Evaluation of Safety and Reduction of Ear Pain in Adults With Acute Otitis Media
Phase: PHASE1
Conditions: Acute Otitis Media
Sponsor: Novus Therapeutics, Inc




StudyTitle ADoubleͲblind,PlaceboͲcontrolled,RandomisedStudytoEvaluatetheSafetyand
ReductionofEarPaininAdultswithAcuteOtitisMedia
NCTNumber NCT03766373
DocumentDescription ClinicalProtocol,Version:Final
DocumentDate 10Jul2018


Novus Therapeutics 
 
Protocol OP0201-C-004 
 
 
Final, 10 Jul 2018 
 
Confidential 
Page 1 of 55 
Protocol Title: 
A Double-blind, Placebo-controlled, Randomised 
Study to Evaluate the Safety and Reduction of Ear 
Pain in Adults with Acute Otitis Media 
Protocol Number: 
OP0201-C-004 
Clinical Phase: 
Phase 1 
Protocol Version and Date: 
Final, 10 Jul 2018 
EudraCT Number 
2018-002765-19 
Sponsor: 
Novus Therapeutics 
19900 MacArthur Blvd, Suite 550 
Irvine, CA 92612 
(949) 238-8090 
 
-CONFIDENTIAL- 
This document and its contents are the property of and confidential to Novus Therapeutics. Any 
unauthorised copying or use of this document is prohibited.
 

Novus Therapeutics 
 
Protocol OP0201-C-004 
 
 
Final, 10 Jul 2018 
 
Confidential 
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SIGNATURE PAGE 
 
Protocol Title: A Double-blind, Placebo-controlled, Randomised Study to Evaluate the Safety 
and Reduction of Ear Pain in Adults with Acute Otitis Media 
The undersigned have reviewed the format and content of this protocol and have approved the 
clinical study protocol. 
Any modifications of the clinical study protocol must be agreed upon by the sponsor and the 
investigator and must be documented in writing. 
Sponsor Approval: 
Signature: 
xxxxxxxxxxxxxxxxxxxx 
 Date: 
xxxxxxxxxx 
 
 
  
 
Name (print): 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx   
 
 
 
  
 
Title: 
xxxxxxxxx 
  
 
 
Investigator Agreement: 
I have read the clinical study protocol and agree to conduct the study as outlined herein. 
Signature: 
 
 
Date: 
 
 
 
 
 
 
Name (print): 
 
 
 
 
 
 
 
 
 
 
 
 

Novus Therapeutics 
 
Protocol OP0201-C-004 
 
 
Final, 10 Jul 2018 
 
Confidential 
Page 3 of 55 
SYNOPSIS 
Protocol Title: 
A Double-blind, Placebo-controlled, Randomised Study to 
Evaluate the Safety and Reduction of Ear Pain in Adults with 
Acute Otitis Media 
Protocol Number: 
OP0201-C-004 
Investigators/Study 
Centres:  
This is a multicentre study. Worldwide Clinical Trials, a contract 
research organisation, will oversee operational aspects of this study 
on behalf of Novus Therapeutics, the sponsor of the study. 
Phase of Development: 
Phase 1 
Rationale 
Acute otitis media (AOM) is usually a short-term inflammation of 
the middle ear (ME), characterised by the rapid onset of 1 or more 
signs or symptoms of acute ear infection such as earache, tugging 
at the ear, fever, or irritability in the presence of a middle ear 
effusion (MEE) (as evidenced by bulging tympanic membrane 
[TM]). AOM results from a dysfunctional eustachian tube (ET). 
Recurrent or persistent AOM may lead to rupture of the TM and/or 
significant damage to the auditory ossicles resulting in permanent 
hearing loss.  
OP0201 is formulated with 2 active ingredients 
(dipalmitoylphosphatidylcholine [DPPC] + cholesteryl palmitate 
[CP]) that are known endogenous surfactant components in human 
nasal passages and ET. OP0201 acts locally to reduce the surface 
tension at the ET, which in turn allows the ET to open in a normal 
way and drain the ME.  
OP0201 is intended to treat and prevent AOM. This study will 
evaluate the safety and immediate (within 60 minutes [min]) 
reduction of ear pain caused by AOM in adults following a single 
intranasal dose of OP0201 20 mg. 
Objectives: 
The objectives of this study are as follows:  
Primary Objective: 
x To assess the safety of intranasal OP0201 20 mg compared 
to placebo 

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Exploratory Objectives:  
x To assess the effect of intranasal OP0201 20 mg compared 
to placebo on ear pain scores using the Visual Analog Scale 
(VAS) 
x To assess the effect of intranasal OP0201 20 mg compared 
to placebo on ear pain scores using the Numeric Rating 
Scale (NRS-11) 
x To assess impression of global change in symptoms as 
measured by Patient Global Impression of Change (PGIC) 
x To assess impression of global change in symptoms as 
measured by Clinical Global Impressions Scale: Global 
Improvement (CGI-I)  
x To assess the effect of intranasal OP0201 20 mg compared 
to placebo on AOM symptoms 
x To assess the blinding efforts as measured by the Blinding 
Index (BI) 
x To evaluate subject experience with the device as measured 
by the Device Experience Questionnaire-Subject 
x To evaluate study staff experience with the device as 
measured by the Device Experience Questionnaire-Study 
Staff Administering the Treatment 
Study Design: 
This will be a single-dose, double-blind, placebo-controlled, 
randomised, parallel-group, proof-of-concept study to evaluate the 
safety and immediate (within 60 min) reduction of ear pain caused 
by AOM in adults following a single dose of intranasal 
OP0201 20 mg or placebo.  
All study-related procedures, including screening, will be 
performed on Day 1. Following Screening, but before any 
treatment-related procedures, eligible subjects will be randomly 
assigned to 1 of the following groups:  
x Single intranasal dose of OP0201 20 mg (4 sprays per 
nostril for a total of 8 sprays) 
x Single intranasal dose of placebo (4 sprays per nostril for a 
total of 8 sprays) 
Ear pain will be assessed in the left and the right ear separately at 
predose and at 10, 20, 30, and 60 min post dose using the VAS and 
the NRS-11. Global impression of change in symptoms will be 
rated by the subject at 10, 20, 30, and 60 min post dose using the 
PGIC. The physician investigator will rate global impression of 

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change at 60 min post dose using the CGI-I. AOM symptoms 
(tinnitus, dizziness, vertigo, and feeling of fullness or muffled 
hearing in the ear) will also be evaluated at predose and at 60 min 
post dose.  
Safety evaluations include vital signs measurements, otoscopy 
examination of the ear, nose, and throat (ENT), appearance of the 
TM, and adverse events (AEs). Vital signs (oral temperature, 
respiratory rate, pulse, and blood pressure) will be measured (after 
3 min of rest in the supine position) predose and at 60 min post 
dose. An ENT examination (otoscopy of the ear, nose, and 
oropharynx) will be performed by the physician investigator 
(physician qualified to perform an otoscopic exam of the ears, 
nose, and oropharynx) at predose and at 60 min post dose. All 
spontaneously reported AEs will be recorded. The appearance of 
the TM (contour, color, fluid, and translucency) will also be 
evaluated using otoscopy by the physician investigator at predose 
and at 60 min post dose. The appearance of the TM will be 
evaluated in both ears separately, regardless of whether AOM is 
bilateral or unilateral.   
After the subject has completed all assessments, except the Device 
Experience Questionnaire, on Day 1, the BI will be administered 
separately to the subject and physician investigator prior to the 
subject leaving the study centre. The Device Experience 
Questionnaire will be administered to the subject following the BI 
before the subject leaves the centre.  
Any study staff who administers treatment to subjects will also 
complete the Device Experience Questionnaire. Study staff only 
need to complete the questionnaire one time for the study, not for 
each subject treated, after all subjects to be treated by study staff 
have completed all Day 1 assessments. 
Subjects will receive a follow-up safety call 1 week (wk) after 
treatment, and reported AEs and concomitant medications will be 
recorded. 
Planned Sample Size: 
Approximately 24 adult subjects with AOM will be randomly 
assigned to OP0201 20 mg or placebo in a 1:1 ratio (12 subjects per 
arm). 
Key Patient Selection 
Criteria: 
Inclusion Criteria:  
Subjects must satisfy all of the following criteria to be included in 
the study:  
1. 0DOHDQGIHPDOHVXEMHFWVPXVWEH 18 years of age. 

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2. Subjects must have confirmed AOM diagnosis with 
moderate to severe bulging of the TM and recent 
(< 48 hours [h]) onset of ear pain. 
3. Have moderate to severe ear pain in affected ear(s), defined 
DVDVFRUHRI 5 (on a scale of 0-10) on the NRS-11 as 
evaluated by the subject at Screening.  
4. Generally good health (other than AOM) as determined by 
evaluation of medical history and physical examination at 
Screening. 
5. Negative urine pregnancy test at Screening for all female 
subjects of childbearing potential. Results must be available 
prior to randomisation. 
6. Able to read and sign written informed consent prior to 
study participation.  
Exclusion Criteria:  
Subjects who meet any of the following criteria will be disqualified 
from entering the study:  
1. Presence of a perforated TM at Screening (must be able to 
rule out perforated TM by speculum examination, 
impedance testing tympanometry, otoscopy, or Valsalva 
maneuver), or had a perforated TM within 6 months prior to 
Screening as determined by medical history  
2. Subjects with tympanostomy tubes 
3. Acute or chronic otitis externa 
4. Chronic otitis media (OM) defined as confirmed presence 
of MEE for 12 wk or longer 
5. Disorders with decreased mucociliary clearance or higher 
viscosity of the mucous (eg, cystic fibrosis, primary ciliary 
dyskinesia, Kartagener’s syndrome) 
6. Clinically relevant blockage of 1 or both nasal passages, as 
determined by the investigator’s medical judgment 
7. Permanent hearing loss irrespective of OM 
8. Subjects with medical conditions that may affect 
interpretation of the safety or efficacy of the study drug as 
determined by the investigator’s medical judgment 
9. Subjects with craniofacial abnormalities (eg, cleft palate or 
Down’s Syndrome) 

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10. Subjects with erythema of the TM without other evidence 
of OM 
11. Seborrheic dermatitis involving the affected external ear 
canal or pinna 
12. Use of medications with known vasoconstrictive properties 
(eg, decongestants [Afrin®, Sudafed®]) currently or within 
2 h prior to Screening  
13. Use of oral analgesics < 2 h prior to Screening or Baseline 
(oral analgesics > 2 h are permitted as long as ear pain 
criteria are met per Inclusion Criteria) 
14. Known hypersensitivity to DPPC, CP, or hydrofluoroalkane 
134a (HFA-134a)  
15. Female subjects who are pregnant or lactating 
16. Clinically significant mental illness that may interfere with 
the conduct of the study (as determined by the investigator 
at Screening) 
17. Exposure to any study drug within 30 days (d) prior to 
Screening 
18. Investigator and study centre personnel directly affiliated 
with this study and/or their immediate families (defined as 
spouse, significant other, parent, child, or sibling, whether 
adopted or biologic) 
19. Subject has a condition or is in a situation that, in the 
investigator’s opinion, may put the subject at significant 
risk, may confound the study results, or may interfere 
significantly with the subject’s participation in the study 
Study Drugs: 
OP0201 is a drug-device combination product for intranasal 
metered dose inhaler delivery. The dry powder active ingredients 
(DPPC + CP) are suspended in propellant (HFA-134a). Each 
metered spray delivers 2.5 mg of OP0201 (20:1 ratio DPPC and 
CP, respectively) in 0.1 mL of HFA-134a. 
Subjects will receive a single intranasal dose of OP0201 20 mg or 
placebo (4 sprays per nostril for a total of 8 sprays). 
Duration of 
Treatment: 
Duration of treatment, including Screening, will be 1 d. Subjects 
will receive a follow-up safety call 1 wk after study drug 
administration and exit the study. 
Safety Endpoints: 
Primary endpoints 

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x AEs recorded over 60 min post dose and at Day 7 for 
intranasal OP0201 20 mg or placebo 
x Change from Baseline in vital signs (oral temperature, 
respiratory rate, pulse, and blood pressure) at 60 min post 
dose for intranasal OP0201 20 mg or placebo 
x Change from Baseline in ENT examination (otoscopy of the 
ear, nose, and oropharynx) findings at 60 min post dose for 
intranasal OP0201 20 mg or placebo 
x Change from Baseline in the appearance of the TM 
(contour, color, fluid, and translucency) at 60 min post dose 
for intranasal OP0201 20 mg or placebo as measured by 
otoscopy 
Efficacy Endpoints 
Exploratory endpoints 
x Responder analysis of ear pain scores at 10, 20, 30, and 
60 min post dose for intranasal OP0201 20 mg or placebo 
using the VAS and the NRS-11 
x Change from Baseline in the VAS and the NRS-11 at 10, 
20, 30, and 60 min post dose for intranasal OP0201 20 mg 
or placebo 
x Pain Intensity Difference (PID) and Sum Pain Intensity 
Difference (SPID) analysis of the VAS and the NRS-11 
over 60 min post dose for intranasal OP0201 20 mg or 
placebo 
x Time to ear pain relief in affected ear(s), recorded as change 
from moderate/severe pain to mild or no pain, following 
intranasal OP0201 20 mg or placebo using the VAS and the 
NRS-11  
x PGIC measured at 10, 20, 30, and 60 min post dose for 
intranasal OP0201 20 mg or placebo 
x CGI-I measured at 60 min post dose for intranasal OP0201 
20 mg or placebo 
x Response on the BI at 60 min post dose for intranasal 
OP0201 20 mg or placebo 
Statistical Analyses: 
Data collected from all randomised subjects will be presented in 
data listings. Both observed values and mean change from baseline 
values for each subject will be given where applicable. 
Continuous variables will be summarised using number of non 
missing observations, mean, standard deviation, median, minimum, 

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and maximum observed values, and observed value ranges (where 
applicable). Categorical variables will be summarised using the 
frequency count and the percentage of subjects in each category. 
Subject disposition data will be summarised. Demographics (sex, 
age, race, and ethnicity), baseline characteristics (weight, height, 
and BMI), and baseline VAS, NRS-11, and otoscopy assessments 
will be summarised using descriptive statistics.  
Safety Analysis 
Safety assessments will include AEs, ENT examination, 
appearance of the TM (otoscopy), and vital signs. 
AEs will be coded in accordance with the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
Incidence for all reported AEs will be summarised overall, by 
intensity (moderate and severe AEs), and for AEs and SAEs 
leading to early termination. The incidence of treatment-emergent 
adverse events (TEAEs) will be summarised as the number and 
percentage of subjects and events reported by treatment and overall 
for each System Organ Class and Preferred Term using the Safety 
Analysis Population, which will include all randomised subjects 
who received any study drug (OP0201 or placebo). TEAEs will 
also be summarised by maximum severity and relationship to study 
drug. 
Prior and concomitant medications will be summarised using 
frequencies and percentages of subjects by treatment using the 
Safety Analysis Population. 
For appearance of the TM, 80% CIs will be calculated for the 
incidence of shifts from Baseline (0-60 min), from normal to 
abnormal for the right ear and, separately, for the left ear. A table 
presenting all changes from Baseline (from/to normal from/to 
abnormal) will be summarised by treatment for all observed 
timepoints. 
Vital signs measurements, ENT examination findings, and 
appearance of the TM will be summarised by treatment using 
descriptive statistics.  
The following will be summarised and listed as other variables 
related to safety: physical examination data, medical history, and 
urine pregnancy test results. 
Exploratory Efficacy Analysis 
PID (change from Baseline) will be computed for each post-dose 
assessment timepoint (10, 20, 30, and 60 min) for both the NRS-11 
and the VAS. Data will be analysed using a longitudinal mixed 

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model for repeated measures with fixed effects for treatment, time, 
treatment-by-time interaction, study site, and baseline pain score. 
Subject will be the random effect. Treatment differences from 
control (placebo) will be estimated from the Least Squares Means 
(LSM) from the analysis model along with 80% confidence 
intervals (CIs) and associated 2-sided p-values.  
SPID will be analysed using a linear model analysis of variance 
(ANOVA) with fixed effects for treatment, site, and baseline pain 
score for the NRS-11 and the VAS. Treatment differences from 
control (Placebo) are estimated using the LSM from the analysis 
model along with 80% CIs and associated 2-sided p-values. 
The ear pain data will be listed. The analysis of ear pain will focus 
on change of pain from Baseline to assessment at 10 min 
(0-10 min), 20 min (0-20 min), 30 min (0-30 min), and 60 min 
(0-60 min). The change of ear pain from Baseline to assessment 
will be described as the change of the sum of pain of right and left 
ear, and in addition as the change in worst reported pain across 
both ears. 
Changes from Baseline in the VAS and NRS-11 scores will be 
summarised by treatment using descriptive statistics for the 
following post-dose timepoints: 10, 20, 30, and 60 min. Statistical 
comparisons of ear pain, as measured by the VAS and the NRS-11, 
between the treatments at 60 min post dose will be performed using 
an ANOVA model. Time to ear pain relief in the affected ears, 
recorded as change from moderate/severe pain to mild or no pain 
using the VAS and the NRS-11, will be summarised by treatment. 
The 75% and 50% responder status will be assessed via a 
 75% reduction and a  50% reduction, respectively, in VAS and 
NRS-11 scores at each post-dose timepoint. The number and 
percentage of subjects achieving each response level ( 75% and 
 50% decrease) in VAS and NRS-11 scoring will be presented by 
treatment group with corresponding 80% CIs. 
The percent decrease in VAS and NRS-11 scores from Baseline to 
each post-dose timepoint will be calculated for each subject. 
Responses on the PGIC at 10, 20, 30, and 60 min post dose will be 
summarised. Responses on the CGI-I at 60 min post dose will be 
summarised. Additionally, PGIC and CGI-I will be analyzed using 
a mixed-effects model for repeated measures with treatment group, 
visit, and site as factors and baseline score (PGIC and CGI-I) as a 
covariate. 

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For all exploratory analyses, a statistically significant difference is 
defined as p < 0.20 and is presented with associated 
80% confidence intervals. 
Analysis of Other Assessments 
Responses on the BI at the end of Day 1 (ie, after all other Day 1 
assessments have been completed except the Device Experience 
Questionnaire) will be summarised. 
The Device Experience Questionnaires will be analysed at a later 
date.  
Additional details will be provided in the Statistical Analysis Plan.  
 

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TABLE OF CONTENTS 
SIGNATURE PAGE ...................................................................................................................... 2 
SYNOPSIS ...................................................................................................................................... 3 
TABLE OF CONTENTS .............................................................................................................. 12 
ADMINISTRATIVE STRUCTURE ............................................................................................ 18 
1 
INTRODUCTION ................................................................................................................ 19 
1.1 Background ....................................................................................................................... 19 
1.1.1 Nonclinical Experience ............................................................................................. 19 
1.1.2 Clinical Experience: .................................................................................................. 19 
1.2 Study Rationale ................................................................................................................. 20 
1.3 Dose Rationale .................................................................................................................. 20 
1.4 Study Endpoint Rationale ................................................................................................. 21 
1.5 Risks and Benefits for Subjects ........................................................................................ 21 
2 
STUDY OBJECTIVES ......................................................................................................... 21 
2.1 Primary Objective ............................................................................................................. 21 
2.2 Exploratory Objectives ..................................................................................................... 22 
3 
INVESTIGATIONAL PLAN ............................................................................................... 22 
3.1 Overall Study Design and Plan ......................................................................................... 22 
3.2 Study Duration .................................................................................................................. 23 
3.3 Selection of Study Population ........................................................................................... 23 
3.3.1 Inclusion Criteria ...................................................................................................... 23 
3.3.2 Exclusion Criteria ..................................................................................................... 23 
3.3.3 Removal of Subjects from Therapy or Assessment .................................................. 24 
3.4 Treatments......................................................................................................................... 25 
3.4.1 Details of Study Treatments ...................................................................................... 25 
3.4.2 Dosage Schedule ....................................................................................................... 26 
3.4.3 Treatment Assignment .............................................................................................. 26 
3.4.4 Drug Packaging and Blinding ................................................................................... 26 
3.4.5 Drug Inventory and Accountability .......................................................................... 27 
3.4.6 Treatment Compliance .............................................................................................. 27 
3.4.7 Prior and Concomitant Illnesses and Treatments ...................................................... 27 

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3.5 Assessments ...................................................................................................................... 28 
3.5.1 Schedule of Assessments .......................................................................................... 28 
3.5.2 Study Procedures ...................................................................................................... 31 
3.5.3 Early Termination Procedures .................................................................................. 32 
3.5.4 Efficacy Assessments ................................................................................................ 33 
3.5.5 Safety Assessments ................................................................................................... 34 
3.5.6 Other Assessments .................................................................................................... 34 
3.5.7 Appropriateness of Measurements ............................................................................ 35 
4 
ADVERSE EVENT REPORTING....................................................................................... 35 
4.1 Definitions and Criteria..................................................................................................... 36 
4.1.1 Adverse Events ......................................................................................................... 36 
4.1.2 Serious Adverse Events ............................................................................................ 36 
4.1.3 Unexpected Adverse Drug Reactions ....................................................................... 37 
4.1.4 Assessing Intensity and Relationship........................................................................ 37 
4.2 Reporting Procedures and Requirements .......................................................................... 38 
4.2.1 Adverse Events ......................................................................................................... 38 
4.2.2 Serious Adverse Events ............................................................................................ 39 
4.3 Procedures for Documenting Pregnancy During Study .................................................... 39 
5 
DATA MANAGEMENT AND STATISTICAL ANALYSIS ............................................. 40 
5.1 Data Management Considerations .................................................................................... 40 
5.2 Statistical Considerations .................................................................................................. 40 
5.2.1 Sample Size Justification .......................................................................................... 40 
5.2.2 Analysis Populations ................................................................................................. 40 
5.2.3 Protocol Deviations ................................................................................................... 41 
5.2.4 Subject Disposition ................................................................................................... 41 
5.2.5 Demographic and Baseline Characteristics .............................................................. 41 
5.2.6 Efficacy Analyses ..................................................................................................... 41 
5.2.7 Safety Analyses ......................................................................................................... 43 
5.2.8 Interim Analyses ....................................................................................................... 45 
5.3 Analysis of Other Assessments ......................................................................................... 45 
6 
STUDY MANAGEMENT ................................................................................................... 45 

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6.1 Ethics and Consent ............................................................................................................ 45 
6.1.1 Regulations and Guidelines ...................................................................................... 45 
6.1.2 Independent Ethics Committees ............................................................................... 45 
6.1.3 Informed Consent...................................................................................................... 45 
6.2 Indemnification ................................................................................................................. 45 
6.3 Discontinuation of the Study by the Sponsor ................................................................... 45 
6.4 Study Documentation........................................................................................................ 46 
6.5 Study Monitoring and Auditing ........................................................................................ 46 
6.6 Retention of Records ......................................................................................................... 46 
6.7 Use of Study Findings ....................................................................................................... 46 
6.8 Publications ....................................................................................................................... 46 
7 
REFERENCES ..................................................................................................................... 48 
8 
APPENDICES ...................................................................................................................... 51 
8.1 Blinding Index Questionnaire ........................................................................................... 51 
8.2 Otoscopy Assessment of the Appearance of the Tympanic Membrane ........................... 52 
8.3  Device Experience Questionnaire-Study Staff Administering Treatment ....................... 54 
 
TABLES 
Table 3.1: Details of Study Drugs ................................................................................................. 26 
Table 3.2: Schedule of Assessments ............................................................................................. 29 
Table 4.1: Adverse Event Causality .............................................................................................. 38 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
ANOVA 
analysis of variance 
AOM 
acute otitis media 
BI 
Blinding Index 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
C 
Celsius 
CGI-I 
Clinical Global Impressions Scale: Global Improvement 
CI 
confidence interval 
CP 
cholesteryl palmitate 
d 
day(s) 
DPPC 
dipalmitoylphosphatidylcholine 
eCRF 
electronic case report form 
ENT 
ear, nose, and throat 
ET 
eustachian tube 
GCP 
Good Clinical Practice 
h 
hour(s) 
HFA-134a 
hydrofluoroalkane 134a 
IB 
Investigator’s Brochure 

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Abbreviation 
Definition 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
LSM 
Least Squares Mean 
MDI 
metered-dose inhaler 
ME 
middle ear 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEE 
middle ear effusion 
min 
minute(s) 
mmHg 
millimeters of mercury 
mo 
month(s) 
NRS 
Numeric Rating Scale 
OM 
otitis media 
OME 
otitis media with effusion 
OTC 
over-the-counter 
PGIC 
Patient Global Impression of Change 
PI 
Principal Investigator 
PID 
Pain Intensity Difference 
PK 
pharmacokinetic 
ppm 
parts per million 
RDS 
respiratory distress syndrome 
SAE 
serious adverse event 

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Abbreviation 
Definition 
SAP 
Statistical Analysis Plan 
SOP 
standard operating procedure 
SPID 
Sum Pain Intensity Difference 
TEAE 
treatment-emergent adverse event 
TM 
tympanic membrane 
URI 
upper respiratory infection 
VAS 
Visual Analog Scale 
WCT 
Worldwide Clinical Trials 
wk 
week(s) 
y 
year(s) 
 
 

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ADMINISTRATIVE STRUCTURE 
 
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1 INTRODUCTION 
1.1 Background 
Acute otitis media (AOM) is usually a short-term inflammation of the middle ear (ME), 
characterised by the rapid onset of one or more signs or symptoms of acute ear infection such as 
earache, tugging at the ear, fever, or irritability in the presence of a middle ear effusion (MEE) 
(as evidenced by bulging tympanic membrane). Otitis media (OM) is frequently preceded by 
upper respiratory infection (URI), including cough and rhinorrhea.1,2,3,4 Bacterial and/or viral 
infection of the ME may occur as a consequence of AOM. OME is fluid in the ME without 
prominent signs or symptoms of acute ear infection.5 The clinical concern with OME is primarily 
conductive hearing loss, but also vestibular problems, ear discomfort, and reduced quality of 
life.5 Morbidity associated with OM is driven by recurrence and persistence of OM. Recurrent or 
persistent AOM and/or OME may lead to rupture of the tympanic membrane (TM) and/or 
significant damage to the auditory ossicles resulting in permanent hearing loss. Data from 
systematic reviews of randomised controlled studies showed only a small benefit of oral 
antibiotic therapy for complete resolution of OME, but no significant impact on hearing levels or 
the rate of subsequent tympanostomy tube insertion.6,7,8 Globally, there is a growing public 
health concern about the emergence of antibiotic resistant bacterial pathogens causing OM.9,10  
Novus is developing OP0201, a non-antibiotic and non-analgesic combination product intended 
to treat and prevent OM. OP0201 comprises a novel formulation of 2 active ingredients 
(dipalmitoylphosphatidylcholine [DPPC] and cholesteryl palmitate [CP]) suspended in propellant 
(hydrofluoroalkane 134a [HFA-134a]). DPPC and CP are known endogenous surfactant 
components in human nasal passages and eustachian tube (ET). Novus predicts proactive use of 
OP0201, at the onset of URI, may prevent ET dysfunction in susceptible patients, significantly 
reducing the incidence of recurrent AOM. Additionally, concomitant treatment of OP0201 with 
antibiotics in patients with AOM may facilitate faster resolution of the AOM, prevent recurrence 
of AOM, and/or prevent the need for a second or third course of antibiotics when AOM does not 
adequately respond to first course antibiotic therapy. Additionally, OP0201 may reduce the 
duration and severity of OME, and/or prevent OME developing after occurrence of AOM.  
1.1.1 Nonclinical Experience 
DPPC:CP 200:1 w/w has been evaluated in proof-of-concept studies in 3 animal species 
(ie, chinchillas, gerbils, and mice).11,12,13,14 Across these studies, the beneficial effects of 
DPPC:CP 200:1 w/w were consistently better than those of no treatment, treatment with 
propellant alone (considered control). No adverse reactions to the intranasal surfactant 
DPPC:CP 200:1 w/w were observed in any of the experimental animal group evaluations. 
Further details about the nonclinical evaluation of DPPC, CP, and HFA-134a are provided in the 
Investigator’s Brochure (IB).15  
1.1.2 Clinical Experience:  
OP0201 has not yet been evaluated in clinical studies in humans.  
In addition to the animal studies of DPPC:CP administered in a formulation that was a 
200:1 w/w ratio, the clinical safety and tolerability of OP0201 (formulation that is 20:1 w/w 

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ratio) for human use is further guided by a limited amount of data from 9 human cases exposed 
to 1 or more doses of other formulations.15 Eight subjects were exposed to DPPC:CP 
administered in a 16:1 w/w ratio in HFA-134a (each 0.1 mL spray delivered 2.5 mg of active 
ingredient), and 1 subject was exposed to DPPC:CP in a 200:1 w/w ratio in HFA-134a (each 
0.1 mL spray delivered 5 mg of active ingredient). None of the subjects reported a serious 
adverse event (SAE), and no deaths due to the study drug were reported.  
1.2 Study Rationale 
OP0201 is formulated with 2 active ingredients (DPPC + CP) that are known endogenous 
surfactant components in human nasal passages and ET. Among phospholipid compounds, 
DPPC is the most hydrophobic and surface active.16,17 The hydrophobic nature of DPPC causes it 
to spread very slowly over an aqueous surface. However, in the presence of a spreading agent 
(ie, CP), phospholipids easily “spread” along a surface pressure gradient of mucosal lined 
lumens.17,18 OP0201 acts locally to reduce the surface tension at the ET, which in turn reduces 
passive opening pressure and allows the ET to open and drain the ME.  
OP0201 is intended to treat and prevent AOM. This study will evaluate the safety and immediate 
(within 60 minutes [min]) reduction of ear pain caused by AOM in adults following a single 
intranasal dose of OP0201 20 mg. 
1.3 Dose Rationale 
The composition of OP0201 is designed to maximise the lowering of the mucosal surface 
tension. Safety and proof-of-concept results from animal pharmacology studies of a formulation 
of DPPC:CP 200:1 w/w are considered supportive of the OP0201 formulation (DPPC:CP 20:1 
w/w) intended for humans. Across several nonclinical pharmacology studies, the beneficial 
effects of DPPC:CP 200:1 w/w were consistently better than those of no treatment and treatment 
with propellant alone (ie, placebo).15 A multiple day repeat dose of 20 mg twice daily for 
10 days (d) was given to chinchillas. The total exposure was 400 mg over 10 d: approximately 
800 to 1100 mg/kg for chinchilla weighing 0.35 to 0.5 kg.12 No AEs were observed in any of the 
animal studies.  
The clinical safety and tolerability of OP0201 (DPPC:CP 20:1 w/w) for human use is further 
guided by a limited amount of data from 9 human cases exposed to1 or more doses of other 
formulations (see Section 1.1.2).  
In this study, subjects will receive a single intranasal dose of OP0201 20 mg or placebo (4 sprays 
per nostril for a total of 8 sprays). Treatment duration will be 1 d.  
The surfactant active ingredients of OP0201 are endogenous to human nasal and respiratory 
mucosal surfaces. Additionally, surfactants have been approved for topical administration via the 
trachea to infants with RDS with a long history of safety and tolerability at much higher 
exposure levels on a mg/kg basis than proposed herein.15 Thus, in this study the maximum, total 
exposure will be 20 mg for 1 d; approximately 0.28 mg/kg for humans weighing 70 kg. 
The propellant, HFA-134a, will be utilised in concentrations similar to that in other relevant 
products (eg, Nasacort HFA®, Aventis Pharmaceuticals, Inc., Bridgewater, NJ), with its safety 
and tolerability supported in publications,19,20,21 as well as in prior approved and marketed nasal 
administration products. 

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1.4 Study Endpoint Rationale 
The primary endpoint in this study is to evaluate the safety of a single intranasal dose of OP0201 
20 mg in adults with AOM. Spontaneously reported AEs, vital signs measurements, and ear, 
nose, and throat (ENT) examination findings will be used to assess the safety of OP0201. The 
ENT examination findings will be used to evaluate any AEs of the ear, nose, and oropharynx that 
occurred during treatment. Vital signs measurements will be used to evaluate whether any 
clinically significant changes in blood pressure, pulse, respiratory rate, and oral temperature 
occurred post dose.  
All efficacy assessments will be exploratory endpoints and were selected to evaluate reduction of 
ear pain and symptoms associated with AOM.  
1.5 Risks and Benefits for Subjects 
To date, no clinical studies of OP0201 have been conducted in humans. Thus, information 
regarding expected risks and benefits is unknown.  
The clinical safety and tolerability of OP0201 (DPPC:CP 20:1 w/w) for human use is guided by 
the limited data from human exposure to other formulations (see Section 1.1.2) and animal 
studies. Of the 9 subjects exposed to study drug containing DPPC and CP, no SAEs or deaths 
were reported. Safety and proof-of-concept results from animal pharmacology studies are 
considered supportive of the formulation intended for humans. Across several nonclinical 
pharmacology studies, the beneficial effects of a formulation of DPPC:CP 200:1 w/w were 
consistently better than those of no treatment and treatment with propellant alone (ie, placebo).15 
No AEs were observed in any of the animal studies.  
DPPC and CP are listed as ingredients in other marketed products indicated for the prevention of 
RDS in premature neonates. The safety and tolerability of these products is summarised in the 
IB.  
Propellant HFA-134a is used in marketed nasal products and is also present in OP0201. 
HFA-134a has a good safety and tolerability profile in patients suffering from perennial allergic 
rhinitis.22   
The most frequent AEs for 578 placebo-treated (HFA-134a) adults and adolescents with seasonal 
or perennial allergic rhinitis from short term (2-6 wk) controlled trials were: nasal discomfort 
(4.8%), epistaxis (1.2%), and headache (1.6%).23 Nasal ulcerations occurred in 2 subjects treated 
with placebo in these studies. The most frequent AEs for 111 placebo-treated (HFA-134a) adults 
and adolescents with perennial allergic rhinitis from a long-term (52 wk) controlled trial were: 
epistaxis (2%; 2/111; 1 mild, 1 moderate intensity). A total of 3 subjects treated with placebo 
withdrew from the study due to an adverse reaction. No erosions or ulcerations were noted in 
subjects who received placebo in this study. No subject experienced a nasal septum perforation 
during the trial. 
2 STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is:  

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x To assess the safety of intranasal OP0201 20 mg compared to placebo 
2.2 
Exploratory Objectives 
The exploratory objectives of this study are: 
x To assess the effect of intranasal OP0201 20 mg compared to placebo on ear pain scores 
using the Visual Analog Scale (VAS) 
x To assess the effect of intranasal OP0201 20 mg compared to placebo on ear pain scores 
using the Numeric Rating Scale (NRS-11) 
x To assess impression of global change in symptoms as measured by Patient Global 
Impression of Change (PGIC)  
x To assess impression of global change in symptoms as measured by the Clinical Global 
Impressions Scale: Global Improvement (CGI-I)  
x To assess the effect of intranasal OP0201 20 mg compared to placebo on AOM 
symptoms 
x To assess the blinding efforts as measured by the Blinding Index (BI) 
x To evaluate subject experience with the device as measured by the Device Experience 
Questionnaire-Subject 
x To evaluate study staff experience with the device as measured by the Device Experience 
Questionnaire-Study Staff Administering the Treatment 
3 INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This will be a single-dose, double-blind, placebo-controlled, randomised, parallel-group, 
proof-of-concept study to evaluate the safety and immediate (within 60 min) reduction of ear 
pain caused by AOM in adults following a single dose of intranasal OP0201 20 mg or placebo.  
All study-related procedures, including screening, will be performed on Day 1. Following 
Screening, but before any treatment-related procedures, eligible subjects will be randomly 
assigned to 1 of the following groups:  
x Single intranasal dose of OP0201 20 mg (4 sprays per nostril for a total of 8 sprays) 
x Single intranasal dose of placebo (4 sprays per nostril for a total of 8 sprays) 
Ear pain will be assessed in the left and the right ear separately, at predose and at 10, 20, 30, and 
60 min post dose using the VAS and the NRS-11. Global impression of change in symptoms will 
be rated by the subject at 10, 20, 30, and 60 min post dose using the PGIC. The physician 
investigator will rate global impression of change at 60 min post dose using the CGI-I. AOM 
symptoms (tinnitus, dizziness, vertigo, and feeling of fullness or muffled hearing in the ear) will 
also be evaluated at predose and at 60 min post dose. 
Safety evaluations include vital signs measurements, ENT examination using otoscopy, 
appearance of the TM, and AEs. Vital signs (oral temperature, respiratory rate, pulse, and blood 

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pressure) will be measured (after 3 min of rest in the supine position) predose and at 60 min post 
dose. An ENT examination (otoscopy of the ear, nose, and oropharynx) will be performed by the 
physician investigator (physician qualified to perform an otoscopic exam of the ears, nose, and 
oropharynx) at predose and at 60 min post dose. All spontaneously reported AEs will be 
recorded. The appearance of the TM (contour, color, fluid, and translucency) will also be 
evaluated using otoscopy by the physician investigator at predose and at 60 min post dose. The 
appearance of the TM will be evaluated in both ears separately, regardless if AOM is bilateral or 
unilateral.  
After the subject has completed all assessments on Day 1, the BI will be administered separately 
to the subject and physician investigator prior to the subject leaving the study centre. The Device 
Experience Questionnaire will be administered to the subject following the BI before the subject 
leaves the centre.  
Any study staff who administer treatment to subjects will also complete the Device Experience 
Questionnaire. Any study staff who administered treatment only needs to complete the 
questionnaire one time for the study, not for each subject treated. 
Subjects will receive a follow-up safety call 1 wk after treatment, and reported AEs and 
concomitant medications will be recorded.  
3.2 
Study Duration 
Duration of treatment, including Screening, will be 1 d. Subjects will receive a follow-up safety 
call 1 wk after study drug administration and exit the study. 
3.3 
Selection of Study Population 
The study population consists of adult subjects with a confirmed diagnosis of AOM. Specific 
entry criteria are detailed in Section 3.3.1 and Section 3.3.2. 
3.3.1 Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study:  
1. 0DOHDQGIHPDOHVXEMHFWVPXVWEH 18 y of age. 
2. Subjects must have confirmed AOM diagnosis with moderate to severe bulging of the 
TM and recent (< 48 hours [h]) onset of ear pain. 
3. Have moderate to severe ear pain in the affected ear(s)GHILQHGDVDVFRUHRI 5 (on a 
scale of 0-10) on the NRS-11 as evaluated by the subject at Screening.  
4. Generally good health (other than AOM) as determined by evaluation of medical history 
and physical examination at Screening. 
5. Negative urine pregnancy test at Screening for all female subjects of childbearing 
potential. Results must be available prior to randomisation. 
6. Able to read and sign written informed consent prior to study participation.  
3.3.2 Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study:  

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1. Presence of a perforated TM at Screening (must be able to rule out perforated TM by 
speculum examination, impedance testing tympanometry, otoscopy, or Valsalva 
maneuver), or had a perforated TM within 6 months (mo) prior to Screening as 
determined by medical history  
2. Subjects with tympanostomy tubes 
3. Acute or chronic otitis externa 
4. Chronic OM defined as confirmed presence of MEE for 12 wk or longer 
5. Disorders with decreased mucociliary clearance or higher viscosity of the mucous 
(eg, cystic fibrosis, primary ciliary dyskinesia, Kartagener’s syndrome) 
6. Clinically relevant blockage of 1 or both nasal passages, as determined by the 
investigator’s medical judgment 
7. Permanent hearing loss irrespective of OM 
8. Subjects with medical conditions that may affect interpretation of the safety or efficacy of 
study drug as determined by the investigator’s medical judgment 
9. Subjects with craniofacial abnormalities (eg, cleft palate, Down’s Syndrome) 
10. Subjects with erythema of the TM without other evidence of OM 
11. Seborrheic dermatitis involving the affected external ear canal or pinna 
12. Use of medications with known vasoconstrictive properties (eg, decongestants [Afrin®, 
Sudafed®]) currently or within 2 h prior to Screening  
13. Use of oral analgesics < 2 h prior to Screening or Baseline (oral analgesics > 2 h are 
permitted as long as ear pain criteria are met per Inclusion Criteria) 
14. Known hypersensitivity to DPPC, CP, or HFA-134a 
15. Female subjects who are pregnant or lactating 
16. Clinically significant mental illness that may interfere with the conduct of the study (as 
determined by the investigator at Screening) 
17. Exposure to any study drug within 30 d prior to Screening. 
18. Investigator and study centre personnel directly affiliated with this study and/or their 
immediate families (defined as spouse, significant other, parent, child, or sibling, whether 
adopted or biologic) 
19. Subject has a condition or is in a situation that, in the investigator’s opinion, may put the 
subject at risk, may confound the study results, or may interfere significantly with the 
subject’s participation in the study 
3.3.3 Removal of Subjects from Therapy or Assessment 
A subject will be considered to have completed the study when he or she completes the 
follow-up safety call on Day 7. If a subject is discontinued at any time after randomisation into 
the study, but before 60 min post dose, the investigator will make every effort to follow the 

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subject and complete the assessments at 60 min post dose/early termination assessments as 
shown in Section 3.5.1. Subjects who discontinue the study prematurely will be replaced.  
A termination electronic case report form (eCRF) page should be completed for every subject 
who receives study drug, whether or not the subject completes the study. The reason for any early 
discontinuation should be indicated on this form. The primary reason for a subject discontinuing 
early should be selected from the following standard categories of early termination: 
x Adverse Event (Adverse Reaction): Clinical events occurred that, in the medical judgment 
of the investigator for the best interest of the subject, are grounds for discontinuation. 
This includes serious and nonserious AEs regardless of relation to the study drug. 
x Death: The subject died. 
x Withdrawal of Consent: The subject desired to withdraw from further participation in the 
study in the absence of an investigator-determined medical need to withdraw. If the 
subject gave a reason for withdrawing, it should be recorded in the eCRF. 
x Protocol Violation: The subject’s findings or conduct failed to meet the protocol entry 
criteria or failed to adhere to the protocol requirements (eg, drug noncompliance, failure 
to complete all assessments). The violation necessitated early discontinuation from the 
study. 
x Lost to Follow-Up: The subject did not complete the follow-up safety call and study 
personnel were unable to contact the subject. 
x Other: The subject was discontinued for a reason other than those listed above, such as 
theft or termination of study by sponsor. 
3.4 
Treatments 
3.4.1 Details of Study Treatments 
OP0201 is a drug-device combination product that comprises a novel formulation of 2 active 
ingredients (DPPC and CP) suspended in propellant (HFA-134a), an inactive ingredient. There 
are no other ingredients (ie, no excipients, no fillers) in the formulation. The drug product is 
formulated as a dry powder suspended in propellant and delivered via a metered-dose inhaler 
(MDI). The active ingredients are synthetically derived and none of the ingredients contain 
animal or human derivatives. 
The OP0201 MDI container should be stored at room temperature between 68°F and 77°F (20°C 
and 25°C, respectively); excursions are permitted from 59°F and 86°F (15°C and 30°C, 
respectively). Store the MDI container with the actuator down.  
The sponsor will provide all study drug materials.  
Information about the study drugs is provided in Table 3.1.  

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Table 3.1: Details of Study Drugs 
 
Active 
Placebo 
Name 
OP0201 
Not applicable 
xxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxx   
Dose 
20 mg (4 sprays per nostril; each 0.1 mL 
spray is 2.5 mg OP0201).  
Total of 8 sprays = 1 dose. 
0 mg (4 sprays per nostril; each 
0.1 mL spray is 0 mg OP0201).  
Total of 8 sprays = 1 dose.  
Route 
Intranasal 
Intranasal 
Formulation 
Metered dose inhaler 
Metered dose inhaler 
Strength 
20 mg 
0 mg 
Abbreviations: USA = United States of America 
 
3.4.2 Dosage Schedule 
Subjects will receive a single intranasal dose (4 sprays per nostril for a total of 8 sprays) of 
OP0201 20 mg or placebo.  
3.4.3 Treatment Assignment 
Following Screening, but before any treatment-related procedures, eligible subjects will be 
randomly assigned in a 1:1 ratio to 1 of the following groups:  
x Single intranasal dose of OP0201 20 mg (4 sprays per nostril for a total of 8 sprays) 
x Single intranasal dose of placebo (4 sprays per nostril for a total of 8 sprays) 
3.4.4 Drug Packaging and Blinding 
OP0201 and placebo will be packaged and labeled by Catalent in accordance with applicable 
national laws.  
Kits containing OP0201 or placebo will be identical in appearance and will be provided to the 
study sites. Kit numbers for OP0201 and placebo will be randomly assigned through the 
Interactive Response Technology system using a randomisation list.  
All subjects and clinical staff will be blinded to the assigned treatment. The PI will be ultimately 
responsible for ensuring that the integrity of the blind is maintained throughout the study, and 
will be required to notify the sponsor in the event of any breaking of the blind for any reason. 
If an SAE occurs during the study that meets the criteria for expedited reporting (ie, is a 
Suspected Unexpected Serious Adverse Reaction), the subject will be unblinded by WCT 
pharmacovigilance. In an emergency situation, the investigator may unblind the study subject’s 
treatment assignment. When possible, the Medical Monitor should be notified prior to 

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unblinding. The investigator should inform the Medical Monitor of the unblinding if there is no 
notification prior to the unblinding. 
3.4.5  Drug Inventory and Accountability 
The investigator must keep an accurate accounting of the number of study drug units delivered to 
the site, dispensed to subjects, and returned to the sponsor at the completion of the study. The 
study drug must be dispensed for subjects by an appropriately qualified study staff member who 
will be administering the treatment to the subject. The study drug is to be used in accordance 
with the protocol by subjects who are under the direct supervision of the investigator. 
Investigators should maintain records that document adequately that the subjects were provided 
the doses specified by the protocol and reconcile all study drugs received at the site before final 
disposition. At the end of the study, or as directed, all study drugs, including unused, partially 
used, and empty containers, as well as devices, will be returned to the sponsor sorted as per 
subject.  
3.4.6 Treatment Compliance 
Administration of study drug will be performed by study personnel to ensure accuracy of study 
drug delivery and compliance. 
3.4.7 Prior and Concomitant Illnesses and Treatments 
3.4.7.1 Prior and Concomitant Illnesses 
Investigators should document all significant illnesses that the subject has experienced within 
6 mo of Screening. Additional illnesses present at the time informed consent is given are to be 
regarded as concomitant illnesses. Illnesses first occurring or detected during the study and/or 
worsening of a concomitant illness during the study are to be documented as AEs on the eCRF. 
3.4.7.2 Prior and Concomitant Treatments 
Prior treatments, defined as those taken within 2 wk before Screening, should be recorded in the 
eCRF as prior medications. Concomitant treatments, defined as treatments taken after the first 
dose of study drug, should be recorded in the eCRF as concomitant medications. Concomitant 
medications will be coded using the latest version of the World Health Organization Drug 
Dictionary. 
Use of medications with known vasoconstrictive properties (eg, decongestants [Afrin®, 
Sudafed®]) currently or within 2 h prior to Screening are not permitted.  
Any medication or therapy that is taken by or administered to the subject during the course of the 
study must be recorded in the eCRF. The entry must include the dose, regimen, route, indication, 
and dates of use. The following medications are prohibited until the end of the treatment period 
on Day 1 (ie, 60 min post dose):  
x Medications with known vasoconstrictive properties (eg, decongestants [Afrin®, 
Sudafed®]) 
x Oral analgesics 

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3.5 
Assessments 
Unless otherwise indicated, all assessments will be performed by the investigator or designated 
study personnel.  
3.5.1 Schedule of Assessments 
The procedures to be performed throughout the study are outlined in the Schedule of 
Assessments (Table 3.2). A detailed description of each assessment may be found in 
Section 3.5.2. 

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Table 3.2: Schedule of Assessments 
Study Period 
Screening/ 
Baseline 
Treatment 
Safety 
Follow-up 
Telephone 
Call/ 
Study 
Exit 
Study Day 
1 
1 
7 
Study Minute 
N/A 
0 
10 20 30 
60/Early 
Termination 
N/A 
Informed Consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Physical Examinationa 
X 
 
 
 
 
 
 
ENT Examinationb,c 
X 
 
 
 
 
X 
 
Urine Pregnancy Testd 
X 
 
 
 
 
 
 
Randomisatione 
X 
 
 
 
 
 
 
Vital Signs and Body Weightf 
X 
 
 
 
 
X 
 
NRS-11g 
Xh 
 
X 
X 
X 
X 
 
VASg 
Xi 
 
X 
X 
X 
X 
 
Otoscopyc,j 
X 
 
 
 
 
X 
 
PGIC 
 
 
X 
X 
X 
X 
 
CGI-Ik 
 
 
 
 
 
X 
 
AOM Symptomsl 
X 
 
 
 
 
X 
 
BIm 
 
 
 
 
 
X 
 
Device Experience Questionnaire-
Subject 
 
 
 
 
 
X 
 
Device Experience Questionnaire-Study 
Staff Administering the Treatmentn 
 
 
 
 
 
X 
 
Study Drug Administrationo 
 
X 
 
 
 
 
 
Prior and Concomitant Medications 
Xp 
------------------X----------------- 
X 
AEs 
 
-------------------X----------------- 
X 
a 
Examination will include general appearance, skin, neck (including thyroid), eyes, heart, lungs, abdomen, lymph nodes, 
extremities, and nervous system.  
b 
Otoscopy of the ear, nose, and oropharynx. 
c 
 To be performed by a physician investigator. 
d 
For all female subjects of childbearing potential. Results must be available prior to randomisation.  

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e 
Subjects will be randomly assigned to OP0201 20 mg or placebo in a 1:1 ratio (OP0201:placebo) following screening 
procedures, but prior to baseline and treatment procedures.  
f 
Oral temperature, respiratory rate, pulse, and BP measured after at least 3 min of rest in the supine position will be performed 
at Baseline and at 60 min post dose. Body weight will be measured at Baseline only. 
g 
Both ears will be evaluated regardless if AOM is bilateral or unilateral.  
h 
Administered to assess pain in both ears during the screening procedures. This score will also serve as the baseline measure 
for affected ear(s).  
i 
To be administered after randomisation.  
j 
Appearance of the TM will be rated for contour (normal, retracted, full, bulging, perforated), color (normal, partly red, 
completely red), fluid behind the TM (no/yes; if yes-yellow, translucent, red, blue, or black), and translucency (translucent, 
semi-opaque, and opaque). Both ears will be evaluated regardless if AOM is bilateral or unilateral. 
k 
To be completed by the physician investigator who evaluated the subject at baseline and post dose. 
l 
AOM symptoms to be evaluated include tinnitus, dizziness, vertigo, and feeling of fullness or muffled hearing in the ear. 
m 
To be administered to the subject and physician investigator separately after completion of all other assessments. 
n 
To be obtained only once by each qualified staff member who administers the study treatment to subjects in this study. 
o 
4 sprays of intranasal OP0201 20 mg or placebo will be delivered to each nostril for a total of 8 sprays. 
p 
Prior medications will only be recorded at Screening. 
Abbreviations: AE = adverse event; AOM = acute otitis media; BI = Blinding Index; BP = blood pressure; CGI-I = Clinical 
Global Impressions Scale: Global Improvement; ENT = ear, nose, and throat; min = minute(s); N/A = not applicable; 
NRS-11 = Numeric Rating Scale; PGIC = Patient Global Impression of Change; TM = tympanic membrane; VAS = Visual 
Analog Scale 
 

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3.5.2 Study Procedures 
3.5.2.1 Screening/Baseline Procedures (Day 1) 
The assessments during the screening/baseline phase will determine the subjects’ eligibility for 
the study and also their ability to comply with protocol requirements by completing all 
screening/baseline assessments.  
The following procedures will be performed and recorded during the screening/baseline period: 
x Written informed consent 
x Demographics 
x Inclusion and Exclusion Criteria 
x Medical history 
x Physical examination 
x ENT examination (physician investigator to perform otoscopy of the ear, nose, and 
oropharynx) 
x Urine pregnancy test (for all female subjects of childbearing potential; results must be 
available prior to randomisation) 
x Vital signs (oral temperature, respiratory rate, pulse, and blood pressure measured after at 
least 3 min of rest in the supine position) and body weight 
x Randomisation 
x NRS-11 (score will be used to assess pain in both ears during Screening and as the 
baseline measure for affected ear(s); both ears will be evaluated regardless if AOM is 
bilateral or unilateral) 
x VAS (to be administered after randomisation; both ears will be evaluated regardless if 
AOM is bilateral or unilateral) 
x Otoscopy (physician investigator to evaluate contour, color, fluid, and translucency) 
x AOM symptoms (tinnitus, dizziness, vertigo, and feeling of fullness or muffled hearing in 
the ear) 
x Prior and concomitant medications 
3.5.2.2 Treatment Procedures (Day 1)  
After completion of all screening/baseline procedures, subjects will receive a single intranasal 
dose (4 sprays per nostril for a total of 8 sprays) of OP0201 20 mg or placebo. Reported AEs will 
be recorded.  
At 10, 20, and 30 min post dose, the following procedures will be performed:  
x NRS-11 (both ears will be evaluated regardless if AOM is bilateral or unilateral) 
x VAS (both ears will be evaluated regardless if AOM is bilateral or unilateral) 

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x PGIC 
x AEs and concomitant medications 
At 60 min post dose, the following procedures will be performed:  
x ENT examination (physician investigator to perform otoscopy of the ear, nose, and 
oropharynx) 
x Vital signs (oral temperature, respiratory rate, pulse, and blood pressure measured after at 
least 3 min of rest in the supine position) 
x NRS-11 (both ears will be evaluated regardless if AOM is bilateral or unilateral) 
x VAS (both ears will be evaluated regardless if AOM is bilateral or unilateral) 
x Otoscopy (physician investigator to evaluate contour, color, fluid, and translucency) 
x PGIC 
x CGI-I (obtained from the physician investigator who evaluated the subject at baseline and 
post dose) 
x AOM symptoms (tinnitus, dizziness, vertigo, and feeling of fullness or muffled hearing in 
the ear) 
x AEs and concomitant medications 
x BI (to be administered separately to the subject and physician investigator after 
completion of all other assessments) 
x Device Experience Questionnaire-Subject 
x Device Experience Questionnaire-Study Staff Administering Treatment 
3.5.2.3 Safety Follow-up Telephone Call/Study Exit 
x AEs and concomitant medications 
3.5.3 Early Termination Procedures 
The following assessments will be administered to subjects who terminate prematurely from the 
study:  
x ENT examination (physician investigator to perform otoscopy of the ear, nose, and 
oropharynx) 
x Vital signs (oral temperature, respiratory rate, pulse, and blood pressure measured after at 
least 3 min of rest in the supine position) 
x NRS-11 (both ears will be evaluated regardless if AOM is bilateral or unilateral) 
x VAS (both ears will be evaluated regardless if AOM is bilateral or unilateral) 
x Otoscopy (physician investigator to evaluate contour, color, fluid, and translucency) 
x PGIC 

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x CGI-I (obtained from the physician investigator who evaluated the subject at baseline and 
post dose) 
x AOM symptoms (tinnitus, dizziness, vertigo, and feeling of fullness or muffled hearing in 
the ear) 
x AEs and concomitant medications 
x BI (to be administered separately to the subject and physician investigator after 
completion of all other assessments) 
x Device Experience Questionnaire-Subject 
3.5.4 Efficacy Assessments 
Numeric Rating Scale (NRS-11): The NRS is commonly used in the clinical assessment of 
pain.24 The NRS requires that subjects select a whole number that best represents the intensity of 
their pain. On the NRS-11, pain scores range from 0 to 11, with 0 representing no pain and 
11 representing the worst pain possible.25,26 Use of the NRS in the emergency department for the 
measurement of acute pain has been validated.24  
The NRS-11 will be administered at Screening to evaluate pain in both ears as part of the 
eligibility requirements. The score obtained at Screening will also serve as a baseline 
measurement for the affected ear(s). The NRS-11 will also be administered at 10, 20, 30, and 
60 min post dose. Ear pain will be scored by the subjects separately for the left and right ear.  
Visual Analog Scale (VAS): The VAS has been widely used for the assessment of pain in clinical 
research.24,26The VAS has also been used to assess acute pain and for the assessment of pain in 
emergency departments.26 The VAS -100 mm version (also labeled as the VAS-10 cm version) 
consists of a 100 mm line anchored by 2 extremes of pain (eg, no pain versus worse pain).25,26 
Subjects mark the line where their pain is best represented between the 2 anchors. Pain intensity 
scores are determined by the distance from the ‘no pain’ anchor to the subject’s mark.  
Ear pain will be scored by the subjects separately for the left and right ear using the VAS, which 
will be administered at Baseline and at 10, 20, 30, and 60 min post dose.  
Patient Global Impression of Change (PGIC): The PGIC is a questionnaire that asks the subject 
to assess the global change in health status since receiving the study drug. The PGIC has been 
used frequently in clinical and observational studies across the spectrum of therapeutic areas and 
products. The PGIC is useful in assessing whether the impact of the study drug is meaningful 
enough to have value to the subject. PGIC instructions are as follows: “How have your 
symptoms been since you received the study treatment?” Scores on the PGIC range from 1 to 7 
with 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 
5 = minimally worse, 6 = much worse, and 7 = very much worse. The PGIC will be evaluated at 
10, 20, 30, and 60 min post dose.  
Clinical Global Impressions Scale: Global Improvement (CGI-I): The CGI-I assesses the 
physician investigator’s global impression of global change from Baseline in symptoms since the 
administration of study drug. The CGI-I instructions are as follows: “How has the subject’s 
symptoms been since they received the study treatment?” Scores range from 1 to 7, with 1 = very 
much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally 

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worse, 6 = much worse, and 7 = very much worse. The CGI-I will be evaluated at 60 min post 
dose.  
AOM Symptoms: The following AOM symptoms will be evaluated predose and at 60 min post 
dose: (1) tinnitus, (2) dizziness, (3) vertigo, and (4) feeling of fullness or muffled hearing in the 
ear. The investigator will record for each subject whether the symptom is present or absent.  
3.5.5 Safety Assessments 
Ear, Nose, and Throat Examination: Examination of the ear, nose, and oropharynx will be 
performed using otoscopy at Screening and at 60 min post dose.  
Otoscopy: Otoscopy assessments will be performed by the physician investigator to assess the 
appearance of the TM in the left and right ear. Measurements will be taken at Baseline and at 
60 min post dose. The TM will be rated for the following variables:  
x Contour: normal, retracted, full, bulging, or perforated 
x Color: normal, partly red, or completely red 
x Fluid behind the TM: no/yes; if yes-yellow, translucent, red, blue, or black 
x Translucency: translucent, semi-opaque, or opaque 
Details of how each variable is to be assessed and categorised are provided in Appendix 8.2. 
Vital Signs: Vital signs will be measured at Baseline and at 60 min post dose or Early 
Termination. Vital signs will include oral temperature (C), respiratory rate (breaths per minute), 
pulse (beats per minute [bpm]), and systolic and diastolic blood pressure (BP) recorded after at 
least 3 min of rest in the supine position. Body weight (kg) will also be collected with the vital 
signs measurements at Baseline only. Repeat measurements may be obtained in the event the 
initial measurements taken at Baseline are out of range.  
Adverse Events: All AEs occurring after the administration of study treatment until the follow-up 
safety call or early termination will be recorded.  
See Section 4, for additional information. 
3.5.6 Other Assessments 
Blinding Index: The BI will evaluate the success of blinding efforts incorporated in the study 
design.27 When the subject completes all study assessments on Day 1, but prior to administering 
the Device Experience Questionnaire, the subject and the physician investigator will be asked to 
indicate which treatment allocation they believe the subject received. If the respondent selects “I 
don’t know”, then the second question asks the respondent to provide a best guess, with a binary 
outcome: real medication or placebo. The final question asks the respondent to indicate the 
reason(s) why they chose their response to question 1 and question 2 (if applicable). The 
reason(s) will be captured as open-ended commentary by the respondent. A sample BI 
questionnaire is provided in Appendix 8.1. 
Device Experience Questionnaire-Subject: The Device Experience Questionnaire-Subject will 
evaluate the subject’s experience with the device during the study. Each subject will be asked to 
rate their agreement (Strongly Disagree, Disagree, Neutral, Agree, or Strongly Agree) to 

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4 questions about using the device. Additional comments related to each question will be 
documented in the questionnaire. Question 5 allows the subjects to provide other comments 
about the device that were not captured by the previous 4 questions. The questionnaire will be 
administered when the subject completes all study assessments on Day 1, including the BI, prior 
to leaving the study centre.  
Device Experience Questionnaire-Study Staff Administering Treatment: The Device Experience 
Questionnaire-Study Staff Administering Treatment will evaluate the study staff’s experience 
with the device during the study. Each study staff administering treatment will be asked to rate 
their agreement (Strongly Disagree, Disagree, Neutral, Agree, or Strongly Agree) to 6 questions 
about using the device. Additional comments related to each question will be documented in the 
questionnaire. Question 7 allows the study staff to provide other comments about the device that 
were not captured by the previous 6 questions. Each study staff who administered treatment to 
subjects will complete one questionnaire for the study, which will be administered after all 
subjects to be treated by study staff have completed all Day 1 assessments.  
3.5.7 Appropriateness of Measurements 
The most recent version of the CONSORT statement on guidelines for parallel group randomised 
trials indicates that information on “how the success of blinding (masking) was assessed” is no 
longer recommended because of a lack of empirical evidence supporting the practice as well as 
theoretical concerns about the validity of any such assessment.28 Conceptually, investigators are 
able to assess the success of blinding by asking participants and others (eg, outcome assessors) 
which treatment they believe was allocated. In theory, if blinding was successful, these people 
should not be able to guess the treatment more frequently than that expected by chance. Tests of 
the success of blinding hinge on that theoretical model. In reality, however, blinding could be 
successful, but people involved in the trial might deduce the treatment through supplementary 
information. Differential levels of side-effects or harms could yield strong clues, as can 
therapeutic benefits, or other pharmacologic/pharmacodynamics properties of the treatment. 
Nevertheless, a blinding assessment (ie, BI) to explore the integrity of the study design and 
masking of treatment will be performed when the subject completes all assessments on Day 1. 
The BI will be performed separately by the physician investigator and subject. Analysis methods 
proposed by Bang and collegues,27 which have been mostly described through simulations rather 
than application in clinical trials, will be used.  
All other assessments to be used in this study are commonly used, standard measurements in 
AOM studies. Assessment of device experience is common in studies of drug-device 
combination products.  
4 ADVERSE EVENT REPORTING 
Throughout the course of the study, all AEs will be monitored and recorded on an AE eCRF, 
including the AE’s description, start and end date, seriousness, severity, action taken, and 
relationship to the study drug. If AEs occur, the first concern will be the safety of the subjects. 
All AEs will be followed until resolved or stable and the outcome documented on the eCRF. 

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4.1 
Definitions and Criteria 
4.1.1 Adverse Events 
Per ICH E2A29: An AE is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Medical interventions such as surgeries, diagnostic procedures, and therapeutic procedures are 
not AEs but the action taken to treat the medical condition. They should be recorded as treatment 
of the AEs. 
Any AE that has an onset on or after the dose of study drug, or any pre-existing condition that 
has worsened on or after the first dose of study drug will be considered a treatment-emergent 
adverse event (TEAE). 
4.1.2 Serious Adverse Events 
An SAE or reaction is any untoward medical occurrence that at any dose: 
x Results in death 
x Is life-threatening 
x Requires inpatient hospitalisation or prolongation of existing hospitalisation 
x Results in persistent or significant disability or incapacity 
x Is a congenital anomaly or birth defect 
x Is an important medical event (eg, intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalisation; development of drug dependency or drug abuse; or malignancy tumors 
[histologically different from primary tumor]) 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe.  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalisation, but may jeopardise the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above. These 
events should also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or 
development of drug dependency or drug abuse. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. An 
SAE is not necessarily severe; eg, an overnight hospitalisation for a diagnostic procedure must 

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be reported as an SAE even though the occurrence is not medically serious. By the same token, a 
severe AE is not necessarily serious: nausea lasting several hours may be rated as severe but may 
not be considered serious. 
4.1.3 Unexpected Adverse Drug Reactions 
An unexpected adverse drug reaction (ADR) is a reaction for which the nature or severity is not 
consistent with the applicable product information (IB). Until product information is amended, 
expedited reporting is required for additional occurrences of the reaction. Reports that add 
significant information on specificity or severity of a known, already documented SAE constitute 
unexpected events. For example, an event more specific or more severe than described in the IB 
would be considered "unexpected.” Specific examples would be (a) acute renal failure as a 
labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a first 
report of fulminant hepatitis. 
Guidance on reporting AEs and SAEs is described in Section 4.2. 
4.1.4 Assessing Intensity and Relationship 
All AEs will be assessed on 2 descriptive parameters: intensity and relationship to the study 
drug: 
x Intensity refers to the severity of an event and references impact on a subject’s 
functioning. 
x Relationship refers to the likelihood that the event being assessed was caused by the 
study drug. 
Intensity 
Each AE will be classified according to the following criteria: 
Mild: 
The AE does not interfere in a significant manner with the subject’s normal 
level of functioning. 
Moderate: 
The AE produces some impairment of functioning, but is not hazardous to 
the subject’s health. 
Severe: 
The AE produces significant impairment of functioning or incapacitation 
and is a definite hazard to the subject’s health. 
When changes in the intensity of an AE occur more frequently than once a day, the maximum 
intensity for the experience should be noted. If the intensity category changes over a number of 
days, those changes should be recorded separately (with distinct onset dates). 
Relationship 
The investigator must assess the causality of an AE (including SAEs) to the use of a study drug 
using a 2-category scale (not related or related) based on clinical judgment and using all 
available information, and may include consideration of the following factors: 

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x Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic 
factors 
x The temporal association between study drug exposure and onset of the AE  
x Whether the manifestations of the AE are consistent with known actions or toxicity of the 
study drug 
x Whether the AE resolved or improved with stopping use of the study drug; judgment 
should be used if multiple products are discontinued at the same time 
x Positive rechallenge 
x Positive dechallenge (resolution upon stopping suspect study drug, in absence of other 
intervention or treatment) 
The causal relationship between the study drug and the AE will be assessed using one of the 
following categories shown in Table 4.1: 
Table 4.1: Adverse Event Causality 
Category 
Definition 
Not Related 
An AE is not associated with study medication if no causal relationship exists 
between the study drug and the AE, but an obvious alternative cause exists, eg, 
the subject’s underlying medical condition or concomitant therapy. 
Related 
An AE is attributed to the study medication if there is reasonable/plausible 
possibility that the AE may have been caused by the study drug: 
 
4.2 
Reporting Procedures and Requirements 
4.2.1 Adverse Events 
AE recording will begin at administration of study drug. Any AEs occurring before the start of 
treatment (ie, before administration of study drug) will be recorded in the medical history. Also, 
the sign, symptom, or disease present before starting the treatment period are only considered 
AEs if they worsen after starting the treatment period. 
If the investigator detects an AE in a study subject after the follow-up safety call and considers 
the event possibly related or related to prior study treatment, the investigator should report it to 
the WCT. 
The investigator should report all AEs on the AE page(s) of the eCRF and source documents, 
regardless of seriousness, severity, and causality. Whenever possible, an AE will be reported 
using a diagnostic term, (eg, “common cold” or “upper respiratory infection” rather than “runny 
nose, cough, mild fever”) and should be described with the attributes described in Section 4.1.4.  

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4.2.2 Serious Adverse Events 
All AEs and SAEs will be reported in the eCRF. Each AE will be assessed to determine whether 
it meets seriousness criteria (Section 4.1.2). If the AE is considered serious, the investigator 
should report this event to WCT as outlined below and also to the independent ethics committee 
(IEC) according to its standard operating procedures (SOPs). 
If the investigator detects an SAE in a study subject after the follow-up safety call, and considers 
the SAE related or possibly related to prior study treatment, the investigator should report it to 
WCT. 
All information about SAEs will be collected and reported via the SAE form and sent by e-mail 
message to xxxxxxxxxxxxxxxxxxxxxxxx or facsimile (contact information will be contained in 
the investigator site file). The investigator should send the initial report within 24 h of becoming 
aware of the SAE. At minimum, the initial report should include the following information: 
x Event 
x Study code 
x Subject number, initials, and date of birth 
x Study drug 
x Reporter name and contact information 
In the case of a “minimum report” (one that solely comprises the information bulleted above), a 
more detailed follow-up report should be sent as soon as more information becomes available but 
no later than 7 calendar days after the date of the initial report. Each SAE should be followed up 
until resolution or stabilisation and for reported deaths, the investigator should supply WCT and 
the IEC with any additional requested information (eg, autopsy reports and terminal medical 
reports). 
The original SAE form should be kept at the study site. The sponsor or its representative will be 
responsible for determining and in turn, reporting SAEs to regulatory authorities according to the 
applicable regulatory requirements. 
SAEs that are ongoing should be followed until resolved. 
4.3 
Procedures for Documenting Pregnancy During Study 
If a female subject becomes pregnant during the study, the investigator will notify WCT 
immediately following pregnancy confirmation. The investigator will also: (1) notify the 
subject’s physician that the subject may have been treated with OP0201 and (2) follow the 
progress of the pregnancy to term and document the outcome of the pregnancy. Subjects who 
become pregnant during the study will not be eligible for any further study treatments. 
Pregnancy outcome information should be forwarded to WCT when available.  

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5 DATA MANAGEMENT AND STATISTICAL ANALYSIS 
5.1 
Data Management Considerations 
In this study, eCRFs will be used. Completed eCRFs for this study will be forwarded to the 
sponsor or its representative where editing and construction of a quality-assured database will 
occur. Data will be quality checked, double-entered, and electronically verified before entry into 
the database. Queries will be issued for any inconsistencies, omissions, and discrepancies and 
will be resolved by the appropriate parties. The statistical analysis of these data will be 
performed by the sponsor or its representative. All AEs will be coded using the latest version of 
the Medical Dictionary for Regulatory Activities (MedDRA). Data management details will be 
outlined in a separate data management plan. 
5.2 
Statistical Considerations 
The information in this section is a summary of the planned statistical analyses. Further details 
are provided in the Statistical Analysis Plan (SAP). The SAP will be developed based on the 
latest version of the clinical protocol and eCRFs, and will be finalised prior to database lock. No 
database may be locked, or analyses completed, until the SAP has been approved. 
The SAP will provide a detailed description for the handling of missing data, patient eligibility 
criteria for the analysis, and statistical methodology for the data summary and analysis of safety 
and efficacy variables. This protocol describes key analyses undertaken by WCT in collaboration 
with Novus Therapeutics. If differences occur between analyses described in the SAP and the 
current protocol, those found in the SAP will supercede analyses outlined in the protocol.  
All statistical reporting will be performed using the validated software SAS® for Windows 
version 9.3 or higher (SAS Institute, Inc., Cary, NC, USA), unless otherwise specified. Data 
collected from all randomised subjects will be presented in data listings. Both observed values 
and mean change from baseline values for each subject will be given where applicable. Data 
listings will be sorted by treatment, subject number, and time point unless otherwise noted. 
Data for individual subjects will be listed. Continuous variables will be summarised using 
number of non missing observations, mean, standard deviation, median, minimum, and 
maximum observed values, and observed value ranges (where applicable). Categorical variables 
will be summarised using the frequency count and the percentage of subjects in each category.   
Any deviations from the analyses described below will be included in the SAP, which will be 
included in the clinical study report. 
5.2.1 Sample Size Justification 
Approximately 24 subjects will be enrolled in this study. On Day 1, eligible subjects will be 
randomly assigned in a ratio of 1:1 (12 subjects per arm) to receive 1 of 2 study treatments 
(20 mg, OP0201 or placebo). 
5.2.2 Analysis Populations 
The Screening Population will include all subjects who signed an Informed Consent Form (ICF) 
and have completed any screening procedures. 
The Randomised Population will include all screened subjects who are assigned a randomisation 
number prior to dosing.  

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The Safety Analysis Population will include all randomised subjects who received any study 
drug (OP0201 or placebo). 
5.2.3 Protocol Deviations 
A protocol deviation plan will be prepared as a separate document. All protocol deviations will 
be documented in the clinical trials management system. A protocol deviation occurs when there 
is any non-adherence to a study procedure or schedule that is specified within the protocol.   
Protocol deviations will be assessed and summarised. Protocol deviations may include but are 
not limited to the following: departure from eligibility criteria, failure to perform the required 
assessments at the specified timepoints, the wrong treatment or dose was administered, or subject 
safety.  
5.2.4 Subject Disposition 
The overall number of subjects screened and the number of subjects in each analysis population 
will be summarised and listed. Any differences between the number of subjects in the analysis 
populations will be explained. Additionally, completer and early termination status will be 
summarised for the Randomised Population. For subjects who discontinue from the study prior 
to completion, the primary reason for early termination will be summarised using frequencies 
and percentages for each category. 
All subject disposition and outcome data will be listed.  
5.2.5 Demographic and Baseline Characteristics  
Demographics (sex, age, race, and ethnicity) and baseline characteristics (weight, height, and 
BMI) will be summarised using the appropriate descriptive statistics as described above for the 
Safety Population. No formal statistical analyses will be conducted. Data analyses will be 
provided by treatment and for all subjects combined (overall), where appropriate.  
Baseline VAS, NRS-11, and otoscopy assessments will be summarised by treatment and overall 
(where applicable) using the appropriate descriptive statistics for all subjects in the Safety 
Analysis Population. 
5.2.6 Efficacy Analyses 
5.2.6.1 Exploratory Analysis 
Pain Intensity Difference (PID) & Sum Pain Intensity Difference (SPID) will be calculated as 
follows:  
x PID will be calculated as: 
ܲܫܦ௧= ܲܫ௧െ ܲܫ஻௔௦௘௟௜௡௘ 
Where t is the post-dose assessment timepoint 
Where baseline is the predose assessment timepoint 
x SPID will be calculated as:  
ܵܲܫܦ௧௜ି௧௜ା௡= ෍
(ܲܫܦ௜) כ (ݐ௜ାଵെ ݐ௜)
௧௜ା௡
௧௜
  

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Where PIDi is the pain intensity difference score calculated at each post-dose 
timepoint 
Where ti is the scheduled assessment time 
Analyses for Continuous Data 
PID (change from Baseline) will be computed for each post-dose assessment timepoint (10, 20, 
30, and 60 min). Data will be analysed using a longitudinal mixed model for repeated measures 
with fixed effects for treatment, time, treatment-by-time interaction, study site, and baseline pain 
score. Subject will be the random effect. Treatment differences from control (placebo) will be 
estimated from the Least Squares Means (LSM) from the analysis model along with 80% 
confidence intervals (CIs) and associated 2-sided p-values. If significance is found using 80% 
CIs, 90% and 95% CIs will also be tested. Only observed cases will be included in the PID 
computations. Graphical displays of the LSM change from Baseline will also be provided by 
treatment.   
Descriptive summaries for each PID timepoint will be provided by treatment along with the 
model output for test differences in the LSM. PID analyses will be conducted for both NRS-11 
and VAS pain scales.   
SPID will be analysed using a linear model analysis of variance (ANOVA) with fixed effects for 
treatment, site, and baseline pain score. Treatment differences from control (placebo) are 
estimated using the LSM from the analysis model along with 80% CIs and associated 2-sided 
p-values. If significance is found using 80% CIs, 90% and 95% CIs will also be tested. SPID 
analyses will be conducted for both NRS-11 and VAS pain scales. Missing data will be handled 
using the Last Observation Carried Forward imputation method.  
The ear pain data will be listed. The analysis of ear pain will focus on change of pain from 
Baseline to assessment at 10 min (0-10 min), 20 min (0-20 min), 30 min (0-30 min), and 
60 min (0-60 min). The change of ear pain from Baseline to assessment will be described as the 
change of the sum of pain of right and left ear, and in addition as the change in worst reported 
pain across both ears. Thereby, worst reported pain across both ears is defined as the worst pain 
of either the right or the left ear determined separately for baseline and the respective assessment. 
These measures will be summarised as described above for continuous variables and analysed 
for treatment effect as further delineated in the SAP. Hodges-Lehmann point estimate and 80% 
2-sided CI for the median of treatment effect differences between active and placebo will be 
provided. If significance is found using 80% CIs, 90% and 95% CIs will also be tested. 
Furthermore, tables providing the incidence of pain score > 0 at each post-baseline timepoint will 
be displayed. Additionally, shift tables for incidence of change from Baseline at each post-
baseline timepoint with three categories (1) 'no change', (2) 'worsening' (ie, higher score than 
baseline), and (3) 'improvement' (ie, lower score than baseline) will be produced to describe 
change from Baseline for right and left ear separately. 
Changes from Baseline in the VAS and NRS-11 scores will be summarised by treatment using 
descriptive statistics for the following post-dose timepoints: 10, 20, 30, and 60 min. Statistical 
comparisons of ear pain, as measured by the VAS and the NRS-11, between the treatments at 
60 min post dose will be performed using an ANOVA model. Time to ear pain relief in the 

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affected ears, recorded as change from moderate/severe pain to mild or no pain using the VAS 
and the NRS-11, will be summarised by treatment. 
The 75% and 50% responder status will be assessed via a  75% reduction and a  50% 
reduction, respectively, in VAS and NRS-11 scores at each post-dose timepoint. The number and 
percentage of subjects achieving each response level ( 75% and  50% decrease) in VAS and 
NRS-11 scoring will be presented by treatment group with corresponding 80% CIs. CIs will be 
calculated using a fixed-effects model and considered statistically significant when the 80% CI 
does not include 1. Figures will be presented illustrating the percentage of responders in pain 
intensity reductions presented by treatment group and level of response.  
The percent decrease in VAS and NRS-11 scores from Baseline to each post-dose timepoint will 
be calculated for each subject as follows: 
%decrease VAS = [(VASbaseline – VASt) ÷ VASbaseline] × 100  
%decrease NRS-11 = [(NRS-11baseline – NRS-11t) ÷ NRS-11baseline] × 100 
Where t = post-dose timepoint (10, 20, 30, or 60 min) 
Responses on the PGIC at 10, 20, 30, and 60 min post dose will be summarised. Responses on 
the CGI-I at 60 min post dose will be summarised. Frequency and percentage of subjects 
reporting AOM symptoms at Baseline and at 60 min post dose will be summarised by treatment 
group. Additionally, PGIC and CGI-I will be analyzed using a mixed-effects model for repeated 
measures with treatment group, visit, and site as factors and baseline score (PGIC and CGI-I) as 
a covariate. This model will be based on a restricted maximum likelihood approach and will 
utilize an unstructured covariance type shared across treatment groups to model the 
within-subject errors. The primary comparison for treatment differences will be the difference in 
LSMs. 
For all exploratory analyses, a statistically significant difference is defined as p < 0.20 and is 
presented with associated 80% CIs. 
5.2.7 Safety Analyses 
The Safety Analysis Population will be used for all safety analyses by treatment and for all 
subjects combined (overall) where appropriate. Safety assessments will include AEs, ENT 
examination, appearance of the TM (otoscopy), and vital signs. Prior and concomitant 
medications will be summarised using frequencies and percentages of subjects by treatment 
using the Safety Analysis Population. Only safety assessments with both predose and post-dose 
data will be analyzed. All other baseline assessments will be listed. 
5.2.7.1 Extent of Exposure 
Extent of exposure will be described by whether the subject took any study drug. All dosing and 
dispensing information will be listed.  
5.2.7.2 Adverse Events 
AEs will be coded in accordance with the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Incidence for all reported AEs will be summarised overall (regardless of 
severity or relationship to study drug), moderate AEs, and severe AEs. Additionally, a summary 

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of SAEs and AEs leading to early termination from the study will be presented along with 
corresponding data listings.   
The incidence of TEAEs will be summarised as the number and percentage of subjects and 
events reported by treatment and overall for each System Organ Class and Preferred Term using 
the Safety Analysis Population. TEAEs will also be summarised by maximum severity and 
relationship to study drug.  
5.2.7.3 Vital Signs 
Vital signs measurements will be summarised using descriptive statistics for all observed 
timepoints. Additionally, all corresponding changes from Baseline to 60 min post dose will be 
summarised by treatment. 
If appropriate, the incidence of clinically meaningful changes will be summarised at 60 min 
post dose. Clinically meaningful changes are defined as: 
x Systolic BP:  80 mmHg RU 140 mmHg 
x Diastolic BP: supine  PP+JRU 90 mmHg 
x Pulse rate:  ESPRU 100 bpm 
x Respiration rate:< 8 or > 20 breaths per minute  
Changes in oral temperature measurements will also be summarised.  
5.2.7.4 Ear, Nose, and Throat Examination 
ENT examination findings will be summarised using descriptive statistics for all observed 
timepoints. Additionally, all corresponding changes from Baseline to 60 min post dose will be 
summarised by treatment.  
5.2.7.5 Otoscopy (Appearance of the Tympanic Membrane) 
For appearance of the TM, 80% CIs will be calculated for the incidence of shifts from Baseline 
(0-60 min), from normal to abnormal for the right ear and, separately, for the left ear. If 
significance is found using 80% CIs, 90% and 95% CIs will also be tested. A table presenting all 
changes from Baseline (from/to normal from/to abnormal) will be summarised by treatment for 
all observed timepoints.  
5.2.7.6 Other Variables Related to Safety 
A complete medical history will be obtained at Screening and data will be listed. Some examples 
of medical history data include previous surgical history, medications, chronic conditions, 
past/present illness, substance/drug abuse, and history of allergies. For each subject, it will be 
documented whether or not the subject has prior experience using an intranasal device. 
Information about prior use of intranasal devices will include how often the device was used, for 
what indication, and type of device(s) (aqueous or propelled) will be obtained.  
A complete physical examination will be conducted at Screening to evaluate each subject’s 
general appearance, skin, neck (including thyroid), eyes, heart, lungs, abdomen, lymph nodes, 
extremities, and nervous system. Physical examination findings will be summarised using the 
appropriate descriptive statistics. Height (cm), body weight (kg), and body mass index 

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(BMI [kg/m2]) will also be collected and summarised as baseline characteristics (Section 5.2.5). 
Evaluation of the ear, nose, and oropharynx will be performed during the ENT examination 
(Section 5.2.7.4).  
A urine pregnancy test will be administered at Screening for all female subjects of childbearing 
potential and results will be listed. 
5.2.8 Interim Analyses 
No interim analyses are planned. 
5.3 
Analysis of Other Assessments 
The BI will be administered following completion of all other assessments, except the Device 
Experience Questionnaire, on Day 1. Responses on the BI will be summarised separately for the 
subject and physician investigator. 
The Device Experience Questionnaires will be analyzed at a later date. 
6 STUDY MANAGEMENT 
6.1 
Ethics and Consent 
6.1.1 Regulations and Guidelines 
The study will be performed in accordance with this protocol, local national laws (as applicable), 
ICH guidelines for Good Clinical Practice (GCP),30 and the most recent guidelines of the 
Declaration of Helsinki. These guidelines are on file at WCT. 
6.1.2 Independent Ethics Committees  
Conduct of the study must be approved by an appropriately constituted IEC. Approval is 
required for the study protocol, IB, protocol amendments, ICFs, subject information sheets, and 
advertising materials. No study drug will be shipped to a site until written IEC authorisation has 
been received by the sponsor or its representative. 
6.1.3 Informed Consent 
For each subject, a written ICF will be obtained before any protocol-related activities. As part of 
this procedure, the investigator or a designated representative must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the study drug in such a manner 
that the subject and (if applicable) appointed guardian are aware of the potential risks, 
inconveniences, or adverse effects that may occur. Subjects should be informed that they may 
withdraw from the study at any time. They will receive all information that is required by local 
regulations and ICH guidelines. The PI or a designated representative will provide the sponsor or 
its representative with a copy of the IEC-approved ICF before the start of the study. 
6.2 
Indemnification 
Indemnification will be discussed in a separate document.  
6.3 
Discontinuation of the Study by the Sponsor 
The sponsor reserves the right to discontinue the study at this site or at multiple sites for safety or 
administrative reasons at any time. In particular, a site that does not recruit at a reasonable rate 

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may be discontinued. Should the study be terminated and/or the site closed for whatever reason, 
all documentation and study drug pertaining to the study must be returned to the sponsor or its 
representative. 
6.4 
Study Documentation 
By signing a copy of country-specific regulatory forms, the PI acknowledges that he/she has 
received a copy of the investigator’s brochure on OP0201 and assures the sponsor that he/she 
will comply with the protocol and the provisions stated in country-specific forms. No changes in 
this protocol can be made without the sponsor’s written approval. 
6.5 
Study Monitoring and Auditing 
This study will be monitored for quality assurance at all stages of its development by the clinical 
research personnel employed by the sponsor or its representative. Monitoring will include 
personal visits and telephone communication to assure that the investigation is conducted 
according to the protocol, SOPs, Guidelines of GCP, and applicable regulatory requirements. 
Quality control procedures will be applied to each stage of data handling to ensure that all data 
are reliable and have been processed correctly. On-site review of eCRFs will include a review of 
forms for completeness and clarity, and consistency with source documents available for each 
subject. Note that a variety of original documents, data, and records will be considered as source 
documents in this trial. The eCRF itself is not to be used as a source document under any 
circumstances.  
Medical advisors and clinical research associates or assistants may request to witness subject 
evaluations occurring as part of this protocol. The investigator and appropriate personnel will be 
periodically requested to attend meetings/workshops organised by the sponsor to assure 
acceptable protocol execution. The study may be subject to audit by the sponsor or by regulatory 
authorities. If such an audit occurs, the investigator must agree to allow access to required 
subject records. By signing this protocol, the investigator grants permission to personnel from 
the sponsor, its representatives, and appropriate regulatory authorities, for on-site monitoring of 
all appropriate study documentation, as well as on-site review of the procedures employed in 
eCRF generation, where clinically appropriate. 
6.6 
Retention of Records 
The investigator must arrange for retention of study records at the site. The nature of the records 
and the duration of the retention period must meet the requirements of the relevant regulatory 
authority. The investigator should take measures to prevent accidental or premature destruction 
of these documents.  
6.7 
Use of Study Findings 
By signing the study protocol, the investigator agrees to the use of results of the study for the 
purposes of national and international registration. If necessary, the authorities will be notified of 
the investigator’s name, address, qualifications, and extent of involvement. Reports covering 
clinical and biometric aspects of the study will be prepared by the sponsor or its representative. 
6.8 
Publications 
As a multicentre trial, the sponsor intends to publish clinical data from all centres participating in 
the investigation. A publication committee selected by the sponsor will submit draft manuscripts 

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to all participating investigators for their comments. In conformity with the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals published by the International 
Committee of Medical Journal Editors (see discussion in Kassirer & Angell, 1991),31 
investigators whose contribution consists solely in the collection of data will not be named 
individually as authors. Rather, those investigators will receive a collective authorship as the 
“OP0201 Study Group” and will be identified in a note. 
Individual investigators and/or their associates subsequently may publish additional findings of 
this study in scientific journals or present them at scientific meetings, provided that the sponsor 
is given ample opportunity to review any proposed abstract, manuscript, or slide presentation 
before its submission. This review is required to ensure that the sponsor is aware of all written 
and oral presentations of the data and does not imply any editorial review or restriction of the 
contents of the presentation or use. 
 
 

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7 REFERENCES 
 
1. Schilder AGM, Chonmaitree T, Cripps AW, et.al. Otitis media. Nature Reviews. 
2016;2:1-18. 
2. Monasta L, Ronfan L, Marchett F, et.al. Burden of disease caused by otitis media: 
systematic review and global estimates. Plos One. 2012;7(4): e36226. 
3. Chonmaitree T, Revai K, Grady JJ, et.al. Viral upper respiratory tract infection and otitis 
media complication in young children. Clinical Infectious Disease. 
2008;46(15 March):815-23. 
4. Heikkinen T, Thint M, Chonmaitree T. Prevalence of various respiratory viruses in the 
middle ear during acute otitis media. N Eng J Med. 1999;340:260-4. 
5. Rosenfeld RM, Shin JJ, Schwarz SR, et al. Clinical Practice Guideline: Otitis Media with 
Effusion (Update). Otolaryngol Head Neck Surg. 2016;154:S1-41. 
6. Van Zon A, Schilder AGM, van der Heijden GJ. Antibiotics for otitis media with 
effusion in children (Protocol). 2011. Cochrane Collaboration. Published by John Wiley 
& Sons, Ltd. Available at: http://www.thecochranelibrary.com. 
7. Van Zon A, van der Heijden GJ, van Dongen TM, Burton MJ, Schilder AG. Antibiotics 
for otitis media with effusion in children, Cochrane Data Syst Rev. 
2012;12(9):CD009163. 
8. Venekamp RP, Burton MJ, van Dongen TM, van der Heijden GJ, von Zon A, Schilder 
AGM. Antibiotics for otitis media with effusion in children. Cochrane Data Syst Rev. 
2016;Cd009163. 
9. Kempf M, Varon E, Lepoutre A, et.al. Decline in antibiotic resistance and changes in the 
serotype distribution of Streptococcus pneumoniae isolates from children with acute otitis 
media; a 2001–2011 survey by the French Pneumococcal Network. Clin Microbiol Infect. 
2015; 21:35-42. 
10. Sillanpää S, Sipilä M, Hyöty H, Rautiainen M, Laranne J. Antibiotic resistance in 
pathogens causing acute otitis media in Finnish children, Int J Ped Otorhinolaryngology. 
2016;85:91-4. 
11. Chandrasekhar SS, Connelly PE, Venkatayan N, Ammar M, Tabor M, Mautone AJ. 
Intranasal metered dose aerosolized surfactant reduces passive opening pressure of the 
Eustachian tube: comparison study in two animal models. Otol Neurology. 2002:23:3-7.  
12. Chandrasekhar SS, Mautone AJ. Otitis Media: Treatment with intranasal aerosolized 
surfactant. Laryngoscope. 2004;114:472-85. 
13. Venkatayan N, Troublefield YL, Connelly PE, Mautone AJ, Chandrasekhar SS. 
Intranasal surfactant aerosol therapy for otitis media with effusion. Laryngoscope. 
2000;110:1857-60. 

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14. Venkatayan N, Connelly PE, Mautone AJ, Troublefield YL, Chandrasekhar SS. Dosage 
regimens of intranasal aerosolized surfactant on otitis media with effusion in an animal 
model. Otolaryngol Head Neck Surg. 2001;124:388-93. 
15. Investigator’s Brochure OP0201 Version 3, 06 Jan 2017. 
16. Taeusch HW, Lu K, Ramierez-Schrempp D. Improving pulmonary surfactants. Acta 
Pharmacologica Sinica. 2002;23:11-5. 
17. Notter RH, Lung surfactants: Basic science and clinical applications. Marcel Dekker, Inc. 
(NY, Basel) 2000. 
18. Colacicco G, Basu MK. Effects of cholesterol and cholesteryl ester on dynamic surface 
tension of dipalmitoyl lecithin. J Colloid Interface Sci .1977; 61(3):516-8. 
19. Chemours Company LLC. Freon 134a aerosol propellant. Toxicity summary for 1,1,1,2-
tetrafluoroethane (HFC-134a). Technical Information. 2016. Report available at 
www.chemours.com/propellants. 
20. Donnell D, Harrison LI, Ward S. Acute safety of the CFC-free propellant HFA-134a 
from a pressurized metered dose inhaler. Eur J Clin Pharmacol. 1995;48(6):473-77. 
21. Dupont. Dymel™ 134a propellant. Material safety data sheet, Version 2.1 revision data. 
23 Jan 2012.  
22. Weber R, Garcia J, Farugi R, Baerji D, Georges G; 405 Investigator Group. Safety and 
clinical relief over 1 year with triamcinolone acetonide hydrofluoroalkane-134a nasal 
aerosol in patients with perennial allergic rhinitis. Allergy Asthma Proc. 
2006;27(3):243-7.  
23. QNASL™ Prescribing Information. 2014. Teva Respiratory, LLC, Horsham, PA, USA.  
24. Bijur PE, Latimer CT, Gallagher J. Validation of a verbally administered numerical 
rating scale of acute pain for use in the emergency department. Acad Emerg Med. 
2003;10(4):390-2.  
25. Jensen MP, Karoly P, Braver S. The measurement of clinical pain intensity: a comparison 
of six methods. Pain. 1986;27:117-26.  
26. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing numerical rating scales, 
verbal rating scales, and visual analogue scales for assessment of pain intensity in adults: 
a systematic literature review. J Pain Symptom Manage. 2011;41(6):1073-93.  
27. Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials. 
2004;25:143-56.  
28. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 
statement: updated guidelines for reporting parallel group randomised trials. BMJ. 
2010:340:c332. doi: 10.1136/bmj.c332. 
29. International Conference on Harmonisation. Clinical safety data management: definitions 
and standards for expedited reporting, ICH E2A. 27 Oct 1994.  
30. International Conference on Harmonisation. Guideline for Good Clinical Practice, 
ICH E6. 10 Jun 1996. 

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31. Kassirer JP, Angell M. On authorship and acknowledgments. N Engl J Med. 
1991;325(21):510-12. 
 
 

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8 APPENDICES 
8.1
Blinding Index Questionnaire 
Version: For Subject to Complete 
Sponsor and Protocol Number: ___________________________________________ 
Subject Number: ____________________ 
 
Instructions: Now that you have completed this study, we want to ask your opinion about which 
treatment (real medication or placebo) you believe was administered to you in this clinical trial. 
Read all of the answer choices before circling your one answer to each question. There are no 
right or wrong answers. Your honest answers will be helpful for current and future research. 
1. Which treatment do you believe you received? (CIRCLE ONE) 
a. Strongly believe I received real medication 
b. Somewhat believe I received real medication 
c. Somewhat believe I received the placebo 
d. Strongly believe I received the placebo 
e. I don’t know 
 
2. If you answered “Don’t know” above, please provide your best guess of the treatment 
you received in this clinical trial: 
(CIRCLE ONE) 
a. I received the real medication 
b. I received placebo 
3. In your own words, please describe the primary reason you believe you received this 
treatment?  
_____________________________________________________________________
This questionnaire was developed with primary reference from Bang H, Flaherty SP, Kolahi J, Park J. Blinding 
assessment in clinical trials: A review of statistical methods and a proposal of blinding assessment protocol. Clin 
Res Regul Aff. 2010;27:42-51.  

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8.2 Otoscopy Assessment of the Appearance of the Tympanic Membrane 
Otoscopy will be performed by the physician investigator to assess the appearance of the TM in 
both ears regardless if AOM is bilateral or unilateral. Appearance of the TM will be evaluated 
for contour, color, fluid, and translucency as follows:  
x Contour will be assessed using 1 of the following categories:  
o Normal 
o Retracted 
o Full 
o Bulging 
o Perforated 
o Not assessable 
The categorisation in normal/abnormal will be as follows: 
o Normal = normal 
o Abnormal = retracted, full, bulging, or perforated 
x Color will be assessed using 1 of the following categories:  
o Normal 
o Partly red 
o Completely red 
o Not assessable  
The categorisation in normal/abnormal will be as follows: 
o Normal = normal 
o Abnormal = partly red or completely red  
x Fluid will be assessed using 1 of the following categories:  
o No 
o Yes; if yes, color of fluid will be rated as yellow, translucent, red, blue, black, or 
not assessable. 
The categorisation in normal/abnormal will be as follows: 
o Normal = no 
o Abnormal = yes 
x Translucency will be assessed using 1 of the following categories 
o Translucent 
o Semi-opaque 
o Opaque 

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o Not assessable  
The categorisation in normal/abnormal will be as follows: 
o Normal = translucent 
o Abnormal = semi-opaque or opaque 
 
For appearance of the TM, 80% CIs will be calculated for the incidence of shifts from Baseline 
(0-60 minutes), from normal to abnormal for the right ear and, separately, for the left ear. If 
significance is found using 80% CIs, 90% and 95% CIs will also be tested. A table presenting all 
changes from Baseline (from/to normal from/to abnormal) will be summarised by treatment for 
all observed timepoints.  

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8.3  Device Experience Questionnaire-Study Staff Administering Treatment 
For Clinical Staff 
Thank you for completing the study activity. 
Please rate your agreement to the following statements and circle your response. 
1. My first reaction to the study inhaler was positive. 
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
2. The study inhaler Instructions for Use were clear and easy to follow.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
3. If I was not instructed, I feel confident that I could have used the product without instruction.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
4. The study inhaler is easy to use.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
5. It was easy to place the study inhaler in the nostril.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
6. It was easy to press down on the study inhaler.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
7. Other comments.  
 
 
 
Thank you, please hand the questionnaire back to the Principal Investigator.  
 
Staff ID  
Site No.  
Date  
 

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For Trial Subjects 
Thank you for completing the study activity. 
Please rate your agreement to the following statements and circle your response. 
1. My first reaction to the study inhaler was positive. 
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
Comments: 
 
 
2. The study inhaler was comfortable in my nostril.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
Comments: 
 
 
3. The spray had a pleasant taste or aroma.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
Comments: 
 
 
4. There was no discomfort or irritation from the spray inside of the nose.  
Strongly 
Disagree 
Disagree 
Neutral 
Agree 
Strongly Agree 
Comments: 
 
 
5. Other comments.  
 
 
 
Thank you, please hand the questionnaire back to the Principal Investigator.  
 
Subject No.  
Site No.  
Date