Clinical trial NCT05788536: A Study of DB-OTO, an Adeno-associated Virus (AAV) Based Gene Therapy, in Children/Infants With Hearing Loss Due to Otoferlin Mutations
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Congenital Hearing Loss Secondary to Biallelic Mutations of the Otoferlin Gene (OTOF)
Keywords: DB-OTO
Gene Therapy
Congenital Hearing Loss
Sensorineural Hearing Loss
Auditory Neuropathy
Pediatric
Cochlear Implant
Otoferlin
Deaf
Hard of hearing
Hearing impaired
Hearing disorder
Fully implantable hearing aid
Child
Infant
CHORD
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2023-03-29
Enrollment: 22
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: Regeneron is conducting a study of an investigational new drug called DB-OTO. DB-OTO is a gene therapy that is being developed to treat children who have hearing loss due to changes in the otoferlin gene.

The purpose of this study is to:

* Learn about the safety of DB-OTO
* Determine how well DB-OTO is tolerated (does not cause ongoing discomfort)
* Evaluate the efficacy of DB-OTO (how well DB-OTO works)

Detailed description: Former Sponsor Decibel Therapeutics

Eligibility criteria: Inclusion Criteria:

1. Presence of pathogenic or likely pathogenic mutations in both alleles of the OTOF gene.
2. 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
3. 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:
   1. Profound sensorineural hearing loss (SNHL; ≥ 90 dB HL) based on behavioral and physiologic measurements (ABR) of inner ear function.
   2. 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:
   1. Profound SNHL (≥ 90 dB HL) based on physiologic measurements (ABR) of inner ear function AND
   2. Behavioral open-set word recognition scores of \< 30% in the ear that would receive DB-OTO
   3. Outer hair cell function is confirmed by presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO OR
   4. Presence of a cochlear microphonic in ears to receive DB-OTO.

   UK \& Spain:

   Infants ≤24 months of age:
   1. 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.
   2. Presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO.

   Children \>24 months to \<18 years of age:
   1. 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.
   2. Presence of otoacoustic emissions (OAE) in the ear(s) to receive DB-OTO OR
   3. Presence of a cochlear microphonic in ears to receive DB-OTO.
4. Willingness of at least 1 parent/legal guardian to consent to vaccinations for the patient in accordance with the country-specific pediatric immunization schedule
5. No clinically significant laboratory findings on clinical laboratory tests at time of Screening
6. No evidence that hearing loss is dependent on body temperature
7. 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:

1. History or presence of other permanent or untreatable hearing loss conditions.
2. Prior or current cochlear implants in the ear(s) to be injected with DB-OTO
3. 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.
4. Prior or current history of malignancies.
5. Prior or current history of meningitis.
6. History of prior treatment with gene therapy.
7. 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 apply, per protocol.

Primary outcomes:
measure: Incidence and severity of treatment-emergent systemic and local adverse events
timeFrame: 5 years
Secondary outcomes:
measure: Auditory brainstem response (ABR) - change in intensity threshold (decibels Hearing Level [dB nHL]) across frequency domains
timeFrame: 5 years
measure: 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
timeFrame: 5 years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center
state: California
city: Jacksonville
country: United States
facility: Nemours Children s Clinic
state: Florida
city: Orlando
country: United States
facility: Nemours Childrens Hospital
state: Florida
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Seattle
country: United States
facility: Seattle Children's Hospital dba Seattle Children's Research Institute
state: Washington
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Las Palmas de Gran Canaria
country: Spain
facility: Hospital Universitario Materno Infantil en las Palmas de Gran Canaria
city: Madrid
country: Spain
facility: Ramon y Cajal University Hospital
city: Pamplona
country: Spain
facility: Clinica Universidad de Navarra
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital, Cambridge University Hospitals NHS FT
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children NHS Foundation Trust
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References: