a Study in Subjects With Otoferlin Mutation-related Hearing Loss Using RNA Base-eDiting Therapy(SOUND)

Study Overview
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Brief Summary
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The purpose of the study is to determine whether HG205 as CRISPR/Cas13 RNA base-editing therapy is safe and effective for the treatment of hearing loss caused by p.Q829X mutation in OTOF gene.

Official Title
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An Open-label, Multiple-cohort, Dose-finding, Investigator-initiated Trial to Evaluate the Safety, Tolerability, and Efficacy of HG205 RNA Base-Editing Therapy in Subjects With OTOF-p.Q829X Mutation-associated Hearing Loss

Conditions
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Congenital Hearing Loss

Intervention / Treatment
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* Genetic: HG205


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or females between 1 and 16 years of age at the time the subject/parent/legal guardian signs the informed consent form. Willing to adhere to the protocol as evidenced by written informed consent or parental permission and subject assent. Molecular diagnosis of biallelic mutations in the OTOF gene with at least one mutation being p.Q829X through collected blood samples at screening; Based on auditory brainstem response (ABR), clinically diagnosed sensorineural hearing loss (SNHL) with the following hearing thresholds: severe (65 dB ≤ hearing threshold < 80 dB) or profound (80 dB ≤ hearing threshold < 95 dB) or complete (hearing threshold ≥ 95 dB) hearing loss in both ears. Acceptable hematology, clinical chemistry, and urine laboratory parameters. Exclusion Criteria: Pre-existing other hearing-loss conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints or complications of surgery. Presence of cochlear implants in the study ear. Complicating systemic diseases or clinically significant abnormal baseline laboratory values. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter hearing function. Prior participation in clinical study with an investigational drug within the past six months. Prior gene therapy treatments. Any condition which leads the investigator to believe that the participant cannot comply with the protocol requirements or that may place the participant at an unacceptable risk for participation.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 16 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HG205<br>Method of Administration: Once Unilateral intracochlear injection/subject; The duration of the study for each subject includes a screening period, enrollment visit, treatment visit, a 26-week follow-up period, and a 5-year long-term safety follow-up after the injection | Genetic: HG205<br>* The study will enroll up to 2 cohorts, evaluating a starting dose plus a higher or lower dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of otological and systemic adverse events | Number of AE(Adverse events),SAE(Serious Adverse Events),DLT(Dose Limiting Toxicities) | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in ABR(Auditory Brainstem Response) intensity threshold (decibels normal hearing level [dB nHL]) | ABR intensity threshold (decibels normal hearing level [dB nHL]) measurement | 26 weeks | 
| Change from baseline in hearing performance by behavioral audiometry with pure-tone audiometry | Behavioral audiometry and pure-tone audiometry measurement | 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Congenital hearing loss, OTOF, Q829X, HG205, CRISPR