A Prospective, Post-Market Clinical Follow-up Investigation to Verify Performance and Safety of Otinova® Ear Spray When Used in the Treatment of External Otitis Symptoms
Phase: NA
Conditions: Otitis Externa
Sponsor: Circius Pharma AB

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 1 of 62 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 
CLINICAL INVESTIGATION PLAN (CIP) 
 
Clinical Investigation Title: 
A prospective, Post-Market Clinical Follow-up 
investigation to verify performance and safety of 
Otinova® Ear Spray when used in the treatment of 
external otitis symptoms 
Clinical Investigation Code: 
CIR_001 
Single identification number: 
CIV-22-01-038706 
Investigational Device(s): 
Otinova® Ear Spray 
Principal Investigator: 
Cristina Ioanes, Carlanderska Sjukhuset, 
Forskningsenheten, Carlandersparken 1, 412 55 
Göteborg   
Sponsor: 
Circius Pharma AB 
Södra långebergsgatan 34-36 
436 32 Askim 
Sweden 
Date: 
09-May-2023 
 
 
Revision 
Version History 
A 
First release 
B 
Addition of Site 02 
C 
Addition of Site 03 
 
 
This clinical investigation will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki. Furthermore, the clinical investigation will be performed in compliance with ISO 
14155:2020, Regulation (EU) 2017/745 and applicable regional or national regulations. 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 2 of 62 
CONFIDENTIAL 
This Clinical Investigation Plan contains privileged or confidential information, which is the property of the Sponsor. 
Information may not be disclosed to a third party without written authorization from the Sponsor. 
 
 
1 
SYNOPSIS 
 
NAME OF THE SPONSOR: 
Circius Pharma AB 
Södra långebergsgatan 34-36 
436 32 Askim 
Sweden 
CLINICAL INVESTIGATION TITLE: 
A prospective, Post-Market Clinical Follow-up investigation to verify performance and safety of 
Otinova® Ear Spray when used in the treatment of external otitis symptoms 
CLINICAL INVESTIGATION CODE: 
CIR_001 
INVESTIGATIONAL DEVICE(S): 
Otinova® Ear Spray 
OVERALL CLINICAL INVESTIGATION DESIGN: 
This is a prospective, single-arm, clinical investigation designed to verify performance and safety of 
Otinova® Ear Spray when used by subjects with external otitis (otitis externa, OE) symptoms in need 
of treatment. Forty (40) subjects suffering from external otitis symptoms will be recruited from 3 sites 
in Sweden and receive treatment with Otinova® Ear Spray per instruction for use (twice daily during 
the test period of 7 days). 
INCLUSION AND EXCLUSION CRITERIA: 
Inclusion Criteria 
 
The subjects must meet all of the following criteria to be eligible to participate in the clinical 
investigation: 
1. Male or female ≥ 5 years old 
2. Clinical diagnosis of otitis externa based on otoscopic exam: 
a. Defined as a clinical score of at least 1, on a scale from 0 to 2 (none, mild/moderate, 
severe), for at least one of the OE signs (swelling, erythema and otorrhea) 
3. Ability to correctly administer Otinova as spray (not requiring tamponade), as judged by the 
Investigator  
4. Subject agrees to refrain from water immersion of the ears during the investigation 
5. Subject agrees to refrain from using other ear treatment products during the investigation 
6. Provision of informed consent 
7. For pediatric patients, provision of informed consent by subject and legal representative(s) 
8. Subject, and if applicable legal representative(s), are willing to comply with the protocol and attend 
all investigation visits.  
 
Exclusion Criteria 
 
Subjects meeting any of the following criteria will not be permitted to participate in the clinical 
investigation: 
1. Duration of OE signs/symptoms longer than 6 weeks 
2. Suspected perforated eardrum or eardrum fitted with drainage tube 
3. Post-mastoid surgery 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 3 of 62 
4. Prior otologic surgery within 6 months of enrollment (must be successfully healed) 
5. Conditions which may make it difficult to evaluate the therapeutic response (e.g malignant OE, 
abscess, granulation, polyps, congenital disorders) 
6. History of malignant tumors in the external ear canal, or currently receiving chemotherapy or 
radiation therapy 
7. Known allergy or sensitivity to any component of the device 
8. Use of topical or systemic antibiotics, corticosteroids or other treatment that could affect the study 
result within 7 days prior to enrolment 
9. Pregnancy or lactation at time of enrolment 
10. Subjects with any other condition that, as judged by the investigator, may make investigation 
procedures inappropriate  
11. Participation in another clinical investigation within 30 days of screening 
 
OBJECTIVES: 
 
Primary Objective 
 
• 
To assess reduction of swelling, erythema and otorrhea by Otinova® Ear Spray when used in 
the treatment of external otitis.  
 
 
Secondary Objectives 
 
1. To assess the reduction of itching, otalgia and tenderness by Otinova® Ear Spray when 
used in the treatment of external otitis 
2. To investigate reduction of pathologic microbes (bacteria, fungi, yeast) in the ear canal by 
Otinova® Ear Spray when used in the treatment of external otitis  
3. To assess the removal of moisture in the ear canal related to external otitis  
4. To assess the volume of the ear canal 
5. To assess the user handling of Otinova® Ear Spray (ease of use of spray, facilitation of 
correct application) 
6. To assess sleep disruption 
7. To assess use of pain relief medication 
8. To assess use of antibiotics  
 
Safety Objective(s) 
 
• 
To assess the safety of Otinova® Ear Spray.  
 
 
PERFORMANCE AND SAFETY ENDPOINTS: 
 
Primary Endpoint  
 
Clinical cure – proportion of subjects who have all signs of swelling, erythema and 
otorrhea scored as 0 on a scale from 0-2 (0=none, 1=mild/moderate, 2=severe) after 7 days 
of treatment, based on otoscopic exam. 
 
 
Secondary Endpoint(s) 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 4 of 62 
1. Clinical improvement – Change in clinical symptoms itching, otalgia and tenderness, 
based on subject reported outcomes, using a score from 0 to 4, where 0 = no symptoms, 1= 
Mild, 2 = Moderate, 3= Severe and 4 = Very Severe): 
a) Change in each of the clinical symptoms itching, otalgia and tenderness from Day 1 to 
Day 7 
b) Change in clinical sum score (0-12) of clinical symptoms itching, otalgia and 
tenderness from Day 1 to Day 7.  
c) Change in each of clinical symptoms (0-4) and clinical sum score (0-12) from Day 1 to 
Day 3 and Day 5. 
2. Microbiological cure - Reduction of pathologic microbes in ear canal. Bacteria and 
fungi/yeast will be analyzed by swabbing the ear canal and analyzing the swab for microbes at 
baseline and after 7 days of treatment. Microbial cure attained if all pre-therapy pathologic 
microbes are absent after 7 days of treatment. 
3. Reduced moisture in ear canal related to otitis externa compared to baseline, based on 
otoscopic exam. Proportion of subjects who have signs of otorrhea at baseline on a scale from 
0-2 (0=none, 1=mild/moderate, 2=severe) and show an improvement of 1 or more points.  
4. Volume of ear canal compared to baseline – reduced swelling (i.e. increased volume) based 
on otoscopic exam. Proportion of subjects who have signs of swelling at baseline on a scale 
from 0-2 (0=none, 1=mild/moderate, 2=severe) and show an improvement of 1 or more 
points. 
5. User handling - Ease of use of spray and facilitation of correct application - usability 
questionnaire 
6. Sleep disruption – Proportion of subjects with less sleep disruption Day 7 compared to Day 1 
- subject diary 
7. Pain relief medication use - subject diary and medication log 
8. Antibiotic use - medication log  
 
 
Safety Endpoint(s) 
Incidence of adverse events (AE), adverse device effects (ADE), serious adverse events (SAE), 
serious adverse device effects (SADE), and device deficiencies (DD) throughout the clinical 
investigation.  
 
 
STATISTICAL METHODS: 
Performance Analysis 
Primary endpoint, clinical cure of swelling, erythema and otorrhea, will be analyzed as proportions of 
subjects cured with exact 95% confidence interval. Secondary endpoints of cure and improvement will 
be analyzed in the same way. Categorical variables will be described with numbers, percentages. 
 
 
Safety Analysis 
All safety variables will be tabulated for the Safety Population: AE, ADE, SAE, SADE and DD. 
 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 5 of 62 
SPONSOR CIP APPROVAL PAGE 
The undersigned, hereby confirms that they have read and understood the content of this Clinical 
Investigation Plan (CIP) and further approves its content. 
 
 
 
 
______________________________ 
 
______________________ 
Mattias Andrup  
 
 
Date (dd-Mmm-yyyy) 
Medical Affairs Director, Circius Pharma AB 
 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 6 of 62 
2 
TABLE OF CONTENTS 
1 
SYNOPSIS ................................................................................................................................................ 2 
SPONSOR CIP APPROVAL PAGE ............................................................................................................ 5 
2 
TABLE OF CONTENTS ...................................................................................................................... 6 
3 
ABBREVIATIONS AND ACRONYMS ............................................................................................ 9 
4 
INTRODUCTION ............................................................................................................................... 10 
4.1 
Background .......................................................................................................................... 10 
5 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL DEVICE .... 12 
5.1 
Manufacturer ...................................................................................................................... 12 
5.1 
Identification of Investigational Medical Device ................................................................. 12 
5.2 
Device Traceability .............................................................................................................. 13 
5.3 
Intended Purpose ................................................................................................................ 13 
5.4 
Indication and Population ................................................................................................... 13 
5.5 
Technical and Functional Features ...................................................................................... 13 
5.6 
Manufacturing and Materials .............................................................................................. 13 
5.7 
Training and Experience ...................................................................................................... 13 
5.8 
Installation and Use ............................................................................................................. 14 
6 
JUSTIFICATION OF CLINICAL INVESTIGATION DESIGN ............................................. 15 
7 
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE, CLINICAL 
PROCEDURE, AND CLINICAL INVESTIGATION ......................................................................... 16 
7.1 
Anticipated Clinical Benefits ................................................................................................ 16 
7.2 
Residual Risks and Anticipated Adverse Device Effects ....................................................... 16 
7.3 
Risks Associated with Participating in the Clinical Investigation ......................................... 17 
7.4 
Possible interactions with concomitant medical treatments .............................................. 17 
7.5 
Risk Control ......................................................................................................................... 17 
7.6 
Benefit-to-Risk Rationale ..................................................................................................... 17 
8 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION ................. 19 
8.1 
Primary Objective ................................................................................................................ 19 
8.2 
Secondary Objectives .......................................................................................................... 19 
8.3 
Hypothesis ........................................................................................................................... 19 
8.4 
Claims and Intended Performance of the Investigational Device ....................................... 19 
8.5 
Risks and Anticipated Adverse Device Effects ..................................................................... 20 
9 
DESIGN OF THE CLINICAL INVESTIGATION ..................................................................... 21 
9.1 
General ................................................................................................................................ 21 
9.1.1 
Primary performance endpoint ....................................................................................... 21 
9.1.2 
Secondary performance endpoints ................................................................................. 21 
9.1.3 
Secondary safety endpoints ............................................................................................ 22 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 7 of 62 
9.2 
Investigational Device(s) and Comparator(s) ...................................................................... 22 
9.3 
Subjects ............................................................................................................................... 22 
9.3.1 
Inclusion Criteria ............................................................................................................. 22 
9.3.2 
Exclusion Criteria ............................................................................................................. 23 
9.3.3 
Relationship of Investigation Population to Target Population ...................................... 23 
9.3.4 
Number of Subjects ......................................................................................................... 24 
9.3.5 
Methods of Assigning Subjects to Different Treatment Arms ........................................ 24 
9.3.6 
Subject Withdrawal, Discontinuation, or Lost to Follow-up ........................................... 24 
9.3.7 
Subject Follow-up and Care ............................................................................................ 25 
9.4 
Clinical Investigation Duration ............................................................................................. 25 
9.5 
Clinical Investigation Procedures ......................................................................................... 26 
9.5.1 
Schedule of Clinical Investigation Procedures /Assessments .......................................... 26 
9.5.2 
Recruitment of subjects .................................................................................................. 26 
9.5.3 
Visit 1 (Day 1) Screening / Baseline Visit ......................................................................... 26 
9.5.4 
Visit 2 (Day 8 +2 days) – Clinic visit ................................................................................. 27 
9.5.5 
Visit 3 (Day 14 +/- 1 day) – Telephone visit ..................................................................... 27 
9.5.6 
Unscheduled visits /contacts .......................................................................................... 28 
9.5.7 
Screening/Baseline Measurements ................................................................................ 28 
9.5.8 
Performance Variables and Measurements .................................................................... 29 
9.5.9 
Safety Variables and Measurements .............................................................................. 31 
9.5.10 
Activities Performed by Sponsor ................................................................................ 31 
9.5.11 
Potential Confounding Factors ................................................................................... 31 
9.5.12 
Samples obtained from subject .................................................................................. 31 
10 
MONITORING PLAN ........................................................................................................................ 32 
10.1 
Subject Records and Source Data ........................................................................................ 32 
10.2 
Access to Source Data and Documentation ........................................................................ 32 
11 
STATISTICAL CONSIDERATIONS .............................................................................................. 33 
11.1 
Statistical Design, Method and Analytical Procedures ........................................................ 33 
11.2 
Sample size .......................................................................................................................... 33 
11.3 
Drop-out Rates .................................................................................................................... 33 
11.4 
Level of Significance and Power .......................................................................................... 33 
11.5 
Pass / Fail Criteria ................................................................................................................ 33 
11.6 
Interim Analysis ................................................................................................................... 33 
11.7 
Reporting of Deviations from the Original Statistical Analysis Plan (SAP) ........................... 34 
11.8 
Subgroups for Analysis ........................................................................................................ 34 
11.9 
Procedures that Take into Account all the Data .................................................................. 34 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 8 of 62 
11.10 
Missing, Unused or Spurious Data .................................................................................. 34 
11.11 
Exclusion of Particular Information from the Testing of the Hypothesis ........................ 34 
12 
DATA MANAGEMENT ..................................................................................................................... 35 
12.1 
Data Retention .................................................................................................................... 35 
12.2 
Monitoring, Audits and Inspections .................................................................................... 36 
13 
AMENDMENTS TO THE CIP ........................................................................................................ 37 
14 
DEVIATIONS FROM THE CIP ...................................................................................................... 38 
15 
DEVICE ACCOUNTABILITY ......................................................................................................... 39 
16 
STATEMENTS OF COMPLIANCE ............................................................................................... 40 
16.1 
Institutional Ethics Review .................................................................................................. 40 
16.2 
Insurance ............................................................................................................................. 40 
17 
INFORMED CONSENT PROCESS ............................................................................................... 41 
18 
ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE DEFICIENCIES . 42 
18.1 
Definitions ........................................................................................................................... 42 
18.2 
Non-reportable adverse events ........................................................................................... 43 
18.3 
Methods for discovering and documenting AE/ADE ........................................................... 43 
18.3.1 
Severity ....................................................................................................................... 44 
18.3.2 
Causality ...................................................................................................................... 44 
18.4 
Methods for Discovering and Documenting Device Deficiencies ........................................ 46 
18.5 
Reporting of SAE/SADE and Device Deficiencies with SADE potential ................................ 46 
18.6 
Foreseeable adverse events and anticipated adverse device effects ................................. 48 
18.7 
Data Monitoring Committee ............................................................................................... 48 
19 
VULNERABLE POPULATION ....................................................................................................... 49 
20 
SUSPENSION OR EARLY TERMINATION OF CLINICAL INVESTIGATION ...... 49 
20.1 
Subject Follow-up ................................................................................................................ 49 
21 
PUBLICATION POLICY ................................................................................................................... 50 
22 
REFERENCES ................................................................................................................................ 51 
23 
APPENDICES .................................................................................................................................. 52 
23.1 
Appendix A – Clinical Investigation Plan Agreement Form ................................................. 52 
23.2 
Appendix B – Clinical Investigation Contact List .................................................................. 55 
23.3 
Appendix C – Declaration of Helsinki .................................................................................. 57 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 9 of 62 
3 
ABBREVIATIONS AND ACRONYMS 
 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ASADE 
Anticipated Serious Adverse Device Effect 
CIP 
Clinical Investigation Plan 
CIR 
Clinical Investigation Report 
CRF 
Case Report Form 
CRO 
DD 
Contract Research Organization 
Device Deficiency 
DMC 
Data Monitoring Committee 
DMP 
Data Management Plan 
DMR 
Data Management Report 
DVP 
Data Validation Plan 
EEA 
European Economic Area 
EU 
European Union 
FDA 
Food and Drug Administration 
FIM 
First in Man 
GDPR 
General Data Protection Regulation 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
ISF 
Investigator Site File 
ISO 
International Organization for Standardization 
MDD 
Medical Device Directive – Council Directive 93/42/EEC 
MDR 
OE 
Medical Device Regulation – Regulation (EU) 2017/745 
Otitis Externa (external otitis) 
PI 
PMCF 
Principal Investigator 
Post-Market Clinical Follow-up 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SMF 
Study Master File 
SOP 
Standard Operating Procedure 
USADE 
Unanticipated Serious Adverse Device Effect 
WMA 
World Medical Association 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 10 of 62 
4 
INTRODUCTION 
4.1 Background 
Otitis externa (OE), also known as external otitis, is an inflammation/eczema of the ear canal1, 
2. Many cases of OE involve infection, with Staphylococcus aureus and Pseudomonas aeruginosa most 
commonly detected1, 3, 4, however a large variety of bacteria, fungi and yeast have been 
identified4.  
OE is also commonly known as ‘Swimmer’s ear’, since one of the most common causes of 
OE is the prolonged moisture or humidity in the ear canal, typically associated with swimming 
or humid climates2. Other risk factors include trauma to the ear canal, dermatological 
conditions such as eczema or psoriasis, hearing aid users2, 5, people with narrow ear canals1, 2, 5 
and under or over production of ear wax1. In cases of OE with infection that are not 
adequately managed, the infection can spread to other parts of the ear causing further 
complications4, 6. 
Diagnosis is a combination of both signs of ear canal inflammation including swelling, 
erythema and otorrhea and symptoms including itching, otalgia and tenderness1, 3, 4.  
It is estimated that approximately 10% of the population will be affected at some stage of their 
lives, including both adults and children2, 4.  
Treatment alternatives for OE includes ear cleaning, earwicks, topical antibiotics, topical 
steroids and antiseptics (e.g. Burow's solution)1.  
Otinova® Ear Spray is a solution consisting of Aluminium Acetate, Aluminium acetotartrate, 
Acetic acid and water, with a pH of 3-4, also called Burow's solution. Otinova® Ear Spray is 
prepared according to the monograph for Burow's solution in the British Pharmacopoeia7. 
Burow's solution is an established treatment for OE8. 
Aluminium Acetate is a combined antiseptic-astringent that has been shown in studies to be 
as effective as topical antibacterial-corticosteroids at improving cure rates in OE1, 2. In in vitro 
studies a 100 % elimination of the bacteria was achieved after up to 40 minutes exposure9, 10. 
When evaluating the effect of Aluminium Acetate on patients suffering from ear infections, it 
was concluded that Aluminium Acetate is an effective bactericide and high cure rates were 
reported10. In a comparative setting, Aluminium Acetate showed similar cure rates as 
antibiotics, with low numbers of adverse events reported11, 12. Children from 5 years of age 
who were diagnosed with OE11 or otitis media13 were successfully and safely treated with 
Aluminium Acetate ear drops.  
The commercially available Otinova® Ear Spray, containing Burow's solution14 will be used 
in this clinical investigation. Burow's solution (including Aluminium Acetate) has been in 
continuous use since the late 19:th century for treating OE9. With the introduction of 
antibiotics there was a marked decline in its use, but with the emergence of an increasing 
number of bacteria resistant to first line antibiotics, Burow’s solution has got new attention to 
treat OE12.  
The Clinical Evaluation Report (CER) covering the Otinova® Ear Spray, including data from 
published clinical investigations using Burow's solution/ Aluminium Acetate, concludes that 
this device is safe and performs well when used in accordance with its intended use. 
The aim of this post-market clinical investigation is to verify performance and safety of 
Otinova® Ear Spray when used according to its intended use. The target population for this 
clinical investigation is individuals suffering from external otitis symptoms. 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 11 of 62 
The clinical investigation will be conducted in compliance with the Declaration of Helsinki, 
ISO 14155:2020, MDR and all approvals (i.e., Independent Ethical Committee (IEC) and if 
applicable biobank approval) will be retrieved before investigation initiation. The clinical data 
retrieved from this clinical investigation will be evaluated and incorporated into the products 
CER. 
 
The costs associated with the investigation are financed by the Sponsor on a per subject 
basis, as described in the clinical investigation agreement between Sponsor and the 
investigation site. 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 12 of 62 
5 
IDENTIFICATION AND DESCRIPTION OF THE INVESTIGATIONAL 
DEVICE 
Otinova® Ear Spray is a spray used to treat ear canal inflammation/eczema, also known as 
Swimmer's Ear (external otitis). Otinova® Ear Spray acts locally, as an astringent, relieves itching 
and has an antibacterial and anti-fungal effect. The device is CE-marked and classified as Class I 
according to MDD Classification rule 515 and has been on the market since 2011.   
 
5.1 Manufacturer 
The legal manufacturer for the investigational medical device is: 
 
Circius Pharma AB 
Södra långebergsgatan 34-36 
436 32 Askim, Sweden 
5.1 Identification of Investigational Medical Device 
Otinova® Ear Spray is a spray solution enclosed in a plastic bottle with an attached spray nozzle. 
The spray nozzle comes with a protective cap. Otinova® Ear Spray contains aluminium acetate 
and aluminium acetotartrate (1.8% aluminium), acetic acid, water, pH 3-4 (Burow’s solution, 
British Pharmacopoeia) 7. Each bottle of Otinova® Ear Spray contains 15 mL of solution (150 
doses)8.  
 
Otinova® Ear Spray is produced in accordance with the British Pharmacopeia. Volume III, 2015, 
(Burow’s solution)7, 16. The total concentration of aluminium is 1.8%. Otinova® Ear Spray 
contains16: 
- 
Aluminium acetate  
- 
Aluminium acetotartrate  
- 
Acetic acid  
- 
Water  
 
Otinova® Ear Spray  fulfils the acceptance criteria for Aluminium Acetate ear drops as described 
in the British Pharmacopoeia7, 14. 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 13 of 62 
5.2 Device Traceability 
The Sponsor and the Principal Investigator (PI) will keep records documenting the location of all 
investigational devices from shipment to the investigation site until the end of the clinical 
investigation. This will be documented in a shipment log stored by the Sponsor and in a device 
accountability log at the investigation site. The device accountability log at site will include 
information on: 
• 
date, lot number and expiry date for each delivered device, 
• 
date and subject identification for each dispensed device, 
• 
date for each device returned to Sponsor from site (if applicable) 
 
The investigational devices will be handled and stored safely, properly and in agreement with the 
provided storage conditions in the Instructions for Use (IFU)8.  
 
The monitor will verify the accountability process at site and document this in the site monitoring 
visit report. 
5.3 Intended Purpose 
Otinova® Ear Spray is intended be used to treat external otitis, e.g. in connection with periods of 
frequent contact with water and/or damp environments, such as swimming/aquatic sports 
holidays. 
 
5.4 Indication and Population 
Otinova® Ear Spray is intended to be used by individuals to treat ear canal 
inflammation/eczema, also known as Swimmer's Ear (external otitis). Otinova® Ear Spray is 
intended to be used in adults and in children over 5 years.  
5.5 Technical and Functional Features 
Otinova® Ear Spray is filled in a transparent, 20 mL, PE, sterilized bottle. The bottles are closed 
with Spray cord and fitted with a 3K pump which functions both as a microbiological safeguard 
and as a dosing system. A transparent cover is placed over the spray cork. A label is placed onto 
the bottle. Each bottle is placed in a labelled carton with one IFU.  
5.6 Manufacturing and Materials 
Manufacturing and packaging of the Otinova® Ear Spray are conducted according to Good 
Manufacturing Practice (GMP) and ISO 13485. 
 
No medicinal substances, human or animal tissues or derivates thereof, or their biological active 
substances, are incorporated in Otinova® Ear Spray. Consequently, no such materials will be in 
contact with any tissues or body fluids.  
5.7 Training and Experience 
Investigator and site personnel training will be conducted by sponsor and Contract Research 
Organization (CRO) representatives prior to subject enrollment to ensure that the Otinova® Ear 
Spray device is used in accordance with the IFU, that complete, accurate and timely data are 
submitted, that protocol requirements are followed, and that complications, adverse events (AEs) 
and adverse device effects (ADEs) are correctly reported and investigated, as appropriate. The 
investigator will ensure that appropriate training relevant to the clinical investigation is given to any 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 14 of 62 
other site personnel involved in the investigation and that new information of relevance to the 
performance of the investigation is forwarded to all personnel involved.  
It is the responsibility of the sponsor to ensure that involved personnel is appropriately trained on 
the Otinova® Ear Spray device. Since the subjects will treat themselves with the Otinova® Ear 
Spray device following the IFU, it is the responsibility of the site personnel to provide guidance as 
required.  
 
5.8 Installation and Use 
The device should be used according to the IFU, as shown below: 
 
• To use Otinova® Ear Spray, hold the bottle upright.  
• Before the spray is used for the first time, pump a few times until an even spray is obtained.  
• Hold the tip of the nozzle against the outer ear canal. 
• Spray 1–2 times in the ear canal, morning and evening.  
• Tilt the head after spraying so that the fluid runs as far as possible down into the ear canal.  
• Wipe away any excess fluid. 
• Otinova® Ear Spray should be used two times per day (morning and evening) for up to 7 
days. 
 
Warnings and precautions 
• Otinova® Ear Spray can cause temporary mild irritation/stinging sensation in the 
ear canal. If the irritation/stinging persists or becomes worse, contact a doctor. 
• Avoid contact with water and do not poke inside the ear.  
• Otinova® Ear Spray should not be used by children younger than 5 years of age, 
unless recommended by a doctor (control of the eardrum). 
• Salt precipitation in, and severe hydration of, the ear canal may occur with 
overdosing and/or long-term use. Do not use Otinova® Ear Spray for a continuous 
period of more than 7 days. 
• 
Otinova® Ear Spray should not be used if the eardrum has been fitted with a 
drainage tube or if the eardrum is suspected to be perforated.   
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 15 of 62 
6 
JUSTIFICATION OF CLINICAL INVESTIGATION DESIGN 
 
As per MEDDEV 2.12/2 rev.2 the decision to conduct a Post-Market Clinical Follow-up (PMCF) 
investigation has been based on the identification of possible residual risks and/or unclarity on 
long term clinical performance that may impact the benefit/risk ratio. The rationale behind the 
PMCF investigation is that the initial CE-marking of the Otinova® Ear Spray was based on 
equivalence, (which is highlighted as one of the circumstances that may justify a PMCF clinical 
investigation in the MEDDEV document) and the increased demand for clinical data under 
Regulation (EU) 2017/745 (MDR). Thus, the PMCF investigation is aiming at confirming the 
clinical performance and safety of the Otinova® Ear Spray, when used according to its approved 
labelling, to create further support for the current claims and intended use. 
 
The PMCF investigation including the Otinova® Ear Spray is planned to start during 2022 at three 
sites in Sweden. In total 40 subjects will be included. The PMCF investigation is planned to confirm 
that the Otinova® Ear Spray continues to demonstrate safety and performance in a population 
with external otitis symptoms when Otinova® Ear Spray is used as intended.  
 
This PMCF investigation is designed as a prospective, multi-center, single-arm, clinical 
investigation to verify clinical performance and safety of the Otinova® Ear Spray as a treatment 
for external otitis symptoms. The objectives of the investigation are to confirm treatment of 
symptoms by Otinova® Ear Spray when used by subjects with external otitis symptoms when 
used as intended.  
 
The follow-up period during the clinical investigation is deemed sufficiently to represent a realistic 
test of the performance of the investigational device and allows any risks associated with adverse 
device effects over that period to be identified and assessed. 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 16 of 62 
7 
BENEFITS AND RISKS OF THE INVESTIGATIONAL DEVICE, CLINICAL 
PROCEDURE, AND CLINICAL INVESTIGATION 
 
When discussing risks and benefits of a medical device, there are different aspects that have to be 
considered, including the potential risks and benefits for the subjects participating in the clinical 
investigation and for future patients with clinical use of the device. 
 
Risk management, including risk analysis, risk evaluation and risk control, related to the devices 
has been conducted in accordance with ISO 14971 and the manufacturer’s risk management 
procedure17. 
7.1 Anticipated Clinical Benefits 
The anticipated clinical benefit of Otinova® Ear Spray includes the treatment of ear canal 
inflammation/eczema. Otinova® Ear Spray acts locally as an astringent and relieves itching. 
Otinova® Ear Spray has an antibacterial and anti-fungal effect and when used as a first line 
treatment and an effective outcome is achieved, Otinova® Ear Spray may reduce the need for 
antibiotics. 
7.2 Residual Risks and Anticipated Adverse Device Effects 
Residual risks are described in alignment with the approved versions of the products’ risk 
management report. 
 
After risk assessment, including implementation and verification of risk control measures, two 
residual risks for the end user (the subject/patient) remained for Otinova18: 
 
The residual risks are described as follows: 
1. Children get access to product and small parts are swallowed causing suffocation 
2. More solution than recommended is administered, causing salt precipitation in outer 
ear canal and in worst case ear drum perforation. 
The first risk was accepted on the basis of the following information provided in the IFU:  
• Store out of the reach of children.  
• Otinova® Ear Spray should not be used by children younger than 5 years of age, unless 
recommended by a doctor (control of the eardrum). 
The second risk was accepted on the basis of the following information provided in the IFU:  
• Spray once or twice into the ear canal, morning and evening. Tilt the head after 
spraying so that the fluid runs as far as possible down into the ear canal. Wipe away 
excess fluid. 
• Salt precipitation in, and severe hydration of, the ear canal may occur with overdosing 
and/or long-term use. Do not use Otinova® Ear Spray for a continuous period of 
more than 7 days. 
• Individual cases of perforated ear drum have occurred in association with extreme salt 
precipitation at high doses for continuous periods of more than 20 days. 
• Otinova® Ear Spray should not be used if the eardrum has been fitted with a drainage 
tube or if the eardrum is suspected to be perforated. 
 
In conclusion, all residual risks for the product are considered acceptable and outweighed by the 
benefits to the patients associated with use of the product. 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 17 of 62 
  
There are no anticipated Adverse Device Effects for the investigational device. 
 
7.3 Risks Associated with Participating in the Clinical Investigation 
Investigation participation is not considered to expose subjects to new device-related risks. The 
clinical investigation procedures follow routine clinical practice except for the microbial swab 
sampling from the ear canal, diary and questionnaires. There may potentially be minor additional 
discomfort for participants as a result of the swab sampling. There may also potentially be minor 
inconvenience for the subjects in the additional assessment time or clinical visits. This is to ensure 
data collection of all variables including those reported by the subject.  
 
7.4 Possible interactions with concomitant medical treatments 
There are no known interactions with concomitant medical teratments. 
 
7.5 Risk Control 
The investigational device shall be used in accordance with the intended use and IFU. The 
investigation team will receive training on the CIP prior to the first subject’s first visit.  
 
Risks related to the processing of subjects’ personal data, and in particular data concerning health, 
will be mitigated by use of pseudonymization, whereby the personal data will no longer be 
attributable to a specific subject without the use of a key which will be kept separately and securely 
by the PI.  
 
Risk management for the investigational device has been conducted by first identifying the possible 
hazards, foreseeable sequences of events and possible harms, and then evaluating and mitigating 
the risks. The following risk control measures have been used in the priority order listed: 
 
1. Eliminate or reduce risks as far as possible (inherent safety by design). 
2. Protective measures in the medical device itself or in the manufacturing process. 
3. Information to the user of the residual risk due to any shortcomings of the protection 
measures adopted. 
 
All risks have been reduced as far as possible, meaning that all safety principles have been applied 
where possible and where safety could be improved. 
 
7.6 Benefit-to-Risk Rationale 
Risk management for the investigational device concluded that the clinical benefit of using the 
device outweigh the residual risks. The investigational devices have been on the market for many 
years and shown to be a low-risk device. 
 
It is not anticipated that the investigational procedures not part of routine clinical practice, e.g., ear 
swab sampling, questionnaires and diary will expose the subjects to additional risks, except for a 
low possibility of discomfort during the swab sampling.  
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 18 of 62 
Risks related to the processing of subjects’ personal data will be mitigated by use of 
pseudonymization.  
 
The additional time for assessment is considered as limited and thus acceptable.  
 
The potential benefits identified for participants of the investigation are more control measures 
than in normal clinical practice to ensure compliance to standard of care. Due to this, there is a 
chance of obtaining better treatment outcomes. Second, there is dedicated time at the clinic to 
ensure realization of this investigation and collection of all included outcome assessments. This 
may result in more time with clinical experts for the participating subjects than in normal clinical 
care and that follow-up and care is less subjected to time restrictions and resources limitations.  
 
This clinical investigation will be conducted in line with applicable regulations and ethical principles 
designed to safeguard investigation subjects. The PI will ensure that appropriate training relevant 
to the investigation is provided to the staff involved. The reporting of adverse events and 
monitoring described in Section 18 and 10 respectively, will assure early detection of any increased 
risk or unanticipated subject safety concerns. 
 
Taken together, the possible benefits for a subject in participating in this clinical investigation are 
considered to outweigh the possible risks. 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 19 of 62 
8 
OBJECTIVES AND HYPOTHESES OF THE CLINICAL INVESTIGATION 
8.1 Primary Objective 
 
The primary objective is: 
 
• To assess reduction of swelling, erythema and otorrhea by Otinova® Ear Spray 
when used in the treatment of external otitis.  
 
 
8.2 Secondary Objectives 
 
The secondary objectives are: 
 
1. To assess the reduction of itching, otalgia and tenderness by Otinova® Ear Spray 
when used in the treatment of external otitis 
2. To investigate reduction of pathologic microbes (bacteria, fungi, yeast) in the ear 
canal by Otinova® Ear Spray when used in the treatment of external otitis  
3. To assess the removal of moisture in the ear canal related to external otitis  
4. To assess the volume of the ear canal 
5. To assess the user handling of Otinova® Ear Spray (ease of use of spray, facilitation 
of correct application) 
6. To assess sleep disruption 
7. To assess use of painrelief medication 
8. To assess use of antibiotics 
 
8.3 Hypothesis 
The null hypothesis (H0) is that less than 50% of the subjects will be cured regarding swelling, 
erythema and otorrhea. 
 
The H1 is that more than 50% of the subjects will be cured regarding swelling, erythema and 
otorrhea.   
 
8.4 Claims and Intended Performance of the Investigational Device  
The claims to be verified in this investigation are:  
 
1. Due to the low pH, Otinova® Ear Spray may help the removal of moisture in the ear 
canal related to external otitis or inflammation of the ear canal. 
2. Due to the astringent effects of aluminium acetate, Otinova® Ear Spray has an astringent 
effect on inflamed tissue on the ear canal, thereby increasing the volume of the ear canal. 
3. Due to the composition, Otinova® Ear Spray may provide a soothing effect on itch 
within the ear canal associated with inflammation/external otitis. 
4. Otinova® Ear Spray is designed to be administered in the form of spray, helping to make 
it easy to use. 
5. Otinova® Ear Spray has an anatomically designed nozzle to help facilitate correct 
application. 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 20 of 62 
6. Otinova® Ear Spray has a bactericidal and fungicidal effect in the ear canal. 
7. Otinova® Ear Spray can be used in children over the age of 5 years. 
8. Where used as first line treatment and an effective outcome is achieved, Otinova® Ear 
Spray may reduce the need for antibiotics. 
 
 
8.5 Risks and Anticipated Adverse Device Effects 
There are no anticipated Adverse Device Effects for the investigational devices and no 
unacceptable risks connected to participating in the investigation. 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 21 of 62 
9 
DESIGN OF THE CLINICAL INVESTIGATION 
9.1 General 
This is a prospective, open, multi-centre, single-arm clinical investigation designed to verify 
performance and safety of Otinova® Ear Spray when used by subjects with external otitis 
symptoms in need of treatment. The outcome will be evaluated and incorporated in the product 
specific CER and serve as a base for continuous investigations. 
 
Following EC approval, 40 subjects suffering from external otitis symptoms will be recruited from 
three sites in Sweden and receive treatment with Otinova® Ear Spray per instruction for use (twice 
daily during the test period, for 7 days). Three visits are planned for each subject, including a 
screening/baseline visit at the clinic, a follow-up visit at the clinic and a follow-up telephone visit 
to assess any safety issue. If considered necessary by the investigator, study nurse or subject, 
additional contacts (e.g., visits/phone calls/video calls) can be arranged. 
 
The overall duration of the investigation is estimated to five months, including a four-month 
recruitment period. Expected duration of each subject’s participation is 14 days. The investigation 
will be considered complete when the last subject has completed the last visit. 
 
9.1.1 Primary performance endpoint 
 
• Clinical cure – proportion of subjects who have all signs of swelling, erythema and 
otorrhea scored as 0 on a scale from 0-2 (0=none, 1=mild/moderate, 2=severe) after 7 
days of treatment, based on otoscopic exam. 
9.1.2 Secondary performance endpoints 
 
1. Clinical improvement – Change in clinical symptoms itching, otalgia and tenderness, 
based on subject reported outcomes, using a score from 0 to 4, where 0 = no symptoms, 
1= Mild, 2 = Moderate, 3= Severe and 4 = Very Severe): 
a. Change in each of the clinical symptoms itching, otalgia and tenderness from Day 
1 to Day 7 
b. Change in clinical sum score (0-12) of clinical symptoms itching, otalgia and 
tenderness from Day 1 to Day 7.  
c. Change in each of clinical symptoms (0-4) and clinical sum score (0-12) from Day 
1 to Day 3 and Day 5. 
 
2. Microbiological cure - Reduction of pathologic microbes in ear canal. Bacteria and 
fungi/yeast will be analyzed by swabbing the ear canal and analyzing the swab for 
microbes at baseline and after 7 days of treatment. Microbial cure attained if all pre-
therapy pathologic microbes are absent after 7 days of treatment. 
 
3. Reduced moisture in ear canal related to otitis externa compared to baseline, based on 
otoscopic exam. Proportion of subjects who have signs of otorrhea at baseline on a scale 
from 0-2 (0=none, 1=mild/moderate, 2=severe) and show an improvement of 1 or more 
points.  
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 22 of 62 
4. Volume of ear canal compared to baseline – reduced swelling (i.e. increased volume) 
based on otoscopic exam. Proportion of subjects who have signs of swelling at baseline 
on a scale from 0-2 (0=none, 1=mild/moderate, 2=severe) and show an improvement of 
1 or more points. 
 
5. User handling - Ease of use of spray and facilitation of correct application – usability 
questionnaire 
 
6. Sleep disruption - Proportion of subjects (and parents) with less sleep disruption Day 7 
compared to Day 1, reported in subject diary. 
 
7. Painrelief medication use - subject diary and medication log 
 
8. Antibiotic use - medication log  
 
9.1.3 Secondary safety endpoints  
 
Incidence of adverse events (AE), adverse device effects (ADE), serious adverse events (SAE), and 
serious adverse device effects (SADE), and device deficiencies (DD) throughout the clinical 
investigation. 
 
9.2 Investigational Device(s) and Comparator(s) 
This PMCF will not use a comparator as baseline values are used as controls.   
 
Subjects will use the investigational devices for a total of 7 days, where the investigational device 
Otinova® Ear Spray, is used twice daily during the complete test period. At baseline visit, Visit 1, 
the subjects will receive one bottle of Otinova® Ear Spray which is sufficient for treatment during 
the entire investigational period.  
 
9.3 Subjects 
9.3.1  Inclusion Criteria 
The subjects must meet all of the following criteria to be eligible to participate in the clinical 
investigation: 
 
1. Male or female ≥ 5 years old 
2. Clinical diagnosis of otitis externa based on otoscopic exam: 
a. Defined as a clinical score of at least 1, on a scale from 0 to 2 (none, 
mild/moderate, severe), for at least one of the OE signs (swelling, erythema 
and otorrhea) 
3. Ability to correctly administer Otinova as spray (not requiring tamponade), as judged 
by the Investigator  
4. Subject agrees to refrain from water immersion of the ears during the investigation 
5. Subject agrees to refrain from using other ear treatment products during the 
investigation 
6. Provision of informed consent 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 23 of 62 
7. For pediatric patients, provision of informed consent by subject and legal 
representative(s) 
8. Subject, and if applicable legal representative(s), are willing to comply with the 
protocol and attend all investigation visits. 
 
9.3.2  Exclusion Criteria 
Subjects meeting any of the following criteria will not be permitted to participate in the clinical 
investigation: 
 
1. Duration of OE signs/symptoms longer than 6 weeks 
2. Suspected perforated eardrum or eardrum fitted with drainage tube 
3. Post-mastoid surgery 
4. Prior otologic surgery within 6 months of enrollment (must be successfully healed) 
5. Conditions which may make it difficult to evaluate the therapeutic response (e.g 
malignant OE, abscess, granulation, polyps, congenital disorders) 
6. History of malignant tumors in the external ear canal, or currently receiving 
chemotherapy or radiation therapy 
7. Known allergy or sensitivity to any component of the device 
8. Use of topical or systemic antibiotics, corticosteroids or other treatment that could 
affect the study result within 7 days prior to enrolment 
9. Pregnancy or lactation at time of enrolment 
10. Subjects with any other condition that, as judged by the investigator, may make 
investigation procedures inappropriate  
11. Participation in another clinical investigation within 30 days of screening 
 
During the investigation, subjects are asked to avoid water inside the ears, by using earplugs or 
cottonswabs during shower and bath. Additionally, subjects are asked to refrain from 
swimmingpools and swimming outdoors. The use of in-ear headphones or removable hearing 
aids should if possible be avoided during treatment. Subjects are also asked to avoid poking 
inside the affected ear. 
 
9.3.3 Relationship of Investigation Population to Target Population 
 
The investigational product, Otinova® Ear Spray, aims to be used by children and adults in a home 
environment. Otinova® Ear Spray can be used by healthcare professionals. No training before use 
is required. In this clinical investigation Otinova® Ear Spray can be used in all subjects with the 
following exceptions, as stated in the IFU: 
 
o Otinova® Ear Spray should not be used by children younger than 5 years of age 
o Otinova® Ear Spray should not be used if the eardrum has been fitted with a 
drainage tube or if the eardrum is suspected to be perforated. 
 
The investigation population, characterized by children from 5 years of age (see Section 19, 
Vulnerable population) and adults suffering from extern otitis symptoms, represents the target 
population.  
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 24 of 62 
9.3.4  Number of Subjects 
 
A total of 40 subjects will be included in the clinical investigation, who are fulfilling all the 
inclusion criteria and none of the exclusion criteria for the clinical investigation. For details linked 
to sample size calculations, see section 11.2.  
9.3.5  Methods of Assigning Subjects to Different Treatment Arms 
 
Not applicable, all subjects will receive the same treatment. 
 
9.3.6  Subject Withdrawal, Discontinuation, or Lost to Follow-up 
 
Subjects are free to discontinue participation in the clinical investigation at any time and are not 
required to give a reason for their decision. However, subjects who discontinue the investigation 
should always be asked about the reason(s) for their discontinuation and about the presence of 
any adverse event (AE) /adverse device effect (ADE) and, if possible, be assessed by an 
investigator. Discontinuation from the clinical investigation will not affect the future treatment 
/care of the subject. 
 
If the subject want to withdraw his / her consent no further data will thereafter be recorded. 
Data collected up to the date of withdraw of informed consent will be used in the data analysis 
and for the Clinical investigation Report (CIR).  
 
Subjects may be withdrawn from the clinical investigation and assessments at any time, if deemed 
necessary by the PI. 
 
Specific reasons for withdrawal of subjects from this clinical investigation are:  
• The decision of a subject to withdraw from the investigation (including if the subject 
withdraws informed consent) 
• The PI deems the subject unfit for the investigation or suspects poor CIP 
compliance; 
• It becomes apparent that the subject no longer meets the eligibility criteria 
• The PI decides to end the treatment with Otinova® Ear Spray (for details see section 
9.3.7) 
• Subject lost to follow-up. 
 
In case of withdrawal, all AEs/ADEs should be followed up. Questionnaires and diaries should 
be collected, if possible. 
 
Incorrectly enrolled subjects will be withdrawn from further investigation and assessments.  
 
To meet the target of 40 subjects completing the investigation, subjects may be replaced if they 
no longer meet the eligibility criteria whilst participating in the investigation and the recruitment 
is still ongoing. In order to ensure inclusion of at least 7 children, the inclusion of subjects 18 
years and older will pause when reaching 33 included adult subjects (see sample size calculations, 
section 11.2). In case of prolonged enrolment period due to possible slow inclusion of children, 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 25 of 62 
the Sponsor has the right to decide whether to instead continue inclusion of adults to reach a 
total of 40 subjects. 
 
9.3.7 Subject Follow-up and Care 
 
Each subject will be treated with Otinova® Ear Spray for 7 days. There will be one follow-up visit 
after 7 days of treatment and an additional follow-up, 14 days after the start of treatment to assess 
any safety issues.  
 
If symptoms increase or new symptoms occur (e.g. increased redness, oedema and/or fever), the 
PI should be contacted immediately by phone. The PI decides how to proceed with further 
treatment and an additional visit (recorded as “unscheduled visit”) at the clinic is scheduled.  
If symptoms are unchanged after 3 days, the subject should contact the PI by phone. The PI 
decides how to proceed with treatment (continuation of use of Otinova® Ear Spray or 
alternative treatment). An additional visit at the clinic (recorded as “unscheduled visit”) can be 
made if deemed necessary by the PI. 
Any additional treatment shall be recorded in the subject’s medical record and in the Medication 
log. Increased or new symptoms shall be recorded as Adverse Events (see section 18.3). 
If the PI decides to end the treatment with Otinova® Ear Spray, the subject will be withdrawn 
from the investigation.  
Please see Section 9.3.6 for procedures that will be taken for subjects that withdraw, discontinue, 
or are lost to follow-up. 
At Visit 2, remaining devices will be collected, and subjects will not be allowed to retain 
remaining devices. The same applies should the investigation be temporarily halted, or early 
terminated. After exit, no additional medical care is needed or required, and no additional follow-
up is needed. It is the responsibility of the PI to follow-up AE:s still ongoing at the end of the 
investigation. 
 
 
9.4  Clinical Investigation Duration 
 
Point of enrolment: 
May 2022 
Enrolment period: 
May 2022-August 2023 
Expected duration of 
each subject’s 
participation: 
14 days 
Total expected duration 
of the clinical 
investigation: 
5 months 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 26 of 62 
9.5  Clinical Investigation Procedures 
The assessments and procedures that will be performed during the clinical investigation are 
shown in the table “Schedule of Clinical Investigation Procedures/ Assessments”. 
 
9.5.1  Schedule of Clinical Investigation Procedures /Assessments 
 
 
Assessment 
Visit 1 
Screening/ 
Baseline 
Visit 2 
Follow-up 
Visit 3 
Follow-up 
 
Day 1 
Day 8  
(+2 days) 
Day 14 
(+/- 1 day) 
Subject information sheet and informed 
consent 
X 
 
 
Subject demographics1 
X 
 
 
Inclusion/Exclusion criteria 
X 
 
 
Relevant medical and surgical history 
X 
 
 
History of OE2 
X 
 
 
Pregnancy test (fertile women) 
X 
 
 
Otoscopic exam incl. score  
X 
X 
 
Microbial swab testing 
X 
X 
 
Concomitant medication 
X 
X 
X 
Adverse event questions 
X 
X 
X 
Device instructions, start of treatment 
X 
 
 
Diary3 instructions 
X 
 
 
Diary review and collection  
 
X 
 
Device collection 
 
X 
 
Usability questionnaire4 
 
X 
 
End of investigation 
 
 
X 
Notes:  
1 Age, gender, height, weight, BMI  
2 Including previous episodes of OE, duration of diagnosis/age of onset, hearing impairment 
3 Diary for collecting data of device usage, symptoms, ear pain medication use, impact of ear pain on sleep 
4 Usability questionnaire including assessment of ease of use of spray and application 
  
9.5.2 Recruitment of subjects 
Subjects will be recruited via advertising. Candidates interested in participating in the study will 
be contacted by the clinic via a telephone call and a pre-screening will be performed to make a 
primary assessment of whether the candidate could be suitable for the investigation or not. 
Candidates who at this time are interested in participation will be scheduled for a first visit at the 
clinic, Visit 1. 
 
9.5.3 Visit 1 (Day 1) Screening / Baseline Visit 
Before any investigation-related procedures are initiated, the informed consent must be signed 
and dated by the subject (or their legally acceptable representative and/or witness, as applicable) 
and by the Investigator who gave the subject the verbal and written information. The original 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 27 of 62 
document will be retained in the Investigator Site File (ISF) and a copy provided to the subject. 
The investigator must obtain written informed consent from the subject before any clinical 
investigation-related procedures are performed, for further details on the informed consent 
process please see section 17.  
In case of bilateral disease, the most severely affected ear, according to PI:s judgment, will be 
selected (subject are allowed to use Otinova® Ear Spray to treat both ears at home, but only the 
selected ear will be analyzed as part of the investigation).  
 
At Visit 1, Day 1 (Clinic visit), the following assessments will be performed: 
• Demographics: 
o Age 
o Gender 
o Height 
o Weight 
o BMI 
• Pregnancy test, if female and fertile 
• Relevant Medical & Surgical history 
• History of OE 
o Previous episodes of OE 
o Duration of diagnosis/age of onset 
o Hearing impairment 
• Relevant concomitant medication 
• Inclusion /Exclusion criteria 
• Otoscopic exam incl. score (score of selected ear in case of bilateral disease). 
Including cleaning of the ear, needed for diagnosis, as deemed by the Investigator.  
• Microbial swab testing (of selected ear in case of bilateral disease) 
• Diary instructions 
• Training of how to use the device – The subject will initiate the treatment under 
supervision at the clinic 
• 
Adverse events questions  
9.5.4 Visit 2 (Day 8 +2 days) – Clinic visit 
 
At visit 2 the following assessments will be performed: 
• Otoscopic exam incl. score (score of selected ear in case of bilateral disease)  
• Microbial swab testing (of selected ear in case of bilateral disease) 
• Concomitant medication 
• Adverse events questions 
• Diary review and collection 
• Device collection 
• Usability questionnaire 
9.5.5 Visit 3 (Day 14 +/- 1 day) – Telephone visit 
• Adverse events questions 
• Concomitant medication 
• End of investigation 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 28 of 62 
 
9.5.6 Unscheduled visits /contacts 
 
If deemed necessary for any reason, e.g., if OE symptoms are increased or unchanged (see Section 
9.3.7) or AEs/ADEs, additional unscheduled visits may be conducted within the course of the 
clinical investigation. Unscheduled visits may be conducted at site or as a telephone or video call. 
All unscheduled visits shall be documented in the eCRF and in the subjects’ medical notes, as 
applicable.  
 
9.5.7 Screening/Baseline Measurements 
 
9.5.7.1 
Demographic data 
At the screening/baseline visit, the following demographic data is to be collected for the subject: 
age, gender, height, weight and BMI. If applicable a pregnancy test will be performed in fertile 
women. 
 
9.5.7.2 
Medical and surgical history 
At visit 1, relevant medical and surgical history e.g. previous otologic surgery, diabetes, hypertonia 
will be documented for each subject. The history regarding relevant diagnoses will be recorded. 
The medical history will be used to assess the subject for any disqualifying medical conditions as 
specified in the exclusion criteria.  
 
9.5.7.3 
History of Otitis Externa 
At visit 1, history of OE will be collected, including: 
 
• previous episodes of OE 
• duration of diagnosis/age at onset  
• hearing impairment  
9.5.7.4 
Otoscopic exam of the ear 
An otoscopic exam of the ear will be conducted at clinic visits by the investigator, using an 
otoscope and/or microscope. The otoscopic exam will provide information related to OE and 
includes OE scores for swelling, erythema and otorrhea. 
 
9.5.7.5 
Microbial testing 
A microbial testing of the earcanal, by using a swab, will be performed at clinic visits by site 
personnel. The microbial swab sample will be analyzed for pathologic microbes (bacteria and 
fungi/yeast). 
 
9.5.7.6 
Concomitant medication 
At visit 1, relevant prior and all concomitant medication will be collected for each subject. The 
prior/concomitant medication will be used to assess the subject for any disqualifying medication 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 29 of 62 
as specified in the exclusion criteria. The subject will be instructed to report ear-pain medication in 
the diary. Concomitant medication, including the diary, will be reviewed at the subsequent visits. 
 
9.5.8  Performance Variables and Measurements 
9.5.8.1 
OE signs 
 
Changes of OE signs between baseline (Visit 1) and after 7 days of treatment (Visit 2) using a 3-
point scale (0 = none, 1 = mild/moderate, 2 = severe), by otoscopic exam. Analyzed as 
proportion of subjects with all signs of swelling, erythema and otorrhea scored as 0. Also, a sum 
score will be created for swelling, erythema and otorrhea. This sum score will be handled as a 
continuous variable. 
 
Score 
Definition 
Description 
Swelling 
0 
None 
Absent 
1 
Mild/Moderate 
Partly occluded ear canal 
2 
Severe 
Complete or almost complete occluded ear canal 
Erythema (redness) 
0 
None 
Absent 
1 
Mild/Moderate 
A light or clearly visible redness of skin in the ear 
canal  
2 
Severe 
Intense redness of skin in ear canal 
Otorrhea (moisture) 
0 
None 
Absent 
1 
Mild/Moderate 
Visible secretions in parts of the ear canal 
2 
Severe 
Secretions that completely or partly obscure the 
tympanic membrane 
 
 
9.5.8.2 
OE symptoms  
 
Changes of OE symptoms itching, otalgia and tenderness using a score from 0 to 4, where 0 
= no symptoms, 1= Mild, 2 = Moderate, 3= Severe and 4 = Very Severe, as reported by the 
subject in a diary. Analyzed as: 
  
a. Change in each of the clinical symptoms itching, otalgia and tenderness from Day 
1 to Day 7. These variables will be regarded as ordered categorical and will be 
described by visit and by change (improved, no change and not improved). 
b. Change in clinical sum score of clinical symptoms itching, otalgia and tenderness 
from Day 1 to Day 7, based on the sum of the three scores (0-12).  
c. Change in clinical symptoms from Day 1 to Day 3 and Day 5. 
 
9.5.8.3 
Pathologic microbes by microbial sampling 
Prescence of pathologic microbes in the ear canal will be assessed by a microbial swab sample. 
Two (2) samplings will be performed, the first at Visit 1 and the second sampling at Visit 2. The 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 30 of 62 
microbial sample will be analyzed for pathologic microbes; bacteria and fungi/yeast. The testing 
will be performed according to the clinic’s routines for swab sampling and the samples will be 
placed in a refrigerator as soon as possible after sampling. The samples will be pseudonymized by 
labelling with Subject ID and Visit number. The samples will be shipped daily to the laboratory 
Unilabs (Skövde, Sweden) or Synlab (Stockholm, Sweden) for analysis. These are accredited 
laboratories, fulfilling the requirements in SS-EN ISO 15189 and ISO/IEC 17025:2018. The 
result of the analysis is the bacterial and fungal species, which could be, but are not limited to, 
Staphylococcus aureus and Pseudomonas aeruginosa. The samples will be destroyed immediately (within 
1-2 days) after analysis. 
 
9.5.8.4 
Moisture in the ear canal 
Reduction of moisture in the ear canal, otorrhea, between baseline (Visit 1) and after 7 days of 
treatment (Visit 2), by otoscopic exam, using a 3-point scale (0 = none, 1 = mild/moderate, 2 = 
severe), by otoscopic exam. Analyzed as proportion of subjects with signs of otorrhea at baseline 
on a scale from 0-2 (0=none, 1=mild/moderate, 2=severe) and show an improvement of 1 or 
more points. 
 
9.5.8.5 
Volume of ear canal  
Change of volume of the ear canal between baseline (Visit 1) and after 7 days of treatment (Visit 
2), by otoscopic exam, using a 3-point scale (0 = none, 1 = mild/moderate, 2 = severe). Reduced 
swelling of the ear canal results in increased volume of the ear canal. Analyzed as proportion of 
subjects with signs of swelling at baseline on a scale from 0-2 (0=none, 1=mild/moderate, 
2=severe) and show an improvement of 1 or more points. 
 
9.5.8.6 
User handling  
Subject experience of user handling of Otinova will be captured at visit 2, through a paper 
questionnaire to be filled out by the subject. The questionnaire will contain questions regarding 
ease of use of spray and ease of application. Each question will be answered by the subject by 
choosing the most correct answer on a scale or replying on a yes or no question. 
 
9.5.8.7 
Subject diary 
 
A subject diary will be used for collecting data of: 
- 
Device usage compliance (morning and evening, yes/no) 
- 
OE symptoms experienced (itching, ear pain, tenderness, scale 0-4, see Section 
9.5.8.2) 
- 
Impact of ear pain on sleep (yes/no), if children: Impact on parents’ sleep (yes/ no), 
see Section 9.5.8.8 
- 
Ear pain medication use (yes/no), see Section 9.5.8.9 
 
9.5.8.8 
Sleep disruption 
Sleep disruption of subject and parent as reported in subject diary. Analyzed as proportion of 
subjects with less sleep disruption Day 7 compared to Day 1 and proportion of parents with less 
sleep disruption Day 7 compared to Day 1. 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 31 of 62 
 
9.5.8.9 
Use of ear pain medication 
Use of pain relief medication for ear pain, as reported in subject diary, replying on a yes or no 
question. 
 
9.5.8.10 Use of antibiotics 
Use of antibiotics for OE symptoms, as listed in Medication log. 
 
9.5.9  Safety Variables and Measurements 
 
All incidences of AEs and DDs will be documented and reported during the clinical investigation. 
AEs will be categorized as AE, ADE, SAE, or SADE. For details related to AE definitions or 
reporting, please see Section 18. 
All events will be followed up until resolved or judged as clinically stable according to the 
investigator, if possible. 
 
From baseline and at all follow-up visits the study personnel will ask the subject if they have 
experienced any adverse events since last visit. The diary will be checked for any new symptoms 
that occurred, together with any new or change in medication. 
 
9.5.10   Activities Performed by Sponsor 
 
The Sponsor is responsible for device training of involved personnel. Device training will be 
documented in applicable training logs. 
Sponsor is also responsible for reporting of DDs discovered by the sponsor. 
Reporting of SAEs according to Section 18.5. 
9.5.11  Potential Confounding Factors 
The use of other OE treatments is a potential confounding factor, which is addressed by subject 
eligibility criteria and in the information provided to subjects. Subject illness, particularly 
infections, during investigation participation is a potential confounding factor, which is addressed 
by adverse event reporting.  
 
9.5.12 Samples obtained from subject 
The samples obtained will be destroyed immediately after analysis (latest within 1-2 days after 
analysis).  
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 32 of 62 
10 MONITORING PLAN 
A detailed description of monitoring activities will be provided in a separate, investigation-
specific risk-based monitoring plan. 
 
10.1 Subject Records and Source Data 
Subject data recorded directly in electronic case report form (eCRF) (and not into the medical 
record) will be considered source data. It is the responsibility of the PI to record essential 
information in the medical records, in accordance with national regulations and requirements. The 
origin of source data in this clinical investigation will be further specified in a separate document 
(“Source Data Location Agreement”).  
 
It is the responsibility of the PI to record essential information in the medical records, in 
accordance with national regulations and requirements. 
 
In general the following information should be recorded in the medical records: 
• 
Investigation code, and or investigational title 
• 
Subject screening number and/or subject ID 
• 
That informed consent for participating in the clinical investigation was obtained, and the 
date of collection 
• 
Diagnosis 
• 
All visits during the investigation period including visit date 
• 
All AEs 
• 
Treatments and medications 
• 
Subject health service identification number, if applicable  
 
The PI is responsible for ensuring the accuracy, completeness, legibility and timeliness of the data 
recorded in the eCRFs. Signed sections of eCRFs will be monitored on a regular basis. 
 
10.2 Access to Source Data and Documentation 
The PI should guarantee access to source documents for the monitor and auditors as well as for 
inspection by appropriate Regulatory Agencies / Competent Authorities, and Independent Ethics 
Committees (IECs), if required. 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 33 of 62 
11 STATISTICAL CONSIDERATIONS 
11.1  Statistical Design, Method and Analytical Procedures 
This is a single arm investigation with no comparison group. No randomization will be 
performed. Both intention to treat (ITT) analyses, as well as per protocol analyses (PP) will be 
performed. Both the ITT and the PP population will be defined at the Clean File meeting before 
the database lock. All included subjects who started treatment will be included in the safety 
analysis set (SAF). 
Continuous variables are described with mean, SD, median and range and categorical variables 
with numbers and percentages. 
Change in dichotomous and ordered categorical variables will be performed with Sign test and 
change in continuous variables will be performed with Fisher’s non-parametric permutation test 
for paired observations. Proportions of cured and improved will be given with exact 95% 
confidence interval. 
No adjustment for confounders can be performed due to the single arm design. 
The primary analysis, clinical cure of swelling, erythema and otorrhea, will be analyzed as 
proportions of subjects cured with exact 95% confidence interval. A Sum score will be created 
for swelling, erythema and otorrhea. This sum score will be handled as a continuous variable. 
Secondary endpoints of cure and improvement will be analyzed in the same way. 
 
All significance tests will be two-sided and conducted at the 5% significance level. 
 
11.2  Sample size 
In order to show that the lower limit of the exact 95% confidence interval for the proportion 
cured regarding swelling, erythema and otorrhea will be higher than 50% with a probability of 
80%, given a 0.75 proportion of cured at significance level 0.05, 33 evaluable subjects are needed. 
A drop-out rate of 10% is assumed and hence the sample size needs to be a minimum of 37 
subjects. In order to account fo drop-outs as well as the inclusion of both children and adults, a 
sample size of 40 subjects was therefore chosen. 
11.3  Drop-out Rates 
A drop-out rate of 10% is expected. 
 
11.4 Level of Significance and Power 
Power for primary analysis is 80% and significance level 0.05. Where possible 95% confidence 
intervals will be given. 
 
11.5  Pass / Fail Criteria 
Pass criteria is to show that percentages cured regarding swelling, erythema and otorrhea is 
significantly higher than 50%. 
 
11.6  Interim Analysis 
No interims analysis will be performed. 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 34 of 62 
11.7  Reporting of Deviations from the Original Statistical Analysis Plan (SAP) 
Any changes from the original Statistical Analysis Plan (SAP) will be amended in a revised SAP.  
 
11.8  Subgroups for Analysis 
For the following subgroups, proportion cured regarding swelling, erythema and otorrhea with 
exact 95% CI and proportion improved regarding itching, otalgia and tenderness with exact 95% 
CI will be calculated: 
• Age 5-17 
• Age 18 and over 
  
11.9  Procedures that Take into Account all the Data 
All ITT analyses will take into account of all data. 
 
11.10  Missing, Unused or Spurious Data 
Outliers will be included in summary tables and listings, and will not be handled separately. 
Available data from prematurely withdrawn subjects will be included in the analysis as far as 
possible. Missing data will be analyzed and imputed with appropriate method.  
 
11.11  Exclusion of Particular Information from the Testing of the Hypothesis 
No exclusion of particular information from the testing of the hypothesis is planned.  

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 35 of 62 
12 DATA MANAGEMENT 
Data management and handling will be conducted according to the investigation specific Data 
Management Plan (DMP) in accordance with applicable guidelines and CRO:s Standard 
Operating Procedures (SOPs). Any deviations, i.e. discrepancies and additions from the process 
defined in the DMP will be described in an investigation specific Data Management Report 
(DMR). 
 
Data will be collected in eCRFs specifically designed for this clinical investigation. The Principal 
Investigator or any other authorized person will record subject data in the eCRF in a precise and 
accurate manner. Abbreviations should not be used unless otherwise instructed in the Data Entry 
Instruction (DEI) document. The Principal Investigator is responsible for all data entered in the 
EDC and for signing-off at the end of the clinical investigation. The data should be recorded as 
soon as they are generated. 
 
The person entering data into the database is not allowed to attempt any personal interpretation or 
to make any decisions on the data other than self-evident corrections as listed in the investigation 
DEI or data handling report. Single data entry type will be applied. Data required to determine 
eligibility for the clinical investigation will be collected in the EDC for screening failures.  
 
Data validation /data cleaning procedures are designed to assure validity and accuracy of clinical 
data. These procedures consist of manual review of clinical data. These procedures consist of 
manual review performed  by the Data Manager and computerized edit checks and queries for 
identifying data values that are outside the allowed range, incomplete or inconsistent, and CIP 
deviations. The Data Validation Plan (DVP) specifies the checks that are to be performed on 
subject data for the clinical investigation. All investigation-specific and standard data validation 
programming will be tested in a separate testing environment prior to use in the clinical 
investigation. 
 
When all data from all endpoints  of all subjects have been entered, discrepancies solved and 
reconciliation with the safety database is complete, the database will be locked and the data will 
be analyzed. 
 
12.1 Data Retention 
The medical records of clinical investigation subjects must be retained in accordance with local 
legislation and in accordance with the maximum period of time permitted by the hospital, 
institution or private practice. 
 
The PI shall retain all clinical investigation records during the investigation and for the period 
required by the applicable regulatory requirements or for at least 10 years after the premature 
termination or completion of the clinical investigation, whichever ever is the longest. The PI 
must take measures to prevent accidental or premature destruction of these documents. The PI 
should contact the Sponsor prior to destruction of any records or reports pertaining to the 
clinical investigation in order to ensure they no longer need to be retained. In addition, if the PI 
leaves the hospital, he/she should provide the Sponsor with the name and address of the person 
who will look after and be responsible for the clinical investigation-related records. If the records 
will be transferred to another person/party, the transfer will be documented at the investigation 
site or at the Sponsor.  

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 36 of 62 
 
The Sponsor will retain the Study Master File (SMF) in line with applicable regulations or for at 
least 10 years after the clinical investigation has ended, or, in the event that the device is 
subsequently placed on the market, at least 10 years after the last device has been placed on the 
market.  
 
12.2 Monitoring, Audits and Inspections 
During the clinical investigation, the monitor will have regular contacts with the investigation site. 
These contacts will include visits to confirm that the facilities remain adequate to specified 
standards and that the investigation team is carrying out the procedure stated in the CIP. All data 
must be accurately recorded in the CRF. Source data verification (SDV), a comparison of data in 
the CRF with the subject’s medical records and other records at the investigation site, will also be 
performed. The CRF and source documents and records must be made accessible during the 
monitoring visit. 
 
The monitor or other Sponsor personnel will be available between visits if the PI or other 
investigation staff at the site needs information and/or advise. Authorized representatives of the 
Sponsor and/or international Regulatory Agencies / Compentent Authorities may visit the site to 
perform audits/inspections, including SDV. 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 37 of 62 
13 AMENDMENTS TO THE CIP 
Any change to the approved clinical investigation documents will be documented and include a 
written justification. Any effects of the implemented changes on other clinical investigation 
documents shall be evaluated and documented. If deemed necessary, affected documents shall be 
properly updated and relevant parties notified. The version number and date of amendments 
shall be documented. 
 
All amendments to the CIP will be documented in an amendment log and communicated to 
relevant parties. 
 
Proposed amendments to the CIP shall be agreed upon between the Sponsor and PI. The 
amendments to the CIP shall be notified to, or approved by, the IEC and Regulatory Agencies / 
Competent Authorities, if required. 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 38 of 62 
14 DEVIATIONS FROM THE CIP 
 
A CIP deviation is a failure to follow, intentionally or unintentionally, the requirements of the 
CIP. Every effort should be made to comply with the requirements of the CIP and the 
investigator is not allowed to deviate from the CIP. Furthermore, waivers from the CIP is 
prohibited. 
 
As required by national regulations or guidelines, requests for deviations and reports of 
deviations will be provided to the IEC if the deviation affects subject’s rights, safety and well-
being, or the scientific integrity of the clinical investigation. 
 
Under emergency circumstances deviations from the CIP may proceed without prior approval by 
the Sponsor and favorable opinion of the IEC if the rights, safety and well-being of human 
subjects need to be protected. Such deviations will be documented and reported to the Sponsor 
and IEC as soon as possible in accordance with national regulations. 
 
When the monitor or Sponsor identifies that the PI is out of compliance, this will be notified to 
the PI in writing, with a request to correct the source of the deviation immediately. Corrective 
action will be implemented to avoid repeated non-compliance, which will usually include re-
training and may include terminating the clinical investigation at the site. 
 
The Sponsor is responsible for analyzing deviations and assessing their significance. Corrective 
action(s) will be implemented to avoid repeated deviations, which may include suspending the 
clinical investigation at the investigation site or disqualify the PI. 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 39 of 62 
15 DEVICE ACCOUNTABILITY 
 
The investigational device will be shipped to the site or be delivered by a sponsor representative, 
as applicable, and kept in a locked area. The sponsor will keep records of the shipped 
investigational devices. A device accountability log will be held on site. 
At the investigation close-out visit, a sponsor representative will collect all remaining unused 
investigational devices. All unused investigational devices will be returned to the sponsor when 
treatment of the last subject has been completed.  
The monitor will verify the accountability process during the site monitoring visits. 
 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 40 of 62 
16 STATEMENTS OF COMPLIANCE 
 
This clinical investigation will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki (Appendix C). Furthermore, the clinical investigation 
will be conducted in compliance with ISO 14155:2020 and applicable regional or national 
regulations.  
 
16.1 Institutional Ethics Review 
The final CIP, including the final versions of the ICF, must be approved or given a favorable 
opinion in writing by an IEC and Regulatory Agency / Competent Authority before enrolment 
of any subject into the clinical investigation. The PI is responsible for informing the IEC of any 
amendment to the CIP as per local requirements. 
 
Any additional requirements imposed by the IEC or Regulatory Agency / Competent Authority 
shall be followed. 
 
16.2 Insurance 
 
The Sponsor will be responsible for ensuring adequate insurance covering any injuries to the 
subject caused by the investigational medical device. 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 41 of 62 
17 INFORMED CONSENT PROCESS 
All subjects, and if pediatric subject also their legal representatives, will receive written and verbal 
information regarding the clinical investigation prior to any investigation-related procedures take 
place. This information will emphasize that participation in the clinical investigation is voluntary 
and that the subject may withdraw from the investigation at any time and for any reason. All 
subjects will be given the opportunity to ask questions about the investigation and will be given 
sufficient time to decide whether to participate in the investigation or not. If any new important 
information arise during the clinical investigation the subject will be informed both orally and in 
writing.  
 
The written subject information explains that the data will be stored in a computer database, 
maintaining confidentiality in accordance with national data legislation, and that authorized 
representatives of the Sponsor, international Regulatory Agencies / Competent Authorities or 
IECs may require direct access to those parts of the medical records relevant to the investigation, 
including medical history, for verification of data. Additionally, the written subject information 
specifies that data will be recorded, collected, processed and may be transferred (to either 
European Economic Area (EEA) countries and / or non-EEA countries). In accordance with 
the General Data Protection Regulation (GDPR) 2016/679, the data will not identify any 
subjects taking part in the investigation. 
 
Before any investigation-related procedures, the informed consent will be signed and dated by the 
subject (and/or legal representative if pediatric subjects), and by the Investigator who gave the 
verbal and written information. If the subject is 15 years or older he/she should also give written 
consent, in addition to the legal representative(s) written consent. If a subject younger than 15, 
who understands the procedures of the investigation, do not want to participate in the 
investigation, this decision must be respected. 
 
The only exception to the above procedure is if a pediatric subject has more than one legal 
representative and not all legal representatives are present at the investigation site at the time for 
consent. The additional legal representative will receive verbal information about the 
investigation through the phone, and will give oral consent prior to any investigation-related 
procedures. It will be documented in the subject’s medical record that verbal information has 
been given to the additional legal representative. The legal representative not present at site 
should have had time to ask questions and think through the decision before giving oral consent. 
Signed consent will be given as soon as possible thereafter, sent in to the site as soon as possible.  
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 42 of 62 
18 ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND DEVICE 
DEFICIENCIES 
The definitions and procedures for reporting Adverse Events (AE), Adverse Device Effects 
(ADE), Serious Adverse Events (SAE), Serious Adverse Device Effects (SADE) and 
Unanticipated Serious Adverse Device Effects (USADE) are presented in the subsections below. 
It is of utmost importance that all staff involved in the investigation is familiar with the 
definitions and procedures and it is the responsibility of the Principal Investigator to ensure this. 
 
18.1 Definitions 
The following definitions are as per ISO 14155:2020. 
Adverse Device Effect (ADE) 
Adverse event related to the use of an investigational medical device. 
 
Note 1: This definition includes adverse events resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
 
Note 2: This definition includes any event resulting from use error or from intentional misuse of 
the investigational medical device. 
 
Note 3: This uncludes ‘comparator’ if the comparator is a medical device. 
 
Adverse Event (AE) 
Untoward medical occurrence, unintended disease or injury, or untoward clinical signs (including 
abnormal laboratory findings) in subjects, users or other persons, whether or not related to the 
investigational medical device and whether anticipated or unanticipated. 
 
Note 1: This definition includes events related to the investigational medical device or the 
comparator. 
 
Note 2: This definition includes events related to the procedures involved. 
 
Note 3: For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices or comparators. 
 
Device Deficiency 
Inadequacy of an investigational medical device related to its identity, quality, durability, reliability, 
safety or performance. This may include malfunctions, use error, or inadequacy in the information 
supplied by the manufacturer. 
 
Note 1: Device deficiencies include malfunctions, use errors, and inadequacy in the information 
supplied by the manufacturer including labelling. 
 
Note 2: This definition includes device deficiencies related to the investigational medical device or 
the comparator. 
 
Serious Adverse Device Effect (SADE) 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 43 of 62 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event.  
 
Serious Adverse Event (SAE) 
Adverse event that led to any of the following: 
a) death,  
b) serious deterioration in the health of the subject, users, or other persons as defined by one or 
more of the following: 
i. 
A life-threatening illness or injury, or 
ii. 
A permanent impairment of a body structure or a body function including chronic 
diseases, or 
iii. 
In-patient or prolonged hospitalization, or 
iv. 
medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or a body function, 
c) foetal distress, foetal death, a congenital abnormality, or birth defect including physical or 
mental impairment. 
 
Note: Planned hospitalization for pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
 
Serious health threat 
Signal from any adverse event or device deficiency that indicates an imminent risk of death or a 
serious deterioration in the health in subjects, users or other persons, and that requires prompt 
remedial action for other subjects, users or other persons. 
 
Note: This would include events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of multiple deaths occurring at 
short intervals. 
 
Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current risk assessment. 
 
Note: Anticipated Serious Adverse Device Effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk assessment. 
 
18.2 Non-reportable adverse events 
Not applicable. 
 
18.3 Methods for discovering and documenting AE/ADE 
All subjects will be carefully monitored for the occurrence of AEs throughout the clinical 
investigation, from the first day to the completion of follow up. Events prior to inclusion will be 
considered medical history. The Principal Investigator will collect safety information using non-
leading questions such as “have you experienced any new health problems or worsening of 
existing conditions?”. Events directly observed or spontaneously volunteered by subjects will also 
be recorded throughout the clinical investigation. 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 44 of 62 
Clearly related signs, symptoms and abnormal diagnostic procedure results should be grouped 
together and reported as a single diagnosis or syndrome whenever possible. 
 
All AEs, including but not limited to events reported by the subject or reported in response to an 
open question by the Principal Investigator or member of the investigation team, which fall into 
any of the previously defined definitions must be recorded as an AE in the CRF and should 
include the following information: 
• 
Brief description of the event (diagnosis) 
• 
Date of event onset (and time, if relevant) 
• 
Date of event resolution (and time, if relevant) 
• 
Severity 
• 
Seriousness 
• 
Causality assessment (i.e. relationship to medical device and/or procedure) 
• 
Event treatment 
• 
Event outcome / resolution 
 
If the AE meets the seriousness criteria it should be subject to expedited reporting as described 
in 18.5. 
 
18.3.1  Severity 
Severity describes the intensity of an AE and will be assessed as: 
1) Mild: asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
2) Moderate: minimal, local or non-invasive intervention indicated, limiting age-appropriate 
instrumental activities of daily living. 
3) Severe or medically significant but not immediately life-threatening: hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care activities of daily living. 
4) Life-threatening consequences; urgent intervention indicated. 
5) Death related to AE. 
 
If an AE changes in severity, it should be reported as an AE of new severity but with the same 
description and identifier. 
 
18.3.2  Causality 
Causality is the relationship between the use of the medical device (including the investigational 
device, the comparator and the medical – surgical procedure) and the occurrence of each AE.  
 
During the causality assessment, clinical judgment shall be used and the relevant documents, such 
as the IB, the CIP or the risk analysis report shall be consulted, as all the foreseeable SAEs and 
the potential risks are listed and assessed there. The presence of confounding factors, such as 
concomitant medication/treatment, the natural history of the underlying disease, other 
concurrent illness or risk factors shall also be considered.  
 
For the purpose of harmonizing reports, each SAE will be classified according to four different 
levels of causality. The Sponsor and the Principal Investigator will use the following definitions to 
assess the relationship of the SAE to the investigational medical device, the comparator, or the 
medical – surgical procedures: 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 45 of 62 
• 
Not related: relationship to the device or procedures can be excluded when: 
o The event has no temporal relationship with the use of the investigational device or 
the procedures related to the investigational device; 
o The serious event does not follow a known response pattern to the medical device (if 
the response pattern is previously known) and is biologically implausible; 
o The discontinuation of medical device application or the reduction of the levels of 
activation/exposure – when clinically feasible – and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact on the serious event; 
o The event involves a body-site or an organ than cannot be affected by the device or 
procedure; 
o The serious event can be attributed to another cause (e.g. an underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment or other risk 
factors); 
o The event does not depend on a false result given by the investigational device used 
for diagnosis, when applicable; 
In order to establish the non-relatedness, not all the criteria listed above might be 
met at the same time, depending on the type of device/procedures and the serious 
event. 
• 
Possible: the relationship with the use of the investigational device or comparator, or the 
relationship with procedures, is weak but cannot be ruled out completely. Alternative causes 
are also possible (e.g. an underlying or concurrent illness/clinical condition or/and an effect 
of another device, drug or treatment). Cases were relatedness cannot be assessed or no 
information has been obtained should also be classified as possible. 
• 
Probable: the relationship with the use of the investigational device or comparator, or the 
relationship with procedures, seems relevant and/or the event cannot bereasonably be 
explained by another cause. 
• 
Causal relationship: the serious event is associated with the investigational device, 
comparator or with procedures beyond reasonable doubt when: 
o The event is known side effect of the product category the device belongs to or of 
similar devices and procedures; 
o The event has a temporal relationship with investigational device use/application or 
procedures; 
o The event involved a body-site or organ that: 
§ 
The investigational device or procedures are applied to; 
§ 
The investigational device or procedures have an effect on; 
o The serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
o The discontinuation of medical device application (or reduction of the level of 
activation/exposure) 
and 
reintroduction 
of 
its 
use 
(or 
increase 
of 
activation/exposure), impact on the serious event (when clinically feasible); 
o Other possible causes (e.g. an underlying or concurrent illness/clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled 
out; 
o Harm to the subject is due to error in use; 
o The event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event. 
The Sponsor and the Principal Investigator will distinguish between AEs related to the 
investigational device, the comparator and those related to the procedures (any procedure 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 46 of 62 
specific to the clinical investigation). An AE can be related to both the procedures and the 
device. Complications of procedures are considered not related if the said procedures would have 
been applied to the subjects also in the absence of device use/application. 
 
Particular attention shall be given to the causality evaluation of USADE, since the occurrence of 
USADE could suggest that the clinical investigation places subjects at increased risk of harm than 
was expected beforehand. 
 
In case of disagreement between the Sponsor and the Principal Investigator assessments of the 
AE, both opinions shall be communicated to concerned parties. 
 
18.4 Methods for Discovering and Documenting Device Deficiencies 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance shall be reported as a device deficiency without unnecessary delay to the Sponsor by 
using the device deficiency form. It is the Principal Investigator’s responsibility to record every 
observed device deficiency together with an assessment. The Sponsor shall review all device 
deficiencies and determine and document in writing whether they could have led to a SADE. 
Device deficiencies that are assessed to or have SADE potential should be subjected to expedited 
reporting as described in section 18.5. 
 
18.5  Reporting of SAE/SADE and Device Deficiencies with SADE potential 
MDR 2017/745 
The following events are considered reportable events according to Regulation (EU) 2017/745: 
• Any SAE that has a causal relationship with the investigational device, the comarator 
or the investigation procedure or where such causal relationship is reasonably 
possible; 
• Any device deficiency that might have led to a SAE if: 
o Suitable action had not been taken or 
o Intervention had not been made or 
o If circumstances had been less fortunate 
• New findings/updates in relation to already reported events. 
 
SAEs/SADEs and device deficiencies with with SADE potential must be reported to the 
Sponsor immediately, but not later than 3 calendar days after investigational site 
investigation personnel’s awareness of the event, regardless of the time that may have 
elapsed from the time the event occurred. 
 
The initial report should contain as much information as possible, but as a minimum the 
following information: 
• 
Subject ID 
• 
SAE ID 
• 
Date of procedure/first use 
• 
Date of event onset 
• 
SAE or DD 
• 
Age (years) 
• 
Patient gender (female, male, other, unknown) 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 47 of 62 
• 
Classification of event: 
o death, 
o life-threatening illness or injury, 
o permanent impairment/chronic disease, 
o hospitalization, 
o medical or surgical intervention, 
o foetal distress, foetal death or congenital physical or mental or birth defect, 
o not applicable1 
• 
Description of event: 
o Nature of the observed symptoms 
o Duration and severity of the symptoms 
o Date of onset of first signs of the event (before it became a SAE) 
o Medical background of the patient 
o Medical care of the patient 
o Comments on the event in relation to already known safety data 
• 
Action/treatment/outcome 
• 
Relationship to procedure (not related, possible, probable, causal) 
• 
Relationship to the device (not related, possible, probable, causal) 
• 
Unanticipated SADE (Yes, No) 
• 
Investigation arm (test group, comparison group, blinded, not applicable) 
• 
Event status (resolved, resolved with sequelae, ongoing, death) 
• 
Date of event resolution (if ongoing enter not applicable) 
 
The Sponsor must also promptly receive a completed report. All SAEs have to be reported 
whether or not they are considered causally related to the investigational medical device, 
comparator or medical – surgical procedure. 
 
SAE/SADE EMERGENCY CONTACT DETAILS 
Name: Mattias Andrup 
Phone: +46 76 882 30 23 
Email: mattias.andrup@circiuspharma.com 
 
Since this is a post-market clinical investigation all SAEs will be handled according to the 
Sponsors vigilance system and in accordance with MDR and the vigilance provisions laid down 
in Article 87 to 90 and in the acts adopted pursuant to Article 91. However, for the SAEs where 
a causal relationship between the SAE and the preceding investigational procedure has been 
established the reporting procedures of clinical investigations as outlined in Article 80 shall be 
followed; the event must be reported to the Regulatory Agencies / Competent Authorities and 
ECs, where the PMCF investigation has commenced. The period for reporting shall take account 
of the severity of the event. Where necessary to ensure timely reporting, the Sponsor may submit 
an initial report that is incomplete followed by a complete report. The Sponsor should inform the 
IEC and Regulatory Agencies / Competent Authorities about reportable events through 
EUDAMED (once established) or as per local requirements. 
 
 
 
 
 
1 This option is only to be selected in case of reportable device deficiencies that did not lead to an SAE. 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 48 of 62 
18.6 Foreseeable adverse events and anticipated adverse device effects 
There are few and mild side-effects reported with regards to the use of Otinova® Ear Spray, 
such as the possibility of temporary mild irritation or stinging in the ear canal. Small amounts of 
salt precipitation in the outer ear canal can occur.  
18.7 Data Monitoring Committee 
Establishment of a Data Monitoring Committee (DMC) is not considered necessary for this 
post-market clinical investigation as 1) there will be only one investigational site, well-experienced 
in clinical investigations and 2) the benefit-risk profile of the investigational devices do not 
indicate a need for a DMC. In case data retrieved during the clinical investigation contradicts this 
decision, it will be reconsidered. 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 49 of 62 
19 Vulnerable Population 
In this clinical investigation, pediatric subjects from the age of 5 will participate. Pediatric subjects 
are per se described as a vulnerable population according to ISO 14155:2020. Therefore, also the 
potential subjects’ legal representatives will receive information both verbally and written about 
the study prior any decision about the subjects’ participation. If not all legal representative(s) are 
present at the time of consent, the additional legal representative(s) will receive oral information 
about the investigation and give oral consent. Written consent will take place as soon as possible 
thereafter. Both the potential subject and the legal representative(s) need to voluntarily agree to 
participate. The subject will be informed about the clinical investigation within his/her ability to 
understand, i.e. additional versions of the subject information have been developed to target 
different ages. If the subject will have specific difficulties to understand the contents of 
participating in the clinical investigation, i.e. as a child may have, additional time will be given for 
questions regarding the investigation as well as consent procedure. For more information on the 
consent process for pediatric subjects, see Section 17. 
 
20 SUSPENSION OR EARLY TERMINATION OF CLINICAL INVESTIGATION 
If the clinical investigation is terminated early or suspended due to reasons of safety, the Sponsor 
will promptly inform the PI(s) and the investigation site(s) of the termination or suspension and 
the reason(s) thereof. The IEC will also be informed promptly and provided with the reason(s) 
for the termination or suspension by the Sponsor or by the PI(s) / investigation site(s). 
 
In addition, CIP violations may result in termination of the Clinical Investigation at a site. 
CIP violations are deviations made without permission as a result of error or fraud/misconduct. 
Where the monitor or Sponsor identifies that the PI is out of compliance, this will be noted to 
the PI in writing, with a request to correct the source of the deviation immediately. Corrective 
actions will be implemented to avoid repeated non-compliance, including re-training. However, 
in case of repeated non-compliance despite implemented corrective actions, the clinical 
investigation will be terminated at the site. 
 
20.1 Subject Follow-up 
If the clinical investigation is prematurely terminated, the Sponsor and the PI(s) will assure 
that adequate consideration is given to the protection of subjects’ interest, including subject 
follow-up. 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 50 of 62 
21 PUBLICATION POLICY 
The clinical investigation will be registered in a publicly accessible database before recruitment of 
the first subject. 
 
A final report of the clinical investigation (CIR) will be completed, even if the investigation is 
prematurely terminated. The report will be prepared by the Sponsor according to the guideline 
presented in Annex D of ISO 14155:2020. 
 
All publications and presentations must be based upon the CIR. 
 
All information supplied by the Sponsor in connection with this investigation will remain the sole 
property of the Sponsor and is to be considered confidential information. No confidential 
information will be disclosed to others without obtaining prior written consent from the Sponsor 
and will not be used except in the conduct of this investigation. 
 
The Sponsor may choose to publish or present data from this clinical investigation. If a PI is 
offered first authorship, he/she will be asked to comment and approve the publication. The 
Sponsor has the right to use the results for registration and internal presentation and for 
promotion. 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 51 of 62 
22 REFERENCES 
 
1. 
Kaushik V, Malik T, Saeed SR. Interventions for acute otitis externa. Cochrane Database Syst 
Rev. 2010(1):CD004740. 
2. 
Hajioff D, MacKeith S. Otitis externa. BMJ Clin Evid. 2015;2015. 
3. 
Rosenfeld RM, Schwartz SR, Cannon CR, Roland PS, Simon GR, Kumar KA, et al. Clinical 
practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2014;150(1 Suppl):S1-S24. 
4. 
Schaefer P, Baugh RF. Acute otitis externa: an update. Am Fam Physician. 2012;86(11):1055-61. 
5. 
Rosenfeld RM, Singer M, Wasserman JM, Stinnett SS. Systematic review of topical antimicrobial 
therapy for acute otitis externa. Otolaryngol Head Neck Surg. 2006;134(4 Suppl):S24-48. 
6. 
Otitis Externa NHS Scotland. 2019. Available from: https://www.nhsinform.scot/illnesses-and-
conditions/ears-nose-and-throat/otitis-externa. 
7. 
Otinova. Product Specification. PS-001-11. 2018. . 
8. 
Otinova. Instructions for Use (English). Otinova_IFU-92510. ARTW-3399. Version 1. 2020-02-
10. 
9. 
Jinnouchi O, Kuwahara T, Ishida S, Okano Y, Kasei Y, Kunitomo K, et al. Anti-microbial and 
therapeutic effects of modified Burow's solution on refractory otorrhea. Auris Nasus Larynx. 
2012;39(4):374-7. 
10. 
Kashiwamura M, Chida E, Matsumura M, Nakamaru Y, Suda N, Terayama Y, et al. The efficacy 
of Burow's solution as an ear preparation for the treatment of chronic ear infections. Otol 
Neurotol. 2004;25(1):9-13. 
11. 
Lambert IJ. A comparison of the treatment of otitis externa with 'Otosporin' and aluminium 
acetate: a report from a services practice in Cyprus. J R Coll Gen Pract. 1981;31(226):291-4. 
12. 
Clayton MI, Osborne JE, Rutherford D, Rivron RP. A double-blind, randomized, prospective 
trial of a topical antiseptic versus a topical antibiotic in the treatment of otorrhoea. Clin 
Otolaryngol Allied Sci. 1990;15(1):7-10. 
13. 
Thorp MA, Gardiner IB, Prescott CA. Burow's solution in the treatment of active mucosal 
chronic suppurative otitis media: determining an effective dilution. J Laryngol Otol. 
2000;114(6):432-6. 
14. 
Aluminium Acetate Ear Drops (Burows solution). British Pharmacopeia. Volume III. 2020. 
15. 
Otinova. Declaration of Conformity. QAD-2816-v.1.0, 2015. 
16. 
Otinova. Classification document. Reg-4324. Version 1. 2020-02-10. 
17. 
Otinova. Risk Management Plan. RISK-4481. 
18. 
Otinova. Risk Management Report. RISK-4483. Version 1. 2020-11-17. 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 52 of 62 
23 APPENDICES 
23.1 Appendix A – Clinical Investigation Plan Agreement Form 
 
Investigation code: CIR_001 
 
CIP version: C, 09-May-2023 
 
 
I agree to the terms of this CIP. I will conduct the investigation according to the procedures 
specified herein.  
 
 
Site No: 01 
 
Principal Investigator 
 
Name: Cristina Ioanes 
 
 
 
Signature: _____________________ 
 
 
 
Date (dd-Mmm-yyyy): ______________ 
 
 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 53 of 62 
Investigation code: CIR_001 
 
CIP version: C, 09-May-2023 
 
 
I agree to the terms of this CIP. I will conduct the investigation according to the procedures 
specified herein.  
 
 
Site No: 02 
 
Principal Investigator 
 
Name: Daniel Wilhelms 
 
 
 
Signature: _____________________ 
 
 
 
Date (dd-Mmm-yyyy): ______________ 
 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 54 of 62 
Investigation code: CIR_001 
 
CIP version: C, 09-May-2023 
 
 
I agree to the terms of this CIP. I will conduct the investigation according to the procedures 
specified herein.  
 
 
Site No: 03 
 
Principal Investigator 
 
Name: Sarah Maleki 
 
 
 
Signature: _____________________ 
 
 
 
Date (dd-Mmm-yyyy): ______________ 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 55 of 62 
23.2 Appendix B – Clinical Investigation Contact List 
 
PRINCIPAL INVESTIGATOR, Site 1 
Name: Cristina Ioanes, MD 
Professional position: Investigator, General practitioner 
Address: Carlandersplatsen 1, 412 55 Göteborg, Sweden 
Phone: +46 31 81 91 21 
E-mail: cristina.ioanes@carlanderska.se 
 
PRINCIPAL INVESTIGATOR, Site 2 
Name: Daniel Wilhelms, MD, PhD 
Professional position: Associate professor in emergency medicine 
Address: Brigadgatan 26, 587 58 Linköping, Sweden 
Phone: +46 703 61 65 19 
E-mail: daniel.wilhelms@cordinator.se 
 
PRINCIPAL INVESTIGATOR, Site 3 
Name: Sarah Maleki, MD 
Professional position: ENT-specialist 
Address: Fågelbacksgatan 9C, 217 44 Malmö, Sweden 
Phone: +46 40 98 50 85 
E-mail: sarah@malekimedical.se 
 
CLINICAL INVESTIGATION SITES 
Site 01 
Name: Carlanderska Sjukhuset, Forskningsenheten 
Address: Carlandersplatsen 1, 412 55 Göteborg, Sweden 
Phone: +46 31 81 91 21 
 
Site 02 
Name: Cordinator Medical Service AB 
Address: Brigadgatan 26, SE-58758 Linköping, Sweden 
Phone: +46 13-465 8060 
 
Site 03 
Name: Öron-Näsa-Hals-Center Malmö 
Address: Fågelbacksgatan 9C, 217 44 Malmö, Sweden 
Phone: +46 40 98 50 85 
  
SPONSOR REPRESENTATIVE 
Name: Mattias Andrup 
Address: Circius Pharma AB, Södra långebergsgatan 34-36, 436 32 Askim, Sweden 
Phone: +46 76 882 30 23 
E-mail: mattias.andrup@circiuspharma.com 
 
CONTRACT RESEARCH ORGANIZATION 
Name: Devicia AB 
Address: Argongatan 2C, 431 53 Mölndal, Sweden, Phone: +46 300 177 94 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 56 of 62 
 
PROJECT MANAGER: 
Name: Nina Åhsberg 
Address: Argongatan 2C, 431 53 Mölndal, Sweden 
Phone: +46 72 555 01 68 
E-mail: nina.ahsberg@devicia.com 
 
BIOSTATISTICIAN 
Name: Statistiska Konsultgruppen 
Address: Thorild Wulffsgatan 1, SE-413 19 Göteborg 
E-mail: info@stat-grp.se 
 
SAFETY OFFICER 
Name: Albina Karic 
Address: Circius Pharma AB, Södra långebergsgatan 34-36, 436 32 Askim, Sweden 
Phone: +46 708314860 
E-mail: albina.karic@circiuspharma.com 
 
CLINICAL DATA MANAGER: 
Name: Matina Starck 
Address: Argongatan 2C, SE-431 53 Mölndal, Sweden 
Phone: +46 (0) 72-551 57 02 
E-mail: matina.starck@devicia.com 
 
CLINICAL INVESTIGATION MONITOR 
Name: TBD 
Address:  
Phone:  
E-mail:  
 
CLINICAL INVESTIGATION PLAN AUTHOR(S) 
Name: Mattias Andrup 
Address: Circius Pharma AB, Södra långebergsgatan 34-36, 436 32 Askim, Sweden 
Phone: +46 76 882 30 23 
E-mail: mattias.andrup@circiuspharma.com 
 
Name: Mats Engström, MD, ENT specialist 
Address: Läkarhuset i Uppsala, Kungsgatan 43, 753 21 Uppsala 
Phone: +46 709 22 02 
E-mail: matsgengstrom@gmail.com 
 
Name: Nina Åhsberg 
Address: Argongatan 2C, 431 53 Mölndal, Sweden 
Phone: +46 72 555 01 68 
E-mail: nina.ahsberg@devicia.com 
 
 
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 57 of 62 
23.3 Appendix C – Declaration of Helsinki 
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
 41st WMA General Assembly, Hong Kong, September 1989  
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington, DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008  
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
 
PREAMBLE 
 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as a 
statement of ethical principles for medical research involving human subjects, including 
research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should 
be applied with consideration of all other relevant paragraphs. 
 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles. 
 
 
GENERAL PRINCIPLES 
 
3. The Declaration of Geneva of the WMA binds the physician with the words, “The health of 
my patient will be my first consideration,” and the International Code of Medical Ethics 
declares that, “A physician shall act in the patient's best interest when providing medical 
care.” 
4. It is the duty of the physician to promote and safeguard the health, well-being and rights of 
patients, including those who are involved in medical research. The physician's knowledge 
and conscience are dedicated to the fulfillment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6. The primary purpose of medical research involving human subjects is to understand the 
causes, development and effects of diseases and improve preventive, diagnostic and 
therapeutic interventions (methods, procedures and treatments). Even the best proven 
interventions must be evaluated continually through research for their safety, effectiveness, 
efficiency, accessibility and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this goal can 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 58 of 62 
never take precedence over the rights and interests of individual research subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, health, 
dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10. Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms 
and standards. No national or international ethical, legal or regulatory requirement should 
reduce or eliminate any of the protections for research subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimises possible harm to the 
environment. 
12. Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients 
or healthy volunteers requires the supervision of a competent and appropriately qualified 
physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate access 
to participation in research. 
14. Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that participation in the 
research study will not adversely affect the health of the patients who serve as research 
subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 
 
RISKS, BURDENS AND BENEFITS 
 
16. In medical practice and in medical research, most interventions involve risks and burdens. 
 
Medical research involving human subjects may only be conducted if the importance of the 
objective outweighs the risks and burdens to the research subjects. 
 
17. All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in 
comparison with foreseeable benefits to them and to other individuals or groups affected by 
the condition under investigation. 
 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
 
18. Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.  
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 59 of 62 
VULNERABLE GROUPS AND INDIVIDUALS 
 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered protection. 
 
20. Medical research with a vulnerable group is only justified if the research is responsive to the 
health needs or priorities of this group and the research cannot be carried out in a non-
vulnerable group. In addition, this group should stand to benefit from the knowledge, 
practices or interventions that result from the research 
 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
 
21. Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant 
sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, potential conflicts of interest, 
incentives for subjects and information regarding provisions for treating and/or compensating 
subjects who are harmed as a consequence of participation in the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial 
provisions 
 
RESEARCH ETHICS COMMITTEES 
 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, the 
sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is to 
be performed as well as applicable international norms and standards but these must not be 
allowed to reduce or eliminate any of the protections for research subjects set forth in this 
Declaration.  
 
The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse 
events. No amendment to the protocol may be made without consideration and approval by the 
committee. After the end of the study, the researchers must submit a final report to the 
committee containing a summary of the study’s findings and conclusions.  
 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 60 of 62 
PRIVACY AND CONFIDENTIALITY 
 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
 
INFORMED CONSENT 
 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family members or 
community leaders, no individual capable of giving informed consent may be enrolled in a 
research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, each 
potential subject must be adequately informed of the aims, methods, sources of funding, any 
possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail, post-study 
provisions and any other relevant aspects of the study. The potential subject must be 
informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
 
After ensuring that the potential subject has understood the information, the physician or 
another appropriately qualified individual must then seek the potential subject’s freely-given 
informed consent, preferably in writing. If the consent cannot be expressed in writing, the non-
written consent must be formally documented and witnessed.       
 
All medical research subjects should be given the option of being informed about the general 
outcome and results of the study. 
 
27. When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician 
or may consent under duress. In such situations the informed consent must be sought by an 
appropriately qualified individual who is completely independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the physician 
must seek informed consent from the legally authorised representative. These individuals 
must not be included in a research study that has no likelihood of benefit for them unless it 
is intended to promote the health of the group represented by the potential subject, the 
research cannot instead be performed with persons capable of providing informed consent, 
and the research entails only minimal risk and minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed consent is 
able to give assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorised representative. The potential 
subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that 
prevents giving informed consent is a necessary characteristic of the research group. In such 
circumstances the physician must seek informed consent from the legally authorised 
representative. If no such representative is available and if the research cannot be delayed, 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 61 of 62 
the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have 
been stated in the research protocol and the study has been approved by a research ethics 
committee. Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorised representative. 
31. The physician must fully inform the patient which aspects of their care are related to the 
research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32. For medical research using identifiable human material or data, such as research on material 
or data contained in biobanks or similar repositories, physicians must seek informed consent 
for its collection, storage and/or reuse. There may be exceptional situations where consent 
would be impossible or impracticable to obtain for such research. In such situations the 
research may be done only after consideration and approval of a research ethics committee. 
 
USE OF PLACEBO 
 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested against 
those of the best proven intervention(s), except in the following circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to 
determine the efficacy or safety of an intervention  
 
and the patients who receive any intervention less effective than the best proven one, placebo, or 
no intervention will not be subject to additional risks of serious or irreversible harm as a result of 
not receiving the best proven intervention.  
 
Extreme care must be taken to avoid abuse of this option 
 
POST-TRIAL PROVISIONS 
 
34. In advance of a clinical trial, sponsors, researchers and host country governments should 
make provisions for post-trial access for all participants who still need an intervention 
identified as beneficial in the trial. This information must also be disclosed to participants 
during the informed consent process. 
 
RESEARCH REGISTRATION AND PUBLICATIONS AND DISSEMINATION OF 
RESULTS 
 
35. Every research study involving human subjects must be registered in a publicly accessible 
database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard 
to the publication and dissemination of the results of research. Researchers have a duty to 
make publicly available the results of their research on human subjects and are accountable 
for the completeness and accuracy of their reports. All parties should adhere to accepted 
guidelines for ethical reporting. Negative and inconclusive as well as positive results must be 

 
Clinical Investigation Code: 
Revision: 
CIR_001 
Version C, 09-May-2023 
 
 
Devicia AB Confidential 
T-1005E Clinical Investigation Plan 
Page 62 of 62 
published or otherwise made publicly available. Sources of funding, institutional affiliations 
and conflicts of interest must be declared in the publication. Reports of research not in 
accordance with the principles of this Declaration should not be accepted for publication. 
 
UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 
 
37. In the treatment of an individual patient, where proven interventions do not exist or other 
known interventions have been ineffective, the physician, after seeking expert advice, with 
informed consent from the patient or a legally authorised representative, may use an 
unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.