phase 2a). Phase 1b is designed with a 3+3 dose escalation design to evaluate the safety, including tolerability, of EN001 and explore efficacy. Phase 2a will evaluate the efficacy and safety of EN001 in comparison with placebo.
-Phase 1b The study was designed using the traditional 3+3 dose escalation method to confirm the maximum tolerated dose (MTD) and determine the recommended phase 2 dose (RP2D).
Dose increase is carried out until the maximum tolerated dose (MTD) is confirmed at the high dose (Cohort 2), which is the maximum planned dose (MPD), or at a lower dose. The maximum tolerated dose (MTD) is defined as the highest dose at which the incidence of dose limiting toxicity (DLT) is lower than 33%. To determine the maximum tolerated dose (MTD), 3-6 test subjects from each dose cohort are enrolled and EN001 is administered twice at 4-week intervals, and dose-limiting toxicity (DLT) is evaluated until 4 weeks (visit 6).
The safety review committee (SRC) is comprised of the principal investigator, sponsor, etc. as members, and EN001 confirmed by the end of each cohort (end of dose-limiting toxicity (DLT) evaluation of the last dosed subject in the cohort). Safety data are comprehensively reviewed to determine all matters related to dose, such as increase or decrease in dose, and finally the recommended phase 2 dose (RP2D) is determined.
-Phase 2a The Phase 2a is a randomized, double-blind, placebo-controlled clinical trial. Eligible subjects will be randomly assigned in a 1:1:1 ratio to Study Group 1 (EN001 Low dose), Study Group 2 (EN001 High dose), or the placebo control group. The efficacy and safety of EN001 will be evaluated in comparison with placebo.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 19 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Individuals who have voluntarily agreed to participate in this clinical trial.
- •Men and women aged 19 years or older at the time of providing written consent.
- •Individuals who meet all of the following genetic and clinical diagnostic criteria:
- •Genetic diagnosis: CMT1A type
- •Clinical diagnosis:
- •Those with a CMT Neuropathy Score version 2 (CMTNSv2) between 2 or more and 20 or less.
- •Those experiencing muscle weakness due to foot dorsiflexion impairment.
- •Women and men of childbearing potential who have agreed to use the appropriate contraceptive method(s) outlined in the protocol during the clinical trial period.
- •Appropriate contraception is defined as follows and is achieved by applying one or more methods of contraception.
- •Hormonal contraceptives
- •Implantation of an intrauterine device or intrauterine system
- •Sterilization procedures (vasectomy, tubal ligation, etc.)
- •Double contraceptive method: male condom along with other contraceptive methods [hormonal contraceptives (oral contraceptives, subcutaneous contraceptives (Implanon, etc.), long-acting contraceptive injections, emergency contraceptive pills), implantation of an intrauterine device or intrauterine system (Loop, Mirena), Infertility procedures (vasectomy, tubal ligation, etc.)]
- •Abstinence: Absolute abstinence. If, in the examiner's judgment, the subject's age, occupation, lifestyle, or sexual orientation warrants contraception, strict abstinence from sexual intercourse is also acceptable. However, periodic abstinence (e.g. Karenda method, ovulation method, symptomatic temperature method), abstinence, and external vaginal ejaculation are not recognized as appropriate contraceptive methods.
排除标准
- •Those with the following comorbidities confirmed at the time of screening
- •Subjects with neuromuscular diseases other than CMT1A or neuropathy- inducing factors (uremia) that may affect the safety and efficacy evaluation of this clinical trial, according to the judgment of the investigator.
- •Individuals diagnosed with type 1 or type 2 diabetes
- •Individuals diagnosed with active pulmonary tuberculosis
- •Patients with uncontrolled hypertension (systolic blood pressure over 180 mmHg or diastolic blood pressure over 110 mmHg)
- •Subjects with other clinically significant diseases, including significant heart, lung, liver, kidney, hematological, immunological or behavioral diseases or malignant tumors, according to the investigator's judgment
- •Individuals who display the specified test abnormalities in laboratory tests at the time of screening:
- •AST or ALT > 3 x ULN
- •Total bilirubin> 1.5 x ULN
- •Serum creatinine > 1.5 x ULN
- •Any one of the serum virus tests (HBsAg, anti-HBc, anti-HCV, HIV Ag/Ab) is positive (If anti-HBc positive) However, registration is possible if the HBV DNA test result is negative. (If anti-HCV positive) However, registration is possible if the HCV RNA test result is negative.
- •Those who have ankle contracture or have undergone surgery that may affect muscle strength measurement tests
- •Medical history and surgical history
- •Those who have undergone orthopedic surgery (bone or ligament correction, artificial joint implantation, osteotomy, arthroscopic surgery) on the lower extremities within 24 weeks before screening
- •Those with a history of stroke or cerebral ischemic attack within 48 weeks before screening
- •Those with a history of coronary artery disease, such as myocardial infarction or incomplete angina, within 48 weeks before screening
- •Those with a history of malignant tumor within 240 weeks before screening (excluding basal cell carcinoma or squamous cell carcinoma that occurs on the skin)
- •Drugs and therapies prohibited from concurrent use
- •Those who participated in another clinical trial and administered/applied clinical trial drugs/medical devices within 4 weeks before screening
- •Those who administered/applied immunosuppressants, chemotherapy, radiation therapy, etc. within 12 weeks before screening
- •Persons who have administered cell therapy or gene therapy throughout their lives
- •Persons who have administered neurotoxic drugs that can accelerate peripheral nerve damage ① Within 1 week of Screening
- •Anti-inflammatory agents or antibiotics: Colchicine, Nitrofurantoin
- •Antiretroviral agents: Zalcitabine, Stavudine
- •Dichloroacetate
- •② Within 55 weeks of Screening
- •Antiarrhythmic agent: Amiodarone
- •Antiparasitic agent: Suramin
- •Persons with hypersensitivity to the components of clinical investigational products
- •Those who have had metal substances (heart pacemaker, nerve stimulator, cochlear implant, etc.) implanted in their body
- •Pregnant, lactating, or planning to become pregnant during the clinical trial period
- •Subjects with a psychiatric disorder (anxiety disorder, claustrophobia, or other significant mental disorder) or a history of drug and alcohol abuse that may affect the clinical trial, according to the judgment of the investigator.
- •Those who are deemed inappropriate to participate in clinical trials according to the judgment of the investigator
结局指标
主要结局
Dose limiting toxicity (DLT) and adverse drug reactions related to discontinuation of investigational product administration
时间窗: Up to 8 weeks
Present the frequency and percentage of dose-limiting toxicity (DLT) occurrence across dose cohorts, along with detailed information on the types of DLTs. Adverse events related to discontinuation of clinical investigational drug administration, discontinuation of clinical investigational drug administration Regarding related adverse drug reactions, the number of subjects in each cohort, incidence rate (%), and Two-sided 95% confidence intervals and number of occurrences are presented.
次要结局
- CMT examination score change(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- Rasch-modified CMTNSv2 score change(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- ONLS score change(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- FDS score change(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- Change in Sensory Nerve Conduction Velocity (Unit: m/s)(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- SF-36v2 score change(At 24 weeks compared to baseline (Visit 2))
- Adverse Event(Up to 24weeks. However, adverse drug reactions that persist at the end of the clinical trial will be followed up until the possible adverse reactions are resolved or it is determined that further follow-up is not meaningful.)
- Vital sign(Up to 24 weeks)
- X-ray(Before administration of investigational product at Baseline and Week 4 and within 4 hours after completion of administration)
- Laboratory examination(Up to 24 week. Serum virus testing is performed only during screening. At Baseline and Week 4, hematological tests, blood chemical tests, TCO2, Mg, and blood coagulation tests are performed before and within 4 hours after administration of the IP.)
- electrocardiography(At Baseline, Week 4, Week 8, Week 12, Week 18, Week 24)
- CMTNSv2 score change(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- Rasch-modified CMTES score change(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- 10MWT score change(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- Change in grade of fatty infiltration in the proximal lower extremities (According to Goutallier classification scale)(At 24 weeks compared to baseline (Visit 2))
- Change in Motor Nerve Conduction Velocity (Unit: m/s)(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- Change in Compound Muscle Action Potential (Unit: ㎷)(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- Change in Sensory Nerve Action Potential (Unit: ㎶)(At 4, 8, 18, and 24 weeks compared to baseline (Visit 2))
- Physical Examinations(Up to 24 weeks)