A Retrospective Mapping of Health Care Utilisation and Current Quality of Life Status in Adult Subjects With a History of Chronic Otitis Media With or Without Cholesteatoma Who Have Undergone a Primary Tympanoplasty
Conditions: Chronic Otitis Media
Sponsor: Cochlear

 
 
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Clinical Investigation Plan 
 
Investigation Title: A retrospective mapping of health care utilisation and 
current quality of life status in adult subjects with a history of chronic otitis 
media with or without cholesteatoma who have undergone a primary 
tympanoplasty 
 
 
 
Short Title: 
MapCOM 
CIP Number: 
CBAS5780 
Date:  
Refer to system version control 
Sponsor 
Cochlear Bone Anchored Solutions AB 
Konstruktionsvägen 14 
PO Box82 
Mölnlycke 435 22 
SWEDEN 
 
 
 
 
 
 
 
 
 
This clinical investigation shall be conducted in accordance with ethical principles that have their 
origin in the Declaration of Helsinki, International Standard ISO 14155 Clinical investigation of 
medical devices for human subjects - Good Clinical Practice, and any regional or national 
regulations, as applicable. 
 
Confidential Information 
The information contained in this document is confidential and should not be copied or distributed to persons not involved 
in the conduct or oversight of the clinical investigation 
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Manufacturer 
Not applicable 
Sponsor Organisation 
 
Cochlear Bone Anchored Solutions AB 
Konstruktionsvägen 14 
PO Box82 
Mölnlycke 435 22 
SWEDEN 
Coordinating Investigator 
 
 
 
  
 
 
Clinical Research Organisation 
(for monitoring of German and French 
sites only)  
 
  
  
  
 
Safety Contact 
Not applicable 
Statistics 
Cochlear Bone Anchored Solutions AB 
Konstruktionsvägen 14 
PO Box82 
Mölnlycke 435 22 
SWEDEN 
 
A complete list of participating Principal Investigators’ names, titles and addresses, and the names 
and addresses of participating institutions (sites) will be maintained by the Sponsor and will be 
provided as a separate Principal Investigator List. The definitive Principal Investigator list will be 
provided in the Clinical Investigation Report. 
 
 
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INVESTIGATOR AGREEMENT 
Coordinating Investigator Approval and Declaration 
By my signature below, I confirm my review and approval of this Clinical Investigational Plan (CIP). 
I also confirm that I will strictly adhere to the requirements therein and undertake to ensure that all 
staff with delegated responsibilities in the conduct of this CIP have read, understood and will strictly 
adhere to the requirements therein. This CIP will not be implemented without prior written approval 
from the Ethics Committee, any applicable National Competent Authorities, and the Sponsor. If 
amendments to this plan become necessary, written approval by the Ethics Committee and any 
applicable National Competent Authorities will be obtained before the changes are clinically 
implemented per the amendment, except under emergency circumstances to protect the rights, 
safety, and well-being of subjects. 
 
Name 
Title 
 
Coordinating Investigator 
Signature 
Date 
 
 
 
Principal Investigator Declaration 
By my signature below, I confirm that I have read, understood and will strictly adhere to the 
requirements therein. I undertake to ensure that all staff with delegated responsibilities in the conduct 
of this CIP have also read, understood and will strictly adhere to the requirements therein. This CIP 
will not be implemented without prior written approval from the Ethics Committee, any applicable 
National Competent Authorities, and the Sponsor. If amendments to this plan become necessary, 
written approval by the Ethics Committee and any applicable National Competent Authorities will be 
obtained before the changes are clinically implemented per the amendment, except under 
emergency circumstances to protect the rights, safety, and well-being of subjects. 
 
Name 
Title 
 
Principal Investigator 
Site Name 
Site Address 
 
 
Signature 
Date 
 
 
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TABLE OF CONTENTS 
1 
Definitions and Abbreviations ......................................................................................................... 7 
2 
Clinical Investigation Synopsis ........................................................................................................ 8 
3 
Schedule of Events ....................................................................................................................... 10 
4 
Background Information and Rationale ........................................................................................ 10 
4.1 
Introduction ......................................................................................................................... 10 
4.1.1 
Treatment interventions ........................................................................................ 11 
4.1.2 
Hearing outcomes ................................................................................................. 11 
4.2 
Findings of Previous Nonclinical and Clinical Studies ........................................................ 12 
4.2.1 
Nonclinical Data .................................................................................................... 12 
4.2.2 
Clinical Data .......................................................................................................... 12 
4.3 
Study Rationale .................................................................................................................. 12 
5 
Medical Device Information ........................................................................................................... 12 
5.1 
Identity and Description of the Investigational Medical Device (IMD) ................................ 12 
5.2 
Identity and Description of the Comparator ........................................................................ 12 
5.3 
Accessory Device Requirements ........................................................................................ 12 
6 
Objectives ..................................................................................................................................... 12 
6.1 
Primary Objective ............................................................................................................... 12 
6.2 
Secondary Objectives ......................................................................................................... 12 
6.3 
Exploratory Objectives ........................................................................................................ 13 
7 
Design of the Clinical Investigation ............................................................................................... 13 
7.1 
General ............................................................................................................................... 13 
7.1.1 
Design Rationale ................................................................................................... 14 
7.2 
Subjects .............................................................................................................................. 15 
7.2.1 
Inclusion Criteria ................................................................................................... 15 
7.2.2 
Exclusion Criteria .................................................................................................. 15 
7.2.3 
Number of Subjects Required ............................................................................... 15 
7.2.4 
Vulnerable Populations ......................................................................................... 16 
7.2.5 
Recruitment and Study Duration ........................................................................... 16 
7.2.6 
Criteria for Subject Withdrawal ............................................................................. 16 
7.2.7 
Randomisation Procedures .................................................................................. 17 
7.2.8 
Post-investigation Medical Care ........................................................................... 17 
7.3 
Performance Evaluations and Procedures ......................................................................... 17 
7.3.1 
Eligibility evaluations and Procedures .................................................................. 17 
7.3.2 
Participant Evaluations and Procedures ............................................................... 18 
7.4 
Safety Evaluations and Procedures ................................................................................... 20 
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7.4.1 
Concomitant Medication and Therapies ............................................................... 20 
7.5 
Equipment Used for Evaluation of Performance and Safety .............................................. 20 
7.6 
Sponsor Role in Conduct of the Clinical Investigation ........................................................ 20 
8 
Risks and Benefits of the Investigational medical device and Clinical Investigation .................... 21 
8.1 
Anticipated Clinical Benefits ............................................................................................... 21 
8.2 
Anticipated Adverse Device Effects .................................................................................... 21 
8.3 
Risks Associated with Participation in the Clinical Investigation ........................................ 21 
8.4 
Risk Mitigation .................................................................................................................... 21 
8.5 
Risk-to-Benefit Rationale .................................................................................................... 22 
9 
Statistical Considerations .............................................................................................................. 22 
9.1 
General Considerations ...................................................................................................... 22 
9.2 
Endpoints ............................................................................................................................ 22 
9.2.1 
Primary Endpoint .................................................................................................. 22 
9.2.2 
Secondary Endpoints ............................................................................................ 22 
9.2.3 
Exploratory Endpoints ........................................................................................... 23 
9.3 
Hypotheses ......................................................................................................................... 23 
9.3.1 
Primary Hypothesis ............................................................................................... 23 
9.3.2 
Secondary Hypothesis .......................................................................................... 23 
9.3.3 
Exploratory Hypothesis ......................................................................................... 23 
9.4 
Sample Size Determination ................................................................................................ 23 
9.5 
Analysis Populations ........................................................................................................... 24 
9.6 
Primary Endpoint Analyses................................................................................................. 24 
9.7 
Secondary Endpoint Analyses ............................................................................................ 25 
9.8 
Exploratory Endpoint Analyses ........................................................................................... 25 
9.9 
Safety Analyses .................................................................................................................. 26 
9.10 Interim Analyses ................................................................................................................. 26 
10 Informed Consent Process ........................................................................................................... 26 
11 Adverse Events and Device Deficiencies ..................................................................................... 27 
12 Device Accountability .................................................................................................................... 27 
13 Deviations from the Clinical Investigation Plan ............................................................................. 27 
14 Data Management ........................................................................................................................ 27 
15 Confidentiality ................................................................................................................................ 28 
16 Ethics Committee and Regulatory Authority Approval .................................................................. 28 
17 Suspension or Premature Termination ......................................................................................... 29 
18 Amendments to the Clinical Investigation Plan ............................................................................. 29 
19 Record Keeping and Retention ..................................................................................................... 29 
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20 Publication Policy .......................................................................................................................... 29 
21 Statements of compliance ............................................................................................................. 30 
22 Quality Control and Assurance ..................................................................................................... 30 
22.1 Monitoring ........................................................................................................................... 30 
22.2 Audits .................................................................................................................................. 30 
23 Trademarks and Copyright ........................................................................................................... 30 
24 References .................................................................................................................................... 30 
25 Change History ............................................................................................................................. 33 
Appendix 1: Information Collected from Medical Records ................................................................... 35 
 
 
 
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childhood (6). The World Health Organization defines OM to be chronic following two weeks of 
otorrhea, whereas other clinical guidelines generally consider that acute OM be classified as COM 
when patients with tympanic perforations continue to discharge mucoid material for a time period of 
greater than six weeks to three months, despite medical intervention (7). Recurrent COM can occur 
due to a combination of several factors and is a significant health burden that affects patient quality of 
life (QoL) (8). COM is one of the most prevalent global chronic infectious diseases and may lead to 
hearing impairment (9), including both conductive hearing loss (CHL) and mixed hearing loss (MHL). 
One of the major causes of COM-associated hearing loss is ossicular discontinuity (10). Hearing 
losses may range from 20 to 60 dB hearing level (HL) and may be irreversible (11, 12). In children, 
the resulting hearing loss can negatively impact their speech development, their ability to learn and 
their behaviour (13, 14). COM in adults has been linked to significantly lower levels of QoL and is 
associated with anxiety and depression (15). Furthermore, if unsuccessfully treated, several life-
threatening complications may arise, including brain abscesses and meningitis (16). 
4.1.1 Treatment interventions 
COM is a multifactorial disease that is difficult to treat as it can be caused by various mechanisms and 
co-infections with more than one type of bacteria and/or virus (17). COM treatments principally aim to 
eradicate infection and restore a healthy middle ear cavity. Current treatment methods include a 
combination of earwax removal and topical and systemic antimicrobials to eliminate the infection. 
Surgical interventions include mastoidectomy and reconstruction of the tympanic membrane (18) in 
order to remove infected tissue and improve hearing (4). Cholesteatomas and ossicular discontinuities 
typically require a combination of more invasive and complex surgeries that aim to remove tissue 
overgrowth or to repair and reconstruct the damaged middle ear ossicles through ossiculoplasty. The 
total ossicular replacement prosthesis (TORP) and partial ossicular replacement prosthesis (PORP) 
are the two most common types of ossicular chain reconstruction surgeries. However, each surgery is 
associated with complications and risk of permanent hearing damage (19). Surgical results are also 
poorly reported and there is a large variation in surgical descriptions and outcomes described in the 
literature (20). Additionally, clinics in developing countries may not have access to the most modern 
surgical methods. 
4.1.2 Hearing outcomes 
Studies use several assessment methodologies and the overall clinical benefits of individual treatments 
in restoring hearing have not been systematically assessed, particularly not over the long-term. It is 
frequently reported that surgeries result in non-discharging ears, but it is also obvious that there is a 
subset of patients who do not show satisfactory improvements in hearing performance following 
surgery and that post-operative hearing outcomes in some patients actually deteriorate (21, 22). The 
condition of the ossicular chain is of key importance to hearing outcomes. A retrospective study of 213 
patients demonstrated that an intact ossicular chain is significantly associated with improved long-term 
hearing outcomes after tympanoplasty for perforated COM (23). Patients with a compromised ossicular 
chain are likely to benefit from bone conduction hearing aids following mastoidectomy (24). It is crucial 
to understand how surgical intervention could affect hearing since there is extensive evidence of mild 
to moderate CHL in COM patients before surgery (25). These patients are also predisposed to 
developing MHL as the disease progresses (26). Studies also stress the need for performing 
audiometry to assess the patients’ type and degree of hearing loss prior to treatment intervention since 
this is not routinely completed (27). Finally, even when audiometry is performed the methodology 
varies, making an accurate comparison difficult. 
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4.2 Findings of Previous Nonclinical and Clinical Studies 
4.2.1 Nonclinical Data 
No relevant non-clinical data is available. 
4.2.2 Clinical Data 
A systematic review investigating long-term hearing outcomes in COM patients treated under the 
current standard of care has been undertaken (28). The systematic review assessed literature 
published between 2008-2018 in order to assess the clinical success rate of COM treatments in 
restoring hearing loss (based on an air-bone gap (ABG) closure within 20 dB) at a minimum follow up 
time of 12-months in both adult and paediatric patients. Key outcomes from the systematic literature 
review indicated that 30.0% of patients have a post-operative air bone gap of ≥20 dB. Data also show 
that 14.7% of patients have post-operative complications, including 7.0% of patients in which a 
perforation of the tympanic membrane persisted at long-term follow up.  
4.3 Study Rationale 
The rational for conducting this primarily descriptive study is to broaden the understanding of the 
treatment pathways and health care interventions that follow a primary tympanoplasty (middle ear 
reconstructive surgery) among patients with COM, with or without cholesteatoma. An improved 
understanding of the treatment pattern will guide clinicians in making well-informed treatment decisions 
in order to improve the hearing and QoL of patients and more efficiently utilise available health care 
resources.  
5 MEDICAL DEVICE INFORMATION 
5.1 Identity and Description of the Investigational Medical Device (IMD) 
Not Applicable. 
5.2 Identity and Description of the Comparator 
Not Applicable. 
5.3 Accessory Device Requirements 
Not Applicable. 
6 OBJECTIVES 
6.1 Primary Objective  
1. Map health care utilisation. 
6.2 Secondary Objectives 
1. Characterise long-term hearing performance.  
2. Collect socio-economic data, demographics and information on service utilisation. 
3. Estimation of health care costs. 
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The subjects shall include men and women aged 18 years or older who underwent primary 
tympanoplasty to improve hearing between 2010-2016 and have a historically documented diagnosis 
of COM, with or without cholesteatoma in the operated ear. Subjects will be screened and 200 subjects 
will be enrolled in the clinical investigation across the 6-9 investigation sites in Germany, Spain and 
France. The study will aim to enrol subjects with an even distribution across all study sites. If any site 
has difficulties with recruitment the remaining sites can recruit more subjects, so the total recruitment 
is not affected, upon agreement with the Sponsor. In view of a possible situation where last recruitment 
efforts may result in exceeding the needed 200 subjects, no more than 10% over recruitment is 
expected. 
In case no other follow-up visit to the clinic is planned within the study recruitment period subjects who 
have had an audiogram done between 2018 and the point of enrolment will be sent the ICF, 
questionnaires and survey via registered mail for completion at home. Subjects who are planned to 
have a follow-up audiogram collected within the study recruitment period will be asked to complete the 
ICF, questionnaires and survey at the time of their appointment. The medical record search for data 
extraction will be done at the clinic. See section 3. Schedule of Events.  
The primary endpoint is to collect categorical data; number and type of contacts with health care 
providers, number and type of interventions and/or procedures and number and type of medications 
and therapies to map health care utilisation. Health care utilisation data will be analysed in patient 
years, from primary tympanoplasty to point of enrolment. Secondary endpoints are PTA4 to give 
information about hearing performance, unit cost for an estimation of health care costs, CSRI survey 
to collect socio-economic data, demographics and information on service utilisation, questionnaires 
(HUI3, COMOT-15, SSQ-12) to assess current patient reported outcome and responses from a 
minimum of 30 subjects per language (29) and audiograms collected within one year of questionnaire 
completeness to validate COMOT-15 in French and Spanish. Exploratory endpoints are data on 
employment status for an estimation of productivity losses and Middle Ear Risk Index factors and 
surgical outcome to develop a scoring system to classify severity of middle ear status and relate to 
surgical outcome, if needed information is available.  
7.1.1 Design Rationale 
This study is designed to collect information regarding health care interventions that follow a primary 
tympanoplasty with residual hearing loss among adult subjects with diagnosis of COM, with or 
without cholesteatoma.  A multicentre set-up is necessary to accurately capture the standard of care 
as this can vary at each site, as determined by treatment practice surveys at potential sites and it is 
important that we capture outcomes on all potential interventions that may be offered as part of 
standard care. The rationale to collect information from subjects who underwent a primary 
tympanoplasty procedure between 2010-2016 is to increase the likelihood of availability of electronic 
medical records data as these systems have only typically been introduced in recent years. This 
inclusion time frame is also important to capture the current standard of care rather than outcomes 
from obsolete procedures and to find enough subjects that have at least five years follow-up data so 
that we may capture patients who have reached a steady state. Subjects with single-sided deafness 
are not eligible for the study as COM with or without cholesteatoma leads to mainly conductive or 
mixed hearing loss. Paediatric subjects are excluded from the study as tympanoplasties are delayed 
until adulthood in some clinics. 
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7.2 Subjects 
Written informed consent must be obtained from the subject or its legally authorised representative 
before any data is collected.  
Eligibility of subjects must be supported by the inclusion and exclusion criteria listed below. 
7.2.1 Inclusion Criteria 
Subjects must meet all of the inclusion criteria described below to be eligible for this clinical 
investigation. 
1. Adult subjects, 18 years or older. 
2. Subjects with conductive or mixed hearing loss.  
3. Subjects with historically documented diagnosis of Chronic Otitis Media (COM) with or without 
cholesteatoma in the operated ear.  
4. Subjects who have undergone primary tympanoplasty type I-V to improve hearing between 
2010-2016.  
5. Subjects with a PTA4 air-bone gap ≥30 dB OR PTA4 air-bone gap between 25-30 dB with an 
air conduction threshold PTA4 ≥40 dB HL within 12 months after primary tympanoplasty in the 
operated ear.  
6. Subjects who have been recommended by their health care professional to try a hearing aid to 
improve hearing in the operated ear.  
7. Pre-op audiogram, maximum 1 year prior to the primary tympanoplasty, and post-op audiogram 
for the primary tympanoplasty are available.  
8. Aided audiogram, unaided if no hearing device is used, available between 2018 and the point 
of enrolment.  
9. Subjects are fluent in the language used for study questionnaires: German, French, Spanish.  
10. Subjects are willing and able to provide written informed consent.  
11. Medical Record data is available throughout the defined data search period, from primary 
tympanoplasty to point of enrolment. 
7.2.2 Exclusion Criteria 
Subjects who meet any of the exclusion criteria described below will not be eligible for this clinical 
investigation. 
1. Subjects are unable or unwilling to comply with the requirements of the study as determined by 
the investigator. 
2. Investigator site personnel directly affiliated with this study and/or their immediate families; 
immediate family is defined as a spouse, parent, child, or sibling. 
3. Cochlear employees or employees of Contract Research Organizations or contractors engaged 
by Cochlear for the purposes of this study.  
7.2.3 Number of Subjects Required 
200 subjects will be enrolled in the clinical investigation, with a maximum estimated overhead of 10% 
taking into consideration the simultaneous recruitment at all sites. It is estimated that approximately 
double the size will need to be screened (30) to meet this sample size. Additionally, to meet the 
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validation requirements on the COMOT-15, a minimum of 30 subjects (29) with complete data are 
required at both the Spanish and French clinics (see section 7.3.2.1 for detailed justification).    
7.2.4 Vulnerable Populations 
Not applicable.  
7.2.5 Recruitment and Study Duration 
The following subject status definitions apply: 
• Enrolled: A subject that has signed the Informed Consent Form (ICF) for the study.  
• Screen Fail: An Enrolled subject that has been determined to not meet one or more eligibility 
criteria. 
• Participated: Subjects who have met eligibility criteria and have started on protocol defined 
events.  
• Withdrawn: An Enrolled subject who withdrew or was withdrawn by the Investigator or Sponsor 
before the expected End of Study.  
• Completed: Enrolled subjects who complete the required tasks and schedule.  
The recruitment period for the clinical investigation is estimated to be approximately 12 months from 
the time of first subject enrolled to the last subject. 
Recruitment of subjects shall be performed in a back-chronological order from the primary 
tympanoplasty surgery. Recruitment shall start with the last subject that has undergone this 
procedure in the year 2016 and chronologically working backwards until recruitment targets are met. 
This process will avoid any recruitment bias. 
The expected duration of each subject’s participation in the clinical investigation is the time it takes 
for the subject to complete and return the ICF, questionnaires and survey. Time for completing the 
questionnaires is estimated to 30-40 minutes. 
Clinical Investigation completion is defined as the recording and completion of the last medical record 
search for the last enrolled subject in the electronic Case Report Forms (eCRF). 
7.2.6 Criteria for Subject Withdrawal 
Subjects can decide to withdraw from the investigation at any time. The Investigator shall ask the 
reason(s). The reason for withdrawal (if available) should be documented in the subject’s source files 
and the referent electronic case report form (eCRF). 
The Investigator or Sponsor may also decide to withdraw a subject from the clinical investigation if it 
is considered to be in the subject’s best interests. 
Subject withdrawal may be for any of the following reasons: 
• 
CIP or GCP deviation 
• 
Subject withdrew consent 
• 
Subject died 
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• 
Sponsor decision 
• 
Investigator decision 
• 
Other (specify) 
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 be replaced if medical record search is not 
completed.  
7.2.7 Randomisation Procedures 
Not applicable. 
7.2.7.1 Blinding Procedures 
Not applicable. 
7.2.8 Post-investigation Medical Care 
No specific care will be provided for the subjects after this study has been completed.  
7.3 Performance Evaluations and Procedures 
7.3.1 Eligibility evaluations and Procedures 
Screening of subjects include searches by site personnel in medical records for inclusion and 
exclusion criteria.   
The search for a primary tympanoplasty to improve hearing can include any primary tympanoplasty 
of types I-V based on the Wullstein classification (31).  
Eligible subjects will be included chronologically based on date of primary tympanoplasty, from most 
recent to least recent. In a first draw, the number of subjects intended to be enrolled at a site plus 
20% (to account for non-responders) will be contacted. To confirm that subjects are alive before they 
are contacted, a search in public death records should be performed according to local regulations 
and practices.  
Subjects will first be contacted via mail or by phone. If they agree to receive a consent form, this will 
either be sent to them by mail or shared directly at the clinic if they are scheduled for an appointment. 
The subject has the right to have sufficient time to read the consent, ask questions and have those 
questions answered by the site personnel responsible for consent. When the consent form is signed 
by the subject at home, it will be sent back to the clinic by registered mail using a pre-filled and 
stamped envelope with the address of the clinic. The date of the consent discussion will be 
documented in the informed consent form and once this is signed by the responsible site staff, a copy 
of the mutually signed form will be shared with the subject.  
If the number of targeted subjects at the clinic is not reached in a first draw, a second and potential 
third draws (in the same way as the first one) will be performed until the targeted number of subjects 
for the site is reached.  
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7.3.2 Participant Evaluations and Procedures 
7.3.2.1 Study data – Questionnaires/survey 
When a subject is enrolled in the investigation, data collection can start. In case subjects are due for 
a follow-up appointment at the clinic, as per standard of care, questionnaires and survey can be 
completed at site. For those subjects where an aided (unaided if no hearing aid used) audiogram 
between 2018 and point of enrolment is available, and who are not scheduled to any appointment at 
the clinic during the investigation period, questionnaires and survey (together with a copy of the 
mutual signed ICF) are sent via mail to be completed at home. All questions regarding the 
questionnaires and survey can be raised with the site personnel. If completed at home, 
questionnaires and survey shall be sent back to the clinic by registered mail using a pre-filled and 
stamped envelope with the address of the clinic. 
The completeness of the questionnaires and survey will be verified by site personnel. Incomplete 
data will be followed-up with the subject, if answered at home by sending a copy of the 
questionnaire/survey back to the subject where incomplete parts requiring an answer are highlighted. 
If the questionnaires and survey are not returned; 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. 
The subjects will be asked to complete the following survey and questionnaires:  
- 
Health care utilisation survey (adapted version of Client Service Receipt Inventory, CSRI) 
- 
Health-Related Quality of Life – Health Utilities Index Mark 3 (HUI3)  
- 
Chronic Otitis Media Outcome Test-15 (COMOT-15) 
- 
Speech, Spatial and Qualities of Hearing Scale (SSQ-12 version) 
Health care utilisation survey 
The Adapted version of the Client Service Receipt Inventory (CSRI) (32),  is a research instrument 
developed in the mid-1980s to collect information on primarily service utilisation and has been used 
in over 500 studies. 
The CSRI can be used at multiple points within a study, thus tracking changes over time. The CSRI 
is also adaptable in administration. Although originally designed to be administered to the service 
user or their carer face to face with a trained interviewer, the CSRI has been successfully 
administered via post for the service user to be completed by themselves. 
The adapted version of CSRI will, in this investigation, collect data referring to the 6 months before 
enrolment regarding demographics (marital status, cohabitation, usual place of residence, education 
level), medical history (chronic diseases, smoking status, date when first diagnosed with chronic ear 
infection, current middle ear issues, recurrent ear infections), hearing rehabilitation (current hearing 
aid or hearing device and category of hearing aid/device and hours per day of usage if applicable), 
health care utilisation related to ear infection and hearing difficulties (number of face-to-face 
consultations with care providers, investigations or diagnostic tests, number of in-patient admissions, 
medications) and employment information (employment status, inability to work in days/hours). 
Health-Related Quality of Life – Health Utilities Index Mark III (HUI3) 
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HUI® is a generic preference-based system for measuring comprehensive health status and Health-
Related Quality of Life (HRQoL) (33). HUI provides descriptive evidence on multiple dimensions of 
health status, a score for each dimension of health and an overall HRQoL score. The scoring systems 
provide utility (preference) scores on a generic scale where dead = 0.00 and perfect health = 1.00. 
HUI3 will be used in this study. The HUI3 classification system is comprised of 8 attributes: Vision, 
Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition and Pain – each with 5 or 6 levels of 
ability/disability (34). The version in this clinical study uses a recall time of 1 week.  
The license to use the HUI questionnaire is purchased from Health Utilities Inc., 88 Sydenham Street, 
Dundas, ON, L9H 2V3 Canada. 
 
Speech, Spatial and Qualities of Hearing Scale (SSQ-12 version) 
The Speech, Spatial, and Qualities of Hearing Scale questionnaire (SSQ-12) (35) was developed in 
the MRC Institute of Hearing Research, UK, and is a scaled-down version of the 49 items SSQ 
questionnaire (36). It is designed to compile a sub-set of items from the longer original 49 version to 
represent the scale as a whole, measuring self-reported auditory disability, reflecting the reality of 
hearing in the everyday world. It has been shown to provide similar results to SSQ-49 (35). It covers:  
• 
Hearing speech in a variety of competing contexts  
• 
The directional, distance and movement components of spatial hearing  
• 
Segregation of sounds and attending to simultaneous speech streams  
• 
Ease of listening  
• 
The naturalness, clarity and identifiability of different speakers, different musical pieces and 
instruments, and different everyday sounds  
 
Chronic Otitis Media Outcome Test-15 (COMOT-15) and validation in French and Spanish 
The subjects will be asked to complete a Chronic Otitis Media Outcome Test-15 (37).  
COMOT-15 is 15-item questionnaire that is a reliable and sensitive instrument for measurement of 
HR-QoL of subjects with COM.  
The instrument consists of three subscales: ear symptoms (questions 1-6), hearing function 
(questions 7-9), and mental health (questions 10-13), which form the overall score (questions 1-13). 
In addition, one question on the general evaluation of the impact of COM on QoL (question 14) and 
one question to indicate the frequency of doctor visits in the last six months as a result of COM 
(question 15) are asked. The total score and the sub-scores are transformed to a 0-100 scale by 
dividing the sum of the raw scores of the items by the sum of spans of the items followed by 
multiplying by 100. Overall scores and sub-scores will be calculated for subjects based on this 
methodology, and compared between interventions, if feasible. COMOT-15 is validated in German 
and will be used in its original version at German-speaking clinics. For non-German speaking clinics, 
the COMOT-15 has been cross-translated and linguistically validated in Spanish and French by a 
certified translation agency (Software and Documentation Localization PLC) using published 
methodology (38). As the COMOT-15 is a COM-specific questionnaire that has already demonstrated 
reliability in additional languages, validation of the instrument in French and Spanish will require that 
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the questionnaire is completed by a minimum of 30 subjects per language, based on the accepted 
subject to item ratio of at least 2 (29).These subjects must have an accompanying audiogram (PTA4 
at minimum) collected within 12 months of questionnaire completeness and completed the SSQ and 
HUI3 questionnaire as part of the investigation. Aided audiograms should be collected if the subject 
is using a hearing device. The widely accepted Cronbach’s alpha value of 0.7 will be used as a cut-
off to measure consistency. 
7.3.2.2 Study data from medical records 
The medical record search for data extraction can start in parallel to the questionnaires/survey being 
answered. 
Data to be collected from the medical records include: 
- 
Demographics and hearing/device history information 
- 
Pre- and post-primary tympanoplasty air and bone conduction audiograms (unaided and when 
applicable aided and PTA4 at minimum) 
- 
Latest available (as per inclusion criteria) air and bone conduction audiograms (unaided and 
when applicable aided and PTA4 at minimum) 
- 
COM-related contacts with health care providers for the operated ear (including name and 
number of interventions and/or procedures, medications and therapies, examinations and Middle 
Ear Risk Index factors and surgical outcomes where applicable)  
More details on the information to be collected can be found in Appendix 1. 
It might be the case in a few sites, that the required audiograms for some subjects were collected in a 
hearing aid partner centre/shop and not in the clinic itself. For these situations, clinics will reach out 
to the responsible audiologist and request a copy of the test. 
For analysis, health care contacts, interventions and/or procedures will be coded using the ICD-10 
coding system. Medication will be coded according to WHO CC ATC.  
7.4 Safety Evaluations and Procedures 
Not applicable. 
7.4.1 Concomitant Medication and Therapies 
All medications and therapies related to COM and its rehabilitation which were prescribed during and 
from primary tympanoplasty must be recorded in the appropriate section of the eCRF.  
7.5 Equipment Used for Evaluation of Performance and Safety 
Not applicable. 
7.6 Sponsor Role in Conduct of the Clinical Investigation 
The Sponsor employees (or designee) shall use standard operating procedures to ensure that clinical 
study procedures and documentation are consistently conducted and compliant with Declaration of 
Helsinki and applicable parts of GCP and any regional or national regulations. 
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The Sponsor shall ensure that the study is quality controlled (monitored) by a monitor who is 
independent from the study, scientifically and clinically competent and has good knowledge of the 
study plan, ICF, sponsor´s SOPs, GCP and applicable laws and regulations.  
The Sponsor shall monitor tasks delegated to other organizations/persons (Sponsors oversight) e.g. 
contract research companies (CRO) or other consultants. 
The Sponsor is responsible for developing a study plan and compile a clinical study report when the 
study is completed.  
The Sponsor shall make sure that electronic systems used in the study are validated, that a Trial 
Master File is created, subjects identity are coded so that reported data is coded but can be linked to 
the respective research person, that all essential study documentation is available in a safe place 
before, during and after the study according to applicable laws and regulations.  
The Sponsor shall also make sure that the investigators have sufficient qualifications, enough 
resources are available at site, collect signed study plans from respectively responsible investigator 
and establish agreements with participating clinics.  
It is the Sponsor´s responsibility to check that there is an EC approval for the study, to register the 
study in a public database and assure that the study results are reported within one year.  
All study deviations will be documented in the CRF to enable analysis and reporting by the Sponsor 
in the Study Report, or to the relevant regulatory authority(s), if applicable. 
8 RISKS AND BENEFITS OF THE INVESTIGATIONAL MEDICAL DEVICE AND 
CLINICAL INVESTIGATION 
8.1 Anticipated Clinical Benefits  
Participation in this study will not directly benefit the subject nor will it alter the subject´s course of 
care. However, information gained from the study may identify shortcomings in the current standard 
of care, which may be used to guide more effective interventions in the future.  
Additionally, by collecting self-reported feedback via the questionnaires from the subjects, the clinical 
personnel can take the opportunity to identify potential needed follow-ups accordingly. 
8.2 Anticipated Adverse Device Effects 
Not applicable. 
8.3 Risks Associated with Participation in the Clinical Investigation 
Participation in the study will not alter the subject´s course of care. Sensitive data concerning the 
subject’s health is being handled in the study. For subjects completing the ICF and 
questionnaires/survey at home, there is a risk that these documents might be lost in transit.   
8.4 Risk Mitigation 
All data collected will be pseudonymised and therefore the risk that any sensitive data will be 
disclosed to unauthorized persons is considered to be minimal. Registered post will be used when 
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sending ICFs and questionnaires/survey. For questionnaires/survey, clinical personnel will complete 
header with subject identification code and request that no personal data is shared on these 
documents, making them pseudonymised. 
8.5 Risk-to-Benefit Rationale 
The benefit of the clinical investigation of potentially identifying shortcomings in the standard of care 
and hence being able to guide more effective interventions in the future is regarded to outweigh the 
minimal anticipated risk for the subjects participating in the clinical investigation. We therefore 
consider it ethical to conduct the investigation.  
9 STATISTICAL CONSIDERATIONS 
9.1 General Considerations 
Descriptive statistics will be used for analysis in this study. All analyses will be made on the full data 
set.  All analyses will be presented as aggregated data without the possibility of identifying data from 
individual subjects.  
9.2 Endpoints 
9.2.1 Primary Endpoint 
1. Categorical data collected from primary tympanoplasty to time of enrolment: 
• 
Number and type of contacts with health care providers 
• 
Number and type of interventions and/or procedures (medical examinations, surgical 
procedures, hearing rehabilitation) 
• 
Number and type of medications and therapies  
9.2.2 Secondary Endpoints 
1. Pre- and post-primary tympanoplasty and a third assessment between 2018 and point of 
enrolment:   
• 
PTA4 (0.5, 1, 2 and 4 kHz) for both air and bone conduction, under unaided and when 
applicable aided conditions.  
2. From primary tympanoplasty to time of enrolment (analysed in patient-years):  
• 
Unit cost 
3. At time of enrolment: 
• 
Client Service Receipt Inventory (CSRI) 
4. At time of enrolment:  
• 
Health Utilities Index Mark III (HUI3) 
• 
Chronic Otitis Media Outcome Test-15 (COMOT-15) 
• 
Speech, Spatial and Qualities of Hearing Scale (SSQ-12) 
5. Responses from a minimum of 30 subjects per language and audiograms collected within one 
year of questionnaire completeness. 
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9.2.3 Exploratory Endpoints 
1. Middle Ear Risk Index factors (preoperative status, intraoperative findings) and surgical 
outcomes, if available.  
2. Data on employment status collected in the CSRI survey used to determine the number of lost 
working hours as a result of COM.  
9.3 Hypotheses 
9.3.1 Primary Hypothesis 
Not applicable.  
9.3.2 Secondary Hypothesis 
Not applicable.  
9.3.3 Exploratory Hypothesis 
Not applicable. 
9.4 Sample Size Determination 
The aim of this investigation is to map health care utilised by subjects with a history of COM, who 
have already had a primary tympanoplasty. Findings from this investigation will primarily help 
estimate the burden in terms of health care costs and impact on HRQoL that follows a first 
tympanoplasty for this subject population. As this study is not testing for differences in treatments or 
strengths of associations (primary objective is to map healthcare utilisation) then it is only necessary 
that the study is capable of capturing all potential interventions that may be offered as standard of 
care for the population. To ensure that enough medical records are sampled to capture all potential 
COM-related interventions included in the standard of care a sample size determination using 
published methods for calculating sample sizes in retrospective studies was undertaken (39). The 
calculation is based on the potential for patients with COM to receive the least likely intervention, 
which was determined to be a bone conduction solution, prescribed at a rate of 2.63% (unpublished 
registry data). Using these data, we estimate that 200 subjects are sufficient to capture the least 
likely intervention in at least four subjects, where the probability of observing this intervention at least 
once is 98% with a 95% confidence interval of 96-100% (Table 1).  
 
 
 
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9.7 Secondary Endpoint Analyses 
Hearing performance 
Audiogram data (see 9.2.2) collected pre- and post- primary tympanoplasty and between 2018 and 
point of enrolment will be compared to investigate how the standard of care impacts the subjects´ 
hearing, when feasible. Wilcoxon signed rank test will be used to compare the audiometric test 
results.  
Survey - CSRI 
Service utilization data collected through the CSRI will be used to map resource usage patterns for 
individual subjects and to determine associations between resource usage and socioeconomic 
status. Applicable events in medical history will be summarised using ICD-10 classification. 
Health care costs  
Direct medical costs associated to COM-related health care utilisation will be calculated for each 
subject using standard cost/unit in each participating country. Costs for individual contacts will be 
assigned with a view to identifying COM related health care cost factors for individual subjects and 
for groups of interventions, where feasible. All comparisons will be presented as aggregated data 
without the possibility of identifying data from individual subjects. 
Estimation of costs will be based on primary outcomes that will be allocated a unit cost. The base 
case analysis will employ standard unit costs from all the included countries on the pooled data on 
utilisation and adjusted to the cost year 2022 and converted into Euros using the World Bank 
conversion factor for purchasing power parity. Health care costs in the population will be based on 
the health care consumption from primary tympanoplasty to enrolment (analysed in patient-years) 
and assumptions on when a state of stability is reached, which will be determined using data 
collected as part of this investigation itself.  
Patient reported outcome 
Attribute levels and scores will be calculated for individual subscales and general scores for each 
subject. If possible, data will also be grouped by intervention type and differences in scores between 
these groups will be analysed. Change in score will be assessed using the Wilcoxon rank sum test and 
sub-group analyses by age and gender may be performed, if feasible. 
Validation of COMOT-15 in French and Spanish 
The validated German version of the COMOT-15 that has been translated, back translated and 
linguistically validated will be used to validate the instruments reliability in French and Spanish. The 
instrument will be administered according to the original procedure and criterion validity will be 
assessed by comparing COMOT-15 scores with PTA4. COMOT-15 properties, including internal 
consistency will be assessed using Cronbach’s alpha, where a value of >0.7 is indicative of 
acceptable reliability for clinical purposes. 
9.8 Exploratory Endpoint Analyses 
Middle Ear Risk Index factors  
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The Middle Ear Risk Index (MERI) will be used to guide the extraction of middle ear status variables 
from the medical records (40). If available, pre-operative factors collected from the medical records 
will be used to populate the MERI, generating a risk score for individual subjects by summing the 
corresponding risk factor scores defined within each section of the index. Subjects will be stratified 
into a low-medium-risk group (MERI: 0–7) and a high-risk group (MERI: 8–15). The relationship 
between pre-operative factors corresponding to those contained in the MERI on the success rate of 
tympanoplasty, based on post-operative ABG, will be investigated using a binary logistic regression 
model. The Spearman correlation coefficient will be used to determine relationships between pre-
operative factors and their influence on post-operative outcomes. 
Estimation of Productivity Losses 
Employment history data will be collected from the CSRI survey and used to estimate productivity 
losses due to COM. Lost productivity will be estimated using the human capital approach, which 
measures lost productivity as the amount of time by which working life is reduced due to illness. To 
calculate productivity losses, lost working hours will be collected from the CSRI survey, valued at the 
market wage and adjusted to account for labour force participation and unemployment. Any hour not 
worked due to COM will be counted as an hour of productivity lost. 
9.9 Safety Analyses 
Not applicable. 
9.10 Interim Analyses 
Not applicable. 
10 INFORMED CONSENT PROCESS 
The Investigator shall obtain written informed consent from the subject as needed, using an approved 
ICF, prior to any data collection for the purpose of this investigation.  
The rationale of the clinical investigation, as well as the risks and benefits, what participation will 
involve, and alternatives to participation will be explained to the subject. Enough time will be provided 
for the subject to enquire about details of the clinical investigation and to decide whether to 
participate. 
All questions about the clinical investigation shall be answered to the satisfaction of the subject or the 
subject’s legally acceptable representative. Subjects shall not be coerced or unduly influenced to 
participate or to continue to participate in a clinical investigation. 
Each subject (or their legally authorised representative) and the person who conducted the informed 
consent discussion, shall sign and date the Informed Consent Form (ICF) accordingly. Where 
required, a 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 at the 
investigational site. 
The subject, or the subject’s legally authorised 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. 
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11 ADVERSE EVENTS AND DEVICE DEFICIENCIES 
Not applicable. 
12 DEVICE ACCOUNTABILITY 
Not applicable. 
13 DEVIATIONS FROM THE CLINICAL INVESTIGATION PLAN 
The Investigator(s) must not deviate from the CIP, except in case of an emergency to protect the 
safety and well-being of the subject(s). Such deviations will be documented by the site personnel in 
the source documentation for the subject and reported to the relevant EC as per institutional 
requirements and to the Sponsor as soon as possible. 
If there is a deviation from CIP-defined assessments or parts thereof are omitted or completed 
incorrectly, the deviation will also be documented by the site personnel in the source documentation 
for the subject. Depending on the type or severity of the deviation the Investigator may be required to 
notify the EC, particularly if the deviation potentially impacts subject safety 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. 
Source data can be medical records, paper-based source data worksheets, questionnaires and 
survey. If electronic medical records do not permit read only access for monitoring purposes or an 
authorized site member is not available to ensure access to the electronic medical records, a certified 
printout must be provided.  
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 
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comprehensive audit trail for all data entered, including updates and queries, and it 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. 
15 CONFIDENTIALITY 
The investigator, site staff and the Sponsor will collect and process personal data of the subjects in 
accordance with governing data privacy regulations [such as the EU GDPR regulations]. Subjects 
have the right to access their data and request for its correction or deletion after withdrawal. 
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. 
16 ETHICS COMMITTEE AND REGULATORY AUTHORITY APPROVAL 
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. 
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. 
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will be discussed and agreed upon prior to investigation start and in accordance with guidelines and 
recommendations provided by the International Committee of Medical Journal Editors (ICMJE) to 
enable communication in a timely manner. All contributors who do not meet the criteria for authorship 
will be listed in an acknowledgments section of the publication. 
Investigators will also be able to publish and/or present the data generated from the clinical 
investigation after mutual agreement between the Coordinating Investigator, the Principal 
Investigators, and the Sponsor when the main publication has been submitted and approved.  
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 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 investigation 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 describing all the activities performed during site qualification, initiation, 
monitoring, and close out. 
22.2 Audits 
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.   
The Investigator will grant the Sponsor representatives the same access privileges offered to relevant 
health authority or regulatory agents, officers, and employees. 
23 TRADEMARKS AND COPYRIGHT 
Not applicable. 
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