DB-OTO-5, DB-OTO-3 for Congenital hearing loss due to biallelic OTOF pathogenic variants

Inclusion criteria

• {"criterion_text":"- 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\n- Patient is aged <18 years and able to perform all necessary assessments to qualify for enrolment and dosing in the corresponding cohort at the time the parent/legal guardian signing the informed consent form (and patient providing assent, when applicable)\n- Presence of biallelic, likely pathogenic or pathogenic OTOF variants\n- No clinically significant laboratory findings on clinical laboratory tests at time of Screening as described in the protocol\n- Audiological Criteria: a. Investigator diagnoses the patient with profound sensorineural hearing loss (SNHL; ≥90 dB HL) based on behavioral and physiologic measurements (ABR) of inner ear function b. 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\n- No evidence from measures of hearing loss that show a dependence on body temperature\n- 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\n- Additional Protocol defined inclusion criteria may apply"}

Exclusion criteria

• {"criterion_text":"- History of prior treatment with gene therapy\n- 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\n- History or presence of other permanent or untreatable hearing loss conditions\n- Prior or current history of malignancies\n- Prior or current history of meningitis\n- History or presence of cochlear implants in the ear(s) to be injected with DB-OTO\n- 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\n- Additional Protocol defined exclusion criteria may apply"}

Primary endpoints

• {"endpoint_text":"- Incidence and severity of treatment-emergent adverse events","definition_or_measurement_approach":"Safety assessed by recording incidence and severity of treatment-emergent adverse events (AE reporting as per protocol)"}
• {"endpoint_text":"- Achievement of a hearing sensitivity threshold of ≤70 dB assessed by average pure tone audiometry (PTA)","definition_or_measurement_approach":"Hearing sensitivity measured by average pure tone audiometry (PTA); achievement defined as average PTA ≤70 dB"}

Secondary endpoints

• {"endpoint_text":"- Auditory Brainstem Response (ABR) to click","definition_or_measurement_approach":"Measured using ABR testing (click stimulus)"}
• {"endpoint_text":"- Achievement of a hearing sensitivity threshold of ≤45 dB assessed by average PTA","definition_or_measurement_approach":"Average PTA ≤45 dB as measured by pure tone audiometry"}
• {"endpoint_text":"- Achievement of hearing sensitivity threshold of ≤25 dB assessed by average PTA","definition_or_measurement_approach":"Average PTA ≤25 dB as measured by pure tone audiometry"}
• {"endpoint_text":"- Speech perception scores by age-appropriate tests","definition_or_measurement_approach":"Speech perception assessed using age-appropriate speech perception tests"}
• {"endpoint_text":"- Speech Awareness Threshold (SAT): achievement of a threshold of ≤70 dB","definition_or_measurement_approach":"SAT measured; achievement defined as SAT ≤70 dB"}
• {"endpoint_text":"- SAT: achievement of a threshold of ≤45 dB","definition_or_measurement_approach":"SAT measured; achievement defined as SAT ≤45 dB"}
• {"endpoint_text":"- SAT: achievement of threshold of ≤25 dB","definition_or_measurement_approach":"SAT measured; achievement defined as SAT ≤25 dB"}
• {"endpoint_text":"- Speech Reception Threshold (SRT): achievement of a threshold of ≤70 dB","definition_or_measurement_approach":"SRT measured; achievement defined as SRT ≤70 dB"}
• {"endpoint_text":"- SRT: achievement of a threshold of ≤45 dB","definition_or_measurement_approach":"SRT measured; achievement defined as SRT ≤45 dB"}
• {"endpoint_text":"- SRT: achievement of a threshold of ≤25 dB","definition_or_measurement_approach":"SRT measured; achievement defined as SRT ≤25 dB"}
• {"endpoint_text":"- Severity in speech perception ability assessed by Global Impression scales, determined by clinician","definition_or_measurement_approach":"Clinician-rated Global Impression scales to assess severity of speech perception ability"}
• {"endpoint_text":"- Severity in speech perception ability assessed by Global Impression scales, determined by parent/legal guardian","definition_or_measurement_approach":"Parent/legal guardian-rated Global Impression scales to assess severity of speech perception ability"}
• {"endpoint_text":"- Change in speech perception ability assessed by Global Impression scales, determined by clinician","definition_or_measurement_approach":"Change from baseline assessed via clinician Global Impression scales"}
• {"endpoint_text":"- Change in speech perception ability assessed by Global Impression scales, determined by parent/legal guardian","definition_or_measurement_approach":"Change from baseline assessed via parent/legal guardian Global Impression scales"}
• {"endpoint_text":"- Average PTA threshold in the subset of patients who achieved an average PTA threshold ≤70 dB","definition_or_measurement_approach":"Average PTA threshold calculated in subset achieving ≤70 dB"}
• {"endpoint_text":"- Average PTA threshold in the subset of patients who achieved an average PTA threshold >70 dB but ≤85 dB","definition_or_measurement_approach":"Average PTA threshold calculated in subset with >70 dB but ≤85 dB"}
• {"endpoint_text":"- Achievement of a hearing sensitivity threshold improvement of ≥10 dB from baseline","definition_or_measurement_approach":"Improvement defined as ≥10 dB gain in hearing sensitivity from baseline PTA"}
• {"endpoint_text":"- Time to an average PTA threshold ≤70 dB","definition_or_measurement_approach":"Time-to-event analysis measuring time from dosing to achieving average PTA ≤70 dB"}
• {"endpoint_text":"- Incidence of patients who regress to >70 dB after having achieved average PTA threshold ≤70 dB","definition_or_measurement_approach":"Incidence count of patients who later revert to average PTA >70 dB after previously achieving ≤70 dB"}
• {"endpoint_text":"- Persistence of an average PTA threshold ≤70 dB","definition_or_measurement_approach":"Assessment of persistence/duration of maintaining average PTA ≤70 dB over follow-up"}

Methods

• Static banners (document: K2_Recruitment_material_PCG_Static Banners) — digital/static online placement targeting caregivers/parents and patient community
• Caregiver flyers (digital and print) (documents: Caregiver Flyer_DIGITAL, Caregiver Flyer_PRINT, Caregiver CHORD Flyer) — targeted at caregivers/parents
• Patient brochure (documents: Recruitment Material_Patient Brochure) — informational brochure for patients/caregivers
• Ads (print and digital) (documents: Ads_PCG_redacted, Print Ads) — targeted advertising in print/digital channels
• Physician referral letter (document: Physician Referral Letter_public) — for clinician-to-patient recruitment/referral
• Social digital images and recordings (documents: SIS and ICF_Social Digital Images/Recordings) — social media/digital outreach materials

Spain

Earliest CTIS Part Ii Submission Date

14-05-2024

Latest Decision Or Authorization Date

26-03-2026

Processing Time Days

681

Number Of Sites

3

Number Of Participants

11

Germany

Earliest CTIS Part Ii Submission Date

17-02-2025

Latest Decision Or Authorization Date

30-04-2026

Processing Time Days

437

Number Of Sites

1

Number Of Participants

4

Primary sponsor

Full Name

Regeneron Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Iqvia Biotech Limited

Responsibilities

sponsorDuties codes: 1, 12, 6, 7, 8, 9 (multiple operational/study management roles)

Name

4g Clinical LLC

Responsibilities

sponsorDuties codes: 3

Name

Q Squared Solutions Limited

Responsibilities

sponsorDuties codes: 4

Name

RTI Health Solutions

Responsibilities

sponsorDuties codes: 15 (Complete Parent/Legal Guardian Interview)

Third parties

• {"country":"United States","full_name":"Andersonbrecon Inc.","duties_or_roles":"sponsorDuties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Iqvia Biotech Limited","duties_or_roles":"sponsorDuties codes: 1, 12, 6, 7, 8, 9","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Transperfect Translations International Inc.","duties_or_roles":"Translation services (code 15)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Preventiongenetics LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Signant Health Management Limited","duties_or_roles":"sponsorDuties codes: 7","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"RTI Health Solutions","duties_or_roles":"Complete Parent/Legal Guardian Interview (code 15)","organisation_type":"Industry"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"sponsorDuties codes: 3","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Q Squared Solutions Holdings LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Charles River Laboratories Inc.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Chillibean Limited","duties_or_roles":"Independent Reviewer Platform (code 15)","organisation_type":"Pharmaceutical company"}