A Study of DB-OTO, an Adeno-associated Virus (AAV) Based Gene Therapy, in Children/Infants With Hearing Loss Due to Otoferlin Mutations (CHORD)

• ClinicalTrials.gov Identifier: NCT05788536
• Recruitment Status: Recruiting
• First Posted: March 29, 2023
• Last Update Posted: April 19, 2024
• Sponsor: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Regeneron Pharmaceuticals

Tracking Information

• First Submitted Date: March 15, 2023
• First Posted Date: March 29, 2023
• Last Update Posted Date: April 19, 2024
• Actual Study Start Date: May 12, 2023
• Estimated Primary Completion Date: April 19, 2031 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: March 15, 2023): Incidence and severity of treatment-emergent systemic and local adverse events [ Time Frame: 5 years ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 11, 2023)

• Auditory brainstem response (ABR) - change in intensity threshold (decibels Hearing Level [dB nHL]) across frequency domains [ Time Frame: 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 [ Time Frame: 5 years ]

Original Secondary Outcome Measures (submitted: March 15, 2023)

• Auditory brainstem response (ABR) - change in intensity threshold (decibels Hearing Level [dB nHL]) across frequency domains [ Time Frame: 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) - change in threshold in treated ear [ Time Frame: 5 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
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.

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Congenital Hearing Loss Secondary to Biallelic Mutations of the Otoferlin Gene (OTOF)

Intervention

• Genetic: DB-OTO

  DB-OTO will be administered as a single intracochlear injection into one ear (Part A).

  • LD Cohort (starting dose)
  • HD Cohort (high dose)
• Genetic: DB-OTO
  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.

Study Arms

• Experimental: DB-OTO - Dose Escalation
  Unilateral intracochlear dosing
  Intervention: Genetic: DB-OTO
• Experimental: DB-OTO - Dose Expansion
  Bilateral intracochlear dosing using the dose selected based on safety and efficacy data from the Dose Escalation phase (Part A).
  Intervention: Genetic: DB-OTO

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 15, 2023): 22
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 19, 2031
• Estimated Primary Completion Date: April 19, 2031 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Clinical Trials Administrator; 844-734-6643; clinicaltrials@regeneron.com

• Listed Location Countries: Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT05788536
• Other Study ID Numbers: DB-OTO-001; 2022-000079-38 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Supporting Materials: Analytic Code
• Time Frame: When Regeneron has received marketing authorization from major health authorities (e.g., FDA, European Medicines Agency (EMA), Pharmaceuticals and Medical Devices Agency (PMDA), etc.) for the product and indication, has made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry), has the legal authority to share the data, and has ensured the ability to protect participant privacy.
• Access Criteria: Qualified researchers can submit a proposal for access to individual patient or aggregate level data from a Regeneron-sponsored clinical trial through Vivli. Regeneron's Independent Research Request Evaluation Criteria can be found at: https://www.regeneron.com/sites/default/files/Regeneron-External-Data-Sharing-Policy-and-Independent-Research-Request-Evaluation-Criteria.pdf
• URL: https://vivli.org/

• Current Responsible Party: Regeneron Pharmaceuticals
• Original Responsible Party: Decibel Therapeutics
• Current Study Sponsor: Regeneron Pharmaceuticals
• Original Study Sponsor: Decibel Therapeutics
• Collaborators: Not Provided

Investigators

• Study Director: Clinical Trial Management; Regeneron Pharmaceuticals

• PRS Account: Regeneron Pharmaceuticals
• Verification Date: April 2024