AB-Intra- and Post-Operative Measures of Auditory Function

Background and Objectives of the Study

Cochlear Implantation A cochlear implant (CI) is a prosthetic device for the inner ear that
bypasses damaged inner ear hair cells and directly stimulates the auditory nerve, thereby
providing audible sensations to patients with sensorineural hearing loss (SNHL). The
implanted part consists of a hermetically sealed electronics package, a receiver coil which
communicates with external components, and a magnet to help align the internal and external
receiver coils. Attached to the implant package is the lead assembly that includes an array
of electrode contacts that is inserted into the cochlea and interacts with its stimulable
elements, the spiral ganglion cells and the cochlear hair cells. Today's CI models have
between 12 and 22 intra-cochlear electrode contacts, each of which can be independently
stimulated. In the healthy cochlea, different pitches are perceived at distinct locations
along the length of the cochlea. This tono-topic organization is utilized when stimulating
the cochlea electrically, as individual contacts can preferentially address neural
populations associated with discrete regions of the cochlea. For example, when a low-pitched
sound is captured by the microphone of the external sound processor, stimulation is routed to
more apical electrodes, while for high-pitched sounds more basal electrode contacts are
engaged.

Performance and Candidacy

Cochlear implants are currently the standard-of-care for patients with significant SNHL and
poor speech understanding. Preservation of the delicate anatomy within the cochlea is
well-known to correlate with hearing and speech understanding outcomes. During electrode
insertion, it is common for the surgeon to make subtle adjustments to insertion parameters
such as the angle of insertion or speed of insertion; such modifications are part of the
standard-of-care of conventional CI surgery. The current state of conventional CI electrode
insertion provides the surgeon with no feedback as to whether and when the delicate
structures of the cochlea are damaged. Such a tool by which the surgeon can obtain real-time
measurements of the electrophysiological function of the cochlea could help improve the
current surgical procedure.

Electrocochleography

One means of achieving this level of feedback is using electrocochleography (ECochG). ECochG
is an objective electrophysiological reflection of peripheral acoustic-electric interactions
within the cochlea. ECochG devices are FDA cleared Class II devices. An example of a cleared
device is the Otometrics device (k143670). The FDA 510(k) clearance letter for this device is
provided (See Appendix). During ECochG measurement, a brief acoustic tone burst with a
defined frequency and level is delivered to the external ear canal. This results in normal
physiologic movements of the outer and the inner cochlear hair cells. These movements produce
small electrical potentials that can be sensed by a recording electrode placed near the
cochlea (e.g., historically, on the promontory or the round window). Averaging of these
recordings in synchrony with the acoustic stimulus allows the small ECochG signal to be
reinforced while any physiological or electrical noise is averaged out.

With ECochG measurements, the functional integrity of different elements of the peripheral
auditory system can be examined. Specifically of interest, ECochG measurements can be
resolved into the cochlear microphonic (CM) - generated by the cochlea's outer hair cells -
and the auditory nerve neurophonic (ANN) - generated by the auditory nerve. By comparing the
energy in the recorded signal at the measurement frequency with the noise floor of the
measurement, behavioral hearing thresholds can be estimated with an accuracy of +/- 10 dB.

Real-Time ECochG monitoring

Advanced Bionics (AB), a manufacturer of FDA-approved CIs, has introduced a software approach
to allow for utilization of ECochG during surgery. The prototype version of the AB-ECochG
system has been successfully utilized in several clinical studies. The technological
characteristics of the ECochG system utilized here are equivalent to existing FDA-approved
systems.

This protocol will utilize the latest system under development from AB that enables data
collection with sufficient speed and precision to provide real-time observations to the
surgeon during CI electrode insertion.

Objectives

This investigation does not involve a novel CI or a modification of an existing implantable
device. The CIs to be used in this study are physically and technologically unchanged and
have current FDA approval (Ultra MS: Model# CI-1600-04, FDA PMA Approval Number P960058/S117;
Ultra Slim J: Model# CI-1600-05, FDA PMA Approval Number P960058/S121). Utilization of the
device in the diagnosis and treatment of disease (i.e., hearing loss) is also unchanged and
consistent with existing FDA-approved indications.

ECochG systems themselves are not novel and have been in clinical use for many years. ECochG
devices are FDA-cleared Class II devices. An FDA 510(k) clearance letter is provided (See
Appendix). Use of ECochG for the purposes described here is consistent with indications
covered under this FDA 510(k) clearance.

The objective of this study is to learn about how ECochG-based observations during
conventional CI surgery can improve outcomes compared to the standard-of-care technique of
blind electrode insertion. Two clinically relevant outcomes will be considered:
post-operative electrode location (i.e., correct electrode placement within the scala
tympani) and hearing performance (i.e., postoperative audiometric thresholds in clinic).

Significance

Compared with previous relevant work, whereby ECochG was recorded near the cochlea before and
after CI electrode insertion, recording ECochG from the vantage point of the CI's apical
electrode within the cochlea during CI electrode insertion has the advantage of closer
proximity to the ECochG signal generators (i.e., cochlear hair cells and the acoustic nerve).
This approach has been shown to result in larger amplitude recording, and, thereby, more
immediate feedback to the surgeon should these potentials change. An added advantage of this
method is that it does not involve any change to the CI device itself, to the way the device
is used, or to the surgical technique to place the device.

The potential utility of ECochG during CI is illustrated by the following scenario: if the CI
electrode touches the delicate structures of the cochlea (i.e., the basilar membrane or the
spiral ligament) during insertion, the ECochG potentials become smaller in amplitude. With a
real-time measurement system used during electrode insertion, decrease in ECochG potentials
could be detected, and the surgeon could more purposely employ their modifications to
insertion technique such as changing the insertion angle to avoid trauma or translocation.

Use of intra-cochlear electrodes for ECochG offers an additional capability of observing
potentials post-operatively in the clinic. ECochG allows an objective method of monitoring
hearing at regular intervals over the early post-operative period and may give insights into
hearing outcomes.

Study Design

A prospective, randomized, multi-center controlled study design will be used in this study.
The total study duration will be up to two years. This study will be conducted in agreement
with the Internal Review Board (IRB). The study will be registered through Clinical
Trials.gov (account created; IRB approved).

Outcome Measures

The post-operative outcome measures of this study will be (1) the CI electrode's scalar
position as indicated by post-operative computed tomography (CT) and (2) post-operative
hearing performance. Following the clinical convention, the surgeon will pre-operatively
select the type of CI electrode (i.e., the MidScala electrode or the SlimJ electrode) that
they would like to use during surgery. As detailed below, the patient will then be randomized
to "audible ECochG signal off" or "audible ECochG signal on."

Hypotheses

The hypotheses of this study are that:

1. Changes in the ECochG signal observed during CI electrode insertion will correlate with
insertion position outcomes as indicated by post-operative CT scan.

2. Participants randomized to "ECochG audible response on" will demonstrate a significantly
lower rate of scalar dislocation compared to participants randomized to "ECochG audible
response off."

3. Changes in the ECochG signal during CI electrode insertion will correlate with
post-operative audiogram.

4. Post-operatively, changes in the ECochG signal over time in clinic will correlate with
changes observed over time in post-operative audiograms.

Participants

In total, 192 participants will be included in this study. This sample size was determined by
a power analysis, detailed below in Statistical Analysis.

Inclusion criteria are:

- Pure-tone audiometry thresholds ≤80 dB HL at 500 Hz

- One year of age and older

- Normal candidacy requirements for cochlear implantation met

- No cochlear abnormality that might prevent full insertion of the CI electrode array

- No additional handicap that would prevent study procedures from being followed

Exclusion criteria are:

- Chronic otitis media

- Malformed cochlea

- Auditory neuropathy spectrum disorder (ANSD)

- Presence of ear tubes

- Prior middle ear surgeries or trauma including disruption of ossicles

At any point in the study, the participants are free to end their involvement without any
effect on their clinical care. Because this study does not involve any changes to the CI, its
use, or the surgical technique, if a participant were to elect to end involvement in the
study, it does not impact their treatment in any way. CI candidates meeting inclusion
criteria will be given the opportunity to participate at the time of their regular
pre-operative clinic visit or on the day of surgery itself.

Randomization

Interested CI candidates meeting study inclusion criteria will be randomized to one of two
treatment arms. Randomization has been accomplished using a "randomized block design" to
ensure that equal numbers of participants are included in each "treatment condition." For
each participating institution, an impartially designed randomization schedule has been drawn
up with the assistance of a biostatistician. The arm to which participants are randomized
will be unknown to the investigators at the time of enrollment and to the participants
themselves. By necessity, surgeons themselves will be "unblinded" on the day of surgery.
Figure 1 depicts the study's randomization arms and post-operative outcome measures.

Arm 1: Audible ECochG Response Off

This condition is identical to the current standard-of-care for conventional CI surgery used
worldwide. The surgeon will perform his or her electrode insertion without ECochG monitoring.
Minute manipulations of the electrode are a normal part of conventional electrode insertion;
manipulations such as redirecting the insertion vector or slowing down insertion speed will
be made, as deemed necessary by the surgeon. A full electrode insertion will be performed, as
appropriate. The ECochG responses will be recorded, but the surgeon will be blinded to this
information during surgery.

Arm 2: Audible ECochG Response On

This condition will have the audible ECochG response on and available to the surgeon. In this
condition, the surgeon perform a conventional electrode insertion while listening to the
running ECochG signal for drop in amplitude (suggesting impending trauma). If no drop is
detected, insertion will proceed to the full electrode length according to the
standard-of-care. If an ECochG amplitude drop is observed, the surgeon will place this
observation in its clinical context and evaluate insertion parameters, (i.e., insertion
vector, insertion speed, etc.), customary practice with conventional CI surgery, but here
supplemented by the ECochG response. In the case of an ECochG amplitude drop that does not
recover, the standard-of-care practice of achieving a full electrode insertion will be
followed.

Protocol timeline

1. Pre-Operative (typically 1-30 days before surgery)

1. Standard counselling regarding CI study; collect consent form for adults or assent
form for pediatric participants; collect data release forms.

2. The surgeon makes his or her CI electrode selection between two options: (1) the
HiFocus SlimJ (lateral wall array) or (2) the HiFocus MidScala. Electrode selection
is a normal component of conventional CI surgery. All CIs models to be utilized in
this study are FDA-approved and will be used within their approved indications
(Ultra MS: Model# CI-1600-04, FDA PMA Approval Number P960058/S117; Ultra Slim J:
Model# CI-1600-05, FDA PMA Approval Number P960058/S121).

3. Pure tone audiometry (standard-of-care pre-operative CI candidacy evaluation). In
pediatric patients, for whom completion of pure tone audiometry may be difficult or
unreliable, auditory brainstem response (ABR) testing can be used to supplement or
estimate behavioural thresholds.

4. Pre-operative CT scan (standard-of-care) for surgical planning.

2. Day of surgery

1. Ensure that no cerumen or surgical preparation fluid is in the external ear canal.
Place the ear piece in the external ear canal and fold the pinna forward, as in the
conventional procedure.

2. Enter the pre-op audiogram into the software.

3. Normal CI surgical approach. A conventional round window or extended round window
entry into the cochlea is prepared.

4. Measure ECochG in response to a 500 Hz tone burst stimulus, at 110 dB SPL, during
insertion of the CI electrode and after insertion of the CI electrode. Figure 2
schematically depicts the intraoperative set-up. Figure 3 shows the non-invasive
surface electrode and earphone array used in ECochG. Figure 4 shows the enclosure
box and monitoring screen.

i) For participants randomized to Arm 1 of the study, the surgeon will perform CI
electrode insertion without ECochG feedback.

ii) For participants randomized to Arm 2 of the study, the surgeon will make insertion
modifications as appropriate in response to ECochG feedback.

3. Initial CI Activation Visit (3-5 weeks after surgery)

a) Audio Assessment i) Unaided pure tone audiometry in the implanted and the unimplanted
ear ii) Bone-conduction thresholds when possible, depending on the patient's residual
hearing status iii) For pediatric patients, unaided audiometric data may be collected as
tolerated, across different visits, to accommodate the unique challenges of hearing
assessment of young children.

b) Measure ECochG responses in clinic (to coincide with audiometry, +/- 1 week) i)
125-2000 Hz (frequency scan) ii) At an acoustic intensity level at or below their
comfortable level through an insert earphone iii) Directly through the CI c) Post-Op CT
scan to identify CI electrode scalar location i) Obtain scan within one month following
surgery ii) Patient identifiers removed from CT scan data and sent to collaborators in
DICOM format for analysis (See Appendix 1).

4. Approximately 3 Month Visit

a) Audio Assessment i) Pure tone unaided audiometry in the implanted and the unimplanted
ear ii) Bone-conduction thresholds when possible, depending on the patient's residual
hearing status b) Measure ECochG responses in clinic (to coincide with audiometry, +/- 1
week) i) 125-2000 Hz (frequency scan) ii) At an acoustic intensity level at or below
their comfortable level through an insert earphone iii) Directly through the CI

5. Approximately 12 Month Visit a) Audio Assessment i) Pure tone unaided audiometry in the
implanted and the unimplanted ear ii) Bone-conduction thresholds as appropriate b)
Measure ECochG responses in clinic (to coincide with audiometry, +/- 1 week) i) 125-2000
Hz frequency scan ii) At an acoustic intensity level at or below their comfortable level
through an insert earphone iii) Directly through the CI Detailed description of
measurements and procedure Pure tone and bone-conduction audiometry Pure tone audiometry
will be performed following the conventional, routine protocol currently in place for
determining CI candidacy. Where possible, pure tone thresholds will be established in
the implanted ear for 125, 250, 500, 750, 1000, 1500, 2000, 3000, 4000, 6000, and 8000
Hz. Testing will be conducted using insert earphones, and where indicated, the
contralateral ear will be masked. Both the implanted and the non-implanted ear will be
measured. If clinically appropriate, bone-conduction testing will be performed as well
following conventional practices. For young children in our cohort, for whom hearing
testing can be uniquely challenging, thresholds obtained across more than one visit will
be permitted and thresholds may be estimated base on auditory brainstem response (ABR)
testing.

In line with the Minimum Reporting Standards for Adult Cochlear Implantation recommendations,
in patients with functionally relevant pre-operative low frequency pure tone averages (125,
250, 500 Hz) < 80 dB HL, post-operative residual hearing will be reported. Each frequency
will be reported individually (125, 250, 500, 1000, 1500, 2000, 4000, and 8000 Hz) rather
than as a pure tone average.

Electrocochleography

In the operating room, a 500 Hz tone burst will be presented to the participant at a 110 dB
SPL through an insert earphone in the external auditory canal. This acoustic stimulus will
provoke movements of remaining inner and outer cochlear hair cells and evoke a response from
the auditory nerve. Tone burst stimuli at 500 Hz have been shown to produce the largest
amplitude ECochG response, therefore, will be used as the default stimulus here. The
resulting cochlear potentials will be recorded using the recording electrode from the apical
aspect of the CI electrode. By averaging the recorded signal synchronized with stimulus
delivery, the responses can be reinforced while unsynchronized noise will average out. This
utilization is consistent with indications covered under this FDA 510(k) clearance.

Intra-operative preparation

The insert earphone will be placed in the external ear canal after cerumen removal. The ear
canal will be surgically prepared, followed by suctioning of prep fluid. Following the
conventional technique, the measurement ear will be folded forward and taped. The surgery
will proceed following the standard-of-care practice consisting of a cortical mastoidectomy,
a facial recess (posterior tympanotomy), and preparation of intracochlear access via the
round window or an extended round window approach. Before the CI electrode will be inserted,
the headpiece will be connected to the implant, and the ECochG software will be triggered to
begin the ECochG recordings. Figure 2 depicts a schematic of the measurement system setup.
Figure 3 shows an example of the noninvasive surface electrode and earphone array. Figure 4
shows the monitor and unit through which the ECochG is observed and recorded.

To facilitate correlation of changes in ECochG potentials during CI electrode insertion and
surgical events that ultimately relate to trauma within the cochlea, the surgeon will
verbally indicate the progress of electrode insertion (e.g., "at the round window," "at the
first marker on the electrode," "at the last marker on the electrode"), which will be
recorded in the software by an assistant and synched with the ECochG signals.

Post-operative ECochG

For post-operative ECochG measurements in the clinic, the setup depicted in Figure 3 will be
utilized. For this testing, the external component of the CI will be temporarily removed
(equivalent to simply taking off a hearing aid) and replaced with an external head coil
component (physically identical to the CI's external head coil) that allows for ECochG
measurement. After connecting the head piece, a frequency scan from 125-2000 Hz will be
presented to the participant at an acoustic intensity level at or below their comfortable
listening level through an insert earphone in the external auditory canal. After measurements
are collected, the participant's own external component will be put back in place. This
measurement takes up to 5 minutes and does not require active participation of the
participant.

CT Scan

A single post-operative CT scan will be conducted to identify the electrode's scalar
location. A post-operative CT scan is often performed as a part of the regular clinical
routine in patients for whom more information about the CI electrode location is needed. The
post-operative CT will be collected per parameters outlined in Appendix 1.

Risks

The chief risks associated with this study are those inherent to CI surgery itself. The use
of intraoperative ECochG has been well-demonstrated to pose no added patient risks, but may,
as discussed above, provide an important benefit. Participation in this study will involve
the following specific considerations:

1. Increased surgical time: The ECochG measurement procedure adds up to 5-15 minutes to the
procedure. During this added procedure time, the Anesthesia team will closely monitor
the patient. If there are any concerns at any time, the study activity will be ceased.

2. Post-operative CT scan: Associated radiation exposure. The implant, sound processor, and
the clinical programming interface (CPI) hardware are all FDA-approved, and their use in
the study is not associated with any additional risk to the patient. ECochG devices are
FDA-cleared Class II devices. For an example of an FDA 510(k) clearance letter for the
Otometrics device (k143670), please see Appendix. The ECochG recording software is not
FDA/Conformité Européenne (CE) certified, but it has been thoroughly tested per AB's
internal quality system. The recording software is not part of the CI operation and does
not introduce any new or changed risk to the patient. It has been verified that the
experimental software does not affect the performance of the FDA-approved software or
hardware. Further, the entire protocol detailed above has been utilized and reported
upon across several institutions validating the feasibility, ease, and safety of this
modification to the convention "no feedback" approach to CI electrode insertion. This
study's principal investigator (PI) also has experience using the current system.

Data Acquisition and Storage

Post-operative audiometric measurements and post-operative CT scan results will be recorded
in the participant's study binder. Results of intra-operative and post-operative ECochG will
be saved by the ECochG software program but will also be printed and kept in the
participant's binder. All files will be archived. The main study results will be transferred
to Excel-files for analysis. Further analyses will be done with Excel, Matlab or statistical
software packages. A member of the Biostatistics Department will assist in statistical
analysis. All results will be made anonymous prior to being shown to any third party. It will
not be possible for any individual study participant to be recognized from his or her study
data.

In addition, we will compare ECochG-based predictions associated with CI electrode scalar
position and hearing outcomes to predications made based on conventional demographic and
audiometric data. To facilitate multivariate analysis, we will extract biographical (e.g.,
age, etiology of hearing loss, duration of deafness) and surgical (e.g., device and electrode
type) factors from the electronic medical record.

Statistical Analysis

Randomization

Block randomization is statistical strategy to prevent unequal numbers of participants from
being randomized to one arm vs the other (here, audible signal "on" versus audible signal
"off"). For example, using a random number generator set to individually assign 100
participants to one of two groups, there is no assurance that an equal numbers of study
participants would end up in the "audible signal on" group, resulting in an unbalanced
overall sample, despite randomization of each participant.

Using a block approach, the total sample is divided into smaller blocks and randomization is
performed within each block with the rule that the number of allocations is balanced within
that block. In our study, although each institution will likely only contribute about 40
participants, we have designed a randomization schedule to allow for 100 participants to be
run for each program. This sample of 100 was divided into 50 blocks of two participants; the
two participants are randomized ensuring that one goes into the "signal off" group and one
goes to the "signal on" group.

Power Analysis

To ensure that our study is appropriately powered to detect a significant difference in the
primary outcomes measures, we performed a power analysis with the assistance of a
biostatistician. Post-operative CT-based indication of scalar position is treated as a
dichotomous variable (i.e., either in the scala tympani or in the scala vestibuli);
post-operative hearing outcomes are treated as a continuous variable.

Scalar Dislocation: Preliminary data indicates that the current state of CI electrode
dislocation from the scala tympani to the scala vestibuli is approximately 35% (or, a
"successful" scala tympani position is achieved at a rate of 65%). For participants
randomized to "ECochG audible signal on," our expectation, driven by preliminary data, is to
decrease the rate of scalar dislocation to approximately 15% (or, a "successful" scala
tympani position rate of 85%). Setting the alpha error rate at 2.5%, a total sample size of
192 participants, or 96 participants in each of the two randomization groups, was determined
using a Fischer exact test. If we permit a 5% error rate, the total sample size drops to 162
patients (81 randomized to audible signal "on"; 81 randomized to signal "off"). While these
numbers of participants are higher than would be possible to achieve at our site alone in an
average two-year period, through a coordinated effort to pool multi-center data, it will be
easily achievable.

Secondary Planned Analysis

Electrode Type: As detailed above, once a participant is enrolled in the study, the surgeon
will select which of two CI electrodes are most appropriate. A secondary analysis comparing
scalar position and hearing preservation outcomes will be performed (i.e., four total
between-group analyses) between the two electrode groups.

Pediatric Participants: This study will include both adult and pediatric participants. A
secondary analysis comparing scalar position and hearing outcomes between adult and pediatric
participants will be performed (again, four total between-group analyses).

Regression Analysis: To model the influence of "ECochG on" on the primary outcome measures in
the context of participant age group and electrode choice, two regression analyses will be
performed - one for the outcome measure of scalar position and one for hearing outcomes.

Hospital Effect Analysis: To determine if there is a meaningful difference in outcome
measures across the different participating hospital settings, a secondary analysis will be
performed as well.

Safeguarding of Protected Health Information (PHI) Upon study enrollment, participants will
be assigned an alphanumeric code that will be used to track their data. A code key will be
maintained by the investigators on a secure server and accessed using password-protected
computers located in a locked office in a secure research space. Participant identity cannot
be discovered from ECochG data. Likewise, CT images and audiometric data will not reveal
participant identity and will be made fully anonymous prior to sharing with any third party.
Participant study binders, labeled using their alphanumeric code only, will be stored in a
locked cabinet, in a locked office, in a secure research area accessible only to the
investigators.

Inclusion Criteria:

- Pure-tone audiometry thresholds ≤80 dB HL at 500 Hz

- One year of age and older

- Normal candidacy requirements for cochlear implantation met

- No cochlear abnormality that might prevent full insertion of the CI electrode array

- No additional handicap that would prevent study procedures from being followed

Exclusion Criteria:

- Chronic otitis media

- Malformed cochlea

- Auditory neuropathy spectrum disorder (ANSD)

- Presence of ear tubes

- Prior middle ear surgeries or trauma including disruption of ossicles