Gene Therapy Trial for OTOF-mediated Hearing Loss

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Akouos Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Otorhinolaryngologic Diseases [C09]

Decision date (initial)

2023-10-05

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Akouos Inc.

External identifiers

EU CT number

2023-505128-76-00

ClinicalTrials.gov

NCT05821959

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response

The objective of Part A is to assess the safety, tolerability, and bioactivity of escalating doses of AAVAnc80-hOTOF.

Conditions and MedDRA coding

Otoferlin gene-mediated hearing loss

Study design 5 periods

Regulatory references

Scientific advice from competent authorities

The Spanish Agency Of Medicines And Medical Devices

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Age seven to 17 years old (inclusive) for Cohort #1a; age two to 17 years old (inclusive) at the time of AAVAnc80-hOTOF administration for Cohorts #1b and #2.
2. Biallelic mutations in the OTOF gene confirmed by: 1) a European Conformity (CE)-marked genetic test for OTOF, including as part of a clinical panel for hearing loss/deafness genes; or 2) a Clinical Laboratory Improvements Amendment (CLIA)-certified or equivalent laboratory’s genetic test for OTOF, including as part of a clinical panel for hearing loss/deafness genes.
3. Clinical presentation of Profound bilateral sensorineural hearing loss as assessed by ABR threshold OR absent or abnormal diagnostic ABR (i.e., no click-evoked ABR for levels up to and including 90 dB nHL, consistent with diagnosis of Profound bilateral sensorineural hearing loss); when afebrile.
4. Preserved OAEs (distortion product OAEs [DPOAEs]), defined as more than one frequency within normal response limits in the speech frequency range, in the study ear.
5. Participants of child-bearing potential (males and females) agree to use effective contraceptive methods for one year after administration of AAVAnc80-hOTOF. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical trials as described in the corresponding Informed Consent Form (ICF). • Females of child-bearing potential include those who have experienced menarche. • Males who have reached sexual maturity are considered to be of child-producing potential unless they have had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
6. Legally authorized representative and/or participant willingness to comply with all trial requirements, as evidenced by successful completion of the informed consent process and participant assent process (where appropriate).
7. Legally authorized representative and/or participant willingness to participate in separate LTFU protocol after completion of this trial.

Exclusion criteria 16

1. Medical or psychological conditions that contraindicate undergoing surgery, general anaesthesia, and/or investigational gene therapy administration, including: a) Recurrent or persistent hypertension with systolic and/or diastolic blood pressure (BP) more than 10mm Hg above the 90th percentile for age b) Recurrent or persistent hepatic dysfunction indicated by bilirubin > 1.5X the upper limit of normal (ULN) for age, AST > 2X the ULN for age, or ALT > 2X the ULN for age c) Renal glomerular dysfunction requiring treatment, including diuretics and/or dialysis; or estimated glomerular filtration rate (GFR) < 60mL/min/1.73m2 d) Recurrent or persistent pulmonary dysfunction that requires intermittent supplemental oxygen or persistent oxygen saturation less than 95% on room air (at rest) e) Recurrent or persistent hemoglobin < 10 g/dL (or equivalent) f) Recurrent or persistent platelet count of < 100,000/mL g) Other applicable conditions
2. Anatomic abnormalities of the ear that preclude the surgical approach, e.g., canal atresia.
3. Congenital malformations of the inner ear, as confirmed by non-contrast, high-definition magnetic resonance imaging (MRI), including but not limited to: cochlear malformations (e.g., Mondini malformation); cochlear nerve dysplasia; congenital atresia; absence of round and oval windows; Scheibe dysplasia; membranous labyrinth; Large Vestibular Aqueduct; and anomalies of the eustachian tube and accessory structures. Note: historic MRI data OR historic computed tomography (CT) data (high resolution, no contrast) obtained prior to enrollment are acceptable, provided the studies are adequate to assess inner ear morphology. A CT scan may be obtained at the discretion of the surgeon to further evaluate the bony anatomy, if the MRI and/or historic imaging studies are indeterminate.
4. Evidence of persistent middle ear dysfunction, as demonstrated by repeated abnormal tympanometry (an immittance measure of middle ear function). Note: in the presence of tympanostomy tubes, large volume tympanograms are not exclusionary.
5. Chronic otitis media or chronic eardrum perforation in the study ear.
6. Hearing loss attributed mainly to past ototoxic exposures (e.g., severe prematurity, hypoxia, ototoxic medication such as chemotherapy).
7. Clinical history consistent with endolymphatic hydrops (documented fluctuating sensorineural hearing loss in the affected ear and/or episodic vertigo attributable to the study ear).
8. Evidence of patent cochlear aqueduct.
9. Bilateral cochlear implants.
10. Prior middle or inner ear surgery in the study ear, with the exception of tympanostomy tubes or tympanocentesis, within six months prior to administration (Day 0).
11. Known sensitivity or contraindications to medications planned for use in the peri-operative period, including corticosteroids.
12. Prior participation in a clinical trial with an investigational drug, within six months prior to administration (Day 0), or any prior participation in a gene therapy clinical trial.
13. Individuals of childbearing potential who are pregnant and/or breastfeeding or unwilling to use effective contraception for one year following AAVAnc80-hOTOF administration.
14. Word recognition score (for individuals capable of performing the assessment) as follows: > 30% in the best aided condition in the study ear or > 30% in the best aided (hearing aid) condition in the contralateral ear, without cochlear implant use.
15. Any other condition that would not allow the potential participant to complete follow-up examinations during the course of the trial and/or, in the opinion of the Investigator, makes the potential participant unsuitable for the trial.
16. Unwillingness or inability of the potential participant (and legally authorized representative, if participant is a minor) to comply with all investigational requirements and follow up.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Frequency of AEs with relationship to the investigational medicinal product and/or to the administration procedure (including the delivery device, used as part of a delivery system), if able to be determined.

Secondary endpoints 1

1. Change from baseline in diagnostic auditory brainstem response (ABR) testing threshold.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Akouos Inc.

Sponsor organisation

Akouos Inc.

Address

645 Summer Street Suite 200

City

Boston

Postcode

02210-2135

Country

United States

Scientific contact point

Organisation

Akouos Inc.

Contact name

Akouos Clinical Trials

Public contact point

Organisation

Akouos Inc.

Contact name

Akouos Clinical Trials

Third parties 2

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Application history

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