The Safety, Tolerability, and Efficacy of EA0010 in Patients With OTOF Mutations-Related Hearing Loss Who Have Received Cochlear Implantation
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 1
- 试验地点
- 1
- 主要终点
- Incidence and severity of Adverse Events (AEs), Serious Adverse Events (SAEs), and Dose-Limiting Toxicities (DLTs) to Week 26
研究概览
简要总结
This study will evaluate the safety, tolerability, and efficacy of EA0010 injection in patients with OTOF-related hearing loss who have already undergone cochlear implantation. Conventional gene therapy generally excludes cochlear implant recipients, based on the concern that the electrode array may compromise the reparative potential of inner ear cells. To further address this clinical issue, the present study is designed to enroll cochlear implant users and administer a single intratympanic injection of EA0010 through the stapes annular ligament into the implanted cochlea. One subject is planned to be enrolled, and post-administration assessments of both safety and efficacy will be performed.
详细描述
This study is a single-center, single-arm, open-label, non-randomized clinical study.
To prevent or mitigate potential immune responses to EA0010, participants will receive daily oral or intravenous dexamethasone (0.3 mg/kg) for nine consecutive days, from 3 days before to 5 days after administration (day -3 to day 5). Investigators may adjust the duration and dosage based on clinical requirements. Participants may be admitted to hospital between Day -3 and Day -1. On the day of surgery (Day 0), EA0010 will be administered via intratympanic injection through the stapes annular ligament into the cochlea under aseptic conditions. Participants will receive adeno-associated virus (AAV) at a dose of 2.0×1011 vg/ear/total virus via unilateral cochlear injection (EA0010 Injection is supplied as Solution A and Solution B, each with a titer of 2.0×1013 vg/mL or subject to the actual labeled titer; the two solutions will be mixed at a 1:1 ratio prior to cochlear injection, with a total volume of 10-40 μL); Participants will be closely monitored for 10 days after cochlear injection, may return home after surgical recovery, and will then undergo a 52-week follow-up; the clinical study will end after the last follow-up visit. Subsequent annual follow-ups may be conducted as needed.
Participants will return to the hospital for safety and efficacy assessments at the time points specified in the protocol (D10±3d, W4±3d, W13±7d, W26±14d, W52±14d/EOS/unscheduled) (excluding circumstances of force majeure) during the study period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 1 Year 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects must meet all of the following inclusion criteria to be enrolled in the study:
- •Age between 1 year and 17 years (inclusive) at the time of signing the ICF, male or female;
- •Confirmed homozygous or compound heterozygous mutation in the OTOF gene as documented in a report issued by a qualified genetic testing institution;
- •Audiometric testing (reports from within 6 months prior to signing the ICF are acceptable): Severe or profound deafness (Click ABR ≥ 80 dBnHL);
- •Has received cochlear implantation and has reasonable expectations;
- •Vital signs, physical examination, laboratory tests (complete blood count, blood biochemistry, coagulation function, urinalysis, etc.), and 12-lead ECG are all normal or show abnormalities judged by the investigator to be clinically insignificant;
- •Subject and/or their legal guardian signs the informed consent form.
排除标准
- •Subjects who meet any of the following criteria are not eligible for enrollment:
- •Presence of other definite genetic mutations causing deafness other than the OTOF gene that may affect the judgment of the treatment effect of the OTOF investigational drug;
- •History of severe allergic reactions to any drug or its components in this study;
- •Prior gene therapy and/or oligonucleotide drug treatment in the ear that has undergone cochlear implantation;
- •Blood AAV2 neutralizing antibody titer > 1:2000;
- •Presence of systemic diseases or receipt of related treatments that may affect hearing or surgical procedures;
- •Inability to undergo general anesthesia;
- •History of major inner ear surgery (judged by the investigator as inappropriate for gene therapy);
- •Other types of deafness unsuitable for otologic surgery, such as deafness caused by middle-inner ear developmental abnormalities or malformations, vestibulocochlear nerve abnormalities, conductive hearing loss, mixed hearing loss, or syndromic malformations as detected by CT/MRI;
- •Otologic diseases that may interfere with the planned surgery or interpretation of study endpoints, such as acute-chronic otitis media, Meniere's disease, acoustic neuroma, sudden deafness with no hearing recovery, etc.;
- •History of drug abuse, or receipt of any known ototoxic drug therapy within 6 months (e.g., aminoglycosides, cisplatin, loop diuretics, etc.), or receipt of antiviral and immunosuppressive therapy within 3 months, or vaccination within 1 month;
- •Subjects currently receiving or likely to receive immunosuppressive therapy other than that required for this study;
- •Allergy or intolerance to glucocorticoids;
- •History of malignant tumors or meningitis;
- •Presence of persistent or active infection; subjects who are HBsAg positive with peripheral blood HBV DNA titer above the lower limit of detection; subjects who are HCV antibody positive with peripheral blood HCV RNA titer above the lower limit of detection; subjects who are HIV antibody positive or have other immunodeficiency diseases; subjects with positive syphilis serology;
- •Subjects of childbearing potential who refuse to use effective contraceptive measures (hormonal, barrier methods, or abstinence) from the time of signing the ICF through 12 months after AAV injection;
- •Female subjects of childbearing potential with a positive serum pregnancy test, or who are currently pregnant or breastfeeding;
- •Subjects who have participated in any other clinical study within 4 weeks prior to the first dose and have already received study drug or treatment (including drug and device clinical studies, excluding non-interventional studies);
- •Unwilling or unable to comply with this study protocol;
- •Subjects whom the investigator judges to have any medical condition that renders them unable to participate in this study or complete the subsequent follow-up.
研究组 & 干预措施
EA0010 Injection Arm
干预措施: EA0010 Injection (Genetic)
结局指标
主要结局
Incidence and severity of Adverse Events (AEs), Serious Adverse Events (SAEs), and Dose-Limiting Toxicities (DLTs) to Week 26
时间窗: Day 0 (injection) through Week 26
AEs, SAEs, and DLTs will be evaluated according to NCI-CTCAE v5.0. Safety evaluation includes: physical examination (including cranial nerve function), laboratory indicators (routine blood test, blood biochemistry, urinalysis, coagulation function), vital signs, ECG, peripheral blood neutralizing antibody testing, and peripheral blood AAV shedding testing.
次要结局
- Incidence and severity of AEs, SAEs, and DLTs of EA0010 injection to Week 52(Week 27 through Week 52)
- Efficacy of EA0010 on hearing levels as measured by pure-tone or behavioral audiometry(Baseline, Week 4, Week 13, Week 26, Week 52, and annually through Year 5)
- Efficacy of EA0010 on auditory function as measured by ABR (Auditory Brainstem Response) testing(Baseline, Day 10, Week 4, Week 13, Week 26, Week 52, and annually through Year 5)