Cochlear Implant With Dexamethasone Eluting Electrode Array (The CI-DEX Study): Pivotal Study
Phase: NA
Conditions: Sensorineural Hearing Loss, Bilateral Hearing Loss
Sponsor: Cochlear

ClinicalTrials.gov ID: NCT04750642    
Approval date: 07 Nov 2022

 
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4 BACKGROUND INFORMATION AND RATIONALE 
4.1 
Introduction 
The Cochlear™ Nucleus® CI632 cochlear implant with Slim Modiolar electrode (CI632) is one of the latest 
product developments from Cochlear™ Limited in an adult population with post-lingual, bilateral, moderate to 
profound sensorineural hearing loss and who have compromised functional hearing with hearing aids or 
would receive no benefit with hearing aids. The Slim Modiolar electrode is the thinnest perimodiolar 
electrode for insertion into the cochlea in the Cochlear™ electrode portfolio. 
During implantation of CI632 and other cochlear implants, corticosteroids (such as dexamethasone) are 
routinely given locally or systemically in association with cochlear implant surgery to inhibit the inflammatory 
response caused by insertion trauma of the electrode array (Kuthubutheen et al., 2016). 
To allow for long-term delivery of dexamethasone, CI632 has been modified to include dexamethasone in the 
electrode within wells (CI632D), which will passively elute directly into the cochlea over at least 
 
The clinical investigation aims to assess if passive elution of dexamethasone reduces the level of fibrosis 
following cochlear implantation, as measured by change in electrode impedance. Reduced impedances would 
indicate less fibrotic obstruction caused by trauma associated with the electrode insertion. The intended 
purpose of the CI632D investigational medical device (IMD) in the proposed clinical investigation is to improve 
the outcomes affected by fibrosis, while maintaining the same indications and benefit of improved hearing as 
a conventional CI632. The investigation will test the traditional benefit of cochlear implant by comparing 
speech perception outcomes pre- and post-operatively. The CI632D IMD may provide additional 
improvements in hearing performance by reducing the fibrosis caused by the cochlear implantation 
procedure. 
 
4.2 
Findings of Previous Nonclinical and Clinical Studies 
4.2.1 
Nonclinical Data 
4.2.1.1 
Data from published studies 
Elution of dexamethasone from an implanted electrode array has the potential to be a clinically viable route 
of administration because it enables prolonged delivery of the drug directly into the cochlea with a consistent 
therapeutic dose, which would standardise a varied clinical practice. The use of dexamethasone-eluting 
cochlear implant (CI) electrode arrays has been found to be associated with no additional insertion trauma or 
risk of infection in animal models (Astolfi et al., 2016, Bas et al., 2016, Douchement et al., 2015, Eshraghi et 
al., 2011, Farhadi et al., 2013, Liu et al., 2015, Nguyen et al., 2015, Niedermeier et al., 2012, Stathopoulos et 
al., 2015, Stathopoulos et al., 2014, Wilk et al., 2016). 
The level of hearing protection observed with dexamethasone in animal studies ranges from no evidence for 
protection against auditory brainstem response (ABR) threshold shifts (Stathopoulos et al., 2014, Wilk et al., 
2016, Wrzeszcz et al., 2015, Chambers et al., 2019) to significant levels of hearing protection (Bas et al., 2016, 
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Eshraghi et al., 2011, Liu et al., 2015) that increases with higher concentrations of dexamethasone (Bas et al., 
2016). 
The benefits of local delivery of corticosteroids via drug-eluting arrays can include reduced infiltration of 
inflammatory cells into the cochlea (Farhadi et al., 2013), reduced bone formation (Chambers et al., 2019), 
reduced formation of fibrotic tissue (Bas et al., 2016, Wilk et al., 2016, Wrzeszcz et al., 2015), better 
preservation of spiral ganglion neurons (Bas et al., 2016, Chambers et al., 2019) and lower electrode 
impedances (Bas et al., 2016, Wilk et al., 2016), compared to the use of electrode arrays that do not elute 
dexamethasone.  
In the absence of surgical trauma, dexamethasone has little influence on hearing thresholds (Stathopoulos et 
al., 2014). Conversely, it is unable to fully protect against threshold increases in the presence of high levels of 
electrode insertion trauma (Wilk et al., 2016, Chambers et al., 2019). These findings suggest that 
dexamethasone may be most effective where surgical trauma is within the mild-to-moderate range.  
A likely consequence of reduced electrode impedances is that lower stimulation levels are required and 
power consumption is reduced. Ramos Miguel et al. (2015) investigated the relationship between the 
thickness of bone between the intracochlear and extracochlear electrodes, which affects resistivity and 
impedance, current and relative power in mathematical and temporal bone models. The investigators found 
that as bone thickness (and impedance) increased, the current generated decreased, increasing power 
consumption for stimulation. Increased impedance would be expected in patients with cochlear ossification, 
which increases resistivity of the tissue. 
4.2.1.2 
Impedance and fibrosis in the presence of a dexamethasone-eluting array 
Twenty-five adult female guinea pigs were bilaterally implanted with a dexamethasone-eluting array (left ear) 
and a non-eluting control array (right ear). The two arrays were connected in a bifurcated design. One week 
after implantation, all arrays were electrically stimulated daily for 4 weeks, and electrode impedance 
measured both before and after stimulation. The study was completed for 16 animals. 
Analysis of histological images and resin-imbedded specimens revealed that the electrode arrays were 
consistently implanted in the scala vestibuli rather than the scala tympani. The mean percentage of fibrotic 
tissue and new bone growth was lower on the side with the dexamethasone-eluting array than the side with 
the standard array, but the difference was not statistically significant. There were no differences between 
groups in the density of spiral ganglion cells after implantation. 
Monopolar (MP1+2) impedance was higher in dexamethasone-eluting arrays on the day of surgery and prior 
to daily electrical stimulation. After daily electrical stimulation, no differences were evident between the 
arrays. There was a positive correlation between the percentage of fibrotic tissue and the change in 
monopolar impedance before and after stimulation with the dexamethasone-eluting array, but not the 
control array.  
In contrast, four point impedance did not differ between electrode arrays for the first week of stimulation, but 
thereafter was significantly lower in the dexamethasone-eluting array than the standard array before and 
after daily stimulation. Four point impedance is a measure of impedance between two intracochlear 
electrodes when charge is passed across them, and reflects the local environment overlying the electrode. 
Four point impedance could therefore be more sensitive to changes at the electrode surface, such as 
adhesion for fibrosis, than monopolar impedance.  
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The results suggest that daily electrical stimulation with dexamethasone-eluting and standard arrays are likely 
to have differing effects on the local electrode-tissue interface. This study is published in Needham et al. 
(2019). 
4.2.1.3 
Long-term electrical stimulation of a dexamethasone-eluting intracochlear array and effects of 
fibrous tissue growth on impedance 
Adult guinea pigs were bilaterally implanted with a dexamethasone-eluting array and a standard non-eluting 
array. The array had a bifurcated design consisting of eight electrodes embedded in a silicone rubber carrier. 
Dexamethasone was loaded into the longer array of each device by back-filling a V-shaped groove in the rear 
surface of the array with a mixture of liquefied silicone rubber (60%) and micronised dexamethasone base 
(40% w/w). Two weeks after implantation, all arrays were electrically stimulated daily for up to 13 weeks and 
electrode impedance was measured before and after stimulation. Histological assessment of fibrous tissue, 
new bone growth and spiral ganglion neuron density was assessed at the end of the 15-week period, along 
with a comparison of hearing thresholds. In total, 17 animals completed 90 days of the study and some 
electrode impedance recordings continued for up to 105 days.  
Impedance was measured on the day of implantation (day 1), at three points prior to the onset of electrical 
stimulation (typically at days 4, 7 and 10), and then immediately preceding and following electrical 
stimulation, which commenced on day 14-15. 
A reduction in MP1+2 impedance relative to switch-on was observed in both the standard and 
dexamethasone-eluting arrays over the course of 15 weeks but there were no significant differences in 
MP1+2 impedance between the arrays.  
Four point impedance in the dexamethasone-eluting array was maintained at a stable level for the duration of 
the study, but a steady increase in four point impedance was observed for the standard array from seven 
weeks. There were significant differences between array types for both pre- and post-implantation data.  
The trans-impedance matrix revealed consistently lower impedance in the dexamethasone-eluting array 
beginning from the day of implantation until day 70 and this trend was maintained up to 100 days after 
implantation for the most apical pairs. 
The percentage of fibrosis observed in the scala tympani was significantly larger in the standard array, as was 
the percentage of loose fibrous tissue. There were no statistical differences in dense fibrous tissue, new bone 
growth, spiral ganglion neuron density or hearing threshold between the different arrays. There was a 
positive and statistically significant correlation between mean four point impedance and both total fibrous 
tissue and loose fibrous tissue. 
In conclusion, this study showed that electrode impedances (four point and trans-impedance matrix) are 
reduced in the presence of dexamethasone and daily electrical stimulation up to 15-week after implantation. 
This outcome suggests a change in the local tissue-electrode interface in the presence of sustained, local 
release of dexamethasone.  
4.2.2. Clinical Data 
4.2.2.1  Data from published studies 
Dexamethasone, hearing thresholds and electrode impedance 
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A review of the literature with the objective of identifying publications related to CI surgery, dexamethasone 
and electrode impedance found evidence that atraumatic surgical techniques that include the use of 
dexamethasone can result in lower electrode impedances (Gu et al., 2016) and better hearing preservation 
(Bento et al., 2016) than surgical procedures that involve cochleostomy. Preservation of hearing and 
vestibular function was achieved for five patients who were given intraoperative dexamethasone infusions 
(8mg) plus postoperative dexamethasone for 6 days (daily doses of 8 mg, 8 mg, 4 mg, 4 mg, 2 mg and 2mg) 
(Usami et al., 2011). When patients who were given dexamethasone preoperatively and during surgery were 
compared with patients who were not given dexamethasone preoperatively (5 mg dexamethasone given 1 
day and then 1 hour before surgery); and during surgery (0.5mL of 5 mg/mL dexamethasone injected into 
round window and then 0.5 mL injected into middle ear cavity after receiver fixation) were compared with 
patients who were not given dexamethasone, there were significantly smaller increases in hearing thresholds 
and significantly more subjects with complete or partial hearing preservation at twelve months in the 
treatment group than in the control group (Cho et al., 2016). However, the use of different electrode array 
types in the two groups is a potential confounding factor. 
Kuthubutheen and colleagues observed significantly lower hearing thresholds at 3 and 12 months after 
surgery in patients who received dexamethasone via transtympanic injection (TT) than those who were given 
oral prednisolone prior to surgery (Kuthubutheen et al., 2017). However, this confounded by lower 
preoperative hearing thresholds in the TT group. There was a tendency for the absolute change in low 
frequency hearing threshold to be smaller in the TT group than the other groups, but this was not statistically 
significant. A greater rate of hearing preservation in the TT group than the oral group was seen at three 
months but not 12 months, but there were no significant differences in speech perception between groups. 
The statistical power of this study was limited by small sample sizes. 
In the studies summarized above, dexamethasone was given as a single dose or multiple doses, but not for an 
extended period comparable to continuous passive drug elution. In a study that compared hearing 
preservation in patients who were given intravenous dexamethasone for three days (nine patients), patients 
who were given additional prolonged oral dexamethasone therapy (five patients) and a no-steroid control 
group (22 patients), the prolonged therapy group was the only group whose hearing thresholds remained 
stable over the six-month study period. Only the extended therapy group had significantly better hearing 
preservation than the control group, but there was no significant difference between the two steroid 
treatment groups (Skarzynska et al., 2018).  
Extended effects on electrode impedances were observed after local application of methylprednisolone prior 
to surgery (Enticott et al., 2011). In this study, a polymeric sponge composed of carboxymethylcellulose and 
hyaluronic acid was presoaked in 125 mg/mL methylprednisolone and applied to the round window 30 
minutes before cochleostomy was performed. Impedances for the middle electrodes were significantly lower 
in the group given the drug compared to the control group up to 9 months after surgery.  
Although they do not involve administering dexamethasone at the time of cochlear implant surgery, two case 
studies suggest that sustained-release dexamethasone could increase the duration of benefit (Plontke et al., 
2017). Both cases involved long-term CI users who experienced symptoms related to vestibulopathy with 
raised CI electrode impedances. In both cases, the patients were initially treated with IV steroids, which 
reduced symptoms and electrode impedances for short periods. Subsequent treatment with a biodegradable 
extended-release dexamethasone implant corresponded to reduced electrode impedances for periods of 
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approximately three to six months. Pharmacokinetic data from animal models indicate that intracochlear 
extended-release dexamethasone implants can provide stable drug concentrations in the scala tympani for 
several weeks (Plontke et al., 2017).  
Factors influencing sound processor battery life. 
The length of time that a fully charged sound processor battery can provide power for stimulation is 
influenced by multiple factors that affect power consumption. These factors include the efficiency of the RF 
link between the sound processor coil and the implant receiver coil, which can be affected by the thickness of 
the skin flap over the implant. Other factors that are determined by the recipient’s individual MAP 
parameters, including the current level, pulse width, rate of stimulation and number of maxima will also 
influence sound processor power consumption. 
There is evidence from published clinical investigations that changes to electrode design can reduce power 
consumption for stimulation and, consequently, improve sound processor battery life. Saunders et al. (2002) 
compared the threshold (T) and comfort (C) loudness levels and impedances in patients implanted with CIs 
with lateral wall or perimodiolar electrode arrays. The radial distance from the modiolus was positively 
correlated with T and C levels for most patients and impedance levels, corrected for electrode surface area, 
were significantly lower for the perimodiolar electrode array. Contrasting results were reported for two 
studies that investigated stimulation levels and battery life in paediatric patients who had been implanted 
with a CI with a straight electrode array in one ear and a perimodiolar device in the other ear. Whereas Park 
et al. (2017) found no differences in T and C levels and battery life between lateral wall and perimodiolar 
devices, Jeong et al. (2015) reported that T and C levels were consistently lower with the perimodiolar device 
than the lateral wall device. This translated to longer battery life in three out of six individuals.  
4.2.2.2.  
Evidence from Cochlear-sponsored studies 
Pilot Evaluation of Combined Investigational Device CI4CID with Controlled Dosage of dexamethasone 
(CLTD5495). 
 
 
 
 
 
The primary objectives of this prospective pilot study were to obtain surgical feedback, to assess the safety of 
the CI4CID over 24 months post-implantation follow-up and to compare clinical outcomes to a population 
implanted with the CI24RE(CA). Longitudinal changes in electrode impedance were also characterized for both 
the CI4CID and CI24RE(CA) electrode.  
Twenty-four subjects were included in the study (10 implanted with the CI4CID and 14 with CI24RE(CA). 
Surgeons rated the ease of insertion of the electrode as uncomplicated or acceptable in all cases for the 
CI4CID and 11/13 cases for CI24RE(CA). Direct comparison between the CI4CID and the CI23RE(CA) indicated 
that the insertion was of ‘similar difficulty’ to the CI24RE(CA). There were no serious device-related adverse 
events. There were two non-serious adverse events related to the CI4CID (electrode translocation with vertigo 
and tinnitus after surgery). Nine possible or definite device-related adverse events were recorded for the 
CI24RE(CA), related to pain, tissue breakdown at implant site, dizziness and balance issues. 
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Group mean MP1+2 electrode impedances were significantly lower for the CI4CID than for the CI24RE(CA) and 
this was consistent across all regions of the electrode array. There were no significant differences between 
intraoperative impedances for the two devices, but the CI4CID had significantly lower group mean 
impedances at subsequent time points.  
For four point impedance, the main effect of device was non-significant. However, post hoc comparisons 
revealed that impedance was significantly greater in the basal region of the CI24RE(CA) than the CI4CID from 
six months and in the medial region at 12 and 24 months. There was a significant increase in impedance in the 
basal region of the CI24RE(CA) between three and six months after surgery. There were no other significant 
changes or trends in any electrode region for either device. 
4.3 
Study Rationale 
The aim of this clinical investigation is to assess the efficacy of long-term delivery over at least 
 of 
dexamethasone from a novel drug-eluting cochlear implant (CI632D) by comparing it to a standard electrode 
that does not elute dexamethasone (CI632). The primary endpoints will be the comparison between CI632D 
and CI632 mean MP1+2 impedance measurements of the available electrodes and speech perception testing 
at 6 months post-cochlear implantation. The intended purpose of the CI632D IMD is the restoration of hearing 
function in an adult population with post-lingual, bilateral, moderate to profound sensorineural hearing loss 
and who have compromised functional hearing with limited or no benefit from appropriately fitted hearing 
aids. Dexamethasone is commonly delivered acutely during cochlear implant procedures. 
 
 
. 
Inflammation is a response to the trauma of cochlear implant electrode insertion and the presence of a 
foreign body (Seyyedi and Nadol, 2014, O'Malley et al., 2017). Chronic unresolved inflammation can result in 
fibrosis or scarring caused by the formation of excess connective tissue. Glucocorticoids, including 
dexamethasone, are commonly used to inhibit the inflammation that occurs as a response to tissue damage. 
Dexamethasone was chosen for use in this study because of its strong anti-inflammatory properties and 
because it has previously been used to treat inflammation in the cochlea, especially in cochlear implant 
surgery (see section 4.2.2). 
Electrode impedance, a measure of the opposition to the flow of alternating current between the electrode 
and surrounding tissue, is influenced by inflammation and fibrotic tissue and is a likely indicator of tissue 
damage that results from device implantation (Choi et al., 2017). There is a long-established connection 
between the presence of inflammatory cells, fibrosis, new bone growth and increased electrode impedances, 
which was demonstrated in an animal model by Clark et al. (1995).  
Over time, fibrotic tissue may ossify leading to the development of new bone in the cochlea and there is 
evidence that bone formation in the cochlea is related to the loss of spiral ganglion cells due to surgical 
trauma (Fayad et al., 2009). Furthermore, last recorded hearing performance was found to be positively 
correlated with spiral ganglion cell counts, and negatively correlated with the relative volume of new bone 
growth in a study with temporal bones from patients who were cochlear implant recipients (Kamakura and 
Nadol, 2016). 
Therefore, reducing inflammation and its consequences after cochlear implant surgery may result in better 
hearing performance for recipients. 
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Figure 6: Cochlear Nucleus 7 Sound Processor. 
 
The following surgical tools and accessories may be used with the CI632D and CI632. 
1) 
BTE Template (Z33011)  
2) 
CI500/CI600 Series Recess Gauge (Z139274)  
3) 
CI500/CI600 Series Implant Template (Z139273)  
4) 
CI500/CI600 Series Sterile Silicone Implant Template (S211296)  
5) 
CI500/CI600 Series Non-Sterile Silicone Implant Template (Z179609) 
6) 
Spacer for Intraoperative Testing (Z33012)  
7) 
Cochleostomy Sizing Tool (S407840)  
8) 
Non-Magnetic Cassette (P782484)  
9) 
Replacement Magnet Cassette (P782485)  
6 OBJECTIVES 
6.1 
Primary Objective  
To show the efficacy of a dexamethasone eluting electrode in an adult population with post-lingual, bilateral, 
moderate to profound sensorineural hearing loss: 
• 
In the reduction of fibrosis (as measured by impedance) when compared to a conventional, non-
dexamethasone eluting electrode. 
• 
In the improvement of speech recognition from preoperative baseline. 
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6.2 
Secondary Objective 
• 
Demonstrate that the safety of a dexamethasone eluting electrode is similar to a standard electrode by 
comparison of adverse events and speech outcomes in an adult population with post-lingual, bilateral, 
moderate to profound sensorineural hearing loss. 
6.3 
Exploratory Objective 
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7 DESIGN OF THE CLINICAL INVESTIGATION 
7.1 
General 
  
Figure 7: Schematic for study. 
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The clinical investigation is a pivotal, prospective, multi-centre, randomised, blinded, two-arm, parallel, 
comparator-controlled trial in an adult population with post-lingual, bilateral, moderate to profound 
sensorineural hearing loss.  
Clinical investigation subjects include adults (age ≥ 18 years old) with post-lingual, bilateral, moderate to 
profound sensorineural hearing loss at 5-25 clinical investigation sites in Australia, New Zealand, and United 
States. Eligibility criteria includes assurance subjects are able to participate in either arm of the trial, present 
with similar profiles to current device indications, and able and willing to complete the clinical investigation. 
Potential subjects will be formally consented to participate in the clinical investigation and all eligibility criteria 
confirmed prior to 1:1 randomisation into one of two arms: implantation with CI632D IMD or CI632 
comparator device.  
Randomised subjects cannot be replaced and will count toward the total trial population. Up to 60 subjects 
will be randomised into each arm for a combined total of up to 120 randomised subjects. A group sequential 
analysis will be completed which may impact the final number of subjects. 
To limit bias during data collection, the subject and clinicians completing questionnaires and speech 
perception testing will be blinded to the randomisation assignment, see Section 7.2.7. The implanting surgeon 
will not be blinded to the randomisation assignment.  
The primary endpoints assess the efficacy of the IMD by measure of impedance and speech perception of 
words in quiet. Secondary endpoints include efficacy assessment via sound processor battery life estimation 
and safety assessment via adverse event collection and speech perception performance tested in specified 
listening conditions. Data collection for endpoint assessment and all other clinical investigation measures are 
listed in the Schedule of Events.  
The Sponsor’s data monitoring requirements are summarised in Section 22.1 and described in detail in a 
separate Monitoring Plan. An Independent Data Monitoring Committee (IDMC) will be used for safety and 
compliance oversight. Activities of the IDMC are documented in the IDMC Charter.  
7.1.1 
Design Rationale 
This clinical investigation will compare the effects of long-term dexamethasone delivery via the CI632D IMD to 
a standard CI632 comparator device. For the assessment, qualifying subjects will be randomised to either the 
IMD or comparator. The current clinical investigation has a prospective design, with 1:1 randomisation to the 
dexamethasone treatment arm (CI632D) or the control arm (CI632).  
The CI632 control arm represents the standard of clinical care for an adult population with post-lingual, 
bilateral, moderate to profound sensorineural hearing loss and who obtains limited benefit from 
appropriately fitted hearing aids. A randomised controlled trial (RCT) research design is appropriate as it has 
high internal and external validity, whereby the differences observed between arms are related to the 
intervention being tested and can be generalized into clinical practice and the general population.  
Subjects and delegated study personnel completing the specified assessments will be blinded to the 
randomisation assignment to ensure that the data are captured without bias. Surgeons will not be blinded to 
the randomisation assignment because of the differences in the appearance of the IMD and comparator 
device. Although dexamethasone is commonly used during surgery, its use will be restricted in both arms of 
the study to avoid confounding effects on the evaluation of extended-release dexamethasone.  
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The clinical investigation will include subjects who are indicated for a cochlear implant following candidacy 
evaluation assessments and those that meet additional eligibility criteria (see sections 7.2.1 and 7.2.2). 
Potential subjects will be given information about the clinical investigation design as part of the informed 
consent process and will be required to consider their ability to commit to completing the study according to 
the CIP. Only subjects that can provide consent for themselves and who meet all inclusion and no exclusion 
criteria will be eligible to participate in the study.  
All subjects will complete a 12-month follow-up period with 7 scheduled post-cochlear implant follow-up 
visits. Data collection requirements are structured to rigorously evaluate the endpoints and correspond to the 
standard of care for cochlear implant recipients. However, additional study visits and data collection outside 
the standard of care are expected and will enable the collection of the required data to fulfil primary and 
secondary endpoints.  
Blinding of subjects and study personnel to randomised treatment will be maintained until final database lock 
to protect the integrity of the data. Database lock will occur when all data have been entered into the 
electronic data capture (EDC) system. After this time it will not be possible to amend the data, which will then 
be ready for analysis. Adverse events will be collected and reviewed by a designated blinded investigator 
throughout the clinical investigation. 
The efficacy of dexamethasone will be evaluated by comparing MP1+2 impedance measurements between 
the IMD and comparator groups at six months post-implantation and also by evaluating the clinical utility of 
the IMD by comparing change in CNC word in quiet speech perception scores at six months post-cochlear 
implant and baseline (primary endpoints). The timing of the primary endpoint measurement is based on an 
evaluation of the impedance data obtained in the feasibility clinical investigation CLTD5495. In this study, 
MP1+2 impendences for both the IMD and comparator device stabilised by four weeks after activation and 
there were no significant differences between adjacent time points for the remainder of the 24 month study 
period. Measurement of MP1+2 impedances, in which the impedance of each intracochlear electrode is 
measured with reference to both extracochlear electrodes (see section 5.1.5), is the standard measurement 
of electrode impedances and is used because it most closely reflects the electrode impedances present during 
normal use of the implant. In addition, four point impedances will be measured as an exploratory endpoint. 
Four point impedance measurements require the stimulation of two electrodes while recording the 
impedance of the intervening two electrodes. The advantage of four point impedance is that, since non-
stimulating electrodes are used for measurement, the impedance of the surrounding tissue can be measured 
without the influence of the electrode-tissue interface, which usually has a much greater impedance.  
The size of the study population has been powered to determine whether the electrode impedances of 
CI632D are lower than the comparator device. However, clinical data on the effects of dexamethasone 
delivery via cochlear implant are limited, and there are no clinical data on dexamethasone delivery via a Slim 
Modiolar electrode array (the electrode array used in the CI632 and CI632D). Therefore, the clinical 
investigation will be completed under a group sequential design where a formal interim analysis occurs 
following the 6 month endpoint of analysis groups of 50, 80, 100 and 120 randomised subjects (see Section 
9.10 Interim Analysis). Enrolment does not need to stop for group analysis and the Sponsor may choose to 
randomise 120 subjects to capture more data for other endpoint analyses. 
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7.2 
Subjects 
Written, informed consent must be obtained from the subjects before any study procedures are initiated. If 
historical exams and assessments meet specified criteria, they do not need to be repeated. 
An independent Sponsor representative (employee of Cochlear™) will confirm certain eligibility criteria prior 
to Randomisation in accordance to inclusion and exclusion criteria. A representative may be either a qualified 
ENT surgeon, audiologist or qualified subject matter expert. A representative will not participate in any other 
capacity in the management of the clinical investigation and will be trained on the CIP and Good Clinical 
Practice (GCP). Following consent of a subject, the site must provide a de-identified audiogram, detailed CT 
read summary and speech perception results to be reviewed by a representative.   
Prior to randomisation of a subject, the representative must have confirmed eligibility, and all screening and 
baseline assessments must be completed and entered into the EDC in accordance with the Schedule of 
Events.  
Throughout the duration of the clinical investigation, source document records must be maintained to 
validate subject data.   
 
 
 
 
 
 
  
7.2.1 
Inclusion Criteria 
Subjects must meet all of the inclusion criteria described below to be eligible for this clinical investigation. 
1. Postlingual, bilateral, moderate to profound sensorineural hearing loss, defined by a pure-tone average 
(PTA):  
a. ≥ 40 dB HL at 250 through 1000 Hz and, 
b. ≥ 65 dB HL at 2000 through 8000 Hz. 
2. Preoperative aided word score is 40% correct or less in the ear to be implanted (60% or less in the 
contralateral ear).  
3. 18 years or older at time of consent. 
4. Willing to be randomised into either a treatment (CI632D) or control (CI632) arm. 
5. Evidence of pneumococcal vaccination (e.g. Pneumovax) according to local guidelines prior to 
randomisation. 
6. Fluent speaker in the local language used to assess clinical performance as judged by the investigator. 
7. Willing and able to provide written informed consent.  
 
 
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7.2.2 
Exclusion Criteria 
Subjects who meet any of the exclusion criteria described below will not be eligible for this clinical 
investigation. 
1. Deafness due to lesions of the acoustic nerve or central auditory pathway. 
2. Diagnosed active middle-ear infections or history of middle ear infection within the past six months prior 
to randomisation. Must not have had surgery, drainage, pain, or need for oral or topical antibiotics within 
the past six months in the ear to be implanted. 
3. Previously reported diagnosis of auditory neuropathy. 
4. Previously reported diagnosis of Large Vestibular Aqueduct Syndrome (LVAS), Meniere’s disease, or 
cochlear hydrops.  
5. Prior history of surgery in the ear to be implanted (excluding grommets). 
6. Current use of grommets or evidence of unhealed tympanic membrane perforation.  
7. Ossification, otosclerosis, malformation or any other cochlear anomaly, such as common cavity, that 
might prevent complete insertion of the electrode array, as confirmed by imaging.  
8. Existing cerebrospinal fluid (CSF) shunts or drains, existing perilymph fistula, skull fracture or CSF leaks. 
9. History of bacterial meningitis.  
10. Known allergic reaction or contraindication to dexamethasone or corticosteroids. 
11. Use of ototoxins and/or steroids (does not include topical or inhaled steroids) up to 30 days prior to 
randomisation. 
Note: Systemic ototoxin and/or steroids therapy must be completed at least 7 days prior to 
Screening/Baseline audiometric and speech testing 
12. Evidence of severe or greater sensorineural hearing loss prior to five years of age, as reported by the 
subject. 
13. Severe to profound sensorineural hearing loss for more than 20 years, as reported by the subject.  
14. Existing contralateral cochlear implant.  
15. Medical plan to implant a contralateral cochlear implant during the clinical investigation. 
16. History of recurrent otitis media or chronic otitis media in the ear to be implanted within the past six 
months prior to randomisation. 
17. Medical or psychological conditions that contraindicate general anaesthesia, surgery or participation in 
the clinical investigation. 
18. Pregnant or breastfeeding women.  Women who plan to become pregnant during the course of the 
investigation. 
19. Unrealistic expectations on the part of the subject, regarding the possible benefits, risks, and limitations 
that are inherent to the surgical procedure(s) and prosthetic devices as determined by the Investigator. 
20. Additional disabilities that may affect the subject’s participation or safety during the clinical investigation. 
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21. Unable or unwilling to comply with all the requirements of the clinical investigation as determined by the 
Investigator. 
22. Investigator site personnel directly affiliated with this study and/or their immediate families; immediate 
family is defined as spouse, parent, child, or sibling. 
23. Cochlear™ employees or employees of Contract Research Organisations or contractors engaged by 
Cochlear for the purposes of this investigation. 
24. Currently participating, or participated within the last 30 days, in another interventional clinical 
investigation/trial involving an investigational drug or device. 
7.2.3 
Number of Subjects Required 
Up to 120 subjects will be randomised into the clinical investigation. Randomisation is 1:1 to the treatment or 
control arm. See Section 9.4 for the sample size calculations. 
The clinical investigation will be completed under a group sequential design where analysis of the primary 
endpoints occurs following the 6-month endpoint for the first 50 randomised subjects. If stopping criteria (see 
Section 9.10) are not met at this first analysis of both primary endpoints, then enrolment will continue, and 
analysis will be completed again for the first 80 randomised subjects at 6 months post-cochlear implant. If 
stopping criteria are not met again, then enrolment will continue, and analysis will be completed again for the 
first 100 randomised subjects at 6-months post-cochlear implant. If stopping criteria is not met again 
enrolment will continue for a total of 120 subjects. Enrolment does not need to stop for group analysis and 
the Sponsor may choose to randomise 120 subjects to capture more data for other endpoint analyses.  
7.2.4 
Vulnerable Populations 
The clinical investigation aims to treat individuals with post-lingual, bilateral, moderate to profound hearing 
loss. There is a risk that subjects will have difficulty completing the informed consent process due to limited 
hearing and potential cognitive impairments, which may be associated with hearing impairment. Recruitment 
must include processes to ensure the investigator discusses the informed consent with all subjects and all 
questions are answered to the subject’s satisfaction. Additional measures taken to review the study with 
potential subjects must be documented in the informed consent process. The Ethics Committee (EC) may 
have additional requirements which must be followed. 
IMD and comparator devices may be provided at no cost to the subject or hospital. This financial model may 
provide added benefit to potential subjects and clinical investigation sites. Subjects may be compensated for 
their time in the clinical investigation in alignment with fair market value. The informed consent process must 
include ensuring subjects are not choosing to participate for the financial benefits, and site personnel must 
not use the financial model to coerce subjects to participate in the clinical investigation. 
Women that are pregnant, breastfeeding or women who plan to become pregnant during the clinical 
investigation are excluded from participation. Women of childbearing potential will be required to take a 
pregnancy test prior to randomisation and agree to use appropriate (as deemed by the Investigator) methods 
to avoid becoming pregnant during their participation in the clinical investigation.  
7.2.5 
Recruitment and Study Duration 
The following subject status definitions apply: 
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• 
Enrolled: A subject that has a signed the Informed Consent form for the study.  
• 
Screen Fail: An Enrolled subject that has been determined to not meet one or more eligibility criteria. 
• 
Participated: Consented subjects who have met all eligibility criteria, have qualified for surgery, and have 
been randomised. 
• 
Implanted: A participating subject who has received the IMD/comparator in accordance to the 
randomisation assignment  
• 
Treatment Failure: A participating subject who has not been successfully implanted or does not receive 
the IMD or comparator treatment in accordance with the randomisation assignment 
• 
Discontinued: An Enrolled subject who withdrew consent, was discontinued by the Investigator or 
Sponsor before the expected End of Study visit or lost to follow-up. Discontinued subjects may still have 
safety follow up data collection until their scheduled End of Study visit, for reasons described in section 
7.2.6. 
• 
Completed: Enrolled subjects who complete the required treatment and visit schedule.  
The recruitment period for the clinical investigation is estimated to be 28 months from the time of first 
subject consent to recruitment of the last subject. If the recruitment numbers increase following the interim 
analysis, the recruitment period is expected to extend approximately one month for every eight enrolments.  
The expected duration of each subject’s participation in the clinical investigation, is 14 months. From the time 
of implant through to the End-of-Study visit is 12 months after implantation.  
Therefore, the anticipated total duration of the clinical investigation is 42 months. Clinical Investigation 
completion is at the last subject’s last visit. In the event of ongoing SAEs/SADEs at the time of a subject’s last 
visit, the subject’s clinical investigation completion will be extended for a further 30 days, or until resolution 
or stabilisation of the event, whichever comes first. 
7.2.6 
Criteria and Procedures for Subject Withdrawal 
Subjects can decide to withdraw from the investigation at any time. The Investigator shall ask the reason(s), 
however subjects have the right to withhold their reason if preferred. The reason for withdrawal should be 
documented in the subject’s source files and the case report form (CRF), if provided. 
The Investigator or Sponsor may also decide to withdraw a subject from the clinical investigation or stop the 
use of the investigational device if it is considered to be in the subject’s best interests. 
Subject withdrawal may be for any of the following reasons: 
• 
Adverse Event (AE) 
• 
Device Deficiency (DD) 
• 
CIP or GCP deviation 
• 
Subject withdrew consent 
• 
Subject lost to follow-up 
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• 
Subject death 
• 
Sponsor decision 
• 
Investigator decision 
• 
Other (specify): Treatment failure 
If subject withdrawal is due to problems related to the IMD and/or comparator safety or performance, the 
Investigator shall ask for the subject's permission to continue in safety follow up (for example, adverse events 
and device deficiencies) until their scheduled End-of-Study visit. 
If a subject is lost to follow-up, every possible effort must be made by the study site personnel to contact the 
subject and determine the reason for discontinuation. At least 3 separate attempts taken to contact the 
subject must be documented. 
Participating subjects who are withdrawn/discontinued will not be replaced.  
7.2.7 
Randomisation Procedures 
Subjects who meet all eligibility criteria with approval by an independent Sponsor representative, will be 
randomised to an intervention based on a computer-generated randomisation schedule prepared by a 
Statistician. Subjects will be randomly assigned to one of two interventions using a ratio of 1:1 within each 
site. Assignment to intervention groups will be determined by a system defined under a randomization plan. 
The investigational medical device or comparators will be packaged and labelled for blinded randomization. 
7.2.7.1 
Blinding Procedures 
The clinical investigation is partially blinded, with the subject and delegated site personnel who will 
administer tests and subject facing questionnaires and program the device being blinded to the treatment 
assignment. This is to reduce risk of bias during these assessments. Training to blinding and unblinding 
procedures will be provided prior to site personnel prior to them completing clinical investigation activities. 
Where required for resourcing reasons, prior approval may be sought from the Sponsor for site personnel to 
be blinded to the subjects they will test, but not the subjects they will not test.  
IMD and comparator packaging will be visually identical with exception of tracking numbers that will not 
identify the device type.  
Investigators performing the cochlear implant surgery will not be blinded to the randomisation assignment. 
Blinding the surgeon is not possible as there are visually apparent differences between the two devices. 
Surgeons and other unblinded site personnel will be instructed to not disclose randomisation assignment 
through discussion, documentation or other means. The surgeon will be instructed to document the “cochlear 
implant” (or similar) was implanted in medical records. The monitor will need to ensure blinded site personnel 
do not become unblinded during discussions. 
The Data Management Plan includes processes for managing the randomisation process. The Sponsor will not 
be blinded to the randomisation assignment. The Sponsor’s delegated monitor(s) will be blinded to the 
randomisation assignment. 
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Investigators completing adverse event assessments will be blinded to the randomisation assignment. The 
IDMC will be aware which randomisation group a subject is randomised, but identification of the group (CI632 
or CI632D) will not be provided to the IDMC. The Sponsor will only analyse data as outlined in this clinical 
investigation plan. The Sponsor will provide data to the IDMC as outlined in the IDMC Charter and as 
requested; the Sponsor will not evaluate this data.  
At the end of the clinical investigation, the database will be locked. After this time point, subjects and blinded 
site-personnel may be unblinded to the randomisation assignment and subjects’ medical records may be 
updated. 
If a subject becomes unblinded or an unblinded site personnel completes assessments with subjects they are 
unblinded to, it must be recorded in the EDC as a protocol deviation. If site personnel become unblinded, 
efforts should be made to assign an alternative blinded site personnel to complete assessments with the 
subject. In the event blinding must be broken, the decision should be documented by the Principal 
Investigator and the Sponsor should be notified.      
Designated Sponsor personnel will have access to the randomisation assignments. If unblinding is required, 
the site may contact the Sponsor to retrieve the subject’s randomisation assignment.  
7.2.8 
Post-investigation Medical Care 
Following the investigation, subjects will continue with standard of care treatment. 
 
7.3 
Evaluations and Procedures 
For each enrolled subject, the clinical investigation will include Screening and Baseline procedures, 
Randomisation assignment to the IMD or comparator, Surgery to implant the assigned device, and seven post-
surgical follow-up visits.  
7.3.1 
Screening/eligibility 
Screening and Baseline may be completed in parallel. If historical exams are available, they must be within the 
timeframes indicated below. The following must be completed prior to Randomisation: 
• 
Written informed consent: must be completed before any study specific procedures are completed. 
• 
Demographics: document age and sex. 
• 
Eligibility: confirm subject meets all inclusion criteria and no exclusion criteria (see section 7.2.1 and 
7.2.2). Source documentation must be available before confirming eligibility. 
• 
Hearing History: document history of hearing loss (may be subject reported) 
• 
Device history: document history with hearing aids and cochlear implant (contralateral ear) (may be 
subject reported) 
• 
Medical History: document medical history. 
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• 
Audiogram: must be completed less than 90 days prior to randomisation and document bilateral, 
moderate to profound hearing loss. (see section 7.3.2.2) 
• 
Speech Perception testing: must be completed less than 90 days prior to randomisation. Subject’s 
own or loaner hearing aid must be optimally fitted using National Acoustics Laboratories’ hearing aid 
fitting formula to confirm eligibility for clinical investigation. (see section 7.3.2.3)  
• 
High Resolution CT imaging: must be completed within 2 years prior to randomisation and show 
entire cochlea per the imaging protocol. (see section 7.3.1.6) 
• 
Health Survey (HS): must be completed within 90 days prior to randomisation. (see section 7.3.2.1) 
• 
Hearing-Impaired Montreal Cognitive Assessment (HI-MoCA): must be completed within 90 days prior 
to randomisation. (see section 7.3.2.1) 
• 
Health Utilisation Index III (HUI3): must be completed within 90 days prior to randomisation. (see 
section 7.3.2.1) 
• 
Dizziness/Tinnitus Questionnaire (DTQ): must be completed within 90 days prior to randomisation. 
(see section 7.3.2.1) 
• 
Dizziness Handicap Inventory (DHI): must be completed within 90 days prior to randomisation as 
required by DTQ. (see section 7.3.2.1) 
• 
Tinnitus Handicap Inventory (THI): must be completed within 90 days prior to randomisation as 
required by DTQ. (see section 7.3.2.1) 
7.3.2. Performance/Effectiveness 
7.3.2.1. 
Description of Questionnaires 
The following subject facing questionnaires will be completed during the clinical investigation at specified 
Visits: 
• 
Hearing-Impaired Montreal Cognitive Assessment (HI-MoCA): clinician guided questionnaire that 
assists in the detection of cognitive impairment. The questionnaire was developed by V. Lin and 
Sunnybrook Health Sciences Centre (Toronto, Canada). 
• 
Health Survey (HS): clinician guided questionnaire to review for potential inflammatory conditions. 
The questionnaire was developed by the Sponsor. 
The Health Survey (HS) is a clinician guided questionnaire that was developed by the Sponsor to collect 
health-related data that may be linked to inflammatory conditions that could affect impedance 
measurements. These include: 
• 
Body temperature  
• 
Blood pressure 
• 
Menstrual cycle phase (if appropriate)  
• 
Relevant medical history, including arthritis, allergies, frequent headaches, other chronic 
inflammatory conditions [information is captured in the Medical History form] 
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• 
Use of antibiotic or anti-inflammatory medication [information captured in the Concomitant 
Medications Form] 
• 
Other applicable informationHealth Utilities Index III (HUI3): a self-administered questionnaire that 
includes a rating scale used to measure general health status and health-related quality of life 
(HRQoL). The questionnaire was developed by Health Utilities Inc. 
• 
Dizziness/Tinnitus Questionnaire (DTQ): clinician guided questionnaire to review dizziness and tinnitus 
characteristics. The questionnaire was developed by the Sponsor. 
• 
Dizziness Handicap Inventory (DHI): self-administered questionnaire that includes a scale to identify 
difficulties that you may be experiencing because of dizziness. The questionnaire was developed by 
Dr. G.P. Jacobson and Dr. C.W. Newman. 
• 
Tinnitus Handicap Inventory (THI): self-administered questionnaire that identifies difficulties that you 
may be experiencing because of tinnitus. The questionnaire was developed by Dr. C.W. Newman, Dr. 
G.P. Jacobson, and Dr. J.B. Spitzer. 
• 
Blinding Questionnaire (BQ): self-administered questionnaire to assess subject’s understanding of 
randomisation assignment. The questionnaire was developed by the Sponsor. 
7.3.2.2. 
Description of Audiometric Testing  
7.3.2.2.1. 
Unaided thresholds 
Unaided audiometric thresholds will be obtained for each ear independently, using the standard audiometric 
technique for pure-tone air and bone conduction testing preoperatively to establish candidacy for cochlear 
implantation and participation in the clinical investigation. Preoperatively, unaided audiometric thresholds 
will be obtained in both ears. Post-operatively unaided audiometric thresholds will be obtained in the 
implanted ear to assess the impact of cochlear implantation.  
• 
Air Conduction:  250, 500, 750, 1000, 1500 2000, 3000, 4000, 6000 & 8000 Hz  
Hearing thresholds that exceed the air conduction limits of the audiometer, where the participant reports 
feeling the acoustic stimuli, shall be recorded as vibrotactile (VT). Appropriate masking will be employed 
where required.  
• 
Bone conduction: 250, 500, 750, 1000, 1500, 2000, 3000 & 4000 Hz 
Where the participant reports feeling rather than hearing the acoustic stimuli, the response shall be 
recorded as vibrotactile (VT). Appropriate masking will be employed where required. 
7.3.2.2.2. 
Aided thresholds: 250, 500, 1000, 2000 & 4000 Hz 
Aided audiometric thresholds will be obtained for both ears preoperatively and the implanted ear post-
operatively using warble tones. The contralateral ear will be plugged for all tests. 
7.3.2.3. 
Description of Speech Perception Testing 
The following speech perception testing will be completed during the clinical investigation: 
1. Two lists of CNC words at 60 dBA in quiet delivered from a speaker located directly in front of the 
listener (S0):  
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Custom Sound EP. FDA reviewed the four point impedance measurement during the IDE review of G200098. 
The Sponsor may provide a laptop to use this software during the cochlear implant operation and at study 
visits. A CP910/CP920 sound processor will be used when testing with Custom Sound EP at all study visits. 
7.3.2.6. 
CT Core Lab 
Anatomy and cochlear implant electrode placement will be reviewed using high resolution CT of preoperative 
and post-operative CT scans. Independent review analysis of CT imaging will be completed by a CT corelab. 
7.3.2.7. 
Schedule of Events 
A table with a schematic overview of the events is provided in section 3. Please refer to section 3 for details 
regarding the timing and frequency of the events. In this section more information about the separate events 
is given. 
7.3.2.7.1. 
Screening and Baseline 
Screening and Baseline is described in section 7.3.1 
7.3.2.7.2. 
Randomisation 
Randomisation may only be completed once all activities under Screening and Baseline are completed, subject 
screening/baseline data is entered into the EDC, and eligibility has been confirmed by an independent 
Sponsor representative. 
The ear to be implanted will need to be determined prior to randomization and must be compliant with the 
inclusion and exclusion criteria. The decision will be made between the investigator, audiologist and subject, 
and the justification for ear selection must be documented. 
7.3.2.7.3. 
Surgery (day 0) 
Data collection from time of Surgery through discharge from hospital includes: 
• 
High Resolution CT: Post insertion to assess electrode placement. Cone beam CT and flat panel CT are 
examples. 
OR 
• 
X-Ray or fluoroscopy (C-arm): required intraoperatively to assess placement of electrode using 
Modified Stenver’s View. X-ray or fluorscopy will be repeated if electrode is repositioned/replaced. 
o If final placement of cochlear implant is not positioned correctly (tip foldover or 
translocation), the subject will remain in the clinical investigation and complete all 
assessments. Outcome will be documented in the CRF. 
• 
Electrode Electrical Testing: must be completed intraoperatively after final placement of electrode. If 
electrode position is altered or second device is used, testing must be repeated. Complete tests in the 
following order: 
1. Impedances (MP1+2 and Four point). 
2. AutoNRT® (standard 9 electrodes). 
• 
Surgical Questionnaire: surgeon’s review of surgical implant. 
• 
Discharge Summary: subject’s stay in hospital. 
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The following requirements are to be followed for the Surgery: 
• 
At the surgeon’s discretion, dexamethasone may be utilised in anaesthesia, IV and take-home pack, 
which will be documented in the CRF.  
• 
Dexamethasone may not be used to treat (e.g. topically) the cochlear implant electrode. 
• 
Dexamethasone may not be used within or near the ear/cochlea. 
• 
Cochlear implant electrode may not be dipped in saline, hyaluronic acid (healon), or other treatment 
prior to insertion. 
• 
The implant procedure must follow Instructions for Use (IFU). A back up CI632D or CI632 may be 
required if preparation/insertion is not possible according to IFU. 
• 
Following impedance and/or NRT testing, if the electrode is re-inserted or replaced with a new device, 
the testing must be repeated  
If the IMD or comparator is inserted but not implanted (eg implanted with commercial device), the subject 
should remain in the clinical investigation for 30 Days or until all AEs are resolved (whichever is longer).  
If the IMD or comparator is implanted and then explanted during Surgery or at a later date, the subject should 
remain in the clinical investigation for 30 Days or until all AEs are resolved (whichever is longer).  
7.3.2.7.4. 
Visit 1: 0-10 days post-Surgery 
Data collection 10 days or less post-insertion and after-effects of anaesthesia have worn off: 
• 
Health Survey (HS): complete prior to impedance measurements. 
• 
Impedance (MP1+2 and Four point). 
• 
High Resolution CT: Post-operative imaging within 3 months (before end of Visit 4 window) to assess 
electrode placement. Cone beam CT and flat panel CT are examples. Not applicable if completed 
intraoperatively. 
7.3.2.7.5. 
Visit 2: 15 Days post-Surgery / Activation (±7 days) 
• 
Health Survey (HS): complete prior to impedance measurements. 
• 
Blinding Questionnaire. 
• 
Impedance (MP1+2 and Four point): measured two times: 
o Before activation. 
o After activation and mapping is complete. 
• 
Cochlear Implant Activation with selected sound processor. 
• 
CI optimisation / Mapping. 
• 
High Resolution CT: Post-operative imaging within 3 months (before end of Visit 4 window) to assess 
electrode placement. Cone beam CT and flat panel CT are examples. Not applicable if completed 
intraoperatively. 
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7.3.2.7.6. 
Visit 3: 30 days after Visit 2 (±5 days) 
Thirty days after the IMD/comparator is activated, the following should be completed: 
• 
Audiogram 
• 
Health Utilisation Index III 
• 
Dizziness/Tinnitus Questionnaire (DTQ) 
• 
Dizziness Handicap Inventory (DHI)  
• 
Tinnitus Handicap Inventory (THI) 
• 
Health Survey: complete before impedance measurements 
• 
Impedance (MP1+2 and Four point) (complete before CI optimisation / Mapping) 
• 
CI optimisation / Mapping 
• 
Battery Life Estimation Test with 900Hz/channel and 8 max. (as required) (complete after CI 
optimisation / Mapping) 
• 
High Resolution CT: Post-operative imaging within 3 months (before end of Visit 4 window) to assess 
electrode placement.  Cone beam CT and flat panel CT are examples. Not applicable if completed 
intraoperatively. 
7.3.2.7.7. 
Visit 4: 3 Months post-Surgery (90 days, ±14 days) 
• 
Audiogram 
• 
Health Utilisation Index III 
• 
Dizziness/Tinnitus Questionnaire (DTQ) 
• 
Dizziness Handicap Inventory (DHI)  
• 
Tinnitus Handicap Inventory (THI) 
• 
Health Survey: complete before impedance measurements 
• 
Speech Perception Testing 
• 
Impedance (MP1+2 and Four point) (complete before CI optimisation / Mapping) 
• 
CI optimisation / Mapping 
• 
Battery Life Estimation Test with 900Hz/channel and 8 maxima. (as required) (complete after CI 
optimisation / Mapping) 
• 
High Resolution CT: Post-operative imaging within 3 months (before end of Visit 4 window) to assess 
electrode placement. Cone beam CT and flat panel CT are examples. Not applicable if completed 
intraoperatively. 
7.3.2.7.8. 
Visit 5: 6 Months post-Surgery (180 days, +14 days) 
• 
Audiogram 
• 
Health Utilisation Index III 
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• 
Dizziness/Tinnitus Questionnaire (DTQ) 
• 
Dizziness Handicap Inventory (DHI)  
• 
Tinnitus Handicap Inventory (THI) 
• 
Health Survey: complete before impedance measurements. 
• 
Blinding Questionnaire 
• 
Speech Perception Testing 
• 
Impedance (MP1+2 and Four point) (complete before CI optimisation / Mapping) 
• 
CI optimisation / Mapping 
• 
Battery Life Estimation Test with 900Hz/channel and 8 max. (as required) (complete after CI 
optimisation / Mapping) 
7.3.2.7.9. 
Visit 6: 9 Month post-Surgery (270 days, ±30 days) 
• 
Audiogram 
• 
Dizziness/Tinnitus Questionnaire (DTQ) 
• 
Dizziness Handicap Inventory: Should be completed in accordance with DTQ. 
• 
Tinnitus Handicap Inventory: Should be completed in accordance with DTQ. 
• 
Health Survey: complete before impedance measurements. 
• 
Impedance (MP1+2 and Four point) (complete before CI optimisation / Mapping) 
• 
CI optimisation / Mapping 
• 
Battery Life Estimation Test with 900Hz/channel and 8 max. (as required) (complete after CI 
optimisation / Mapping). 
7.3.2.7.10. Visit 7: 12 Month post-Surgery (365 days, +30 days) 
• 
Audiogram 
• 
Health Utilisation Index III 
• 
Dizziness/Tinnitus Questionnaire (DTQ) 
• 
Dizziness Handicap Inventory (DHI)  
• 
Tinnitus Handicap Inventory (THI) 
• 
Health Survey: complete before impedance measurements. 
• 
Speech Perception Testing 
• 
Impedance (MP1+2 and Four point) (complete before CI optimisation / Mapping) 
• 
CI optimisation / Mapping 
• 
Battery Life Estimation Test with 900Hz/channel and 8 max. (as required) (complete after CI 
optimisation / Mapping). 
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7.3.2.7.11. End-of-Study 
Document reason for Subject’s study completion. Ensure device deficiencies, device exposure, adverse 
events, concomitant medication and deviations are reviewed, and end dates recorded where appropriate. 
 
 
7.3.2.8. 
Collected from point of Consent 
• 
Concomitant Medication: includes all prescription medications, routine over-the counter medications, 
and any use of steroids. Concomitant medications should be reviewed at each visit. 
• 
Protocol Deviations: approved and unapproved deviations 
7.3.2.9. 
Collected from point of Randomisation 
• 
Adverse Events and review of ongoing adverse events.  Adverse events should be reviewed at each 
visit. 
7.3.2.10. Collected from point of Surgery 
• 
Device Exposure 
• 
Device Deficiency 
7.3.2.11. Remote Programming 
Cochlear™’s Remote Programming tool may be used as an alternative data collection option, should a subject 
not be able to return to clinic due to the impact of the COVID-19 pandemic at Visit 3, Visit 4, Visit 5, Visit 6 and 
Visit 7.  Equipment (which may include laptop, pod, virtual machine, sound processor cables and N6 Sound 
Processor) will be mailed to subject by the clinic to complete the impedance testing. The subjects own N7 
Sound Processor may be used as well. After testing is completed, the subject mails the equipment back to the 
clinic. 
The following assessments may be completed with Remote Programming: 
• 
Impedance (MP1+2 and four point) (complete before CI optimisation / Mapping) 
• 
CI optimisation / Mapping 
• 
Battery Life Estimation Test with 900Hz/channel and 8 max. (as required) (complete after CI 
optimisation / testing) 
Use of Remote Programming will be recorded in the eCRF. Protocol deviations are required to be entered if 
the subject cannot attend the clinic for other assessments. 
7.3.2.12. Electrical Testing 
Electrocochleography (ECochG) is permitted outside of the clinical investigation. ECochG and other cochlear 
implant electrical testing not specified within this clinical investigation plan must be completed after clinical 
investigation required electrical testing (e.g. impedance or NRT).  
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7.3.3 Safety Evaluations and Procedures 
The risks and anticipated ADEs for the CI632D and CI632, as identified in Sections 8.2 and 8.3 of the CIP, will 
be assessed in the clinical investigation via reporting of all AEs/ADEs from the time of first subject 
randomisation until last subject last visit. Individual collection of adverse events will end when the subject 
exits the clinical investigation. Safety data review will be conducted by the Sponsor’s Safety Officer in 
accordance with the Sponsor’s standard operating procedures. 
Safety data review will be conducted by an Independent Data Monitoring Committee (IDMC) in accordance 
with the defined Charter for operations. 
Upon review of data available in the CRF, the Sponsor or IDMC may query data or request de-identified source 
documents to review the event. 
7.3.3.1. Concomitant Medication and Therapies 
Concomitant Medications recorded in the CRF includes all prescription medications, routine over-the counter 
medications, and any use of steroids. Dexamethasone cannot be delivered into the ear or used to treat the 
electrode (Section 7.3.1.). There are no further prohibited medications under this clinical investigation. 
Medications taken for anaesthesia purposes during surgery will not be recorded unless their use deviates 
from normal clinical practice. 
7.4. Equipment Used for Evaluations and Procedures 
The clinical investigation includes use of equipment to complete assessments. Equipment including software, 
firmware, sound equipment (e.g. speakers) are used to assess impedance measurements and speech 
perception performance. Software and firmware should be kept current at the direction of the Sponsor. 
Versions of applicable software and firmware used for each subject assessment should be documented. For 
equipment used in this clinical investigation, records of equipment calibration requirements and the 
calibration records must be maintained in site files and copies provided to the Sponsor. As part of the Site 
Initiation Visit, requirements and records should be provided to the Sponsor and records to be confirmed to 
be up-to-date. Records will be monitored at interim monitoring visits, in accordance with the Sponsor’s 
Monitoring Plan. 
Custom Sound® and Custom Sound® EP software or the latest Cochlear software platform for advanced 
objective measurements, will be used to measure MP1+2 impedances, four point impedances and other 
collected data points. Four point impedances will be measured during stimulation of two intracochlear 
electrodes while measuring impedances on two separate intracochlear electrodes. Measurement of four 
point impedances with Custom Sound EP software allows assessment of tissue impedance without measuring 
the impedance of the interface and aims to provide information about fibrous tissue growth around the 
electrode array. Upload of all Custom Sound data to Sponsor database for analysis is required, which may be 
done automatically or manual file sharing.  
The Sponsor may provide equipment to utilise Remote Programming should the COVID-19 pandemic impact a 
subject’s ability to visit the clinic. Equipment (may include laptop, pod, virtual machine, sound processor 
cables and N6 Sound Processor) will be mailed to subject by the clinic to complete the impedance testing and 
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returned after the visit. The use of equipment will be logged and reviewed as per the Sponsor’s Monitoring 
Plan.  
Speech perception performance in quiet for monosyllabic word and sentence lists will be assessed using a 
loudspeaker configuration with the signal from the front, zero Azimuth (S0) at head height and 1 metre 
distance. The Sponsor may provide equipment (such as laptop, software, microphone and speaker) if the 
clinical site does not have it available.  
 
7.5. Sponsor Role in Conduct of the Clinical Investigation 
The Sponsor may support certain activities at the clinical investigation site. Sponsor representatives may be 
present in the operating room with the surgical team and subject. The representative will not provide medical 
assistance and will not discuss the trial with the subject. During the surgery or during study visits, the sponsor 
representative may assist in completing the electrical testing of the cochlear implant. 
The Sponsor may pay for third party clinical trial support (“coordinator”) at clinical investigation sites should 
there be resource constraints, which may support subject recruitment, data entry and reporting under the 
authority of the Principal Investigator. The coordinator will be required to comply with hospital policy and will 
be trained on the CIP and GCP. The coordinator will not complete any activities on behalf of the Sponsor. 
An independent Sponsor representative will review evidence of subject eligibility before the subject is 
accepted for randomisation. This representative will not work in any other capacity of the clinical 
investigation and will be trained on the CIP and GCP.  
 
8. BENEFITS AND RISKS OF THE INVESTIGATIONAL MEDICAL DEVICE AND CLINICAL 
INVESTIGATION 
8.1 
Anticipated Clinical Benefits  
The anticipated clinical benefits include the benefits associated with the CI632, as described in the Physician’s 
Guide. Benefits may include: 
• 
detection of medium to loud environmental sounds at comfortable listening levels. 
• 
detection of conversational speech at comfortable listening levels. 
• 
limited improvement in the recognition of environmental sounds. 
• 
limited ability to use the telephone. 
• 
improvement in speech recognition in a quiet environment in the implanted ear. 
• 
improvement in speech recognition in a noisy environment. 
• 
improvement in overall sound quality. 
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• 
reduced tinnitus. 
• 
reduced fatigue when listening. 
The additional potential clinical benefits of the CI632D relate to release of therapeutic dose of 
dexamethasone into the cochlea over a period of 30 days. This is anticipated to aid in minimising the 
inflammatory response to electrode insertion. Possible benefits could include: 
• 
Reduced formation of fibrosis within the cochlea, as measured by decreased electrical impedance. 
• 
Reduced electrode electrical impedance, possibly resulting in improved sound processor battery life. 
The clinical investigation may require more appointments than standard of care. Study subjects may receive 
benefit from extra medical attention. 
 
8.2 
Anticipated Adverse Device Effects 
Prospective recipients should be advised of the following possible effects of receiving a cochlear implant, as 
described in the CI632 Physicians Guide: 
Adverse effects 
• 
Normal risks associated with surgery and general anaesthesia. 
• 
Increased surgical and anaesthetic risks for certain populations. 
• 
Complications most frequently associated with this surgical procedure—stimulation of the facial 
nerve, taste disturbance and tinnitus. 
• 
Complications that may require additional medical treatment, surgery and/or removal of the device, 
such as: 
− 
Acute Otitis Media (AOM) 
− 
facial nerve injury leading to temporary facial nerve weakness 
− 
perilymph fistula 
− 
Concurrent Cerebrospinal Fluid (CSF) leakage 
− 
vestibular dysfunction 
− 
subdural injury 
− 
subcutaneous haematoma 
− 
irritation, inflammation or breakdown of the skin flap; infection; and in some cases, extrusion 
of the device caused by the presence of a foreign body under the skin 
− 
decreased hearing ability caused by the electrode array migrating partially or completely out 
of the cochlea 
− 
perforation of external ear structures, such as the tympanic membrane or canal wall, by the 
electrode lead 
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− 
perception of non-auditory sensations and poorer performance than expected from 
misplacement of the electrode array 
− 
Electrical stimulation may result in increased tinnitus, temporary facial nerve stimulation, 
temporary dizziness, or temporary pain 
− 
The long-term effects of electrode insertion trauma or chronic electrical stimulation are 
unknown. Such effects may include new bone growth in the cochlea or deterioration of the 
nerve cells. These effects may preclude replacement of the electrode array or may lead to 
eventual deterioration of cochlear response.  
− 
Failure of component parts (both external and internal) could result in the perception of an 
uncomfortably loud sound sensation, intermittent sound, or no sound. 
− 
Failure of various component parts of the implanted device could require removal or 
replacement of the implant, or a reduction in the number of electrodes used. 
Meningitis 
• 
Before implantation, candidates should consult their primary care physician and implanting surgeon 
regarding vaccination status against micro-organisms that cause meningitis. 
• 
Meningitis is a known risk of inner ear surgery and candidates should be appropriately counselled of 
this risk. Certain preoperative conditions may increase the risk of meningitis with or without an implant. 
These conditions include: 
− 
Mondini’s syndrome and other congenital cochlear malformations.  
− 
CSF shunts or drains. 
− 
recurrent episodes of bacterial meningitis before implantation. 
− 
perilymph fistulas and skull fracture/defect with CSF communication. 
Loss of residual hearing 
Inserting the electrode into the cochlea may result in complete loss of residual hearing in the implanted ear. 
8.3 
Risks Associated with Participation in the Clinical Investigation 
The surgical procedure may result in adverse effects, as described in the Investigators Brochure for CI632D. 
The risks for undergoing the cochlear implant surgery are the same as the risks if not participating in the 
clinical investigation. If the subject is randomised to the IMD arm, there may be risks associated with the 
dexamethasone delivered via the cochlear implant. The likelihood of experiencing these risks is minimal given 
the small amount of dexamethasone that will be eluted.  
The clinical investigation may include some inconveniences to the subject as the number of follow-up visits 
may be more than if the subject was not participating. Follow-up visits may be longer in duration than a 
routine cochlear implant follow-up. Some of the required assessments and exams may result in discomfort for 
the subject. Subjects may feel discomfort during the process of identifying the most appropriate program 
settings.  
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8.3.1 Risks specifically associated with the CI632D 
The additional risks associated with the use of the investigational dexamethasone-eluting electrode array 
have been assessed. One residual risk has been identified as a “High” risk and relates to the possibility that 
introduction of the therapeutic substance may adversely affect local immunity, leading to an increased risk of 
infection.  
However, the hazards analysis indicates that the residual likelihood of infection is not expected to be any 
higher than the residual likelihood of meningitis and other central nervous system infections for the CI632 and 
therefore a residual likelihood of ‘remote’ has been assigned. Together with the severity of “catastrophic’, this 
results in a residual risk that is rated “High”.  
Other residual risks related to the presence of dexamethasone, including the risks related to long-term 
presence of the implant in the body, variation in drug release, instability or interactions with other drugs have 
been assigned residual likelihoods of “remote” or “improbable”, with a risk level of “medium”. 
8.4 
Risk Mitigation 
• 
All surgeons will receive surgical training in the use and handling of the CI632 and CI632D as part of 
study initiation. In addition, the Sponsor’s surgical support may be present during surgeries 
performed by the investigational site(s). There is no difference to the implant technique or device 
handling between CI632 and CI632D. 
• 
All reported AEs, ADEs and DDs will be regularly reviewed by the Sponsor’s Clinical review Board for 
the duration of the study to facilitate early detection and appropriate intervention if events are 
unanticipated with respect to incidence, severity, or outcome. 
• 
An Independent Data Monitoring Committee (IDMC) will review all SADEs and infection-related AEs 
for the duration of the study to facilitate early detection and appropriate intervention if events are 
unanticipated with respect to incidence, severity, or outcome. 
• 
Inclusion in the study requires evidence of pneumococcal vaccination prior to randomisation. 
• 
Defined eligibility criteria to address preoperative conditions that may increase risk of meningitis.  
8.5 
Benefit-to Risk Rationale 
Benefits of a cochlear implant to the recipient may include improved detection and recognition of 
environmental sounds, improved detection and recognition of conversational speech, limited ability to use 
the telephone and overall improvement in sound quality. The clinical safety (risks) and benefit relevant to the 
anticipated performance of CI600-series devices, including CI632, were evaluated in the CI600 series Clinical 
Evaluation Report (CER) and it was concluded that the device is effective and has a favourable safety profile. 
The CI600 series cochlear implants are commercially available in multiple countries. Cochlear™-sponsored 
clinical investigations and a systematic literature review, coupled with the design verification/validation and 
post-market surveillance data, established that the benefits of the CI600-series devices outweigh the risks.  
The anticipated additional benefits of dexamethasone, compared with a conventional CI electrode, that will 
be investigated in this study are reduced fibrosis in the cochlea as measured by electrode impedances, and 
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improved battery life due to reduced power consumption for stimulation. The additional risks that may be 
posed by the dexamethasone-eluting electrode incorporated into the CI632D have been assessed and do not 
alter the conclusion that the potential benefits outweigh the risks for the investigational device. 
It is anticipated speech outcomes for CI632D will be non-inferior to CI632. 
Delivery of dexamethasone to the middle and inner ear via intratympanic or transtympanic injection, or 
application to the round window is widely used and accepted in cochlear implant surgery (see Section 4.2.2.1) 
and delivery of dexamethasone via the round window is included in the FDA-approved recommended hearing 
preservation surgery technique for Med-El cochlear implants 
(https://www.accessdata.fda.gov/cdrh docs/pdf/P000025S084c.pdf). Intratympanic delivery of 
dexamethasone has been shown to result in highly localized delivery of a relatively small quantity of drug with 
much lower systemic concentrations than intravenous delivery (Bird et al., 2011). Consequently, the risks of 
systemic side-effects are reduced. The total quantity of dexamethasone incorporated into the CI632D is 
approximately 15 to 110-fold smaller than the quantities used for local application in the studies referred to in 
Section 4.2.2.1, further reducing the risk of adverse effects. 
9. STATISTICAL CONSIDERATIONS 
9.1. General Considerations 
A detailed summary of statistical analysis is documented in the Statistical Analysis Plan (SAP). 
9.2. Endpoints 
9.2.1. 
Primary Endpoints 
1. Difference between CI632D and CI632 mean MP1+2 impedance measurements of the available 
electrodes at 6 months post-cochlear implantation.  
2. Difference between CI632D mean speech perception performance for open-set monosyllabic word 
recognition in quiet in the unilateral listening condition at six months post-implant compared to 
preoperative baseline. 
9.2.2. 
Secondary Endpoints 
1. Comparison of CI632D and CI632 procedural and device related adverse events at 6 Months and 12 
Months post-cochlear implant.  
2. Difference between CI632D and CI632 mean speech perception performance for an open-set 
monosyllabic word recognition in quiet in the unilateral listening condition at six months post-
cochlear implant.  
3. Difference between CI632D and CI632 mean speech perception performance for sentence recognition 
in quiet in the unilateral listening condition at six months post-cochlear implant. 
4. Comparison of CI632D and CI632 Custom Sound® estimated remaining battery life of the sound 
processor at all data collection time points. 
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9.3.1.2. 
Primary Endpoint #2 
Mean CNC word score in quiet will show at least 10% improvement with the CI632D (“treatment” arm) at 6 
months post-implant compared to “treatment” arm’s preoperative Baseline, is as follows: 
H0: CI632D CNC word6 Month < CI632D CNC wordBaseline + 10% 
H1: CI632D CNC word6 Month ≥ CI632D CNC wordBaseline +10% 
9.3.2. 
Secondary Hypothesis 
Three secondary endpoints are planned; one related to adverse events and two related to mean change in 
speech perception performance.  
Analyses of secondary endpoints, as well as other assessments, will be performed but there are no plans for 
formal prespecified hypothesis tests for these analyses with type I error control. It is recognized that this may 
limit the ability for such analyses to support labelling claims with inferential quantities.  
9.3.3. 
Exploratory Hypothesis 
There are no exploratory hypotheses. 
 
9.4. Sample Size Determination 
The following evidence was used to support the sample size calculation of the first primary endpoint: 
Cochlear™’s feasibility clinical investigation CLTD5495 comparing outcomes of the dexamethasone eluting 
CI400 Combined Investigational Device (CI4CID) and standard CI24RE(CA) device. At 6 months post-activation 
MP1+2 impedance data showed a decrease of 3.8 kOhms for the CI4CID compared to the CI24RE(CA). The 
CI4CID standard deviation from its mean was 1.0 while the CI24RE(CA) standard deviation was 1.7. The 
electrode array used in this clinical investigation is the Contour Advance electrode. 
CI632 predicate device is the Cochlear™ Nucleus® CI532 cochlear implant with Slim Modiolar electrode 
(CI532). Six month mean MP1+2 impedance data for 43 subjects under the clinical investigation CLTD5446 
provides similar results to the CI24RE(CA) control group of the CLTD5495 clinical investigation, with mean 
MP1+2 impedance measuring at 7.9 kOhms with a standard deviation of 1.7. 
Considering results from CLTD5495 and CLTD5446, the following assumptions have been made regarding this 
clinical investigation: 
Using an independent t-test (SigmaPlot 13.0) the sample size has been calculated to have reasonable power 
to detect a 1.5 kOhm decrease difference in MP1+2 impedance at 6 months post-cochlear implant for those 
implanted with the CI632D IMD compared to those implanted with the CI632 comparator device.  
This change of 1.5 kOhms to be detected is based on clinical consensus and has taken into consideration the 
significant mean impedance reduction (3.8 kOhms) observed in the CI4CID feasibility clinical investigation 
CLTD5495. Due to the nature behind the design of CI632, it is likely there will be less insertion trauma as it is a 
precurved electrode designed to stay closer to the medial wall of the cochlea.  
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An expected standard deviation (SD) of the change is 2.0 kOhms. This SD of the change to be detected is 
based on the SD of the mean impedance of 1.7 observed in separate clinical investigations for CI24RE(CA) and 
CI532. The expected standard deviation of the mean in the current study has been chosen to be more 
conservative, allowing for increased impedance variability between the two arms.  
A significance level α = 0.025 (one-tailed). 
A desired power of 0.9 
The sample size for a 1:1 allocation has been calculated to have reasonable power to detect a decrease in 
mean (SD) MP1+2 impedance of 1.5 kOhm (1.5) for the CI632D IMD compared to the CI632 comparator 
device at 6 months post-implantation.  
A 1.5 kOhms drop in impedance is expected to result in a mean increase in battery life of 1.79 hours for 
recipients with high powered maps, demonstrating a meaningful clinical benefit. This calculation is based on 
prior investigation using the DEE battery model (D1672865). 
In the absence of literature to support a clinically meaningful change in impedance values for cochlear 
implants, the Sponsor positions 1.5kOhms effect size as clinically meaningful as shown by the battery life 
model increasing battery life by a mean of 1.79 hours. An improvement of 1.79 hours in battery life clearly 
equates to a meaningful duration of time for a cochlear implant recipient, such as a round trip commute to 
work, multiple meetings at work, a child’s soccer game, meal out with friends, etc. The clinical investigation is 
powered to capture the 1.5kOhm effect size. 
Based on these assumptions, a minimum sample size of 39 subjects in both arms is required to reject the null 
hypothesis of equivalent or higher MP1+2 impedance for the CI632D IMD compared to the CI632 comparator 
device at 6 months post-implantation with a power > 0.9. An increased sample size of 100 subjects 
(approximately 50 subjects in each arm) will be included, which will allow for the possibility of non-normally 
distributed data (approximately 15%) and subject attrition (approximately 10%). In addition, the population is 
extended to 120 randomised subjects to account for uncertainty in the estimates used in the power 
calculation, with approximately 60 subjects in each arm. 
The following evidence and assumpters were used to support the same size calculation of the second primary 
endpoint:  
CI632 predicate device is the Cochlear™ Nucleus® CI532 cochlear implant with Slim Modiolar electrode 
(CI532). Six month mean CNC word in quiet data 96 subjects under the clinical investigation CLTD5685 
provided a mean change of 46 ± 22.6 (SD) word improvement from baseline  
A significance α = 0.025 (one-tailed). 
A desired power of 0.9 
A 10% improvement at 6 Months post-cochlear implant is required to reject the null hypothesis. Based on 
these assumptions, a minimum sample size of 10 subjects is required to reject the null hypothesis of 
equivalent or lower CNC words in quiet for the CI632D at six month post-cochlear implant compared to 
baseline with a power > 0.9. To account for non-normally distributed data (approximately 15%) and subject 
attrition (approximately 10%), not less than 13 subjects need to be randomised to CI632D (“treatment” 
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group) and successfully implanted. More than 13 subjects will be randomised to the treatment to meet 
sample size requirements for the first primary endpoint.  
As the CI632D is a novel medical device, a group sequential analysis strategy is planned. The first analysis will 
occur with the first 50 randomised subjects completing the 6 month endpoint. If stopping criteria are not met, 
the analysis will be repeated at 80 subjects, 100 subjects and 120 subjects.  
 
 
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9.5. Analysis Populations 
Analyses of endpoints will include the following populations: 
• 
Intent-to-Treat (ITT): all subjects that are randomised. Analysis will be based on randomisation 
assignment.  
• 
As-Treated (AT): subjects that receive a CI632 or CI632D. Analysis will be based on treatment received 
(rather than randomisation assignment). 
• 
Per-protocol (PP): subjects that receive a CI632 or CI632D in accordance with randomisation 
assignment and do not have a translocated electrode as confirmed by imaging. 
In addition to these populations, there may be subgroup analysis which could include geography, sex, age or 
race. The complete analysis strategy will be outlined in the Statistical Analysis Plan (SAP).  
9.6. Endpoint Analyses 
9.6.1. 
Primary Endpoint Analyses 
There are two primary endpoints.  
Primary analysis of MP1+2 impedances will include the ITT population evaluating mean differences at 6 
months post-cochlear implantation based on a t-test at the one-sided 0.025 alpha level. If there is evidence of 
non-normality (based on a Shapiro-Wilks test at the 0.05 alpha level), a non-parametric alternative will be 
employed for the primary endpoint.  
Primary analysis of speech perception performance will include the cohort of subjects randomised to CI632D 
and for whom CI632D is their first cochlear implant in the ITT population, evaluating the difference at 6 
months post-cochlear implantation compared to baseline via a one-sample sample t-test at the one-sided 
0.025 alpha level. If there is evidence of non-normality (based on a Shapiro-Wilks test at the 0.05 alpha level), 
a non-parametric alternative will be employed for the primary endpoint. 
For both endpoints, analysis may include description of population differences in the final analysis. Additional 
analysis may include both the AS and PP analyses groups. Missing data will be analysed under a multiple 
imputation strategy that will be outlined in the Statistical Analysis Plan (SAP). 
9.6.2. 
Secondary Endpoint Analyses 
See Section 9.7 for Safety Analysis under the secondary endpoint. There are two speech perception endpoints 
at six months post-implantation. There are no formal statistical hypothesis planned for these endpoints; 
analyses will be based on descriptive statistics and nominal 95% confidence limits, with results reported 
separately by randomized group. The ITT population will be used for primary analysis for each endpoint. A 
secondary analysis will include the Per Protocol group. Missing data will be analysed under a multiple 
imputation strategy that will be outlined in the Statistical Analysis Plan (SAP). Analysis of estimated remaining 
battery life of CI632D and CI632 Custom Sound® will be conducted.  
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9.6.3. 
Exploratory Endpoint Analyses 
All exploratory endpoints will be included in the final analysis for each time point. Further detail of analysis, 
including management of missing data, can be found in the SAP. Formal hypothesis testing is not planned for 
exploratory endpoints. 
9.7. Safety Analyses 
Safety analysis will be completed with the AT population at both 6 months and 12 months post-cochlear 
implantation. The rate of AE type will be compared between treatment and control arm.  
For AE/ADEs and DDs, data will be tabled to present event type, severity, device/procedural relationship, 
count and percentage, and subjects with event will be summarised by randomisation group. Any subjects who 
died, who discontinued an intervention due to an AE/ADEs, or who experienced a severe or an SAE/SADEs will 
be summarised separately. In addition to Secondary Endpoint Analyses, AE/ADE and DD frequency data will 
be provided to the IDMC in accordance to the IDMC Charter. 
9.8. Interim Analyses 
Group sequential analysis based on an O’Brien-Fleming like alpha spending function, will be completed for the 
primary endpoints following the collection of 6 Month data for subjects at the following intervals: the first 50 
randomised subjects, first 80 randomised subjects, first 100 randomised subjects, and first 120 randomised 
subjects. If the null hypothesis cannot be rejected for both primary endpoints following analysis at each 
interval (stopping criteria), then further analysis will take place at the subsequent interval until the final 
analysis of the 120 randomised subjects. 
The first primary endpoint will be analysed first. The second primary endpoint will be analysed if the null 
hypothesis is rejected. Analysis of secondary or exploratory endpoints will not occur until both the primary 
endpoint null hypotheses are rejected, or 120 randomised subjects are analysed. 
Prior to final analysis at study completion, group sequential analysis may be used as part of Premarket 
Approval (PMA) if both primary endpoint null hypotheses are rejected.  
9.9. Sub-Group Analyses 
Sub-group analyses may be completed as an additional analysis to any endpoint. Sub-groups may include 
analysis of specific clinical investigation sites, sex, age, race or specific procedural/device outcome (such as 
translocation). Detail of sub-group analysis can be found in the SAP. 
10. INFORMED CONSENT PROCESS 
The Investigator shall obtain written informed consent from the subject using an approved ICF prior to any 
clinical investigation-related examination or activity. The rationale of the clinical investigation, as well as the 
benefits and risks, what participation will involve, and established alternatives to participation will be 
explained to the subject in native non-technical language, understandable to the subject. Ample time will be 
provided for the subject to enquire about details of the clinical investigation and to decide whether to 
participate. 
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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. They shall not waive or appear to waive their legal 
rights. 
Each subject (or their legally designated representative) and the person who conducted the informed consent 
discussion, shall sign and personally date the Informed Consent Form (ICF). Where required, an independent 
and impartial witness shall sign and personally date the ICF. A copy of the signed ICF shall be given to the 
subject. The original signed ICF shall be archived in the Investigator’s Site File or subject file at the 
investigational site. 
This process shall be documented in the subject’s source documents. 
The subject, or the subject’s legally designated 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 must be documented as an update to the ICF 
and re-consent of the subject. 
11. ADVERSE EVENTS AND DEVICE DEFICIENCIES 
11.1. Definitions 
11.1.1. Adverse Event  
An adverse event (AE) is 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 and whether anticipated or unanticipated. 
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 the use of investigational 
medical devices or comparators. 
11.1.2. Adverse Device Effect 
An adverse device effect (ADE) is an AE related to the use of an investigational medical device. 
NOTE 1: This includes any AE resulting from insufficient or inadequate instructions for use, deployment, 
implantation, installation or 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. 
NOTE 3: This includes ‘comparator’ if the comparator is a medical device. 
11.1.3. Serious Adverse Event 
A serious adverse event (SAE) is any AE that led to any of the following: 
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1) death,  
2) serious deterioration in the health of the subject, users, or other persons as defined by one or more of the 
following: 
• 
a life-threatening illness or injury, or 
• 
a permanent impairment of a body structure or a body function including chronic diseases, or 
• 
in-patient or prolonged hospitalisation, or 
• 
medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to 
a body structure or a body function, 
3) foetal distress, foetal death or a congenital abnormality, or birth defect including physical or mental 
impairment. 
NOTE: Planned hospitalisation for a pre-existing condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a SAE. 
11.1.4. Serious Adverse Device Effect 
A serious adverse device effect (SADE) is an ADE that has resulted in any of the consequences characteristic of 
a SAE. 
11.1.5. Unanticipated Serious Adverse Device Effect 
An unanticipated serious adverse device effect (USADE) is a SADE, which by its nature, incidence, severity, or 
outcome has not been identified in the current version of the Investigator’s Brochure. 
USADE are also known as a UADE (Unanticipated Adverse Device Effect) for the purposes of US FDA reporting. 
NOTE: An anticipated serious adverse device effect is an effect, which by its nature, incidence, severity, or 
outcome has been identified in the Investigator’s Brochure. 
11.1.6. Device Deficiency 
A Device Deficiency (DD) is an inadequacy of a medical device with respect to its identity, quality, durability, 
reliability, usability, safety, or performance. 
NOTE 1: Device Deficiencies include malfunctions, use errors, and inadequacy in the information supplied by 
the manufacturer including labelling. 
NOTE 2: This definition includes device deficiencies related to the IMD or the comparator. 
11.1.7. Serious Health Threat 
A signal from any adverse event or device deficiency that indicates an imminent risk of death or a serious 
deterioration in the health in subjects, users or other persons, and that requires prompt remedial action for 
other subjects, users or other persons. 
NOTE: This would include events that are of significant and unexpected nature such that they become 
alarming as a potential serious health hazard or possibility of multiple deaths occurring at short intervals. 
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particularly if the deviation potentially impacts subject safety, performance of IMD and/or comparator, or 
data integrity. 
All CIP deviations will be documented in the eCRF to enable analysis and reporting by the Sponsor in the 
Clinical Investigation Report (CIR), or to the relevant regulatory authority(s), if applicable. 
Gross misconduct on behalf of an Investigator, such as intentional non-compliance with CIP or GCP 
requirements or fraud, will result in disqualification of the Principal Investigator and/or Investigational Site 
from participation in the investigation. Data provided by the Principal Investigator or Investigational Site will 
be excluded from the per-protocol analysis group. 
14. DATA MANAGEMENT 
The CRF will capture the datapoints necessary to determine the subject status according to the criteria 
described in section 7.2.5. 
14.1. Source Data 
Source data will be captured in clinic notes, paper-based source data worksheets, or printed directly from 
testing software. No data will be entered directly into EDC. If electronic medical records do not permit read 
only access for monitoring purposes, a certified printout must be provided, indicated by a dated signature by 
a member of the site team or generated through a validated process. 
An Origin of Source Data Form will be used to capture the location of source data kept at each site, outlining 
the individual site’s process for certification. 
14.2. Methods for Data Entry and Collection 
Data collection will be performed using Medidata Rave for electronic data capture (EDC) on electronic Case 
Report Forms (eCRFs). Site staff will be trained on the completion of the eCRFs prior to obtaining access to the 
system and will have their own Login/Password. Access to clinical study information will be based on an 
individual’s role and responsibilities. 
Medidata Rave uses role-based user permissions for data entry, viewing, and reporting options. All 
communications between users and the EDC server are encrypted. Web servers are protected by a managed 
firewall. This application is designed to be in compliance with applicable regulations including 21 CFR Part 11. 
The application will include programmed data consistency checks and supports manual generation of data 
clarifications/queries, including documentation of site responses. The application maintains a comprehensive 
audit trail for all data entered, including updates and queries, and documents the time that each entry 
occurred and who made the entry. 
Principal Investigators will affirm that the data for each subject at their site is accurate and complete by way 
of an electronic signature. 
In addition, de-identified electronically generated data will be collected from clinical fitting software, x-ray 
imaging, CT imaging, questionnaires and other methods. The unamended data file shall be regarded as the 
source. 
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14.3. Database Lock 
A Data Quality Review Meeting (DQRM) will be conducted every month and will also review the locking. 
Prior to database lock the Principal Investigator at the site shall electronically sign to verify the accuracy and 
completeness of the data. Where this responsibility is delegated to a suitably qualified Investigator it will be 
documented on the site signature and delegation log. 
In final analyses, all dataset shall be frozen and locked before analyses. 
Following database lock, raw datasets will be generated to enable analysis. The analysis are outlined in the 
Statistical Analysis Plan (SAP). 
 
15. CONFIDENTIALITY 
The investigator and site staff will collect and process personal data of the subjects in accordance with 
governing data privacy regulations. 
Data will be reported to the Sponsor on CRFs or related documents (for example, questionnaires). Subjects 
will be identified on CRFs and other related documents only by a unique subject identification code and shall 
not include the subject’s name or other personal identifiable information. Completed CRFs or related 
documents are confidential and will only be available to the Investigator and site staff, the Sponsor and their 
representatives, and if requested to the Ethics Committee and national regulatory authorities. Publications or 
submission to a regulatory authority shall not disclose the identity of any subject. 
All cochlear implants and sound processors are registered to Cochlear™ using the recipient’s name and other 
identifying information. Cochlear will follow the same procedures and policies to protect confidentiality for 
recipients with a commercial or investigational cochlear implant. 
16. ETHICS COMMITTEE AND REGULATORY AUTHORITY APPROVAL 
This clinical investigation will be conducted under the following regulatory pathways: 
Country 
Pathway 
Australia 
CTN  
US 
Investigational Device Exemption (IDE) 
NZ 
Not applicable 
The clinical investigation will not commence prior to the written favourable opinion or approval from the EC 
and or regulatory authority (if appropriate) is obtained. 
The final Sponsor-approved version of the CIP, Informed Consent Form, and other necessary documents shall 
be submitted to the EC. A copy of the EC opinion/approval shall be provided to the Sponsor. 
The Investigator shall forward to the Sponsor, for review and approval, any amendment made to the 
approved ICF and any other written information to be provided to the subject prior to submission to the EC. 
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The Sponsor and Principal Investigator will continue communications with the EC, as required by national 
regulations, the clinical investigational plan, or the responsible regulatory authority. 
Any additional requirements imposed by the EC or regulatory authority will be implemented by the Sponsor. 
The Investigator shall submit the appropriate documentation if any extension or renewal of the EC approval is 
required. In particular, substantial amendments to the CIP, the ICF, or other written information provided to 
subjects will be approved in writing by the EC. 
The Investigator shall report to the EC any new information that may affect the safety of the subjects or the 
conduct of the clinical investigation. The Investigator will 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 requirements. 
The clinical investigation is covered by clinical trial insurance, meeting the requirements of the participating 
countries. 
17. SUSPENSION OR PREMATURE TERMINATION 
The Sponsor will discontinue the clinical investigation site if: 
1. major non-adherence to the CIP or GCP principles is occurring 
2. it is anticipated that the subject recruitment will not be adequate to meet the objectives of the clinical 
investigation 
An ongoing clinical investigation may be discontinued in case of: 
1. device failure 
2. serious or intolerable ADE, leading to the explant or discontinued use of the device 
3. subject’s death 
18. AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
No changes in the CIP or investigation procedures shall be made without mutual agreement of the 
Coordinating Investigator and the Sponsor. This agreement will be documented as a CIP amendment.  
Amendments will require notification to the Ethics Committees (ECs) by the Principal Investigators (and to the 
relevant regulatory authority(s) by the Sponsor, if applicable). 
19. RECORD KEEPING AND RETENTION 
Data generated from the clinical investigation will be stored in a limited-access file area and be accessible only 
to representatives of the study site, the Sponsor and its representatives, and relevant health 
authorities/regulatory agencies. All reports and communications relating to study subjects will identify 
subjects only by subject unique identification code. Complete subject identification will be maintained by the 
Investigator. This information will be treated with strict adherence to professional standards of 
confidentiality. 
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21. STATEMENTS OF COMPLIANCE 
This clinical investigation shall be conducted in accordance with ethical principles that have their origin in the 
Declaration of Helsinki, International Standard ISO 14155:2020 Clinical investigation of medical devices for 
human subjects - Good Clinical Practice, and any regional or national regulations, as applicable. 
22. QUALITY CONTROL AND ASSURANCE 
In accordance with Cochlear™’s Quality Management System, all clinical investigations shall be conducted 
according to internationally recognised ethical principles for the purposes of obtaining clinical safety and 
performance data about medical devices. 
The Sponsor employees (or designee) shall use standard operating procedures (SOP) to ensure that clinical 
study procedures and documentation are consistently conducted and compliant with the ISO 14155 Standard, 
Good Clinical Practice (GCP), and applicable local regulations. 
22.1. Monitoring 
The Sponsor will perform on-site and remote monitoring visits as frequently as necessary to oversee conduct, 
data collection and record keeping by sites. The clinical investigation monitoring plan is a separate document 
for the sponsor to follow, describing all the activities performed during site qualification, initiation, 
monitoring, and close out. 
In accordance with applicable regulations, GCP, and sponsor’s/CRO’s procedures, monitors will contact the 
site prior to the start of the study to review with the site staff the CIP, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and sponsor’s requirements. When reviewing data collection 
procedures, the discussion will also include identification and documentation of source data items. 
The sponsor/designee will monitor the site activity to verify that the: 
• 
Data are authentic, accurate and complete 
• 
Safety and rights of subjects are being protected 
• 
Study is conducted in accordance with the currently approved CIP 
• 
Any other study agreements, GCP, and all applicable regulatory requirements are met. 
The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct 
access to all relevant documents. 
22.2. Audits 
To ensure compliance with GCP, the CIP, study procedures and applicable regulatory and EC requirements, an 
independent audit of the study may be conducted. The investigator/institution will be informed of the 
outcome for audits involving their site.  
In addition, inspections by regulatory health authority representatives and EC(s) are possible. An Investigator 
must, in reasonable time, upon request from a relevant health authority or regulatory agency, permit access 
to requested records and reports, and copy and verify any records or reports made by the Investigator. Upon 
notification of a visit by a regulatory authority, the Investigator will contact the Sponsor immediately.   
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The Investigator will grant the Sponsor representatives the same access privileges offered to relevant health 
authority or regulatory agents, officers, and employees, for the purposes of a Sponsor audit of the site, or in 
preparation for an inspection. 
Audits and inspections may occur at any time during or after completion of the study. 
23. TRADEMARKS AND COPYRIGHT 
ACE, Advance Off-Stylet, AOS, Ardium, AutoNRT, Autosensitivity, Baha, Baha SoftWear, BCDrive, Beam, Bring 
Back the Beat, Button, Carina, Cochlear, 科利耳, コクレア, 코클리어, Cochlear SoftWear, Contour, コントゥ
ア, Contour Advance, Custom Sound, DermaLock, Freedom, Hear now. And always, Hugfit, Human Design, 
Hybrid, Invisible Hearing, Kanso, LowPro, MET, MP3000, myCochlear, mySmartSound, NRT, Nucleus,Osia, 
Outcome Focused Fitting, Off-Stylet, Piezo Power, Profile, Slimline, SmartSound, Softip, SoundArc,  True 
Wireless, the elliptical logo, Vistafix, Whisper, WindShield and Xidium are either trademarks or registered 
trademarks of the Cochlear group of companies. 2022 
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Signature Page for VV-TMF-01100 v13.0
Signature Page for VV-TMF-01100 v13.0
Reason for signing: Approved
Name: 
Role: A
Date of signature: 07-Nov-2022 03:43:53
GMT+0000
Reason for signing: Approved
Name: 
Role: A
Date of signature: 07-Nov-2022 04:07:46
GMT+0000
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