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Trial registered on ANZCTR


Registration number
ACTRN12618001556235
Ethics application status
Approved
Date submitted
8/06/2018
Date registered
17/09/2018
Date last updated
17/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase I/II non-randomized, controlled trial, evaluating the safety and efficacy of neurotrophin gene therapy delivered during cochlear implant surgery
Scientific title
Cochlear implant-driven neurotrophin gene electrotransfer clinical trial to enhance the bionic ear
Secondary ID [1] 295150 0
Therapeutic Goods Administration, Clinical Trial Notification reference no. CT-2018-CTN-01136-1
Universal Trial Number (UTN)
U1111-1215-4685
Trial acronym
CINGT
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
hearing loss 308248 0
deafness 309291 0
Condition category
Condition code
Ear 307271 307271 0 0
Deafness

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This Trial Involves the use of a Medical Device, is comparator controlled, and involves gene therapy. It is a multicentre trial. The gene therapy is based on delivery of naked DNA encoding neurotrophins (Brain-derived neurotrophic factor and Neurotrophin-3) which promote regrowth of the auditory nerve. The DNA is transferred to target cells in the cochlea during the cochlear implant procedure using electrotransfer via a modified cochlear implant electrode array. This delivery device is a single use device. Following the delivery of the DNA the surgical procedure of the cochlear implant continues as per routine practice. This is a phase I/II trial where 15 cochlear implant recipients receive the neurotrophin gene therapy and in addition 15 subjects are a comparator group who receive the identical cochlear implant device but no gene therapy. The read out is a series of audiometric studies over 12 months.

A typical cochlear implant surgical procedure is approximately 2 hours and the gene therapy protocol will increase this by approximately fifteen minutes. The surgeon performing the cochlear implant surgery will delivery the DNA therapy, aided by technical assistance remote from the patient.
Intervention code [1] 301485 0
Treatment: Other
Intervention code [2] 301486 0
Treatment: Devices
Comparator / control treatment
This is a phase I/II trial where 15 cochlear implant recipients receive the neurotrophin gene therapy and in addition 15 subjects are a comparator group who receive the identical cochlear implant device but no gene therapy. The read out is a series of audiometric studies over 12 months.

The comparator cochlear implant group are undergoing usual care, with additional assessments: The cochlear implant surgery is performed by the regular surgeon as per normal; the additional assessments of hearing function will be performed by audiologists; blood tests will be undertaken using standard Pathology Lab services.
Control group
Active

Outcomes
Primary outcome [1] 306227 0
Primary outcome:
Safety (composite)
- Number of patients reported with total adverse events (AE) - any untoward medical occurrence in a participant enrolled into this study regardless of its causal relationship to study treatment.,
- Number of serious adverse events - A serious adverse event (SAE) is defined as a AE that: Results in death, is immediately life threatening, requires inpatient hospitalisation, requires prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital abnormality or birth defect

Adverse events and serious adverse events are being assessed by medical records and patient reporting.
Timepoint [1] 306227 0
Iterative studies out to 12 months: -1, 0, 1, 2, 3, 4, 6, 12, 26, 38, 52 weeks
Secondary outcome [1] 347918 0
Pure tone audiometry (PTA) is a psychometric assessment of hearing sensitivity. This is used in the initial patient screening for recruitment as a criteria for admission into the trial. The hearing loss as measured by PTA hearing loss (HL) threshold, is required to be of greater or equal than 70 dB HL for each testable octave frequency from 250Hz through to 4 kHz.

Timepoint [1] 347918 0
Iterative studies out to 12 months: -1, 0, 1, 2, 3, 4, 6, 12, 26, 38, 52 weeks
Secondary outcome [2] 350790 0
CNC word recognition test
Timepoint [2] 350790 0
Iterative studies out to 12 months: -1, 0, 1, 2, 3, 4, 6, 12, 26, 38, 52 weeks
Secondary outcome [3] 350791 0
The AUSTIN Sentence test (SRT) is evaluating the speech reception threshold, determined as 50% correct sentences, using noise as a masker. This speech outcome measure, in conjunction with CNC and CUNY sentence test, provide a comprehensive assessment of speech perception.

Timepoint [3] 350791 0
Iterative studies out to 12 months: -1, 0, 1, 2, 3, 4, 6, 12, 26, 38, 52 weeks
Secondary outcome [4] 350792 0
Speech understanding, spatial perception and the clarity and quality of sounds (composite), measured by the Speech Spatial and Qualities Questionnaire (SSQ)
Timepoint [4] 350792 0
Iterative studies out to 12 months: -1, 0, 1, 2, 3, 4, 6, 12, 26, 38, 52 weeks
Secondary outcome [5] 350793 0
Cochlear nerve function (neural response telemetry)
Timepoint [5] 350793 0
Iterative studies out to 12 months: -1, 0, 1, 2, 3, 4, 6, 12, 26, 38, 52 weeks
Secondary outcome [6] 350794 0
Auditory brainstem response (eABR)
Timepoint [6] 350794 0
Iterative studies out to 12 months: -1, 0, 1, 2, 3, 4, 6, 12, 26, 38, 52 weeks

Eligibility
Key inclusion criteria
1. Informed consent is obtained before any trial-related activities are performed (trial-related activities are any procedure/s that would not have been performed during the normal management of the subject)
2. Male or female, aged 21 to 85 years old, inclusive.
3. Mobile, able, and willing to participate in the study.
4. Subjects with severe to profound bilateral hearing loss. Pure tone audiometric thresholds of greater than or equal to 70 dB HL for each testable octave frequency from 250Hz through to 4kHz and sentence recognition scores less than or equal to 50%. Subject responses will be monitored for vibrotactile sensation, particularly for the low-frequency stimuli (e.g., 125 and 250 Hz). A frequency that elicits vibrotactile responses at levels below 70 dB HL will be considered "not testable" for hearing threshold and only those frequencies that are testable for hearing threshold will be considered for patient inclusion/exclusion in the study.
5. Able to communicate well with the investigator, to understand and comply with the requirements of the study
6. Meet surgical requirements/eligibility
7. Subjects must weigh at least 40 kg to participate in the study, and must have a body mass index (BMI) of less than 45 kg/m2. BMI = Body weight (kg) / [Height (m)]2
Minimum age
21 Years
Maximum age
85 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients conditions involving cochlea abnormalities that would prevent the insertion of an array or cause excessive perilymph flow during surgery, as judged by the Principal Investigator (e.g. cochlea aplasia, and bone formation within the cochlea)
2. Patients with indication of tympanic membrane or middle ear abnormalities as judged by the Principal Investigator following a thorough review of all of the trial hearing assessments.
3. Patients with an existing cochlear implant or past cochlear implant in the candidate study ear
4. Patients with serious concomitant conditions (such as a history of a serious cardiac event, renal impairment, hepatic impairment, major surgery etc.)
5. Patients with pacemakers and defibrillators
6. Patients with concomitant malignant or pre-malignant conditions
7. Patients with a condition predisposing to, or with a history of, or experiencing neural line tumours
8. Hearing loss due to any other cause that would not be expected to respond to cochlear implantation, for example central auditory lesions or lack of an auditory nerve
9. Patients who will require ototoxic drugs as routine therapy over the course of the study, such as oncology patients on platinum-based chemotherapy
10. Vestibular disequilibrium which in the opinion of the investigator would be incompatible with planned vestibular assessments.
11. Any contraindication to the planned surgery or anaesthesia as determined by the surgeon or anaesthetist
12. Previous surgery or otologic history in the study ear, as judged by the investigator that would affect the surgical implantation of the cochlear implant
13. Mental incapacity, unwillingness or language barrier precluding adequate understanding of the trial procedure or cooperation with the trial site personnel, as judged by the investigator that may affect their ability to take part in the trial.
14. Females of childbearing potential who are pregnant, breast-feeding, or intend on becoming pregnant
15. Involvement in any other clinical trial within 30 days prior to this trial.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a first-in-human study and as such, there are no prior studies indicating the variance in objective outcomes: neural response telemetry thresholds and growth functions, and electrically-evoked auditory brainstem response (eABR) thresholds and growth functions with the treatment (Bionic array directed gene electrotransfer of neurotrophin -encoding naked DNAs). The primary outcome of the study is safety, rather than efficacy (improvement in hearing); but the secondary outcomes are focused on assessing hearing function, to gain data on variance, that will enable future clinical trials to be powered appropriately so that a determination can be made of whether the hearing of the cochlear implant recipients with the gene therapy treatment is equivalent, better or worse than that of the reference group receiving a cochlear implant device without the neurotrophin gene augmentation treatment. The selection of 15 patients for each of the gene therapy and reference groups was adopted based on data from associated pre-clinical studies modelling the human cochlear neurotrophin gene augmentation treatment. This was the Pinyon et al. Science Translational Medicine 6, 233ra54 (2014) (DOI: 10.1126/scitranslmed.3008177) publication, where eABR measurements demonstrated significant increase in sensitivity to electrical stimulation-driven hearing with groups of 5 guinea-pigs each for the neurotrophin and control DNA delivery. Given the intrinsically greater variation in hearing with cochlear implants in humans compared with the former acutely chemically-deafened guinea-pig model, the treatment groups were tripled in size to 15 subjects per group. Repeated measures Analysis of Variance will be used to test for differences in electrophysiological responses to electrically-evoked stimulation of the cochlear nerve via the implanted cochlear implants.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 11113 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 22926 0
2050 - Camperdown

Funding & Sponsors
Funding source category [1] 299737 0
Government body
Name [1] 299737 0
National Health and Medical Research Council
Address [1] 299737 0
GHD Building Level 1, 16 Marcus Clarke St, Canberra, ACT, 2601
Country [1] 299737 0
Australia
Funding source category [2] 299740 0
Charities/Societies/Foundations
Name [2] 299740 0
Garnett Passe and Rodney Williams Memorial Foundation
Address [2] 299740 0
372-376 Albert St, East Melbourne, VIC 3002
Country [2] 299740 0
Australia
Funding source category [3] 299741 0
Commercial sector/Industry
Name [3] 299741 0
Cochlear Ltd
Address [3] 299741 0
Macquarie University, 1 University Ave, Macquarie Park NSW 2109
Country [3] 299741 0
Australia
Primary sponsor type
University
Name
UNSW Sydney
Address
UNSW Sydney, Kensington, NSW 2052
Country
Australia
Secondary sponsor category [1] 299076 0
None
Name [1] 299076 0
Address [1] 299076 0
Country [1] 299076 0
Other collaborator category [1] 280167 0
University
Name [1] 280167 0
Macquarie University
Address [1] 280167 0
Macquarie University, North Ryde NSW 2109
Country [1] 280167 0
Australia
Other collaborator category [2] 280168 0
University
Name [2] 280168 0
University of Sydney
Address [2] 280168 0
The University of Sydney NSW 2006
Country [2] 280168 0
Australia
Other collaborator category [3] 280169 0
University
Name [3] 280169 0
Bionics Institute (University of Melbourne)
Address [3] 280169 0
384-388 Albert St, East Melbourne VIC 3002
Country [3] 280169 0
Australia
Other collaborator category [4] 280170 0
Commercial sector/Industry
Name [4] 280170 0
Cochlear Ltd
Address [4] 280170 0
Macquarie University, 1 University Ave, Macquarie Park NSW 2109
Country [4] 280170 0
Australia
Other collaborator category [5] 280171 0
University
Name [5] 280171 0
Descartes University
Address [5] 280171 0
4 Avenue de l'Observatoire, 75006 Paris
Country [5] 280171 0
France
Other collaborator category [6] 280172 0
University
Name [6] 280172 0
University College London
Address [6] 280172 0
330 Grays Inn Rd, Kings Cross, London WC1X 8DA
Country [6] 280172 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300627 0
Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 300627 0
Research Ethics and Governance Office
Royal Prince Alfred Hospital
Camperdown, NSW, 2050
Ethics committee country [1] 300627 0
Australia
Date submitted for ethics approval [1] 300627 0
23/10/2017
Approval date [1] 300627 0
09/03/2018
Ethics approval number [1] 300627 0
X17-0378 & HREC/17/RPAH/575
Ethics committee name [2] 300631 0
Macquarie University Human Research Ethics Committee
Ethics committee address [2] 300631 0
Macquarie University NSW 2109
Ethics committee country [2] 300631 0
Australia
Date submitted for ethics approval [2] 300631 0
10/04/2018
Approval date [2] 300631 0
26/04/2018
Ethics approval number [2] 300631 0
5201800321
Ethics committee name [3] 300632 0
University of New South Wales Human Research Ethics Committee
Ethics committee address [3] 300632 0
UNSW Sydney, Kensington NSW 2052
Ethics committee country [3] 300632 0
Australia
Date submitted for ethics approval [3] 300632 0
19/03/2018
Approval date [3] 300632 0
18/05/2018
Ethics approval number [3] 300632 0
HREC/17/RPAH/575

Summary
Brief summary
The purpose of this unblinded, non-randomized, phase I/II trial in patients who require a cochlear implant, is to evaluate the safety and efficacy of localised cochlear neurotrophin gene therapy, by comparing patients receiving a cochlear implant (control group) and patients receiving the gene therapy in conjunction with the cochlear implant (treatment group). The study of the control and treatment groups will not be conducted in parallel because of the logistics around the audiometric assessment of the subjects, which requires extension of the study across a two-year time frame. The first stage of this trial will be carried out with the control group and the second stage of the trial, which is likely to commence in 2018, will be conducted with the neurotrophin gene therapy treatment group. All subject measures will be identical for both groups, as well as all trial procedures, apart from the treatment and surgical procedures surrounding the delivery of the neurotrophin-encoding DNA to the cochlea, which is an amendment to the normal cochlear implant surgery protocol.

For the treatment group, at surgery, prior to insertion of the cochlear implant electrode array into the patient’s cochlea, a cochlear gene delivery electrode array is inserted, naked DNA is injected and then a brief train of electrical pulses lasting less than one second is used to deliver the DNA locally to the cells closest to the electrodes. DNA dispersed through the cochlear tissue, but outside this local electric field, is not taken up by cells and degrades. This somatic cell gene electrotransfer process adds about fifteen minutes to the surgery time. The cochlear gene delivery electrode array is withdrawn after the DNA delivery (BaDGE process) and the cochlear implant itself is then implanted as normal.
Participants will be enrolled in the trial for a total of 52 weeks. Data will be collected in the form of completed case record forms, blood tests, questionnaires and adverse events, alongside audiological measurements. Subjects will be followed up at multiple centres for the duration of the trial. They will be recruited from the Sydney Cochlear Implant Centre, cochlear implant surgery will take place at the Royal Prince Alfred Hospital (Sydney), and follow-up visits will take place at both the Australian Hearing Hub (Macquarie University) and the Sydney Cochlear Implant Centre
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84266 0
Prof Gary Housley
Address 84266 0
Translational Neuroscience Facility
School of Medical Sciences
Level 3 Room 3SW, Wallace Wurth Building
UNSW SYDNEY NSW 2052 AUSTRALIA
Country 84266 0
Australia
Phone 84266 0
+61293851057
Fax 84266 0
Email 84266 0
g.housley@unsw.edu.au
Contact person for public queries
Name 84267 0
Prof Gary Housley
Address 84267 0
Translational Neuroscience Facility
School of Medical Sciences
Level 3 Room 3SW, Wallace Wurth Building
UNSW SYDNEY NSW 2052 AUSTRALIA
Country 84267 0
Australia
Phone 84267 0
+61293851057
Fax 84267 0
Email 84267 0
g.housley@unsw.edu.au
Contact person for scientific queries
Name 84268 0
Prof Gary Housley
Address 84268 0
Translational Neuroscience Facility
School of Medical Sciences
Level 3 Room 3SW, Wallace Wurth Building
UNSW SYDNEY NSW 2052 AUSTRALIA
Country 84268 0
Australia
Phone 84268 0
+61293851057
Fax 84268 0
Email 84268 0
g.housley@unsw.edu.au

No information has been provided regarding IPD availability
Summary results
No Results