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

The proposed study is a Phase I/IIa, randomized, open-label, multi-center, First In Human trial of an Advanced Therapy Investigational Medicinal Product (ATIMP) to investigate the safety of Rincell-1 as a treatment for neural hearing loss.

All participants will be recruited from adult patients who have been assessed as being eligible to receive a unilateral cochlear implant (CI) on the National Health Service at a UK CI Centre.

Trial participants will meet UK NICE criteria for cochlear implantation, and will be:

• Cohort 1: Patients with hearing loss due to bilateral progressive presbycusis (aged-related hearing loss)
• Cohort 2: Patients with postsynaptic Auditory Neuropathy Participants will be randomized (3:2), by cohort, to receive either Standard Care unilateral CI plus a single dose of Rincell-1 administered at the same time as CI surgery, or Standard Care unilateral CI alone. Each cohort will have up to a total of 10 participants: 6 in the CI+Rincell-1 arm, and 4 in the standard care CI arm. A total of up to 12 participants across the two cohorts will be dosed with Rincell-1.

Subjects will be followed up to 52 weeks post-implantation.

Inclusion criteria

Cohort 1 Only

• Aged 60-74 years (inclusive) at time of consent
• Hearing Loss due to bilateral progressive presbycusis
• Approved for unilateral cochlear implantation as per UK NICE criteria (TA566)
• Documented threshold of ≥70dB in both ears at 1000, 2000 and 4000 Hz, and ≥50dB in both ears at 500 Hz, at time of eligibility

Cohort 2 Only

• Aged 18-74 years (inclusive) at time of consent
• 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 and significantly impaired speech perception abilities, in individuals who do not receive adequate benefit from acoustic HAs
• Approved for unilateral cochlear implantation as per UK NICE criteria TA566 and NHS England SSC1442

All participants (Cohort 1 and Cohort 2)

• Capable and willing to provide written informed consent
• History, examination and pre-operative imaging suggesting a healthy middle ear in the ear to be implanted, and a structurally normal and fully patent cochlea with no evidence of a widened vestibular aqueduct
• Both ears deemed suitable for cochlear implantation
• Pre-operative imaging suggesting adequate access for surgical approach for the injection of Rincell-1
• Willingness to be implanted with an Advanced Bionics HiRes Ultra 3D CI and suitable as per device IFU indication
• A MoCA-HI score of >24
• English speaker with sufficient comprehension and expressive language to complete questionnaires and speech tests

Exclusion criteria

Cohort 2 Only

• 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)

• History of prelingual hearing loss
• History of significant hearing loss caused by infection or head trauma
• History of previous cochlear implantation, in either ear
• Documented hearing loss secondary to ototoxic medications
• Suspected or confirmed hearing loss that is wholly or partly unexplained by anatomic or physiologic abnormalities (non-organic hearing loss)
• Evidence of current conductive hearing loss defined as 20dB or greater average air-bone gap over three of the following frequencies: 500, 1000, 2000, 3000 or 4000 Hz
• History of diagnosed sudden SNHL, Ménière's disease, otosclerosis, cholesteatoma, acoustic neuroma, meningitis or confirmed/suspected autoimmune inner ear disease
• In the ear to be implanted, evidence of anatomical or morphological issues apparent on 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 or injection of Rincell-1
• Any known contraindications or concerns about medical fitness for cochlear implantation surgery and the additional surgical steps required for Rincell-1 injection (including BMI ≥35)
• Any known contraindications or concerns about suitability for any of the trial medicinal products (refer to section 5.2, the IB, NIMP manual (Protocol Appendix 1) and relevant SmPCs)
• Diagnosis of active, moderate to severe autoimmune disorders or any immune disorder requiring immunosuppression in the past 5 years
• History of documented severe/significant allergic reaction that required treatment
• Malignancy under current active treatment or previous malignancy considered at substantial risk for progression or recurrence during trial interval, as determined by the Investigator
• Previous or current CNS neoplasms or head and neck cancer
• Previous recipient of a gene therapy, any other type of ATMP, cell or organ transplantation, or recipient of multiple blood transfusions within the past 5 years
• Unable to be imaged using X-ray and/or MRI (including having any other implanted medical device that is MRI conditional)
• Currently pregnant or breastfeeding
• Unwilling to follow contraception requirements of the trial
• Current or future participation in another interventional research study or any hearing-related research study during the course of trial participation
• Diagnosis of any syndrome, disorder or disease that is auditory, neurological, neurocognitive, psychological or developmental in nature (including speech and language disorders and dyslexia) which, in the Investigator's judgement, could impact the trial assessments
• Laboratory confirmed pre-formed specific anti-HLA antibodies to the cell product
• Any other reason, medical or otherwise, which, in the Investigator's judgment, could interfere with the participant's compliance with the protocol (including undertaking of daily objective testing) or interpretation of the study results, makes participating difficult or burdensome for the participant or compromises participant safety