What is this research project about?

The CINGT trial comes from extensive studies in animals that showed improvement in performance of cochlear implants when auditory nerve fibres were re-grown towards the implant electrode array. This is done by delivering small molecules (neurotrophic factors) that enhance the growth and survival potential of neurons to targeted cells in the hearing organ (the cochlea). This is known as a gene therapy and the way in which the molecules are delivered to the cells is new. This first-time in humans study will investigate whether the benefits to hearing that were seen in the pre-clinical studies is also seen in people who obtain a cochlear implant.

These small molecules (neurotrophic factors) occur naturally in the cochlea and support the auditory (hearing) nerve fibres. However, in patients with hearing loss who require a cochlear implant, these nerve fibres are normally shrunken and the natural supply of neurotrophins is reduced. Therefore we are aiming by delivering the neurotrophic factors into the cochlea during surgery, to encourage the nerve fibres to regrow close to the cochlear implant electrodes, potentially making sound even clearer.

Thus, this clinical trial is seeking to evaluate the possible benefit of a new treatment that stimulates neurotrophin production in the cochlea. This is achieved by using a cochlear implant very similar to the type you would receive as a normal cochlear implant, only it has been modified to allow neurotrophins to be delivered into the cochlea via a process that has been established through extensive research out of the UNSW Sydney Translational Neuroscience Facility, directed by the clinical trial lead chief investigator Professor Gary Housley, in collaboration with scientists, engineers and clinicians from several other Institutions, including the Graduate School of Biomedical Engineering at UNSW Sydney, Cochlear Ltd, the Bionics Institute in Melbourne, The University of Sydney, NextSense, and the Macquarie University Hearing Hub.

In this clinical trial for ‘cochlear implant neurotrophin gene therapy’ the surgeries will be performed at the Royal Prince Alfred Hospital by the clinical trial principal clinical investigator, Associate Professor Catherine Birman. Dr. Birman will proceed with a routine cochlear implant procedure using the latest model of cochlear implant from Cochlear Ltd (model CI622). Patients who are members of the study “Reference Group” will have a routine cochlear implant surgery, and contribute to the study by agreeing to undergo a series of in-depth assessments of hearing performance and well-being that will be identical to the clinical assessments of the “Gene Therapy Group”.

Why is this project being done?

The CINGT clinical trial, which is supported by multiple research institutions, will provide insights into the potential benefits of this new molecule delivery system. This is very important as it is the only way to investigate the quality of hearing that is provided when this gene therapy is included in the cochlear implant surgery.

What is the process?

- Fifteen cochlear implant recipients will receive a normal cochlear implant system (the Control Group). This group allows us to establish what happens in patients receiving the cochlear implant alone without the additional gene therapy treatment in order to compare with the other group.
- Fifteen cochlear implant recipients will receive the neurotrophin gene therapy treatment during their implant surgery (Gene Therapy Group). This is an investigational treatment for people with hearing loss, which means that it is not an approved procedure in Australia and must be tested to see if it is an effective treatment.
Both groups will receive their cochlear implant at the Royal Prince Alfred Hospital. The study will follow cochlear implant function and improvements in hearing for a year at both NextSense sites and at Macquarie University’s Australian Hearing Hub.  
The Gene Therapy Group comprises subjects who receive the neurotrophin gene. Here Dr. Birman will undertake the routine cochlear implant surgery under general anaesthesia as normal, but just before inserting the CI622 electrode array, Dr. Birman will insert a cochlear implant ‘gene delivery array’ into the cochlea and the equivalent of one drop of DNA solution will be delivered and then a few brief electrical pulses lasting less than a second will be passed between the electrodes to drive the DNA into the target cells.  The gene delivery array will then be withdrawn and discarded and the cochlear implant procedure will then proceed as normal, with insertion of the permanent cochlear implant array.
We anticipate that in the Gene Therapy Group, the neurotrophins will promote the controlled growth of the auditory nerve fibres towards the implant array within a few weeks and this may be detectable from the functional measurements of cochlear implant performance. 
Previous animal studies indicates that the production of the neurotrophins arising from the gene electrotransfer will cease within a few weeks.  It is possible that an improvement in hearing arising from the regrowth of the cochlear nerve fibres will be sustained by use of the cochlear implant, but it is also possible that any change in auditory nerve fibre properties will normalize with this loss of “neurotrophin gene expression” by the targeted cells.  It is highly unlikely that hearing performance with the cochlear implant following the neurotrophin gene would be poorer than if the gene therapy was not used, but the transient nature of the expression of the neurotrophins means that if there were any concerns that the treatment was causing unforeseen impacts on hearing or health in general, then this would normalize if there was a pause in using the cochlear implant device.

What does participation in this study involve?

Participation involves 11 visits over a 52-week period currently at three sites - NextSense, Royal Prince Alfred Hospital, and the Australian Hearing Hub at Macquarie University. Additional sites include NextSense Newcastle and NextSense Wollongong.
The 11 visits are identical for both groups (reference and gene therapy groups) and they span over one year after your cochlear implant surgery, details of each visit is as follows:
Visit #1:
Recruitment (prior to visit 1) the participant information sheet and consent form (PISCF) will be given to take home, read, and discuss with their family, friends and health care professional.
At visit 1, the research team will go through the entire form to explain the benefits and risks, and answer any questions you or your family may have. After careful consideration, if you chose to voluntarily accept to take part; a consent form will be signed by you and the Principle Investigator.
Visit #2:
Your cochlear implant device CI622 will be surgically implanted by Professor Catherine Birman at the Royal Prince Alfred Hospital.  Before your surgery, the research team will also give you the supplementary information which is routinely provided to all patients undergoing cochlear implant, detailed in the documents ‘Cochlear Implantation Risk Fact Sheet’ and ‘Consent – Cochlear Implant and implant testing’.
Visit #3:
Your cochlear implant will be ‘switched on’ around one week after receiving your cochlear implant. Your health care professionals at NextSense will spend time programming (i.e. ‘mapping’) your cochlear implant at this visit and all following visits (4 to 11) to monitor and maximise the sound quality.
Visit #4:
Cochlear implant mapping to monitor and maximise sound quality (2 weeks after surgery)
Visit #5:
Cochlear implant mapping to monitor and maximise sound quality (3 weeks after surgery)
Visit #6:
Cochlear implant mapping to monitor and maximise sound quality (4 weeks after surgery)
Visit #7:
Cochlear implant mapping to monitor and maximise sound quality (6 weeks after surgery)
Visit #8:
Cochlear implant mapping to monitor and maximise sound quality (12 weeks after surgery)
Visit #9:
Cochlear implant mapping to monitor and maximise sound quality (26 weeks after surgery)
Visit #10:
Cochlear implant mapping to monitor and maximise sound quality (38 weeks after surgery)
Visit #11:
The end of the Study. You will be referred back to your health care professional at NextSense, who will provide you with ongoing management and care of your cochlear implant. (52 weeks after surgery)

What are we hoping to gain from this trial?

It is possible that the gene therapy treatment could improve hearing and speech outcomes. This would then stimulate further development of cochlear implants where the tonal qualities of sound, critical to appreciating music, or communicating in tonal languages such as Mandarin, Cantonese and Thai, can be improved.  This may help enrich the quality of life for many people with profound hearing loss and pave the way for other potential gene therapy treatments of hearing disorders.The contribution to understanding how repair of the hearing organ alongside the cochlear implant can improve hearing is a major legacy of participation in the CINGT clinical trial programme.

Who Are We Looking For?

We are seeking volunteers for a twelve month clinical trial that will investigate the possibility of improving the quality of hearing achieved using cochlear implants. This will be done by providing a treatment during the surgery that stimulates the auditory nerve fibres in the cochlea to regrow towards the cochlear implant electrodes. The study has two treatment groups to compare between:

1. Group 1 is the Control Group who provides very important baseline data

2. Group 2 which is the the Gene Therapy Group.

More information about patient participation in these two groups is provided following the background information.

Clinical Trial Registration and Ethics Committee Approvals

The trial is registered on the Australia New Zealand Clinical Trials Registry (ANZCTR) (link) with UNSW Sydney as the Host Institution (ACTRN12618001556235). The trial is registered through the Australian Therapeutic Goods Administration as combination Medical Device and Drug trial; The neurotrophin gene therapy will be provided as part of the cochlear implant surgical procedure performed at the Royal Prince Alfred Hospital in Camperdown, Sydney. The lead Ethics Committee overseeing the full duration of the trial is the Royal Prince Alfred Hospital (RPAH) Human Research Ethics Committee (HREC)- through the Clinical Trial Subcommittee. Following the surgical procedure, patients will attend NextSense and the Macquarie University Hearing Hub for their hearing assessments. The studies include approvals from the UNSW Sydney and Macquarie University HRECs.