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

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

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)

Study Overview

• Status: Recruiting
• Conditions: Congenital Hearing Loss Secondary to Biallelic Mutations of the Otoferlin Gene (OTOF)
• Intervention / Treatment: Genetic: DB-OTO; Genetic: DB-OTO

Detailed Description

Former Sponsor Decibel Therapeutics

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Phone Number: 844-734-6643; Email: clinicaltrials@regeneron.com

Study Locations

• Germany
  • Tübingen, Germany, 72076
    • Recruiting
    • University Hospital Tübingen
    • Contact: Hubert Lowenheim; Email: hubert.loewenheim@uni-tuebingen.de
• Japan
  • Nagano
    • Matsumoto-shi, Nagano, Japan, 390-8621
      • Recruiting
      • Shinshu University Hospital
      • Contact: Yutaka Takumi; Email: takumi@shinshu-u.ac.jp
• Spain
  • Las Palmas de Gran Canaria, Spain, 35016
    • Withdrawn
    • Hospital Universitario Materno Infantil en las Palmas de Gran Canaria
  • Madrid, Spain, 28034
    • Recruiting
    • Ramon y Cajal University Hospital
    • Contact: Ruben Polo; Email: rubenpolo1979@gmail.com
  • Navarre
    • Pamplona, Navarre, Spain, 31008
      • Recruiting
      • Clinica Universidad de Navarra- Pamplona
      • Contact: Manuel Jesus Manrique Rodriguez; Email: mmanrique@unav.es
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Recruiting
    • Addenbrooke's Hospital, Cambridge University Hospitals NHS FT
    • Contact: Manohar Bance; Email: mlb59@cam.ac.uk
  • London, United Kingdom, WC1N 3JH
    • Recruiting
    • Great Ormond Street Hospital For Children NHS Foundation Trust
    • Contact: Robert Nash; Email: r.nash@ucl.ac.uk
• United States
  • California
    • Los Angeles, California, United States, 90024
      • Recruiting
      • University of California Los Angeles Medical Center
      • Contact: Akira Ishiyama; Email: ishiyama@g.ucla.edu
    • San Diego, California, United States, 92123
      • Recruiting
      • Rady Children's Hospital
      • Contact: Daniela Carvalho; Email: dcarvalho@rchsd.org
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Recruiting
      • Nemours Children s Clinic
      • Contact: Evie Landry; Email: evie.Landry@nemours.org
    • Orlando, Florida, United States, 32827
      • Recruiting
      • Nemours Childrens Hospital
      • Contact: Cedric Pritchett; Email: cedric.Pritchett@nemours.org
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital - Main
      • Contact: Eliot Shearer; Email: Eliot.Shearer@childrens.harvard.edu
  • New York
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Irving Medical Center
      • Contact: Lawrence Lustig; Email: lustig@columbia.edu
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Recruiting
      • Cincinnati Children's Hospital Medical Center
      • Contact: John Greinwald, Jr.; Email: john.greinwald@cchmc.edu
  • Washington
    • Seattle, Washington, United States, 98105
      • Recruiting
      • Seattle Children's Hospital
      • Contact: Jay Rubenstein; Email: rubinj@uw.edu
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Medical College of Wisconsin
      • Contact: Sarah Mleziva; Email: smleziva@mcw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Willingness of at least 1 parent/legal guardian to provide written informed consent (and patient to provide assent, when applicable) and willingness to comply with trial protocol; to consent to genetic testing for the patient (and patient to provide assent, when applicable) in order to evaluate a panel of hearing loss-related genes; and to consent to vaccinations for the patient (and patient to provide assent, when applicable) in accordance with the country-specific pediatric immunization schedule as described in the protocol
2. Patient is aged <18 years and able to perform all necessary assessments to qualify for enrollment and dosing in the corresponding cohort at the time the parent/legal guardian signing the informed consent form (and patient providing assent, when applicable)
3. Presence of biallelic, likely pathogenic or pathogenic OTOF variants
4. No clinically significant laboratory findings on clinical laboratory tests at time of Screening as described in the protocol

5. Audiological Criteria:

   1. Investigator diagnoses the patient with profound sensorineural hearing loss (SNHL; >90 dB HL) based on behavioral and physiologic measurements (ABR) of inner ear function
   2. Outer hair cell presence is confirmed via presence of otoacoustic emissions (≥6 dBSNR) at ≥3 frequencies from 1 to 8 kHz in the ear(s) to be injected with DB-OTO. Alternatively, for children >24 months to <18 years of age, outer hair cell presence can be confirmed via presence of the cochlear microphonic in the ear(s) to be injected with DB-OTO.
6. No evidence from measures of hearing loss that show a dependence on body temperature
7. From study start and for the duration of the short-term follow-up period (48 weeks): 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, for 48 weeks and in cases of early withdrawal, for at least 12 months after DB-OTO administration.

Key Exclusion Criteria:

1. History of prior treatment with gene therapy
2. Surgical anatomy that would preclude or meaningfully impact 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
3. History or presence of other permanent or untreatable hearing loss conditions
4. Prior or current history of malignancies
5. Prior or current history of meningitis
6. History or presence of cochlear implants in the ear(s) to be injected with DB-OTO
7. History of risk factor(s) for auditory neuropathy not caused by OTOF pathogenic variants including but not limited to: prematurity, low birth weight, hyperbilirubinemia, Neonatal Intensive Care Unit (NICU) admission, and/or low Apgar scores as described in the protocol

Note: Other protocol-defined inclusion/exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DB-OTO - Unilateral Dose Escalation; Part A: Unilateral intracochlear dosing	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.; Genetic: DB-OTO; DB-OTO will be administered as a single intracochlear injection into one ear (Part A).; LD Cohort (lower dose); HD Cohort (high dose) - not implemented
Experimental: DB-OTO - Bilateral Dose Expansion; Part B: Bilateral intracochlear dosing using the dose selected based on safety and efficacy data from Part A.	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.; Genetic: DB-OTO; DB-OTO will be administered as a single intracochlear injection into one ear (Part A).; LD Cohort (lower dose); HD Cohort (high dose) - not implemented

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Incidence and severity of Treatment-Emergent Adverse Events (TEAEs)	Up to week 104
Achievement of a hearing sensitivity threshold of ≤70 dB assessed by average Pure Tone Audiometry (PTA)	Up to week 104

Secondary Outcome Measures

Outcome Measure	Time Frame
Auditory Brainstem Response (ABR) to click	Up to week 48
Speech perception scores by age-appropriate tests	Up to week 48
Average PTA threshold in the subset of patients who achieved an average PTA threshold >70 dB but ≤85 dB	Up to week 48
Achievement of a hearing sensitivity threshold improvement of ≥10 dB from baseline	Up to week 48
Achievement of a score ≥3 on the Early Speech Perception (ESP) test	At week 104
Achievement of hearing sensitivity threshold of ≤45 dB assessed by average PTA	Up to week 104
Achievement of hearing sensitivity threshold of ≤25 dB assessed by average PTA	Up to week 104
Achievement of a score of 4 on the ESP test	At week 104
Speech Awareness Threshold (SAT): achievement of a threshold of ≤70 dB	Up to week 104
SAT: achievement of a threshold of ≤45 dB	Up to week 104
SAT: achievement of threshold of ≤25 dB	Up to week 104
Average PTA threshold in the subset of patients who achieved an average PTA threshold ≤70 dB	Up to week 104
Time to an average PTA threshold ≤70 dB	Up to week 104
Persistence of an average PTA threshold ≤70 dB	Up to week 104
Incidence of patients who regress to >70 dB after having achieved average PTA threshold	Up to week 104
Severity in speech perception ability assessed by Global Impression scales (clinician and parent/legal guardian)	Up to week 48
Change in speech perception ability assessed by Global Impression scales (clinician and parent/legal guardian)	Up to week 48
Presence of auditory brainstem response (ABR) to click at ≤90 dB normalized Hearing Level (nHL)	At week 104
Speech perception scores by age-appropriate tests (other than ESP)	At week 104
Severity in speech perception ability assessed by Global Impression scales (clinician and parent/legal guardian)	At week 104
Change in speech perception ability assessed by Global Impression scales (clinician and parent/legal guardian)	At week 104
Change from baseline on LittlEARS®	At week 104
Change in scores on LittlEARS®	At week 104
Change from baseline on Auditory Skills Checklist	At week 104
Change in scores on Auditory Skills Checklist	At week 104
Change from baseline on MacArthur-Bates Communicative Development Inventories (MB-CDI)-Words and Gestures	At week 104
Change in scores on MB-CDI-Words and Gestures	At week 104
Change from baseline on MB-CDI -Words and Sentences	At week 104
Change in scores on MB-CDI -Words and Sentences	At week 104
Change from baseline on MB-CDI-III Vocabulary and Grammar	At week 104
Change in scores on MB-CDI-III Vocabulary and Grammar	At week 104
Clinical assessments of speech production: articulation	At week 104
Clinical assessments of speech production: speech intelligibility	At week 104

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Valayannopoulos V, Bance M, Carvalho DS, Greinwald JH Jr, Harvey SA, Ishiyama A, Landry EC, Lowenheim H, Lustig LR, Manrique M, Nash R, Polo R, Pritchett CV, Rubinstein JT, Shearer AE, Del Castillo I, Anderson JJ, Corrales CE, Quigley TM, Riggs WJ, Weber P, Wilson G, Irvin SC, Hassan HE, Chen Y, Liu R, Drummond MC, Sabin LR, Musser BJ, Yancopoulos GD, Kyratsous CA, Herman GA, Baras A, Whitton JP; CHORD Study Group. DB-OTO Gene Therapy for Inherited Deafness. N Engl J Med. 2026 Mar 12;394(11):1074-1083. doi: 10.1056/NEJMoa2400521. Epub 2025 Oct 12.

Helpful Links

• Patients, Caregivers & HCPs: Contribute to Genetic Hearing Loss Research

Study record dates

Study Major Dates

• Study Start (Actual): June 27, 2023
• Primary Completion (Estimated): February 28, 2032
• Study Completion (Estimated): February 28, 2032

Study Registration Dates

• First Submitted: March 15, 2023
• First Submitted That Met QC Criteria: March 15, 2023
• First Posted (Actual): March 29, 2023

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Child; Gene Therapy; Pediatric; Infant; Cochlear Implant; Deaf; Sensorineural Hearing Loss; Congenital Hearing Loss; DB-OTO; Auditory Neuropathy; Otoferlin; Hard of hearing; Hearing impaired; Hearing disorder; Fully implantable hearing aid; CHORD
• Additional Relevant MeSH Terms: Neurologic Manifestations; Nervous System Diseases; Otorhinolaryngologic Diseases; Sensation Disorders; Ear Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hearing Loss; Hearing Loss, Sensorineural; Hearing Disorders; Deafness, Autosomal Recessive 9; Auditory neuropathy
• Other Study ID Numbers: DB-OTO-001; 2022-000079-38 (EudraCT Number); 2024-511342-40-00 (Ctis: EUCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All Individual Patient Data (IPD) that underlie publicly available results will be considered for sharing

IPD Sharing 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 or has globally discontinued development of the product for all indications on or after April 2020 and has no plans for future development
• made the study results publicly available (e.g., scientific publication, scientific conference, clinical trial registry)
• the legal authority to share the data, and
• ensured the ability to protect participant privacy.

• IPD Sharing 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No