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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Regeneron Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

4 Mar 2024 → ongoing

Decision date (initial)

2025-03-10

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Regeneron Pharmaceuticals Inc.

External identifiers

EU CT number

2024-511342-40-00

EudraCT number

2022-000079-38

ClinicalTrials.gov

NCT05788536

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Therapy, Others, Efficacy

To evaluate the safety and efficacy of DB-OTO in pediatric patients diagnosed with biallelic OTOF pathogenic variants

Secondary objectives 1

1. To evaluate efficacy of DB-OTO in pediatric patients diagnosed with biallelic OTOF pathogenic variants in domains of hearing and age-appropriate speech perception

Conditions and MedDRA coding

Congenital Hearing Loss Secondary to Biallelic Pathogenic Variants of the Otoferlin Gene (OTOF)

Regulatory references

Scientific advice from competent authorities

Medicines And Healthcare Products Regulatory Agency, Food And Drug Administration, European Medicines Agency, Spanish Agency For Medicines And Health Products, Paul-Ehrlich-Institut

EMA paediatric investigation plan (PIP)

EMEA-000018-PIP27-82

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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 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)
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: 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
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
8. Additional Protocol defined inclusion criteria may apply

Exclusion criteria 8

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
8. Additional Protocol defined exclusion criteria may apply

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Incidence and severity of treatment-emergent adverse events
2. Achievement of a hearing sensitivity threshold of ≤70 dB assessed by average pure tone audiometry (PTA)

Secondary endpoints 20

1. Auditory Brainstem Response (ABR) to click
2. Achievement of a hearing sensitivity threshold of ≤45 dB assessed by average PTA
3. Achievement of hearing sensitivity threshold of ≤25 dB assessed by average PTA
4. Speech perception scores by age-appropriate tests
5. Speech Awareness Threshold (SAT): achievement of a threshold of ≤70 dB
6. SAT: achievement of a threshold of ≤45 dB
7. SAT: achievement of threshold of ≤25 dB
8. Speech Reception Threshold (SRT): achievement of a threshold of ≤70 dB
9. SRT: achievement of a threshold of ≤45 dB
10. SRT: achievement of a threshold of ≤25 dB
11. Severity in speech perception ability assessed by Global Impression scales, determined by clinician
12. Severity in speech perception ability assessed by Global Impression scales, determined by parent/legal guardian
13. Change in speech perception ability assessed by Global Impression scales, determined by clinician
14. Change in speech perception ability assessed by Global Impression scales, determined by parent/legal guardian
15. Average PTA threshold in the subset of patients who achieved an average PTA threshold ≤70 dB
16. Average PTA threshold in the subset of patients who achieved an average PTA threshold >70 dB but ≤85 dB
17. Achievement of a hearing sensitivity threshold improvement of ≥10 dB from baseline
18. Time to an average PTA threshold ≤70 dB
19. Incidence of patients who regress to >70 dB after having achieved average PTA threshold ≤70 dB
20. Persistence of an average PTA threshold ≤70 dB

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Regeneron Pharmaceuticals Inc.

Sponsor organisation

Regeneron Pharmaceuticals Inc.

Address

777 Old Saw Mill River Road

City

Tarrytown

Postcode

10591-6717

Country

United States

Scientific contact point

Organisation

Regeneron Pharmaceuticals Inc.

Contact name

Medical Affairs

Public contact point

Organisation

Regeneron Pharmaceuticals Inc.

Contact name

Medical Affairs

Third parties 12

Locations

2 EU/EEA countries · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 42 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications