Conditions: Chronic Sinusitis Chronic Rhinosinusitis (Diagnosis)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 71
Healthy volunteers: no

Brief summary:
This is a Phase II, Randomized, Blinded, Sham Procedure-Controlled, Parallel-Group Trial to Evaluate the Efficacy, Safety and Tolerability of LYR-210 in Adult Subjects with Chronic Sinusitis.

Detailed description:
LYR-210 is a drug depot, which contains the anti-inflammatory medication mometasone furoate (MF) pre-loaded in a single use applicator. LYR-210 is intended to be placed bilaterally into the sino-nasal passages by an otolaryngologist. Once in place, each LYR-210 drug depot is designed to gradually deliver sustained topical doses of MF to the inflamed mucosal sinus tissue over 24 weeks.

Arms:
arm 1: In-office bilateral placement of the LYR-210 drug depot (mometasone furoate low dose) in the middle meatus arm 2: In-office bilateral placement of the LYR-210 drug depot (mometasone furoate high dose) in the middle meatus arm 3: In-office bilateral sham procedure

Interventions: intervention 1: LYR-210 intervention 2: Sham comparator
Intervention descriptions: intervention 1: A single administration of LYR-210 depot intervention 2: Sham comparator

Protocol document:
Prot_000.pdf: 
LYRA THERAPEUTICS, INC.
STUDY LYR-210-2018-002
VERSION 8.0 (30JUN2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 1 OF 129
COVER PAGE
CLINICAL STUDY PROTOCOL
Protocol Number:
LYR-210-2018-002
Study Title:
A Phase II, Randomized, Blinded, Sham Procedure-
Controlled, Parallel-Group Trial to Evaluate the Efficacy,
Safety and Tolerability of LYR-210 in Adult Subjects with 
Chronic Sinusitis (LANTERN Study)
EUDRACT Number:
2018-004621-89
Sponsor:
Lyra Therapeutics, Inc.
480 Arsenal Way
Watertown, MA USA 02472
Current Version 8.0:
30 June 2020
Confidentiality Statement
The information contained in this document, is the property of the Sponsor and is confidential. 
This information may not be disclosed, reproduced or distributed to anyone other than personnel 
directly involved in the conduct of the study and in response to a relevant Institutional Review 
Board/Ethics Committee and Review by a Regulatory Authority as required by the applicable 
laws and regulations, without the written authorization of the Sponsor, except to the extent 
necessary to obtain written informed consent from those individuals to whom the study drug may 
be administered. These restrictions will continue to apply after the study has closed.


LYRA THERAPEUTICS, INC. 
STUDY LYR-210-2018-002
VERSION 8.0 (30JUN2020) 
PROPRIETARY AND CONFIDENTIAL
PAGE 2 OF 129
SPONSOR SIGNATURE PAGE
Protocol Number:
LYR-210-2018-002
Study Title:
A Phase II, Randomized, Blinded, Sham Procedure-Controlled, 
Parallel-Group Trial to Evaluate the Efficacy, Safety and Tolerability 
of LYR-210 in Adult Subjects with Chronic Sinusitis (LANTERN 
Study) 
Sponsor:
Lyra Therapeutics, Inc.
480 Arsenal Way
Watertown, MA USA 02472 
Current Version 8.0:
30 June 2020
Signed:  
Yina Kuang, Ph.D. 
Senior Manager, Clinical and Preclinical Sciences
Date:  
(DD-MMM-YYYY)
Signed:  
Vineeta Belanger, Ph.D. 
Senior Vice President, Clinical Affairs
Date:  
            (DD-MMM-YYYY) 
Signed:  
Yina Kuang, Ph.D. 
Senior Manager, Clinical and Preclinical Sciences
Date:  
(DD
(
-MMM-
M YYYY)
Y
Signed:  
Vineeta Belanger, Ph.D. 
Senior Vice President, Clinical Affairs
Date:  
           (DD
(
-MMM-
M YYYY) 
Y


LYRA THERAPEUTICS, INC.
STUDY LYR-210-2018-002
VERSION 8.0 (30JUNE2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 3 OF 129
INVESTIGATOR AGREEMENT SIGNATURE PAGE
I hereby agree to participate in this clinical investigation sponsored by Lyra Therapeutics, Inc., (hereinafter 
“Study Sponsor”). I agree to conduct this investigation in accordance with this version of the protocol. I 
agree to protect the rights, safety, and welfare of subjects under my care. I agree that the study will be 
conducted according to the principles of the ICH E6 guideline for GCP, the ethical principles that have their 
origins in the World Medical Association Declaration of Helsinki, and local regulatory authority or ethics 
committee requirements as appropriate. I agree to supervise all use of the investigational product and to 
ensure appropriate informed consent is obtained from all subjects prior to inclusion in this study.
I understand that this investigation will be monitored by the Study Sponsor and/or a designee employed by 
the Study Sponsor. This monitoring will involve periodic inspection of my investigational site and ongoing 
review of the data that is submitted by me to the Study Sponsor. I am also aware that I may be inspected by 
a representative of the local regulatory authority or ethics committee to verify compliance with applicable 
federal regulations related to clinical research on human subjects.
I am aware that the Study Sponsor reserves the right to discontinue this investigation at any time. In the 
event that I decide to discontinue my participation as an Investigator in this study, I will notify the Study 
Sponsor with suitable written notice and in accordance with the Clinical Trial Agreement prior to 
discontinuing. I understand that I am obligated to complete the follow up of the subjects already 
participating in the investigation.
I agree to provide to the Study Sponsor my current curriculum vitae along with the current curriculum vitae 
of those physicians at this institution who will be using this investigational product or participating in this 
study as Sub-Investigators under my supervision. These CVs include education, training, and the extent and 
type of our relevant experience with pertinent dates and locations. I certify that I have not been involved in 
an investigation that was terminated for noncompliance at the insistence of a Study Sponsor, or a local 
regulatory authority or ethics committee. 
I understand that this investigation, protocol, and trial results are confidential, and I agree not to disclose 
any such information to any person other than a representative of Study Sponsor or local regulatory 
authority or ethics committee without the prior written consent of the Study Sponsor.
Investigational Site:
Name: 
Phone Number: 
Address: 
Investigator:
Name (Print): 
Signature: 
Date of Signature:  
(DD-MMM-YYYY) 


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VERSION 8.0 (30JUNE2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 4 OF 129
TABLE OF CONTENTS
COVER PAGE...............................................................................................................................1 
SPONSOR SIGNATURE PAGE..................................................................................................2 
INVESTIGATOR AGREEMENT SIGNATURE PAGE ..........................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES.........................................................................................................................8 
LIST OF FIGURES.......................................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................10 
1.
SYNOPSIS ............................................................................................................................12 
2.
INTRODUCTION................................................................................................................31 
2.1 
Chronic Sinusitis ........................................................................................................31 
2.2 
Product Rationale .......................................................................................................31 
2.3 
Study Rationale ..........................................................................................................32 
3.
STUDY OBJECTIVES AND ENDPOINTS ......................................................................34 
4.
INVESTIGATIONAL PLAN..............................................................................................40 
4.1 
Overall Study Design .................................................................................................40 
4.1.1 
Screening Stage........................................................................................42 
4.1.2 
Treatment Stage........................................................................................42 
4.1.3 
Post-Treatment Follow-Up Stage.............................................................43 
4.1.4 
End of the Trial.........................................................................................43 
4.2 
Rationale for Study Design ........................................................................................43 
4.3 
Discontinuation of Study Subjects .............................................................................43 
4.4 
Criteria for Study Termination...................................................................................44 
4.5 
Data Monitoring Committee (DMC)..........................................................................44 
5.
SELECTION OF SUBJECTS.............................................................................................46 
5.1 
Subject Screening.......................................................................................................46 
5.2 
Subject Informed Consent..........................................................................................46 
5.3 
Inclusion Criteria........................................................................................................46 
5.4 
Exclusion Criteria.......................................................................................................47 
6.
TREATMENT OF SUBJECTS ..........................................................................................50 
6.1 
Randomization............................................................................................................50 
6.2 
Study Product Administration....................................................................................50 
6.2.1 
Pre-procedure Medication........................................................................50 
6.2.2 
Study Product Preparation........................................................................50 
6.2.3 
Study Product Administration..................................................................50 
6.2.4 
Enrollment Failure....................................................................................51 
6.2.5 
End of Day 1 Visit....................................................................................51 
6.3 
Blinding......................................................................................................................51 
6.3.1 
Procedures for Breaking the Blind Prior to Study Completion................52 
6.3.2 
Revealing Randomization ........................................................................52 
6.4 
Prior and Concomitant Medications...........................................................................52 
6.4.1 
Prior Medications .....................................................................................52 
6.4.2 
Prohibited Concomitant Medications.......................................................53 
6.4.3 
Permitted Concomitant Medications........................................................53 
6.4.4 
Rescue Concomitant Medications and Treatment....................................54 


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6.5 
Removal Procedure ....................................................................................................54 
6.6 
Treatment Compliance ...............................................................................................55 
7.
DRUG PRODUCT MATERIALS AND MANAGEMENT .............................................56 
7.1 
Investigational Product...............................................................................................56 
7.1.1 
Product Description..................................................................................56 
7.1.2 
Dosage and Administration......................................................................56 
7.1.3 
Active Ingredient: Mometasone Furoate..................................................57 
7.1.4 
Inactive Ingredients..................................................................................57 
7.1.5 
Applicator.................................................................................................57 
7.2 
Drug Product Management ........................................................................................58 
7.2.1 
Packaging and Labeling ...........................................................................58 
7.2.2 
Storage......................................................................................................58 
7.2.3 
Product Traceability .................................................................................58 
7.2.4 
Product Accountability.............................................................................58 
7.2.5 
Product Return..........................................................................................59 
8.
STUDY ASSESSMENTS.....................................................................................................60 
8.1 
Study Schedule of Assessment...................................................................................60 
8.2 
Assessment of Subject Characteristics.......................................................................64 
8.2.1 
Demographics...........................................................................................64 
8.2.2 
Medical and Surgical History...................................................................64 
8.3 
Assessment of Efficacy ..............................................................................................64 
8.3.1 
Subject Reported Outcomes.....................................................................64 
8.3.1.1 
Chronic Sinusitis Cardinal Symptom 
Assessment ........................................................................65 
8.3.1.2 
22-Item Sino-Nasal Outcome Test (SNOT-22)
Questionnaire.....................................................................65 
8.3.1.3 
Saline Irrigation Use..........................................................66 
8.3.1.4 
36-item Short Form Health Survey version 2
(SF-36v2®) Questionnaire .................................................66 
8.3.1.5 
End-of-Treatment Questionnaire.......................................67 
8.3.2 
Sinus Inflammation Imaging....................................................................67 
8.3.3 
Nasal Polyp Assessment...........................................................................67 
8.3.4 
The University of Pennsylvania Smell Identification Test 
(UPSITTM) ................................................................................................68 
8.4 
Assessment of Safety..................................................................................................68 
8.4.1 
Physical Examination...............................................................................68 
8.4.2 
Vital Signs................................................................................................68 
8.4.3 
Laboratory Assessments...........................................................................68 
8.4.3.1 
Hematology........................................................................69 
8.4.3.2 
Blood Chemistry................................................................69 
8.4.3.3 
Morning Serum Cortisol....................................................69 
8.4.4 
Nasal Endoscopy Assessments.................................................................69 
8.4.5 
Ophthalmologic Assessments...................................................................69 
8.4.6 
Pharmacokinetic Analysis........................................................................70 
8.4.7 
In Vivo Drug Dissolution Analysis of LYR-210......................................70 
8.4.8 
Pregnancy or Breast Feeding....................................................................70 


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8.4.9 
Adverse Events and Serious Adverse Events...........................................71 
8.4.9.1 
Adverse Event (AE)...........................................................71 
8.4.9.2 
Serious Adverse Event (SAE) ...........................................72 
8.4.9.3 
Relationship to Study Drug Product and 
Procedure...........................................................................72 
8.4.9.4 
Severity of Adverse Events ...............................................74 
8.4.9.5 
Expectedness of Serious Adverse Events..........................74 
8.4.9.6 
Reporting ...........................................................................74 
8.4.10 
Safety Monitoring.....................................................................................76 
9.
SAFETY INFORMATION OF STUDY DRUG PRODUCT...........................................77 
9.1 
Safety Rationale of Study Drug Doses and Polymers................................................77 
9.1.1 
Existing Non-clinical Safety Data............................................................77 
9.1.2 
Nonclinical Toxicology Assessment of LYR-210 ...................................77 
9.1.3 
Phase I Clinical Study of LYR-210 (2500 μg).........................................80 
9.1.4 
Systemic and Local Dose Safety of LYR-210 (7500 μg) ........................82 
9.1.4.1 
Systemic Safety .................................................................82 
9.1.4.2 
Local Safety.......................................................................84 
9.1.5 
Product Safety Rationale Conclusion.......................................................85 
9.2 
Anticipated Risks .......................................................................................................85 
9.2.1 
Expected ARs Associated with Endoscopic Procedures and 
LYR-210 Administration/Removal..........................................................85 
9.2.2 
Expected ARs Associated with Mometasone Furoate or Nasal 
Implant......................................................................................................86 
10. STATISTICAL ANALYSIS................................................................................................88 
10.1 
Analysis Populations..................................................................................................88 
10.2 
Disposition and Population Assignment ....................................................................88 
10.3 
Demographic and Other Baseline Characteristics......................................................89 
10.4 
Prior and Concomitant Medications...........................................................................89 
10.5 
Safety Analyses..........................................................................................................89 
10.6 
Efficacy Analyses.......................................................................................................90 
10.6.1 
Primary Efficacy Endpoint Analysis........................................................90 
10.6.1.1 
Handling of Missing Data..................................................91 
10.6.1.2 
Assessment of Treatment Effect Across Study 
Regions, Across Nasal Allergy Groups and 
Across Polyp Groups .........................................................92 
10.6.2 
Key Secondary Efficacy Endpoint Analysis ............................................92 
10.6.2.1 
CFBL in CS7DA4S at Week 24........................................92 
10.6.2.2 
Percentage of Subjects with Improved bilateral 
Zinreich score ....................................................................93 
10.6.2.3 
Time-to-Treatment Failure ................................................93 
10.6.3 
Non-Key Secondary Efficacy Endpoint Analysis....................................94 
10.6.4 
Exploratory Endpoint Analysis ................................................................94 
10.6.5 
Pharmacokinetic Analyses .......................................................................95 
10.6.5.1 
Pharmacokinetic Concentrations .......................................95 
10.6.5.2 
Pharmacokinetic Parameters..............................................95 
10.7 
Sample Size................................................................................................................95 
9.1.1
Existing Non-clinicalal Safafetety y y Da
Da
Datata............................................................77
9.1.2
No
Nonc
nclilininica
cal l To
Toxixicolology
gy Asssses
essm
smen
ent of
of LYR
YR-210 ...................................77
9.1.3
Phase I Clinical Study of LYR-210 (2500 μg).........................................80
80
9.1.4
Systemic and Local Dose Safety of LYR-210 (7500 μg) ........................82
82
9.1.4.1
Systemic Safety .................................................................82
9.1.4.2
Local Safety.......................................................................84
9.1.5
Product Safety Rationale Conclusion.......................................................85
9.2
Anticipated Risks .......................................................................................................85
9.2.1
Expected ARs Associated with Endoscopic Procedures and 
LYR-210 Administration/Removal..........................................................85
9.2.2
Expected ARs Associated with Mometasone Furoate or Nasalal 
Implant......................................................................................................86


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11. REGULATORY OBLIGATIONS......................................................................................97 
11.1 
Statements of Compliance..........................................................................................97 
11.2 
Site Selection and Training ........................................................................................97 
11.3 
Ethics Committee (EC) Approval ..............................................................................98 
11.4 
Informed Consent.......................................................................................................98 
11.5 
Protocol Amendments................................................................................................99 
11.6 
Protocol Deviations....................................................................................................99 
11.7 
Study Monitoring .....................................................................................................100 
11.8 
Data Quality Assurance............................................................................................100 
11.9 
Record Retention......................................................................................................101 
11.10 Auditing
101 
11.11 Use and Publication of Study Results ......................................................................102 
11.12 Confidentiality..........................................................................................................102 
11.13 Early Study Discontinuation ....................................................................................102 
12. CLINICAL RISK AND BENEFIT ANALYSIS..............................................................104 
13. LIST OF REFERENCES ..................................................................................................108 
14. APPENDICES ....................................................................................................................111 
14.1 
Daily Electronic Subject Reported Outcome (ePRO) ..............................................111 
14.2 
22-Item Sino-Nasal Outcome Test (SNOT-22)........................................................113
14.3 
LYR-210 Phase II End Of Treatment Questionnaire ...............................................114 
14.4 
36-item Short Form Health Survey version 2 (SF-36v2®) Questionnaire................116
14.5 
Summary and Outcome of Protocol Changes ..........................................................123 
14.5.1 
Summary of Protocol Changes from Version 4.0 (Applicable 
for New Zealand, Australia and Europe)................................................124 
14.5.2 
Summary of Protocol Changes from Version 7.0 (Applicable 
for United States)....................................................................................127 
14.1
Dailily Electronic Sub
ubjej ct Reporteted Ou
Outcom
ome (ePRO) ..............................................111
14
1 .2
22-Item Sino-Nasal Ou
Outcome Te
Test (SN
SNOT
OT-22
22)........................................................113
14.3
LYR-210 Phase II End Of Treatment Questionnaire ...............................................114
14.4
36-item Short Form Health Survey version 2 (SF-36v2®) Question
onnaire................11
116
14.5
Summary and Outcome of Protocol Changes ..........................................................123
14.5.1
Summary of Protocol Changes from Version 4.0 (Applicable 
for New Zealand, Australia and Europe)................................................124
14.5.2
Summary of Protocol Changes from Version 7.0 (Applicable 
for United States)....................................................................................127
y
y
CLINICAL RISK AND BENEFIT ANALYSIS..............................................................10
104


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LIST OF TABLES
Table 1: 
Schedule of Assessments for Subjects Randomized and Enrolled .............62 
Table 2: 
Categorized Survey Items for Separate Domains of the SNOT-22
Instrument ...................................................................................................66 
Table 3. 
SF-36v2® Health Survey Measurement Model...........................................66 
Table 4: 
Sinus Histological Score Summary of the 180-Day Rabbit Study .............78 
Table 5. 
Sinus Histological Score Summary of the 28-day Study............................79 
Table 6: 
Number of Subjects with Plasma MF Concentration < or ≥ 20 
pg/mL (ITT Population)..............................................................................80 
Table 7: 
Comparison of Systemic Exposure of LYR-210 (7500 μg) with 
Clinical Studies showing Systemic Safety of Chronic Use of MF 
Products.......................................................................................................83 
Table 8: 
Summary of Clinical Studies showing Local Tissue Safety of 
Chronic Intranasal use of Mometasone Furoate..........................................84 
Table 9: 
Summary of Expected ARs Associated with LYR-210
Administration or Removal Procedure........................................................85 
Table 10: 
Summary of Expected ARs Associated with Mometasone Furoate ...........86 
Table 4:4:
Sinus Histological Score Su
Summararary of the 180-Day Rabbitit Study .............78
Ta
Table 5.
Si
Sinu
nus Hi
Histstololog
ogicicalal Scorere Sum
umma
mary
ry of ththe 28
28-da
day St
St d
udy............................79
Table 6: 
Number of Subjects with Plasma MF Concentration < or ≥ 20
pg/mL (ITT Population)..............................................................................80
Table 7:
Comparison of Systemic Exposure of LYR-210 (7500 μg
μg) with 
Clinical Studies showing Systemic Safety of Chronic Use of MF 
Products.......................................................................................................83
Table 8: 
Summary of Clinical Studies showing Local Tissue Safety of 
Chronic Intranasal use of Mometasone Furoate..........................................84
Table 9: 
Summary of Expected ARs Associated with LYR-210
Administration or Removal Procedure........................................................85
85
Table 10: 
Summary of Expected ARs Associated with Mometasone Furoatete ...........86
86


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LIST OF FIGURES
Figure 1: 
Study Design Schematic .............................................................................40 
Figure 2: 
LYR-210 Images.........................................................................................56 
Figure 3: 
Chemical Structure of Mometasone Furoate...............................................57 
Figure 4: 
Chemical Structures of Inactive Ingredients...............................................57 
Figure 5: 
Applicator, Ready for LYR-210 Administration ........................................58 
Figure 6: 
Comparison of Plasma MF Concentration of LYR 210 and 
Nasonex® over 28 Days .............................................................................79 
Figure 7: 
In Vitro and In Vivo Percentage of Release of MF in LYR-210
(2500 μg) Over Time ..................................................................................81 
Figure 8: 
In vitro Cumulative Percentage of Release of MF from LYR-210
(7500 μg) Over Time ..................................................................................83 
Fi
Figu
g re 6:
Comparison
on of Plasma
ma MF Co
Co
Conc
nc
ncen
en
entrt ation of LYR 210 and
nd 
Nasonex® over 28 Days .............................................................................79
79
Figure 7:
In Vitro and In Vivo Percentage of Release of MF in LYR
YR-210
(2500 μg) Over Time ..................................................................................81
Figure 8:
In vitro Cumulative Percentage of Release of MF from LYR-210
(7500 μg) Over Time ..................................................................................83


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation / Term
Definition
AE
adverse event
AECS
acute exacerbation of chronic sinusitis
CS7DA4S
composite score of 7-day average scores of 4 CS cardinal symptoms
CFBL
change from baseline
CFR
code of federal regulations
COPD
chronic obstructive pulmonary disorder
CPmin
the minimum of the conditional power of the promising zone
CRF
case report form
CSsNP
chronic sinusitis without nasal polyps
CSwNP
chronic sinusitis with nasal polyps
CS
chronic sinusitis
CT
computed tomography
CTCAE
common terminology criteria for adverse events
CYP3A4
cytochrome P-450 3A4
DMC
data monitoring committee
EC
ethics committee
EOS
end-of-study
EOT
end-of-treatment
ePRO
electronic subject reported outcome
ESS
endoscopic sinus surgery
ET
early termination
FAS
full analysis set
FDA
food and drug administration
GCP
good clinical practice
GEE
generalized estimating equation
HEENT
head, ears, eyes, nose and throat 
HRS
Hours
IB
investigator brochure
ICF
informed consent form
ICH
international council for harmonization
IFU
instructions for use
IgA
immunoglobulin-a
IgG
immunoglobulin-g
INCS
intranasal corticosteroid spray
IOP
intraocular pressure
IRB
institutional review board
IRT
interactive response technology


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Abbreviation / Term
Definition
ITT
intention to treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
kg
Kilogram
LOCF
last observation carried forward
mcg
Microgram
MedDRA
medical dictionary for regulatory activities
MF
mometasone furoate
mg
Milligram
mL
Milliliter
mmHg
millimeters of mercury
mo
Month
NCI
national cancer institute
PAR
perennial allergic rhinitis
PAS
per-protocol analysis set
pg
Picogram
PK
Pharmacokinetics
PP
per protocol
SAE
serious adverse event
SAP
statistical analysis plan
SAR
seasonal allergic rhinitis
SD
standard deviation
SF-36v2
36-item short form health survey version 2
SNOT
sino-nasal outcome test
SOP
standard operating procedure
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
UADE
unexpected adverse device effect
UPSIT
University of Pennsylvania smell identification test
URTI
upper respiratory tract infection
US
United States
USP
united states pharmacopeia
WHO ATC
world health organization anatomical therapeutic classification


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1.
SYNOPSIS
Sponsor Lyra Therapeutics, Inc.
480 Arsenal Way
Watertown, MA 02472, USA
Protocol Title
A Randomized, Blinded, Sham Procedure-Controlled, 
Parallel-Group, Phase II Trial to Evaluate the Efficacy, 
Safety and Tolerability of LYR-210 in Adult Subjects with 
Chronic Sinusitis (CS) (LANTERN Study)
Protocol Number LYR-210-2018-002
Phase of Development
Phase II
Trial Location
Worldwide
Number of sites Up to 25 sites 
Study Population Adult CS subjects who have failed previous medical 
management and have not undergone endoscopic sinus 
surgery (ESS)
Estimated Number of Subjects
Approximately 70 subjects
Investigational Product
LYR-210 System, 2500 μg and 7500 μg
Active Ingredient
Mometasone Furoate (MF)
Study Objectives
Endpoints
Primary
To evaluate the efficacy of LYR-
210 in improving the composite 
score of 7-day average scores of
4 CS cardinal symptoms
(CS7DA4S) at Week 4
- Change from baseline (CFBL) in CS7DA4S score at
Week 4
The 4 CS cardinal symptoms include nasal
blockage/obstruction/congestion, facial pain/pressure,
reduction/loss of sense of smell, and anterior/posterior
nasal discharge. Each symptom is scored on a 0-3 scale
as follows: 0 = none, 1 = mild, 2 = moderate, and 3 =
severe.
Key Secondary
To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score at end of treatment 
- CFBL in CS7DA4S score at Week 24


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To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- Percentage of subjects with at least 1-point decrease in
the bilateral Zinreich score in at least 1 pair of the
anterior ethmoid, maxillary, posterior ethmoid, frontal, or
sphenoid sinuses at Week 24
Each sinus is scored on a 0-5 scale per the Zinreich
modified Lund-Mackay scoring system and based on the
percentage of opacification as follows: 0 = 0%, 1 = 1%
to 25%, 2 = 26% to 50%, 3 = 51% to 75%, 4 = 76 % to
99%, and 5 = 100% or completely occluded.
To evaluate the
time to 
treatment failure 
- Time to treatment failure
A treatment failure is defined as, after subject
enrollment, subject being recommended by treating
physician for oral corticosteroid or ESS due to
worsening of CS symptoms, or the subject complaint of
persistent CS symptoms with an average CS7DA4S score
over the preceding 30 days greater than or equal to the
Baseline CS7DA4S score.
Other Secondary
To evaluate the safety and 
tolerability of LYR-210
- Severity and percentage of subjects reporting treatment-
emergent adverse events (TEAEs) and serious adverse
events (TESAEs) through Weeks 2, 4, 12, and 24
- Severity and percentage of subjects reporting Day 1
administration procedure and Week 24 removal
procedure related AEs and SAEs
- Severity and percentage of subjects reporting product
related AEs and SAEs on Day 1 and through Weeks 2, 4,
12, and 24
- Percentage of subjects with abnormal and clinically
significant abnormal laboratory values (hematology and
chemistry, vital signs) on Day 1 and at Weeks 4, 12, and
24
- Morning serum cortisol levels on Day 1 and at Weeks 4,
12, and 24
- Severity and percentage of subjects with adverse nasal
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findings requiring medical treatment in one or both 
nostrils on Day 1 and at Weeks 2, 4, 12, and 24
- Percentage of subjects with elevated intraocular pressure
(IOP) in one or both eyes at Weeks 4, 12, and 24
- Percentage of subjects with a clinically significant
increase of IOP at Weeks 4, 12, and 24
A clinically significant increase of IOP is defined as IOP
in one or both eyes > 28 mmHg or an increase of IOP
from Baseline in one or both eyes >= 10 mmHg.
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 24
To evaluate the time to onset of 
action of LYR-210
- Time to onset of action
Time to onset of action is defined as, within the first 30
days, the time when all subsequent mean CFBL in the
CS7DA4S score of the LYR-210 is statistically
significantly greater than that for the sham procedure.
To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score and the 7-day average score 
of each of the 4 cardinal CS 
symptoms
- CFBL in the CS7DA4S score at Weeks 8, 12, 16, and 20
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, and anterior/posterior nasal
discharge at Weeks 1, 2, 3, 4, 8, 12, 16, 20, and 24
To evaluate the effect of LYR-
210 in improving CS disease-
specific quality of life as per 22-
item sino-nasal outcome test 
(SNOT-22) questionnaire 
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 2, 4, 8, 12, 16,
20, and 24
To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus and
OMC pairs at Week 24
- CFBL in total Zinreich score at Week 24
To evaluate the effect of LYR-
210 in reducing subjects’ needs 
- Percentage of subjects with use of oral antibiotics for CS
through Weeks 4, 8, 12, 16, 20, and 24


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for medical or surgical treatment 
for CS
- Percentage of subjects with use of oral corticosteroid for
CS through Weeks 4, 8, 12, 16, 20, and 24
- Percentage of subjects with use of intranasal
corticosteroid sprays for CS through Weeks 4, 8, 12, 16,
20, and 24
- Percentage of subjects being recommended by treating
physician for ESS through Weeks 4, 8, 12, 16, 20, and 24
To evaluate the pharmacokinetics 
of LYR-210
- Plasma MF concentrations at Days 3, 7, 14, 21 and
Weeks 4, 12, 24
Plasma PK samples at Days 3, 7, 14, 21 will only be
measured in approximately 15 randomized and
successfully enrolled subjects at US sites.
To evaluate the effect of LYR-
210 in improving subjects’
general quality of life as per 36-
item short form health survey 
version 2 (SF-36v2)
questionnaire
- CFBL in SF-36v2 physical health, mental health, and
domain scores at Week 24
To evaluate LYR-210 in 
improving smell function
assessed by the University of 
Pennsylvania Smell Identification 
Test (UPSITTM)
- CFBL in UPSIT score at Week 24
Exploratory 
To evaluate the percentage of
subjects experiencing acute 
exacerbations of CS (AECS) 
- Percentage of subjects experiencing AECS through
Weeks 4, 8, 12, 16, 20, and 24
AECS is defined as a sudden worsening of symptoms in a
subject resulting in the treating physician reporting an
escalation of treatment.
To assess effect of LYR-210 in 
reducing polyp severity within 
middle meatus in subgroup of CS 
subjects with nasal polyps 
(CSwNP)
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
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To assess efficacy of LYR-210 in 
improving CS7DA4S score, the 
7-day average score of each of 4
CS cardinal symptoms, the
SNOT-22 total and subdomain
scores, and the SF-36v2 physical
health, mental health, and domain
scores in the subgroups of CS
subjects without nasal polyps
(CSsNP) and CSwNP subjects
- CFBL in the CS7DA4S score at Weeks 1, 2, 3, 4, 8, 12,
16, 20, and 24
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal
discharge in CSsNP and CSwNP subjects at Weeks 1, 2,
3, 4, 8, 12, 16, 20, and 24
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores in CSsNP and CSwNP
subjects at Weeks 2, 4, 8, 12, 16, 20, and 24
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores in CSsNP and CSwNP
subjects at Week 24
To assess efficacy of LYR-210 in 
reducing sinus inflammation in 
CSsNP and CSwNP subjects 
- Percentage of subjects with at least 1-point decrease in
the bilateral Zinreich score in at least 1 pair of the
anterior ethmoid, maxillary, posterior ethmoid, frontal, or
sphenoid sinuses in CSsNP and CSwNP subjects at
Week 24
- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus, and
OMC pairs in CSsNP and CSwNP subjects at Week 24
- CFBL in total Zinreich score at in CSsNP and CSwNP
subjects at Week 24
To assess effect of LYR-210 in 
improving smell function in 
CSsNP and CSwNP subjects 
- CFBL in UPSIT score in CSsNP and CSwNP subjects at
Week 24
To assess the safety of subjects 
post LYR-210 treatment
- Severity and percentage of subjects reporting AEs and
SAEs through Week 28 and Week 48
- Percentage of subjects with abnormal and clinically
significant abnormal laboratory values (hematology and
chemistry, vital signs) at Week 28
- Morning serum cortisol levels at Week 28
- Plasma MF concentrations at Week 28


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- Severity and percentage of subjects with adverse nasal
endoscopic findings and adverse nasal endoscopic
findings requiring medical treatment in one or both
nostrils at Week 28
- Percentage of subjects with elevated IOP in one or both
eyes at Week 48
- Percentage of subjects with a clinically significant
increase of IOP at Week 48
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 48
To assess the durability of 
efficacy post LYR-210 treatment
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
subjects at Week 28
- CFBL in the CS7DA4S score at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal
discharge in CSsNP and CSwNP subjects at Weeks 28,
32, 36, 40, 44, and 48
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores at Week 48
Study Design
This global, multicenter study will be conducted in a randomized, sham procedure-controlled, 
parallel-group, subject-blinded fashion in approximately 70 adult CS subjects who have failed 
previous medical management and have not undergone ESS. Subjects enrolled in the study will 
include patients who have not had ESS but their symptoms are not adequately controlled on 
medical management and are seeking further treatment. This may include subjects who are 
considering sinus surgery or those who have decided against it. The efficacy and safety of 
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assessed. Additionally, LYR-210 (2500 μg) and LYR-210 (7500 μg) will be compared to 
evaluate dose related responses.
The study will consist of three stages: 
x
Screening and Washout Stage: 2 -4 weeks
x
Treatment Stage: 24 weeks
x
Post-Treatment Follow-Up Stage: 24 weeks
Screening and Washout Stage
After providing written informed consent, subjects who are qualified to participate in this study 
will have an initial Screening visit. Immediately following the initial Screening visit, subjects 
will undergo a minimum of 2-week but a maximum of 4-week washout period. During this 
washout period, except for recommended twice daily saline irrigation, subjects will receive no 
active treatment for CS or any prohibited or rescue medications specified in the study protocol.
Beginning at least 7 days prior to LYR-210 administration/sham procedure on Day 1, subjects 
will record cardinal symptoms of CS on the electronic subject reported outcomes (ePRO) 
questionnaire.
Treatment Stage
The total duration of the Treatment Stage will be approximately 24 weeks. 
On Day 1, before any treatment, subjects will be randomized in a 1:1:1 ratio to one of the 
following study arms: 
x
Arm 1: bilateral administration of LYR-210 (2500 μg)
x
Arm 2: bilateral administration of LYR-210 (7500 μg)
x
Control Arm: bilateral sham procedure
Subjects will be stratified for treatment assignment according to the following criteria:
x
Nasal Allergy (Yes vs No)
x
Nasal polyps (Yes vs No)
Subjects who are assigned to the active treatment arms will have the LYR-210 administered 
bilaterally into the middle meatus on Day 1. Subjects who are assigned to the sham procedure 
arm, will undergo bilateral mock administration (i.e., sham procedure) on Day 1 consisting of 
bilateral insertion of an applicator (without LYR-210 loaded) into the middle meatus until the 
applicator tip touches the ethmoid bulla for a minimum of 20 seconds, followed by withdrawal 
of the applicator. 
Prior to LYR-210 administration/sham procedure, all subjects will receive topical anesthetic and 
decongestant sprays for endoscopic assessment. Subjects will also receive anesthetic and 


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decongestant soaked cottonoid or pledget in each nostril to prepare middle meatuses for the 
insertion procedure. To maintain the subject blind to treatment assignment, each subject will 
wear an eye mask (i.e., blindfold) at the time of the LYR-210 administration/sham procedure. 
The study clinic staff, including the Investigator and study coordinator, will be unblinded to 
LYR-210 treatment vs the sham procedure but will remain blinded as to the dose administered 
to subjects who receive LYR-210.
All subjects will return to clinic for the scheduled follow up assessments at Week 2, 4, 12 and 
24 visits and will remain blinded at these visits. Subjects will receive telephone follow-ups at
Weeks 8, 16, and 20 to record AEs and concomitant medications/procedures that they have had 
since their last follow-up assessment.
At the Week 24 visit, all subjects will return to clinic for the end-of-treatment (EOT) visit 
assessments. Subjects who receive LYR-210 will have bilateral depot removed using standard 
surgical tools. Sham control subjects will undergo a sham removal procedure to remain blinded.
If spontaneous dislodgement of LYR-210 occurs before the scheduled Week 24/EOT visit in 
subjects who receive either dose of LYR-210, subjects are required to call the study clinic 
immediately to report the event. If a subject experiences dislodgement of one of the two LYR-
210 depots, the subject will continue the study treatment unless an early treatment 
discontinuation is recommended by the treating physician or subject requests depot removal 
from the remaining side of the nose. If depots spontaneously dislodge from both sides of the 
nose, the subject will complete Week 24/EOT assessments and subsequently, the post-treatment 
follow-up stage.
If medically warranted per the treating physician’s discretion (for example, needing an ESS as 
rescue treatment), early depot removal may be performed at an Unscheduled early-termination 
(ET) visit (an Unscheduled EOT visit). Any subject who undergoes an ET visit is required to 
complete the assessments scheduled for the Week 24/EOT visit, and all safety follow up visits 
post treatment.
Post-treatment Follow-Up Stage
All subjects will undergo a Post-treatment Follow-up Stage that will be approximately 24 
weeks. Subjects will have 2 additional safety follow up visits during this stage, the Week 28 and
a final Week 48/end-of-study (EOS) safety visits. Subjects will receive telephone follow-ups at
Weeks 32, 36, 40, and 44 to record AEs and concomitant medications/procedures that they have 
had since their last follow-up assessment. Except for the cases of spontaneous depot 
dislodgement, subjects should remain blinded until the study database is locked.
Blinding
Except for the cases of spontaneous depot dislodgement, subjects should remain blinded to their 
treatment assignment (LYR-210 or sham) until the final study database is locked. The Sponsor 


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will be blinded to subjects’ study treatment assignments until database lock for the primary data 
analysis after all enrolled subjects have completed Week 28 visit or withdrawn from study, 
whichever comes first.
Assessments
Enrolled subjects will be asked to complete a daily ePRO questionnaire to assess the 
instantaneous morning scores of 4 CS cardinal symptoms including nasal 
blockage/obstruction/congestion, reduction/loss of sense of smell, facial pain/pressure, and 
anterior/posterior nasal discharge. In addition, the ePRO will capture use of daily saline 
irrigation by the subjects. Subjects will also complete a validated CS-specific quality of life 
questionnaire, the SNOT-22, on Day 1 before treatment, at Week 2 and every 4 weeks after the 
Day 1 visit. Subjects will complete a general quality of life questionnaire, the SF-36v2, on Day 
1 before the LYR-210 administration/sham procedure, and at Week 24/EOT and Week 48/EOS 
visits. At EOT visit, an end-of-treatment questionnaire will be administered. 
Subjects will be asked to complete the UPSITTM test for smell dysfunction at the Day 1 visit 
before the LYR-210 administration/sham procedure, and at Week 24/EOT and Week 28 visits.
Sinus inflammation will be assessed by MRI without contrast prior to the Day 1 visit and within 
7 days after the LYR-210 removal/sham removal at the Week 24/EOT visit, unless medically 
contraindicated. If a subject is experiencing or recovering from a cold, acute exacerbation of 
nasal allergy, or upper respiratory tract infection at the Week 24/EOT visit, the MRI assessment 
should be performed 4 weeks after resolution of the adverse event. If a subject requires oral 
corticosteroid as rescue during the 24-week treatment period, the follow-up MRI should be 
performed before receiving the rescue treatment instead of at Week 24/EOT visit. 
Nasal cavities will be assessed by endoscopy on Day 1 before the LYR-210
administration/sham procedure, and at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits.
Subjects are required to wear a blindfold if any endoscopy examination is performed at these 
visits to remain blinded to treatment assignment. Local nasal safety evaluation will be 
performed at these visits to document presence of epistaxis, mucosal erosion or ulceration, 
perforation, infection, and any other local nasal adverse effects. For CSwNP subjects, real-time, 
qualitative endoscopic evaluation of change of polyp severity in the middle meatus will be 
performed by site Investigators at Week 24/EOT visit after LYR-210 removal/sham removal 
procedure and at Week 28 visit by comparing to that of the Day 1 visit. 
Ophthalmologic assessments will include IOP and slit-lamp examination during Screening, and 
within 7 days of Week 24/EOT and Week 48/EOS visits. IOP assessment will also be performed 
at Weeks 4 and 12 visits.
Plasma samples for PK will be collected from all subjects on Day 1 before the LYR-210
administration/sham procedure, and at Week 4, 12, 24/EOT, and 28 visits. Additional plasma 
PK samples will be collected at Days 3, 7, 14±1 (Week 2), 21±1 from approximately 15 


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randomized and successfully enrolled subjects at participating US sites for a minimum of 6 
subjects for each LYR-210 dose. The concentration of MF in plasma will be measured by a 
central laboratory.
Routine safety assessments will be performed during the study including vital signs and
physical exams. Samples for hematology, chemistry, and serum cortisol will be collected at 
Screening, Weeks 4, 12, 24/EOT, and 28 visits. An additional hematology, chemistry, and 
cortisol sample will be collected within 72 hours prior to LYR-210 administration/sham 
procedure for Baseline value. All post Screening serum cortisol samples will be evaluated by a 
central laboratory.
For female subjects of childbearing potential, a serum pregnancy test will be performed at 
Screening visit and a urine pregnancy test will be performed on Day 1 prior to randomization to 
confirm eligibility for participating in the study. A urine pregnancy test will be performed at 
every 4 weeks in clinic during the treatment stage in these female subjects.
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
events (AEs) or untoward findings. Any AEs observed by the Investigator or reported by the 
subjects, whether or not attributed to the investigational procedure or product, will be monitored 
and evaluated throughout the study. If AEs occur, the first concern will be the safety and 
welfare of the subject. Appropriate medical intervention will be undertaken per the treating 
physician’s discretion. 
Data Monitoring Committee (DMC)
An independent DMC will be formed by charter to assist in examining safety data periodically 
during the study. 
Concomitant Medications: Prohibited, Permitted, and Rescue
Subjects participating in the study are free to use any appropriate concomitant medications if
medically warranted per treating physician’s discretion. However, a standardized concomitant 
medications regimen is recommended during the washout and treatment stages to avoid 
confounding the efficacy or safety assessments of LYR-210.
Prohibited Concomitant Medications:
Use of the following medications is prohibited for the duration of the study: 
x
Oral/ocular/intramuscular/intravenous/intranasal corticosteroids (except for oral or
intranasal corticosteroids permitted as rescue medication only);
x
Anti-allergy medications, including: first generation antihistamines; leukotriene receptor
antagonists, nasal cromolyn sodium or sodium cromoglycate, nedocromil sodium,
atropine, ipratropium bromide, or guaifenesin;


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x
Oral decongestants;
x
Inhaled anti-cholinergic medications (except for a stable regimen for chronic obstructive
pulmonary disease (COPD) subjects);
x
Any potent cytochrome P-450 3A4 (CYP3A4) inhibitors (ketoconazole and ritonavir);
x
Any monoclonal antibody;
x
Any allergen immunotherapy (except for a stable dose and regimen);
x
Oral anti-fungal medication.
Subjects who received prohibited medications will be considered to have a protocol deviation
and may require withdrawal from the study.
Permitted Concomitant Medications:
At the discretion of the Investigator, the following concomitant medications may be used in 
accordance with the restrictions described for each treatment:
x
All subjects will be provided with saline and instructions for daily intranasal saline
irrigation twice a day starting from washout till Week 24/EOT.
x
If sinus infection is suspected at any time during the study, treatment with antibiotics
will be allowed after a clinic visit and per Investigator’s judgment.
x
Subjects who have been on a stable regimen of inhaled corticosteroids for asthma for a
minimum of 3 months prior to the Screening visit should remain on the same dosage
throughout the study. Inhaled corticosteroid use must be limited to a stable low- or
medium-dose as defined by guidelines established by the 2018 Global Initiative for
Asthma Management and Prevention [1].
x
Perennial allergic rhinitis (PAR) subjects who have been on a stable regimen of a non-
sedating oral antihistamine for a minimum of 3 months prior to the Screening visit
should remain on the same dosage throughout the study.
Rescue Medications and Treatment:
The following rescue medication is recommended for an acute exacerbation of the following 
conditions that result in the subject contacting the Investigator who determines an initiation of 
rescue therapy:
x
Any time during the 24-week treatment stage:
- After a clinic visit and per Investigator’s judgment, antibiotics for sinus infection.
- After a clinical visit and evaluation for worsening or uncontrolled severe CS
symptoms, the Investigator using his/her best judgement may give a course of oral
corticosteroids. Typical indications include persistent sinus infection after an initial


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course of antibiotics while starting another course of antibiotics, uncontrolled sinus 
inflammation not responding to an INCS, or a flare-up of asthma. The rationale for 
the use of oral corticosteroid must be recorded.  
x
After the Week 4 visit only:
- For acute allergic symptoms: Non-sedating oral antihistamine such as loratadine
(10 mg per day) or equivalent.
- For severe acute nasal blockage (score of 2 or more over the past 3 days): a course
of oxymetazoline spray for a maximum of 3 consecutive days and a total maximum
of 10 days during the treatment period. Oxymetazoline cannot be used within 24
hours before MRI assessments.
- For worsening CS symptoms: intranasal MF sprays with dose and duration per
Investigator’s recommendation.
- For worsening or uncontrolled severe CS symptoms: ESS as rescue treatment per
Investigator’s recommendation.
Diagnosis and Main Criteria for Inclusion: 
Inclusion Criteria:
A subject must meet all of the following criteria to be eligible for this study:
1. Age ≥18.
2. A CS subject who
a.
has twelve weeks or longer of two or more of the following symptoms:
• nasal blockage/obstruction/congestion
• nasal discharge (anterior, posterior, or both)
• facial pain/pressure
• reduction/loss of sense of smell
and one or more of the following findings:
• evidence of inflammation within paranasal sinuses or ostiomeatal complex on
MRI
• evidence of purulence coming from paranasal sinuses or ostiomeatal complex
• nasal polyps
b.
has a composite score of 7-day average scores of 4 CS cardinal symptoms [2, 3]
(CS7DA4S) ≥7 (0-3 scale for each of the symptoms) at Day 1 visit, and


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c.
has had at least two trials of medical treatments in the past, one of which must
include intranasal corticosteroid sprays (INCS) for a minimum of 4 weeks.
3. Must be able to cease treatment with intranasal corticosteroid and decongestant sprays at
Screening.
4. Ability to tolerate topical anesthesia.
5. Has been informed of the nature of the study and has provided written informed consent
as approved by the Institutional Review Board (IRB)/Ethics Committee (EC) of the
respective clinical site or regulatory authority if applicable by national law.
6. Agrees to comply with all study requirements.
Exclusion Criteria:
A subject who meets any of the following criteria will be excluded from this study:
1. With previous balloon sinuplasty or any endo-nasal surgery (including sinus surgery),
except for septoplasty or surgical manipulation to nasal turbinates more than 6 months
prior to the Screening visit.
2. Seasonal allergic rhinitis (SAR) subjects with symptoms and/or, based on time of year,
would anticipate onset of symptoms within 4 weeks of randomization.
3. Perennial allergic rhinitis (PAR) subjects whose symptoms are well controlled by
regular use of intranasal corticosteroids.
4. With severe asthma or with one or more exacerbations of asthma requiring systemic
corticosteroid use within the 6 months prior to the Screening visit. Subjects with
moderate or severe asthma will also be excluded if they have not been on a stable
regimen of inhaled corticosteroids for asthma for a minimum of 3 months prior to the
Screening visit.
5. Endoscopic exclusion criteria:
a.
Complete/near complete middle meatal obstruction preventing proper placement
and/or visualization of LYR-210.
b. Evidence of mucosal erosion or ulceration.
c.
Ongoing nasal infection.
d. Evidence of nasal septal perforation.
6. MRI exclusion criteria:
a.
A bilateral Zinreich score < 4 in all 3 pairs of the posterior ethmoid, frontal, or
sphenoid sinuses (0-5 scale for each of sinuses) on Screening MRI.


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b. Anatomic variation which, in the opinion of the Investigator, would adversely
impact placement of LYR-210.
c.
Structural, non-inflammatory related CS (e.g., large concha bullosa, tumor).
d. Sinus disease extended into orbital or intracranial space.
e. Evidence of mycetoma/fungal ball, allergic fungal rhinosinusitis.
f.
Sinus mucocele.
7. History or clinical evidence or suspicion of invasive fungal sinusitis, allergic fungal
rhinosinusitis, or atrophic rhinitis.
8. Known history of hypersensitivity or intolerance to corticosteroids.
9. Oral-steroid or monoclonal antibody (Xolair, Nucala) dependent condition.
10. Having had systemic corticosteroids within 1 month prior to Screening visit.
11. Known history of hypothalamic pituitary adrenal axial dysfunction or having a clinically
significant out of normal range morning serum cortisol level at screening.
12. Previous pituitary or adrenal surgery.
13. Has had more than 1 episode of epistaxis with frank bleeding requiring medical attention
within 2 months of Screening visit or more than 1 episode of epistaxis with frank
bleeding within 1 month of Screening visit.
14. Has had acute exacerbation of nasal allergy or chronic sinusitis, upper respiratory tract
infection (URTI), or common cold within 4 weeks of the Screening visit.
15. Had dental procedure/implant on maxillary dentition within 4 weeks of the Screening
visit.
16. Has past or present acute or chronic intracranial or orbital complications of CS (e.g.,
brain abscess, related problems with eyes or central nervous system).
17. History or diagnosis (in either eye) of glaucoma or ocular hypertension
(IOP > 21 mmHg).
18. With prior cataract surgery or presence (in either eye) of posterior subcapsular cataract
of grade 2 or higher, nuclear sclerosis of grade 3 or higher, or cortical cataract of grade 2
or higher or involving a minimum of center optic zone of 3 mm diameter.
19. Past or present functional vision in only one eye.
20. Diagnosed with ongoing rhinitis medicamentosa.


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21. Known history of immune dysfunction including immune deficiency (IgG subclass
deficiency or IgA deficiency) or autoimmune disease (e.g., Wegener’s granulomatosis,
sarcoidosis).
22. Past, present, or planned organ transplant or chemotherapy with immunosuppression.
23. History or diagnosis of ciliary dysfunction (e.g., cystic fibrosis, primary ciliary
dyskinesia [Kartagener syndrome]).
24. Past or present systemic vasculitis (e.g., granulomatosis with polyangiitis).
25. Evidence of disease or condition expected to compromise survival or ability to complete
follow-up assessments.
26. Pregnant or breast feeding. Females of child-bearing potential must test negative for
pregnancy at the time of screening based on a serum pregnancy test and reverified at the
time of enrollment based on a urine pregnancy test. Both male and female subjects of
reproductive potential must agree to use highly effective methods of birth control,
throughout the study.
27. Previously participated in LYR-210 Phase I clinical study or received an experimental
treatment in another clinical study within 5 half-lives of Screening visit.
28. Currently participating in an investigational drug or device study.
29. Determined by the Investigator as not suitable to be enrolled for reasons not already
specified if the health of the subject or the validity of the study outcomes may be
compromised.
Investigational Product, Dosage and Mode of Administration: 
The LYR-210 System is a combination product comprised of a single-use applicator, pre-loaded 
with the LYR-210 drug depot, an anti-inflammatory drug depot. The LYR-210 drug depot 
contains mometasone furoate (MF), an FDA-approved drug indicated for therapeutic and 
prophylactic management of seasonal and perennial allergic rhinitis (AR), nasal polyps, a 
phenotype of CS disease, as well as asthma. The LYR-210 drug depot is designed to gradually 
soften over time and made of bioabsorbable polymers that have been used as components of 
approved pharmaceutical drugs and/or medical devices.
Each LYR-210 drug depot contains a total MF dose of 2500 μg or 7500 μg [referred to as LYR-
210 (2500 μg) or LYR-210 (7500 μg), or LYR-210 for either dose in this document]. LYR-210
is intended to be administered bilaterally into the ESS-naïve middle meatus by an 
otolaryngologist under endoscopic visualization via the provided single use applicator. Once 
administered, each LYR-210 is designed to gradually deliver sustained doses of MF to the 
inflamed mucosal tissue over a 24-week resident time. Bilateral placement of LYR-210 (2500
μg) is designed to deliver a total dose of 5,000 μg MF over the 24 weeks, or an average daily 


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dose of 30 μg MF per human subject (or 15 μg MF per nostril).  In the case of LYR-210 (7500
μg), a total dose of 15,000 μg MF will be delivered over the 24 weeks with an average daily 
dose of 89 μg MF per human subject (or 45 μg MF per nostril). LYR-210 can be removed at 
24-weeks or earlier at the physician’s discretion using standard instruments.
The LYR-210 drug depot has a tubular braid configuration with a uniform diamond pattern 
throughout and an uncompressed dimension of 13 mm in diameter and 10 mm in length in its 
unconstrained state. It is designed to be self-retaining against the mucosal tissue to allow 
effective drug transfer for up to 24 weeks. The depot is comprised of a base structure and a drug 
formulation matrix. The base structure is composed of poly(L-lactide-co-glycolide) and poly(L-
lactide-co-ε-caprolactone) elastomer to provide 3-dimensional structure and elasticity. The drug 
formulation matrix consists of an active ingredient, MF, embedded in the inactive ingredients 
containing poly(L-lactide-co-ε-caprolactone) and poly(L-lactide) to control the release rate of 
MF. 
Duration of Study: 
The total duration of the study, including the enrollment period, is approximately 22 months. 
Each enrolled subject is planned to participate in the study for a total duration of approximately 
12 months, which includes the Screening/Washout, Treatment, and Post-treatment Follow-up
stages. The active treatment period will be 24 weeks. The end of the trial is defined as the date 
of the last EOS visit of the last subject of the study.
Statistical Methods:
Analysis Sets:
x
Safety (SAF) analysis set: All randomized subjects who received the study treatment
(Sham procedure or a dose of LYR-210) or treatment attempt on Day 1. Subjects will be
analyzed according to the treatment received or attempted. This is the primary analysis
set for assessment of safety.
x
Intention-to-treat (ITT) analysis set: All randomized subjects who received the study
treatment (Sham procedure or a dose of LYR-210) or treatment attempt on Day 1 and
have post-Day 1 assessments available. This is the primary analysis set for assessment of
efficacy. Subjects will be analyzed according to the treatment they were assigned to at
randomization.
x
Per-Protocol (PP) analysis set: All randomized subjects who received the study
treatment, have specific post-Day 1 assessments, and are without major protocol
deviations at the time of the primary analysis.
x
Pharmacokinetic (PK) analysis set: All SAF patients with at least one evaluable drug
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Data collected in this study will be presented using listings, as well as, summary tables and 
figures. Continuous data will be summarized by treatment group using the following descriptive 
statistics: the number of observations (n), mean, standard deviation, median, minimum and 
maximum). Categorical data will be summarized by treatment group as number and percentage 
of subjects in each category. Individual subject’s data will be presented in listings.
Subject Disposition and Demographic Characteristics:
Analysis set assignment will be summarized for all enrolled subjects by randomized treatment.
Subject disposition will be summarized for the ITT set. Demographics and other baseline 
characteristics and study drug exposure will be summarized for the SAF and ITT sets.
Safety Analyses:
Safety will be assessed through AEs and changes in laboratory tests, vital signs, morning serum 
cortisol levels, nasal endoscopy assessment, IOP and slit-lamp examination using the SAF set .
AEs will be coded by using the Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary. 
The number and percentage of subjects with incidence of the safety endpoints will be presented 
by treatment group, where subjects will be classified according to the treatment received. There 
will be no formal statistical tests comparing treatments on safety endpoints and there will be no 
imputation of missing data. 
Efficacy Analyses:
All efficacy analyses will be carried out after the last subject completes the Week 28 visit or 
withdraws prematurely prior to Week 28.
All efficacy endpoints will be assessed using the ITT (primary analysis population) and PP
analysis sets with available data for the endpoint.
For the primary efficacy endpoint (CFBL in the CS7DA4S score at Week 4) analysis, 
descriptive statistics will be presented for each treatment group. The null and alternative 
hypotheses to be tested are:
H0: μL2500 = μC
H0: μL7500 = μC
vs.
vs.
H1: μL2500 < μC
H1: μL7500 < μC
where μL2500, μL7500 and μC are true mean value of, the CFBL in the CS7DA4S score at Week 4
for the LYR-210 (2500 μg), LYR-210 (7500 μg) and sham procedure (control) groups, 
respectively. An analysis of covariance (ANCOVA) model for CFBL in CS7DA4S score at 
Week 4 will be used to determine which of the two null hypotheses stated above can be rejected. 
This ANCOVA model will include terms for baseline CSD7A4S score as a covariate and the  
fixed  effects of treatment group (LYR-210 7500 μg, LYR-210 2500 μg, sham procedure) and 


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the randomization stratification variables, presence of nasal allergy and presence of nasal 
polyps. 
Secondary analyses of efficacy endpoints will also be performed in subjects in the PP analysis 
set with available data.
To assess consistency of treatment difference across study region, descriptive statistics of the 
primary endpoint will be presented by treatment group within each region. All subgroups to be 
assessed for treatment effect consistency on the primary endpoint will be detailed in the formal 
SAP.
The key secondary endpoints and other non-key secondary and exploratory efficacy endpoints 
that are continuous variables will be compared in the same manner as the primary endpoint. For 
dichotomous efficacy endpoints treatments will be compared at each time point measured using 
logistic regression adjusting for relevant baseline value and the randomization strata variables 
and other baseline covariates to be specified in the formal SAP. Each secondary endpoint will 
be compared between each LYR-210 dose and sham at a one-sided 0.05 level of significance. 
There will be no adjustment of the significance level adjusting for multiple comparisons.
As further exploratory analyses comparing treatments on all endpoints measured over time, 
generalized estimating equation (GEE) linear regression (for continuous outcomes) and GEE 
logistic regression (for dichotomous outcomes) will be used to compare treatments over time.
Sample Size:
Per the null and alternative hypotheses described above, and under the assumptions that μC = -
1.30 and μL2500 and/or μL7500 = -3.00 (approximately 130% larger decrease than the assumed 
control mean of -1.3) and that the true SD within each treatment group is at most 2.4, then an 
evaluable sample size of 63 patients (21 per treatment group) yields 73% power to reject at least 
one null hypothesis in favor of the alternative at a one-sided 0.05 level of significance. An 
additional 6-9 patients will be enrolled to account for potential subject dropout.
Handling of Missing Data:
The primary analysis on the efficacy endpoints will be performed based on subjects in the ITT 
analysis set with available data. Additional secondary analysis will be performed using the
above ANCOVA model for all subjects in the ITT analysis set. Two imputation approaches will 
be carried out: (a) Last observation carried forward (LOCF) single imputation method; and (b) 
multiple imputation. This will be carried out on the primary endpoint and the key secondary 
endpoint of CFBL in CS7DA4S score at Week 24.
For remaining secondary efficacy endpoints, sensitivity analyses of continuous variable will be 
conducted on all ITT subjects where missing data are first imputed by LOCF prior to carrying 
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2.
INTRODUCTION
2.1
Chronic Sinusitis
Chronic sinusitis (CS), commonly referred as chronic rhinosinusitis (CRS) by the medical 
community, is a common condition defined by symptomatic inflammation of the paranasal 
sinuses lasting longer than 12 weeks. The cardinal symptoms of CS include nasal 
blockage/obstruction/congestion, facial pain/pressure, anterior/posterior nasal discharge, and 
reduction/loss of sense of smell [2, 3]. The underlying cause of CS-related symptoms is 
inflammation of mucosal tissue leading to impairment of mucociliary clearance. 
CS affects 10.9% European population [4] and 12.5% of the US population [5], and is the 5th most 
common condition in people under age 65 in the US [6]. CS results in 18 million annual office
visits [6], and the economic implications are at more than $9 billion each year in US alone [7]. The 
socioeconomic cost data outside of the US is limited, however, a 2002 randomized and 
controlled study by a university hospital in Netherland reported that, over a 24-week treatment 
period, the total direct and indirect treatment costs of a regular CS subject was €3661, and this 
number was as high as €8908 for a complicated CS subject [8].
Despite the high prevalence of the disease, no approved drug therapy for the treatment of CS is 
available. Evidence-based medical management supports the off-label use of an oral or topical 
corticosteroid therapy with or without antibiotics. The most common first-line therapy is topical 
intranasal corticosteroids (INCS) with adjunctive use of daily saline irrigation [9]. However, 
inefficient drug delivery to the inflamed mucosal tissues [10] and/or poor subject compliance limit 
the effectiveness of such therapy [11]. Second line medical therapy generally used for 
management of flare-ups and worsening inflammation or severe nasal polyps includes a short
course (1-3 weeks) of oral corticosteroids [2, 3]. While effective initially, improvements are not 
sustained for more than 3 months [12, 13]. Additionally, oral corticosteroids can lead to systemic 
side effects including mood disturbance, gastrointestinal issues, diabetes, cataracts, glaucoma, 
osteoporosis and rarely avascular necrosis of the hip and shoulder [14, 15]. Approximately half (40-
60%) of CS subjects do not benefit from this recommended medical regimen, and so become 
potential candidates for endoscopic sinus surgery (ESS) [16]. However, many surgical candidates 
opt out of surgical treatment [17].
2.2
Product Rationale
Mometasone furoate (MF) is a potent, topically active, anti-inflammatory corticosteroid drug 
indicated for both therapeutic and prophylactic management of seasonal and parenteral allergic 
rhinitis [18], nasal polyps [18], a phenotype of CS disease , as well as asthma [17]. Both rhinitis and 
sinusitis are characterized by an inflammation of the mucosal membrane of the sino-nasal
cavities. Despite the effectiveness of MF topical therapy in management of rhinitis and nasal 
polyposis, results from pharmacokinetic studies in adults and children suggest that systemic 
exposure to MF after intranasal administration is negligible, underscoring MF as an ideal choice 


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of safe drug for developing a new drug formulation for this group of underserved subject
population [19].
Drug-eluting drug delivery systems have demonstrated the ability to provide therapy directly at 
the local site of disease in a sustained fashion while eliminating systemic effects of the drug in 
many therapeutic areas[20, 21]. More recently, local drug delivery systems were approved by the 
FDA for CS subjects immediately following sinus surgery [22, 23] or subjects with recurrent 
polyposis post ESS procedure(s) [24, 25]. The American Rhinologic Society (ARS) endorsed the 
utilization of steroid-eluting drug delivery systems into the paranasal sinuses for their 
demonstrated improvement of subjects outcomes and limiting the need for oral steroids [26].
An ideal treatment for CS would provide local, sustained, anti-inflammatory drug delivery in 
subjects as an option, prior to sinus surgery. Such a therapy would be safe yet provide sustained 
drug delivery via a single administration. It would conform to irregularly shaped sino-nasal
cavities and maintain prolonged mucosal contact time with local drug absorption and minimal 
depletion. It would also allow easy removal at the end of treatment.
The LYR-210 System is a combination product comprised of a single-use applicator, pre-loaded 
with the LYR-210 drug depot, containing a total dose of 2500 μg or 7500 μg mometasone 
furoate [referred to as LYR-210 (2500 μg) or LYR-210 (7500 μg) or LYR-210 for either dose in 
this document]. LYR-210 is a miniaturized local drug delivery implant designed to fit within, 
and conform to, the confined space of a subject’s ESS-naïve middle meatus. LYR-210 consists 
of an active ingredient MF embedded in the inactive ingredients composed of bioabsorbable
polymers with a wide range of medical applications that aid in the controlled and sustained 
delivery of MF to the sino-nasal mucosal tissue from a single drug administration.
LYR-210 is intended to be administered bilaterally into the non-operated middle meatus by an 
otolaryngologist under endoscopic visualization via a provided single use applicator. The 
administration of LYR-210 is office-based and performed with topical anesthesia. Once 
administered, LYR-210 was designed to gradually release 2500 μg or 7500 μg of MF to the 
inflamed mucosal tissue over 24 weeks, from a single administration. Bilateral placement of 
LYR-210 (2500) μg is designed to deliver a total dose of 5000 μg MF over the 24 weeks, or an 
average daily dose of 30 μg MF per human subject (or 15 μg MF per nostril). In the case of 
LYR-210 (7500 μg), a total dose of 15000 μg MF will be delivered over the 24 weeks with an 
average daily dose of 89 μg MF per human subject (or 45 μg MF per nostril). LYR-210 can be 
removed at 24-weeks or earlier at the physician’s discretion using standard instruments.
2.3
Study Rationale
LYR-210 has undergone non-clinical safety assessments to demonstrate suitability for human 
study. A summary of non-clinical studies of LYR-210 is provided in Investigator Brochure (IB, 
Section 4.2). LYR-210 (2500 μg) was assessed in a multi-centered, prospective, open-label, 
single-arm study (clinicaltrials.gov ID: NCT02967731) in 20 adult CS subjects who had failed 


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previous medical management and have not undergone ESS. A summary of this Phase I study is 
provided in IB (Section 5).
The Phase I study concluded that LYR-210 (2500 μg) is safe and well-tolerated in ESS-naïve CS 
subjects and leads to sustained symptom improvement, measured by a CS disease specific 22-
item sino-nasal outcome test (SNOT-22) questionnaire [27], in subjects. These initial clinical 
experiences with LYR-210 (2500 μg) in CS subjects suggest encouraging clinical benefits 
without the need for surgery, while avoiding safety risks associated with prolonged oral steroid 
treatment. The main limitations in the Phase I study, however, include the small sample size and 
lack of a concurrent control group. Therefore, the potential contribution of a placebo effect is 
unknown. A larger clinical study which is randomized and blinded to a control will reduce the 
potential for treatment and assessment bias and will improve the veracity of detected safety and 
efficacy, particularly in the use of self-reported ePRO instruments for assessment of CS 
symptoms.
Additionally, CS subject symptom severity can be stratified with being “normal” defined on the 
SNOT-22 score as <8, “Mild” as 8-20 inclusive, “moderate” as >20-50 and “severe” as >50 [28].
After 24 weeks of treatment with LYR-210 (2500 μg), although 20% subject had achieved 
optimal “normal” symptom scores, some remained symptomatic (data on file with Lyra 
Therapeutics). These results indicate room for further symptom reduction in more subjects, 
possibly with more optimal drug dosing.
Lyra Therapeutics is conducting a global, multicenter study in a randomized, sham procedure-
controlled, parallel-group, subject-blinded fashion in approximately 70 adults CS subjects who 
have failed previous medical management and have not undergone ESS. Subjects enrolled in the 
study will include patients who have not had ESS but their symptoms are not adequately 
controlled on medical management and are seeking further treatment. This may include patients 
who are considering sinus surgery or those who have decided against it. The efficacy and safety 
of LYR-210 (2500 μg) and LYR-210 (7500 μg) versus a sham procedure control will be 
assessed. Additionally, LYR-210 (2500 μg) and LYR-210 (7500 μg) will be compared to 
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3.
STUDY OBJECTIVES AND ENDPOINTS
The study objectives and endpoints are:
Study Objectives
Endpoints
Primary
To evaluate the efficacy of LYR-
210 in improving the composite 
score of 7-day average scores of 
4 CS cardinal symptoms 
(CS7DA4S) at Week 4
- Change from baseline (CFBL) in CS7DA4S score at
Week 4
The 4 CS cardinal symptoms include nasal
blockage/obstruction/congestion, facial pain/pressure,
reduction/loss of sense of smell, and anterior/posterior
nasal discharge. Each symptom is scored on a 0-3 scale
as follows: 0 = none, 1 = mild, 2 = moderate, and 3 =
severe.
Key Secondary
To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score at end of treatment 
- CFBL in CS7DA4S score at Week 24
To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- Percentage of subjects with at least 1-point decrease in
the bilateral Zinreich score in at least 1 pair of the
anterior ethmoid, maxillary, posterior ethmoid, frontal, or
sphenoid sinuses at Week 24
Each sinus is scored on a 0-5 scale per the Zinreich
modified Lund-Mackay scoring system and based on the
percentage of opacification as follows: 0 = 0%, 1 = 1%
to 25%, 2 = 26% to 50%, 3 = 51% to 75%, 4 = 76 % to
99%, and 5 = 100% or completely occluded.
To evaluate the time to treatment 
failure 
- Time to treatment failure
A treatment failure is defined as, after subject
enrollment, subject being recommended by treating
physician for oral corticosteroid or ESS due to
worsening of CS symptoms, or the subject complaint of
persistent CS symptoms with an average CS7DA4S score
over the preceding 30 days greater than or equal to the
Baseline CS7DA4S score.
Other Secondary


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To evaluate the safety and 
tolerability of LYR-210
- Severity and percentage of subjects reporting treatment-
emergent adverse events (TEAEs) and serious adverse
events (TESAEs) through Weeks 2, 4, 12, and 24
- Severity and percentage of subjects reporting Day 1
administration procedure and Week 24 removal
procedure related AEs and SAEs
- Severity and percentage of subjects reporting product
related AEs and SAEs on Day 1 and through Weeks 2, 4,
12, and 24
- Percentage of subjects with clinically significant
abnormal and clinically significant abnormal laboratory
values (hematology and chemistry, vital signs) on Day 1
and at Weeks 4, 12, and 24
- Morning serum cortisol levels on Day 1 and at Weeks 4,
12, and 24
- Severity and percentage of subjects with adverse nasal
endoscopic findings and adverse nasal endoscopic
findings requiring medical treatment in one or both
nostrils on Day 1 and at Weeks 2, 4, 12, and 24
- Percentage of subjects with elevated intraocular pressure
(IOP) in one or both eyes at Weeks 4, 12, and 24
- Percentage of subjects with a clinically significant
increase of IOP at Weeks 4, 12, and 24
A clinically significant increase of IOP is defined as IOP
in one or both eyes > 28 mmHg or an increase of IOP
from Baseline in one or both eyes >= 10 mmHg.
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 24
To evaluate the time to onset of 
action of LYR-210
- Time to onset of action
Time to onset of action is defined as, within the first 30
days, the time when all subsequent mean CFBL in the
CS7DA4S score of the LYR-210 is statistically
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To evaluate the efficacy of LYR-
210 in improving CS7DA4S 
score and the 7-day average score 
of each of the 4 cardinal CS 
symptoms
- CFBL in the CS7DA4S score at Weeks 8, 12, 16, and 20
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, and anterior/posterior nasal
discharge at Weeks 1, 2, 3, 4, 8, 12, 16, 20, and 24
To evaluate the effect of LYR-
210 in improving CS disease-
specific quality of life as per 22-
item sino-nasal outcome test 
(SNOT-22) questionnaire 
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 2, 4, 8, 12, 16,
20, and 24
To evaluate the effect of LYR-
210 in reducing sinus 
inflammation as per magnetic 
resonance imaging (MRI)
- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus and
OMC pairs at Week 24
- CFBL in total Zinreich score at Week 24
To evaluate the effect of LYR-
210 in reducing subjects’ needs 
for medical or surgical treatment 
for CS
- Percentage of subjects with use of oral antibiotics for CS
through Weeks 4, 8, 12, 16, 20, and 24
- Percentage of subjects with use of oral corticosteroid for
CS through Weeks 4, 8, 12, 16, 20, and 24
- Percentage of subjects with use of intranasal
corticosteroid sprays for CS through Weeks 4, 8, 12, 16,
20, and 24
- Percentage of subjects being recommended by treating
physician for ESS through Weeks 4, 8, 12, 16, 20, and 24
To evaluate the pharmacokinetics 
of LYR-210
- Plasma MF concentrations at Days 3, 7, 14, 21 and
Weeks 4, 12, 24
Plasma PK samples at Days 3, 7, 14, 21 will only be
measured in approximately 15 randomized and
successfully enrolled subjects at US sites.
To evaluate the effect of LYR-
210 in improving subjects’
general quality of life as per 36-
item short form health survey 
version 2 (SF-36v2)
questionnaire
- CFBL in SF-36v2 physical health, mental health, and
domain scores at Week 24


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To evaluate LYR-210 in 
improving smell function
assessed by the University of 
Pennsylvania Smell Identification 
Test (UPSITTM)
- CFBL in UPSIT score at Week 24
Exploratory 
To evaluate the percentage of
subjects experiencing acute 
exacerbations of CS (AECS) 
- Percentage of subjects experiencing AECS through
Weeks 4, 8, 12, 16, 20, and 24
AECS is defined as a sudden worsening of symptoms in a
subject resulting in the treating physician reporting an
escalation of treatment.
To assess effect of LYR-210 in 
reducing polyp severity within 
middle meatus in subgroup of CS 
subjects with nasal polyps 
(CSwNP)
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
subjects at Week 24
To assess efficacy of LYR-210 in 
improving CS7DA4S score, the 
7-day average score of each of 4
CS cardinal symptoms, the
SNOT-22 total and subdomain
scores, and the SF-36v2 physical
health, mental health, and domain
scores in the subgroups of CS
subjects without nasal polyps
(CSsNP) and CSwNP subjects
- CFBL in the CS7DA4S score at Weeks 1, 2, 3, 4, 8, 12,
16, 20, and 24
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal
discharge in CSsNP and CSwNP subjects at Weeks 1, 2,
3, 4, 8, 12, 16, 20, and 24
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores in CSsNP and CSwNP
subjects at Weeks 2, 4, 8, 12, 16, 20, and 24
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores in CSsNP and CSwNP
subjects at Week 24
To assess efficacy of LYR-210 in 
reducing sinus inflammation in 
CSsNP and CSwNP subjects 
- Percentage of subjects with at least 1 point of decrease in
the bilateral Zinreich score in at least 1 pair of the
posterior ethmoid, frontal, or sphenoid sinuses in CSsNP
and CSwNP subjects at Week 24


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- CFBL in bilateral Zinreich scores of posterior ethmoid,
frontal, sphenoid, maxillary, anterior ethmoid sinus, and
OMC pairs in CSsNP and CSwNP subjects at Week 24
- CFBL in total Zinreich score at in CSsNP and CSwNP
subjects Week 24
To assess effect of LYR-210 in 
improving smell function in 
CSsNP and CSwNP subjects 
- CFBL in UPSIT score in CSsNP and CSwNP subjects at
Week 24
To assess the safety of subjects 
post LYR-210 treatment
- Severity and percentage of subjects reporting AEs and
SAEs through Week 28 and Week 48
- Percentage of subjects with abnormal and clinically
significant abnormal laboratory values (hematology and
chemistry, vital signs) at Week 28
- Morning serum cortisol levels at Week 28
- Plasma MF concentration at Week 28
- Severity and percentage of subjects with adverse nasal
endoscopic findings and adverse nasal endoscopic
findings requiring medical treatment in one or both
nostrils at Week 28
- Percentage of subjects with elevated IOP in one or both
eyes at Week 48
- Percentage of subjects with a clinically significant
increase of IOP at Week 48
- Percentage of subjects with newly identified or worsened
cataract in one or both eyes by slit-lamp examination at
Week 48
To assess the durability of 
efficacy post LYR-210 treatment
- Percentage of subjects with improvement from Baseline
in nasal polyp severity within middle meatus in CSwNP
subjects at Week 28
- CFBL in the CS7DA4S score at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in 7-day average score of nasal
blockage/obstruction/congestion, reduction/loss of sense
of smell, facial pain/pressure, anterior/posterior nasal


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discharge in CSsNP and CSwNP subjects at Weeks 28, 
32, 36, 40, 44, and 48    
- CFBL in total SNOT-22 score and SNOT-22 rhinologic,
extra-nasal rhinologic, ear-facial, sleep dysfunction, and
psychological subdomain scores at Weeks 28, 32, 36, 40,
44, and 48
- CFBL in SF-36v2 physical health, mental health, and
each of the health domain scores at Week 48


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4.
INVESTIGATIONAL PLAN
4.1
Overall Study Design
This global, multicenter study will be conducted in a randomized, sham procedure-controlled, 
parallel-group, subject-blinded fashion in approximately 70 adults CS subjects who have failed 
previous medical management and have not undergone ESS. Subjects enrolled in the study will 
include patients who have not had ESS but their symptoms are not adequately controlled on 
medical management and are seeking further treatment. This may include patients who are 
considering sinus surgery or those who have decided against it. The efficacy and safety of LYR 
210 (2500 μg) and LYR-210 (7500 μg) versus a sham procedure only control will be assessed. 
Additionally, the study results of LYR-210 (2500 μg) and LYR-210 (7500 μg) will be compared 
to evaluate dose related responses.
The study will consist of three stages: 
x
Screening and Washout Stage: 2 - 4 weeks
x
Randomized and Blinded Treatment Stage: 24 weeks
x
Blinded Post-Treatment Follow-Up Stage: 24 weeks
The overall flow diagram of subject enrollment and follow up schedule is shown in Figure 1.
Figure 1:
Study Design Schematic


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4.1.1
Screening Stage
After providing written informed consent, subjects who are qualified to participate in this study 
will have an initial Screening visit. Immediately following the initial Screening visit, subjects
will undergo a minimum of 2-week but a maximum of 4-week washout period. During this 
washout period, subjects will receive no active treatment for CS but are recommended to start 
daily saline irrigation twice a day. Subjects will be provided with saline and instructions for daily 
intranasal saline irrigations while participating in the study.
Medications that are prohibited during the washout period (and during the study) are listed in 
Section 6.4.2. Beginning at least 7 days prior to Day 1 visit, subjects will record the severity of 
the 4 cardinal symptoms of CS and the use of saline irrigation each day in the morning on the 
electronic subject reported outcomes (ePRO) questionnaire.
4.1.2
Treatment Stage
The total duration of the Treatment Stage will be 24 weeks. Subjects who complete the study 
Screening assessments and the washout period and meet all eligibility criteria on Day 1 will be 
stratified according to the presence or absence of nasal allergy and nasal polyps and, then, 
randomized in a 1:1:1 ratio to receive LYR-210 (2500 μg), LYR-210 (7500 μg), or sham 
procedure. Subjects who are assigned to the experimental arms will have the LYR-210
administered bilaterally into the middle meatus (Section 6.2) and, then, removed at Week 24
(Section 6.5). Subjects who are assigned to the sham procedure arm, will undergo bilateral mock 
administration (i.e., sham procedure) on Day 1. Enrolled subjects will undergo scheduled study 
visits at Weeks 2, 4, 12, and 24 during the treatment duration. Subjects will receive phone 
follow-ups at Weeks 8, 16, and 20 to record AEs and concomitant medications/procedures that 
they have had since last follow-up assessment. [NOTE: Female subjects of childbearing potential 
will be asked to return to the clinic for urine pregnancy test at Weeks 8, 16, and 20.] All subjects
will remain blinded and undergo the assessments and procedures scheduled for these visits 
(Section 8.1).
At the Week 24 visit, all subjects will return to clinic for the end-of-treatment (EOT) visit 
assessments. Subjects who receive LYR-210 will have bilateral depot removed using standard 
surgical tools. Sham control subjects will undergo a sham removal procedure to remain blinded.
If medically warranted per the treating physician’s discretion (for example, needing an ESS as 
rescue treatment), early depot removal before the schedule EOT visit at Week 24 may be 
performed at an unscheduled early-termination (ET) visit (an unscheduled EOT visit). Any 
subject who undergoes an ET visit is required to complete the assessments scheduled for the 
Week 24/EOT visit, and all safety follow up visits post treatment.
If spontaneous dislodgement of LYR-210 occurs before Week 24 in subjects who receive either 
dose of LYR-210, subjects are required to call the study clinic immediately to report the event. If


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a subject experiences a dislodgement of one of the two LYR-210 depots, the subject will 
continue the study treatment unless an early treatment discontinuation is recommended by the 
treating physician or subject requests depot removal from the remaining side of the nose. If 
depots spontaneously dislodge from both sides of the nose, subject will complete Week 24/EOT 
assessments and subsequently, the post-treatment follow-up stage.
4.1.3
Post-Treatment Follow-Up Stage
After the Week 24/EOT visit, all enrolled subjects will undergo a blinded Post-treatment Follow-
up Stage that will be approximately 24 weeks. Subjects will have 2 additional scheduled safety 
follow up visits, the Week 28 and a final Week 48/EOS visit. Subjects will receive phone follow-
ups at Weeks 32, 36, 40, and 44 to record AE and concomitant medications/procedures that they 
have had since last follow-up assessment. Except for the cases of depot dislodgement, subjects
should remain blinded until the study database is locked.
4.1.4
End of the Trial
The end of the trial is defined as the date of the last EOS visit of the last subject of the study.
4.2
Rationale for Study Design
The goal of treatment is to reduce the symptoms of adult CS with a well-tolerated product. The 
study design and endpoints are adequate for assessment of safety and efficacy of LYR-210 in the 
context of a Phase II study of subjects with CS. Blinding and randomization will reduce the 
potential for treatment and assessment bias and will improve the veracity of detected safety and 
efficacy, particularly in the use of self-reported ePRO instruments for assessment of CS
symptoms. The parallel arm study design and 1:1:1 randomization scheme of LYR-210
(2500 μg): LYR-210 (7500 μg): sham procedure permits adequate statistical comparison of 
groups for efficacy assessment and safety signal detection. The ePRO of daily morning cardinal 
symptoms and the SNOT-22 subject reporting instruments have been selected because they are 
specific to the subject population to be enrolled in this study. Other efficacy endpoints involving 
objective changes in the sino-nasal cavities (i.e., inflammation and polyps), smell dysfunction 
improvement, and general quality of life improvement are appropriate for development and 
further refinement of study endpoints in the clinical program. Although MF is well-characterized 
as a treatment in other indications, chronic assessments of local nasal and ophthalmologic 
parameters in this study’s CS population and in the context of in situ delivery via drug-depot are 
appropriate for associating safety results with local MF levels. Summarized in Section 9.1 is the 
safety rationale for the selection of drug doses and polymers in LYR-210 in this Phase II study.
4.3
Discontinuation of Study Subjects
Subjects will be encouraged to complete the study through the treatment and post-treatment 
follow up periods. Each subject is free to discontinue from the study at any time, for any reason, 
and without penalty or loss of benefit. Participation in the study treatment may be discontinued 
for any of the following reasons:


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x
Occurrence of any medical condition or circumstance that exposes the subject to
substantial risk and/or does not allow the subject to adhere to the requirements of the
protocol, including early removal of LYR-210 (Section 6.5).
x
Any serious AE (SAE, Section 8.4.9.2), clinically significant AE, severe laboratory
abnormality, intercurrent illness, or other medical condition that indicates to the
Investigator that continued participation is not in the best interest of the subject.
x
Subject’s decision to withdraw.
x
Requiring ESS as rescue treatment.
x
If deviations to the use of prohibited medications occur after randomization and study
treatment, the Investigator in consultation with the Sponsor and Sponsor’s medical
monitor will decide on a case-by-case basis whether the subject may continue in the
study based on the time the prohibited medication was administered and its
pharmacology.
x
Subject’s failure to comply with protocol requirements or study related procedures.
x
Termination of the study by the Sponsor or a regulatory authority that has provided
approval to proceed.
Subjects who withdraw or are withdrawn from the study treatment will be requested to return to 
the clinic for the assessments and procedures scheduled for the EOT visit and the safety follow 
up visits post EOT (Section 8.1).
The Investigator or study staff will document the reason(s) for subject discontinuation on the 
Case Report form (CRF), notify the IRB/EC as required by their Institution’s procedures, and 
notify the Sponsor the reason for discontinuation.
4.4
Criteria for Study Termination
If the Sponsor, the Investigator, the medical monitor, the data monitoring committee (DMC), 
Institutional Review Board (IRB)/Ethics Committee (EC), and/or appropriate regulatory officials 
discover conditions arising during the study that indicate the study should be halted or that the 
study center should be terminated, appropriate action may be taken after consultation among (at 
a minimum) the Sponsor, the IRB/EC, and the medical monitor. Refer to Section 11.13 for
additional information.
4.5
Data Monitoring Committee (DMC)
An independent DMC will be formed by charter to assist in examining safety data periodically 
during the study and will include independent physicians with appropriate experience of clinical 
trials but who are not participating in this study. The DMC will:
x
Review the safety and tolerability data at predefined time points. The first study level
safety review will occur after the 30th subject has completed 4 weeks of treatment or
early terminated from the study, whichever occurs first. A second safety review will
occur after all enrolled subjects have completed the Week 4 follow-up. The timing
and details of subsequent data review will be detailed in the DMC charter.


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x
Review the safety data at ad hoc time points if significant safety concerns are
identified during the study.
x
Review events that may impact subject continuation and make recommendations
regarding study progression.
x
Review any other data, as appropriate.
The membership, responsibilities and operating procedures of the DMC will be described in a
DMC Charter.


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5.
SELECTION OF SUBJECTS
5.1
Subject Screening
All subjects evaluated for participation in this study will be screened for study eligibility. A 
delegated member of the Institution’s research team will review the subject’s medical history to 
screen for study eligibility. All subjects who meet initial eligibility requirements will be asked to 
participate in the study. Each subject will indicate his or her willingness to participate in the 
study by signing an IRB/EC-approved informed consent form (ICF).
Each subject will be assigned a unique subject identification number upon signing informed 
consent. Subjects who are assigned a subject ID but do not meet the eligibility criteria will be 
considered Screen Failures. 
If the Investigator believes rescreening is warranted, a subject can be rescreened upon 
consultation with the study Medical Monitor or study Sponsor. Subject numbers assigned to 
subjects who fail screening should not be reused. Investigators must account for all subjects who 
sign an ICF. If the subject is found to be not eligible at this visit, the investigator/designee should 
still complete the applicable electronic case report forms (eCRF).
5.2
Subject Informed Consent
Prior to enrollment in the study, all subjects must review and complete an IRB/EC-approved 
ICF. All potential subjects must complete the consent process prior to undergoing procedures 
performed specifically for this study that are outside the standard of care for the institution. 
Failure to obtain a signed ICF renders the subject ineligible for the study. Sites will comply with 
ICH Guidelines for obtaining informed consent.
5.3
Inclusion Criteria
A subject must meet all of the following criteria to be eligible for this study:
1. Age ≥18.
2. A CS subject who
a.
has twelve weeks or longer of two or more of the following symptoms:
• nasal blockage/obstruction/congestion
• nasal discharge (anterior, posterior, or both)
• facial pain/pressure
• reduction/loss of sense of smell
and one or more of the following findings:
• evidence of inflammation within paranasal sinuses or ostiomeatal complex
on MRI


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• evidence of purulence coming from paranasal sinuses or ostiomeatal
complex
• nasal polyps
b.
has a composite score of 7-day average scores of 4 CS cardinal symptoms [2, 3]
(CS7DA4S) ≥7 (0-3 scale for each of the symptoms) at Day 1 visit, and
c.
has had at least two trials of medical treatments in the past, one of which must
include intranasal corticosteroid sprays (INCS) for a minimum of 4 weeks.
3. Must be able to cease treatment with intranasal corticosteroid and decongestant
sprays at Screening.
4. Ability to tolerate topical anesthesia.
5. Has been informed of the nature of the study and has provided written informed
consent as approved by the IRB/ EC of the respective clinical site or regulatory
authority if applicable by national law.
6. Agrees to comply with all study requirements.
5.4
Exclusion Criteria
A subject who meets any of the following criteria will be excluded from this study:
1. With previous balloon sinuplasty or any endo-nasal surgery (including sinus surgery),
except for septoplasty or surgical manipulation to nasal turbinates more than 6
months prior to the Screening visit.
2. Seasonal allergic rhinitis (SAR) subjects with symptoms and/or, based on time of
year, would anticipate onset of symptoms within 4 weeks of randomization.
3. Perennial allergic rhinitis (PAR) subjects whose symptoms are well controlled by
regular use of intranasal corticosteroids.
4. With severe asthma or with one or more exacerbations of asthma requiring systemic
corticosteroid use within the 6 months prior to the Screening visit. Subjects with
moderate or severe asthma will also be excluded if they have not been on a stable
regimen of inhaled corticosteroids for asthma for a minimum of 3 months prior to the
Screening visit.
5.
Endoscopic exclusion criteria:
a. Complete/near complete middle meatal obstruction preventing proper placement
and/or visualization of LYR-210.
b. Evidence of mucosal erosion or ulceration.
c. Ongoing nasal infection.
d. Evidence of nasal septal perforation.
6. MRI exclusion criteria:
a.
A bilateral Zinreich score < 4 in all 3 pairs of the posterior ethmoid, frontal, or
sphenoid sinuses (0-5 scale for each of the sinuses) on Screening MRI.


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b. Anatomic variation which, in the opinion of the Investigator, would adversely
impact placement of LYR-210.
c.
Structural, non-inflammatory related CS (e.g., large concha bullosa, tumor).
d. Sinus disease extended into orbital or intracranial space.
e.
Evidence of mycetoma/fungal ball, allergic fungal rhinosinusitis.
f.
Sinus mucocele.
7. History or clinical evidence or suspicion of invasive fungal sinusitis, allergic fungal
rhinosinusitis, or atrophic rhinitis.
8. Known history of hypersensitivity or intolerance to corticosteroids.
9. Oral-steroid or monoclonal antibody (Xolair, Nucala) dependent condition.
10. Having had systemic corticosteroids within 1 month prior to Screening visit.
11. Known history of hypothalamic pituitary adrenal axial dysfunction or having a
clinically significant out of normal range morning serum cortisol level at screening.
12. Previous pituitary or adrenal surgery.
13. Has had more than 1 episode of epistaxis with frank bleeding requiring medical
attention within 2 months of Screening visit or more than 1 episode of epistaxis with
frank bleeding within 1 month of Screening visit.
14. Has had acute exacerbation of nasal allergy or chronic sinusitis, upper respiratory
tract infection (URTI), or common cold within 4 weeks of the Screening visit.
15. Had dental procedure/implant on maxillary dentition within 4 weeks of the Screening
visit.
16. Has past or present acute or chronic intracranial or orbital complications of CS (e.g.,
brain abscess, related problems with eyes or central nervous system).
17. History or diagnosis (in either eye) of glaucoma or ocular hypertension (IOP > 21
mmHg).
18. With prior cataract surgery or presence (in either eye) of posterior subcapsular
cataract of grade 2 or higher, nuclear sclerosis of grade 3 or higher, or cortical
cataract of grade 2 or higher or involving a minimum of center optic zone of 3 mm
diameter.
19. Past or present functional vision in only one eye.
20. Diagnosed with ongoing rhinitis medicamentosa.
21. Known history of immune dysfunction including immune deficiency (IgG subclass
deficiency or IgA deficiency) or autoimmune disease (e.g., Wegener’s
granulomatosis, sarcoidosis).
22. Past, present, or planned organ transplant or chemotherapy with immunosuppression.
23. History or diagnosis of ciliary dysfunction (e.g., cystic fibrosis, primary ciliary
dyskinesia [Kartagener syndrome]).
24. Past or present systemic vasculitis (e.g., granulomatosis with polyangiitis).


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25. Evidence of disease or condition expected to compromise survival or ability to
complete follow-up assessments.
26. Pregnant or breast feeding. Females of child-bearing potential must test negative for
pregnancy at the time of screening based on a serum pregnancy test and reverified at
the time of enrollment based on a urine pregnancy test. Both male and female
subjects of reproductive potential must agree to use highly effective methods of birth
control, throughout the study.
27. Previously participated in LYR-210 Phase I clinical study or received an
experimental treatment in another clinical study within 5 half-lives of Screening visit.
28. Currently participating in an investigational drug or device study.
29. Determined by the Investigator as not suitable to be enrolled for reasons not already
specified if the health of the subject or the validity of the study outcomes may be
compromised.


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6.
TREATMENT OF SUBJECTS
6.1
Randomization
Subjects who complete the study Screening assessments and the washout period, and meet all
eligibility criteria on Day 1 will be, before any treatment, randomized in a 1:1:1 ratio to one of 
the following study arms: 
x
Arm 1: bilateral administration of LYR-210 (2500 μg)
x
Arm 2: bilateral administration of LYR-210 (7500 μg)
x
Control Arm: bilateral sham procedure
Subjects will be stratified for treatment assignment according to the following criteria:
x
Nasal allergy (Yes vs No)
x
Nasal polyps (Yes vs No)
For any reason, if the Investigator is unable to successfully administer LYR-210 or perform 
sham procedure into both middle meatuses in a subject (as described in Section 6.2), this subject 
will be considered as an Enrollment Failure.
Randomization will be conducted using Interactive Response Technology (IRT) and treatment 
will be assigned according to a randomization scheme generated by the Sponsor’s unblinded 
biostatistician. The person generating the randomization scheme will not be involved in the 
collection, review, and/or analysis of study data before database lock and unblinding.
6.2
Study Product Administration
6.2.1
Pre-procedure Medication
Prior to LYR-210 administration or the sham procedure, all subjects will receive topical 
anesthetic and decongestant sprays for endoscopic assessment. Subjects will further receive 
anesthetic and decongestant soaked cottonoids or pledgets in each nostril to prepare the middle 
meatus for the study product insertion procedure.
6.2.2
Study Product Preparation
LYR-210 and the sham procedure article will be provided to the study site as described in 
Section 7.2.1. Preparation of LYR-210 or the sham procedure article should be performed in 
accordance with the instructions of use (IFU) provided in a separate document and should not 
start until the subject has been prepared and is ready for the administration procedure.
6.2.3
Study Product Administration
LYR-210 is designed to be administered intranasally under endoscopy visualization. Subjects 
who are assigned to either dose of LYR-210 will have LYR-210 administered bilaterally into the 
middle meatus. Subjects who are assigned to the sham procedure arm, will undergo bilateral 
mock administration (i.e., sham procedure), consisting of a bilateral insertion of an applicator 


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(without LYR-210 loaded) into the middle meatus until the applicator tip touches the ethmoid 
bulla for a minimum of 20 seconds, followed by withdrawal of the applicator. To maintain 
subject blinding to the treatment assignment, each subject will wear an eye mask (i.e., blindfold) 
at the time of the LYR-210 administration/sham procedure. An independent, unblinded case 
manager may be present during day 1 visit to assist product administration.
Following administration procedure, all enrolled subjects will rest for at least 1 hour and be 
monitored to ensure there is no epistaxis that requires medical attention.
6.2.4
Enrollment Failure
The Investigator will be allowed up to two attempts at LYR-210 administration or at the sham 
procedure per side. A treatment attempt is defined as that an applicator of a LYR-210 or sham
article is inserted to a subject’s left or right nostril for an attempt of investigational product
administration. If the Investigator is unable to administer LYR-210 bilaterally or perform sham 
procedure successfully into both middle meatuses of a subject, the Investigator will remove any
LYR-210 already administered and treat the subject with any appropriate therapy, if necessary. 
The subject will be considered as an Enrollment Failure as described in Section 6.1. Subjects
will be followed within 7 (± 2) days via telephone for AE and concomitant medication 
assessment.
6.2.5
End of Day 1 Visit
Prior to discharge at Day 1 visit, all enrolled subjects will be provided with clear instructions and 
the following reminders:
x
That they are currently enrolled in an investigational study for up to 12 months.
x
To avoid nose blowing for the rest of the day post-procedure.
x
To wipe or gently blow their nose during the treatment stage.
x
To sneeze with mouth open to avoid over-pressurization to the nose.
x
To call the study clinic if they have any unexpected epistaxis.
x
To call the study clinic immediately should the subject experience severe discomfort
or if LYR-210 falls out of the nose.  If this occurs - instruct subject to retain the depot
(place in a plastic bag/vial and store in a freezer if possible) and return to the clinic at
the next clinic visit.
6.3
Blinding
Except for the cases of spontaneous depot dislodgement, subjects should remain blinded to their 
treatment assignment (LYR-210 or sham) until the final study database is locked. To maintain 
subject blinded (LYR-210 or sham), each subject will wear an eye mask (i.e., blindfold) at the 
time of the LYR-210 administration/sham procedure and at all post Day 1 visits (scheduled or 
unscheduled) if an endoscopy assessment is performed.


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The investigational site staff will be blinded regarding the impending treatment assignment until 
after a study subject has completed all baseline assessments required on Day 1 visit (Section 8.1)
prior to randomization assignment. After randomization assignment, the investigational site staff, 
including the Investigator and study coordinator, will be unblinded as to whether the subjects 
receive LYR-210 administration or sham procedure. The study clinic staff, including the 
Investigator and study coordinator, will be blinded as to the dose administered to subjects 
receiving LYR-210.
The Sponsor will be blinded to subjects’ study treatment assignments until database lock for the 
primary data analysis after all enrolled subjects have completed Week 28 visit or withdrawn 
from study, whichever comes first.
6.3.1
Procedures for Breaking the Blind Prior to Study Completion
Breaking the blind is expressly forbidden except in the event of spontaneous dislodgment of
LYR-210, or a medical emergency where the identity of the treatment assignment must be 
known in order to properly treat the subject. If breaking the blind is required because of a 
medical emergency, decision to unblind lies solely with the investigator.
In all cases where the code is broken, the Investigator must record the date and reason for code 
breaking. The unblinding should be noted in the subject’s eCRF. 
6.3.2
Revealing Randomization
In the absence of a medical emergency or inadvertent unblinding due to depot dislodgement, the 
blinded randomization for this study will not be revealed until all data are entered in the 
database, edit checks are performed, queries are closed, CRFs are signed by the Investigator at
each site, and the database is officially locked per study unblinding plan.
6.4
Prior and Concomitant Medications
Subjects participating in the study are free to use any appropriate concomitant medications if 
medically warranted per treating physician’s discretion. However, a standardized concomitant 
medications regimen is recommended during the washout and treatment stages to avoid 
confounding the efficacy or safety assessments of LYR-210.
All medications taken by subjects during the course of the study will be recorded. 
6.4.1
Prior Medications
Beginning at Screening, all medications and other treatments taken by subjects will be recorded 
on the CRF. In addition, all subjects will be required to refrain from use of prohibited 
medications (Section 6.4.2) beginning at Screening.
Subjects may be permitted to continue medications that do not meet exclusionary criteria (see 
also Section 6.4.3). If any additional concomitant medications are to be administered during the 
study, or a dose adjustment is required for any existing concomitant medication, the Investigator 


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should contact the Sponsor’s medical monitor for approval prior to administration, provided the 
safety of the subject would not be compromised.
6.4.2
Prohibited Concomitant Medications
The following medication that could potentially affect symptoms of CS or the safety assessment 
of LYR-210 will not be allowed during the Screening and washout period or during the treatment 
stage:
x
Oral/ocular/intramuscular/intravenous/intranasal corticosteroids (except for oral or
intranasal corticosteroids permitted as rescue medication only);
x
Anti-allergy medications, including: first generation antihistamines; leukotriene receptor
antagonists, nasal cromolyn sodium or sodium cromoglycate, nedocromil sodium,
atropine, ipratropium bromide, or guaifenesin;
x
Oral decongestants;
x
Inhaled anti-cholinergic medications (except for a stable regimen for chronic obstructive
pulmonary disease (COPD) subjects);
x
Any monoclonal antibody;
x
Any potent cytochrome P-450 3A4 (CYP3A4) inhibitors (ketoconazole and ritonavir);
x
Any allergen immunotherapy (except for a stable dose and regimen);
x
Oral anti-fungal medication.
Subjects who received prohibited medications will be considered a protocol deviation and may 
require withdrawal from the study as detailed in Section 4.3.
6.4.3
Permitted Concomitant Medications
At the discretion of the Investigator, the following concomitant medications may be used in 
accordance with the restrictions described for each treatment:
x
All subjects will be provided with saline and instructions for daily intranasal saline
irrigation twice a day starting from washout till Week 24/EOT.
x
If a sinus infection is suspected at any time during the study, treatment with antibiotics
will be allowed after a clinic visit and per Investigator’s judgment.
x
Subjects who have been on a stable regimen of inhaled corticosteroids for asthma for a
minimum of 3 months prior to the Screening visit should remain on the same dosage
throughout the study. Inhaled corticosteroid use must be limited to a stable low- or
medium-dose as defined by guidelines established by the 2018 Global Initiative for
Asthma Management and Prevention [1].
x
Perennial allergic rhinitis (PAR) subjects who have been on a stable regimen of a
non-sedating oral antihistamine for a minimum of 3 months prior to the Screening visit
should remain on the same dosage throughout the study.


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6.4.4
Rescue Concomitant Medications and Treatment
The following rescue medications are recommended in the event of an acute exacerbation of the 
following conditions that result in the subject contacting the Investigator who determines an 
initiation of rescue therapy:
x
Any time during the 24-week treatment stage:
- After a clinic visit and per Investigator’s judgment, antibiotics for sinus infection.
- After a clinical visit and evaluation for worsening or uncontrolled severe CS
symptoms, the Investigator using his/her best judgement may give a course of oral
corticosteroids. Typical indications include persistent sinus infection after an initial
course of antibiotics while starting another course of antibiotics, uncontrolled sinus
inflammation not responding to an INCS, or a flare-up of asthma. The rationale for
the use of oral corticosteroid must be recorded.
x
After the Week 4 visit only:
- For acute allergic symptoms: non-sedating oral antihistamine such as loratadine
(10 mg per day) or equivalent.
- For severe acute nasal blockage (score of 2 or more over the past 3 days): a course of
oxymetazoline spray for a maximum of 3 consecutive days and a total maximum of
10 days during the treatment period. Oxymetazoline cannot be used within 24 hours
before MRI assessments.
- For worsening CS symptoms: intranasal MF sprays with dose and duration per
Investigator’s recommendation.
- For worsening or uncontrolled severe CS symptoms: ESS as rescue treatment per
Investigator’s recommendation.
6.5
Removal Procedure
Subjects who receive LYR-210 will have the bilateral drug depots removed at the Week 24/EOT
visit or earlier in an Unscheduled early termination (ET) visit if medically warranted per the 
treating physician’s discretion (for example, requiring an ESS as rescue treatment). The removal 
procedure will be performed under endoscopic visualization after topical anesthetic and 
decongestant sprays applied to each nostril.  Standard surgical tools are used to remove LYR-
210. LYR-210 is made of polymers designed to gradually soften over time. Care should be taken
to remove LYR-210 in one piece or in sections should any disintegration of LYR-210 occur.
To keep the subjects enrolled in the sham procedure group fully blinded in the post-treatment 
safety follow up stage, all sham control subjects will undergo a sham removal procedure either at 
the scheduled Week 24 visit or earlier in an unscheduled early termination (ET) visit if the 
subjects request early depot removal.


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6.6
Treatment Compliance
Administration and removal of LYR-210 and the sham procedure article will be performed in a 
clinical setting by trained personnel who will be responsible for ensuring and recording 
compliance with all treatment procedures.


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7.
DRUG PRODUCT MATERIALS AND MANAGEMENT
7.1
Investigational Product
7.1.1
Product Description
The LYR-210 System is a combination product comprised of a single-use applicator, pre-loaded 
with the LYR-210 drug depot, containing mometasone furoate (MF), an FDA-approved drug 
indicated for therapeutic and prophylactic management of seasonal and perennial allergic rhinitis 
(AR), nasal polyps, a phenotype of CS disease, as well as asthma. The LYR-210 drug depot is 
made of bioabsorbable polymers designed to gradually soften over time. It has a tubular braid 
configuration with a uniform diamond pattern throughout and dimensions of 13 mm in diameter 
and 10 mm in length in the unconstrained state (Figure 2). It is designed to be self-retaining 
against the mucosal tissue to allow effective drug transfer for up to 24 weeks. The depot is 
comprised of a base structure and a drug formulation matrix. The base structure is composed of 
poly(L-lactide-co-glycolide) and poly(L-lactide-co-ε-caprolactone) elastomer to provide a 3-
dimensional structure and elasticity. The drug formulation matrix consists of the active 
ingredient, MF, embedded in the inactive ingredients containing poly(L-lactide-co-ε-
caprolactone) and poly(L-lactide) to control the release rate of MF. All these polymers are 
currently being used as components of approved pharmaceutical drugs and/or medical devices.
Figure 2:
LYR-210 Images 
7.1.2
Dosage and Administration
Each LYR-210 drug depot contains either 2500 μg or 7500 μg MF. LYR-210 is intended to be 
administered bilaterally into the ESS-naive middle meatus by an otolaryngologist under 
endoscopic visualization via a provided single use applicator. Once administered, each LYR-210
is designed to gradually deliver MF to the inflamed mucosal tissue over 24 weeks with a single 
drug administration. Bilateral placement of LYR-210 (2500 μg) is designed to deliver a total 
dose of 5,000 μg MF over the 24 weeks, or an average daily dose of 30 μg MF per human 
subject (or 15 μg MF per nostril).  In the case of LYR-210 (7500 μg), a total dose of 15,000 μg 
MF will be delivered over the 24 weeks with an average daily dose of 89 μg MF per human 
subject (or 45 μg MF per nostril). 


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7.1.3
Active Ingredient: Mometasone Furoate
Mometasone furoate, USP, is the active pharmaceutical ingredient. It is a potent, topically active, 
anti-inflammatory corticosteroid, having the chemical name of 9α,21-dichloro-11ꞵ,17α-
dihydroxy-16α-methylpregna-1,4-diene-3,20-dione 17-(2-furoate), with an empirical formula of 
C27H30Cl2O6 and a molecular weight of 521.43 g/mol. It has the chemical structure shown in 
Figure 3.
Figure 3:
Chemical Structure of Mometasone Furoate
7.1.4
Inactive Ingredients
The inactive ingredients are poly(L-lactide-co-ε-caprolactone) (L-PLCL) and poly(L-lactide) (L-
PLA), shown in Figure 4A and Figure 4B, respectively.
Figure 4:
Chemical Structures of Inactive Ingredients
7.1.5
Applicator
LYR-210 is designed to be administered intranasally under endoscopy visualization via a single 
use applicator that contains the drug depot (Figure 5). The applicator compresses LYR-210 just 
prior to use, accesses the treatment site, and administers the drug depot. The applicator is 
constructed from materials commonly used in medical devices with well-established 
biocompatibility: polycarbonate, polytetra-fluoroethylene, Pebax® (comprised of polyamide and 
polyether), polyethylene, nylon, and stainless steel. 


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Figure 5:
Applicator, Ready for LYR-210 Administration
7.2
Drug Product Management
7.2.1
Packaging and Labeling
LYR-210 will be packaged and labeled appropriately for the blinded clinical study, as required 
by regional legislation and industry guidelines.
The Sponsor or designee will ship study products to the sites as needed. Specific instructions for 
ordering product will be provided to the sites.
7.2.2
Storage
It is recommended that LYR-210 be stored at 15 °C to 25 °C (59 °F to 77 °F) and in the original 
packaging to protect from moisture and light. The labeled expiry dates of LYR-210 are specified 
on the label. The location of drug product storage must be locked, and access must only be 
allowed to the study team or a designated person involved with the study team.
7.2.3
Product Traceability
Traceability of LYR-210 or the sham procedure articles shall be achieved by assigning each 
depot and applicator a unique serial number, designated next to the “SN” symbol on the label. 
7.2.4
Product Accountability
The Sponsor will supply sufficient quantities of LYR-210 and the sham procedure articles to 
allow completion of the study. The Investigator or designee must maintain accurate records to 
document the disposition of all product received by the clinical site. Required information 
includes the date received, date used, lot number, product description, expiry date, and a subject 
identifier for product that has been administered. Investigational sites will use a form to 
document product disposition which will be reviewed by the study monitor during routine 
monitoring visits. When enrollment in the Clinical Study is complete, any unused investigational 
product will be returned to Sponsor or discarded per Sponsor authorization along with a final 


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Accountability Log. The Accountability Log must document the disposition of all investigational 
product including those that have been returned to the Sponsor.
7.2.5
Product Return
All products that are not administered into a subject must be returned to the Sponsor or designee
or discarded per Sponsor authorization. Applicators successfully used for administration may be 
disposed on site after the study procedure is complete. For all investigational product that are 
associated with a malfunction, the product and all ancillary components (e.g., applicator) 
remaining from the index procedure should be returned to the Sponsor. The Investigator will 
inform the Sponsor of any complaints or malfunctions during the study. The Sponsor will 
investigate all product complaints and malfunctions. Instructions for returning product will be 
provided to the sites by the Sponsor.


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8.
STUDY ASSESSMENTS
8.1
Study Schedule of Assessment
The schedule of study assessments for subjects is summarized in Table 1 below and detailed in 
Sections 8.2, 8.3, and 8.4.
Enrolled subjects will be asked to complete an ePRO questionnaire daily in the morning to assess 
the 4 cardinal symptoms of CS including nasal blockage/obstruction/congestion, reduction/loss 
of sense of smell, facial pain/pressure, and anterior/posterior nasal discharge. In addition, the 
ePRO will capture the recommended daily use of nasal saline irrigation by the subject. Subjects 
will also complete a validated CS-specific quality of life questionnaire, the SNOT-22, throughout 
the study; and a general quality of life questionnaire, the SF-36v2, on Day 1 and at Week 
24/EOT and Week 48/EOS visits. At the Week 24/EOT visit, an end-of-treatment questionnaire 
will be administered. 
Subjects will be asked to complete the UPSITTM for smell dysfunction on Day 1 before the LYR-
210 administration/sham procedure, and at Week 24/EOT and Week 28 visits.
Sinus inflammation will be assessed by MRI without contrast before the LYR-210
administration/sham procedure during Screening and at the Week 24/EOT visit, unless medically 
contraindicated. If a subject is experiencing or recovering from a cold, acute exacerbation of 
nasal allergy, or upper respiratory tract infection at this visit, perform assessment 4 weeks after 
resolution of the adverse event. If a subject requires oral corticosteroid as rescue during the 24-
week treatment period, the follow-up MRI should be performed before receiving the rescue 
treatment instead of at Week 24/EOT visit.
Nasal cavities will be assessed by endoscopy before the LYR-210 administration/sham 
procedure on Day 1, at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits. Subjects are 
required to wear a blindfold if endoscopy examination is performed at these visits to remain 
blinded to treatment assignment. Local nasal safety evaluation will be performed at these visits 
to document presence of epistaxis, mucosal erosion or ulceration, perforation, infection, and any 
other local nasal adverse effects. For CSwNP subjects, real-time, qualitative endoscopic 
evaluation of change of polyp severity within middle meatus will be performed by site 
Investigators at the Week 24/EOT visit after LYR-210 removal/sham removal procedure and at
Week 28 visit by comparing to that of the Day 1 visit.
Ophthalmologic assessments will include IOP and slit-lamp examination for cataract 
development at Screening, Week 24/EOT and Week 48/EOS visits. IOP assessment will be also 
performed at Week 4 and Week 12 visits.
Plasma samples for PK will be collected from all subjects on Day 1 before the LYR-210
administration/sham procedure, and at Weeks 4 and 12, Week 24/EOT, and Week 28 visits.


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Additional plasma PK samples will be collected at Days 3, 7, 14 (Week 2), 21 from
approximately 15 randomized and successfully enrolled subjects at participating US sites. The 
concentration of MF in plasma will be measured by a central laboratory.
Routine safety assessments will be performed during the study including vital signs and physical 
exams at all clinic visits. Samples for hematology, blood chemistry, and cortisol will be collected 
during Screening, at Weeks 4 and 12, Week 24/EOT, and Week 28 visits. An additional 
hematology, chemistry, and serum cortisol sample will be collected within 72 hours prior to 
LYR-210 administration/sham procedure for Baseline value. All post-Screening serum cortisol 
samples will be evaluated by a central laboratory. 
For female subjects of childbearing potential, a serum pregnancy test will be performed at 
Screening visit and a urine pregnancy test will be performed on Day 1 prior to randomization to 
confirm eligibility for participating in the study. A urine pregnancy test will be performed every 
4 weeks in clinic during the treatment stage in these female subjects.
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
events (AEs) or untoward findings. Any AEs observed by the Investigator or reported by the 
subjects, whether or not attributed to the investigational procedure or product, will be monitored 
and evaluated throughout the study. If AEs occur, the first concern will be the safety and welfare 
of the subject. Appropriate medical intervention will be undertaken at the treating physician’s 
discretion. 
Additional visits may occur as clinically warranted.  At these Unscheduled Visits, any of these 
assessments may be performed per the treating physician’s discretion. 


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Table 1:
Schedule of Assessments for Subjects Randomized and Enrolled
Evaluation
Screening
Procedure 
Day a
Treatment Stage a
(24 weeks)
Post-Treatment Stage a
(24 weeks)
Visits #
1
2 b
3 b
4 b
5 b
6 b
7 b
8
Study Day/Week
DAY 
-28 to -14
DAY 1
WK 2
(±1
day)
WK 4
(±3 
days)
WK 8
(±3 
days) r
WK 12
(±3 
days)
WK 16
(±3 
days) r
WK 20
(±3 
days) r
WK 24 /
EOT
(±3 
days)
WK 28
(±7 
days)
WK 32 
(±7
days) r
WK 36 
(±7
days) r
WK 40 
(±7
days) r
WK 44 
(±7
days) r
WK 48 /
EOS 
(±7 
days)
Informed Consent
X c
Demographics
X
Medical History 
X
Vital Signs
X
X d
X
X
X
X d
X
X
Physical Exam 
X
X d
X
X
X d
X
X
Pregnancy Test f
X e
X d,e,t
X e
X e
X e
X e
X e
X e
Hematology/Chemistry f
X
X d,t
X
X
X d
X
Morning Serum Cortisol f,g
X
X d,t
X
X
X d
X
Magnetic Resonance Imaging
X h
X p,q
Ophthalmology Assessment i
X h
X j
X j
X p
X
UPSIT TM
X d
X d
X
Endoscopy
X
X k, m
X
X
X
X k,m
X k
Eligibility Assessment
X
X d
Washout Period
X l
Randomization
X d
Baseline LYR-210/Sham Procedure
X
Plasma Pharmacokinetics s
X d
X
X
X d
X
LYR-210/Sham Removal Procedure
X
Daily ePRO 
X n
SNOT-22 Questionnaire
X
X d
X
X
X
X
X
X
X d
X
X
X
X
X
X
SF-36v2 Questionnaire
X d
X d
X
End-of-Treatment Questionnaire
X
Concomitant Medications/Procedures
X
Adverse Events o
X


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Abbreviations: UPSIT = university of pennsylvania smell identification test; CS = chronic sinusitis; ePRO = electronic patient reported outcomes; EOT = end of-
treatment; EOS = end-of-study; SF-36v2 = short form health survey version 2; SNOT = sino-nasal outcome test; WK=week
a:
Subjects remain blinded starting from the time of randomization
b:
Subjects will wear a blindfold during any endoscopy procedure or endoscopy imaging.
c:
To be obtained before any study related assessments occur.
d:
Occurs before the LYR-210 or sham administration and removal procedures. 
e: 
Complete a serum pregnancy test at initial Screening visit and a urine pregnancy test in clinic at all subsequent visits during the treatment stage for female 
subjects of childbearing potential.
f: 
Investigators must document their review of each laboratory report.
g:
Blood samples will be collected during the morning hours before 10:00 AM (i.e., before 1000 HRS). Screening cortisol samples will be performed locally 
at the study site. Cortisol samples collected at all post-Screening visits will be sent to a central laboratory for testing. 
h:
Performed anytime between Screening and Day 1 visits.
i: 
Performed by a blinded ophthalmologist/optometrist. 
j: 
IOP assessment only.
k:
For CSwNP subjects, endoscopic evaluation of severity of polyps within middle meatus will be performed by the site Investigator at the time of imaging 
recording.  Polyp severity evaluation should occur after topical anesthetic and decongestant sprays are administered, but before anesthetic and decongestant 
soaked pledgets or cottonoids are applied. 
l: 
For a minimum of 2 weeks on all prohibited medications before the Day 1 visit. Subjects will start daily saline irrigation twice a day during washout.
m: 
Local nasal safety and polyp assessments to be performed before LYR-210/sham insertion on Day 1 or after LYR-210/sham removal at EOT visit.
n:
Daily instantaneous morning (between 06:00:00AM and 11:59:59AM) CS symptoms to be recorded by the subject on ePRO questionnaire beginning at 
least in the preceding 7 days prior to Day 1 visit.
o:
All adverse events shall be reported after subject signs informed consent.
p:
To be performed within 7 days after removal procedure. 
q:
If a subject is experiencing or recovering from a cold, acute exacerbation of nasal allergy, or upper respiratory tract infection at EOT visit, perform 
assessment 4 weeks after resolution of the adverse event. If a subject requires oral corticosteroid as a rescue treatment, perform follow-up MRI before 
receiving the rescue treatment instead of at EOT visit.
r:
Phone follow up to collect any potential AEs and use of concomitant medications/procedures.
s:
Additional plasma PK samples will be collected at Days 3, 7, 14±1 (Week 2), and 21±1 in approximately 15 randomized and successfully enrolled subjects 
at participating US sites.
t:
Samples can be collected within 72 hours prior to LYR-210 administration/sham procedure.


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8.2
Assessment of Subject Characteristics
8.2.1
Demographics
Demographic information (age, sex, ethnicity, and race) will be obtained during Screening as 
specified in the Study Schedule of Assessments (Section 8.1).
8.2.2
Medical and Surgical History
Medical and surgical history information will be obtained during Screening as specified in the Study 
Schedule of Assessments (Section 8.1).
A general medical history will be collected. In addition, the medical history will document 
conditions, focusing specifically on the following body systems: Head, Eyes, Ears, Nose, Throat 
(HEENT). The medical history will also include an assessment of the subject’s lifetime history of the 
following: 
x
Chronic sinusitis
x
Asthma
x
Chronic obstructive pulmonary disease (COPD)
x
Perennial allergic rhinitis (PAR)
x
Seasonal allergic rhinitis (SAR)
x
Sensitivity to Non-steroidal anti-inflammatory drugs (NSAIDs)
x
Smoking
Subjects will also be assessed if they had the following history of surgery or injury in the past:
x
Endoscopic sinus surgery (ESS)
x
Septoplasty
x
Sinuplasty
x
Polypectomy
x
Nasal surgery involving nasal turbinates
x
Facial trauma
8.3
Assessment of Efficacy
8.3.1
Subject Reported Outcomes
Subject symptom improvement, use of saline irrigation, and the overall experience of study will be 
captured using an ePRO system. Subjects will be instructed on the method for completing the ePRO.
At all clinic visits, the ePRO will be completed prior to any intranasal procedure or clinic 
assessments.


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8.3.1.1
Chronic Sinusitis Cardinal Symptom Assessment
For assessment of the 4 cardinal symptoms of CS, the ePRO will be completed by subjects on a daily 
basis as specified in the Schedule of Events (Section 8.1). Subjects will start recording their 
symptoms on the ePRO at least 7 days preceding the Day 1 visit. A minimum of 5 daily entries are 
required for composite score calculation over the preceding 7 days prior to Day 1 (not including Day 
1) for assessing subject’s eligibility for participating in the study.
The 4 cardinal symptoms of CS, as defined in the 2012 European position paper on rhinosinusitis 
and nasal polyps (EPOS-2012) [2] and the 2016 international consensus statement on allergy and 
rhinology: rhinosinusitis (ICAR:RS-2016) guidelines [3], include nasal 
blockage/obstruction/congestion, reduction/loss of sense of smell, facial pain/pressure, and nasal 
discharge (anterior/posterior nasal drip). 
Subjects will score the severity of their morning (between 06:00:00AM to 11:59:59AM)
instantaneous symptoms of CS on a 4-point scale (Section14.1):
x
0 = absent symptoms (no sign/symptom evident)
x
1 = mild symptoms (sign/symptom present but minimal awareness; easily tolerated)
x
2 = moderate symptoms (definite awareness of sign/symptom that is bothersome but
tolerable)
x
3 = severe symptoms (sign/symptom that is hard to tolerate; causes interference with
activities of daily living and/or sleeping)
8.3.1.2
22-Item Sino-Nasal Outcome Test (SNOT-22) Questionnaire
The ePRO will also be used to collect responses to the SNOT-22 questionnaire at the time points 
specified in the Schedule of Events (Section 8.1).
The SNOT-22 questionnaire is a 22-item disease-specific quality of life instrument validated for use 
in CS [27] (Section 14.2). Subjects score the severity of their symptoms and social/emotional 
consequences of CS on a 6-point scale: 
x
0 = no problem
x
1 = very mild problem
x
2 = mild or slight problem
x
3 = moderate problem
x
4 = severe problem
x
5 = problem as bad as it can be
The scores are summed; higher scores on the SNOT-22 instrument total score or subdomain scores 
as defined in Table 2 [29] indicate higher severity of symptoms or social/emotional consequences of 
CS.


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Table 2:
Categorized Survey Items for Separate Domains of the SNOT-22 Instrument
SNOT-22 Domains
Survey Items
Score Range
Rhinologic Symptoms
#1, #2, #3, #4, #7, #12
0–30
Extra-Nasal Rhinologic Symptoms
#5, #6, #7
0–15
Ear/Facial Symptoms
#3, #8, #9, #10, #11
0–25
Psychological Dysfunction
#16, #17, #18, #19, #20, #21, #22
0–35
Sleep Dysfunction
#13, #14, #15, #16, #17
0–25
SNOT-22 = 22-item Sino-nasal Outcome Test
8.3.1.3
Saline Irrigation Use
The ePRO will also be used to collect the frequency of daily saline irrigation by the subjects. 
8.3.1.4
36-item Short Form Health Survey version 2 (SF-36v2®) Questionnaire 
At Day-1, Week 24/EOT, and Week 48/EOS visits, subjects will complete the SF-36v2®
questionnaire by ePRO. SF-36v2® is a generic health survey that asks 36 questions to measure 
functional health and well-being of a subject (Section 14.4). It is a valid measure of physical and 
mental health and the most frequently used PRO instrument in clinical trials today [30]. Additionally, 
the SF-36v2® provides scores for each of the eight health domains and psychometrically based 
physical component summary (PCS) and mental component summary (MCS) scores (Table 3) [31].
The items of the SF-36v2 are transformed and summed to a norm-based scores (Mean = 50, SD = 
10) scale for each PCS and MCS domain in which higher scores indicate a better health-related QoL.
Table 3.
SF-36v2® Health Survey Measurement Model
SF-36v2 Components and Domains
Survey Items
Physical Component Summary (PCS)
Physical Functioning (PF)
#3a, #3b, #3c, #3d, #3e, #3f, #3g, #3h, #3i, #3j
Role -Physical (RP)
#4a, #4b, #4c, #4d
Bodily Pain (BP)
#7, #8
General Health (GH)
#1, #11a, #11b, #11c, #11d 
Mental Component Summary (MCS)
Vitality (VT)
#9a, #9e, #9g, #9i
Social Functioning (SF)
#6, #10
Role-Emotional (RE)
#5a, #5b, #5c
Mental Health (MH)
#9b, #9c, #9d, #9f, #9h


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8.3.1.5
End-of-Treatment Questionnaire
At Week 24/EOT visit, subjects will complete an end-of-treatment questionnaire by ePRO 
(Section 14.3). The questionnaire will query subjects about their general experience and satisfaction 
with their assigned study treatment. Subjects will describe their experiences by answering multi-
choice questions or providing narrative responses.
8.3.2
Sinus Inflammation Imaging
Sinus inflammation will be assessed by MRI without contrast at the time points specified in the 
Schedule of Events (Section 8.1), unless medically contraindicated. The Screening MRI should be 
performed anytime between the Screening and Day 1 visits. The follow up MRI will be conducted 
within 7 days after the LYR-210 removal/sham procedure at Week 24/EOT visit. If a subject is 
experiencing or recovering from a cold, acute exacerbation of nasal allergy, or upper respiratory tract 
infection at the EOT visit, the MRI will be performed 4 weeks after resolution of the adverse event. 
If a subject requires oral corticosteroid as rescue during the 24-week treatment period, the follow-up
MRI should be performed before receiving the rescue treatment instead of at Week 24/EOT visit.
The sinus inflammation will be assessed using the Zinreich modified Lund-Mackay scoring system
(referred herein as the Zinreich scores)[32] where each sinus is assigned a score based on the 
percentage of opacification as follows: 
x
0 = 0%
x
1 = 1% to 25%
x
2 = 26% to 50%
x
3 = 51% to 75%
x
4 = 76 % to 99%
x
5 = 100% or completely occluded
The ostiomeatal complex (OMC) is given a score of 0 to 2 as follows:
x
0 = completely patent
x
1 = partially occluded
x
2 = completely occluded
Each sinus pair has a bilateral Zinreich score in the range of 0 to 10, and the OMC pair in the range 
of 0 to 4, and the total sum of all sinuses and OMCs in the range of 0-54.
8.3.3
Nasal Polyp Assessment
Visualization and assessment of nasal polyps will be conducted using endoscopy at the time points 
specified in the Schedule of Events (Section 8.1). At the Day 1 visit, prior to the LYR-210
administration/sham procedure, an endoscopic assessment of nasal passageway for eligibility will be 
conducted after topical anesthetic and decongestant sprays are administered, but before any 


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anesthetic and decongestant soaked pledget or cottonoid is applied for the LYR-210
administration/sham procedure. The follow up endoscopic assessment of the nasal passageway will 
be conducted at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits.
Investigators will evaluate the severity of nasal polyps in the middle meatus at the Week 24/EOT 
and Week 28 visits by grading polyp severity as “better,” “worse,” or “the same” in comparison to 
the Baseline severity evaluated at Day 1 visit before the insertion procedure.
8.3.4
The University of Pennsylvania Smell Identification Test (UPSITTM)
The UPSIT will be conducted at 3 time points during the study as specified in the Schedule of 
Events (Section 8.1). At Day 1 and Week 24/EOT visits, the UPSITTM will be conducted prior to the 
LYR-210 administration/sham procedure and prior to the LYR-210 removal/sham procedure
endoscopy assessment.
The UPSITTM is composed of 40 odorants embedded on scent strips that are released when scratched 
with a sharply tipped object [33]. The UPSIT is comprised of 4 booklets, each containing 10 
microencapsulated (scratch & sniff) odors. The UPSIT is a forced-choice test, and subjects will be 
instructed to identify each odorant with alternatives accompany each test item. The total olfaction 
score using the UPSIT is defined as the number of odorants correctly identified out of the 40 odors 
tested, with higher scores designating better olfactory performance. 
8.4
Assessment of Safety
8.4.1
Physical Examination
A physical examination including a careful assessment of all body systems, including the skin, eyes, 
ears, nose and throat, respiratory will be performed at all clinic visits as specified in the Schedule of 
Events (Section 8.1). Height (cm) will only be measured at Screening visit. Weight (kg) and body 
mass index (BMI) will be measured at all visits.
8.4.2
Vital Signs
Vital signs will be measured at all clinic visits as specified in the Schedule of Events (Section 8.1).
Vital sign measurements will include blood pressure (systolic and diastolic, mmHg), and pulse rate
(beats per minute), aural/oral temperature (°C), and respiration rate (breaths per minute). All 
measurements will be obtained after the subject has been resting supine for at least 5 minutes.
8.4.3
Laboratory Assessments
Laboratory testing will be performed at clinic visits as specified in the Schedule of Events 
(Section 8.1). Any unused duplicated samples collected for the purpose of this study will be 
destroyed after the completion of the study.


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8.4.3.1
Hematology
Samples for hematology assessments will be obtained during Screening, within 72 hours prior to 
LYR-210 administration/sham procedure, and at Weeks 4 and 12, Week 24/EOT, and Week 28
visits as specified in the Schedule of Events (Section 8.1).
Hematology assessments will include a leukocyte count with differential (neutrophils, eosinophils, 
lymphocytes, monocytes, and basophils), erythrocytes, hematocrit, hemoglobin, and platelet count.
Testing will be performed according to the standard of care at the investigational site.
8.4.3.2
Blood Chemistry
Samples for blood chemistry assessments will be obtained during Screening, within 72 hours prior to 
LYR-210 administration/sham procedure, and at Weeks 4 and 12, Week 24/EOT, and Week 28
visits as specified in the Schedule of Events (Section 8.1).
Clinical blood chemistry laboratory analytes will include electrolytes (sodium, potassium, chloride, 
and bicarbonate), blood urea nitrogen, serum creatinine, glucose, total bilirubin, aspartate 
aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, uric acid, 
total protein, albumin, calcium, magnesium, and phosphate. 
Testing will be performed according to the standard of care at the investigational site unless 
otherwise noted in the Lab Manual.
8.4.3.3
Morning Serum Cortisol
Samples for serum cortisol will be collected during the morning hours before 10:00 (i.e., before 
1000 HRS) during Screening, within 72 hours prior to LYR-210 administration/sham procedure, and 
at Weeks 4 and 12, Week 24/EOT, and Week 28 visits as specified in the Schedule of Events 
(Section 8.1).
All serum cortisol samples, except for Screening, will be sent to a central laboratory for testing.  
8.4.4
Nasal Endoscopy Assessments
Nasal cavities will be assessed by endoscopy on Day 1 before the LYR-210 administration/sham 
procedure, and at Weeks 2, 4 and 12, Week 24/EOT, and Week 28 visits as specified in the Schedule 
of Events (Section 8.1). Local nasal safety evaluation will be performed at these visits to document 
presence of epistaxis, mucosal erosion or ulceration, perforation, infection, and any other adverse 
local nasal observations. 
8.4.5
Ophthalmologic Assessments
The ophthalmologic assessment of IOP and slit-lamp examination to identify cataract development 
will be conducted at Screening, Week 24/EOT, and Week 48/EOS visits as specified in the Schedule 
of Events (Section 8.1). IOP assessment will also be performed at Weeks 4 and 12 visits.


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Assessments will be conducted by a blinded ophthalmologist/optometrist. 
8.4.6
Pharmacokinetic Analysis
Blood samples for assessment of plasma PK will be at Day 1, Weeks 4 and 12, Week 24/EOT, and 
Week 28 visits as specified in the Schedule of Events (Section 8.1). Additional plasma PK samples 
will be collected at Days 3, 7, 14 (Week 2), 21 from approximately 15 randomized and successfully 
enrolled subjects at participating US sites for a minimum of 6 subjects for each LYR-210 dose.
At the Day 1 visit, the blood sample for plasma PK analysis will be collected prior to the LYR-210
administration/sham procedure. Subsequent blood samples may be collected at any time of the day 
during the scheduled study visits.
The concentration of MF in plasma will be measured at a central core lab.
8.4.7
In Vivo Drug Dissolution Analysis of LYR-210
All removed or spontaneously dislodged LYR-210 will be collected and returned to Lyra 
Therapeutics if allowed by the individual hospital standard operating procedures (SOPs).
Instructions for the processing and return of removed LYR-210 will be provided. 
The mass of remaining MF in LYR-210 will be measured at Lyra Therapeutics.
8.4.8
Pregnancy or Breast Feeding
Females of child-bearing potential must test negative for pregnancy at the time of Screening visit
based on a serum pregnancy test and re-verified prior to randomization at Day 1 visit based on a 
urine pregnancy test. Females who can confirm that they are surgically sterile or have been 
postmenopausal for at least 1 year prior to signing the ICF do not need to undergo a pregnancy test.
Urine pregnancy test will be performed to successfully enrolled female subjects of child-bearing 
potential every 4 weeks during the treatment stage.
Female subjects who are of childbearing potential are required to practice a highly effective form of 
birth control to continue in the study and for 4 weeks after the removal procedure. Male subjects of 
reproductive potential who are having intercourse with female partners of childbearing potential 
must agree to use 2 forms of contraception, 1 of which must be a barrier method, during the study 
and for 4 weeks after the removal procedure. Acceptable barrier methods include a condom and 
diaphragm. 
Definition of Childbearing Potential and Highly Effective Contraceptive Methods:
A woman is considered of childbearing potential (i.e., fertile), following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
A
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A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. 
A high follicle stimulating hormone (FSH) level in the post-menopausal range may be used to 
confirm a post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
For women of childbearing potential, the following methods of contraception, when used 
consistently and correctly, are considered reliable for participation in the study: 
x
Combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation: oral, intravaginal, or transdermal
x
Progestogen-only hormonal contraception associated with inhibition of ovulation: oral,
injectable or implantable
x
Intrauterine device (IUD)
x
Intrauterine hormone-releasing system (IUS)
x
Bilateral tubal; occlusion
x
Vasectomized partner (provided that partner is the sole sexual partner and that
vasectomized partner has received medical assessment of the surgical success)
x
Sexual abstinence (refraining from heterosexual intercourse during the entire study
period; the reliability of sexual abstinence needs to be evaluated in relation to the
duration of the clinical study and the preferred and usual lifestyle of the subject).
If a female subject who has successfully received bilateral placement of either dose of the LYR-210
becomes pregnant during the treatment stage, the Investigator must notify the Sponsor within 24 
hours of becoming aware of the event on a Pregnancy Report Form. The Investigator must continue 
to follow the pregnancy until the completion of the pregnancy, including the outcome and the 
condition of the newborn at 8 weeks post-partum (if applicable). If not all information on the 
Pregnancy Report Form is available at the time of the initial report, follow-up reports should be 
provided to the Sponsor in a timely manner. Additional subsequent follow-up is not needed when a 
newborn baby is healthy.
8.4.9
Adverse Events and Serious Adverse Events
8.4.9.1
Adverse Event (AE)
Throughout the course of the study, all efforts will be made to remain alert to possible AEs or 
untoward findings. If AEs occur, the first concern will be the safety and welfare of the subject.
Appropriate medical intervention will be undertaken. Any AE observed by the Investigator or 
reported by the subjects, whether or not ascribed to the investigational procedure or product, will be 
recorded on the subject’s AE Case Report Form. A new AE Case Report Form will be used for each 
AE. All on-going AEs that result in early termination from the study or are deemed to be study 


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product or procedure related by the Site Investigator will be followed up until resolution or 
stabilization of the AE.
Documentation regarding the AE should be made as to the nature, date of onset, end date, severity, 
and relationship to study drug, action(s) taken, seriousness, and outcome of any sign or symptom 
observed by the physician or reported by the subject upon indirect questioning.
An AE is any untoward medical occurrence (signs, symptoms, abnormal laboratory findings) in a 
subject regardless of relationship to the investigational product or procedure. Each adverse event is 
considered to be either expected or unexpected as described below. The site is required to report AEs 
that occur in the study. These events shall also be classified according to the suspected causality by 
the study Investigator. 
A Treatment Emergent AE (TEAE) is an AE that occurs or worsens on or after initiation of the 
LYR-210 administration/sham procedure.
8.4.9.2
Serious Adverse Event (SAE)
An SAE is any untoward medical occurrence that:
x
Results in, leads to, or contributes to, a death;
x
Is life-threatening (“Life-threatening” refers to an event in which the subject was at risk
of death at the time of the event. It does not refer to an event which hypothetically might
have caused death if it were more severe);
x
Results in subject hospitalization or prolongation of existing hospitalization;
x
Results in persistent or significant disability/incapacity (i.e., permanent impairment of a
body function or permanent damage to a body structure);
x
Results in fetal distress, fetal death or a congenital anomaly/birth defect;
x
Is an important medical event which may jeopardize the subject and may require medical
or surgical intervention to prevent one of the above outcomes.
The Investigator will assess each AE for its seriousness. Please note the term “serious” AE is not 
synonymous with a “severe” AE, which may be used to describe the intensity of an event 
experienced by the subject (Section 8.4.9.4). Any treatment related SAE (Section 8.4.9.5) will be 
followed until resolution of the event, or until the subjects withdraw from the study.
8.4.9.3
Relationship to Study Drug Product and Procedure
The Investigator should initially classify the causality of an AE and determine the relationship 
between an AE and the study product or procedure.


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8.4.9.3.1
Relationship to Study Drug Product 
The relationship between an AE and the LYR-210 study drug product will be determined by the 
Investigator on the basis of his or her clinical judgment and the following definitions: 
x
Definitely Related: The AE follows a reasonable temporal sequence from administration
of the investigational product; the AE follows a known or expected response pattern to
the investigational product.
x
Possibly Related:The AE follows a reasonable temporal sequence from administration
of the investigational product; the AE follows a known or expected response pattern to
the investigational product but could readily have been produced by a number of other
factors.
x
Not Related: An AE for which sufficient information exists to indicate that the etiology
is unrelated to the investigational product. One or more of the following variables apply:
o The AE does not follow a reasonable temporal sequence following administration of
the investigational product;
o The AE is readily explained by the subject’s clinical state or other therapies.
For events that are determined to be definitely or possibly related, additional information on the 
timing of the event in relation to the LYR-210 study drug product administration will be captured.
8.4.9.3.2
Relationship to Study Procedure
The Relationship between an AE and the LYR-210 administration/sham procedure (within 24 hours) 
will be determined by the Investigator on the basis of his or her clinical judgment and the following 
definitions: 
x
Definitely Related: The AE follows a reasonable temporal sequence from performance
of the study procedure; the AE follows a known or expected response pattern to the study
procedure.
x
Possibly Related:The AE follows a reasonable temporal sequence from performance of
the study procedure; the AE follows a known or expected response pattern to the study
procedure but could readily have been produced by a number of other factors.
x
Not Related: An AE for which sufficient information exists to indicate that the etiology
is unrelated to the study procedure. One or more of the following variables apply:
o The AE does not follow a reasonable temporal sequence following the study
procedure;
o The AE is readily explained by the subject’s clinical state or other therapies.


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For events that are determined to be definitely or possibly related to the study LYR-210
administration/sham procedure, additional information on the timing of the event in relation to the 
study procedure will be captured.
8.4.9.4
Severity of Adverse Events
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an adverse 
event as determined by the Investigator or reported to him/her by the subject. The assessment of 
severity is made irrespective of relationship to study procedure or product or seriousness of the event 
and should be evaluated according to the following scale:
x
Mild: Event is noticeable to the subject but is easily tolerated and does not interfere with
the subject’s daily activities.
x
Moderate:Event is bothersome, possibly requiring additional therapy, and may interfere
with the subject’s daily activities.
x
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and
interferes with the subject’s daily activities.
8.4.9.5
Expectedness of Serious Adverse Events
The expectedness of a product or procedure related SAE should be determined by Sponsor based 
upon existing safety information about the investigation product or study procedure using these 
explanations:
x
Unexpected: An SAE that is not listed in the study protocol, Investigator’s brochure, or
prescribing information for the registered formulation of MF or is not listed at the
specificity or severity that has been observed.
x
Expected: An SAE that is listed in the Investigator’s Brochure (IB) or prescribing
information for the registered formulation of MF or is listed at the specificity and severity
that has been observed.
8.4.9.6
Reporting
8.4.9.6.1
Adverse Event Reporting
Adverse events are to be collected from the time a subject signs informed consent until the 
completion of all follow-up visits. At each office visit during the study, AEs that have occurred since 
the previous office visit must be recorded. All subjects will be evaluated for AEs or complications 
associated with the study procedure or the investigational product. The Investigator will determine 
the severity and relationship of each event, as defined above.
AEs observed during the course of this study, regardless of severity or relationship to the study 
procedure or investigational product will be recorded on the appropriate CRF. 


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Documentation of all new AEs or changes in previously reported AEs will be recorded. Pre-existing 
diseases or conditions will not be reported as AEs unless there has been a substantial increase in 
severity or frequency of the problem which cannot be attributed to the expected progression of the 
disease or condition.
The Investigator will review the results of all clinical and laboratory tests as they become available.
For each laboratory test result, the Investigator will ascertain whether the result represents an 
abnormal (e.g., clinically significant) change from Baseline for that individual subject. If this 
laboratory test result is determined to be an abnormal change from Baseline for that subject, the 
value will be considered to be an AE.
The description of the AE will include the date of onset, date of resolution (ongoing), severity, 
seriousness, relationship of the event to the investigational product and to the study procedure, and 
any procedure required. Specific procedures implemented in response to the AE will also be 
recorded. For all AEs, the Investigator is required to supply any additional data that may be deemed 
necessary by the Sponsor or designee.
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) throughout the study (Version 21.1 will be used at the start of the study).
8.4.9.6.2
Serious Adverse Event Reporting
The Investigator will be required to report all SAEs that occur throughout the course of the study. 
Information such as the Investigator name, study name/protocol number, subject identification 
number, the description of the SAE, the Investigator’s assessment as to the relationship to the 
investigational product and the study procedure, and the reporting source should be included in the 
initial report. Any additional supporting documentation may be requested by the Sponsor or designee
as necessary. This also includes forwarding pertinent follow-up information (e.g., clinic discharge 
summary) as it becomes available. A completed SAE form needs to be submitted with each follow-
up. Reports relating to the subject’s subsequent medical course must be submitted to the Sponsor 
until the event has resolved or, in case of permanent impairment, until the event stabilizes, and the 
overall clinical outcome has been ascertained.
Each SAE should be reported to the Sponsor or designee within 24 hours of knowledge of the event. 
The Sponsor will ensure that all SAEs are reported to the relevant authorities and Investigators, as 
required by local regulations. 
8.4.9.6.3
Expedited Reporting
Any serious and unexpected suspected adverse reactions (SUSARs) and unexpected adverse device 
effect (UADE) will be reported by the Sponsor or designee to the appropriate Regulatory Authorities 
in accordance with applicable local guidelines. 
The SUSARs meet all the following criteria:


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x
Suspected adverse reaction
x
Serious
x
Unexpected
x
Assessed as related to study treatment
A UADE is any serious adverse effect on health or safety, any life-threatening problem or death 
caused by, or associated with a device, if that effect, problem, or death was not previously identified 
in nature, severity, or degree of incidence in the application; or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects.
8.4.10
Safety Monitoring
Subject will be closely monitored throughout the trial with high priority for subject safety. The 
sponsor will establish Safety/Medical Monitoring team early in the study. The team will be 
responsible for developing a Safety/Medical Monitoring Plan (MMP) which will define in detail the 
objectives, scope and roles and responsibilities of each team member involved. 
Subject safety monitoring encompasses, but is not limited to, providing advice to sites and the 
project team for protocol-related issues, providing input into decisions requiring medical advice and 
routine safety monitoring of the study, review of serious and non-serious AEs, various data listings, 
lab results, vital signs, and other clinical data may be undertaken. Reviews of blinded aggregate data 
as well as individual subject data may be undertaken to identify outliers and trends that may impact 
safety of the subject and consistency of data.


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9.
SAFETY INFORMATION OF STUDY DRUG PRODUCT
9.1
Safety Rationale of Study Drug Doses and Polymers
LYR-210 is designed to be administered intranasally under endoscopy visualization via a single use
applicator that contains the drug depot. Bilateral placement of LYR-210 (2500 μg) is designed to 
deliver a total dose of 5000 μg MF over the 24 weeks with an average daily dose of 30 μg MF per 
subject (or 15 μg MF per nostril).  In the case of LYR-210 (7500 μg), a total dose of 15000 μg MF 
will be delivered over the 24 weeks with an average daily dose of 89 μg MF per subject (or 45 μg 
MF per nostril). The safety of LYR-210 (2500 μg) and LYR-210 (7500 μg) are supported by the 
extensive clinical and nonclinical data from existing marketed MF containing pharmaceutical 
products and medical devices, the non-clinical toxicology assessment of LYR-210, and the Phase I 
clinical study of LYR-210 (2500 μg) in adult CS subjects. 
9.1.1
Existing Non-clinical Safety Data
A significant amount of non-clinical data exists in the public domain to support the use of MF doses 
at the daily exposure levels expected from LYR-210 at either the 2500 μg or 7500 μg strength
dosage unit.  Non-clinical studies conducted to support Nasonex® (mometasone furoate monohydrate 
Nasal Spray 50 mcg) [18] and Asmanex® Twisthaler® (mometasone furoate Inhalation Powder, 110 
mcg, 220 mcg, Merck & Co., Inc) [17] are particularly relevant.  In both rats and dogs, observed 
effects were associated with well-defined pharmacological effects of glucocorticoids, with some 
progestational-like effects seen at the highest doses evaluated.  Carcinogenicity studies (mice and 
rats) were reported using nose-only inhalation with the no human risk of carcinogenicity identified 
for the therapeutic dose of MF.
Additionally, a comprehensive literature review was conducted for each of the polymers used as the 
inactive ingredients and the base structure in LYR-210.  All of these polymers are currently being 
used as components of approved pharmaceutical drugs and/or medical devices. A detailed summary 
of these studies is provided in the IB (Section 4.1 for more detail).
9.1.2
Nonclinical Toxicology Assessment of LYR-210
LYR-210 was placed in the maxillary sinus cavity of New Zealand White rabbits to evaluate in vivo 
drug release kinetics, and local and systemic toxicity. During the development of LYR-210,
preclinical drug matrices with various configurations and drug doses were tested in more than 110 
rabbits over various duration for up to 6 months.  Two studies that were most relevant to LYR-210
(2500 μg) and LYR-210 (7500 μg) human drug matrices are described below and a detailed 
summary of these studies is provided in the Investigator Brochure (IB, Section 4.2).
x
Study 1 is a 180-day non-GLP rabbit study in which a 3-months drug formulation
representative of the LYR-210 (2500 μg) in the first 3 months was assessed. The in vivo drug
release profile of LYR-210 was compared to that of in vitro. Local safety assessments were
performed at 28, 90 and 180 days compared to a drug-free depot (a “placebo” drug depot
without MF) by endoscopy and histopathology.
9.1.1
Existing Non-clinical Safety Da
D ta
A significant amount of non-clininical data ex
exisi ts in n the public domain to support the use of MF doses 
at the
h  daily exposure levels exp
xpected frfrom
om LYR-21
210 atat eitither ththe 2500 μg or
or 7500 μg strength
do
d sage unit.  Non- lclinic lal studidies
es conducted
ed to su
supp
ppor
ort t Na
Nasonex® (mometasone furoate monohydrate 
Nasal Spray 50 mcg) [18] and Asmanex® Tw
T isthaler® (mometasone furoate Inhalation Powder, 110 
mcg, 220 mcg, Merck & Co., Inc) [17] are particularly relevant.  In both rats and dogs, observed 
effects were associated with well-defined pharmacological effects of glucocorticoids, with some
progestational-like effects seen at the highest doses evaluated.  Carcinogenicityty studies (mice and 
rats) were reported using nose-only inhalation with the no human risk of carcinogenicity identified
ed 
for the therapeutic dose of MF.
Additionally, a comprehensive literature review was conducted for each of the polymers used as the
inactive ingredients and the base structure in LYR-210.  All of these polymers are currently being
used as components of approved pharmaceutical drugs and/or medical devices. A detailed summary 
of these studies is provided in the IB (Section 4.1 for more detail).
9.1.2
Nonclinical Toxicology Assessment of LYR-210
LYR-210 was placed in the maxillary sinus cavity of New Zealand White rabbits to evaluate in vivo 
drug release kinetics, and local and systemic toxicity. During the development of LYR-210,
preclinical drug matrices with various configurations and drug doses were tested in more than 110 
rabbits over various duration for up to 6 months.  Two studies that were most relevant to LYR-210
(2500 μg) and LYR-210 (7500 μg) human drug matrices are described below and a detailed 
summary of these studies is provided in the Investigator Brochure (IB, Section 4.2).
x
Study 1 is a 180-day non-GLP rabbit study in which a 3-months drug formulation
representative of the LYR-210 (2500 μg) in the first 3 months was assessed. The in vivo dr
drug
release profile of LYR-210 was compared to that of in vitro. Local safety asses
essm
smen
entst  werere
performed at 28, 90 and 180 days compared to a drug-free depot (a “placeb
e o”
o” drug depo
p t
without MF) by endoscopy and histopathology.


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x
Study 2 is a 28-day non-GLP rabbit study in which a 24-week drug release formulation fully
representative of the LYR 210 (7500 μg) human drug depot was assessed. The primary
purposes of the study were to compare the MF pharmacokinetics with Nasonex® over 28
days and assess the local and systemic toxicology of LYR 210 by a weekly nasal
examination and at the end of the 28 days for a change in intraocular pressure, a slit-lamp
examination for cataract, an endoscopy and histopathologic evaluation of sinus cavity, as
well as change of serum cortisol level.
The 180-day rabbit study assessed the rabbit drug depot with a control drug-free depot.
Histopathological sections were scored for inflammation, epithelial injury, and bone remodelling at 
days 28, 90, and 180.  The scoring system used ranged from 0 to 4, with 0 designating no findings 
while a value of 4 designated severe changes. 
Average scores for inflammation, epithelial injury and bone remodelling across days 28, 90 and 180 
are summarized in Table 4. All variables scores indicated minimal to mild changes with average 
values ranging between 1 and 2. At each time period where the drug or the drug-free matrices 
physically contacted the mucosa, there was evidence of focal attenuation or flattening of the 
respiratory epithelial layer, but the epithelium remained intact.  Focal bone remodelling at the 
depot/mucosal layer contact points was observed in some sinuses, but bone loss was not observed in 
either group.   
Table 4:
Sinus Histological Score Summary of the 180-Day Rabbit Study
Time 
Points
Testing Group (n)
Inflammation 
Score
(0-4 scale)
Epithelial Ulceration 
Score
(0-4 scale)
Bone Remodelling 
Score
(0-4 scale)
Day 28
Drug Free Depot (n=4)
1.50 ± 0.58
1.50 ± 0.58
1.75 ± 0.50
Drug Depot (n=4)
1.25 ± 0.50
1.50 ± 0.58
1.00 ± 0.00
Day 90
Drug Free Depot (n=5)
1.80 ± 0.84
1.40 ± 0.55
1.80 ± 0.45
Drug Depot (n=4)
1.00 ± 0.00
1.25 ± 0.50
2.00 ± 0.82
Day 180
Drug Free Depot (n=4)
2.00 ± 0.00
1.75 ± 0.50
1.00 ± 0.00
Drug Depot (n=4)
2.00 ± 0.00
1.25 ± 0.50
1.25 ± 0.50
n represents number of matrices; values are shown as mean ± standard deviation.
In the 28-day rabbit study, plasma MF concentrations measured over 28 days from both LYR-210
and NASONEX treated rabbits are shown in Figure 6. After LYR-210 placement, the mean MF 
concentrations measured from 6 rabbits peaked initially within the first 24 hours to be 105.6±25.5 
pg/mL and gradually decreased to 82.6±10.1 pg/mL by 48 hours. Beyond this time point, MF 
concentrations remained stable over the remaining duration of study with an average plasma drug 
concentration of 73 pg/mL from Day 1 to Day 28. These pharmacokinetics results confirmed a 
controlled and sustained release kinetics from LYR-210. Importantly, the plasma MF concentrations 
measured from this rabbit study closely match with the predicted values under steady-state using a 
one-compartment pharmacokinetic model and the in vitro drug release data. 
x
Study 2 is a 28-day non-GLP rabbit stutudy in which a 24-week drug release formulation fully
rerepr
pres
esen
entative of the LYR 210 (7500 μg
μg) huma
man drug depot was assessssed
ed. The primary
purposes of the study we
were to comparare ththe e MF
MF pharmacokinetics with Nasonex® over 28
days and assess the loca
c l and systemic toxicology y of LYR 210 by a weekly nasal
examination and at the end of the 28 days for a ch
change
ge in intraocular pressure, a slit-lamp
examination for cataractct, an
an endoscop
opy an
and hihiststop
opathologic evaluation of sinus cavity, as
well as change of serum cortisol lev
evel.
The 180-day rabbit study assessed the rabbit drug depot with a control drug-free depot.
Histopathological sections were scored for inflammation, epithelial injury, and bone remodelling at
days 28, 90, and 180.  The scoring system used ranged from 0 to 4, with 0 designating no findings
while a value of 4 designated severe changes.
Average scores for inflammation, epithelial injury and bone remodelling across days 28, 90 and 180 
are summarized in Table 4. All variables scores indicated minimal to mild changes with average 
values ranging between 1 and 2. At each time period where the drug or the dr
drug
ug-free matrices
physically contacted the mucosa, there was evidence of focal attenuation or flattening of the 
respiratory epithelial layer, but the epithelium remained intact.  Focal bone remodelling at the 
depot/mucosal layer contact points was observed in some sinuses, but bone loss was not observed in 
either group.   
Table 4:
Sinus Histological Score Summary of the 180-Day Rabbit Study
Time 
Points
Testing Group (n)
Inflammation 
Score
(0-4 scale)
Epithelial Ulceration
Score
(0-4 scale)
Bone Remodelling 
Score
(0-4 scale)
Day 28
Drug Free Depot (n=4)
1.50 ± 0.58
1.50 ± 0.58
1.75 ± 0.50
Drug Depot (n=4)
1.25 ± 0.50
1.50 ± 0.58
1.00 ± 0.00
Day 90
Drug Free Depot (n=5)
1.80 ± 0.84
1.40 ± 0.55
1.80 ± 0.45
Drug Depot (n=4)
1.00 ± 0.00
1.25 ± 0.50
2.00 ± 0.82
Day 180
Drug Free Depot (n=4)
2.00 ± 0.00
1.75 ± 0.50
1.00 ± 0.00
Drug Depot (n=4)
2.00 ± 0.00
1.25 ± 0.50
1.25 ± 0.50
n represents number of matrices; values are shown as mean ± standard deviation.
In the 28-day rabbit study, plasma MF concentrations measured over 28 days from both LYR-210
and NASONEX treated rabbits are shown in Figure 6. After LYR-210 placement, the mean MF 
concentrations measured from 6 rabbits peaked initially within the first 24 hours to be 105.6±25.5 
pg/mL and gradually decreased to 82.6±10.1 pg/mL by 48 hours. Beyond this time point, MF
concentrations remained stable over the remaining duration of study with an average plasma drug 
concentration of 73 pg/mL from Day 1 to Day 28. These pharmacokinetics results confirmed a
controlled and sustained release kinetics from LYR-210. Importantly, the plasma MF concentratioions 
measured from this rabbit study closely match with the predicted values under steady-state using a
one-compartment pharmacokinetic model and the in vitro drug release data. 


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Figure 6:
Comparison of Plasma MF Concentration of LYR 210 and Nasonex® over 28 
Days
N=6 animals for all data points representing LYR 210, except for N = 3 animals for time points between baseline and the first 24 
hours. N=6 animals at baseline and N=3 animals for all other data points representing Nasonex. Data represents mean ± standard
deviation.
Safety assessments of potential local and systemic effects of LYR-210 indicated the drug matrices
were well tolerated. As expected, LYR-210 affected some clinical pathology parameters (e.g., 
cholesterol, triglycerides, and creatinine) and serum cortisol concentrations with these changes 
associated with the initial release of MF into the systemic circulation. However, it is also possible 
that stress associated with surgery could have contributed to some of the observed systemic changes. 
The nasal and ophthalmological examination results indicated that LYR-210 did not cause local
adverse effects to the nasal passages and the eyes. Similar to the 180-day study, histopathology 
evaluation of the maxillary sinuses indicated no concern of local sinus tissue toxicity (Table 5).
Table 5.
Sinus Histological Score Summary of the 28-day Study
Description (n)
Day
Inflammation Score
(0-4 scale)
Epithelial Ulceration 
Score
(0-4 scale)
Bone Remodelling 
Score
(0-4 scale)
Rabbit Drug Depot
(n = 12)
28
0.67 ± 0.49
0.33 ± 0.65
1.42 ± 0.90
n represents number of drug matrices; values are presented as mean ± standard deviation.
Figure 6:
Comparison of Plasma MF Co
C ncentrtration of LYR 210 and Nasonex® over 28
Days
N=6 animals for all data points representing LYR 210, except for N = 3 animals for time points between baseline and the first 24 
hours. N=6 animals at baseline and N=3 animals for all other data points representing Nasonex. Data represents mean ± standard
deviation.
Safety assessments of potential local and systemic effects of LYR-210 indicated the drug matrices
were well tolerated. As expected, LYR-210 affected some clinical pathology parameters (e.g., 
cholesterol, triglycerides, and creatinine) and serum cortisol concentrations with these changes 
associated with the initial release of MF into the systemic circulation. However, it is also possible 
that stress associated with surgery could have contributed to some of the observed systemic changes. 
The nasal and ophthalmological examination results indicated that LYR-210 did not cause local
adverse effects to the nasal passages and the eyes. Similar to the 180-day study, histopathology
evaluation of the maxillary sinuses indicated no concern of local sinus tissue toxicity (Table 5).
Table 5.
Sinus Histological Score Summary of the 28-day Study
Description (n)
Day
Inflammation Score
(0-4 scale)
Epithelial Ulceration
Score
(0-4 scale)
Bone Remodelling 
Score
(0
(0-4 sc
scala e)
Rabbit Drug Depot
(n = 12)
28
0.67 ± 0.49
0.33 ± 0.65
1.42 ± 0.90
n rerepresents number of drug matrices; values are presented as mean ± standard deviation.


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9.1.3
Phase I Clinical Study of LYR-210 (2500 μg) 
LYR-210 (2500 μg) was evaluated in an open-label Phase I clinical study (clinicaltrials.gov ID: 
NCT02967731) in 20 adult CS subjects who had failed medical management and were deemed 
candidates for ESS. Each subject received bilateral placement of LYR-210 (2500 μg) for up to 24 
weeks. The study results published in January 2019 in Int Forum Allergy Rhinol. [34]. A brief 
summary of the Phase I clinical study is provided here, and more details can be found in Section 5 of 
the IB.
The Phase I study concluded that LYR-210 (2500 μg) is safe and well-tolerated in ESS-naïve CS 
subjects and leads to sustained symptom improvement in subjects. Specifically, there was no product 
related serious adverse event reported. No local nasal adverse events (AEs), including epistaxis, 
nasal burning, nasal dryness, nasal irritation, and nasal septal perforation, were reported.  No subject 
had intraocular hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported.  
Mean changes from baseline over time in morning serum cortisol levels were minimal and not 
statistically significant. No AEs indicative of adrenal insufficiency were reported.  These results 
indicated low level of systemically circulated steroid from LYR-210 (2500 μg).  
The MF plasma concentrations were monitored in all 20 subjects at baseline (before administration) 
and 1 hour, 1 week, 4 weeks, and 12 weeks post bilateral administration of LYR-210 (2500 μg).  The 
plasma concentrations of MF were undetectable in about 50% subjects and near the lower limit of 
quantification (LLOQ, 20 pg/mL) in the other 50% subjects through a period of 12 weeks post LYR-
210 (2500 μg) administration (Table 6).
Table 6:
Number of Subjects with Plasma MF Concentration < or ≥ 20 pg/mL (ITT 
Population)
MF plasma concentration
Number of subjects
Baseline
1 hour
1 week
4 weeks
12 weeks
< 20 pg/mL (LLOQ)
20
11
10
16
10
t 20 but < 35 pg/mL
0
9
10
4
10
LLOQ=lower limit of quantification.
Thirty-five drug matrices were collected after removal or dislodgement and tested for remaining MF 
in the depot. Shown in Figure 7 is the percentage of MF released at the time of LYR-210
dislodgement or removal. This result confirmed controlled and sustained drug release of the MF over 
the 24 weeks of treatment duration that is characterized by a near linear drug release kinetics.
9.1.3
Phase I Clinical Study of LYR-210 (2
(2500 μg) 
LYR-210 (2500 μg) was evalua
uated in an op
open
en-lalabe
be
b l Ph
Phase
s I clinical study (clinicaltrials.gov ID: 
NC
NCT02967731) in 20 adult CS subjectsts who
ho had f iailed d medical manageme tnt and were deemed 
candidates for ESS. Each subjectct received d bibilateraral l plplac
acem
ement of LYR-210 (2500 μg) for up to 24 
we
weeks. The study results publblisished in Janua
u ry 2019 in In
Int Forum Allergy Rhinol. [34]. A brief 
summary of the Phase I clinical study is provided here, and more details can be found in Section 5 of 
the IB.
The Phase I study concluded that LYR-210 (2500 μg) is safe and well-tolerated in ESS-naïve CS 
subjects and leads to sustained symptom improvement in subjects. Specifically, there was no product
related serious adverse event reported. No local nasal adverse events (AEs), including epistaxis, 
nasal burning, nasal dryness, nasal irritation, and nasal septal perforation, were reported.  No subject 
had intraocular hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported.  
Mean changes from baseline over time in morning serum cortisol levels were minimal and not 
statistically significant. No AEs indicative of adrenal insufficiency were reported.  These results
indicated low level of systemically circulated steroid from LYR-210 (2500 μg).  
The MF plasma concentrations were monitored in all 20 subjects at baseline (before administration) 
and 1 hour, 1 week, 4 weeks, and 12 weeks post bilateral administration of LYR-210 (2500 μg).  The 
plasma concentrations of MF were undetectable in about 50% subjects and near the lower limit of 
quantification (LLOQ, 20 pg/mL) in the other 50% subjects through a period of 12 weeks post LYR-
210 (2500 μg) administration (Table 6).
Table 6:
Number of Subjects with Plasma MF Concentration < or ≥ 20 pg/mL (ITT
Population)
MF plasma concentration
Number of subjects
Baseline
1 hour
1 week
4 weeks
12 weeks
< 20 pg/mL (LLOQ)
20
11
10
16
10
t 20 but < 35 pg/mL
0
9
10
4
10
LLOQ=lower limit of quantification.
Thirty-five drug matrices were collected after removal or dislodgement and tested for remaining MF
MF
in the depot. Shown in Figure 7 is the percentage of MF released at the time of LYR-21
210
did sls odgement or removal. This result confirmed controlled and sustained drug relea
e se
se of the MF
M over 
ththt e e 24 weeks of treatment duration that is characterized by a near linear drug relea
ease kininetics.


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Figure 7:
In Vitro and In Vivo Percentage of Release of MF in LYR-210 (2500 μg) Over 
Time
In vitro data represents mean ± standard deviation. N=3 samples at each time point for in vitro data. Dashed lines 
represent linear regression fitting to guide the eyes.
The in vitro drug dissolution studies were conducted by submerging the drug matrices in a pH 7.4 
PBS with 2% SDS solution at 37 qC that provided infinite drug sink conditions.  The in vitro drug
dissolution profile (also shown in Figure 7) indicates that, although the in vitro drug release rate is 
faster than that of in vivo, the MF release from LYR-210 (2500 μg) follows near linear kinetics, 
which is in line with the Phase I clinical results. The in vitro drug release rate is approximately twice 
the rate of the in vivo drug release rate measured from the Phase I clinical study. This is expected, as 
in the Phase I clinical study, LYR-210 (2500 μg) was placed in the middle meatus of nasal cavity 
and only exposed to a moderately humid environment with a surrounding temperature up to 34 qC
[35]. The established in vitro-in vivo correlation enables the projection of an in vivo drug release 
profile from an in vitro profile.
Based on the in vivo drug release profile, bilateral placement of LYR-210 (2500 μg) delivers 
approximately an average of 30 μg MF per day over a period of 24 weeks.  While LYR-210 (2500 
μg) follows a substantially linear drug release profile, the corresponding in vitro cumulative drug 
release can be described as a combination of zero-order and first-order release kinetics using 
Equation (1).
ܯܨ ܴ݈݁݁ܽݏ݁݀% = ቂݔ
௞బ
஽బݐ+ (1 −ݔ)(1 −݁ି௞ೌ௧)ቃ× 100%
(1)
Figure 7:
In Vitro and In Vivo Percentage of Re
Release of MF in LYR-210 (2500 μg) Over 
Time
In vitro data represents mean ± standard deviation. N=3 samples at each time point for in vitro data. Dashed lines 
represent linear regression fitting to guide the eyes.
The in vitro drug dissolution studies were conducted by submerging the drug matrices in a pH 7.4
PBS with 2% SDS solution at 37 qC that provided infinite drug sink conditions.  The in vitro drug
dissolution profile (also shown in Figure 7) indicates that, although the in vitro drug release rate is 
faster than that of in vivo, the MF release from LYR-210 (2500 μg) follows near linear kinetics, 
which is in line with the Phase I clinical results. The in vitro drug release rate is approximately twice 
the rate of the in vivo drug release rate measured from the Phase I clinical study. This is expected, as 
in the Phase I clinical study, LYR-210 (2500 μg) was placed in the middle meatus of nasal cavity
and only exposed to a moderately humid environment with a surrounding temperature up to 34 qC
[35]. The established in vitro-in vivo correlation enables the projection of an in vivo drug release 
profile from an in vitro profile.
Based on the in vivo drug release profile, bilateral placement of LYR-210 (2500 μg) delivers 
approximately an average of 30 μg MF per day over a period of 24 weeks.  While LYR-210 (2500
μg) follows a substantially linear drug release profile, the corresponding in vitro cumulative drug
release can be described as a combination of zero-order and first-order release kinetics using 
Equation (1).
ܯܨܴ݈݁݁ܽݏ݁݀% = ቂݔ
௞బ
஽బݐ+ (1 −ݔ)(1 −݁ି௞ೌ௧)ቃ× 100%
(1)


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Where ܦ଴ is the total drug dose in the depot (i.e. 2500 μg herein), ݇଴ the zero-order drug release rate
constant, ݇௔ the first-order drug release rate constant, ݔ the fractional factor of zero-order drug
release.
The drug concentration in plasma can therefore be estimated using a simple one-compartment 
pharmacokinetic model shown below (Equation (2)):
݈ܲܽݏ݉ܽ ܯܨ ܿ݋݊ܿ݁݊ݐݎܽݐ݅݋݊=
ଶ௫௞బᇲி
௞௏ವ(1 −݁ି௞௧) +
ଶ(ଵି௫)௞ೌᇲ஽బி
(௞ೌᇲି௞)௏ವ൫݁ି௞௧−݁ି௞ೌᇲ௧൯
(2)
where ݇଴
ᇱ(0.505 μg/h for LYR-210 (2500 μg)) and ݇௔ᇱ(3.71x10-3 h-1 for LYR-210 (2500 μg)) are
respectively the projected in vivo zero-order and first-order drug release rate constants, ݔthe 
fractional factor of zero-order drug release (0.919 for LYR-210 (2500 μg)), ܨthe fraction of drug 
absorption (0.8 herein), ݇the elimination rate constant (0.1195 h-1, estimated from reference [18]), ܸ஽
the volume of distribution at the steady state (418 L h-1, estimated from reference [36]), ܦ଴the dose of
a single depot (2500 μg herein), ݐthe time.  Based on this pharmacokinetic model, it can be 
estimated that the systemic MF concentration of LYR-210 (2500 μg) under steady state is 
approximately 15.2 pg/mL, which closely matches the Phase I clinical study result as shown in Table
6 and validated the pharmacokinetics modeling.
9.1.4
Systemic and Local Dose Safety of LYR-210 (7500 μg) 
9.1.4.1
Systemic Safety
Lyra Therapeutics has conducted drug dissolution studies to assess the in vitro drug release profile of 
LYR-210 (7500 μg) and modeled its pharmacokinetics as described above. LYR-210 (7500 Pg) has 
a comparable in vitro drug dissolution profile to LYR-210 (2500 μg) (i.e. combination of zero-order
and first-order drug release kinetics but with more contribution from the latter, Figure 8).  Bilateral 
placement of LYR-210 (7500 μg) will deliver an average of 89 μg MF per day per subject over a 
period of 24 weeks.  Using the same pharmacokinetic model (Equation (2)) and a ݇଴
ᇱof 1.200 μg/h ,  
݇௔ᇱof 1.23x10-3 h-1, and ݔof 0.738 that are derived from curve-fitting in Figure 8, it is estimated that 
the bilateral administration of LYR-210 (7500 μg) would result in a plasma MF concentration of 
approximately 38.4 pg/mL at the steady state. 
Where ܦ଴is the total drug dose in the depot (i.e. 2500
00 μg herein), ݇଴the zero-order drug release rate
constant, ݇௔the first
f
-order drug
ug release ratate cons
nstatant, ݔthe fractional
f
factor of zero-order drug
release.
Th
The drug concentration in plasma can therefefore be
be estim
imatated using a simple one-compartment 
pharmacokinetic model shown below (Equation (2)):
݈ܲܽݏ݉ܽܯܨܿ݋݊ܿ݁݊ݐݎܽݐ݅݋݊=
ଶ௫௞బᇲி
௞௏ವ(1 −݁ି௞௧) +
ଶ(ଵି௫)௞ೌᇲ஽బி
(௞ೌᇲି௞)௏ವ൫݁ି௞௧−݁ି௞ೌᇲ௧൯
(2)
where ݇଴
ᇱ(0.505 μg/h for LYR-210 (2500 μg)) and ݇௔ᇱ(3.71x10-3 h-1 for LYR-210 (2500 μg)) are
respectively the projected in vivo zero-order and first-order drug release rate constants, ݔthe
fractional factor of zero-order drug release (0.919 for LYR-210 (2500 μg)), ܨthe fraction of drug
absorption (0.8 herein), ݇the elimination rate constant (0.1195 h-1, estimated from reference [18]), ܸ஽
ܸ
the volume of distribution at the steady state (418 L h-1, estimated from reference [36]), ܦ଴the dose of
a single depot (2500 μg herein), ݐthe time.  Based on this pharmacokinetic model, it can be 
estimated that the systemic MF concentration of LYR-210 (2500 μg) under steady state is
approximately 15.2 pg/mL, which closely matches the Phase I clinical study result as shown in Table
6 and validated the pharmacokinetics modeling.
9.1.4
Systemic and Local Dose Safety of LYR-210 (7500 μg) 
9.1.4.1
Systemic Safety
Lyra Therapeutics has conducted drug dissolution studies to assess the in vitro drug release profile of 
LYR-210 (7500 μg) and modeled its pharmacokinetics as described above. LYR-210 (7500 Pg) has
a comparable in vitro drug dissolution profile to LYR-210 (2500 μg) (i.e. combination of zero-order
and first-order drug release kinetics but with more contribution from the latter, Figure 8).  Bilateral
placement of LYR-210 (7500 μg) will deliver an average of 89 μg MF per day per subject over a
period of 24 weeks.  Using the same pharmacokinetic model (Equation (2)) and a ݇଴
ᇱof 1.200 μg/h h , 
݇௔ᇱof 1.23x10-3 h-1, and ݔof 0.738 that are derived from curve-fitting in Figure 8, it is estimated that
the bilateral administration of LYR-210 (7500 μg) would result in a plasma MF concentration of 
ap
approximately 38.4 pg/mL at the steady state. 


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Figure 8:
In vitro Cumulative Percentage of Release of MF from LYR-210 (7500 μg) Over 
Time
In vitro data represents mean ± standard deviation. N=9 samples at each time point. Hollow symbols represent the best 
fitting of in vitro release data using Equation (1).
This estimated systemic exposure of LYR-210 (7500 μg) is higher than that of Nasonex®, expected 
due to the low bioavailability of the latter (< 1%).  However, the Cmax value of LYR-210 (7500 μg) 
is estimated to be significantly lower than that of the approved dose of Asmanex® Twisthaler® (400
μg, BID); and the AUC24h is comparable to that of Asmanex® Twisthaler® (400 μg, BID).  
Moreover, a 5-day clinical study on a higher dose of Asmanex® Twisthaler® (800 μg, BID) indicated 
that this dose of MF was also safe and well-tolerated and did not cause clinically significant effects 
on clinical laboratory test results or on vital signs [37], although its systemic exposure is 4-fold higher 
than the projected average exposure of LYR-210 (7500 μg).  These data further support the systemic 
safety of LYR-210 (7500 μg).
Table 7:
Comparison of Systemic Exposure of LYR-210 (7500 μg) with Clinical Studies 
showing Systemic Safety of Chronic Use of MF Products
Drug product
Dose (Pg)
Cmax
(pg/mL)
AUC (Duration) 
(pg h/mL)
AUC24h
(pg h/mL)*
References
Nasonex
200 QD
5.77
29.6 (12 h)
29.6
Nasonex [18]
800 TID
25.5
64 (8 h)
192
Daley-Yates 2004 [38]
Asmanex
Twisthaler
400 BID
114
634 (12 h)
1268
Asmanex Twisthaler [39]
400 BID
90.2
646 (12 h)
1292
Kosoglou 2013 [40]
800 BID
383
2820 (12 h)
5640
Kosoglou 2014 [37]
LYR-210
15000 / 24 
95
175518 (168 d)
1045
Lyra Therapeutics 
Figure 8:
In vitro Cumulative Percentage
g  of Re
Relelease of MF from LYR-210 (7500 μg) Over 
Time
In vitro data represents mean ± standarard deviation. N=
N=9 samples at each time point. Hollow symbols represent the best 
fitting of in vitro release data using Equation (1).
Th
This estimated syste i
mic exposure of LY
LYR-210 (750
5 0 μg
μg) is higher ththan that of Nasonex®, expected 
due to the low bioavailability of the latter (< 1%).  Howeve
ver, the Cmax value of LYR-210 (7500 μg) 
is estimated to be significantly lower than that of the approved dose of Asmanex® Twisthaler® (400
μg, BID); and the AUC24h is comparable to that of Asmanex® Twisthaler® (400 μg, BID).  
Moreover, a 5-day clinical study on a higher dose of Asmanex® Twisthaler® (800 μg, BID) indicated d 
that this dose of MF was also safe and well-tolerated and did not cause clinically significant effects
on clinical laboratory test results or on vital signs [37], although its systemic expo
p sure is 4-fold higher 
than the projected average exposure of LYR-210 (7500 μg).  These data further support the systemic 
safety of LYR-210 (7500 μg).
Table 7:
Comparison of Systemic Exposure of LYR-210 (7500 μg) with
th Clinical Studies
showing Systemic Safety of Chronic Use of MF Products
Drug product
Dose (Pg)
Cmax
(pg/mL)
AUC (Duration) 
(pg h/mL)
AUC24h
(pg h/mL)*
References
Nasonex
200 QD
5.77
29.6 (12 h)
29.6
Nasonex [18]
800 TID
25.5
64 (8 h)
192
Daley-Yates 2004 [38]
Asmanex
Twisthaler
400 BID
114
634 (12 h)
1268
Asmanex Twisisththalalerer [39
[39]
400 BID
90.2
646 (12 h)
1292
Kosoglou 2013 [40]
800 BID
383
2820 (12 h)
5640
Kosoglglou 201
0 4 [37]
LYR-210
15000 / 24 
95
175518 (168 d)
d
1045
Lyra Therapeutics


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(7500 μg)
weeks
estimated value
QD=once a day, BID= twice a day, TID = three times a day, h = hour, PI=prescription information.
* AUC24h was obtained by normalizing the literature reported AUC to the respective dosing schedule.
9.1.4.2
Local Safety 
Topical administration of LYR-210 (7500 μg) over a treatment duration of 24 weeks is also 
anticipated to be safe to local nasal tissue supported by the long-term clinical use of Nasonex®.
Summarized in Table 8 are clinical studies showing local tissue safety of high dose and/or long-term 
intranasal use of MF in the form of nasal sprays or nasal implants. Based on these data, it can be 
expected that bilateral placement of LYR-210 (7500 μg) with 15,000 Pg MF delivered over 24 
weeks, with an average daily dose of approximately 89 Pg MF per human subject, or 45 Pg MF per 
nostril, is not expected to cause adverse effects on the nasal mucosa or an elevation of intraocular 
pressure. 
Table 8:
Summary of Clinical Studies showing Local Tissue Safety of Chronic Intranasal 
use of Mometasone Furoate
References
Study Design
Condition & 
Number of 
Subjects in MF 
Treatment 
Group
MF Drug Form, Dose, 
and Duration
Safety Outcome
Local Tissue safety -Nasal Mucosa
Minshall, 
1998 [41]
Multicenter, 
open label study
Adult subject
diagnosed with 
PAR, N=52
MFNS 100 mcg QD in 
each nostril for 12 
months
No adverse tissue changes 
in nasal mucosa in nasal 
biopsies.
Fokkens, 
2012 [2]
Randomized, 
active-
controlled, open 
label study 
Adult subjects
diagnosed with 
PAR, N=42
MFNS 100 mcg QD in 
each nostril for 12 
months
No appreciable change in 
epithelial thickness, the 
percentage of goblet cells 
in nasal biopsies.
Local Tissue safety -Eyes
Bross-
Soriano, 
2004 [42]
Double-blind, 
placebo and 
active-controlled
Adult subjects
diagnosed with 
rhinitis regardless 
of its etiology, 
N=90 
MFNS 100 mcg QD in 
each nostril for 12 
months
No clinically significant 
change to intraocular 
pressure.
Forwith 
2011 [22]
Multicenter, 
open-label
CS subject
underwent 
bilateral ESS, 
N=50
PROPEL implant (MF 
370 mcg) in each 
ethmoid sinus over 30 
days
No clinically significant 
change from baseline to 
intraocular pressure and 
lens opacity.
Marple, 
2012 [23]
Multicenter, 
intra-subject
placebo-
controlled
CS subject
underwent 
bilateral ESS, 
N=105
PROPEL implant (MF 
370 mcg) in one ethmoid 
sinus and a non-drug-
releasing depot in the 
other ethmoid sinus over 
30 days
No clinically significant 
change from baseline to 
intraocular pressure.
(7500 μg)
weeks
estimated value
QD=onc
nce a da
day, BID= twice a day, TID = three times
es a day, h = hour, PI=prescription informatatioion.
* AUC24h was obtained by normalizining the literaturere repor
orteted AU
AU
AUC to the respective dosing schedule.
9.1.
1 4.2
Local Safety 
Topical administration of LYR-21
210 (7500 μg
μg) overer a trereatatme
m nt duration of 24 weeks is also
an
anticipated to be safe to local na
nasal tissue sup
u ported by the long-term clinical use of Nasonex®.
Summarized in Table 8 are clinical studies showing local tissue safety of high dose and/or long-term
intranasal use of MF in the form of nasal sprays or nasal implants. Based on these data, it can be
expected that bilateral placement of LYR-210 (7500 μg) with 15,000 Pg MF delivered over 24
weeks, with an average daily dose of approximately 89 Pg MF per human subject, or 45 Pg MF per 
nostril, is not expected to cause adverse effects on the nasal mucosa or an elevation of intraocular 
pressure. 
Table 8:
Summary of Clinical Studies showing Local Tissue Safety of Chronic Intranasal 
use of Mometasone Furoate
References
Study Design
Condition & 
Number of 
Subjects in MF 
Treatment 
Group
MF Drug Form, Dose,
and Duration
Safety Outcome
Local Tissue safety -Nasal Mucosa
Minshall, 
1998 [41]
Multicenter,
open label study
Adult subject
diagnosed with 
PAR, N=52
MFNS 100 mcg QD in 
each nostril for 12 
months
No adverse tissue changes
in nasal mucosa in nasal 
biopsies.
Fokkens, 
2012 [2]
Randomized, 
active-
controlled, open 
label study 
Adult subjects
diagnosed with 
PAR, N=42
MFNS 100 mcg QD in 
each nostril for 12 
months
No appreciable change in
epithelial thickness, the
percentage of goblet cells
in nasal biopsies.
Local Tissue safety -Eyes
Bross-
Soriano,
2004 [42]
Double-blind, 
placebo and 
active-controlled
Adult subjects
diagnosed with 
rhinitis regardless
of its etiology, 
N=90 
MFNS 100 mcg QD in 
each nostril for 12 
months
No clinically significant 
change to intraocular 
pressure.
Forwith 
2011 [22]
Multicenter,
open-label
CS subject
underwent 
bilateral ESS, 
N=50
PROPEL implant (MF
370 mcg) in each 
ethmoid sinus over 30 
days
No clinically significant 
change from baseline to 
intraocular pressure and 
lens opacity.
Marple, 
2012 [23]
Multicenter,
intra-subject
placebo-
controlled
CS subject
underwent 
bilateral ESS, 
N=105
PROPEL implant (MF
370 mcg) in one ethmoid 
sinus and a non-drug-
releasing depot in the 
other ethmoid sinus over 
30 days
No clinically significant 
change from baseline to 
intraocular pressurere.


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Han, 2014 
[24]
Randomized, 
sham-controlled, 
subject blinded
CRSwNP subject
with prior ESS, 
N=100
One SINUVA implant
(MF 1350 mcg) for 60 
days in conjunction with 
MFNS 100 mcg QD in 
each nostril for 90 days
No clinically significant 
increases in intraocular 
pressure or cataract 
formation.
MFNS=mometasone furoate nasal spray, QD=once a day, SAR= seasonal allergic rhinitis, PAR= perennial 
allergic rhinitis, ESS= ethmoid sinus surgery, CS=chronic sinusitis, CRSwNP=chronic rhinosinusitis with nasal 
polyps
9.1.5
Product Safety Rationale Conclusion
In summary, both LYR-210 (2500 μg) and LYR-210 (7500 μg) release the drug in zero-order 
kinetics over 24 weeks in vivo.  Bilateral placement of LYR-210 (2500 μg) and LYR-210 (7500 μg) 
will deliver an average daily dose of 30 μg and 89 μg MF per human subject, or 15 μg and 45 μg 
MF per nostril, respectively.  Based on literature review and Lyra Therapeutics’ non-clinical
toxicology assessments and Phase I clinical results, these two doses of LYR-210 are expected to be 
safe regarding both local and systemic safety in the proposed Phase II clinical study.
9.2
Anticipated Risks
Lyra Therapeutics has completed a risk analysis and all identified risks have been mitigated to the 
fullest extent possible. Potential expected adverse reactions (ARs) to the subject are similar to those 
associated with endoscopy procedures and current therapies using local or systemic delivery of MF 
that is utilized in several commercially approved MF drug products (Nasonex® [18], Asmanex®
Twisthaler® [39], and Sinuva™ [43]) to treat chronic sinusitis with nasal polyps and respiratory 
diseases. 
9.2.1
Expected ARs Associated with Endoscopic Procedures and LYR-210
Administration/Removal
LYR-210 is inserted into the middle meatus at the drug administration and removed from the middle 
meatus at the end of treatment using minimally invasive endoscopic techniques. The risks associated 
with any general endoscopic procedures (within 24 hours of procedure) are relevant to the 
administration or removal of the LYR-210. The possible expected ARs and the highest incidence 
rates reported in clinical studies of similar products and/or LYR-210 Phase I study that are related to 
endoscopic procedures are summarized in Table 9.
Table 9:
Summary of Expected ARs Associated with LYR-210 Administration or 
Removal Procedure
Incidence rate >5% and ≤ 10%
Procedural headache
Incidence rate >0% and ≤ 5%
Han, 2014 
[24]
Randomized, 
sh
s am-controlled, 
subject blinded
CRSwNP subjec
ect
with prior ESS, 
N=
N 100
One SI
SINU
NUVA implant
(MF 13
1350 mcg) for 60 
da
days in n conjunction with 
MF
M NS 100
00 mcg QD in 
each nostril for 90 days
No clinically significant 
increases inin intraocular 
pressure or cataract 
formation.
MFNS=mometasone furoate nasal spray, QD=once a day, SAR=
R= seasonal allergic rhinitis, PAR= perennial
allergic rhinitis, ESS= ethmoid sinus surgery, CS=chronic sinusitis,s, CRSwNP=chronic rhinosinusitis with nasal 
polyps
9.1.5
Product Safety Rationale Conclusion
In summary, both LYR-210 (2500 μg) and LYR-210 (7500 μg) release the drug in zero-order 
kinetics over 24 weeks in vivo.  Bilateral placement of LYR-210 (2500 μg) and d LY
LYR-210 (7500 μg) 
will deliver an average daily dose of 30 μg and 89 μg MF per human subject, or 15 μg and 45 μg 
MF per nostril, respectively.  Based on literature review and Lyra Therapeutics’ non-clinical
toxicology assessments and Phase I clinical results, these two doses of LYR-210 are expected to be
safe regarding both local and systemic safety in the proposed Phase II clinical study.
9.2
Anticipated Risks
Lyra Therapeutics has completed a risk analysis and all identified risks have been mitigated to the
fullest extent possible. Potential expected adverse reactions (ARs) to the subject are similar to those 
associated with endoscopy procedures and current therapies using local or systemic delivery of MF 
that is utilized in several commercially approved MF drug products (Nasonex® [18], Asmanex®
Twisthaler® [39], and Sinuva™ [43]) to treat chronic sinusitis with nasal polyps and respiratory 
diseases. 
9.2.1
Expected ARs Associated with Endoscopic Procedures and LYR-210
Administration/Removal
LYR-210 is inserted into the middle meatus at the drug administration and removed from the middle
meatus at the end of treatment using minimally invasive endoscopic techniques. The risks associated 
with any general endoscopic procedures (within 24 hours of procedure) are relevant to the
administration or removal of the LYR-210. The possible expected ARs and the highest incidence 
rates reported in clinical studies of similar products and/or LYR-210 Phase I study that are related to 
endoscopic procedures are summarized in Table 9.
Table 9:
Summary of Expected ARs Associated with LYR-210 Administration or
Removal Procedure
Incidence rate >5% and ≤ 10%
Procedural headache
Incidence rate >0% and ≤ 5%


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Dizziness
Epistaxis (moderate)
Facial pain
Nasal congestion
Nasal discomfort
Parosmia
Post procedural discomfort
Presyncope
Rare events without incidence rates reported but potential to endoscopy procedure
Nasopharyngitis
Pharyngitis
9.2.2
Expected ARs Associated with Mometasone Furoate or Nasal Implant
The possible expected ARs and the highest incidence rates reported in clinical studies of MF drug 
products (Nasonex® [18], Asmanex® Twisthaler® [39], and Sinuva™ [44]) and/or LYR-210 Phase I 
study are summarized in Table 10.
Table 10:
Summary of Expected ARs Associated with Mometasone Furoate
Incidence rate > 40% and ≤ 60%
Headache
Rhinitis 
Upper respiratory tract infection
Viral Infection
Incidence rate > 20% and ≤ 40%
Candidiasis
Epistaxis/blood-tinged mucus
Musculoskeletal pain
Pharyngitis
Incidence rate > 10% and ≤ 20%
Alteration of HPA axis (endocrine)
Arthralgia (joint pain)
Back pain
Coughing
Dysmenorrhea
Dyspepsia (indigestion)
Dysphonia
Earache
Fatigue
Flu-like symptoms
Nasal congestion
Nasal odor
Nasal Pharyngitis
Sinusitis 
Incidence rate > 5% and ≤ 10%
Abdominal pain
Diarrhea
Dizziness
Epista ixis (m
(moderate)
Facial pain
Nasal congestion
Nasal discomfort
Parosmia
Post procedural discomfort
Presyncope
Rare events without incidence rates reported but potential to endoscopy procedure
Nasopharyngitis
Pharyngitis
9.2.2
Expected ARs Associated with Mometasone Furoate or Nasal Implant
The possible expected ARs and the highest incidence rates reported in clinical studies of MF drug
products (Nasonex® [18], Asmanex® Twisthaler® [39], and Sinuva™[44]) and/or LYR-210 Phase I 
study are summarized in Table 10.
Table 10:
Summary of Expected ARs Associated with Mometasone Furoate
Incidence rate > 40% and ≤ 60%
Headache
Rhinitis 
Upper respiratory tract infection
Viral Infection
Incidence rate > 20% and ≤ 40%
Candidiasis
Epistaxis/blood-tinged mucus
Musculoskeletal pain
Pharyngitis
Incidence rate > 10% and ≤ 20%
Alteration of HPA axis (endocrine)
Arthralgia (joint pain)
Back pain
Coughing
Dysmenorrhea
Dyspepsia (indigestion)
Dysphonia
Earache
Fatigue
Flu-like symptoms
Nasal congestion
Nasal odor
Nasal Pharyngitis
Sinusitis
Incidence rate > 5% and ≤ 10%
Abdominal pain
Diarrhea


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Facial Pain
Flatulence
Lower respiratory tract infection
Menstrual disorder
Myalgia (muscle pain)
Nasal discomfort
Nausea
Pain
Rhinorrhea
Sinus congestion
Sneezing
Incidence rate >0% and ≤ 5%
Abnormal hepatic function
Adverse drug reaction (rash)
Catarrh
Chest pain
Conjunctivitis
Dizziness
Dry throat
Ear infection
Edema
Gastroenteritis
Hypertension
Insomnia
Nasal burning
Nasal dryness
Nasal irritation
Parosmia
Presyncope
Pruritus
Pyrexia (fever)
Rhinalgia (nose pain)
Tooth ache
Urinary tract infection
Vomiting
Rare events without incidence rates reported but potential to corticosteroids or 
biodegradable implants
Cataract
Glaucoma
Impaired local wound healing
Nasal ulcer (mucosal erosion, ulceration, perforation)
Reduced bone mineral density
Septum perforation
Sinus perforation
Susceptibility to infection
Swallowing or aspiration of implant or fragments 
Facial Pain
Flatatululen
ence
ce
Lower respiratory tract infection
Menstrual disorder
Myalgia (muscle pain)
Nasal discomfort
Nausea
Pain
Rhinorrhea
Sinus congestion
Sneezing
Incidence rate >0% and ≤ 5%
Abnormal hepatic function
Adverse drug reaction (rash)
Catarrh
Chest pain
Conjunctivitis
Dizziness
Dry throat
Ear infection
Edema
Gastroenteritis
Hypertension
Insomnia
Nasal burning
Nasal dryness
Nasal irritation
Parosmia
Presyncope
Pruritus
Pyrexia (fever)
Rhinalgia (nose pain)
Tooth ache
Urinary tract infection
Vomiting
Rare events without incidence rates reported but potential to corticosteroids or 
biodegradable implants
Cataract
Glaucoma
Impaired local wound healing
Nasal ulcer (mucosal erosion, ulceration, perforation)
Reduced bone mineral density
Septum perforation
Sinus perforation
Susceptibility to infection
Swallowing or aspiration of implant or fragments 


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10.
STATISTICAL ANALYSIS
A Statistical Analysis Plan (SAP) will be developed and finalized before database lock and will 
describe the subject analysis sets to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  Analyses will be carried out using SAS Version 9.4 or higher.
10.1
Analysis Populations
The following analysis sets are defined for analysis purposes:
x
Safety (SAF) analysis set: The SAF analysis set will consist of all randomized subjects
who received the study treatment (Sham procedure or a dose of LYR-210) or treatment
attempt on Day 1. Subjects will be analyzed according to the treatment actually received
or attempted. This is the primary analysis set for safety analyses.
x
Intention-to-treat (ITT) set: The ITT analysis will consist of all randomized subjects who
received the study treatment (Sham procedure or a dose of LYR-210) or treatment
attempt and have post-Day 1 assessments available. Subjects will be analyzed according
to the treatment they were assigned to at randomization. This is the primary analysis set
for efficacy analyses.
x
Per-Protocol (PP) analysis set: The PP analysis set will include all randomized subjects
who received the study treatment, have specific post-Day 1 assessments (i.e., non-
missing data for the assessment being analyzed), and are without major protocol
deviations at the time of the primary analysis. This is a secondary analysis set for the
primary, key secondary, and remaining secondary efficacy analyses. Major protocol
deviations and the definition of the PP analysis set will be identified and finalized based
on blinded review of the data, prior to the data extraction for the primary analysis and
unblinding of the treatment code.
x
Pharmacokinetic (PK) analysis set: The PK analysis set will include all SAF subjects
with at least one evaluable drug concentration post-Day 1. Subjects will be analyzed
according to the successful bilateral treatment received (“actual treatment”). As
concentration data is required to assign the PK analysis set, this can only be done at study
unblinding, at the time of the primary analysis.
10.2
Disposition and Population Assignment
Analysis set assignment will be summarized for all enrolled subjects by randomized treatment.
Subject disposition will be summarized for the ITT set by randomized treatment group and will 
include the total number and percentage of subjects randomized into the study, treated, completed 
the study treatment and the study. The number and percentage of subjects prematurely discontinuing 
from the study treatment and the study will be presented for each treatment group.  Subjects who 
discontinued are categorized into reason for discontinuation; the number and percentage of subjects 
in each category will also be summarized for each treatment group.


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10.3
Demographic and Other Baseline Characteristics
All demographic (age, race, ethnicity, height, weight and BMI) and baseline disease characteristics 
recorded at screening and prior to LYR-210 administration/sham procedure will be summarized, by 
treatment group, for the SAF and ITT analysis sets.  Summaries will include n, mean, standard 
deviation, median, quartiles, and minimum and maximum for continuous variables, and number and 
percentage of subjects in each category for categorial variables.
Medical history, serology, and pregnancy test results will only be listed by subject.
10.4
Prior and Concomitant Medications
Prior medications are those medications that were stopped prior to investigational product 
administration. Concomitant medications are medications that are taken at least once after 
investigational product administration. Medications stopping on the same day as investigational 
product administration will be considered as concomitant medications.
All prior and concomitant medications will be listed. In addition, for each treatment group, the 
number and percentage of subjects taking at least one concomitant medication will be presented.
10.5
Safety Analyses
All safety analyses will be performed using the SAF analysis set. There will be no formal statistical 
tests comparing treatments on safety endpoints and there will be no imputation of missing data.
Treatment-emergent adverse events (TEAEs) are defined as AEs that first occurred or worsened in 
severity during and after the administration of study treatment.
Adverse events will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities (MedDRA). For each study treatment, numbers of TEAEs and incidence rates (number 
and percentage of subjects with at least one TEAE) will be tabulated by preferred term and system 
organ class. 
TEAEs by maximum severity, TEAEs by highest relationship to study procedure and product, 
TESAEs, TEAEs leading to death, and TEAEs leading to discontinuation of study treatment will be 
tabulated as (a) total number of such TEAEs occurring across all subjects; and (b) number and 
percentage of subjects with at least one such TEAE for each treatment group overall and by 
preferred term and system organ class.   Note that subjects experiencing >1 event within the same 
system organ class will be tabulated only under the maximum severity and highest relationship 
experienced for that system organ class; similarly, subjects experiencing >1 event within the same 
preferred term will be tabulated only under the maximum severity and highest relationship 
experienced for that preferred term.
All laboratory test results, vital signs measurements, morning serum cortisol levels and IOP will be 
summarized for each treatment group using descriptive statistics by visit for actual value and for 
percentage change from baseline. The incidence of treatment-emergent abnormal and clinically 


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significantly abnormal laboratory, vital sign, morning serum cortisol levels, IOP values and slit-lamp 
examination findings will be summarized by visit for each treatment group using frequency counts 
and percentages of subjects.
10.6
Efficacy Analyses
All efficacy analyses will be carried out after the last subject completes the Week 28 visit or 
withdraws study prematurely prior to Week 28. Each efficacy analysis will be performed based on 
both the ITT and PP analysis sets.
10.6.1
Primary Efficacy Endpoint Analysis
The primary endpoint is CFBL in the composite score of 7-day average scores of the 4 CS cardinal 
symptoms (CS7DA4S) at Week 4. The 4 cardinal symptoms include nasal blockage 
/obstruction/congestion score facial pain/pressure, reduction/loss of sense of smell, and 
anterior/posterior nasal discharge. Specifically, the score for each of the 4 individual components (on
a scale of 0-3) of this composite score will be collected each day by daily electronic patient reported 
outcome (ePRO). The total score across these 4 components will then be calculated each day to 
create a total composite score for each day. At each of Day 1 (prior to procedure) and Week 4 visits,
the average of the total composite score across the preceding 7 days prior to the visit will be 
calculated for each subject. This 7-day per-subject average total composite score is hereafter referred 
to as CS7DA4S. The null and alternative hypotheses to be tested are:
H0: μL2500 = μC
H0: μL7500 = μC
vs.
vs.
H1: μL2500 < μC
H1: μL7500 < μC
where μL2500, μL7500 and μC are true mean primary endpoint for the LYR-210 (2500 μg) treatment, 
the LYR-210 (7500 μg) treatment, and the control (Sham) treatment, respectively. Descriptive 
statistics (number of observations[n], mean, standard deviation, median, minimum and maximum) of 
the Baseline CS7DA4S score, the Week 4 CS7DA4S score, and the CFBL to Week 4 CS7DA4S
score will be presented for each treatment group. 
The primary efficacy analysis will be performed based on subjects in the ITT analysis set with 
available baseline and Week 4 CS7DA4S score. An analysis of covariance (ANCOVA) model for 
CFBL in CS7DA4S score at Week 4 will be used to determine which of the two null hypotheses
stated above can be rejected. This ANCOVA model will include terms for baseline CSD7A4S score 
as a covariate and the fixed  effects of treatment group (LYR-210 7500 μg, LYR-210 2500 μg, sham 
procedure) and the randomization stratification variables, presence of nasal allergy and presence of 
nasal polyps. 
Additional secondary analyses of the primary efficacy endpoint will be performed using this 
ANCOVA model for the following:


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x
Secondary analyses of the endpoint will also be performed in subjects in the PP analysis set
with available data.
x
All subjects in the ITT analysis set. Missing Week 4 CS7DA4S data will be imputed as
described in Section 10.6.1.1.
x
Assessment of treatment effect across study regions, across nasal allergy groups and across
polyp groups will be performed as described in Section 10.6.1.2.
10.6.1.1
Handling of Missing Data
The primary efficacy endpoint analysis will be performed based on subjects in the ITT analysis set
with available CS7DA4S data at Baseline and Week 4 visit. At each of these visits, a subject is 
considered as having an available (NON-missing) CS7DA4S score if the daily ePRO score is 
available (NON-missing) for at least 5 of the preceding 7 days prior to the time point.
For the secondary analyses based on all subjects in the ITT analysis set regardless of available data 
status, two imputation approaches will be carried out for subjects who have missing Week 4 
CS7DA4S data: (a) Last observation carried forward (LOCF) single imputation method; and (b) 
multiple imputation. 
LOCF will be carried out as follows: the CS7DA4S score at each visit will be calculated in a similar 
manner as described above for the Baseline and Week 4 visits (i.e., 7-day average scores of the 4 CS 
cardinal symptoms at that visit).   If Week 4 CS7DA4S is missing, then the last available CS7DA4S 
calculated at a post-baseline visit prior to Week 4 will be carried forward and be used as the Week 4 
CS7DA4S.
The multiple imputation approach will be carried out as follows:
A. Assuming the missing CS7DA4S pattern at Baseline, Weeks 1, 2, 3 and 4 will not be exactly
monotone across visits through Week 4, then a non-monotone missing pattern in CS7DA4S will
be imputed 50 times to make 50 copies of a dataset with a monotone missing CS7DA4S data
pattern; the Monte Carlo Markov Chain approach will be used for this imputation.
B. For each of these 50 imputed datasets, missing CS7DA4S at Week 4 will be imputed using the
monotone linear regression approach: the imputation regression model will include treatment
group, study center/region, randomization strata variables, CS7DA4S measured at Baseline and
Weeks 1, 2, and 3 scores, and Baseline subject and demographic characteristics that will be
fully specified in the SAP.
C. The above-mentioned analysis of covariance comparing treatments on the mean primary
endpoint will be carried out on each of the 50 imputed datasets. The estimate of the treatment
differences in least square means vs. Sham and their standard errors from each imputed dataset
will be combined across the imputed datasets using PROC MIANALYZE in SAS in order to


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calculate one overall estimate of treatment effect vs. Sham and its standard error for each Lyra 
dose group. From these overall estimates, one t-test statistic and its p-value for each LYR-210
dose vs. Sham, assessing whether the above null hypotheses can be rejected, will be calculated 
and presented.
10.6.1.2
Assessment of Treatment Effect Across Study Regions, Across Nasal Allergy 
Groups and Across Polyp Groups
To assess consistency of treatment difference across study region, descriptive statistics of the 
primary endpoint will be presented by treatment group within each region. An exploratory analysis 
of covariance on the primary endpoint, with independent variables of treatment group, region,
baseline CS7DA4S score, and treatment by region interaction, will be carried out on the ITT analysis 
set with available data.
Similar analyses will be presented to assess consistency of treatment effect across nasal allergy 
groups (yes/no) and polyp groups (yes/no). Assessment of consistency across subgroups such as 
baseline CS7DA4S (below median, at or above median), sex and age (below median, at or above 
median) will be conducted as well. All subgroups to be assessed for treatment effect consistency on 
the primary endpoint will be detailed in the statistical analysis plan. These analyses will be carried 
out on the ITT analysis set with available data.
10.6.2
Key Secondary Efficacy Endpoint Analysis
The key secondary endpoints are:
x
CFBL in CS7DA4S score at Week 24
x
Percentage of subjects with at least 1-point decrease in bilateral Zinreich score in at least
one pair of the anterior ethmoid, maxillary, posterior ethmoid, frontal, or sphenoid
sinuses at Week 24
x
Time to treatment failure:  A treatment failure is defined as, after subject enrollment, the
subject being recommended by treating physician for oral corticosteroid or ESS due to
worsening of CS symptoms, or the subject complaint of persistent CS symptoms with an
average CS7DA4S score over the preceding 30 days greater than or equal to the Baseline
CS7DA4S score.
For each key secondary endpoint, each LYR-210 dose will be compared to sham at a one-sided 0.05 
level of significance. There will be no adjustment of the significance level for multiple comparisons 
across the secondary endpoints. 
10.6.2.1
CFBL in CS7DA4S at Week 24
The first key secondary efficacy endpoint is CFBL in CS7DA4S at Week 24. The primary analysis 
population for this key secondary efficacy endpoint analysis is ITT subjects with available 
CS7DA4S data at Baseline and Week 24 visit. At each of these visits, a subject is considered as 


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having an available (NON-missing) CS7DA4S score if the daily ePRO score is available for at least 
5 of the preceding 7 days prior to the time point.
The analysis will be carried out using an ANCOVA model for change from baseline in CS7DA4S 
score at Week 24 which  includes terms for the baseline CS7DA4S score as a covariate, and fixed  
effects for  treatment group and the randomization stratification variables, presence of nasal allergy 
and presence of nasal polyps.
Additional analyses will be performed for the first key secondary endpoint of CFBL in CS7DA4S at 
Week 24, using this ANCOVA model for the following:
x
Subjects in the PP analysis set with available Baseline and Week 24 CS7DA4S score.
x
All subjects in the ITT analysis set. Missing Week 24 CS7DA4S data will be imputed by
LOCF and by multiple imputation (details of imputation of missing data are discussed in
Section 10.6.1.1).
x
Assessment of homogeneity across study regions, across nasal allergy groups and across
polyp groups will be performed in the same manner as for the primary endpoint as described
in Section 10.6.1.2.
10.6.2.2
Percentage of Subjects with Improved bilateral Zinreich score
The second key secondary endpoint is the percentage of subjects with at least 1-point decrease in 
bilateral Zinreich score in at least one pair of the anterior ethmoid, maxillary, posterior ethmoid, 
frontal, or sphenoid sinuses post treatment. Treatment groups will be compared using logistic 
regression adjusting for the baseline total Zinreich score and randomization strata. This analysis will 
be performed using subjects in the ITT analysis set with available post-treatment MRI data and 
repeated with the PP analysis set. There will be no imputation of missing data.
10.6.2.3
Time-to-Treatment Failure
The third key secondary endpoint is the time-to-treatment failure. A treatment failure is defined as, 
after subject enrollment, the subject being recommended by treating physician for oral corticosteroid 
or ESS due to worsening of CS symptoms, or the subject complaint of persistent CS symptoms with 
an average CS7DA4S score over the preceding 30 days greater than or equal to the baseline 
CS7DA4S score. Time to treatment failure will be analyzed using a Cox proportional hazards model 
with fixed effects for available baseline CS7DA4S score, treatment group and the randomization 
stratification variables. Kaplan-Meier plots of time to treatment failure will be presented for each 
treatment group. There will be no imputation of missing data; subjects without the event through 
Week 24 will be censored at the end of their follow-up period. This analysis will be performed using 
subjects in the ITT analysis set with available data and repeated using subjects in the PP set analysis 
set with available data.


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10.6.3
Non-Key Secondary Efficacy Endpoint Analysis
The non-key secondary efficacy endpoints that are continuous variables will be compared between 
treatments at each post-Day 1 in the same manner as the primary endpoint for the ITT set with 
available data and the PP set. In addition, for analyses on all ITT regardless of missing data status, 
LOCF will be used to impute missing secondary efficacy continuous endpoint data. For 
questionnaires (e.g., SNOT-22) at a given visit, if responses are missing for <50% of the questions at 
that visit then the missing responses will be imputed with the median of non-missing responses at 
that visit. Otherwise, if responses are missing for ≥50% of the questions at that visit, the entire 
questionnaire score at that visit will be considered missing and such missing questionnaire scores 
will be imputed as missing data in the same manner as for the other non-key secondary endpoints.
For non-secondary dichotomous efficacy endpoints, the number and percentage of subjects with the 
outcome will be presented for each treatment group.  The proportion of subjects will be analyzed 
using a logistic regression model with effects for baseline CS7DA4S score, treatment group and the 
randomization stratification variables, presence of nasal allergy and presence of nasal polyps. The 
analysis will be carried out on the ITT analysis set with available data and repeated using subjects in 
the PP analysis set with available data.
Secondary efficacy endpoints involving time-to-event endpoints will be analyzed as specified in 
Section 10.6.2.3.
10.6.4
Exploratory Endpoint Analysis
A one-sided 0.05 level of significance will be used to compare treatments for each exploratory 
efficacy endpoint at each visit; there will be no adjustment for multiple comparisons. These analyses 
will be performed in the ITT analysis set with available data and repeated using subjects in the PP 
analysis set. There will be no imputation of missing data for these analyses.
The exploratory efficacy endpoints that are continuous variables will be compared between 
treatments at each post-Baseline time point in the same manner as the primary endpoint.  For 
dichotomous efficacy endpoints, treatments will be compared using logistic regression adjusting for
baseline score and randomization strata.  
As further exploratory analyses on all endpoints measured longitudinally at various visits during the 
study, generalized estimating equation (GEE) linear regression (for continuous outcomes) and GEE 
logistic regression (for dichotomous outcomes) will be used to compare treatments over time; the 
assumed within-subject correlation matrix structure will be unstructured; if the unstructured model 
does not converge, then an autoregressive (1) structure will be assumed. Included as independent 
variables for each outcome variable will be treatment group, visit, treatment-by-visit and the baseline 
value of the variable being analyzed. If the treatment-by-visit interaction is not significant at the 0.10 
level of significance, it will be removed from the GEE model.  This will be carried out on ITT
subjects with available data.


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10.6.5
Pharmacokinetic Analyses 
The PK analyses will be performed based on subjects in the PK analysis set.
10.6.5.1
Pharmacokinetic Concentrations 
PK concentration will be summarized for subjects in the PK analysis set with available data by
treatment group as follows:
x
A listing by subject of all concentrations, nominal times post dose, and actual times.
Deviations from the nominal times per protocol will be given in a separate listing. In listings,
concentrations below the lower limit of quantification (LLOQ) will be reported as “<LLOQ”,
where LLOQ will be the actual value of LLOQ (to be determined).
x
A descriptive statistics summary of concentrations by dose and nominal time post dose,
including number (n), mean, standard error, standard deviation, coefficient of variation (CV),
median, minimum, maximum, geometric mean, geometric CV%, and the number of
concentrations ≥LLOQ. The “<LLOQ” values will be set to zero based on the Beal’s method
M7 [45].
10.6.5.2
Pharmacokinetic Parameters
PK parameters of MF will be estimated using a standard noncompartmental PK approach based on 
individual plasma concentration-time data as data permit (e.g. the availability of the PK study 
cohorts at Day 3, 7, 14, and 21). Actual PK sampling times will be used in the derivation of PK 
parameters. The PK parameters including Cmax and Tmax will be calculated from the plasma 
concentrations versus time profiles. Total drug exposure up to the last measured concentration 
(AUC0-last) and the 12-hour average drug exposure (AUC0-12h average) will be calculated. The AUC0-last
will be defined as the area under the concentration time curve from the time of dose until the last 
concentration above the LLOQ.  The AUC0-12h average is a value derived from AUC0-last by dividing it 
by the corresponding total dose time (in hour) and then multiplying by 12.
10.7
Sample Size
The primary endpoint is CFBL in CS7DA4S score at Week 4. The null and alternative hypotheses to 
be tested are:
H0: μL2500 = μC
H0: μL7500 = μC
vs.
vs.
H1: μL2500 < μC
H1: μL7500 < μC
where μL2500, μL7500 and μC are true mean primary endpoint for the LYR-210 (2500 μg) treatment, 
the LYR-210 (7500 μg) treatment, and the control (Sham) treatment, respectively. Each null 
hypothesis will be tested at the one-sided 0.05 level of significance. Under the assumptions that μC =
-1.30 and μL2500 and/or μL7500 = -3.00 (conservatively based on the mean of this endpoint for LYR-


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210 in Phase I study, and approximately 130% larger decrease than the assumed control mean of -
1.30) and that the true standard deviation of the primary endpoint within each treatment group is at 
most 2.4, then an evaluable sample size of 63 subjects (21 per treatment group) yields 73% power to 
reject at least one null hypothesis in favor of the alternative at a one-sided 0.05 level of significance. 
An additional 6-9 subjects will be enrolled to account for potential subject dropout.


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11.
REGULATORY OBLIGATIONS
11.1
Statements of Compliance 
This clinical investigation shall be conducted in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, the International Council for Harmonization (ICH) Good 
Clinical Practices (GCP), United States Food and Drug Administration (USFDA) Guidelines and all 
applicable regulatory requirements. The Sponsor will not commence the clinical study until all 
required approval is obtained from the relevant ECs and, if applicable, Regulatory Authorities. All 
required study documentation will be archived as required by Regulatory Authorities.
Prior to initiating the trial, the investigator will provide the Sponsor or designee all required
documents according to ICH GCP guidelines, and at a minimum:
x
A signed FDA Form 1572
x
A current (i.e. updated no more than 24 months prior) curriculum vitae for the Principal
x
Investigator and each sub-investigator listed on the FDA Form 1572. A copy of the
current medical license for the investigator and each sub-investigator
x
A letter from the IRB/EC stipulating approval of the protocol, the informed consent
document, and any other material provided to potential trial subjects with information
regarding the trial (e.g. advertisements)
x
The current IRB/EC membership list for the reviewing IRB/EC
x
A signed Investigator Protocol Agreement
x
A completed financial disclosure form for the investigator and all sub-investigators
x
A current laboratory certification for the local reference laboratory and curriculum vitae
of the laboratory director
x
A list of current laboratory normal values for the reference laboratory
11.2
Site Selection and Training 
The Sponsor will select Investigators with appropriate training and experience to participate in this 
Clinical Investigation. Sites will be selected based upon the qualifications of the Principal 
Investigator at the site as well as other parameters including proven ability and infrastructure to 
perform clinical studies. The complete list of all site Investigators and the relevant clinical sites will 
be maintained within the Sponsor’s Trial Master File. 
In addition to specific training relating to use of the investigational product, the training of the 
Investigator and appropriate clinical site personnel will be the responsibility of the Sponsor (or 
designee) and may be conducted during an Investigator Meeting, a Site Initiation Visit, or other 
appropriate venue. Training will include, but not be limited to, the Clinical Protocol and 
Investigators’ Brochure, CRF completion, GCP, and Clinical Study personnel responsibilities. All 
training will be documented prior to engaging in study-related activities.


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11.3
Ethics Committee (EC) Approval
The Clinical Protocol and Informed Consent Form (ICF) must have the approval of a properly 
constituted EC responsible for approving clinical studies prior to commencing the study at that site. 
Any additional approval requirement(s) of the EC will be followed. Any advertisements used to 
recruit subjects or any subject facing documents will also be reviewed and approved by the EC prior 
to use. 
No investigative procedures other than those defined in this Clinical Protocol will be undertaken on 
the enrolled subjects without the written agreement of the EC and Sponsor. Each site Principal 
Investigator will advise their EC of the progress of this clinical investigation on a regular basis, 
according to EC reporting requirements. Approvals for the continuation of the study at each 
investigational site must be kept current and notifications forwarded to the Sponsor. 
The Sponsor or its designee will submit reports as required by ECs and local and national 
regulations. These reports may include SAEs, withdrawal of EC or Regulatory Authority’s approval, 
annual progress reports, recall information, and final reports. 
11.4
Informed Consent
The Investigators have both an ethical and legal responsibility to ensure that each subject being 
considered for inclusion in this study is given a full explanation of the Clinical Protocol. 
All foreseeable risks and potential benefits which might occur with the use of the investigational 
product will be discussed with the subject. The subject will be informed that, should an unexpected 
adverse product- or study procedure related AE occur, which presents an unreasonable risk to 
participating subjects, he/she will be notified. The subject will be informed that his/her medical 
records are available for review by representatives of the Sponsor or designee, the EC, and the 
appropriate Regulatory Authority, as necessary. 
The subject will be informed that the information obtained during the study will be used to evaluate 
the safety and performance of the investigational product. However, his/her confidentiality will be 
maintained at all times. The subject will be told that he/she is free to refuse study participation or to 
withdraw from the study at any time without compromising future medical care.
The subject must be made aware and agree that personal information may be reviewed during an 
audit by Regulatory Authority and properly authorized persons. However, personal information will 
be treated as strictly confidential and will not be publicly available. As part of the informed consent 
process, the Investigator will obtain subjects’ permission for the Sponsor personnel or designees, 
EC, and Regulatory Authority to review, in confidence, any pertinent records relating to the subjects
in this clinical investigation. 
A sample subject ICF template with standard wording suggested for this study will be provided to 
each Investigator. A copy of the informed consent form from each site must be forwarded to the 


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Sponsor for review and approval to assure compliance with the ICH requirements prior to submitting 
it to the EC.
The EC-approved written consent form is to be reviewed with the subject by the Investigator or 
designee and will be signed by each subject prior to enrolling in the study. The Investigator or 
designee is responsible for maintaining each subject’s ICF in the study file and providing each 
subject with a copy of the ICF.
If new information becomes available that can significantly affect a subject’s future health and 
medical care, that information shall be provided to the subject affected in written form. If relevant, 
all affected subjects shall be asked to confirm their continuing informed consent in writing. 
11.5
Protocol Amendments 
The Clinical Protocol, eCRFs, ICF and other subject information, or other clinical investigation 
documents shall be amended as needed throughout the clinical investigation, and a justification 
statement shall be included with each amended section of a document. Proposed amendments to the 
Protocol shall be agreed upon between the Sponsor and Principal Investigator. The amendments to 
the Protocol and the subject’s ICF (if required) shall be provided to and approved by, the local 
Regulatory Authorities and ECs, as required. For non-substantial changes (e.g., minor logistical or 
administrative changes, change of monitor[s], telephone numbers, renewal of insurance) not 
affecting the rights, safety, and well-being of human subjects, or not related to the clinical 
investigation objectives or endpoints, a simple notification to the EC and, where appropriate, local 
Regulatory Authority can be sufficient. The version number and date of amendments shall be 
documented.
11.6
Protocol Deviations 
The Investigator agrees to conduct the study according to the Clinical Protocol and agrees that all 
persons delegated to perform study procedures will do so as well. An Investigator is not permitted to 
deviate from the Protocol without the prior written approval of the Sponsor unless there are concerns 
of subject’s safety. Under emergency circumstances, deviations from the Protocol to protect the 
rights, safety, and well-being of human subjects may proceed without prior approval of the Sponsor 
and the EC. Such deviations shall be documented and reported to the Sponsor and the EC (as 
required) as soon as possible.
A protocol deviation is a failure to comply with the requirements specified within this clinical study 
protocol. Examples of protocol deviations may include enrollment of a study subject who does not 
meet all of the inclusion/exclusion criteria specified in the protocol, visits performed outside of the 
protocol specified visit window, and missed study visits. Each site Investigator shall conduct this 
clinical study in accordance with this clinical study protocol, local regulatory authority regulations, 
GCP, and any conditions of approval imposed by their ECs. 


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The Investigator agrees to inform the EC of all protocol deviations according to Institutional 
requirements. The occurrence of protocol deviations will be monitored by the Sponsor personnel or 
designee on an ongoing basis. Deviations from the protocol include, but are not limited to, the use of 
prohibited medications or therapies and out of window visits. All protocol deviations should be 
documented and explained. Major protocol violations are defined as those that could impact the 
performance evaluation such as a subject is ineligible, missing key data, received an unauthorized 
treatment, etc. All subjects with protocol deviations will continue to be followed for safety and 
performance assessments. 
If an Investigator is found to be repeatedly non-compliant with the Clinical Trial Research 
Agreement, study Protocol or any other conditions of the Clinical Study, the Sponsor at its sole 
discretion, will either undertake remedial measures to secure compliance or terminate the 
Investigator's participation in the study.
11.7
Study Monitoring
An appropriate representative of the Sponsor or designee (Study Monitor) will verify subject data 
and ensure compliance with GCP, Clinical Protocol and other study requirements, according to the 
guidelines set forth in the monitoring SOPs and applicable regulatory requirements. The Study 
Monitor will ensure the Investigator continues to have appropriate staff and facilities to conduct the 
Clinical Study safely and effectively. Monitoring will be performed in accordance with a pre-
specified monitoring plan that is in compliance with applicable SOPs.
Completed CRFs will be verified by the monitor at the investigational sites at regular intervals 
throughout the study. The Investigator will allow the monitor and/or representative of the Sponsor, 
and any regulatory body to review and inspect the study files, subject CRFs, subject medical records 
and other related study documents as required.
All CRFs will be reviewed for completeness and clarity. Missing or unclear data will be investigated 
by the monitor and will be retrieved, clarified and completed by study personnel as necessary 
throughout the study. The Sponsor or their authorized representative may request additional 
documentation from the Investigator such as physician procedure notes or physician written 
summaries when adverse events are observed and reported. 
11.8
Data Quality Assurance
The Investigator/designees will maintain accurate source documentation as part of subject case 
histories. Electronic data capture will be utilized for collecting subject data in the clinical database.
Each site is required to have a computer and internet connection available for site entry of clinical 
data. Only authorized users will get access to the eCRF as appropriate to their study responsibilities. 
Site users must have successfully undergone EDC training prior to entering data into the eCRF. The 
Sponsor and CRO will ensure that an appropriate eCRF is developed to capture the data accurately.
The database will allow users to enter data and manage modifications documented by an audit trail.
Appropriate queries will be raised to resolve any missing or inconsistent data within the clinical 


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database. Data management will ensure that all data has been entered, cleaned, closed and signed by 
the Investigator prior to database lock. 
Data Management procedures will be completed in accordance with the CRO’s Standard Operating 
Procedures. The details will be provided in the Data Management Plan for the study.
The Sponsor will also ensure that AE data collected in the eCRF are consistent with information 
provided to the service providers Pharmacovigilance department. The coding of an AE, medical 
history and concomitant medication terms will be performed by the service provider. Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary and 
AEs/medical history terms will be coded using MedDRA.
11.9
Record Retention
Each Investigator will maintain all records pertaining to this Clinical Study as required by local 
regulations, the relevant EC and the Institution. The Investigator will maintain all study related 
documentation including all correspondence, records of financial interest, individual subject records, 
informed consent forms, all investigational product accountability records, the protocol with any/all 
amendments, all correspondence with and approval from all regulatory agencies, the budget 
agreement, the Investigator agreement, and copies of case report forms. 
Essential documents should be retained until at least 2-years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with the sponsor. 
It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. No study document will be destroyed without prior written 
agreement between the Sponsor and the Investigator. In addition, in accordance with the Clinical 
Trial Agreement (CTA), the Sponsor should be contacted if the Investigator plans to leave the 
investigational site so that appropriate arrangements can be made for the transfer of the records to 
the appropriate designee at the study site.
11.10
Auditing
The Investigator will make all pertinent records available including source documentation for 
inspection by their EC or a Regulatory Authority and for auditing by the Sponsor or designee. This 
information will be considered confidential. The Sponsor’s or designee’s audit will be independent 
of and separate from routine internal monitoring or quality control function and will serve to 
evaluate the study conduct and compliance with the Protocol, SOPs, GCP, and the applicable 
regulatory requirements.
In the event that an Investigator is contacted by a Regulatory Authority or EC in relation to this 
Clinical Study, the Investigator will notify the Sponsor immediately and must provide the Sponsor 


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with copies of any associated correspondence (e.g. EC Audit Reports, warning letters). The Sponsor 
will provide any necessary support in responding to Regulatory Authority and EC audit requests.
11.11
Use and Publication of Study Results
All unpublished documentation (such as the Clinical Protocol, CRFs, IFU, and IB) given to the 
Investigator is strictly confidential. All recipients must agree not to disclose the information herein 
contained to any person without the prior written authorization of the Sponsor. The submission of 
these documents to the EC is expressly permitted. The Investigator agrees that the Sponsor maintains 
the right to use the results of this study in their original form and/or in a global report for submission 
to governmental and Regulatory Authority of any country.
The data and results from the Clinical Study are the sole property of the Sponsor. The Sponsor shall 
have the right to access and use all data and results generated during the clinical investigation. An 
Investigator may only publish data generated by this Clinical Study in accordance with the terms of 
the Clinical Trial Research Agreement. 
11.12
Confidentiality
The Investigator has a responsibility to ensure that subject anonymity is protected and maintained. 
He or she must also ensure that their identities are protected from any unauthorized parties. All study
data will be stored and archived in line with national and local laws and regulations on the protection 
of personal data. 
Subjects will be informed that the Sponsor or designee will have access to their medical records. 
Data relating to the study may be made available to third parties (e.g., in the case of an audit 
performed by a Regulatory Authority) provided the data are treated confidentially and that the 
subject’s privacy is guaranteed. Subject’s participation in the study will be treated as confidential 
and subject’s will not be referred to by name in any report of the study. Subject confidentiality will 
be maintained throughout the Clinical Study in a manner that ensures the information can always be 
tracked back to the source data. For this purpose, a unique subject identification code will be used 
that allows identification of all data reported for each subject. The identity of the subjects will not be 
disclosed in any study records and subjects’ data will be described using the unique subject
identifier. Subject data will be processed electronically to determine the outcome of this study, and 
to provide to health authorities. Subjects will be advised that all data may be transferred to other 
countries.
11.13
Early Study Discontinuation
The Sponsor reserves the right to discontinue the Clinical Study at any stage, with suitable written 
notice to the Investigator. The Investigator may also discontinue participation in the Clinical Study
with suitable written notice to the Sponsor.
Specific instances that may precipitate site termination include but are not limited to the following 
reasons:


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x
The discovery of an unexpected, serious, or unacceptable risk to subjects enrolled in the
study
x
A decision by the Sponsor to suspend or discontinue testing, evaluation, or development
of the investigational product
x
Failure of the Investigator to enroll subjects into the study at an acceptable rate
x
Failure of the Investigator to comply with pertinent regulations of IRB/EC or appropriate
regulatory authorities
x
Failure of the Investigator to comply with the protocol
x
Submission of knowingly false information from the research facility to the Sponsor, the
study monitor, IRB/EC or regulatory authority
x
Insufficient adherence to protocol requirements consistent with the United States Code of
Federal Regulations (CFR) 21 CFR 312, [insert AUS / NZ standards], the European
Clinical Trial Directive 2001/20/EC, or other relevant national regulations, as appropriate
x
Study termination and follow-up will be performed in compliance with the conditions set
forth in International Council for Harmonization (ICH) E6(R2) on Good Clinical Practice
(GCP) as well as 21 CFR 312.56b, Australian Clinical Trial Handbook, Medsafe
guidelines on the regulations of therapeutic products in New Zealand , the European
Clinical Trial Directive 2001/20/EC, and other relevant national regulations, as
appropriate, which require a Sponsor to ensure an Investigator’s compliance with these
requirements and to promptly secure a plan for compliance or discontinue shipments of
the study drug to the Investigator and end the Investigator’s participation in the study.
If the study is discontinued for any reason, the Sponsor will provide guidelines to the institutions on 
how to safely exit subjects and appropriately close the study. Additionally, if the study is suspended, 
the Sponsor will promptly work with the Investigators/institutions to inform the local Regulatory 
Authorities of the termination or suspension and the reason(s) for the termination or suspension. The 
Investigator should also notify the EC promptly and provide the reason(s) for the termination or 
suspension by the Sponsor or by the Investigator/institution. An appropriate schedule for termination 
will be instituted.


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12.
CLINICAL RISK AND BENEFIT ANALYSIS
Despite the high prevalence of disease, there is no approved drug therapy for the treatment of CS. 
Evidence-based therapies typically involve chronic off-label use of intranasal corticosteroids 
sprays (INCS) with adjunctive use of saline irrigation, and culture directed antibiotics [9]. however,
the effect of INCS is limited by inefficient drug delivery into the deep nasal passage and/or poor 
subject compliance [10, 11].  Second line medical therapy generally used for management of flare-ups 
and worsening inflammation or severe nasal polyps includes a short course (1-3 weeks) of oral 
corticosteroids [2, 3]. While effective initially, improvements are generally not sustained for more than 
3 months [12, 13]. Additionally, oral corticosteroids can lead to systemic side effects including mood 
disturbance, gastrointestinal issues, diabetes, cataracts, glaucoma, osteoporosis and rarely avascular 
necrosis of the hip and shoulder [14, 15]
Subjects enrolled in this Phase II study will include patients who have not had functional endoscopic 
sinus surgery but their symptoms are not adequately controlled on medical management and are 
seeking further treatment. This may include patients who are considering sinus surgery or those who 
have decided against it. The anticipated benefits over existing medical therapies, for subjects in this 
trial (who have failed previous medical management and have limited treatment options) are 
increased control of and local delivery of a known effective anti-inflammatory corticosteroid drug 
(mometasone furoate) to a targeted area that is difficult to reach by intranasal sprays for an extended 
duration of time without the need for daily use compliance. Subjects are expected to experience 
decreased sino-nasal symptoms, assessed and recorded by daily ePRO and the SNOT-22 subject 
reporting instruments (see Section 8.3.1 Subject Reported Outcomes), as well as improvement of
their general physical and mental health assessed by SF-36v2 questionnaire. 
Phase I study subjects had bilateral placement of LYR-210 (2500 μg) under topical anesthesia with 
endoscopic guidance. At the week-24 visit, LYR-210 (2500 μg) was removed using standard 
instruments. No local nasal AEs, including epistaxis, nasal burning, nasal dryness, nasal irritation, 
and nasal septal perforation, were reported.  Mean changes from baseline over time in intraocular 
pressure (IOP) were minimal and not statistically significant. No subject had intraocular 
hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported. Mean changes 
from baseline over time in morning serum cortisol levels were minimal and not statistically 
significant. No AEs indicative of adrenal insufficiency were reported. There were no adverse events 
associated with systemic levels of MF. No change in morning serum cortisol levels or intraocular 
pressures were noted (see Section 5.2 of the IB).  
The safety of the active ingredient in LYR-210, mometasone furoate, has been demonstrated across a 
range of commercially approved nasal and oral medication dosage forms including Nasonex® [46],
Asmanex® Twisthaler® [17], Sinuva™ [44] and PropelTM [47] for the treatment  of allergic rhinitis and 
nasal polyps, asthma, nasal polyps in patients who have  had ethmoid sinus surgery, or maintaining 
patency following sinus surgery, respectively.
12.
CLINICAL RISK AND BENE
NEFIT AN
ANALYSIS
Despite the high prevalence of disease, therere e is no o appr
pr
p oved drug therapy for the treatment of CS. 
Evidence-based therapies typically involve chro inic f
off-f label use of intranasal corticosteroids
sprar ys (INCS) with adjuj nctive use of saline irrigation, and
nd culture directed antibiotics [9]. however,
the effect of INCS is limited by
by ine
nefficient dru
r g de
deliliverery ininto the deep nasal passage and/or poor 
su
subject compliance [10, 11].  Sec
econ
ond line med
edical therapy generally used for management of flare-ups s 
and worsening inflammation or severe nasal polyps includes a short course (1-3 weeks) of oral 
corticosteroids [2, 3]. While effective initially, improvements are generally not sustained for more than 
3 months [12, 13]. Additionally, oral corticosteroids can lead to systemic side effects including mood 
disturbance, gastrointestinal issues, diabetes, cataracts, glaucoma, osteoporosis and rarely avascular 
necrosis of the hip and shoulder [14, 15]
Subjects enrolled in this Phase II study will include patients who have not had functional endoscopic 
sinus surgery but their symptoms are not adequately controlled on medical management and are 
seeking further treatment. This may include patients who are considering sinus surgery or those who 
have decided against it. The anticipated benefits over existing medical therapies, for subjects in this 
trial (who have failed previous medical management and have limited treatment options) are 
increased control of and local delivery of a known effective anti-inflammatory corticosteroid drug
(mometasone furoate) to a targeted area that is difficult to reach by intranasal sprays for an extended 
duration of time without the need for daily use compliance. Subjects are expected to experience 
decreased sino-nasal symptoms, assessed and recorded by daily ePRO and the SNOT-22 subject
reporting instruments (see Section 8.3.1 Subject Reported Outcomes), as well as improvement of
their general physical and mental health assessed by SF-36v2 questionnaire. 
Phase I study subjects had bilateral placement of LYR-210 (2500 μg) under topical anesthesia with
endoscopic guidance. At the week-24 visit, LYR-210 (2500 μg) was removed using standard 
instruments. No local nasal AEs, including epistaxis, nasal burning, nasal dryness, nasal irritation,
and nasal septal perforation, were reported.  Mean changes from baseline over time in intraocular 
pressure (IOP) were minimal and not statistically significant. No subject had intraocular 
hypertension (IOP >21 mmHg) and no AEs indicative of high IOP were reported. Mean changes 
from baseline over time in morning serum cortisol levels were minimal and not statistically 
significant. No AEs indicative of adrenal insufficiency were reported. There were no adverse events 
associated with systemic levels of MF. No change in morning serum cortisol levels or intraocular 
pressures were noted (see Section 5.2 of the IB).  
The safety of the active ingredient in LYR-210, mometasone furoate, has been demonstrated acros
oss s a
range of commercially approved nasal and oral medication dosage forms including Nasonex® [46],
Asmanex® Twisthaler® [17], Sinuva™ [44] and PropelTM [47] for the treatment  of allergic rhinitis and 
na
n sa
s l polyps, asthma, nasal polyps in patients who have  had ethmoid sinus surgery
r , or
or ma
m intaini ing
pa
pa
p tet ncy following sinus surgery, respectively.


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In terms of the bioabsorbable polymers; polyester families have a long history of use in 
bioabsorbable medical sutures such as Vicryl® (PLGA 10:90) and Monocryl® (PGCL 75:25) from 
Ethicon (Bridgewater, NJ, USA) and the PLCL suture from Catgut GmbH (Markneukirchen, 
Germany). These polymers are also used extensively as inactive ingredients for sustained release of 
parenteral drugs [48] (see Section 4.1 of the IB).  
Risks Analysis
Potential risks to the trial subjects are similar to those associated with endoscopy procedures and 
current therapies using local or systemic delivery of MF. More detailed information regarding 
clinical safety data can be found Section 9 (Safety Information of Study Drug Product) and in the IB 
(Section 6 Summary of Data and Guidance for the Investigator and Section 7 Reference Safety 
Information).
In clinical evaluations to date (Phase I clinical study) treatment-emergent adverse events (TEAE)
that occurred in more than 1 subject (TEAEs) have been adverse drug reaction (rash), facial pain, 
nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, headache, and nasal odor, 
and were reported in 14/20 subjects (see Section 5.2 of IB). All these events were considered to be 
non-serious, mild or moderate in severity, and anticipated risks related to endoscopic procedures. 
There were no reported AEs due to the removal procedure.
The possible risks and the highest incidence rates reported in clinical studies of similar products 
and/or LYR-210 Phase I study that are related to endoscopic procedures include procedural 
headache, epistaxis (moderate), facial pain, nasal congestion, nasal discomfort, parosmia, post 
procedural discomfort and presyncope (see Section 5.2 of IB).
Subjects will be closely monitored as part of the trial with subject safety monitored according to 
Medical Monitoring Plan (MMP) which defines in detail objectives, scope and roles and 
responsibilities of each team member involved (see Section 8.4.10 Safety Monitoring). Safety 
monitoring will be followed strictly in accordance with the study MMP.
An independent Data Monitoring Committee (DMC) will be formed by charter to assist in 
examining safety data periodically during the study (see Section 4.5 Data Monitoring Committee).
The DMC can recommend treatment discontinuation for individual subjects as well as to halt the 
entire study temporarily or permanently. Predefined stopping rules will guide the DMC review 
process. 
Extensive inclusion and exclusion criteria will also apply (see Sections 5.3 Inclusion Criterion and 
5.4 Exclusion Criterion) for which both the risks with MF and endoscopy procedures have been fully 
considered.  These include those contraindications detailed in the product literature for approved MF 
Nasal Sprays, such as excluding those subjects with localized infection, those who have experienced 
recent nasal surgery and those who are immunosuppressed (Nasonex® product literature).  
In terms of the bioabsorbable polymers; polylyes
e ter fami
mililies have a long history of use in 
bioabso
sorb
rbab
ablele medical sutures such as Vicrylyl® (P
( LGA 
A 10:90) and Monocryl® (P
(PGCL 75:25) from 
Ethicon (Bridgewater, NJ, USA)
A  and the PLC
LCL suture from Catgut GmbH (Markneukirchen, 
Germany). These polymers arere also used extensively as ininactive ingredients for sustained release of 
pa
parenteral drugs
gs [48] (s(see
ee Sec
ectition
on 4.1.1 of the IB
IB). 
Ri
Risks Analysis
Potential risks to the trial subjects are similar to those associated with endoscopy procedures and 
current therapies using local or systemic delivery of MF. More detailed information regarding 
clinical safety data can be found Section 9 (Safety Information of Study Drug Product) and in the IB
(Section 6 Summary of Data and Guidance for the Investigator and Section 7 Reference Safety 
Information).
In clinical evaluations to date (Phase I clinical study) treatment-emergent adverse events (TEAE)
that occurred in more than 1 subject (TEAEs) have been adverse drug reaction (rarash), facial pain, 
nasopharyngitis, pharyngitis, sinusitis, upper respiratory tract infection, headache, and nasal odor, 
and were reported in 14/20 subjects (see Section 5.2 of IB). All these events were considered to be
non-serious, mild or moderate in severity, and anticipated risks related to endoscopic procedures. 
There were no reported AEs due to the removal procedure.
The possible risks and the highest incidence rates reported in clinical studies of similar products 
and/or LYR-210 Phase I study that are related to endoscopic procedures include procedural
headache, epistaxis (moderate), facial pain, nasal congestion, nasal discomfort, parosmia, post
procedural discomfort and presyncope (see Section 5.2 of IB).
Subjects will be closely monitored as part of the trial with subject safety monitored according to
Medical Monitoring Plan (MMP) which defines in detail objectives, scope and roles and 
responsibilities of each team member involved (see Section 8.4.10 Safety Monitoring). Safety 
monitoring will be followed strictly in accordance with the study MMP.
An independent Data Monitoring Committee (DMC) will be formed by charter to assist in 
examining safety data periodically during the study (see Section 4.5 Data Monitoring Committee).
The DMC can recommend treatment discontinuation for individual subjects as well as to halt the 
entire study temporarily or permanently. Predefined stopping rules will guide the DMC review 
process. 
Extensive inclusion and exclusion criteria will also apply (see Sections 5.3 Inclusion Criterion and 
5.4 Exclusion Criterion) for which both the risks with MF and endoscopy procedures have been fully 
considered.  These include those contraindications detailed in the product literature for r ap
appr
prov
oved MF
Nasal Sprays, such as excluding those subjects with localized infection, those who have experienced 
rerecent nasal surgery and those who are immunosuppressed (Nasonex® product literatuturere).)   


LYRA THERAPEUTICS, INC.
STUDY LYR-210-2018-002
VERSION 8.0 (30JUNE2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 106 OF 129
Following the use of intranasal corticosteroids, instances of increased intraocular pressure have been 
reported (Nasonex®). Subjects who have had past or present acute or chronic intracranial or orbital 
complications of CS (e.g., brain abscess, related problems with eyes or central nervous system) or a 
history/diagnosis (in either eye) of glaucoma or ocular hypertension (IOP > 21 mmHg) will be 
excluded from this trial. Nasonex is also not recommended in cases of nasal septum perforation; 
again, subjects with evidence of mucosal erosion and ulceration or nasal septal perforation will be 
excluded from this trial. In addition, subject who have had more than 1 episode of epistaxis bleeding 
requiring medical attention within 2 months of screening visit or more than 1 episode of epistaxis 
with frank bleeding within 1 month of screening visit, will be excluded (epistaxis is mentioned in 
Section 4.4 Special warnings and precautions of the summary of product characteristics (SmPC) of
Nasonex®).
Subjects with complete/near complete middle meatal obstruction preventing proper placement and/or 
visualization of LYR-210, will also be excluded. 
Strict subject withdrawal/discontinuation criteria will also apply (see Section 4.3 Discontinuation of 
Study Subjects) including any serious AE (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition that indicates to the Investigator that 
continued participation is not in the best interest of the subject. Subjects will be withdrawn from the 
study if they require systemic corticosteroid medication or surgical intervention.
Prior and concomitant medications criteria is specified (see Sections 6.4.2 Prohibited Concomitant 
Medications and 6.4.3 Permitted Concomitant Medications) to avoid confounding the efficacy and 
safety assessment and LYR-210 and specific rescue medication is recommended for an acute 
exacerbation of symptoms that has lasted ≥ 7 days and resulted in the subject contacting the 
Investigator (see Section 6.4.4 Rescue Concomitant Medications).
In the Phase I study, in 5 of the 20 subjects, 1 of the bilaterally administered LYR-210 was expelled 
through the nose while sneezing or coughing between week-9 and week-21 post treatment; 4 of the 5 
dislodgements occurred after week 14. The final drug depot retention rate was 86.1% at week 24 
visit, the highest retention rate reported to date (see Section 5.3 of IB). No AEs were associated with 
these drug depot dislodgements. In the Phase II study, if spontaneous dislodgement of LYR-210
occurs before the scheduled removal visit at Week 24, subjects are required to call the study clinic 
immediately. Subject will remain in the study unless an early treatment discontinuation is 
recommended by the treating physician subject requests depot removal from the remaining side of 
the nose, or depots spontaneously dislodged from both sides of the nose (see Section 4.1.2).
Only Investigators with substantial experience in endoscopic interventions will be allowed to 
participate in the Study. Once selected, Investigators will undergo product-specific training prior to 
enrolling subjects.
Through a systematic analysis of relevant commercially approved MF drugs and based on the Phase 
Following the use of intranasal corticosteroids,s  instanc
nces
es of increased intraocular pressure have been 
reported (Nasonex®). Subjects who have had past or pr
present acute or chronic intntracranial or orbital 
complications of CS (e.g., brainin abscess, related problems with eyes or central nervous system) or a 
hihists ory/diagnosis (in either eye
ye) of glaucoma or ocular hy
hypertension (IOP > 21 mmHg) will be 
ex
excluded from ththisis tririalal. Na
Naso
sone
nex x isis alslso not t recomm
mmen
ende
d d d inin cases of nasal septum perforation;
again, subjects with evidence of mucosal ero
rosion an
and lulce
ceration or nasal septal perforation will be 
excluded from this trial. In addition, subject who have had more than 1 episode of epistaxis bleeding 
requiring medical attention within 2 months of screening visit or more than 1 episode of epistaxis 
with frank bleeding within 1 month of screening visit, will be excluded (epistaxis is mentioned in 
Section 4.4 Special warnings and precautions of the summary of product characteristics (SmPC) of
Nasonex®).
Subjects with complete/near complete middle meatal obstruction preventing proper placement and/or 
visualization of LYR-210, will also be excluded. 
Strict subject withdrawal/discontinuation criteria will also apply (see Section 4.3 Discontinuation of 
Study Subjects) including any serious AE (SAE), clinically significant AE, severe laboratory 
abnormality, intercurrent illness, or other medical condition that indicates to the Investigator that
continued participation is not in the best interest of the subject. Subjects will be withdrawn from the 
study if they require systemic corticosteroid medication or surgical intervention.
Prior and concomitant medications criteria is specified (see Sections 6.4.2 Prohibited Concomitant 
Medications and 6.4.3 Permitted Concomitant Medications) to avoid confounding the efficacy and 
safety assessment and LYR-210 and specific rescue medication is recommended for an acute 
exacerbation of symptoms that has lasted ≥ 7 days and resulted in the subject contacting the 
Investigator (see Section 6.4.4 Rescue Concomitant Medications).
In the Phase I study, in 5 of the 20 subjects, 1 of the bilaterally administered LYR-210 was expelled 
through the nose while sneezing or coughing between week-9 and week-21 post treatment; 4 of the 5 
dislodgements occurred after week 14. The final drug depot retention rate was 86.1% at week 24 
visit, the highest retention rate reported to date (see Section 5.3 of IB). No AEs were associated with 
these drug depot dislodgements. In the Phase II study, if spontaneous dislodgement of LYR-210
occurs before the scheduled removal visit at Week 24, subjects are required to call the study clinic 
immediately. Subject will remain in the study unless an early treatment discontinuation is 
recommended by the treating physician subject requests depot removal from the remaining side of 
the nose, or depots spontaneously dislodged from both sides of the nose (see Section 4.1.2).
Only Investigators with substantial experience in endoscopic interventions will be allowed to
participate in the Study. Once selected, Investigators will undergo product-specific traininining pr
prioi r to 
enrolling subjects.
Th
Th
T rough a systematic analysis of relevant commercially approved MF drugs and based d on
on the Phase
se


LYRA THERAPEUTICS, INC.
STUDY LYR-210-2018-002
VERSION 8.0 (30JUNE2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 107 OF 129
I clinical results of LYR-210 and the safety assessments and measures implemented in the Phase II 
clinical trial, the potential benefits of LYR-210 outweigh the potential associated risks and support 
conducting the proposed Phase II clinical trial. 
I clc inical resultsts of LY
LYR-21
210 an
and ththe sa
safefetyty assessm
smen
entsts and
nd mea
easu
sureres im
implplem
emented in the Phase II 
clinical trial, the potential benefits of LYR-210 outweigh the potential associateted risks and support 
conducting the proposed Phase II clinical trial. 


LYRA THERAPEUTICS, INC.
STUDY LYR-210-2018-002
VERSION 8.0 (30JUNE2020)
PROPRIETARY AND CONFIDENTIAL
PAGE 108 OF 129
13.
LIST OF REFERENCES
1. Global Initiative for Asthma. 2018 GINA report: Global strategy for asthma management and
prevention. Availalble at: Accessed October 2, 2018.
2. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps
2012. Rhinology. 2012; 1-298.
3. Orlandi RR, Kingdom TT, Hwang PH. International consensus statement on allergy and
rhinology: Rhinosinusitis executive summary. International Forum of Allergy & Rhinology. 2016;
6:S3-S21.
4. Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe – an underestimated
disease. A GA2LEN study. Allergy. 2011; 66:1216-1223.
5. Hamilos DL. Chronic rhinosinusitis: Epidemiology and medical management. The Journal of
Allergy and Clinical Immunology. 2011; 128:693-707; quiz 708-9.
6. Benninger MS, Ferguson BJ, Hadley JA, et al. Adult chronic rhinosinusitis: definitions, diagnosis,
epidemiology, and pathophysiology. Otolaryngology–Head and Neck Surgery. 2003; 129:S1-S32.
7. Smith KA, Orlandi RR, Rudmik L. Cost of adult chronic rhinosinusitis: A systematic review. The
Laryngoscope. 2015; 125:1547-1556.
8. van Agthoven M, Uyl-de Groot CA, Fokkens WJ, et al. Cost analysis of regular and filgrastim
treatment in patients with refractory chronic rhinosinusitis. Rhinology. 2002; 40:69-74.
9. Rudmik L, Hoy M, Schlosser RJ, et al. Topical therapies in the management of chronic
rhinosinusitis: An evidence-based review with recommendations. International Forum of Allergy &
Rhinology. 2013; 3:281-298.
10. Moeller W, Schuschnig U, Meyer G, et al. Ventilation and aerosolized drug delivery to the
paranasal sinuses using pulsating airflow - a preliminary study. Rhinology. 2009; 47:405-12.
11. Nabi S, Rotenberg BW, Vukin I, et al. Nasal spray adherence after sinus surgery: Problems and
predictors. Journal of Otolaryngology - Head & Neck Surgery. 2012; 41:S49-55.
12. Vaidyanathan S, Barnes M, Williamson P, et al. Treatment of chronic rhinosinusitis with nasal
polyposis with oral steroids followed by topical steroids: A randomized trial. Annals of Internal
Medicine. 2011; 154:293-302.
13. Van Zele T, Gevaert P, Holtappels G, et al. Oral steroids and doxycycline: Two different
approaches to treat nasal polyps. Journal of Allergy and Clinical Immunology. 2010; 125:1069-
1076.e4.
14. Rudmik L, Soler ZM. Medical therapies for adult chronic sinusitis: A systematic review. The
Journal of the American Medical Association. 2015; 314:926-939.
15. Poetker DM, Reh DD. A comprehensive review of the adverse effects of systemic
corticosteroids. Otolaryngologic Clinics of North America. 2010; 43:753-768.
16. Young LC, Stow NW, Zhou L, et al. Efficacy of medical therapy in treatment of chronic
rhinosinusitis. Allergy Rhinol (Providence). 2012; 3:e8-e12.
17. Sanjay P, Dodds A, Miller E, et al. Cancelled elective operations: an observational study from a
district general hospital. Journal of Health Organization and Management. 2007; 21:54-58.
18. Merck & Co., Inc. NDA 20762 Drug Approval Package, NASONEX®(mometasone furoate
monohydrate) Nasal Spray, 50 mcg. Availalble at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020762_nasonex_toc.cfm. Accessed
September 29, 2018.
19. Zitt M, Kosoglou T, Hubbell J. Mometasone furoate nasal spray: A review of safety and
systemic effects. Drug Safety. 2007; 30:317-326.


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PROPRIETARY AND CONFIDENTIAL
PAGE 109 OF 129
20. Walters T, Bafna S, Vold S. Efficacy and safety of sustained release dexamethasone for the
treatment of ocular pain and inflammation after cataract surgery: results from two phase 3 studies.
Journal of Clinical & Experimental Ophthalmology. 2016; 7:1-11.
21. Westphal M, Ram Z, Riddle V, et al. Gliadel® wafer in initial surgery for malignant glioma:
long-term follow-up of a multicenter controlled trial. Acta Neurochirurgica. 2006; 148:269-275.
22. Forwith KD, Chandra RK, Yun PT, et al. ADVANCE: A multisite trial of bioabsorbable steroid-
eluting sinus implants. Laryngoscope. 2011; 121:2473-2480.
23. Marple BF, Smith TL, Han JK, et al. Advance II: A prospective, randomized study assessing
safety and efficacy of bioabsorbable steroid-releasing sinus implants. Otolaryngology - Head and
Neck Surgery. 2012; 146:1004-1011.
24. Han JK, Forwith KD, Smith TL, et al. RESOLVE: A randomized, controlled, blinded study of
bioabsorbable steroid-eluting sinus implants for in-office treatment of recurrent sinonasal polyposis.
International Forum of Allergy & Rhinology. 2014; 4:861-870.
25. Kern RC, Stolovitzky JP, Silvers SL, et al. A phase 3 trial of mometasone furoate sinus implants
for chronic sinusitis with recurrent nasal polyps. International Forum of Allergy & Rhinology. 2018;
8:471-481.
26. American Rhinologic Society. ARS position statement on drug-eluting implant. Availalble at:
https://www.american-rhinologic.org/index.php?option=com_content&view=article&id=32:drug-
eluting-implants&catid=26:position-statements&Itemid=197. Accessed May 15, 2019.
27. Hopkins C, Gillett S, Slack R, et al. Psychometric validity of the 22-item Sinonasal Outcome
Test. Clinical Otolaryngology. 2009; 34:447-454.
28. Toma S, Hopkins C. Stratification of SNOT-22 scores into mild, moderate or severe and
relationship with other subjective instruments. Rhinology. 2016; 54:129-33.
29. DeConde AS, Bodner TE, Mace JC, et al. Response shift in quality of life after endoscopic sinus
surgery for chronic rhinosinusitis. JAMA Otolaryngology-- Head & Neck Surgery. 2014; 140:712-
719.
30. Scoggins JF, Patrick DL. The use of patient-reported outcomes instruments in registered clinical
trials: Evidence from ClinicalTrials.gov. Contemporary Clinical Trials. 2009; 30:289-292.
31. Optum. PSF-36v2® Health Survey Measurement Model. Availalble at:
https://www.optum.com/content/dam/optum/resources/Manual%20Excerpts/SF-36v2-Health-
Survey-Measurement-Model.pdf. Accessed June 1, 2020.
32. Likness MM, Pallanch JF, Sherris DA, et al. Computed tomography scans as an objective
measure of disease severity in chronic rhinosinusitis. Otolaryngology--Head and Neck Surgery.
2014; 150:305-311.
33. Doty RL, Shaman P, Dann M. Development of the university of pennsylvania smell
identification test: A standardized microencapsulated test of olfactory function. Physiology &
Behavior. 1984; 32:489-502.
34. Douglas RG, Psaltis AJ, Rimmer J, et al. Phase 1 clinical study to assess the safety of a novel
drug delivery system providing long-term topical steroid therapy for chronic rhinosinusitis.
International Forum of Allergy & Rhinology. 2019; 9:378-387.
35. Keck T, Leiacker R, Riechelmann H, et al. Temperature Profile in the Nasal Cavity. The
Laryngoscope. 2000; 110:651-654.
36. Crim C, Pierre LN, Daley-Yates PT. A review of the pharmacology and pharmacokinetics of
inhaled fluticasone propionate and mometasone furoate. Clinical Therapeutics. 2001; 23:1339-1354.
37. Kosoglou T, Hubbell J, Kantesaria B, et al. An evaluation of the systemic bioavailability of
mometasone furoate (MF) after oral inhalation from a MF/formoterol fumarate metered-dose inhaler


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PAGE 110 OF 129
versus an MF dry-powder inhaler in healthy subjects. Clinical Pharmacology in Drug Development. 
2014; 3:229-234.
38. Daley-Yates PT, Kunka RL, Yin Y, et al. Bioavailability of fluticasone propionate and
mometasone furoate aqueous nasal sprays. European Journal of Clinical Pharmacology. 2004;
60:265-268.
39. Merck & Co., Inc. NDA 21067 Drug Approval Package, ASMANEX® TWISTHALER® 110
mcg, 220 mcg (mometasone furoate inhalation powder). Availalble at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021067s000_AsmanexTOC.cfm.
Accessed October 8, 2018.
40. Kosoglou T, Hubbell J, Xuan F, et al. Comparison of the systemic bioavailability of mometasone
furoate after oral inhalation from a mometasone furoate/formoterol fumarate metered-dose inhaler
versus a mometasone furoate dry-powder inhaler in patients with chronic obstructive pulmonary
disease. International Journal of Chronic Obstructive Pulmonary Disease. 2013; 8:107-116.
41. Minshall E, Ghaffar O, Cameron L, et al. Assessment by nasal biopsy of long-term use of
mometasone furoate aqueous nasal spray (Nasonex) in the treatment of perennial rhinitis.
Otolaryngology–Head and Neck Surgery. 1998; 118:648-54.
42. Bross-Soriano D, Hanenberg-Milver C, Schimelmitz-Idi J, et al. Effects of three nasal topical
steroids in the intraocular pressure compartment. Otolaryngology–Head and Neck Surgery. 2004;
130:187-91.
43. Intersect ENT, Inc. NDA 209310 Drug Approval Package, SINUVATM (mometasone furoate)
sinus implant. Availalble at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209310Orig1s000TOC.cfm. Accessed
February 08, 2019.
44. Ozkadif S, Eken E. Three-dimensional reconstruction of multidetector computed tomography
images of paranasal sinuses of New Zealand rabbits. Turkish Journal of Veterinary and Animal
Science. 2013; 37:675-681.
45. Beal SL. Ways to Fit a PK Model with Some Data Below the Quantification Limit. Journal of
Pharmacokinetics and Pharmacodynamics. 2001; 28:481-504.
46. Young LC, Stow NW, Zhou L, et al. Efficacy of medical therapy in treatment of chronic
rhinosinusitis. Allergy & Rhinology (Providence, R.I.). 2012; 3:e8-e12.
47. Perloff JR, Palmer JN. Evidence of bacterial biofilms in a rabbit model of sinusitis. American
Journal of Rhinology & Allergy. 2005; 19:1-6.
48. Chaubal M. Polylactides/Glycolides - Excipients for injectable drug delivery & beyond. Drug
Delivery Technology. 2002; 2:34-36.


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PROPRIETARY AND CONFIDENTIAL
PAGE 111 OF 129
14.
APPENDICES
14.1
Daily Electronic Subject Reported Outcome (ePRO)
Below you will find questions about 4 major symptoms of your chronic sinusitis and your daily use 
of saline irrigation. We would appreciate your answering these questions to the best of your ability. 
There are no right or wrong answers. 
Please rate your 4 major symptoms as how bad they have been within the past one hour by selecting
the severity that best describes how you feel.
1. Please rate your nasal blockage/obstruction/congestion:
0 = absent symptoms 
(no sign/symptom evident) 
1 = mild symptoms 
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms 
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms 
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
2. Please rate your nasal discharge (anterior/posterior nasal drip):
0 = absent symptoms 
(no sign/symptom evident) 
1 = mild symptoms 
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms 
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms 
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
3. Please rate your facial pain/pressure:
0 = absent symptoms 
(no sign/symptom evident) 
1 = mild symptoms 
14.1
Daily Electronic Subject Reported Ou
O tcome (ePRO)
Below you will find questions about 4 major symp
mptoms of your chronic sinusitis and your daily use 
ofof saline irrigation. We would appreciate yo
your ans
nswe
we
w riring
ng these questions to the best of your ability. 
Th
Ther
e e are no right or wrong answers. 
Please rate your 4 major symptoms as how bad the
hey ha
h ve
ve been within the past one hour by selecting
the severity that best describes how you feel.
1. Please rate your nasal blockage/obstruction/congestion:
0 = absent symptoms
(no sign/symptom evident) 
1 = mild symptoms
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
2. Please rate your nasal discharge (anterior/posterior nasal drip):
0 = absent symptoms
(no sign/symptom evident) 
1 = mild symptoms
(sign/symptom present but minimal awareness; easily tolerated) 
2 = moderate symptoms 
(definite awareness of sign/symptom that is bothersome but tolerable) 
3 = severe symptoms
(sign/symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping)
3. Please rate your facial pain/pressure:
0 = absent symptoms
(no sign/symptom evident) 
1 = mild symptoms
$33(1',&(6+$9(%((1
5(029('

SAP_001.pdf: 
Lyra Therapeutics Inc. 
PROTOCOL LYR-210-2018-002 
Statistical Analysis Plan 
Page 1 of 58 
Document: 
LYR-210_Main SAP_v1.0_06Oct2020 
Version No.: 
1.0 
Version Date: 
06Oct2020 
Effective Date: 
02Dec2019 
STATISTICAL ANALYSIS PLAN 
LYR-210-2018-002 
A Phase II, Randomized, Blinded, Sham Procedure-Controlled, Parallel-Group Trial to Evaluate the Efficacy, Safety 
and Tolerability of LYR-210 in Adult Subjects with Chronic Sinusitis (LANTERN Study)
AUTHOR: SUSAN TERBLANCHÉ 
VERSION NUMBER AND DATE: V1.0, 06OCT2020 


Lyra Therapeutics Inc. 
PROTOCOL LYR-210-2018-002 
Statistical Analysis Plan 
Page 2 of 58 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan (SAP) v1.0 (dated 06OCT2020) for protocol LYR-210-2018-002.
Name 
Signature 
Date 
Author: 
Susan Terblanché 
Refer to eSignature 
Position: 
Biostatistician I 
Company: 
IQVIA 
Upon review of this document, the undersigned approves this version of the SAP, authorizing that the content is 
acceptable for the reporting of this study. 
Name 
Signature 
Date 
Approved By: 
Lindsay Brayton 
Refer to eSignature 
Position: 
Senior Clinical Project Manager 
Company: 
Lyra Therapeutics Inc. 
Approved By: 
Yina Kuang 
Refer to eSignature 
Position: 
Associate Director, Clinical Affairs 
Company: 
Lyra Therapeutics Inc. 
Document: 
LYR-210_Main SAP_v1.0_06Oct2020 
Version No.: 
1.0 
Version Date: 
06Oct2020 
Effective Date: 
02Dec2019 


Lyra Therapeutics Inc. 
PROTOCOL LYR-210-2018-002 
Statistical Analysis Plan 
Page 3 of 58 
MODIFICATION HISTORY 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from Previous Authorized 
Version 
0.1 
14AUG2020 
Kimara Lynch 
Not Applicable – First Version 
0.2 
21SEP2020 
Susan Terblanché 
•
Implementation of Sponsor’s, Senior Biostatistician’s
and Medical Writer’s comments
•
Various minor edits for clarification purposes
1.0 
30SEP2020 
Susan Terblanché 
•
Implementation of Sponsor’s comments
•
Various minor edits for clarification purposes
1.0 
02OCT2020 
Susan Terblanché 
•
Section 4.2: Added text about analysis of data
collected after cut-off date
•
Section 5.6: Updated derivation of CS7DA4S on Day
1 to include the Day 1 score
•
Section 5.6: Added text about recording of prohibited
rescue medications
•
Section 5.7: Update “one day of” to “one day prior
to” for use of Mometasone Furoate as reason for
exclusion of a subject from the PKAS
•
Section 5.7: Update identification of Mometasone
Furoate used by subjects
•
Section 15.2.4.1: Add analysis of CS7DA4S by nasal
polyps subgroup and missing data imputation.
•
Signature Page: Updated Lyra team members’ titles
•
Minor updates for readability
1.0 
16OCT2020 
Susan Terblanché 
•
Section 5.7: Clarified analysis of PK timepoints if
subjects have used Mometasone Furoate
Document: 
LYR-210_Main SAP_v1.0_06Oct2020 
Version No.: 
1.0 
Version Date: 
06Oct2020 
Effective Date: 
02Dec2019 


Lyra Therapeutics Inc. 
PROTOCOL LYR-210-2018-002 
Statistical Analysis Plan 
Page 4 of 58 
TABLE OF CONTENTS 
1.
INTRODUCTION
9 
2.
STUDY OBJECTIVES
9 
2.1. 
Primary Objective ........................................................................................................................................... 9 
2.2. 
Key Secondary Objectives............................................................................................................................... 9 
2.3. 
Other Secondary Objectives ........................................................................................................................... 9 
2.4. 
Exploratory Objectives ................................................................................................................................. 10 
3.
STUDY DESIGN
11 
3.1. 
General Description ....................................................................................................................................... 11 
3.2. 
Schedule of Assessments ................................................................................................................................ 12 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 12 
4.
PLANNED ANALYSES
13 
4.1. 
DMC Meetings ............................................................................................................................................... 14 
4.2. 
Primary Data Analysis .................................................................................................................................. 14 
4.3. 
Final Data Analysis ........................................................................................................................................ 14 
5.
ANALYSIS SETS
15 
5.1. 
Process for Analysis Set Assignment ............................................................................................................ 15 
5.2. 
All Subjects Consented Analysis Set [CONS].............................................................................................. 16 
5.3. 
All Subjects Randomized Analysis Set [RND] ............................................................................................ 16 
5.4. 
Safety Analysis Set [SAF] .............................................................................................................................. 16 
5.5. 
Intention-to-Treat Analysis Set [ITT] .......................................................................................................... 17 
5.6. 
Per Protocol Analysis Set [PPAS] ................................................................................................................. 17 
5.7. 
Pharmacokinetic Analysis Set [PK] ............................................................................................................. 18 
Document: 
LYR-210_Main SAP_v1.0_06Oct2020 
Version No.: 
1.0 
Version Date: 
06Oct2020 
Effective Date: 
02Dec2019 


Lyra Therapeutics Inc. 
PROTOCOL LYR-210-2018-002 
Statistical Analysis Plan 
Page 5 of 58 
5.8. 
Assignment of Actual Treatment .................................................................................................................. 19 
6.
GENERAL CONSIDERATIONS
19 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 19 
6.2. 
Post-Treatment Day ....................................................................................................................................... 19 
6.3. 
Baseline ........................................................................................................................................................... 20 
6.4. 
Unscheduled Visits, Retests and Early Termination Data ......................................................................... 20 
6.5. 
Derived Timepoint ......................................................................................................................................... 20 
6.6. 
Windowing Conventions ............................................................................................................................... 20 
6.6.1. 
Daily Diary Visit Assignment 
21 
6.7. 
Common Calculations ................................................................................................................................... 22 
7.
STATISTICAL CONSIDERATIONS
23 
7.1. 
Sample Size ..................................................................................................................................................... 23 
7.2. 
Summary Statistics ........................................................................................................................................ 23 
7.3. 
Missing Data ................................................................................................................................................... 23 
7.4. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 23 
7.5. 
Multicenter Studies ........................................................................................................................................ 24 
7.6. 
Examination of Subgroups ............................................................................................................................ 24 
7.7. 
Statistical Tests .............................................................................................................................................. 26 
7.8. 
Multiple Comparisons/Multiplicity .............................................................................................................. 26 
7.9. 
Software Version ............................................................................................................................................ 26 
8.
OUTPUT PRESENTATIONS
26 
9.
DISPOSITION AND WITHDRAWALS
26 
9.1. 
Protocol Deviations ........................................................................................................................................ 27 
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
27 
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10.1. Derivations ..................................................................................................................................................... 28 
11.
SURGICAL AND MEDICAL HISTORY
29 
12.
MEDICATIONS
29 
13.
STUDY TREATMENT EXPOSURE
29 
13.1. Derivations ..................................................................................................................................................... 30 
14.
SALINE IRRIGATION COMPLIANCE
30 
14.1. Derivations ..................................................................................................................................................... 30 
15.
EFFICACY OUTCOMES
31 
15.1. Primary Efficacy ............................................................................................................................................ 31 
15.1.1. 
Primary Efficacy Endpoint and Derivation 
31 
15.1.2. 
Missing Data Imputation Methods for Primary Efficacy Endpoint 
32 
15.1.3. 
Primary Analysis of Primary Efficacy Endpoint 
32 
15.1.4. 
Sensitivity Analysis of Primary Efficacy Endpoint 
32 
15.1.5. 
Supportive Analysis of Primary Efficacy Endpoint 
34 
15.1.5.1. 
Assessment of Consistency of Treatment Effect Across Region 
34 
15.1.5.2. 
Assessment of Treatment Effect Across Subgroups Described in Section 7.6 
34 
15.2. Secondary Efficacy ........................................................................................................................................ 34 
15.2.1. 
Key Secondary Efficacy Endpoints and Derivation 
34 
15.2.1.1. 
CFBL in CS7DA4S at Week 24 
34 
15.2.1.2. 
Proportion of Subjects with at Least 1-point Decrease in Bilateral Zinreich Score in at Least One 
Pair of Anterior Ethmoid, Maxillary, Posterior Ethmoid, Frontal or Sphenoid Sinuses at Week 24 
35 
15.2.1.3. 
Time-to-Treatment Failure 
36 
15.2.2. 
Other Secondary Efficacy Endpoints and Derivations 
36 
15.2.2.1. 
Time-to-Onset of Action 
36 
15.2.2.2. 
CFBL in CS7DA4S and 7-day Average Score of Individual Symptoms at Additional Timepoints 37 
15.2.2.3. 
22-Item Sino-Nasal Outcome Test (SNOT-22) Questionnaire 
37 
15.2.2.4. 
Change from Baseline in Bilateral Zinreich Anterior Ethmoid, Maxillary, Posterior Ethmoid, 
Frontal, Sphenoid and OMC Sinus Scores, and Total Score at Week 24 
38 
15.2.2.5. 
36-Item Short Form Health Survey Version 2 (SF-36v2) Questionnaire
38 
15.2.2.6. 
University of Pennsylvania Smell Identification Test (UPSITTM) 
40 
15.2.3. 
Missing Data Imputation Methods for Secondary Efficacy Endpoints 
40 
15.2.3.1. 
Missing Data Imputation Methods for Key Secondary Efficacy Endpoints 
40 
15.2.3.2. 
Missing Data Imputation Methods for Other Secondary Efficacy Endpoints 
40 
15.2.4. 
Analysis of Key and Other Secondary Efficacy Endpoints 
41 
15.2.4.1. 
Analysis of CFBL in CS7DA4S Individual and Total Scores at Weeks 8, 12, 16, 20 and 24 
41 
15.2.4.2. 
Analysis of Zinreich Score 
41 
15.2.4.3. 
Analysis of Time-to-Treatment Failure 
42 
15.2.4.4. 
Analysis of Time-to-Onset of Action 
42 
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15.2.4.5. 
Analysis of SNOT-22 and SF-36v2 Domain and Total Scores 
42 
15.2.4.6. 
Analysis of UPSITTM 
43 
15.3. Exploratory Efficacy ..................................................................................................................................... 43 
15.3.1. 
Exploratory Efficacy Endpoints and Derivations 
43 
15.3.1.1. 
Acute Exacerbation of Chronic Sinusitis 
43 
15.3.1.2. 
Improvement from Baseline in Nasal Polyp Severity Within Middle Meatus 
43 
15.3.1.3. 
CFBL in Endpoints by Absence or Prescence of Nasal Polyps 
43 
15.3.1.4. 
CFBL in Endpoints at Post-Treatment Visits 
44 
15.3.2. 
Missing Data Imputation Methods for Exploratory Efficacy Endpoints 
44 
15.3.3. 
Analysis of Exploratory Efficacy Endpoints 
44 
16.
SAFETY OUTCOMES
45 
16.1. Adverse Events ............................................................................................................................................... 45 
16.1.1. 
All TEAEs and Post-Treatment AEs 
46 
16.1.1.1. 
Severity 
47 
16.1.1.2. 
TEAE Relationship to Study Treatment 
47 
16.1.1.3. 
TEAE Relationship to Study Procedure 
47 
16.1.2. 
Serious Adverse Events 
47 
16.1.3. 
TEAEs Leading to Discontinuation of Study Treatment 
48 
16.1.4. 
TEAEs and Post-Treatment AEs Leading to Discontinuation of Study 
48 
16.1.5. 
Adverse Events Leading to Death 
48 
16.2. Laboratory Evaluations ................................................................................................................................ 48 
16.2.1. 
Laboratory Standardization 
49 
16.2.2. 
Pregnancies 
50 
16.3. Vital Signs ....................................................................................................................................................... 50 
16.4. Physical Examination .................................................................................................................................... 51 
16.5. Other Safety Assessments ............................................................................................................................. 51 
16.5.1. 
Ophthalmology Assessment 
51 
16.5.2. 
Ophthalmology Specific Derivations 
51 
16.6. Nasal Endoscopy Assessment ........................................................................................................................ 52 
17.
PHARMACOKINETIC ANALYSES
52 
18.
REFERENCES
53 
APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 
54 
Paper Size, Orientation and Margins ...................................................................................................................... 54 
Dates and Times ......................................................................................................................................................... 54 
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Spelling Format.......................................................................................................................................................... 54 
Presentation of Treatment Groups .......................................................................................................................... 54 
Presentation of Visits ................................................................................................................................................. 54 
Listings ....................................................................................................................................................................... 55 
APPENDIX 2. 
PARTIAL DATE CONVENTIONS 
57 
Algorithm for Treatment Emergence of Adverse Events ....................................................................................... 57 
Algorithm for Prior/Concomitant Medications ...................................................................................................... 57 
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1. INTRODUCTION
This document describes the rules and conventions to be used in the presentation and analysis of efficacy, safety and 
pharmacokinetics (PK) data for protocol LYR-210-2018-002. It describes the data to be summarized and analyzed, 
including specifics of the statistical analyses to be performed. This statistical analysis plan (SAP) is based on 
protocol version 8.0 dated 30th of June 2020. 
A separate SAP has been prepared for the Data Monitoring Committee (DMC) meetings. 
2. STUDY OBJECTIVES
2.1. PRIMARY OBJECTIVE 
The primary objective is to evaluate the efficacy of LYR-210 in improving the composite score of 7-day average 
scores of 4 chronic sinusitis (CS) cardinal symptoms (CS7DA4S) at Week 4. 
2.2. KEY SECONDARY OBJECTIVES 
The key secondary objectives are: 
•
To evaluate the efficacy of LYR-210 in improving CS7DA4S score at end of treatment.
•
To evaluate the effect of LYR-210 in reducing sinus inflammation as per magnetic resonance imaging (MRI).
•
To evaluate the time-to-treatment failure.
2.3. OTHER SECONDARY OBJECTIVES 
The other secondary objectives are: 
•
To evaluate the safety and tolerability of LYR-210.
•
To evaluate the time-to-onset of action of LYR-210.
•
To evaluate the efficacy of LYR-210 in improving CS7DA4S score and the 7-day average score of each of the 4
CS cardinal symptoms.
•
To evaluate the effect of LYR-210 in improving CS disease-specific quality of life as per 22-item sino-nasal
outcome test (SNOT-22) questionnaire.
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•
To evaluate the effect of LYR-210 in reducing sinus inflammation as per MRI.
•
To evaluate the effect of LYR-210 in reducing subjects’ needs for medical or surgical treatment for CS.
•
To evaluate the PK of LYR-210.
•
To evaluate the effect of LYR-210 in improving subjects’ general quality of life as per 36-item short form
health survey version 2 (SF-36v2) questionnaire.
•
To evaluate LYR-210 in improving smell function assessed by the University of Pennsylvania Smell
Identification Test (UPSITTM).
2.4. EXPLORATORY OBJECTIVES 
The exploratory objectives are: 
•
To evaluate the percentage of subjects experiencing acute exacerbations of CS (AECS).
•
To assess effect of LYR-210 in reducing polyp severity within middle meatus in subgroup of CS subjects with
nasal polyps (CSwNP).
•
To assess efficacy of LYR-210 in improving of the below scores in the subgroups of CS subjects without nasal
polyps (CSsNP) and CSwNP subjects:
o
CS7DA4S score
o
The 7-day average score of each of 4 CS cardinal symptoms
o
The SNOT-22 total and subdomain scores
o
The SF-36v2 physical health, mental health, and domain scores
•
To assess efficacy of LYR-210 in reducing sinus inflammation in CSsNP and CSwNP subjects.
•
To assess effect of LYR-210 in improving smell function in CSsNP and CSwNP subjects.
•
To assess the safety of subjects, post LYR-210 treatment.
•
To assess the durability of efficacy post LYR-210 treatment.
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3. STUDY DESIGN
3.1. GENERAL DESCRIPTION 
This global, multicenter study will be conducted in a randomized, Sham procedure-controlled, parallel-group, 
subject-blinded fashion in approximately 70 adult CS subjects who have failed previous medical management and 
have not undergone endoscopic sinus surgery (ESS). The efficacy and safety of LYR-210 (2500 𝜇g) and LYR-210 
(7500 𝜇g) versus a Sham procedure only control will be assessed. Additionally, LYR-210 (2500 𝜇g) and LYR-210 
(7500 𝜇g) will be compared to evaluate dose related responses. 
The study will consist of three stages: 
•
Screening and washout stage: 2 to 4 weeks.
o
During washout, subjects will receive no active treatment for CS but will be recommended to start daily
saline irrigation twice a day.
•
Randomized and blinded treatment stage: 24 weeks.
o
Subjects who complete washout and meet all Day 1 eligibility criteria on Day 1 will be stratified according
to presence or absence of: 1) nasal allergy (yes vs. no), 2) nasal polyps (yes vs. no).
o
Subjects will be randomized in a 1:1:1 ratio to receive LYR-210 (2500 𝜇g) bilaterally, LYR-210 (7500 𝜇g)
bilaterally or Sham procedure bilaterally. Subjects who are assigned to the experimental arms will have the
LYR-210 administered bilaterally on Day 1 into the middle meatus and then, removed at Week 24.
Subjects who are assigned to the Sham procedure will undergo bilateral mock administration on Day 1 and
then, undergo a Sham removal procedure to remain blinded.
o
If spontaneous dislodgement of LYR-210 occurs before Week 24 in subjects who receive either dose of
LYR-210, subjects are required to call the study clinic immediately to report the event. If a subject
experiences a dislodgement of one of the two LYR-210 depots, the subject will continue the study
treatment unless an early treatment discontinuation is recommended by the treating physician or subject
requests depot removal from the remaining side of the nose. If depots spontaneously dislodge from both
sides of the nose, subject will complete Week 24/End of Treatment (EOT) assessments and subsequently,
the post-treatment follow-up stage.
•
Blinded post-treatment follow-up stage: 24 weeks.
o
After the Week 24/EOT visit, subjects will undergo post-treatment follow-up for approximately 24 weeks.
o
Except for depot dislodgement, subjects should remain blinded until the final study database is locked.
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The overall flow diagram of subject enrolment and follow-up schedule is shown in Figure 1: Study Design 
Schematic below: 
Figure 1: Study Design Schematic 
3.2. SCHEDULE OF ASSESSMENTS 
Schedule of assessments can be found in Section 8.1 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
•
The Study Design Schematic was presented in the protocol in Section 4.1. The protocol version 8 did not
include the LYR-210 7500 µg treatment arm. An updated version that differs from the protocol is included in
the SAP in Section 3.1.
•
The endpoint regarding the reduction in subjects’ need for specified concomitant medications and medical or
surgical treatment for CS will not be analyzed as the data was not collected.
•
Section 10.1 of the protocol defines the safety analysis set (SAF) as consisting of all randomized subjects who
received the study treatment or treatment attempt on Day 1. For the purposes of the SAP, this has been re-
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defined to remove the randomization criteria. It is possible a subject may receive treatment without being 
formally randomized. Hence the SAF should not contain the randomization restriction. 
•
Section 10.2 of the protocol states that subject disposition will be summarized for the Intention-to-Treat analysis
set (ITT). For the SAP this has been updated to use the All Subjects Consented analysis set (CONS). The ITT
for this study includes the condition that subjects will have a post-Day 1 assessment. It is recommended that
disposition summaries include all subjects enrolled into the study. Restricting to the ITT will lead to an
incomplete summary of subject disposition.
•
Section 10.6.1.1 of the protocol describes the one missing value analysis approach as multiple imputation with
treatment group as an independent variable in the multiple imputation model. This approach will be
conservatively adjusted to apply control-based multiple imputation.
•
Section 10.6.1.2 of the protocol describes the model to assess treatment effect across study regions but excludes
the stratification variables. The model for the SAP includes the stratification variables. Per ICH E9 all statistical
tests/models should be adjusted for any stratification variables.
•
Section 10.6.1.2 of the protocol states that subgroup analysis will be performed to assess the treatment effect for
the subgroups outlined in Section 7.6 of this SAP and the same model as the region analysis will be used. Due
to the small sample size, for the purpose of the SAP one ANCOVA model will be fitted per subgroup to keep
the model parsimonious.
•
Section 10.6.3 of the protocol states that missing responses to questionnaires at a visit will be imputed using the
median of non-missing responses at that visit. For SNOT-22 the literature on this scale indicates that missing
responses should be imputed using the mean value of the responses if more than 50% of responses are complete
at a visit. The SAP follows this approach and not the protocol defined approach (Hopkins, Gillett, Slack , Lund,
& Browne, 2009).
•
Section 10.6.4 of the protocol states that, for the generalized estimating equation (GEE) exploratory analysis, if
the treatment-by-visit interaction is not significant at the 0.10 level of significance it will be removed from the
GEE model. This SAP does not include this criterion, as this is not standard practice. The interaction term will
remain in the model even if not significant.
4. PLANNED ANALYSES
The following analyses will be performed for this study: 
•
Analyses for the DMC meetings.
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•
Primary data analysis.
•
Final data analysis.
4.1. DMC MEETINGS 
There were two planned timepoints for DMC meetings to review the safety and tolerability data: 
o
DMC 1: After the first 30 enrolled subjects completed the Week 4 visit or terminated early from the study,
whichever occurs first.
o
DMC 2: After all subjects completed the Week 4 visit or terminated early from the study, whichever occurs
first.
These two DMC analyses have been described in a separate SAP which was authorized prior to each of the DMC 
analyses. Refer to the DMC SAP for further details. 
4.2. PRIMARY DATA ANALYSIS 
The trigger for the planned primary data analysis is when all subjects have completed the Week 28 visit (that is 
when all subjects have completed the last visit during the treatment stage at Week 24 or early terminated from the 
study or treatment, whichever occurs first, plus 4 weeks post-treatment follow-up). All planned analyses described 
in this SAP, except for analysis for visits after Week 28 (which will be analyzed as part of the Final Analysis, see 
Section 4.3), will be performed by IQVIA Biostatistics following: 
•
Sponsor authorization of this SAP.
•
Sponsor authorization of the analysis sets as relevant (refer to Section 5 for details).
•
The relevant data cut-off being reached and the database lock for primary data analysis (refer to the latest
version of the Interim Database Lock Plan for specific details).
o
No data collected or protocol deviations recorded after the cut-off date will be included in the analysis.
•
Study unblinding (refer to the latest version of the unblinding plan for specific details around blinding).
o
Project teams will be unblinded, subjects to remain blinded until end of study.
4.3. FINAL DATA ANALYSIS 
The trigger for the planned final data analysis is when all subjects have completed the Week 48 visit or early 
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terminated from the study, whichever occurs first. 
All planned analyses relevant to the final data analysis identified in this SAP will be performed by IQVIA 
Biostatistics following final database lock. The final analyses will include: 
•
Disposition
•
Concomitant medications during the Post-Treatment period
•
CS7DA4S score by Post-Treatment visit
•
7-day average score of each of 4 CS cardinal symptoms by Post-Treatment visit
•
SNOT-22 by Post-Treatment visit
•
SF-36 by Post-Treatment visit
•
Adverse events (AEs) during the Post-Treatment period
•
Vital Signs by Post-Treatment visit
•
Physical examination by Post-Treatment visit
•
Ophthalmology assessments by Post-Treatment visit
Analysis Sets will be defined as per the primary data analysis. 
5. ANALYSIS SETS
Agreement and authorization of subjects included/excluded from each analysis set will be conducted prior to the 
unblinding of the study (Section 4.2). 
5.1. PROCESS FOR ANALYSIS SET ASSIGNMENT 
•
Preliminary analysis set assignments to each of the analysis sets will be prepared and shared with the sponsor
based on an “as clean as possible” data transfer from data management prior to the interim database lock for the
primary data analysis.
o
An “as clean as possible” transfer refers to a data transfer where at most there can be limited list of known
open queries on the data.
•
This preliminary analysis set assignments will be used in the discussions and decisions during the blind data
review.
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o
During the blind data review the impact of those open queries on the data should be assessed with regards
to the influence it might have on the analysis set assignments.
•
Based on the discussion and decisions made during the blind data review, the final “blinded” analysis set
assignments for each analysis set (excluding the PK analysis set, refer to Section 5.7) will be prepared and
authorized prior to the interim database lock.
o
“Blinded” analysis set assignment refers to the fact that there are a few reasons that might lead to exclusion
from various analysis sets which cannot be assessed in a blinded manner. For example, randomized arm
assignment differing to actual arm assignment is a major protocol deviation and will lead to exclusion from
the per-protocol analysis set which can only be determined after lock.
o
The outcome of the blind data review will be documented in a Blind Data Review Report and an Excel file
indicating the analysis set assignment for all subjects.
•
Following primary analysis interim database lock and study unblinding, the various reasons leading to exclusion
from analysis sets based on unblinded data will be assessed. The final analysis set assignments will be prepared
and shared with the sponsor for final authorization and use in the primary and final data analyses.
5.2. ALL SUBJECTS CONSENTED ANALYSIS SET [CONS] 
The all subjects consented (CONS) analysis set will include all subjects who provide informed consent for this 
study. 
Subjects will be included in CONS based on the availability of a date of informed consent, as recorded on the 
Demography electronic case report form (eCRF). 
5.3. ALL SUBJECTS RANDOMIZED ANALYSIS SET [RND] 
The all subjects randomized (RND) analysis set will include all subjects in the CONS set who are randomized to 
study treatment regardless of whether the subject receives study treatment. For analyses and displays based on RND, 
subjects will be classified according to randomized treatment. 
Subjects will be included in RND based on the availability of a randomization date, as recorded on the 
Randomization eCRF. 
5.4. SAFETY ANALYSIS SET [SAF] 
The safety (SAF) analysis set will contain all subjects who receive the study treatment (Sham procedure or a dose of 
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LYR-210) or have a treatment attempt on Day 1. Subjects will be analyzed according to the treatment actually 
received or attempted. This is the primary analysis set for safety analyses. 
Subjects will be included in SAF based on the availability of a procedure date regardless of whether the bilateral 
insertion procedure was successful, as recorded on the Procedure eCRF page. 
5.5. INTENTION-TO-TREAT ANALYSIS SET [ITT] 
The Intention-To-Treat (ITT) analysis set will include all randomized subjects who receive the study treatment 
(Sham procedure or a dose of LYR-210) or have a treatment attempt on Day 1 and have post-Day 1 assessments 
available. This is the primary analysis set for assessment of efficacy. Subjects will be analyzed according to the 
treatment they were assigned to at randomization. 
For post-Day 1 assessments availability, the following assessments will be considered: MRI (vendor data), UPSIT 
(UPSIT eCRF), endoscopy (Endoscopy eCRF), a single cardinal CS symptom (electronic patient reported outcomes 
[ePRO]), or the ePRO questionnaires of SNOT-22 or SF-36v2. 
5.6. PER PROTOCOL ANALYSIS SET [PPAS] 
The per-protocol analysis set (PPAS) will contain all randomized subjects who received the study treatment, have 
post-Day 1 assessments as specified in Section 5.5, and are without major protocol deviations at the time of the 
primary analysis. A major protocol deviation is defined as any protocol deviation potentially affecting the evaluation 
of the primary and key secondary efficacy endpoints. It is to be noted that a protocol deviation classified as major by 
the Biostatistical team (resulting in the exclusion of a subject from the PPAS) might be classified as critical, major 
or even minor by the Clinical team as the Clinical and Biostatistical teams are using different criteria. Please refer to 
the Protocol Deviations Management Plan for the criteria used by the Clinical team to classify each protocol 
deviation as critical, major or minor. 
This analysis set will be used to perform supportive analysis for the primary, key secondary, and other secondary 
efficacy including CS7DA4S, 7-day average score of individual symptoms, SNOT-22, and MRI analyses. Major 
protocol deviations and other reasons for exclusion from the PP analysis set will be identified and finalized by 
IQVIA Biostatistics based on blinded review of the data, prior to the data extraction for the primary analysis and 
unblinding of the treatment code. 
Major protocol deviations and other reasons for excluding subjects from the PPAS include: 
•
Insufficient essential efficacy data
o
The primary efficacy variable is the change from baseline (CFBL) in the CS7DA4S score at Week 4. The
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CFBL for this score will be derived in the ePRO data at the Week 4 timepoint. The subject must have a 
non-missing CFBL value for CS7DA4S at Week 4. 
•
Non-eligibility with the protocol specified inclusion/exclusion criteria
o
The subject must have a composite score of CS7DA4S ≥ 7 at Day 1, as derived by IQVIA Biostatistics. A
minimum of five daily entries are required for composite score calculation over the seven days leading up
to and including Day 1 for assessing the subject’s eligibility for participating in the study.
•
Use of prohibited rescue medications prior to Week 4 visit, as identified in a regular Medical Data Review and
recorded in the Clinical Trial Management System (CTMS) log for protocol deviations. Such medications
include:
o
Oral antihistamine, excluding perennial allergic rhinitis patients who have been on a stable dose of
antihistamine since screening
o
Nasal decongestants
o
Intranasal corticosteroid sprays
•
Insufficient exposure to the study treatment
o
The subject must have been exposed to the treatment for at least 16 weeks. Exposure will be derived as
described in Section 13.1.
•
Actual and planned treatments are not the same
o
This will be identified at study unblinding, at the time of the primary analysis, by comparing the subject’s
allocated treatment arm to the kit type of the kit administered to the subject. The randomization data
provided by the randomization vendor will be used.
•
Pregnancy: Pregnant subjects are not allowed to participate in the study. Pregnancy results are recorded on the
Urine Pregnancy Test, and Serum Pregnancy Test eCRFs.
5.7. PHARMACOKINETIC ANALYSIS SET [PK] 
The PK analysis set (PKAS) will contain all subjects in the SAF set who received LYR-210 and have at least one 
evaluable plasma drug concentration data point post-Day 1 available. As concentration data are required to assign 
the PK analysis set, this can only be done at study unblinding, at the time of the primary analysis. Subjects will be 
analyzed according to the actual treatment successfully received. 
Subjects who have used any Mometasone Furoate drugs within one day prior to a PK blood draw would be 
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identified by “MOMETASONE” in the Base Name of concomitant medications. These PK blood draw timepoints 
will be excluded from analysis. Similarly, results from PK blood draw timepoints after subjects reported any depot 
dislodgement will also not be analyzed. 
5.8. ASSIGNMENT OF ACTUAL TREATMENT 
If a subject receives a study treatment or treatment attempt that is different from their randomized treatment, then the 
assignment of the actual treatment will be as per the bilateral treatment received or attempted. 
6. GENERAL CONSIDERATIONS
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events. 
Reference start date is defined as the day of LYR-210 administration/Sham procedure or treatment attempt. Study 
Day will appear in every listing where an assessment date or event date appears. 
•
If the date of the event is on or after the reference start date, then:
𝑆𝑡𝑢𝑑𝑦 𝐷𝑎𝑦= 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑒𝑣𝑒𝑛𝑡−𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1 
•
If the date of the event is prior to the reference start date, then:
𝑆𝑡𝑢𝑑𝑦 𝐷𝑎𝑦 = 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑒𝑣𝑒𝑛𝑡−𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒 
In the situation where the event date is partial or missing, the event date will appear partial or missing in the listings 
and any corresponding Study Day and durations will appear missing in the listings. 
6.2. POST-TREATMENT DAY 
The Post-Treatment Day will be calculated for data collected after the Week 24/EOT visit as follows: 
𝑃𝑜𝑠𝑡 𝑇𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝐷𝑎𝑦= 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑒𝑣𝑒𝑛𝑡−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑊𝑒𝑒𝑘 24/𝐸𝑂𝑇 𝑣𝑖𝑠𝑖𝑡 
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6.3. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to LYR-210 
administration/Sham procedure or treatment attempt (including screening and unscheduled assessments). In the case 
where the last non-missing measurement and the reference start date coincide (and time is not collected), that 
measurement will be considered baseline, but AE and medications commencing on the reference start date will be 
considered post-baseline. 
The baseline CS7DA4S score is the average of the 7 days leading up to and including Day 1, that is Day -6 to Day 1 
(refer to Section 15.1.1 for further details on the calculation of the CS7DA4S scores). 
6.4. UNSCHEDULED VISITS, RETESTS AND EARLY TERMINATION 
DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled measurements 
will not be included in by-visit summaries if a nominal visit is performed in the same visit window but will 
contribute to the Last Observation Carried Forward (LOCF) value, and the worst-case value where required (e.g. 
overall post-baseline abnormal summaries). 
In the case of a retest (same visit number assigned), the latest available measurement for that visit will be used for 
by-visit summaries. 
Listings will include scheduled, unscheduled, retest and early termination data. 
6.5. DERIVED TIMEPOINT 
An EOT timepoint will be derived and presented in the by-visit summaries.  Data collected at the Week 24 visit or 
EOT visit will be pooled together under this EOT timepoint.  This derived timepoint is for information purpose only 
and will not be included in any statistical models. That is, only descriptive statistics will be presented for this 
timepoint. 
6.6. WINDOWING CONVENTIONS 
All assessments (scheduled, unscheduled, and early termination visits), excluding daily diary data (refer to Section 
6.6.1), will be windowed as per Table 1: Scheduled Visit Windows to ensure all assessments fall into a scheduled 
visit in order to ensure all data are presented. 
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If more than one assessment is mapped to the same analysis visit, the following rules for selection of the assessment 
to use in the analysis will be applied: 
•
If a nominal and an unscheduled/early termination assessment are mapped to the same analysis visit, the
nominal assessment will be selected over the unscheduled/early termination assessment. However, if the
nominal assessment result is missing and the unscheduled or early termination assessment result is non-missing,
the unscheduled/early termination assessment will be selected.
•
In all other scenarios the visit closest to the target day will be selected. If two assessments were performed
equally close to an analysis visit’s target day, one prior to and one after, the assessment before the analysis
visit’s target day will be assigned to that analysis visit (except for the follow-up MRI assessment which is
scheduled to be performed within 7 days after the Week 24/EOT visit).
Table 1: Scheduled Visit Windows 
Assigned Visit 
Target Day 
Visit Windowing 
Lower Limit 
Upper Limit 
Screening 
-28
-1
Baselinea 
1 
-28
1 
Week 2b 
15 
2 
22 
Week 4b 
29 
23 
43 
Week 8b 
57 
44 
71 
Week 12b 
85 
72 
99 
Week 16b 
113 
100 
127 
Week 20b 
141 
128 
155 
Week 24b 
169 
156 
183 
4 weeks post-treatmentc 
28 
14 
42 
8 weeks post-treatmentc 
56 
43 
70 
12 weeks post-treatmentc 
84 
71 
98 
16 weeks post-treatmentc 
112 
99 
126 
20 weeks post-treatmentc 
140 
127 
154 
24 weeks post-treatmentc 
168 
155 
182 
a See Section 6.3, the planned timepoint for Baseline is Day 1.
b For Weeks 2 to 24, target day is calculated relative to the reference start date (refer to Section 6.1). 
c For post-treatment visits, target day is calculated relative to end of treatment date (refer to Section 6.2). 
6.6.1. DAILY DIARY VISIT ASSIGNMENT 
The daily diary data do not associate assessments with visits. The date of assessment is collected and will be used to 
assign the ePRO data to specific visits as required for the definition of various endpoints. The CS7DA4S score is the 
average of the total daily scores for the 4 CS cardinal symptoms over the 7 days leading up to and including a visit 
(refer to Section 15.1.1). 
The selection of the total daily scores to use to derive CS7DA4S and the 7-day average CS score for the 4 symptoms 
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for a respective visit is displayed in Table 2: Daily Diary Visit Assignment. For example, in order to derive the 
Week 2 CS7DA4S, the average of the 7 total daily scores for relative days 9 to 15 will be used. 
Table 2: Daily Diary Visit Assignment 
Target Day 
CS7DA4S Range 
Assigned Visit 
Lower Limit 
Upper Limit 
Baselinea 
1 
-6
1 
Week 1b 
8 
2 
8 
Week 2b 
15 
9 
15 
Week 3b 
22 
16 
22 
Week 4b 
29 
23 
29 
Week 8b 
57 
51 
57 
Week 12b 
85 
78 
85 
Week 16b 
113 
107 
113 
Week 20b 
141 
135 
141 
Week 24 
169 
163 
169 
4 weeks post-treatmentc 
28 
21 
28 
8 weeks post-treatmentc 
56 
49 
56 
12 weeks post-treatmentc 
84 
77 
84 
16 weeks post-treatmentb 
112 
105 
112 
20 weeks post-treatmentc 
140 
133 
140 
24 weeks post-treatmentc 
168 
161 
168 
a See Section 6.3, the planned timepoint for Baseline is Day 1. 
b For Weeks 2 to 24, target day is calculated relative to the reference start date (refer to Section 6.1) 
c For post-treatment visits, target day is calculated relative to end of treatment date (refer to Section 6.2). 
6.7. COMMON CALCULATIONS 
The following common calculations will be applicable: 
•
For quantitative measurements, change from baseline at visit X will be calculated as:
𝐶ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒= 𝑟𝑒𝑠𝑢𝑙𝑡 𝑣𝑎𝑙𝑢𝑒 𝑎𝑡 𝑣𝑖𝑠𝑖𝑡 𝑋−𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒 
•
For quantitative measurements, percent change from baseline at visit X will be calculated as:
% 𝐶ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒= 100% × 𝑟𝑒𝑠𝑢𝑙𝑡 𝑣𝑎𝑙𝑢𝑒 𝑎𝑡 𝑣𝑖𝑠𝑖𝑡 𝑋−𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒
•
The duration of the bilateral insertion/sham procedure in minutes will be calculated as the difference between the
beginning time of the first study article preparation and the time of completion of the procedure, as captured on
the LYR-210 Administration/Sham Procedure eCRF:
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑖𝑛𝑠𝑒𝑟𝑡𝑖𝑜𝑛 𝑜𝑟 𝑠ℎ𝑎𝑚 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒 𝑖𝑛 𝑚𝑖𝑛𝑢𝑡𝑒𝑠
= 𝑡𝑖𝑚𝑒 𝑜𝑓 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒−𝑏𝑒𝑔𝑖𝑛𝑛𝑖𝑛𝑔 𝑡𝑖𝑚𝑒 𝑜𝑓 𝑎𝑟𝑡𝑖𝑐𝑙𝑒 𝑝𝑟𝑒𝑝𝑎𝑟𝑎𝑡𝑖𝑜𝑛 
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•
The duration of the depot/sham removal procedure in minutes will be calculated as the difference between the
start and end times of the removal procedure, as captured on the End of Treatment eCRF:
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑟𝑒𝑚𝑜𝑣𝑎𝑙 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒 𝑖𝑛 𝑚𝑖𝑛𝑢𝑡𝑒𝑠
= 𝑒𝑛𝑑 𝑡𝑖𝑚𝑒 𝑜𝑓 𝑟𝑒𝑚𝑜𝑣𝑎𝑙 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒−𝑠𝑡𝑎𝑟𝑡 𝑡𝑖𝑚𝑒 𝑜𝑓 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒 
7. STATISTICAL CONSIDERATIONS
7.1. SAMPLE SIZE 
Per the null and alternative hypotheses described in Section 7.8 and under the assumption that μC = -1.30 and μL2500 
and/or μL7500=-3.00 (conservatively set, based on the mean of this endpoint for LYR-210 in Phase I study, and 
approximately 130% larger decrease than the assumed control mean of -1.30) and that the true standard deviation 
(SD) of the primary endpoint within each treatment group is at most 2.4, then an evaluable sample size of 63 
subjects (21 per treatment group) yields 73% power to reject at least one null hypothesis in favor of the alternative at 
a one-sided 0.05 level of significance. An additional 6-9 subjects will be enrolled to account for potential subject 
dropout. 
7.2. SUMMARY STATISTICS 
For continuous data, descriptive statistics (i.e., n [number of subjects with available data], mean, SD, median, 
minimum, and maximum values) will be presented by treatment group and visit, when applicable. 
For categorical data, the number and percentages of subjects in each category will be presented by treatment group 
and visit, when applicable. 
7.3. MISSING DATA 
Missing efficacy data for the primary and secondary endpoints will be handled as described in Sections 15.1.2 and 
15.2.3, respectively. No missing data methods will apply for exploratory endpoints. 
Missing safety data will not be imputed. 
7.4. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates and factors will be used in the primary and secondary analyses when an analysis of 
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covariance (ANCOVA) is performed. For details of their inclusion in the models please refer to Section 15. 
•
Covariates:
o
Baseline value of the concerned endpoint
•
Factors:
o
Treatment group (fixed effect)
o
Randomization stratification variables
•
Nasal allergy (Yes/No)
•
Nasal polyps (Yes/No)
7.5. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers internationally. Randomization to 
treatment arms is not stratified by country, region or center. Approximately 25 sites will participate in the study. 
Data from all centers will be pooled together in the analyses. 
In order to assess the treatment effect across regions, descriptive statistics for the primary endpoint will be presented 
for each treatment for each region. Geographic region will be categorized as follows: 
Geographic Region 
Identifier Code in Subject ID 
Australasia 
Australia (036) and New Zealand (554) 
Europe 
Czech (203) and Poland (616) 
In addition, an exploratory ANCOVA on the primary endpoint will include region and treatment-by-region 
interaction as factors (fixed effects). Please refer to Section 15.1.5 for more details. It is to be noted that should data 
be too sparse for at least one treatment group in at least one region (i.e. less than 5 ITT subjects for at least one 
treatment group in at least one region), only descriptive statistics by region will be provided. 
7.6. EXAMINATION OF SUBGROUPS 
Subgroup analyses will be conducted as stated in the exploratory analysis sections to assess the consistency of 
treatment difference across the subgroups. It should be noted that the study was not designed to detect treatment 
differences with high statistical power within subgroups. 
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The following subgroups will be relevant to the exploratory analysis for this study: 
•
Nasal allergy:
o
Yes.
o
No.
•
Nasal polyps:
o
Yes.
o
No.
•
Baseline CS7DA4S:
o
Below median.
o
At or above median.
•
Sex:
o
Male.
o
Female.
•
Age:
o
Below median.
o
At or above median.
•
Region:
o
See Section 7.5.
•
Baseline Total Bilateral Zinreich Score as assessed by MRI:
o
Below median.
o
At or above median.
In the subgroups above, median is referencing the overall median for the ITT analysis set, regardless of the 
treatment group. 
If data are too sparse for at least one treatment group in a subgroup (i.e. less than 5 ITT subjects for at least one 
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treatment group in a subgroup), only descriptive statistics by treatment group will be provided for that subgroup. 
That is, no statistical inferences will be performed for that subgroup. 
7.7. STATISTICAL TESTS 
The default significance level will be 5% and all tests will be one-sided, unless otherwise specified in the description 
of the analyses. Two-sided 90% CIs will be presented for all outputs were relevant. 
7.8. MULTIPLE COMPARISONS/MULTIPLICITY 
The primary objective of this study is to test the following null and alternative hypotheses: 
𝐻0: μ𝐿2500 =  μC  vs.  𝐻1: μ𝐿2500  <  μC
𝐻0: μ𝐿7500  =  μC  vs.  𝐻1: μ𝐿7500  <  μC
where μL2500, μL7500 and μC are the true mean values of the CFBL in the CS7DA4S score at Week 4 for the LYR-
210 2500 µg, LYR-210 7500 µg, and control (Sham procedure) treatment groups, respectively. 
Given the exploratory nature of the study, no adjustment to the overall alpha-level of the study will be made for 
multiple comparisons and multiplicity. That is, only nominal p-values will be provided for the primary efficacy 
endpoint, key secondary endpoints, non-key secondary endpoints, and exploratory efficacy endpoints. 
7.9. SOFTWARE VERSION 
All analyses will be conducted using SAS version 9.4 or higher. 
8. OUTPUT PRESENTATIONS
APPENDIX 1 shows conventions for presentation of data in outputs. 
The table, figure and listing (TFL) shells provided with this SAP describe the presentations for this study and 
therefore the format and content of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
9. DISPOSITION AND WITHDRAWALS
All subjects who provide informed consent will be accounted for in this study. 
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Subject disposition will be summarized for the CONS analysis set overall and by randomized treatment group. The 
number of patients screened, and screen failed will be presented. The number and percentage of subjects randomized 
into the study, treated and had a treatment attempt, who completed/discontinued early from the study treatment 
(including reasons for discontinuation) and who completed/discontinued early from the study (including reasons for 
discontinuation) will be presented. 
Subjects’ randomization details, end of treatment status, removal procedure and end of study status will be listed. 
Analysis set assignment will be summarized for the CONS analysis set overall and by randomized treatment. The 
reasons for exclusion from each analysis set will be listed and summarized overall and by randomized treatment 
group. 
9.1. PROTOCOL DEVIATIONS 
All protocol deviations will be recorded in the CTMS log for the duration of the study. Deviations will be assessed 
and categorized as critical, major or minor. Site level IDs will be replicated for all subjects at that site and presented 
in the summary outputs as subject level deviations. 
A table will be produced summarizing the type and severity of each protocol deviation overall and by randomized 
treatment group for the ITT analysis set. The summary will be presented on the number and percentage of subjects 
with each type and severity of deviation. All reported PDs will be listed. 
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic data and other baseline characteristics will be listed and summarized by treatment group for the ITT 
analysis set. No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline subject characteristics will be reported for this study: 
•
Age (years) – as reported on the Demography eCRF page
•
Sex (Female/Male) and female childbearing potential
•
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other
Pacific Islanders, White, Other)
•
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown)
•
Region (Australasia, Europe)
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•
Height (cm)
•
Weight (kg) at Baseline
•
BMI (kg/m2) at Baseline – refer to Section 10.1
•
The baseline symptom scores for the 4 individual cardinal CS symptoms and total CS7DA4S
•
Time since CS onset
•
Characteristics of subjects’ CS disease relevant medical history, as captured on the Chronic Sinusitis
disease relevant medical history eCRF, including chronic sinusitis, asthma, perennial allergic rhinitis,
seasonal allergic rhinitis, sensitivity to non-steroidal anti-inflammatory drugs (NSAID), chronic
obstructive pulmonary disease (COPD) and smoking status.
•
Characteristics of CS disease relevant surgical history
•
Time since disease relevant surgery.
10.1. DERIVATIONS 
•
Time since onset of CS:
𝑇𝑖𝑚𝑒 𝑠𝑖𝑛𝑐𝑒 𝐶𝑆 𝑜𝑛𝑠𝑒𝑡 (𝑦𝑒𝑎𝑟𝑠) = 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑖𝑛𝑓𝑜𝑟𝑚𝑒𝑑 𝑐𝑜𝑛𝑠𝑒𝑛𝑡−𝑑𝑎𝑡𝑒 𝑜𝑓 𝐶𝑆 𝑜𝑛𝑠𝑒𝑡
365.25
•
Time since disease relevant surgery will be calculated as:
𝑇𝑖𝑚𝑒 𝑠𝑖𝑛𝑐𝑒 𝑠𝑢𝑟𝑔𝑒𝑟𝑦 (𝑦𝑒𝑎𝑟𝑠) = 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑖𝑛𝑓𝑜𝑟𝑚𝑒𝑑 𝑐𝑜𝑛𝑠𝑒𝑛𝑡−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑠𝑢𝑟𝑔𝑒𝑟𝑦
365.25
For all the above calculations if the start and/or end date is/are partial, only the available segment(s) of the date that 
appear in both dates will be used in the calculation. For example, if only the year of the start date is available, and 
the month and year of the end date are available, the calculation will only be between the start and end years. If only 
month level is used the calculation should be divided by 12 to obtain the duration in years. No division will occur if 
only year is available. 
•
BMI (kg/m2) will be derived as follows:
𝐵𝑀𝐼 = 𝑊𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔
(𝐻𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑚)2
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11.
SURGICAL AND MEDICAL HISTORY
CS disease relevant medical/surgical history will be listed and summarized for the ITT analysis set as per Section 
10. All other Medical and Surgical History will be listed only for the SAF analysis set.
Medical and Surgical History will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
23.0 or later. 
12.
MEDICATIONS
Medications other than CS medical treatment history (see Section 10) will be coded World Health Organization 
Drug Dictionary (WHO-DD) version March 2020 or later. No Anatomical Therapeutic Class (ATC) coding will be 
performed for this study. 
See APPENDIX 2 for handling of partial dates for medications. In the case where it is not possible to define a 
medication as prior, concomitant, or post-treatment, the medication will be classified by the worst case; i.e. 
concomitant. 
•
‘Prior’ medications are medications which started and stopped prior to the bilateral insertion/Sham procedure or
treatment attempt.
•
‘Concomitant’ medications are medications which:
o
started prior to the bilateral insertion/Sham procedure/treatment attempt AND were ongoing or ended after
the bilateral insertion/Sham procedure/treatment attempt;
o
started on the day of the bilateral insertion/Sham procedure/treatment attempt;
o
started after the bilateral insertion/Sham procedure/treatment attempt but before or on the removal/Sham
removal + 28 days.
•
‘Post-treatment’ medications are medications which started after the bilateral removal/Sham procedure + 28
days.
Prior, Concomitant and Post Medications will be listed by WHO drug name concatenated with base name for the 
SAF analysis set. 
13.
STUDY TREATMENT EXPOSURE
Descriptive statistics of exposure to study treatment in weeks will be presented for each treatment group in the ITT 
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analysis set. 
The duration of exposure will be based on the difference of the date of successful bilateral insertion procedure taken 
from the LYR-210 Administration/Sham Procedure eCRF and the relevant event date. The event date is defined by 
whichever of the following events occurs first for a subject: 
•
Date of end of treatment (date collected on the End of Treatment eCRF) for subjects completing or early
discontinuing treatment
•
Depot dislodgement (date collected by the randomization vendor). If only one depot was dislodged, this will not
be considered as an event. If both depots dislodged, but not simultaneously, the date of the second dislodgement
will be considered as the event date.
Duration of exposure will not be calculated for subjects with an unsuccessful treatment attempt. 
13.1. DERIVATIONS 
Duration of exposure is calculated as below and will be rounded to 1 decimal place: 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑤𝑒𝑒𝑘𝑠) = 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑒𝑣𝑒𝑛𝑡−𝑑𝑎𝑡𝑒 𝑜𝑓 𝑖𝑛𝑠𝑒𝑟𝑡𝑖𝑜𝑛 𝑝𝑟𝑜𝑐𝑒𝑑𝑢𝑟𝑒+ 1
7
14.
SALINE IRRIGATION COMPLIANCE
Compliance to daily saline irrigation will be presented descriptively by treatment group for the ITT analysis sets as 
collected in the ePRO. 
Compliance will be presented as a percentage of the days saline irrigation was done relative to the duration of the 
washout and treatment periods (days). The washout period information is collected on the Washout Period eCRF. 
14.1. DERIVATIONS 
Compliance is calculated as below and will be rounded to 1 decimal place: 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 𝑝𝑒𝑟 𝑝𝑒𝑟𝑖𝑜𝑑 (%)
= 𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑎𝑦𝑠 𝑠𝑎𝑙𝑖𝑛𝑒 𝑖𝑟𝑟𝑖𝑔𝑎𝑡𝑖𝑜𝑛 𝑤𝑎𝑠 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑤𝑎𝑠ℎ𝑜𝑢𝑡/𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑤𝑎𝑠ℎ𝑜𝑢𝑡/𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 (𝑑𝑎𝑦𝑠)
× 100 
o
Duration of washout period is defined as:
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𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑤𝑎𝑠ℎ𝑜𝑢𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 (𝑑𝑎𝑦𝑠) = 𝑤𝑎𝑠ℎ𝑜𝑢𝑡 𝑠𝑡𝑜𝑝 𝑑𝑎𝑡𝑒−𝑤𝑎𝑠ℎ𝑜𝑢𝑡 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1 
o
Duration of treatment period is the same as the duration of exposure as noted in Section 13.1 but will be
converted from weeks to days (multiply by 7).
15.
EFFICACY OUTCOMES
15.1. PRIMARY EFFICACY 
15.1.1. PRIMARY EFFICACY ENDPOINT AND DERIVATION 
The primary efficacy endpoint is CFBL in CS7DA4S score at Week 4. The 4 CS cardinal symptoms are: 
•
nasal blockage/obstruction/congestion
•
facial pain/pressure
•
reduction/loss of sense of smell
•
anterior/posterior nasal discharge.
Each symptom is scored on a 4-point scale and is collected on ePRO: 
•
0 = none
•
1 = mild
•
2 = moderate
•
3 = severe
The CS7DA4S score is calculated as: 
•
Add together the four individual symptom scores per day as recorded by the subject to derive the total daily
score
o
Total daily scores will only be calculated in cases where all four individual symptom scores are available
•
Calculate the average of the total daily scores across the 7 days leading up to and including this visit. This is the
CS7DA4S score at the relevant visit
o
Subject is considered to have sufficient data available to calculate the CS7DA4S score at any given
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timepoint if the total daily score is available for at least 5 of the total 7 days 
o
CS7DA4S scores will be rounded to 1 decimal place
The change from baseline in CS7DA4S at Week 4 will be calculated as detailed in Section 6.7. 
15.1.2. MISSING DATA IMPUTATION METHODS FOR PRIMARY EFFICACY ENDPOINT 
The primary analysis will not include any missing data imputation methods. The primary analysis of the primary 
efficacy endpoint will include subjects in the ITT analysis set with available CS7DA4S data at Baseline and Week 4 
visit. 
15.1.3. PRIMARY ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
The CFBL for CS7DA4S at Week 4 will be analyzed using the ITT analysis set. The following analysis will be 
performed for the CFBL CS7DA4S score at Week 4: 
•
Summary statistics for the Baseline CS7DA4S score, the Week 4 CS7DA4S score and the CFBL at Week 4
•
An ANCOVA model for CFBL at Week 4. The ANCOVA model will include the baseline CSD7A4S score as a
covariate, treatment group and the randomization stratification variables (nasal allergy, nasal polyps) as fixed
effects.
Each hypothesis as described in Section 7.8 will be tested at a one sided 0.05 alpha level of significance by the 
ANCOVA model. The LS means and SE of each treatment group, the LS mean difference of each LYR-210 
procedure against the Sham procedure and their SEs, 90% CIs, and p-values estimated by the model will also be 
provided. 
15.1.4. SENSITIVITY ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
The following sensitivity analyses to the primary analysis of the primary endpoint will be performed: 
Sensitivity to the analysis set 
The primary analysis of the primary efficacy endpoint will be repeated for the PPAS. 
Sensitivity analyses to missing data 
•
LOCF single imputation method:
o
The CS7DA4S will be calculated as described in Section 15.1.1 for baseline, Week 1, Week 2, Week 3
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and Week 4 
o
If Week 4 CS7DA4S score is missing, then the last available post baseline CS7DA4S prior to Week 4 will
be carried forward and will be used as the Week 4 CS7DA4S score and the same analysis as for the
primary analysis of the primary efficacy endpoint will be repeated (refer to Section 15.1.3).
•
Multiple imputation will be implemented using 3 steps:
o
First, intermittent missing CS7DA4S data will be imputed under the missing at random (MAR)
assumption using a multivariate joint Gaussian imputation model and the Monte Carlo Markov Chain
(MCMC) method. A separate imputation model will be estimated for each treatment group separately. The
imputation models will include the baseline CS7DA4S values as a covariate and the stratification variables 
and weekly CS7DA4S (Weeks 1 to 4) as factors. The MAR mechanism assumed that subjects have 
unobserved values in line with similar subjects with available data in their treatment group, taking into 
account their values observed prior to the weeks with missing data. The MAR assumption is reasonable 
for the Sham patients as it accounts for the trial effect while no active treatment is taken. It is also a 
reasonable assumption for the LYR-210 subjects as subjects will remain on randomized treatment while 
intermittent missing data may occur and thus, may be modeled based on similar subjects from their 
randomized treatment group. The MCMC method will be used with a random seed number of 2575, 
multiple chains, a burn-in of 200 iterations, and non-informative prior. During this step, 50 imputed 
datasets will be created. 
o
Second, for each of these 50 imputed datasets, monotone missing weekly CS7DA4S data will be imputed
using sequential linear regression multiple imputation approach also using a MAR approach, where a
separate regression model will be estimated for imputation of each post-baseline timepoint (i.e., Weeks 1,
2, 3, and 4).  Each regression model will include the treatment group, region, the two stratification
variables, and all previous weekly CS7DA4S scores (Baseline and Weeks 1 to Week 4), as appropriate. In
other words, to impute Week 1, the model will include the treatment group, region, the two stratification
variables and baseline CS7DA4S scores. Similarly, to impute Week 2, the model will include the
treatment group, region, the two stratification variables, baseline CS7DA4S scores, and CS7DA4S scores
at Week 1 (observed and imputed values). Missing CS7DA4S scores at Weeks 3 and 4 will be similarly
imputed, one after the other. The random seed number for this step will be 210. No rounding or range
restrictions will be applied to imputed weekly average values.
o
Finally, each of the 50 imputed datasets will be analyzed using the following method: change from
baseline in CS7DA4S score at Week 4 will be calculated based on the observed and imputed data and
analyzed using the ANCOVA model as described in Section 15.1.3. For each LYR-210 dose group, results
from the analysis of each imputed dataset i.e., LS mean differences between treatment groups and their
SEs, will be combined using PROC MIANALYZE in SAS as per Rubin’s rule (Rubin, 1987) to produce a
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pooled estimate of the LS mean difference between treatment groups and a pooled estimate of its SE. 
From these pooled estimates, one t-test statistic and its p-value, assessing whether the null hypotheses in 
Section 7.8 can be rejected, will be calculated and presented for each LYR-210 dose vs. Sham. 
15.1.5. SUPPORTIVE ANALYSIS OF PRIMARY EFFICACY ENDPOINT 
Supportive analyses to the primary analysis of the primary efficacy endpoint will be performed using the ANCOVA 
model specified in Section 15.1.3 for the following: 
15.1.5.1. 
Assessment of Consistency of Treatment Effect Across Region 
To assess the consistency of treatment difference across region, descriptive statistics of the primary endpoint will be 
presented by treatment group within each region. The primary analysis of the primary efficacy endpoint will be 
repeated but will also include the region and treatment-by-region interaction as fixed effect. Should this interaction 
be statistically significant at the 0.15 level of significance, LS means and SE of each treatment group by region will 
be provided as well as the LS mean difference of each LYR-210 procedure against the Sham procedure and their 
SEs, 90% CIs, and p-values by region. 
It is to be noted that should data be too sparse for at least one treatment group in at least one region (i.e., less than 5 
ITT subjects for at least one treatment group in at least one region), only description statistics by region will be 
provided. 
15.1.5.2. 
Assessment of Treatment Effect Across Subgroups Described in Section 7.6 
To assess the consistency of treatment difference across subgroups, descriptive statistics of the primary endpoint 
will be presented by treatment group within each subgroup. An exploratory analysis of covariance on the CFBL of 
CS7DA4S score at Week 4 will be carried out on the ITT analysis set for subjects with available data. The 
ANCOVA model will include the baseline CS7DA4S score as a covariate, the stratification variables, and treatment 
group as a fixed effect and will be repeated for each subgroup of interest. 
If data is too sparse for at least one treatment group in at least one subgroup (i.e., less than 5 ITT subjects for at least 
one treatment group in at least one subgroup), only descriptive statistics by subgroup will be provided. 
15.2. SECONDARY EFFICACY 
15.2.1. KEY SECONDARY EFFICACY ENDPOINTS AND DERIVATION 
15.2.1.1. 
CFBL in CS7DA4S at Week 24 
CFBL at Week 24 will be derived as described in Section 15.1.1. 
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15.2.1.2. 
Proportion of Subjects with at Least 1-point Decrease in Bilateral Zinreich Score in at 
Least One Pair of Anterior Ethmoid, Maxillary, Posterior Ethmoid, Frontal or Sphenoid 
Sinuses at Week 24 
Sinus inflammation will be assessed by MRI at time points specified in the schedule of events in Section 8.1 of the 
protocol. The sinus inflammation will be assessed using the Zinreich modified Lund-Mackay scoring system 
(Likness, et al., 2014). The Zinreich score for each sinus will be assessed by Medical Metrics, Inc. (MMI) and all 
analysis will use the data collected by MMI. Six areas of each sinus (left and right) will be assessed: 
•
Anterior ethmoid
•
Maxillary
•
Posterior Ethmoid
•
Frontal
•
Sphenoid
•
Ostiomeatal Complex (OMC)
Each area will be assigned a score based on the percentage of opacification as follows: 
•
0=0%
•
1=1%-25%
•
2=26%-50%
•
3=51% to 75%
•
4=76% to 99%
•
5=100% or completely occluded
The OMC is given a score of 0 to 2 as follows: 
•
0=completely patent
•
1=partially occluded
•
2=completely occluded
The bilateral Zinreich score for each area will be derived by IQVIA Biostatistics by adding the score for both 
sinuses together. The range of the score will be 0-10 except for OMC which will have a range of 0-4. The bilateral 
Zinreich score for each area will only be calculated if both sinus scores are non-missing. The total bilateral score 
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will be the sum of all 6 areas and will have a range of 0-54. The total bilateral score will only be calculated when all 
bilateral scores for each of the 6 areas are present. The baseline bilateral Zinreich score for each area and baseline 
total score will be the value recorded at screening. The individual and total Zinreich scores for all areas at all visits 
will be summarized and listed. 
The key secondary endpoint will be the proportion of subjects with at least 1-point decrease from baseline in the 
Zinreich score in at least 1 pair of the anterior ethmoid, maxillary, posterior ethmoid, frontal or sphenoid sinuses at 
Week 24. 
15.2.1.3. 
Time-to-Treatment Failure 
Time-to-treatment failure, in days, will be derived as: 
𝑇𝑖𝑚𝑒 (𝑑𝑎𝑦𝑠) = 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑓𝑎𝑖𝑙𝑢𝑟𝑒−𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1 
Where treatment failure is defined as: 
•
after subject enrollment, the subject being recommended by treating physician for oral corticosteroid or ESS
due to worsening of CS symptoms as collected on the Follow-up eCRF
OR 
•
the subject complaining of persistent CS symptoms, i.e., has an average CS7DA4S score over the preceding 30
days greater than or equal to the baseline CS7DA4S score as defined by IQVIA Biostatistics.
o
The earliest timepoint at which to calculate this score is Day 31. For each day post-Day 30, the average
CS7DA4S over the preceding 30 days will be derived and compared to the baseline CS7DA4S score
o
The average CS7DA4S for at least 21 of the preceding 30 days should be available for this derivation.
Subjects without the event will be censored at their follow-up period. That is, should a subject reach Week 24 
without having met the criteria for the time-to-treatment failure, the subject will be censored at the date of the Week 
24 visit; should a subject discontinue early from the study before Week 24 without having met the criteria for the 
time-to-treatment failure, the subject will be censored at the date of discontinuation from study. 
Time-to-treatment failure will be derived at different timepoints: Weeks 2 (15 days), 4 (29 days), 8 (57 days), 12 (85 
days), 16 (113 days), 20 (141 days) and 24 (169 days). These timepoints are independent of the scheduled visits. 
15.2.2. OTHER SECONDARY EFFICACY ENDPOINTS AND DERIVATIONS 
15.2.2.1. 
Time-to-Onset of Action 
Onset of action is defined as, within the first 30 days of treatment, the time when all subsequent mean CFBL in the 
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CS7DA4S score of the LYR-210 is statistically significantly greater than that for the Sham procedure. 
For this endpoint, the CS7DA4S will be calculated daily from Days 8 to 30. That is, the CS7DA4S at Day 8 will be 
the average of the total daily scores for the 4 CS cardinal symptoms over Days 2 to 8, the CS7DA4S at Day 9 will be 
the average of the total daily scores for the 4 CS cardinal symptoms over Days 3 to 9, and so on up to Day 30 which 
will be the average of the total daily scores for the 4 CS cardinal symptoms over Days 24 to 30. 
Then, the CFBL to each of these daily CS7DA4S values will be calculated. 
15.2.2.2. 
CFBL in CS7DA4S and 7-day Average Score of Individual Symptoms at Additional 
Timepoints 
CFBL in CS7DA4S will be derived for Weeks 8, 12, 16 and 20 as per Section 6.7. 
In addition, the 7-average score of each individual symptom will be calculated at each visit only if at least 5 of the 
previous 7 days have available scores. Then, the CFBL in the 7-day average score of each individual cardinal CS 
symptom score will be calculated for Weeks 1, 2, 3, 4, 8, 12, 16, 20 and 24 as per Section 6.7. 
15.2.2.3. 
22-Item Sino-Nasal Outcome Test (SNOT-22) Questionnaire 
SNOT-22 questionnaire data will be collected in ePRO. Subjects score the severity of their symptoms and 
social/emotional consequences of CS over the past two weeks on a 6-point scale: 
•
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 scores are summed within each domain as per Table 3: Categorized Survey Items for Separate Domains of the 
SNOT-22 Instrument (DeConde, Bodner, Mace, & Smith, 2014), where higher scores indicate a higher severity of 
symptoms or social/emotional consequences of CS. For each domain, if less than 50% of the domain items are 
missing at a visit for a subject, the missing items will be imputed with the mean of subject’s non-missing items at 
that visit prior to the domain score calculation. Otherwise if 50% or more of a domain items are missing at a visit for 
a subject, the subject’s domain score will be set to missing at that visit. 
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Table 3: Categorized Survey Items for Separate Domains of the SNOT-22 Instrument 
SNOT-22 Domains 
Survey Items 
Score Range 
Rhinologic Symptoms 
#1, #2, #3, #4, #7, #12 
0–30 
Extra-Nasal Rhinologic Symptoms 
#5, #6, #7 
0–15 
Ear/Facial Symptoms 
#3, #8, #9, #10, #11 
0–25 
Psychological Dysfunction 
#16, #17, #18, #19, #20, #21, #22 
0–35 
Sleep Dysfunction 
#13, #14, #15, #16, #17 
0–25 
The total SNOT-22 score will also be calculated as the sum of all 22 questions and will have a range of 0-110. For 
the total score, if less than 50% of the items are missing at a visit for a subject, the missing items will be imputed 
with the mean of the subject’s non-missing items at that visit prior to the total score calculation. Otherwise if 50% or 
more of the questionnaire items are missing at a visit for a subject, the total score will be set to missing at that visit 
for that subject. 
CFBL in the total and subdomain SNOT-22 scores will be derived for Weeks 2, 4, 8, 12, 16, 20 and 24 as per 
Section 6.7. If a subject’s CFBL in total SNOT-22 score is greater than 8.9 (i.e. the score decreased by more than 
8.9), the subject is considered to have achieved a minimally important clinical difference. 
15.2.2.4. 
Change from Baseline in Bilateral Zinreich Anterior Ethmoid, Maxillary, Posterior 
Ethmoid, Frontal, Sphenoid and OMC Sinus Scores, and Total Score at Week 24 
The bilateral Zinreich anterior ethmoid, maxillary, posterior ethmoid, frontal, and sphenoid scores at Week 24 will 
be calculated as defined in Section 15.2.1.2. The bilateral Zinreich OMC and total Zinreich scores will also be 
calculated as defined in Section 15.2.1.2. 
Then, the CFBL in each of these endpoints will be calculated at Week 24 as per Section 6.7. 
15.2.2.5. 
36-Item Short Form Health Survey Version 2 (SF-36v2) Questionnaire 
The SF-36v2 questionnaire is a multi-purpose, short-form health survey with 36 questions/items. It yields 8 
functional health and well-being domains as well as 2 psychometrically-based physical and mental overall 
component summary measures, where lower scores imply higher disability (i.e., a score of zero is equivalent to 
maximum disability and a score of 100 is equivalent to no disability). 
The 8 domains of the SF-36 are (refer to Table 4: SF-36v2® Health Survey Measurement Model): 
•
Physical Functioning (PF)
•
Role-Physical (RP)
•
Bodily Pain (BP)
•
General Health (GH)
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•
Vitality (VT)
•
Social Functioning (SF)
•
Role-Emotional (RE)
•
Mental Health (MH)
The two overall component summary measures are (refer to Table 4: SF-36v2® Health Survey Measurement 
Model): 
•
Physical Component Summary (PCS)
•
Mental Component Summary (MCS)
Table 4: SF-36v2® Health Survey Measurement Model 
SF-36v2 Components and Domains 
Survey Items 
Physical Component Summary (PCS) 
Physical Functioning (PF) 
#3a, #3b, #3c, #3d, #3e, #3f, #3g, #3h, #3i, #3j 
Role -Physical (RP) 
#4a, #4b, #4c, #4d 
Bodily Pain (BP) 
#7, #8 
General Health (GH) 
#1, #11a, #11b, #11c, #11d 
Mental Component Summary (MCS) 
Vitality (VT) 
#9a, #9e, #9g, #9i 
Social Functioning (SF) 
#6, #10 
Role-Emotional (RE) 
#5a, #5b, #5c 
Mental Health (MH) 
#9b, #9c, #9d, #9f, #9h 
There is also a single item (item #2) that assesses health transition, which is not included in the scoring of the scales 
and overall component summary measures. Scoring will be performed with the Optum software as follows: 
•
First, 10 items are reverse-coded (Questions #1, #6, #7, #8, #9a, #9d, #9e, #9h, #11b and #11d) to ensure
that across all questions, a higher score will indicate a better health state. An algorithm for an algebraic
summation of the item scores is applied to produce domain-specific raw scale scores that account for
missing item responses i.e., when calculating the raw domain scores, if at least half the item scores for a
domain are non-missing, the missing item scores are replaced by the average of the non-missing item
scores for the domain before applying the algorithm for an algebraic summation. Otherwise if 50% or more
of the item scores for a domain are missing, the raw domain score is set to missing.
•
Domain-specific raw scale scores are then transformed to a 0 to 100 range, after which a norm-based (T-
score) transformation is applied so that each scale ranges from 0 to 100, with a mean of 50 and a standard
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deviation of 10. The norm-based transformation is applied so that domain-specific scale scores can be 
meaningfully compared between each other. 
The PCS and MCS are computed by aggregating domain scores using factor score coefficients. The aggregated 
component summary scores are also standardized to have a mean of 50 with a standard deviation of 10. 
The Eight domain scores and the two summary scores will be calculated using software provided by the publisher, 
OptumTM. The CFBL in the 8 domains and 2 overall component summary measures will be calculated at each visit 
as per Section 6.7. 
15.2.2.6. 
University of Pennsylvania Smell Identification Test (UPSITTM) 
The UPSITTM is composed of 40 odorants embedded on scent strips that are released when scratched with a sharply 
tipped object (Doty, Shaman, & Dann, 1984). The UPSITTM is comprised of 4 booklets, each containing 10 
microencapsulated (scratch & sniff) odours. The UPSITTM is a forced-choice test, and subjects will be instructed to 
identify each odorant with alternatives accompanying each test item. The total olfaction score using the UPSITTM is 
defined as the number of odorants correctly identified out of the 40 odours tested, with higher scores designating 
better olfactory performance. 
The total olfaction score will be collected on the UPSIT eCRF page. The change from baseline in UPSITTM total 
score will be calculated at each post-baseline visit as per Section 6.7. 
15.2.3. MISSING DATA IMPUTATION METHODS FOR SECONDARY EFFICACY ENDPOINTS 
15.2.3.1. 
Missing Data Imputation Methods for Key Secondary Efficacy Endpoints 
For the primary analysis of the CFBL in CS7DA4S score at Week 24 key secondary efficacy endpoint, LOCF and 
multiple imputation will also be used to impute missing data for sensitivity analyses (refer to Section 15.1.4). 
For bilateral Zinreich score and time-to-treatment failure, no imputation for missing data will be performed. 
15.2.3.2. 
Missing Data Imputation Methods for Other Secondary Efficacy Endpoints 
The primary analysis of the other secondary efficacy endpoints will be performed based on the observed-case. That 
is, no missing data will be imputed. 
Additionally, LOCF will be used to impute missing data of endpoints based on CS7DA4S and SNOT-22 for 
sensitivity analyses.  Multiple imputation will also be performed for endpoints based on CS7DA4A as sensitivity 
analysis, but not for the endpoints based on SNOT-22. No sensitivity analyses to the missing data imputation 
method will be performed for any other non-key secondary efficacy endpoint. 
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15.2.4. ANALYSIS OF KEY AND OTHER SECONDARY EFFICACY ENDPOINTS 
15.2.4.1. 
Analysis of CFBL in CS7DA4S Individual and Total Scores at Weeks 8, 12, 16, 20 and 
24 
The analysis of the CFBL in CS7DAS total score will be conducted using an ANCOVA model as per Section 
15.1.3. Week 24 is considered a key secondary endpoint, while Weeks 8, 12, 16, and 20 are considered as non-key 
secondary endpoints and all other visits as exploratory endpoints. 
Additionally, the 7-day average score of nasal blockage/obstruction/congestion, reduction/loss of sense of smell, 
facial pain/pressure and anterior/posterior nasal discharge at Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24 will be analyzed as 
per Section 15.1.3. 
This analysis will be repeated for the ITT and PP analysis sets. 
The same three sensitivity and supportive subgroup analyses as for the primary endpoint as detailed in Sections 
15.1.4 and 15.1.5.2 will be repeated for the CS7DA4S total scores at all Weeks. Furthermore, the analysis of the 
CS7DA4S total score at all Weeks by CSsNP and CSwNP subgroups will be repeated with missing data imputed as 
per Section 15.1.2. 
For all other endpoints, the sensitivity analyses based on the PP analysis set and based on the ITT analysis set but 
with missing data imputed based on LOCF will be performed. That is, no sensitivity analysis based on the ITT 
analysis set with missing data imputed based on the multiple imputation method will be performed for the other 
secondary efficacy endpoints. 
Additionally, a plot of the LS means and SE for CFBL for CS7DA4S total and individual symptom scores at each 
timepoint up to Week 24 and Week 48 will be provided for the primary and final data analysis, respectively. 
15.2.4.2. 
Analysis of Zinreich Score 
The number and percentage of subjects at Week 24 in the ITT analysis set with and without at least a 1-point 
decrease in one of the six bilateral Zinreich sinuses score as defined in Section 15.2.1.2 will be provided by 
treatment group. 
A logistic regression adjusting for the baseline total bilateral Zinreich score and stratification variables (nasal allergy 
and nasal polyps) will be used to compare treatment groups. The responder indicator will be set to 1 for subjects 
who achieve at least a 1-point decrease in any score at Week 24 compared to baseline. Subjects for whom the 
decrease cannot be calculated, for example due to early termination, will be excluded from the analysis. 
Odds ratios together with the 90% CI will be presented to compare treatment groups. This analysis will be repeated 
for the PP analysis set. 
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As non-key secondary analyses, the CFBL in each of the 5 bilateral Zinreich sinuses score, Zinreich OMC score and 
total Zinreich score at Week 24 will be analyzed using an ANCOVA model as specified in Section 15.1.3 replacing 
the baseline CS7DA4S with the appropriate baseline bilateral Zinreich sinuses score, Zinreich OMC score or 
baseline Zinreich total score. This analysis will be repeated for the PP analysis set. 
Additionally, the logistic regression and ANCOVA models will be repeated on the subgroups as per baseline median 
total bilateral Zinreich score, for the ITT analysis set. 
15.2.4.3. 
Analysis of Time-to-Treatment Failure 
The number and percentage of subjects with and without treatment failure will be presented based on the ITT 
analysis set. For subjects without treatment failure, the censoring reason will be summarized. Time-to-treatment 
failure (days) will be analyzed for the ITT analysis set using a Cox proportional hazards model with fixed effects for 
baseline CS7DA4S score, treatment group and the stratification variables (nasal allergy and nasal polyps). The 
Hazard ratio of each LYR-210 treatment group vs. the Sham treatment group, its 90% CI and p-values will be 
presented. 
Additionally, Kaplan-Meier results will be displayed for the 25%, 50% and 75% quartiles, along with Kaplan-Meier 
estimates of probability of treatment failure at different timepoints: Weeks 2, 4, 8, 12, 16, 20 and 24. These 
timepoints are independent of the scheduled visits. Kaplan-Meier plots of time-to-treatment failure will be produced 
for each treatment group. 
15.2.4.4. 
Analysis of Time-to-Onset of Action 
Each daily CFBL in CS7DA4S values will be summarized and analyzed as the primary efficacy endpoint (see to 
Section 15.1.3). 
The daily LS mean CFBL (+/- SE) in CS7DA4S up to Day 30 will be presented graphically for each treatment group 
in the ITT analysis set with an indicator as to when the LYR-210 treatment groups are statistically significantly 
greater than the Sham group. 
For each LYR-210 group, the time-to-onset action will be the earliest day at which statistical significance is reached 
in comparison with the Sham group, when statistical significance is also reached for all subsequent visits. For 
example, if Days 10, 13, 14 and all subsequent days reached statistical significance for a LYR-210 group against the 
Sham group, time-to-onset of action will be Day 13 even if statistical significance was reached at Day 10 because 
statistical significance was not reached at Days 11 and 12. 
15.2.4.5. 
Analysis of SNOT-22 and SF-36v2 Domain and Total Scores 
For each post-Day 1 visit, the questionnaires will be compared between treatments using an ANCOVA model as 
described for the primary endpoint in Section 15.1.3 for the ITT analysis set. The CS7DA4S baseline score in 
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Section 15.1.3 will be replaced by the baseline score for the domain/total score of interest in the ANCOVA model. 
The summary of SNOT-22 will include the proportion of subjects who have achieved a minimally clinical important 
difference. 
Additionally, a plot of the biweekly LS means and SE for CFBL for SNOT-22 total score over time up to Week 24 
and Week 48 by treatment group will be provided for the primary and final data analyses, respectively. 
The analysis for SNOT-22 will be repeated for the PP analysis set. In addition, analysis for SNOT-22 in the ITT 
analysis set will be repeated where missing data will be imputed using the LOCF method outlined in Section 15.1.4. 
15.2.4.6. 
Analysis of UPSITTM 
The UPSITTM score at Week 24 will be analyzed for the ITT analysis set using an ANCOVA model outlined in 
Section 15.1.3. The Baseline CS7DA4S score will be replaced by the baseline UPSITTM score in the model. 
15.3. EXPLORATORY EFFICACY 
15.3.1. EXPLORATORY EFFICACY ENDPOINTS AND DERIVATIONS 
15.3.1.1. 
Acute Exacerbation of Chronic Sinusitis 
The percentages of subjects reporting acute exacerbation of CS (AECS) at Weeks 4, 8, 12, 16, 20 and 24 are 
exploratory endpoints, where AECS will be assessed by the investigator. AECS is defined as a sudden worsening of 
symptoms in a subject resulting in the treating physician reporting an escalation of treatment. This will be reported 
by the investigator on the Follow-up eCRF. 
15.3.1.2. 
Improvement from Baseline in Nasal Polyp Severity Within Middle Meatus 
The percentage of subjects with improvement from baseline in nasal polyp severity within the middle meatus in 
CSwNP subjects at Week 24 will be analyzed. Investigators will evaluate the severity of nasal polyps in the middle 
meatus using endoscopy at the Week 24/EOT visit by grading polyp severity as “better,” “worse,” or “the same” in 
comparison to the Baseline severity evaluated at Day 1 before the insertion procedure. A subject will be considered 
to have an improvement from baseline if both sinuses are assessed to be “better” than baseline or one side is 
assessed to be “better” than baseline and the other side to be “the same” as baseline. 
15.3.1.3. 
CFBL in Endpoints by Absence or Prescence of Nasal Polyps 
The secondary endpoints analysis will be repeated using the subgroups of subjects without nasal polyps (CSsNP), 
and subjects with nasal polyps (CSwNP). The endpoints to be summarized by these subgroups are: 
•
CFBL in CS7DA4S score at Weeks 1, 2, 3, 4, 8, 12, 16, 20 and 24
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•
CFBL in 7-day average score of individual cardinal CS symptoms at Weeks 1, 2, 3, 4, 8, 12, 16, 20 and 24
•
CFBL in SNOT-22 domain and total scores at Weeks 2, 4, 8, 12, 16, 20 and 24
•
CFBL in SF-36 domain and overall component summary measure scores at Week 24
•
Percentage of subjects with at least 1-point decrease in any area for the bilateral Zinreich score at Week 24
•
CFBL in each of the 5 bilateral Zinreich sinus scores, Zinreich OMC score and Zinreich total score at Week 24
•
CFBL in USPITTM total olfaction score at Week 24
15.3.1.4. 
CFBL in Endpoints at Post-Treatment Visits 
The secondary endpoint analysis will be repeated for the post-treatment visits. The endpoints to be explored for 
these visits are: 
•
Proportion of subjects with improvement from baseline in nasal polyp severity within the middle meatus at
Week 28
•
CFBL in CS7DA4S total score at Weeks 28, 32, 36, 40, 44 and 48
•
CFBL in 7-day average score of individual cardinal CS symptoms at Weeks 28, 32, 36, 40, 44 and 48
•
CFBL in SNOT-22 domain and total scores at Weeks 28, 32, 36, 40, 44 and 48
•
CFBL in SF-36 domain and overall component summary measure scores at Week 48
•
CFBL in UPSIT at Week 28.
15.3.2. MISSING DATA IMPUTATION METHODS FOR EXPLORATORY EFFICACY
ENDPOINTS 
No missing data methods will be used for exploratory analysis. 
15.3.3. ANALYSIS OF EXPLORATORY EFFICACY ENDPOINTS 
The exploratory efficacy endpoints that are continuous will be compared between treatments at each post-baseline 
timepoint in the same manner as the primary efficacy analysis in Section 15.1.3 for the ITT analysis set. For the 
efficacy endpoints to be analyzed by CSsNP and CSwNP subgroups, the analysis will be a repeat of Section 15.1.3, 
however the model will not include the presence of nasal polyps as a fixed effect. 
For dichotomous exploratory efficacy endpoints, treatments will be compared in the same manner as the proportion 
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of subjects with at least 1-point decrease from baseline in the Zinreich score in at least 1 pair of the anterior ethmoid, 
maxillary, posterior ethmoid, frontal or sphenoid sinuses key secondary endpoint in Section 15.2.4.2, replacing the 
baseline bilateral Zinreich score with the baseline CS7DA4S score. This analysis will be carried out for the ITT 
analysis set. 
In addition, for all endpoints measured longitudinally at various visits during the study, a generalized estimating 
equation (GEE) linear regression and logistic regression will be used to compare treatments over time for continuous 
and dichotomous endpoints, respectively. The estimates, SE, 90% CIs and p-values will be presented for each visit. 
In the GEE, only treatment stage timepoints will be analyzed; assessments with only one follow-up timepoint will 
not be analyzed.  
The assumed within-subject correlation matrix structure will be unstructured. If the unstructured model does not 
converge, then an autoregressive (1) structure will be assumed. Included as independent variables for each outcome 
endpoint will be treatment group, visit, treatment-by-visit, stratification variables, and the baseline value of the 
endpoint being analyzed. This will be carried out on ITT subjects with available data for the below endpoints: 
•
CFBL in CS7DA4S total score
•
CFBL in 7-day average score of individual cardinal CS symptoms
•
CFBL in SNOT-22 domain and total scores
16.
SAFETY OUTCOMES
All outputs for safety outcomes will be based on the SAF. 
There will be no statistical comparisons between the treatment groups for safety data, unless otherwise specified 
with the relevant section. 
16.1. ADVERSE EVENTS 
AEs will be coded using MedDRA version 23.0 or later. 
•
Prior AEs are defined as any AE starting before the bilateral insertion/Sham procedure.
•
Treatment emergent adverse events (TEAEs) are defined as any AE starting or worsening on or after the
bilateral insertion/Sham procedure, but before or on 28 days after the removal/Sham procedure.
•
Post-treatment AEs are defined as any AE starting or worsening more than 28 days after the removal/Sham
procedure.
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See APPENDIX 2 for the handling of partial dates for AEs. In the case where it is not possible to define an AE as 
treatment emergent or not, the AE will be classified by the worst case (i.e. treatment emergent). 
An overall summary of the number and percentage of subjects as well as the number of events within each of the 
categories below will be provided: 
•
TEAEs
•
TEAEs by maximum severity
•
TEAEs by highest relationship to study treatment
•
TEAEs by highest relationship to study procedure
•
Serious TEAE
•
Serious TEAEs by maximum severity
•
Serious TEAEs by highest relationship to study treatment
•
Serious TEAEs by highest relationship to study procedure
•
TEAE leading to treatment discontinuation
•
TEAE leading to study discontinuation
•
TEAE leading to death
•
Post-treatment AEs
•
Post-treatment AEs by maximum severity
•
Post-treatment SAEs
•
Post-treatment SAEs by maximum severity
•
Post-treatment SAEs leading to study discontinuation
•
Post-treatment SAEs leading to death.
Listings will include all AEs regardless of whether they are treatment emergent. 
16.1.1. ALL TEAES AND POST-TREATMENT AES 
Incidence of TEAEs and post-treatment AEs will be presented by System Organ Class (SOC) and Preferred Term 
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(PT). If a subject reports a TEAE or post-treatment AE more than once within that SOC/PT, the subject will be 
counted only once for that SOC/PT. 
In the summary tables, TEAEs and post-treatment AEs will be presented by decreasing frequency of total events 
overall within each SOC and then similarly by decreasing frequency of total events overall within each PT. System 
organ class or PTs with equal frequencies will be sorted alphabetically. 
Summaries will present TEAEs and post-treatment AEs broken down further by maximum severity. Summaries will 
also present TEAEs by relationship to study treatment and relationship to study procedure. 
16.1.1.1. 
Severity 
Severity is classified as mild, moderate or severe (increasing severity). TEAEs starting on or after the bilateral 
insertion/Sham procedure, and post-treatment AEs starting 28 days after removal procedure with a missing severity 
will be classified as severe for analysis purposes. If a subject reports an AE more than once within that SOC/PT, the 
AE with the worst-case severity will be used in the corresponding severity summaries. 
16.1.1.2. 
TEAE Relationship to Study Treatment 
Relationship, as indicated by the Investigator, is classified as “Not Related”, “Possible Related” or “Definitely 
Related” (increasing severity of relationship). A “related” TEAE is defined as a TEAE with a relationship to study 
treatment as “Possibly Related” or “Definitely Related”. TEAEs starting on or after the bilateral insertion/Sham 
procedure with a missing relationship to study treatment will be regarded as “Related”. If a subject reports the same 
AE more than once within that SOC/PT, the AE with the worst-case relationship to study treatment will be used in 
the corresponding relationship summaries. 
16.1.1.3. 
TEAE Relationship to Study Procedure 
The same conventions as noted in Section 16.1.1.2 will be applied to the relationship to study procedure for Day 1 
insertion procedure and Week 24 removal procedure as indicated by the investigator. A TEAE related to the 
insertion/removal procedure is an AE that occurred within one day after the insertion/removal procedure. 
16.1.2. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events eCRF. A summary of 
serious TEAEs and post-treatment SAEs by SOC and PT will be prepared, including events leading to death. If a 
subject reports a serious TEAE/post-treatment SAE more than once within that SOC/PT, the subject will be counted 
only once for that SOC/PT. 
Additionally, a listing of all SAEs will be provided, including events leading to death. 
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16.1.3. TEAES LEADING TO DISCONTINUATION OF STUDY TREATMENT 
TEAEs leading to early discontinuation of study treatment will be identified as an AE for which the “Action taken” 
is reported as “Study treatment discontinuation” on the Adverse Event eCRF. A summary of TEAEs leading to early 
discontinuation of study treatment by SOC and PT will be prepared. 
Additionally, a listing of all TEAEs leading to permanent discontinuation of study treatment will be provided. 
16.1.4. TEAES AND POST-TREATMENT AES LEADING TO DISCONTINUATION OF STUDY
TEAEs and post-treatment AEs leading to study discontinuation will be identified as an AE for which the question 
“Did the AE cause the subject to discontinue from the study?” is reported as “Yes” on the Adverse Events eCRF. A 
summary of TEAEs leading to study discontinuation by SOC and PT will be prepared. If a subject reports a TEAE 
leading to study discontinuation more than once within that SOC/PT, the subject will be counted only once for that 
SOC/PT. 
Additionally, a listing of all AEs leading to study discontinuation will be provided. 
16.1.5. ADVERSE EVENTS LEADING TO DEATH 
TEAEs and post-treatment AEs leading to death are those events for which “Outcome” is reported as “Death” on the 
Adverse Events eCRF, or the seriousness criteria is indicated as “Death”. A summary of TEAEs and post-treatment 
AEs leading to death by SOC and PT will be prepared. 
Additionally, a listing of all AEs leading to death will be provided. 
16.2. LABORATORY EVALUATIONS 
Results from the local and central laboratories will be included in the reporting for this study. 
•
Local Laboratories:
o
Hematology
o
Chemistry
o
Serum cortisol levels at screening
•
Central laboratories:
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o
Morning Serum cortisol after screening
The local laboratory results will be converted to standard units by data management and transferred to biostatistics 
for use in the analysis. 
Quantitative laboratory measurements reported as “< X”, that is below the lower limit of quantification, or “> X”, 
that is above the upper limit of quantification, will be converted to X for quantitative summaries. 
The following summaries will be provided for laboratory data: 
•
Observed values and change from baseline by visit for quantitative measurements.
•
Shift from baseline according to investigator assessment (abnormal CS, abnormal NCS, or normal as indicated
by the investigator on the Hematology, Blood Chemistry, and Adverse Events eCRFs).
Since the results are originating from various local laboratories, a single set of reference ranges is not available for 
use in the analysis. Prior to summarizing, the lab results will be normalized as described in Section 16.2.1. 
The laboratory tests to be presented in the analysis tables are listed in the protocol Sections 8.4.3.1 to 3. Any other 
lab test will be listed only. 
16.2.1. LABORATORY STANDARDIZATION 
As the results are from local laboratories, laboratory parameters will have different normal ranges in the database. 
Prior to the analysis, observed values of all subjects will be standardized to a unique set of normal range using the 
location-scale standardization formula (Chuang-Stein, 1992): 
𝑠= 𝐿𝑆+ (𝑥−𝐿𝑋) 𝑈𝑆−𝐿𝑆
𝑈𝑋−𝐿𝑋
where: 
s = standardized observed value; 
x = original observed value; 
LS = Lower Limit of the normal range chosen to be the standard normal range; 
US = Upper Limit of the normal range chosen to be the standard normal range; 
LX = Lower Limit of the normal range associated with the original observed value; 
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UX = Upper Limit of the normal range associated with the original observed value; 
It is to be noted that the choice of the standard normal range is arbitrary for all laboratory parameters except serum 
cortisol. Serum cortisol is collected by both central and local laboratories and for analysis purposes the central 
laboratory ranges will be used as the standard normal range. 
16.2.2. PREGNANCIES 
A serum pregnancy test will be conducted on females of child bearing potential at screening and prior to 
randomization on day 1. Urine pregnancy tests will be conducted thereafter at the time points specified in the 
schedule of assessments in Section 8.1 of the protocol. These data will be listed only. 
16.3. VITAL SIGNS 
The following vital signs measurements will be reported for this study: 
•
Systolic Blood Pressure (mmHg)
•
Diastolic Blood Pressure (mmHg)
•
Pulse Rate (bpm)
•
Respiration Rate (breaths/min)
•
Weight (kg)
•
Body Mass Index (kg/m2)
•
Temperature (⁰C) (to be listed only)
The following summaries will be provided for vital signs data: 
•
Observed, change from baseline by visit for quantitative measurements
•
Incidence of abnormal values according to investigator criteria
•
Shift from baseline according to investigator assessment (abnormal CS, abnormal NCS, or normal as indicated
by the investigator on the eCRF).
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16.4. PHYSICAL EXAMINATION 
A physical examination will be conducted at Screening, Day 1, and Weeks 4, 12, 24, 28 and 48. This will consist of 
an assessment of all body systems including the skin, eyes, ears, nose and throat. These data will be listed only. 
16.5. OTHER SAFETY ASSESSMENTS 
16.5.1. OPHTHALMOLOGY ASSESSMENT 
Ophthalmologic assessments will be performed at the site and result reported on the Ophthalmology Examination 
eCRF. 
•
Intraocular pressure (IOP) results will be summarized as follows:
o
Observed values and change from baseline in IOP by visit
o
Incidence of elevated IOP in one or both eyes
o
Clinically significant increase of IOP in one or both eyes
o
Shift from baseline according to investigator assessment (abnormal or normal as indicated by the
investigator on the eCRF)
•
In addition, the slit-lamp examination results will be reported in a descriptive summary table.
o
The summary will include the number and percentage of subjects with newly identified or worsened
cataracts in one or both eyes as assessed per the protocol schedule of events.
o
A further classification between abnormal not affecting vision and abnormal affecting vision will also be
presented.
o
For subjects with different results for left and right eyes, the worst-case result will be reported for the relevant
visit, that is abnormal affecting vision.
16.5.2. OPHTHALMOLOGY SPECIFIC DERIVATIONS 
•
Elevated IOP is defined as results > 21 mmHg in one or both eyes.
•
A clinically significant increase of IOP is defined as IOP in one or both eyes > 28 mmHg or an increase of IOP
from Baseline in one or both eyes >= 10 mmHg.
•
Newly identified or worsened cataracts will be identified as follows:
o
Mature or Morgagnian cataract present reported as “Yes”
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o
Nuclear cataract reported at a higher grade than the Screening result
o
Cortical cataract reported at a higher grade than the Screening result
o
Central Optical zone involvement reported as “Yes”
o
Posterior subcapsular cataract reported at a higher grade than the Screening result.
16.6. NASAL ENDOSCOPY ASSESSMENT 
Nasal cavities will be assessed by endoscopy procedure as per the schedule of events in Section 8.1 of the protocol. 
The severity and percentage of subjects with adverse nasal endoscopic findings in one or both nostrils will be 
summarized by visit and by treatment group. 
17.
PHARMACOKINETIC ANALYSES
The PK analyses will be performed based on subjects in the PK analysis set with available data by treatment group 
as follows: 
•
Concentrations, nominal times post-dose, and actual times will be listed.
o
In listings, concentrations below the lower limit of quantification (LLOQ) will be reported as
“<LLOQ”, where LLOQ will be the actual value of LLOQ.
•
A separate listing will present deviations from the nominal times per protocol.
•
Descriptive statistics will be presented for concentrations by dose and nominal time post-dose including
number (n), mean, SE, standard deviation, coefficient of variation (CV), median, minimum, maximum,
geometric mean, geometric CV%, and the number of concentrations greater than or equal to LLOQ.
o
The “<LLOQ” values will be set to zero based on the Beal’s method M7 (Beal, 2001).
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18.
REFERENCES
Beal, S. (2001). Ways to Fit a PK Model with Some Data Below the Quantification Limit. Journal of Pharmacokinetics 
and Pharmacodynamics, 481-504. 
Chuang-Stein, C. (1992). Summarizing laboratory data with different reference ranges in multi-center clinical trials. 
Drug Information Journal, 26(1);77-84. 
DeConde, A. S., Bodner, T. E., Mace, J. C., & Smith, T. L. (2014). Response Shift in Quality of Life After Endoscopic 
Sinus Surgery for Chronic Rhinosinusitis. JAMA Otolaryngol Head Neck Surgery, 140:712-719. 
Doty, R. L., Shaman, P., & Dann, M. (1984). Development of the University of Pennsylvania Smell Identification Test: 
a standardized microencapsulated test of olfactory function. Physiology & Behavior, 32:489-502. 
Hopkins, C., Gillett, S., Slack , R., Lund, V., & Browne, J. (2009). Psychometric validity of the 22‐item Sinonasal 
Outcome Test. Clinical Otolaryngology, 34: 447-454. 
Likness, M. M., Pallanch, J. F., Sherris, D. A., Kita, H., Mashtare Jr., T. L., & Ponikau, J. U. (2014). Computed 
tomography scans as an objective measure of disease severity in chronic rhinosinusitis. Otolaryngology 
Head and Neck Surgery, 150:305-311. 
O'Kelly, M., & Ratitch, B. (2104). Clinical Trials with Missing Data: A Guide for Practitioners. Chichester: John Wiley 
& Sons, Ltd. 
Optum. 
(n.d.). 
PSF-36v2® 
Health 
Survey 
Measurement 
Model. 
Retrieved 
from 
https://www.optum.com/content/dam/optum/resources/Manual%20Excerpts/SF-36v2-Health-Survey-
Measurement-Model.pdf. 
Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and Sons. 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter. and the page orientation will be landscape. Margins will provide 1 inch (2.54 cm) of 
white space all around the page. 
DATES AND TIMES 
Depending on data available, dates and times will take the form DDMMMYYYY HH:MM. 
SPELLING FORMAT 
United States English. 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in the given order: 
•
LYR-210 2500µg
•
LYR-210 7500µg
•
Sham
PRESENTATION OF VISITS 
For tables and figures, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name 
Screening 
Scr 
Baseline 
BL 
Week 2 
WK 2 
Week 4 
WK 4 
Week 8 
WK 8 
Week 12 
WK 12 
Week 16 
WK 16 
Week 20 
WK 20 
Week 24 
WK 24 
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Statistical Analysis Plan 
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Long Name (default) 
Short Name 
Week 28 
WK 28 
Week 32 
WK 32 
Week 36 
WK 36 
Week 40 
WK 40 
Week 44 
WK 44 
Week 48 
WK 48 
For Listings the visit will be presented as derived in Section 6.6. 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
•
Randomized treatment group (or treatment received if it’s a safety output) in order of LYR-210 2500 µg, LYR-
210 7500 µg and Sham procedure.
o
For listings where non-randomized subjects are included, these will appear in a category after the
randomized treatment groups labeled “Randomized, Not Treated” and “Screen Failure”.
•
Subject ID
•
Parameter (where applicable)
•
Date (where applicable)
GENERAL CONVENTIONS 
•
Decimal precision:
o
If the original data has N decimal places, then the summary statistics should have the following decimal
places:
•
Minimum and maximum: N
•
Mean and median: N + 1
•
SD: N + 2
o
Percentages will be presented to 1 decimal place
o
Zero count will not have percentage reported
o
Odd ratios will be presented to 2 decimal places
•
Ordering of footnotes:
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Statistical Analysis Plan 
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o
Abbreviations
o
Definitions
o
Formulae
o
P-value significance footnote
o
Symbols. They will appear in the same order as they are defined in the table or listing, from left to right.
o
Specific notes
o
Common notes from table to table should appear in the same order.
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Statistical Analysis Plan 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS 
Start Date 
Stop Date 
Action 
Known 
Known/Partial/ 
Missing 
If start date < insertion procedure, then Prior 
If insertion procedure <= start date <= removal 
procedure + 28 days , then TEAE 
If start date > removal procedure + 28 days, then Post-
Treatment AE 
Partial, but known components 
show that AE started before 
insertion procedure  
Known/Partial/ 
Missing 
Assumed Prior 
Partial, known components show 
that AE started on/after insertion 
procedure but before/on removal 
procedure + 28 days 
OR  
Missing 
Known/Partial/ 
Missing 
Assumed TEAE 
Partial, known components show 
that AE started after removal 
procedure + 28 days 
Known/Partial/ 
Missing 
Assumed Post-Treatment AE 
ALGORITHM FOR PRIOR/CONCOMITANT MEDICATIONS 
Start Date 
Stop Date 
Action 
Known 
Known 
If stop date < insertion procedure, assign as Prior 
If stop date >= insertion procedure and start date <= removal procedure+28 days, 
assign as Concomitant 
If start date > removal procedure+28 days, assign as Post-Treatment.  
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Statistical Analysis Plan 
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Start Date 
Stop Date 
Action 
Partial 
If known date parts of stop date < insertion procedure, assign as Prior 
If known date parts of stop date >= insertion procedure and start date <= removal 
procedure+28 days, assign as Concomitant 
If start date > removal procedure+28 days, assign as Post-Treatment 
Missing 
If stop date is missing could never be assumed a Prior medication 
If start date <= removal procedure+28 days, assign as Concomitant 
If start date > removal procedure+28 days, assign as Post-Treatment 
Partial 
Known 
If stop date < insertion procedure, assign as Prior 
If stop date >= insertion procedure and known date parts of start date <= removal 
procedure+28 days, assign as Concomitant 
If known date parts of start date > removal procedure+28 days, assign as Post-
Treatment 
Partial 
If known date parts of stop date < insertion procedure, assign as Prior 
If known date parts of stop date >= insertion procedure and known date parts start 
date <= removal procedure+28 days assign as Concomitant 
If known date parts of start date > removal procedure+28 days, assign as Post-
Treatment 
Missing 
If stop date is missing could never be assumed a Prior medication 
If known date parts of start date <= removal procedure+28 days, assign as 
Concomitant 
If known date parts of start date > removal procedure+28 days, assign as Post-
Treatment 
Missing 
Known 
If stop date < insertion procedure, assign as Prior 
If stop date >= insertion procedure, assign as Concomitant 
Cannot be assigned as Post-Treatment 
Partial 
If known date parts of stop date < removal procedure+28 days, assign as Prior 
If known date parts of stop date >= removal procedure+28 days, assign as 
Concomitant 
Cannot be assigned as ‘Post-Treatment’ 
Missing 
Assign as Concomitant 
Document: 
LYR-210_Main SAP_v1.0_06Oct2020 
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Version Date: 
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Effective Date: 
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