Clinical trial NCT03818815
Conditions: Acute Otitis Media
Sponsor: Novus Therapeutics, Inc
Start date: 2019-02-21; Completion date: 2020-03-26
Enrollment: 103 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to develop a better understanding of the safety, tolerability and efficacy of intranasal OP0201 as an adjunct treatment to oral antibiotics for the treatment of Acute Otitis Media (AOM) in infants and children.

Detailed description:

Arms: arm 1: OP0201 20mg per day+oral Amoxicillin-clavulanate in two divided doses for 10 days arm 2: Placebo 0 mg per day+oral Amoxicillin-clavulanate in two divided doses for 10 days
Interventions: intervention 1: OP0201 intervention 2: Placebo intervention 3: Amoxicillin-clavulanate
Intervention descriptions: intervention 1: OP0201 20mg per day in two divided doses for 10 days intervention 2: Placebo 0mg per day in two divided doses for 10 days intervention 3: Oral Amoxicillin-clavulanate in two divided doses for 10 days

Protocol documents:
Prot_000.pdf: 
 
 
 
Study Title A Study to Assess the Safety, Tolerability, and Efficacy of OP0201 as an Adjunct 
Treatment for Acute Otitis Media in Infants and Children Aged 6 to 24 Months 
NCT Number NCT03818815    
Document Description Clinical Protocol, Amendment 3 
Document Date 21 Aug 2019 
 


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Protocol OP0201-C-006 - Amendment 3 
 
1 
TITLE PAGE 
Protocol Title: 
A Study to Assess the Safety, Tolerability, and Efficacy of OP0201 as an Adjunct Treatment for Acute 
Otitis Media in Infants and Children Aged 6 to 24 Months 
Protocol Number: OP0201-C-006 
Amendment Number: 3 
Product: OP0201 metered dose inhaler 
Study Phase: 2a 
Sponsor Name: Novus Therapeutics, Inc. 
Legal Registered Address: Novus Therapeutics, Inc., 19900 MacArthur, Suite 550, Irvine, California, 
US, 92612 
Regulatory Agency Identifying Number(s): US FDA IND 106778 
Date of Amendment 3: 21 August 2019 
Date of Protocol: 15 January 2019 
 
 
 


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Protocol OP0201-C-006 - Amendment 3 
 
2 
Sponsor Signatory: 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
Mai D. Sirimanne, MBA 
Vice President, Clinical Development 
Novus Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
 
Medical Monitor name and contact information can be found in Appendix 2. 
 
 


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Protocol OP0201-C-006 - Amendment 3 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
 
Table 1 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 3 
21 August 2019 
Yes 
US 
Amendment 2 
05 June 2019 
Yes 
US 
Amendment 1 
8 March 2019 
No 
US 
Original Protocol 
15 January 2019 
- 
- 
 
Amendment 3 (21 August 2019) 
Overall Rationale for the Amendment: 
This Phase 2a, double-blind, placebo-controlled exploratory study represents the first evaluation 
of OP0201 in treating acute otitis media (AOM) and in reducing the likelihood of middle ear 
effusion (MEE) following AOM in children. Enrollment is ongoing and the treatment code 
remains blinded. This amendment does not change the overall study design (ie, no change to 
sample size, inclusion/exclusion criteria, study Participant assessments or the study visit 
schedule, treatment dose or duration).  
The following changes are intended to address a request by the Food and Drug Administration 
(FDA) and to further inform the design of future clinical studies.  
1. An additional secondary efficacy endpoint has been added to address FDA’s request to 
include an evaluation of AOM cure rate. This new secondary efficacy endpoint is 
specifically defined as “complete or near complete resolution of symptoms (AOM cure), 
defined as an Acute Otitis Media Severity of Symptoms (AOM-SOS) score ≤2,(1) 
assessed at the Day 4 Visit, Day 12 Visit and Day 28 Visit by in-clinic AOM-SOS score 
assessments”. 
2. To reposition the key secondary efficacy endpoint (“no MEE [OME] assessed at the 
Day 12 Visit by pneumatic otoscopy”) as an additional primary efficacy endpoint. 
Persistent MEE would most likely lead to recurrence of AOM. This endpoint is proposed 
to evaluate likelihood of MEE at completion of therapy. Both treating an AOM event 
(“no bulging of the tympanic membrane (TM) assessed at Day 4 Visit by pneumatic 
otoscopy”) and/or reducing the proportion of children with OME (“no MEE [OME] 
assessed at the Day 12 Visit by pneumatic otoscopy”) are clinically important endpoints. 
It is unknown which efficacy endpoint will be most sensitive to establishing a clinically 
meaningful OP0201 treatment effect. Accordingly, it is important that we study both 
endpoints by testing them as a family of primary endpoints; ie, a statistically significant 


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Protocol OP0201-C-006 - Amendment 3 
 
4 
result for either endpoint will be considered criterion for success. Appropriate control for 
multiplicity – the step-up Hochberg procedure – is also included. 
Table 2 
Description of Changes in Amendment 3 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Rationale 
Section 2.1 Study Rationale 
Updated to state that AOM 
resolution for primary efficacy 
endpoints will be determined by 
evidence of no bulging of the 
TM early in the course of the 
treatment and no MEE (OME) 
at the conclusion of the 
treatment. 
To reposition the key secondary 
efficacy endpoint as a primary 
efficacy endpoint as both 
treating an AOM event and 
reducing likelihood of MEE 
(OME) represent clinically 
important endpoints (see 
amendment rationale above). 
Section 1.1 Statistical Methods 
Section 9.1 Statistical 
Hypotheses 
Section 9.2 Power Calculation 
Section 9.3 Populations for 
Analyses 
Section 9.4 Statistical Analyses 
Updated power calculations and 
efficacy analysis for the 
additional primary endpoint. 
Updated statistical sections to 
include new secondary endpoint 
for the evaluation of AOM cure. 
To restate the overall power for 
the study based on study design 
assumptions to detect a 
treatment effect in at least 1 of 
the 2 endpoints (based on a 40% 
of placebo responder rate at 
Day 4 and 30% of placebo 
responder rate at Day 12). 
To address FDA’s request to 
include an evaluation of AOM 
cure (see amendment rationale 
above). 
Section 1.1 Objectives and 
Endpoints 
Section 3.0 Objectives and 
Endpoints 
 
Moved “No MEE (OME) 
assessed at the Day 12 Visit by 
pneumatic otoscopy” from 
secondary to primary endpoint. 
Added secondary endpoint for 
“complete or near complete 
resolution of symptoms (AOM 
cure)”.  
To update to align with 
proposed amendment of primary 
and secondary endpoints (see 
amendment rationale above). 


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Protocol OP0201-C-006 - Amendment 3 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Removed secondary endpoint 
“Probability of MEE on Days 4, 
12, and 28 determined from 
tympanograms using a derived 
algorithm”. 
The derived algorithm is not a 
well-recognized interpretation of 
tympanogram results. 
 
Revised tympanogram 
secondary endpoint wording to 
“Normal tympanogram 
(Type A) assessed at the Day 4 
Visit, the Day 12 Visit, and the 
Day 28 Visit by tympanometry”. 
To clarify secondary endpoint 
wording to analyze 
“improvement” since it is 
assumed tympanogram will be 
abnormal at baseline. 
 
Updated clinical success 
definition for AOM relapse and 
AOM recurrence endpoints as 
(1) no moderate to severe 
bulging of the TM (Key Action 
Statement 1A), and (2) no mild 
bulging of TM and no recent 
(less than 48 hours) onset of ear 
pain (otalgia) (Key Action 
Statement 1B), and (3) no mild 
bulging of the TM and no 
intense erythema of the TM 
(Key Action Statement 1B). 
To clarify definition wording to 
analyze clinical success based 
on resolution of all AOM 
diagnostic signs and symptoms.  
Section 8.2 Safety Assessments 
Tympanometry removed as a 
safety assessment. 
Tympanometry was incorrectly 
listed as a safety assessment and 
has been removed to align with 
Study Objectives and Endpoints 
as described in Section 1.0 and 
Section 3.0. 


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Protocol OP0201-C-006 - Amendment 3 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4.1 Efficacy Analysis 
Descriptive statistics updated to 
include gender and race as 
primary efficacy endpoint 
sub-groups. 
To ensure comprehensive 
sensitivity analyses of the 
primary efficacy endpoint. 
  


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Protocol OP0201-C-006 - Amendment 3 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ................................3 
TABLE OF TABLES .............................................................................................................10 
TABLE OF FIGURES ...........................................................................................................11 
1.0 
PROTOCOL SUMMARY ........................................................................................12 
1.1 
Synopsis ...........................................................................................................12 
1.2 
Schema ............................................................................................................17 
1.3 
Schedule of Activities .....................................................................................18 
2.0 
INTRODUCTION......................................................................................................20 
2.1 
Study Rationale ..............................................................................................20 
2.2 
Background ....................................................................................................21 
2.3 
Benefit/Risk Assessment ................................................................................22 
3.0 
OBJECTIVES AND ENDPOINTS ..........................................................................24 
3.1 
Endpoint Rationale ........................................................................................24 
4.0 
STUDY DESIGN ........................................................................................................27 
4.1 
Overall Design ................................................................................................27 
4.2 
Scientific Rationale for Study Design ...........................................................28 
4.3 
Justification for Dose .....................................................................................28 
4.4 
End of Study Definition .................................................................................29 
4.5 
Dose Escalation Criteria ................................................................................29 
4.6 
Study Stopping Criteria ................................................................................29 
4.6.1 
Stopping Criteria for Individual Participants ....................................29 
5.0 
STUDY POPULATION ............................................................................................30 
5.1 
Inclusion Criteria ...........................................................................................30 
5.2 
Exclusion Criteria ..........................................................................................30 
5.3 
Lifestyle Considerations ................................................................................31 
5.4 
Screen Failures ...............................................................................................31 
5.4.1 
Criteria for Stopping the Study ..........................................................31 
6.0 
STUDY TREATMENT .............................................................................................32 
6.1 
Study Treatment(s) Administered ................................................................32 
6.1.1 
The Drug-device Study Treatment ....................................................32 
6.1.2 
OP0201 ..............................................................................................32 
6.1.3 
Placebo ..............................................................................................33 
6.1.4 
Standard Antibiotic ............................................................................33 


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Protocol OP0201-C-006 - Amendment 3 
 
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6.2 
Preparation/Handling/Storage/Accountability ...........................................33 
6.3 
Measures to Minimize Bias: Randomization and Blinding........................33 
6.4 
Study Treatment Compliance .......................................................................34 
6.5 
Concomitant Therapy ....................................................................................34 
6.5.1 
Excluded Medications .......................................................................34 
6.5.2 
Other Concomitant Medications ........................................................35 
6.6 
Dose Modification ..........................................................................................35 
6.7 
Treatment After the End of the Study .........................................................35 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................36 
7.1 
Discontinuation of Study Treatment ............................................................36 
7.2 
Participant Discontinuation/Withdrawal from the Study .........................36 
7.3 
Lost to Follow-up ...........................................................................................36 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ....................................................38 
8.1 
Efficacy Assessments .....................................................................................38 
8.2 
Safety Assessments .........................................................................................39 
8.2.1 
Physical Examinations .......................................................................39 
8.2.2 
Vital Signs .........................................................................................39 
8.2.3 
Otoscopy ............................................................................................39 
8.2.4 
Acute Otitis Media Symptom Burden ...............................................39 
8.3 
Other Assessments .........................................................................................40 
8.4 
Adverse Events ...............................................................................................40 
8.4.1 
Time Period and Frequency for Collecting AE and SAE 
Information ........................................................................................40 
8.4.2 
Method of Detecting AEs and SAEs .................................................41 
8.4.3 
Follow-up of AEs and SAEs .............................................................41 
8.4.4 
Regulatory Reporting Requirements for SAEs .................................41 
8.4.5 
Adverse Events of Special Interest ....................................................41 
8.4.6 
Medical Device Incidents (Including Malfunctions) .........................41 
8.5 
Treatment of Overdose ..................................................................................43 
8.6 
Pharmacokinetics ...........................................................................................43 
8.7 
Pharmacodynamics ........................................................................................43 
9.0 
STATISTICAL CONSIDERATIONS .....................................................................44 
9.1 
Statistical Hypotheses ....................................................................................44 
9.2 
Power Calculation ..........................................................................................44 
9.3 
Populations for Analyses ...............................................................................45 
9.4 
Statistical Analyses.........................................................................................45 
9.4.1 
Efficacy Analyses ..............................................................................45 
9.4.2 
Safety Analyses .................................................................................47 
9.5 
Interim Analyses ............................................................................................47 
9.6 
Safety Monitoring Committee ......................................................................47 


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Protocol OP0201-C-006 - Amendment 3 
 
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10.0 
REFERENCES ...........................................................................................................48 
11.0 
APPENDICES ............................................................................................................50 
Appendix 1 
Abbreviations ...................................................................................51 
Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations ..........53 
Regulatory and Ethical Considerations ............................................................53 
Adequate Resources .........................................................................................53 
Financial Disclosure.........................................................................................54 
Insurance ..........................................................................................................54 
Informed Consent Process ...............................................................................54 
Data Protection.................................................................................................54 
Administrative Structure ..................................................................................54 
Medical Monitor ..............................................................................................55 
Dissemination of Clinical Study Data..............................................................55 
Data Quality Assurance ...................................................................................55 
Source Documents ...........................................................................................55 
Study and Study Center Closure ......................................................................56 
Publication Policy ............................................................................................56 
Appendix 3 
Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................57 
Appendix 4 
Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................61 
Appendix 5 
Signature of Investigator ................................................................63 
Appendix 6 
Protocol Amendment History .........................................................64 
 
 
 


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Protocol OP0201-C-006 - Amendment 3 
 
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TABLE OF TABLES 
Table 1 
Document History ..............................................................................................3 
Table 2 
Description of Changes in Amendment 3 ..........................................................4 
Table 3 
Schedule of Activities ......................................................................................18 
Table 4 
Study Objectives and Endpoints ......................................................................24 
Table 5 
Description of Changes in Amendment 2 ........................................................64 
Table 6 
Description of Changes in Amendment 1 ........................................................68 
 


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Protocol OP0201-C-006 - Amendment 3 
 
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TABLE OF FIGURES 
Figure 1 
Study Schema...................................................................................................17 
Figure 2 
Algorithm for the Diagnosis of Otitis Media ...................................................22 
 
 


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Protocol OP0201-C-006 - Amendment 3 
 
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1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: 
A Study to Assess the Safety, Tolerability, and Efficacy of OP0201 as an Adjunct Treatment for Acute 
Otitis Media in Infants and Children Aged 6 to 24 Months 
Rationale: 
Novus Therapeutics, Inc. is developing OP0201 metered dose inhaler (“OP0201”), a drug-device 
combination product comprised of a 20:1 fixed combination of dipalmitoylphosphatidylcholine (DPPC; a 
phospholipid surfactant) and cholesteryl palmitate (CP; a neutral phospholipid spreading agent) 
suspended in a propellant (hydrofluoroalkane-134a [HFA-134a]). There are no other ingredients (ie, no 
excipients, no fillers) in the formulation other than the active ingredients and the propellant. None of these 
ingredients contain any animal or human derivatives. 
Both DPPC and CP are highly endogenous surfactants in the human respiratory tract, Eustachian tube 
(ET) and nasopharynx. The product is administered via an intranasal pressurized metered dose inhaler 
(pMDI). Together these 2 active ingredients effectively absorb the mucosal air-liquid interface and reduce 
the interfacial surface tension and passive opening pressure of the ET to promote “de-sticking” and 
restoration of the physiologic activity of the ET. In the setting of inflammation in the nasopharynx, the ET 
fails to open as it should and therefore the middle ear is not ventilated. It is well established that 
Eustachian tube dysfunction (ETD) is an important underlying cause of otitis media. To date, there is no 
drug product that has been approved to treat or prevent otitis media. 
The study treatment will be delivered as a local treatment through each nostril using a pMDI device. This 
device holds the canister that contains the drug product. The device has an angled tip to deliver the drug 
towards the lateral wall of the nasal cavity so that the usual nasal mucociliary clearance pathway can 
facilitate delivery of the drug to the ET. 
The purpose of this study is to develop a better understanding of the safety, tolerability, and efficacy of 
intranasal OP0201 as an adjunct treatment to oral antibiotics for acute otitis media (AOM) in infants and 
children, and to assist in the design of future clinical studies. The study will assess whether 20 mg per day 
intranasal OP0201 (10 mg administered twice daily [BID] for a total of 20 doses [over approximately 
10 days]) as an adjunct treatment to 20 doses of oral antibiotics is at least 25 percentage points more 
effective than placebo in AOM resolution as evidenced by no bulging of the tympanic membrane(s) 
(TM[s]) at the Day 4 Visit or is at least 25 percentage points more effective than placebo in reducing the 
likelihood of MEE (OME) assessed at the Day 12 Visit. OP0201 has an acceptable safety and tolerability 
profile when given to healthy adult volunteers and adults with otitis media or ETD. To date only 1 child 
has been exposed via the intranasal route to the active ingredients in OP0201 (Investigator’s Brochure 
[IB]). This study will provide further data on the safety and tolerability of intranasal OP0201 in infants 
and children. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
The primary objectives of the study are to evaluate 
the safety, tolerability, and efficacy of intranasal 
OP0201 compared with placebo in accelerating 
AOM resolution by reducing and/or eliminating 
middle ear effusion (MEE) in infants and children 
when given as an adjunct treatment to oral 
antibiotics as assessed using pneumatic otoscopy. 
• 
Incidence, seriousness, severity, and relatedness to 
study treatment of adverse events (AEs) and shifts 
from baseline (normal, abnormal) in vital signs, 
physical examination (including visual 
examination of the nasopharynx and oropharynx), 
and examination of TM (via otoscopy and 
endoscopy). 


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Protocol OP0201-C-006 - Amendment 3 
 
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Objectives 
Endpoints 
• 
No bulging of the TM assessed at the Day 4 Visit 
by pneumatic otoscopy. 
• 
No MEE (OME) assessed at the Day 12 Visit by 
pneumatic otoscopy. 
Secondary 
 
• 
The secondary objectives of the study are to 
evaluate the efficacy of intranasal OP0201 
compared with placebo in accelerating and 
maintaining AOM resolution, and reducing the 
likelihood of MEE (OME) in infants and children 
when given as an adjunct treatment to oral 
antibiotics as assessed using other measures (ie, 
tympanometry, Acute Otitis Media Severity of 
Symptom [AOM-SOS] score, AOM recurrence, 
and AOM relapse rates). 
The following secondary endpoints will be evaluated at 
the stated visits: 
• 
No MEE assessed at the Day 4 Visit and the 
Day 28 Visit by pneumatic otoscopy. 
• 
No bulging of the TM assessed at the Day 12 Visit 
and the Day 28 Visit by pneumatic otoscopy. 
• 
Normal tympanogram (Type A) assessed at the 
Day 4 Visit, the Day 12 Visit, and the Day 28 
Visit by tympanometry. 
• 
Complete or near complete resolution of 
symptoms (AOM cure), defined as an AOM-SOS 
score ≤2, assessed at the Day 4 Visit, the Day 12 
Visit, and the Day 28 Visit by in-clinic AOM-SOS 
score assessments. 
• 
Change from baseline in AOM-SOS score over 
the planned 10-day treatment period by 
parent/caregiver diary data. 
• 
At least a 50% reduction from baseline in the 
AOM-SOS score assessed at the Day 4 Visit, the 
Day 12 Visit, and the Day 28 Visit by in-clinic 
AOM-SOS score assessments. 
• 
AOM treatment failure (clinical failure)* at the 
Day 12 Visit. 
• 
AOM relapse defined as those with clinical 
success# at the Day 12 Visit and return for an 
interim/sick visit before Day 17 and have AOM. 
• 
AOM recurrence defined as those with clinical 
success# at the Day 12 Visit and return for an 
interim/sick visit from Day 17 through Day 28 and 
have AOM. 
 
*Treatment failure (clinical failure) is defined as (1) 
moderate to severe bulging of the TM (Key Action 
Statement 1A), or (2) mild bulging of TM and recent 
(less than 48 hours) onset of ear pain (otalgia) (Key 
Action Statement 1B), or (3) mild bulging of the TM 
and intense erythema of the TM (Key Action 
Statement 1B). 
#Clinical success for AOM relapse and AOM 
recurrence endpoints is defined as (1) no moderate to 
severe bulging of the TM (Key Action Statement 1A), 
and (2) no mild bulging of TM and no recent (less than 
48 hours) onset of ear pain (otalgia) (Key Action 
Statement 1B), and (3) no mild bulging of the TM and 


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Protocol OP0201-C-006 - Amendment 3 
 
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Objectives 
Endpoints 
no intense erythema of the TM (Key Action 
Statement 1B). 
Other 
 
• 
Another objective of this study is to obtain 
feedback from parents/caregivers on the pMDI 
device to optimize design of the device for pivotal 
studies. 
• 
Parent/caregiver’s input on device experience at 
the Day 12 Visit. 
Overall Design: 
This is a Phase 2a, single center, double-blind, randomized, placebo-controlled, parallel group study to 
assess the safety, tolerability, and efficacy of 20 mg per day intranasal OP0201 (10 mg administered BID 
for a total of 20 doses) as an adjunct therapy to oral antibiotic treatment of AOM in infants and children 
aged 6 to 24 months (inclusive). Participants will be followed for up to 20 days after study treatment is 
discontinued. The total duration of study participation for each Participant is up to 30 days, which 
includes 4 clinic visits: Visit 1: (Day 1) Screening/Enrollment and initiation of the study treatment and 
oral antibiotics administration; Visit 2: (Day 4 [+2]); Visit 3: (Day 12 [+2]); and Visit 4: (Day 28 [±2]) 
Study Exit. On Day 1 potential Participants’ parents/legal guardians in attendance at the study center will 
be told about the study and those Participants whose parents/legal guardian provide written informed 
consent will be evaluated for study eligibility. Those who meet all inclusion and no exclusion criteria will 
be enrolled and randomized (1:1 ratio) to receive a total of 20 intranasal doses (over approximately 
10 days) with 20 mg per day OP0201 (10 mg BID) or placebo as an adjunct treatment to standard oral 
antibiotics (amoxicillin-clavulanate given BID for 20 doses). 
Parents/caregivers of the Participants will complete an electronic daily diary on all days when study 
treatment is given (approximately 10 days) to record BID administration of the oral antibiotic and study 
treatment, and to record daily AOM-SOS scores. 
At each study visit, assessments include a physical examination (including visual examination of the 
nasopharynx and oropharynx) and measurement of vital signs, pneumatic otoscopy to assess TM of each 
ear, endoscopic examination with image capture of each ear when possible, and tympanogram of each ear 
(to be performed when possible). Adverse events (AEs) and concomitant medication use will be recorded. 
At the Day 12 Visit, parents/caregivers will complete the Device Experience Questionnaire. 
Parents/caregivers will be instructed to contact the Investigators if concerned about the Participant’s 
status. An interim evaluation will be scheduled if a parent/caregiver notifies the Investigators that the 
Participant shows no improvement, has significantly worsened, or has recurrence of signs and symptoms 
of AOM or develops symptoms that may be related to the study treatment. If a child failed treatment, 
based on clinical judgment, after receiving antibiotics and study treatment for at least 48 to 72 hours, and 
additional antimicrobial therapy is deemed advisable, the child will receive guideline-concordant therapy. 
Number of Investigators and Study Centers: 
One Principal Investigator at 1 study center along with up to 4 satellite sites in the US are expected to 
participate in this study. 
Number of Participants: 
Approximately 140 Participants with AOM in at least 1 ear will be randomly assigned to study treatment 
such that approximately 70 evaluable Participants per treatment group complete the study. 
Treatment Groups and Duration: 
Twice daily treatment with 10 mg intranasal OP0201 or 0 mg intranasal placebo for a total of 20 doses, as 
well as standard oral antibiotic treatment for a total of 20 doses, will be initiated on Day 1. The first dose 
of the intranasal study treatment will be administered in the study center under supervision of the study 
staff. 


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Protocol OP0201-C-006 - Amendment 3 
 
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Statistical Methods: 
Power Calculation 
The power calculation is based on a 2-sided Pearson chi square test of each of the 2 endpoints in the 
primary efficacy endpoint family and control for Type 1 error using the step-up Hochberg procedure. The 
minimally important difference in proportions for both endpoints is approximately 0.25. With 
70 Participants randomized per treatment group, and assuming a 12% dropout rate with dropouts counted 
as failures, this Phase 2a study will have 87% power to detect a treatment effect in at least 1 of the 
2 endpoints assuming 40% of placebo-treated Participants will have no bulging TM at Day 4 and 30% of 
placebo-treated Participants will have no MEE at Day 12.  
Populations for Analyses 
Four populations will be considered. 
Screened population is defined as all Participants whose parent/legal guardian signs the informed consent 
form. 
Safety population is defined as all Participants who received at least 1 intranasal spray of study treatment 
and will be used to assess the safety and secondary efficacy endpoints. 
Intent-to-treat (ITT) population is defined as all randomized Participants and will be used to assess the 
primary efficacy endpoint family. 
Per-Protocol (PP) population is defined as the subset of the ITT population who have no protocol 
violations affecting the primary efficacy endpoint family and will be used to confirm results from the 
primary efficacy endpoint family. 
Statistical Analyses 
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
describe the Participant population sets to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. 
Safety Analyses 
Safety will be evaluated using the safety population. 
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened in 
severity after administration of study treatment and no later than 2 calendar days after the last dose of 
study treatment. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). For 
each study treatment, numbers of TEAEs and incidence rates will be tabulated by primary system organ 
class (SOC) and by preferred term within each primary SOC. 
Treatment-emergent AEs, TEAEs related to study treatment, serious adverse events (SAE), and TEAEs 
leading to discontinuation of study treatment will be summarized. 
Vital sign measurements and changes from baseline will be summarized. 
Test results from otoscopy, AOM-SOS, physical examination, nasopharynx, and oropharynx will be 
summarized. 
Efficacy Analyses 
The primary efficacy endpoint family consists of 2 endpoints: (1) no bulging of the TM at the Day 4 Visit 
assessed by pneumatic otoscopy and (2) no MEE (OME) at the Day 12 Visit assessed by pneumatic 
otoscopy. The step-up Hochberg procedure will be used to adjust for multiplicity. Specifically, the 
endpoint with the highest p-value will be tested first at the 0.05 significance level and, if significant, both 
endpoints will be declared significant; if the endpoint with the highest p-value is not significant at the 
0.05 level, the other endpoint will be tested at the 0.025 significance level. A positive treatment effect on 
efficacy will be concluded if at least 1 of the 2 endpoints is significant.  


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Protocol OP0201-C-006 - Amendment 3 
 
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In general, categorical variables (including binary outcomes) will be summarized as frequencies and 
percentages and will be analyzed using logistic regression to control for covariates, including the 
randomization stratifiers. Continuous variables will be summarized by numbers of observations, means, 
measures of variances, percentiles, and ranges and will be analyzed using general linear models to control 
for covariates. 
Safety Monitoring Committee: Yes 
The Safety Monitoring Committee (SMC) will review blinded safety data for all Participants when 
approximately 25% of enrolled Participants have completed the Day 12 Visit. Safety data will be 
evaluated on an ongoing basis to ensure it is safe to continue study enrollment and treatment. The 
composition, responsibilities, and meeting schedule of the SMC will be specified in a separate charter 
document. 
 


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Protocol OP0201-C-006 - Amendment 3 
 
 
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1.2 
Schema 
Figure 1 
Study Schema 
 
 
Visit 1 
 
Visit 2 
 
Visit 3 
 
Visit 4 
 
 
 
 
 
 
 
Days 
 
Screening/ 
Enrollment 
  
 
  
 
 
 
 
Study Exit 
 
 
 
 
 
 
 
Day 
1 
 
 
  
Day 
4 (+2) 
  
 
Day 
12 (+2) 
 
 
 
 
Day 
28 (±2) 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol OP0201-C-006 - Amendment 3 
 
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1.3 
Schedule of Activities 
Table 3 
Schedule of Activities 
Procedure 
Visit 
Screening/ 
Enrollment 
Visit 1 
Visit 2 
Visit 3 
Study Exit 
Visit 4/Early 
Discontinuationf 
Study Day 
Day 1 
Day 4 (+2) 
Day 12 (+2) 
Day 28 (±2) 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Demographics 
X 
 
 
 
Medical/surgical/ear history 
X 
 
 
 
Baseline otitis media risk factors 
X 
 
 
 
AOM-SOS scorea 
X 
X 
X 
X 
Physical examinationb 
X 
X 
X 
X 
Height and weight 
X 
 
 
 
Vital signs (temperature, pulse, and 
respiratory rate) 
X 
X 
X 
X 
Pneumatic otoscopy of each earc 
X 
X 
X 
X 
Tympanogram of each earc 
X 
X 
X 
X 
Endoscopic examination with image 
capture of each ear (when possible) 
using the iPhone application 
X 
X 
X 
X 
Randomization to OP0201 or 
placebo 
X 
 
 
 
Train parent/caregiver on study 
treatment administration 
X 
 
 
 
Train parent/caregiver on daily 
completion of AOM-SOS score and 
daily electronic diary 
X 
 
 
 
Nasal saline rinse and/or nasal 
suction, as neededd 
X 
X 
X 
X 
Observe parent/caregiver administer 
first dose of intranasal study 
treatment 
X 
 
 
 
Dispense 10-day supply of study 
treatment 
X 
 
 
 
Safety observatione 
X 
 
 
 
Check electronic diary, study 
treatment adherence, AOM-SOS 
assessment adherence/retrain as 
needed 
 
X 
X 
 


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AOM-SOS = Acute Otitis Media Severity of Symptom 
a The AOM-SOS scale is scored by the parent/caregiver once daily at home for the total duration of the antibiotic 
and study treatment period. At the screening visit the parent/caregiver will be asked to score the AOM-SOS scale 
as part of the screening criteria for the study. Parents/caregivers must not be informed of the score required to 
meet study enrollment criteria. 
b Physical examination including visual examination of the nasopharynx and oropharynx at each visit. 
c Otoscopy and tympanometry (when possible) to be performed prior to the first dose of the study treatment on 
Day 1. When possible, otoscopy and tympanometry to be performed 30 minutes following administration of the 
first dose of the study treatment on Day 1. Trained otoscopists who have undergone comprehensive educational 
program (enhancing proficiency in otitis media) for training in the diagnosis of AOM will perform the otoscopy 
assessments. This training includes training on cerumen removal, which is required (as needed) prior to 
performing pneumatic otoscopy or tympanogram. 
d Train parent/caregiver on nasal saline rinse and/or nasal suction on Day 1 and remind parent/caregiver of rinse 
and/or suction during the study treatment period, as needed. 
e Safety observation for 30 minutes following administration of the first dose of study treatment.  
f 
If a Participant exits the study prior to the Day 28 Study Exit visit, all Day 28 final measurements should be 
performed and recorded on the appropriate eCRF. 
g 
Device Experience Questionnaire should only be completed for all Early Discontinuation Participants if they exit 
prior to Day 12 and did NOT complete the questionnaire. 
 
Procedure 
Visit 
Screening/ 
Enrollment 
Visit 1 
Visit 2 
Visit 3 
Study Exit 
Visit 4/Early 
Discontinuationf 
Study Day 
Day 1 
Day 4 (+2) 
Day 12 (+2) 
Day 28 (±2) 
Concomitant medications 
X 
X 
X 
X 
Adverse event 
X 
X 
X 
X 
Device Experience Questionnaire 
 
 
X 
Xg 


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Protocol OP0201-C-006 - Amendment 3 
 
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2.0 INTRODUCTION 
2.1 
Study Rationale 
Novus Therapeutics, Inc. is developing OP0201, a drug-device combination product comprised 
of a 20:1 fixed combination of dipalmitoylphosphatidylcholine (DPPC; a phospholipid 
surfactant) and cholesteryl palmitate (CP; a neutral phospholipid spreading agent) suspended in a 
propellant (hydrofluoroalkane-134a [HFA-134a]). There are no other ingredients (ie, no 
excipients, no fillers) in the formulation other than the active ingredients and the propellant. 
None of these ingredients contain any animal or human derivatives. 
Both DPPC and CP are highly endogenous surfactants in the human respiratory tract, Eustachian 
tube (ET) and nasopharynx. The product is administered via an intranasal pressurized metered 
dose inhaler (pMDI). Together these 2 active ingredients effectively absorb the mucosal 
air-liquid interface and reduce the interfacial surface tension and passive opening pressure of the 
ET to promote “de-sticking” and restoration of the physiologic activity of the ET. In the setting 
of inflammation in the nasopharynx, the ET fails to open as it should and therefore the middle 
ear is not ventilated. It is well established that Eustachian tube dysfunction (ETD) is an important 
underlying cause of otitis media. To date, there is no drug product that has been approved to treat 
or prevent otitis media. 
OP0201 is a focal, intranasal treatment and is not anticipated to have either focal or systemic 
toxic effects since both active ingredients, DPPC and CP, are ubiquitous in nearly every cell of 
the human body, including those of the nasopharynx and respiratory system. Safety data from 
3 nonclinical pharmacology studies did not identify adverse effects of repeated once or twice 
daily (BID) intranasal dosing over multiple days in gerbils, mice, or chinchillas (Investigator’s 
Brochure [IB]). Single and cumulative total doses on a mg/kg basis used in Phase 1 studies in 
adults were less than single or cumulative total dose exposure from products currently approved 
and marketed. Concentrations of surfactants, including DPPC, in the ET and respiratory system 
of persons with otitis media are reduced compared to ontologically healthy persons (IB). The 
intranasal administration of OP0201 is not anticipated to attain levels in the nasopharynx and 
respiratory system that are supraphysiologic. 
The study treatment will be delivered as a local treatment through each nostril using a pMDI 
device. This device holds the canister that contains the drug product. The device has an angled 
tip to deliver the drug towards the lateral wall of the nasal cavity so that the usual nasal 
mucociliary clearance pathway can facilitate delivery of the drug to the ET. 
The purpose of this study is to develop a better understanding of the safety, tolerability, and 
efficacy of intranasal OP0201 as an adjunct treatment to oral antibiotics for acute otitis media 
(AOM) in infants and children, and to assist in the design of future clinical studies. The study 
will assess whether 20 mg per day intranasal OP0201 (10 mg administered BID for a total of 


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Protocol OP0201-C-006 - Amendment 3 
 
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20 doses [over approximately 10 days]) as an adjunct treatment to 20 doses of oral antibiotics is 
at least 25 percentage points more effective than placebo in AOM resolution as evidenced by no 
bulging of the tympanic membrane(s) (TM[s]) at the Day 4 Visit and/or more effective than 
placebo in reducing the likelihood of MEE (OME) as evidenced by no MEE at the Day 12 Visit. 
For both endpoints, the minimal clinically meaningful difference in proportions for indication of 
efficacy of OP0201 is approximately 0.25. OP0201 has an acceptable safety and tolerability 
profile when given to healthy adult volunteers and adults with otitis media or ETD. To date only 
1 child has been exposed via the intranasal route to the active ingredients in OP0201 (IB). This 
study will provide further data on the safety and tolerability of intranasal OP0201 in infants and 
children. 
2.2 
Background 
It has been established that many (approximately 70%) of young children with AOM will have 
persistent middle ear effusion (MEE, or otitis media with effusion [OME]) 2 to 3 weeks after a 
diagnosis of AOM, despite treatment with oral antibiotics.(2) It has been reported that negative 
effects of OME include ear discomfort/fullness, conductive hearing loss, and vestibular 
problems, as well as affecting quality-of-life and school performance.(3,4,5,6) 
An algorithm that used bulging and opacification of the TM has been previously shown to 
correctly classify 99% of ears regarding a confirmed diagnosis of AOM (Figure 2).(7) Bulging of 
the TM was the main finding that otoscopists used to discriminate AOM from OME. Information 
regarding the presence or absence of other signs and symptoms added little to the diagnostic 
process. Overall, 92% of children with AOM had a bulging TM compared with 0% of children 
with OME. Opacification and/or an air fluid level was the main finding that otoscopists used to 
discriminate OME from no effusion. In total, 97% of children diagnosed with OME had an 
opaque TM compared with 5% of children diagnosed with no effusion. 
On Day 7 of a 10-day antibiotic (amoxicillin/clavulanate) treatment course, 44% of children with 
AOM still had bulging TM (with or without symptoms).(8) If an otoscopic assessment was made 
earlier in the 10-day antibiotic treatment course, ie, Day 4 to Day 6, an estimated additional 10% 
to 15% of children would have bulging TM still present (with or without symptoms) (based on 
personal communication with Alejandro Hoberman, MD, Principal Investigator, 2018). 
Antibiotics are prescribed to treat a presumed bacterial infection of the middle ear associated 
with AOM, but there are no drug products available to treat the underlying cause of otitis media 
(ie, ETD) and facilitate draining the MEE. 


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Protocol OP0201-C-006 - Amendment 3 
 
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Figure 2 
Algorithm for the Diagnosis of Otitis Media 
 
AOM = acute otitis media; TM = tympanic membrane; OME = otitis media with effusion 
2.3 
Benefit/Risk Assessment 
The active components of OP0201, DPPC and CP, are endogenous surfactant compounds in 
several products that have been approved by health authorities, including the Food and Drug 
Administration (FDA). HFA-134a, utilized as the propellant in OP0201, is also utilized as a 
propellant in other approved intranasal and orally inhaled products for adults and children. 
The clinical safety and tolerability of OP0201 (20:1 weight/weight [w/w]) for human use is 
guided by data from animal studies of DPPC:CP (200:1 weight/weight [w/w]), data from 
9 human cases exposed to 1 or more doses of DPPC:CP in HFA-134a (200:1 w/w or 16:1 w/w) 
(see IB), and from 15 adult healthy volunteers exposed to intranasal OP0201 30 mg per day 
(n = 12) or placebo (n = 3) as 2 sprays to each nostril 3 times a day × 14 days with no severe or 
serious adverse events (SAEs) reported and there was no consistent or unexpected pattern of AEs 
(Novus Study OP0201-C-002). 
Based on a diminished beneficial effect of DPPC:CP (200:1 w/w) when combined with 
phenylephrine in animal model studies, it may be prudent to avoid co-administration of 
phenylephrine containing products during the use of OP0201 (IB). 
The composition of OP0201 is designed to maximize the lowering of mucosal surface tension. 
Since the drug product mechanism involves reduction of the interfacial surface tension of the ET, 
the optimum ratio of DPPC to CP was evaluated by determining the reduction in surface tension 
at different ratios. An integrated dissolution and surface tension monitoring system was utilized 


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Protocol OP0201-C-006 - Amendment 3 
 
23 
to measure the surface tension of phosphate buffered saline (pH 7) into which the finished 
product actuations were fired from the canister. Surface tension lowering of product formulated 
with DPPC only, CP only, and combined DPPC + CP in 5:1, 10:1, and 20:1 ratios found that the 
maximum surface tension reduction occurs with combined DPPC + CP at 20:1 ratio. Higher 
ratios did not result in further significant surface tension reduction and would render the minor 
CP component difficult to accurately quantify. Hence the DPPC + CP 20:1 ratio was selected for 
further development. 
Refer to Section 4.0 for details on study procedures, dose, and study design justification. 
See the IB for further details regarding OP0201. 
The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 
This study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH) Good Clinical Practice (GCP) and applicable regulatory requirements. 


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Protocol OP0201-C-006 - Amendment 3 
 
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3.0 OBJECTIVES AND ENDPOINTS 
3.1 
Endpoint Rationale 
This Phase 2a exploratory study is the first evaluation of OP0201 in treating AOM and in 
reducing the likelihood of MEE (OME) after AOM. The primary objectives of the study are to 
evaluate the safety, tolerability, and efficacy of intranasal OP0201 compared with placebo in 
accelerating AOM resolution by reducing and/or eliminating MEE in infants and children when 
given as an adjunct treatment to oral antibiotics as assessed using pneumatic otoscopy. The 
safety endpoints address the primary objective of safety evaluation. The primary efficacy 
endpoint family consists of “No bulging of the TM at the Day 4 Visit as assessed by pneumatic 
otoscopy” and “No MEE (OME) at the Day 12 Visit as assessed by pneumatic otoscopy.” No 
bulging of the TM was chosen because modulating bulging TM, a hallmark sign of AOM, would 
be the most clinically meaningful demonstration that OP0201 is effective in treating AOM. 
Clinical experts were surveyed as to what would be considered a clinically meaningful numeric 
difference between OP0201 and placebo on this endpoint, and consensus indicated that an 
approximate 0.25 difference in proportions between treatment groups would represent a 
clinically meaningful benefit in treating AOM. No MEE was chosen because decreasing the 
likelihood of residual MEE which occurs frequently after completion of a course of antibiotic 
therapy(2) would be the most clinically meaningful demonstration that OP0201 reduces OME 
which is also associated with a higher likelihood of recurrence of AOM.(9) There are no 
established guidelines for defining a minimal clinical meaningful benefit of treatment for quickly 
resolving MEE after treating AOM. However, restoration of hearing is dependent on resolving 
MEE, and in a recent study of children with COME,(10) acceptable hearing was observed in 33% 
of placebo-treated children (age 2 to 8 years) at week 5 and a 0.15 increase in the proportion with 
hearing resolution was considered clinically meaningful. A significant treatment effect on either 
AOM treatment or on reduction of the proportion of children with MEE (OME) would constitute 
a successful study in terms of efficacy. 
Table 4 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
The primary objectives of the study are to evaluate 
the safety, tolerability, and efficacy of intranasal 
OP0201 compared with placebo in accelerating 
AOM resolution by reducing and/or eliminating 
MEE in infants and children when given as an 
adjunct treatment to oral antibiotics as assessed 
using pneumatic otoscopy. 
• 
Incidence, seriousness, severity, and relatedness to 
study treatment of adverse events (AEs) and shifts 
from baseline (normal, abnormal) in vital signs, 
physical examination (including visual 
examination of the nasopharynx and oropharynx), 
and examination of TM (via otoscopy and 
endoscopy). 
• 
No bulging of the TM assessed at the Day 4 Visit 
by pneumatic otoscopy. 
• 
No MEE (OME) assessed at the Day 12 Visit by 
pneumatic otoscopy. 


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Protocol OP0201-C-006 - Amendment 3 
 
25 
Secondary 
 
• 
The secondary objectives of the study are to 
evaluate the efficacy of intranasal OP0201 
compared with placebo in accelerating and 
maintaining AOM resolution, and reducing the 
likelihood of MEE (OME) in infants and children 
when given as an adjunct treatment to oral 
antibiotics as assessed using other measures (ie, 
tympanometry, Acute Otitis Media Severity of 
Symptoms (AOM-SOS) score, AOM recurrence, 
and AOM relapse rates). 
The following secondary endpoints will be evaluated at 
the stated visits: 
• 
No MEE assessed at the Day 4 Visit and the 
Day 28 Visit by pneumatic otoscopy. 
• 
No bulging of the TM assessed at the Day 12 Visit 
and the Day 28 Visit by pneumatic otoscopy. 
• 
Normal tympanogram (Type A) assessed at the 
Day 4 Visit, the Day 12 Visit, and the Day 28 
Visit by tympanometry. 
• 
Complete or near complete resolution of 
symptoms (AOM cure), defined as an AOM-SOS 
score ≤2, assessed at the Day 4 Visit, the Day 12 
Visit, and the Day 28 Visit by in-clinic AOM-SOS 
score assessments.  
• 
Change from baseline in AOM-SOS score over 
the planned 10-day treatment period by 
parent/caregiver diary data. 
• 
At least a 50% reduction from baseline in the 
AOM-SOS score assessed at the Day 4 Visit, the 
Day 12 Visit, and the Day 28 Visit by in-clinic 
AOM-SOS score assessments. 
• 
AOM treatment failure (clinical failure)* at the 
Day 12 Visit. 
• 
AOM relapse defined as those with clinical 
success# at the Day 12 Visit and who return for an 
interim/sick visit before Day 17 and have AOM. 
• 
AOM recurrence defined as those with clinical 
success# at the Day 12 Visit and who return for an 
interim/sick visit from Day 17 through Day 28 and 
have AOM. 
 
*Treatment failure (clinical failure) is defined as (1) 
moderate to severe bulging of the TM (Key Action 
Statement 1A[11]), or (2) mild bulging of TM and 
recent (less than 48 hours) onset of ear pain (otalgia) 
(Key Action Statement 1B[11]), or (3) mild bulging of 
the TM and intense erythema of the TM (Key Action 
Statement 1B[11]). 
#Clinical success for AOM relapse and AOM 
recurrence endpoints is defined as (1) no moderate to 
severe bulging of the TM (Key Action 
Statement 1A[11]), and (2) no mild bulging of TM and 
no recent (less than 48 hours) onset of ear pain 
(otalgia) (Key Action Statement 1B[11]), and (3) no 
mild bulging of the TM and no intense erythema of the 
TM (Key Action Statement 1B[11]). 
Other 
 
• 
Another objective of this study is to obtain 
feedback from parents/caregivers on the pMDI 
• 
Parent/caregiver’s input on device experience at 
the Day 12 Visit. 


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Protocol OP0201-C-006 - Amendment 3 
 
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device to optimize design of the device for pivotal 
studies. 


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Protocol OP0201-C-006 - Amendment 3 
 
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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 2a, single center, double-blind, randomized, placebo-controlled, parallel group 
study to assess the safety, tolerability, and efficacy of 20 mg per day intranasal OP0201 (10 mg 
administered BID for a total of 20 doses) as an adjunct therapy to oral antibiotic treatment of 
AOM in infants and children aged 6 to 24 months (inclusive). Participants will be followed for 
up to 20 days after study treatment is discontinued. The total duration of study participation for 
each Participant is up to 30 days, which includes 4 clinic visits: Visit 1: (Day 1) 
Screening/Enrollment and initiation of the study treatment and oral antibiotics administration; 
Visit 2: (Day 4 [+2]); Visit 3: (Day 12 [+2]); and Visit 4: (Day 28 [±2]) Study Exit. On Day 1 
potential Participants’ parents/legal guardians in attendance at the study center will be told about 
the study and those Participants whose parents/legal guardian provide written informed consent 
will be evaluated for study eligibility. Those who meet all inclusion and no exclusion criteria will 
be enrolled and randomized (1:1 ratio) to receive a total of 20 intranasal doses (over 
approximately 10 days) with 20 mg per day OP0201 (10 mg BID) or placebo as an adjunct 
treatment to standard oral antibiotics (amoxicillin-clavulanate given BID for 20 doses). 
Parents/caregivers of the Participants will complete an electronic daily diary on all days when 
study treatment is given (approximately 10 days) to record BID administration of the oral 
antibiotic and study treatment, and to record daily AOM-SOS scores. 
At each study visit, assessments include a physical examination (including visual examination of 
the nasopharynx and oropharynx) and measurement of vital signs, pneumatic otoscopy to assess 
TM of each ear, endoscopic examination with image capture of each ear when possible, and 
tympanogram (to be performed when possible) of each ear. Adverse events and concomitant 
medication use will be recorded. At the Day 12 Visit, parents/caregivers will complete the 
Device Experience Questionnaire. The study assessments are summarized in Table 3. 
An unscheduled interim/sick visit may occur for safety purposes or if AOM symptoms have 
relapsed or worsen. Applicable procedures (eg, physical, otoscopy, tympanometry) will be 
performed and recorded in the electronic case report form (eCRF). 
Parents/caregivers will be instructed to contact the Investigators if concerned about the 
Participant’s status. An interim evaluation will be scheduled if a parent/caregiver notifies the 
Investigators that the Participant shows no improvement, has significantly worsened, or has 
recurrence of signs and symptoms of AOM or develops symptoms that may be related to the 
study treatment. If a child failed treatment, based on clinical judgment, after receiving antibiotics 
and study treatment for at least 48 to 72 hours, and additional antimicrobial therapy is deemed 
advisable, the child will receive guideline-concordant therapy.(3) 


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4.2 
Scientific Rationale for Study Design 
Otitis media is a very common disease seen in pediatric practice and in the US, it is the most 
common reason children are prescribed antibiotics. Otitis media is a serious condition that can 
result in life-long adverse consequences including irreversible hearing loss. Morbidity from otitis 
media is driven by recurrence and/or persistence of otitis media, as well as disease progression 
that leads to ruptured TM and/or damage to structures of the middle ear. Both intratemporal and 
intracranial complications can occur resulting in serious consequences and, in rare cases, death. 
More than $5 billion is spent annually in the US on management of pediatric otitis media (IB). 
Novus Therapeutics, Inc. is developing OP0201, a drug-device combination product comprised 
of 2 surfactant active ingredients DPPC and CP suspended in propellant (HFA-134a) to both 
treat and prevent otitis media. Both DPPC and CP are highly endogenous surfactants in the 
human respiratory tract. The product is administered via an intranasal pMDI. Together these 
2 active ingredients effectively absorb the mucosal air-liquid interface and reduce the interfacial 
surface tension and passive opening pressure of the ET to promote “de-sticking” and restoration 
of physiologic activity of the ET. In the setting of inflammation in the nasopharynx, the ET fails 
to open as it should and therefore the middle ear is not ventilated. 
This study will be conducted in the very young pediatric population (6 to 24 months, inclusive) 
as the targeted disease occurs more frequently in this age group, and the risk to this population 
from the compound (given in addition to a course of antibiotics), which is found naturally in 
human tissues, is considered to be very low. Parents/caregivers will be instructed to contact the 
Investigators if concerned about the Participant’s status. The use of randomization, a placebo and 
blinding are employed in this study to eliminate bias in evaluating safety, tolerability, and 
efficacy. 
4.3 
Justification for Dose 
OP0201 is a local treatment to the nasopharynx and ET. Systemic concentrations of OP0201 
would not be possible in guiding dose selection correlated with efficacy, as the components of 
OP0201 are endogenous to the human body. Furthermore, the drug product is intended to have a 
local effect at the site of delivery. Thus, a maximum practical dose and dosing interval is 
proposed for evaluation of OP0201 in humans. Input from expert clinicians indicates that a 
maximum dosing interval for an infant, child, adolescent, or adult that would be acceptable is 
BID. Data from the nonclinical pharmacology studies indicated that BID dosing was more 
efficacious than once daily dosing (see IB Section 4.2.1.3). It has also been determined that the 
practical maximum number of sprays into each nostril at each dosing interval would be 2 sprays. 
In vivo studies evaluating the effects of 1 or 2 sprays on reducing surface tension indicate that 
there is a greater reduction of surface tension after 2 sprays. It is unlikely that patients/caregivers 
will comply if 3 or more sprays need to be given per nostril per dosing interval. Taking all of the 
above information into consideration, the maximum number of sprays per nostril in this Phase 2a 
study is 2 sprays per nostril given BID. An ongoing Phase 1 adult safety study (Novus 


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Protocol OP0201-C-006 - Amendment 3 
 
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Study OP0201-C-002) has established that 2 sprays per nostril 3 times a day (a research dosing 
interval not considered to be practical for studies in patients) for 14 consecutive days is safe. 
4.4 
End of Study Definition 
A Participant is considered to have completed the study if he/she has completed all visits of the 
study including the last scheduled procedure shown in Table 3. 
The end of the study is defined as the date of the last visit of the last Participant in the study. 
4.5 
Dose Escalation Criteria 
Not applicable. 
4.6 
Study Stopping Criteria 
4.6.1 
Stopping Criteria for Individual Participants 
Study treatment for any individual Participant will be stopped if the Participant experiences an 
SAE or a clinically significant possibly study treatment-related AE, which in the opinion of the 
Principal Investigator, Medical Safety Physician and Sponsor’s medical representative, warrants 
discontinuation of the study for that Participant’s wellbeing. 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
3. Male and female infants and children aged 6 to 24 months (inclusive). 
4. Diagnosis of AOM(11) - moderate to severe bulging of the TM (Key Action 
Statement 1A[11]), or mild bulging of TM and recent (less than 48 hours) onset of ear pain 
(otalgia) (Key Action Statement 1B[11]), or mild bulging of the TM and intense erythema 
of the TM (Key Action Statement 1B[11]).  
5. Score of 5 or more on the 5-question version of the AOM-SOS scale.(12) 
6. Intact TM in both ears (eg, no perforation). 
7. Written informed consent by the infant/child’s parent/legal guardian and their willingness 
to ensure that study instructions are followed, all study-related visits are attended, that 
treatment administration is given, and the parent/caregiver assessments are recorded 
according to the study protocol. 
8. Parent/Legal Guardian has a smartphone or internet access to receive the electronic 
survey. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Allergy to penicillin or cephalosporin. 
2. History or presence of immunodeficiency disorders. 
3. Antimicrobial therapy within the 3 days (ie, 72 hours) prior to Day 1. 
4. Use of intranasal treatments other than intranasal saline within 7 days prior to Day 1. 
5. Craniofacial abnormalities (eg, cleft palate or Down’s Syndrome) that may interfere with 
ET function. 
6. Disorders with decreased mucociliary clearance or higher viscosity of the mucous (eg, 
cystic fibrosis, primary ciliary dyskinesia, Kartagener’s syndrome). 
7. Clinically relevant blockage of 1 or both nasal passages, as determined by the 
Investigator’s medical judgment. 
8. Participants with any condition that would in the Investigator’s opinion put the 
Participant at significant risk, may confound study results, may interfere significantly 


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with the Participant’s participation, or have any factor that may present bias in the 
Participant selection. 
9. Persons employed by the Sponsor or Investigator. 
5.3 
Lifestyle Considerations 
Participants must refrain from immersing their head fully under water (eg, swimming) from the 
time of signed informed consent until after the final follow-up visit (Day 28). 
5.4 
Screen Failures 
Screen failures are defined as Participants whose parents/legal guardian provide written informed 
consent for their participation in the clinical study but are not subsequently assigned to study 
treatment. A minimal set of screen failure information is required to ensure transparent reporting 
of screen failure Participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography (eg, age, gender, race), reasons for screen failure (eg, note which eligibility 
criteria was not met), and any SAE.  
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened. 
5.4.1 
Criteria for Stopping the Study 
If 1 or more Participants experience study treatment-related SAEs or 2 or more Participants 
experience any study treatment-related severe AEs, the study will be stopped. 


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6.0 STUDY TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a Participant according to the study protocol. 
The study treatment is to be used in accordance with the protocol for Participants who are under 
the direct supervision of a qualified Investigator. 
6.1 
Study Treatment(s) Administered 
6.1.1 
The Drug-device Study Treatment 
The study treatment (OP0201 and the placebo) is manufactured using Good Manufacturing 
Processes (GMP) with development phase appropriate compliance with global Health Authority 
guidelines(13) by Sciarra Laboratories, Inc., Hicksville, New York, US. It is considered a 
drug-device combination product because the drug is expelled from a pressurized canister via an 
actuating device. 
The study treatment is supplied in mechanical packing parts that includes a pressurized canister 
with a securely attached metering valve where the OP0201 or placebo is contained, an actuator 
device into which the canister is seated, and an angled tip on the device to deliver the drug to the 
nostrils. The pressurized canisters are labeled to deliver 100 actuations (sprays) per canister. 
Parents/caregivers will be given a demonstration of the administration of the study treatment and 
will need to be trained on study treatment administration on Day 1, prior to the first dose (which 
will be given under supervision of the study center staff). 
All Medical Device Incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the Investigator throughout the study (see Section 8.4.6). 
Participants’ parents/caregivers will be trained on the proper administration of the study 
treatment and antibiotics on Day 1, prior to the first dose. The first dose will be administered 
under the supervision of the study staff by the parent/caregiver. 
6.1.2 
OP0201 
OP0201 is the active drug. It is a drug-device combination product comprised of DPPC:CP 
(approximately 20:1 w/w in HFA 134a) for intranasal administration. 
Each spray of OP0201 delivers 2.5 mg of active ingredients. Participants randomized to OP0201 
will receive 2 sprays per nostril BID (morning and evening, at a total daily dose of 20 mg) for a 
total of 20 doses. 
See the IB for further details regarding OP0201. 


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6.1.3 
Placebo 
Placebo is the propellant without any active ingredients (HFA 134a only) and provides a total 
daily dose of 0 mg. 
All Participants will receive the same intranasal dosing regimen of placebo (given as 2 sprays to 
each nostril BID) for a total of 20 doses. 
6.1.4 
Standard Antibiotic 
Participants will be prescribed a standard 10-day (20 doses) oral antibiotic treatment course of 
amoxicillin-clavulanate at a total dose of 90 mg/6.4 mg/kg/day administered orally in 2 divided 
doses (12-hourly). 
Children categorized as initial antibiotic treatment failure (no clinical improvement within 48 to 
72 hours) will receive appropriate antibiotic therapy which may include intramuscular 
ceftriaxone 75 mg/kg at the time of treatment failure, and a repeat dose in 48 hours. 
6.2 
Preparation/Handling/Storage/Accountability 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
Only Participants enrolled in the study may receive study treatment and only authorized study 
center staff may supply study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized study center 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
The Investigator, a member of the study center staff, or a pharmacist must maintain an adequate 
record of the receipt and distribution of all study treatment using the Drug Accountability Form. 
These forms must be available for inspection at any time. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
On Day 1, Participants will be assigned a unique number (randomization number) in ascending 
numerical order. The randomization number encodes the Participant’s assignment to study 
treatment according to the randomization schedule generated prior to the study by the Statistics 
Department of IQVIA. This is a double-blind study with limited access to the randomization 
code. OP0201 and placebo will be identical in physical appearance. The specific treatment each 
Participant will receive (OP0201 or placebo) will not be disclosed to the Investigator, study 


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center staff, Participant, Sponsor, study vendors, or the Safety Monitoring Committee (SMC). 
The treatment codes will be held by the Clinical Supplies Department of the Sponsor. 
Participants will be randomly allocated in a 1:1 ratio to receive OP0201 or placebo as adjunct 
treatment to 20 doses of protocol defined oral antibiotic treatment. 
Randomization will be stratified by daycare attendance (yes, no) and age (≥6 to <12 months, 
≥12 to ≤24 months). Daycare attendance “yes” is defined as exposure to 3 or more children 
outside of the home for 10 or more hours per week. 
6.4 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. Any deviations 
from the protocol defined study treatment regimen must be recorded in the eCRFs. 
Parents/caregivers of Participants will be issued a study diary in which they will be instructed to 
record daily the date and time of study treatment and antibiotic administration. If a study 
treatment or antibiotic dose is missed or a partial dose is given, this should also be recorded, and 
the dosing should resume at the next scheduled time. 
At the Day 4 Visit and the Day 12 Visit, previously dispensed study treatment and the diary will 
be retrieved by the Investigator and compliance assessed. Parents/caregivers exhibiting poor 
compliance as assessed by diary completion should be counseled on the importance of good 
compliance to the study dosing regimen. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the Participant has received within the 7 days before enrollment 
(prior therapy) or receives during the study period and after first dose of study treatment 
(concomitant therapy) must be recorded on the eCRF along with: 
• Reason for use. 
• Date of administration including start and end date. 
• Dosage information including dose, route, and frequency. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1 
Excluded Medications 
Participants must abstain from taking antimicrobial therapy within the 3 days (ie, 72 hours) prior 
to Day 1. Excluded medications/therapy is listed below: 
• Any intranasal treatments other than saline rinse. 


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• Any systemic or locally administered drug containing phenylephrine. 
The use of an excluded medication/therapy is a protocol violation and must be recorded in the 
eCRF. 
6.5.2 
Other Concomitant Medications 
Other concomitant medication may be considered on a case-by-case basis by the Investigator in 
consultation with the Medical Monitor, if required for the wellbeing of the Participant. 
6.6 
Dose Modification 
Dose modifications are not planned in this study. 
6.7 
Treatment After the End of the Study 
The Sponsor will not provide any additional care to Participants after they leave the study. 


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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
If a clinically significant finding is identified, the Investigator or qualified designee will 
determine if the Participant should continue with the study treatment and if any change in 
Participant management is needed, and/or if they should remain in the study. Any new clinically 
relevant finding should be reported as an AE. 
7.1 
Discontinuation of Study Treatment  
The Investigator may use their discretion in deciding whether to discontinue the Participant from 
the study. If the Participant is discontinued from the study early, see Table 3 for data to be 
collected at the time of study discontinuation. The reason that the study treatment is stopped 
should be documented on the appropriate eCRF. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
Participants who meet any of the following criteria should not receive further study treatment 
and should be exited from the study. See Table 3 for data to be collected at the time of Study 
Exit. 
• Investigator or Sponsor (or its designee) decides to discontinue Participants from the study 
for safety, behavioral, compliance, or administrative reasons. 
• Parent/legal guardian of Participant indicates that they no longer want the Participant to 
participate in the study. If the parent/legal guardian of the Participant withdraws consent for 
disclosure of future information, the Sponsor may retain and continue to use any data 
collected before such a withdrawal of consent. 
Notification of early Participant withdrawal from the study and the reason for discontinuation 
will be clearly documented and noted in the eCRF. If the Participant exits the study prior to the 
Day 28 Study Exit visit, all of the Day 28 final measurements should be performed and recorded 
on the appropriate eCRF. 
7.3 
Lost to Follow-up 
A Participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
and is unable to be contacted by the study center.  
The following actions must be taken if a Participant fails to return to the study center for a 
required study visit: 
• The study center must attempt to contact the parent/caregiver of the Participant and 
reschedule the missed visit as soon as possible and counsel the parent/caregiver of the 


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Participant on the importance of maintaining the assigned visit schedule and ascertain 
whether or not he/she wishes the Participant to continue in the study. 
• Before a Participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the parent/caregiver of the Participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the Participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
Participant’s medical record. 
• Should the Participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study and not returning for scheduled visits. 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
This section provides a high-level summary of the study assessments to be performed. For details 
as to when these assessments are performed see Table 3. 
• Study procedures and their timing are summarized in Table 3. 
• Protocol waivers or exemptions are not allowed. 
• Safety concerns should be discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the Participant should continue or discontinue study treatment. 
• Adherence to the study design requirements, including those specified in Table 3, is essential 
and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
Participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all Participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the Participant’s routine clinical management (eg, audiology 
hearing test) and obtained before signing of the informed consent form (ICF) may be utilized 
for screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in Table 3. 
8.1 
Efficacy Assessments 
Pneumatic otoscopy* to evaluate each TM for: 
− TM: intact, perforated 
− Color (check all that apply): gray, pink, pale yellow, white, amber, blue 
− Translucency: translucent, opaque, semi-opaque 
− Mobility: none, 1+, 2+, 3+, 4+ 
− Air fluid interface: yes, no 
− Distinct erythema: yes, no 
− Position: neutral, retracted, 1+ bulging, 2+ bulging, 3+ bulging 
− Otorrhea: no, serous, purulent 
*Note: Trained otoscopists who have undergone comprehensive educational program (ePROM, 
enhancing proficiency in otitis media) for training in the diagnosis of AOM will perform the 
otoscopy assessments in this study. This training includes training on cerumen removal, which is 
required (as needed) prior to performing pneumatic otoscopy. 
Tympanometry will be performed, when possible, to assess middle ear function (ie, TM 
mobility, ET function) by measuring the amount of sound energy reflected back when a small 
probe is placed in each ear canal. The output of the right ear and left ear tympanometry will be a 


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tympanogram tracing recorded using a 226 Hz probe tone and a positive (+300 decaPascals 
[daPa]) to negative (-600 daPa) air-pressure sweep at fast speed. Each tympanogram will be 
classified as Type A (normal), Type B (abnormal), or Type C (abnormal). 
AOM-SOS score will be recorded daily by parent/caregiver during the 10-day course of study 
treatment and antibiotics, and recorded in-clinic at Day 4, Day 12, and Day 28. 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in Table 3. 
8.2.1 
Physical Examinations 
• A complete physical examination will be performed to assess any physical abnormalities and 
will include, at a minimum, assessment of the following body systems: overall status of the 
skin, head, neck, trunk, eyes, ears, heart, and lungs (eg, breathing sounds), abdomen, 
extremities, and lymph nodes. 
• Physical examination will also include visual examination of the nasopharynx and 
oropharynx using a light source (for local effects). 
• Height and weight will be measured and recorded on Day 1. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 
Vital Signs 
• Temperature (as Celsius or Fahrenheit degrees) will be assessed and method obtained 
recorded. 
• Respiration rate (per minute) will be measured by counting at least 30 seconds and 
multiplying accordingly. 
• Pulse rate (beats/minute) will be assessed after the Participant has been at rest (seated) for 
approximately 5 minutes in a quiet setting without distractions with a completely automated 
device. Manual techniques will be used only if an automated device is not available. A total 
of 1 pulse reading should be recorded. 
8.2.3 
Otoscopy 
Pneumatic otoscopy and an endoscope-iPhone application that captures a video segment will be 
performed to assess the appearance of the TM. 
8.2.4 
Acute Otitis Media Symptom Burden 
Parents/caregivers will record the AOM symptom burden daily during the 10-day course of study 
treatment and antibiotics using the 5-question version of the AOM-SOS Scale. Each of the 
following 5 questions will be rated on a 6-point Likert scale (0 [no], 1 [almost none], 2 [a little], 
3 [some], 4 [a lot], and 5 [an extreme amount]) (total score ranges from 0 to 25): (1) Over the 
past 12 hours, has your child been tugging, rubbing, or holding the ear(s) more than usual?, 


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(2) Over the past 12 hours, has your child been crying more than usual?, (3) Over the past 
12 hours, has your child been more irritable or fussy than usual?, (4) Over the past 12 hours, has 
your child been having more difficulty sleeping than usual?, (5) Over the past 12 hours, has your 
child been having fever or feeling warm to touch? 
8.3 
Other Assessments 
1. Otalgia (per Investigator judgment in consultation with parent/caregiver): yes, no. 
Information used by the Investigator to confirm diagnosis. Data will be collected in the eCRF 
and summarized. 
2. Endoscopic examination with image capture of each ear when possible, using an endoscope 
iPhone application (Pitt CMU iTM). Information used by the Investigator to confirm 
agreement of findings with Sub-investigators. Data will not be collected in the eCRF or 
analyzed.  
3. Parent/caregiver’s input on Device Experience Questionnaire. Data will be collected in the 
eCRF and summarized in data listings.  
8.4 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
Adverse events will be reported by the parent/caregiver of the Participant. 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
Participant to discontinue the study treatment or study (see Section 7.0). 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information  
All SAEs will be collected from the time of signed informed consent obtained until the Study 
Exit. 
All AEs will be collected from the time of signed informed consent obtained until the Study Exit. 
Medical occurrences that begin before the start of study treatment but after obtaining signed 
informed consent will be recorded as pretreatment-emergent AEs in the AE section of the eCRF. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, within 30 days 
of Study Exit, and he/she considers the event to be reasonably related to the study treatment or 
study participation, the Investigator must promptly notify the Sponsor. 


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The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
8.4.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the parent/caregiver of the Participant is the preferred method 
to inquire about AE occurrences.  
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
Participant at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the Participant is lost to follow-up (as defined 
in Section 7.3). Further information on follow-up procedures is given in Appendix 3. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of Participants and the safety of a 
study treatment under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Boards (IRB), and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and forwarded to 
Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB, if appropriate according to local 
requirements. 
8.4.5 
Adverse Events of Special Interest 
Not applicable. 
8.4.6 
Medical Device Incidents (Including Malfunctions) 
Instructions for documenting Medical Device Incidents are provided in Appendix 4. 
Medical devices are being provided for use in this study for delivering the study treatment via 
pMDI. In order to fulfill regulatory reporting obligations worldwide, the Investigator is 


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responsible for the detection and documentation of events meeting the definitions of incident or 
malfunction that occur during the study with such devices.  
The definition of a Medical Device Incident can be found in Appendix 4. 
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes outlined in 
Section 8.4.3 and Appendix 3 of the protocol. 
8.4.6.1 
Time Period for Detecting Medical Device Incidents 
• Medical Device Incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the medical 
device is used.  
• If the Investigator learns of any incident at any time after a Participant has discontinued from 
the study, and such incident is considered reasonably related to a medical device provided for 
the study, the Investigator will promptly notify the Sponsor. 
The method of documenting Medical Device Incidents is provided in Appendix 4. 
8.4.6.2 
Follow-up of Medical Device Incidents 
• All Medical Device Incidents involving an AE will be followed and reported in the same 
manner as other AEs (see Appendix 3). This applies to all Participants, including those who 
discontinue study treatment. 
• The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident. 
• New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the Investigator. 
8.4.6.3 
Prompt Reporting of Medical Device Incidents to Sponsor 
• Medical Device Incidents will be reported to the Sponsor within 24 hours after the 
Investigator determines that the event meets the protocol definition of a Medical Device 
Incident. 
• The Medical Device Incident Report Form will be sent to the Sponsor by email. 
• The same individual will be the contact for the receipt of medical device reports and SAE. 
8.4.6.4 
Regulatory Reporting Requirements for Medical Device Incidents 
• The Investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the Sponsor to fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies. 


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• The Investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB. 
8.5 
Treatment of Overdose 
It is unknown what dose of study treatment within a 24-hour time period would be considered an 
overdose. Both active ingredients in the study treatment are endogenous to the human respiratory 
system in very large quantities compared with the maximum study treatment dose of 20 mg per 
day of surfactant. Even if a Participant were to be administered an entire canister of the study 
treatment into the nostrils in 1 day, the total exposure to the active pharmaceutical ingredient 
would be 250 mg (up to approximately 35 mg/kg for a 6 to 24-month old child who usually 
weighs approximately 7 to 13 kg), which is far less than exposures on a mg/kg basis for 
approved surfactant products that are usually given over 1 to 2 days (see Table 4 of the IB). 
HFA-134a is not endogenous to the human respiratory system. Symptoms potentially related to 
misuse or inhalation abuse are: anesthetic effects, light-headedness, dizziness, confusion, 
incoordination, drowsiness, unconsciousness, irregular heartbeat with a strange sensation in the 
chest, heart thumping, apprehension, feeling of fainting, dizziness, or weakness. Vapors are 
heavier than air and can cause suffocation by reducing oxygen available for breathing. However, 
the maximum amount of 10 mL of HFA-134a per study treatment canister would not be 
sufficient exposure to be considered an overdose. If symptoms described above were 
experienced with a suspected HFA-134a overdose, the suggested treatment would be to deliver 
oxygen and other necessary supportive care per the Investigator’s judgment. 
In the event of an overdose, the Investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the Participant for any AE/SAE for at least 2 days. 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
8.6 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.7 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 


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9.0 STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses  
The primary objective of this study is to demonstrate safety, tolerability, and efficacy of 
intranasal OP0201 compared with placebo in accelerating AOM resolution by reducing and/or 
eliminating MEE or in reducing the likelihood of MEE (OME) in infants and children and 
accordingly reducing the likelihood of AOM recurrences during follow-up when given as an 
adjunct treatment to oral antibiotics. 
The primary efficacy endpoint family consists of 2 endpoints: (1) no bulging of the TM at the 
Day 4 Visit as assessed by pneumatic otoscopy, the most influential outcome in the overall 
assessment of efficacy of OP0201 as a treatment for AOM, and (2) no MEE at the Day 12 Visit 
as assessed by pneumatic otoscopy, the most influential outcome in the overall assessment of 
efficacy of OP0201 as a treatment to prevent OME. The hypothesis set is as follows: 
Null hypothesis (AOM treatment): 
There is no difference between treatment groups in proportion of Participants with no bulging of 
the TM at the Day 4 Visit. 
Alternative hypothesis (AOM treatment): 
There is a difference between treatment groups in proportion of Participants with no bulging of 
the TM at the Day 4 Visit. 
Null hypothesis (OME reduction): 
There is no difference between treatment groups in proportion of Participants with no MEE at 
the Day 12 Visit. 
Alternative hypothesis (OME reduction): 
There is a difference between treatment groups in proportion of Participants with no MEE at the 
Day 12 Visit.  
9.2 
Power Calculation 
The power calculation is based on a 2-sided Pearson chi square test of each of the 2 endpoints in 
the primary efficacy endpoint family and control of Type 1 error using the step-up Hochberg 
procedure.(14) The minimally important difference in proportions for both endpoints is 
approximately 0.25. With 70 Participants randomized per treatment group, and assuming a 12% 
dropout rate with dropouts counted as failures, this Phase 2a study will have 87% power to detect 
a treatment effect in at least 1 of the 2 endpoints assuming 40% of placebo-treated Participants 
will have no bulging TM at Day 4 and 30% of placebo-treated Participants will have no MEE at 
Day 12. 


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9.3 
Populations for Analyses 
Four populations will be considered. The screened population will be all Participants whose 
parent/legal guardian signs the ICF. Safety data and secondary efficacy endpoints will be 
analyzed using the safety population defined as all Participants who received at least 1 intranasal 
spray of study treatment. The intent-to-treat (ITT) population is defined as all randomized 
Participants and will be used to assess the primary efficacy endpoint family. The per-protocol 
population is defined as the subset of the ITT population who have no protocol violations 
affecting the primary efficacy endpoint family and will be used to confirm results from the 
primary efficacy endpoint family. 
9.4 
Statistical Analyses 
The Statistical Analysis Plan (SAP) will be developed and finalized before database lock and 
will describe the Participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the primary and secondary efficacy endpoints. 
In general, categorical variables (including binary outcomes) will be summarized as frequencies 
and percentages and will be analyzed using logistic regression to control for covariates, including 
the randomization stratifiers. Continuous variables will be summarized by numbers of 
observations, means, measures of variances, percentiles, and ranges and will be analyzed using 
general linear models to control for covariates. All statistical tests will be 2-sided with 0.05 
significance levels. 
9.4.1 
Efficacy Analyses 
The analysis of the primary efficacy endpoint family will compare the 2 treatment groups 
(OP0201, placebo) with respect to the proportion of Participants with no bulging of the TM at 
the Day 4 Visit as well as the proportion of Participants with no MEE at the Day 12 Visit using 
the ITT population for which Participants with missing data at the Day 4 Visit will be considered 
as having bulging TM and those with missing data at the Day 12 Visit will be considered as 
having MEE. A sensitivity analysis will be done that defines the endpoints as no bulging of the 
TM at the Day 4 Visit and no recurrence of bulging TM throughout the remainder of the study, 
and no MEE at the Day 12 Visit and no recurrence of MEE throughout the remainder of the 
study. Sensitivity analyses will also be done using the per-protocol population. Treatment groups 
will be statistically compared using generalized estimating equations (GEE), if possible, with an 
alternative method (eg, logistic regression) at each visit as an alternative if GEE convergence 
cannot be achieved. Randomization stratifiers (daycare attendance [yes, no] and age group [≥6 to 
<12 months, ≥12 to ≤24 months]) and degree of TM bulging at baseline will be covariates. 
Tympanic membrane bulging at baseline will also be evaluated as a potential effect modifier. 
The step-up Hochberg procedure will be used to control the familywise Type 1 error. 
Specifically, the endpoint with the highest p-value will be tested first at the 0.05 significance 


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level and, if significant, both endpoints will be declared significant; if the endpoint with the 
highest p-value is not significant at the 0.05 level, the other endpoint will be tested at the 0.025 
significance level. A positive treatment effect on efficacy will be concluded if at least 1 of the 
2 endpoints in the primary efficacy endpoint family is significant 
Descriptive statistics will be provided for the primary efficacy endpoint family by the following 
sub-groups: age stratum (≥6 to <12 months, ≥12 to ≤24 months), race (Caucasian, 
non-Caucasian), gender (male, female), laterality of disease (unilateral, bilateral), history of 
recurrent AOM defined as 3 or more episodes in the preceding 6 months or 4 or more episodes 
over the course of 12 months (yes, no), and daycare attendance stratum defined as exposure to 
3 or more children outside of the home for 10 or more hours per week (yes, no). 
All secondary efficacy endpoints will be evaluated in the safety population, without adjustment 
for multiplicity; therefore, p-values for these endpoints will be used only to aid in 
decision-making regarding whether any should be elevated in importance in future studies. These 
endpoints are: 
• No MEE assessed at the Day 4 Visit and the Day 28 Visit by pneumatic otoscopy. 
• No bulging of the TM assessed at the Day 12 Visit and the Day 28 Visit by pneumatic 
otoscopy. 
• Normal tympanogram (Type A) assessed at the Day 4 Visit, the Day 12 Visit, and the Day 28 
Visit by tympanometry. 
• Complete or near complete resolution of symptoms (AOM cure), defined as an AOM-SOS 
score ≤2, assessed at the Day 4 Visit, the Day 12 Visit, and the Day 28 Visit by in-clinic 
AOM-SOS score assessments.  
• Change from baseline in AOM-SOS score over the planned 10-day treatment period by 
parent/caregiver diary data. 
• At least a 50% reduction from baseline in the AOM-SOS score assessed at the Day 4 Visit, 
the Day 12 Visit, and the Day 28 Visit by in-clinic AOM-SOS score assessments. 
• AOM treatment failure (clinical failure)* at the Day 12 Visit. 
• AOM relapse defined as those with clinical success# at the Day 12 Visit and who return for 
an interim/sick visit before Day 17 and have AOM. 
• AOM recurrence defined as those with clinical success# at the Day 12 Visit and who return 
for an interim/sick visit from Day 17 through Day 28 and have AOM. 
 
*Treatment failure is defined as (1) moderate to severe bulging of the TM (Key Action 
Statement 1A[11]), or (2) mild bulging of TM and recent (less than 48 hours) onset of ear pain 
(otalgia) (Key Action Statement 1B[11]), or (3) mild bulging of the TM and intense erythema of 
the TM (Key Action Statement 1B[11]). 
 
#Clinical success for AOM relapse and AOM recurrence endpoints is defined as (1) no moderate 
to severe bulging of the TM (Key Action Statement 1A[11]), and (2) no mild bulging of the TM 


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and no recent (less than 48 hours) onset of ear pain (otalgia) (Key Action Statement 1B[11]), and 
(3) no mild bulging of the TM and no intense erythema of the TM (Key Action Statement 1B[11]).  
 
For the AOM cure endpoint, a sensitivity analysis will be done where AOM cure will be defined 
as AOM-SOS score = 0.  
 
Treatment groups will be statistically compared on proportions using GEE (or an alternative 
method), and analyses of differences in means will be done using either general linear models or 
mixed models for repeated measures to control for covariates.  
9.4.2 
Safety Analyses 
Safety will be assessed by incidence, seriousness, severity, and relatedness to study treatment of 
AEs and shifts from baseline (normal, abnormal) in vital signs, physical examination, and 
examination of the nasopharynx and oropharynx for local effects. 
The Medical Dictionary for Regulatory Activities will be used to code AEs to system organ class 
(SOC) and preferred term. An AE that began or worsened in severity after first dose of study 
treatment and no later than 2 calendar days after the last dose of study treatment will be 
considered a treatment-emergent adverse event (TEAE). 
Treatment-emergent adverse event incidence will be tabulated by primary SOC and by preferred 
term within each primary SOC. Summary tables will be provided for all TEAEs, serious AEs, 
treatment-related TEAEs and all AEs leading to discontinuation of study treatment. 
No formal testing of treatment group differences will be performed for AEs. 
Shifts from baseline in vital signs, physician examination, nasopharynx and oropharynx 
examination results will be summarized for each visit. 
9.5 
Interim Analyses 
No interim analysis is planned. 
9.6 
Safety Monitoring Committee 
An SMC will be established for the purpose of monitoring the safety of Participants in this study. 
The SMC will review blinded safety data for all Participants when approximately 25% of 
enrolled Participants have completed Day 12. Safety data will be evaluated on an ongoing basis 
to ensure it is safe to continue study enrollment and treatment. The composition, responsibilities, 
and meeting schedule of the SMC will be specified in a separate charter document. 


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10.0 REFERENCES 
1. Shaikh N, Kurs-Lasky M, Hoberman A. Modification of the acute otitis media symptom 
severity scale. Int J Pediatr Otorhinolaryngol. 2019;122:170-4. 
2. Shurin PA, Pelton SI, Donner A, Klein JO. Persistence of middle-ear effusion after acute 
otitis media in children. N Engl J Med. 1979;300:1121-1123. 
3. Rosenfeld RM, Schwartz SR, Pynnonen MA, et al. Clinical practice guideline: 
Tympanostomy tubes in children. Otolaryngol Head Neck Surg. 2013;149(1):1-35. 
4. Rosenfeld RM, Shin JJ, Schwartz SR, et al. Clinical practice guideline: Otitis media with 
effusion (update). Otolaryngol Head Neck Surg. 2016;154(1S):S1-S41. 
5. Schilder AGM, Chonmaitree T, Cripps AW, et al. Otitis Media. Nat Rev Dis Primers. 
2016;2:16063. Doi:10.1038/nrdp.2016.63. 
6. Jafari Z, Malayeri S, Bahramian E. The effect of age and history of recurrent otitis media on 
dichotic listening and verbal memory in children. Ann Otol Rhinol Laryngol. 2016. 
7. Shaikh N, Hoberman A, Rockette HE, Kurs-Lasky M. Development of an Algorithm for the 
Diagnosis of Otitis Media. Academic Pediatrics. 2012;12:214–218. 
8. Hoberman A, Paradise JL, Rockette HE, et. al. Reduced-Concentration Clavulanate for 
Young Children with Acute Otitis Media. Antimicrob Agents Chemother. 2017;61(7):1-10. 
9. Hoberman A, Paradise, JL, Rockette HE, Kearney DH, Bhatnagar S, Shope TR, Martin JM, 
Kurs-Lasky M, Copelli SJ, Colborn K, Block SL, Labella JJ, Lynch TG, Cohen NL, Haralam 
MA, Pope MA, Nagg JP, Green MD, Shaikh N. Shortened antimicrobial treatment for acute 
otitis media in young children. N Engl J Med 2016;375:2446-2456. 
10. Francis NA, Cannings-John R, Waldron CA, Thomas-Jones E, Winfield T, Shepherd V, 
Harris D, Hood K, Fitzsimmons D, Roberts A, Powell C, Gal M, Butler CC. Oral steroids for 
resolutions of otitis media with effusion in children (OSTRICH): A double-blinded, placebo-
controlled randomised trial. Lancet 2018;392:557-568. 
11. Lieberthal AS, Carroll AE, Chonmaitree T, et al. The diagnosis and management of acute 
otitis media. Pediatrics. 2013;131:e964-e999. 
12. Shaikh N, Hoberman A, Paradise JL, et al. Responsiveness and construct validity of a 
symptom scale for acute otitis media. Pediatr Infect Dis J. 2009;28(1):9-12. 
13. US FDA Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension and Spray 
Drug Products, July 2002. 


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14. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 
1988;75:800-802. 


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11.0 APPENDICES 


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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
ANOVA 
Analysis of variance 
AOM 
Acute otitis media 
AOM-SOS 
Acute Otitis Media Severity of Symptoms 
BID 
Twice daily 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CP 
Cholesteryl palmitate 
CRF 
Case report form 
DPPC 
Dipalmitoylphosphatidylcholine 
eCRF 
Electronic case report form 
ET 
Eustachian tube 
ETD 
Eustachian tube dysfunction 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Processes 
HFA-134a 
Hydrofluoroalkane-134a 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
MEE 
Middle ear effusion 
OME 
Otitis media with effusion 
pMDI 
Pressurized metered dose inhaler 
SAE 
Serious adverse event 
SMC 
Safety Monitoring Committee 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse events 
TM 
Tympanic membrane 


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Abbreviation 
Definition 
w/w 
Weight/weight 


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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
− Applicable ICH GCP Guidelines. 
− Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB by the Investigator and reviewed and approved 
by the IRB before the study is initiated. 
• Any amendments to the protocol will require IRB and regulatory authority approval, when 
applicable, before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to Participants. 
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB. 
− Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures. 
− Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
• After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 5). The study will not 
start at any study center at which the Investigator has not signed the protocol. 
Adequate Resources 
The Investigator is responsible for supervising any individual or party to whom the Investigator 
delegates study-related duties and functions conducted at the study center. 
If the Investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the Investigator/institution should ensure this individual or 
party is qualified to perform those study-related duties and functions and should implement 
procedures to ensure the integrity of the study-related duties and functions performed and any 
data generated. 


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Financial Disclosure 
Investigators and Sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Insurance 
The Sponsor has obtained liability insurance, which covers this study as required by local law 
and/or national regulations and/or ICH guidelines, whichever is applicable. The terms of the 
insurance will be kept in the study files. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
Participant’s parent/legal guardian and answer all questions regarding the study. 
• The parent/legal guardian of the Participant must be informed that participation is voluntary. 
The Participant’s parent/legal guardian will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the IRB or 
study center. 
• The research record must include a statement that written informed consent was obtained 
before the Participant was entered in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the Participant’s parent/legal guardian. 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any Participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; Participant names 
or any information which would make the Participant identifiable will not be transferred. 
• The Participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the Participant. 
• The Participant must be informed that his/her research records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 
Administrative Structure 
See Section 9.6 for information regarding the SMC. 


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Medical Monitor 
Melodie Armstrong, MD, MPH 
Email: melodie.armstrong@iqvia.com 
Phone: 913-708-7648 
Mobile: 816-406-9312 
Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study. The 
study will be registered on clinicaltrials.gov and appropriate reporting to ensure compliance with 
clinicaltrials.gov will be met. 
Data Quality Assurance 
• All Participant data relating to the study will be recorded on printed or eCRFs unless 
transmitted to the Sponsor or designee electronically (eg, daily diary data). The Investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the case report form (CRF). 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• Monitoring will be carried out as determined by the risk assessment process conducted on the 
study. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized study center personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of Participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.  
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s Participants. Source 
data should be attributable, legible, contemporaneous, original, accurate, and complete. Changes 


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to source data should be traceable, should not obscure the original entry, and should be explained 
if necessary (eg, via an audit trail). 
• Source documents provide evidence for the existence of the Participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study center. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
Study and Study Center Closure 
The Sponsor designee reserves the right to close the study center or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centers will be closed upon study 
completion. A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of Participants by the Investigator. 
• Discontinuation of further study treatment development. 
Publication Policy 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice. Novus Therapeutics, Inc. as the 
Sponsor, has proprietary interest in the study and thus will be involved in reviewing, at a 
minimum, any abstract or manuscript prior to submission in order to allow the Sponsor to 
protect proprietary information and to provide comments. For this study, authorship and 
abstracts or manuscript composition will reflect joint cooperation between the Investigator 
and Novus Therapeutics, Inc. personnel. Authorship will be (1) established prior to the 
writing of abstracts or manuscripts, (2) determined by mutual agreement and (3) in line with 
International Committee of Medical Journal Editors authorship requirements. 


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Appendix 3 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of Adverse Events 
Adverse Event Definition 
• 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease (new or exacerbated) in a Participant. 
• 
An AE that occurs after informed consent is signed and prior to exposure to study treatment is a 
pretreatment AE. 
• 
An AE that first occurs or worsens in severity after informed consent is signed and occurs after 
administration of study treatment, whether or not considered related to the study treatment, is a TEAE. 
 
Events Meeting the Adverse Event Definition 
• 
Any safety assessments (eg, vital signs measurements), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the Investigator (ie, not 
related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed even though it may have been present before the start of the 
study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE 
or SAE. Such instances will be captured in the efficacy assessments. However, the signs, symptoms, 
and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if they fulfill the 
definition of an AE or SAE. 
 
Events NOT Meeting the Adverse Event Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the Participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the Participant’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
 


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Definition of Serious Adverse Events 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A serious adverse event is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the Participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the Participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d) Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the Participant or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 


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Recording and Follow-up of Adverse Events and/or Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. Each event must be 
recorded separately. 
• 
It is not acceptable for the Investigator to send photocopies of the Participant’s medical records in lieu 
of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested. In this case, all 
Participant identifiers, with the exception of the Participant number, will be redacted on the copies of 
the medical records before submission. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the Participant, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not 
be confused with a SAE. Severe is a category utilized for rating the intensity of an event; and both AEs 
and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
The Investigator must assess the causality of an AE (including SAEs) to the use of a study treatment 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: 
• 
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. 
• 
The temporal association between drug exposure and onset of the AE. 
• 
Whether the manifestations of the AE are consistent with known actions or toxicity of the 
investigational product. 
• 
Whether the AE resolved or improved with stopping use of the investigational product. Judgment 
should be used if multiple products are discontinued at the same time. 
• 
Positive rechallenge. 
• 
Positive dechallenge (resolution upon stopping suspect study treatment, in the absence of other 
intervention or treatment). 
• 
The causal relationship between at study treatment and the AE will be assessed using 1 of the 
following categories: 


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o 
Not Related: An AE is not associated with study medication if no causal relationship exists 
between the study treatment and the AE, but an obvious alternative cause exists, eg, the 
Participant’s underlying medical condition or concomitant therapy. 
o 
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 treatment. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested to elucidate the nature and/or causality of the 
AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of the 
information. 
 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE will be the electronic data collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the study center will use the paper 
SAE data collection tool (see next section). 
• 
The study center will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given study center, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• 
If a study center receives a report of a new SAE from a Participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the study 
center can report this information on a paper SAE form (see next section) or to the Medical 
Monitor/SAE coordinator by telephone. 
 
SAE Reporting via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this information to 
the Medical Monitor/SAE coordinator. 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete and sign the 
SAE CRF pages within the designated reporting time frames. 


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Appendix 4 
Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting  
Definitions of a Medical Device Incident 
The detection and documentation procedures described in this protocol apply to all Sponsor 
medical devices provided for use in the study (see Section 6.1) for the list of Sponsor medical 
devices. 
Medical Device Incident Definition 
• A Medical Device Incident is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labeling or the instructions for use 
which, directly or indirectly, might lead to or might have led to the death of a 
Participant/user/other person or to a serious deterioration in his/her state of health. 
• Not all incidents lead to death or serious deterioration in health. The nonoccurrence of such a 
result might have been due to other fortunate circumstances or to the intervention of health 
care personnel. 
It is sufficient that: 
• An incident associated with a device happened. 
 
AND 
 
• The incident was such that, if it occurred again, might lead to death or a serious deterioration 
in health. 
A serious deterioration in state of health can include any of the following: 
• Life-threatening illness. 
• Permanent impairment of body function or permanent damage to body structure. 
• Condition necessitating medical or surgical intervention to prevent 1 of the above. 
• Fetal distress, fetal death, or any congenital abnormality or birth defects. 
Examples of Incidents 
• A Participant, user, caregiver, or healthcare professional is injured as a result of a medical 
device failure or its misuse. 
• A Participant’s study treatment is interrupted or compromised by a medical device failure. 
• A misdiagnosis due to medical device failure leads to inappropriate treatment. 
• A Participant’s health deteriorates due to medical device failure. 


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Documenting Medical Device Incidents 
Medical Device Incident Documenting 
• Any Medical Device Incident occurring during the study will be documented in the 
Participant’s medical records, in accordance with the Investigator’s normal clinical practice, 
and on the appropriate form of the eCRF. 
• For incidents fulfilling the definition of an AE or an SAE, the appropriate AE/SAE eCRF 
page will be completed as described in Appendix 3. 
• The eCRF will be completed as thoroughly as possible and signed by the Investigator before 
transmittal to the Sponsor or designee. 
• It is very important that the Investigator provides his/her assessment of causality (relationship 
to the medical device provided by the Sponsor) at the time of the initial AE or SAE report 
and describes any corrective or remedial actions taken to prevent recurrence of the incident. 
• A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident. This includes any 
amendment to the device design to prevent recurrence. 


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Appendix 5 
Signature of Investigator 
PROTOCOL TITLE: A Study to Assess the Safety, Tolerability, and Efficacy of OP0201 as an 
Adjunct Treatment for Acute Otitis Media in Infants and Children Aged 6 to 24 Months 
PROTOCOL NO: OP0201-C-006 
VERSION: Amendment 3 
This protocol is a confidential communication of Novus Therapeutics, Inc. I confirm that I have 
read this protocol, I understand it, and I will work according to this protocol. I will also work 
consistently with the ethical principles that have their origin in the Declaration of Helsinki and 
that are consistent with Good Clinical Practices and the applicable laws and regulations. 
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to Sponsor or CRO. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
__________________________ Date: ________ 
Printed Name: ___________________________ 
Investigator Title: ___________________________ 
 
Name/Address of Center:  
___________________________ 
 
 
 
 
 
___________________________ 
 
 
 
 
 
___________________________ 
 


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Appendix 6 
Protocol Amendment History 
Amendment 2 (05 June 2019) 
Overall Rationale for the Amendment: 
Novus Therapeutics filed the original protocol to the US Food and Drug Administration (FDA) 
Investigational New Drug (IND) application on 21 January 2019. On 22 March 2019 the 
Biometric team (ie, Biostatisticians) at FDA sent an email communication to Novus with some 
suggested changes to this exploratory study, which this amendment addresses. These changes 
include (1) use of a hierarchical gatekeeping procedure for testing the primary and key secondary 
efficacy endpoints, (2) use of a sensitivity analysis of the primary efficacy endpoint in which 
responders must have no bulging of the tympanic membrane (TM) at the Day 4 Visit and no 
recurrence of bulging TM through the remainder of the study, (3) a clear definition of clinical 
success at the Day 12 Visit for the acute otitis media (AOM) relapse and AOM recurrence 
efficacy endpoints, and (4) a clear definition of treatment failure (clinical failure) in 
Section 6.1.4. In addition, the sample size for the study has been increased to approximately 
140 Participants planned for enrollment to improve the likelihood of detecting the minimum 
clinically important difference between treatment groups. Relevant changes to the power 
calculation have been made due to the change in sample size.  
Table 5 
Description of Changes in Amendment 2 
Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
Section 1.1 Rationale and 
Section 2.1 Study Rationale 
Updated to state that AOM 
resolution for primary and 
secondary efficacy endpoints 
will be determined by no 
bulging of the tympanic 
membrane rather than by a 
reduced proportion of children 
with bulging tympanic 
membrane(s). 
To define AOM resolution for 
primary and secondary efficacy 
endpoints based on no bulging 
of the tympanic membrane as 
this is how AOM resolution is 
standardly assessed by 
clinicians. 
To define a minimum clinically 
important difference in the 
proportions between treatment 
groups for the primary efficacy 
endpoint. 
Section 1.1 Overall Design, 
Number of Participants and 
Statistical Methods  
Updated time window from at 
least 72 hours to at least 48 to 
72 hours after which concordant 
To address FDA request to 
further clarify description of 
treatment failure. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1 Overall Design 
Section 9.0 Statistical 
Considerations (9.1 Statistical 
Hypothesis, 9.2 Power 
Calculation, 9.3 Populations for 
Analyses, 9.4 Statistical 
Analyses [9.4.1 Efficacy and 
9.4.2 Safety Analyses]) 
antibiotic therapy will be 
administered in case of 
treatment failure. 
Updated number of study 
Participants from approximately 
50 to approximately 140. 
Updated relevant statistical 
sections.  
To ensure that study will have 
80% power to detect an 
approximate 0.25 difference 
(based on a 40% placebo 
response rate) in proportions for 
the primary efficacy endpoint 
using a 2-sided significance 
level of 0.05. Relevant changes 
to the power calculation have 
been made due to the change in 
sample size. Definitions for 
safety population, intent-to-treat 
population, per-protocol 
population, and 
treatment-emergent adverse 
events have been updated to 
align with the Statistical 
Analysis Plan. To include a 
hierarchical gatekeeping 
procedure for testing the 
primary and key secondary 
efficacy endpoints. To update 
text for sensitivity and subgroup 
analyses. To align definitions of 
efficacy endpoints to match 
Section 1.1 and Section 3.0 (see 
below). 
Section 1.1 Objectives and 
Endpoints and Section 3.0 Study 
Objectives and Endpoints  
Updated objectives and 
endpoints.  
To provide rationale for choice 
of primary and key secondary 
efficacy endpoints. To define 
AOM resolution based on no 
bulging of the tympanic 
membrane and to define OME 
prevention based on no MEE. 
To more clearly define efficacy 
endpoints based on a consistent 
convention to state the variable 
being assessed, timepoint at 


CONFIDENTIAL 
Protocol OP0201-C-006 - Amendment 3 
 
66 
Section # and Name 
Description of Change 
Brief Rationale 
which variable will be assessed 
and how variable will be 
assessed. To remove proportion 
of Participants with AOM, OME 
or no MEE on Days 4, 12 and 
28 as this was inadvertently 
listed as a secondary endpoint.  
To address FDA request to 
define clinical success at the 
Day 12 Visit for the AOM 
relapse and AOM recurrence 
efficacy endpoints. 
All reference to AOM-SOS 
score was removed from 3 
secondary endpoints. 
Definitions of “treatment failure 
at Day 12 Visit” and “clinical 
success” relating to the AOM 
recurrence and relapse efficacy 
endpoints are now anchored to 
the entry criteria definition of 
AOM, which is: “moderate to 
severe bulging of the TM, or 
mild bulging of TM and recent 
(less than 48 hours) onset of ear 
pain (otalgia), or mild bulging of 
the TM and intense erythema of 
the TM.” 
Section 5.1 Inclusion Criteria 
Added the term “otalgia” to 
describe ear pain. 
To ensure consistency with data 
field captured in the eCRF. 
Section 6.1.1 The Drug-device 
Study Treatment 
Updated 60 actuations per 
canister to 100 actuations per 
canister. 
Additional dose content 
uniformity (DCU) test data 
supports the OP0201 canister 
can deliver up to 100 actuations 
per canister. 


CONFIDENTIAL 
Protocol OP0201-C-006 - Amendment 3 
 
67 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1.4 Standard 
Antibiotic 
Updated description for 
treatment failure. 
To address FDA request to 
further clarify description for 
treatment failure. 
Section 6.4 Study Treatment 
Compliance 
Updated on Days 4 and 12 to at 
the Day 4 Visit and the Day 12 
Visit. 
To ensure consistent format 
within document. 
Section 8.1 Efficacy Assessment 
Section 8.3 Other Assessments 
Deleted other assessments from 
Section 8.1 Efficacy 
Assessments and added 
Section 8.3 Other Assessments. 
Other assessments including 
otalgia, endoscopic examination 
with iPhone application and 
parent/caregiver Device 
Experience Questionnaire were 
inadvertently listed under 
Section 8.1 Efficacy 
Assessments. Assessments have 
been moved to newly created 
Section 8.3 Other Assessments. 
Section 9.4.3 Other Analyses 
Deleted this section. 
No analysis will be included in 
the execution of the Statistical 
Analysis Plan for the 
parent/caregiver Device 
Experience Questionnaire.  
Section 10.0 References 
Francis et al, 2018 citation 
added to reference list. 
Reference added to support 
rationale for key secondary 
endpoint. 
 


CONFIDENTIAL 
Protocol OP0201-C-006 - Amendment 3 
 
68 
Amendment 1 (8 March 2019) 
Overall Rationale for the Amendment: 
The purpose of Protocol Amendment 1 is to provide clarification and updates to the original 
version of the protocol. 
Table 6 
Description of Changes in Amendment 1 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Overall Design 
Tympanometry assessment 
changed to when possible 
Satellite sites to be added cannot 
perform the tympanometry 
assessment due to unavailability 
of tympanometry diagnostic tool 
Section 1.1 Number of 
Investigators and Study Centers 
Up to 3 satellite sites to be 
added 
To support enrollment  
Section 1.1 Safety Monitoring 
Committee 
Changed wording to indicate 
that SMC will meet when 
approximately 25% of 
Participants have completed 
D12 
To account for slower 
enrollment than planned 
Section 1.3 Schedule of 
Activities 
Tympanometry assessment 
changed to when possible 
Satellite sites to be added cannot 
perform the tympanometry 
assessment due to unavailability 
of tympanometry diagnostic tool 
Section 1.3 Schedule of 
Activities 
Removed in clinic for safety 
observation 
Participants enrolled at the 
satellite sites may be observed 
for safety in Participant’s home 
Section 4.1 Overall Design 
Tympanometry assessment 
changed to when possible 
Satellite sites to be added cannot 
perform the tympanometry 
assessment due to unavailability 
of tympanometry diagnostic tool 
Section 5.1 Inclusion Criteria 
Re-ordered inclusion  
Ensure consistency with data 
fields captured in eCRF  
Section 5.1 Inclusion Criteria 
Added criteria that parent/legal 
guardian have a smartphone or 
Electronic survey is mandatory 
for Participants 


CONFIDENTIAL 
Protocol OP0201-C-006 - Amendment 3 
 
69 
Section # and Name 
Description of Change 
Brief Rationale 
internet access to receive the 
electronic survey 
Section 6.1.1 The Drug-device 
Study Treatment 
Removed in clinic for first dose 
administration 
Participants enrolled at the 
satellite sites will be 
administered the first dose in 
Participant’s home 
Section 6.5 Concomitant 
Therapy 
Removed time of administration  Ensure consistency with data 
fields captured in eCRF 
Section 8.1 Efficacy 
Assessments 
Added semi-opaque to 
translucency category of 
pneumatic otoscopy  
Ensure consistency with data 
fields captured in eCRF 
Section 8.1 Efficacy 
Assessments 
Tympanometry assessment 
changed to when possible 
Satellite sites to be added cannot 
perform the tympanometry 
assessment due to unavailability 
of tympanometry diagnostic tool 
Section 8.2.2 Vital Signs 
Changed time at rest to 
approximately 5 minutes 
Given age of Participants it is 
realistically difficult to have 
them sit still for exactly 5 
minutes as originally specified 
Section 8.2.2 Vital Signs 
Removed television and 
cellphones as prohibited 
distractions 
Given age of Participants, using 
a cellphone or iPad will assist in 
keeping them at rest 
Section 9.6 Safety Monitoring 
Committee 
Change wording to indicate that 
SMC will meet when 
approximately 25% of 
Participants have completed 
D12 
To account for slower 
enrollment than planned 
Section 9.4.1 Efficacy Analysis 
Descriptive statistics updated to 
primary and key secondary 
efficacy endpoints. Gender and 
race were removed from the 
sub-groups 
To streamline the number of 
planned subgroup analyses 
 

SAP_001.pdf: 
 
 
 
Study Title A Study to Assess the Safety, Tolerability, and Efficacy of OP0201 as an Adjunct 
Treatment for Acute Otitis Media in Infants and Children Aged 6 to 24 Months 
NCT Number NCT03818815    
Document Description Statistical Analysis Plan, V1.0 
Document Date 07 Jan 2020 
 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Protocol Title: 
A Study to Assess the Safety, Tolerability, and Efficacy of OP0201 as an 
Adjunct Treatment for Acute Otitis Media in Infants and Children Aged 6 
to 24 Months  
 
Protocol Version: 
Amendment 3 (21 August 2019) 
Protocol Number: 
OP0201-C-006 
 
Statistical Analysis 
Plan Author: 
Janice M. Pogoda, PhD 
Version: 
Version 1.0 
Release Date: 
January 7, 2020 
 
Study Phase: 
2a 
Product: 
OP0201 
Indication: 
Acute Otitis Media  
 
Sponsor: 
 
Novus Therapeutics, Inc. 
19900 MacArthur Blvd., Suite 550 
Irvine, California 92612, USA 
 
 
 
 
 
 


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Novus Therapeutics, Inc. 
Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
 
CONFIDENTIALITY STATEMENT 
 
This document and its contents are the property of and confidential to Novus Therapeutics. Any 
unauthorized copying or use of this document is prohibited. 
 
 


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Novus Therapeutics, Inc. 
Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
APPROVALS 
 
 
 
 
 
 
 
Janice M. Pogoda, PhD 
Program Statistician 
Consultant to Novus Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 
Mai D. Sirimanne, MBA 
Vice President, Clinical Development 
Novus Therapeutics, Inc. 
 
Date 
 
 
 
 
 
 
 


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Novus Therapeutics, Inc. 
Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
REVISION HISTORY 
 
Version 
Date 
Author(s) 
Summary of Revision(s) 
1.0 
07Jan2020 
J. Pogoda 
New document 
 
 
 


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Novus Therapeutics, Inc. 
Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
TABLE OF CONTENTS 
APPROVALS .................................................................................................................................3 
REVISION HISTORY ..................................................................................................................4 
LIST OF ABBREVIATIONS .......................................................................................................8 
PREFACE .......................................................................................................................................9 
1. 
BACKGROUND ..............................................................................................................10 
2. 
STUDY OBJECTIVES ....................................................................................................10 
2.1 
Primary Objectives.............................................................................................................10 
2.2 
Secondary Objectives.........................................................................................................10 
2.3 
Other Objective ..................................................................................................................10 
3. 
STUDY DESIGN ..............................................................................................................10 
4. 
TREATMENT GROUPS AND STUDY ENDPOINTS ...............................................10 
4.1 
Treatment Group Comparisons ..........................................................................................10 
4.2 
Study Endpoints .................................................................................................................11 
4.2.1 
Safety Endpoints ...................................................................................................11 
4.2.2 
Primary Efficacy Endpoint Family .......................................................................11 
4.2.3 
Secondary Efficacy Endpoints .............................................................................11 
4.2.4 
Other Endpoints ....................................................................................................12 
5. 
SAMPLE SIZE AND POWER .......................................................................................12 
6. 
TREATMENT ASSIGNMENT, BLINDING, AND UNBLINDING ..........................12 
6.1 
Treatment Assignment .......................................................................................................12 
6.2 
Blinding..............................................................................................................................12 
7. 
ANALYSIS POPULATIONS .........................................................................................12 
8. 
REPORTING AND ANALYSIS CONVENTIONS ......................................................13 
8.1 
Programming Environment ................................................................................................13 
8.2 
Reporting Conventions ......................................................................................................13 
8.3 
General Analysis Conventions ...........................................................................................13 
8.4 
Subgroups ..........................................................................................................................14 
8.5 
Missing Data ......................................................................................................................14 
8.6 
Study Period and Time Point Definitions ..........................................................................14 
8.7 
Visit Windows ...................................................................................................................15 
9. 
STUDY POPULATION ..................................................................................................16 
9.1 
Subject Disposition ............................................................................................................16 
9.2 
Informed Consent and Eligibility.......................................................................................16 
9.3 
Visit Summaries and 10-Day Diary ...................................................................................16 


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Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
9.4 
Protocol Deviations ............................................................................................................17 
9.5 
Analysis Populations ..........................................................................................................17 
9.6 
Demographic and Baseline Characteristics .......................................................................17 
9.7 
Medical History .................................................................................................................17 
10. 
TREATMENTS................................................................................................................17 
10.1 
Study Treatment Exposure .................................................................................................17 
10.2 
Study Treatment and Oral Antibiotic Compliance ............................................................18 
10.2.1 Study Treatment Compliance ...............................................................................18 
10.2.2 Oral Antibiotic Compliance .................................................................................19 
10.3 
Device Incidents.................................................................................................................19 
10.4 
Device Experience .............................................................................................................19 
10.5 
Prior and Concomitant Medications ..................................................................................19 
11. 
SAFETY PARAMETERS ...............................................................................................20 
11.1 
AEs .....................................................................................................................................20 
11.2 
Vital Signs ..........................................................................................................................21 
11.3 
Physical Examination.........................................................................................................21 
11.4 
Ear Examination.................................................................................................................21 
12. 
EFFICACY PARAMETERS ..........................................................................................22 
12.1 
Bulging TM ........................................................................................................................22 
12.2 
MEE ...................................................................................................................................23 
12.3 
Tympanogram ....................................................................................................................24 
12.4 
AOM-SOS Scale ................................................................................................................24 
12.5 
AOM Treatment Failure ....................................................................................................25 
12.6 
AOM Relapse.....................................................................................................................26 
12.7 
AOM Recurrence ...............................................................................................................26 
13. 
STATISTICAL METHODS ...........................................................................................27 
13.1 
Logistic Regression ............................................................................................................27 
13.2 
GLM ...................................................................................................................................27 
13.3 
Missing Observations.........................................................................................................27 
13.4 
Multiplicity ........................................................................................................................27 
14. 
SAFETY MONITORING COMMITTEE ....................................................................28 
15. 
SEQUENCE OF PLANNED ANALYSES ....................................................................28 
15.1 
Final Analysis ....................................................................................................................28 
16. 
CHANGES FROM THE PROTOCOL .........................................................................28 
REFERENCES .............................................................................................................................29 
APPENDIX A:  SCHEDULE OF ACTIVITIES ......................................................................30 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
APPENDIX B: TABLES OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS ...32 
 


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Novus Therapeutics, Inc. 
Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
AOM 
acute otitis media 
AOM-SOS 
Acute Otitis Media Severity of Symptom 
ATC 
Anatomical-Therapeutic-Chemical 
BID 
twice per day 
BMI 
body mass index 
CSR 
Clinical Study Report 
eCRF 
electronic case report form 
EOS 
end of study 
GLM 
general linear model 
ICH 
International Conference on Harmonisation 
LS 
least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEE 
middle ear effusion 
mITT 
modified intent-to-treat 
N/A 
not applicable 
OME 
otitis media with effusion 
OP0201 
OP0201 nasal aerosol 
pMDI 
pressurized metered dose inhaler 
PP 
per protocol 
PT 
Preferred Term 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SE 
standard error 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
TFLs 
tables, figures, and listings 
TM 
tympanic membrane 
WHO-DD 
World Health Organization Drug Dictionary 
 


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Novus Therapeutics, Inc. 
Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
PREFACE 
The purpose of this statistical analysis plan (SAP) is to outline the planned analyses and 
reporting to support the completion of the Clinical Study Report (CSR) for Novus Therapeutics 
Protocol OP0201-C-006. The planned analyses identified in this SAP will be included in 
regulatory submissions and/or future manuscripts. Also, exploratory analyses not necessarily 
identified in this SAP may be performed to support the clinical development program. Any post-
hoc, or unplanned, analyses not identified in this SAP will be clearly identified in the CSR. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the United States of America Food and Drug Administration and International 
Conference on Harmonisation (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical Trials.1 All work 
planned and reported for this SAP will follow internationally accepted guidelines published by 
the American Statistical Association2 for statistical practice. 
The following documents were also considered in preparation for writing this SAP:  
 
• Clinical Research Protocol OP0201-C-006, Amendment 3 (21 August 2019) 
• ICH E3 Guideline: Structure and Content of Clinical Study Reports3 
• ICH E6 Guideline on Good Clinical Practice4 
• ICH E8 General Considerations for Clinical Trials5 
• ICH E9 Statistical Principles for Clinical Trials6 
• Statistical Analysis Plans: Principles and Practice7 
The SAP is a supplement to the study protocol, which should be referred to for additional details 
on study design, study conduct, and other operational aspects of the study. 
 
 
 
 
 
 


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Novus Therapeutics, Inc. 
Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
1. 
BACKGROUND 
It has been established that most young children with acute otitis media (AOM) will have 
persistent middle ear effusion (MEE) or otitis media with effusion (OME) 2 to 3 weeks after 
AOM diagnosis, despite treatment with oral antibiotics. Bulging tympanic membrane (TM) and 
recent onset of acute symptoms are the main findings that clinicians use to discriminate AOM 
from OME. The purpose of this study is to develop a better understanding of the safety, 
tolerability, and efficacy of intranasal OP0201 as an adjunct treatment to oral antibiotics for 
AOM in infants and children, and to assist in the design of future clinical trials.  
2. 
STUDY OBJECTIVES  
2.1 
Primary Objectives 
The primary objectives of the study are to evaluate the safety, tolerability, and efficacy of 
intranasal OP0201 compared with placebo in accelerating AOM resolution by reducing and/or 
eliminating MEE in infants and children when given as an adjunct treatment to oral antibiotics as 
assessed using pneumatic otoscopy. 
2.2 
Secondary Objectives 
The secondary objectives of the study are to evaluate the efficacy of intranasal OP0201 
compared with placebo in accelerating and maintaining AOM resolution, and reducing the 
likelihood of  MEE (OME) in infants and children when given as an adjunct treatment to oral 
antibiotics as assessed using other measures (ie, tympanometry, Acute Otitis Media Severity of 
Symptom (AOM-SOS) score, and AOM recurrence and AOM relapse rates). 
2.3 
Other Objective 
Another objective of this study is to obtain feedback from parents/caregivers on the pressurized 
metered dose inhaler (pMDI) device to optimize design of the device for pivotal studies. 
3. 
STUDY DESIGN 
This is a Phase 2a, single-center, double-blind, randomized, placebo-controlled, parallel-group 
study to assess the safety, tolerability, and efficacy of 20 mg per day intranasal OP0201 (10 mg 
administered twice/day (BID) over 10 days for a total of 20 doses) as an adjunct therapy to oral 
antibiotic treatment of AOM in infants and children aged 6 to 24 months (inclusive). Subjects 
will be followed for up to 20 days after study treatment is discontinued. The total duration of 
study participation for each subject is up to 30 days, which includes 4 clinic visits. An 
unscheduled interim/sick visit may occur for safety purposes or if AOM symptoms have relapsed 
or worsened. The Schedule of Activities is in Appendix A. 
4. 
TREATMENT GROUPS AND STUDY ENDPOINTS 
4.1 
Treatment Group Comparisons 
The treatment groups to be compared are OP0201 and placebo. 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
4.2 
Study Endpoints 
4.2.1 Safety Endpoints 
• 
Incidence, seriousness, severity, and relationship to IP of treatment-emergent adverse events 
(TEAEs) 
• 
Shifts from baseline (normal, abnormal) in vital signs (temperature, respiratory rate and 
pulse) 
• 
Shifts from baseline (normal, abnormal) in physical examination, including visual 
examination of the nasopharynx and oropharynx 
• 
Shifts from baseline in examination of the TM (via otoscopy and endoscopy) 
4.2.2 Primary Efficacy Endpoint Family 
The primary efficacy endpoint family is comprised of the following endpoints: 
• 
No bulging of the TM assessed at the Day 4 visit by pneumatic otoscopy  
• 
No MEE (OME) assessed at the Day 12 visit by pneumatic otoscopy 
4.2.3 Secondary Efficacy Endpoints 
Secondary efficacy endpoints are: 
• 
No MEE assessed at the Day 4 and Day 28 visits by pneumatic otoscopy 
• 
No bulging of the TM assessed at the Day 12 and Day 28 visits by pneumatic otoscopy 
• 
Normal tympanogram (Type A) assessed at the Day 4, Day 12, and Day 28 visits by 
tympanometry 
• 
Complete or near complete resolution of symptoms (AOM cure), defined as an AOM-SOS 
score < 2, assessed at the Day 4 Visit, the Day 12 Visit and the Day 28 Visit.  
• 
Change from baseline in the AOM-SOS score over the 10-day planned treatment period by 
parent/caregiver diary data  
• 
At least a 50% reduction from baseline in the in-clinic AOM-SOS score, assessed at the 
Day 4, Day 12, and Day 28 visits 
• 
AOM treatment failure (clinical failure) at the Day 12 Visit, with treatment failure defined as 
moderate to severe bulging of the TM, or mild bulging of TM with recent (less than 48 
hours) onset of ear pain (otalgia), or mild bulging of the TM with intense erythema of the 
TM. 
• 
AOM relapse defined as those with clinical success at the Day 12 visit and who return for an 
interim/sick visit before Day 17 and have AOM. Clinical success is defined as no moderate 
to severe bulging of the TM, and no mild bulging of the TM with recent (less than 48 hours) 
onset of ear pain (otalgia), and no mild bulging of the TM with intense erythema of the TM. 
• 
AOM recurrence defined as clinical success at the Day 12 visit and return for an interim/sick 
visit from Day 17 through Day 28 and have AOM. Clinical success is defined as no moderate 
to severe bulging of the TM, and no mild bulging of the TM with recent (less than 48 hours) 
onset of ear pain (otalgia), and no mild bulging of the TM with intense erythema of the TM. 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
4.2.4 Other Endpoints 
• 
Parent/caregiver’s input on device experience on Day 12. 
5. 
SAMPLE SIZE AND POWER 
The power calculation is based on a 2-sided Pearson chi square test of each of the two endpoints 
in the primary efficacy endpoint family and control of type 1 error using the step-up Hochberg 
procedure.8 The minimally important difference in proportions for both endpoints is 
approximately 0.25. With 70 subjects randomized per treatment group, an assumed dropout rate 
of 10%, and using multiple imputation as described in Section 13.3, this study will have 93% 
power to detect a treatment effect in at least one of the two endpoints assuming 40% of placebo-
treated subjects will have no bulging TM at Day 4 and 30% of placebo-treated subjects will have 
no MEE at Day 12. A summary of sample size requirements is as follows: 
 
 
Total N 
Power 
100 
82% 
102 
82% 
120 
88% 
132 
91% 
140 
93% 
 
6. 
TREATMENT ASSIGNMENT, BLINDING, AND UNBLINDING 
6.1 
Treatment Assignment 
Following Screening, but before any treatment-related procedures, eligible subjects will be 
randomly assigned in a 1:1 ratio to either OP0201or placebo. The randomization schedule will be 
generated by the University of Pittsburgh Statistics Department. Randomization will be stratified 
by daycare attendance (yes, no) and age (≥ 6 to <12 months, ≥ 12 to ≤ 24 months). Daycare 
attendance will be defined as exposure to 3 or more children outside of the home for 10 or more 
hours per week. A fixed block size of 4 will be used.  
6.2 
Blinding 
OP0201 and placebo will be identical in physical appearance. The specific treatment each subject 
will receive (OP0201 or placebo) will not be disclosed to the Investigator, study center staff, 
subject, Sponsor, study vendors, or the Safety Monitoring Committee (SMC). The treatment 
codes will be held by the University of Pittsburgh Statistics Department. 
7. 
ANALYSIS POPULATIONS 
Screened Population: Subjects whose parent/legal guardian signed the informed consent form. 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
Safety Population: Subjects who received at least one intranasal spray of study treatment. 
Subjects will be summarized and analyzed based on treatment received. 
Modified Intent to treat (mITT) Population: Subjects who were randomized excluding the first 3 
subjects dosed (subject numbers 1001, 1002 and 1003), as there was a known device malfunction 
for these subjects. Subjects will be summarized and analyzed based on randomization 
assignment, regardless of treatment received. 
Per Protocol (PP) Population: Subset of the mITT population with no protocol violations that 
may have affected the primary efficacy endpoint family.  
8. 
REPORTING AND ANALYSIS CONVENTIONS  
8.1 
Programming Environment 
SAS® version 9.4 or higher (SAS Institute, Cary, North Carolina) will be used for statistical 
analyses and the production of tables, figures, and listings (TFLs).  
8.2 
Reporting Conventions 
Tables of contents for TFLs to be produced are shown in Appendix B. Mock-up TFLs to be 
produced are provided in separate documents from the SAP. Sponsor approval of mock-up TFLs 
is included with Sponsor approval of the SAP. Final TFLs will be appended to the final CSR. 
The following reporting conventions will be followed: 
• 
Font size is to be no smaller than 9pt. 
• 
Titles and footnotes must appear on every page of the TFL. 
• 
Treatment group names and order in tables and figures will be Placebo, OP0201 (20 mg). 
Some tables and figures may also display All Subjects as a third grouping.   
• 
Tables and figures will present summaries/analyses by study time point or analysis visit 
window, as appropriate.  
• 
Table column headers and figure legends will include subgroup sample sizes (“N = xx”). 
Sample sizes reported as part of descriptive statistics (“n”) will be the number of non-missing 
observations. 
• 
Listings will be produced for all study population, safety, and efficacy data collected, either 
on the electronic case report form (eCRF) or through third-party vendors, and will be ordered 
by unique subject identifier, parameter, date, data collection time if applicable, nominal study 
visit, and analysis visit window if applicable (see Section 8.7). Listings will also include site 
identifier. 
8.3 
General Analysis Conventions 
Categorical variables will be summarized using frequencies and percentages.  Percentages will 
be reported to one decimal place. Unless otherwise noted in Section 12, categorical variables will 
be analyzed using chi square tests of association (or Fisher’s exact test if any contingency table 
cell has less than 5 observations) or logistic regression to adjust for covariates. 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
Continuous variables will be summarized using descriptive statistics (e.g., n, mean, standard 
deviation (SD), least-squares (LS) mean with standard error (SE), distribution percentiles, 
range). The number of decimal places for minimums and maximums will be the same as the 
original data. The number of decimal places for means, medians, and interquartile ranges will be 
the same as the original data plus one. The number of decimal places for measures of variance 
will be the same as the original data plus two. Unless otherwise noted in Section 12, continuous 
variables will be analyzed using t-tests, general linear models to adjust for covariates, or non-
parametric alternatives. 
Data with qualifiers (e.g., “<”) will be listed with but summarized without the qualifier. 
P-values will be presented in summary tables to three decimal places. P-values < 0.001 will be 
presented as “< 0.001.” 
Statistical tests will be two-sided with 0.05 significance levels unless otherwise noted. 
8.4 
Subgroups 
Summary statistics for the primary efficacy endpoint family will be provided for the following 
subgroups: 
 
• 
Male, female 
• 
White, non-white 
• 
Unilateral, bilateral disease at baseline 
• 
History, no history of recurrent AOM, defined as 3 or more episodes in the preceding 6 
months or 4 or more episodes over the course of 12 months 
• 
Age stratum (≥ 6 to <12 months, ≥ 12 to ≤ 24 months)  
• 
Daycare attendance stratum (exposed, not exposed to 3 or more children outside of the home 
for 10 or more hours per week) 
• 
Study site 
8.5 
Missing Data 
Listings will present data as reported. Missing or partially missing dates that are required for 
date-dependent definitions (e.g., TEAEs, concomitant medications) will be assumed to be the 
most conservative date possible. For example, an adverse event (AE) with a completely missing 
start date will be considered treatment-emergent. Missing observations will not be imputed for 
summaries. Handling of missing observations for statistical inference is described in Section 
13.4. 
8.6 
Study Period and Time Point Definitions 
Screening: Day 1 up to dosing. 
 


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Baseline Observation: for a given parameter for a given randomized subject, the last observed 
value before the first dose of study treatment or planned first dose of study treatment if not 
dosed. 
 
Study Day 1: for a given randomized subject, the day of actual first dose of study treatment or 
planned first dose of study treatment if not dosed. 
 
Study Day:  
• 
Study day = date of assessment – date of dosing + 1, for assessments on or after first dose 
• 
Study day = date of assessment – date of dosing, for assessments before first dose 
 
Study Time: time of assessment – time of first dose 
 
Duration:  
• 
Duration in days = end date – start date + 1 
• 
Duration in minutes = end time – start time 
(Nominal Visit) Analysis Time Point: analysis based on data collected at the (nominal visit) time 
point, where nominal visits are as shown below in Section 8.7. 
 
End of Study (EOS), Subject-Level: the date of completion of the last planned study visit or date 
of discontinuation for any reason. 
 
EOS, Study-Level: the date when all randomized subjects have reached Subject-Level EOS. 
8.7 
Visit Windows 
Visit windows are based on Study Day. Observations will be assigned to an analysis window 
according to the tables below. Observations that cannot be assigned to an analysis window based 
on the tables below will be excluded from summaries and analyses (but will still be listed). For 
subjects not dosed, planned date of first dose will be used in Study Day calculations, if 
necessary. 
 
For otoscopy and tympanogram parameters: 
Nominal Visit 
 
Target 
Study Day 
Min Study 
Day Per 
Protocol 
Max Study 
Day Per 
Protocol 
Min Study 
Day for 
Analyses 
Max Study 
Day for 
Analyses 
Visit 1  
(Day 1 Pre-Dose) 
1 (pre-dose) 
1 
1 (pre-dose) 
N/A 
1 (pre-dose) 
30 Minutes 
Post-Dose 
1 (post-dose) 
1 (post-dose) 
1 (post-dose) 
1 (post-dose) 
1 (post-dose) 
Visit 2 (Day 4) 
4 
4 
6 
4 
6 
Visit 3 (Day 12) 
12 
12 
14 
12 
14 
Visit 4 (Day 28) 
28 
26 
30 
26 
30 
N/A, not applicable 
 


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For all other parameters collected in-clinic: 
Nominal Visit 
 
Target 
Study Day 
Min Study 
Day Per 
Protocol 
Max Study 
Day Per 
Protocol 
Min Study 
Day for 
Analyses 
Max Study 
Day for 
Analyses 
Visit 1 (Day 1) 
1 (pre-dose) 
1 
1 (pre-dose) 
N/A 
1 (pre-dose) 
Visit 2 (Day 4) 
4 
4 
6 
4 
6 
Visit 3 (Day 12) 
12 
12 
14 
12 
14 
Visit 4 (Day 28) 
28 
26 
30 
26 
30 
N/A, not applicable 
 
For AOM-SOS score collected by diary: 
Nominal Visit 
 
Target 
Study Day 
Min Study 
Day Per 
Protocol 
Max Study 
Day Per 
Protocol 
Min Study 
Day for 
Analyses 
Max Study 
Day for 
Analyses 
Visit 1 (Day 1) 
1 (pre-dose) 
1 
1 (pre-dose) 
N/A 
1 (pre-dose) 
Diary Day x, x=2-10 
x 
x 
x 
x 
x 
N/A, not applicable 
 
If multiple valid, non-missing observations exist within a given window, the observation to be 
used will be: 
1. the observation closest to the target study day of the nominal visit in question, or 
2. the latest observation if the multiple observations are equidistant from the target study 
day of the nominal visit, or  
3. the average (arithmetic or geometric, as appropriate) of the observations if the multiple 
observations have the same actual time point. 
9. 
STUDY POPULATION 
The study population will be described by the parameters below. Listings and summaries will 
include all randomized subjects unless otherwise noted. 
9.1 
Subject Disposition 
Frequencies and percentages of subjects who discontinued the study treatment and/or study will 
be summarized. Reasons for discontinuation will also be summarized. The listing of subject 
disposition will include dates and times (if applicable) of randomization, dosing, and EOS; and 
reasons for study treatment and/or study discontinuation (if applicable).  
9.2 
Informed Consent and Eligibility 
Informed consent (for the Screened Population) and eligibility parameters will be listed. Reasons 
for screen failure will be summarized. 
9.3 
Visit Summaries and 10-Day Diary 
Listings of visit summaries and 10-day diary entries will be provided. 


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9.4 
Protocol Deviations 
A listing of protocol deviations will include protocol version and the category of the deviation 
(to be determined). Frequency and percentage of subjects in each deviation category will be 
summarized.  
9.5 
Analysis Populations 
The analysis populations defined in Section 7 will be described in terms of the identification of 
subjects in each population and the frequency distribution of each population. The number of 
randomized subjects will also be described. Number of screened subjects will be the denominator 
for percentage of subjects randomized, and the number randomized will be the denominator for 
percentage of subjects in the Safety, mITT, and PP populations. 
A listing of analysis populations will be produced showing the analysis population(s) to which 
each subject belonged. 
9.6 
Demographic and Baseline Characteristics 
Demographic and other baseline characteristics will be summarized both overall and by 
treatment group. Parameters will include sex; age at informed consent; age stratum for 
randomization; race; ethnicity; weight, height, and body mass index (BMI) at screening; baseline 
otitis media risk factors (private or public health insurance, mother’s education level, attends 
daycare, at least 3 other children in household, smoker in household), study site, and 
tympanogram status (yes or no).  
9.7 
Medical History 
Reported medical conditions will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA), version 21.0, to a System Organ Class (SOC) and Preferred Term (PT). 
Medical history will be summarized by SOC and PT. 
10. 
TREATMENTS 
Treatments include study treatment, oral antibiotic treatment, device incidents, device 
experience, prior medications, and concomitant medications. 
10.1 Study Treatment Exposure 
Exposure to study treatment will be expressed as total exposure, mean daily exposure, and 
duration of exposure.  
 
Exposure per study treatment administration Ea (mg) will be calculated as 
 
𝐸𝐸𝑎𝑎(𝑚𝑚𝑚𝑚) = (𝑆𝑆𝐿𝐿𝑎𝑎+ 𝑆𝑆𝑅𝑅𝑎𝑎) 𝑥𝑥 2.5 
 
where  
 
a = 1 to A, A = total number of administrations 


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SL_a = number of sprays to the left nostril during administration a 
SR_a = number of sprays to the right nostril during administration a 
 
Total exposure ET (mg) will be calculated as 
 
𝐸𝐸𝑇𝑇(𝑚𝑚𝑚𝑚) = ෍𝐸𝐸𝑎𝑎 (𝑚𝑚𝑚𝑚)
𝐴𝐴
𝑎𝑎=1
 
 
 
Duration of Exposure ED (days) is defined as the total number of days that treatment was 
administered, ie, 
 
 
 
 
 
ED = date of last dose – date of first dose + 1 
 
Mean daily exposure EM (mg) will be calculated for each subject as 
 
 
 
 
 
 
      EM  (mg) =   
𝐸𝐸𝑇𝑇 (𝑚𝑚𝑚𝑚)
𝐸𝐸𝐷𝐷 (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) 
 
and will be rounded to the nearest hundredth. 
 
Listings and summaries will be based on the Safety Population. Listings will show each study 
treatment administration per nostril and will also display cumulative total exposure, duration of 
exposure, and mean daily exposure. 
10.2 Study Treatment and Oral Antibiotic Compliance 
10.2.1 Study Treatment Compliance 
Study treatment compliance will be expressed as both overall and mean daily percent 
compliance. For mean daily percent compliance, only days on which exposure occurred will be 
counted. 
 
Percent compliance will be calculated for each study day of exposure as 
 
𝐶𝐶𝑑𝑑= 100 𝑥𝑥 (𝑆𝑆𝐿𝐿𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐿𝐿𝑑𝑑+ 𝑆𝑆𝑅𝑅𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐿𝐿𝑑𝑑)/8 
 
rounded to the nearest tenth, where  
 
d = 1 to D, D = total number of study days of exposure 
SL_ACTUAL_d = actual number of sprays to the left nostril on day d 
SR_ACTUAL_d = actual number of sprays to the right nostril on day d 
 
For subjects who prematurely discontinue treatment, percent compliance will be calculated only 
for study days prior to discontinuation. 
 


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Percent overall compliance CT will be calculated as 
 
𝐶𝐶𝑇𝑇= 100 𝑋𝑋 
∑
ቀ𝑆𝑆𝐿𝐿𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐿𝐿𝑑𝑑+ 𝑆𝑆𝑅𝑅𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐿𝐿𝑑𝑑ቁ
𝐷𝐷
𝑑𝑑=1
𝑆𝑆𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸𝐸
 
 
rounded to the nearest tenth, where 
 
 
 
 
 
 
 
 
 
 
SEXPECTED = ED x 8 
 
with ED as defined in Section 10.1. 
 
Mean daily percent compliance CM will be calculated for each subject as 
 
 
𝐶𝐶𝑀𝑀= 
∑
𝐶𝐶𝑑𝑑
𝐷𝐷
𝑑𝑑=1
𝐸𝐸𝐷𝐷
 
 
 
 
 
 
and will be rounded to the nearest hundredth. 
 
Listings and summaries will be based on the Safety Population. Listings will show compliance 
for each study day and will also display cumulative overall compliance and mean daily 
compliance. 
10.2.2 Oral Antibiotic Compliance 
Oral antibiotic exposure will be collected by diary as number of administrations. Daily and 
overall antibiotic compliance will be calculated as 100 x (number of administrations / expected 
number of administrations) rounded to the nearest tenth. For daily compliance, the expected 
number is 2. For overall compliance, the expected number is the number of days of study 
participation x 2; ie, for subjects who prematurely discontinue from the study, compliance will 
be calculated only for study days prior to discontinuation. Oral antibiotic compliance will be 
listed and summarized for the Safety Population. 
10.3 Device Incidents 
A listing of device incidents will be provided for the Safety Population. 
10.4 Device Experience 
The Device Experience questionnaire will be completed by parents/caregivers at the Day 12 
visit. Data will be listed for the Safety Population. 
10.5 Prior and Concomitant Medications 
Medication use from 7 days prior to enrollment to EOS will be coded to generic terms, including 
2nd-level Anatomical-Therapeutic-Chemical (ATC) drug class, using the World Health 
Organization Drug Dictionary (WHO-DD), version 01Mar2018B3 Enhanced. Aside from 
parameters collected on the eCRF, listings will include date and time of study treatment dosing, 
WHO-DD drug class and preferred drug name, and Study Day. Frequencies and percentages of 


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subjects reporting or receiving each medication will be summarized by WHO-DD drug class and 
preferred name within drug class.  
Medications that were stopped prior to study treatment dosing will be considered “prior” 
medications, medications that were stopped earlier than 7 days before enrollment will be 
ignored, and all other medications will be considered “concomitant.” Medications recorded with 
insufficient exposure dates to determine whether or not they were concomitant will be 
considered concomitant. 
Prior medications will be listed and summarized separately from concomitant medications. 
Listings and summaries for prior medications will be based on all subjects randomized. Listings 
and summaries for concomitant medications will be based on the Safety Population. 
11. 
SAFETY PARAMETERS 
Safety parameters will be listed and summarized for the Safety Population unless otherwise 
noted. 
11.1 AEs 
AEs reported from time of informed consent through EOS will be coded according to MedDRA® 
version 21.0. Each reported AE will be mapped to a PT and SOC. Aside from parameters 
collected on the eCRF, listings will include MedDRA PT and SOC, Study Day, whether or not 
the AE is ongoing, and AE duration. For AEs that are ongoing, AE end date will be imputed with 
subject-level EOS date for the duration calculation. 
TEAEs will be AEs that began or worsened in severity during or after first dose of study 
treatment and no later than 2 calendar days after last dose of study treatment. AEs with 
insufficient date or time information to determine whether or not they were treatment-emergent 
will be considered treatment-emergent. AEs that began or worsened in severity from 2 calendar 
days after last dose through EOS will be defined as non-treatment-emergent (non-TEAEs). AEs 
that began or worsened in severity after informed consent but before the first dose will be 
counted as pre-treatment AEs.  
All TEAEs will be listed. In addition, separate listings will be done for: 
• 
Treatment-emergent SAEs (TESAEs) 
• 
TEAEs that resulted in study treatment interruption or dose reduction 
• 
TEAEs that results in study treatment discontinuation (excluding deaths) 
• 
TEAEs that resulted in death 
• 
Pre-treatment AEs among the Screened Population  
• 
Non-TEAEs 
Listings will be done for the Safety Population. 
Incidence of all TEAEs will be summarized by SOC and PTs within SOCs, sorted alphabetically 
by SOC and PT within SOC. In addition, separate summaries will be done for: 
• 
TEAEs assessed as related to study treatment 


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• 
TEAEs by severity 
• 
TESAEs 
• 
TESAEs assessed as related to study treatment 
• 
Pre-treatment AEs among the Screened Population 
• 
Non-TEAEs 
In summaries by relationship to study treatment, missing relationship will be considered related. 
In summaries by AE severity, missing severity will be counted as severe.  
An overall summary of TEAEs (collapsed over all SOCs and PTs) will show incidence of all 
TEAEs as well as: 
• 
TEAEs assessed as related to study treatment 
• 
TESAEs 
• 
TESAEs assessed as related to study treatment 
• 
Severe TEAEs 
• 
Moderate TEAEs 
• 
Mild TEAEs 
• 
TEAEs that resulted in study treatment interruption or dose reduction 
• 
TEAEs that results in discontinuation from the study or study treatment (excluding deaths) 
• 
TEAEs that resulted in death 
Summaries of TEAEs and TESEAs (separately) in descending order of incidence among all 
subjects combined will show incidence of PTs only. 
11.2 Vital Signs  
Vital signs will be collected at each study visit. Observed values for oral temperature, respiratory 
rate, and pulse will be summarized at each time point. Changes from baseline will also be 
summarized for each post baseline time point. Listings will include changes from baseline. 
11.3 Physical Examination 
Physical examination will be done at each study visit. Findings for each body system, including 
extended data for throat and nose, will be summarized. Body system shifts from baseline to 
normal/abnormal status will also be summarized. 
11.4 Ear Examination 
Examination of each ear will be done at each study visit. Summaries, by ear and visit, will be 
done for: TM findings (intact, perforated,), color (gray, pink, pale yellow, white, amber, blue), 
translucency (translucent, semi-opaque, opaque), mobility (none, 1+, 2+, 3+, 4+), air fluid 
interface (yes, no), otalgia (yes, no), distinct erythema (yes, no), position of the TM (neutral, 
retracted, 1+ bulging, 2+ bulging, 3+ bulging), otorrhea (no, serous, purulent), and diagnosis (no 
effusion, OME, AOM).   


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Shift tables will summarize changes from baseline in normal/abnormal status, where “abnormal” 
will be limited to “definitely abnormal” defined as follows: 
• 
TM findings: perforated 
• 
Color: pale yellow, white, amber, blue  
• 
Translucency: semi-opaque or opaque 
• 
Mobility: none 
• 
Air fluid interface: yes 
• 
Otalgia: yes 
• 
Distinct erythema: yes 
• 
Position of TM: retracted, 1+ bulging, 2+ bulging, 3+ bulging 
• 
Otorrhea: serous, purulent 
• 
Diagnosis: AOM, OME 
Parameters will be summarized within treatment group for (a) first or only affected ear and (b) 
second or non-affected ear. Since either one ear or both ears can have AOM at baseline, this 
approach will allow descriptive comparisons between OP0201 and placebo treatment groups on 
number of affected ears (ie, one or both ears) and shifts from baseline, by visit, for both affected 
and non-affected ears at baseline. 
12. 
EFFICACY PARAMETERS 
Efficacy parameters will be listed for the mITT population. For the family of primary efficacy 
endpoints, summaries and analyses will be done using the mITT population unless otherwise 
noted. For secondary efficacy endpoints, complete-cases analyses will be done using the mITT 
population, whereby for each endpoint only subjects with complete data are included. Results 
from statistical analyses of treatment group differences in secondary endpoints may be reported 
to aid in interpretation and to assist in the design of future clinical trials. 
12.1 Bulging TM 
The presence/absence of bulging TM will be evaluated as part of the ear examination (see 
Section 11.4) done at each study visit; each ear will be evaluated separately.  
 
A listing of bulging TM will be produced separately from the listing of ear examination 
parameters noted in Section 11.4. 
 
Endpoints 
The definition of bulging TM will be presence of 1+, 2+, or 3+ bulging on ear examination. 
Note: at least mild bulging is an inclusion criterion. 
 
No bulging TM at the Day 4 visit is one of two endpoints in the primary efficacy endpoint family 
(see Section 13.5). The hypothesis set to be tested is: 


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Ho: PA = PP 
vs. 
HA: PA ≠ PP 
 
where PA and PP are the population proportions for OP0201 and placebo, respectively, for no 
bulging TM 4 days after the start of a 10-day treatment regimen.  
 
The following sensitivity analyses will be done: 
• 
PP analysis population 
• 
Complete case (ie, mITT subjects who completed the Day 4 visit; see Section 13.3) 
• 
Complete case with the endpoint defined as no bulging TM at the Day 4 visit and no 
recurrence of bulging TM (see Section 12.7) throughout the remainder of the study, assessed 
at the Day 28 visit. In this instance, “complete case” is equivalent to mITT subjects who 
completed the Day 28 visit. 
No bulging TM assessed at the Day 12 and Day 28 visits are secondary endpoints.  
Summaries and Analyses (see Section 13) 
No bulging TM will be summarized and analyzed separately by visit using logistic regression. 
Summary tables will include frequencies and percentages of no bulging TM for each treatment 
group by visit and p-values for the differences. Crude rates of no bulging TM by treatment group 
and visit will be graphically displayed using bar charts. 
12.2 MEE 
Otoscopy will be performed at each study visit (as well as 30 minutes post-dose on Day 1, for 
safety only) to evaluate the presence/absence of MEE; each ear will be evaluated separately, and 
a listing will show presence/absence of MEE for each ear separately. 
 
Endpoints 
 
No MEE at the Day 12 visit is one of two endpoints in the primary efficacy endpoint family (see 
Section 13.5). The following sensitivity analyses will be done: 
• 
PP analysis population 
• 
Complete case (ie, mITT subjects who completed the Day 12 visit; see Section 13.3) 
• 
Complete case with the endpoint defined as no MEE at the Day 12 visit and no recurrence of 
MEE throughout the remainder of the study. In this instance, “complete case” is equivalent to 
mITT subjects who completed the Day 28 visit. 
The hypothesis set to be tested is: 
 
Ho: PA = PP 
vs. 
HA: PA ≠ PP 


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where PA and PP are the population proportions for OP0201 and placebo, respectively, for no 
MEE 12 days after the start of a 10-day treatment regimen.  
 
No MEE at the Day 4 and Day 28 visit are secondary endpoints.  
Summaries and Analyses (see Section 13) 
No MEE will be summarized and analyzed separately by visit using logistic regression. 
Summary tables will include frequencies and percentages of no MEE for each treatment group 
by visit and p-values for the differences. Crude rates of no MEE by treatment group and visit will 
be graphically displayed using bar charts. 
12.3 Tympanogram 
For a subset of the mITT population, tympanograms will be performed at each study visit to 
assess middle ear function. Each ear will be rated separately as Type A, Type B, or Type C.  
Endpoints 
Secondary endpoints based on tympanogram will be: 
• 
Normal tympanogram (Type A) in either ear, assessed at the Day 4, 12, and 28 visits  
A listing of tympanogram parameters will show peak height, gradient width, peak pressure, 
values derived, test results, ear canal volume value, predictive value, and rating. 
Summaries and Analyses 
Summary tables will include frequencies and percentages of shifts from baseline for each 
treatment group by visit. Crude rates of normal tympanogram by treatment group and visit will 
be graphically displayed using bar charts. There will be no statistical analysis of normal 
tympanogram. 
12.4 AOM-SOS Scale 
The AOM-SOS scale is scored by the parent/caregiver once daily at home and recorded in a 
diary over the 10-day duration of the antibiotic and study treatment period and also at in-clinic 
visits on Day 1, 4, 12 and 28. The scale consists of 5 questions rated on a 6-point scale, with 
lower scores associated with better symptom status: 0 = no, 1 = almost none, 2 = a little, 3 = 
some, 4 = a lot, 5 = an extreme amount. A total score for each day will be calculated in the 
AOM-SOS analysis data set (ie, not in the eCRF) as the sum of the 5 individual scores. Missing 
observations for individual questions will not be possible, which is a built-in feature of the data 
collection instrument; either all 5 questions will have responses or none of the 5 questions will 
have responses. 
At the screening visit the parent/caregiver will be asked to score the AOM-SOS scale as part of 
the screening criteria for the study; a score of at least 5 is an inclusion criterion. This is the only 
baseline assessment of the AOM-SOS scale. 
 


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Listings for AOM-SOS scale will show observed values at each time point collected for both 
diary and in-clinic, the 10-day mean from diary, and absolute and percent changes from baseline 
in the in-clinic AOM-SOS scores for Days 4, 12, and 28. 
Endpoints 
Secondary endpoints based on the AOM-SOS scale will be: 
• 
10-day mean AOM-SOS total score based on diary data, calculated for each subject as the 
mean total score over the 10-day treatment period. If the Day 4 assessment is missing from 
the diary, the Day 4 in-clinic assessment may be used but only if done on Study Day 4. If 
more than 10 days of AOM-SOS scores are available, only the first 10 days will be used to 
calculate the mean. If less than 10 days of AOM-SOS scores are available, 10-day mean 
score will not be calculated. 
• 
Complete or near complete resolution of symptoms (AOM cure), defined as in-clinic AOM-
SOS score < 2, assessed at the Day 4, 12, and 28 visits.  
• 
AOM-SOS response, defined as at least a 50% reduction from baseline in the in-clinic AOM-
SOS score, assessed at the Day 4, 12, and 28 visits.  
Since a Day 4 assessment should be available from both the diary and the in-clinic visit, the in-
clinic assessment will be used for the resolution and response endpoints. If the in-clinic 
assessment is not available, the Day 4 diary assessment will be used. 
In a sensitivity analysis, AOM cure will be defined as AOM-SOS score = 0. 
Summaries and Analyses (see Section 13) 
The 10-day mean AOM-SOS total score will be analyzed using a general linear model (GLM) 
with baseline AOM-SOS total score included as a covariate.  A summary table will include 
means and SDs for each treatment group and a p-value for the difference.  
AOM cure and AOM-SOS response will be summarized and analyzed separately by visit using 
logistic regression with baseline AOM-SOS total score included as a covariate. Summary tables 
will include frequencies and percentages of AOM cure and AOM-SOS response for each 
treatment group by visit and p-values for the differences.  
12.5 AOM Treatment Failure 
AOM treatment failure (clinical failure) will be defined as: 
• 
moderate to severe bulging of the TM, or 
• 
mild bulging of the TM with 
o recent (less than 48 hours) onset of ear pain (otalgia), or 
o intense erythema of the TM 
AOM treatment failure (clinical failure) will be available in the eCRF and will not be 
programmatically derived. As a cross-check, a listing will be provided that shows degree of 
bulging TM, otalgia, and erythema in each ear and AOM treatment failure status at Day 12.  


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Endpoints 
AOM treatment failure (clinical failure) at the Day 12 visit will be a secondary endpoint.  
Summaries and Analyses (see Section 13) 
AOM treatment failure (clinical failure) will be analyzed using logistic regression. A summary 
table will include frequencies and percentages of treatment failure and  a p-value for the 
treatment group difference.  
12.6 AOM Relapse 
AOM relapse will be defined as clinical success at the Day 12 visit and return for an interim/sick 
visit before Day 17 with AOM at that visit. Clinical success is defined as: 
• 
no moderate to severe bulging of the TM, and 
• 
no mild bulging of the TM with 
o recent (less than 48 hours) onset of ear pain (otalgia), or 
o intense erythema of the TM 
Clinical success will be available in the eCRF and will not be programmatically derived. AOM 
relapse status will be shown in a listing.  
Endpoints 
AOM relapse will be a secondary endpoint and will be assessed using the subset of the mITT 
population that achieved clinical success at the Day 12 visit. Subjects in this subset who did not 
have an interim/sick visit before Day 17 at which AOM was diagnosed and who discontinued the 
study before Day 17 will be excluded from summaries and analyses.  
Summaries and Analyses (see Section 13) 
AOM relapse will be analyzed using logistic regression. A summary table will include 
frequencies and percentages of relapse and a p-value for the treatment group difference. 
12.7 AOM Recurrence 
AOM recurrence will be defined as clinical success at the Day 12 visit and return for an 
interim/sick visit Day 17 through Day 28 (including the Day 28 visit, which can be out-of-
window) with AOM at that visit. Clinical success is defined as in Section 12.6.  
 
AOM recurrence status will be shown in a listing.  
Endpoints 
AOM recurrence will be a secondary endpoint and will be assessed using the subset of the mITT 
population that achieved clinical success at the Day 12 visit. Subjects in this subset who did not 
have an interim/sick visit Day 17 through Day 28 at which AOM was diagnosed and who 
discontinued the study before Day 28 will be excluded from summaries and analyses.  
Summaries and Analyses (see Section 13) 


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Statistical Analysis Plan 
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AOM recurrence will be analyzed using logistic regression. A summary table will include 
frequencies and percentages of recurrence and a p-value for the treatment group difference. 
13. 
STATISTICAL METHODS 
13.1 Logistic Regression 
Logistic regression models will include treatment group as a main effect and the randomization 
stratifiers (age group, daycare attendance) and an appropriate baseline value (if applicable) as 
covariates. Model-based LS means and SEs will be reported for each treatment group, along with 
a p-value for the treatment group comparison. For sparse data, two-sided Fisher’s exact tests will 
be used (ie, with no covariate adjustment). 
13.2 GLM 
GLMs will include treatment group as a main effect and the randomization stratifiers and an 
appropriate baseline value (if applicable) as covariates. Model-based LS means and SEs will be 
reported for each treatment group, along with a p-value for the treatment group comparison.  
Model assumptions will be evaluated using diagnostic tools such as Q-Q and scatter plots of 
residuals, and sensitivity analyses using alternative methods (e.g., rank-based) will be considered 
if there appear to be substantial deviations from model assumptions. Outlier assessment will be 
done using visual inspection (e.g., box-and-whisker plots) and potential outliers will be 
investigated for data entry accuracy and biological consistency. If unexplainable outliers are 
present, a sensitivity analysis may be done excluding the outliers to assess their effect on the 
analysis conclusion. 
13.3 Missing Observations 
For the primary efficacy analysis, multiple imputation will be used for missing observations with 
only treatment group included in the imputation model; ie, the observed within-treatment-group 
Bernoulli distribution of response will be the distribution from which random values are drawn 
to replace missing observations. The number of imputations will be the percentage of subjects 
with missing data, rounded up to an integer. Results from multiple imputations will be combined 
using the Rubin method.8 A complete-case sensitivity analysis will also be done, whereby for 
each endpoint only subjects with complete data are included. For secondary endpoints, only 
complete-case analyses will be done. 
13.4 Multiplicity 
The familywise type 1 error rate for the primary efficacy endpoint family will be 0.05 and will be 
controlled using the Hochberg procedure.9 Specifically, the p-value of the endpoint with the 
highest p-value will be compared against the 0.05 significance level and, if significant, both 
endpoints will be declared significant; if the endpoint with the highest p-value is not significant 
at the 0.05 level, the other endpoint will be tested at the 0.025 significance level. A positive 
treatment effect on efficacy will be concluded if at least one of the two endpoints is significant.  


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Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
14. 
SAFETY MONITORING COMMITTEE 
An SMC will review blinded safety data for all subjects when approximately 25% of enrolled 
subjects have completed Day 12 (Visit 3). Safety data will be evaluated on an ongoing basis to 
ensure it is safe to continue study enrollment and treatment. The composition, responsibilities, 
and meeting schedule of the SMC will be specified in a charter document. 
15. 
SEQUENCE OF PLANNED ANALYSES 
15.1 Final Analysis 
The only planned analysis is the final analysis, which will occur after study-level EOS, all 
clinical data have been entered into the data capture system, AE and concomitant medication 
data have been coded, quality control checks have been completed, all data queries have been 
resolved, protocol deviations have been identified, and the database has been locked. 
16. 
CHANGES FROM THE PROTOCOL 
 
Protocol 
Change 
Primary efficacy analysis to be done using the 
ITT population defined as all randomized 
subjects. 
ITT population replaced by mITT population 
which excludes the first 3 subjects dosed. 
Subjects with missing data at the Day 4 Visit 
will be considered as having bulging TM and 
those with missing data at the Day 12 Visit 
will be considered as having MEE. 
Multiple imputation will be used for missing 
data for the primary efficacy analysis, with a 
complete-case sensitivity analysis added. 
GEE will be used for analyses of repeating 
binary endpoints. 
All binary endpoints will be analyzed separately 
by visit using logistic regression. 
Secondary efficacy endpoints, which included 
“normal tympanogram,” will be statistically 
analyzed. 
Tympanogram findings will not be analyzed 
and will be reported as descriptive statistics 
only. 
Secondary efficacy endpoints will be 
analyzed using the Safety population. 
Complete-case analyses using the mITT 
population will be done for secondary efficacy 
endpoints. 


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Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
REFERENCES 
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), September 1998. 
2. American Statistical Association (ASA). (2018) Ethical Guidelines for Statistical Practice. 
Prepared by the Committee on Professional Ethics, April 2018. 
http://www.amstat.org/ASA/Your-Career/Ethical-Guidelines-for-Statistical-Practice.aspx. 
3. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), November 1995. 
4. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Good Clinical 
Practice (E6), April 1996. 
5. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, General 
Considerations for Clinical Trials (E8), July 1997. 
6. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), September 1998. 
7. Johnson JR, Fitts D. Statistical Analysis Plans: Principles and Practice. Workshop Number 8. 
Presented at the Society for Clinical Trials 2007 Annual Meeting Montreal, Canada Sunday 
May 20, 2007. http://docshare01.docshare.tips/files/9381/93818340.pdf. 
8. Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons, 
1987. 
9. Hochberg Y. A sharper Bonferroni procedure for multiple significance testing. Biometrika 
1988:75;800–2. 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
APPENDIX A:  SCHEDULE OF ACTIVITIES  


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Protocol OP0201-C-006 
Statistical Analysis Plan 
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APPENDIX B: TABLES OF CONTENTS FOR TABLES, FIGURES, AND 
LISTINGS 
 
TABLES 
NUMBER 
TITLE 
POPULATION 
Study Population 
14.1.1 
Subject Disposition 
all randomized 
14.1.2 
Eligibility 
all randomized 
14.1.3 
Reasons for Screen Failure 
Screened excluding 
randomized 
14.1.4 
Protocol Deviations 
all randomized 
14.1.5 
Analysis Populations 
all randomized 
14.1.6 
Baseline Characteristics 
all randomized 
14.1.7.1 
Medical History 
all randomized 
14.1.7.2 
Baseline Symptoms 
all randomized 
14.1.8 
Pre-Treatment Adverse Events 
Screened 
Treatments 
14.1.9.1 
Study Treatment Exposure 
Safety 
14.1.9.2.1 
Study Treatment Compliance 
Safety 
14.1.9.2.2 
Oral Antibiotic Compliance 
Safety 
14.1.10.1 
Prior Medications 
all randomized 
14.1.10.2 
Concomitant Medications 
Safety 
Efficacy Endpoints 
14.2.1.1 
Bulging TM 
mITT 
14.2.1.2 
Bulging TM 
Per Protocol 
14.2.1.3 
Bulging TM 
Complete Case 
14.2.1.4 
Bulging TM and No Recurrence 
mITT 
14.2.1.5 
Bulging TM by age group 
mITT 
14.2.1.6 
Bulging TM by sex 
mITT 
14.2.1.7 
Bulging TM by race 
mITT 
14.2.1.8 
Bulging TM by disease laterality 
mITT 
14.2.1.9 
Bulging TM by history of recurrent AOM 
mITT 
14.2.1.10 
Bulging TM by daycare attendance 
mITT 
14.2.1.11.1 
Bulging TM by study site 
mITT 
14.2.2.1 
MEE 
mITT 
14.2.2.2 
MEE 
Per Protocol 
14.2.2.3 
MEE 
Complete Case 
14.2.2.4 
MEE and No Recurrence 
mITT 
14.2.2.5 
MEE by age group 
mITT 
14.2.2.6 
MEE by sex 
mITT 
14.2.2.7 
MEE by race 
mITT 
14.2.2.8 
MEE by disease laterality  
mITT 
14.2.2.9 
MEE by history of recurrent AOM  
mITT 
14.2.2.10 
MEE by daycare attendance 
mITT 
14.2.2.11.1 
MEE by study site 
mITT 
14.2.3.1 
Tympanogram Shifts from Baseline 
Tympanogram Subset 
14.2.4.1 
AOM-SOS Scale Score – 10-Day Mean  
mITT 
14.2.5.1.1 
AOM Cure 
mITT 


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Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
14.2.5.1.2 
AOM Cure – Sensitivity Analysis 
mITT 
14.2.6.1 
AOM-SOS Response 
mITT 
14.2.7.1 
AOM Treatment Failure, AOM Relapse, AOM Recurrence 
mITT 
Safety Endpoints 
14.3.1.1 
Summary of TEAE Incidence 
Safety 
14.3.1.2.1 
Incidence of TEAEs by System Organ Class (SOC) and Preferred Term (PT) 
Safety 
14.3.1.2.2 
Incidence of TEAEs Related to Study Treatment by SOC and PT 
Safety 
14.3.1.2.3 
Incidence of TEAEs by Severity, by SOC and PT 
Safety 
14.3.1.2.4 
TEAEs by PT in Descending Order of Incidence 
Safety 
14.3.1.3.1 
Incidence of TESAEs by SOC and PT 
Safety 
14.3.1.3.2 
Incidence of TESAEs Related to Study Treatment by SOC and PT 
Safety 
14.3.1.3.3 
TESAEs by PT in Descending Order of Incidence 
Safety 
14.3.1.4 
Non-TEAEs 
Safety 
14.3.9.1 
Vital Signs, Observed Values and Changes from Baseline 
Safety 
14.3.9.2.1 
Physical Exam, Observed 
Safety 
14.3.9.2.2 
Physical Exam, Shifts from Baseline 
Safety 
14.3.9.3.1 
Ear Exam, Observed 
Safety 
14.3.9.3.2 
Ear Exam, Shifts from Baseline 
Safety 
14.3.9.4.1 
Nose and Throat Exam, Observed 
Safety 
14.3.9.4.2 
Nose and Throat Exam, Shifts from Baseline 
Safety 
 
 
 
 


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Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
FIGURES 
NUMBER 
TITLE 
POPULATION 
Exploratory Endpoints 
14.2.1 
Bulging TM 
mITT 
14.2.2 
MEE 
mITT 
14.2.3 
Tympanogram 
mITT 
 
 


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Protocol OP0201-C-006 
Statistical Analysis Plan 
Final, Version 1.0, January 7, 2020   
LISTINGS 
NUMBER 
TITLE 
POPULATION 
Study Population 
16.2.1 
Subject Disposition 
all randomized 
16.2.2.1 
Informed Consent 
Screened 
16.2.2.2 
Eligibility 
all randomized 
16.2.2.3 
Reasons for Screen Failure 
Screened excluding 
randomized 
16.2.2.4 
Protocol Deviations 
all randomized 
16.2.3 
Analysis Populations 
all randomized 
16.2.4.1 
Demographic Characteristics (incl ht/wt/bmi) 
all randomized 
16.2.4.2 
Baseline otitis media risk factors 
all randomized 
16.2.4.3.1 
Medical History 
all randomized 
16.2.4.3.2 
Baseline Symptoms 
all randomized 
16.2.4.4 
Pre-Treatment Adverse Events 
Screened 
Treatments 
16.2.5.1 
Study Treatment Exposure 
Safety 
16.2.5.2.1 
Study Treatment Compliance 
Safety 
16.2.5.2.2 
Oral Antibiotic Compliance 
Safety 
16.2.5.3 
Device Incidents 
Safety 
16.2.5.4 
Device Experience 
Safety 
16.2.5.5 
Prior Medications 
all randomized 
16.2.5.6 
Concomitant Medications 
Safety 
Efficacy Endpoints 
16.2.6.1 
Bulging Tympanic Membrane & MEE 
mITT 
16.2.6.2 
Tympanogram 
mITT 
16.2.6.4.1 
AOM-SOS Scale, Diary 
mITT 
16.2.6.4.2 
AOM-SOS Scale, Clinic 
mITT 
16.2.6.5 
AOM Treatment Failure, Relapse, and Recurrence 
mITT 
Safety Endpoints & Other Clinical Observations/Measurements 
16.2.7.1 
Treatment-Emergent Adverse Events (TEAEs) 
Safety 
14.3.2.1 
Treatment-Emergent Serious Adverse Events (TESAEs) 
Safety 
14.3.2.2 
TEAEs Resulting in Study Treatment Interruption or Dose Reduction 
Safety 
14.3.2.3 
TEAEs Resulting in Study or Study Treatment Discontinuation 
Safety 
14.3.2.4 
TEAEs Resulting in Death 
Safety 
16.2.7.2 
Non-TEAEs 
Safety 
16.2.9.1 
Vital Signs 
Safety 
16.2.9.2 
Physical Examination 
Safety 
16.2.9.3 
Ear Examination 
Safety 
16.2.9.4 
Nose Examination 
Safety 
16.2.9.5 
Throat Examination 
Safety 
16.2.9.6 
Visit Summaries 
Safety 
16.2.9.7 
10-Day Diary Entries 
Safety 
16.2.9.8 
Comments 
all randomized