Trans-impedance Matrix
Conditions: Hearing Loss
Sponsor: Cochlear

 
 
Official Title:  
Exploration of the specificity of an algorithm to detect anomalous 
 
electrode position 
 
NCT Number:  
NCT03294681 
 
Document Date:  14 May 2018 

 
 
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Clinical Investigation Plan 
 
Exploration of the specificity of an algorithm to detect anomalous electrode 
position 
 
Trans-impedance matrix 
 
CLTD5676 
 
 
Date: 14 May 2018 
 
Version number: 2.0  
 
Windchill number: D1210600, v 2.B 
 
Author(s): 
 
 
 
 

 
 
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Sponsor  
Cochlear Technology Centre Belgium 
Schaliënhoevedreef 20 I 
2800 Mechelen 
Belgium 
 
Manufacturer  
Cochlear Limited  
1 University Avenue  
Macquarie University  
NSW 2109, Australia 
Coordinating Investigator  
 
 
Complejo Hospitalario Universitario Insular 
Materno Infantil ; Avenida Marítima Del Sur, 
S/n, 35016 Las Palmas de Gran Canaria, 
Spain 
Principal Investigators  
Please refer to Appendix I 
Clinical Research Organisation 
Spanish monitoring activities: 
 
 
            
 
German monitor activities: 
 
 
Australian monitoring activities: 
  
  
 
 
 

 
 
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Table of contents 
 
1 
Clinical Investigation Synopsis .................................................................................. 6 
2 
Terms and Abbreviations ............................................................................................ 8 
3 
Introduction .................................................................................................................. 8 
4 
Identification and description of the devices........................................................... 11 
5 
Justification for the design of the clinical investigation ......................................... 12 
6 
Risks and benefits of the device and clinical investigation .................................... 13 
6.1 
Anticipated clinical benefits .................................................................................... 13 
6.2 
Anticipated adverse device effects ......................................................................... 13 
6.3 
Residual risks related to the device ........................................................................ 13 
6.4 
Risks associated with participation in the clinical investigation ............................... 14 
6.5 
Risk mitigation ........................................................................................................ 14 
6.6 
Risk-to-benefit rationale ......................................................................................... 14 
7 
Objectives and hypothesis........................................................................................ 14 
8 
Design of the clinical investigation .......................................................................... 15 
8.1 
General .................................................................................................................. 15 
8.2 
Treatment schedule ................................................................................................ 16 
8.3 
Subjects ................................................................................................................. 17 
8.3.1 
Inclusion Criteria ............................................................................................................ 17 
8.3.2 
Exclusion Criteria ........................................................................................................... 17 
8.3.3 
Criteria and procedures for subject’s withdrawal or discontinuation ............................. 17 
8.3.4 
Point of enrolment .......................................................................................................... 17 
8.3.5 
Total expected duration of the clinical investigation ...................................................... 17 
8.3.6 
Expected duration of each subject's participation ......................................................... 17 
8.3.7 
Number of subjects required to be included in the clinical investigation ....................... 18 
8.3.8 
Estimated time needed to select this number (i.e. enrolment period) ........................... 18 
8.4 
Procedures ............................................................................................................. 18 
8.4.1 
Pre-Operative ................................................................................................................ 18 
8.4.2 
Surgery .......................................................................................................................... 18 
8.4.3 
First Activation ............................................................................................................... 19 
8.4.4 
3 months post-op ........................................................................................................... 19 
8.5 
Monitoring Plan ...................................................................................................... 19 
9 
Statistical Considerations ......................................................................................... 20 
9.1 
Sample Size Calculation ........................................................................................ 20 
9.2 
Candidate algorithm exploration ............................................................................. 20 
9.3 
Insertion property analysis ...................................................................................... 21 

 
 
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9.4 
Association analysis of trans-impedance and intra-cochlear voltage measurements 
with the NRT thresholds and intra-cochlear electrode array position over time ................. 21 
10 
Data Management ...................................................................................................... 21 
11 
Amendments to the CIP ............................................................................................ 21 
12 
Deviations from the CIP ............................................................................................ 21 
13 
Device accountability ................................................................................................ 22 
14 
Statements of compliance ........................................................................................ 22 
14.1 
Declaration of Helsinki and compliance with standards .......................................... 22 
14.2 
Ethics Committee Approval .................................................................................... 22 
14.3 
Audits and Supervision ........................................................................................... 22 
14.4 
Study Records ........................................................................................................ 22 
15 
Informed consent process ........................................................................................ 23 
15.1 
Obtaining informed consent .................................................................................... 23 
15.2 
Data Privacy ........................................................................................................... 23 
16 
(Serious) Adverse Events ((S)AE), Adverse Device Effects (ADE) and device 
deficiencies ................................................................................................................ 24 
16.1 
Definitions .............................................................................................................. 24 
16.1.1 
Adverse event - AE ........................................................................................................ 24 
16.1.2 
Adverse device effect - ADE .......................................................................................... 24 
16.1.3 
Serious Adverse event - SAE ........................................................................................ 24 
16.1.4 
Serious Adverse Device Effect – SADE ........................................................................ 24 
16.1.5 
Device deficiency ........................................................................................................... 24 
16.2 
Reporting process for Serious Adverse Events ...................................................... 25 
16.3 
Recording and assessment of AEs ......................................................................... 25 
16.4 
Data Monitoring Committee .................................................................................... 25 
16.5 
List of anticipated Adverse Device Effects .............................................................. 25 
16.6 
Device deficiency reporting requirements ............................................................... 25 
17 
Suspension or premature termination ..................................................................... 26 
18 
Publication Policy ...................................................................................................... 26 
19 
Bibliography ............................................................................................................... 27 
20 
Change History .......................................................................................................... 27 
21 
Appendix I: List of investigators............................................................................... 28 
 
 
 
 
 
 

 
 
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Signature Page 
 
By signing this page the Sponsor, Coordinating Investigator and Principal Investigator agree 
to conduct this investigation in accordance with the current investigational plan. Substantial 
amendments to the clinical investigation plan, the informed consent, or other written 
information provided to subjects must be approved in writing by the Ethics Committee, the 
Sponsor, the Coordinating Investigator and the Principal Investigators before the changes are 
clinically implemented, except under emergency circumstances to protect the rights, safety 
and well-being of the subjects. 
 
Sponsor Signature 
 
 
 
PRINT NAME 
 
DATE  
 
 
General Manager Cochlear 
Technology Centre Belgium 
SIGNATURE 
 
TITLE 
 
Coordinating Investigator Signature  
 
 
 
PRINT NAME 
 
DATE  
 
 
Coordinating Investigator 
SIGNATURE 
 
TITLE 
 
Principal Investigator Signature 
 
 
 
PRINT NAME 
 
DATE  
 
 
Principal Investigator 
SIGNATURE 
 
TITLE 
 

 
 
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1 Clinical Investigation Synopsis 
Name of CE marked 
/ 
TGA 
approved 
devices: 
Custom Sound™ EP 5 (CSEP); Nucleus CP900 Series processor; 
Nucleus Programming Pod; Cochlear™ Nucleus® Profile with Slim 
Modiolar Electrode (CI532) or Contour Advance Electrode (CI512) 
Study number and 
short study title: 
CLTD5676 Trans-impedance matrix 
Coordinating 
Investigator: 
 Complejo Hospitalario Universitario 
Insular Materno Infantil; Avenida Marítima Del Sur, S/n, 35016 Las 
Palmas de Gran Canaria – Spain 
Principal 
Investigator(s) and 
sites: 
Refer Appendix I 
 
Study start (Mmm 
yyyy): 
Sep 2017 
Total expected 
duration of the 
clinical investigation: 
19 months 
Enrolment period: 
16 months 
Expected duration 
per subject: 
3 months 
Study design: 
Descriptive, prospective with sequential enrolment 
Number of subjects: 
154 
Inclusion criteria: 
1. Candidate for cochlear implantation with the CI532 or CI512 
devices 
2. 18 years of age or older at the time of enrolment 
3. Normal cochlea anatomy, established via pre-operative CT. 
4. Willingness to participate in and to comply with all requirements 
of the protocol 
Exclusion criteria: 
1. Prior cochlear implantation in the ear to be implanted 
2. Ossification or any other cochlear anomaly that might prevent 
complete insertion of the electrode array 
3. Abnormal cochlear anatomy on pre-operative CT or MRI 
imaging 
4. Additional handicaps that would prevent participation in 
evaluations  
5. Pregnant and breast feeding women, prisoners, or anyone in 
custody 
6. Unrealistic expectations on the part of the subject, regarding the 
possible benefits, risks and limitations that are inherent to the 
procedure 
Primary objective(s): 
To explore the specificity (the number of true negative responses 
divided by the number of negative (non-anomalous) cases) of a 
candidate algorithm that has the ability to detect low incidence 
deviations from a normal electrode position using trans-impedance 
measurements  

 
 
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Secondary 
objective(s): 
1. To explore the association between the trans-impedance and 
intra-cochlear voltage measurements, NRT thresholds and the 
intra-cochlear electrode array position.  
2. To investigate changes in the trans-impedance and intra-
cochlear voltages along with NRT thresholds over time to 
identify the stability of the measurements.  
3. To establish a database of trans-impedance and intra-cochlear 
voltages, NRT thresholds and CT/DVT images for educational, 
research and development purposes. 
Treatment and 
follow up schedule: 
Procedure 
Pre-
op 
Surgery 
First 
Activation 
3 
months 
post-op 
Informed Consent 
X 
  
 
 
Demographics, Medical 
& Hearing History 
X 
 
 
 
Surgical questionnaire 
 
X 
 
 
Voltage tomography and 
impedance matrix 
 
X (after electrode 
insertion) 
X 
X 
Auto NRT thresholds 
  
X (after electrode 
insertion) 
X 
X 
CT/DVT Scan 
X  
X (after electrode 
insertion, may be 
done after surgery) 
 
 
(S)AE, ADE, DD 
  
X 
X 
X 
Protocol deviations 
 
X 
X 
X 
Primary endpoint: 
Trans-impedance and intra-cochlear voltage measurements for 
each electrode contact after electrode insertion with post-operative 
CT/DVT Scan. 
Secondary 
endpoints: 
1. NRT thresholds for each electrode contact during surgery and 
pre-operative CT/DVT Scan co-registered with the post-
operative CT/DVT Scan collected for the primary endpoint. 
2. Trans-impedance and intra-cochlear voltage measurements 
and NRT thresholds for each electrode contact at first activation 
and 3 months post-operative 
3. Validated database entry of trans-impedance and intra-cochlear 
voltage measurement and NRT thresholds during surgery, at 
first activation and three months post-operative as well as the 
pre-operative and post-operative CT/DVT Scans respectively.  
 
 

 
 
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2 Terms and Abbreviations 
Term 
Definition 
Trans-impedance 
measurement 
An impedance measurement is a calculated measurement 
obtained by dividing the voltage difference between two 
electrodes by the current applied to obtain this voltage.  A 
trans-impedance measurement is similar to an impedance 
measurement except that the current applied to obtain the 
voltage is not applied to electrodes from which the voltage 
measurement is obtained. 
Specificity 
The true negative rate.  The measure of the proportion of 
negatives that are correctly identified as such (i.e., the 
percentage of normal insertions, as verified by CT/DVT scan, 
that are correctly identified via an algorithm as not having an 
anomalous position). 
 
Abbreviation 
Definition 
TIM 
Trans-impedance matrix 
CSEP 
Custom Sound™ Electro Physiology 
EC 
Ethics Committee 
NRT 
Neural Response Telemetry 
PIC 
Patient Informed Consent form 
DICOM 
Digital Imaging and Communications in Medicine 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form 
AE 
Adverse Event 
CPM 
Clinical Project Manager 
GCP 
Good Clinical Practice 
DD 
Device Deficiencies 
 
3 Introduction 
At the beginning of 2017 the global number of cochlear implant (CI) recipients have reached 
approximately 400’000. CIs are indicated for ears with moderately severe to profound 
hearing loss as referenced in the current labelling. It is anticipated that this number will 
significantly increase over the coming years because of the ageing of the population globally 
and an increase in awareness regarding the restorative hearing benefits a CI can bring. 
Given these expectations on future CI demands CI manufacturers need to focus their 
developments on the expectations of health care systems as well as patients’ needs and 
requirements of professionals.  
Severe to profound deafness is typically caused by a degeneration of the inner hair cells 
(IHCs) in the inner ear are responsible for the initiation of neural spikes. In their absence, the 
information to the auditory cortex is affected. A CI bridges the IHCs by direct electrical 
stimulation of the peripheral auditory nerve. For optimal patient outcomes, it is important that 

 
 
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the CI electrode (see figure 1) is surgically placed in the inner ear (in scala tympani), close to 
the excitable tissue. 
 
 
Figure 1: Optimal position of perimodiolar electrode array 
 
For various reasons, the intra-cochlear position of the electrode may be suboptimal. The 
insertion angle may be too shallow or too deep; the electrode may buckle; a perimodiolar 
array may take a lateral trajectory away from the nerve; or the tip may fold over. Ramos et al. 
(in press, 2016) has addressed risk mitigation of sub-optimal intra-cochlear electrode 
placement after insertion. These modalities occur at a low incidence rate (a few percent, Dirr 
el al. 2013, Grolman et al. 2008, Zuniga et al. 2016), but may be associated with degraded 
hearing outcomes (Zeh & Baumann HNO 2015 63 (8):557-576.) It is therefore desirable to be 
able to detect these anomalies in the operating theatre so that the surgeon has the 
opportunity to correct them.   
 
The gold standard to verify the electrode position currently is through radiological imaging 
techniques, such as CT scan or X-ray. This imaging increases the cost and duration of the 
procedure and often includes radiation which may put the patient at risk of ‘radiation-related’ 
disease according to the Recommendations of the International Commission on Radiological 
Protection. In other instances, the logistical burden of obtaining intra-operative imaging leads 
to the electrode array placement being verified post-operatively, meaning either the electrode 
position is left uncorrected or an additional surgery is required.  
 
An alternative to medical imaging may be objective measures. State of the art implant 
systems can not only stimulate but also contain a measurement amplifier, e.g. to capture the 
auditory nerve’s response to electrical stimulation, known as electrically evoked compound 
action potential (eCAP).  The amplifier is also capable of measuring the voltage on an 
arbitrary electrode pair; this capability is routinely used to obtain impedance measurements 
during surgery by measuring the voltage on the stimulating electrode pair and dividing this 
voltage by the current applied(R=V/I).  In addition to this routine measure, the amplifier can 
also be configured to measure the intra-cochlear voltage field -resulting from the stimulation 
of one electrode pair- along the entire electrode array; i.e. the electrical spread curve.  This 
technique is known as electrical voltage telemetry (EVT) or electrical field imaging (EFI). The 
full set of electrical spread curves, normalised by the current is known as the trans-
impedance 1 matrix (TIM). An example is shown in figure 2.  
                                               
1 Since the stimulation and recording electrode are not necessarily identical, this value is called a trans-impedance 
instead of an impedance  
 

 
 
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Figure 2: Trans-impedance measure for electrode 11 
 
Literature (Vanpoucke, 2004) reports that there is significant variability in these curves, due 
to the variation in anatomy, electrode position and tissue reaction. However, it has been 
observed that the information contained in a trans-impedance matrix can be correlated to 
some aspects of the electrode array position (Vanpoucke et al. 2012, Zuniga et al. 2016) and 
algorithms are being developed that use trans-impedance and intra-cochlear voltage 
measurements to provide feedback on the electrode array position.  One such algorithm, 
developed by Ramos et al. uses this information to detect whether the electrode tip has 
folded over or whether the electrode array is potentially outside the cochlea.  However, given 
the variability between ears, the tuning of the threshold parameter in this algorithm (is the 
implantation normal or not?) needs to be explored to determine the sensitivity and the 
specificity.  
 
The long-term aim is for this and other proposed algorithms, when implemented in a device 
that communicates with the cochlear implant, to provide feedback on the electrode array 
position immediately after or during insertion of the electrode. If sufficiently sensitive, the 
feedback provided by such algorithms can help surgeons make informed decisions on the 
appropriate course of action, which may include obtaining imaging to confirm the position of 
the electrode array and subsequent repositioning before closure of the surgical procedure, to 
achieve optimal outcomes. This will reduce the need for post-operative radiological 
diagnostics and avoid unnecessary re-operations to correct inappropriate placement of the 
electrode array.  In addition, if it can be demonstrated that an algorithm has sufficient 
diagnostic specificity (the ability to correctly diagnose successful electrode insertions), its 
feedback might replace the need for routine intra-operative radiological imaging to confirm 
good electrode placement. 
 
This clinical investigation will gather trans-impedance and intra-cochlear voltage 
measurements intra- and post-operatively.  These measurements can be used to 
characterise the electrical properties of the electrode array and the surrounding tissue in the 
cochlea after insertion.  This data will be used to explore the specificity of the Prof. Ramos 
candidate algorithm.  Given the low incidence of anomalous electrode position cases in 
normal clinical practice (Dirr et al. 2013) and the inability to deliberately generate anomalous 
electrode positions in patients; this study is only focussed on exploring the specificity.2 
(negative results divided by true negative cases) of the algorithm.  An exploration of the 
sensitivity (positive results divided by true positive cases) of the candidate algorithm is out of 
scope for this study.  A separate in vitro study where anomalous insertions can be purposely 
created will be conducted to explore the sensitivity.  
 
                                               
2 For statistical purposes, it is assumed that this study will show the algorithm able to achieve ≥98% specificity with 
a 90% confidence. 

 
 
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For the purpose of quantifying the accuracy of a diagnostic algorithm, the following 
terminology is used: 
 
Positive case – a case in which electrode insertion results in an anomalous position. 
 
Negative case – a case in which electrode insertion is successful and position is not 
anomalous. 
 
True positive response – The candidate algorithm correctly detects the presence of 
an anomalous electrode position.  
 
False positive response – The candidate algorithm incorrectly indicates an 
anomalous electrode position when none is present. 
 
True negative response– The candidate algorithm correctly indicates no anomalous 
electrode position when none is present.   
 
False negative response – The candidate algorithm fails to detect an anomalous 
electrode position even though one is present. 
 
Sensitivity - the number of true positive responses divided by the number of positive 
cases (anomalous positions). 
 
Specificity - the number of true negative responses divided by the number of 
negative (non-anomalous) cases. 
 
Positive predictive value – the probability that given a positive response the electrode 
position is anomalous 
 
Negative predictive value – the probability that given a negative response the 
electrode position is not anomalous 
 
 
The candidate algorithm is provided with the trans-impedance measurements and indicates 
whether a tip fold-over or array outside the cochlea have been detected.  For the feedback 
from this algorithm to be clinically useful it must be shown that the specificity is sufficiently 
high to ensure that the surgeon is not unnecessarily prompted to take action (confirmation of 
electrode position by imaging) when not required.  Current methods for detecting anomalous 
electrode position without relying on imaging either use manually-perceived force feedback 
from the electrode array (Dirr et al. 2013, Pile et al. 2013) or measurement of neural activity, 
(Grolman et al. 2008, Zuniga et al. 2016).  Dirr et al. shows a positive predictive value of 29% 
using the sense of increased physical resistance during insertion whereas Grolman did not 
comment on the positive predictive value of the spread of excitation technique and Zuniga 
stated it was not clear. In the current study the aim is to show that using an algorithm based 
on the trans-impedance matrix a positive predictive value of twice that observed by Dirr et al. 
can be achieved, thus the aim is a positive predictive value of 60%. 
 
Following the initial analysis as outlined in this investigation plan, future candidate algorithms 
developed for the purpose of detecting anomalous electrode position will be evaluated using 
the data as collected within the current investigation.   
4 Identification and description of the devices 
The following devices will be used in this investigation: 
Implant 
CI532, CI512 
CE marked / TGA approved 
Sound processor 
CP900 series 
CE marked / TGA approved 
Software 
CSEP 5 
CE marked / TGA approved 
Interface 
Nucleus Programming Pod 
CE marked / TGA approved 
 

 
 
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All hardware and software used in this clinical investigation has market approval in the 
European Union and in Australia. The use of all software and hardware in this clinical 
investigation is according to the current labelling and instructions for use.  
The CSEP software, CP900 series sound processor and CI532 and CI512 implants are all 
used routinely by cochlear implant and hearing care professionals. The CP900series sound 
processor is available at the clinic in case the recipient is aided with another sound 
processor. CSEP is incorporated in clinical routine to perform objective measurements which 
may help to create hearing profiles for cochlear implant recipients. All components will be 
available at the investigational sites as part of the clinical routine practice.   
The Investigators will be trained on the trans-impedance and intra-cochlear voltage 
measurement that forms part of this study. 
Please refer to the package insert and user guides of the devices for further information. 
 
5 Justification for the design of the clinical investigation 
Several researchers have demonstrated the utility of trans-impedance matrix and other 
voltage measurements (Hey et al. 2015, Vanpoucke et al. 2004, Vanpoucke et al. 2012) to 
identify the intra-cochlear electrode positioning. The current investigation is designed to both 
evaluate a candidate algorithm for detecting the occurrence of gross anomalies in position 
(e.g. tip fold-over3 or the electrode array not in the cochlea) and to provide a robust dataset in 
a clinically representative sample of cochlear implant recipients that can be used to test the 
specificity and sensitivity of future electrode position feedback algorithms. Such algorithms 
have potential clinical application in providing objective feedback to the surgeon at the time 
of electrode insertion to inform the surgeon on electrode placement without additional 
radiological imaging, and may in future lead to improved clinical outcomes for cochlear 
implant recipients. 
 
No large database of combined high quality imaging of the intra-cochlear electrode position 
and reliable trans-impedance measurements exist. It is only relatively recently that it has 
become possible to determine accurate intra-cochlear electrode position, as a result of 
advances in scanner technology. Also, the trans-impedance measurements (contained in 
Custom Sound™ Electro Physiology) that will be used in the study only recently became 
available. Earlier versions of this tool did not provide sufficient resolution to accurately 
measure the electrical spread curves. 
 
To explore the decision algorithm, a large dataset is needed. This study will systematically 
collect a large pool of trans-impedance measurements of CI recipients combined with state 
of the art imaging of the implanted electrode as part of the clinical routine. Image analysis will 
allow an expert radiologist/ENT surgeon to determine for each implantation whether it is a 
normal case or not. The trans-impedance measurements will be analysed by the decision 
algorithm, and the agreement with the human experts will be established. This exploration of 
the specificity of the candidate algorithm is the main target of this study, thus being evaluated 
on the bench without patient involvement.   
 
At this point in time, little is known about the stability of the trans-impedance measurements 
over time. In the first months after implantation, the electrode will be encapsulated in a tissue 
sheath. Our assumption is that this may influence the electrical spread curves and therefore 
the performance of the classification algorithm. The study design therefore includes two post-
operative measurements. During these sessions, the response of the auditory nerve to 
electrical stimulation will be monitored as well with a technique known as neural response 
                                               
3 Where the electrode array tip turns back on itself during insertion into the cochlea. 

 
 
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telemetry (NRT). The study visits that are performed are in line with routine clinical practice, 
to minimise the additional commitment required by subjects and clinicians in participating in 
the required test sessions. 
 
The study participants will be recruited from adults CI candidates in the participating study 
centres. Since the cochlear anatomy in children is identical to adults and the same electrode 
types are used, there is no need to include children in the study. 
6 Risks and benefits of the device and clinical investigation 
6.1 Anticipated clinical benefits 
Patients participating in this study will follow routine cochlear implantation and treatment.  
Electrode position will be measured making use of CT scans routinely performed during CI 
treatment. There is no anticipated clinical benefit for the patients through participation in the 
clinical investigation.  
 
However, understanding the specificity of the candidate algorithm, and characterisation of 
the measures in the clinical setting, is expected to benefit cochlear implant patients in the 
future through a more consistent positioning of the electrode array. Additionally, it is possible 
that the use of such algorithms will in future eliminate the need for post-operative imaging 
and so benefit implanted patients through reduced exposure to radiation.  
6.2 Anticipated adverse device effects 
The potential adverse device effects while using the components listed in section 4 to 
generate electrical stimulation of the cochlea during surgery and during the routine visits after 
surgery are no greater than that posed through the clinical routine via NRT, facial nerve 
monitoring, etc. All devices used in this clinical investigation are CE marked and TGA 
approved. 
   
The study participants will undergo a standard cochlear implantation surgery, and are 
therefore identical to the risks in cochlear implant surgery as described by the package 
insert. No feedback on analysis of the intra-operative measurements will be provided to the 
surgeon during the operation. 
 
The trans-impedance and Auto NRT measurements will be performed with the CSEP 
software and therefore be subject to the standard adverse events associated with the use of 
this software. The measurements will be performed by expert clinicians trained on the use of 
this software in normal clinical practice. The risks of participating in this study are therefore 
identical to the risks in normal clinical care. 
 
The candidate algorithm is run on the data by an independent party at specified intervals on 
the data collected by the above-mentioned components. The person who performs the 
analysis does so in de-identified data after study closure. The algorithm evaluation will be 
conducted on the bench without any patient involvement. Thus, there are no anticipated 
adverse events resulting from the use of the algorithm.  
 
6.3 Residual risks related to the device 
The residual risks (e.g. overstimulation) including instructions for mitigation are listed in the 
labelling and investigators are instructed to follow these.  

 
 
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6.4 Risks associated with participation in the clinical investigation 
Participants in the clinical investigation are exposed to the risks associated with standard 
cochlear implant surgery, general anaesthesia, and NRT measures as well as CT scans before 
and after surgery within the routine clinical procedures. The trans-impedance and voltage 
measurement being an interventional measurement prolongs the surgery by 1 minute. This will 
always happen in consultation with the surgeon and the anaesthetist and may even be 
conducted during the wake up phase after anaesthesia not to put the patient at an additional 
risk.  
Interactions with concomitant medical treatments are not envisaged during the clinical 
investigation. Please see the labelling associated with the components used in this study. 
6.5 Risk mitigation 
This study will follow routine clinical practice and risk mitigation.  
As precaution to avoid any risks associated with data protection the patient’s identity and all 
information collected during the investigation will be kept strictly confidential and in accordance 
with EU and Australian data protection laws. Each participant’s data will be given a unique 
code and the list of codes will be kept by the investigator as described in the data privacy 
section. 
No other risks are expected that would exceed the clinical routine practice of CI implantation 
and clinical follow-up. 
The risk of electrode position determination by an experimental telemetry processing algorithm 
is mitigated by executing the algorithm on the exported data completely independent of clinical 
procedures and by keeping the outcomes of these algorithms blind to the investigators until 
the study is officially closed. The patient management is not dependent on the findings from 
this study. 
6.6 Risk-to-benefit rationale 
The risks associated with this study will be kept to a minimum. The study population consists 
of conventional CI candidates, scheduled for CI treatment. Besides the trans-impedance and 
intra-cochlear voltage measurements, the study will capture data that are collected during 
routine clinical practice. The trans-impedance and intra-cochlear voltage measurements will 
be collected with the CE marked and TGA approved CSEP application.  Collection of this 
data takes less than 1 minute per session in addition to the clinical routine measures and 
does not create any additional risks beyond a slight prolongation of the surgical procedure 
with the measurement time (only for the intra-operative measurement session). 
 
The benefit-risk profile for this study is considered positive given the low risks and the 
potential for future improvement of CI treatment including access to a non-invasive 
measurement of electrode array positioning and thereby minimization radiation exposure 
through radiological imaging currently routinely used for detection of electrode position.  
7 Objectives and hypothesis 
Primary objective(s): 
To explore the specificity (the number of true negative responses 
divided by the number of negative (non-anomalous) cases) of a 
candidate algorithm that has the ability to detect low incidence 
deviations from a normal electrode position using trans-
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Secondary 
objective(s): 
1. To explore the association between the trans-impedance and 
intra-cochlear voltage measurements, NRT thresholds and 
the intra-cochlear electrode array position.  
2. To investigate changes in the trans-impedance and intra-
cochlear voltages along with NRT thresholds over time to 
identify the stability of the measurements.  
3. To establish a database of trans-impedance and intra-
cochlear voltages, NRT thresholds and CT/DVT images for 
educational, research and development purposes. 
Primary endpoint: 
Trans-impedance and intra-cochlear voltage measurements for 
each electrode contact after electrode insertion with post-
operative CT/DVT Scan. 
Secondary endpoints: 
1. NRT thresholds for each electrode contact during surgery 
and pre-operative CT/DVT Scan co-registered with the post-
operative CT/DVT Scan collected for the primary endpoint. 
2. Trans-impedance and intra-cochlear voltage measurements 
and NRT thresholds for each electrode contact at first 
activation and 3 months post-operative 
3. Validated database entry of trans-impedance and intra-
cochlear voltage measurement and NRT thresholds during 
surgery, at first activation and three months post-operative as 
well as the pre-operative and post-operative CT/DVT Scans 
respectively.  
Hypothesis 
H0: The specificity of an algorithm that will detect low incidence 
deviations from a normal intra-cochlear electrode insertion will be 
< 98%. 
H1: The specificity of an algorithm that will detect low incidence 
deviations from a normal intra-cochlear electrode insertion will be 
≥ 98%.  
8 Design of the clinical investigation 
8.1 General 
The current clinical investigation is designed as descriptive research with sequential 
enrolment. The treatment schedule is according to the clinical routine visit schedule by 
prospectively adding a one minute trans-impedance and voltage measurement to the clinical 
routine measurements. The purpose of the clinical investigation is to collect and describe the 
characteristics of the trans-impedance and voltage measurements to explore the specificity 
of a candidate algorithm that has been developed to detect certain anomalous electrode 
array positions. Insertions will be classified based on the electrode position in relation to the 
cochlea structures as determined from pre- and post-operative CT scans. The classification 
will establish an insertion as either normal or showing one or more anomalous properties. 
The study will then provide the candidate algorithm with the 154 classified insertions to 
explore the specificity of the algorithm, this should allow a specificity of up to 98% to be 
established with a 90% confidence4. The trans-impedance and voltage measurements are 
obtained at repeated visits to evaluate the candidate algorithm specificity over time. 
                                               
4 Assuming up to 9 anomalous insertions in the sample of 154 implantations. 

 
 
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Blinding procedures are not appropriate for the voltage and trans-impedance measures to be 
collected with the clinical routine software CSEP, as it is not possible to conceal the 
presence, or absence, of the devices from the investigators.  
Since the candidate algorithm to detect certain anomalous electrode array positions has not 
been implemented in any CE marked and TGA approved software, no real time feedback on 
any insertion related events will be provided to the clinician nor surgeon throughout the 
surgery nor aftercare. The surgeon and the clinician shall not deviate from their established 
clinical routine measures as CT imaging, x-ray or objective measures to detect anomalous 
electrode array positions and are advised not to interpret the voltage and trans-impedance 
measures.  
In addition, the data will be analysed to establish the normative range of trans-impedance 
and voltage measurements in CI532 and CI512 electrode arrays, the correlation to NRT 
measurement, to correlation to electrode-to-modiolus distance (from CT/DVT Scans) and the 
normal variations of those measures over time. 
The CT/DVT imaging before and after surgery and the CSEP measurements during and after 
surgery is part of the clinical routine in CI treatment and patients will be selected who follow 
this clinical routine.  
In addition, the measurements, CT/DVT scans and classifications will be de-identified and 
stored in a database to support the further development and validation of algorithms. Those 
insertions showing the presence of anomalous properties will be excluded from the dataset 
that is presented to the candidate algorithm but will be included in this database. To allow for 
the exclusion of these insertions an additional 9 subjects are added to the study. 
Depending on the recommended practice in the clinics the measures of surgeries performed 
by experienced and unexperienced surgeons will be collected. For retracement the name of 
the inserting surgeon is labelled on the surgical questionnaire.     
8.2 Treatment schedule 
The treatment schedule includes a pre-operative assessment, the CI surgery, the first 
activation visit and well as the 3 months’ post-operative visit. The CT scans before and after 
surgery are part of the clinical routine test battery.   
Procedure 
Pre-op 
Surgery 
First 
Activation 
3 months 
post-op 
Informed Consent 
X 
  
 
 
Demographics, Medical & 
Hearing History 
X 
 
 
 
Surgical questionnaire 
 
X 
 
 
Voltage tomography and 
impedance matrix 
 
X (after electrode 
insertion) 
X 
X 
Auto NRT thresholds 
  
X (after electrode 
insertion) 
X 
X 
CT/DVT Scan 
X  
X (after electrode 
insertion, may be 
done after surgery) 
 
 
(S)AE, ADE, DD 
  
X 
X 
X 
Protocol deviations 
 
X 
X 
X 
 
The Demographic, Medical and Hearing History is part of the pre-op assessment. The surgical 
questionnaire applies after the surgery to collect information on insertion related events and 

 
 
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the name of the surgeon who has inserted the electrode array. The Auto NRT thresholds, the 
voltage tomography and impedance matrix applies during surgery as well as during the first 
activation session and three months after surgery. An active follow-up on the occurrence of 
(S)AE, ADE, DD applies. Protocol Deviations will be documented as soon as possible after 
occurrence. The acceptable visit window tolerance is +/-1 month. 
8.3 Subjects  
8.3.1 
Inclusion Criteria 
1. Candidate for cochlear implantation with the CI532 or CI512 device 
2. 18 years of age or older at the time of enrolment 
3. Normal cochlea anatomy, established via pre-operative CT 
4. Willingness to participate in and to comply with all requirements of the protocol 
8.3.2 
Exclusion Criteria 
1. Prior cochlear implantation in the ear to be implanted 
2. Ossification or any other cochlear anomaly that might prevent complete insertion of the 
electrode array 
3. Abnormal cochlear anatomy on pre-operative CT or MRI imaging 
4. Additional handicaps that would prevent participation in evaluations  
5. Pregnant and breast feeding women, prisoners, or anyone in custody 
6. Unrealistic expectations on the part of the subject, regarding the possible benefits, risks 
and limitations that are inherent to the procedure 
8.3.3 
Criteria and procedures for subject’s withdrawal or discontinuation 
Subjects can decide to withdraw from the investigation without indicating any reasons. The 
investigator may decide to discontinue a patient due to major non-compliance with the CIP 
requirements (e.g. visit schedule not met).  The investigator may also decide to discontinue a 
patient’s involvement in the study for several reasons, including the subject not reasonably 
following the visit schedule described in Chapter 8.2, the subject no longer satisfying the 
Inclusion/Exclusion criteria (e.g., subject becomes pregnant during the study or develops a 
handicap that prevents the ability to sufficiently perform the tests) or if there are any reportable 
(S)AE, ADE, DD. If a subject withdraws or is withdrawn from the study, that subject will still be 
provided with routine CI aftercare and maintenance at the investigational sites as part of the 
clinical routine.  
8.3.4 
Point of enrolment 
Subjects who satisfy the inclusion criteria will be provided with a clear explanation of the Patient 
Informed Consent (PIC) with sufficient time for discussion and clarification to ensure the patient 
understands the requirements and expectations. Subjects are enrolled into the clinical 
investigation when they have signed the Informed Consent Form. 
8.3.5 
Total expected duration of the clinical investigation 
19 months 
8.3.6 
Expected duration of each subject's participation 
3 months 

 
 
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8.3.7 
Number of subjects required to be included in the clinical investigation 
154, assuming that 9 recipients will not be suitable for the evaluation of the algorithm due to 
the occurrence of an insertion anomaly. 
8.3.8 
Estimated time needed to select this number (i.e. enrolment period) 
16 months 
8.4 Procedures 
The procedure of this clinical investigation follows the clinical routine battery of CI treatment 
by implementing a pre-operative visit, the surgery, the first activation as well as a 3 months’ 
post-operative visit.  
Protocol deviations, (S)AE, ADE, DD will be actively collected and reported according to 
national and regional requirements at each study visit after the patient has signed the PIC. 
8.4.1 
Pre-Operative  
The patient will be provided the Patient Informed Consent (PIC) to review, to discuss with the 
principal investigator of the study and to sign.  One version of the signed PIC will be collected.  
Within the clinical routine, the CT/DVT Scan will be performed along with the collection of 
standard medical and hearing history.   
Demographics, Medical and Hearing History will be completed as part of the pre-operative 
assessment. 
8.4.2 
Surgery  
After electrode array insertion, the extra-cochlear electrode lead is placed and the plate 
electrode is covered by skin flap.  The NRT, trans-impedance and voltage measurements are 
performed using CSEP. The CSEP measurements take approximately 11 minutes for Auto-
NRT with conditioning on 22 electrodes and 1 minute for trans-impedance and voltage 
measurements. Since Auto-NRT is part of the clinical routine, the additional time effort for this 
study is 1 minute. 
The following sequence applies: 
1. Auto NRT with conditioning on 22 electrodes 
2. Trans-impedance and voltage measurements 
The CT/DVT scan of the intra-cochlear electrode array positioning will be conducted as part of 
the clinical routine battery.  
Within the surgical questionnaire the number of surgeries of the implanting surgeon, insertion 
related events as well as the corrective actions (if applicable) are documented. This information 
will be entered into the corresponding CRF after review by the surgeon. 
In case the electrode array placement needs to be corrected as part of the clinical and surgical 
routine, the following workflow maintains:  
1. If not already done as described before: Run the trans-impedance and voltage 
measurements before removing the electrode array.  
2. Correct the electrode array placement as per normal clinical routine. 
3. After successful reinsertion / corrective action of the position of the electrode array, run the 
Auto-NRT, trans-impedance and voltage measurements again. 
The intra-operative measures with CSEP will be exported as cdx/csv files and transferred in 
an anonymized form to Cochlear.  

 
 
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An active follow-up on the occurrence of (S)AE, ADE, DD applies. Protocol Deviations (if 
applicable) will be documented as soon as possible after occurrence. 
8.4.3 
First Activation 
At the end of the first activation CSEP 5 will be used to perform an NRT threshold measurement 
on 22 electrodes followed by the trans-impedance and intra-cochlear voltage measurement.  
In some clinics, it is part of the clinical routine to measure NRT on 22 electrodes at the start of 
the first activation visit.  These clinics should continue following routine practice and only 
perform the trans-impedance and voltage measurements at the conclusion of the first 
activation visit. The effort of those measures may take approximately 12 minutes.  
Following the conclusion of the clinical session the measures with CSEP for this session will 
be exported as cdx/csv file and transferred in an anonymized form to Cochlear. 
An active follow-up on the occurrence of events applies. Protocol Deviations (if applicable) will 
be documented as soon as possible after occurrence. 
8.4.4 
3 months post-op 
At the end of the first activation CSEP 5 will be used to perform an NRT threshold measurement 
on 22 electrodes followed by the trans-impedance and intra-cochlear voltage measurement. 
The effort of those measures may take approximately 12 minutes.  
Following the conclusion of the clinical session the measures with CSEP for this session will 
be exported as cdx/csv file and transferred in an anonymized form to Cochlear. 
An active follow-up on the occurrence of events applies. Protocol Deviations (if applicable) will 
be documented as soon as possible after occurrence. 
8.5 Monitoring Plan 
The sponsor will appoint a study monitor to perform regular visits at the study site, as defined 
in the Monitoring Plan. Prior to the first subject enrolment, an initiation visit will be performed 
by the clinical project manager or delegate and the study monitor ensuring that assigned study 
personnel are familiar with this Clinical Investigation Plan and procedures and device handling, 
trained in Good Clinical Practice (GCP) compliance, eCRF completion, event reporting, and 
maintenance of study related documentation. 
The study monitor will ensure compliance with the clinical investigation plan and EN ISO 
14155, accurate data recording on the eCRFs, will raise data clarifications, will monitor 
recruitment rates and adherence to follow-up schedules. The study monitor will also check the 
upkeep of the investigator file. The investigator shall permit and assist the study monitor to 
carry out verification of completed eCRFs against data in the source documents. 
Source documents are defined as any printed, optical or electronic document containing 
source data (hospital records, audiograms, speech test results, laboratory notes, device 
accountability records, radiographs, records kept at the investigational site) necessary for the 
reconstruction and evaluation of the clinical investigation. The extent of source data verification 
is defined in the Monitoring Plan. The investigator shall provide all requested documentation 
in a timely and organized manner. 
The study monitor shall inform the sponsor about any problems relating to facilities, technical 
equipment or medical staff at the study site.  
The study monitor shall provide the clinical project manager with written reports, after each 
visit or contact with the investigational site. 
The investigator has to inform the sponsor about any additional local requirements that may 
impact the work of a monitor especially if access to source data may be limited by local 

 
 
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regulations. This is to ensure any necessary action to be taken before the study start to allow 
proper monitoring according to the EN ISO 14155 Standard. 
9 Statistical Considerations 
9.1 Sample Size Calculation 
An in-depth description of the statistical characterisation and correlation will be part of the 
Statistical Analysis Plan.  Final statistical analysis will be conducted on a clean and complete 
database after database closure.  
The candidate algorithm provides the ability to detect gross electrode position anomalies (eg. 
tip fold-over or electrode not in the cochlea). It provides binary outputs; a value of zero 
(negative result) or a value of one (positive result). A value of zero indicates that the 
algorithm concluded that an anomalous position has not occurred and the value of one 
indicates that the algorithm concluded that an anomalous position has occurred. To be useful 
as a tool that can replace routine use of X-rays and CT scans, the algorithm is required to 
have a minimal false positive rate.  To ensure that this expectation is reasonably fulfilled, the 
98% specificity target is set to be the lower bound of the 90% binomial confidence interval for 
the specificity of the algorithm.  An iterative approach was adopted to estimate the required 
patient sample size which takes into account the likelihood of anomalous position events.  It 
was assumed that the occurrence of a tip fold-over (the principal form of position anomaly 
under consideration) follows a binomial distribution with a positive probability of around 4% 
based on the weighted average percentage for tip fold-overs in pre-curved arrays reported by 
Grolman et al. 2009 and Zuniga et al. 2016.  Using the Clopper-Pearson method a sample 
size of 154 was selected, which gives an 89% chance of 9 or less tip fold-overs taking place, 
resulting in at least 145 ‘normal’ insertions.  If the algorithm correctly diagnoses all 145 
insertions, the lower bound of the two-tailed 90% confidence interval for specificity will be 
97.97% which is approximately 98%.  In other words, if the algorithm correctly identifies all 
145 cases as ‘normal’ then it can be concluded that its specificity is 98% or better with 90% 
confidence. 
This entails that the false positive rate is no more than 2%, or that no more than 1 out of 50 
insertions with normal position will be indicated as anomalous, and potentially receive 
medical imaging just to reveal that the insertion is normal.  Assuming the incidence of tip 
fold-overs to be around 4% for pre-curved arrays, the 98% specificity will provide a positive 
predictive value of over 60%5 which is meets the target positive predictive value from section 
3. 
In conclusion, 154 implantations are required.  
9.2 Candidate algorithm exploration 
To explore the specificity of the candidate algorithm it will be provided with the trans-impedance 
data collected at surgery, first activation and 3 months post-operatively for insertions that has 
been determined not to contain any anomalous electrode array position based on the CT 
Scans.   
In each instance the result of the algorithm will be analysed to determine the specificity based 
on the amount of positive and negative results returned by the algorithm. 
                                               
5 For the sample size calculation, it is assumed that the sensitivity (true positive) of the candidate algorithm is 90%. 

 
 
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9.3 Insertion property analysis 
From an isotropic voxel set (i.e. DICOM data) with the Ramos et al. algorithm to extract 
radiological parameters automatically from CT/DVT images and via surgical questionnaire the 
following parameters will be collected: Insertion related events (Tip-foldover, Scala 
displacement, Electrode extrusion/shallow-insertion, Over-insertion), Homogeneity Factor and 
Modiolar Proximity 
For the exploration of the candidate algorithm insertions that have insertion related events or 
a poor medial lateral should be excluded from the dataset. These insertions should still be 
included in the database, with the appropriate classification. 
9.4 Association analysis of trans-impedance and intra-cochlear voltage 
measurements with the NRT thresholds and intra-cochlear electrode array 
position over time 
The intra-cochlear electrode position properties will be correlated against the trans-impedance 
and voltage measurements as well as the NRT thresholds using pairwise Pearson product-
moment correlation coefficient.   
For each implanted ear the trans-impedance and voltage measurements as well as the NRT 
thresholds will be compared across the three measurement times (intra-operative, first 
activation and 3 months) to determine the stability.  Any changes in one of the measurements 
will be compared with the others to check for co-variance. 
10 Data Management 
Data collection is performed through 
 a 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. 
 is a system that has been verified and validated by the vendor. Installation of the 
system within Cochlear has been validated as well. Study-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 study-specific data 
in 
can only be accessed by those that have been allocated their individual account, 
which are personnel of the investigational sites, clinical project managers, study monitors and 
data management. 
The patient’s identity and all clinical information collected during the investigation will be de-
identified (coded) and kept strictly confidential in accordance with Australian and EU data 
protection laws. Each participant will be given a unique code and the list of codes will be kept 
by the investigator as described in the data privacy section. 
11 Amendments to the CIP 
No changes in the study procedures shall be effected without mutual agreement of the 
investigator or investigators and the sponsor. All changes must be documented by signed CIP 
amendment. Ethics Committee (EC) needs to approve substantial changes to the CIP. 
12 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 soon as possible.  

 
 
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13 Device accountability 
Not applicable. The devices used within the study are CE marked / TGA approved and part of 
the clinical routine (CSEP (5), the Nucleus Programming Pod, CP900 series sound processor, 
CI532 and CI512) 
14 Statements of compliance 
14.1 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 EN ISO 14155:2011 and any regional or 
national regulations, as appropriate. 
14.2 Ethics Committee Approval 
The clinical investigation shall not commence prior to the written favourable opinion or approval 
from the EC is obtained.  Since all study hardware and software has a CE-mark and the study 
would not entail additional invasive or otherwise stressful examinations, no CA approval will 
be sought. 
The investigator shall submit the final version of the Clinical investigation plan, the informed 
consent and all subsequently required documents to the Ethics Committee. A copy of the 
Ethics Committee opinion or approval shall be provided to the sponsor.  
Sponsor and investigator shall continue the communication with the EC as required by national 
regulations, the clinical investigational plan or the responsible EC.  
Any additional requirements imposed by the EC shall be followed. 
The investigator shall submit the appropriate documentation if any extension or renewal of the 
EC approval is required. In particular substantial amendments to the clinical investigation plan, 
the informed consent, or other written information provided to subjects must be approved in 
writing by the EC. 
The investigator will report to the EC any new information that may affect the safety of the 
subjects or the conduct of the clinical investigation. The investigator shall send written status 
summaries of the investigation to the EC regularly as per local EC requirements. 
Upon completion of the clinical investigation, the investigator shall provide the EC with a brief 
report of the outcome of the clinical investigation as per local EC requirement. 
The clinical investigation is covered by a clinical trial insurance meeting the requirements of 
the participating countries. National requirements are specified in the national Informed 
Consent (IC).  
14.3 Audits and Supervision 
Study sites and study documentation may be subject to quality assurance audits during the 
course of the clinical investigation. In addition, regulatory bodies at their discretion may conduct 
inspections, during and after study completion. 
14.4 Study Records 
The investigational site will receive and has to maintain an Investigators File which does 
include without limitation at a minimum the signed Clinical Investigation Plan, the EC approval 
letter, completed Informed Consent Forms, (S)AE, ADE, DD reports, Investigator copies of all 
CRFs, correspondence with the sponsor and third parties (if applicable) related to the Study, 
a subject identification list, and a site delegation and signature sheet. All study records and 

 
 
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source documents shall be archived at the investigational centre for at least 15 years after the 
end of the study. 
15 Informed consent process 
15.1 Obtaining informed consent 
The investigator must obtain written informed consent from the subject prior to any clinical 
investigation related examination or activity, and after explaining the rationale for and the 
details, aims and objectives of the study, the risks and benefits and alternative treatments, and 
the extent of the subject’s involvement. Ample time must 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 should be answered to the satisfaction of the subject or the 
subject’s legally acceptable representative. Subjects must not be coerced or unduly influenced 
to participate or to continue to participate in a clinical investigation. 
Each subject and the person who conducted the informed consent discussion must sign and 
date the informed consent form. Where required, a witness must sign and personally date the 
consent form. 
A copy of the information leaflet and consent form must be given to the subject. All signed 
Informed Consent Forms must be archived in the Investigators File at the investigational site, 
according to the requirements of the country’s health regulations, but for a minimum of 15 
years after completion of the clinical investigation.  
The subject or the subject’s legally acceptable representative must 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 
must be documented. 
The investigator shall forward any amendment made to the approved subject informed consent 
for review to the sponsor or study monitor and any other written information to be provided to 
the subject, prior to submission to his EC.  
15.2 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 (for example, cdx/csv files), imaging items (for example, CT Scan), 
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 his or her identification code. The 
identification code consists of STUDY IDENTIFIER-SiteID-PATIENT NUMBER. 
 
SiteID consists of country code 
 and center code 
.   
 
PATIENT NUMBER consecutive numbering based on the point of enrolment at each 
site, e.g. the first patient enrolled is - 01 
 

 
 
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16 (Serious) Adverse Events ((S)AE), Adverse Device Effects (ADE) 
and device deficiencies  
16.1 Definitions 
16.1.1 Adverse event - AE 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical signs 
(including an abnormal laboratory finding) in subjects, users or other persons whether or not 
related to the medical device. This does include events related to the medical device or the 
comparator as well as events related to the procedures involved.  
For users or other persons this is restricted to events related to the medical device. 
 
16.1.2 Adverse device effect - ADE 
Adverse event related to the use of a medical device. 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 medical device. This 
definition includes any event resulting from use error or from intentional misuse of the medical 
device. 
16.1.3 Serious Adverse event - SAE 
A serious adverse event is any adverse event that: 
 
led to a death, 
 
led to a serious deterioration in the health of the subject that either: 
o resulted in a life-threatening illness or injury, or 
o resulted in a permanent impairment of a body structure or a body function, or 
o required in-patient hospitalization or prolongation of existing hospitalization, or 
o resulted in medical or surgical intervention to prevent life threatening illness or 
injury or permanent impairment to a body structure or a body function. 
 
led to foetal distress, foetal death or a congenital abnormality or birth defect. 
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. 
This includes device deficiencies that might have led to a SAE if a) suitable action had not 
been taken or b) intervention had not been made or c) if circumstances had been less 
fortunate. These are handled under the SAE reporting system. 
16.1.4 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. 
16.1.5 Device deficiency 
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance. Device deficiencies include malfunctions, use 
errors, and inadequate labelling. 

 
 
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16.2 Reporting process for Serious Adverse Events 
The investigator shall report all Serious Adverse Events without delay to the sponsor. 
Name of contact person of the sponsor (Germany and Spain): 
 
Fax: 
 
Tel: 
 
 
Name of contact person of the sponsor (Australia): 
 
Tel: 
 
 
The sponsor has to report all SAEs and SADEs using the applicable report form as per national 
requirement. 
The investigator has to report all SAEs and SADEs to his or her EC using the applicable report 
form as per national requirement. 
Appropriate treatment of the subject shall be initiated but the study follow up shall continue 
when ethical.  
16.3 Recording and assessment of AEs 
Subjects shall be carefully monitored during the clinical investigation for potential AEs and shall 
be routinely questioned about adverse events at study visits.  
For all adverse events sufficient information shall be obtained by the investigator and recorded 
in the CRF. The investigator shall attempt to assess the relationship between the device and 
the adverse event. Appropriate treatment of the subject shall be initiated but the study follow 
up shall continue when ethical.  
16.4 Data Monitoring Committee 
The decision to establish a Data Monitoring Committee (DMC) shall be guided by the risk 
analysis, taking into account both the risks associated with the use of the medical device and 
the risks associated with subject's participation in the clinical investigation. This study is a 
non-invasive study without any additional risks for the recipients that goes beyond the clinical 
routine for CI treatment with CE marked and TGA approved medical products. Therefore it is 
justified not to establish a DMC for the planned study. 
16.5 List of anticipated Adverse Device Effects 
For this clinical investigation the listed items in section 6.2 of this CIP are anticipated Adverse 
Device Effects. 
Medical occurrences that are related to pre-existing conditions (for example, diabetes, cardial 
problems) are considered as unexpected adverse events in the frame of the clinical 
investigation. 
16.6 Device deficiency reporting requirements 
The investigator shall report any device deficiency without unjustifiable delay to the sponsor.  
Name of contact person of the sponsor (Germany and Spain): 
 
Fax: 
 
Tel: 
 
 
Name of contact person of the sponsor (Australia): 
 
 

 
 
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17 Suspension or premature termination 
The sponsor may withdraw from sponsorship of the clinical investigation if, 
 
major non-adherence to the CIP is occurring 
 
it is anticipated that the subject recruitment will not be adequate to meet the 
objectives of the clinical investigation 
Should the sponsor withdraw from sponsorship of the clinical investigation, the sponsor will 
continue sponsorship for the subjects already recruited into the study. 
An ongoing clinical investigation can be discontinued in case of: 
 
device failure 
 
serious or intolerable adverse device effect, leading to the explant or 
discontinued use of the device 
 
subject’s death 
 
investigator’s decision 
 
subject’s decision 
18 Publication Policy 
The clinical investigation will be registered at the public study register ClinicalTrials.gov. 
Investigators will be able to publish and/or present their own data as well as processing their 
own data with their own algorithms throughout the study. 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 delay the publication or presentation for 90 days. 
After finishing the study it is planned to generate two joint publications by the clinical 
investigators and the sponsor. One journal is going to address rather the medical/surgical 
aspects and the other journal the technical aspects of this investigation. The responsibility for 
writing the publication is with the Coordinating Investigator. The 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 six Principal Investigators, the six Co-Investigators 
and the CPM will be part of the author list of both journals. In case the journal has a restriction 
of less than 11 authors, the surgeons may rather be part of the medical/surgical publication 
and the audiologists/engineers rather be part of the technical publication. The joint publication 
must 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.   
The Clinical Investigator Agreement will include details on publication.  
All public presentations of data collected from this study shall be approved by the Clinical 
Project Manager prior to use. Where information is presented that was collected in a particular 
site, that clinical head shall also approve the use of the data. This is to avoid customers from 
one clinic attending a conference in another and discovering their data being presented to 
them without any warning. 

 
 
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19 Bibliography 
M. Hey et al., “The Intra-Cochlear Impedance-Matrix (IIM) test for the Nucleus® cochlear 
implant,” Biomedical Engineering / Biomedizinische Technik, vol. 60, no. 2, Jan. 2015. 
Marx, M., Risi, F., Escudé, B., Durmo, I., James, C. J., Lauwers, F., Fraysse, B. (2013). 
Reliability of cone beam computed tomography in scalar localization of the electrode array: a 
radio histological study. European Archives of Oto-Rhino-Laryngology : doi:10.1007/s00405-
013-2448-6. 
Ruivo, J., Mermuys, K., Bacher, K., Kuhweide, R., Offeciers, E., & Casselman, J. W. (2009). 
Cone beam computed tomography, a low-dose imaging technique in the postoperative 
assessment 
of 
cochlear 
implantation. 
Otology 
& 
Neurotology, 
30(3), 
299–303. 
doi:10.1097/MAO.0b013e31819679f9. 
Vanpoucke FJ, Boermans PP, Frijns JH. (2009) Assessing the placement of a cochlear 
electrode array by multidimensional scaling. IEEE Trans Biomed Eng. 2012 Feb;59(2):307-10. 
doi: 10.1109/TBME.2011.2173198.  
F. J. Vanpoucke, A. J. Zarowski, and S. A. Peeters, “Identification of the Impedance Model of 
an Implanted Cochlear Prosthesis From Intracochlear Potential Measurements,” IEEE 
Transactions on Biomedical Engineering, vol. 51, no. 12, pp. 2174–2183, Dec. 2004. 
M. G. Zuniga et al., “Tip Fold-over in Cochlear Implantation: Case Series,” Otology & 
Neurotology, vol. 38, no. 2, pp. 199–206, Feb. 2017. 
F. Dirr et al., “Value of routine plain X-ray position checks after cochlear implantation,” Otology 
& Neurotology, vol. 34, no. 9, pp. 1666–1669, 2013. 
W. Grolman et al., “Spread of excitation measurements for the detection of electrode array 
foldovers: a prospective study comparing 3-dimensional rotational x-ray and intraoperative 
spread of excitation measurements,” Otology & Neurotology, vol. 30, no. 1, pp. 27–33, 2009. 
Zeh R, Baumann U. Inpatient rehabilitation of adult CI users: Results in dependency of duration 
of deafness, CI experience and age. HNO. 2015 Aug;63(8):557-76. doi: 10.1007/s00106-015-
0037-2. 
ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological 
Protection. ICRP Publication 103. Ann. ICRP 37 (2-4). 
20 Change History 
Version 
Number 
Date  
(DD Mon YYYY) 
Summary of changes 
1.0 
10.05.2017 
Approved version 
2.0 
14.05.2018 
Extended study duration, HEARing CRC added 
 
 
 

 
 
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21 Appendix I: List of investigators 
Site ID 
Name of Investigator 
Address 
Telephone, email 
 
 
 
 
Complejo Hospitalario 
Universitario Insular Materno 
Infantil ; Avenida Marítima Del 
Sur, S/n, 35016 Las Palmas de 
Gran Canaria, Spain 
 
 
 
 
 
Clinica Universitaria de Navarra, 
Avda. Pio XII, N°36; 31008 
Pamplona, Spain 
 
 
 
 
 
 
Klinikum der J. W. Goethe-
Universität Frankfurt,  
Theodor-Stern-Kai 7,  
60590 Frankfurt a. M., Germany 
 
 
 
 
 
 
Universitätsklinikum Erlangen  
Hals-Nasen-Ohren-Klinik  
Waldstr. 1,  
91054 Erlangen, Germany 
 
 
 
 
 
Klinik für Hals-, Nasen-, 
Ohrenheilkunde, Kopf- und 
Halschirurgie 
Arnold-Heller-Straße 3 
Haus 27 
24105 Kiel, Germany 
 
 
 
 
 
HEARing CRC  
550 Swanston Street 
Carlton, VIC, Australia 3053