A Study of DB-OTO, an AAV Based Gene Therapy, in Children/Infants With Hearing Loss Due to Otoferlin Mutations

Study Overview
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Brief Summary
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This is a first-in-human, multicenter, Phase 1/2, open-label, 2-part trial with a single-ascending dose patient cohort (Part A) and a bilateral expansion patient cohort (Part B) to evaluate the safety, tolerability, and preliminary efficacy of DB-OTO, an AAV based gene therapy in pediatric patients with biallelic OTOF mutations

Official Title
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A PHASE 1/2, OPEN-LABEL, MULTICENTER TRIAL WITH A SINGLE ASCENDING DOSE COHORT WITH UNILATERAL INTRACOCHLEAR INJECTION FOLLOWED BY A BILATERAL INJECTION EXPANSION COHORT TO EVALUATE THE SAFETY, TOLERABILITY, AND EFFICACY OF DB-OTO IN CHILDREN AND INFANTS WITH BIALLELIC hOTOF MUTATIONS

Conditions
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Congenital Hearing Loss Secondary to Biallelic Mutations of the Otoferlin Gene (OTOF)

Intervention / Treatment
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* Biological: DB-OTO
* Biological: DB-OTO


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of pathogenic or likely pathogenic mutations in both alleles of the OTOF gene. Patient is <18 years of age and of the appropriate age to qualify for enrollment in the corresponding age cohort at the time the parent/legal guardian signs the informed consent form. Participant to provide assent, when applicable Audiological Criteria: US: Investigator determines that minimal benefit has been provided by amplification of the ear to receive DB-OTO. Investigator determines the patient meets cochlear implantation criteria in both ears according to the recommended cochlear implant label Infants ≤24 months of age: Profound sensorineural hearing loss (SNHL; ≥ 90 dB HL) based on behavioral and physiologic measurements (ABR) of inner ear function. Outer hair cell function is confirmed by presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO Children >24 months to <18 years of age: Profound SNHL (≥ 90 dB HL) based on physiologic measurements (ABR) of inner ear function AND Behavioral open-set word recognition scores of < 30% in the ear that would receive DB-OTO Outer hair cell function is confirmed by presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO OR Presence of a cochlear microphonic in ears to receive DB-OTO. UK & Spain: Infants ≤24 months of age: Absence of an ABR neural signal in response to a click stimulus ≤85 dB nHL in the ear(s) to be injected with DB-OTO. Presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO. Children >24 months to <18 years of age: Absence of an ABR neural signal in response to a click stimulus ≤85 dB nHL in the ear(s) to be injected with DB-OTO. Presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO OR Presence of a cochlear microphonic in ears to receive DB-OTO. Willingness of at least 1 parent/legal guardian to consent to vaccinations for the patient in accordance with the country-specific pediatric immunization schedule No clinically significant laboratory findings on clinical laboratory tests at time of Screening No evidence that hearing loss is dependent on body temperature From study start and for the duration of the short-term follow-up period (18 months): Female patients of childbearing potential and fertile males, must agree to use highly effective contraception. Female patients must agree not to become pregnant. Fertile male patients must agree not to father a child or donate sperm. Exclusion Criteria: History or presence of other permanent or untreatable hearing loss conditions. Prior or current cochlear implants in the ear(s) to be injected with DB-OTO History of risk factor(s) for auditory neuropathy not caused by OTOF mutations including: prematurity, low birth weight, hyperbilirubinemia, neonatal intensive care unit (NICU) admission, and/or low Apgar scores. Prior or current history of malignancies. Prior or current history of meningitis. History of prior treatment with gene therapy. Surgical anatomy that would preclude the planned surgical approach as indicated by medical imaging (eg, computed tomography [CT] or magnetic resonance imaging [MRI]) in the ear(s) to be injected with DB-OTO. Note: additional inclusion/exclusion criteria may apply, per protocol.

Ages Eligible for Study
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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
Interventional Model Description: DB-OTO will be administered as a single intracochlear injection into one (Part A) or both ears (Part B). For bilateral injections (Part B), patients will receive DB-OTO in 1 surgical session.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DB-OTO - Dose Escalation<br>Unilateral intracochlear dosing | Biological: DB-OTO<br>* DB-OTO will be administered as a single intracochlear injection into one ear (Part A). LD Cohort (starting dose) HD Cohort (high dose)<br>|
| Experimental: DB-OTO - Dose Expansion<br>Bilateral intracochlear dosing using the dose selected based on safety and efficacy data from the Dose Escalation phase (Part A). | Biological: DB-OTO<br>* DB-OTO will be administered as a single intracochlear injection into both ears (Part B). For bilateral injections (Part B), patients will receive DB-OTO in 1 surgical session.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent systemic and local adverse events |  | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Auditory brainstem response (ABR) - change in intensity threshold (decibels Hearing Level [dB nHL]) across frequency domains |  | 5 years | 
| Behavioral audiometry with pure-tone audiometry - change in intensity thresholds (dB HL) in treated ear across frequency domains, and speech awareness threshold (SAT) and speech reception threshold (SRT)- change in threshold in treated ear |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Auditory Neuropathy, Pediatric, Cochlear Implant, Otoferlin, Deaf, Hard of hearing, Child, DB-OTO, Gene Therapy, Congenital Hearing Loss, Sensorineural Hearing Loss, Hearing impaired, Hearing disorder, Fully implantable hearing aid, Infant, CHORD