Association Between Intra-Operative Cochlear Response Telemetry and Hearing Preservation
Conditions: Hearing Impairment, Sensorineural
Sponsor: Cochlear

 
 
 
 
 
Clinical Investigation Plan 
 
Investigation Title:  Association Between Intra-Operative Cochlear 
Response Telemetry and Hearing Preservation (CREST) 
 
Investigation Number: CLTD 5667 
 
Document Number:  D1041816 
 
Version Number: 3.0 
 
Date: 23 August, 2017 
 
Authors: Kerrie Plant & Pam Dawson 
 
 
 

 
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QMS Document No.:  
D1041816 
Association Between Intra-Operative Cochlear Response Telemetry and 
Hearing Preservation:  Clinical Investigation Plan 
Version: 3.0 
 
 
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Document Type: Clinical Investigation Plan 
Manufacturer and Sponsor Information 
Manufacturer 
Cochlear Limited 
1 University Avenue 
Macquarie University 
NSW 2109 
Phone +61 2 9428 6555 
 
US Study Sponsor 
Cochlear Americas 
Dr Aaron Parkinson 
Principal Clinical Project Manager 
Centennial, CO 80111 USA 
Phone +1 303 264 2537 
 
European Study Sponsor 
Cochlear Europe  
Dr Chris James 
Clinical Project Manager 
Cochlear France SAS 
135 Rte de St Simon 
Toulouse 31100 France   
Phone +33 53 463 8584 
 
Australian Study Sponsor 
Cochlear Limited 
Dr Kerrie Plant 
Clinical Studies Manager 
Level 1, 174 Victoria Parade 
East Melbourne VIC 3002 
Phone +61 3 8662 3103 
 
A complete list of participating Principal Investigators names, titles, and addresses, and the names 
and addresses of participating institutions (sites) will be maintained by the Sponsor and will be 
distributed as a separate Principal Investigator List (PIL) document.   

 
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Association Between Intra-Operative Cochlear Response Telemetry and 
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Document Type: Clinical Investigation Plan 
1 SPONSOR AND COORDINATING INVESTIGATOR SIGNED 
AGREEMENT 
 
Investigation Title 
Association Between Intra-Operative Cochlear Response Telemetry 
and Hearing Preservation (CREST) 
Investigation Number 
CLTD 5667 
 
Signature on behalf of Sponsor 
I agree with the content in this clinical investigation plan, including all appendices. 
Name 
Title 
 
 
 
Signature 
Date 
(dd-mmm-yyyy) 
 
 
 
Signature of Principal Investigator 
I agree to the content of this clinical investigation plan, including all appendices. 
Name 
Title 
 
 
 
Signature 
Date 
(dd-mmm-yyyy) 
 
 
 
 
 

 
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Association Between Intra-Operative Cochlear Response Telemetry and 
Hearing Preservation:  Clinical Investigation Plan 
Version: 3.0 
 
 
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Document Type: Clinical Investigation Plan 
Table of Contents 
1 
Sponsor and Coordinating Investigator Signed Agreement ............................................................ 3 
2 
Synopsis .......................................................................................................................................... 7 
3 
Identification and description of the investigational device ........................................................... 11 
4 
Justification for the design of the clinical investigation .................................................................. 13 
5 
Risks and benefits of the investigational device and clinical investigation ................................... 15 
5.1 
Anticipated Clinical Benefits ................................................................................................ 15 
5.2 
Anticipated Adverse Device Effects .................................................................................... 15 
5.3 
Residual risks related to the use of the investigational device ........................................... 15 
5.4 
Risks associated with participation in the clinical investigation .......................................... 15 
5.5 
Possible interactions with concomitant medical treatments ................................................ 15 
5.6 
Risk mitigations ................................................................................................................... 15 
5.7 
Risk to benefit rationale ....................................................................................................... 16 
6 
Objectives and Hypotheses ........................................................................................................... 17 
6.1 
Primary Objective ................................................................................................................ 17 
6.2 
Secondary Objectives ......................................................................................................... 17 
6.3 
Primary Hypotheses ............................................................................................................ 17 
6.4 
Secondary Hypotheses ....................................................................................................... 17 
7 
Design of the Clinical Investigation ............................................................................................... 18 
7.1 
General ................................................................................................................................ 18 
7.1.1 
Design and Randomisation ................................................................................... 18 
7.1.2 
Primary Endpoint ................................................................................................... 18 
7.1.3 
Secondary Endpoints ............................................................................................ 18 
7.1.4 
Exploratory Analyses............................................................................................. 18 
7.2 
Methods............................................................................................................................... 19 
7.3 
Procedures .......................................................................................................................... 20 
7.3.1 
Audiometric Thresholds and Tympanometry ........................................................ 20 
7.3.2 
Surgical Preparation .............................................................................................. 20 
7.3.3 
Surgery .................................................................................................................. 20 
7.3.4 
Intra-Operative Cochlear Response Telemetry Recording and Surgical Video.... 20 
7.3.5 
Electrode Impedance Measures ........................................................................... 21 
7.3.6 
Imaging .................................................................................................................. 21 
7.3.7 
Surgical Questionnaire .......................................................................................... 22 
7.3.8 
Post-Operative Cochlear Response Telemetry Recording ................................... 22 

 
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7.4 
Investigational device and comparator ............................................................................... 22 
7.5 
Subjects............................................................................................................................... 22 
7.5.1 
Inclusion Criteria .................................................................................................... 22 
7.5.2 
Exclusion Criteria .................................................................................................. 22 
7.6 
Monitoring Plan ................................................................................................................... 23 
8 
Statistical Considerations .............................................................................................................. 23 
9 
Data Management ......................................................................................................................... 25 
10 Amendments to the CIP ................................................................................................................ 25 
11 Deviations from the CIP ................................................................................................................ 25 
12 Device accountability ..................................................................................................................... 25 
13 Statements of compliance ............................................................................................................. 26 
13.1 Declaration of Helsinki and compliance with standards ...................................................... 26 
13.2 Ethics Committee and Regulatory Agency Approval .......................................................... 26 
14 Informed consent process ............................................................................................................. 26 
14.1 Obtaining informed consent ................................................................................................ 26 
14.2 Data Privacy ........................................................................................................................ 27 
15 Reporting process for adverse events, adverse device effects and device deficiencies .............. 27 
15.1 Definitions............................................................................................................................ 27 
15.1.1 
Adverse event (AE) ............................................................................................... 27 
15.1.2 
Adverse device effect (ADE) ................................................................................. 27 
15.1.3 
Device deficiency (DD).......................................................................................... 28 
15.1.4 
Serious adverse event (SAE) ................................................................................ 28 
15.1.5 
Serious adverse device effect (SADE) .................................................................. 28 
15.1.6 
Unanticipated serious adverse device effect (USADE) ........................................ 28 
15.2 Reporting process for adverse events, adverse device effects and device deficiencies .... 28 
15.3 Data Monitoring Committee ................................................................................................ 29 
15.4 Device Deficiency Reporting Requirements ....................................................................... 29 
16 Incident reporting ........................................................................................................................... 29 
17 Vulnerable population .................................................................................................................... 29 
18 Suspension or premature termination ........................................................................................... 29 
19 Publication Policy .......................................................................................................................... 30 
20 References .................................................................................................................................... 31 
20.1 Internal References ............................................................................................................. 31 
20.2 External References ............................................................................................................ 31 

 
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20.3 Referenced Literature ......................................................................................................... 31 
21 Change History .............................................................................................................................. 33 
22 Definitions ...................................................................................................................................... 34 
22.1 Definitions from ISO 14155:2011 ........................................................................................ 34 
22.2 Other definitions .................................................................................................................. 35 
23 Appendix A:  Instructions for Masking ........................................................................................... 36 

 
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Association Between Intra-Operative Cochlear Response Telemetry and 
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Document Type: Clinical Investigation Plan 
2 SYNOPSIS 
Investigation title 
Association between Intra-Operative Cochlear Response 
Telemetry and Hearing Preservation (CREST) 
Investigation number 
CLTD 5667 
Name of investigational 
device 
Cochlear Response Telemetry (CRT):  a system comprising both 
hardware and software for monitoring the electrophysiological 
cochlear response to acoustic clicks or short tone bursts. The 
CRT system is not approved by regulatory agencies. 
Investigation start  
March 2017 
Total expected duration of 
the clinical investigation 
17 months 
Enrolment period 
12 months 
Expected duration per 
subject 
5 months 
Investigational design 
Prospective, multi-center, observational (non-randomized) 
investigation consisting of a pre-operative visit and treatment 
visits at the time of implantation (Day 0), at 4-6 weeks post-
surgery follow-up visit (FUV1) and at 3 months post-activation 
follow-up visit (FUV2).   Subjects will be allocated into two groups 
according to their residual hearing at FUV1. 
Visit Schedule: 
Pre-Operative Visit      POV1 (up to 90 days before D0) 
Intra-Operative Visit    D0 
Follow-Up Visit 1         FUV1 (4-6 weeks post-surgery +/- 1 week)   
Follow-Up Visit 2         FUV2 (3M post-activation +/- 2 weeks) 
Number of subjects 
Globally:  Minimum 86 (Up to 125 depending on monitoring of 
accruing data affecting proportion of subjects allocated to each 
group)  
US:  Up to 50;  
Europe:  Up to 40;  
Australia:  Up to 35. 
 
 

 
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Document Type: Clinical Investigation Plan 
Inclusion criteria 
• 
Candidate for cochlear implantation (with CI522, CI532 or 
Hybrid-L24 according to local indications 
• 
18 years of age or older at the time of enrolment 
• 
Pre-operative audiometric threshold in the implanted ear 
at 500 Hz of better than or equal to 80 dB HL 
• 
Willingness to participate in and to comply with all 
requirements of the protocol 
Exclusion criteria 
• 
Prior cochlear implantation in the ear to be implanted 
• 
Ossification or any other cochlear anomaly that might 
prevent complete insertion of the electrode array 
• 
Abnormal cochlear/nerve anatomy on pre-operative CT or 
MRI imaging (excluding a mild Mondini malformation or 
Large Vestibular Aqueduct Syndrome) 
• 
Deafness due to lesions of the acoustic nerve or central 
auditory pathway 
• 
Diagnosis of auditory neuropathy 
• 
Active middle-ear infection 
• 
Additional handicaps that would prevent participation in 
evaluations 
• 
Unrealistic expectations on the part of the subject, 
regarding the possible benefits, risks and limitations that 
are inherent to the procedure and investigational device 
Primary objective 
To examine whether compromised cochlear microphonic (CM) 
response during cochlear implant surgery results in poorer 
acoustic hearing preservation at FUV1 compared to preserved 
CM. 
Secondary objectives 
1. To examine whether compromised cochlear microphonic 
(CM) response during cochlear implant surgery results in 
poorer acoustic hearing preservation at FUV2 compared 
to preserved CM. 
2. To investigate whether pre-operative acoustic hearing 
influences the onset of the CM response during insertion 
of the electrode array. 
Primary endpoint 
Deterioration in average low frequency post-operative hearing 
threshold levels (HTLs) at FUV1 in the implanted ear for subjects 
with compromised CM compared to subjects with preserved CM 
during surgery 
Secondary endpoints 
1. Deterioration in average low frequency post-operative 
HTLs at FUV2 in the implanted ear for subjects with 
compromised CM compared to subjects with preserved 
CM during surgery 
2. Association of pre-operative high frequency HTLs with 
onset of CM response during electrode array insertion  

 
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Document Type: Clinical Investigation Plan 
Exploratory analyses 
Additional exploratory analyses may be performed.  These may 
include: 
• 
Comparison of the primary endpoint for three groups 
defined by compromised, preserved, and transient CM 
• 
Predictors of the incidence of compromised CM during 
surgery including influence of electrode type, insertion 
depth and surgical events 
• 
Association of pre-operative high frequency HTLs with 
change in latency of CM during electrode array insertion 
• 
Investigation of the influence of demographic and surgical 
factors on the morphology and time-course of the CM 
response during insertion and post-operatively 
• 
Investigation of the relationship of CM thresholds to 
postoperative HTLs in the implanted ear 
• 
Examination of the degree of reduction in CM amplitude 
that occurs in response to a range of surgical events 
• 
Characterization of changes in electrode impedances as 
a function of CRT observations during and post-surgery 
• 
Characterization of changes in different components of 
the electrocochleography (ECoG) responses over time  
• 
Examination of whether the ratio of the CM amplitude 
over the ANN amplitude (uVrms) is correlated with lower 
(better) HTLs (FUV2) at 250Hz, 500Hz and 1kHz 
• 
Examination of hearing preservation for compromised CM 
and preserved CM groups which have been classified 
using different criteria of CM amplitude reduction and time 
course 
 

 
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Investigation Schedule 
Procedure 
POV1 
Pre-operative 
D0 
Surgery 
FUV1 
4-6 Weeks Post-Surgery 
(+/- 1 week) 
FUV2 
3-Month Post-Activation 
(+/- 2 weeks) 
Medical and Hearing History 
X 
 
 
 
Otoscopy (Check for Wax Occlusion) 
X 
X 
X 
X 
Cochlear Response Telemetry (CRT) 
 
X 
X (either FUV1 or FUV2) 
Audiometry  & Tympanometry 
X 
 
X 
X 
Surgical Questionnaire 
 
X 
 
 
Impedance Measures  
(Standard, 4-point, Voltogram) 
 
X 
X (either FUV1 or FUV2) 
Optional (where obtained at sites as 
part of routine clinical management): 
Imaging (MRI Pre-Operative; X-Ray or 
Cone Beam CT Post-Operative) 
X 
X 
 

 
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3 IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL 
DEVICE 
Cochlear Response Telemetry (CRT) is a system comprising both hardware and software for 
monitoring the electrophysiological cochlear response (via electric potentials generated within the 
cochlea and auditory nerve) to acoustic clicks or short tone bursts.  There are three components to an 
acoustic electrocochleogram (ECoG).  The cochlear microphonic (CM) is a phase-following response 
that matches the acoustic stimulus and is generated predominately by outer hair cells. It is a 
transducer current in the stereocilia and follows the waveform of the acoustic stimulus.  The auditory 
nerve neurophonic (ANN) is a neural response and represents the correlate to neural phase-locking.   
Figure 1 illustrates the morphology and time course of the CAP (and SP) and the CM (upper and lower 
subplots respectively) in response to a 500 Hz acoustic input.  The CM, being frequency following (or 
phase-locked), can be observed to follow the input signal, i.e. in the lower panel below the peaks are 2 
ms apart.   
 
Figure 1. An example trace of an electrocochleogram measured in response to a 500 Hz 
stimulus.  In the upper panel (A) is shown the ANN.   In the lower panel (B) is shown the CM.   
The CRT system comprises the following components: 
• 
DT9847 or DT9837 USB powered Digital to analog converter 
• 
FiiO E12A Power amplifier 
• 
Dell Laptop 
• 
2 or 4 port bus powered USB 2.0 Hub 
• 
ER3C Insert earphone 
• 
CochlearTM Nucleus® Freedom® Programming Pod 

 
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         Association Between Intra-Operative Cochlear Response Telemetry  
and Hearing Preservation:  Clinical Investigation Plan 
Version: 2.0 
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• 
CochlearTM Nucleus® Freedom® Programming Shoe 
• 
CochlearTM Nucleus® Freedom® Programming Cable 
• 
CochlearTM Nucleus® Freedom® Processing Unit 
• 
CochlearTM Nucleus® Freedom® Coil Magnet 
• 
CochlearTM Nucleus® Freedom® N24 Coil 
• 
Cables (USB, BNC, Audio) 
Acoustic stimulation is achieved via a signal generator coupled to an insert Etymotic earphone 
(ER3C).  Triggering of the external acoustic generator is achieved by delivering a sync pulse from the 
programming pod such that the recordings from the implant are synchronized with the acoustic input.  
A block diagram of the CRT system is illustrated in Figure 2.   
 
Figure 2.  Functional diagram of the CRT measurement method.  The bi-directional RF link of 
the Nucleus® cochlear implant permits both stimulation and recording with the device 
(receiver-stimulator coil and electronic unit, reference electrodes ECE1/2 and electrode array) 
and the signal generator and insert earphone permit acoustic stimulation of the cochlea. 
The investigational CRT system will be used in the current clinical investigation in adults who meet the 
inclusion and exclusion criteria for enrolment.  The system will be used for acute measurement only 
during surgery and post-operative assessment.   

 
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Subjects will be implanted with commercially available CI522, CI532 or Hybrid-L24 (US only) cochlear 
implants.  Subjects will receive standard follow-up as for any patient implanted with the devices in 
addition to the study procedures.   
4 JUSTIFICATION FOR THE DESIGN OF THE CLINICAL 
INVESTIGATION 
Significant advancements in implantable device technology and refinements to surgical technique 
have led to progressive improvement in the ability to preserve acoustic hearing after implantation.  
However, although hearing preservation has been demonstrated with a range of devices (Adunka et 
al. 2004; Gantz and Turner 2004; Gstoettner et al. 2009; Fraysse et al. 2006; Gantz et al. 2009; 
Lesinski-Schiedat et al. 2011; Lenarz et al. 2013; Lenarz et al. 2009; Skarzynski et al. 2010; Roland et 
al. 2016), it is not yet possible to guarantee for an individual candidate that acoustic hearing will be 
preserved.  Although the cause of post-operative hearing loss is likely multifactorial, events that occur 
during surgery are likely to be of influence.  In order to understand the influence of such surgical 
factors, it is important to develop monitoring and diagnostic tools for use in the clinical setting, and to 
determine the specific intra-operative events that are associated with acoustic hearing loss.  
Furthermore, if reliable intra-operative tools were developed it may be possible to provide near real-
time feedback to the surgeon as to change in acoustic hearing status during electrode insertion, and 
for the surgeon to modify or refine the surgical technique to minimize risk to loss of acoustic hearing.  
The potential clinical applicability of use of acoustic ECoG measures during cochlear implantation has 
been investigated by a number of researchers, both with respect to predicting outcomes after 
implantation (Fitzpatrick et al. 2014; McClellan et al. 2014; Formeister et al. 2015) and in 
understanding the relationship between observed electrophysiological change in cochlear function 
with post-operative hearing preservation (Dalbert et al. 2015; Dalbert et al. 2016; Mandala et al. 2012; 
Adunka et al. 2016; Campbell et al. 2015).   
To facilitate ease of measurement of the ECoG responses, the University of Melbourne in 
collaboration with Cochlear Limited have developed a prototype software and hardware system 
(termed Cochlear Response Telemetry, CRT).  The system utilizes the in-built cochlear implant 
amplifier of the implant receiver-stimulator to record the evoked responses to acoustic stimuli from 
intra-cochlear electrodes.  Recent research at the University of Melbourne and Royal Victorian Eye 
and Ear Hospital Cochlear Implant Clinic (Campbell et al. 2016) has demonstrated 15dB better low 
frequency hearing preservation in patients with preserved CM responses during surgery than in those 
where the CM was shown to reduce in amplitude during the surgical procedure without recovery.  
Furthermore, the preliminary findings from that study suggest that the real-time monitoring of the CM 
might in the future inform optimal electrode placement and identify events in surgery that might be 
detrimental to ensuring acoustic hearing preservation. 
The present investigation primarily aims to confirm the Campbell et al. 2016 finding of better low 
frequency hearing preservation with preserved intra-operative CM responses in a much larger group of 
cochlear implant recipients across different centers. Hearing preservation will be investigated at 4-6 
weeks and 3 months post-implantation. Of primary interest will be the hearing preservation at 4-6 
weeks post-implantation, which is less likely to be impacted by factors other than potentially traumatic 
surgical events. In contrast to the Campbell et al. (2016) study, this study’s categorization of hearing 
preservation will not include 250 Hz. This acoustic frequency is less likely to be sensitive to the CM 
measurement, since the hair cell population for 250 Hz lies deeper than the typical electrode array 
insertion. In the present study, acoustic hearing deterioration will be measured across a range of 

 
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         Association Between Intra-Operative Cochlear Response Telemetry  
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Document Type: Clinical Investigation Plan 
frequencies below 1500Hz (500Hz, 750Hz and 1000 Hz), where acoustic hearing preservation for 
electroacoustic stimulation (EAS) is considered beneficial for spatial hearing and speech 
understanding (Gifford et al. 2013; Gifford et al. 2014). Specifically, deterioration will be calculated as 
the average change in threshold across the frequencies 500 Hz, 750 Hz and 1000 Hz where there is 
preoperative hearing better than or equal to 80 dB HL in the implanted ear at those frequencies. Prior 
research has suggested that audiometric thresholds greater than 80 dB HL are more likely to be 
impacted by the presence of detrimental factors such as cochlear dead regions (Baer et al. 2002; 
Zhang et al. 2014), and spectral distortion and/or broadening of auditory filters with the higher hearing 
aid output levels needed for audibility (Ching et al. 1988; Hornsby and Ricketts 2001). Unlike the 
Campbell et al. (2015) study, the present study will exclude in the definition of the preserved CM in 
those subjects with a transient reduction in CM amplitude.  This decision was made to enable more 
clearly the impact of change in cochlear microphonic on hearing preservation, without uncertainty 
relating to the impact of transient CM amplitude reduction.   
Furthermore, to inform Cochlear’s future technology and product development of intra-operative 
monitoring tools that utilize ECoG measures, it is of interest to examine the influence of pre-operative 
acoustic hearing status on the characteristics of the CM response during intra-cochlear insertion of the 
electrode array. Understanding further the factors that influence the characteristics of the CM 
response (e.g. onset and latency) might enable reference markers to be incorporated within future 
software monitoring tools as to expected behavior of the CM response for cochlear implant recipients 
with varying characteristics.  Additionally, it may be possible to provide reference data regarding 
expected responses for different electrode types.  The CRT system provides the capability to 
interleave measures of electrode impedance with the ECoG recordings, which is expected to provide 
an ability to track the progressive entry of electrodes into the cochlea during insertion (through 
observed reduction in impedance when electrodes are in contact with perilymph).  The combined use 
of such impedance measures and ECoG recordings will be used to characterize the CM response as a 
function of the number of electrode contacts inside the cochlea.  Earlier CM onset is expected with 
better high frequency acoustic hearing, since the electrode array initially advances through the basal 
region of the cochlea passing the outer hair cells that are responsive to the high frequencies. Although 
maximum hair cell response to the 500 Hz acoustic tone occurs in the apical region the cochlea, hair 
cell populations in the basal region will also respond to the travelling wave. Latency change will be 
measured between two CM onset points and is predicted to increase as the advancing electrode 
passes surviving inner and outer hair cells populations. If there is no measurable high frequency 
hearing, it is hypothesized that CM amplitude will increase without an increase in latency as the 
electrode advances towards the apex.   
Postoperative CRT sweeps will be conducted immediately following the wound closure (baseline) and 
at either 4-6 weeks post-surgery or at 3 months post-implantation. This will allow changes over time in 
different components of the ECoG to be characterized. The relationship between hearing threshold 
levels (HTLs) in the implanted ear and ECoG responses at FUV1 or FUV2 (e.g. CM and acoustic 
neurophonic response (ANN) thresholds) will also be examined. 
Findings from the study will likely inform future development of commercial technology for both intra 
and post-operative monitoring of the ECoG responses with cochlear implant recipients.   

 
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5 RISKS AND BENEFITS OF THE INVESTIGATIONAL DEVICE AND 
CLINICAL INVESTIGATION 
5.1 Anticipated Clinical Benefits 
There are no anticipated clinical benefits to individuals enrolled in the study, since the study does not 
involve any modification to surgical procedure or clinical management.  Although there are no direct 
benefits anticipated, the information obtained from the study will potentially be useful in improving 
understanding of the potential benefits of CRT, and in guiding future research directions and clinical 
application of the technology.   
5.2 Anticipated Adverse Device Effects  
There are no anticipated adverse device effects related to use of the investigational device.  The 
investigational device will be used to monitor ECoG responses during the implantation procedure.  The 
surgeon will conduct the procedure as per standard clinical practice and individuals will be exposed 
only to the normal risks associated with routine cochlear implantation.   
5.3 Residual risks related to the use of the investigational device 
All residual risks for the investigational device are described in the Patient Informed Consent Form 
(PICF).    
Electrode conditioning, especially at high current levels, may result in very loud or non-auditory 
percepts that could cause discomfort in awake subjects.  During intra-operative testing under 
anesthetic the sound will not be perceived.  However, during the follow-up visits at 3 post-surgery the 
level at which the sound is comfortable will need to be assessed from the subject providing feedback 
to the clinician.   Similarly, the sound presented to the ear through the acoustic pathway will need to be 
checked for comfort during the follow-up visit.   
5.4 Risks associated with participation in the clinical investigation 
All supplied equipment is non-sterile. There is potential for non-sterile equipment of the CRT to enter 
the sterile surgical field.  In order to mitigate this potential risk, all investigational sites must ensure the 
following non-sterile equipment is placed in a sterile bag(s): Freedom processor, RF coil and 
programming cable.  The following non-sterile equipment must be isolated from the sterile field using 
the best surgical practices of the hospital performing the surgery: insert earphone foam tip and tubing.  
5.5 Possible interactions with concomitant medical treatments 
It is possible that prescription of glucocorticoids such as dexamethasone may influence post-
implantation hearing preservation within the examined cohort.  A surgical questionnaire will be 
administered to document use of concomitant medications for each subject. 
5.6 Risk mitigations 
The investigators or qualified delegates will conduct the CRT measurements and will be trained in the 
use of the software and associated hardware system prior to commencement of the investigation.   

 
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All investigators will be informed in advance of the following potential hazards and mitigations 
associated with use of the investigational device or investigation procedure: 
a) All supplied CRT equipment is provided non-sterile.  Therefore the Freedom processor, RF coil 
and programming cable must be placed in a sterilized bag for all intra-operative measures.   The 
insert foam tip and tubing used to deliver the acoustic stimulus, and all other non-sterile 
equipment must be isolated from the sterile field. 
 
b) It is important to ensure that the correct routine (intra-operative or post-operative) be selected 
in the software to avoid risk to overly loud and/or non-auditory percept being elicited through 
inappropriate use of the intra-operative conditioning parameters during the post-operative visits.  
The software will provide a warning on initiation of the intra-operative routine to minimize the 
risk of inappropriate use of this routine post-operatively. 
 
c) It is important that the equipment used as part of the CRT research tool must not be connected 
to mains power or a mains powered accessory during all testing. 
 
d) The surgeon will use his/her discretion as to the acceptable extension to the operating time for 
each individual, and will terminate use of the CRT tool as needed. 
 
Pre-operative, peri-operative and post-operative use of concomitant medications will be documented 
for each subject.  Use of glucocorticoids will follow each surgeon’s and investigational site’s standard 
clinical protocol.   
5.7 Risk to benefit rationale 
With reference to the risk management summary there are no unacceptable hazards.  The software 
and hardware that will be used has been fully tested for functionality and safety according to 
verification procedures at Cochlear Limited which demonstrates conformity with the relevant AIMD 
90/385 essential requirements.  The findings from this clinical investigation will be important to 
informing future potential application of this technology in the clinical setting.   

 
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6 OBJECTIVES AND HYPOTHESES 
6.1 Primary Objective 
To examine whether compromised CM during cochlear implant surgery results in poorer post-
implantation acoustic hearing preservation at FUV1 compared to preserved CM. 
6.2 Secondary Objectives 
1. To examine whether compromised cochlear microphonic (CM) response during cochlear 
implant surgery results in poorer acoustic hearing preservation at FUV2 compared to 
preserved CM. 
2. To investigate whether pre-operative acoustic hearing influences the onset of the CM 
response during insertion of the electrode array. 
6.3 Primary Hypotheses 
Null Hypothesis: 
The deterioration in average low frequency post-operative HTLs at FUV1 in the implanted ear for 
subjects with intra-operative compromised CM will be equal to or less than subjects with preserved 
CM. 
Alternative Hypothesis: 
The deterioration in average low frequency post-operative HTLs at FUV1 in the implanted ear for 
subjects with intra-operative compromised CM will be greater than subjects with preserved CM. 
6.4 Secondary Hypotheses 
1) Deterioration in average low frequency post-operative hearing at FUV2 in the implanted ear for 
subjects with intra-operative compromised CM compared to subjects with intra-operative 
preserved CM. 
Null Hypothesis: 
The deterioration in average low frequency post-operative HTLs at FUV2 in the implanted ear for 
subjects with intra-operative compromised CM will be equal to or less than subjects with 
preserved CM. 
Alternative Hypothesis: 
The deterioration in average low frequency post-operative HTLs at FUV2 in the implanted ear for 
subjects with intra-operative compromised CM will be greater than subjects with preserved CM. 
2) 
Association of pre-operative high frequency HTLs with onset of CM response during electrode 
array insertion.  
Null Hypothesis: 
There is no association between pre-operative high frequency HTLs and onset of CM response. 
Alternative Hypothesis: 
There is a positive association between pre-operative HTLs and onset of CM response. 

 
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7 DESIGN OF THE CLINICAL INVESTIGATION 
7.1 General 
7.1.1 
Design and Randomisation 
The design of the clinical investigation is a prospective, observational (non-randomized) multi-center 
investigation. 
7.1.2 
Primary Endpoint 
Deterioration in average low frequency post-operative hearing threshold levels (HTLs) at FUV1 in the 
implanted ear for subjects with compromised CM compared to subjects with preserved CM during 
surgery. 
7.1.3 
Secondary Endpoints 
1. Deterioration in average low frequency post-operative HTLs at FUV2 in the implanted ear for 
subjects with compromised CM compared to subjects with preserved CM during surgery 
2. Association of pre-operative high frequency HTLs with onset of CM response during electrode 
array insertion  
7.1.4 
Exploratory Analyses 
Additional exploratory analyses may be performed.  These may include: 
• 
Comparison of the primary endpoint for three groups defined by compromised, preserved, and 
transient CM. 
• 
Predictors of the incidence of compromised CM during surgery including influence of electrode 
type, insertion depth and surgical events. 
• 
Association of pre-operative high frequency acoustic hearing thresholds with change in 
latency of CM during electrode array insertion. 
• 
Investigation of the influence of demographic and surgical factors on the morphology and 
time-course of the CM curve during insertion and post-operatively. 
• 
Investigation of the relationship of CM thresholds to postoperative HTLs in the implanted ear  
• 
Examination of the degree of reduction in CM amplitude that occurs in response to a range of 
surgical events. 
• 
Characterization of changes in electrode impedance as a function of CRT observations during 
and post-surgery. 
• 
Characterization of changes in different components of the electrocochleography (ECoG) 
changes over time.  
• 
Examination of whether the ratio of the CM amplitude over the ANN amplitude (uVrms) is 
correlated with lower (better) HTLs (FUV2) at 250Hz, 500Hz and 1kHz. 
• 
Examination of hearing preservation for compromised CM and preserved CM groups which 
have been classified using different criteria of CM amplitude reduction and time course. 

 
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7.2 Methods 
A pre-operative screening visit (or multiple visits if required) will be conducted to ensure eligibility for 
enrollment and will typically occur as part of routine clinical assessment at each of the participating 
centers.  
A pre-operative interview (as part of the informed consent process) will be conducted by the surgeon 
and/or audiologist to inform the candidate about all aspects of the study and evaluation schedule.  
After reviewing the Informed Consent Form, the candidate will be given the opportunity to review and 
ask questions about the Informed Consent Form and/or the study prior to signing the Informed 
Consent Form.  The candidate will be offered the opportunity to take the form home to discuss with 
family members should they choose to do so.  If he or she signs the Informed Consent Form, the 
candidate will then be given a copy of the signed Informed Consent Form to take home.   
A candidate will not be considered enrolled until a properly executed Informed Consent Form has 
been obtained and, along with the results of the pre-operative candidacy evaluation, reviewed and 
approved by the local Cochlear regional representative (evidenced by the return of a signed study 
approval form to the investigator).   
A pre-operative evaluation will be conducted (pre-operative visit 1, POV1) to provide a baseline (pre-
operative) measure of acoustic hearing status, and to document hearing and medical history.  Where 
required, the pre-operative evaluation may occur over multiple clinical sessions.  Information collected 
during the pre-operative session will be recorded on the appropriate case report form (CRF).  There 
will be no pre-determined period required between candidacy and baseline measures.  However, 
candidacy must be re-assessed if more than 90 days have elapsed prior to the surgical date.  A 
hearing and medical history will be obtained and documented during the pre-operative evaluation.   
Implant surgery will be conducted (at D0).  A video recording will be made during the surgical 
procedure to enable analysis of the CRT in response to specific surgical events.   The video will be 
made via the operative microscope imaging system during the entire insertion, commencing just prior 
to cochlear opening and ending after closure of the deep (subcutaneous/muscle) layer.  The video will 
be time-stamped to the CRT recordings.  Measures of electrode impedance will be obtained during the 
surgery.  At the completion of each subject’s surgical procedure a questionnaire will be completed by 
the surgeon to document aspects of the surgical procedure (including surgical approach, 
administration of corticosteroids, and ease and depth of electrode insertion).   
Post-operative assessment at 4-6 weeks (+/- 1 week) post-activation and 3 months (+/- 2 weeks) post-
activation will be conducted, and involve a series of clinical tests including otoscopy, audiometry, 
tympanometry and electrode impedance assessment.  At either 4-6 weeks post-surgery (+/- 1 week), 
or 3 months (+/- 2 weeks) post-activation, post-operative CRT will also be conducted. 
If an intra-or post-operative imaging is performed as part of the routine clinical management at 
participating site, that data will be analyzed to provide an estimate of electrode array position.   
Medical and audiological care throughout the clinical investigation, and at the conclusion of the 
investigation, will be as per standard clinical protocol for each investigational site, with the exception of 
the additional measurements taken as outlined.        

 
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7.3 Procedures 
7.3.1 
Audiometric Thresholds and Tympanometry 
Unaided audiometric thresholds will be obtained for each ear, with insert earphones, using the 
standard audiometric technique for pure-tone air-conduction testing. All pre- and post-implantation 
testing will be completed using a clinical audiometer calibrated to appropriate standards.   Pure tone 
threshold exploration will be completed using the adaptive Hughson & Westlake procedure (1944). 
As these subjects have measurable low-frequency hearing, it is important that appropriate 
consideration be made for masking (procedure outlined in Appendix A).   
Testing for both ears will include the following: 
• 
Air conduction thresholds:  125, 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 6000, 8000 Hz; 
• 
Bone conduction thresholds: 250, 500, 750, 1000, 1500, 2000, 3000, 4000 Hz; 
• 
Tympanometry in each ear 
Note that responses to pure-tone stimuli presented will need to be confirmed as an auditory (‘heard’) 
versus vibrotactile (‘felt’) response and recorded accordingly.  
7.3.2 
Surgical Preparation 
Preparation for surgery will occur as per standard clinical procedures and following recommendations 
in the Cochlear Response Telemetry Research Tool User Guide to ensure the sterile field is not 
compromised.  The surgical team must take necessary precautions during preparation to ensure that 
fluid has not flooded the external ear canal, since that might influence the delivery of the acoustic 
stimulus to the cochlea.  The surgical team must ensure that the drapes are thin and not doubled over 
at the site where the external coil will be magnetically coupled with the receiver-stimulator.    
Video recording of all surgeries is required, to enable analysis of the CRT in response to specific 
surgical events.   The video will be made via the operative microscope imaging system during the 
entire insertion, with recording to commence just prior to cochlear opening and ending after closure of 
the deep (subcutaneous/muscle) layer.  The video will be time-stamped to the CRT recordings.   
7.3.3 
Surgery 
Surgery will be conducted as per each surgeon’s standard clinical practice.   No feedback will be 
provided to the surgeon as to the status of the cochlear microphonic during insertion.   
7.3.4 
Intra-Operative Cochlear Response Telemetry Recording and Surgical 
Video 
Intra-operative video recording will be obtained prior to cochlear opening and conducted during 
electrode insertion and until the closure of the subcutaneous/muscle layer.   
After the receiver-stimulator package is positioned and secured, the transmitting coil and sound 
processor will be placed in a sterile sleeve or bag and subsequently the coil magnet placed in position 
over the implant package.  Electrode conditioning will be conducted when the most apical electrode 
(electrode 22) is first placed into the basal turn of the cochlea, just prior to advancement of the array, 
or in a saline solution prior to insertion.  On the stabilization of the impedance of the apical electrode, 
the surgeon will be informed that the insertion may commence.  Intra-operative recordings obtained 
during electrode insertion will typically use a 500 Hz acoustic stimulus (of 6 ms duration and an inter-

 
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stimulus interval of 70 ms) presented at 100 dB HL, with recording on the most apical electrode 
(electrode 22).  
The surgical video will be time-stamped to the CRT recordings. This will be achieved with the surgeon 
clicking surgical tweezers in front of the microscope 3 times at the end of the surgery, whilst the 
operator records the current index on the CM monitoring trace that will be updating in real-time.  The 
operator of the CRT software will also capture surgical events using the software time-stamped to the 
CM recording.   
Monitoring of the CM will continue throughout the surgical procedure until closure of the deep 
(subcutaneous/muscle) layer.     
Post-insertion measures will be obtained (after closure of the subcutaneous/muscle layer) using a 
frequency sweep and an electrode sweep routine.   
7.3.5 
Electrode Impedance Measures 
Electrode impedance will be measured using the standard measurement technique used in the 
Custom Sound programming software, as well as using an investigational measure of 4-point 
impedance using the CRT tool and the Freedom processor. 
Conventional impedance measurements are taken between two electrodes which are also the 
stimulating electrodes.  Stimulating through platinum electrodes induces a platinum-tissue interface 
impedance, which depends on the size of the electrodes and the type of stimulation used.  Therefore, 
when traditional impedance measurements are taken, the impedance measured includes the tissue 
impedance as well as the interface impedance at both recording electrodes. 
Four-point impedance uses recording electrodes which are different from the stimulating electrodes.  
This means that no interface impedance is set up at the recording electrode, and that the impedance 
measured is predominately the tissue impedance.  Some impedance is added by the electronics of the 
implant and the electrodes themselves.  Usually, in four-point impedance the recording electrodes are 
adjacent intracochlear electrodes (ICEs) and the stimulating electrodes are the two ICEs on either side 
of the recording electrodes.  In this method, the stimulation current should flow through the tissue 
between the two recording electrodes, and hence the impedance measured should be the impedance 
of the tissue in between the recording electrodes.   
Four-point impedance measurements allow the user to investigate the impedance of the tissue, 
without interference from the platinum-tissue interface impedance, which is typically much higher.  
This approach aims to provide information about the fibrous tissue growth around the electrode array 
with less sensitivity to variation in the impedance of individual electrodes.  
7.3.6 
Imaging 
Where post-operative radiological imaging of the cochlea is obtained at participating centers, as part of 
routine clinical management, the scans will be analyzed to provide an estimate of intracochlear 
electrode insertion depth (angle relative to round window).  Where possible, scala placement will be 
determined using a co-registration procedure or high resolution ConeBeam.  There will not be specific 
imaging requirements within the CIP, however where obtained during routine clinical procedure the 
information will be collected and analyzed.   

 
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7.3.7 
Surgical Questionnaire 
The surgeon will complete the surgical questionnaire to document aspects of the surgical procedure, 
including but not limited to surgical approach, use of corticosteroids, and ease and depth of electrode 
insertion.   
7.3.8 
Post-Operative Cochlear Response Telemetry Recording 
Post-insertion measures will be obtained using a frequency sweep (with recording from electrode 22 
for signals with frequency 250, 500, 1000, and 2000 Hz delivered at a maximum comfortable listening 
level) and an electrode sweep (with recording using a 500 Hz acoustic signal presented at a maximum 
comfortable listening level and recording on electrodes 22, 20, 18, 16, 14, 12, 10, 8, 6, 4 and 2).  The 
signal level (typically comprising a 12 ms duration stimulus and 50 ms inter-stimulus interval) will be 
controlled to ensure comfortable loudness presentation.   
7.4 Investigational device and comparator 
Comparison of endpoints are made based on subjects with and without a compromised CM response. 
7.5 Subjects  
7.5.1 
Inclusion Criteria 
• 
Candidate for cochlear implantation (with CI522, CI532 or Hybrid-L24 according to local 
indications 
• 
18 years of age or older at the time of enrolment  
• 
Pre-operative audiometric threshold in the implanted ear at 500 Hz of better than or equal to 80 
dB HL 
• 
Willingness to participate in and to comply with all requirements of the protocol 
7.5.2 
Exclusion Criteria 
• 
Prior cochlear implantation in the ear to be implanted 
• 
Ossification or any other cochlear anomaly that might prevent complete insertion of the 
electrode array 
• 
Abnormal cochlear/nerve anatomy on pre-operative CT or MRI imaging (excluding a mild 
Mondini malformation or Large Vestibular Aqueduct Syndrome) 
• 
Deafness due to lesions of the acoustic nerve or central auditory pathway 
• 
Diagnosis of auditory neuropathy 
• 
Active middle-ear infection 
• 
Additional handicaps that would prevent participation in evaluations 
• 
Unrealistic expectations on the part of the subject, regarding the possible benefits, risks and 
limitations that are inherent to the procedure and investigational device 

 
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7.6 Monitoring Plan 
The study will be monitored for data quality, and adherence to ISO14155 or equivalent FDA guidelines 
and regulatory requirements as outlined in the study monitoring plan.  Site initiation and training will be 
provided to ensure that study site personnel understand the protocol and schedule of activities, 
mechanics of the study device, study staff responsibilities, data capture and regulatory requirements.  
Due to the short nature of the study, Interim Monitoring activity (remote or on-site) will be completed 
once a site completes a multiple of 5 study subjects (i.e., after 5, 10, 15 etc. subjects are completed) 
or in the event of protocol compliance or GCP concerns. Completed CRT data will be collated and 
reviewed by the Sponsor throughout the duration of the study, to ensure that data collection is 
complete and consistent with the requirements of the investigation.  The study close-out effort will be 
conducted at the conclusion of the site’s participation in the study.   
8 STATISTICAL CONSIDERATIONS 
The primary hypothesis will be tested with a between-groups t-test or non-parametric Mann-Whitney U 
test using a one-sided alpha level of 0.05. This analysis will compare group mean low frequency 
postoperative hearing deterioration at FUV1 in the implanted ear for subjects with compromised CM 
compared to subjects with preserved CM.  Compromised CM will be defined as a CM with an 
irreversible reduction in amplitude during surgery; specifically a ≥30% reduction in maximum CM 
amplitude that does not recover to within 10% of the maximum amplitude. Preserved CM will be 
defined as a CM with <30% amplitude reduction at any point during the surgery. Subjects not falling 
into the compromised or preserved CM groups will not be included in the analysis. The mean or 
median threshold drop for the CM compromised and CM preserved groups will be separately 
calculated as the mean or median of individual subjects’ low frequency deterioration (4-6 week post-
surgery threshold minus pre-operative threshold in the implanted ear) for the corresponding CM group. 
For each subject, the low frequency deterioration will be calculated as the average deterioration 
across the frequencies 500 Hz, 750 Hz and 1000 Hz, where there is preoperative hearing better than 
or equal to 80 dB HL in the implanted ear. For example, if a subject’s preoperative hearing threshold is 
better than or equal to 80 dB HL at 500 Hz and 750 Hz but is 90 dB HL at 1 kHz, the hearing 
deterioration (post-operative threshold minus preoperative threshold) will be computed at 500 Hz and 
750 Hz only and then averaged. It is possible that a subject could have hearing deterioration 
measured at 500 Hz only, if preoperative thresholds at 750 Hz and 1 kHz exceed 80 dB HL.  Non-
measurable post-operative thresholds will be assigned a value 1 dB above the level at which the limits 
of the audiometer were reached.  Vibrotactile responses will not be included in the analyses.   
Sample Size Estimation 
Prospective sample size estimation for a two-sample t-test has been conducted, given that the study 
uses a between-groups design to investigate its primary hypothesis. Specifically, the planned sample 
size would provide 80% power at the one-tailed 0.05 alpha level to detect at least 15 dB greater 
deterioration in low frequency acoustic hearing threshold for subjects with compromised CM compared 
to preserved CM.  
The following general assumptions have been made: 
• 
A difference in mean hearing preservation of 15 dB for the compromised CM versus preserved 
CM groups. This difference is considered clinically meaningful, based on clinical consensus. 

 
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• 
An expected standard deviation of 25 dB HL. It is more conservative, but is based on the SD 
of 22.26 dB HL observed in low frequency hearing preservation at 3 months post-operative in 
the US multi-site clinical trial with 52 cochlear implant recipients using the CI422 straight 
electrode array (IDE G120234). This trial is considered relevant since the majority of subjects 
in the prospective trial will be similarly implanted with the Slim Straight array (CI522). 
Furthermore, in the calculation of the SD for this previous trial, low frequency hearing 
preservation has been calculated in the same manner as it will be in the prospective study (as 
the average change in threshold (post-activation minus pre-operative) across the frequencies 
500 Hz, 750 Hz and 1000 Hz where there is preoperative hearing ≤80 dB HL in the implanted 
ear).  
• 
One-sided 0.05 alpha level, given that the primary endpoint is based on a directional 
hypothesis. 
• 
A desired power of 0.8.  
Based on the above assumptions, a minimum sample size of 36 subjects with preserved and 36 
subjects with compromised CMs is required to reject a false null hypotheses of equivalent or worse 
hearing preservation for those subjects with preserved CM (using SigmaPlot 13.0).  
This minimum sample size will be increased for the following four reasons.  
a. The sample size will be increased by 15% to 41 subjects per group to allow for the possibility 
that the hearing threshold data is non-normally distributed and that a nonparametric statistical 
analysis will be required. This 15% increase is based on what is known as the minimum 
asymptotic relative efficiency (ARE) of the Mann-Whitney U test relative to the paired or 
matched-pairs t-test.  It can be proven that the ARE (or Pitman efficiency) is never less than 
86.4%.  When the sample size is increased by 15%, the equivalent power should be achieved, 
since 1.15 is approximately 1/0.864. 
b. The sample size will be increased to a total of 43 subjects per group to allow for the prediction 
that approximately 5% of cochlear implant recipients will not exhibit an intraoperative CM 
response (Dalbert et al. 2015).  
Considering the following assumptions, a total sample size of 125 subjects may be required. 
c. The sample size may need to be further increased to 52 subjects, to allow for the prediction 
that approximately 20% of subjects will show a transient intraoperative CM drop that recovers 
by the end of the surgery (unpublished data, 14/1171H, Royal Victorian Eye and Ear Hospital 
Human Research Ethics Committee). This transient CM drop will not be categorised as a 
preserved CM or as a compromised CM due to uncertainty as to the likely impact of such a 
change on hearing preservation. 
d. The total sample size of 104 subjects (52 subjects in each group) may need to be further 
increased by 20%, given that the allocation of subjects to groups occurs post-implantation, 
and so there is no ability to control the allocation of subjects. This increase to the total sample 
size in anticipation of unequal groups allows for a marked difference in group size up to a ratio 
of 2.0, with no loss in statistical power.  
Both the proportion of subjects with a transient intraoperative CM drop and the allocation of 
subjects in the preserved CM versus compromised CM groups are nuisance parameters not 

 
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directly related to a potential difference in outcome between the groups.  Since “breaking the 
blind”, i.e. having access to the outcomes by CM groups, is not required to assess these 
parameters, modifications to the sample size may be made to the planned enrolment to ensure 
adequate power in the case that the assumptions outlined here (i.e. 20% of subjects show a 
transient CM drop, the allocation ratio between groups is different than 2.0).  Such modifications 
do not affect the type I error rate of the study. 
9 DATA MANAGEMENT 
Source data collection is performed through DataLabs or alternative web-based system for electronic 
data capturing. Site personnel will be trained to use this system. Data validity has to be confirmed by 
the investigator through an electronic signature. An audit trail is kept by this system and data 
clarifications may be generated by the system and Sponsor personnel after review of data. 
DataLabs or the alternative web-based system has been verified and validated by the vendor. 
Installation of the system within Cochlear has been validated as well. Investigation-specific 
implementations are validated by Data Management and consist of verification that all required items 
are included, validity of edit checks and appropriate functionality of conditional fields. The 
investigation-specific data in DataLabs can only be accessed by those that have been allocated their 
individual account, which are personnel of the investigational sites, Clinical Project Managers, 
Investigation Monitors and Data Management.  Electronic data saved within the CRT system and the 
surgical videos will be stored in a centralized and secure location.   
10 AMENDMENTS TO THE CIP 
No changes in the CIP or investigation procedures shall be effected without mutual agreement of the 
Principal Investigators and the Sponsor. Changes related to the scientific intent of the study shall be 
documented in the CIP and requires signatures from the Sponsor and the coordinating investigator. 
Such changes will require notification to the Ethics Committees by the Principal Investigators (and the 
Competent Authority by the Sponsor – if applicable). Changes relating to the investigation sites shall 
be documented in a separate Principal Investigator List (PIL) and referenced in the CIP.  
11 DEVIATIONS FROM THE CIP 
The investigator is not allowed to deviate from the CIP except under emergency circumstances to 
protect the rights, safety and well-being of the subjects. Such deviation shall be documented and 
reported to the Sponsor and the EC as required.  
The procedure for recording and reporting CIP deviations shall be via a CIP Deviation CRF in the EDC 
system.  Analysis of CIP deviations shall be undertaken by the Sponsor and Data Management.   
In the event of a CIP deviation, the investigator shall notify the Sponsor within the required notification 
window.  The Sponsor shall notify the EC and competent authority where necessary, of all CIP 
deviations annually.   
12 DEVICE ACCOUNTABILITY 
Investigational devices shall be tracked and returned to the Sponsor upon completion of the study. 

 
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13 STATEMENTS OF COMPLIANCE 
13.1 Declaration of Helsinki and compliance with standards 
The clinical investigation shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki (2013), the ISO 14155:2011 Standard, and any regional or national 
regulations, as appropriate. 
13.2 Ethics Committee and Regulatory Agency Approval 
The clinical investigation shall not commence in a particular region prior to the written favorable 
opinion or approval from the local Ethics Committee (EC), and regional regulatory agency (i.e., 
Competent Authority, Food and Drug Administration, or other relevant agency) is obtained. 
The Principal Investigator shall submit the final approved version of the CIP, the approved PIC and all 
subsequently approved documents to the EC and regulatory agency (RA) where applicable.  A copy of 
the EC and RA opinion/approval shall be provided to the Sponsor if not directly communicated.  
The investigator shall forward any amendment made to the approved PIC any other written information 
to be provided to the subject for review and approval by the Sponsor prior to submission to the EC.  
The Sponsor and Principal Investigator shall continue the communication with the RA and EC as 
required by national regulations, the clinical investigational plan or the responsible RA and EC.  
Any additional requirements imposed by the EC or RA shall be followed. 
The investigator shall submit the appropriate documentation if any extension or renewal of the EC or 
RA approval is required. In particular, substantial amendments to the CIP, the PIC, or other written 
information provided to subjects shall be approved in writing by the EC and RA. 
The investigator will report to the RA and EC any new information that may affect the safety of the 
subjects or the conduct of the clinical investigation. The investigator/sponsor shall send written status 
summaries of the investigation to the RA and EC regularly as per local RA and EC requirements. 
Upon completion of the clinical investigation, the investigator/sponsor shall provide the RA and EC 
with a brief report of the outcome of the clinical investigation as per local RA and EC requirements. 
The clinical investigation is covered by a clinical trial insurance meeting the requirements of the 
participating countries. 
14 INFORMED CONSENT PROCESS 
14.1 Obtaining informed consent 
The investigator shall obtain written informed consent using an approved Patient Informed Consent 
Form (PIC) from the subject prior to any clinical investigation related examination or activity. The 
rationale for and the details, aims and objectives of the investigation, the risks and benefits and 
alternative treatments, and the extent of the subject’s involvement shall be explained. Ample time shall 
be provided for the subject to inquire about details of the clinical investigation and to decide whether to 
participate. All questions about the clinical investigation shall be answered to the satisfaction of the 
subject or the subject’s legally acceptable representative. Subjects shall not be coerced or unduly 
influenced to participate or to continue to participate in a clinical investigation. 

 
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A copy of the signed PIC shall be given to the subject. The original signed PIC shall be archived in the 
Investigator’s File at the investigational site, according to the requirements of the country’s health 
regulations 
The subject or the subject’s legally acceptable representative shall be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to continue 
participation in the clinical investigation. The communication of this information shall be documented. 
14.2 Data Privacy 
Subjects will be identified on CRFs or similar documents (for example, questionnaires) by a unique 
subject identification code. Completed CRFs or similar documents are confidential documents and will 
only be available to the Sponsor and their representatives, the investigator, the investigational 
statistician, and if requested to the Ethics Committee and national regulatory authorities.  
The investigator and site staff will not include the name of any subject in any CRF or other forms, 
electronic files, imaging items (for example, x-ray), publication, or submission to a regulatory authority; 
will not otherwise disclose the identity of any subject; and, in any CRF, will refer to each subject by 
their identification code. The Patient ID log CRF is explicitly excluded from this requirement. 
15 REPORTING PROCESS FOR ADVERSE EVENTS, ADVERSE DEVICE 
EFFECTS AND DEVICE DEFICIENCIES 
15.1 Definitions 
All definitions are according to 21 CFR Part 812, 50, 54, 56 & 11 as well as the EN ISO 14155:2011 
standard. 
15.1.1 Adverse event (AE) 
Any untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons whether or not related to the 
investigational medical device.  
NOTE 1: This definition includes events related to the investigational medical device or the 
comparator. 
NOTE 2: This definition includes events related to the procedures involved.   
NOTE 3: For users and other persons, this definition is restricted to events related to 
investigational medical devices. 
15.1.2 Adverse device effect (ADE) 
Adverse device effect is an adverse event related to the use of an investigational medical device. 
NOTE 1: This includes any adverse event resulting from insufficiencies or inadequacies in the 
instructions for use, the deployment, the implantation, the installation, the operation, or any 
malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse 
of the investigational medical device. 

 
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15.1.3 Device deficiency (DD) 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, safety or performance. 
NOTE: Device deficiencies include malfunctions, use errors, and inadequate labelling. 
15.1.4 Serious adverse event (SAE) 
A serious adverse event is any adverse event that: 
1) led to a death, 
2) led to a serious deterioration in the health of the subject that either resulted in 
a) a life-threatening illness or injury, or 
b) a permanent impairment of a body structure or a body function, or 
c) in-patient hospitalization or prolonged hospitalization, or 
d) medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function, 
3) led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE. Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without 
serious deterioration in health, is not considered a serious adverse event. 
15.1.5 Serious adverse device effect (SADE) 
A serious adverse device effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
15.1.6 Unanticipated serious adverse device effect (USADE) 
An unanticipated serious adverse device effect is a serious adverse device effect which by its nature, 
incidence, severity or outcome has not been identified in the risk analysis report (for the investigational 
device or its comparator). 
15.2 Reporting process for adverse events, adverse device effects 
and device deficiencies 
The investigator shall report all serious adverse events without delay to the Sponsor.  Investigators are 
to inform their respective EC/IRBs and the Sponsor immediately if an unanticipated adverse device 
effect is suspected (no more than 10 working days after the investigator learns of the effect).  If the 
case is determined to be an unanticipated adverse device effect, the investigator will fill out an 
“Unanticipated Adverse Device Effect Form”.  The Sponsor will report the results of an evaluation of 
the unanticipated adverse device effect to all reviewing ECs and investigators within 10 working days 
after first receiving notice of the event. 

 
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The details of the Medical Monitor for the clinical investigation are: 
Name of Medical Monitor 
Mike Brownen 
Phone number (business hours) 
+1 (866) 9228673 
Phone number (after hours) 
+16828886884 
E-mail 
mbrownen@cochlear.com 
 
If applicable:  The Sponsor is responsible to report all SAEs, SADEs and USADEs to the relevant RAs 
in the clinical investigation in accordance with local regulations. 
The investigator has to report all AEs, SAEs, SADEs and USADEs to their EC and / or RA (if 
applicable) using the applicable report form and reporting timelines as per national requirement.  
Subjects shall be carefully monitored during the clinical investigation for potential adverse events and 
shall be routinely questioned about adverse events at investigation visits. For all adverse events, 
information obtained by the investigator shall be recorded in the Adverse Event CRF. The investigator 
shall attempt to assess the relationship between the investigational device and the adverse event.  
15.3 Data Monitoring Committee 
Since routine surgical procedures will be applied, a DMC will not be established. 
15.4 Device Deficiency Reporting Requirements 
The investigator shall report any device deficiency without unjustifiable delay to the Sponsor.  
Name of Medical Monitor 
Mike Brownen 
Phone number (business hours) 
+1 (866) 9228673 
Phone number (after hours) 
+16828886884 
E-mail 
mbrownen@cochlear.com 
16 INCIDENT REPORTING 
Not applicable for this clinical investigation. 
17 VULNERABLE POPULATION 
Not applicable for this clinical investigation. 
18 SUSPENSION OR PREMATURE TERMINATION 
The Sponsor will withdraw from sponsorship of the clinical investigation if: 
1) 
major non-adherence to the CIP is occurring 
2) 
it is anticipated that the subject recruitment will not be adequate to meet the objectives of the 
clinical investigation 

 
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Should the Sponsor withdraw from sponsorship of the clinical investigation, the Sponsor will continue 
sponsorship for the subjects already recruited into the investigation. 
An ongoing clinical investigation can be discontinued in case of: 
1) 
device failure 
2) 
serious or intolerable adverse device effect, leading to the explant or discontinued use of the 
device 
3) 
subject’s death 
4) 
investigator’s decision 
5) 
subject’s decision 
19 PUBLICATION POLICY 
A description of this clinical investigation will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. 
It is planned to generate a joint publication by the Principal Investigator(s) and the Sponsor. The 
responsibility for writing the publication is with the Coordinating Investigator or the Sponsor.  
Authorship will be based on contribution of complete datasets and contribution to paper preparation 
according to the rules of the journal chosen for publication. The joint publication shall be reviewed by 
the Sponsor at least 30 days in advance to any release of publication. If the publication contains 
information that the Sponsor at his discretion finds worth protecting in the form of a patent or 
trademark etc., the Sponsor has the right to delay the publication or presentation for 90 days.  
Following acceptance of the joint paper, the investigators will be able to publish as they wish. The 
publishing investigator will provide the Sponsor with a manuscript copy of the abstract and paper at 
least 30 days in advance of publication or presentation. If the publication contains information that the 
Sponsor at his discretion finds worth protecting in the form of a patent or trademark etc., the Sponsor 
has the right to withhold the publication or presentation for 90 days. 

 
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20 REFERENCES 
20.1 Internal References 
ID 
Document Title 
Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
20.2 External References 
List in alphabetical order the standards of practice and external references referenced in this template. 
ID 
Document Title 
Number 
1 
Clinical investigation of medical devices for human subjects – Good 
clinical practice 
ISO 14155:2011 
2 
World Medical Association Declaration of Helsinki – Ethical Principles 
for Medical Research Involving Human Subjects (2013) 
N/A 
3 
Code of Federal Regulations Title 21 CFR Part 812, 50, 54, 56 & 11 
 
 
20.3 Referenced Literature 
Adunka, O. F., C. K. Giardina, E. J. Formeister, B. Choudhury, C. A. Buchman, and D. C. Fitzpatrick. 
2016. 'Round window electrocochleography before and after cochlear implant electrode insertion', 
Laryngoscope, 126: 1193-200. 
Adunka, O., J. Kiefer, M. H. Unkelbach, T. Lehnert, and W. Gstoettner. 2004. 'Development and 
evaluation of an improved cochlear implant electrode design for electric acoustic stimulation', 
Laryngoscope, 114: 1237-41. 
Baer, T., Moore, B. C. J., Kluk, K. 2002. Effects of low pass filtering on the intelligibility ofspeech in 
noise for people with and without dead regions at high frequencies. Journal of the Acoustical Society 
of America, 112, 1133-1144. 
Campbell, L., A. Kaicer, R. Briggs, and S. O'Leary. 2015. 'Cochlear response telemetry: intracochlear 
electrocochleography via cochlear implant neural response telemetry pilot study results', Otol 
Neurotol, 36: 399-405. 
Campbell, L., Kaicer, A., Sly, D., Iseli, C., Wei, B., Briggs, R. and O’Leary, S. 2016. Intraoperative 
Real-time Cochlear Response Telemetry Predicts Hearing Preservation in Cochlear Implantation. 
Otology & Neurotology, 37: 332-338. 
Ching, T. Y., Incerti, P., Hill, M. 2004. Binaural benefits for adults who use hearing aids and cochlear 
implants in opposite ears. Ear and Hearing, 25, 9-21. 

 
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and Hearing Preservation:  Clinical Investigation Plan 
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Dalbert, A., A. Huber, D. Veraguth, C. Roosli, and F. Pfiffner. 2016. 'Assessment of Cochlear Trauma 
During Cochlear Implantation Using Electrocochleography and Cone Beam Computed Tomography', 
Otol Neurotol, 37: 446-53. 
Dalbert, A., J. H. Sim, R. Gerig, F. Pfiffner, C. Roosli, and A. Huber. 2015. 'Correlation of 
Electrophysiological Properties and Hearing Preservation in Cochlear Implant Patients', Otol Neurotol, 
36: 1172-80. 
Fitzpatrick, D. C., A. P. Campbell, B. Choudhury, M. T. Dillon, M. Forgues, C. A. Buchman, and O. F. 
Adunka. 2014. 'Round window electrocochleography just before cochlear implantation: relationship to 
word recognition outcomes in adults', Otol Neurotol, 35: 64-71. 
Formeister, E. J., J. H. McClellan, W. H. Merwin, 3rd, C. E. Iseli, N. H. Calloway, H. F. Teagle, C. A. 
Buchman, O. F. Adunka, and D. C. Fitzpatrick. 2015. 'Intraoperative round window 
electrocochleography and speech perception outcomes in pediatric cochlear implant recipients', Ear 
Hear, 36: 249-60. 
Fraysse, B., A. R. Macias, O. Sterkers, S. Burdo, R. Ramsden, O. Deguine, T. Klenzner, T. Lenarz, M. 
M. Rodriguez, E. Von Wallenberg, and C. James. 2006. 'Residual hearing conservation and 
electroacoustic stimulation with the nucleus 24 contour advance cochlear implant', Otol Neurotol, 27: 
624-33. 
Gantz, B. J., M. R. Hansen, C. W. Turner, J. J. Oleson, L. A. Reiss, and A. J. Parkinson. 2009. 'Hybrid 
10 clinical trial: preliminary results', Audiol Neurootol, 14 Suppl 1: 32-8. 
Gantz, B. J., and C. Turner. 2004. 'Combining acoustic and electrical speech processing: 
Iowa/Nucleus hybrid implant', Acta Otolaryngol, 124: 344-7. 
Gifford, R. H., Dorman, M. F., Sheffield, S. W., et al. (2014). Availability of binaural cues for bilateral 
implant recipients and bimodal listeners with and without preserved hearing in the implanted ear. 
Audiology & Neurotology, 19, 57-71. 
Gifford, R. H., Dorman, M. F., Skarzynski, H., et al. (2013). Cochlear implantation with hearing 
preservation yields significant benefit for speech recognition in complex listening environments. Ear 
and Hearing, 34, 413-425. 
Gstoettner, W., S. Helbig, C. Settevendemie, U. Baumann, J. Wagenblast, and C. Arnoldner. 2009. 'A 
new electrode for residual hearing preservation in cochlear implantation: first clinical results', Acta 
Otolaryngol, 129: 372-9. 
Hornsby, B. W., Ricketts, T. A. 2001. The effects of compression ratio, signal-to-noise ratio, and level 
on speech recognition in normal-hearing listeners. Journal of the Acoustical Society of America, 109, 
2964-2973. 
Lenarz, T., C. James, D. Cuda, A. Fitzgerald O'Connor, B. Frachet, J. H. Frijns, T. Klenzner, R. 
Laszig, M. Manrique, M. Marx, P. Merkus, E. A. Mylanus, E. Offeciers, J. Pesch, A. Ramos-Macias, A. 
Robier, O. Sterkers, and A. Uziel. 2013. 'European multi-centre study of the Nucleus Hybrid L24 
cochlear implant', Int J Audiol, 52: 838-48. 
Lenarz, T., T. Stover, A. Buechner, A. Lesinski-Schiedat, J. Patrick, and J. Pesch. 2009. 'Hearing 
conservation surgery using the Hybrid-L electrode. Results from the first clinical trial at the Medical 
University of Hannover', Audiol Neurootol, 14 Suppl 1: 22-31. 

 
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Lesinski-Schiedat, A., A. Buechner, M. Schuessler, and T. Lenarz. 2011. 'Hybrid-L and CI422 for 
treatment of partial deafness', Journal of Hearing Science, 1: 63-65. 
Mandala, M., L. Colletti, G. Tonoli, and V. Colletti. 2012. 'Electrocochleography during cochlear 
implantation for hearing preservation', Otolaryngol Head Neck Surg, 146: 774-81. 
McClellan, J. H., E. J. Formeister, W. H. Merwin, 3rd, M. T. Dillon, N. Calloway, C. Iseli, C. A. 
Buchman, D. C. Fitzpatrick, and O. F. Adunka. 2014. 'Round window electrocochleography and 
speech perception outcomes in adult cochlear implant subjects: comparison with audiometric and 
biographical information', Otol Neurotol, 35: e245-52. 
Roland, J. T., Jr., B. J. Gantz, S. B. Waltzman, A. J. Parkinson, and Group Multicenter Clinical Trial. 
2016. 'United States multicenter clinical trial of the cochlear nucleus hybrid implant system', 
Laryngoscope, 126: 175-81. 
Skarzynski, H., A. Lorens, A. Piotrowska, and P. H. Skarzynski. 2010. 'Hearing preservation in partial 
deafness treatment', Med Sci Monit, 16: CR555-62. 
Zhang, T., Dorman, M. F., Gifford, R. H., et al. 2014. Cochlear dead regions constrain the benefit of 
combining acoustic stimulation with electric stimulation. Ear and Hearing, 35, 410-417. 
Unpublished Literature: 
Unpublished data. Electrocochleography in Cochlear Implant Recipients. The Royal Victorian Eye and 
Ear Hospital Human Research Ethics Committee #14/1171H 
21 CHANGE HISTORY 
List the details of the changes made since the previous approval.  
Version 
Change 
Author 
Date 
1.0 
IDE Submission 
Kerrie Plant & Pam 
Dawson 
19 December, 2016 
2.0 
Amendments requested from FDA 
Kerrie Plant & Pam 
Dawson 
9 March, 2017 
3.0 
Clarification re FUV1 and FUV2 windows 
added 
Aaron Parkinson 
23 August, 2017 

 
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22 DEFINITIONS 
22.1 Definitions from ISO 14155:2011 
Term 
Description 
Adverse event (AE) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, 
users or other persons whether or not related to the investigational medical 
device. 
NOTE 1: This definition includes events related to the investigational 
medical device or the comparator 
NOTE 2: This definition includes events related to the procedures 
involved.   
NOTE 3: For users and other persons, this definition is restricted to 
events related to investigational medical devices. 
Adverse device effect 
(ADE) 
Adverse device effect is an adverse event related to the use of an 
investigational medical device. 
NOTE 1: This includes any adverse event resulting from insufficiencies 
or inadequacies in the instructions for use, the deployment, the 
implantation, the installation, the operation, or any malfunction of the 
investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or 
from intentional misuse of the investigational medical device. 
Device deficiency (DD) 
A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety or performance. 
NOTE: Device deficiencies include malfunctions, use errors, and 
inadequate labelling. 
Incident 
Any malfunction or deterioration in the characteristics and/or performance of 
a device, as well as any inadequacy in the labelling or the instructions for 
use which, directly or indirectly, might lead to or might have led to the death 
of a subject, or USER or of other persons or to a serious deterioration in 
their state of health. 
Serious adverse event 
(SAE) 
A serious adverse event is any adverse event that: 
a) led to a death, 
b) led to a serious deterioration in the health of the subject that either 
resulted in 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function, or 
3) in-patient hospitalization or prolonged hospitalization, or 
4) medical or surgical intervention to prevent life-threatening illness or injury 
or permanent impairment to a body structure or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE Planned hospitalization for a pre-existing condition, or a procedure 
required by the CIP, without serious deterioration in health, is not 
considered a serious adverse event. 

 
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Term 
Description 
Serious adverse device 
effect (SADE) 
A serious adverse device effect is an adverse device effect that has resulted 
in any of the consequences characteristic of a serious adverse event. 
Unanticipated serious 
adverse device effect 
(USADE) 
An unanticipated serious adverse device effect is a serious adverse device 
effect which by its nature, incidence, severity or outcome has not been 
identified in the risk analysis report (for the investigational device or its 
comparator). 
22.2 Other definitions 
Term 
Description 
CA 
Competent Authority 
CER 
Clinical Evaluation Report 
EC 
Ethics Committee, alternatively referred to as Institutional Review Board in 
the U.S. 
RA 
Regulatory Agency 
IB 
Investigator’s brochure is a compilation of the current clinical and non-
clinical information on the investigational device(s) relevant to the clinical 
investigation. 
NCA 
National Competent Authority 
PASS 
Post-authorization safety studies mandated by medical device regulators  
PIC 
Patient Informed Consent  
PICF 
Patient Informed Consent Form 
PIL 
Principal Investigator List 
SAP 
Statistical Analysis Plan 
CRT 
Cochlear Response Telemetry 
CM 
Cochlear Microphonic 
SRT 
Speech Reception Threshold 
DMC 
Data Monitoring Committee 
AuSTIN 
Australian Speech Test in Noise 
CRF 
Case Report Form 
EC 
Ethics Committee 
ECoG 
Electrocochleography 
POV 
Pre-operative Visit 
FUV 
Follow-Up Visit 
 
 
 

 
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23 APPENDIX A:  INSTRUCTIONS FOR MASKING 
a) Pure tone threshold is established in the test ear 
b) Masking noise is introduced to the non-test ear at the initial masking level (10 dB above the 
established threshold in the non-test ear).  Pure tone threshold is then re-established. 
c) Level of the masking tone or noise is increased subsequently by 5 dB.  If there is a response 
to the tone in the presence of the noise, the level of the noise is increased by 5 dB.  If there is 
no response to the tone in the presence of the noise, the level of the tone is increased by 5 dB 
steps until a response is obtained. 
d) A plateau has been reached when the level of the noise can be increased over a range of 15 
to 20 dB without shifting the threshold of the tone.  This corresponds to a response to the tone 
at the same HL when the masker is increased in three to four consecutive levels. 
e) Masked pure tone threshold corresponds to the HL of the tone at which a masking plateau has 
been established.