Gene Therapy Trial for Otoferlin Gene-mediated Hearing Loss

Study Overview
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Brief Summary
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Part A of this trial will evaluate the safety and tolerability of a single unilateral administration of one of two dose levels of AAVAnc80-hOTOF and will evaluate the Akouos delivery device to safely achieve the intended product performance.

Detailed Description
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The following two dose levels will be tested sequentially: 4.1E11 total vg/cochlea 8.1E11 total vg/cochlea

Official Title
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A Phase 1/2 Trial of AAVAnc80-hOTOF Gene Therapy in Individuals With Sensorineural Hearing Loss Due to Biallelic Otoferlin Gene Mutations

Conditions
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Sensorineural Hearing Loss, Bilateral

Intervention / Treatment
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* Combination Product: AAVAnc80-hOTOF via Akouos Delivery Device


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 7 to 17 years old (inclusive) for Cohort #1a; age 2 to 17 years old (inclusive) at the time of AAVAnc80-hOTOF administration for Cohorts #1b and #2 Biallelic mutations in the otoferlin gene Clinical presentation of Profound bilateral sensorineural hearing loss as assessed by ABR Preserved distortion product otoacoustic emissions (DPOAEs) Able and willing to comply with all study requirements, including willingness to participate in a separate long term follow-up study after completion of this trial Exclusion Criteria: Persistent ear infections, anatomic or other abnormalities of the ear, and/or medical conditions that would contraindicate undergoing surgery, anesthesia, and/or administration of investigational gene therapy Bilateral cochlear implants Prior participation in a clinical trial with an investigational drug, within six months prior to administration, or any prior participation in a gene therapy clinical trial

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1a and Cohort 1b<br>Cohort 1a: Participants aged 7 to 17 years old (inclusive) to receive intracochlear administration of AAVAnc80-hOTOF (dose level 1) in the study ear using a sterile, one-time use investigational medical device Cohort 1b: Participants aged 2 to 17 years old (inclusive) at the time of AAVAnc80-hOTOF administration to receive intracochlear administration of AAVAnc80-hOTOF (dose level 1) in the study ear using a sterile, one-time use investigational medical device | Combination Product: AAVAnc80-hOTOF via Akouos Delivery Device<br>* AAVAnc80-hOTOF is a sterile suspension intended to be administered via a one-time unilateral intracochlear administration using the Akouos Delivery Device.<br>|
| Experimental: Cohort 2<br>Cohort 2: Participants aged 2 to 17 years old (inclusive) at the time of AAVAnc80-hOTOF administration to receive intracochlear administration of AAVAnc80-hOTOF (dose level 2) in the study ear using a sterile, one-time use investigational medical device | Combination Product: AAVAnc80-hOTOF via Akouos Delivery Device<br>* AAVAnc80-hOTOF is a sterile suspension intended to be administered via a one-time unilateral intracochlear administration using the Akouos Delivery Device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events (AEs) | AEs with relationship to the investigational medicinal product and/or to the administration procedure (including the delivery device) | through trial completion, approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Auditory Brainstem Response (ABR) Threshold | Changes from baseline in ABR intensity threshold (decibels normal hearing level [dB nHL]) | through trial completion, approximately 2 years | 
| Performance of the Akouos Delivery Device | Performance based on the frequency of device deficiencies observed during delivery of AAVAnc80-hOTOF to the intracochlear space | through trial completion, approximately 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Otoferlin, Auditory neuropathy (AN), Deafness, autosomal recessive 9 (DFNB9), Hearing loss, Hearing loss, bilateral, Hearing loss, sensorineural