Feasibility of Structural and Functional Imaging of the Middle Ear and Its Constituents by Optical Coherence Tomography
Phase: NA
Conditions: Image, Body
Sponsor: Erasmus Medical Center

NL81519.078.22 / 2021-01 
 
Feasibility of middle ear OCT imaging 
 
 
 
Feasibility of structural and functional imaging of the middle ear and its constituents 
by optical coherence tomography 
 
Protocol ID 
2021-01 
Short title 
Feasibility of middle ear OCT imaging 
EudraCT number  
n/a 
Version 
0.4 
Date 
14 May 2022 
Principal investigator(s) (in 
Dutch: hoofdonderzoeker/ 
uitvoerder) 
 
R.M. Metselaar 
 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Department of Otorhinolaryngology and Head and 
Neck Surgery 
Erasmus Medical Center 
Rotterdam, The Netherlands 
Subsidising party 
 
Independent expert (s) 
n/a (cf Article 4(1) WMO) 
 
 
 
 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
 
Prof.dr. R.J. Baatenburg de Jong, head 
of department 
Department of Otorhinolaryngology and 
Head and Neck Surgery 
Erasmus Medical Center 
Rotterdam, The Netherlands 
 
 
 
25-05-2022 
Principal Investigator: 
 
Dr. R.M. Metselaar, otologist 
Department of Otorhinolaryngology and 
Head and Neck Surgery 
Erasmus Medical Center 
Rotterdam, The Netherlands 
 
25-05-2022 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE .............................................................................. 7 
2. 
OBJECTIVES ................................................................................................................10 
3. 
STUDY DESIGN ...........................................................................................................11 
4. 
STUDY POPULATION ..................................................................................................12 
4.1 
Population (base) ...................................................................................................12 
4.2 
Inclusion criteria .....................................................................................................12 
4.3 
Exclusion criteria ....................................................................................................12 
4.4 
Sample size calculation ..........................................................................................13 
5. 
TREATMENT OF SUBJECTS .......................................................................................14 
6. 
INVESTIGATIONAL PRODUCT ....................................................................................15 
6.1 
Name and description of investigational product(s) ................................................15 
6.2 
Summary of findings from non-clinical studies ........................................................15 
6.3 
Summary of findings from clinical studies ...............................................................15 
6.4 
Summary of known and potential risks and benefits ...............................................15 
6.5 
Description and justification of route of administration and dosage .........................15 
6.6 
Dosages, dosage modifications and method of administration ...............................15 
6.7 
Preparation and labelling of Investigational Medicinal Product ...............................15 
6.8 
Drug accountability .................................................................................................15 
7. 
NON-INVESTIGATIONAL PRODUCT ...........................................................................16 
8. 
METHODS ....................................................................................................................17 
8.1 
Study parameters/endpoints ...................................................................................17 
8.1.1 
Main study parameter/endpoint .......................................................................17 
8.1.2 
Secondary study parameters/endpoints (if applicable) ....................................17 
8.1.3 
Other study parameters (if applicable) .............................................................17 
8.2 
Randomisation, blinding and treatment allocation ..................................................17 
8.3 
Study procedures ...................................................................................................17 
8.4 
Withdrawal of individual subjects ............................................................................18 
8.4.1 
Specific criteria for withdrawal (if applicable) ...................................................19 
8.5 
Replacement of individual subjects after withdrawal ...............................................19 
8.6 
Follow-up of subjects withdrawn from treatment .....................................................19 
8.7 
Premature termination of the study .........................................................................19 
9. 
SAFETY REPORTING ..................................................................................................20 
9.1 
Temporary halt for reasons of subject safety ..........................................................20 
9.2 
AEs, SAEs and SUSARs ........................................................................................20 
9.2.1 
Adverse events (AEs) ......................................................................................20 

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9.2.2 
Serious adverse events (SAEs) .......................................................................20 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) .........................21 
9.3 
Annual safety report ...............................................................................................21 
9.4 
Follow-up of adverse events ...................................................................................21 
9.5 
Data Safety Monitoring Board (DSMB) / Safety Committee ....................................21 
10. 
STATISTICAL ANALYSIS ..........................................................................................22 
10.1 
Primary study parameter(s) ....................................................................................22 
10.2 
Secondary study parameter(s) ...............................................................................22 
10.3 
Other study parameters ..........................................................................................22 
10.4 
Interim analysis (if applicable) ................................................................................22 
11. 
ETHICAL CONSIDERATIONS ...................................................................................23 
11.1 
Regulation statement .............................................................................................23 
11.2 
Recruitment and consent........................................................................................23 
11.3 
Objection by minors or incapacitated subjects (if applicable) ..................................23 
11.4 
Benefits and risks assessment, group relatedness .................................................23 
11.5 
Compensation for injury .........................................................................................23 
11.6 
Incentives (if applicable) .........................................................................................24 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION .........................25 
12.1 
Handling and storage of data and documents ........................................................25 
12.2 
Monitoring and Quality Assurance ..........................................................................25 
12.3 
Amendments ..........................................................................................................25 
12.4 
Annual progress report ...........................................................................................25 
12.5 
Temporary halt and (prematurely) end of study report ............................................26 
12.6 
Public disclosure and publication policy ..................................................................26 
13. 
STRUCTURED RISK ANALYSIS...............................................................................27 
13.1 
Potential issues of concern .....................................................................................27 
13.2 
Synthesis ...............................................................................................................28 
14. 
REFERENCES ..........................................................................................................29 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
CCMO 
Central Committee on Research Involving Human Subjects; in Dutch: 
Centrale Commissie Mensgebonden Onderzoek 
CT 
Computed Tomography 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
EU 
European Union 
EudraCT European drug regulatory affairs Clinical Trials  
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
MRI 
Magnetic Resonance Imaging 
OCT 
Optical Coherence Tomography 
OM 
Otitis Media 
(S)AE 
(Serious) Adverse Event  
Sponsor 
The sponsor is the party that commissions the organisation or performance 
of the research, for example a pharmaceutical company, academic hospital, 
scientific organisation or investigator. A party that provides funding for a 
study but does not commission it is not regarded as the sponsor, but 
referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TM 
Tympanic membrane 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 
 
 
 
 
 

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SUMMARY 
 
Rationale: Various middle ear diseases can affect anatomical structures of the middle ear in 
different ways. Unfortunately, current methods for assessing the structure and function of the 
constituents of the middle ear are limited and often fail to provide all clinically relevant data. 
Optical coherence tomography (OCT) is a technology that can provide valuable, additional 
information. Aurisvue is a newly developed prototype OCT-device for structural and 
functional imaging of the middle ear. 
Objective: To assess the feasibility and the clinical potential of structural and functional OCT 
imaging with Aurisvue in patients with various middle ear problems. 
Study design: Observational study 
Study population: Adult patients presenting with various middle ear complaints at the ENT-
department of the Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus 
Medical Center, Rotterdam, the Netherlands. 
Main study parameters/endpoints: Percentage of patients in which structural OCT imaging 
was feasible (i.e., the OCT images showed a discernible tympanic membrane (TM) and at 
least one of the ossicles). 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: The burden is minimal: patient examination with Aurisvue is similar to 
the conventional examination with a standard otoscope and will take approximately 5 to 10 
minutes. The risks are negligible: imaging is done with light levels well below the maximum 
permissible exposure level and sound levels to induce movement of the TM and the ossicular 
chain are well below the hazardous threshold. 

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1. INTRODUCTION AND RATIONALE 
The middle ear is an anatomical part of the auditory system that consists of the tympanic 
membrane (TM), the tympanic cavity and the ossicles. The physical function of the middle 
ear is to adapt the air-pressure waves to the inner ear’s fluid-filled cavity. Acoustic pressure 
waves are captured by the tympanic membrane and subsequently transferred by the 
malleus, the incus and the stapes. The footplate of the stapes is located in the oval window, 
resulting in vibration of the perilymph in the inner ear. The hair cells in the inner ear convert 
these vibrations into electrical impulses that are transmitted into the central nervous system. 
The normal middle ear contains air with normobaric pressure. 
In patients with otitis media (OM), either acute or chronic, the tympanic cavity is filled with 
fluid. When this is due to an infection of the upper airway, the patient suffers from acute otitis 
media. Acute OM is very common, with an incidence rate of almost 11% and more than half 
of these occurring in children under 5 years old1. Fluid may accumulate in the middle ear, 
followed by bacteria and viruses, resulting in the formation of biofilm and in middle ear 
inflammation. The increased pressure in the middle ear cavity leads to bulging of the TM and 
may lead to typical symptoms such as pain and fever and common complications are TM 
rupture and hearing loss (prevalence of 31 per 10.0001). The chronic type of OM is not a 
result of a classic bacterial or viral infection, but appears to result from problematic aeration 
of the tympanic cavity. This can be due to Eustachian tube dysfunction and/or hampered 
ventilation of the middle ear mucosa. Treatment options of OM include observation, 
medication to reduce the symptoms, antibiotic therapy or surgical placement of 
tympanostomy tubes2. 
A special type of OM is cholesteatoma. In this condition, the skin of the tympanic membrane 
grows into the middle ear cavity and the mastoid leading to erosion and finally destruction of 
bony structures including the ossicles and the mastoid, the facial nerve and the semicircular 
canals (vestibular system). Patients usually suffer from a chronically discharging ear, hearing 
loss and sometimes vertigo. 
Hearing loss related to the middle ear can be due to perforation or retraction of the tympanic 
membrane, middle ear effusion, erosion or dislocation of the ossicles and ankylosis of the 
stapes (otosclerosis). All these conditions can cause a conductive hearing loss. To determine 
the cause of this type of hearing loss, otoscopy is the first diagnostic procedure. This is 
performed with a hand-held otoscope or with a binocular microscope. Because the tympanic 
cavity is sealed by the TM which is partially transparent, visualization of the middle ear 
structures is not as straightforward. Computed tomography (CT) and magnetic resonance 
imaging (MRI) are the most common imaging modalities for imaging middle ear pathology3. 
High-resolution CT scanning can be used to visualize the middle ear including the ossicles 

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and the inner ear, but very small structures like the stapes arch can be difficult to identify. 
Differentiation of cholesteatoma from other types of tissue and from fluid is difficult with CT. 
Moreover, CT involves radiation exposure. MRI is used in special cases when soft tissue 
structures need to be visualized. These are the internal auditory canal, fluid in the cochlea 
and labyrinth and cholesteatoma. Currently, there is no functional imaging modality available 
to identify the location of reduced transduction of vibration in case of conductive hearing loss. 
Therefore, the ossicular chain is often best inspected during surgery. The availability of an 
imaging technology that is able to identify middle ear structures in high resolution and assess 
the transduction of acoustic vibrations by the ossicular chain, might reduce the burden on the 
patient, provide additional insight to the clinician to more accurately diagnose the cause of 
conductive hearing loss, improve surgical planning and evaluate the result of a reconstructive 
procedure. 
 
Optical coherence tomography (OCT) is an interferometric imaging modality that produces 
depth-resolved images of semi-transparent media4. It was first developed for ophthalmology 
and is routinely used in clinical practice for over a decade. It enables volumetric, high-
resolution imaging of, for example, the chorioretinal complex, where many different layers 
can be visualized. Similar to ultrasound, Doppler-OCT, an extension to OCT, can also be 
used to measure motion, e.g., blood flow5. Due to the semi-transparent nature of the TM, 
OCT may also be used for imaging of the middle ear to identify the TM, any fluid behind the 
TM and the ossicular chain (see Figure 1). Doppler-OCT can be used to measure the 
vibrations of the various components of the auditory system (i.e., the TM and the ossicles; 
OCT-vibrometry, see Figure 2)6. 
 
 
Figure 1. In vivo OCT imaging of a normal subject’s left ear. A) Shows a 1×1cm2 2D cross-section of the middle 
ear in the transverse plane. B) Shows a 1×1×1cm3 3D volume render of the middle ear as seen from the 
perspective of the ear canal with the TM digitally removed. Tympanic membrane (TM), malleus (M), incus (IN), 
incudo-stapedial joint (IS), stapedius tendon (ST), chorda tympani nerve (CT), cochlear promontory (CP), round-
window niche (RW).7 

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Figure 2.  (a)-(b) Overlay of vibratory response (color scale) on the morphological image (gray scale) of the 
middle ear. (a) Pure tone stimulus was at 800 Hz and 70 dB SPL. (b) Bone stimulus calibrated to give similar 
vibratory response at the cochlear promontory. (c) Morphological image showing the 3 regions of interest (ROI) 
used to generate the plots in (d) and (e). (d) Plot of the displacement for the ROI at the TM and bone (Cochlear 
Promontory or Incus) resulting from air and bone stimulation. (e) Displacement data from (d) plotted relative to the 
vibratory response at the cochlear promontory.8 
 
Preliminary results from many different prototype research instruments have been published, 
primarily focused on imaging of the TM and any adjacent fluid, although other diseases were 
also explored9–12. Despite the heterogeneous set of devices, methodologies and diseases, 
the results indicate that application of OCT in otology is promising and could provide clinically 
relevant information that is currently not available. 
 
To the best of our knowledge, no systems have been approved in the EU for clinical use in 
otology. Aurisvue CIM is a novel, handheld, clinical prototype OCT device, developed by 
Acoustic Insight. It features both structural OCT imaging and functional OCT imaging (OCT-
vibrometry) and is specifically designed for middle ear imaging. In this study, we aim to 
identify clinically relevant applications of Aurisvue for middle ear imaging. Based on the 
results from this study, Aurisvue will be further developed for specific clinical applications and 
evaluated in future trials. 
 
 
 

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2. OBJECTIVES 
Primary Objective: 
o To assess the feasibility of structural OCT imaging with Aurisvue in clinically relevant 
subjects with middle ear problems. 
 
Secondary Objectives:  
o To assess the feasibility of functional OCT imaging with Aurisvue in clinically relevant 
subjects with middle ear problems. 
o To assess the clinical potential of structural and functional OCT imaging with Aurisvue 
in clinically relevant subjects with middle ear problems. 
 

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3. STUDY DESIGN 
This study is an observational study. No treatment intervention for study purposes is included 
and all patients will receive routine clinical care. The study is intended to explore the 
feasibility and possibilities of OCT for structural and functional imaging of the middle ear.  
 
The duration of the study will be approximately one year. Patients will be recruited from those 
visiting the Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus 
Medical Center, Rotterdam, the Netherlands. 
 
Patients included in the study will be imaged at least once with Aurisvue. If a patient returns 
to the site within the duration of the study and relevant physiological or pathological changes 
to the middle ear are expected (due to, for example, treatment or the natural history of the 
disease), the patient may be imaged again. Except for assessment with Aurisvue, no study 
related procedures are prescribed, and patients will receive the usual standard of care. 
 

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4. STUDY POPULATION 
4.1 Population (base)  
Approximately 100 patients will be recruited from those visiting the ENT-department with 
various middle ear problems, as assessed by the otolaryngologist. Because a heterogenous 
study population is needed to evaluate a wide range of abnormalities of the middle ear, 
patients will be stratified according to the table below. 
 
condition 
Max. number of patients 
chronic suppurative otitis media 
10 
conductive hearing loss of unknown origin 
20 
conductive hearing loss after head trauma 
10 
cholesteatoma 
10 
perforated tympanic membrane 
10 
total middle ear prosthesis TORP in situ 
10 
partial middle ear prosthesis PORP in situ 
10 
interpositioned incus in situ 
10 
cochlear implant in situ 
10 
previous tympanoplasty 
10 
glomus tumor in middle ear (glomus tympanicum) 
10 
sclerosis of the tympanic membrane (myringosclerosis) 
10 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a patient must meet all of the following 
criteria: 
- 
age 18 or older, 
- 
competent, willing and able to cooperate. 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation 
in this study in case of: 
- 
any acute or chronic condition that would limit the ability of the patient to participate in the 
study, per attending physician’s indication, including: 
o abnormally narrow or stenotic external ear canal, 

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o external otitis, 
o significant exostosis of the ear canal, 
o radical cavity, 
o movement disorder causing inability to keep head still during imaging. 
- 
refusal to give informed consent 
- 
pregnancy or breastfeeding 
 
4.4 Sample size calculation 
Due to the exploratory nature of this study, no formal sample size calculation can be 
performed. The study aims to include patients with various middle ear problems (disease). 
For each specific disease, not more than the specified maximum number of patients will be 
included. The total number of included patient will not exceed 100. 
 

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5. TREATMENT OF SUBJECTS 
Not applicable as this is not an intervention study. 
  

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6. INVESTIGATIONAL PRODUCT  
6.1 Name and description of investigational product(s) 
Product name: Aurisvue CIM 
Aurisvue is an optical coherence tomography (OCT) system designed specifically for 
assessing the structure and function of the middle ear. 
For further details, please refer to chapter 1 (section 2.1) of the IMDD. 
6.2 Summary of findings from non-clinical studies 
Not applicable because sufficient data is available from clinical studies to assess the basic 
safety and potential applicability of the technology.  
6.3 Summary of findings from clinical studies 
Please refer to chapter 6, section 2 of the IMDD. 
6.4 Summary of known and potential risks and benefits 
Please refer to chapter 5 of the IMDD. 
6.5 Description and justification of route of administration and dosage 
Not applicable. 
6.6 Dosages, dosage modifications and method of administration 
Not applicable. 
6.7 Preparation and labelling of Investigational Medicinal Product 
Not applicable. 
6.8 Drug accountability 
Not applicable. 
 

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7. NON-INVESTIGATIONAL PRODUCT 
Not applicable, the study does not concern any non-investigational products. 
 
 

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8. METHODS 
8.1 Study parameters/endpoints 
8.1.1 
Main study parameter/endpoint 
Presence of a discernible TM and the number of discernible ossicles on structural OCT 
imaging. 
8.1.2 
Secondary study parameters/endpoints (if applicable) 
- 
Number of middle ear structures (TM, ossicles) on which OCT-vibrometry measurements 
by Aurisvue succeeded. 
- 
For diagnostic correlation with other clinical data sources (only as far as they are 
available from the standard of care): 
o microscopic otoscopy (description) 
o CT-scan 
o MRI-scan 
o pure-tone audiogram 
o tympanogram 
o surgical report (if available) 
- 
Number of AEs and SAEs 
- 
PREMs 
8.1.3 
Other study parameters (if applicable) 
- 
Demographic characteristics 
- 
Clinical diagnosis of middle ear disease 
- 
Description of relevant interventions before or during study period (if applicable)  
 
8.2 Randomisation, blinding and treatment allocation 
Not applicable. 
8.3 Study procedures 
Discernible TM and discernible ossicles on structural OCT imaging. 
OCT images acquisition by Aurisvue will be performed on both ears of every patient. The 
acquisition process consists of positioning the Aurisvue’s handheld interface in the ear canal 
of the patient and collecting data during a period of a few minutes. Several two- or three-
dimensional scans may be acquired during this time, each focusing on regions of interest in 
the middle ear. During acquisition, the OCT images are displayed on the monitor of the 

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computer to guide the operator. Data may be processed at a later stage to improve image 
quality. The processed images will be evaluated by a medical specialist to identify the 
anatomic features. Visibility of the TM and of the ossicles will be registered as outcomes 
(primary endpoint). 
 
Number of middle ear structures (TM, ossicles) on which OCT-vibrometry measurements by 
Aurisvue succeeded. 
The assessment procedure for OCT-vibrometry is similar to the structural imaging described 
above. In OCT-vibrometry mode, Aurisvue will produce a sound stimulus and will 
subsequently measure differences between repeated scans. Vibrometry is successful if the 
signal on the region of interest is sufficient to determine the amplitude of the vibration that 
matches the characteristics of the stimulus. 
 
Diagnostic correlation with other clinical data sources from the standard of care. 
Procedures/assessments may include: 
o microscopic otoscopy (description) 
o CT scan 
o MRI scan 
o pure-tone audiogram 
o tympanogram 
o surgical report (if available) 
These procedures/assessments will all follow the standard of care at the clinical site. Both 
the results of the assessments and the interpretation thereof by the clinician will be used to 
evaluate the diagnostic correlation with structural and functional imaging results by Aurisvue. 
 
PREMs (for subjects). 
Patients will be asked about their experience with otoscopy with Aurisvue compared to 
regular or microscopic otoscopy (one question). 
 
Number of AEs and SAEs 
These will be reported as detailed in section 9 (Safety reporting). 
8.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 

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8.4.1 
Specific criteria for withdrawal (if applicable) 
Not applicable. 
 
8.5 Replacement of individual subjects after withdrawal 
Subjects will only be replaced in case the first visit (i.e., the first, full assessment procedure 
with Aurisvue) was not completed for purposes that were unrelated to the performance or the 
characteristics of Aurisvue. 
8.6 Follow-up of subjects withdrawn from treatment 
Not applicable. 
8.7 Premature termination of the study 
The study will be terminated in case the performance of the device is insufficient to warrant 
further inclusion or follow-up of study subjects or if regulatory requirements are no longer met 
(e.g., if the manufacturer cannot support the study any longer because it stops pursuing the 
use of OCT technology for middle ear problems). 
 
 

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9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise the patient’s health or 
safety.  The sponsor will notify the accredited METC without undue delay of a temporary halt 
including the reason for such an action. The study will be suspended pending a further 
positive decision by the accredited METC. The investigator will take care that all subjects are 
kept informed.  
9.2 AEs, SAEs and SUSARs 
9.2.1 
Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the investigational medical device. All adverse 
events reported spontaneously by the subject or observed by the investigator or his staff will 
reported by the investigator to the Sponsor by filling out the corresponding eCRF. The 
Sponsor will record all AEs, based on NCI CTCAE reporting standards13. 
9.2.2 
Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
o results in death, 
o is life-threatening (at the time of the event), 
o requires hospitalisation or prolongation of existing inpatients’ hospitalisation, 
o results in persistent or significant disability or incapacity, 
o is a congenital anomaly or birth defect; or 
o any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs that may be related to the Aurisvue device or Aurisvue 
operating procedures to the sponsor and the manufacturer without undue delay after 
obtaining knowledge of the events, except for the following SAEs: None 
 
The sponsor will report these SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 

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death or are life threatening followed by a period of maximum of 8 days to complete the initial 
preliminary report. All other SAEs will be reported within a period of maximum 15 days after 
the sponsor has first knowledge of the serious adverse events. 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable (no investigational medicinal product). 
9.3 Annual safety report 
Not applicable (no investigational medicinal product). 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol. 
9.5 Data Safety Monitoring Board (DSMB) / Safety Committee 
Not applicable. 

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10. STATISTICAL ANALYSIS 
10.1 Primary study parameter(s) 
The presence of a discernible TM and the number of discernible ossicles on structural OCT 
imaging will be reported by descriptive statistics. This will be the primary source of 
information for the primary objective of this study: To assess the feasibility of structural OCT 
imaging with Aurisvue in clinically relevant subjects with middle ear problems. 
Because the occurrence of missing data (e.g., no OCT was acquired) is of interest for the 
primary objective of this study, no imputation will be performed. Instead, missing data will be 
reported as such, including the reasons of such missing data. 
10.2 Secondary study parameter(s)  
Answering the first secondary objective (‘To assess the feasibility of functional OCT imaging 
with Aurisvue in clinically relevant subjects with middle ear problems’) will be done in the 
same way as described above for the primary objective, albeit based on functional OCT-
vibrometry measurements using a sound stimulus rather than the structural OCT images. 
For the second secondary objective (‘To assess the clinical potential of structural and 
functional OCT imaging with Aurisvue in clinically relevant subjects with middle ear 
problems’), the data obtained by Aurisvue will be (qualitatively) correlated with other clinical 
data sources. Similarities such as Aurisvue image information consistent with other imaging 
modalities) and dissimilarities (such as characteristics visible on Aurisvue images but not on 
another imaging modality) will be evaluated. 
AEs, SAEs and questionnaires will be included in answering the primary and both secondary 
objectives. Again, missing data will be reported and not imputed. 
Patient reported experience measures (PREMs) will be recorded immediately after the 
measurements with Aurisvue are completed. 
10.3 Other study parameters 
All other study parameters may be used to stratify the data used to answer the primary and 
secondary objectives. Again, because no power calculation was performed, no definite 
conclusions may be drawn from this analysis, but it may be used to produce new hypotheses 
for future testing. 
10.4 Interim analysis (if applicable) 
Not applicable. 

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11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted in accordance with the principles of the Declaration of Helsinki 
(October, 2013), the Medical Research Involving Human Subjects Act (WMO; July 1, 2021), 
the Guidelines for Good Clinical Practice E6(R2) (EMA/CHMP/ICH/135/1995, Dec 1, 2016) 
and the EU Medical Device Regulations (2017/745). 
11.2 Recruitment and consent 
Patients scheduled for a visit at the ENT-department will be screened based on the available 
information (medical records and/or referral information). Prospective participants will be 
informed by the otolaryngologist at their visit and are provided with additional information by 
letter (brochure) that they take home. The researcher contacts the participant at least 2 days 
later by phone and, when the patient decides to participate, schedules the appointment for a 
research visit. During the research visit, any questions regarding the study can be answered 
and the participant will be asked to provide written informed consent for the study. Costs for 
travelling and parking will be reimbursed. 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable. 
11.4 Benefits and risks assessment, group relatedness 
Subjects do not benefit from participation. The risk is minimal (see chapter 5 of the IMDD for 
the full risk assessment and benefit-risk analysis). The burden of participation is low: the 
assessment with Aurisvue is expected to take approximately 10 minutes of extra time during 
a study visit. 
11.5 Compensation for injury 
The sponsor and investigator have a liability insurance which is in accordance with article 7 
of the WMO. 
The sponsor (also) has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research 
subjects through injury or death caused by the study. 
The insurance applies to the damage that becomes apparent during the study or within 4 
years after the end of the study. 

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In addition, the manufacturer of the Aurisvue has a product liability insurance that covers the 
product liability of the non-CE-marked Aurisvue within the scope of this clinical investigation. 
11.6 Incentives (if applicable) 
Not applicable. 

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12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Access to patient information is restricted to members of the study team and to legitimate 
authorities only. No identifiable data on participants will be stored within the context of this 
study, except for the informed consent forms and the enrolment log. All data will be 
pseudonymized: data will be encoded by a patient code that is specific for this study and is 
unrelated to the clinical patient ID. The key to the patient code is available only to the 
investigator and the site’s study team. All data will be stripped from identifiable information by 
the site prior to submitting such data to the study systems. 
All data will be entered into an electronic data capture system (Castor EDC). Larger data 
points, such as large (three-dimensional) images or videos, will be pseudonymized and 
uploaded in the same system. 
Processing of the data and presentation of the results of this study will be strictly anonymous. 
An export of the data stored in the EDC system will be shared with Acoustic Insight, the 
manufacturer of the Aurisvue, according to the provisions of the collaboration agreement and 
as specified in the patient information file. 
12.2 Monitoring and Quality Assurance  
Based on the NFU risk table (see Annex 2 of NFU Richtlijn Kwaliteitsborging Mensgebonden 
Onderzoek, December 2020), the following risks were estimated: 
For patients: 
 
Negligible 
For research data: 
Negligible 
Overall: 
 
Negligible 
Monitoring will be done by personnel that is not part of the Investigator’s study team and will 
be performed in accordance with Annex 3 of the beforementioned NFU Guideline (column 
‘Verwaarloosbaar risico: Geneesmiddelen-, Medische hulpmiddelenen Voedingsonderzoek’). 
12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 

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numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination. 
 
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC.  
12.6 Public disclosure and publication policy 
Relevant results of this study will be submitted for presentation at scientific meetings and/or 
for publication in a scientific journal. Authorship of any scientific publication and/or public 
disclosure will be in accordance with the guidelines of the International Committee of Medical 
Journal Editors (ICMJE).  

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13. STRUCTURED RISK ANALYSIS  
Please refer to chapter 5 of the IMDD for more details on the risk analysis. Here, the items 
that are specifically of interest for patient safety are listed. 
13.1 Potential issues of concern 
a. Level of knowledge about mechanism of action 
OCT is based on the fundamentals of interferometry, which were established in the 19th 
century. OCT itself has been studied intensively since its inception in the early 90’s. Different 
variations have been developed as well, including Doppler or phase-sensitive OCT, 
polarization-sensitive OCT and OCT-vibrometry. These have all been extensively evaluated 
theoretically and practically. 
 
b. Previous exposure of human beings with the test product(s) and/or products with a similar 
biological mechanism 
OCT is a well-established clinical imaging modality in ophthalmology14, including pediatric 
ophthalmology15. It is also used in various other medical applications, such as dermatology16, 
gastroenterology17, urology18, dentistry19 and for intravascular imaging20. OCT uses near 
infrared light to probe the tissue with intensities that are well below the maximum permissible 
exposure of light. 
Aurisvue employs this well-known OCT technology for the application of structural and 
functional imaging of the middle ear. No OCT-device for imaging of the middle ear is 
currently approved for use in the EU. However, PhotoniCare’s Otosight has been approved 
for clinical use by the FDA and clinical trials with both Otosight and Ossiview (Audioptics 
Medical Inc, USA) are registered (NCT03890107, NCT04722770, NCT05085379). Both 
devices use OCT technology that is similar to Aurisvue. 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human 
cell material? 
OCT has been demonstrated in animals and ex-vivo human tissue. 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings 
OCT is primarily used to image semi-transparent tissue. Media without scattering of the light 
(e.g., air, water) are not resolved on OCT. Fully opaque media block the light of the OCT 
beam and prevent imaging at larger depths. The tissues of interest in the middle ear are 
semi-transparent. 
 

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e. Analysis of potential effect 
N/a. There is no treatment intervention. Harmful effects from OCT imaging are not expected 
since the light levels used are below the maximum permissible exposure levels. 
 
f. Pharmacokinetic considerations 
Not applicable. 
 
g. Study population 
No increased risks are expected due to the specific characteristics of the study population. 
 
h. Interaction with other products 
Not applicable. 
 
i. Predictability of effect 
Not applicable. 
 
j. Can effects be managed? 
Not applicable. 
13.2 Synthesis 
There are three main potential sources of risk for patients: optical power, acoustical power 
and malfunction of the integrated camera. 
- 
The intensity of the OCT beam is below the maximum permissible exposure level for 
continuous illumination of tissue. Aurisvue employs two scanners for lateral imaging. 
Typical imaging duration is a few minutes. The probability of harm due to optical power is 
therefore improbable. The severity of the harm is moderate (CTCAE grade 2). The risk 
related to optical power is deemed to be insignificant (and thus acceptable). 
- 
Likewise, the sound used to induce movement of the TM and ossicular chain for OCT-V 
measurements is well below the hazardous threshold, even when used continuously. The 
probability of harm directly due to acoustic power is therefore improbable. The severity of 
this harm is moderate (CTCAE grade 2). This risk directly related to acoustic power is 
deemed to be insignificant (and thus acceptable). 
In addition, there is an indirect risk related to unexpected exposure to an acoustical 
stimulus, which may cause a patient to suddenly move his head. The probability of harm 
due to sudden movement of the patient’s head caused by unexpected acoustical 
exposure is improbable. The severity of this harm is severe (CTCAE grade 3). The risk 

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related to this sudden movement is deemed to be acceptable. It is addressed in the 
Aurisvue’s instructions for use and will be addressed during training. 
- 
Malfunctioning of the integrated camera limits the feedback to the operator with respect 
to the location of the device and may therefore result in inadvertent contact of the 
speculum with the tympanic membrane. The probability of harm due to a malfunctioning 
camera is improbable. The severity of this harm is severe (CTCAE grade 3). The risk 
related to a malfunctioning camera is deemed to be acceptable. It is addressed in the 
Aurisvue’s instructions for use and will be addressed during training. 
 
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