Clinical trial NCT03781804
Conditions: Chronic Rhinosinusitis
Sponsor: Optinose US Inc.
Start date: 2018-11-27; Completion date: 2022-01-19
Enrollment: 332 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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 (CS) with or 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 a 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 documents:
Prot_000.pdf: 
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Protocol Number OPN-FLU-CS-3205 
 
 
 
Page 1 of 85 
 
Protocol Amendment 6.0/dated 07JAN2022 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 With or 
Without the Presence of Nasal Polyps  
 
 
Protocol Number: 
OPN-FLU-CS-3205 
Brief Title: 
Re-Open 1 
Development Phase: 
3b 
IND Number: 
110089 
EudraCT Number 
2019-000368-12 
Sponsor: 
OptiNose US, Inc. 
1020 Stony Hill Road, Suite 300 
Yardley, PA 19067 
Protocol Date: 
Amendment 6.0 dated 07JAN2022 
 
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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Page 2 of 85 
 
Protocol Amendment 6.0/dated 07JAN2022 FINAL 
VERSION HISTORY 
Version 
Explanation of Change(s) and Reason/Justification for 
Changes 
Date 
0.0 
Original Protocol 
29 August 2018 
0.1 
Synopsis: Updated for consistency with protocol. 
Schedule of Study Procedures and Evaluations: Removed “X” 
from “Review proper use of EDS from Visit 6,” since it’s the 
final visit. 
Synopsis and Safety Sections of Protocol: Weights will be 
collected at each visit. Therefore, this was removed from 
physical examinations and added to vitals signs sections. 
Synopsis and Section 4.1, (Inclusion Criteria 7): The symbols 
before 25% were changed from “>” to “≥.” 
Synopsis and Section 4.2, (Exclusion Criteria 32): Fasenra 
(benralizumab) has been added to the list of disallowed 
medications. 
Section 5.7 (Treatment Compliance): Removed reference to 
patients noting compliance in daily diary. 
Section 7.2 (Efficacy Assessments): Clarification in the 
definition of acute exacerbation of chronic sinusitis that one “or 
more” symptoms may be present; and added when multiple 
exacerbations may be considered 1 event. 
Section 7.4.5 (Laboratory Variables), Table 4: Clarified that 
urine samples will be done by dipstick and not sent to the central 
laboratory for analysis. 
Other: Minor editorial changes throughout 
05 October 2018 
1.0 
Amendment 1 
Title page and Synopsis: Added EudraCT Number 
Synopsis (Investigational Product, Dose, and Mode of 
Administration): “1 or” has been deleted; subjects required to 
administer 2 sprays per nostril of study drug 
Synopsis, and Sections 2.1 and 3.2.1.1: Identified the co-primary 
endpoint for nasal symptoms to a composite score, ie, composite 
score of nasal symptoms (CSNS) 
Synopsis, Schedule of Study Procedures and Evaluations, Figure 
3, and Sections 2.5, 3.1, and 6.1: Extended single-blind run-in 
period from 14 to 21 days 
Synopsis and Section 4.1:  
• 
Clarified Inclusion Criterion 9: congestion score based 
on Nasal Symptom Scale and subject diary eligibility is 
over a 7-day period during the first 14 days of the 
single-blind run-in period 
• 
Added Inclusion Criterion 12: to allow subjects with 
aspirin-exacerbated respiratory disease on stable therapy 
Synopsis and Section 4.2: 
• 
Revised Exclusion Criterion 8: to include exclusion of 
subjects with evidence of complicated sinus disease and 
those with paranasal sinus or nasal tumors; provide 
clarification on the definition of mucocele 
13 February 2019 


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Page 3 of 85 
 
Protocol Amendment 6.0/dated 07JAN2022 FINAL 
• 
Added new Exclusion Criterion 9: to exclude subjects 
with paranasal sinus or nasal tumors 
• 
Clarification of Exclusion Criterion 18 (previously 17): 
timing around previous respiratory infection and 
antibiotic use and screening computed tomography (CT) 
scan 
Synopsis, Schedule of Study Procedures and Evaluations, 
Sections 6, and 7.2: Added assessment of nasal polyp grading 
Synopsis, Schedule of Study Procedures and Evaluations, and 
Section 7.2: Added nasal polyp grading at Weeks 4, 12, and 24 
to efficacy assessments 
Synopsis (Primary Efficacy Analysis): Replaced with methods 
of analyses for co-primary outcome variables from the primary 
estimand 
Synopsis and Section 9.1: Typographical error in the standard 
deviation used for sample size determination; corrected from 
2.1 to 1.9 
Schedule of Study Procedures and Evaluations: 
• 
Added lines for demographics; nasal and sinus 
endoscopic assessment; and chronic sinusitis treatment 
and history 
• 
Consolidated prior and concomitant medications/ 
procedures/nondrug therapy into a single line item 
Section 2.2: Edited for consistency throughout protocol 
Sections 3.1 and 6.1: Provided additional information for the 
timing of the pretreatment CT scans. 
Section 4.3: Added intraocular pressure >21 mmHg, nasal septal 
perforation, and new onset or worsening of cataracts to 
withdrawal criteria 
Sections 5.1, 5.2, 5.4, 5.5, 5.7, and 8.1: Replaced “OPN-375” 
with “study drug,” as appropriate 
Sections 5.1, 6.2, and 6.3: Corrected number of study kits to be 
distributed at which visits 
Section 6: Number of days a subject must be symptom free 
before the CT scan at Week 24 was changed from “21” to “28” 
Section 6.1: Added clarification on the use of CT scans obtained 
prior to Visit 1 
Section 7.4.1: Added height to be collected during screening 
physical examination 
Section 8.5.2: Contact for reporting serious adverse events has 
been changed from Ashfield Safety and Pharmacovigilance to 
PPD 
Section 9.3 Paragraph 6 discussing “missing data” removed 
Section 9.3.2 (Primary Estimand [Previously “Primary Efficacy 
Analysis”]): Replaced with methodology detailing the primary 
estimand and analyses for co-primary outcome variables 
Section 9.6: Further clarification and detail is provided on the 
planned interim analysis 
Amendment 4, Item 3.4: Modified criteria for subcapsular 
cataracts 


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
Other: Minor editorial changes throughout 
2.0 
Throughout protocol: Replaced “chronic sinusitis” with “chronic 
rhinosinusitis” 
Title page: Added Brief Title “Re-Open 1” 
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 
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 
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 
Schedule of Study Procedures and Evaluations and 
Section 7.4.1: Changed physical examination from “full” to 
“brief” 
List of Abbreviations and Definitions of Terms has been 
updated as applicable. 
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. 
Attachment 5: Added to provide details of the substudy. 
Minor editorial changes have been made throughout the protocol 
as appropriate. 
05 DEC 2019 
3.0 
Synopsis: Updated for consistency with protocol 
Schedule of Study Procedures and Evaluations:  
• 
Added “SARS-CoV-2 Serology Testing” to Visit 6 to 
determine if subject carries the antibodies 
15 June 2020 


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Page 5 of 85 
 
Protocol Amendment 6.0/dated 07JAN2022 FINAL 
• 
Removed “X” from “Nasal Examination from Visit 3 
and Visit 5”. Given the potential risks associated 
endoscopy and COVID-19 the frequency of these exams 
was reduced. Also, given the well-established safety 
profile of OPN-375, nasal examinations at the interim 
visits are not deemed necessary and efficacy measures 
are not required at interim timepoints. 
• 
Removed “X” from “Nasal Polyp Grading from Visit 3 
and Visit 5” and section 7.2 because nasal exams will 
not be required at these visits. 
• 
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. 
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. 
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 
Synopsis and Section 4.1, (Inclusion Criterion 13) 
• 
Removed “oral steroids” to address an inconsistency in 
protocol. Oral steroids are not allowed within 1 month 
of screening. 
Synopsis and Section 4.2, (Exclusion Criteria 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 
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 


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
• 
Added “hospitalized with respiratory symptoms due to 
SARS-CoV-2 (COVID-19) to address new concerns 
related to COVID-19 pandemic. 
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  
• 
Removed 1st bullet referencing Nasal Exam and Nasal 
Polyp Grading at Visit 3 (Week 4) and Visit 5 (Week 
12) 
• 
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 7.4.3 Ocular examinations and Attachment 5 
• 
 “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 3: Clarified Nasal exam to be performed at Visit 1 
and Visit 6 
Minor editorial changes have been made throughout the protocol 
as appropriate 
4.0 
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. 
• 
Clarified Exclusion criteria 28 
• 
Added Exclusion Criterion 36 (have a recent change in 
vision). 
• 
Removed Early Termination (ET) from endpoints 
• 
Added clarification “in ethmoid and maxillary sinuses” 
to co-primary endpoint 
• 
Removed ocular examination from safety endpoints. 
• 
Removed “ET” from Key Secondary Efficacy Analysis 
20 August 2020 


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
• 
Updated statistical primary efficacy analysis 
Schedule of Study Procedures and Evaluations:  
• 
Removed ocular examination from procedures and 
assessments. 
• 
Added smoking history to 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:  
• 
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. 
• 
Removed “SARS CoV-2 Serology Test” language 
removed but will still be performed 
Section 7.1.1: Added smoking history to medical history. 
Section 7.4: Removed ocular examination from section. 
Section 7.4.3: Updated ocular examination performance to be 
removed pre 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: Replaced modified Intent to Treat Analysis Set 
(mITT) with “Full Analysis Set (FAS)” section  
Section 9.3: Clarifications to the Estimands, handling of missing 
data, and statistical analysis addressing FDA suggestions have 
been added  


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
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. 
Section 9.8: Clarified interim analysis section. 
Attachment 4: The eye examination worksheet has been 
removed  
Minor editorial changes have been made throughout the protocol 
as appropriate. 
4.1 
Corrected Version History – The last four reference numbers in 
version history section 1.0 had an administrative formatting 
issue while finalizing the version 4.0 protocol. These have been 
corrected and reverted to original reference numbers. 
21 August 2020 
5.0 
Changes to the Key Secondary Objectives and the Statistical 
Analysis Section are being amended. The SF-36 Mental and 
Physical subscale analyses are being 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-3206) have been added to 
this protocol. These analyses will be performed once both 
studies have completed. In addition, a number of 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.  
Details of Changes 
Synopsis: 
• 
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 sample size from 378 to approximately 333 
subjects with approximately 125 subjects with CRS 
without nasal polyps 
• 
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 polyps and subjects 
16 July 2021 


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
with and without a history of surgery) will now be 
performed 
Section 2.5: Number of Subjects and Duration of Study 
• 
This section was updated to reflect the new sample size 
of approximately 333 subjects with approximately 125 
CRS without nasal polyp subjects 
Section 3.2.1.2: Key Secondary Endpoints 
• 
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 9.3.6: Sensitivity Analysis – Tipping Point 
• 
Clarifying text around the statistical analysis added 
Section 9.5: Other Secondary Efficacy Analyses 
• 
Updated section to match additional secondary analyses 
added to the protocol 
Section 9.6: Subgroup Analyses 
• 
Section added to clarify sub-group analyses that will be 
completed in the statistical analysis 
Section 9.7: Type I Error Multiplicity 


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
• 
Additional clarifying text was added to explain α if 
unblinded interim analysis does not occur 
Section 9.7.2: Type I Error Control for Key Secondary 
Endpoints 
• 
Updated key secondary endpoints made in Section 2.2 
were updated in this section 
Section 9.7.3: Type I Error Control for Key Secondary 
Endpoints from Pooled Data Studies OPN-FLU-CS-3205 and 
OPN-FLU-CS-3206 
• 
Added Section 9.7.3 to reflect changes made to the 
pooled key secondary analyses in Section 2.2 
Section 9.9: 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 
Minor editorial changes have been made throughout the protocol 
as appropriate 
6.0 
Key secondary objectives are being amended based upon 
updated FDA feedback. Due to lack of enrollment and therefore 
the inability to perform an analysis, the sub-study initially 
planned to be included in this study was removed. 
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 
• 
Removed substudy from study design 
• 
Updated key secondary endpoints to reflect updated key 
secondary objectives 
• 
Updated Key Secondary Efficacy Analysis to reflect 
updated key secondary endpoints 
Section 2.2 Key Secondary Objectives 
• 
Updated key secondary objectives 
Section 2.3 Other Secondary Objectives 
• 
Updated other secondary objectives to include previous 
key secondary objectives listed in Amendment 5.0 
Section 3.1 Study Overview 
07 January 2022 


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
• 
Updated study overview to reflect removal of substudy 
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 secondary endpoints to reflect updated 
secondary objectives 
Section 4.2 Exclusion Criteria 
• 
Removed “nasal candidiasis” under exclusion criterion 
Number 26 due to redundancy 
Section 9.2.3 Full Analysis Set (FAS) 
• 
Clarified FAS subject inclusion 
Section 9.3.3 Primary Estimand 
• 
Clarified poor score assignment for intercurrent event #1 
Section 9.3.4 Estimator and Estimation Method – Primary 
Analysis 
• 
Removed redundant verbiage 
Section 9.4.1 ANCOVA on Ranked APOV Values  
• 
Clarified description of sensitivity analysis of the APOV 
co-primary endpoint 
Section 9.5 Key Secondary Efficacy Analyses – Pooling of 
Study 3205 and Study 3206 
• 
Clarified analyses completed for updated key secondary 
endpoints 
Section 9.6 Other Secondary Efficacy Analysis 
• 
Clarified analyses completed for secondary endpoints 
Section 9.7 Subgroup Analyses 
• 
Added stratification groups for planned analyses 
Section 9.8.2 Type I Error Control for Key Secondary Endpoints 
• 
Updated section to reflected updated key secondary 
endpoints 
Section 14 References 
• 
Added references to reflect updated Section 9, Statistical 
Analysis 
Removal of Attachment 4: Substudy to Evaluate Clinical 
Biomarkers and to Characterize Microbiome and Cytokine 
Profiles (originally to be used to evaluate clinical biomarkers to 
characterize the microbiome and cytokine profiles) 
Minor editorial changes have been made throughout the protocol 
as appropriate 


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Protocol Amendment 6.0/dated 07JAN2022 FINAL 
Signature Page for Sponsor: 
 
Clinical Study Protocol No. OPN-FLU-CS-3205 
 
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, 
With or 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 6.0/dated 07JAN2022 FINAL 
Signature Page for Principal Investigator: 
 
Protocol No. OPN-FLU-CS-3205 
 
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, 
With or 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 6.0/dated 07JAN2022 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, With or Without the Presence of Nasal Polyps 
SPONSOR: OptiNose US, Inc. 
DEVELOPMENT PHASE: 3b 
IND Number: 110089 
EudraCT Number: 2019-000368-12 
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 from Study OPN-FLU-CS-3205 with Study OPN-FLU-CS-3206, 
which is a separate study being conducted in parallel to this study. It has identical study objectives and study 
design but only includes subjects with CRS without nasal polyps:  
• 
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 
• 
frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening 
of symptoms that requires an 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 with or without nasal polyps. 
STUDY POPULATION: Approximately 333 subjects will be randomly assigned to receive OPN-375 186 μg 
or 372 μg, or placebo (approximately 111 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 childbearing 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) 


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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, purulent discharge, or polyps 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: 
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 a polyp extending outside the ostiomeatal complex/middle turbinate (anterior or inferior) that is below 
the inferior turbinate attachment as determined by the nasoendoscopy at screening 
11. have a nasal septum perforation 


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12. have had more than 1 episode of epistaxis with frank bleeding in the month before Visit 1 (Screening)  
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, or 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) inhibitor (eg, ritonavir, atazanavir, clarithromycin, 
indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin, conivaptan, 
lopinavir, voriconazole, cobicistat) 
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 doctor is not 
exclusionary 
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. 


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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 and nasal polyp grading. 
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/ET in the APOV in the ethmoid and maxillary sinuses  
 
Key Secondary Endpoints: 
• 
change from baseline to Week 4 on CSNS score in subjects from studies OPN-FLU-CS-3205 and OPN-
FLU-CS-3206 who were symptomatic at trial entry despite reported use of an intranasal steroid for treatment 
of CRS within 30 days of Visit 1from studies OPN-FLU-CS-3205 and OPN-FLU-CS-3206 
• 
frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a worsening of 
symptoms that requires escalation of treatment, from studies OPN-FLU-CS-3205 and OPN-FLU-CS-3206 
 
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:  
Sample Size Determination: Sample size requirements were 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. 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 111 subjects/group (333 total subjects) is sufficient to detect a 0.8 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 1.9. This sample size is also 
adequate to detect an 11.3% 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 27%. Approximately 
333 subjects will be randomized (111 subjects/group) to have at least 120 subjects without nasal polyps be 
included. 
 


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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 
instantaneous AM CSNS. 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 instantaneous AM CSNS, respectively, 
are the repeated measures. 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), nasal polyp status (present, 
absent), 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 (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 (CS-
3205, CS-3206), and the logarithm of follow-up time as an offset variable. 
 
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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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 
Nasal polyp grading 
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 
 
 
 
Treatment compliance  
 
X 
X 
X 
X 
X 
X 
X 
Provide/collect subject diary 
X 
 
 
 
X 
 
 
 


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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 
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 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 
VERSION HISTORY ............................................................................................................. 2 
SYNOPSIS ............................................................................................................................. 14 
SCHEDULE OF STUDY PROCEDURES AND EVALUATIONS ................................. 19 
TABLE OF CONTENTS ..................................................................................................... 21 
LIST OF IN-TEXT TABLES .............................................................................................. 25 
LIST OF IN-TEXT FIGURES ............................................................................................ 25 
LIST OF ATTACHMENTS ................................................................................................ 25 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 26 
1 
INTRODUCTION ......................................................................................................... 28 
1.1 
Background ...........................................................................................................28 
1.2 
Clinical Experience ...............................................................................................31 
1.3 
Rationale for the Study .........................................................................................32 
2 
STUDY OBJECTIVES ................................................................................................. 34 
2.1 
Primary Objective .................................................................................................34 
2.2 
Key Secondary Objectives ....................................................................................34 
2.3 
Other Secondary Objectives .................................................................................34 
2.4 
Safety Objectives ..................................................................................................36 
2.5 
Number of Subjects and Duration of Study ..........................................................36 
2.6 
Termination of Study ............................................................................................36 
3 
STUDY DESIGN ........................................................................................................... 37 
3.1 
Study Overview ....................................................................................................37 
3.2 
Endpoints ..............................................................................................................38 
3.2.1 
Efficacy Endpoints ............................................................................38 
3.2.1.1 
Primary Endpoint ...............................................................................38 
3.2.1.2 
Key Secondary Endpoints .................................................................38 
3.2.1.3 
Other Secondary Endpoints ...............................................................39 
3.2.2 
Safety Endpoints ................................................................................40 
3.3 
Method of Treatment Assignment or Randomization ..........................................40 
3.4 
Breaking the Blind ................................................................................................41 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................. 42 
4.1 
Inclusion Criteria ..................................................................................................42 


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4.2 
Exclusion Criteria .................................................................................................43 
4.3 
Withdrawal and Removal of Subjects ..................................................................45 
4.4 
Follow-Up for Drug Discontinuation/Subject Withdrawal from Study ...............46 
5 
STUDY DRUG ............................................................................................................... 47 
5.1 
Study Drug Treatment and Dosing .......................................................................47 
5.2 
Clinical Supplies ...................................................................................................48 
5.3 
Packaging and Labeling ........................................................................................48 
5.4 
Dispensing and Return of Study Drug ..................................................................48 
5.5 
Storage and Reconciliation of Supplies ................................................................48 
5.6 
Concomitant Medication ......................................................................................49 
5.6.1 
Allowed Concomitant Medications ...................................................49 
5.6.2 
Rescue Medication ............................................................................49 
5.6.3 
Prohibited Medications ......................................................................50 
5.7 
Treatment Compliance ..........................................................................................50 
6 
VISIT SCHEDULE SUMMARY ................................................................................. 51 
6.1 
Visit 1 (Screening/Single-blind Placebo Run-in) .................................................51 
6.2 
Visit 2 (Day 1, Baseline; Randomization) ............................................................52 
6.3 
Visits 3, 4, and 5 (Weeks 4, 8, and 12) .................................................................52 
6.4 
Subject Contact (Week 16 and Week 20) .............................................................53 
6.5 
Visit 6 (Week 24 End-of-Double-blind/Early Termination) ................................53 
6.6 
Unscheduled Visits ...............................................................................................53 
7 
STUDY PROCEDURES AND ASSESSMENTS ........................................................ 54 
7.1 
Medical History, Demographics, and Baseline Characteristics ............................54 
7.1.1 
Medical History .................................................................................54 
7.1.2 
Information Pertaining to Chronic Rhinosinusitis .............................54 
7.1.3 
Demographic Information and Baseline Characteristics ...................54 
7.2 
Efficacy Assessments ...........................................................................................54 
7.3 
Health Economic Assessments .............................................................................57 
7.4 
Safety Assessments ...............................................................................................58 
7.4.1 
Physical Examination ........................................................................58 
7.4.2 
Nasal Examination .............................................................................58 
7.4.3 
Ocular examinations ..........................................................................58 


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7.4.4 
Vital Signs and Weight ......................................................................59 
7.4.5 
Laboratory Variables .........................................................................59 
8 
SAFETY MONITORING AND REPORTING .......................................................... 61 
8.1 
Adverse Events .....................................................................................................61 
8.2 
Adverse Reactions ................................................................................................62 
8.3 
Suspected Adverse Reactions ...............................................................................62 
8.4 
Unexpected Adverse Reactions or Adverse Events ..............................................62 
8.5 
Serious Adverse Events ........................................................................................63 
8.5.1 
Life-Threatening Adverse Events ......................................................63 
8.5.2 
Serious Adverse Event Reporting .....................................................63 
8.6 
Non-Serious Adverse Event Reporting ................................................................64 
8.7 
Pregnancy .............................................................................................................64 
9 
STATISTICAL ANALYSIS ......................................................................................... 65 
9.1 
Sample Size Determination ..................................................................................65 
9.2 
Analysis Sets .........................................................................................................65 
9.2.1 
Intent-to-treat Analysis Set ................................................................65 
9.2.2 
Safety Analysis Set ............................................................................65 
9.2.3 
Full Analysis Set (FAS) .....................................................................65 
9.2.4 
Per-Protocol Analysis Set (PPS) .......................................................66 
9.3 
Primary Estimand, Intercurrent Events, and Estimation ......................................66 
9.3.1 
Co-primary Endpoints .......................................................................66 
9.3.2 
Potential Intercurrent Events .............................................................66 
9.3.3 
Primary Estimand ..............................................................................66 
9.3.4 
Estimator and Estimation Method - Primary Analysis ......................67 
9.3.5 
Supplementary Analysis ....................................................................68 
9.4 
Sensitivity Analyses ..............................................................................................68 
9.4.1 
ANCOVA on Ranked APOV Values ................................................68 
9.4.2 
Tipping Point Analysis ......................................................................69 
9.5 
Key Secondary Efficacy Analyses - Pooling of Study 3205 and Study 3206 ......69 
9.6 
Other Secondary Efficacy Analyses .....................................................................69 
9.7 
Subgroup Analyses ...............................................................................................71 
9.8 
Type I Error Control for Multiplicity ...................................................................71 


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9.8.1 
Co-primary Efficacy Endpoints .........................................................71 
9.8.2 
Type I Error Control for Key Secondary Endpoints .........................72 
9.9 
Safety Analysis .....................................................................................................72 
9.9.1 
Adverse Events (AEs) .......................................................................73 
9.9.2 
Other Safety Endpoints ......................................................................73 
9.10 
Interim Analysis ....................................................................................................73 
10 DATA QUALITY ASSURANCE ................................................................................. 75 
10.1 
Case Report Forms ...............................................................................................75 
10.2 
Source Documents ................................................................................................75 
10.3 
Record Retention ..................................................................................................75 
11 QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 76 
12 REGULATORY AND ETHICAL CONSIDERATIONS .......................................... 77 
12.1 
Ethical Conduct of the Study ................................................................................77 
12.2 
Informed Consent Process ....................................................................................77 
12.3 
Privacy of Personal Data ......................................................................................77 
12.4 
Future Use of CT Scans ........................................................................................78 
13 ADMINISTRATIVE CONSIDERATIONS ................................................................ 79 
13.1 
Monitoring ............................................................................................................79 
13.2 
Protocol Amendments and Deviations .................................................................79 
13.2.1 
Protocol Amendment .........................................................................79 
13.2.2 
Protocol Deviations ...........................................................................79 
13.3 
Financing and insurance .......................................................................................79 
13.4 
Publication policy .................................................................................................80 
14 REFERENCES .............................................................................................................. 81 
 
 
 
 
 
 
 


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LIST OF IN-TEXT TABLES 
TABLE 1: STUDY DRUG DOSING – DOUBLE-BLIND TREATMENT PHASE ...... 47 
TABLE 2: NASAL SYMPTOM SCALE............................................................................ 55 
TABLE 3: PATIENT GLOBAL IMPRESSION OF CHANGE (PGIC) SCALE .......... 57 
TABLE 4: NASAL POLYP GRADING SCALE ............................................................... 57 
TABLE 5: LABORATORY MEASUREMENTS ............................................................. 59 
TABLE 6: ADVERSE EVENT SEVERITY ...................................................................... 62 
 
LIST OF IN-TEXT FIGURES 
Figure 1: Closed-Palate Bi-directional™ Delivery System ....................................................31 
Figure 2: OPN-375 Exhalation Delivery System ...................................................................31 
Figure 3: Study Flow Diagram ...............................................................................................38 
 
LIST OF ATTACHMENTS 
ATTACHMENT 1: 
BECLOMETHASONE – EQUIVALENT DOSES ..........................83 
ATTACHMENT 2: 
RADIATION ASSOCIATED WITH CT SCANS ............................84 
ATTACHMENT 3: 
KEY ASSESSMENTS FOR NASAL EXAMINATION..................85 


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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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NP 
NB 
Nasal Polyps 
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 
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 
WPOV 
Average Percent of Opacified Volume in Worst Sinus between Maxillary and 
Ethmoid Sinus  
WPOV-E 
Average Percent of Opacified Volume in Worst Ethmoid Sinus 
WPOV-M 
Average Percent of Opacified Volume in Worst Maxillary Sinus 


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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).  


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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, 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 


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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 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. 


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Figure 1: 
Closed-Palate Bi-directional™ Delivery System 
 
Schematic A 
Schematic B 
 
A = Cross-sectional view from the left side. 
 
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 


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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 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 


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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 from Study OPN-FLU-CS-3205 with 
Study OPN-FLU-CS-3206, which is a separate study being conducted in parallel to this study. It 
has identical study objectives and study design but only includes subjects with CRS without 
nasal polyps:  
• 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 
• frequency of acute exacerbations of CRS over the 24-week treatment period, defined as a 
worsening of symptoms that requires an escalation of treatment 
 
2.3 
Other Secondary Objectives 
The following 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: 
• change from baseline to Week 24/ET in subject symptoms and functioning, as measured by 
Sinonasal Outcome Test-22 (SNOT-22) total score 
• 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 for the CRS 
with NP and CRS without NP sub-groups 
• change from baseline in symptoms as measured by a CSNS: congestion, facial pain or pressure 
sensation, and nasal discharge (anterior and/or posterior) to end of Week 4, 8, and 12 for the 
total population, for the CRS with NP and without NP sub-groups, and in patients with and 
without previous sinus surgery 
• change from baseline to Week 4, 8, and 12 on facial pain or pressure sensation, nasal discharge 
(anterior and/or posterior), nasal congestion, and sense of smell, as measured by average AM 


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instantaneous symptom scores and PM reflective symptom scores for the total population, for 
CRS with and without NP, and patients with and without previous sinus surgery 
• change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses for 
CRS with NP and without NP sub-groups and in patients with and without previous sinus 
surgery 
• 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 (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, for the CRS with 
NP and without NP sub-groups, 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 NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 
• time to first acute exacerbation of CRS, defined as a worsening of symptoms that requires 
escalation of treatment 
• percent of subjects requiring rescue medication after Week 4 
• change from baseline to Week 24/ET in the 36-Item Short Form Health Survey version 2 
(SF36v2) mental component score (MCS) 
• change from baseline to Week 24/ET in the SF36v2 physical component score (PCS) 
• 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) 
− EuroQol-5 (EQ-5D) 


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− 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 Study OPN-FLU-CS-3205 with 
Study OPN-FLU-CS-3206, which is a separate study being conducted in parallel to this study. It 
has identical study objectives and study design but only includes subjects with CRS without 
nasal polyps: 
• 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 333. Approximately 333 subjects will be 
randomly assigned to receive 1 of the 2 active treatments or placebo (111 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 with or 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, polyps, 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. When the number of subjects with polyps reaches 50% of 
the total population, no additional subjects with polyps will be enrolled. 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. 


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A study flow diagram is shown in Figure 3. 
Figure 3: 
Study Flow Diagram 
Single-blind 
Lead-In 
Double-blind Treatment 
Pretreatment 
Randomization 
 
 
End of 
Double-blind 
 
----------------------------------------   186 µg OPN-375 BID (n=111)   ---------------------------------------- 
----------------------------------------  372 µg OPN-375 BID (n=111)   ---------------------------------------- 
----------------------------------------    Placebo BID (n=111)   ---------------------------------------- 
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 total 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 
• change from baseline to Week 4 on CSNS score in subjects from studies OPN-FLU-CS-3205 
and OPN-FLU-CS-3206 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 escalation of treatment, from studies OPN-FLU-CS-
3205 and OPN-FLU-CS-3206 
 


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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 for the CRS with and without NP subgroups 
• 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, for the CRS with NP and without NP sub-groups, and in patients 
with and without previous sinus surgery 
• change from baseline to Weeks 4, 8, and 12 for the total population, for the CRS with NP and 
without NP sub-groups, and in patients with and without previous sinus surgery: 
− in average AM instantaneous (evaluation of symptom severity immediately preceding 
the time of scoring) and 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 
CRS with NP and without NP sub-groups and in 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, for the CRS with NP and without NP 
sub-groups, 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 NP and 
without NP sub-groups, and in subjects with and without previous sinus surgery 
• time to first acute exacerbation of CRS, defined as a worsening of symptoms that requires 
escalation of treatment 
• percent of subjects requiring rescue medication after Week 4 


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• 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: 
− 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 from both 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 the Global PSQI Score from studies OPN-FLU-CS-
3205 and OPN-FLU-CS-3206 
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 


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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 
Randomization will be stratified by presence of nasal polyps of grade 1 or larger at baseline 
(Present vs Absent) and previous sinus surgery (Yes vs No) (previous sinus surgery is defined as 
evidence of ethmoidectomy [partial or total], or maxillary antrostomy). A maximum of 
189 Approximately 125 of the subjects without polyps will be randomized into the study . 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 polyps 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 


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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, 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 a polyp extending outside the OMC/middle turbinate (anterior or inferior) that is below 
the inferior turbinate attachment as determined by the nasoendoscopy at screening 


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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)  
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, or 
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. have 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)  


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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) 
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 doctor 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 


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• 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. 
 
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. 


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An instruction sheet on the use of study drug will be provided by the Sponsor or their designee to 
be given to the subjects. 
 
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. 
 


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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. 
 
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. 


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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, 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 


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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 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 


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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 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 


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these 7 components yields 1 global score. The PSQI takes approximately 3-5 minutes to 
complete 
• 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 


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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% 
• 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. 
• Polyp grading of each nasal cavity, determined by a nasal polyp grading scale score measured 
by nasoendoscopy (Table 4) (Lildholdt et al, 1995; Lildholdt et al, 1997). The baseline 
assessment of polyp grading is performed at Visit 1 (Screening) and Visit 6/Week 24/ET by 
the examining physician. 
Table 4: Nasal Polyp Grading Scale 
Score 
Description 
0 
No polyps 
1 
Mild polyposis - polyps not reaching below the inferior border of the middle turbinate 
2 
Moderate polyposis - polyps reaching below the inferior border of the middle concha, but not 
the inferior border of the inferior turbinate 
3 
Severe polyposis - large polyps reaching below the lower inferior border of the inferior 
turbinate 
 
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: 
• those with polyps present who have: 
− used a topical intranasal corticosteroid (≥8 weeks duration) 
− used a short-course of systemic corticosteroid (1- to 3-week duration) 


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− SNOT-22 total score ≥20 
− Lund-Mackay CT score ≥1 
• those without polyps present who have: 
− 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 
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 and a polyp grading sheet. 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 


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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 5. The total amount of blood to be taken from each subject for these 
study-specific measurements is approximately 7 mL. 
Table 5: 
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.  


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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 clinical 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 6. 


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Table 6: 
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 


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in the IB. Additionally, AEs that are listed in the IB as occurring with the same class of drugs, or 
as 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 


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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. 
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 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). 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 
111 subjects per group (333 total subjects) is sufficient to detect a 0.8 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 1.9. This 
sample size is also adequate to detect an 11.3% difference between treatments in average percent 
opacification using a 2-sided test at the 5% significance level with 88% power, and assuming a 
SD of 27 percent. Approximately 333 subjects (111 subjects per group) will be randomized to 
have at least 120 subjects without nasal polyps be included. 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) on or before Week 4 (i.e., Week 2 and/or Week 
4) 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. 


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9.2.4 Per-Protocol Analysis Set (PPS) 
The PPS analysis set excludes subjects from the FAS population due to major protocol 
deviations with potential to substantively 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.  
Determination of the major protocol deviations will be made prior to unblinding 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 with or 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 nominal Study Day 28. 
AND 
• 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 time point) 
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: 


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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%’ is 
assigned; if baseline APOV < 75%, a poor score is defined as baseline APOV + 
25%. The rationale for assignment of a poor score is provided in the SAP. Also, 
further detail regarding 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). 
2. Nasal surgery: composite strategy with poor 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 poor 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 instantaneous AM CSNS. 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 instantaneous AM CSNS, 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), nasal 
polyp status (present, absent), treatment (OPN-375 186 µg, OPN-375 372 µg, placebo), week (2, 
4), treatment-by-day interaction, and the continuous covariate baseline 7-day average total 
instantaneous AM CSNS with baseline-by-week interaction.  


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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), nasal polyp status (present, absent), 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. 
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 poor scores assigned. 
3. Treatment discontinuation: composite strategy with poor scores assigned. 
The estimator and estimation methods for the co-primary endpoints, as well as the assignment of 
poor scores, 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. The method described by Koch, et. al. (1982) using extended Mantel-
Haenszel statistics will be used to perform nonparametric treatment comparisons, adjusting for 


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the baseline covariate. Implementation of this method is described in Stokes, et. al., Chapter 7 
(2012). 
9.4.2 Tipping Point Analysis 
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. 
 
9.5 
Key Secondary Efficacy Analyses - Pooling of Study 3205 and Study 3206  
The following analyses are based on the key secondary endpoints which are defined by pooling 
the data from Study OPN-FLU-CS-3205 and Study OPN-FLU-CS-3206; further details are 
provided in the SAP: 
• 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 (CS-3205, CS-3206), 
and the logarithm of follow-up time as an offset variable.  
 
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.  


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The following secondary endpoints will be analyzed with MMRM models; further details will be 
provided in the SAP: 
• Changes from baseline in average instantaneous and reflective AM and PM CSNS and 
symptom scores (facial pain or pressure sensation, nasal discharge, and nasal congestion)  
• 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 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 
o number and percentage of missing work days over the past 4 weeks 
o 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 
• 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 Kaplan-Meier method and log-rank test will be used to estimate and compare the 
distributions of time to first exacerbation between OPN-375 and placebo. 


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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 percent of subjects requiring rescue medication from Week 4 to Week 12; subjects 
without use of any rescue medication during the period Week 4 to Week 12 will be referred to 
as rescue-free subjects. 
• The percentage of subjects who meet the eligibility criteria for surgery at Week 24 
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.  
The total number of times a subject requires rescue medication after Week 4 to Week 12 will be 
tabulated. Rescue free subjects will be assigned a zero (‘0’) for this tabulation. This endpoint will 
be analyzed with an ANCOVA model based on ranks. 
Change from baseline to Week 24/ET for SF-6D will be summarized as described in the SAP.  
9.7 
Subgroup Analyses 
The co-primary endpoints will be analyzed according to the primary estimand, with the 
subgroups defined based on actual polyp and surgical status, for the following stratification 
subgroups: 
1. Subjects with polyps versus without polyps at baseline 
2. Subjects with prior sinus surgery versus without prior sinus surgery at baseline 
In addition, the following secondary endpoints will be analyzed for the stratification groups, 
using the statistical models described in Section 9.6 for these endpoints; further detail on these 
statistical methods will be provided in the SAP:  
• Change from baseline CSNS, other than the primary, and the individual daily nasal symptom 
scores that are components of the CSNS 
• Change from baseline SNOT-22 total  
• Change from baseline WPOV-E, WPOV-M, and WPOV 
• Zinreich modification of Lund-MacKay Staging System score for the worst sinus between 
maxillary and ethmoid sinuses 
 
9.8 
Type I Error Control for Multiplicity 
9.8.1 Co-primary Efficacy Endpoints 
The primary hypotheses of this trial are that at least one OPN-375 dose 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. If the 
unblinded interim analysis occurs, then α=0.0001 will be spent on this interim analysis and the 
family-wise Type 1 error probability for the test of the primary hypothesis will be α=0.0499. 


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Details of this IA and the approach to control for Alpha will be are contained in the detailed in 
the Interim Analysis SAP (IASAP). 
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 test low dose comparison; otherwise, stop. 
2. Test each co-primary endpoint for OPN-375 low dose (186 μg) vs placebo: If p < 0.05 for 
both endpoints, then proceed to test key secondary endpoints; otherwise, stop. 
There are two comparisons for each dose: OPN-375 high dose (372 μg) vs placebo and OPN-375 
low dose (186 μg) vs placebo. The order of the testing is as follows:  
1. 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  
2. OPN-375 372 μg versus placebo in the APOV in the ethmoid and maxillary sinuses change 
from baseline to Week 24/ET 
3. OPN-375 186 μg versus placebo in the change from baseline in the 7-day average 
instantaneous AM CSNS at the end of Week 4 
4. OPN-375 186 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 
There are four planned comparisons among the two key secondary efficacy endpoints. These 
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 both 
primary hypotheses are met, as follows:  
1. 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 
2. 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 
3. OPN-375 372 μg versus placebo in the frequency of acute exacerbations of CRS over 24 
weeks 
4. OPN-375 186 μg versus placebo in the frequency of acute exacerbations of CRS over 24 
weeks 
 
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. 


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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 
An interim analysis is planned for both co-primary endpoints in this study to evaluate the sample 
size assumptions as follows:  
1. A blinded, pooled IA of co-primary endpoint change from baseline in the 7-day average 
instantaneous AM CSNS to assess the variance. This IA is planned to occur when 
approximately 50% of randomized subjects have reached Week 4 CSNS endpoint. Since 
subjects need only to have completed the CSNS endpoint assessment, the blinded IA of 
CSNS variance will occur first.  
2. A blinded, pooled IA of co-primary endpoint change from baseline to Week 24/ET APOV to 
assess variance. This IA is planned to occur after approximately one-third of randomized 
subjects have completed the study (Week 24/ET). Based on the results of this blinded IA of 
APOV, an unblinded IA of APOV to assess the conditional probability of rejecting the null 
hypothesis at the end of the study, given the observed interim result (Conditional Power), 
will be considered according to the following decision criteria: 
a. If SD <= 29.7%, (i.e. within 10% of target), then no unblinded IA will be performed. 
b. If observed SD > 29.7%, then perform unblinded IA at the earliest feasible time post 
the blinded IA. This unblinded IA will be performed by an independent, unblinded 
statistician not involved in the conduct of the study. 
The complete details of this interim analysis is provided in the IASAP. In the event the 
unblinded IA occurs, a partial unblinding of specified data and personnel will occur. The plan, 


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procedures, and methods for this unblinded interim analysis are detailed in the IASAP as well.  
Under the assumption that an unblinded IA will occur as planned, and assuming a non-binding 
futility boundary, the Type 1 error probability for the interim analysis is conservatively 
assumed to be α<0.0001; therefore, the Type 1 error probability for the final analysis is 
α=0.0499 (two-sided test). 
If the unblinded analysis is not performed the Type 1 error probability for the final analysis will 
remain at α=0.05 (two-sided test). 
 


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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  


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• 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 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.  
 


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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 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. 
Koch GG, Amara IA, Davis GW, Gillings DB. A review of some statistical methods for 
covariance analysis of categorical data. Biometrics. 1982;38(3):563-595. 
 


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Lildholdt T, Rundcrantz H, Bende M, et al. Glucocorticoid treatment for nasal polyps. The use of 
topical budesonide, intramuscular betamethasone, and surgical treatment. Arch Otolaryngol 
Head Neck Surg. 1997;123(6):595-600. 
Lildholdt T, Rundcrantz H, Lindqvist N. Efficacy of topical corticosteroid powder for nasal 
polyps: a double-blind, placebo-controlled study of budesonide. Clin Otolaryngol. 
1995;20(1):26-30. 
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. 
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;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. 
Stokes ME, Davis CS, Koch GG. Categorical Data Analysis Using SAS, Third Edition. 2012. 
Cary, NC: SAS Institute, Inc. 
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 6.0/dated 07JAN2022 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: 
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Protocol Number OPN-FLU-CS-3205 
Statistical Analysis Plan 
 
CONFIDENTIAL AND PROPRIETARY 
Page 1 of 71 
14 February 2022 
 
CONFIDENTIAL 
 
Statistical Analysis Plan 
OPN-375 (fluticasone propionate delivered by exhalation delivery 
system) 
OPN-FLU-CS-3205 
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 With or 
Without the Presence of Nasal Polyps 
 
IND Number: 
110089 
EudraCT Number: 
2019-000368-12 
Date of Plan: 
14 February 2022 
Based on: 
Protocol Amendment 6, Date: 07 January 2022 
CRF Version 1.0 Date: 
10 March 2021 
 
 
Author: Thomas Dobbins 


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Protocol Number OPN-FLU-CS-3205 
Statistical Analysis Plan 
 
CONFIDENTIAL AND PROPRIETARY 
Page 2 of 71 
14 February 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:    14 February 2022  
 
 
 


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Statistical Analysis Plan 
 
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Page 3 of 71 
14 February 2022 
Table of Contents 
1 ABBREVIATIONS ........................................................................................................7 
2 INTRODUCTION .........................................................................................................9 
3 STUDY OVERVIEW .................................................................................................. 10 
3.1 General Study Design and Study Schema ...................................................................... 10 
3.2 Study Procedures and Assessments ................................................................................ 11 
3.3 Study Objectives............................................................................................................ 14 
3.3.1 Primary Objective .................................................................................................. 14 
3.3.2 Key Secondary Objectives ..................................................................................... 14 
3.3.3 Other Secondary Objectives ................................................................................... 14 
3.3.4 Safety Objectives ................................................................................................... 17 
3.4 Study Endpoints ............................................................................................................ 17 
3.4.1 Primary Endpoint ................................................................................................... 17 
3.4.2 Key Secondary Endpoints ...................................................................................... 17 
3.4.3 Other Secondary Endpoints .................................................................................... 17 
3.4.4 Safety Endpoints .................................................................................................... 20 
3.4.5 HEOR Endpoints and Assessments ........................................................................ 20 
3.5 Investigational Product, Dosage and Mode of Administration ........................................ 21 
3.6 Method of Treatment Assignment or Randomization ..................................................... 21 
4 GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS ....................... 23 
4.1 Unblinding and Responsibility for Analyses .................................................................. 23 
4.2 Design considerations for Sample Size and Power ......................................................... 23 
4.3 Multi-Centers ................................................................................................................ 23 
4.4 Randomization Stratification Factors ............................................................................. 24 
4.5 Interim Analysis (IA) ..................................................................................................... 24 
4.5.1 Alpha Spending for the IA and final analyses ......................................................... 24 
4.6 Considerations for statistical analysis resulting from the COVID-19 PHE...................... 25 
4.6.1 Co-Primary Endpoints............................................................................................ 25 
4.6.2 Secondary Endpoints ............................................................................................. 25 
5 ANALYSIS POPULATION SETS.............................................................................. 28 
5.1 Enrolled Subjects ........................................................................................................... 28 
5.2 Single-Blind Run-In Set................................................................................................. 28 
5.3 Intent-to-treat (ITT) Analysis Set ................................................................................... 28 
5.4 Safety Analyses Set ....................................................................................................... 28 
5.5 Full Analysis Set (FAS) ................................................................................................. 28 
5.6 Per Protocol Analysis Set (PPS)..................................................................................... 28 
6 STUDY POPULATION SUMMARY ......................................................................... 29 
6.1 Subject Disposition ........................................................................................................ 29 
6.1.1 Subject Disposition with respect to Intercurrent Events .......................................... 29 


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6.2 Demographics ............................................................................................................... 29 
6.3 Subject Characteristics ................................................................................................... 29 
6.4 CRS History .................................................................................................................. 29 
6.5 Prior Medications .......................................................................................................... 29 
6.6 Medical History ............................................................................................................. 30 
6.7 Chronic Rhinosinusitis (CRS) Treatment History........................................................... 30 
6.8 Nasal and Sinus Endoscopic Assessment ....................................................................... 30 
6.9 Urine Drug Screening .................................................................................................... 30 
6.10 
Protocol Deviations/Violations .............................................................................. 30 
7 STATISTICAL METHODS FOR EFFICACY ANALYSES .................................... 31 
7.1 Primary Estimand, Intercurrent Events, and Estimation .................................................. 31 
7.1.1 Co-primary Endpoints ............................................................................................ 31 
7.1.2 Intercurrent Events ................................................................................................. 31 
7.1.3 Primary Estimand .................................................................................................. 31 
7.1.4 Rationale and Definition of Poor Scores for the Primary Estimand ......................... 32 
7.1.5 Estimator and Estimation Method - Primary Efficacy Analysis ................................ 33 
7.2 Sensitivity Analyses ...................................................................................................... 33 
7.2.1 Supplementary Estimand ......................................................................................... 33 
7.2.2 ANCOVA on Ranked APOV Values ..................................................................... 34 
7.2.3 Observed Cases Analysis ....................................................................................... 34 
7.2.4 Tipping Point Analysis........................................................................................... 35 
7.3 Estimation - Key Secondary Efficacy Endpoints .............................................................. 35 
7.3.1 CSNS in Subjects on INS at Baseline – Pooled Analysis ........................................ 35 
7.3.2 Acute CRS Exacerbations – Pooled Analysis ......................................................... 35 
7.4 Multiplicity - Type I Error Control ................................................................................ 36 
7.4.1 Type I Error Control for Key Secondary Endpoints ................................................ 37 
7.5 Estimation - Other Secondary Efficacy Endpoints .......................................................... 37 
7.5.1 Averages of Daily Nasal Symptom Diary – Individual & CSNS............................. 37 
7.5.2 SNOT-22 Total Score and Domain Scores ............................................................. 38 
7.5.3 Percentage of Opacified Volume ............................................................................ 38 
7.5.4 Qualitative CT Scan Assessment ............................................................................ 39 
7.5.5 PSQI Global and Component Scores ...................................................................... 40 
7.5.6 SF36v2 – MCS and PCS Domains ......................................................................... 41 
7.5.7 SF36v2 – Individual Health Domains..................................................................... 41 
7.5.8 PGIC - “Subject” Global Impression of Change ..................................................... 41 
7.5.9 QIDS-SR Total Score and Severity of Depression Categories ................................ 42 
7.5.10 
Time to First CRS Exacerbation Event ............................................................... 42 
7.5.11 
SIT Scores ......................................................................................................... 43 
7.6 Health Economic Outcomes Research (HEOR) Endpoints ............................................. 43 
7.6.1 Surgical Intervention Assessment (SIA) ................................................................. 43 
7.6.2 EQ-5D-5L.............................................................................................................. 44 
7.6.3 Health and Performance Questionnaire (HPQ) ....................................................... 44 
7.6.4 SF-6D .................................................................................................................... 44 
7.7 Per Protocol Analysis .................................................................................................... 45 
7.8 Subgroup Analyses ........................................................................................................ 45 


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7.8.1 Subgroup Analysis of Co-Primary Endpoints ......................................................... 45 
7.8.2 Subgroup Analysis of Daily Nasal Symptom Scores .............................................. 45 
7.8.3 Subgroup Analysis of SNOT-22 Total and Domain Scores .................................... 45 
7.8.4 Subgroup Analysis of APOV in Individual Sinuses ................................................ 45 
7.8.5 Subgroup Analysis of POV in the Worst Sinus....................................................... 45 
7.8.6 Models for Subgroup Analyses .............................................................................. 46 
8 SAFETY ANALYSIS .................................................................................................. 47 
8.1 Study Drug Exposure and Administration ...................................................................... 47 
8.2 Adverse Events .............................................................................................................. 47 
8.3 Clinical Laboratory Tests ............................................................................................... 48 
8.4 Urine Pregnancy Test .................................................................................................... 48 
8.5 Nasal Examinations ....................................................................................................... 48 
8.6 Ocular Examinations ..................................................................................................... 48 
8.7 Vital Signs ..................................................................................................................... 48 
8.8 Physical Examination .................................................................................................... 48 
8.9 Concomitant Medications .............................................................................................. 48 
8.10 
Rescue Medications ............................................................................................... 49 
9 DATA HANDLING RULES AND DEFINITIONS ................................................... 50 
9.1 Data Handling Conventions ........................................................................................... 50 
9.1.1 Study Days and Duration ....................................................................................... 50 
9.1.2 Visit Windows for Repeated Measures Efficacy Analyses ...................................... 50 
9.1.3 Baseline Value ....................................................................................................... 52 
9.1.4 Enrollment Date ..................................................................................................... 52 
9.1.5 Week 24/End of Treatment (ET) ............................................................................ 52 
9.2 Demographic Variable Definitions................................................................................. 52 
9.2.1 Age ........................................................................................................................ 52 
9.2.2 Body Mass Index (BMI) ........................................................................................ 52 
9.3 Efficacy Endpoint Variable Definitions ......................................................................... 53 
9.3.1 Daily Nasal Symptoms Diary Assessments ............................................................ 53 
9.3.2 Quantitative (Volumetric) Measurement of CT Scan Image ................................... 54 
9.3.3 SNOT-22 Total and Domain Scores ....................................................................... 55 
9.3.4 SF36v2 and PCS Domain Scores ........................................................................... 56 
9.3.5 Acute CRS Exacerbations ...................................................................................... 56 
9.3.6 Qualitative CT Scan Image Assessment ................................................................. 57 
9.3.7 Pittsburgh Sleep Quality Index (PSQI) ................................................................... 59 
9.3.8 PGIC - “Subject” Global Impression of Change ..................................................... 59 
9.3.9 Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR) ........... 60 
9.3.10 
Smell Identification Test (SIT) ........................................................................... 61 
9.4 Health Economic Outcomes Research (HEOR) Endpoints ............................................. 61 
9.4.1 EQ-5D-5L.............................................................................................................. 61 
9.5 Therapy and Safety Endpoint Variable Definitions ........................................................ 62 
9.5.1 Prior and Concomitant Medication ......................................................................... 62 
9.5.2 Treatment Emergent Adverse Events (TEAEs) ...................................................... 62 


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10 
STATISTICAL ANALYSES IMPLEMENTATION SPECIFICATIONS ........... 63 
10.1 
Declarations and Multiple Imputation Considerations ............................................ 63 
10.2 
Multiple Imputation Method – PMM with J2C ....................................................... 63 
10.3 
Multiple Imputation Method – Tipping Point ......................................................... 64 
10.4 
Multiple Imputation – Statistical Analysis and Inference ........................................ 65 
10.5 
MMRM Model convergence contingencies ............................................................ 66 
11 
CHANGES FROM THE PROTOCOL .................................................................. 67 
12 
REFERENCES ........................................................................................................ 68 
13 
APPENDICES.......................................................................................................... 70 
13.1 
Appendix 1: PSQI Scoring ..................................................................................... 70 
 
 
 


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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 
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) has been developed after review of Sponsor Protocol 
OPN-FLU-CS-3205 (Amendment 6.0, dated 07 January 2022) and the corresponding 
electronic case report form (eCRF). This SAP describes the statistical methods to be used for 
the analysis and reporting of all efficacy and safety data collected during the conduct of 
Protocol OPN-FLU-CS-3205.  
 
This SAP supersedes the statistical considerations identified in original Protocol OPN-FLU-
CS-3205, as well as the SAP dated 19 April 2021, which is based on Protocol Amendment 4.1 
and is the basis for the IASAP dated 8 June 2021.  This SAP contains all changes incorporated 
into Protocol Amendment 6.0, and there are no deviations from this amendment presented in 
this SAP. If additional analyses are performed to supplement the planned analyses described 
in this SAP they will be identified as such in the Clinical Study Report (CSR). 
 
This SAP is being written with consideration of the recommendations outlined in the following 
International Conference on Harmonization (ICH) Guidance for Industry documents:  
 
• E9: Statistical Principles for Clinical Trials  
• E9-R1 Addendum: Estimands and Sensitivity Analysis 
• ICH E3: Structure and Content of Clinical Study Reports 
 
This SAP also incorporates the recent FDA Guidance regarding the COVID-19 Public Health 
Emergency (PHE): 
• FDA Guidance on the Conduct of Clinical Trials of Medical Products during COVID-
19 Public Health Emergency: Guidance for Industry, Investigators, and Institutional 
Review Boards, (11 May 2020) 
 


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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 with or without the presence of nasal polyps. In addition, a 
sub-study will be conducted (in select sites in the US and Canada only) to evaluate clinical 
biomarkers to characterize the microbiome and cytokine profiles in a subset of subjects at selected 
study centers as detailed in Protocol Attachment 6.0. 
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, polyps, 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. When the number of subjects with polyps reaches 50% 
of the total population, no additional subjects with polyps will be enrolled.  
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. 


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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 
(i.e., blood pressure, pulse) and weight, and through collection of information for concomitant 
medications. 
Refer to the Schedule of Study Procedures and Evaluations in Table 3.1 for the timing of all tests, 
procedures, and assessments that will be performed during the study. 
A study flow diagram is shown in Figure 3.1 
 
Figure 3.1:  Study Flow Diagram 
Single-blind 
Lead-In 
Double-blind Treatment 
Pretreatment 
Randomization 
↓ 
 
End of 
Double-blind 
↓ 
 
  186 µg OPN-375 BID (n=126)   → 
  372 µg OPN-375 BID (n=126)   → 
    Placebo BID (n=126)    → 
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 
3.2 
Study Procedures and Assessments 
The study procedures and assessments are outlined in Table 3.1 below.  


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Table 3.1: 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 
  Nasal polyp grading 
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 
 
 
 
Treatment compliance  
 
X 
X 
X 
X 
X 
X 
X 
Provide/collect subject diary 
X 
 
 
 
X 
 
 
 
Review subject’s diary entries 
 
X 
X 
X 
X 
 
 
 


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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 
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 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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3.3 
Study Objectives 
3.3.1 
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 AM instantaneous 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 
3.3.2 
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 from studies OPN-FLU-CS-3205 and OPN-
FLU-CS-3206, which has identical study objectives and study design but only includes subjects 
with CRS without nasal polyps): 
• change from baseline to Week 4 in CSNS  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 
3.3.3 
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: 
• change from baseline in AM/PM instantaneous and AM/PM reflective 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, for 
the CRS with NP and without NP sub-groups, and in subjects with and without previous 
sinus surgery 
• change from baseline to Week 4, 8, and 12 for the total population, for CRS with and 
without NP, and subjects with and without previous sinus surgery, on facial pain or 
pressure sensation, nasal discharge (anterior and/or posterior), nasal congestion, and 


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sense of smell as measured by average AM/PM instantaneous symptom scores and 
AM/PM reflective symptom scores 
• change from baseline to Week 24/ET in APOV in the ethmoid sinuses (APOV-E)  
• change from baseline to Week 24/ET in APOV in the maxillary sinuses (APOV-M)  
• change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses 
for CRS with NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 
• change from baseline to Week 24/ET in APOV in the ethmoid sinuses (APOV-E) for 
CRS with NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 
• change from baseline to Week 24/ET in APOV in the maxillary sinuses (APOV-M) for 
CRS with NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 
• change from baseline in the volume of the nasal cavity opacified 
• change from baseline to defined time points in subject symptoms and functioning, as 
measured by SNOT-22 total score and sub-domain scores for the total population and 
for the CRS with NP and CRS without NP sub-groups 
• 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 
in the worst maxillary sinus, in the worst ethmoid sinus, and in the worst sinus between 
maxillary and ethmoid sinuses 
• change from baseline to Week 24/ET in percent of sinus volume occupied by disease 
in the worst maxillary sinus, in the worst ethmoid sinus, and in the worst sinus between 
maxillary and ethmoid sinuses, in subjects with NP and without NP sub-groups and in 
subjects 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 
• 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 
subjects with NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 


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• time to first acute exacerbation of CRS, defined as a worsening of symptoms that 
requires escalation of treatment 
• change from baseline to Week 24/ET in the 36-Item Short Form Health Survey version 
2 (SF36v2) mental component score (MCS) 
• change from baseline to Week 24/ET in the SF36v2 physical component score (PCS) 
• 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 
global and component scores 
− 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 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) 
− 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 Study OPN-FLU-CS-3205 with Study 
OPN-FLU-CS-3206, which has identical study objectives and study design but only includes 
subjects with CRS without nasal polyps): 
• 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 


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3.3.4 
Safety Objectives 
To evaluate the safety of OPN-375 by monitoring AEs throughout the study; results of nasal 
examination, vital signs measurements (i.e., blood pressure, pulse), and weight; and monitoring 
concomitant medication usage. 
3.4 
Study Endpoints 
3.4.1 
Primary Endpoint 
Co-primary Endpoints: 
• change from baseline to the end of Week 4 in average total 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 
3.4.2 
Key Secondary Endpoints 
Key Secondary Endpoints include: 
• change from baseline to Week 4 in CSNS 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 from studies OPN-FLU-CS-3205 and OPN-FLU-CS-3206 
• frequency of acute exacerbations of CRS over the 24-week treatment period, defined as 
a worsening of symptoms that requires escalation of treatment, from studies OPN-FLU-
CS-3205 and OPN-FLU-CS-3206 
3.4.3 
Other Secondary Endpoints 
• change from baseline in AM/PM instantaneous and AM/PM reflective 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, for 
the CRS with NP and without NP sub-groups, and in subjects with and without previous 
sinus surgery 
• change from baseline to Weeks 4, 8, and 12 for the total population, for the CRS with 
NP and without NP sub-groups, and in subjects with and without previous sinus 
surgery: 


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− in average AM/PM instantaneous (evaluation of symptom severity immediately 
preceding the time of scoring) 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 
 nasal discharge (anterior and/or posterior) score 
 facial pain or pressure sensation score 
 sense of smell score 
• change from baseline to Week 24/ET in APOV in the ethmoid sinuses (APOV-E)  
• change from baseline to Week 24/ET in APOV in the maxillary sinuses (APOV-M)  
• change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses 
for CRS with NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 
• change from baseline to Week 24/ET in APOV in the ethmoid sinuses (APOV-E) for 
CRS with NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 
• change from baseline to Week 24/ET in APOV in the maxillary sinuses (APOV-M) for 
CRS with NP and without NP sub-groups and in subjects with and without previous 
sinus surgery 
• change from baseline to Week 4, 8, 12 and 24/ET in the SNOT-22 total and sub-domain 
scores for the total population and for CRS with NP and without NP sub-groups and in 
subjects 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) 
− WPOV-M, WPOV-E, WPOV in subjects with NP and without NP sub-groups 
and in subjects with and without previous sinus surgery 


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− 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 NP and without NP sub-groups, and in subjects with and without 
previous sinus surgery 
− Change from baseline in the volume of the nasal cavity opacified 
• time to first acute exacerbation of CRS, defined as a worsening of symptoms that 
requires escalation of treatment 
• 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 
• QIDS Severity of Depression at Week 24/ET 
• change from baseline to Week 24/ET for: 
− 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  
The following secondary endpoints are defined by pooling the data from Study OPN-FLU-CS-
3205 and Study OPN-FLU-CS-3206: 
• 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 
• change from baseline to Week 24/ET the Global PSQI Score  


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3.4.4 
Safety Endpoints 
Safety Endpoints include: 
• Prior-concomitant and concomitant medications 
• Vital signs and weight 
• Nasal and endoscopic assessments 
• Nasal examinations 
• Adverse Events 
 
3.4.5 
HEOR Endpoints and Assessments 
Health economic information related to chronic rhinosinusitis will be collected during the study 
and will include information on criteria for eligibility for escalation of care to surgical intervention 
(independent of actual surgery performed) for 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 Health Productivity 
Questionnaire (HPQ). 
Objective criteria for being eligible for surgical intervention are listed below for subgroups of 
subjects with and without polyps.  
Subjects with polyps present at baseline who meet the following criteria: 
• used a topical intranasal corticosteroid (≥8 weeks duration)  
• used a course of systemic corticosteroid (1- to 3-week duration)  
• SNOT-22 total score ≥20 
• Lund-Mackay CT score ≥1 
Subjects without polyps present at baseline who have: 
• 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 (i.e., macrolide or trimethoprim/sulfamethoxazole) (≥12 weeks duration)  
• SNOT-22 total score ≥20 
• Lund-Mackay CT score ≥1 
The World Health Organization (WHO) Health and Performance Questionnaire (HPQ) is a work 
productivity questionnaire which asks about employment status, work absences, and on-the-job 
productivity. Based on HPQ work productivity questions, a comparison of health economic 
measures during the double-blind treatment phase related to CRS will include: 
− percent of subjects indicating that they are willing to consider sinus surgery at baseline and 
Week 24/ET 


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− percent of subjects who meet the minimal objective criteria for surgical intervention (as 
defined in Section 7.6.1) 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  
3.5 
Investigational Product, Dosage and Mode of Administration 
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 the Protocol Section 3.3. Study drug 
packaging is described in Protocol Section 5.3. 
As shown in Table 3.2, the study drug dosage during the double-blind treatment phase will be 186 
μg or 372 μg of OPN-375 BID or placebo BID. 
 
Table 3.2: Study Drug Dosing 
 
OPN-375 Dosage 
 
 
186 μg Twice a Day 
372 μg Twice a Day 
Placebo 
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. 
 
3.6 
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 


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• OPN-375 372 μg BID 
• Placebo BID 
Randomization will be stratified by: 
• presence of nasal polyps of grade 1 or larger at baseline (Present vs Absent)  
• 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. 


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4 
GENERAL CONSIDERATIONS FOR STATISTICAL ANALYSIS 
4.1 
Unblinding and Responsibility for Analyses 
This trial is conducted as a double-blind study. During the conduct of the study, the subject, 
investigator, and study personnel at each center, and the Sponsor 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 scheme. The randomization scheme will be maintained 
within the Interactive Web Response System (IWRS). 
The official, final database is the responsibility of OptiNose, US, Inc. and its designated personnel, 
and will not be unblinded until medical review has been performed, protocol deviations and per- 
protocol population have been identified, and data have been declared final and complete. 
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 un-blinding will be documented in the source document and in the appropriate 
section of the CRF. Additionally, the documentation received from the IWRS indicating the blind 
break will be retained in a secure manner, in the subject’s source documents. 
A partial unblinding of specified data and personnel will occur for an interim analysis of this study. 
The plan, procedures, and methods for this interim analysis are the subject and scope of a separate 
IASAP, and are summarized briefly in Section 4.5. 
The statistical analysis of data from this trial, as specified in this SAP, will be the responsibility of 
OptiNose US, Inc. and its designated personnel. 
4.2 
Design considerations for Sample Size and Power 
Sample size assumptions for CSNS were based on previous Phase 3 studies of OPN 375 in subjects 
with nasal polyposis. Sample size assumptions for APOV were based on data from a study 
evaluating the change in maxillary and ethmoid opacification in chronic sinusitis patients treated 
with an intramuscular dose of triamcinolone (Pallanch 2013).  
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 111 subjects per group (333 
total subjects) is sufficient to detect a -0.8 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 of 1.9.  
This sample size is also adequate to detect an -11.3% difference between treatments in average 
percent opacification using a 2-sided test at the 5% significance level with 88% power, and 
assuming a standard deviation of 27 percent.  
The sample size was estimated for the co primary efficacy endpoints using Power Analysis and 
Sample Size Software (PASS 15) (NCSS, 2017). 
4.3 
Multi-Centers 
Although this is a multi-center study, a central randomization is used with IWRS; therefore, there 
are no planned analyses by study center, and study site will not be included as a factor in statistical 
models.  


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4.4 
Randomization Stratification Factors 
There are two stratification factors for randomization:  1) presence of nasal polyps of grade 1 or 
larger at baseline (Present vs Absent) and 2) previous sinus surgery (Yes vs No).   
Both factors will be included in the analysis model as categorical covariates.  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 major protocol violation and these subjects will be removed from the per-protocol 
analyses.     
4.5 
Interim Analysis (IA) 
The Interim Analysis Statistical Analysis Plan (IASAP), dated 19 March 2021 (original) and June 
8, 2021 (revised) describes the statistical methods to be used for the interim analysis (IA) of the 
co-primary CSNS and APOV endpoints, respectively, and these IASAPs are considered an 
addendum to the SAP Version 4.0 dated 19 April 2021. All statistical methods, data handling 
conventions and rules defined in the SAP Version 4.0 apply to the original and revised IASAP.  
Original IASAP (19 March 2021) is the reference for the blinded IA CSNS: 
1. A blinded, pooled IA of co-primary endpoint Composite Score of Nasal Symptoms (CSNS) to 
assess the variance of change from baseline to Week 4 in CSNS. This IA is planned to occur 
when approximately 50% of randomized subjects have reached Week 4 CSNS endpoint. 
Revised IASAP (8 June 2021) is the reference for the IA of APOV: The revised IASAP added a 
blinded IA of APOV endpoint and made the unblinded IA of APOV conditional on the outcome 
of this analysis as described below. 
2. A blinded, pooled IA of co-primary endpoint change from baseline to Week 24/ET in Average 
of Percentage Opacified Volume (APOV) to assess variance. This IA is planned to occur after 
approximately one-third of randomized subjects have completed the study (Week 24/ET).  
Based on the results of this blinded IA of APOV, an unblinded IA of APOV to assess the 
conditional probability of rejecting the null hypothesis at the end of the study, given the 
observed interim result (Conditional Power), will be considered according to the following 
decision criteria: 
a) If SD <= 29.7%, (i.e. within 10% of target), then no unblinded IA will be performed. 
b) If observed SD > 29.7%, then perform unblinded IA at the earliest feasible time post the 
blinded IA. This unblinded IA will be performed by an independent, unblinded 
statistician not involved in the conduct of the study. 
As of the date of this final SAP, the blinded IA of both CSNS and APOV co-primary endpoints 
have occurred and resulted in a decision to not increase sample size based on variability; 
consequently, the planned unblinded IA of APOV did not occur.  
4.5.1 
Alpha Spending for the IA and final analyses 
Assuming a single unblinded interim analysis of APOV at 1/3 of the planned enrollment with a 
target sample size of 111 per group, and a futility bound, the Type 1 error probability for the 


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interim analysis is α<0.0001, and the Type 1 error probability for the final analysis is α=0.0499 
(two-sided test).     
Since the unblinded interim analysis of APOV did not occur, no Type 1 error probability was 
spent; therefore, the Type 1 error probability for the final analysis is α=0.05 (two-sided test). 
4.6 
Considerations for statistical analysis resulting from the COVID-19 PHE 
4.6.1 
Co-Primary Endpoints 
Since the co-primary efficacy variable CSNS is based on electronic diaries used by subjects during 
this study, as described in Section 9.3.1, there is no anticipated impact of COVID-19 on the 
subject’s ability to complete the diaries per the protocol.  Therefore, there is no anticipated impact 
of COVID-19 on this co-primary endpoint. 
For the co-primary endpoint APOV, the endpoint CT scan will occur at the Week 24 visit, or the 
ET visit if the subjects discontinues the study prior to Week 24. Since subjects must visit the clinic 
for the CT scan, subjects may be impacted by COVID-19 in a manner similar to other acute 
illnesses as described in the Protocol, Amendment 6, Section 6.  In this circumstance a subject 
must be symptom-free for at least 28 days prior to undergoing the Week 24/ET CT scan, and 
consequently the Week 24/ET visit may be delayed. Subjects are instructed to continue on 
treatment until the EOS CT scan can be completed.  There is no anticipated impact of such a delay 
on the APOV co-primary endpoint. 
Thus, there is no practical impact of the COVID-19 PHE on either of the co-primary endpoints.  
4.6.2 
Secondary Endpoints 
The following secondary efficacy variables are PROs which are self-administered by subjects 
during study visits: 
• 
Sinonasal Outcome Test (SNOT-22) – a subject-completed questionnaire that consists of 
22 symptoms and social emotional consequences of their nasal disorder. 
• 
EuroQol-5 (EQ-5D) – a subject-completed 2-page questionnaire including the EQ-5D 
descriptive system and the EQ Visual Analogue Scale (EQ VAS). 
• 
36-Item Short Form Health Survey Version 2 (SF-36v2) – a subject-completed, 
multipurpose, 36-item subject-completed validated questionnaire that measures 8 
domains of health. 
• 
Short Form-6 Dimension (SF-6D) – a subject-completed single health state index derived 
from the 8 domains from the SF-36v2. 
• 
Pittsburgh Sleep Quality Index (PSQI) – a self-rated, validated questionnaire, which 
assesses sleep quality and disturbances over a 1-month time interval. 
• 
Quick Inventory of Depressive Symptomatology (QIDS) – a subject-completed 16-item 
questionnaire to assess the severity of depressive symptoms. 


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• 
Health and Work Performance Questionnaire (HPQ) – a subject-completed Health 
economic information questionnaire. 
• 
Smell Identification Test (SIT) – a subject-completed test comprised of 4 booklets each 
containing 10 microencapsulated (scratch and sniff) odors. 
• 
Patient Global Impression of Change (PGIC) – a subject-completed global impression of 
change scale assessment questionnaire. 
4.6.2.1 Remote Study Visits 
A COVID-19 Supplemental Guidance Document for Protocol CS-3205 has been provided to 
Investigators which includes detailed instructions for handling the PROs where remote visits are 
necessary. 
For any subjects participating in study visits remotely, all PROs required for the visit will be sent 
by email to the subject or by courier directly to the subject’s home for completion prior to the study 
visit.  Site staff are instructed to notify study subjects to complete the self-administered PROs 
within two days prior to the remote study visit. At the time of this remote visit, the site staff are 
instructed to collect and document the information provided in the PROs in the patient’s chart. 
Subject-completed hard copies of all PROs will be collected at the subject’s next in-person visit 
or sent to the site by courier.  
As subjects will complete the PROs before the virtual study visit, it will prevent the risk of study 
staff influencing subject responses. The site staff will verify the PROs were completed by the 
subjects at the virtual visit and the subjects will share their completed PRO responses. The 
subject’s responses will be documented in the subject’s chart.  
Site staff are instructed to review the PRO responses provided during the virtual study visit with 
the hard copies of the PROs submitted by the subject after their visit. If any discrepancies are 
noted, site staff are instructed to update the Electronic Data Capture (EDC) system with the data 
from the hard copy. The hard copy subject-completed PROs are considered the source record and 
data from these will be reported in the EDC. Additionally, the study Monitoring Plan will include 
a requirement for monitors to confirm discrepant data during monitoring visits.  
4.6.2.2 Sensitivity Analyses 
The number and percentage of virtual visits will be summarized by study visit, overall and by 
treatment group, in order to assess the extent of the virtual visits in the study.  Also, a tabulated 
listing of discrepancies between verbal responses reported at the virtual visit and reported on the 
PRO hard copies will be provided for each PRO. 
A sensitivity analysis of the impact of virtual clinic visits will depend on the extent of the virtual 
visits at Baseline and Week 24/ET.  If there are not sufficient virtual visits to include a term in the 
statistical model, then a statistical analysis excluding subjects with a virtual visit at Week 24/ET 
will be performed. The treatment difference and 95% confidence interval will be reported to assess 
consistency with the pre-specified analysis result.   


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If there are a sufficient number of virtual visits to include in a statistical model then a categorical 
variable for visit type (in-clinic, virtual) and treatment-by-visit type interaction will be included in 
the statistical model.  The treatment difference and 95% confidence interval in each subgroup will 
be reported to assess consistency with the pre-specified analysis result. 
It is assumed that both the number and percentage of data discrepancies between the verbal report 
and the hard copy report will be small. A statistical analysis excluding subjects with discrepant 
results at Week 24/ET will be performed. The treatment difference and 95% confidence interval 
will be reported to assess consistency with the pre-specified analysis result. 
Modification of these analyses or other sensitivity analyses of secondary endpoints may be 
considered, as appropriate, once the extent of the virtual visits is determined. 
 
 


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5 
ANALYSIS POPULATION SETS 
5.1 
Enrolled Subjects 
This set will include all subjects screened and who have signed the informed consent. 
5.2 
Single-Blind Run-In Set 
The single-blind run-in set includes all subjects who received at least one dose of placebo EDS in 
the placebo run-in period. 
5.3 
Intent-to-treat (ITT) Analysis Set 
The ITT analysis set will include all subjects who are randomized regardless of whether they 
received double-blind treatment.  
5.4 
Safety Analyses 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. 
5.5 
Full Analysis Set (FAS) 
The FAS will include all subjects in the ITT set who receive at least one dose of randomized study 
treatment during the double-blinded treatment phase and have a baseline efficacy measurement for 
APOV endpoint, and also have a baseline value and at least one post-baseline value (7-day average 
AM instantaneous CSNS score) on or before Week 4 (i.e., Week 2 and/or Week 4) 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. 
5.6 
Per Protocol Analysis Set (PPS) 
The PPS analysis set excludes subjects from the FAS population due to major protocol deviations 
with potential to substantively 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.  
Determination of the major protocol deviations will be made prior to unblinding of the database 
and documented in a separate report.  Examples may include but are not necessarily limited to: 
• Subjects who did not use study medication for more than 15 consecutive days in a given 
month 
• Subjects who used a prohibited medication (e.g., oral steroids) 
• Subjects who have sinus surgery during the study 
• Subjects with an acute sinus exacerbation, for example as evidenced by taking antibiotics 
for sinus infection, within 28 days of a study-directed CT scan (screening or Week 24/ET) 


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6 
STUDY POPULATION SUMMARY 
All study population summaries will be based on the Safety Analysis Set, (reference Section 5.4), 
and summarized by treatment group and total population, unless otherwise indicated.   
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error (SE) of the mean, median, minimum, and maximum. Descriptive statistics for categorical 
variables include subject counts and percentages. Percentages are based on the number of subjects 
in the analysis set for whom there are non-missing data at the specified visit, unless otherwise 
specified. Counts of “missing” will be presented if at least one treatment group has missing data. 
6.1 
Subject Disposition 
The number of subjects in the Enrolled Set, Single-Blind Analysis Set, ITT Analysis Set, Safety 
Analysis Set, FAS, PPS will be summarized using descriptive statistics by treatment group and 
overall. 
Subjects who completed the study, and subjects who discontinued the study prior to week 24, will 
be summarized by treatment group and overall, and reasons for study discontinuation will be 
summarized.   
The denominator for calculating percentages in the Subject Disposition displays will be the ITT 
Analysis Set.  
6.1.1 
Subject Disposition with respect to Intercurrent Events  
Subject disposition with respect to Intercurrent Events will be summarized for both the primary 
and supplemental estimands defined in Sections 7.1.3 and 7.2.1, respectively. The efficacy FAS 
population will be used for the Subject Disposition with respect to Intercurrent Events.  
A subject listing of intercurrent events including subject outcomes under each estimand definition 
will be provided. 
6.2 
Demographics 
The continuous variables of subject age, weight (kg), height (cm), and body mass index (BMI) 
(kg/m2), and the categorical variables of subject sex, ethnicity, and race will be summarized.  
6.3 
Subject Characteristics 
The following subject characteristics will be summarized:  nasal polyp status at baseline, prior 
sinus surgery status.  
6.4 
CRS History 
Information pertaining to subjects’ chronic sinusitis history will be summarized. 
6.5 
Prior Medications 
All prior medications will be coded using the World Health Organization dictionary of medical 
codes (WHO Drug, Version December 2018 or later). The incidence of prior medications will be 
summarized by therapeutic class and preferred term. Subjects are counted only once in each 


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therapeutic class category, and only once in each preferred term category.  Prior medications will 
include all medications taken on or before the first dose of double-blind treatment. Further details 
on the definition of prior medications is provided in Section 9.5.1. 
6.6 
Medical History 
A complete medical history will be obtained before randomization to ensure subjects qualify for 
the study.  Medical, surgical and smoking history will be summarized. 
6.7 
Chronic Rhinosinusitis (CRS) Treatment History 
Information pertaining to subjects’ CRS treatment history will be summarized.  
6.8 
Nasal and Sinus Endoscopic Assessment 
Results of the nasal and sinus endoscopic assessment performed during the placebo run-in period 
will be summarized. 
6.9 
Urine Drug Screening 
Drug screen will be performed at the screening/placebo run-in period. Positive findings indicating 
drug abuse will lead to screen failure. Urine drug screen findings will be listed. 
6.10 
Protocol Deviations/Violations 
Protocol violations and deviations considered to be major will be listed by treatment group.  
Reference Section 5.6 for definition of Per Protocol Analysis Set. 
 


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7 
STATISTICAL METHODS FOR EFFICACY ANALYSES 
Hypotheses testing and statistical inference for efficacy endpoints and the strategy for control of 
Type I error probability is described in Section 7.4. All statistical tests are 2-sided tests at the 5% 
level of significance.  Statistical significance is defined as p < 0.05 (two-sided test).  Nominal p-
values will be provided for all other efficacy endpoints not included in the formal testing strategy. 
7.1 
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 µg and 372 µg of OPN-375 (fluticasone propionate) 
with placebo in subjects with documented CRS with or without nasal polyps. 
7.1.1 
Co-primary Endpoints 
1. Change from baseline to the end of Week 4 in the 7-day average AM, instantaneous 
CSNS; CSNS includes congestion, facial pain or pressure sensation, and nasal discharge 
(anterior and/or posterior).  Further details on the daily nasal symptoms diary and the 
derivation of the CSNS and the 7-day average are provided in Section 9.3.1. 
AND 
2. The change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary 
sinuses. 
The APOV is the average percentage of volume opacified across both maxillary and 
ethmoid sinuses (all 4 sinuses). Further details on derivation of APOV is provided in 
Section 9.3.2. 
7.1.2 
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; i.e., study discontinuation for nasal surgery 
3. Discontinuation from study treatment 
7.1.3 
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; further detail regarding the assignment of 
a worst score to the diary data are provided in Section 9.3.1.  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%. 


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The rationale for assignment of a poor score is provided in Section 7.1.4 below.  
Further detail regarding the handling of a missing POV in individual sinuses is 
provided in Section 9.3.2. 
Systemic corticosteroid use for other indications will be considered a treatment and 
study discontinuation event (reference criteria 3c). 
2. Nasal surgery: composite strategy with poor 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 poor 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 Section 7.1.5 for each of the co-primary endpoints. 
7.1.4 
Rationale and Definition of Poor Scores for the Primary Estimand 
The majority of the clinical endpoints in this study, including the co-primary endpoints, are defined 
for a range of values which have a defined minimum and maximum value. For these endpoints, a 
worst score can be defined based on the maximum, or minimum, score in the range depending on 
which value represents a worst score.  The analyses of interest are based on a comparison of the 
change from baseline values for these endpoints.  Given the assignment of a worst score, i.e., the 
most extreme value possible for an endpoint, the magnitude of the change score depends directly 
on the baseline value.  For subjects with lower baseline scores, reflective of mild or moderate CRS, 
the resulting change score may be too extreme and not reflective of a change that is observed in 
the clinic. Consequently, a statistical analysis using these extreme values can result in subjects 
with unrealistic change scores; even a few such subjects can have a large, unintended influence on 
the assessment of treatment effect. In this sense, assignment of a worst score can produce a change 
score that is artificial and arbitrary, and this approach is not recommended (O'Kelly & Ratitch, 
2014). 
Instead, a ‘poor score’ (O'Kelly & Ratitch, 2014) is assigned to subjects with intercurrent events 
(1) and (2) defined above based on the upper 97.5th percentile of the distribution of the change 
scores observed in the clinic. The definition of a poor score and documentation of pre-specified 
poor scores assigned to each clinical endpoint is provided in the SAP Addendum, Blinded Review 
of Clinical Endpoints in CRS for Assignment of Poor Scores (26 October 2021). 
   
 


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7.1.5 
Estimator and Estimation Method - Primary Efficacy 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 instantaneous AM CSNS. Estimation is based on a mixed-
effects model for repeated measures (MMRM) where changes from baseline to Week 2 and Week 
4, in the 7-day average instantaneous AM CSNS, respectively, are the repeated measures. The 7-
day windows used to define the 7-day average instantaneous AM CSNS from baseline through 
Day 84 (Week 12) are provided in Section 9.1.2.1, Table 9.1. 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 7.1.3, criteria 3,c), 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. 
Contingencies in the event of an issue with MMRM model convergence are described in Section 
10.5. 
The MMRM model will include categorical effects for previous sinus surgery (Y,N), nasal polyp 
status (present, absent), treatment (OPN-375 186 µg, OPN-375 372 µg, placebo), Week (2, 4), 
treatment-by-day interaction, and the continuous covariate: baseline 7-day average total 
instantaneous AM CSNS, with baseline-by-day interaction. The model-based LS mean difference 
between each active treatment group and placebo (active-placebo), 95% CI, and p-value will be 
displayed. 
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), nasal polyp status (present, absent), treatment (OPN-375 186 
µg, OPN-375 372 µg, placebo), and baseline APOV. The model-based LS mean difference 
between each active treatment group and placebo (active-placebo), 95% CI, and p-value will be 
displayed. 
For the treatment policy estimand, (reference Section 7.1.3, 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 & Ratitch, 2014).   Further detail on the MI 
implementation, and statistical analysis and inference is provided in Section 10. 
7.2 
Sensitivity Analyses  
7.2.1 
Supplementary Estimand 
A sensitivity analysis of the co-primary endpoints based on an alternative estimand will be 
performed. 


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Supplementary estimand: 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 supplementary 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 Week 24/ET scan, 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 Section 7.1.5 for each of the co-primary endpoints. 
2. Nasal surgery; i.e., study discontinuation for nasal surgery: composite strategy with poor 
scores assigned. 
3. Treatment discontinuation: composite strategy with poor scores assigned. 
For the supplementary estimand, the estimator and estimation methods for the co-primary 
endpoints, as well as the composite strategy with poor score assignments, are the same as 
for the primary estimand described above. 
7.2.2 
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. The method described by Koch, et. al. (1982) using extended Mantel-
Haenszel statistics will be used to perform nonparametric treatment comparisons, adjusting for the 
baseline covariate.  Implementation of this method is described in Stokes, et. al., Chapter 7 (2012). 
7.2.3 
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 7.1.5, with the exception that in the 
observed cases population there are no missing data; consequently, no imputation is required. 


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7.2.4 
Tipping Point Analysis 
If the analyses of both co-primary endpoints are statistically significant, then an additional 
sensitivity analysis of the primary estimand will be performed to determine the smallest constant, 
δ, 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 described in Section 
7.1.5 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.”   
For the co-primary APOV endpoint, a worsening of treatment values means that APOV values in 
the active treatment groups would increase at Week 24/ET; therefore, δ > 0.    The value δ* provides 
a measure of the robustness of the primary analysis result.  The larger the value of δ* the more 
robust are the results of the primary analysis to the impact of missing data, and, conversely, the 
smaller the value of δ* the more sensitive the results of the primary analysis are to missing data. 
Ultimately however, a Tipping Point analysis is a numerical search procedure. A value of the 
Tipping Point, if reached, needs to be interpreted in the context of its clinical plausibility. 
For the treatment policy estimand, (reference Section 7.1.3, criteria 3, c), missing data due to study 
discontinuation for APOV endpoint will be imputed under MAR assumption in both active 
treatment and placebo groups, then the constant δ is applied (added) to the imputed values in the 
active treatment groups. Further detail on the implementation is provided in Section 10. 
For the CSNS co-primary endpoint, it is anticipated that there will be an insufficient number of 
early study discontinuations (discontinuations prior to Week 4) to warrant a formal Tipping Point 
analysis.  If this is not the case, then a Tipping Point analysis will be performed for the CSNS co-
primary endpoint using the same approach as described above. 
7.3 
Estimation - Key Secondary Efficacy Endpoints 
The following key secondary endpoints (defined in Section 3.4.2) are included in the strategy 
for strong control of the Type I error probability in the trial. For the key secondary endpoints, 
intercurrent events will be addressed as described in Section 7.1.3 for the primary estimand. 
The analyses of these key secondary endpoints are defined by pooling the data from Study OPN-
FLU-CS-3205 and Study OPN-FLU-CS-3206.  
7.3.1 
CSNS in Subjects on INS at Baseline – Pooled Analysis 
Change from baseline to Week 4 in CSNS in subjects who were symptomatic at trial entry despite 
reported use of an intranasal steroid (INS) 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). 
7.3.2 
Acute CRS Exacerbations – Pooled Analysis 
How an acute CRS exacerbation is defined and captured in this study is described in Section 9.3.5. 
The frequency of acute sinus exacerbations over 24 weeks will be compared between OPN-375 


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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 addition, the model 
will include a categorical effect for protocol (CS-3205, CS-3206), and the logarithm of exposure 
time as an offset variable. 
Regarding intercurrent events, use of systemic corticosteroids is included in the definition of acute 
exacerbation; subjects who have surgery or study discontinuation events will be censored at the 
time of the intercurrent event.  Subjects who discontinue treatment are followed to study 
completion or intercurrent event as described in Section 7.1.3. 
7.4 
Multiplicity - Type I Error Control  
The study hypothesis encompasses the primary and key secondary endpoints; therefore, hypothesis 
tests for these endpoints are included in the strategy for strong control of the Type I error in the 
study.  The familywise Type 1 error probability for the test of the primary hypothesis is α=0.05, 
since the planned unblinded interim analysis of APOV endpoint did not occur (reference Section 
4.5.1). 
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 test low dose comparison; otherwise, 
stop. 
2. Test each co-primary endpoint for OPN-375 low dose (186 μg) vs placebo: If 
• p < 0.05 for both endpoints, then proceed to test key secondary endpoints; otherwise, 
stop. 
There are two comparisons for each dose: OPN-375 high dose (372 μg) vs placebo and OPN-375 
low dose (186 μg) vs placebo. The order of the testing is as follows:  
1. 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  
2. OPN-375 372 μg versus placebo in the APOV in the ethmoid and maxillary sinuses change 
from baseline to Week 24/ET 
3. OPN-375 186 μg versus placebo in the change from baseline in the 7-day average 
instantaneous AM CSNS at the end of Week 4 
4. OPN-375 186 μg versus placebo in the APOV in the ethmoid and maxillary sinuses change 
from baseline to Week 24/ET 


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7.4.1 Type I Error Control for Key Secondary Endpoints 
There are four planned comparisons among the two key secondary efficacy endpoints. These 
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 both 
primary hypotheses are met, as follows:  
1. OPN-375 372 μg versus placebo in change from baseline to Week 4 in CSNS  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 
2. OPN-375 186 μg versus placebo in change from baseline to Week 4 in CSNS  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 
3. OPN-375 372 μg versus placebo in the frequency of acute exacerbations of CRS over 24 
weeks 
4. OPN-375 186 μg versus placebo in the frequency of acute exacerbations of CRS over 24 
weeks 
7.5 
Estimation - Other Secondary Efficacy Endpoints 
All statistical analyses in this section that reference the primary MMRM and ANCOVA models 
described in Section 7.1.5 will include the same factors as their respective primary models, except 
for the baseline covariate. The baseline covariate for the specific endpoint described in this section 
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 contrasts, assigning equal weight to 
each dose, to obtain the inferential statistics for combined doses and for the comparison: combined 
doses versus placebo. 
Intercurrent events for secondary endpoints will be addressed as described in Section 7.1.3 for the 
primary estimand, unless otherwise indicated. For the treatment policy estimand, (reference 
Section 7.1.3, criteria 3,c), missing data due to study discontinuation will be handled as described 
in Section 7.1.5 for the primary MMRM and ANCOVA models, respectively. Further details on 
the MI method for endpoints based on the ANCOVA model are described in Section 10. 
7.5.1 
Averages of Daily Nasal Symptom Diary – Individual & CSNS 
Details on the daily nasal symptoms diary and the derivation of the CSNS is provided in Section 
9.3.1. For the 7-day averages of AM, PM, and instantaneous, reflective individual nasal 
symptoms scores, the worst score of ‘3’ will be applied to the individual symptom scores for the 
composite strategy, per the primary estimand.   For the 7-day average of AM, PM, and 
instantaneous, reflective CSNS scores, the worst score of ‘9’ will be applied;  further details 
regarding the assignment of a worst score to the diary data are provided in Section 9.3.1. The 7-
day windows used to define the 7-day averages from baseline though Day 84 (Week 12) are 
provided in Section 9.1.2.1, Table 9.1. 


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The following individual and CSNS endpoints will be analyzed: 
• Changes from baseline to Weeks 4, 8 and 12 in the 7-day average of AM, PM, and 
instantaneous, reflective individual nasal symptoms scores (16 endpoints at each time point: 
four individual nasal symptom scores each at four endpoints). 
• Changes from baseline to Weeks 4, 8 and 12 in the 7-day average of AM, PM, and 
instantaneous, reflective CSNS scores (4 endpoints at each time point). 
These endpoints will be analyzed using the MMRM model described in Section 7.1.5 with the 
repeated measures including Week 4, 8, 12. The model-based LS mean difference between each 
active treatment group and placebo (active-placebo), 95% CI, and nominal p-value will be 
displayed for each analysis time point. 
7.5.2 
SNOT-22 Total Score and Domain Scores 
The SNOT-22 instrument is described in Section 9.3.3.    For SNOT-22 total score, a poor score 
is defined as follows: for a subject with a baseline SNOT-22 total score ≥ 92, a value of ‘110’ is 
assigned; if baseline SNOT-22 total score < 92, a poor score is defined as baseline SNOT-22 total 
score + 18 for the composite strategy, per the primary estimand.  For the individual Domain SNOT-
22 scores, the worst value for the respective domain (Table 9.4) will be applied. 
Changes from baseline to Weeks 4, 8, 12 and 24/ET in SNOT-22 total scores and each of the 5 
Domain scores will be analyzed using the MMRM model described in Section 7.1.5 where the 
repeated measures include change from baseline in SNOT-22 total scores at Week 4, 8, 12, and 
24/ET. The model-based LS mean difference between each active treatment group and placebo 
(active-placebo), 95% CI, and nominal p-value will be displayed for each analysis time point. 
7.5.2.1 SNOT-22 in Subjects on INS at Baseline – Pooled Analysis 
The following analysis is defined by pooling the data from Study OPN-FLU-CS-3205 and Study 
OPN-FLU-CS-3206.  Change from baseline to Week 24/ET in SNOT-22 total score in subjects 
who report using an intranasal, topically acting nasal steroid (INS) for the treatment of CRS within 
30 days of Visit 1 will be analyzed using the same MMRM model described above, and the model 
will include a categorical effect term for protocol (CS-3205, CS-3206). 
7.5.3 
Percentage of Opacified Volume 
Percentage of opacified volume, and average (APOV) and worst POV (WPOV) are defined in 
Section 9.3.2.  For APOV-E, APOV-M, WPOV, WPOV-E, WPOV-M the following endpoints are 
analyzed. 
7.5.3.1 Average Percentage of Opacified Volume in the Individual Sinuses 
Change from baseline in APOV-E and APOV-M will be analyzed with the ANCOVA model 
described in Section 7.1.5. A poor score is assigned as defined in Section 7.1.3 for the APOV co-
primary endpoint. The model-based LS mean difference between each active treatment group and 
placebo (active-placebo), 95% CI, and nominal p-value will be displayed. 


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7.5.3.2 Percentage of Opacified Volume (POV) in the Worst Sinus 
i. 
Change from baseline to Week 24/ET in the WPOV sinus at baseline. 
For WPOV, a poor score is defined as follows: for a subject with a baseline WPOV ≥ 
71%, a value of ‘100%’ is assigned; if baseline WPOV < 71%, a poor score is defined as 
baseline WPOV + 29%. 
ii. 
Change from baseline to Week 24/ET in the WPOV-E sinus at baseline. 
For WPOV-E, a poor score is defined as follows: for a subject with a baseline WPOV-E 
≥ 67%, a value of ‘100%’ is assigned; if baseline WPOV-E < 67%, a poor score is defined 
as baseline WPOV-E + 33%. 
iii. 
Change from baseline to Week 24/ET in the WPOV-M sinus at baseline. 
For WPOV-M, a poor score is defined as follows: for a subject with a baseline WPOV-
M ≥ 69%, a value of ‘100%’ is assigned; if baseline WPOV-M < 69%, a poor score is 
defined as baseline WPOV-M + 31%. 
Changes from baseline to Week 24/ET for (i) WPOV (ii) WPOV-E, and (iii) WPOV-M will be 
analyzed with the ANCOVA model described in Section 7.1.5. The model-based LS mean 
difference between each active treatment group and placebo (active-placebo), 95% CI, and 
nominal p-value will be displayed. 
7.5.4 
Qualitative CT Scan Assessment 
The protocol for qualitative CT scan imaging assessments is based on the Image Review Charter 
(IRC) – Revision C, (29 January 2020). Qualitative CT scan assessments will be performed at 
baseline and Week 24/ET in accordance with the IRC for Lund-Mackay Staging (LM) and Zinreich 
Modification of the Lund-Mackay Staging (ZLM). Further detail on LM and ZLM image scoring 
metrics and adjudication procedure, and the definitions of the analysis variables derived from these 
scoring metrics is provided in Section 9.3.6.  
For LM total score, a poor score is defined as follows: for a subject with a baseline LM total score 
≥ 18, a value of ‘24’ is assigned; if baseline LM total score < 18, a poor score is defined as baseline 
LM total score + 6 for the composite strategy, per the primary estimand. 
For ZLM total score, a poor score is defined as follows: for a subject with a baseline ZLM total 
score ≥ 39, a value of ‘50’ is assigned; if baseline ZLM total score < 39, a poor score is defined as 
baseline ZLM total score + 11 for the composite strategy, per the primary estimand. 
Other LM and ZLM efficacy endpoints will be assigned scores for the composite strategy, per the 
primary estimand, as listed in Table 7.1. 
 
 
 
 


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Table 7.1 
Worst Score Assignment for LM and ZLM efficacy variables 
Efficacy Variable 
LM worst score 
ZLM worst score 
Ethmoid + Maxillary 
12 
30 
Sinus Pair 
  4 
10 
 
7.5.4.1 Lund-Mackay (LM) Staging 
Changes from baseline to Week 24/ET in the LM Total Score, LM scores for ethmoids and 
maxillary sinuses combined, and the LM score for each sinus pair will be analyzed using the 
ANCOVA model described in Section 7.1.5. The model-based LS mean difference between each 
active treatment group and placebo (active-placebo), 95% CI, and nominal p-value will be 
displayed. 
A sensitivity analysis of reviewer agreement will be provided as a ‘3X3’ cross-classification 
table of Reviewer 1 versus Reviewer 2 assigned LM scores. 
7.5.4.2 Zinreich Modification of the Lund-Mackay Staging (ZLM) 
Changes from baseline to Week 24/ET in the ZLM Total Score, ZLM scores for ethmoid (L, R) 
and maxillary (L, R) sinuses combined, the ZLM score for each sinus pair (ethmoid, maxillary) 
and the ZLM score for the worst sinus among maxillary (L, R) and ethmoid (L, R) sinuses 
(WZLM) will be analyzed using the ANCOVA model described in Section 7.1.5. The model-based 
LS mean difference between each active treatment group and placebo (active-placebo), 95% CI, 
and nominal p-value will be displayed. 
A sensitivity analysis of reviewer agreement will be provided as a ‘6X6’ cross-classification table 
of Reviewer 1 versus Reviewer 2 assigned ZLM scores. 
7.5.5 
PSQI Global and Component Scores 
The Pittsburgh Sleep Quality Index (PSQI) is a validated, self-rated questionnaire, which assesses 
sleep quality and disturbances over a 1-month time interval; further details on the PSQI instrument 
are provided in Section 9.3.7. PSQI is measured at baseline, Week 12, and Week 24/ET.  For PSQI 
Global score, a poor score is defined as follows: for a subject with a baseline PSQI Global score ≥ 
17, a value of ‘21’ is assigned; if baseline PSQI Global score < 17, a poor score is defined as 
baseline PSQI Global score + 4 for the composite strategy, per the primary estimand. For PSQI 
component scores, the worst score for the component will be assigned. 
Changes from baseline to Week 12 and Week 24/ET in PSQI Global score and component scores 
(reference Appendix, Section 13.1) will be analyzed using the MMRM model described in Section 
7.1.5, where the repeated measures include change from baseline scores at Week 12 and 24/ET. 
The model-based LS mean difference between each active treatment group and placebo (active-
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7.5.5.1 PSQI Global Score – Pooled Analysis 
This analysis is defined by pooling the data from Study OPN-FLU-CS-3205 and Study OPN-FLU-
CS-3206.  
Change from baseline to Week 24/ET in PSQI Global score will be analyzed using the MMRM 
model described above and the model will include a categorical effect term for protocol (CS-
3205, CS-3206). 
7.5.6 
SF36v2 – MCS and PCS Domains 
The SF36v2 instrument is described in Section 9.3.4.  For SF36v2 MCS domain score, a poor 
score is defined as follows: for a subject with a baseline MCS Domain score ≤ 18, a value of ‘0’ 
is assigned; if baseline MCS Domain score > 18, a poor score is defined as baseline MCS 
Domain score  ̶ 18 for the composite strategy, per the primary estimand. 
For SF36v2 PCS domain score, a poor score is defined as follows: for a subject with a baseline 
PCS Domain score ≤ 11, a value of ‘0’ is assigned; if baseline PCS Domain score > 11, a poor 
score is defined as baseline PCS Domain score  ̶ 11 for the composite strategy, per the primary 
estimand. 
The change from baseline to Week 24/ET in SF-36v2 PCS and MCS t-scores, respectively, will 
be analyzed using the ANCOVA model described in Section 7.1.5. The model-based LS mean 
difference between each active treatment group and placebo (active-placebo), 95% CI, and 
nominal p-value will be displayed. 
7.5.7 
SF36v2 – Individual Health Domains 
The SF36v2 instrument is described in Section 9.3.4.  For SF36v2 Individual Health Domain 
scores, the worst SF36v2 Individual Health Domain score of ‘0’ will be assigned for the 
composite strategy, per the primary estimand. 
The change from baseline to Week 24/ET in SF-36v2 Health Domain scores will be analyzed 
using the ANCOVA model described in Section 7.1.5. The model-based LS mean difference 
between each active treatment group and placebo (active-placebo), 95% CI, and nominal p-value 
will be displayed. 
7.5.8 
PGIC - “Subject” Global Impression of Change 
PGIC and endpoints “Improved” and “Much Improved” are defined in Section 9.3.8. PGIC is 
measured at Weeks 4 and 24/ET.  For PGIC endpoints, the worst score of “Not Improved” will be 
assigned for each endpoint (Table 9.6) for the composite strategy, per the primary estimand. 
The proportion of subjects “Improved” or “Much Improved” will be compared between treatments 
(each active versus placebo) based on a logistic regression MMRM using the generalized linear 
mixed model (GLMM).  The logistic regression MMRM model will include categorical effects 
for previous sinus surgery (Y,N), nasal polyp status (present, absent), treatment (OPN-375 186 
µg, OPN-375 372 µg, placebo), week (4, 24/ET) and treatment-by-week interaction,. Treatment 
group comparisons will be estimated from the least squares mean difference between treatments 
from treatment-by-visit interaction and will be presented as odds ratios with accompanying p-


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values and 95% confidence intervals. The model-based LS Mean estimate of the percentage 
response in each treatment group will also be presented. 
Model parameters will be estimated using restricted pseudo-likelihood with Newton-Raphson 
ridging optimization and the Kenward-Roger method for calculating the denominator degrees of 
freedom. An unstructured covariance matrix will be used to estimate within-subject error. The 
logistic regression MMRM will be implemented in SAS PROC GLIMMIX. 
7.5.9 
QIDS-SR Total Score and Severity of Depression Categories 
The QIDS-SR Total Score and Severity of Depression categories are described in Section 9.3.9.  
For QIDS-SR total score, a poor score is defined as follows: for a subject with a baseline QIDS-
SR total score ≥ 22, a value of ‘27’ is assigned; if baseline QIDS-SR total score < 22, a poor score 
is defined as baseline QIDS-SR total score + 5 for the composite strategy, per the primary 
estimand. 
Change from baseline to Week 24/ET for QIDS-SR total scores will be analyzed using the 
ANCOVA model described in Section 7.1.5. The model-based LS mean difference between each 
active treatment group and placebo (active-placebo), 95% CI, and nominal p-value will be 
displayed. 
The proportion of subjects reporting “None” or “Mild” depression (Table 9.7) will be compared 
between treatments (each active versus placebo) based on a logistic regression at Week 24/ET. 
The logistic model will include categorical effects for previous sinus surgery (Y, N), nasal polyp 
status (present, absent), treatment (OPN-375 186 µg, OPN-375 372 µg, placebo), and baseline 
QIDS-SR total score. Model-based odds ratios between each active treatment group and placebo 
(active-placebo), 95% CI, and nominal p-value will be displayed. 
The statistical analyses of the proportion of subjects reporting “None” or “Mild” depression will 
include all subjects with a baseline and Week 24/ET QIDS-SR total score; no imputation of 
QIDS-SR depression categories will be performed. 
7.5.10 Time to First CRS Exacerbation Event 
How an acute CRS exacerbation is defined and captured in this study, as well as the definition of 
time to first acute CRS exacerbation is described in Section 9.3.5. The analyses of the frequency 
of acute CRS exacerbation events is described in Section 7.3.2 
Subjects who complete the study without an acute CRS event will be censored at Week 24/ET. 
Regarding intercurrent events, use of systemic corticosteroids is included in the definition of acute 
exacerbation; subjects who have surgery or study discontinuation events will be censored at the 
time of the intercurrent event.  Subjects who discontinue treatment are followed to study 
completion or intercurrent event as described in Section 7.1.3. 
The Kaplan-Meier method will be used to estimate the time to first acute CRS exacerbation event, 
and the median, 25th and 75th percentiles of time to first acute CRS exacerbation events (in weeks). 
A figure for Kaplan-Meier estimates by treatment group and 95% CI for the median time (in 
weeks) will be presented.  
The stratified log-rank test will be used to compare the time to first acute CRS exacerbation event  
between each active treatment group and placebo including stratification factors sinus surgery 


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status (Y vs N) and nasal polyp status (present vs absent) at baseline.  The nominal p-value from 
the stratified log-rank test will be presented.  
7.5.11 SIT Scores 
The Smell Identification Test (SIT) is described in Section 9.3.10. The SIT is administered at 
baseline and Week 24/ET. The SIT score represents the number of correct answers to the 40 
response items.  For SIT scores, a worst score of ‘10’ will be assigned, per the primary estimand.  
A SIT score of ‘10’ is the expected number of correct responses due to chance alone; i.e., a SIT 
score of ’10’ is consistent with total anosmia. 
Change from baseline to Week 24/ET in SIT scores will be analyzed using the ANCOVA model 
described in Section 7.1.5. The model-based LS mean difference between each active treatment 
group and placebo (active-placebo), 95% CI, and nominal p-value will be displayed. 
7.6 
Health Economic Outcomes Research (HEOR) Endpoints 
7.6.1 
Surgical Intervention Assessment (SIA) 
The surgical intervention assessment (SIA) is performed at baseline and Week 24/ET. This 
assessment includes a question to the subject as well as an objective assessment.  
For the question, subjects are asked, “If symptoms of CRS were to continue at the current severity 
level would subject consider undergoing sinus surgery if it were recommended to subject today by 
subject's physician?”   
 The Surgical Intervention Assessment (SIA) is based on the following pre-defined, objective 
criteria used to create a standardized determination of whether or not a subject is eligible for sinus 
surgery.   
a) Subjects with polyps present at baseline will have to have all of the following: 
• used a topical intranasal corticosteroid (≥8 weeks duration) 
• used a short-course of systemic corticosteroid (1- to 3-week duration) 
• SNOT-22 total score ≥20 
• Lund-Mackay CT score ≥1 
b) Subjects without polyps present at baseline will have to have all of the following: 
• 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 
(i.e., macrolide or trimethoprim/sulfamethoxazole) (≥12 weeks duration) 
• SNOT-22 total score ≥20 
• Lund-Mackay CT score ≥1 
A subject who satisfies the criteria in either (a) or (b) above is defined to have the event: eligible 
for sinus surgery. Only subjects who have SIA completed at both baseline and Week 24/ET will 
be included in the analysis. 


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The number and percentage of subjects answering Yes/No to the surgery question, and the number 
and percentage of subjects who are eligible for surgery (Yes/No) based on SIA within each active 
treatment group and placebo will be summarized in a ‘2x2’ contingency table representing baseline 
versus Week 24/ET. McNemar’s test will be used to assess the extent to which subjects improve 
(‘Yes’ at baseline to ‘No’ at Week 24/ET) versus worsen (‘No’ at baseline versus ‘Yes’ at Week 
24/ET) within each treatment group, and the odds ratio (improved versus worsened) and 95% 
confidence interval will be presented for each treatment group.  
The proportion of subjects who meet the SIA eligibility criteria for surgery at Week 24/ET will be 
compared between treatments with a logistic regression model including categorical effects for 
previous sinus surgery (Y, N), nasal polyp status (present, absent), treatment (OPN-375 186 µg, 
OPN-375 372 µg, placebo), and baseline SIA eligibility (Yes, No) as a covariate.  Treatment group 
comparisons will be estimated from the least squares mean difference between treatments and will 
be presented as odds ratios with accompanying p-values and 95% confidence intervals.  
The same logistic model will be used for the proportion of subjects answering ‘yes’ to the 
surgery question at week 24/ET, with baseline response as a covariate. 
7.6.2 
EQ-5D-5L 
The EQ-5D-5L is described in Section 9.4.1; subjects complete the EQ-5D-5L at baseline and 
Week 24/ET.  For each of the 5 dimensions, the number and percentage of subjects in each of the 
5 levels will be summarized within each active treatment group and placebo in a ‘5x5’ contingency 
table representing baseline versus Week 24/ET. Only subjects who have completed the EQ-5D-5L 
at both baseline and Week 24/ET and have complete data for each dimension will be included in 
the summary. 
For the EQ-5D-5L Visual Analogue Scale (VAS), the change from baseline to Week 24/ET VAS 
will be analyzed using the ANCOVA model described in Section 7.1.5. The model-based LS mean 
difference between each active treatment group and placebo (active-placebo), 95% CI, and 
nominal p-value will be displayed.  A worst VAS score of ‘0’ will be assigned for the composite 
strategy, per the primary estimand. 
7.6.3 
Health and Performance Questionnaire (HPQ) 
The World Health Organization (WHO) Health and Performance Questionnaire (HPQ) is a work 
productivity questionnaire which asks about employment status, work absences, and on-the-job 
productivity.  The HPQ is measured at baseline, and at weeks 4, 8, 12, and 24/ET.  HPQ variables 
will be defined and summarized outside of this analysis plan. 
7.6.4 
SF-6D 
The SF-6D provides a means for using the SF-36 in economic evaluation by estimating a 
preference-based single index measure for health from these data using general population values. 
The SF-6D can be used to obtain quality adjusted life years (QALYs) from the SF-36 for use in 
cost utility analysis.  SF-6D will be scored and summarized outside of this analysis plan. 


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7.7 
Per Protocol Analysis 
As a sensitivity analysis, the co-primary endpoints will be analyzed using the Per Protocol Set, 
defined in Section 5.6, according to the primary estimand and estimation methods used in the 
primary analyses and described in Sections 7.1.1−7.1.5. 
7.8 
Subgroup Analyses 
The following endpoints will be analyzed according to the primary estimand for the following 
stratification subgroups: 
1. Subjects with versus without polyps at baseline 
2. Subjects with versus without prior sinus surgery at baseline  
These subgroups are defined based on a subject’s actual polyp status and actual nasal 
surgery status at baseline. 
7.8.1 
Subgroup Analysis of Co-Primary Endpoints 
a) Change from baseline to the end of Week 4 in the 7-day average AM, instantaneous CSNS 
b) Change from baseline to Week 24/ET in the APOV in the ethmoid and maxillary sinuses. 
7.8.2 
Subgroup Analysis of Daily Nasal Symptom Scores 
a) Changes from baseline to Weeks 4, 8 and 12 in the 7-day average of AM, PM, and 
instantaneous, reflective individual nasal symptoms scores (16 endpoints at each time point: 
four individual nasal symptom scores each at four endpoints). 
b) Changes from baseline to Weeks 4, 8 and 12 in the 7-day average of AM, PM, and 
instantaneous, reflective CSNS scores (4 endpoints at each time point) – except primary 
endpoint covered above. 
7.8.3 
Subgroup Analysis of SNOT-22 Total and Domain Scores  
a) Changes from baseline to Weeks 4, 8, 12 and 24/ET in SNOT-22 total scores and each of 
the 5 Domain scores. 
7.8.4 
Subgroup Analysis of APOV in Individual Sinuses 
a) change from baseline to Week 24/ET in APOV-E 
b) change from baseline to Week 24/ET in APOV-M 
7.8.5 
Subgroup Analysis of POV in the Worst Sinus 
c) change from baseline to Week 24/ET in WPOV 
d) change from baseline to Week 24/ET in WPOV-E  
e) change from baseline to Week 24/ET in WPOV-M  
f) change from baseline to Week 24/ET in WZLM 


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7.8.6 
Models for Subgroup Analyses  
The primary estimand and models described in described in Sections 7.1.3-7.1.5 will also include 
the 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. 
For the APOV endpoint, the subgroup analysis will be based on the same MI dataset created for 
the primary analysis. 
 


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8 
SAFETY ANALYSIS 
The Safety Analysis Set defined in Section 5.4 will be used for all safety analyses specified in this 
section unless otherwise noted.  Safety and tolerability will be assessed by clinical review of all 
relevant parameters including adverse events, laboratory tests, and physical and vital sign 
measurements. 
All safety summaries will be descriptive and will be displayed by treatment group in the following 
order (left to right): Placebo, OPN-375 186 μg, OPN-375 372 μg, and OPN-375 combined doses. 
8.1 
Study Drug Exposure and Administration 
Study drug exposure will be measured by study duration which is defined in Section 9.1.1.   
Summary statistics for the duration of drug exposure will be calculated and presented using the 
Kaplan-Meier method which will display in a figure the proportion of subjects with continuing 
drug exposure over the duration of the study, by treatment group. A corresponding table will 
include the summary statistics for duration of exposure, including minimum, maximum, and 
quartiles, median duration and 95% confidence interval for the median duration.    
Compliance is calculated as follows. 
𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶= 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 ∙4
 ∙100 
8.2 
Adverse Events 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 21.0 or greater.  Treatment emergent adverse events (TEAEs) are defined as 
adverse events with onset dates on or after the first dose of DB study drug.  Further details 
regarding the definition of TEAEs are provided in Section 9.5.2. 
All AE summaries will include total number of TEAEs and total number of subjects with TEAEs 
unless otherwise stated.  The incidence of adverse events will be summarized using descriptive 
statistics by system organ class and preferred term.  Subjects are counted only once in each system 
organ class category, and only once in each preferred term category.  For the summaries by 
severity, subjects are counted at the greatest severity and will not have the number of events 
included. Additional summaries by severity will provide all adverse events for overall TEAEs and 
treatment related TEAEs. 
An overall summary of adverse events will include number (%) of subjects with TEAEs (and 
number of AEs), treatment-related TEAEs, SAEs, severe TEAEs, TEAEs that resulted in treatment 
discontinuation, and fatal AEs; this overall AE summary will be presented for the Safety Analysis 
set. 
Additionally, summaries will be presented for all TEAEs by system organ class and preferred term 
(overall and by severity). TEAEs determined by the investigator to be treatment-related (overall 
and by severity) will be summarized.  Serious AEs will also be summarized.  TEAEs causing 
permanent discontinuation from treatment will be summarized, and AEs resulting in death will be 
summarized. 
A summary of adverse events that started during the placebo run-in period will be presented for 
both Safety Analysis set and the Enrolled Subjects set. 


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Listings for pre-treatment AEs, fatal AEs, serious AEs, and TEAEs leading to discontinuation will 
also be presented. 
8.3 
Clinical Laboratory Tests 
Blood and urine samples will be collected at Screening (Visit 1) only. Screening laboratory values 
will be provided in the listings. No summary statistics will be created.  
8.4 
Urine Pregnancy Test 
For women of childbearing potential, urine pregnancy tests will be performed at the site during 
every visit. Urine pregnancy test results will be provided in a listing. 
8.5 
Nasal Examinations 
The nasal examination will be performed during the placebo run-in period and again at the Week 
24/ET visit. The nasal examination will be performed via nasoendoscopy.  Sites will be provided 
with a nasal examination worksheet and a polyp grading sheet. At the nasal examination, the 
subject is evaluated for epistaxis and non-active bleeding, septal erosion/ulceration/perforation, 
ulcerations in areas of the nose other than septum, and mucosal candidiasis. A summary of the 
key safety assessments from the nasal examination is provided in the Protocol, Attachment 3.  
Findings of the nasal examination will be collected on the nasal examination CRF. Findings from 
the nasal examination worksheet that are deemed to be clinically significant by the Investigator 
will also be recorded on the AE CRF.  The nasal examination findings will be summarized with 
descriptive statistics.  
8.6 
Ocular Examinations 
An ocular examination is an unscheduled visit and be 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. 
Results of Ocular Examinations will be presented in the Subject Listings. 
8.7 
Vital Signs 
Vitals signs at each visit and changes from baseline to each visit will be summarized using 
descriptive statistics.  
8.8 
Physical Examination 
A brief physical examination will be performed on all subjects at Screening (Visit 1). Height will 
be collected.  Results of the brief physical examination will be presented in the Subject Listings. 
8.9 
Concomitant Medications   
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.  Specifically, 
concomitant medications are defined as non-study medications with a start date on or after the first 
dose of study medication inclusive. Medications that started prior to the first dose of study 
medication but continued during treatment will also be defined as concomitant. Further details 
regarding the definition of concomitant medications are provided in Section 9.5.1. 


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Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHODrug), Version December 2010 or later, and summarized descriptively by 
treatment group and drug class with subject counts.   
Concomitant medications will be summarized by therapeutic class and preferred term for the 
Safety Analysis Dataset. For each subject, multiple records of the same concomitant medication 
will be counted only once within each therapeutic class and preferred term.   
All concomitant medications will be provided in a listing for the placebo run-in period based on 
the Safety Analysis set and Enrolled Subjects set.  
8.10 
Rescue Medications 
The incidence of rescue medication use during the placebo-run period will be presented in the 
Subject Listings. 


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9 
DATA HANDLING RULES AND DEFINITIONS 
9.1 
Data Handling Conventions 
9.1.1 
Study Days and Duration 
Study Day 1 is the date of first dose of randomized treatment with study drug after randomization; 
it is typically the date of randomization. 
Study days will be numbered relative to the first day of randomized study drug administration.  
• Study days will be numbered relative to study start (i.e., ..., –2, –1, 1, 2, ...; with Day 1 
being the start of study drug and Day –1 being the day before the start of study drug). 
• The elapsed time since Day 1 for an event (e.g. onset of an adverse event) will be 
calculated as [date of event – date of Day 1 + 1]. 
• For the purpose of converting days to years or months, one year = 365.25 days, and one 
month = 30.44 days. 
Study Duration is defined as follows:  
(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
−𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷) + 1 
9.1.2 
Visit Windows for Repeated Measures Efficacy Analyses 
All efficacy measures that are repeated (repeated measures) over the duration of the study and 
analyzed with statistical models for repeated measures (i.e., linear and logistic MMRM models) 
will have efficacy windows defined for these analyses.   
For efficacy measures that occur only once post-baseline during the study at Week 24/ET, the 
nominal study visit (Week 24/ET) will be used for the efficacy analyses.  
All safety analyses will be based upon nominal visit days. 
9.1.2.1 Efficacy Windows for 7-Day Average Daily Nasal Symptom Diaries and CSNS 
As discussed in Section 9.3.1 below, electronic diaries will be used by subjects during the single-
blind placebo run-in period and during the first 12-weeks of the 24-week double-blind treatment 
period in this study to capture daily nasal symptoms and the CSNS. Table 9.1 displays the efficacy 
windows defined for the 7-day average Daily Nasal Symptoms diary and CSNS for each study 
week from baseline (Visit 2) through Week 12 (Visit 5).  Scheduled study visits corresponding to 
study endpoints are included and highlighted in the table for reference. 
The efficacy windows defined in Table 9.1 may yield intermittent missing data due to a missing 
7-day average from the daily nasal symptom diary, as described in Section 9.3.1.  Missing data 
will be estimated within the MMRM models under the assumption they are Missing at Random 
(MAR), conditional on the observed values and the statistical model (Mallinckrodt, Lane, Schnell, 
Peng, & Mancuso, 2008). 
 
 
 


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Table 9.1: Windows for 7-Day Average Individual Daily Nasal Symptom Diary and CSNS 
Study Visit 
Study Week 
Nominal Visit Day 
Interval (Days) 
2 
Baseline 
  1 
[ -7,  -1] 
 
  1 
  7 
[  2,   6] 
 
  2 
14 
[  7, 13] 
 
  3 
21 
[14, 20] 
3 
  4 
28 
[21, 27] 
 
  5 
35 
[28, 34] 
 
  6 
42 
[35, 41] 
 
  7 
49 
[42, 48] 
4 
  8 
56 
[49, 55] 
 
  9 
63 
[56, 62] 
 
10 
70 
[63, 69] 
 
11 
77 
[70, 76] 
5 
12 
84 
[77, 83] 
 
9.1.2.2 Efficacy Windows for Repeated Measures based on Clinic Visits 
Several secondary efficacy endpoints in this study are based on efficacy measures that are repeated 
over several clinical visits; these include the SNOT-22 Total and Domain Scores, PSQI Global 
and Component Scores, PGIC, and HPQ.  Since these endpoints include repeated measures, they 
are analyzed using MMRM models.  
Table 9.2 displays the windows for the efficacy measures at each scheduled clinic visit. If multiple 
observations for a subject occur within the same visit window, the observation closest to the 
nominal visit day will be used; in the case of two equidistant observations the later one will be 
used. The efficacy windows defined in Table 9.2 may yield intermittent missing data due to a 
missed clinic visit.  Missing data will be estimated within the MMRM models under the 
assumption they are MAR, conditional on the observed values and the statistical model 
(Mallinckrodt, Lane, Schnell, Peng, & Mancuso, 2008). 
Subjects who discontinue from double-blind study prematurely are instructed to fill out the 
assessments in the Week 24/ET visit form.  For efficacy endpoints described above, these data will 
be windowed as defined in Table 9.2 and used at the defined visit.  For example, if a subject has 
an ET visit on Day 50 the value will be used as the Week 8 visit value, and the subsequent visits 
Week 12 and Week 24/ET will be missing.  If a subject has an ET visit on Day 120, the value will 
be used as the Week 24/ET visit value and there is no monotone missing data for this subject. 
 
 
 


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Table 9.2: Windows for Repeated Measures based on Clinic Visits 
Visit Number 
Nominal Visit Day 
Interval (Days) 
2: Baseline 
   1 
[ -21  , 1] 
3: Week 4 
  28 
[    2, 42] 
4: Week 8 
  56 
[  43, 70] 
5: Week 12 
  84 
[  71, 98] 
6: Week 24/ET 
168 
[  ≥ 99   ] 
 
9.1.3 
Baseline Value 
Baseline is defined as the last measurement prior to receiving the first dose of double-blind 
treatment. For nasoendoscopy nasal examination, the assessment at Screening (Visit 1) will be 
used as the baseline assessment; for CT scan, the date of the procedure during the placebo run-in 
period will be considered the baseline visit.  For all other procedures, the assessment at Visit 2 
(Day 1) is considered the baseline assessment.  
For the individual daily nasal symptom scores and CSNS, the 7-day average of the last 7 days in 
the run-in period immediately prior to randomization is considered the baseline value. Reference 
Section 9.3.1 and Table 9.1 above for further details. 
9.1.4 
Enrollment Date 
The enrollment date is the date the subject signed informed consent to be enrolled into the study. 
i.e., screening visit date (Visit 1).  
9.1.5 
Week 24/End of Treatment (ET) 
Week 24/ET value is the last non-missing post-baseline value for each subject.  This value will 
occur either at Week 24 or earlier if, for example, the subject discontinues the study prior to Week 
24.  
9.2 
Demographic Variable Definitions 
9.2.1 
Age 
Subject age will be calculated as the integer part of the number of years from date of birth to the 
date of signing the informed consent form, using the following formula: 
Age = integer part of [(date of informed consent – date of birth + 1)/365.25]. 
9.2.2 
Body Mass Index (BMI) 
Body mass index (BMI) calculation: BMI (kg/m2) = [weight (kg)] / [height (m)]2  
 


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9.3 
Efficacy Endpoint Variable Definitions 
9.3.1 
Daily Nasal Symptoms Diary Assessments 
Electronic diaries will be used by subjects during the single-blind placebo run-in period and during 
the first 12-weeks of the 24-week double-blind treatment phase in this study to capture daily nasal 
symptoms (i.e., 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 period. Subjects will be instructed to 
complete the electronic diary twice daily immediately before dosing (AM and PM). 
Each morning and evening subjects will record their nasal symptom severity scores using the nasal 
symptoms scoring scale (Table 9.3) to evaluate their symptoms both immediately preceding the 
time of scoring (instantaneous), and based on reflection of symptoms over the past 12 hours, with 
regard to nasal congestion, nasal discharge (anterior and/or posterior), facial pain or pressure 
sensation, and sense of smell.   
AM and PM assessment scores, and instantaneous and reflective scores, are all considered to be 
separate and distinct measures of nasal symptoms and will be analyzed separately.   
Composite Score of Nasal Symptoms (CSNS): The CSNS is defined as the sum of the nasal 
congestion, nasal discharge and facial pain/pressure for each type of assessment (instantaneous or 
reflective) at each time point (AM or PM), resulting in four CSNS per day.   
Table 9.3: Nasal Symptoms Scoring Scale 
Score 
Description 
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 
Note: Sense of smell, scored as 0=normal, 1=slightly impaired, 2=moderately impaired, 3=absent. 
 
For statistical analyses, the daily AM and PM, instantaneous and reflective, individual nasal 
symptoms scores, and the CSNS will be averaged weekly, defined as the average of the daily 
scores for the 7 study days prior to the nominal day associated with each 7-day week; for example, 
for Week 2, Day 14 is the nominal day and the 7-day average is calculated based on study days 7 
to 13.  
Table 9.1 displays the efficacy windows defined for the 7-day average Daily Nasal Symptoms 
diary and CSNS for each study week from baseline (Visit 2) through Week 12 (Visit 5). 
The 7-day average diary score will be derived for each nasal symptom (range 0-3) and CSNS 
(range 0-9) by time point (AM or PM) and measure (instantaneous or reflective). Thus, there are 
sixteen 7-day average scores representing the individual nasal symptoms scores: 2 (AM, PM) * 2 
(instantaneous, reflective) * 4 nasal symptoms (congestion, discharge, facial pressure, sense of 
smell), and there are four 7-day average CSNS scores: 2 (AM, PM) * 2 (instantaneous, reflective). 
The 7-day average AM, instantaneous CSNS score is the primary efficacy variable in this study. 


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Missing Diary Data 
On any given study day, for time (AM, PM), or measure (instantaneous, reflective), if any of the 
3 nasal symptom scores is missing then the CSNS score will be missing for that study day, time, 
and measure. For both individual symptoms and the CSNS, the average 7-day value will be missing 
only if there are missing values for all 7 days.  For the first week (Study Days 2-6, Table 9.1), the 
average 5-day value will be missing only if there are missing values for all 5 days. 
Intercurrent Events (IE) 
 If an intercurrent event occurs, under the composite strategy per the primary estimand, a worst 
score of ‘3’ will be assigned to each of the daily nasal symptoms scores recorded on the day of the 
IE and for the remaining days in the week in which the IE occurs; that is, the 7-day average score 
will include actual scores for days up to the IE and then a worst score for diary days recorded on 
or after the day of the IE.  Since CSNS is a composite score as defined above, a worst score of ‘9’ 
is assigned. Subsequent 7-day average scores will be assigned a worst score for the remainder of 
the CSNS study period. 
9.3.2 
Quantitative (Volumetric) Measurement of CT Scan Image 
The protocol for quantitative (volumetric) measurement of CT scan imaging is based on the Image 
Review Charter (IRC) – Revision C, (29 January 2020).   Quantitative measurement of Sinus 
Volume and Opacification Volume will be performed by a trained analyst under the supervision 
of a Biomedical Engineer using a validated software system as described in the IRC. 
The following quantitative variables are defined for each of the four sinuses: Maxillary (Left, 
Right), Ethmoid (Left, Right). 
Sinus Volume (SV):  the total volume of the specified sinus cavity regardless of the amount of 
mucosal inflammation that may be present. Total Sinus Volume will consist of both the soft tissue 
and air signal within the specified sinus. Sinus Volume will be reported in cubic millimeters. 
Opacification Volume (OV):  the total volume of the soft tissue and mucosal inflammation as 
visualized in the specified sinus. Opacification Volume will be reported in cubic millimeters. 
Percentage of Opacified Volume (POV):   𝑃𝑃𝑃𝑃𝑃𝑃= 𝑂𝑂𝑂𝑂𝑆𝑆𝑆𝑆∙100%
⁄
   
Missing Volumetric Measurements 
Volumetric measurements (SV, OV) of a sinus may be missing due to technical issues that are 
unrelated to disease measurement; these measurements are reported as ‘Unable to Assess.’ 
If the volumetric measurements in any sinus are missing at baseline, then the subject will be 
excluded from the FAS population.  If either of the volumetric measurements in any sinus is 
missing at Week 24/ET, then the volumetric measurement for that sinus will be replaced by the 
baseline volumetric measurement. 
Average Percentage of Opacified Volume (APOV) 
APOV is the average percentage of opacified volume across both maxillary (L, R) and ethmoid 
(L, R) sinuses (all 4 sinuses) at each time point (Baseline, Week 24/ET).  Larger values of APOV, 


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i.e., higher percentages of opacified volume, indicate greater severity of CRS; therefore, negative 
values for change from baseline APOV indicate improvement from baseline.  
APOV-E is the average percentage of opacified volume in the ethmoid (L, R) sinuses at each time 
point (Baseline, Week 24/ET).   
APOV-M is the average percentage of opacified volume in the maxillary (L, R) sinuses at each 
time point (Baseline, Week 24/ET).   
Worst Percentage of Opacified Volume (APOV) 
WPOV is the worst sinus across the maxillary (L, R) and ethmoid (L, R) sinuses (all 4 sinuses) at 
baseline. In the event of a tie, the rule is: use the right sinus, then use the ethmoid sinus. 
WPOV-E is the worst ethmoid (L, R) sinus at baseline. In the event of a tie, the rule is: use the 
right sinus. 
WPOV-M is the worst maxillary (L, R) sinus at baseline. In the event of a tie, the rule is: use the 
right sinus. 
The endpoint analyzed is the change from baseline to Week 24/ET in the WPOV sinus; this is 
similarly defined for WPOV-E, WPOV-M. 
 
9.3.3 
SNOT-22 Total and Domain Scores 
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. 
Five domain scores will be derived from the SNOT-22 for efficacy evaluation (Table 9.4): 
Rhinologic Symptoms; Extra-Nasal Rhinologic symptoms, Ear and Facial Symptoms; Sleep 
Function; Psychological Issues; and the total score (sum of all items).  
 
Table 9.4: SNOT-22 Domain and Total Scores 
Domain 
Sum of Items 
Range 
Rhinologic Symptoms 
1, 2, 3, 6, 21, 22 
0-30 
Extra-Nasal Rhinologic Symptoms 
4, 5, 6 
0-15 
Ear/Facial Symptoms  
2, 7, 8, 9, 10 
0-25 
Psychological Dysfunction 
14, 15, 16, 17, 18, 19, 20 
0-35 
Sleep Dysfunction  
11, 12, 13, 14, 15 
0-25 
TOTAL SCORE 
Sum of all 22 items 
0-110 
 


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9.3.4 
SF36v2 and PCS Domain Scores 
The SF-36 is the most widely used general health-related quality of life instrument in clinical trials, 
with a rich and diverse body of psychometric supporting data.  The 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 two summary measures of physical and mental health, respectively: the PCS and 
MCS.  
The SF-36v2 includes algorithms for interval level scoring for all eight scales ranging from 0 (for 
worse health) to 100 (best possible health as measured by the questionnaire), as well as the same 
standardized scoring (mean = 50, standard deviation = 10) for the SF-36 summary scores (PCS 
and MCS).  
The SF-36v2 scoring will be performed according to the current SF-36v2 algorithm and 
specifications for missing data using proprietary software provided by Optum PRO CoRE. The 
resulting t-scores will be analyzed as described in Sections 7.5.6, 7.5.7. 
9.3.5 
Acute CRS Exacerbations 
An acute exacerbation of chronic rhinosinusitis event is defined as a worsening of symptoms 
requiring antibiotic or corticosteroid use, specifically: 
• An acute worsening of one or more of the cardinal diagnostic symptoms of chronic 
rhinosinusitis (listed below), lasting at least 3 days, that causes the subject to seek medical 
care: 
− facial pain or pressure 
− nasal congestion/blockage 
− rhinorrhea 
− reduction in sense of smell 
AND 
• An escalation of treatment, defined as either initiation of treatment with antibiotics or 
systemic steroids, or the escalation of treatment involving an unscheduled acute care visit 
(e.g., emergency room or out subject clinic) or in-subject care, for increased symptoms 
related to sinusitis. 
Date of onset of a CRS exacerbation event is defined by on the earliest onset date reported on the 
Exacerbation CRF; differentiation between CRS exacerbation events will also be determined from 
the onset dates reported on the Exacerbation CRF.   If CRS exacerbation event 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.  
Duration of double blind period for each subject will be derived for this analysis as: 
Duration (days) = (Week 24/ET visit date – Date of Day 1) + 1. 


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This duration of DB period will be the follow-up (exposure) time for analysis; subjects who did 
not experience any CRS exacerbation events during the DB period will be assigned ‘0’ for 
frequency. 
The time (weeks) to first acute CRS exacerbation event is defined as:  
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝐶𝐶𝐶𝐶 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒−𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟+ 1
7
 
9.3.6 
Qualitative CT Scan Image Assessment 
The protocol for qualitative CT scan imaging assessments is based on the Image Review Charter 
(IRC) – Revision C, (29 January 2020).  Qualitative CT scan assessments will be performed at 
baseline and Week 24/ET in accordance with the IRC for Lund-Mackay Staging and Zinreich 
Modification of the Lund-Mackay Staging. 
As described in the IRC, two radiologist reviewers and a third adjudicating radiologist reviewer 
will independently review and score the CT scan images. When there are discrepant scores 
between the two primary reviewers, the adjudicating reviewer will review the image and choose a 
score recorded by one of the primary reviewers. 
Specifically, the adjudicated value is assigned as follows, where R3 represents the adjudicating 
radiologist, and R1, R2 represent the Radiologist reviewers: 
• If R1 and R2 agree, then the adjudicated value is the value of R1 and R2. 
•  If R1 and R2 both have an integer value and they disagree, then R3 reviews the CT scan 
image and chooses one of those integer values and that is also the adjudicated value. 
• If one of R1 or R2 is ‘Unable to Assess,’ then R3 reviews the CT scan image and records 
either the integer value of R1 or R2 or ‘Unable to Assess.’ 
 
Lund-Mackay (LM) Staging 
The LM sinus (Lund and Mackay, 1993) score will be graded separately for all 10 sinuses listed 
in Table 9.5, as well as the ostiomeatal complex, (12 total LM scores).  The sinuses are scored:  0 
(no abnormality), 1 (partial opacification), or 2 (total opacification), and the ostiomeatal complex 
is scored: 0 (not obstructed), or 2 (obstructed).   
LM Scores for the sinuses will be derived from the Zinreich Modification of the Lund-Mackay 
Staging System (ZLM) scores, which are defined below.   
• ZLM scores of 0 will = 0 on LM 
• ZLM scores of 1, 2, 3, or 4 will = 1 on LM 
• ZLM scores of 5 will = 2 on LM 
• The LM score for the OMC is captured as defined above. 
 
 


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The following variables are defined based on LM scores: 
• LM Total Score: sum of 12 LM scores.  Therefore, the total LM score for a CT scan ranges 
from 0-24.  
• LM scores for ethmoids and maxillary sinuses combined: The sum of the two ethmoid 
and one maxillary sinuses listed in Table 9.5, including the left and right sinus for each. 
The score for the total of six sinuses ranges from 0 to 12. 
• LM Score for each Sinus Pair:  For each of the 5 sinuses listed in Table 9.5, the left and 
right sinus pair is summed. Each sinus pair listed in Table 9.5 will be analyzed separately. 
These variables range from 0 to 4. 
 
Zinreich Modification of the Lund-Mackay Staging (ZLM) 
The Zinreich Modification of the Lund-Mackay Staging System (Zinreich 2004), the ZLM score, 
is also graded separately for all 10 sinuses listed in Table 9.5.  The scoring is a follows.  
   Score 0:  0% opacification of the sinus 
   Score 1:  1% to 25% opacification of the sinus 
   Score 2:  26% to 50% opacification of the sinus 
   Score 3:  51% to 75% opacification of the sinus 
   Score 4:  76% to 99% opacification of the sinus 
         Score 5:  100% opacification of the sinus 
The following variables are defined based on ZLM scores: 
• ZLM Total Score: sum of 10 ZLM scores.  Therefore, the total ZLM score for a CT scan 
ranges from 0-50.  
• ZLM scores for ethmoids and maxillary sinuses combined: The sum of the two ethmoid 
and one maxillary sinuses listed in Table 9.5, including the left and right sinus for each. 
The score for the total of six sinuses ranges from 0 to 30. 
• ZLM Score for each Sinus Pair:  For each of the 5 sinuses listed in Table 9.5, the left and 
right sinus pair is summed. Each sinus pair listed in Table 9.5 will be analyzed separately. 
These variables range from 0 to 10. 
• WZLM score is the score for the worst sinus among the anterior ethmoid (L, R), posterior 
ethmoid (L, R), and maxillary (L, R) sinuses (all 6 sinuses) at baseline. In the event of a 
tie, the rule is: use the right sinus, then use the ethmoid sinus, then use the anterior ethmoid 
sinus.  The change in this sinus at Week 24/ET is the endpoint of interest. 
 
 
 


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Table 9.5: Sinuses (Left and Right) Assessed and Scored  
Sinus (Left, Right) 
 LM Score 
 ZLM Score 
Ethmoid Anterior 
 
 
Ethmoid Posterior 
 
 
Frontal 
 
 
Maxillary 
 
 
Sphenoid 
 
 
Ostiomeatal Complex 
 
 
 
Missing Qualitative CT Scan Image Measurements 
Qualitative LM and ZLM measurements of a sinus may be missing due to technical issues that are 
unrelated to disease measurement; these measurements are reported as ‘Unable to Assess’ through 
the adjudication process. 
Rules for handling missing qualitative ZLM scores in an individual sinus are as follows:  If the 
qualitative CT scan measurements in any sinus are missing at baseline, then the subject will be 
excluded from the FAS population.  If the qualitative CT scan measurement in any sinus are 
missing at Week 24/ET, then the measurement for that sinus will be replaced by the corresponding 
baseline measurement. As described above, LM scores are derived from ZLM scores, except for 
the LM Ostiomeatal Complex which will use this missing data rule as well. 
9.3.7 
Pittsburgh Sleep Quality Index (PSQI) 
PSQI is a validated, self-rated questionnaire, which assesses sleep quality and disturbances over a 
1-month time interval. Nineteen individual items scored 0 (no difficulty) to 3 (severe difficulty) 
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 a global score (range 0 to 21). Higher scores indicate worse 
sleep quality. Refer to Section 7.5.5 for analysis and Section 13.1, Appendix 1: PSQI Scoring for 
the scoring algorithm of the PSQI instrument (Buysse, DJ 1989). 
9.3.8 
PGIC - “Subject” Global Impression of Change 
“Subject” Global Impression of Change (PGIC) is assessed based on a 7-point Likert scale as 
shown in Table 9.6. Two endpoints are defined based on a dichotomization of the scale.  Category 
1 (Improved) is defined as any improvement (minimally, much, very much); Category 2 (Much 
Improved) is defined as improvement (much, very much). Reference Section 7.5.8 for analysis. 
 


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Table 9.6: Subject Global Impression of Change (PGIC) Scale 
Since starting the study drug, how would you rate the change in your symptoms? 
Score 
Description 
Category 1 
Category 2 
1 
Very much improved 
Improved 
Improved 
2 
Much improved 
Improved 
Improved 
3 
Minimally improved 
Improved 
Not improved 
4 
No change 
Not improved 
Not improved 
5 
Minimally worse 
Not Improved 
Not Improved 
6 
Much worse 
Not improved 
Not improved 
7 
Very much worse 
Not Improved 
Not Improved 
Missing 
Missing 
Not Improved 
Not Improved 
 
 
 
 
9.3.9 
Quick Inventory of Depressive Symptomatology – Self Report (QIDS-SR)  
The 16-item QIDS-SR (Rush et al, 2003) is designed to assess the severity of depressive 
symptoms. The QIDS-SR is a self-report version and assesses all the criterion symptom domains 
designated by the American Psychiatric Association Diagnostic and Statistical Manual of Mental 
Disorders – 5th Edition to diagnose a major depressive episode.  
Sixteen individual items are scored 0 to 3 with lower scores indicating lower severity of depression. 
The 7-day period prior to assessment is the usual time frame for assessing symptom severity. 
Severity of depression will be assessed based on the total score (range 0-27) and categories of the 
severity of depression as shown in Table 9.7. 
If any item Q1-Q5, Q10-Q16 is missing, or if either of ((Q6 and Q7) or (Q8 and Q9)) are missing, 
then the total QIDS-SR score is missing. If either of Q6 or Q7 is answered and either of Q8 or Q9 
is answered the questionnaire can be categorized by severity of depression as described in Table 
9.7.   
The QIDS-SR total score is the summation of the following items: 
• The highest score from Q1-Q4 
• Response from Q5 
• The highest score from Q6-Q9 
• Responses from Q10, Q11, Q12, Q13, Q14 
• The highest score from Q15 and Q16 
 
 
 
 
 


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Table 9.7: QIDS-SR Severity of Depression Categories 
QIDS Score 
Severity of Depression 
  0 –  5:  None 
  6 – 10: Mild 
11 – 15:  Moderate 
16 – 20: Severe 
21 – 27: Very Severe 
9.3.10 Smell Identification Test (SIT) 
SIT is a smell identification test assessing olfaction and is comprised of 4 booklets each containing 
10 microencapsulated (scratch and sniff) odors, producing 40 multiple choice response items each 
with one correct and 3 incorrect answers. SIT scores range from 0-40, with a higher score 
indicating better olfaction and a score of ‘10’ suggesting total anosmia (Doty, et. al., 1984). Forced 
choice response alternatives accompany each test item. The test provides an indication of smell 
loss (anosmia; mild, moderate or severe hypersomnia) as well as an index to detect malingering.  
9.4 
Health Economic Outcomes Research (HEOR) Endpoints 
9.4.1 
EQ-5D-5L 
The EQ-5D-5L is a standardized measure of health status developed to provide a simple, generic 
measure of health for clinical and economic appraisal. 
The five-level EQ-5D (EQ-5D-5L) 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. And 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. EQ-5D-5L dimension is scored using algorithms 
obtained from the EuroQol Group authors. 
Each dimension is coded according to the level selected by the subject as follows: 1= no problems, 
2=slight problems, 3=moderate problems, 4=severe problems, 5=extreme problems.  Missing 
dimension values and ambiguous values (2 values selected for the same domain) coded as ‘9’ will 
be changed to missing in the analysis dataset.     
The EQ VAS records the subject’s self-rated present health on a vertical visual analogue scale, in 
response to the statement, “We would like to know how good or bad is your health TODAY.” The 
endpoints on the VAS are labelled 100: ‘The best health you can imagine’ and 0: ‘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 VAS is scored as collected and should have a number between 


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0-100.  Missing values coded as ‘999’ for this instrument will be changed to missing in the analysis 
dataset. 
 
9.5 
Therapy and Safety Endpoint Variable Definitions 
9.5.1 
Prior and Concomitant Medication 
A prior medication is defined as any non-study medication that started before the date of first dose 
of study drug. 
Concomitant medication is defined as any non-study medication that:  
• Started before the date of first dose of study drug and is ongoing throughout the study or 
ends on/after the date of first study medication administration. 
• Started on/after the date of first dose of study drug and is ongoing or ends during the 
course of study medication. 
The start/stop dates recorded in the CRF will be used to determine when a medication is considered 
prior-to or after first dose of study drug.  A medication can be considered both prior and 
concomitant if it was started prior to the first dose of study drug and continues to be taken after 
the first dose of study medication.   
Unresolved missing start dates will be handled as follows for determination of concomitance: 
partial dates will be imputed in such a way as to consider the non-study medication as prior and/or 
concomitant if it is possible that the missing information could lead to a prior and/or concomitant 
outcome. 
9.5.2 
Treatment Emergent Adverse Events (TEAEs) 
A treatment emergent adverse event (TEAE) is defined as an adverse event with onset date on or 
after the first dose of randomized study drug.   
All reports of adverse events should include the severity and relationship to study drug that are 
determined by the investigators.  In the event of missing information, the following rules will be 
applied for the adverse event summaries: 
• AEs with missing onset dates will be included as treatment- emergent (unless end date 
is prior to the first dose date)   
• AEs with missing severity will be counted as severe in severity 
• AEs with missing relationship to study drug will be counted as related  
 


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10 
STATISTICAL ANALYSES IMPLEMENTATION SPECIFICATIONS 
This section contains the specifications required to implement the statistical methods for efficacy 
analyses described in Section 7 with a multiple imputation (MI) method for missing data. These 
specifications are given in sufficient detail such that an independent reviewer can replicate the 
efficacy analysis and results based on the methods described in Section 7 and the additional MI 
implementation specifications contained in this section. 
These specifications incorporate the guidance for pre-specifying details of MI provided in (O'Kelly 
& Ratitch, 2014) Chapter 6.  Multiple imputation procedures are implemented in a three step 
process: Step 1: Multiple Imputation, Step 2: Statistical Analyses, Step 3: Statistical Inference.  
Each of these steps are described for the MI procedures presented herein. 
SAS® (SAS Institute), software Version 9 or higher will be used to implement all statistical 
methods, and to produce all Tables and Figures containing analyses results and summary 
descriptive statistics.   
10.1 
Declarations and Multiple Imputation Considerations 
a) Random Number Seed: 07091993 
A random number seed is specified for each invocation of an MI procedure in SAS. Specifying 
a seed enables the numeric results of the multiple imputation procedures to be reproduced. 
b) Number of multiple imputations (M): 40 
This is the number of imputation datasets that will be generated for all imputation procedures. 
M=40 is chosen since the fraction of missing information, and the relative increase in variance, 
are anticipated to be small. 
c) Discreteness of the efficacy variables  
For the efficacy measures that occur only once post-baseline during the study at Week 24/ET, 
the endpoint value is Week 24/ET.  For the following efficacy variables the Week 24/ET value 
is a discrete random variable: WPOV-E, WPOV-M, WPOV, LM, ZLM, and WZLM scores, 
QIDS total score, SIT scores.  The MI method described below imputes the Week 24/ET value 
as a continuous variable.  Consequently, imputed values will be real numbers; these imputed 
values will not be rounded to nearest integers as this may introduce bias and is not 
recommended (O'Kelly & Ratitch, 2014). For each of these efficacy variables, and including 
APOV, SF36v2 t-scores, and EQ-5D-5L VAS scores as well, imputation values obtained from 
the MI may be outside the defined range of the variable.  If a value outside this range is obtained 
in the imputation, the imputed value will be truncated at the maximum or minimum value 
depending on which of these values it exceeds.  
10.2 
Multiple Imputation Method – PMM with J2C 
As described in Section 7.1.3 for the treatment policy estimand, missing data due to study 
discontinuation will be imputed with a multiple imputation method (MI) for the following efficacy 


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variables: APOV, WPOV-E, WPOV-M, WPOV; LM, ZLM, and WZLM scores; SF36-v2 scores, 
QIDS total score, SIT score, and EQ-5D-5L VAS. 
Multiple imputation with a PMM and J2C method will be conducted using the sequential modeling 
method as described in (O'Kelly & Ratitch, 2014), Chapter 7.  To implement J2C method, first the 
initial dataset is used to impute missing data in the control group with multiple imputation under 
MAR assumption. The initial dataset used is the analysis dataset – in this case a dataset with a 
single post-baseline observation at Week 24/ET; this dataset is referred to as EFF. Therefore, MI 
is performed on a single post-baseline observation with missing data. 
The statistical model used to estimate parameters in the imputation of missing data for analysis 
variable in the control group under MAR assumption includes the following terms: treatment, 
baseline covariate, nasal polyp status (present, absent), pervious sinus surgery (Y, N).  This model 
is implemented in PROC MI with MONOTONE REGRESSION statement. The output dataset is 
referred to as EFF_MI_MAR. This dataset, after some data manipulation to restore the missing 
data in the active active treatment arms, is the input dataset for implementation of J2C method in 
SAS, which involves three steps for imputing a single time point.  
Step 1: Remove subjects in the active treatment groups with complete data at Week 24/ET 
(OUTPUT REST_V6). Keep remaining subjects (OUPUT IMPUTE_V6): 
a) Subjects in active treatment groups with data to be imputed at Week 24/ET 
b) Control subjects with observed and multiply imputed data under MAR at Week 
24/ET 
Step 2: Multiple imputation of Week 24/ET missing data (INPUT IMPUTE_V6) using a regression 
of Week 24/ET analysis variable on baseline value of endpoint only (OUTPUT 
IMPUTED_V6). 
Since the regression method uses only observed data to estimate regression parameters for 
the MI, only control subjects are used for the imputation of missing values at Week 24/ET 
in the active treatment groups.   
Step 3: Reassemble (concatenate) datasets (REST_V6, IMPUTED_V6). 
The final, reassembled dataset will include M=40 imputations of all subjects with missing data at 
Week 24/ET imputed using J2C method.  This dataset, labeled EFF_MI_J2C for reference, is 
used in the statistical analysis described in Section 10.4. 
10.3 
Multiple Imputation Method – Tipping Point 
Tipping Point analyses will be conducted using the sequential modeling method as described in, 
(O'Kelly & Ratitch, 2014), Chapter 7, and specifically the third (sequential) approach described 
Section 7.4.7 of the book.  First, the initial analysis dataset is used to impute missing data in the 
control group with multiple imputation under MAR assumption; the MI is performed as described 
above in Section 10.2 and dataset EFF_MI_MAR is used as the input dataset to the Tipping Point 
analysis. 


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The Tipping Point analysis will then be performed on the PEFF_MI_MAR dataset. A constant, δ, 
will be applied to the imputed values in the active treatment groups; δ will be defined in units of 
the within-group standard deviation (σ) of change from baseline in APOV; that is, δ = c ∙ σ, where 
the constant c is a fraction. An estimate of σ will be obtained from the root mean square error 
(RMSE) of the primary analysis model described in Section 7.1.5. To find the tipping point, the 
sequence of fractions c = 0.25, 0.50, 0.75, 1.0, and so on in 0.25 increments, will be chosen until 
the tipping point is reached. However, this search will employ an efficient numerical searching 
algorithm to find the Tipping Point value δ*.   Since the APOV endpoint has a range from 0-100, 
imputed values with δ added cannot exceed the maximum value of 100.  Therefore, any imputed 
values with δ added that exceed the maximum score of 100 will be assigned the maximum score 
of 100.   
Note that it is possible a Tipping Point does not exist. If the Tipping Point is not reached for value 
of δ such that all missing data in the active treatment groups are assigned the maximum score, then 
a Tipping Point does not exist. 
The output dataset for the Tipping Point analysis will be labelled PEFF_ MI_TP_D for reference, 
where D will represent the current value of δ in the search. 
10.4 
Multiple Imputation – Statistical Analysis and Inference 
Statistical Analysis 
The ANCOVA statistical model for the primary efficacy analysis described in Section 7.1.5 will 
be used to analyze the MI dataset EFF_MI_J2C (primary analysis) and MI_PEFF_TP_D (Tipping 
Point sensitivity analysis).  The statistical analysis is performed separately on each of the M=40 
complete datasets. The summary statistics resulting from these analyses are output to SAS ODS 
datasets: DIFFS (least squares mean (LSM) estimates of differences between treatments), 
LSMEANS (LSM estimates for each treatment group, and SOLUTIONF (model parameter 
estimates).  Note the SAS PROC MI procedure produces a SAS variable _Imputation_; this SAS 
variable identifies each of the M=40 MI datasets for analyses and inference. 
Statistical Inference 
The statistical method for combining the summary statistics obtained from the statistical analysis 
of each of the M=40 MI datasets is well established (Rubin’s method); it is based on obtaining an 
overall estimate of mean and variance from these MI summary statistics, forming a test statistic 
for the hypothesis test and estimating the degrees of freedom, and obtaining a p-value and a 
confidence interval for formal statistical inference.  Rubin’s method is described in (O'Kelly & 
Ratitch, 2014), Chapter 6, Section 6.4. 
This method is implemented in SAS PROC MIANALYZE; the procedure is designed to accept 
the SAS ODS output from the statistical analysis. If the unadjusted degrees of freedom is very 
large compared to the complete-data degrees of freedom, then adjusted degrees of freedom will be 
used. 
 


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10.5 
MMRM Model convergence contingencies 
Model convergence is not anticipated to be an issue with the linear and logistic MMRM models 
used for the analysis of data from this trial; however, in the event a convergence issue arises for 
any analyses, in each case, both a heterogeneous Toeplitz and Toeplitz covariance structure will 
be considered in sequence in place of the unstructured covariance.  In this case, the empirical 
sandwich estimator will be used as a sensitivity analysis to correct for potential model 
misspecification. 
 
 


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11 
CHANGES FROM THE PROTOCOL  
The following changes were made to this SAP post Protocol Amendment 6.0. 
Section 3.3.3 and 3.4.3 (Objectives and Endpoints) 
The following objectives and secondary endpoints were added: 
• change from baseline to Week 24/ET in APOV in the ethmoid sinuses (APOV-E)  
• change from baseline to Week 24/ET in APOV in the maxillary sinuses (APOV-M)  
• change from baseline to Week 24/ET in APOV in the ethmoid sinuses (APOV-E) for CRS 
with NP and without NP sub-groups and in subjects with and without previous sinus surgery 
• change from baseline to Week 24/ET in APOV in the maxillary sinuses (APOV-M) for CRS 
with NP and without NP sub-groups and in subjects with and without previous sinus surgery 
• change from baseline in the volume of the nasal cavity opacified 
The following objective and secondary endpoint was removed: 
• percent of subjects requiring rescue medication after Week 4 
Section 7.2 Sensitivity Analyses 
• Section 7.2.3  Added an Observed Cases Sensitivity Analysis 
Section 7.5.3 and Section 9.3.2 (Percentage of Opacified Volume) 
• Clarified the definition of WPOV, WPOV-E, WPOV-M and the corresponding endpoints 
• Added the definition of APOV-E and APOV-M and the corresponding endpoints 
Section 7.5.4 and Section 9.3.6 (Qualitative CT Scan Assessment) 
• Clarified the definition of WZLM and the corresponding endpoints 
 
 
 
 
 
 


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12 
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Rush, A. J., Trivedi, M. H., Ibrahim, H. M., Carmody, T. J., Arnow, B., Klein, D. K., Keller, M. 
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13 
APPENDICES 
13.1 
Appendix 1: PSQI Scoring 


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