Conditions: Chronic Rhinosinusitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 223
Healthy volunteers: no

Brief summary:
This is a 24-week randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy and safety of intranasal administration of 186 and 372 μg twice daily (BID) of OPN-375 in subjects with chronic Rhinosinusitis (CRS) without nasal polyps

Detailed description:
The primary objective of this study is to compare the efficacy of intranasal administration of twice-daily doses of 186 and 372 µg of OPN-375 (fluticasone propionate) with placebo in subjects with chronic rhinosinusitis using the following co-primary endpoints:

1. A change from baseline in symptoms as measured by the average morning composite score of nasal congestion, facial pain or pressure sensation, and nasal discharge (anterior and/or posterior) at the end of Week 4.
2. A change from baseline to Week 24/Early Termination (ET) in the average percent of the volume opacified in the ethmoid and maxillary sinuses.

Arms:
arm 1: OPN-375 186 μg BID x 24 Weeks arm 2: OPN-375 372 μg BID x 24 Weeks arm 3: Matching Placebo BID x 24 Weeks

Interventions: intervention 1: OPN-375
Intervention descriptions: intervention 1: OPN-375, BID

Protocol document:
Prot_000.pdf: 
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Page 1 of 81 
Protocol Amendment 4.0/dated 11May2022 FINAL 
CLINICAL STUDY PROTOCOL  
A 24-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter 
Study Evaluating the Efficacy and Safety of Intranasal Administration of 186 and 372 μg of 
OPN-375 Twice a Day (BID) in Subjects with Chronic Rhinosinusitis Without the Presence 
of Nasal Polyps 
 
 
Protocol Number: 
OPN-FLU-CS-3206 
Brief Title: 
Re-Open 2 
Development Phase: 
3b 
IND Number: 
110089 
EudraCT Number 
2019-000648-86 
Sponsor: 
OptiNose US, Inc. 
1020 Stony Hill Road, Suite 300 
Yardley, PA 19067 
Protocol Date: 
Amendment 4.0 dated 11May2022 
STATEMENT OF CONFIDENTIALITY 
This document contains scientific and commercial information proprietary to OptiNose US, Inc. 
that is privileged or confidential and is intended solely for the purpose of this clinical 
investigation. It should be kept secure and its contents should not be disclosed to any third party 
without the prior written consent of OptiNose. 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
VERSION HISTORY 
Version 
Explanation of Change(s) and Reason/Justification 
for Changes 
Date 
0 
Original Protocol 
06 February 2019 
0.1 
Synopsis and Sections 2.2, 3.2.1.2, 7.2, and 9.4.2: Key secondary 
objectives/endpoints at Week 24 for SNOT-22, and performance 
of computed tomography scans should include mention of early 
termination (ET) of subjects; “/ET” added where appropriate 
Synopsis (Primary Efficacy Analysis: Modified for consistency 
with Section 9.3.2.4 of protocol 
Schedule of Study Procedures and Evaluations: Removed row 
with prior medications/procedures/ nondrug therapy history 
(following “medical/surgical history” row; combined with prior 
medications and concomitant medications later in table 
Section 5.1 (last sentence in section): Replaced “OPN-375” with 
“study drug,” as appropriate 
Section 6.3: Typographical error for Study Visit when subjects are 
to receive 3 study treatment kits; corrected from “Visit 6” to 
Visit 5 
Other: Minor editorial changes throughout 
22 February 2019 
1.0 
Title page: Added Brief Title “Re-Open 2” 
Throughout protocol: Replaced “chronic sinusitis” with “chronic 
rhinosinusitis” 
Synopsis: Updated for consistency with protocol 
Synopsis and Section 3.1: updated to include the description of a 
substudy that has been added to evaluate clinical biomarkers to 
characterize the microbiome and cytokine profiles in a subset of 
subjects at specified study centers 
Synopsis and Section 4.1: 
• 
Revised Inclusion Criterion 5 to include “bilateral 
disease on a prior computed tomography (CT) scan 
performed within 14-days of Visit 1” 
• 
Revised Inclusion Criterion 13 regarding cessation of 
applicable steroid treatment from “baseline” visit to 
“screening” visit and removed “oral steroids” to address 
an inconsistency in the protocol. Oral steroids are not 
allowed within 1 month of screening. 
Synopsis and Section 4.2: 
• 
Added to Exclusion Criterion 8: odontogenic sinusitis 
• 
Clarified Exclusion Criterion 17 by adding “eosinophilic 
granulomatosis with polyangiitis” to describe Churg-
Strauss syndrome 
• 
Clarified Exclusion Criterion 18: Revised to include 
“influenza, or SARS-CoV-2 (COVID-19)” to address 
new concerns related to COVID-19 pandemic. 
Synopsis, Section 4.2 (Exclusion Criteria 34), and Section 5.6.3:  
• 
Revised to include “cobicistat” to examples of 
cytochrome P450 3A4 inhibitors 
Schedule of Study Procedures and Evaluations:  
10 July 2020 


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Page 3 of 81 
Protocol Amendment 4.0/dated 11May2022 FINAL 
• 
Added “SARS-CoV-2 Serology Testing” to Visit 6 to 
determine if subject carries the antibodies 
• 
Added abbreviation for “End of Study (EOS)” to be 
consistent in use of terminology 
• 
Updated superscript comments to be consistent with 
protocol 
Schedule of Study Procedures and Evaluations and Section 6.5: 
• 
Added clarification to Visit 6 if subject cannot complete 
EOS CT scan at the Week 24 visit and continues 
treatment due to issues related to COVID-19 pandemic 
or due to any upper respiratory infection. 
Schedule of Study Procedures and Evaluations and Section 
7.4.1: Changed physical examination from “full” to “brief” 
Schedule of Study Procedures and Evaluations and Table 5; 
• 
Removed “on site visit” and “office” to clarify urine 
pregnancy test must be completed at each visit  
• 
Added a requirement for subjects who continue 
treatment past Week 24/Visit 6 to have an additional 
pregnancy test completed upon returning to site. 
• 
Added “Blood Sample for SARS-CoV-2 serology 
testing” to Week 24/Visit 6 to determine if subject 
carries the antibodies 
Sections 2.3, 3.2.1.3, 7.2 (Other Secondary Efficacy 
Assessments)/7.3 (Health Economics): 
• 
Revised the secondary objective relating to the percent 
of sinus volume occupied by disease, from evaluating 
“each” maxillary and ethmoid sinus occupied by disease 
to evaluating the “worst” maxillary and “worst” ethmoid 
sinus 
• 
Added, as part of the Health Economic assessments, the 
impact of treatment on subjects approved for surgery 
who no longer elect to undergo surgery 
Section 5.6.1: 
• 
Removed “no more than” from first sentence for 
clarification 
• 
Corrected an inconsistency in the second sentence that 
subjects must be on a stable dose for at least “3 months” 
before Visit 1 (Screening) with plans to continue use 
throughout the study. 
Section 1.3 Updated language to be more general and not specify 
countries 
Section 3.1, 6.0 and 6.1 
• 
Clarified timeline for CT completion at baseline. 
Section 4.3  
• 
Removed “receives systemic corticosteroids (oral or 
parenteral)” from reasons as subjects will no longer be 
withdrawn from the study per FDA request 
• 
Added “hospitalized with respiratory symptoms due to 
SARS-CoV-2 (COVID-19) to address new concerns 
related to COVID-19 pandemic. 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
Section 5.1  
• 
Included clarification regarding dispensing additional 
study treatment for subjects that cannot complete the 
EOS CT scan at week 24 in IWRS due to issues related 
to COVID-19 pandemic or due to any Upper Respiratory 
Infection. 
Section 6  
• 
Bullet 2 - clarified use of CT scan performed within 14 
days prior to Visit 1 
• 
Bullet 3 - added influenza, SARS CoV-2 (COVID-19) 
and “until EOS CT scan can be completed” 
Section 7.1.1 
• 
Added smoking history data collection for subject 
medical history 
Section 7.4.3 Ocular examinations and Attachment 4 
• 
 “Ophthalmologist” updated to “Examiner” with 
definition to allow for additional options to perform the 
eye exam in the current environment. 
• 
Removed “Slit lamp examination” and ‘LOCS grading”, 
only visual acuity, cataract assessment and IOP values 
will be collected to allow for exam to be done by a 
qualified healthcare provider and providing for 
assessments as requested by FDA.  
Attachment 5: Added to provide details of the substudy. 
List of References 
• 
Added the reference to, “The 16-item inventory of 
depressive symptomatology (QIDS), clinician rating 
(QIDS-C), and self-report (QIDS-SR): A psychometric 
evaluation in patients with chronic major depression.” 
List of Abbreviations and Definitions of Terms has been updated 
as applicable. 
Minor editorial changes have been made throughout the protocol 
as appropriate 
2.0 
The COVID-19 Pandemic has made it very difficult to schedule 
and perform the ocular examinations outlined in the protocol. 
Given the extensive assessment of ocular safety in the previous 
clinical studies with OPN-375 it was deemed appropriate to 
remove the scheduled ocular assessments from this protocol. If 
subjects report visual acuity changes during the study, an ocular 
exam will be performed. 
Details of changes in study protocols 
Synopsis: 
• 
Removed Early Termination (ET) from objectives 
• 
Removed ocular examination from safety objective 
• 
Removed “(intraocular pressure [IOP] at screening of > 
21 mm Hg)” from Exclusion criteria 26  
• 
Clarified Exclusion criteria 28 
• 
Added Exclusion Criterion 36 (have a recent change in 
vision). 
• 
Removed Early Termination (ET) from endpoints 
28 Aug 2020 


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Page 5 of 81 
Protocol Amendment 4.0/dated 11May2022 FINAL 
• 
Added clarification “in ethmoid and maxillary sinuses” 
to co-primary endpoint 
• 
Removed ocular examination from safety endpoints. 
• 
Removed “ET” from Key Secondary Efficacy Analysis 
• 
Updated statistical primary efficacy analysis 
Schedule of Study Procedures and Evaluations: 
• 
Removed ocular examination from procedures and 
assessments. 
• 
Removed superscript “d” explaining previous ocular 
examination schedule. 
• 
Added superscript “j” clarifying SARS-CoV-2 blood 
draw sample 
Section 2.1, 2.2 and 2.3: Removed “ET” from objectives 
Section 2.4: Removed ocular examination from section. 
Section 3.2: Removed Early Termination (ET) from endpoints 
Section 3.2.2: Removed ocular examination from section. 
Section 3.2.1.1: Added clarification “in ethmoid and maxillary 
sinuses” to co-primary endpoint 
Section 4.2: 
• 
Removed “(intraocular pressure [IOP] at screening of > 
21 mm Hg)” from Exclusion criteria 26  
• 
Clarified Exclusion criteria 28 
• 
Added Exclusion Criterion 36 (have a recent change in 
vision) 
Section 4.3: 
• 
Added sentence, “Subjects wishing to withdraw from 
study treatment will be encouraged to continue in the 
study and have all scheduled study procedures 
performed.” 
• 
Updated subject withdrawal reasons 
Section 5.6.1: Clarified use of oxymetazoline or other topical 
nasal decongestant 
Section 5.6.2, 6.1 and 6.2: Added “for CRS symptoms” to 
clarify use of rescue medication 
Section 6: 
• 
Removed ocular examination from section. 
• 
Clarified when baseline CT scan should be performed. 
Section 6.5: 
• 
Removed verbiage around subjects who discontinue 
study drug early during the DB treatment phase. 
Section 7.4: Removed ocular examination from section. 
Section 7.4.3: Updated ocular examination performance to be 
removed per explanation above. 
Section 8.1: Added, “discontinuation from the study treatment or 
discontinuation from the study” to what may be considered AEs 
Section 9.2.1: Replaced modified Intent to Treat Analysis Set 
(mITT) with “Intent-to-treat Analysis Set” section 
Section 9.2.3: Replaced “Efficacy Analysis” with “Full Analysis 
Set (FAS)” section 
Section 9.3: Clarifications to the Estimands, handling of missing 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
data, and statistical analysis addressing FDA suggestions have 
been added 
Section 9.6: Clarifications to the Type 1 Error Control for 
Multiplicity have been added.  
Section 9.7.1: Added verbiage “study participation and/or study 
treatment discontinuation” to be more specific. 
Section 9.7.2: Removed ocular examination from section. 
Attachment 4: The eye examination worksheet has been 
removed 
Minor editorial changes have been made throughout the protocol 
as appropriate. 
3.0 
The Key Secondary Objectives and the Statistical Analysis 
Section are amended. The SF-36 Mental and Physical subscale 
analyses are moved to Secondary Objectives. Additional key 
secondary objectives evaluating pooled data from this study and 
an ongoing similarly designed Phase 3 study (Study OPN-FLU-
CS-3205) have been added. These analyses will be performed 
once both studies have completed. In addition, other updates to 
the Statistical section of this protocol have been made including 
to the sample size section and a small adjustment to the study 
power assessment based on interim analysis results from Study 
OPN-FLU-CS-3205.  
Details of Changes 
Synopsis: 
• 
Study design updated to remove microbiome and 
cytokine substudy 
• 
SF-36 MCS and PCS was moved from Key Secondary 
Variables to Secondary Variables 
• 
Insertion of Key Secondary Variables from a pooled 
analysis of studies OPN-FLU-CS-3205 and OPN-FLU-
CS-3206 
• 
Updated key secondary endpoints to reflect changes to 
key secondary objectives 
• 
Updated the statistical section to reflect the changes in 
sample size and key secondary variables 
Section 2.2: Key Secondary Objectives 
• 
Removal of SF-36 MCS and PCS from key secondary 
objectives 
• 
Addition of key secondary objectives from pooled 
analyses for changes in SNOT-22 in subjects entering 
study using an intranasal steroid, changes in the Global 
Pittsburgh Sleep Index score, and moving the 
assessments of acute exacerbations from study 3205 
alone to a pooled analysis 
Section 2.3: Other Secondary Objectives 
• 
Updated secondary objectives where analyses on sub-
groups (subjects with and without a history of surgery) 
will now be performed 
Section 3.2.1.2: Key Secondary Endpoints 
15 October 2021 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
• 
This section was updated to reflect the changes to the 
Key Secondary Outcome variables to be consistent with 
the Key Secondary Objectives 
Section 3.2.1.3: Other Secondary Endpoints 
• 
This section was updated to reflect changes to the 
secondary endpoints to be consistent with the other 
secondary objectives 
Section 3.3: Method of Treatment Assignment or Randomization 
• 
Section was updated to reflect the new sample size 
Section 9.1: Sample Size Determination 
• 
Sample size calculations and background was updated to 
reflect changes consistent in the protocol. 
Section 9.2.3: Full Analysis Set (FAS) 
• 
Full analysis set clarifying text was added  
Section 9.2.4: Per Protocol Analysis Set (PPS) 
• 
Per-protocol analysis set was added to clarify additional 
analyses to be completed  
Section 9.3.2: Potential Intercurrent Events 
• 
Added clarifying text for the intercurrent events were 
added 
Section 9.3.3: Primary Estimand 
• 
This section was updated to reflect clarification to the 
intercurrent events consistent with previous sections of 
the protocol 
Section 9.3.4: Estimator and Estimation Method – Primary 
Analysis 
• 
Clarifying text for the treatment policy estimand was 
added to be consistent with changes made to the 
statistical analysis 
Section 9.3.5: Supplementary Analysis 
• 
Clarifying text for the intercurrent events were added to 
this section 
Section 9.4: Sensitivity Analyses  
• 
Section was updated to clarify sensitivity analyses being 
completed on the primary estimand and APOV co-
primary endpoints 
• 
Clarifying text around the statistical analysis added 
Section 9.4: Key Secondary Efficacy Analyses 
• 
Updated section to match key secondary analyses added 
to the protocol 
Section 9.6: Other Secondary Efficacy Analyses 
• 
Updated section to match additional secondary analyses 
added to the protocol 
Section 9.7: Subgroup Analyses 
• 
Section added to clarify sub-group analyses that will be 
completed in the statistical analysis 
Section 9.8: Type I Error Multiplicity 
• 
Additional clarifying text was added to explain α if 
unblinded interim analysis does not occur 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
Section 9.8.2: Type I Error Control for Key Secondary 
Endpoints 
• 
Updated key secondary endpoints made in Section 2.2 
were updated in this section 
Section 9.8.3: Key Secondary Endpoints from Pooled Data 
Studies OPN-FLU-CS-3205 and OPN-FLU-CS-3206 
• 
Added Section 9.8.3 to reflect changes made to the 
pooled key secondary analyses in Section 2.2 
Section 9.10: Interim Analysis 
• 
Clarifying text was added to explain planned interim 
analysis 
Section 12.4: Future Use of CT Scans 
• 
Description of future potential use of data for 
commercial purposes have been included in the protocol 
Attachment 4 removed because study design was updated to 
remove microbiome and cytokine substudy 
Minor editorial changes have been made throughout the protocol 
as appropriate. 
4.0 
The key secondary objectives/endpoints and the statistical 
analysis are amended. Key secondary objectives evaluating 
Study OPN-FLU-CS-3206 have been added. Key secondary 
objectives evaluating pooled data from this study and a 
completed study, similarly designed Phase 3 study (Study OPN-
FLU-CS-3205), have also been added, as well as pooled 
analyses evaluating the non-polyp population. These analyses 
will be performed once both studies have completed. Other 
updates to the statistical section of have been based on the 
updates to the objectives and endpoints. 
Detailed List of Changes 
Synopsis 
• 
Removed SNOT-22 total score from key secondary 
objectives 
• 
Removed change in SNOT-22 total score in subjects on 
previous INS for treatment of CRS and change in sleep 
quality using the Global Pittsburgh Sleep Quality Index from 
baseline to week 24/ET using a pooled study population 
from Study OPN-FLU-CS-3205 and OPN-FLU-CS-3206 
from key secondary objectives 
o Replaced with change from baseline to Week 4 on 
CSNS total score in subjects previously on an INS 
for treatment of CRS within 30 days of Visit 1 and 
frequency of acute exacerbations of CRS over the 
24-week treatment period 
• 
Addition of pooled nonpolyp population analysis assessing 
frequency of acute exacerbations 
• 
Addition of assessing 4 separate cardinal CRS symptoms 
and time to first acute exacerbation of CRS 
• 
Updated key secondary endpoints to reflect updated key 
secondary objectives 
11May2022 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
• 
Updated statistical analysis: primary efficacy and key 
secondary analysis were updated to reflect updated key 
secondary objectives/endpoints 
Section 2.2 Key Secondary Objectives 
• 
Removed SNOT-22 total score  
• 
Removed change in SNOT-22 total score in subjects on 
previous INS for treatment of CRS and change in sleep 
quality using the Global Pittsburgh Sleep Quality Index from 
baseline to week 24/ET using a pooled study population 
from Study OPN-FLU-CS-3205 and OPN-FLU-CS-3206 
from key secondary objectives 
o Replaced with change from baseline to Week 4 on 
CSNS total score in subjects previously on an INS 
for treatment of CRS within 30 days of Visit 1 and 
frequency of acute exacerbations of CRS over the 
24-week treatment period 
• 
Addition of pooled nonpolyp population analysis assessing 
frequency of acute exacerbations 
• 
Addition of assessing 4 separate cardinal CRS symptoms 
and time to first acute exacerbation of CRS 
Section 2.3 Other Secondary Objectives 
• 
Updated where analyses on sub-groups (subjects with and 
without a history of surgery) will now be performed 
• 
Updated other secondary objectives to include previous key 
secondary objectives listed 
Section 3.2.1.2 Key Secondary Endpoints 
• 
Updated key secondary endpoints to reflect updated key 
secondary objectives 
Section 3.2.1.3 Other Secondary Endpoints 
• 
Updated other secondary endpoints to include previous key 
secondary objectives 
Section 9.2.4 Per-Protocol Analysis Set (PPS) 
• 
Per-protocol analysis set definition was updated 
Section 9.3.4 Estimator and Estimation Method – Primary 
Analysis 
• 
Updated description of time for CSNS from week to days 
Section 9.4.2 Observed Case Analysis Section was added 
Section 9.5 Key Secondary Efficacy Analyses 
• 
Clarified analyses completed for updated key secondary 
endpoints 
Section 9.6 Other Secondary Efficacy Analyses 
• 
Clarified analyses completed for secondary endpoints 
Section 9.7 Subgroup Analyses 
• 
Added stratification groups and planned analyses 
Section 9.8 Type I Error Control for Multiplicity 
• 
Updated section to reflect updates to the key secondary 
endpoints 
Minor editorial changes have been made throughout the protocol 
as appropriate. 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
Signature Page for Sponsor: 
 
Clinical Study Protocol No. OPN-FLU-CS-3206 
 
Title: A 24-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter 
Study Evaluating the Efficacy and Safety of Intranasal Administration of 186 and 372 μg of 
OPN-375 Twice a Day (BID) in Subjects with Chronic Rhinosinusitis, Without the Presence of 
Nasal Polyps 
 
 
The study will be conducted in compliance with the clinical study protocol, international good 
clinical practice principles (International Conference on Harmonization [ICH]-Good Clinical 
Practice [GCP]), and regulatory authority requirements. 
 
Approved by the following: 
 
 
 
________________________________________________________________________ 
John Messina, Sr. Vice President Clinical Research & Medical Affairs 
 
 
 
_________________________________________________________________________ 
Jennifer Carothers, Vice President Global Clinical Operations & Outsourcing 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
Signature Page for Principal Investigator: 
 
Protocol No. OPN-FLU-CS-3206 
 
Title: A 24-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter 
Study Evaluating the Efficacy and Safety of Intranasal Administration of 186 and 372 μg of 
OPN-375 Twice a Day (BID) in Subjects with Chronic Rhinosinusitis, Without the Presence of 
Nasal Polyps 
 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol and in accordance with the accepted version of the Declaration of Helsinki. 
 
 
Principal Investigator Name: 
(Printed) 
 Signature:  
 
Date: 
 
 
 
 
 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
SYNOPSIS 
TITLE OF STUDY: A 24-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter 
Study Evaluating the Efficacy and Safety of Intranasal Administration of 186 and 372 μg of OPN-375 Twice a 
Day (BID) in Subjects with Chronic Rhinosinusitis, Without the Presence of Nasal Polyps 
SPONSOR: OptiNose US, Inc. 
DEVELOPMENT PHASE: 3b 
IND Number: 110089 
EudraCT Number: 2019-000648-86  
STUDY OBJECTIVES:  
Primary Objectives: 
The primary objective of this study is to compare the efficacy of intranasal administration of twice-daily doses of 
186 and 372 μg of OPN-375 (fluticasone propionate) with placebo in subjects with chronic rhinosinusitis (CRS) 
using the following co-primary endpoints:  
• 
change from baseline in symptoms as measured by a composite score of nasal symptoms (CSNS): 
congestion, facial pain or pressure sensation, and nasal discharge (anterior and/or posterior) at the end of 
Week 4 
and 
• 
change from baseline to Week 24/ET in the average percent of opacified volume (APOV) in the ethmoid and 
maxillary sinuses 
Key Secondary Objectives:  
The following key secondary objectives will compare the efficacy of twice daily doses of 186 and 372 µg of 
OPN-375 with placebo by pooling the data in subjects from studies OPN-FLU-CS-3206 and OPN-FLU-CS-3205, 
which is a separate study being conducted in parallel to this study.  
• 
change from baseline to Week 4 on CSNS (AM, Instantaneous) score in subjects who were symptomatic at 
trial entry despite reported use of an intranasal steroid for treatment of CRS within 30 days of Visit 1  
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening of 
symptoms that requires an escalation of treatment 
The following key secondary objective will compare the efficacy of twice daily doses of 186 and 372 µg of OPN-
375 with placebo by pooling the data in subjects with CRS without nasal polyps, from studies OPN-FLU-CS-
3206 and OPN-FLU-CS-3205, which is a separate study being conducted in parallel to this study.  
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening of 
symptoms that requires an escalation of treatment 
The following key secondary objectives of this study will compare the efficacy twice-daily doses of 186 and 372 
μg of OPN-375 with placebo on:  
• 
change from baseline to the end of Week 4 in four separate cardinal CRS symptoms, as measured by a CSNS 
(AM, Instantaneous): congestion, facial pain or pressure sensation, nasal discharge (anterior and/or 
posterior), and sense of smell 
• 
time to first acute exacerbation of CRS, defined as a worsening of symptoms that requires escalation of 
treatment 
Safety Objective:  
• 
to evaluate the safety of OPN-375 by monitoring adverse events (AEs) throughout the study; results of nasal 
examination, vital signs measurements (ie, blood pressure, pulse), and weight; and monitoring concomitant 
medication usage 
STUDY DESIGN: 24-week randomized, double-blind, placebo-controlled, parallel-group, multicenter study to 
evaluate the efficacy and safety of intranasal administration of 186 and 372 μg of OPN-375 BID in subjects with 
CRS without nasal polyps. 
STUDY POPULATION: Approximately 210 subjects will be randomly assigned to receive OPN-375 186 μg or 
372 μg, or placebo (70 subjects in each treatment group); subjects will be randomized using a 1:1:1 ratio. 
DIAGNOSIS AND MAIN CRITERIA FOR ENROLLMENT:  
Potential subjects must meet the following criteria to enter this study: 
1. men or women aged 18 years and older at baseline visit 
2. women of child-bearing potential must be abstinent, or if sexually active,  


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Protocol Amendment 4.0/dated 11May2022 FINAL 
a. 
be practicing an effective method of birth control (eg, prescription oral contraceptives, contraceptive 
injections, contraceptive patch, intrauterine device, double-barrier method [eg, condoms, diaphragm, 
or cervical cap with spermicidal foam, cream, or gel], or male partner sterilization) before entry and 
throughout the study, or 
b. be surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise 
be incapable of pregnancy), or 
c. 
be postmenopausal (amenorrhea for at least 1 year) 
3. women of child-bearing potential must have a negative urine pregnancy test at Visit 1 (Screening) 
4. must have a history of CRS and be currently experiencing 2 or more of the following symptoms, 1 of which 
has to be either nasal congestion or nasal discharge (anterior and/or posterior nasal discharge) for equal to or 
greater than 12 weeks:  
• 
nasal congestion  
• 
nasal discharge (anterior and/or posterior nasal discharge)  
• 
facial pain or pressure 
• 
reduction or loss of smell 
5. endoscopic evidence of nasal mucosal disease, with edema or purulent discharge; or polyps/polypoid tissue 
<Grade 1 in middle meatus, bilaterally, or presence of bilateral disease on a prior computed tomography (CT) 
scan performed within 14 days of Visit 1 
6. must have confirmatory evidence via a CT scan of bilateral sinus disease (have at least 1 sinus on each side of 
nose with a Lund-Mackay score of ≥1) 
7. baseline CT scan must show a combined ≥25% opacification of the ethmoid sinuses and ≥25% opacification 
of at least 1 maxillary sinus 
8. must have at least moderate symptoms (as defined in protocol) of nasal congestion as reported by the subject, 
on average, for the 7-day period preceding Visit 1 (Screening) run-in 
9. must have an average morning score of at least 1.5 for congestion on the Nasal Symptom Scale (as defined in 
protocol) recorded on the subject diary over a 7-day period during the first 14 days of the -single-blind run-in 
period 
10. must demonstrate an ability to correctly complete the daily diary during the run-in period to be eligible for 
randomization 
11. subjects with comorbid asthma or chronic obstructive pulmonary disorder (COPD) must be stable with no 
exacerbations (eg, no emergency room visits, hospitalizations, or oral or parenteral steroid use) within the 
3 months before Visit 1 (Screening). Inhaled corticosteroid use must be limited to stable doses of no more than 
1,000 μg/day of beclomethasone (or equivalent) for at least 3 months before Visit 1 (Screening) with plans to 
continue use throughout the study. 
12. subjects with aspirin-exacerbated respiratory disease, who have undergone aspirin desensitization and are 
receiving daily aspirin therapy, must be receiving therapy for at least 6 months prior to Visit 1 
13. must be able to cease treatment with intranasal steroids, inhaled corticosteroids (except permitted doses listed 
above for asthma and COPD) at the screening visit 
14. must be able to cease treatment with oral and nasal decongestants and antihistamines at Visit 1 (Screening) 
15. must be able to use the exhalation delivery system (EDS) correctly; all subjects will be required to demonstrate 
correct use with the practice EDS at Visit 1 (Screening) 
16. must be capable, in the opinion of the investigator, of providing informed consent to participate in the study. 
Subjects must sign an informed consent document indicating that they understand the purpose of and 
procedures required for the study and are willing to participate in the study. 
 
Potential subjects who meet any of the following criteria will be excluded from entering this study: 
17. women who are pregnant or lactating 
18. inability to have each nasal cavity examined for any reason, including nasal septum deviation 
19. inability to achieve bilateral nasal airflow 
20. is currently taking XHANCE® 
21. have previously used XHANCE for more than 1 month and did not achieve an adequate symptomatic response  
22. the nasal/sinus anatomy prevents the accurate assessment of sinus volume via CT scan 
23. history of sinus or nasal surgery within 6 months before Visit 1 or has not healed from a prior sinus or nasal 
surgery 


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24. have current evidence of odontogenic sinusitis, sinus mucocele (the affected sinus is completely opacified and 
either the margins are expanded and/or thinned OR there are areas of complete bone resorption resulting in 
bony defect and extension of the “mass” into adjacent tissues), evidence of allergic fungal sinusitis, or evidence 
of complicated sinus disease (including, but not limited to, extension of inflammation outside of the sinuses 
and nasal cavity) 
25. have a paranasal sinus or nasal tumor 
26. have polyp grade ≥1 (polyp that is free on 5 sides and has a stalk) on either side of the nose as determined by 
the nasoendoscopy at screening 
27. have a nasal septum perforation 
28. have had more than 1 episode of epistaxis with frank bleeding in the month before Visit 1 (Screening)  
29. have evidence of significant mucosal injury, ulceration (eg, exposed cartilage) on Visit 1 (Screening) nasal 
examination/nasoendoscopy 
30. have current, ongoing rhinitis medicamentosa (rebound rhinitis) 
31. have significant oral structural abnormalities (eg, a cleft palate) 
32. have a diagnosis of cystic fibrosis 
33. history of eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) or dyskinetic ciliary 
syndromes 
34. symptom resolution or last dose of antibiotics for purulent nasal infection, acute sinusitis, upper respiratory 
tract infection, influenza, or SARS-CoV-2 (COVID-19) has not occurred before Visit 1 or was less than 
4 weeks before the CT scan. Potential subjects presenting with any of these infections may be rescreened 
4 weeks after symptom resolution. 
35. planned sinonasal surgery during the period of the study 
36. allergy, hypersensitivity, or contraindication to corticosteroids or steroids 
37. has used oral steroids in the past for treatment of CRS and did not experience any relief of symptoms 
38. has a steroid eluting sinus stent still in place within 30 days of Visit 1 
39. allergy or hypersensitivity to any excipients in study drug 
40. exposure to any glucocorticoid treatment with potential for systemic effects (eg, oral, parenteral, intra-articular, 
or epidural steroids, high dose topical steroids) within 1 month before Visit 1 (Screening); except as noted in 
inclusion criteria for subjects with comorbid asthma or COPD 
41. have nasal candidiasis 
42. history or current diagnosis of any form of glaucoma or ocular hypertension 
43. history of IOP elevation on any form of steroid therapy 
44. history or current diagnosis of the presence (in either eye) of a cataract unless both natural intraocular lenses 
have been removed 
45. history of immunodeficiency 
46. any serious or unstable concurrent disease, psychiatric disorder, or any significant condition that, in the opinion 
of the investigator could confound the results of the study or could interfere with the subject's participation or 
compliance in the study 
47. have a positive drug screen or a recent (within 1 year of Visit 1 [Screening]) history of drug or alcohol abuse, 
or dependence that, in the opinion of the investigator could interfere with the subject's participation or 
compliance in the study 
48. have participated in an investigational drug clinical trial within 30 days of Visit 1 (Screening) 
49. have received mepolizumab (Nucala®), reslizumab (Cinquair®), dupilumab (Dupixent®), omalizumab 
(Xolair®), or benralizumab (Fasenra™) within 6 months of Visit 1 (Screening) 
50. is using strong cytochrome P450 3A4 (CYP3A4) inhibitor (eg, ritonavir, atazanavir, clarithromycin, indinavir, 
itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, lopinavir, 
voriconazole, cobicistat) 
51. is an employee of the investigator or study center, with direct involvement in the proposed study or other studies 
under the direction of that investigator or study center, or is a family member of the employee or the investigator 
52. patients who report unexplained worsening of vision within the past 3 months (e.g. difficulty reading or seeing 
traffic signs from a distance.) A diagnosis of presbyopia established by an eye doctor is not exclusionary. 


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INVESTIGATIONAL PRODUCT, DOSE AND MODE OF ADMINISTRATION: Twice daily doses of 186 
and 372 μg of OPN-375. Subjects will be instructed to administer 2 sprays per nostril approximately every 12 
hours for 24 weeks. The active treatment will contain a formulation of fluticasone propionate that delivers 93 µg 
per spray. 
REFERENCE THERAPY, DOSE, AND METHOD OF ADMINISTRATION: Placebo twice daily delivered 
intranasally by the EDS device for the 7- to up to 21-day single-blind placebo run-in period and the 24-week 
double-blind treatment phase. 
ASSESSMENTS: 
Efficacy Assessments: During the double-blind phase, electronic diaries will be completed twice daily by the 
subject to capture daily nasal symptoms (ie, symptom scores for nasal congestion, nasal discharge [anterior 
and/or posterior], facial pain or pressure sensation, and sense of smell), and use of approved rescue medication 
after the Week 4 visit to Week 12. Subject-completed questionnaires will be used to measure the symptoms and 
social/emotional consequences of the subject’s nasal disorder (SNOT-22), health-related quality of life 
(EuroQol-5 D [EQ-5D] SF-36v2, and Short Form-6 dimension [SF-6D]), sleep quality and disturbances 
(Pittsburgh Sleep Quality Index [PSQI]), depressive symptoms (Quick Inventory of Depressive Symptomatology 
[QIDS]), work productivity, and objective smell test (Smell Identification Test [SIT]). Subjects will assess their 
global impression of change since starting the study drug using the Patient Global Impression of Change (PGIC) 
scale. Health economic information related to CRS will also be collected using the Health and Work Performance 
Questionnaire (HPQ). Objective changes in disease severity will be assessed via sinus CT scan. 
Safety Assessments: Safety will be assessed by monitoring of AEs throughout the study, nasal examination, vital 
signs measurements (ie, blood pressure, pulse), weight, and through collection of information for concomitant 
medications. 
ENDPOINTS: 
Efficacy 
Primary:  
Co-Primary Endpoints: 
• 
change from baseline to the end of Week 4 in average instantaneous morning (AM) scores (evaluation of 
symptom severity immediately preceding the time of scoring) of: 
o 
nasal congestion  
o 
nasal discharge (anterior and/or posterior) 
o 
facial pain/pressure sensation 
The baseline CSNS is the average of the total instantaneous AM scores over the last 7 days of the single 
blind run-in period, and at the end of Week 4, scores are averaged over 7 days before Week 4. 
• 
change from baseline to Week 24 in the APOV in the ethmoid and maxillary sinuses 
Key Secondary Endpoints: 
• 
change from baseline to Week 4 on CSNS score (AM, Instantaneous) in subjects who were symptomatic at 
trial entry despite reported use of an intranasal steroid for treatment of CRS within 30 days of Visit 1 in 
subjects from studies OPN-FLU-CS-3206 and OPN-FLU-CS-3205 (pooled data) 
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening of 
symptoms that requires an escalation of treatment, in subjects from studies OPN-FLU-CS-3206 and OPN-
FLU-CS-3205 (pooled data) 
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening of 
symptoms that requires an escalation of treatment in subjects with CRS without NP, from studies OPN-FLU-
CS-3206 and OPN-FLU-CS-3205 (pooled data) 
• 
change from baseline to the end of Week 4 in four separate cardinal CRS symptoms, as measured by CSNS 
(AM, Instantaneous): congestion, facial pain or pressure sensation, nasal discharge (anterior and/or 
posterior), and sense of smell for 3206 alone 
• 
time to first acute exacerbation of CRS, defined as a worsening of symptoms that requires escalation of 
treatment for 3206 alone 
Safety Endpoints: 
• 
monitoring AEs throughout the study; results of nasal examination, vital signs measurements (ie, blood 
pressure, pulse), and weight; and monitoring concomitant medication usage 
DURATION OF THE STUDY:  
The duration of each subject’s enrollment is expected to be approximately 26 weeks. 
STATISTICAL ANALYSIS:  


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Sample Size Determination: Sample size requirements were based on a previous Phase 3 studies of OPN-375 in 
subjects with nasal polyposis and data from a study evaluating the change in maxillary and ethmoid opacification 
in CRS patients treated with an intramuscular dose of triamcinolone. Based on the results for changes from 
baseline in morning symptoms among subjects with nasal polyps in the previous studies conducted with OPN-
375, a sample of 70 subjects per group (210 total subjects) is sufficient to detect a 0.9 scale difference in morning 
symptoms score between treatments (OPN-375 vs placebo) using a 2-sided test at the 5% significance level with 
88% power, and assuming a standard deviation (SD) of 1.7. This sample size is also adequate to detect a 9% 
difference between treatment groups in average percent opacification using a 2-sided test at the 5% significance 
level with 88% power, and assuming a SD of 17%.  
 
Primary Efficacy Analysis: For the co-primary endpoint CSNS, the estimator is the mean difference between 
treatments (active versus placebo) in change from baseline to the end of Week 4 in the 7-day average total CSNS 
(instantaneous AM). Estimation is based on a mixed model for repeated measures (MMRM), where changes from 
baseline to Week 2 and Week 4 in the 7-day average total CSNS (instantaneous AM), respectively, are the 
repeated measures, including categorical effects for previous sinus surgery (Y,N), treatment (OPN-375 186 µg, 
OPN-375 372 µg, placebo), week (2, 4) treatment-by-week interaction, and the continuous covariate baseline 7-
day average total CSNS (instantaneous AM) with baseline-by-week interaction. For the co-primary endpoint 
APOV, the estimator is the mean difference between treatments (active versus placebo) in the change from 
baseline to Week 24/ET APOV. Estimation is based on an ANCOVA model including categorical effects for 
previous sinus surgery (Y,N), treatment (OPN-375 186 µg, OPN-375 372 µg, placebo), and baseline APOV. 
 
Key Secondary Efficacy Analysis: 
Change from baseline to Week 4 on CSNS score in subjects who were symptomatic at trial entry despite reported 
use of an intranasal steroid for treatment of CRS within 30 days of Visit 1 will be analyzed using the same 
MMRM model described for the co-primary endpoint CSNS, and the model will include a categorical effect term 
for protocol (OPN-FLU-CS-3205, OPN-FLU-CS-3206). The same model will be used for the analysis of CSNS 
component scores and sense of smell in the CRS without nasal polyps population. 
The frequency of acute sinus exacerbations over 24 weeks will be compared between OPN-375 dose groups and 
placebo using generalized linear model (GLM) for data from the negative binomial distribution that is commonly 
referred to as the negative binomial (NB) regression model. The NB model will include the same model terms as 
the primary models; in additional, the model will include a categorical effect for protocol (OPN-FLU-CS-3205, 
OPN-FLU-CS-3206), and the logarithm of follow-up time as an offset variable. The same model will be used for 
the pooled analysis of the frequency of acute sinus exacerbations over 24 weeks in the CRS without nasal polyps 
population. 
 
The analysis of the following key secondary endpoints are based on the data from Study OPN-FLU-CS-3206 
only:  
• 
change from baseline to the end of Week 4 in four separate cardinal CRS symptoms, as measured by CSNS 
(AM, Instantaneous): congestion, facial pain or pressure sensation, nasal discharge (anterior and/or 
posterior), and sense of smell will be analyzed using the same MMRM model described above. 
• 
The Kaplan-Meier method and log-rank test will be used to estimate and compare the distributions of time to 
first acute CRS exacerbation between each OPN-375 dose and placebo. 
 
Safety Analysis: 
All safety summaries will be descriptive; no statistical inference procedures will be applied. All safety summaries 
will be presented by OPN-375 dose level (186 μg and 372 μg) and total OPN-375, and placebo. 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS 
Period 
Pretreatment 
(Screening/ 
Run-in) 
Double-Blind Treatment 
Visit 
1 
2 
3 
4 
5 
Subject Contact 
6** 
Procedures and assessments 
Single-Blind 
Placebo Run-in 
(7 up to 21 days) 
Baseline 
(Randomization) 
Day 1 
Week 4a 
±7 days 
Week 8a 
±7 days 
Week 12a 
±7 days 
Week 16 
±7 days 
Week 20 
±7 days 
Week 24a/ET 
±7 days 
Informed consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical/surgical/smoking history 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Confirm ability to use EDSb 
X 
 
 
 
 
 
 
 
Serum chemistry, hematology, 
urinalysis 
X 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
Blood Sample for SARS-CoV-2 
Serology Testingj 
 
 
 
 
 
 
 
X 
Brief physical examination 
X 
 
 
 
 
 
 
 
Urine pregnancy testc 
X 
X 
X 
X 
X 
 
 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
 
 
X 
Nasal and sinus endoscopic 
assessment 
X 
 
 
 
 
 
 
 
CRS treatment and history 
X 
 
 
 
 
 
 
 
Nasal examinationd 
X 
 
 
 
 
 
 
X 
CT with Lund-Mackay scoring 
Xe 
 
 
 
 
 
 
Xf 
Exacerbation assessment 
 
 
X 
X 
X 
X 
X 
X 
Surgical intervention assessment 
 
X 
 
 
 
 
 
X 
SNOT-22 
 
X 
X 
X 
X 
 
 
X 
EQ-5D 
 
X 
 
 
 
 
 
X 
SF-36v2 
 
X 
 
 
 
 
 
X 
PSQI 
 
X 
 
 
X 
 
 
X 
QIDS 
 
X 
 
 
 
 
 
X 
HPQ 
 
X 
X 
X 
X 
 
 
X 
SIT 
 
X 
 
 
 
 
 
X 
PGIC 
 
 
X 
 
 
 
 
X 
Dispense/collect study drug 
(OPN-375) 
Xg 
X 
X 
X 
X 
 
 
X 
Review proper use of EDS  
X 
X 
X 
X 
X 
 
 
 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
Period 
Pretreatment 
(Screening/ 
Run-in) 
Double-Blind Treatment 
Visit 
1 
2 
3 
4 
5 
Subject Contact 
6** 
Procedures and assessments 
Single-Blind 
Placebo Run-in 
(7 up to 21 days) 
Baseline 
(Randomization) 
Day 1 
Week 4a 
±7 days 
Week 8a 
±7 days 
Week 12a 
±7 days 
Week 16 
±7 days 
Week 20 
±7 days 
Week 24a/ET 
±7 days 
Treatment compliance  
 
X 
X 
X 
X 
X 
X 
X 
Provide/collect subject diary 
X 
 
 
 
X 
 
 
 
Review subject’s diary entries 
 
X 
X 
X 
X 
 
 
 
Contact IWRSh 
X 
X 
X 
X 
X 
 
 
X 
AE collectioni 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medication/procedures/nondrug 
therapy 
X 
X 
X 
X 
X 
X 
X 
X 
Contact with subject 
 
 
 
 
 
X 
X 
 
AE=adverse event; CRF=case report form; DB=double-blind; EDS=Exhalation Delivery System; EOS=End of Study; ET=early termination; HPQ=Health and 
Work Performance Questionnaire; IWRS=interactive web response system; PGIC=Patient Global Impression of Change; EQ-5D=EuroQol-5; SF-36v2=36-Item 
Short Form Health Survey version 2; SNOT-22=Sinonasal Outcome Test – 22; PSQI = Pittsburgh Sleep Quality Index; QIDS = Quick Inventory of Depressive 
Symptomatology, SIT = Smell Identification Test. 
**If subject cannot complete EOS CT scan at the Week 24 visit, subject should continue treatment until an EOS CT scan can be completed. If subject continues 
treatment; 
• 
Complete Subject Contacts approximately every 4 weeks to assess safety until subject can complete the EOS CT scan  
• 
When EOS CT scan has been completed and subject returns to study site, perform additional SNOT-22, and urine pregnancy test (women of 
childbearing potential only) 
a All visits up to Visit 6 (Week 24) should be scheduled based on the date of the Day 1 visit. If necessary, visits may be performed within the time window 
shown; however, subsequent visits should be scheduled based on the date of the Day 1 visit. 
b The assignment of a kit number for the demonstrator model EDS is not performed by IWRS, rather, the study staff will dispense a demonstrator model EDS kit 
and record the kit number in the drug dispensing log. This practice EDS is only used at the site at Visit 1 (Screening) and is not to be sent home with the 
subject. 
c Women of child-bearing potential only; urine pregnancy tests will be performed at each visit, not including subject contacts. Subjects continuing treatment past 
Week 24/Visit 6 will need an additional pregnancy test completed upon returning to site. 
d Nasoendoscopy will be performed using a rigid or flexible endoscope. The examiner must be able to visualize the middle meatus with the scope. 
Decongestants and/or local anesthetics may be used for the nasoendoscopic procedure. 
e The CT scan should be performed after diary eligibility is confirmed and prior to Day 21 of the screening run-in period. 
f For the Week 24 study visit, the CT examination should be performed prior to the on-site visit. 
g Demonstrator model EDS kit (see footnote b) and single-blind placebo dispensation only. 
h At Visit 1 (Screening), the IWRS will be contacted to obtain the subject ID number, the identifier for the single-blind kit to be dispensed and to track 
enrollment. IWRS will be contacted at Visit 2 to randomly assign subjects to treatment. At Visit 2 through – Visit 5, IWRS will be used to assign the study 


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Page 19 of 81 
Protocol Amendment 4.0/dated 11May2022 FINAL 
drug kit(s) to be dispensed. If a subject cannot complete the EOS CT scan at Visit 6 (Week 24), study staff should not complete Visit 6 in IWRS. Subjects 
should continue study treatment until an EOS CT scan can be completed. Study staff will dispense additional study medication via the “Unscheduled Visit’ 
functionality in IWRS. IWRS will be contacted for each ‘Unscheduled Visit,’ at which time one treatment kit will be dispensed. 
i The period of observation for collection of AEs extends from the time the subject gives informed consent until completion of the double-blind treatment period 
or an early termination visit. Serious adverse events will be reported through 30 days after the last dose of study drug administration. 
j Blood sample for SARS-CoV-2 serology test at Visit 6 should be completed unless the subject declines testing.


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TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................. 12 
SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS ................................. 17 
TABLE OF CONTENTS ..................................................................................................... 20 
LIST OF IN-TEXT TABLES .............................................................................................. 24 
LIST OF IN-TEXT FIGURES ............................................................................................ 24 
LIST OF ATTACHMENTS ................................................................................................ 24 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 25 
1 
INTRODUCTION ......................................................................................................... 27 
1.1 
Background ...........................................................................................................27 
1.2 
Clinical Experience ...............................................................................................30 
1.3 
Rationale for the Study .........................................................................................31 
2 
STUDY OBJECTIVES ................................................................................................. 32 
2.1 
Primary Objective .................................................................................................32 
2.2 
Key Secondary Objectives ....................................................................................32 
2.3 
Other Secondary Objectives .................................................................................32 
2.4 
Safety Objectives ..................................................................................................34 
2.5 
Number of Subjects and Duration of Study ..........................................................34 
2.6 
Termination of Study ............................................................................................34 
3 
STUDY DESIGN ........................................................................................................... 35 
3.1 
Study Overview ....................................................................................................35 
3.2 
Endpoints ..............................................................................................................36 
3.2.1 
Efficacy Endpoints ............................................................................36 
3.2.1.1 
Primary Endpoint ...............................................................................36 
3.2.1.2 
Key Secondary Endpoints .................................................................36 
3.2.1.3 
Other Secondary Endpoints ...............................................................37 
3.2.2 
Safety Endpoints ................................................................................38 
3.3 
Method of Treatment Assignment or Randomization ..........................................38 
3.4 
Breaking the Blind ................................................................................................39 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 40 
4.1 
Inclusion Criteria ..................................................................................................40 
4.2 
Exclusion Criteria: ................................................................................................41 


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4.3 
Withdrawal and Removal of Subjects ..................................................................43 
4.4 
Follow-Up for Drug Discontinuation/Subject Withdrawal from Study ...............44 
5 
STUDY DRUG ............................................................................................................... 45 
5.1 
Study Drug Treatment and Dosing .......................................................................45 
5.2 
Clinical Supplies ...................................................................................................46 
5.3 
Packaging and Labeling ........................................................................................46 
5.4 
Dispensing and Return of Study Drug ..................................................................46 
5.5 
Storage and Reconciliation of Supplies ................................................................46 
5.6 
Concomitant Medication ......................................................................................46 
5.6.1 
Allowed Concomitant Medications ...................................................47 
5.6.2 
Rescue Medication ............................................................................47 
5.6.3 
Prohibited Medications ......................................................................47 
5.7 
Treatment Compliance ..........................................................................................48 
6 
VISIT SCHEDULE SUMMARY ................................................................................. 49 
6.1 
Visit 1 (Screening/Single-Blind Placebo Run-in) .................................................49 
6.2 
Visit 2 (Day 1, Baseline; Randomization) ............................................................50 
6.3 
Visits 3, 4, and 5 (Weeks 4, 8, and 12) .................................................................50 
6.4 
Subject Contact (Week 16 and Week 20) .............................................................51 
6.5 
Visit 6 (Week 24 End-of-Double-Blind/Early Termination) ................................51 
6.6 
Unscheduled Visits ...............................................................................................51 
7 
STUDY PROCEDURES AND ASSESSMENTS ........................................................ 52 
7.1 
Medical History, Demographics, and Baseline Characteristics ............................52 
7.1.1 
Medical History .................................................................................52 
7.1.2 
Information Pertaining to Chronic Rhinosinusitis .............................52 
7.1.3 
Demographic Information and Baseline Characteristics ...................52 
7.2 
Efficacy Assessments ...........................................................................................52 
7.3 
Health Economic Assessments .............................................................................55 
7.4 
Safety Assessments ...............................................................................................55 
7.4.1 
Physical Examination ........................................................................56 
7.4.2 
Nasal Examination .............................................................................56 
7.4.3 
Ocular examinations ..........................................................................56 
7.4.4 
Vital Signs and Weight ......................................................................56 


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7.4.5 
Laboratory Variables .........................................................................56 
8 
SAFETY MONITORING AND REPORTING .......................................................... 58 
8.1 
Adverse Events .....................................................................................................58 
8.2 
Adverse Reactions ................................................................................................59 
8.3 
Suspected Adverse Reactions ...............................................................................59 
8.4 
Unexpected Adverse Reactions or Adverse Events ..............................................59 
8.5 
Serious Adverse Events ........................................................................................60 
8.5.1 
Life-Threatening Adverse Events ......................................................60 
8.5.2 
Serious Adverse Event Reporting .....................................................60 
8.6 
Non-Serious Adverse Event Reporting ................................................................61 
8.7 
Pregnancy .............................................................................................................61 
9 
STATISTICAL ANALYSIS ......................................................................................... 62 
9.1 
Sample Size Determination ..................................................................................62 
9.2 
Analysis Sets .........................................................................................................62 
9.2.1 
Intent-to-treat Analysis Set ................................................................62 
9.2.2 
Safety Analysis Set ............................................................................62 
9.2.3 
Full Analysis Set (FAS) .....................................................................62 
9.2.4 
Per-Protocol Analysis Set (PPS) .......................................................62 
9.3 
Primary Estimand, Intercurrent Events, and Estimation ......................................63 
9.3.1 
Co-primary Endpoints .......................................................................63 
9.3.2 
Potential Intercurrent Events .............................................................63 
9.3.3 
Primary Estimand ..............................................................................63 
9.3.4 
Estimator and Estimation Method – Primary Analysis .....................64 
9.3.5 
Supplementary Analysis ....................................................................65 
9.4 
Sensitivity Analyses ..............................................................................................65 
9.4.1 
ANCOVA on Ranked APOV Values ................................................65 
9.4.2 
Observed Cases Analysis ..................................................................65 
9.4.3 
Tipping Point .....................................................................................65 
9.5 
Key Secondary Efficacy Analyses ........................................................................66 
9.6 
Other Secondary Efficacy Analyses .....................................................................66 
9.7 
Subgroup Analyses ...............................................................................................68 
9.8 
Type I Error Control for Multiplicity ...................................................................68 


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9.8.1 
Co-primary Efficacy Endpoints .........................................................68 
9.8.2 
Type I Error Control for Key Secondary Endpoints .........................68 
9.9 
Safety Analysis .....................................................................................................70 
9.9.1 
Adverse Events (AEs) .......................................................................70 
9.9.2 
Other Safety Endpoints ......................................................................70 
9.10 
Interim Analysis ....................................................................................................70 
10 DATA QUALITY ASSURANCE ................................................................................. 71 
10.1 
Case Report Forms ...............................................................................................71 
10.2 
Source Documents ................................................................................................71 
10.3 
Record Retention ..................................................................................................71 
11 QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 72 
12 REGULATORY AND ETHICAL CONSIDERATIONS .......................................... 73 
12.1 
Ethical Conduct of the Study ................................................................................73 
12.2 
Informed Consent Process ....................................................................................73 
12.3 
Privacy of Personal Data ......................................................................................73 
12.4 
Future Use of CT Scans ........................................................................................74 
13 ADMINISTRATIVE CONSIDERATIONS ................................................................ 75 
13.1 
Monitoring ............................................................................................................75 
13.2 
Protocol Amendments and Deviations .................................................................75 
13.2.1 
Protocol Amendment .........................................................................75 
13.2.2 
Protocol Deviations ...........................................................................75 
13.3 
Financing and insurance .......................................................................................75 
13.4 
Publication policy .................................................................................................75 
14 REFERENCES .............................................................................................................. 77 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1: Study Drug Dosing – Double-blind Treatment Phase.............................................45 
Table 2:  Nasal Symptom Scale .............................................................................................53 
Table 3: Patient Global Impression of Change (PGIC) Scale ...............................................55 
Table 4:  Laboratory Measurements .......................................................................................57 
Table 5:  Adverse Event Severity ...........................................................................................59 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Closed-Palate Bi-directional™ Delivery System ....................................................29 
Figure 2: OPN-375 Exhalation Delivery System ...................................................................30 
Figure 3: Study Flow Diagram ...............................................................................................36 
 
LIST OF ATTACHMENTS 
ATTACHMENT 1: 
BECLOMETHASONE – EQUIVALENT DOSES ..........................79 
ATTACHMENT 2:  
RADIATION ASSOCIATED WITH CT SCANS ............................80 
ATTACHMENT 3:  
KEY ASSESSMENTS FOR NASAL EXAMINATION..................81 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Definition 
AE 
Adverse event 
AM 
Morning 
ANCOVA 
Analysis of covariance 
APOV 
Average percent of opacified volume 
BID 
Twice a day 
BOCF 
Baseline Observation Carried Forward 
CFR 
Code of Federal Regulations 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CRS 
Chronic rhinosinusitis 
CSNS 
Composite score of nasal symptoms 
CT 
Computed tomography 
CYP3A4 
Cytochrome P450 3A4 
DB 
Double-blind 
DCF 
Data Clarification Form 
EC 
Ethics Committee 
ECP 
Eosinophil cationic protein 
EDS 
Exhalation Delivery System 
EOS 
End of Study 
EQ-5D 
EuroQol-5 
EQ VAS 
EQ Visual Analogue Scale 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EVA 
Electronic visual acuity 
ET 
Early termination 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLM 
Generalized linear model 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
HPQ 
Health and Work Performance Questionnaire 
IA 
Interim analysis 
IASAP 
Interim analysis Statistical Analysis Plan 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IFN 
Interferon 
IL 
Interleukin 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IWRS 
Interactive web response system 
J2C 
Jump to Control 
LS 
Least-squares 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MCP 
Multiple comparison procedure/milk clotting protease 
MCS 
Mental component score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MIP 
Mycoplasma immunoglobulin protease 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed-effect model for repeated measures 
mSv 
Millisievert 


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NB 
Negative binomial 
OD 
Right eye 
OMC 
Ostiomeatal complex 
OS 
Left eye 
PASS 15 
Power Analysis and Sample Size Software 
PBO 
Placebo 
PCS 
Physical component score 
PGIC 
Patient Global Impression of Change 
PM 
Evening 
PMM 
Pattern Mixture Model 
PPS 
Per-Protocol Analysis Set 
PSQI 
Pittsburgh Sleep Quality Index 
QIDS 
Quick Inventory of Depressive Symptomatology 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SF-36v2 
36-Item Short Form Health Survey Version 2 
SF-6D 
Short Form-6 dimension 
SIT 
Smell Identification Test 
SNOT-22 
Sinonasal Outcome Test-22 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumor necrosis factor 
TSLP 
Thymic stromal lymphopoietin 
US 
United States 
WHO 
World Health Organization 
WHODrug 
World Health Organization Drug Dictionary 


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1 
INTRODUCTION 
OptiNose has developed OPN-375 (proprietary name XHANCE®) as an intranasal drug delivery 
system with the intention to improve the performance of fluticasone propionate in the treatment of 
nasal inflammatory diseases by facilitating deposition of the topical steroid in regions affected by 
local inflammation. Delivery of drug using an Exhalation Delivery System (EDS) is intended to 
improve reproducibility of nasal delivery, particularly deposition of the topical steroid to the 
middle meatus where the sinuses ventilate and drain (ostiomeatal complex [OMC]). OPN-375 is 
also intended to address user preference associated with reduced drip-out (posterior and anterior) 
and taste, and to improve tolerability and efficiency by significantly reducing loss of drug to 
nontarget sites such as the gastrointestinal (GI) tract and lungs. 
Fluticasone propionate is an androstane glucocorticoid with high lipophilicity, high selectivity and 
affinity for the glucocorticoid receptor, low oral and nasal systemic absorption, and rapid 
metabolic clearance (Crim 2001). It is approved in many countries for use in the treatment of 
dermatosis (topical), rhinitis (intranasal), and asthma and chronic obstructive pulmonary disease 
(COPD) (inhaled) and is one of the most well studied and characterized glucocorticoids in clinical 
use today. 
Information available on OPN-375 for the treatment of chronic rhinosinusitis (CRS) with and 
without nasal polyposis is summarized in the following sections. For the most comprehensive 
information on the safety and efficacy of OPN-375 refer to the most recent version of the 
Investigator’s Brochure (IB). 
The terms "Sponsor" or “designee” used throughout this document refers to those companies or 
individuals listed on the Contact Information page(s), which will be provided as a separate 
document. 
 
1.1 
Background 
A clinical development program for OPN-375 (XHANCE) in adults with nasal polyposis has been 
completed. XHANCE is currently approved for the treatment of nasal polyps in patients 18 years 
of age or older. In the clinical study subject of this protocol, OptiNose intends to study the efficacy 
and safety of OPN-375 in subjects with CRS.  
Sinusitis is defined as symptomatic inflammation of the paranasal sinuses and nasal cavity. If the 
duration of sinusitis is more than 12 weeks, with or without acute exacerbations, it is deemed to 
be CRS (Bachert et al, 2014; Fokkens et al, 2012). It is variously estimated that approximately 4% 
of patients with CRS have concurrent nasal polyps (with estimated prevalence in the low, single 
digits for the population as a whole). Chronic rhinosinusitis affects approximately 5% to 15% of 
the general population in Europe and the United States (US) (Hamilos, 2011), and the prevalence 
of physician-diagnosed CRS was found to be 2% to 4% (Chen et al, 2003; Shashy et al, 2004). 
Chronic rhinosinusitis has significant impact on healthcare resource utilization and work 
productivity, with approximately 12 billion dollars in direct medical costs and 20 billion dollars in 
lost productivity in 2016 (Rudmik 2017). Chronic rhinosinusitis also has a significant impact on 
health-related quality of life, and patients with this condition scored lower on measures of bodily 
pain and social functioning than those with serious chronic conditions including angina, back pain, 
congestive heart failure, and COPD (Gliklich and Metson, 1995).  
The etiology and pathogenesis of CRS is multifactorial. Although a number of factors have been 
found to be associated with CRS, including ciliary impairment, allergy, asthma, aspirin sensitivity, 


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and an immunocompromised state, there is no clearly delineated single molecular pathway or 
single antecedent trigger that leads to the development of CRS. Nevertheless, persistent 
inflammation of the nasal cavity and the paranasal sinuses, progressing from mucosal injury to 
tissue change, is sine qua non in the pathophysiology of CRS with or without nasal polyps (Akdis 
et al, 2013). Evidence of inflammation is generally present throughout the nasal cavity, including 
around the OMC, where the sinuses ventilate and drain into the nasal cavity.  
Consistent with the location of the inflammation, the most common symptom associated with CRS 
is nasal obstruction, followed by facial congestion-pressure/pain-fullness, discolored anterior and 
posterior nasal discharge, and hyposomia. The presence of 2 or more symptoms, 1 of which should 
be nasal obstruction/congestion or nasal discharge, persisting beyond 12 weeks, is highly sensitive 
for the diagnosis of CRS (Meltzer et al, 2004). However, diagnosis based on symptoms alone is 
relatively nonspecific. Visualization of discharge from the OMC by nasal examination with nasal 
endoscopy, the presence of polyps in the nasal cavity, or radiographic imaging showing 
inflammation of the paranasal sinuses is typically needed to confirm the diagnosis (Bhattacharyya 
and Lee, 2010). 
Intranasal topical corticosteroids, though not formally indicated, are first-line pharmacotherapy for 
CRS with or without nasal polyps (Bachert et al, 2014; Fokkens et al, 2012; Rosenfeld et al, 2015). 
Qualitative syntheses and meta-analyses have been performed on the reported clinical trials in 
patients without nasal polyps (10 and 7 trials for qualitative synthesis and meta-analysis, 
respectively) and in patients with nasal polyps (38 and 26 trials for qualitative synthesis and meta-
analysis, respectively) (Fokkens et al, 2012). The studies included patients with prior sinus surgery, 
without sinus surgery, or a mixed population with regard to sinus surgery. The meta-analyses 
demonstrated that treatment with intranasal corticosteroids improved symptoms to a greater extent 
than placebo in CRS patients both with and without nasal polyps. However, the efficacy of 
intranasal corticosteroids in CRS patients without nasal polyps was modest, with several of the 
trials failing to demonstrate a significant treatment effect compared with placebo. It is also notable 
that among the CRS patients without nasal polyps only those who had prior sinus surgery showed 
symptomatic improvement. Adverse events associated with intranasal corticosteroids generally 
were local at the site of administration, not serious, and consisted mainly of epistaxis, nasal 
irritation and headache (Fokkens et al, 2012).  
Clinical guidelines suggest that for patients who do not respond to intranasal corticosteroids after 
3 months of treatment, a course of systemic antibiotic treatment may be considered.  
Endoscopic sinus surgery is generally effective in reducing the symptoms of CRS with or without 
nasal polyps (Chester et al, 2009); however, the 5-year revision rate for surgery approaches 20%, 
with the revision rate generally being higher for patients with CRS with nasal polyps (21% vs 
16%) than for those without nasal polyps (Hopkins et al, 2009). Furthermore, although surgery is 
effective, the insufficiency of symptomatic relief with surgery is strongly suggested by the finding 
that the use of symptomatic medical therapy prior to surgery and after surgery is not meaningfully 
changed (Bhattacharyya and Lee, 2010).  
Clinical guidelines notwithstanding, and despite the large number of clinical trials conducted, it is 
notable that in the US, no intranasal corticosteroid has been approved for the treatment of CRS. 
Oral steroids may reduce the need for surgery but there are concerns about significant side effects 
with long-term oral steroid use. 
OPN-375 contains a liquid suspension of fluticasone propionate that it delivers to the nasal mucosa 
with a drug delivery system designed to deposit the drug aerosol high and deep into the nasal 


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cavity. Fluticasone propionate is a synthetic corticosteroid that has long been commercially 
available in the US. It is currently approved as monotherapy and in various combinations, and in 
multiple formulations for multiple indications including creams (for inflammatory dermatoses and 
other dermatological conditions), inhalers (for asthma and other respiratory conditions), and nasal 
sprays. 
OPN-375 delivers active medication using an EDS. It is composed of a pharmaceutical industry 
standard amber glass vial containing a suspension of fluticasone propionate, a standard metering 
spray pump, and plastic casework with an asymmetrically shaped sealing nosepiece and a flexible 
mouthpiece. The casework defines the drug delivery system’s outer shape and includes the 
moveable mouthpiece and sealing nosepiece. The user inserts the sealing nosepiece into 1 nostril, 
so it seals well with the flexible nasal tissues, and inserts the mouthpiece between the lips. After 
taking a deep breath, the user blows into the OPN-375 mouthpiece. Static positive pressure is 
created and subsequently released through the actuation of the spray by pressing the vial, which 
concurrently releases the orally-generated pressure/airflow. Blowing through the mouth against a 
resistance also causes the soft palate to seal closed, separating the oral cavity from the nasal 
cavities. A nasal spray applicator extends from the metering pump to the tip of the nosepiece. Upon 
actuation, the design of the EDS allows for air to be channeled from the mouthpiece to the sealing 
nosepiece when the pump is actuated. Under these conditions, exhaled air creates a positive 
intranasal pressure, accompanies the aerosol expelled by the spray pump applicator beyond the 
nasal valve, and places at least 50% of the initially deposited metered spray beyond the head of 
the inferior turbinate and at least 30% of the initially deposited dose in the upper posterior region 
of the nasal cavity beyond the head of the inferior turbinate and above the inferior meatus, 
including the OMC (middle meatus). This pattern of delivery produced by OPN-375 is intended 
to place topical steroid in the region of the nasal cavity where the paranasal sinuses ventilate and 
drain.  
Figure 1 presents a schematic view of closed-palate Breath-Powered™ Bi-Directional™ delivery 
and an image of OPN-375. 
Figure 1: 
Closed-Palate Bi-directional™ Delivery System 
Schematic A 
Schematic B 
 
A = Cross-sectional view from the left side. 


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B = Cross-sectional view from the top. 
 
The OPN-375 EDS is pictured below (Figure 2). 
Figure 2: 
OPN-375 Exhalation Delivery System 
 
Before each device is used for the first time, it is necessary to prime the unit. To prime, shake then 
actuate and spray into the air 7 times or until a fine mist appears. 
 
1.2 
Clinical Experience 
There were two Phase 3, randomized, double-blind, placebo-controlled, parallel-group, 
multicenter studies (OPN-FLU-NP-3101 and OPN-FLU-NP-3102) designed to assess the efficacy 
and safety of 3 doses of OPN-375 (93, 186, and 372 μg twice a day [BID]) compared with placebo 
in adult subjects with bilateral nasal polyposis followed by an 8-week, open-label extension phase 
(372 μg BID) to assess safety. Both clinical studies were identical in design. 
In these studies, all 3 doses of OPN-375 produced statistically significant greater reductions than 
placebo on the co-primary measures of nasal congestion/obstruction and total polyp grade. 
Sensitivity analyses conducted on the co-primary outcome variables, including a tipping point 
analysis, indicated that the results obtained were robust. The 186-µg and 372-µg groups had 
numerically larger magnitudes of effect compared with the 93-µg group.  
Results obtained from secondary measures in the pivotal studies were generally consistent with 
the primary efficacy results. In the open-label phases of the pivotal trials, the improvements from 
baseline in efficacy assessments seen at the end of the double-blind phases generally continued to 
increase through Week 24. Data from responder analyses demonstrate that OPN-375 substantially 
reduces polyp grade and the magnitude of reduction continues to increase with longer-term 
treatment within the period studied.  
Clinically meaningful improvements with OPN-375 treatment were also observed broadly in other 
signs and symptoms of the disease and in physical, mood, and social parameters relevant to quality 
of life. Analyses of the Patient Global Impression of Change (PGIC) indicated that treatment with 


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OPN-375 not only produced statistically significant benefits but that the magnitude of change 
perceived by the subject was clinically meaningful. 
There were two Phase 3, open-label, multicenter studies (OPN-FLU-CS-3203, 12-month; OPN-
FLU-CS-3204, 3-month) designed to assess the safety and efficacy of OPN-375 372 μg BID in 
subjects with chronic sinusitis with or without nasal polyps. 
Subjects in the open-label studies also had considerable improvement in symptoms and in 
objectively observed local signs of disease. A substantial proportion of subjects with intranasal 
edema at study entry no longer had evidence of edema on examination at study completion, a 
finding consistent with an intranasal deposition profile that places topically -acting fluticasone 
propionate in the areas beyond the nasal valve including the area of the middle meatus/OMC. In 
subjects with polyps, extensive reductions in polyp grade were observed and polyps were 
eliminated from at least 1 side of the nose in approximately 50% of subjects. In the 12-month study 
the improvement in polyp grade, polyp elimination, and edema increased over time, suggesting 
benefit with continued treatment over the observed period.  
The most commonly reported adverse events (AEs) in the active treatment groups were associated 
with local effects at the site of administration in the nasal cavity (epistaxis, nasal congestion, nasal 
mucosal disorder [primarily erythema], and nasal septum ulceration) or associated with the 
underlying disease (acute sinusitis or nasopharyngitis). Most local AEs were identified as a result 
of intensive active monitoring of all subjects at scheduled intervals by skilled endoscopic nasal 
examination at each visit and were not spontaneously reported. The majority of these AEs were 
mild and importantly, are known to have resolved with continued use of study drug. No deaths 
were reported, 18 subjects receiving OPN-375 reported serious adverse events (SAEs) during the 
placebo controlled and open-label studies. One placebo-treated subject reported treatment-related 
SAEs, and the overall rate of discontinuations due to AEs was approximately 4% among all 
subjects who received OPN−375.  
 
1.3 
Rationale for the Study 
Patients with CRS currently have limited medical options for treatment. While some symptoms 
may be reduced, patients are often left with symptoms due to the suboptimal delivery method of 
current treatments (Fokkens et al, 2012). Standard nasal spray pumps suffer from a number of 
drawbacks and are considered suboptimal for reliable drug delivery to target sites beyond the nasal 
valve (Aggarwal et al, 2004). OPN-375, with its breath assisted mechanism of delivery, provides 
specific benefits over current nasal drug delivery systems including increased reliability of 
delivery of topical medication to the anatomical sites, which are central to the pathology of CRS. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to compare the efficacy of intranasal administration of twice 
daily doses of 186 and 372 µg of OPN-375 (fluticasone propionate) with placebo in subjects with 
CRS using the following co-primary endpoints: 
• change from baseline in symptoms as measured by a composite score of nasal symptoms 
(CSNS): congestion, facial pain or pressure sensation, and nasal discharge (anterior and/or 
posterior) at the end of Week 4 
and 
• change from baseline to Week 24/ET in the average percent of opacified volume (APOV) in 
the ethmoid and maxillary sinuses 
 
2.2 
Key Secondary Objectives 
The following key secondary objectives will compare the efficacy of twice daily doses of 186 
and 372 µg of OPN-375 with placebo by pooling the data in subjects from studies OPN-FLU-
CS-3206 and OPN-FLU-CS-3205, which is a separate study being conducted in parallel to this 
study.  
• 
change from baseline to Week 4 on (AM, Instantaneous) CSNS score in subjects who were 
symptomatic at trial entry despite reported use of an intranasal steroid for treatment of CRS 
within 30 days of Visit 1  
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a 
worsening of symptoms that requires an escalation of treatment 
The following key secondary objective will compare the efficacy of twice daily doses of 186 and 
372 µg of OPN-375 with placebo by pooling the data in subjects with CRS without nasal polyps, 
from studies OPN-FLU-CS-3206 and OPN-FLU-CS-3205, which is a separate study being 
conducted in parallel to this study.  
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a 
worsening of symptoms that requires an escalation of treatment 
The following key secondary objectives of this study will compare the efficacy twice-daily doses 
of 186 and 372 μg of OPN-375 with placebo on:  
• 
change from baseline to the end of Week 4 in four separate cardinal CRS symptoms, as 
measured by CSNS (AM, Instantaneous): congestion, facial pain or pressure sensation, nasal 
discharge (anterior and/or posterior), and sense of smell 
• 
time to first acute exacerbation of CRS, defined as a worsening of symptoms that requires 
escalation of treatment 
 
2.3 
Other Secondary Objectives 
Secondary objectives of this study are to compare the effect of twice daily doses of 186 and 372 µg 
of OPN-375 with placebo in: 


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• change from baseline to Week 24/ET in subject symptoms and functioning, as measured by 
Sinonasal Outcome Test-22 (SNOT-22) total score for the total population and in patients with 
and without previous sinus surgery 
• change from baseline to Weeks 4, 8, 12, and 24/ET in subject symptoms and functioning, as 
measured by SNOT-22 total and sub-domain scores for the total population and in patients 
with and without previous sinus surgery 
• change from baseline in symptoms as measured by a CSNS: congestion, facial pain or pressure 
sensation, and nasal discharge (anterior and/or posterior) to the end of Week 4, 8, and 12 for 
the total population and in patients with and without previous sinus surgery 
• change from baseline to Week 4, 8, and 12 for the total population and patients with and without 
previous sinus surgery, on facial pain or pressure sensation, nasal discharge (anterior and/or 
posterior), nasal congestion, and sense of smell as measured by average AM instantaneous 
symptom scores and PM reflective symptom scores 
• change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses for 
patients with and without previous sinus surgery 
• change from baseline to Week 24/ET in the percent of opacification of the combined volume 
of the ethmoid and maxillary sinuses 
• change from baseline to Week 24/ET in the Lund-Mackay Staging System total score, scores 
for the maxillary and ethmoid sinuses, and scores for each sinus pair  
• change from baseline to Week 24/ET in percent of sinus volume occupied by disease for the 
worst maxillary sinus (WPOV-M), for the worst ethmoid sinus (WPOV-E), and for the worst 
sinus between the maxillary and ethmoid sinuses (WPOV) for the total population and in 
patients with and without previous sinus surgery 
• change from baseline to Week 24/ET in the Zinreich modification of Lund-Mackay Staging 
System total score, scores for the maxillary and ethmoid sinuses combined, and scores for each 
sinus pair 
• change from baseline to Week 24/ET in Zinreich modification of the Lund Mackay Staging 
System score for the worst sinus between maxillary and ethmoid sinuses in the total population 
and in subjects with and without previous sinus surgery 
• change in patient-reported outcomes from baseline to Week 24/ET as measured by: 
− change in sleep quality from baseline to Weeks 12 and 24/ET, using the PSQI 
− percent of subjects improved as indicated in the Patient Global Impact of Change (PGIC) 
at Week 4 and Week 24/ET 
− SF-36v2, 8 individual, physically and emotionally based domains (physical functioning, 
role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and 
mental health) standardized scores 
− change in the severity of depression from baseline to Week 24/ET and severity of 
depression at Week 24/ET as measured by the Quick Inventory of Depression 
Symptomatology (QIDS) 
− change in severity of olfactory symptoms from baseline to Week 24/ET as measured by 
the Smell Identification Test (SIT) 


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− EuroQol-5 (EQ-5D) 
− Short Form-6 dimension (SF-6D) derived scores from the SF-36v2 
− assessment of health economic measures during the double-blind treatment phase related 
to CRS (eg, criteria for surgical intervention for CRS is met [independent of actual 
surgery performed], subjects who entered the study approved for surgery [with a 
scheduled surgery date] who no longer elect to undergo surgery, missed work or school 
days/lost productivity) by Health and Work Performance Questionnaire (HPQ) 
The following secondary objectives will compare the efficacy of twice daily doses of 186 and 
372 µg of OPN-375 with placebo by pooling the data from studies OPN-FLU-CS-3206 and 
OPN-FLU-CS-3205, which is a separate study being conducted in parallel to this study.  
• change from baseline to Week 24/ET in subject symptoms and functioning, as measured by 
Sinonasal Outcome Test-22 (SNOT-22) total score in subjects who report using an intranasal, 
topically acting nasal steroid for the treatment of CRS within 30 days of Visit 1 
• change in sleep quality from baseline to Week 24/ET, using the Global Pittsburgh Sleep Quality 
Index (PSQI) Score 
 
2.4 
Safety Objectives 
to evaluate the safety of OPN-375 by monitoring AEs throughout the study; results of nasal 
examination, vital signs measurements (ie, blood pressure, pulse), and weight; and monitoring 
concomitant medication usage 
 
2.5 
Number of Subjects and Duration of Study 
The total planned number of subjects is approximately 210. Approximately 210 subjects will be 
randomly assigned to receive 1 of the 2 active treatments or placebo (70 subjects in each group); 
subjects will be randomized using a 1:1:1 ratio. 
The expected participation period for a subject is approximately 26 weeks, including a 
pretreatment phase consisting of a Screening visit followed by a 7- to up to 21-day single-
blind- placebo run-in period and a 24-week double-blind treatment phase. 
 
2.6 
Termination of Study 
Premature termination of the trial may occur because of a regulatory authority decision, change in 
opinion of the Institutional Review Board (IRB)/Ethics Committee (EC), drug safety problems, or 
at the discretion of the Sponsor or their designee. If the study is prematurely terminated, the 
Sponsor or their designee will promptly notify the investigators. 


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3 
STUDY DESIGN  
3.1 
Study Overview 
This is a 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy and safety of intranasal administration of OPN-375 (186 and 372 μg 
twice daily) in subjects with CRS without the presence of nasal polyps.  
Subjects must sign an informed consent before any study-related procedure is performed. Subjects 
who meet eligibility criteria at Visit 1 (Screening) will enter a 7- to 21-day -single-blind placebo 
run-in period to determine disease status and to ensure that they can comply with study procedures. 
At Visit 1 (Screening), nasoendoscopy-related (nasal examination and assessment of nasal cavity 
for presence of edema, polypoid tissue/polyps [<Grade 1], or mucopurulence) procedures will be 
performed for all subjects. During the single-blind- run-in period, subjects will administer morning 
and evening doses of the study drug (placebo) and will complete a daily diary (electronic) 
immediately before the morning and evening doses including recording of both instantaneous 
(evaluation of symptom severity immediately preceding the time of scoring) and reflective 
(evaluation of symptom severity over the past 12 hours) scores for nasal symptoms. 
Subjects determined to meet diary eligibility criteria over a 7-day period during the first 14 days 
of the single-blind run-in period, will have a sinus computed tomography (CT) scan performed. 
The CT scan should be performed after diary eligibility is confirmed and prior to Day 21 of the 
screening run-in period. CT scans performed prior to Day 21 and within 2 weeks prior to Visit 1 
as part of routine clinical care may be utilized if the scan meets the CT scan standards outlined in 
the Imaging Charter for this protocol. The resultant scan will be reviewed centrally to confirm 
study eligibility prior to randomization. 
Those subjects meeting disease severity eligibility criteria (symptom severity and sinus 
opacification) will be randomly assigned through an interactive web response system (IWRS) to 
receive 1 of 2 active treatments or placebo: 186 or 372 μg of OPN-375 or placebo BID for the 
24-week double-blind treatment phase. During the first 12 weeks of the double-blind phase, 
electronic diaries will be completed twice daily by the subject to capture symptom scores for nasal 
congestion, nasal discharge, (anterior and/or posterior), facial pain or pressure sensation, and sense 
of smell, as well as use of approved rescue medication after the Week 4 visit. Subject-completed 
questionnaires will be used to measure the symptoms and social/emotional consequences of the 
subject’s nasal disorder (SNOT-22), health-related quality of life (EQ-5D, SF-36v2, and SF-6D), 
sleep quality and disturbances (PSQI), depressive symptoms (QID), work productivity, and 
objective smell test (SIT). Subjects will assess their global impression of change since starting the 
study drug using the PGIC scale. Health economic information related to CRS will also be 
collected (HPQ). Objective changes in disease severity will be assessed via sinus CT scan. 
Safety will be assessed by monitoring of AEs, performing nasal examination, measuring vital signs 
(ie, blood pressure, pulse) and weight, and through collection of information for concomitant 
medications. 
Refer to the Schedule of Study Procedures and Evaluations, for the timing of all tests, procedures, 
and assessments that will be performed during the study. 
A study flow diagram is shown in Figure 3. 


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Figure 3: 
Study Flow Diagram 
Single-Blind 
Lead-In 
Double-Blind Treatment 
Pretreatment 
Randomization 
 
End of Double-Blind 
 
----------------------------------------186 µg OPN-375 BID (n=70)---------------------------------------- 
----------------------------------------372 µg OPN-375 BID (n=70)---------------------------------------- 
----------------------------------------Placebo (n=70)---------------------------------------- 
Visit 1 
7 up to 21 days 
Screening 
/Run-in 
Visit 2 
Day 1 
/Randomization 
/Baseline 
Visit 3 
Week 4 
Visit 4 
Week 8 
Visit 5 
Week 
12 
Subject 
Contact 
Week 16 
Subject 
Contact 
Week 20 
Visit 6 
Week 24 
/End of Double-Blind 
/Early Termination 
BID=twice a day. 
 
3.2 
Endpoints 
3.2.1 
Efficacy Endpoints 
3.2.1.1 Primary Endpoint 
Co-primary Endpoints 
• change from baseline to the end of Week 4 in average instantaneous AM scores (evaluation of 
symptom severity immediately preceding the time of scoring) of: 
− nasal congestion  
− nasal discharge (anterior and/or posterior)  
− facial pain/pressure sensation 
The baseline CSNS is the average of the total instantaneous AM scores over the last 7 days of the 
single-blind run-in period, and the end of Week 4, scores are averaged over the 7 days before 
Week 4. 
• change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses. 
3.2.1.2 Key Secondary Endpoints 
Key Secondary Endpoints include: 
• 
change from baseline to Week 4 on CSNS score (AM, Instantaneous) in subjects who were 
symptomatic at trial entry despite reported use of an intranasal steroid for treatment of CRS 
within 30 days of Visit 1 in subjects from studies OPN-FLU-CS-3206 and OPN-FLU-CS-
3205 (pooled data) 
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a 
worsening of symptoms that requires an escalation of treatment, in subjects from studies 
OPN-FLU-CS-3206 and OPN-FLU-CS-3205 (pooled data) 
• 
Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a 
worsening of symptoms that requires an escalation of treatment in subjects with CRS without 
NP, from studies OPN-FLU-CS-3206 and OPN-FLU-CS-3205 (pooled data) 
• 
change from baseline to the end of Week 4 in four separate cardinal CRS symptoms, as 
measured by CSNS (AM, Instantaneous) : congestion, facial pain or pressure sensation, nasal 
discharge (anterior and/or posterior), and sense of smell 
• 
time to first acute exacerbation of CRS, defined as a worsening of symptoms that requires 
escalation of treatment 


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3.2.1.3 Other Secondary Endpoints 
• change from baseline to Weeks 4, 8, 12, and Week 24/ET in the SNOT-22 total and sub-domain 
scores for the total population and in patients with and without previous sinus surgery 
• change from baseline in symptoms as measured by a CSNS: congestion, facial pain or pressure 
sensation, and nasal discharge (anterior and/or posterior) at the end of Week 4, 8, and 12 for 
the total population and in patients with and without previous sinus surgery 
• change from baseline to Weeks 4, 8, and 12 for the total population and in patients with and 
without previous sinus surgery: 
− in average AM/PM instantaneous (evaluation of symptom severity immediately 
preceding the time of scoring), (except Week 4 (AM) – key secondary endpoint) and 
AM/PM reflective (evaluation of symptom severity over the past 12 hours), averages 
are based on scores recorded in the diary for the 7 days before each time point for: 
 nasal congestion 
 sense of smell score 
 nasal discharge (anterior and/or posterior) score 
 facial pain or pressure sensation score 
 
• change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses for 
patients with and without previous sinus surgery 
• change from baseline to the Week 24/ET for CT related assessments: 
− Lund-Mackay Staging System total score, scores for ethmoids and maxillary sinuses 
combined, and scores for each sinus pair (eg, ethmoid, maxillaries, frontal, and sphenoid, 
and ostiomeatal complex) 
− percent of sinus volume occupied by disease in the worst maxillary sinus (WPOV-M), 
percent of sinus volume occupied by disease in the worst ethmoid sinus (WPOV-E), and 
percent of sinus volume occupied by disease in the worst sinus between maxillary and 
ethmoid sinuses (WPOV) for the total population and in patients with and without 
previous sinus surgery 
− Zinreich modification of the Lund-Mackay Staging System total score, scores for 
ethmoids and maxillary sinuses combined, and for each sinus pair (eg, ethmoids, 
maxillary, frontal, and sphenoid) 
− Zinreich modification of the Lund-Mackay Staging System score for the worst sinus 
between maxillary and ethmoid sinuses in the total population and in subjects with and 
without previous sinus surgery 
− change of percent of opacification of the combined volume of the ethmoid and maxillary 
sinuses 
• change from baseline to Week 12 and Week 24/ET in the PSQI global and component scores 
• percent of subjects indicating improvement on the PGIC at Week 4 and Week 24/ET 
• severity of depression at Week 24/ET as measured by QIDS 
• change from baseline to Week 24/ET for: 


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− the MCS of the SF36v2 
− the PCS of the SF36v2 
− SF-36v2 individual domains 
− QIDS total score 
− SIT scores 
− EQ-5D VAS and dimensions  
− SF-6D derived scores  
• comparison of health economic measures during the double-blind treatment phase related to 
CRS: 
− percent of subjects indicating that they are willing to consider sinus surgery at 
baseline and Week 24/ET 
− percent of subjects who meet the minimal objective criteria for surgical intervention 
(as defined in Section 7.3) at baseline and Week 24/ET 
− percent of subjects approved for surgery who no longer elect to undergo a surgery 
Week 24/ET 
− number and percentage of missed work days and the percentage of productive hours 
lost while at work from the HPQ  
• 
change from baseline to Week 24/ET in SNOT-22 total score in subjects who report using an 
intranasal, topically acting nasal steroid for the treatment of CRS within 30 days of Visit 1 in 
subjects with CRS without NP, from studies OPN-FLU-CS-3206 and OPN-FLU-CS-3205 
(pooled data) 
• 
change from baseline to Week 24/ET the Global PSQI Score in subjects with CRS without 
NP, from studies OPN-FLU-CS-3206 and OPN-FLU-CS-3205 (pooled data) 
 
3.2.2 
Safety Endpoints 
• assessment of safety through AEs, nasal examination, vital signs measurements, weight, and 
concomitant medication usage 
 
3.3 
Method of Treatment Assignment or Randomization 
Subjects will be randomly assigned to treatment according to a computer-generated randomization 
code. Randomization will be coordinated centrally through an IWRS. The system will provide 
subject identification numbers at Visit 1 (Screening), which are subsequently linked to the 
treatment assignments at randomization. Following completion of all baseline evaluations on Day 
1, subjects who meet all eligibility requirements will be randomly allocated to 1 of the 3 treatment 
groups using a 1:1:1 ratio:  
• OPN-375 186 μg BID 
• OPN-375 372 μg BID  
• Placebo BID 


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Randomization will be stratified by previous sinus surgery (Yes vs No) (previous sinus surgery is 
defined as evidence of ethmoidectomy [partial or total], or maxillary antrostomy). An IWRS will 
be used in this study to track enrollment, randomly assign subjects to treatment groups, and manage 
study drug supplies. At Visit 1 (Screening) and at each double-blind treatment phase study visit 
through Week 24, site staff will contact the IWRS and provide requested information to uniquely 
identify the subject. The IWRS will then provide the identifier (kit number) for the single-blind 
placebo kit at Visit 1 (Screening). The IWRS will then provide the identifier (kit number) for the 
double-blind study drug kit(s) to be dispensed at the respective double-blind visit.  
 
3.4 
Breaking the Blind 
This is a double-blind study. During the conduct of the study, the subject, investigator and study 
personnel at each center, and the Sponsor and/or its designated personnel directly involved in the 
clinical study will remain blinded to study treatment. The investigator will not be provided with 
the randomization code. The randomization codes will be maintained within the IWRS, which will 
allow the investigator to break the blind for an individual subject, if necessary. The investigator 
should contact the Sponsor or their designee to discuss individual situations before breaking the 
blind.  
If a medical emergency occurs and a decision regarding the subject's condition/treatment requires 
knowledge of the treatment assignment, the study blind may be broken for the specific subject via 
the IWRS; the investigator will immediately notify the Medical Monitor of the situation. The date, 
time, and reason for unblinding must be documented in the source document and in the appropriate 
section of the case report form (CRF). Additionally, the documentation received from the IWRS 
indicating the code break must be retained, in a secure manner, in the subject’s source documents.  


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Potential subjects must meet the following criteria to enter this study: 
1. men or women aged 18 years and older at baseline visit 
2. women of child-bearing potential must be abstinent, or if sexually active:  
a. be practicing an effective method of birth control (eg, prescription oral 
contraceptives, contraceptive injections, contraceptive patch, intrauterine device, 
double-barrier method [eg, condoms, diaphragm, or cervical cap with spermicidal 
foam, cream, or gel], or male partner sterilization) before entry and throughout the 
study, or 
b. be surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal 
ligation, or otherwise be incapable of pregnancy), or 
c. be postmenopausal (amenorrhea for at least 1 year) 
3. women of child-bearing potential must have a negative urine pregnancy test at Visit 1 
(Screening)  
4. must have a history of CRS and be currently experiencing 2 or more of the following 
symptoms, one of which has to be either nasal congestion or nasal discharge (anterior and/or 
posterior nasal discharge) for equal to or greater than 12 weeks:  
• nasal congestion 
• nasal discharge (anterior and/or posterior nasal discharge) 
• facial pain or pressure 
• reduction or loss of smell 
5. endoscopic evidence of nasal mucosal disease, with edema, purulent discharge; or polypoid 
tissue/polyps (<Grade 1) in middle meatus, bilaterally, or presence of bilateral disease on a 
prior CT scan performed within 14 days of Visit 1 
6. must have confirmatory evidence via CT of bilateral sinus disease (have at least 1 sinus on 
each side of nose with a Lund-Mackay score of ≥1) 
7. baseline CT scan must show a combined ≥25% opacification of the ethmoid sinuses and 
≥25% opacification of at least 1 maxillary sinus 
8. must have at least moderate symptoms (as defined in Section 7.2) of nasal congestion as 
reported by the subject, on average, for the 7-day period preceding Visit 1 (Screening) run-in 
9. must have an average morning score of at least 1.5 for congestion on the Nasal Symptom 
Scale (as defined in Section 7.2) recorded on the subject diary over a 7-day period during the 
first 14 days of the single-blind -run-in period 
10. must demonstrate an ability to correctly complete the daily diary during the run-in period to 
be eligible for randomization 
11. subjects with comorbid asthma or COPD must be stable with no exacerbations (eg, no 
emergency room visits, hospitalizations, or oral or parenteral steroid use) within the 3 months 
before Visit 1 (Screening). Inhaled corticosteroid use must be limited to stable doses of no 


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more than 1,000 μg/day of beclomethasone (or equivalent, see Attachment 1) for at least 3 
months before Visit 1 (Screening) with plans to continue use throughout the study. 
12. Subjects with aspirin-exacerbated respiratory disease, who have undergone aspirin 
desensitization and are receiving daily aspirin therapy, must be receiving therapy for at least 
6 months prior to Visit 1. 
13. must be able to cease treatment with intranasal steroids, inhaled corticosteroids (except 
permitted doses listed above for asthma and COPD) at the screening visit 
14. must be able to cease treatment with oral and nasal decongestants and antihistamines at 
Visit 1 (Screening) 
15. must be able to use the EDS correctly; all subjects will be required to demonstrate correct use 
of the practice EDS at Visit 1 (Screening), see Section 6.1 
16. must be capable, in the opinion of the investigator, of providing informed consent to 
participate in the study. Subjects must sign an informed consent document indicating that 
they understand the purpose of and procedures required for the study and are willing to 
participate in the study. 
 
4.2 
Exclusion Criteria: 
Potential subjects who meet any of the following criteria will be excluded from entering this study: 
1. women who are pregnant or lactating 
2. inability to have each nasal cavity examined for any reason, including nasal septum deviation 
3. inability to achieve bilateral nasal airflow 
4. is currently taking XHANCE 
5. have previously used XHANCE for more than 1 month and did not achieve an adequate 
symptomatic response  
6. the nasal/sinus anatomy prevents the accurate assessment of sinus volume via CT scan 
7. history of sinus or nasal surgery within 6 months before Visit 1 or has not healed from a prior 
sinus or nasal surgery 
8. have current evidence of odontogenic sinusitis, sinus mucocele (the affected sinus is 
completely opacified and either the margins are expanded and/or thinned OR there are areas 
of complete bone resorption resulting in bony defect and extension of the “mass” into 
adjacent tissues), evidence of allergic fungal sinusitis, or evidence of complicated sinus 
disease (including, but not limited to, extension of inflammation outside of the sinuses and 
nasal cavity) 
9. have a paranasal sinus or nasal tumor 
10. have polyp grade ≥1 (polyp that is free on 5 sides and has a stalk) on either side of the nose 
as determined by the nasoendoscopy at screening 
11. have a nasal septum perforation 
12. have had more than 1 episode of epistaxis with frank bleeding in the month before Visit 1 
(Screening)  


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13. have evidence of significant mucosal injury, ulceration (eg, exposed cartilage) on Visit 1 
(Screening) nasal examination/nasoendoscopy 
14. have current, ongoing rhinitis medicamentosa (rebound rhinitis) 
15. have significant oral structural abnormalities (eg, a cleft palate) 
16. have a diagnosis of cystic fibrosis 
17. history of eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) or 
dyskinetic ciliary syndromes 
18. symptom resolution or last dose of antibiotics for purulent nasal infection, acute sinusitis, 
upper respiratory tract infection, influenza, or SARS-CoV-2 (COVID-19) has not occurred 
before Visit 1 or was less than 4 weeks before the CT scan. Potential subjects presenting with 
any of these infections may be rescreened 4 weeks after symptom resolution 
19. planned sinonasal surgery during the period of the study 
20. allergy, hypersensitivity, or contraindication to corticosteroids or steroids 
21. has used oral steroids in the past for treatment of CRS and did not experience any relief of 
symptoms 
22. has a steroid eluting sinus stent still in place within 30 days of Visit 1 
23. allergy or hypersensitivity to any excipients in study drug 
24. exposure to any glucocorticoid treatment with potential for systemic effects (eg, oral, 
parenteral, intra-articular, or epidural steroids, high dose topical steroids) within 1 month 
before Visit 1 (Screening); except as noted in inclusion criteria for subjects with comorbid 
asthma or COPD 
25. have nasal candidiasis 
26. history or current diagnosis of any form of glaucoma or ocular hypertension 
27. history of IOP elevation on any form of steroid therapy 
28. history or current diagnosis of the presence (in either eye) of a cataract unless both natural 
intraocular lenses have been removed 
29. history of immunodeficiency 
30. any serious or unstable concurrent disease, psychiatric disorder, or any significant condition 
that, in the opinion of the investigator could confound the results of the study or could 
interfere with the subject's participation or compliance in the study 
31. have a positive drug screen or a recent (within 1 year of Visit 1 [Screening]) history of drug 
or alcohol abuse, or dependence that, in the opinion of the investigator could interfere with 
the subject's participation or compliance in the study 
32. have participated in an investigational drug clinical trial within 30 days of Visit 1 (Screening)  
33. have received mepolizumab (Nucala®), reslizumab (Cinquair®), dupilumab (Dupixent®), 
omalizumab (Xolair®), or benralizumab (Fasenra™) within 6 months of Visit 1 (Screening) 
34. is using strong cytochrome P450 3A4 (CYP3A4) inhibitors (eg, ritonavir, atazanavir, 
clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, 
telithromycin, conivaptan, lopinavir, voriconazole, cobicistat) 


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35. is an employee of the investigator or study center, with direct involvement in the proposed 
study or other studies under the direction of that investigator or study center, or is a family 
member of the employee or the investigator 
36. patients who report unexplained worsening of vision within the past 3 months (e.g. difficulty 
reading or seeing traffic signs from a distance). A diagnosis of presbyopia established by an 
eye care professional is not exclusionary. 
 
4.3 
Withdrawal and Removal of Subjects 
Subjects will be informed that they are free to withdraw from study treatment and/or the study at 
any time at their own request without prejudice to their future medical care, or that they may be 
withdrawn at any time at the discretion of the investigator or Sponsor for safety, nonadherence to 
protocol requirements, or administrative reasons (eg, termination of study by Sponsor). Subjects 
wishing to withdraw from study treatment will be strongly encouraged to continue in the study and 
have all scheduled study procedures performed. 
A subject must be withdrawn from treatment for the following reasons: 
• subject becomes pregnant 
• A subject’s study treatment will be discontinued if the investigator or Sponsor 
considers it in the subject’s best interest to stop treatment, (eg, for safety or significant 
tolerability reasons such as an AE). Subjects who have one of the following AEs must 
be withdrawn from study treatment. 
• IOP of >21 mm Hg 
• nasal septal perforation 
• new onset or worsening of cataract 
A subject may also be withdrawn from study treatment for the following reasons: 
• lack of efficacy 
• protocol violation 
A subject may be withdrawn from the study for the following reasons: 
• withdrawal of consent 
• adverse event 
• protocol violation that makes it unsafe for the subject to continue in the study 
• termination of the study 
• lost to follow up 
• public health measure 
• other 
If a subject withdraws from the study after starting study treatment, appropriate follow-up must be 
conducted wherever possible. 
 


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4.4 
Follow-Up for Drug Discontinuation/Subject Withdrawal from Study 
If a subject does not return for a scheduled visit, every effort should be made to contact the subject. 
In any circumstance, every effort should be made to document the subject’s outcome, if possible. 
The investigator should inquire about the reason for withdrawal, request the return of all 
investigational product, and request the subject return for a final study visit. 
The date and the reason for subject withdrawal from the study must be recorded on the CRF.  


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5 
STUDY DRUG 
5.1 
Study Drug Treatment and Dosing 
For the single-blind, run-in period, subjects will be dispensed a single-blind kit at Visit 1 
(Screening). Eligible subjects will receive a double-blind study drug kit at Visit 2, Day 1 
(Baseline). Thereafter, at scheduled visits (every 4 weeks through Week 8 during the double-blind 
treatment phase) subjects will receive 1 kit. At Week 12, subjects will receive 3 kits. 
If subject cannot complete the EOS CT scan at Week 24, study staff should not complete Visit 6 
in IWRS. Subjects should continue study treatment until an EOS CT scan can be completed, study 
staff will dispense additional study treatment via the “Unscheduled Visit” functionality in IWRS. 
IWRS will be contacted for each “Unscheduled Visit,” at which time one treatment kit will be 
dispensed. 
The IWRS will assign study drug kit numbers as described in Section 3.3. Study drug packaging 
is described in Section 5.3. 
As shown in Table 1, the study drug dosage during the double-blind treatment phase will be 186 
or 372 μg of OPN-375 BID or placebo BID. 
Table 1: 
Study Drug Dosing – Double-blind Treatment Phase 
 
OPN-375 Dosage 
Placebo BID 
 
186 μg BID 
372 μg BID 
Time 
AM 
PM 
AM 
PM 
AM 
PM 
Bottle 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
1 
2 
Left nostril 
PBO 
93 
PBO 
93 
93 
93 
93 
93 
PBO 
PBO 
PBO 
PBO 
Right nostril 
PBO 
93 
PBO 
93 
93 
93 
93 
93 
PBO 
PBO 
PBO 
PBO 
BID=twice a day; AM=morning; PBO=placebo; PM=evening. 
Throughout the study, subjects will be instructed to shake the study drug before use. They will 
also be instructed that it is only necessary to prime each unit before it is used for the first time as 
follows: 
• To prime study drug, shake then actuate and spray into the air 7 times or until a fine mist 
appears. Note that it is not necessary to prime before every administration when it is being 
used regularly each day.  
During the single-blind run-in and the double-blind treatment phases, the same dosing procedure 
will be followed for both the AM and PM doses on each day. The study staff will instruct the 
subject that before the AM and PM doses on each day, they will pick up the unit marked 1, shake 
it, then administer 1 spray to the right nostril followed by 1 spray to the left nostril, and then to 
pick up the unit marked 2 and repeat the same procedure.  
The first dose of double-blind study drug should be administered in the PM on the day of 
randomization. Throughout the study, subjects will be instructed to administer study drug 
approximately every 12 hours. If a subject misses a dose, the dose should be taken as soon as 
remembered, but not within 2 hours of the next scheduled dose. In such cases the subject should 
wait until the next scheduled dosing time to administer a dose.  
The study staff will instruct subjects to report study drug they perceive to be broken or 
malfunctioning and to return to the study site for evaluation and identification of the problem. 
An instruction sheet on the use of study drug will be provided by the Sponsor or their designee to 
be given to the subjects. 
 


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5.2 
Clinical Supplies 
The fluticasone propionate suspension formulation is a milky, pale, white liquid contained within 
an EDS. Each actuation delivers 93 µg of fluticasone propionate through the sealing nosepiece. 
Once primed, study drug contains not less than 120 metered sprays. 
The placebo used in this investigation will be a formulation identical to the active with the omission 
of the drug substance fluticasone propionate and will be delivered by an identical delivery system 
to the active formulation. 
 
5.3 
Packaging and Labeling 
The practice EDS is to be used only at Visit 1 (Screening) to confirm a subject’s ability to use the 
EDS and will be packaged in a demonstrator model EDS kit containing 1 unit. 
Study drug will be packaged identically for each unit of study drug and placebo, and each study 
drug kit, including the single-blind kit, and will consist of 2 units, 1 marked “1” and 1 marked “2”; 
each unit will contain either 120 sprays of study drug or placebo as necessary to maintain the blind.  
Labeling will contain all information required by local regulations. 
 
5.4 
Dispensing and Return of Study Drug 
The investigator or designee at each site will maintain accurate records of study drug, including to 
whom study drug has been dispensed, dates and quantity. All study drug should be returned to 
storage, and accounted for, including dates and quantity (subject by subject accounting). Any study 
drug unit accidentally or deliberately destroyed will also be documented. 
 
5.5 
Storage and Reconciliation of Supplies 
All study drug will be supplied by the Sponsor and should be stored securely in a locked facility. 
All study drug must be stored at room temperature (between 15°C and 25°C: 59°F and 77°F, with 
excursions permitted from 15°C and 30°C: 59°F and 86°F). Avoid exposure to extreme heat, cold 
or light. Shake study drug before each use. Keep all study drug in the manufacturer’s packaging. 
The shelf life of the product will be supported by ongoing stability studies.  
All used and unused study drug units will be returned to the Sponsor or designee at the end of the 
study. Reasons for departure from the expected dispensing or return of study drug units must be 
recorded. 
 
5.6 
Concomitant Medication 
All pre-study medications used within 1 month before Visit 1 (Screening) must be recorded in the 
CRF. For subjects with comorbid asthma or COPD, pre-study inhaled steroid (beclomethasone or 
equivalent) use within the 3 months before Visit 1 (Screening) must be recorded in the CRF.  
Concomitant medications include all medications and other treatments taken by the subject during 
the study, including those treatments initiated prior to the start of the study. All concomitant 
medications must be recorded on the CRF. 


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5.6.1 
Allowed Concomitant Medications 
In subjects with comorbid asthma at study entry (ie, Visit 1 [Screening]), inhaled corticosteroid 
use must be limited to stable doses of ≤1000 μg/day of beclomethasone HFA (or equivalent; see 
Attachment 1). Subjects must be on a stable dose for at least 3 months before Visit 1 (Screening) 
with plans to continue use throughout the study.  
Other concomitant medications allowed include: 
• Antibiotic medications for bacterial infections that develop during the study. 
• Intranasal saline spray with the exception of use within 2 hours before or after study 
drug administration. 
• Saline lavage only for those subjects regularly using it before study entry; subjects may 
not initiate use during the study(saline lavage must not be performed within 2 hours 
before or after study drug administration or within 48 hours prior to a CT scan) 
• Intranasal antibiotics in conjunction with lavage, but must not be given within 2 hours 
before or after study drug administration. 
• Stable doses (within 2 weeks of Visit 1 [Screening]) of leukotriene receptor 
antagonists, beta-blockers, and neuroleptics. 
• Low to medium strength topical corticosteroids for dermatologic purposes  
• Montelukast sodium (Singulair) for subjects using it before study entry provided its use 
is continued throughout the study. 
• Aspirin use for desensitization only for those subjects who were receiving therapy prior 
to study entry and whose symptoms were stable. 
• Oxymetazoline or other topical nasal decongestant as part of the nasal examination only 
but may not be used within 24 hours of CT scan being performed 
5.6.2 
Rescue Medication 
Use of rescue medication for CRS symptoms is not allowed during the single-blind run-in or before 
the Week 4 visit of the double-blind treatment phase. Subjects will be allowed to use over-the-
counter non-sedating antihistamine (eg, cetirizine, levocetirizine, desloratadine) at the label-
recommended, usual dose per day as rescue medication following the Week 4 visit.  
Other concomitant medications are allowed, if not specially listed below as prohibited. 
5.6.3 
Prohibited Medications 
• Exposure to any glucocorticoid treatment with potential for systemic effects (eg, oral 
or parenteral steroids, high dose topical steroids) within 1 month before the screening 
visit through completion of the study; except as noted for subjects with comorbid 
asthma or COPD. 
• Any systemic, inhaled, intranasal and topical corticosteroids (except low to medium 
strength topical corticosteroids as noted above)  
• XHANCE 
(fluticasone 
propionate), 
mepolizumab, 
reslizumab, 
dupilumab, 
omalizumab, or benralizumab 
• Use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (eg, ritonavir, atazanavir, 
clarithromycin, 
indinavir, 
itraconazole, 
nefazodone, 
nelfinavir, 
saquinavir, 


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ketoconazole, telithromycin, conivaptan, lopinavir, voriconazole, cobicistat) because 
increased systemic corticosteroid AEs may occur 
• Steroid Eluting Sinus Implant (Propel®, SINUVA®) 
 
5.7 
Treatment Compliance 
At each visit after Visit 1 (Screening), subjects will be instructed to bring their partially used/empty 
study drug units back to the study site at each study visit where it will be visually inspected. At 
each study visit, all subjects will be reminded of the importance of compliance with their assigned 
regimen with an emphasis on correct use of study drug and the administration of and timing of 
doses. 


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6 
VISIT SCHEDULE SUMMARY 
Procedures to be performed at each study visit, and the visit time windows, are indicated in the 
Schedule of Study Procedures and Evaluations. Additional information related to the individual 
study visits is presented below: 
• CT scans are required at Baseline and Week 24/ET to evaluate eligibility criteria and primary 
and secondary endpoints. All CT scans will be sent to a central imaging core lab for review 
and analysis. The baseline CT scan should be performed after all other screening assessments 
are completed for subjects who remain eligible (unless utilizing CT scan performed within 14-
days prior to Visit 1). 
• Subjects who develop an acute upper respiratory tract infection, acute sinusitis, influenza, or 
SARS-CoV-2 (COVID-19) during the study must be symptom free for at least 28 days prior 
to undergoing the Week 24/EOS CT scan. Subjects should continue treatment with study 
medication until EOS CT scan can be completed. 
• For the Week 24 study visit, if the nasal examination or CT scan, cannot be performed on the 
same day as the study visit, they should be performed before the on-site study visit. 
 
6.1 
Visit 1 (Screening/Single-Blind Placebo Run-in) 
After informed consent has been obtained, subjects will undergo all Visit 1 (Screening) procedures 
to determine study eligibility. 
Subjects will be instructed on the use of OPN-375. They will then be provided with an EDS to 
practice administration of a dose and to assure that they can correctly use OPN-375 (eg, able to 
obtain a seal, sequence). The assignment of a kit number for the practice EDS is not performed by 
IWRS; rather, the study staff will dispense a practice EDS kit and record the kit number in the 
drug dispensing log. This kit is only to be used at the site at Visit 1 (Screening) and is not to be 
sent home with the subject. 
Subjects who meet eligibility criteria at Visit 1 (Screening) will enter a 7- to 21-day, single-blind, 
placebo run-in period to confirm symptom severity and to ensure that they can comply with study 
procedures. Subjects will be given a single-blind- placebo drug kit (containing 2 placebo units) 
assigned through the IWRS and an electronic diary and will be instructed on their use. 
During the single-blind run-in period, subjects will administer morning and evening doses of the 
study drug (placebo) as described in Section 5.1. Subjects will be required to keep a daily diary of 
nasal symptoms. The electronic diary will be completed immediately before the morning and 
evening doses and will include recording of both instantaneous (evaluation of symptom severity 
immediately preceding the time of scoring) and reflective (evaluation of symptom severity over 
the past 12 hours) scores for nasal symptoms (see Section 7.2). Subjects will be instructed that the 
use of rescue medication for CRS symptoms is not allowed. Subjects will be instructed to bring 
the single-blind placebo drug kit and the diary with them to their next visit (Visit 2, Day 1 
[Baseline]).  
The site staff will monitor the electronic diary transmission reports to ensure that subjects are 
recording both morning and evening nasal symptoms and that the data are being transmitted to the 
data base. Site staff should follow-up with subjects as necessary to counsel them on completion of 
the electronic diaries. The site staff will evaluate the subject’s severity scores, entered remotely 
into the electronic diaries, and will be notified when the subject meets eligibility criteria pertaining 


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to their symptoms. When a subject reaches an average congestion severity score of at least 1.5 
over a 7-day period during the first 14 days of the single-blind run-in period, they will be scheduled 
to have the CT scan to assess remaining eligibility requirements. The CT scan should be performed 
after diary eligibility is confirmed and prior to day 21 of the screening run-in period. CT scans 
performed prior to Day 21 and within 2 weeks before Visit 1, as part of routine clinical care, may 
be utilized providing the scan meets the CT scan standards outlined in the Imaging Charter for this 
protocol. 
 
6.2 
Visit 2 (Day 1, Baseline; Randomization) 
Once it is confirmed that the eligibility criteria based on the CT scan are met, the remainder of 
study procedures should be performed.  
Subjects who then meet all eligibility criteria at Visit 2, Day 1 (Baseline) will be randomly assigned 
through the IWRS to 1 of 3 arms: 186 or 372 μg of OPN-375 BID, or placebo BID. Study drug 
will be administered as described in Section 5.1. Subjects will be given 1 double-blind- study drug 
kit (containing 2 devices) assigned through the IWRS and an electronic diary and will be instructed 
on their use. Subjects will be instructed to bring the study drug kits and diary with them to their 
next visit.  
Subjects will be required to keep an electronic daily diary of nasal symptoms. The diary will be 
completed immediately before the morning and evening doses and will include recording of both 
instantaneous and reflective scores for nasal symptoms (see Section 7.2). Subjects will be 
instructed that the use rescue medication for CRS symptoms is not allowed. 
The site staff will monitor the electronic diary transmission reports to ensure that subjects are 
recording both morning and evening nasal symptoms and that the data are being transmitted to the 
data base. Site staff should follow-up with subjects as necessary to counsel them on completion of 
the electronic diaries. 
 
6.3 
Visits 3, 4, and 5 (Weeks 4, 8, and 12) 
During the 24-week double-blind treatment phase, subjects will return to the study site at Weeks 
4, 8 and 12 to have efficacy and safety assessments performed. 
At all visits during the double-blind treatment phase, treatment compliance will be monitored as 
described in Section 5.7. Subjects will be given a double-blind- study drug kit (containing 
2 devices) assigned through the IWRS at Visit 3/Week 4 and Visit 4/Week 8. Subjects will receive 
3 kits at Visit 5/Week 12. Subjects will be instructed to bring the study drug kits with them to each 
visit. 
Subjects will be required to keep a daily diary of nasal symptoms through Week 12. The diary will 
be completed immediately before the morning and evening doses and will include recording of 
both instantaneous and reflective scores for nasal symptoms (see Section 7.2). Subjects will also 
be instructed that the use of rescue medication for CRS symptoms is not allowed until after the 
Week 4 visit; starting at the Week 4 visit, they will be instructed to record use of the approved 
rescue medication in the electronic diary. Subjects will be instructed to bring the diary with them 
to all study visits. 
The site staff will continue to monitor electronic diary transmission reports throughout the first 
12 weeks of double-blind treatment to ensure that subjects are recording both morning and evening 


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nasal symptoms and rescue medication use and that the data are being transmitted to the data base. 
Site staff should follow-up with subjects as necessary to counsel them on completion of the 
electronic diaries. 
 
6.4 
Subject Contact (Week 16 and Week 20) 
Subjects will be contacted at Weeks 16 and 20 (approximately every 4 weeks after Visit 5 (Week 
12) and before Visit 6 (Week 24) to obtain information on treatment compliance, exacerbation 
assessment, AEs, and concomitant medications. 
 
6.5 
Visit 6 (Week 24 End-of-Double-Blind/Early Termination)  
Subjects who complete the 24-week double-blind treatment phase, and those who prematurely 
withdraw from the study for any other reason during this phase should return to the study site and 
have the end-of-study/ET from study visit performed, including a CT scan. If a subject could not 
complete EOS CT scan at the Week 24 visit, subject should have all other scheduled procedures 
performed and continue on study treatment until an EOS CT scan can be completed. Additional 
treatment kits can be dispensed via the ‘Unscheduled Visit’ functionality and the Visit 6 contact 
should not be completed in IWRS. If subject continues treatment, study staff will complete subject 
contacts approximately every 4 weeks to assess safety until subject can complete the EOS CT scan. 
When EOS CT scan has been completed and subject returns to study site, study staff will perform 
an additional SNOT-22, urine pregnancy test (women of child-bearing potential only), and contact 
IWRS to complete Visit 6. 
 
6.6 
Unscheduled Visits 
The Investigator may, at their discretion, arrange for a subject to have an unscheduled 
assessment(s) at any time, especially in the case of AEs that require follow-up. 


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7 
STUDY PROCEDURES AND ASSESSMENTS 
7.1 
Medical History, Demographics, and Baseline Characteristics 
7.1.1 
Medical History 
A complete medical history will be obtained before randomization to ensure subjects qualify for 
the study. Data collected will include medical, surgical and smoking history. 
7.1.2 
Information Pertaining to Chronic Rhinosinusitis 
Information pertaining to the subject’s CRS, including date of initial diagnosis, number of 
exacerbations in the previous year, prior treatments for the condition (eg, surgery, medication) will 
be collected. 
7.1.3 
Demographic Information and Baseline Characteristics 
Demographic information will include age, sex, race, and ethnicity. 
 
7.2 
Efficacy Assessments 
Electronic diaries will be used by subjects during the single-blind placebo -run-in period and 
double-blind treatment phase in this study to capture daily nasal symptoms (ie, symptom scores 
for nasal congestion, nasal discharge [anterior and/or posterior], facial pain or pressure sensation, 
and sense of smell) and the use of approved rescue medication after the Week 4 visit through Week 
12 of the double-blind phase. The Schedule of Study Procedures and Evaluations indicates the 
timing of all assessments; further information on each evaluation is provided below.  
The electronic diaries will be preprogrammed to transmit subject-entered data daily to the 
electronic diary data base. The site staff will monitor the electronic diary transmission reports to 
ensure that subjects are recording both morning and evening nasal symptoms and rescue 
medication use and that the data are being transmitted to the data base. Site staff should follow-up 
with subjects as necessary to counsel them on completion of the electronic diaries. 
Additional information on the nasal examination can be found in Section 7.4.2. 
The following efficacy evaluations will be performed: 
• At Visit 1 (Screening), study personnel should provide each subject with the 
description for each symptom severity (ie, mild, moderate, severe) using the definitions 
provided in Table 2. Each subject will then be asked to provide the severity of their 
nasal symptoms, on average, over the past 7 days. Subjects must report at least 
moderate severity of nasal symptoms to enter the study. 
• An electronic diary will be provided to each subject. Subjects will be instructed to 
complete the electronic diary twice daily immediately before dosing (morning and 
evening) during the single-blind placebo run-in period (for eligibility) and during the 
first 12 weeks of the double-blind treatment phase. Subjects will report both 
instantaneous (evaluation of symptom severity immediately preceding the time of 
scoring) and reflective (evaluation of symptom severity over the past 12 hours) scores 
for:  
• nasal congestion symptoms, nasal discharge (anterior and/or posterior) symptoms, and facial 
pain or pressure sensation symptoms, scored on the scale in Table 2 


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Table 2:  
Nasal Symptom Scale 
Score 
Descriptiona 
0 
None 
1 
Mild – symptoms clearly present, but minimal awareness, and easily tolerated 
2 
Moderate – definite awareness of symptoms that is bothersome but tolerable 
3 
Severe – symptoms that are hard to tolerate, cause interference with activities or daily living 
a Scale will also be used by subjects to score nasal congestion/obstruction symptoms for the 7-day 
period preceding Visit 1 (Screening). 
Note: Sense of smell, scored as 0=normal, 1=slightly impaired, 2=moderately impaired, 3=absent. 
 
• SNOT-22 is a subject-completed questionnaire that consists of 22 symptoms and 
social/emotional consequences of their nasal disorder. Each item is rated as follows: 0=no 
problem, 1=very mild problem, 2=mild or slight problem, 3=moderate problem, 4=severe 
problem, 5=problem as bad as it can be. The SNOT-22 is validated in CRS (Hopkins 2009). 
The recall period is the past 2 weeks. The SNOT-22 takes approximately 5 minutes to 
complete. 
• Recording of each dose of approved rescue medication after the Week 4 visit through Week 
12 
• The EQ-5D consists of 2 pages: the EQ-5D descriptive system and the EQ visual analogue 
scale (EQ VAS). The descriptive system comprises 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no 
problems, slight problems, moderate problems, severe problems, and extreme problems. 
The subject is asked to indicate his/her health state by ticking the box next to the most 
appropriate statement in each of the 5 dimensions. This decision results in a 1-digit number 
that expresses the level selected for that dimension. The digits for the 5 dimensions can be 
combined into a 5-digit number that describes the subject’s health state. The EQ VAS 
records the subject’s self-rated health on a vertical VAS, where the endpoints are labelled 
‘The best health you can imagine’ and ‘The worst health you can imagine’. The VAS can 
be used as a quantitative measure of health outcome that reflect the subject’s own 
judgement. The EQ-5D takes 1-2 minutes to complete. 
• SF-36v2 is a multipurpose, 36-item subject-completed validated questionnaire that 
measures 8 domains of health: physical functioning, role limitations due to physical health, 
bodily pain, general health perceptions, vitality, social functioning, role limitations due to 
emotional problems, and mental health. The SF-36v2 survey with a 4-week recall will be 
used. It yields scale scores for each of these 8 health domains, and 2 summary measures of 
physical and mental health: the PCS and MCS. The SF-36v2 takes approximately 
10 minutes to complete. (Optum.com Web site) 
• SF-6D is a single health state index derived from the 8 domains from the SF-36v2 (using 
all but the general health domain and combining role physical and role emotional) 
• PSQI is a validated, self-rated questionnaire, which assesses sleep quality and disturbances 
over a 1-month time interval. Nineteen individual items generate 7 "component" scores: 
subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep 
disturbances, use of sleeping medication, and daytime dysfunction. The sum of scores for 
these 7 components yields 1 global score. The PSQI takes approximately 3-5 minutes to 
complete 


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• The 16-item QIDS (Rush et al, 2003) is designed to assess the severity of depressive 
symptoms. The QIDS is available in a self-rated version and assesses all the criterion 
symptom domains designated by the American Psychiatry Association Diagnostic and 
Statistical Manual of Mental Disorders - 5th Edition to diagnose a major depressive episode. 
The 7-day period prior to assessment is the usual time frame for assessing symptom 
severity. The psychometric properties of the QIDS, has been established in various study 
samples. The time required to complete the QIDS is approximately 2-4 minutes.  
• SIT is a test comprised of 4 booklets each containing 10 microencapsulated (scratch and 
sniff) odors. Forced choice response alternatives accompany each test item. The test 
provides an absolute indication of smell loss (anosmia; mild, moderate or severe 
hyposomia) as well as an index to detect malingering. The test is self-administered and 
takes 10-15 minutes. 
• Acute exacerbations of CRS are defined as worsening of symptoms requiring antibiotic or 
corticosteroid use, specifically: 
• an event characterized by acute worsening of one or more of the cardinal diagnostic 
symptoms of CRS (listed below), lasting at least 3 days, that cause the subject to seek 
medical care: 
− facial pain or pressure 
− nasal congestion/blockage 
− rhinorrhea  
− reduction in sense of smell 
AND 
− escalation of treatment, defined as either initiation of antibiotics or oral steroids, 
or the escalation of treatment involving an unscheduled acute care visit (eg, 
emergency room or acute care outpatient clinic) or inpatient care, for increased 
symptoms of CRS or for acute sinusitis. 
*If an exacerbation start date is less than 7 days after the end date of a previous 
exacerbation, the entire period will be treated as a single exacerbation. 
• Antibiotic use for acute sinusitis during study participation will be captured. 
• Assessments from CT scan will be performed for both the baseline CT scan and the 
Week 24/ET (Visit 6) CT scan 
• Lund-Mackay Staging System: Lund-Mackay system (Lund and Mackay, 1993) assigns to each 
of 10 sinus cavities (left and right maxillary, anterior ethmoid, posterior ethmoid, sphenoid, 
and frontal) a score of 0 (no opacification), 1 (partial opacification), or 2 (total opacification) 
based on the extent of mucosal thickening within that sinus, plus a 0-2 score for each OMC. 
The total Lund-Mackay score for a CT scan ranges from 0-24. 
• Zinreich Modification of the Lund-Mackay Staging System (Zinreich 2004): Zinreich modified 
the Lund-Mackay system by creating subdivisions within “partial opacification” and 
increasing the range of scores to 0-5 based on percent opacification: 0 = 0%, 1 = 1%-25%, 2 = 
26%-50%, 3 = 51%-75%, 4 = 76%-99%, and 5 = 100% 


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• Percent of sinus volume occupied by disease for the worst maxillary and the worst ethmoid 
sinus: calculated using the methods outlined in the imaging charter 
• Subject global impression of change will be assessed using a subject-completed PGIC scale as 
shown in Table 3. The PGIC takes less than 1 minute to complete. 
Table 3: Patient Global Impression of Change (PGIC) Scale 
Since starting the study drug, how would you rate the change in your symptoms? 
Score 
Description 
1 
Very much improved 
2 
Much improved 
3 
Minimally improved 
4 
No change 
5 
Minimally worse 
6 
Much worse 
7 
Very much worse 
Note: Subjects will be considered improved if they have a PGIC of 1, 2, or 3 (very much 
improved, much improved, or minimally improved). Subjects with missing values will be 
considered not improved. 
 
7.3 
Health Economic Assessments 
Health economic information related to bilateral CRS will be collected during the study and will 
include information on criteria for surgical intervention (independent of actual surgery performed), 
subjects approved for surgery, who no longer elect to undergo surgery, and missed work or school 
days/lost productivity. The investigator will ask the subject if he/she would consider surgery and 
the subject will complete the HPQ (1-2 minutes to complete). 
Objective criteria for surgical intervention are as follows: 
• used topical intranasal corticosteroid (≥8 weeks duration) 
• used either a short course of broad-spectrum/culture-directed systemic antibiotic (2 to 3 weeks 
duration) or a prolonged course of systemic low-dose -anti-inflammatory antibiotic (ie, 
macrolide or trimethoprim/sulfamethoxazole) (≥12 weeks duration) 
• SNOT-22 total score ≥20 
• Lund-Mackay CT score ≥ 1 
• subjects who enter the study approved for surgery with a scheduled surgery date, who no longer 
elect to undergo surgery 
• The work productivity questionnaire asks about employment status, work absences, and on-the-
job productivity. Subjects will also be asked to provide annual salary and postal code 
information at screening which will be used to inform overall cost to employers from lost work 
productivity. 
 
7.4 
Safety Assessments 
Refer to the Schedule of Study Procedures and Evaluations, for the timing of all safety 
assessments. 
Safety will be assessed by performing a physical examination and evaluating clinical laboratory 
variables at Visit 1 (Screening), and throughout the study based on monitoring of AEs (as 


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described in Section 8), performing nasal examination, measuring vital signs (ie, blood pressure, 
pulse) and weight, and through collection of information for concomitant medications. 
7.4.1 
Physical Examination 
A brief physical examination will be performed on all subjects at Visit 1 (Screening). Height will 
be collected. 
7.4.2 
Nasal Examination 
The nasal examination will be performed via nasoendoscopy; see Section 6, Visit Schedule 
Summary, regarding completion of this assessment, including visit time windows. The sites will 
be provided with a nasal examination worksheet. A summary of the key safety assessments from 
the nasal examination is provided in Attachment 3. Findings from the nasal examination worksheet 
that are deemed to be clinically significant by the Investigator will be recorded on the AE CRF 
beginning at Visit 1 (Screening). 
7.4.3 
Ocular examinations 
An ocular examination must promptly be performed if a subject experiences any unexplained 
worsening in vision during the study (e.g. difficulty reading or seeing traffic signs from a distance). 
The examiner must be a health care provider with expertise in examination and diagnosis of 
conditions of the eye. Reports will be forwarded to the investigator. 
7.4.4 
Vital Signs and Weight 
Vital signs include systolic and diastolic blood pressure measurements and pulse rate. Before vital 
signs are measured, the subject should be at rest for at least 5 minutes. Weight will be measured at 
each visit. 
7.4.5 
Laboratory Variables 
Blood and urine samples will be collected at Visit 1 (Screening) for evaluation of laboratory 
variables shown in Table 4. The total amount of blood to be taken from each subject for these 
study specific- measurements is approximately 7 mL. 


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Table 4:  
Laboratory Measurements 
Hematology 
Serum chemistry 
• 
hemoglobin concentration 
• 
red blood cell count 
• 
mean corpuscular volume (MCV) 
• 
white blood cells (total and differential) 
• 
platelet count 
• 
hematocrit 
• sodium 
• potassium 
• calcium 
• chloride 
• urea 
• creatinine 
• total bilirubin 
• alkaline phosphatase 
• alanine transferase (ALT) 
• aspartate transferase (AST) 
• gamma-glutamyltransferase (GGT) 
• albumin 
• total protein 
• glucose 
Urinalysis (dipstick) 
Urine Drug Screen 
• pH 
• glucose 
• protein 
• ketone bodies 
• indicators of red and white blood cells 
• cocaine 
• phencyclidine 
• amphetamines class 
• benzodiazepines class 
• barbiturates class 
• opiates class 
• propoxyphene 
• methaqualone 
• methadone 
• Women of child-bearing potential only: A urine pregnancy test will be performed at each visit, not 
including Subject Contacts. Subjects continuing treatment past Week 24/Visit 6 will need an 
additional pregnancy test completed upon returning to site. 
 
At Visit 6/Week 24/ET, a blood sample will be obtained for SARS-CoV-2 serology testing. 
Blood samples and urine drug screens will be analyzed at a central laboratory facility. Urine 
samples will be analyzed by dipstick and a microscopic analysis will be performed if the results 
of dipstick indicate abnormalities to be further investigated. All laboratory reports must be 
reviewed, signed, and dated by the investigator. A legible copy of all reports must be filed with 
the subject’s source documentation.  
If any laboratory tests are performed as part of a subject’s standard of care after Visit 1 (Screening) 
and before Visit 2, Day 1 (Baseline), and a change from the Visit 1 (Screening) laboratory test 
result is considered by the investigator to be clinically significant, the investigator should reassess 
the subject’s eligibility. If any laboratory tests are performed as part of a subject’s standard of care 
after the subject is randomized, and a change from the Visit 1 (Screening) laboratory test result is 
considered by the investigator to be clinically significant, it should be considered an AE if it meets 
the definition provided in Section 8.1. Significant abnormal values occurring during the study will 
be followed until repeat test results return to normal, stabilize, or are no longer clinically 
significant. 


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8 
SAFETY MONITORING AND REPORTING 
8.1 
Adverse Events 
An AE is any untoward medical occurrence associated with the use of an investigational product 
in humans, whether or not considered related to the investigational product. This includes any 
occurrence that was new in onset or aggravated in severity or frequency from the baseline 
condition.  
In this study, symptoms of CRS are collected as part of the primary and secondary endpoints. 
Changes or worsening of symptoms of CRS should not be reported as AEs. All events that meet 
the definition of a SAE will be reported as SAEs, regardless of whether they are protocol-specific 
assessments.  
Abnormal results of diagnostic procedures, including laboratory test abnormalities, or from the 
nasal examination are considered AEs if they result in: 
• discontinuation from the study treatment or discontinuation from the study 
• require treatment or any other therapeutic intervention 
• require further diagnostic evaluation which confirms a clinically significant abnormality 
(excluding a repetition of the same procedure that rules out an abnormality) 
• are associated with clinical signs or symptoms that would have a significant clinical impact, as 
determined by the investigator 
Subjects are encouraged to report AEs spontaneously or in response to general, non-directed 
questioning. All non-serious AEs are to be followed until the subject completes the study or is lost 
to follow-up. 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
is crucial for the protection of subjects, is the responsibility of the investigators and the Sponsor, 
and is mandated by regulatory agencies worldwide. 
Each AE is to be documented on the CRF with reference to intensity, date of occurrence, duration, 
frequency, treatment, action taken regarding study drug, and outcome. Furthermore, each AE is to 
be classified as being serious or non-serious. Additionally, the investigator has to assess whether 
the AE is drug related (adverse drug reaction) or not. Changes of AEs and dates of ending have to 
be documented on the CRF. 
Surgical procedures, planned before enrollment of the subject in the study, are not considered AEs 
if the condition(s) was (were) known before study inclusion. In the latter case, the medical 
condition should be reported in the subject’s medical history. 
For the purposes of this study, the period of observation for collection of AEs extends from the 
time the subject gives informed consent until completion of the end-of-study visit or an early 
termination visit. SAEs will be reported through 30 days after the last dose of study drug 
administration. 
The maximum severity (intensity) of the AE will be categorized by the investigator as shown in 
Table 5. 


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Table 5:  
Adverse Event Severity 
Code 
Descriptor 
Definition 
1 
Mild 
The subject is aware of the symptom, but easily tolerates it 
2 
Moderate 
The subject has discomfort enough to cause interference with usual activity. 
3 
Severe 
The subject is incapacitated to work or perform the usual activities 
 
8.2 
Adverse Reactions 
An AE is considered related to study drug (adverse reaction) if there is evidence to suggest a causal 
relationship between the treatment and the AE. 
 
8.3 
Suspected Adverse Reactions 
“Suspected adverse reactions” means any AE for which there is a reasonable possibility that the 
drug caused the AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the AE. A “suspected adverse reaction” implies a lesser degree 
of certainty about causality than “adverse reaction” which means any AE caused by a drug. 
An AE is considered to be a suspected adverse reaction if: 
• The AE is a single occurrence of an uncommon AE that is known to be strongly 
associated with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson 
Syndrome).  
• The AE occurs 1 or more times and is not commonly associated with drug exposure, 
but is otherwise uncommon in the population exposed to the drug (eg, tendon rupture). 
• The AE is part of an aggregate analysis of specific AEs observed in a clinical trial (such 
as known consequences of the underlying disease or condition under investigation or 
other events that commonly occur in the study population independent of drug therapy) 
that indicates those AEs occur more frequently in the drug treatment group than in a 
concurrent or historical control group.  
Suspected adverse reactions are the subset of all AEs for which there is a reasonable possibility 
that the drug caused the event. Inherent in this definition and in the requirement to report them, is 
the need for the Sponsor to evaluate the available evidence and make a judgment about the 
likelihood that the drug actually caused the AE.  
 
8.4 
Unexpected Adverse Reactions or Adverse Events 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the IB or is 
not listed at the specificity or severity that has been observed. “Unexpected,” as used in this 
definition, also refers to AEs or suspected adverse reactions that are mentioned in the IB as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under investigation. 
The suspected adverse reactions listed in the IB (ie, “expected”) are those observed with the 
investigational drug and for which a causal relationship between the event and the drug is 
suspected or confirmed. Thus, AEs that would be anticipated to occur as part of the disease process 
are considered unexpected for the purposes of reporting because they would not be listed in the IB. 
Additionally, AEs that are listed in the IB as occurring with the same class of drugs, or as 


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anticipated from the pharmacological properties of the drug, even though they have not been 
observed with the drug under investigation, will be considered unexpected until they have been 
observed with the drug under investigation.  
 
8.5 
Serious Adverse Events 
An AE or suspected adverse reaction is considered “serious” if at any dosage, in the view of either 
the investigator or Sponsor, it meets one or more of the following criteria:  
• is fatal 
• is life-threatening 
• results in inpatient hospitalization or prolongation of existing hospitalization 
• results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• is a congenital anomaly/birth defect 
Other important medical events that may not be immediately life-threatening or result in death or 
hospitalization, based upon appropriate medical judgment, are considered SAEs if they are thought 
to jeopardize the subject and/or require medical or surgical intervention to prevent one of the 
outcomes defining an SAE. Since SAEs are critically important for the identification of significant 
safety problems, it is important to take into account both the investigator’s and the Sponsor’s 
assessment. If either the Sponsor or investigator believes that the event is serious, the event must 
be considered serious and evaluated by the Sponsor for expedited reporting. 
All SAEs must be reported to the Sponsor or their designee within 24 hours after the investigator 
becomes aware of the event, along with a determination as to whether it is associated with the 
study drug, device, or procedure.  
8.5.1 
Life-Threatening Adverse Events 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or Sponsor, its occurrence places the subject at immediate risk of death. It does not 
include an AE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. As with the definition of serious, the determination of whether an AE is life-
threatening can be based on the opinion of either the investigator or Sponsor. Thus, if either 
believes that it meets the definition of life-threatening, it must be considered life-threatening for 
reporting purposes.  
8.5.2 
Serious Adverse Event Reporting 
All SAEs must be reported within 24 hours to: 
PPD 
Safety Email: safety@optinose.com 
Safety Fax: 1-267-521-0750 
Note: If the contact information above changes during the course of the study, written notification 
will be provided by the Sponsor or their designee to the investigator, and a protocol amendment 
will not be required. 


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It is imperative that PPD be informed within 24 hours after the investigator becomes aware of a 
SAE so that reporting to the Regulatory Agencies can be met within the required time frame 
(7 or 15 calendar days). 
Because of the need to report to health authorities all SAEs in a timely manner, it is vitally 
important that an investigator report any AEs that would be considered serious within 24 hours, 
even if the investigator does not consider the AE to be clinically significant or drug-related. 
Should the investigator become aware of an SAE (regardless of relationship to study drug) that 
occurs within 30 days after stopping the study drug, the SAE must be reported in accordance with 
the procedures specified in this protocol. There is no time limit on the collection of SAEs that are 
considered related to study drug. 
All SAEs that are not resolved by the end of the study, or that were not resolved upon 
discontinuation of the subject’s participation in the study, are to be followed until either: the AE 
resolves, the AE stabilizes, the AE returns to baseline values (if a baseline value is available), or 
it is shown that the AE is not attributable to the study drug or study conduct. 
Medical and scientific judgment is to be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as for important medical events that were not immediately 
life-threatening or did not result in death or hospitalization but are jeopardizing the subject or 
require intervention to prevent one of the outcomes listed above.  
 
8.6 
Non-Serious Adverse Event Reporting 
Non-SAEs will be recorded in the clinical data base in a timely manner to permit review by the 
Sponsor. 
 
8.7 
Pregnancy 
Following administration of study drug, pregnancy cases in any female subject will be reported if 
known until the subject completes or withdraws from the study. The pregnancy will be reported 
immediately by phone and by faxing/emailing a completed Pregnancy Report to the Sponsor or 
their designee within 24 hours of knowledge of the event. The pregnancy will not be processed as 
an SAE; however, the investigator will follow the subject until completion of the pregnancy and 
must assess the outcome in the shortest possible time but not more than 30 days after completion 
of the pregnancy. The investigator should notify the Sponsor or their designee of the pregnancy 
outcome by submitting a follow-up Pregnancy Report. If the outcome of the pregnancy meets the 
criteria for immediate classification of an SAE (eg, spontaneous or therapeutic abortion [any 
congenital anomaly detected in an aborted fetus is to be documented], stillbirth, neonatal death, or 
congenital anomaly), the investigator will report the event by phone and by faxing/emailing a 
completed SAE form to the Sponsor or designee within 24 hours of knowledge of the event. 
Pregnancy in the partners of research subjects does not need to be reported. 


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9 
STATISTICAL ANALYSIS 
A detailed Statistical Analysis Plan (SAP) will be prepared after the protocol is approved. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. Statistical analysis principles to address all study 
objectives are provided below. 
 
9.1 
Sample Size Determination 
Sample size assumptions were originally generated based on previous Phase 3 studies of OPN-375 
in subjects with nasal polyposis and data from a study evaluating the change in maxillary and 
ethmoid opacification in CRS patients treated with an intramuscular dose of triamcinolone 
(Pallanch 2013). Updated standard deviation estimates for both co-primary endpoints in this 
amendment are based on a blinded interim analysis of Protocol OPN-FLU-CS-3205. Based on the 
results for changes from baseline in morning symptoms among subjects with nasal polyps in the 
previous studies conducted with OPN-375, a sample of 70 subjects per group (210 total subjects) 
is sufficient to detect a 0.9 scale difference in 7-day average CSNS (AM instantaneous) between 
treatments (OPN-375 vs placebo) using a 2-sided test at the 5% significance level with 88% power, 
and assuming a standard deviation (SD) of 1.7. This sample size is also adequate to detect a 9% 
difference between treatments in average percent opacification (APOV) using a 2-sided test at the 
5% significance level with 88% power, and assuming a SD of 17%. The sample size was estimated 
for the co-primary efficacy endpoints using Power Analysis and Sample Size Software (PASS 15) 
(NCSS, 2017). 
 
9.2 
Analysis Sets 
9.2.1 
Intent-to-treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all subjects who are randomized regardless of 
whether they received double-blind treatment.  
9.2.2 
Safety Analysis Set 
The safety analysis set will include all randomized subjects who receive at least one dose of 
randomized study drug. The treatment group assignment in this population will be defined by the 
treatment actually received. The safety population will be used for the analysis of safety. 
9.2.3 
Full Analysis Set (FAS) 
The FAS will include all subjects in the ITT set who receive at least one dose of randomized 
study drug during the double-blinded treatment phase, and have at least one baseline efficacy 
measure for APOV endpoint, and also have a baseline value and at least one post-baseline value 
(7-day average AM instantaneous CSNS score) for the CSNS endpoint. Subjects will be included 
in the treatment group to which they were randomized.  
The FAS population will be the primary study population for all efficacy analyses in this study. 
9.2.4 
 Per-Protocol Analysis Set (PPS) 
The PPS analysis set excludes subjects from the FAS population that may substantially affect the 
results of the primary efficacy analysis. The PPS population will be used for a sensitivity analysis 
for primary and key secondary efficacy endpoints.  


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Determination of the subjects excluded from the PPS will be made prior to unblinding treatment 
codes of the database and documented in a separate report. 
 
9.3 
Primary Estimand, Intercurrent Events, and Estimation 
Primary Objective and Population: The primary objective is to compare the efficacy of intranasal 
administration of twice-daily doses of 186 and 372 µg of OPN-375 (fluticasone propionate) with 
placebo in subjects with documented CRS without nasal polyps. 
9.3.1 
Co-primary Endpoints 
• Change from baseline to the end of Week 4 in 7-day average instantaneous AM CSNS 
(evaluation of symptom severity immediately preceding the time of scoring) 
− nasal congestion 
− nasal discharge (anterior and/or posterior) 
− facial pain or pressure sensation 
The baseline CSNS will be the average of the CSNS over the last 7 days of the placebo run-in 
period prior to randomization. The CSNS at Week 4 will be the average of the CSNS over the 
7 days prior to Day 28. 
AND 
• 
The change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses 
(APOV is the average percentage of volume opacified across both maxillary and ethmoid 
sinuses (all 4 sinuses) at each timepoint) 
9.3.2 
Potential Intercurrent Events 
The potential intercurrent events are as follows:  
1. Need for systemic corticosteroids for CRS exacerbation or worsening of CRS nasal/sinus 
symptoms 
2. Need for nasal surgery 
3. Discontinuation from study treatment 
9.3.3 
Primary Estimand 
The primary efficacy estimand is the difference between each active treatment of twice-daily 
doses of 186 µg and 372 µg of OPN-375 and placebo for each of the co-primary endpoints.  
For the primary estimand, intercurrent events will be addressed as follows: 
1. Systemic corticosteroids use for CRS exacerbation or worsening of CRS nasal/sinus 
symptoms: a composite strategy will be employed with a poor score assigned to this 
event.  
For CSNS, a value of ‘9’ will be assigned. For APOV, a poor score is defined as follows: 
for a subject with a baseline APOV ≥ 75%, a value of ‘100%’ will be assigned; if 
baseline APOV < 75%, a poor score is defined as baseline APOV + 25%. Further detail 
regarding the definition of a poor score and the handling of a missing within-instrument 
data in these endpoints is provided in the SAP.  
Systemic corticosteroid use for other indications will be considered a treatment and study 
discontinuation event (Reference criteria 3). 


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2. Nasal surgery: composite strategy with worst scores assigned as above. 
3. Treatment Discontinuation: treatment policy strategy; subjects may continue in the study 
until one of the following three mutually exclusive outcomes:  
a) Subject completes Week 24/ET CT scan. In the absence of an intercurrent event 
(systemic corticosteroids, nasal surgery) use the endpoint value; 
b) An intercurrent event (systemic corticosteroids for CRS exacerbation or 
worsening of CRS nasal/sinus symptoms, nasal surgery) occurs: Use composite 
strategy and assign worse score as described above (reference criteria 1, 2); 
c) Subject discontinues the study. Missing data due to study discontinuation 
following treatment discontinuation will be imputed; further detail on the 
imputation method is provided in the estimation section for each of the co-
primary endpoints. 
9.3.4 
Estimator and Estimation Method – Primary Analysis 
Estimator and estimation method (CSNS): For the co-primary endpoint CSNS, the estimator is 
the mean difference between treatments (active versus placebo) in change from baseline to the 
end of Week 4 in the 7-day average total CSNS (instantaneous AM). Estimation is based on a 
mixed model for repeated measures (MMRM) where changes from baseline to Weeks 2, 4 in the 
7-day average total CSNS (instantaneous AM), respectively, are the repeated measures. The 
MMRM model will employ Restricted Maximum Likelihood (REML) for parameter estimation 
and the Kenward-Roger method for calculating the denominator degrees of freedom. An 
unstructured covariance matrix will be used to estimate within-subject error. For the treatment 
policy estimand, (reference Section 9.3.3, criteria 3c), missing data due to study discontinuation 
will be estimated within the MMRM model under the assumption that the missing data are 
missing at random (MAR) and that early discontinuation from the study (prior to Week 4) is 
unlikely to reflect a treatment effect. 
The MMRM model will include categorical effects for previous sinus surgery (Y,N), treatment 
(OPN-375 186 µg, OPN-375 372 µg, placebo), week (2, 4) treatment-by-week interaction, and 
the continuous covariate baseline 7-day average total CSNS (instantaneous AM) with baseline-
by-week interaction.  
Estimator and estimation method (APOV): For the co-primary endpoint APOV, the estimator is 
the mean difference between treatments (active versus placebo) in the change from baseline to 
Week 24/ET APOV. Estimation is based on an ANCOVA model including categorical effects 
for previous sinus surgery (Y,N), treatment (OPN-375 186 µg, OPN-375 372 µg, placebo), and 
baseline APOV. 
For the treatment policy estimand, (reference Section 9.3.3, criteria 3,c), missing data due to 
study discontinuation will be imputed with a pattern mixture model (PMM) multiple 
imputation (MI) using the Jump–to-Control (J2C) method. The PMM assumes that the missing 
data at Week 24/ET on the control arm (placebo) is MAR, and the missing data on the active 
treatment arms have the profile of the control arm at Week 24/ET.  
Multiple imputation using a PMM with J2C method will be conducted using the sequential 
modeling method as described in (O’Kelly et al, 2014). Further detail on the MI implementation, 
and statistical analysis and inference is provided in the SAP. 
 


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9.3.5 
Supplementary Analysis 
A supplementary analysis of the primary estimand will be performed.  
Supplementary estimand: A supplementary efficacy estimand is the difference between each 
active treatment of twice-daily doses of 186 µg and 372 µg of OPN-375 and placebo in each of 
the co-primary endpoints, irrespective of systemic corticosteroid use. 
That is, for the supplemental estimand, intercurrent events will be addressed as follows: 
1. Systemic corticosteroids use for all indications: treatment policy strategy; consider outcomes 
irrespective of systemic corticosteroid use; subjects may continue in the study until one of the 
following two mutually exclusive outcomes:  
a. Subject completes the study, use the endpoint value; 
b. Subject discontinues the study. Missing data due to study discontinuation following 
treatment discontinuation will be imputed; further detail on the imputation method is 
provided in the estimation section for each of the co-primary endpoints. 
2. Nasal surgery: composite strategy with worst scores assigned. 
3. Treatment discontinuation: composite strategy with poor scores assigned. 
The estimator and estimation methods for the co-primary endpoints are the same as for the 
primary estimand described above. 
 
9.4 
Sensitivity Analyses 
9.4.1 
ANCOVA on Ranked APOV Values 
A sensitivity analysis of the primary estimand and APOV co-primary endpoint will be performed 
based on ranked APOV values after modification of the primary estimand as follows. For the 
composite strategy, a worst score of 100% is assigned; for the treatment policy strategy, baseline 
APOV is assigned (BOCF). Baseline and endpoint APOV values are then ranked. Ranked APOV 
values will be analyzed with an ANCOVA model including categorical effects for previous sinus 
surgery and treatment. Further detail is provided in the SAP. 
9.4.2 
Observed Cases Analysis 
A sensitivity analysis will be performed for both co-primary endpoints based on the FAS, observed 
cases population. For each co-primary endpoint, the observed cases population is defined to 
include all subjects who have an observed value for that endpoint, irrespective of an intercurrent 
event, and the observed value is used in the analysis. For both co-primary endpoints, the estimator 
and estimation methods are the same as described in Section 9.3.4, with the exception that in the 
observed cases population there are no missing data; consequently, no imputation is required. 
9.4.3 
Tipping Point 
If the analysis of both co-primary endpoints is statistically significant, then an additional 
sensitivity analysis will be performed to determine the smallest constant, δ, when applied to the 
imputed missing data in the active treatment groups, that will yield a mean treatment difference 
such that the result using the primary analysis model is no longer statistically significant. The 
constant δ represents a worsening of treatment values and the smallest value, say δ*, that yields a 
non-significant result for the primary analysis is called the “Tipping Point.” Further detail on the 
Tipping Point analysis is provided in the SAP. 
 


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9.5 
Key Secondary Efficacy Analyses  
The analysis of the following key secondary endpoints are based on pooling the data from Study 
OPN-FLU-CS-3205 and Study OPN-FLU-CS-3206 (pooled data): 
• 
Change from baseline to Week 4 on CSNS score in subjects who were symptomatic at trial 
entry despite reported use of an intranasal steroid for treatment of CRS within 30 days of 
Visit 1 will be analyzed using the same MMRM model described for the co-primary endpoint 
CSNS and the model will include a categorical effect term for protocol (CS-3205, CS-3206). 
• 
The frequency of acute sinus exacerbations over 24 weeks will be compared between 
OPN-375 dose groups and placebo using generalized linear model (GLM) for data from the 
negative binomial distribution that is commonly referred to as the negative binomial (NB) 
regression model. The NB model will include the same model terms as the primary models; 
in additional, the model will include a categorical effect for protocol (OPN-FLU-CS-3205, 
OPN-FLU-CS-3206), and the logarithm of follow-up time as an offset variable. The same 
model will be used for the pooled analysis of the frequency of acute sinus exacerbations over 
24 weeks in the CRS without Nasal Polyps population. 
The analysis of the following key secondary endpoints are based on the data from Study OPN-
FLU-CS-3206 only:  
• 
change from baseline to the end of Week 4 in four separate cardinal CRS symptoms, as 
measured by (AM, Instantaneous) CSNS: congestion, facial pain or pressure sensation, nasal 
discharge (anterior and/or posterior), and sense of smell will be analyzed using the same 
MMRM model described above. 
• 
The Kaplan-Meier method and log-rank test will be used to estimate and compare the 
distributions of time to first acute CRS exacerbation between each OPN-375 dose and 
placebo. 
 
9.6 
Other Secondary Efficacy Analyses 
All statistical analyses in this section that reference the primary MMRM and ANCOVA models 
described in Section 9.3.4 will include the same factors as their respective primary models, 
except for the baseline covariate. The baseline covariate for the specific endpoint will be used, 
unless otherwise specified. 
In addition, a combined dose group (OPN-375 186 μg, OPN-375 372 μg) is defined in all models 
of primary and secondary endpoints by including appropriate model contrasts, assigning equal 
weight to each dose, to obtain the inferential statistics for combined doses, and for the 
comparison: combined dose versus placebo. 
Intercurrent events for secondary endpoints will be addressed as described in Section 9.3.3 for 
the primary estimand, unless otherwise indicated, and poor scores assigned to secondary 
endpoints are defined in the SAP. For the treatment policy estimand, missing data due to study 
discontinuation will be handled as described in Section 9.3.4 for the primary MMRM and 
ANCOVA models, respectively.  
The following secondary endpoints will be analyzed with MMRM models; further details will be 
provided in the SAP: 


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• 
Change from baseline in average instantaneous and reflective AM and PM CSNS and 
symptom scores (facial pain or pressure sensation, nasal discharge, sense of smell, and nasal 
congestion) – (except AM, instantaneous symptom scores – key secondary endpoints) 
• 
Change from baseline SNOT-22 total scores and sub-domain scores 
• Change from baseline to Week 24/ET in SNOT-22 total score in subjects from pooling studies 
OPN-FLU-CS-3205 and OPN-FLU-CS-3206 who report using an intranasal, topically acting 
nasal steroid for the treatment of CRS within 30 days of Visit 1 
• 
Change from baseline to Week 24/ET PSQI global and component scores  
• 
Change from baseline to Week 24/ET the Global PSQI Score from pooling studies OPN-
FLU-CS-3205 and OPN-FLU-CS-3206 
• 
Change from baseline to Week 4, 8, 12, and 24/ET in HPQ endpoints 
− number and percentage of missing work days over the past 4 weeks 
− percentage of productive work hours lost over the past 4 weeks 
The following secondary endpoints will be analyzed using an ANCOVA model; further details 
will be provided in the SAP. Change from baseline to Week 24/ET: 
• Lund-Mackay Staging System total score, scores for ethmoids and maxillary sinuses 
combined, and scores for each sinus pair (e.g., ethmoids, maxillary, frontal, sphenoid, and 
ostiomeatal complex), 
• WPOV-E, WPOV-M, WPOV 
• Zinreich modification of the Lund-Mackay Staging System total score, scores for ethmoids 
and maxillary sinuses combined, and for each sinus pair (e.g., ethmoids, maxillary, frontal, 
and sphenoid 
• Zinreich modification of the Lund-Mackay Staging System score for the worst sinus between 
maxillary and ethmoid sinuses 
• percent of opacification of the combined volume of the ethmoid and maxillary sinuses 
• SF36v2 MCS Domain, PCS Domain, and individual health domains 
• QIDS total score 
• SIT scores 
Change from baseline to Week 24/ET for EQ-5D VAS scores will be analyzed with the 
ANCOVA model described above; EQ-5D dimensions will be summarized. Further details will 
be provided in the SAP. 
The percent of subjects considered improved (ie, subjects with ratings of 1 [very much 
improved] or 2 [much improved]) based on the PGIC at weeks 4 and 24/ET will be analyzed 
with a logistic regression MMRM model; further details will be provided in the SAP. 
The following endpoints will be analyzed using a logistic regression model; further details will 
be provided in the SAP: 
• 
QIDS Severity of Depression at Week 24/ET 
• 
The percentage of subjects who meet the eligibility criteria for surgery at Week 24 


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The percent of subjects indicating that they are willing to consider sinus surgery at baseline and 
Week 24, and the percent of subjects approved for surgery who no longer elect to undergo a 
surgery Week 24 within each treatment group will compared with McNemar’s test.  
Change from baseline to Week 24/ET for SF-6D will be summarized as described in the SAP. 
 
9.7 
Subgroup Analyses 
The following endpoints will be analyzed according to the primary estimand by subgroup: Subjects 
with prior sinus surgery versus without prior sinus surgery at baseline. Further detail on the 
statistical methods will be provided in the SAP. 
• 
Co-primary endpoints (CSNS, APOV) 
• 
All CSNS endpoints other than the primary, 
• 
All individual daily nasal symptoms scores that are components of the CSNS (as well as sense 
of smell) 
• 
SNOT-22 total score 
 
9.8 
Type I Error Control for Multiplicity 
9.8.1 
Co-primary Efficacy Endpoints 
The primary hypothesis of this trial is that OPN-375 high dose (372 μg) group will be superior to 
the placebo group in both co-primary endpoints.  
The familywise Type 1 error probability for the test of the primary hypothesis is α=0.05. The 
strategy for strong, familywise control of the Type I error is based on closed testing procedure as 
follows.  
1. Test each co-primary endpoint for OPN-375 high dose (372 μg) vs placebo: If p < 0.05 for both 
endpoints, then proceed to key secondary endpoints; otherwise, stop. The order of the testing is 
as follows:  
a. OPN-375 372 μg versus placebo in the change from baseline in the 7-day average CSNS 
(instantaneous AM) at the end of Week 4  
b. OPN-375 372 μg versus placebo in the APOV in the ethmoid and maxillary sinuses 
change from baseline to Week 24/ET 
9.8.2 
Type I Error Control for Key Secondary Endpoints 
The following planned comparisons are defined based on pooled data from Study OPN-FLU-CS-
3205 and Study OPN-FLU-CS-3206. Testing will continue based on closed testing procedure, with 
α=0.05, if the primary hypothesis is met, as follows:  
1. OPN-375 372 μg versus placebo in the frequency of acute exacerbations of CRS over 24 weeks 
2. OPN-375 372 μg versus placebo in the frequency of acute exacerbations of CRS over 24 weeks 
in CRS without NP population 
3. OPN-375 372 μg versus placebo in change from baseline to Week 4 on CSNS score in subjects 
who were symptomatic at trial entry despite reported use of an intranasal steroid for treatment 
of CRS within 30 days of Visit 1 


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The following planned comparisons are defined based on Study OPN-FLU-CS-3206. Testing will 
continue based on closed testing procedure, with α=0.05, if the key secondary hypotheses (1-3) 
are met, as follows: 
4. Test each co-primary endpoint for OPN-375 low dose (186 μg) vs placebo: If p < 0.05 for 
both endpoints, then proceed to next endpoints; otherwise, stop. The order of the testing is as 
follows:  
a. OPN-375 372 μg versus placebo in the change from baseline in the 7-day average 
CSNS (instantaneous AM) at the end of Week 4  
b. OPN-375 372 μg versus placebo in the APOV in the ethmoid and maxillary sinuses 
change from baseline to Week 24/ET 
5. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in nasal 
congestion  
6. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in nasal 
discharge (anterior and/or posterior) 
7. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in facial pain 
or pressure sensation 
8. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in sense of 
smell 
9. OPN-375 372 μg versus placebo in time to first acute exacerbation of CRS 
The following planned comparisons are defined based on pooled data from Study OPN-FLU-CS-
3205 and Study OPN-FLU-CS-3206. Testing will continue based on closed testing procedure, with 
α=0.05, if the primary hypothesis is met, as follows:  
10. OPN-375 186 μg versus placebo in the frequency of acute exacerbations of CRS over 24  
11. OPN-375 186 μg versus placebo in the frequency of acute exacerbations of CRS over 24 
weeks in CRS without NP population 
12. OPN-375 186 μg versus placebo in change from baseline to Week 4 on CSNS score in 
subjects who were symptomatic at trial entry despite reported use of an intranasal steroid for 
treatment of CRS within 30 days of Visit 1 
The following planned comparisons are defined based on Study OPN-FLU-CS-3206. Testing will 
continue based on closed testing procedure, with α=0.05, if the key secondary hypotheses (9-11) 
are met, as follows: 
13. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in nasal 
congestion in CRS without NP population 
14. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in nasal 
discharge (anterior and/or posterior) 
15. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in facial pain 
or pressure sensation 
16. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in sense of 
smell 
17. OPN-375 186 μg versus placebo in time to first acute exacerbation of CRS 
 


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9.9 
Safety Analysis 
All safety summaries will be descriptive; no statistical inference procedures will be applied. All 
safety summaries will be presented by OPN-375 dose level 186 μg, 372 μg, and OPN-375 
combined doses and placebo. 
9.9.1 
Adverse Events (AEs) 
All reported AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 20 or higher. Treatment emergent AEs (TEAEs) are defined as AEs with onset dates on or 
after the start of double-blind study drug. The incidence of TEAEs during the study period will be 
tabulated by treatment group and body system (or System Organ Class [SOC] and preferred term) 
overall, by severity, and by relationship to study drug using subject counts and percent. Those AEs 
with missing onset dates or missing severity will be included as treatment-emergent. If an AE is 
reported more than once during the double-blind study phase, the greatest severity and the worst-
case attribution will be used for presentation in tables. 
Deaths, SAEs, and AEs causing discontinuation of study participation and/or study treatment will 
be tabulated by treatment group with subject counts and percent. Adverse events for individual 
subjects will be listed, along with information regarding onset, duration, severity, and relationship 
to study drug. 
9.9.2 
Other Safety Endpoints 
Baseline physical examination findings and clinical laboratory data will be summarized. Vital 
signs and weight will be summarized using descriptive statistics including mean values and change 
from baseline values, as well as numbers of subjects with values outside limits of the normal range 
at each time point. 
Prior/concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHODrug), Version December 2010 or later, and summarized by drug class with 
subject counts and percent. 
9.10 
Interim Analysis 
A blinded interim analysis is planned for both co-primary endpoints in this study to evaluate the 
sample size assumptions as follows:  
1. Co-primary endpoint change from baseline in the 7-day average CSNS (instantaneous AM) 
to assess the variance. 
2.  Co-primary endpoint change from baseline to Week 24/ET APOV to assess variance.  
This interim analysis is planned to occur when at least 50% of subjects have reached Week 24/ET 
endpoint for APOV. At this time it is anticipated that at least 75% of subjects will have reached 
the Week 4 endpoint for CSNS. The complete details of this interim analysis is provided in the 
IA-SAP.  
 


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10 DATA QUALITY ASSURANCE 
10.1 
Case Report Forms 
Clinical data will be entered on CRFs for transmission to the Sponsor or their designee. Data on 
CRFs must correspond to and be supported by source documentation maintained at the study 
center. All study forms and records transmitted to the Sponsor or their designee must carry only 
coded identifiers such that personally identifying information is not transmitted.  
Any changes made to data after collection will be made through the use of Data Clarification 
Forms (DCF). Data reported on the CRFs, which are derived from source documents, should be 
consistent with the source documents or the discrepancies should be explained. CRFs will be 
considered complete when all missing and/or incorrect data have been resolved.  
 
10.2 
Source Documents 
Source documents are considered to be all information in original records and certified copies of 
original records of clinical findings, observations, data, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. 
The investigator agrees to allow inspections of the study site and any source documentation, by 
clinical research and audit personnel from the Sponsor or their designee, and external auditors or 
representatives of regulatory authorities. Direct access to the subject’s medical/clinical records is 
necessary to verify and corroborate the data recorded on the CRFs.  
 
10.3 
Record Retention 
Study records and source documents need to be preserved for at least 15 years after the completion 
or discontinuation of/withdrawal from the study or 2 years after the last approval of a marketing 
application in an ICH region, whichever is the longer time period. 


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11 QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor or their designee will perform the quality assurance and quality control activities of 
this study; however, responsibility for the accuracy, completeness, and reliability of the study data 
presented to the Sponsor lies with the investigator generating the data.  
The Sponsor may arrange audits as part of the implementation of quality assurance to ensure that 
the study is being conducted in compliance with the protocol, Standard Operating Procedures, 
GCP, and all applicable regulatory requirements. Audits will be independent of and separate from 
the routine monitoring and quality control functions. 


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12 REGULATORY AND ETHICAL CONSIDERATIONS 
12.1 
Ethical Conduct of the Study 
This study will be conducted in accordance with the accepted version of the Declaration of 
Helsinki and/or all relevant federal regulations, as set forth in Parts 50, 56, 312, Subpart D, of Title 
21 of the Code of Federal Regulations (CFR), and in compliance with GCP guidelines. 
Institutional Review Boards will review and approve this protocol and informed consent. All 
subjects are required to give written informed consent prior to participation in the study. This study 
will be performed in accordance with GCP by qualified investigators. The study specifically 
incorporated the following features: 
• multi-center, placebo controlled, double-blind, study design 
• prospectively stated objectives and analytical plan; 
• accepted, pre-specified outcome measures for safety and efficacy; 
• site initiation meeting prior to study start and a detailed protocol to promote consistency 
across sites; and 
• compliance with GCP, with assessment via regular monitoring. 
Quality assurance procedures will be performed at study sites and during data management to 
assure that safety and efficacy data are adequate and well documented. 
 
12.2 
Informed Consent Process 
Subjects will be provided with an informed consent form that will explain the objectives of the 
study and its potential risks and benefits. The subject should have adequate time to read the 
informed consent and to ask the investigator any questions. The investigator must be satisfied that 
the subject has understood the information provided before written consent is obtained. If there is 
any doubt as to whether the subject has understood the written and verbal information, the subject 
should not enter the study. A copy of the signed informed consent form will be given to the subject 
and the original filed in the site file. 
 
12.3 
Privacy of Personal Data 
The collection and processing of personal data from subjects enrolled in this study will be limited 
to those data that are necessary to investigate the efficacy, safety, quality, and utility of the 
investigational product(s) used in this study. These data must be collected and processed with 
adequate precautions to ensure confidentiality and compliance with applicable data privacy 
protection laws and regulations. The Sponsor ensures that the personal data are  
• processed fairly and lawfully 
• collected for specified, explicit, and legitimate purposes and not further processed in a 
way incompatible with these purposes 
• adequate, relevant, and not excessive in relation to said purposes 
• accurate and, where necessary, kept up to date 
Explicit consent for the processing of personal data will be obtained from the participating subject 
before collection of data. Such consent should also address the transfer of the data to other entities 


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and to other countries. The subject has the right to request through the investigator access to his/her 
personal data and the right to request rectification of any data that are not correct or complete. 
Reasonable steps should be taken to respond to such request, taking into consideration the nature 
of the request, the conditions of the study, and the applicable laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel (or their designee) whose responsibilities require access to personal data agree 
to keep the identity of study subjects confidential. 
 
12.4 
Future Use of CT Scans 
In addition to the main study, subjects will be asked to consent to the release and use of their 
de-identified CT scans for publications, presentations, training, commercial, and marketing 
materials. Subjects agreeing to the use of their CT scans for this purpose, will be asked to sign 
a separate consent form. 
The de-identified CT scans will be transferred to the sponsor or its representative. The de-
identified CT scans will not be labeled with any patient identifying information. The privacy of 
personal data will be maintained as described in section 12.3 above. 
 


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13 ADMINISTRATIVE CONSIDERATIONS 
13.1 
Monitoring 
The study will be monitored to ensure that the study is conducted and documented properly 
according to the protocol, GCPs, and all applicable regulatory requirements.  
On-site visits will be made at appropriate times during the period of the study. Monitors 
(eg, Clinical Research Associates) must have direct access to source documentation in order to 
check the consistency of the data recorded in the CRFs. Additionally, remote monitoring may be 
conducted. 
The investigator will make available to the Monitor source documents, medical records, and source 
data necessary to complete CRFs. In addition, the investigator will work closely with the Monitor 
and, as needed, provide them appropriate evidence that the conduct of the study is being done in 
accordance with applicable regulations and GCP guidelines.  
 
13.2 
Protocol Amendments and Deviations 
13.2.1 
Protocol Amendment 
A protocol amendment will be required if changes to a protocol significantly affect the safety of 
subjects, the scope of the investigation, or the scientific quality of the study. Protocol amendments 
must not be implemented without prior IRB/EC approval, except when necessary to eliminate 
apparent immediate hazards to the subjects. If a protocol change is implemented immediately to 
protect the subjects, the IRB/EC and regulatory authority must be subsequently notified. 
Documentation of amendment approval by the investigator and IRB must be provided to the 
Sponsor or their designee. When the change(s) involves only administrative aspects of the study, 
the IRB only needs to be notified. 
13.2.2 
Protocol Deviations 
No deviations from the protocol are anticipated. However, should a protocol deviation occur, the 
Sponsor or their designee must be informed as soon as possible. Protocol deviations and/or 
violations and the reasons they occurred will be included in the study report. Reporting of protocol 
deviations to the IRB and in accordance with applicable regulatory authority mandates is an 
investigator responsibility. 
 
13.3 
Financing and insurance 
Financial aspects of the study are addressed in a separate clinical study agreement.  
The investigator is required to have adequate current insurance to cover claims for negligence 
and/or malpractice. The Sponsor will provide insurance coverage for the clinical study as required 
by national regulations.  
 
13.4 
Publication policy 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
The investigator should be aware that intellectual property rights (and related matters) generated 
by the investigator and others performing the clinical study will be subject to the terms of a clinical 
study agreement that will be agreed between the Institution and the Sponsor or their designee. With 


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respect to such rights, the Sponsor or their designee will solely own all right and interest in any 
materials, data, and intellectual property rights developed by investigators and others performing 
the clinical study described in this protocol, subject to the terms of any such agreement. In order 
to facilitate such ownership, investigators will be required to assign all such inventions either to 
their Institution or directly to the Sponsor or their designee, as will be set forth in the clinical study 
agreement. 


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14 REFERENCES 
Aggarwal R, Cardozo A, Homer JJ. The assessment of topical nasal drug distribution. Clin 
Otolaryngol Allied Sci. 2004;29(3):201-5. 
Akdis CA, Bachert C, Cingi C, et al. Endotypes and phenotypes of chronic sinusitis: a PRACTALL 
document of the European Academy of Allergy and Clinical Immunology and the American 
Academy of Allergy, Asthma and Immunology. J Allergy Clin Immuno. 2013;131(6):1479-1490. 
American 
Nuclear 
Society. 
Radiation 
Dose 
Calculator. 
http://www.ans.org/pi/resources/dosechart/; accessed 02 March 2014. 
Bachert C, Pawankar R, Zhang L, et al. ICON: chronic rhinosinusitis. World Allergy Organ J. 
2014;7(1):25. 
Bhattacharyya N and Lee LN. Evaluating the diagnosis of chronic rhinosinusitis based on clinical 
guidelines 
and 
endoscopy. 
Otolaryngol 
Head 
Neck 
Surg. 
2010;143(1):147-51. 
http://doi.org/10.1016/j.otohns.2010.04.012. 
Cardis E, Vrijheid M, Blettner M, et al. Risk of cancer after low doses of ionising radiation: 
retrospective cohort study in 15 countries. BMJ. 331(7508):77. 2005. 
Chen Y, Dales R, Lin M. The epidemiology of chronic rhinosinusitis in Canadians. Laryngoscope. 
2003;113(7):1199–1205. 
Chester AC, Antisdel JL, Sindwani R. Symptom-specific outcomes of endoscopic sinus surgery: 
a systematic review. Otolaryngol Head Neck Surg. 2009;140(5):633–9. 
Crim C, Pierre L, Daley-Yates P. A review of the pharmacology and pharmacokinetics of inhaled 
fluticasone propionate and mometasone furoate. Clin Thera. 2001: 23(9):1339-1354. 
Fokkens WJ, Lund VJ, Mullol J, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 
2012. Rhinology. 2012;50(suppl 23): 1-298. 
Gliklich RE and Metson R. The health impact of chronic sinusitis in patients seeking 
otolaryngologic care. Otolaryngol Head Neck Surg. July 1995;113(1):104-109. 
Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. J Allergy Clin 
Immunol. 2011;128(4):693–707. 
Hopkins C, Slack R, Lund V, et al. Long-term outcomes from the English national comparative 
audit of surgery for nasal polyposis and chronic rhinosinusitis. Laryngoscope. 2009;119(12):2459-
65. 
Huda W and Vance A. Patient radiation doses from adult and pediatric CT. Am J of Roentgenology. 
2007;188(2):540-6. 
Lund VJ, Mackay IS. Staging in rhinosinusitis. Rhinology. 1993; 31:183–184. [PubMed: 
8140385]. 
Meltzer EO, Hamilos DL, Hadley JA, et al. Rhinosinusitis: establishing definitions for clinical 
research and patient care. J Allergy Clin Immunol. 2004; 114(6 Suppl):155-212. 
NCSS, LLC. PASS 15 Power Analysis and Sample Size Software. 2017. Kaysville, Utah, USA. 
ncss.com/software/pass. 
O'Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for Practitioners. John Wiley & 
Sons, LTD. 2014. 


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Protocol Number OPN-FLU-CS-3206 
 
 
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Pallanch J, Yu L, Delone D, et al. 3-D volumetric computed tomographic scoring as an objective 
outcome measure for chronic rhinosinusitis: Clinical correlations and comparison to Lund-Mackay 
scoring. Int Forum Allergy Rhinol. 2013 December ; 3(12): 963–972. 
RadiologyInfo.org. 
Radiation 
dose 
in 
x-ray 
and 
CT 
exams. 
http://www.radiologyinfo.org/en/safety/index.cfm?pg=sfty_xray. Accessed 02-Mar-14. 
Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, et al. Clinical Practice Guideline (Update): Adult 
Sinusitis. Otolaryngol Head Neck Surg. 2015;152(2 Suppl):S1–39. 
Rudmik L1. Economics of Chronic Rhinosinusitis. Curr Allergy Asthma Rep. 2017 Apr;17(4):20. 
Rush JA, Trivedi MH, Ibrahim HM, et al. The 16-item inventory of depressive symptomatology 
(QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): A psychometric evaluation in 
patients with chronic major depression. Biol Psychiatry. 2003;54(5):573-583. 
Shashy RG, Moore EJ, Weaver A. Prevalence of the chronic sinusitis diagnosis in Olmsted 
County, Minnesota. Arch of Otolaryngol Head Neck Surg. 2004;130(3):320–323. 
US 
Environmental 
Protection 
Agency. 
Radiation 
protection. 
http://www.epa.gov/radiation/understand/perspective.html. Accessed 15-Sep-15. 
Zinreich SJ. Imaging for staging of rhinosinusitis. Ann Otol Rhinol Laryngol. Suppl. 2004; 193:19–
23. [PubMed: 15174756]. 
 
 
 


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Protocol Amendment 4.0/dated 11May2022 FINAL 
ATTACHMENT 1: BECLOMETHASONE – EQUIVALENT DOSES 
 
 


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ATTACHMENT 2:  RADIATION ASSOCIATED WITH CT SCANS 
CT scans are required at Baseline and Week 24/ET to evaluate eligibility criteria and primary and 
secondary endpoints. All CT scans will be sent to a central imaging core lab for review and 
analysis.  
Radiation due to the CT scans required for this study is a risk to the subjects enrolled in this study. 
The expected dosing for each modality/view is shown below. 
 
MODALITY: VIEW 
SCREENING 
(MSV) 
WEEK 24 / 
DELAYED WEEK 24 
(MSV) 
TOTAL 
(MSV) 
Thin-Slice CT 
2.0 
2.0 
4.0 
 
The total estimated radiation dose for a subject that undergoes all study-required imaging is 
expected to be approximately 4 millisievert (mSv) (American Nuclear Society). Based on a large 
study of cancer risk associated with exposure to radiation, it was estimated that the excess relative 
risk for cancer is 0.97 per Sv (Cardis et al, 2005). The excess relative risk of the radiation that each 
subject would receive from participation in this study is therefore 0.97/Sv * 4 mSv * 1 Sv/ 
1000 mSv=0.0039. To help place the radiation risk estimate for this study into perspective, a 
person will be exposed to 0.03 mSv of radiation during a typical coast-to-coast round-trip airplane 
flight (Radiologyinfo.org), and the public is exposed to approximately 3 - 6.2 mSv / year from 
background radiation (Huda et al, 2005 and United States Environmental Protection Agency). 


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ATTACHMENT 3:  KEY ASSESSMENTS FOR NASAL EXAMINATION 
The nasal examination worksheet will be provided to the sites as a separate document. The 
worksheet is formatted as a series of questions with check boxes and fields for narrative text. The 
nasal examination worksheet will be completed by the physician who performs the examination. 
If decongestants and/or local anesthetics are administered as preparation for the nasoendoscopy, 
these will be recorded on the form. Please note that if decongestants and/or local anesthetics are 
administered for the initial Visit 1 (Baseline/Day 1) nasoendoscopy for a subject, the same must 
be used for the Week 24/Visit 6/ET examination. The investigator will use the information from 
the nasal examination worksheet to complete the nasal examination, and concomitant medication 
CRFs.  
EPISTAXIS  
• 
Non-active bleeding, but evidence of recent bleeding (eg, darker blood, appearing thicker or 
‘solid’ as clots) 
• 
Active bleeding  
♦ blood tinged mucus 
♦ mild bleeding, medical intervention not indicated 
♦ clinically evident bleeding, medical intervention necessary  
• 
Origin of bleeding  
• 
Is the bleeding related to injury/nasal trauma?  
SEPTAL EROSION/PERFORATION  
• 
Location  
♦ anterior, including the nasal valve area  
♦ posterior to nasal valve  
♦ both 
• 
Severity 
♦ evidence of epithelial erosion  
♦ evidence of ulceration through the epithelial layer with exposed cartilage  
♦ perforation 
− diameter of perforation 
• 
Is the septal erosion/perforation related to injury/trauma? 
ULCERATION / EROSION (located in area other than septum) 
• 
Severity 
♦ epithelial surface abnormally eroded/abraded, but not clinically significant 
and expected to resolve rapidly 
♦ deeper than surface abrasion, limited clinical significance but may require 
monitoring or recommendation for routine care 
♦ deeper ulcers with possible effect on underlying structures, depth is clinically 
significant, intervention or specific care may be warranted 
MUCOSAL CANDIDIASIS 
• evidence of tightly adhered white material that does not scrape off  
 
LOCAL ANESTHETICS AND / OR DECONGESTANTS ADMINISTERED FOR 
ENDOSCOPY WILL BE RECORDED 

SAP_001.pdf: 
OptiNose US, Inc. 
 
Protocol Number OPN-FLU-CS-3206 
 
CONFIDENTIAL AND PROPRIETARY 
Page 1 of 15 
11 May 2022 
 
 
CONFIDENTIAL 
 
Statistical Analysis Plan 
OPN-375 (fluticasone propionate delivered by exhalation delivery 
system) 
OPN-FLU-CS-3206 
A 24-Week Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter 
Study Evaluating the Efficacy and Safety of Intranasal Administration of 186 and 372 μg of 
OPN-375 Twice a Day (BID) in Subjects with Chronic Rhinosinusitis Without the Presence 
of Nasal Polyps 
 
IND Number: 
110089 
EudraCT Number: 
2019-000368-12 
Date of Plan: 
11 May 2022 
Based on: 
Protocol Amendment 4, Date: 11 May 2022 
CRF Version 1.0 Date: 
10 March 2021 
 
 
Author: Thomas Dobbins 


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Protocol Number OPN-FLU-CS-3206 
 
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Page 2 of 15 
11 May 2022 
The undersigned have reviewed and agree on the content of this Statistical 
Analyses Plan. 
 
Review and Approval Signatures 
 
 
Name: 
John Messina 
Signature:  _______________________ 
Title: 
SVP. Clinical Research 
and Medical Affairs 
 
Date:  ___________________________ 
 
 
 
 
 
 
 
 
 
Name: 
Thomas Dobbins 
Signature:  
 
Title: 
Author, Statistician,  
The Griesser Group 
 
Date:    11 May 2022  
 
 
 


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Table of Contents 
1 ABBREVIATIONS ........................................................................................................4 
2 INTRODUCTION .........................................................................................................6 
3 STUDY OVERVIEW ....................................................................................................7 
3.1 General Study Design and Study Schema ........................................................................ 7 
3.2 Unique Secondary Objectives and Endpoints ................................................................... 7 
3.2.1 Key Secondary Objectives/Endpoints added to Protocol CS-3206 ............................7 
3.2.2 Other Secondary Endpoints ......................................................................................7 
4 GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS .........................9 
4.1 Sample Size Determination .............................................................................................. 9 
4.2 Randomization and Stratification Factors ......................................................................... 9 
4.3 Interim Analysis .............................................................................................................. 9 
5 STATISTICAL METHODS FOR EFFICICY ANALYSES ..................................... 11 
5.1 Adjustments to the Statistical Models ............................................................................ 11 
5.2 Estimation – Secondary Endpoints ................................................................................. 11 
5.3 Multiplicity – Type I Error Control ................................................................................ 11 
5.3.1 Co-primary Efficacy Endpoints .............................................................................. 11 
5.3.2 Type I Error Control for Key Secondary Endpoints ................................................ 12 
5.4 Subgroup Analyses ........................................................................................................ 13 
5.5 Additional Sensitivity Analyses – Supplementary Estimands ......................................... 14 
 
 
 


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1 
ABBREVIATIONS 
Abbreviation or Term 
Definition 
AE 
Adverse event 
AM 
Morning 
ANCOVA 
Analysis of covariance 
APOV 
Average percent of opacified volume 
APOV-E 
Average percent of opacified volume in the ethmoid sinuses 
APOV-M 
Average percent of opacified volume in the maxillary sinuses 
BID 
Two times a day 
BOCF 
Baseline Observation Carried Forward 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRS 
Chronic Rhinosinusitus 
CSNS 
Composite score of nasal symptoms 
CI 
Confidence Interval 
CT 
Computed tomography 
DB 
Double-blind 
DCF 
Data Clarification Form 
EDS 
Exhalation Delivery System 
EOS 
End of Study 
EQ-5D 
EuroQol-5 
EQ VAS 
EQ Visual Analogue Scale 
EVA 
Electronic visual acuity 
ET 
Early termination 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
GLM 
Generalized linear model 
GLMM 
Generalized linear mixed model 
HEOR 
Health Economics & Outcomes Research 
HPQ 
Health and Work Performance Questionnaire 
IA 
Interim analysis 
IE 
Intercurrent Event 
IASAP 
Interim analysis Statistical Analysis Plan 
ICH 
International Conference on Harmonization 
INS 
Intranasal Steroid 
IOP 
Intraocular pressure 
ITT 
Intent-to-Treat 
IWRS 
Interactive web response system 
J2C 
Jump-to-Control 
LS 
Least Squares 
LM 
Lund-Mackay Staging 
MAR 
Missing at Random 
MCS 
Mental component score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MMRM 
Mixed-effect model for repeated measures 
NB 
Negative Binomial 
PASS 15 
Power Analysis and Sample Size Software 
PBO 
Placebo 
PCS 
Physical component score 
PGIC 
Subject Global Impression of Change 
PHE 
Public Health Emergency 
PM 
Evening 
PMM 
Pattern Mixture Model 
POV 
Percent of Opacified Volume 


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PRO 
Patient Reported Outcome 
PSQI 
Pittsburgh Sleep Quality Index 
QIDS 
Quick Inventory of Depressive Symptomatology 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
SE 
Standard Error 
SF-36v2 
36-Item Short Form Health Survey Version 2 
SF-6D 
Short Form-6 dimension 
SIT 
Smell Identification Test 
SNOT-22 
22-item Sinonasal Outcomes Test 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
WHO 
World Health Organization 
WHODrug 
World Health Organization Drug Dictionary 
WPOV-E 
Worst Percentage of Opacified Volume in the Ethmoid Sinuses 
WPOV-M 
Worst Percentage of Opacified Volume in the Maxillary Sinuses 
WPOV 
Worst Percentage of Opacified Volume among the Maxillary and  
Ethmoid Sinuses 
ZLM 
Zinreich Modification of Lund-Mackay Staging 
WZLM 
Worst ZLM score for the worst sinus among Maxillary and Ethmoid 
Sinuses 


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2 
INTRODUCTION 
This Statistical Analysis Plan (SAP) references Protocol OPN-FLU-CS-3206 (Amendment 
4.0, dated 11 May 2022) and the corresponding electronic case report form (eCRF).  There are 
no deviations from this amendment presented in this SAP.  
Protocol OPN-FLU-CS-3206 is the second of the two pivotal randomized, controlled clinical 
trials intended to provide substantial evidence supporting an indication for the treatment of 
CRS, and this study is identical in design to Protocol OPN-FLU-CS-3205 with one important 
exception. Protocol OPN-FLU-CS-3205 enrolled a subject population including subjects with 
or without the presence of Nasal Polyps at baseline. Protocol OPN-FLU-CS-3206 included 
only subjects without Nasal Polyps present at baseline.   
In the interest of clarity and efficiency, the OPN-FLU-CS-3205 SAP, (14 February, 2022) is 
the Statistical Analysis Plan of reference for this clinical program. The OPN-FLU-CS-3205 
SAP encompasses the efficacy and safety endpoints, estimand, statistical methods, and data 
handling rules used in the CRS development program.  Thus, the CS-3205 SAP is the primary 
reference for the statistical analyses of efficacy and safety endpoints, as well as the statistical 
estimands and methods, endpoint definitions, and data handling rules, unless otherwise 
indicated in this document. 
 
The focus of this OPN-FLU-CS-3206 SAP is to document changes and additions to secondary 
endpoints, to highlight the changes to statistical models as a result of no stratification for polyp 
status, and to specify the hypothesis testing strategy to control the family-wise Type I error 
probability in study OPN-FLU-CS-3206. 
 
If additional analyses are performed to supplement the planned analyses they will be identified 
as such in the Clinical Study Report (CSR). 
 
 
 
  
 
 


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3 
STUDY OVERVIEW 
3.1 
General Study Design and Study Schema 
This is a 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study 
designed to assess the efficacy and safety of intranasal administration of OPN-375 (186 and 372 μg 
twice daily) in subjects with CRS without the presence of nasal polyps.  
All Study Procedures and Evaluations,  as well as the timing of all tests, procedures, and 
assessments, are identical to study OPN-FLU-CS-3205; reference the OPN-FLU-CS-3205 SAP 
for the study flow diagram and schedule of assessments. 
3.2 
Unique Secondary Objectives and Endpoints  
This section describes the secondary Objectives and Endpoints which are not common to both 
protocols.  The hypothesis testing strategy including these endpoints is described in Section 5.3. 
3.2.1 
Key Secondary Objectives/Endpoints added to Protocol CS-3206 
• Frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a 
worsening of symptoms that requires an escalation of treatment in subjects with CRS 
without NP, from studies OPN-FLU-CS-3206 and OPN-FLU-CS-3205 (pooled data) 
• Change from baseline to the end of Week 4 in four separate cardinal CRS symptoms, as 
measured by (AM, Instantaneous) CSNS: congestion, facial pain or pressure sensation, 
nasal discharge (anterior and/or posterior), and sense of smell. 
• Time to first acute exacerbation of CRS, defined as a worsening of symptoms that 
requires escalation of treatment 
3.2.2 
Other Secondary Endpoints  
Note that the secondary endpoints in OPN-FLU-CS-3205 refer to the population of subjects 
without and without Nasal Polyps at baseline, and the same endpoints in OPN-FLU-CS-3206 refer 
to the population of subjects without Nasal Polyps at baseline. 
The following change to Protocol OPN-FLU-CS-3206 is due to the addition of AM, Instantaneous  
DNS symptoms to key secondary endpoints. 
• change from baseline to Weeks 4, 8, and 12 for the total population and in patients with and 
without previous sinus surgery: 
− in average AM/PM instantaneous (evaluation of symptom severity immediately 
preceding the time of scoring), (except Week 4 (AM) – key secondary endpoint) and 
AM/PM reflective (evaluation of symptom severity over the past 12 hours), averages 
are based on scores recorded in the diary for the 7 days before each time point for: 


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 nasal congestion 
 sense of smell score 
 nasal discharge (anterior and/or posterior) score 
 facial pain or pressure sensation score 
The following secondary endpoint was added to Protocol OPN-FLU-CS-3206: 
• change from baseline to Week 24/ET in the percent of opacification of the combined 
volume of the ethmoid and maxillary sinuses 
 


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4 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS 
Reference OPN-FLU-CS-3205 SAP for the statistical considerations common to both protocols.  
The following considerations are unique to Protocol OPN-FLU-CS-3206. 
4.1 
Sample Size Determination 
Sample size assumptions were originally generated based on previous Phase 3 studies of OPN-375 
in subjects with nasal polyposis and data from a study evaluating the change in maxillary and 
ethmoid opacification in CRS patients treated with an intramuscular dose of triamcinolone 
(Pallanch 2013).  
Updated standard deviation estimates for both co-primary endpoints in this amendment are based 
on a blinded interim analysis of Protocol OPN-FLU-CS-3205. Based on the results for changes 
from baseline in morning symptoms among subjects with nasal polyps in the previous studies 
conducted with OPN-375, a sample of 70 subjects per group (210 total subjects) is sufficient to 
detect a 0.9 scale difference in 7-day average AM instantaneous CSNS between treatments 
(OPN-375 vs placebo) using a 2-sided test at the 5% significance level with 88% power, and 
assuming a standard deviation (SD) of 1.7.  
This sample size is also adequate to detect a 9% difference between treatments in average percent 
opacification (APOV) using a 2-sided test at the 5% significance level with 88% power, and 
assuming a SD of 17%.  
The sample size was estimated for the co-primary efficacy endpoints using Power Analysis and 
Sample Size Software (PASS 15). 
4.2 
Randomization and Stratification Factors 
In Protocol OPN-FLU-CS-3206 there is a single stratification factor for randomization:  previous 
sinus surgery (Yes vs No).  The entry criteria for this study excluded subjects with Nasal Polyps 
Present at baseline.  
This stratification factor is included in the analysis model as a categorical covariate.  In the event 
that a stratification error occurs, i.e., a subject is incorrectly stratified, in the primary analyses the 
subject will be analyzed as randomized (stratified), consistent with the ITT principle. The error 
will be documented as a protocol violation; however, these subjects will be included in the per-
protocol analyses. 
4.3 
Interim Analysis  
A blinded interim analysis was planned for both co-primary endpoints in this study to evaluate the 
sample size assumptions as follows:  
1. Co-primary endpoint change from baseline in the 7-day average instantaneous AM CSNS 
to assess the variance. 
2.  Co-primary endpoint change from baseline to Week 24/ET APOV to assess variance.  


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This interim analysis was planned to occur when at least 50% of subjects reached Week 24/ET 
endpoint for APOV, and at least 75% of subjects reached the Week 4 endpoint for CSNS. The 
complete details of this interim analysis are provided in the Protocol OPN-FLU-CS-3206 Interim 
Statistical Analysis Plan (IASAP) (23 September, 2021). 
The blinded IA of both CSNS and APOV co-primary endpoints have occurred and resulted in a 
decision to not increase sample size.  Reference the OPN-FLU-CS-3205 SAP for further detail 
regarding the IA of Protocol OPN-FLU-CS-3205. 
 


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5 
STATISTICAL METHODS FOR EFFICICY ANALYSES 
5.1 
Adjustments to the Statistical Models 
In Protocol OPN-FLU-CS-3205 randomization was stratified by Nasal Polyp status at baseline 
(Absent, Present), and Prior Nasal Surgery (Yes, No).  All statistical models in the OPN-FLU-CS-
3205 SAP include categorical terms for both Nasal Polyp status and Prior Nasal Surgery. 
In Protocol OPN-FLU-CS-3206 randomization was stratified only by Prior Nasal Surgery (Yes, 
No) since the subject population consisted only of subjects without Nasal Polyps at baseline.  
Therefore, for all statistical models referenced in OPN-FLU-CS-3205 SAP the categorical term 
for Nasal Polyp status is removed for the analyses of the efficacy endpoints in Protocol OPN-FLU-
CS-3206.   
There are no other changes to the statistical models or methods in the efficacy analyses of Protocol 
OPN-FLU-CS-3206. 
5.2 
Estimation – Secondary Endpoints 
For the secondary endpoints added to Protocol OPN-FLU-CS-3206, and described in Section 3.2, 
the statistical methods are described in OPN-FLU-CS-3205 SAP.  However, the pooled endpoints, 
from both protocols, will be included in the Integrated Summary of Efficacy (ISE) SAP and fully 
described there. 
5.3 
Multiplicity – Type I Error Control 
5.3.1 
Co-primary Efficacy Endpoints 
The primary hypothesis of this trial is that OPN-375 high dose (372 μg) group will be superior to 
the placebo group in both co-primary endpoints.  
The familywise Type 1 error probability for the test of the primary hypothesis is α=0.05. The 
strategy for strong, familywise control of the Type I error is based on closed testing procedure as 
follows.  
1. Test each co-primary endpoint for OPN-375 high dose (372 μg) vs placebo: If p < 0.05 for both 
endpoints, then proceed to key secondary endpoints; otherwise, stop.  The order of the testing 
is as follows:  
a) OPN-375 372 μg versus placebo in the change from baseline in the 7-day average 
instantaneous AM CSNS at the end of Week 4  
b) OPN-375 372 μg versus placebo in the APOV in the ethmoid and maxillary sinuses change 
from baseline to Week 24/ET 


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5.3.2 
Type I Error Control for Key Secondary Endpoints 
The following planned comparisons are defined based on pooled data from Study OPN-FLU-CS-
3205 and Study OPN-FLU-CS-3206. Testing will continue based on closed testing procedure, with 
α=0.05, if the primary hypothesis is met, as follows:  
2. OPN-375 372 μg versus placebo in the frequency of acute exacerbations of CRS over 24 weeks 
3. OPN-375 372 μg versus placebo in the frequency of acute exacerbations of CRS over 24 weeks 
in CRS without NP population 
4. OPN-375 372 μg versus placebo in change from baseline to Week 4 on CSNS score in subjects 
who were symptomatic at trial entry despite reported use of an intranasal steroid for treatment 
of CRS within 30 days of Visit 1 
The following planned comparisons are defined based on Study OPN-FLU-CS-3206. Testing will 
continue based on closed testing procedure, with α=0.05, if the key secondary hypotheses (2-4) 
are met, as follows: 
5. Test each co-primary endpoint for OPN-375 low dose (186 μg) vs placebo: If p < 0.05 for both 
endpoints, then proceed to next endpoints; otherwise, stop. The order of the testing is as 
follows:  
a) OPN-375 372 μg versus placebo in the change from baseline in the 7-day average 
instantaneous AM CSNS at the end of Week 4  
b) OPN-375 372 μg versus placebo in the APOV in the ethmoid and maxillary sinuses 
change from baseline to Week 24/ET 
6. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in nasal 
congestion  
7. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in nasal 
discharge (anterior and/or posterior) 
 
8. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in facial pain 
or pressure sensation 
 
9. OPN-375 372 μg versus placebo in change from baseline to the end of Week 4 in sense of 
smell 
 
10. OPN-375 372 μg versus placebo in time to first acute exacerbation of CRS 
The following planned comparisons are defined based on pooled data from Study OPN-FLU-CS-
3205 and Study OPN-FLU-CS-3206. Testing will continue based on closed testing procedure, with 
α=0.05, if the key secondary hypotheses (5-10) are met, as follows: 
 


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11. OPN-375 186 μg versus placebo in the frequency of acute exacerbations of CRS over 24  
12. OPN-375 186 μg versus placebo in the frequency of acute exacerbations of CRS over 24 weeks 
in CRS without NP population 
13. OPN-375 186 μg versus placebo in change from baseline to Week 4 on CSNS score in subjects 
who were symptomatic at trial entry despite reported use of an intranasal steroid for treatment 
of CRS within 30 days of Visit 1 
The following planned comparisons are defined based on Study OPN-FLU-CS-3206. Testing will 
continue based on closed testing procedure, with α=0.05, if the key secondary hypotheses (11-13) 
are met, as follows: 
14. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in nasal 
congestion in CRS without NP population 
15. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in nasal 
discharge (anterior and/or posterior) 
 
16. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in facial pain 
or pressure sensation 
 
17. OPN-375 186 μg versus placebo in change from baseline to the end of Week 4 in sense of 
smell 
 
18. OPN-375 186 μg versus placebo in time to first acute exacerbation of CRS 
 
5.4 
Subgroup Analyses 
The following endpoints will be analyzed according to the primary estimand by subgroup: subjects 
with prior sinus surgery versus without prior sinus surgery at baseline.  
•  Co-primary endpoints (CSNS, APOV) 
• All CSNS endpoints other than the primary, 
• All individual daily nasal symptoms scores that are components of the CSNS (as well as sense 
of smell) 
• SNOT-22 Total Score 
The same MMRM models for used for CSNS and DNS and the same ANCOVA model for APOV 
will include appropriate terms for treatment-by-subgroup interaction as well as the appropriate 
contrasts to obtain the within-subgroup inferential statistics.  The model-based, within-subgroup 
LS mean difference between each active treatment group and placebo (active-placebo), 95% CI, 
and nominal p-value will be displayed, as well as the treatment-by-subgroup interaction nominal 
p-value. 


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5.5 
Additional Sensitivity Analyses – Supplementary Estimands 
Several alterations of the primary estimand regarding the handling of intercurrent events are 
considered as sensitivity analyses (supplementary estimands) for protocols OPN-FLU-CS-3206 
and OPN-FLU-CS-3205.  The primary estimand is defined in Protocol OPN-FLU-CS-3206, 
Section 9.3.3, and is identical to the primary estimand in protocol OPN-FLU-CS-3205.  
While these supplementary estimand sensitivity analyses are pre-specified in this SAP for protocol 
OPN-FLU-CS-3206, they will also be applied post-hoc to protocol OPN-FLU-CS-3205.  These 
sensitivity analyses will be performed for both co-primary endpoints.  The statistical methods for 
analyses and handling of missing data are fully described in the OPN-FLU-CS-3205 SAP. 
Table 5.1 contains a summary of the primary estimand and all supplementary estimands defined 
based on alterations of the primary estimand in the handling of intercurrent events specifically for 
use of systemic steroids and nasal surgery. The imputation method for missing data for each co-
primary endpoint under the treatment policy strategy for treatment discontinuation intercurrent 
event is fully described in the OPN-FLU-CS-3205 SAP. 
 


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Table 5.1 Summary of Primary and Supplementary Estimands and the Handling of Intercurrent Events 
Estimand 
Intercurrent Events 
 
Systemic Corticosteroids 
Nasal Surgery 
Treatment/Study Discontinuation 
Primary1 
Composite Strategy for CRS3; 
Poor Score4 
Composite Strategy; Poor Score 
Treatment Policy Strategy6  
Supplementary – S12 
Treatment Policy Strategy  
Composite Strategy; Poor Score 
Composite Strategy; Poor Score 
Additional Sensitivity 
 
 
 
Supplementary SE-2 
Treatment Policy Strategy 
Composite Strategy: Worst Score5 
Treatment Policy Strategy 
Supplementary SE-3 
Composite Strategy; Poor Score 
Composite Strategy; Poor Score 
Treatment Policy Strategy 
Supplementary SE-4 
Composite Strategy; Worst Score 
Composite Strategy; Worst Score 
Treatment Policy Strategy 
1. Primary Estimand in Protocols OPN-FLU-CS-3206 and OPN-FLU-CS-3205 
2. Supplementary Estimand in Protocols OPN-FLU-CS-3206 and OPN-FLU-CS-3205 
3. Systemic corticosteroids use for CRS exacerbation or worsening of CRS nasal/sinus symptoms: Composite Strategy 
Systemic corticosteroid use for other indications is defined as treatment and study discontinuation event.  
Modified Treatment Policy Strategy:  Subject continues in the study; if an IE for systemic steroids for CRS or nasal surgery occurs, a poor 
score is assigned as defined in (4); otherwise, treatment policy strategy is followed as defined in (6) 
4. Poor Scores:  For CSNS, a value of ‘9’ is assigned.  For APOV, a poor score is defined as follows: for a subject with a baseline APOV ≥ 
75%, a value of ‘100%’ is assigned; if baseline APOV < 75%, a poor score is defined as baseline APOV + 25% 
5. Worst Scores: For CSNS, a value of ‘9’ is assigned.  For APOV, a value of ‘100%’ is assigned 
6. Treatment Policy Strategy; subjects may continue in the study until one of the following two mutually exclusive outcomes: 
a) Subject completes Week 4, use CSNS endpoint value; completes Week 24/ET CT scan, use APOV endpoint value; 
b) Subject discontinues the study. Missing data due to study discontinuation following treatment discontinuation is imputed; a full 
description of the imputation method for each co-primary endpoint is provided in the OPN-FLU-CS-3205 SAP.