First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant

Inclusion Criteria:

Cohort 1 Only

1. Aged 60-74 years (inclusive) at time of consent

2. Hearing Loss due to bilateral progressive presbycusis

3. Approved for unilateral cochlear implantation as per UK NICE criteria (TA566)

4. Documented threshold of ≥70dB in both ears at 1000, 2000 and 4000 Hz, and ≥50dB inboth ears at 500 Hz, at time of eligibility Cohort 2 Only

5. Aged 18-74 years (inclusive) at time of consent

6. Postsynaptic AN characterised by:

• normal outer hair cell function evidenced by normal OAEs and/or CM response,and aberrant or absent ABRs

• disparity between relatively preserved pure-tone audiometric thresholds andsignificantly impaired speech perception abilities, in individuals who do notreceive adequate benefit from acoustic HAs

7. Approved for unilateral cochlear implantation as per UK NICE criteria TA566 and NHSEngland SSC1442 All participants (Cohort 1 and Cohort 2)

8. Capable and willing to provide written informed consent

9. History, examination and pre-operative imaging suggesting a healthy middle ear inthe ear to be implanted, and a structurally normal and fully patent cochlea with noevidence of a widened vestibular aqueduct

10. Both ears deemed suitable for cochlear implantation

11. Pre-operative imaging suggesting adequate access for surgical approach for theinjection of Rincell-1

12. Willingness to be implanted with an Advanced Bionics HiRes Ultra 3D CI and suitableas per device IFU indication

13. A MoCA-HI score of >24

14. English speaker with sufficient comprehension and expressive language to completequestionnaires and speech tests

Exclusion Criteria:

Cohort 2 Only

1. ECochG measurements and genetic testing suggestive of synaptopathy or myelinopathy,including but not limited to: Otoferlin, CABP2, SLC17A8, KARS2, DIAPH3, GJB2, OPA1,MPZ, PMP22 or SLC52 A2 and A3 mutations. All participants (Cohort 1 and Cohort 2)

2. History of prelingual hearing loss

3. History of significant hearing loss caused by infection or head trauma

4. History of previous cochlear implantation, in either ear

5. Documented hearing loss secondary to ototoxic medications

6. Suspected or confirmed hearing loss that is wholly or partly unexplained by anatomicor physiologic abnormalities (non-organic hearing loss)

7. Evidence of current conductive hearing loss defined as 20dB or greater averageair-bone gap over three of the following frequencies: 500, 1000, 2000, 3000 or 4000Hz

8. History of diagnosed sudden SNHL, Ménière's disease, otosclerosis, cholesteatoma,acoustic neuroma, meningitis or confirmed/suspected autoimmune inner ear disease

9. In the ear to be implanted, evidence of anatomical or morphological issues apparenton pre-operative imaging including inner, middle and outer ear malformations (including evidence of a hypoplastic/absent auditory nerve and/or bony/absent IAM)and any known factor that may restrict full insertion of the electrode array orinjection of Rincell-1

10. Any known contraindications or concerns about medical fitness for cochlearimplantation surgery and the additional surgical steps required for Rincell-1injection (including BMI ≥35)

11. Any known contraindications or concerns about suitability for any of the trialmedicinal products (refer to section 5.2, the IB, NIMP manual (Protocol Appendix 1)and relevant SmPCs)

12. Diagnosis of active, moderate to severe autoimmune disorders or any immune disorderrequiring immunosuppression in the past 5 years

13. History of documented severe/significant allergic reaction that required treatment

14. Malignancy under current active treatment or previous malignancy considered atsubstantial risk for progression or recurrence during trial interval, as determinedby the Investigator

15. Previous or current CNS neoplasms or head and neck cancer

16. Previous recipient of a gene therapy, any other type of ATMP, cell or organtransplantation, or recipient of multiple blood transfusions within the past 5 years

17. Unable to be imaged using X-ray and/or MRI (including having any other implantedmedical device that is MRI conditional)

18. Currently pregnant or breastfeeding

19. Unwilling to follow contraception requirements of the trial

20. Current or future participation in another interventional research study or anyhearing-related research study during the course of trial participation

21. Diagnosis of any syndrome, disorder or disease that is auditory, neurological,neurocognitive, psychological or developmental in nature (including speech andlanguage disorders and dyslexia) which, in the Investigator's judgement, couldimpact the trial assessments

22. Laboratory confirmed pre-formed specific anti-HLA antibodies to the cell product

23. Any other reason, medical or otherwise, which, in the Investigator's judgment, couldinterfere with the participant's compliance with the protocol (including undertakingof daily objective testing) or interpretation of the study results, makesparticipating difficult or burdensome for the participant or compromises participantsafety