ENLIGHTEN 2: A Phase III, Randomized, Blinded, Controlled, Parallel-Group Trial to Evaluate the Efficacy and Safety of LYR-210 for the Treatment of Chronic Rhinosinusitis in Adults
Phase: PHASE3
Conditions: Chronic Sinusitis, Chronic Rhinosinusitis (Diagnosis)
Sponsor: Lyra Therapeutics

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STUDY LYR-210-2021-005 
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CLINICAL STUDY PROTOCOL 
 
Protocol Number: 
LYR-210-2021-005 
Current Version/Date: 
4.0/ 29 March 2024 
NCT/EUDRACT #: 
NCT05295459/ 2021-006911-27 
EU CT #: 
2023-506268-15-00 
Study Title: 
ENLIGHTEN 2: A Phase III, Randomized, Blinded, 
Controlled, Parallel-Group Trial to Evaluate the Efficacy 
and Safety of LYR-210 for the Treatment of Chronic 
Rhinosinusitis (CRS) in Adults  
Short Title: 
Efficacy and Safety of LYR-210 for the Treatment of 
Chronic Rhinosinusitis (CRS) 
 
Sponsor: 
Lyra Therapeutics, Inc. 
480 Arsenal Way 
Watertown, MA USA 02472 
617-393-4600 
 
GCP Statement  
This study is to be performed in full compliance with the protocol, Good Clinical Practices 
(GCP), as defined by United States Food and Drug Administration (USFDA) and International 
Council for Harmonisation (ICH), Regulation EU # 536/2014, Declaration of Helsinki and 
applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities 
 
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. 

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STUDY LYR-210-2021-005 
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Sponsor Signature Page 
 
Protocol Number: 
LYR-210-2021-005 
Current Version/Date: 
4.0/ 29 March 2024  
NCT/EUDRACT #: 
NCT05295459/ 2021-006911-27 
EU CT #: 
2023-506268-15-00 
Study Title: 
ENLIGHTEN 2: A Phase III, Randomized, Blinded, 
Controlled, Parallel-Group Trial to Evaluate the Efficacy 
and Safety of LYR-210 for the Treatment of Chronic 
Rhinosinusitis (CRS) in Adults  
Short Title: 
Efficacy and Safety of LYR-210 for the Treatment of 
Chronic Rhinosinusitis (CRS) 
Sponsor: 
Lyra Therapeutics, Inc. 
480 Arsenal Way 
Watertown, MA USA 02472 
 
 
 

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Co-Lead Investigator Signature Page 
 
Protocol Number: 
LYR-210-2021-005 
Current Version/Date: 
4.0/ 29 March 2024 
NCT/EUDRACT #: 
NCT05295459/2021-006911-27 
EU CT #: 
2023-506268-15-00 
Study Title: 
ENLIGHTEN 2: A Phase III, Randomized, Blinded, 
Controlled, Parallel-Group Trial to Evaluate the Efficacy 
and Safety of LYR-210 for the Treatment of Chronic 
Rhinosinusitis (CRS) in Adults  
Short Title: 
Efficacy and Safety of LYR-210 for the Treatment of 
Chronic Rhinosinusitis (CRS) 
 
Sponsor: 
Lyra Therapeutics, Inc. 
480 Arsenal Way 
Watertown, MA USA 02472 
 
 
 

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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 participants 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, Regulation 
EU # 536/2014 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 participants 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 participants. 
I am aware that the Study Sponsor reserves the right to discontinue this investigation at any time. If 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 participants already participating in the 
investigation. 
I agree to provide to the Study Sponsor my current curriculum vitae (CV) along with the current CV 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. 
 
Investigator:  
Name (Print): _________________________________________________________________  
 
Signature: _____________________________ 
Date of Signature: ___________________ 
 
(DD MMM YYYY) 
 
Site Number: __________________________ 
 
 
 

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Clinical Study Protocol Synopsis 
Short title: 
ENLIGHTEN 2 
Complete title: 
ENLIGHTEN 2: A Phase III, Randomized, Blinded, Controlled, 
Parallel-Group Trial to Evaluate the Efficacy and Safety of LYR-210 
for the Treatment of Chronic Rhinosinusitis (CRS) in Adults  
Protocol number 
LYR-210-2021-005 
Study design: 
Multicenter, phase III, randomized, blinded, controlled, parallel group  
Investigational 
product: 
LYR-210 System (7500 µg) 
Active 
ingredient: 
Mometasone furoate (MF) 
Background 
Therapy 
Nasal saline irrigation 
Study locations 
US and Europe 
Number of sites 
Approximately 60 sites 
Enrollment: 
Approximately 180 adult randomized participants with symptomatic 
CRS without nasal polyps or with grade 1 nasal polyps (limit of 
approximately 30 participants with nasal polyps) 
Randomization 
2 treatment:1 control 
Treatment: 
Bilateral LYR-210 in treatment participants vs sham procedure (no 
product) in control participants. All participants will continue daily 
saline irrigation. 
Inclusion 
criteria: 
A participant must meet all the following criteria to be eligible for 
this study: 
1. Age ≥18. 
2. Diagnosed as having CRS, defined by duration of 12 weeks or 
longer with 2 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 
3. Bilateral ethmoid disease, defined as each side of anterior and/or 
posterior ethmoid sinus is ≥5% opacified upon the screening 
computed tomography (CT), as determined by the Central Imaging 
Core Lab/ Central Reviewer. 

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4. Mean 3 cardinal symptom (3CS) score over the preceding 7 days 
≥5 (0-3 scale for each of the symptoms) as determined within 7 
days of Day 1 (the determination for eligibility can be made on 
any day from Day -7 through Day 1).  
5. Undergone at least 2 trials of medical treatments in the past, 1 of 
which must include intranasal corticosteroid sprays (INCS) for a 
minimum of 4 weeks with written medical record or confirmed via 
patient report and documented in the medical report record and are 
no longer using INCS at Screening. 
6. Has been informed of the nature of the study and provided written 
informed consent as approved by the IRB/EC of the respective 
clinical site or regulatory authority, if applicable by national law. 
7. Agrees to comply with all study requirements. 
8. If currently on a waiting list for sinonasal surgery, willing to be 
removed from the waiting list or have preplanned surgery date 
cancelled for the duration of the study. [Note: this does not 
preclude a participant from receiving or being recommended for 
sinonasal surgery as rescue treatment during the study]. 
Exclusion 
criteria: 
A participant who meets any of the following criteria will be excluded 
from this study: 
1. Inability to tolerate topical anesthesia or endoscopic procedure. 
2. Previous ethmoidectomy, or surgery of the middle meatus and/or 
middle turbinate preventing proper placement and retention of 
LYR-210. NOTE: any previous ethmoidectomy is exclusionary. 
3. Previous nasal surgery or polypectomy within 3 months of 
Screening visit. 
4. Presence of nasal polyp grade 2 or higher (ie, polyps extending 
outside the middle meatus) on either side. 
5. Seasonal allergic rhinitis (SAR) with symptoms and/or, based on 
time of year, would anticipate onset of symptoms within 24 weeks 
of randomization. NOTE: mild SAR symptoms, as assessed by the 
Investigator, are not exclusionary. 
6. Perennial rhinitis with symptoms that are well controlled by 
regular use of intranasal corticosteroids. 
7. Severe asthma or experienced 1 or more exacerbations of asthma 
requiring systemic corticosteroid (SCS) use within the 6 months 
prior to the Screening visit. Participants 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. 

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8. Endoscopic exclusion criteria at Screening or Day 1 visit:  
a) Obstruction of middle meatus or degenerated middle turbinate 
preventing proper placement and retention of LYR-210. 
b) Evidence of mucosal erosion or ulceration. 
c) Acute nasal/sinus infection or purulence.  
d) Evidence of nasal septal perforation. 
9. Screening CT exclusion criteria: 
a) Anatomic variation that, in the opinion of the investigator, 
would adversely impact placement of LYR-210. 
b) Structural, noninflammatory related CRS (eg, large concha 
bullosa preventing proper matrix placement, tumor). 
c) Sinus disease extended into orbital or intracranial space. 
d) Evidence of mycetoma/fungal ball, allergic fungal 
rhinosinusitis. 
e) Sinus mucocele. 
10. History or clinical evidence or suspicion of invasive fungal 
sinusitis, allergic fungal rhinosinusitis, atrophic rhinitis, or 
odontogenic sinusitis. 
11. Known history of hypersensitivity or intolerance to corticosteroids. 
12. Oral steroid or monoclonal antibody (Xolair, Nucala, Dupixent, 
etc.) dependent condition, including biologics use within 3 months 
of screening and systemic steroids use within 1 month of 
screening. NOTE: monoclonal antibodies for this exclusion are 
limited to those that target T2 inflammatory pathways and/or are 
known to impact CRS-related inflammation and symptoms. 
13. SCS administered within 1 month prior to Screening visit. 
14. Known history of hypothalamic pituitary adrenal axial 
dysfunction. 
15. Previous pituitary or adrenal surgery. 
16. 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. 
17. Acute exacerbation of nasal allergy or CRS, upper respiratory tract 
infection (URTI), or common cold within 4 weeks of the 
Screening visit or during the screening/run-in period. The 
infection/exacerbation must be resolved, and antibiotic or other 
medication use must be discontinued prior to screening. 
18. Dental procedure/implant on maxillary dentition within 4 weeks of 
the Screening visit. 

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19. Past or present acute or chronic intracranial or orbital 
complications of CRS (eg, brain abscess, related problems with 
eyes or central nervous system). 
20. History or diagnosis (in either eye) of glaucoma or ocular 
hypertension (IOP >21 mm Hg). 
21. 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. 
22. Loss of functional vision in 1 or both eyes. 
23. Diagnosed with ongoing rhinitis medicamentosa. 
24. Known history of immune dysfunction including immune 
deficiency (IgG subclass deficiency or IgA deficiency) or 
autoimmune disease (eg, Wegener’s granulomatosis, sarcoidosis) 
that requires immunomodulatory therapy. NOTE: Autoimmune 
conditions that do not require immunomodulatory therapy are not 
exclusionary. 
25. Currently positive for COVID-19 or residual sinonasal symptoms 
from a previous COVID-19 infection within the past 6 months. 
26. Past, present, or planned organ transplant or chemotherapy with 
immunosuppression within the past 5 years. 
27. History or diagnosis of ciliary dysfunction (eg, cystic fibrosis, 
primary ciliary dyskinesia [Kartagener syndrome]).  
28. Past or present systemic vasculitis (eg, granulomatosis with 
polyangiitis). 
29. Evidence of disease or condition expected to compromise survival 
or ability to complete follow-up assessments. 
30. 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 on Day 1 prior to 
randomization based on a urine pregnancy test. Both male and 
female participants of reproductive potential must agree to use 
highly effective methods of birth control throughout the study. 
31. Previously received an experimental treatment in another clinical 
study within 5 half-lives or 30 days (whichever is longer) of 
Screening visit or prior participation in another LYR-210 clinical 
trial.  
32. Currently participating in another drug or device study.  

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33. Determined by the investigator as not suitable for reasons not 
already specified if the health of the participant or the validity of 
the study outcomes may be compromised. 
Objective:  
Evaluate the efficacy and safety of LYR-210 compared with sham 
control for treatment in adults with CRS. 
Primary efficacy 
endpoint: 
Change from baseline (CFBL) in the 7-day average composite score of 
3 cardinal symptoms (3CS) of nasal blockage/obstruction/congestion, 
anterior/posterior nasal discharge, and facial pain/pressure at Week 24 
in participants without nasal polyps. 
Key secondary 
efficacy 
endpoints: 
1. CFBL in the 7-day average composite score of 3CS at Week 
24. 
2. CFBL in the 22-item Sino-Nasal Outcome Test (SNOT-22) 
total score at Week 24. 
3. CFBL in the percent opacification of the bilateral anterior and 
posterior ethmoids at Week 20, as determined by 3-D 
volumetric CT analysis. 
4. Rescue treatment requirement through Week 24. (This 
endpoint will be descriptively summarized in this study and the 
statistical testing will be conducted on pooled data from this 
[ENLIGHTEN 2] study and the [ENLIGHTEN 1] study.) 
 
The above key secondary and below secondary endpoints will be 
analyzed for all participants. 
Secondary 
endpoints 
1. CFBL in 3CS score at Weeks 2, 4, 8, 12, 16, and 20 
2. CFBL in the symptom score for individual cardinal symptoms of 
nasal blockage/obstruction/congestion, anterior/posterior nasal 
discharge, and facial pain/pressure at Weeks 2, 4, 8, 12, 16, 20 
and 24 
3. CFBL in loss of smell score at Weeks 4, 8, 12, 16, 20, and 24, for 
all participants and for participants with baseline score ≥2 
4. Improvement of ≥1 point, ≥2 points, and ≥3 points from baseline 
in 3CS score at Week 24 
5. CFBL in SNOT-22 total score at Weeks 4, 8, 12, 16, and 20 
6. CFBL in SNOT-22 subdomain scores at Weeks 4, 8, 12, 16, 20, 
and 24 
7. Improvement of ≥8.9 and ≥12 from baseline in SNOT-22 total 
score at Week 24 

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8. CFBL in the Zinreich score of the bilateral anterior and posterior 
ethmoids at Week 20 
9. Time to first rescue treatment requirement through Week 24 
10. Rescue medication use through Week 24 
11. Sinonasal surgery requirement through Week 24 
12. Total systemic corticosteroids (SCS) dose prescribed through 
Week 24 
13. Number of days on SCS through Week 24 
14. Acute exacerbation of CRS (AECRS), defined as a sudden 
worsening of CRS symptoms resulting in escalation of treatment 
by the Investigator, through Week 24 
15. Conversion to a nonsurgical candidate through Week 24 
16. CFBL in 36-Item short form health survey, version 2 (SF-36v2) 
physical health, mental health, and domain scores at Week 24 
17. CFBL in EuroQoL 5-dimension, 5-level (EQ-5D-5L) score at 
Week 24 
18. Improvement of ≥1 category and ≥2 categories from baseline in 
the severity of CRS-related symptoms as indicated by the PGIS at 
Week 24 
19. Overall change of “very much better” or “much better” in the 
CRS-related symptom severity as indicated by the PGIC at Week 
24 
20. CFBL in Medical Outcomes Study Sleep Scale (MOS Sleep-R) 
score at Week 24 
21. CFBL in Work Productivity and Activity Impairment-Specific 
Health Problem (WPAI-SHP), version 2.0 at Weeks 4, 12, and 24 
22. CFBL in Fordyce Emotions Questionnaire (FEQ) at Weeks 4, 8, 
12, 16, 20, and 24 
 
Safety endpoints 
1. Treatment-emergent adverse events (TEAEs) and serious 
adverse events (TESAEs) through Week 24. 
2. Abnormal (clinically significant) laboratory values 
(hematology and chemistry) through Week 24. 
3. Newly identified adverse findings in middle meatus including 
epistaxis, mucosal erosion or ulceration, and perforation 
through Week 24. 
4. Clinically significant increase of IOP through Week 24. 
5. Newly identified or worsened cataract in 1 or both eyes by slit-
lamp examination through Week 24. 

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Key study 
assessments 
• Cardinal symptoms (CS) questionnaire 
• SNOT-22 
• Work Productivity and Activity Impairment-Specific Health 
Problem (WPAI-SHP), version 2.0 
• Fordyce Emotions Questionnaire (FEQ) 
• 36-Item short form health survey, version 2 (SF-36v2) 
• EuroQoL 5-dimension, 5-level (EQ-5D-5L) 
• Patient Global Impression of Severity (PGIS) 
• Patient Global Impression of Change (PGIC) 
• Medical Outcomes Study Sleep Scale (MOS Sleep-R) 
• Endoscopic nasal examination 
• Ocular examination (visual acuity [VA], intraocular pressure 
[IOP], and slit lamp) 
• 3-D volumetric (CT) score 
• Bilateral ethmoid Zinreich score 
• Adverse events (AEs) 
 
 
 

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Abbreviations and Acronyms 
AE 
Adverse event 
AECRS 
Acute exacerbation of CRS 
ANCOVA 
Analysis of covariance 
CFBL 
Change from baseline 
CFR 
Code of Federal Regulations (US) 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CRO 
Clinical research organization 
CRS 
Chronic rhinosinusitis 
CS 
Cardinal symptoms 
CT 
Computed tomography 
CTRA 
Clinical trial research agreement 
CV 
Curriculum vitae 
EC 
Ethics Committee 
EDC 
Electronic data capture 
EIU 
Exposure in utero 
EQ-5D-5L 
EuroQoL 5-dimension, 5-level 
EOS 
End of study 
EOT 
End of treatment 
ePRO 
Electronic patient-reported outcomes questionnaire 
ET 
Early treatment termination 
EU MDR 
European Medical Device Regulations (2017/745) 
FEQ 
Fordyce Emotions Questionnaire 
FESS 
Functional endoscopic sinus surgery 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practices 
HPLC 
High performance liquid chromatography 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
INCS 
Intranasal corticosteroid spray 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISE 
Integrated summary of efficacy 
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
Kg 
Kilogram 
K-M 
Kaplan-Meier 
LC-MS 
Liquid chromatography mass spectrometry 
MCID 
Minimum clinically important difference 

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MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Mometasone furoate 
MOS Sleep-R 
Medical Outcomes Study Sleep scale 
MRM 
Multiple repeated measures 
OMC 
Ostiomeatal complex 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PP 
Per-protocol 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Seasonal allergic rhinitis 
SCS 
Systemic corticosteroids 
SD 
Standard deviation 
SF-36v2 
36-Item Short Form Health Survey, version 2 
SNOT-22 
22-item Sino-Nasal Outcome Test 
SUSAR 
Serious and unexpected suspected adverse reaction 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
TMF 
Trial master file 
UADE 
Unanticipated adverse device effect 
URTI 
Upper respiratory tract infection 
VA 
Visual acuity 
WHO 
World Health Organization 
WPAI-SHP 
Work Productivity and Activity Impairment -Specific Health Problem 
WPS 
Worst possible score 
 
 
 

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Table of Contents 
Sponsor Signature Page .................................................................................................................. 2 
Co-Lead Investigator Signature Page ............................................................................................. 3 
Investigator Agreement Signature Page.......................................................................................... 4 
Clinical Study Protocol Synopsis ................................................................................................... 5 
Abbreviations and Acronyms ....................................................................................................... 12 
Table of Tables and Figures .......................................................................................................... 17 
1. 
Background and Purpose ...................................................................................................... 18 
1.1 
Background ................................................................................................................. 18 
1.2 
Investigator information/report of prior investigations .............................................. 19 
1.3 
Purpose ....................................................................................................................... 19 
2. 
Study Objectives and Endpoints ........................................................................................... 19 
2.1 
Study objectives .......................................................................................................... 19 
2.1.1 
Primary objective .................................................................................................... 19 
2.1.2 
Secondary objective ................................................................................................ 19 
2.2 
Study endpoints .......................................................................................................... 20 
2.2.1 
Primary estimand/Primary efficacy endpoint ......................................................... 20 
2.2.2 
Key secondary efficacy endpoints .......................................................................... 20 
2.2.3 
Additional secondary endpoints .............................................................................. 21 
2.2.4 
Safety endpoints ...................................................................................................... 22 
3. 
Investigational Plan ............................................................................................................... 22 
3.1 
Study design ............................................................................................................... 22 
3.1.1 
Study Design Rationale........................................................................................... 23 
3.2 
Study size and duration............................................................................................... 23 
3.3 
Study population ......................................................................................................... 24 
3.3.1 
Inclusion criteria ..................................................................................................... 24 
3.3.2 
Exclusion criteria .................................................................................................... 24 
3.4 
Concomitant medications ........................................................................................... 27 
3.4.1 
Permitted medications ............................................................................................. 27 
3.4.2 
Prohibited medications............................................................................................ 27 
3.4.3 
Rescue medications and treatment .......................................................................... 28 
3.5 
Methods and procedures ............................................................................................. 28 
3.5.1 
Eligibility assessment.............................................................................................. 29 
3.5.2 
Screening visit and run-in stage .............................................................................. 29 
3.5.3 
Day 1 visit, pretreatment ......................................................................................... 29 
3.5.4 
Randomization and blinding ................................................................................... 30 
3.5.5 
Treatment procedure (active and sham) .................................................................. 30 
3.5.6 
Telephone/virtual visits ........................................................................................... 31 
3.5.7 
Clinic follow-up visits............................................................................................. 31 
3.5.8 
End of study (Week 24) .......................................................................................... 32 

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3.6 
Data collection ............................................................................................................ 32 
3.7 
Study assessments, endpoints, and activities .............................................................. 32 
3.7.1 
CRS Cardinal Symptoms ePRO.............................................................................. 32 
3.7.2 
SNOT-22 questionnaire .......................................................................................... 33 
3.7.3 
Patient Global Impression of Severity (PGIS) ........................................................ 33 
3.7.4 
Patient Global Impression of Change (PGIC) ........................................................ 33 
3.7.5 
Work Productivity and Activity Impairment (WPAI-SHP) questionnaire ............. 33 
3.7.6 
General quality of life questionnaires (SF-36v2, EQ-5D-5L) ................................ 33 
3.7.7 
Sleep questionnaire (MOS Sleep-R) ....................................................................... 34 
3.7.8 
Happiness questionnaire (FEQ) .............................................................................. 34 
3.7.9 
End-of-treatment questionnaire .............................................................................. 34 
3.7.10 Blinding questionnaire ............................................................................................ 34 
3.7.11 Nasal endoscopy ..................................................................................................... 34 
3.7.12 SCS rescue .............................................................................................................. 34 
3.7.13 Sinonasal surgery (actual or planned) for CRS....................................................... 35 
3.7.14 Sinus CT scoring ..................................................................................................... 35 
3.7.15 Conversion to nonsurgical candidacy ..................................................................... 35 
3.7.16 Physical examination .............................................................................................. 35 
3.7.17 Vital signs ............................................................................................................... 36 
3.7.18 Ocular examination ................................................................................................. 36 
3.7.19 Laboratory Evaluations ........................................................................................... 36 
4. 
Risk/Benefit Analysis ........................................................................................................... 36 
4.1 
Benefits ....................................................................................................................... 36 
4.2 
Potential risks ............................................................................................................. 37 
4.2.1 
COVID-19 exposure and infection ......................................................................... 37 
4.2.2 
LYR-210 administration or removal procedures and endoscopy procedures ......... 37 
4.2.3 
Exposure to mometasone furoate or bioabsorbable nasal implant .......................... 38 
4.3 
Risk mitigation ........................................................................................................... 39 
5. 
Investigational Product Information ..................................................................................... 40 
5.1 
Investigational product description ............................................................................ 40 
5.2 
Investigational product management .......................................................................... 40 
5.3 
Product return ............................................................................................................. 41 
5.4 
Packaging, labeling, and storage ................................................................................ 41 
6. 
Monitoring Procedures.......................................................................................................... 41 
6.1 
Investigational site monitoring ................................................................................... 41 
6.2 
Investigators................................................................................................................ 42 
7. 
Adverse Event Definitions and Reporting ............................................................................ 42 
7.1 
Adverse events and treatment-emergent adverse events ............................................ 42 
7.2 
Serious adverse events ................................................................................................ 43 
7.3 
Relationship to investigational product or study procedure ....................................... 44 

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7.4 
Severity of adverse events .......................................................................................... 45 
7.5 
Expectedness of serious adverse events ..................................................................... 45 
7.6 
Reporting adverse events ............................................................................................ 45 
7.7 
Reporting serious adverse events ............................................................................... 46 
7.7.1 
Initial reports ........................................................................................................... 46 
7.7.2 
Follow-up reports .................................................................................................... 46 
7.8 
Exposure in utero ........................................................................................................ 47 
7.9 
Expedited reporting .................................................................................................... 47 
7.10 
Safety monitoring ....................................................................................................... 47 
7.11 
Stopping rules for individual participants .................................................................. 48 
8. 
Protocol Deviations ............................................................................................................... 48 
9. 
Statistical Considerations ...................................................................................................... 49 
9.1 
Study hypothesis ......................................................................................................... 49 
9.2 
Sample size estimation ............................................................................................... 49 
9.3 
Statistical analysis....................................................................................................... 49 
9.3.1 
Analysis sets............................................................................................................ 49 
9.3.2 
Analysis methods .................................................................................................... 50 
9.3.3 
Methods for handling missing data ......................................................................... 50 
9.3.4 
Participant disposition and demographic characteristics ........................................ 51 
9.3.5 
Safety analyses ........................................................................................................ 51 
9.3.6 
Efficacy analyses .................................................................................................... 51 
9.3.7 
Interim analyses ...................................................................................................... 51 
10. Administrative Information .................................................................................................. 51 
10.1 
Statements of compliance ........................................................................................... 51 
10.2 
Protocol amendments ................................................................................................. 52 
10.3 
Data quality assurance ................................................................................................ 52 
10.4 
Investigational site selection ....................................................................................... 52 
10.5 
Training ...................................................................................................................... 53 
10.6 
Informed consent process ........................................................................................... 53 
10.7 
Confidentiality and Data Protection ........................................................................... 54 
10.8 
Institutional Review Board/Ethics Committee ........................................................... 55 
10.9 
Investigator responsibilities ........................................................................................ 55 
10.10 
Sponsor responsibilities .............................................................................................. 56 
10.11 
Early study termination .............................................................................................. 56 
11. Reports and Records ............................................................................................................. 57 
11.1 
Records ....................................................................................................................... 57 
11.2 
Reporting requirements .............................................................................................. 58 
12. Publications ........................................................................................................................... 58 
13. References ............................................................................................................................. 59 
14. Appendices ............................................................................................................................ 62 

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14.1 
Schedule of Assessments ............................................................................................ 63 
14.2 
Nasal Polyp Grading Scale ......................................................................................... 65 
14.3 
Contraception and Pregnancy Information ................................................................. 66 
14.4 
CRS Cardinal Symptoms (CS) Questionnaire (Daily ePRO) [SAMPLE] ................. 68 
14.5 
Sino-Nasal Outcomes Test (SNOT-22) Questionnaire [SAMPLE] ........................... 70 
14.6 
Work Productivity and Activity Impairment (WPAI-SHP) Questionnaire [SAMPLE]
 
71 
14.7 
Fordyce Emotions Questionnaire (FEQ) [SAMPLE] ................................................. 73 
14.8 
36-Item Short Form Health Survey (SF-36v2) [SAMPLE] ....................................... 74 
14.9 
EuroQol (EQ-5D-5L) Questionnaire [SAMPLE] ....................................................... 80 
14.10 
Patient Global Impression of Severity (PGIS) Scale [SAMPLE] .............................. 82 
14.11 
Patient Global Impression of Change (PGIC) Questionnaire [SAMPLE] ................. 83 
14.12 
Medical Outcomes Study Sleep Scale (MOS Sleep-R) [SAMPLE] .......................... 84 
14.13 
Blinding Questionnaire [SAMPLE] ........................................................................... 89 
14.14 
End of Treatment Questionnaire [SAMPLE] ............................................................. 90 
14.15 
Table of Protocol Changes ......................................................................................... 93 
 
Table of Tables and Figures 
Table 1. Attributes of the Primary Estimand ................................................................................ 20 
Table 2. Summary of Expected Adverse Events Associated with LYR-210 Administration or 
Removal Procedure and Endoscopy Procedures........................................................................... 37 
Table 3. Summary of Adverse Reactions Associated with Mometasone Furoate or Bioabsorbable 
Nasal Implant ................................................................................................................................ 38 
Table 4. Schedule of Assessments ................................................................................................ 63 
Table 5. Enlighten 2: Summary of Protocol Changes from Version 3.0 to Version 4.0. ............. 93 
Table 6. Enlighten 2: Summary of Protocol Changes from Version 3.1 to Version 4.0……….. 94 
Figure 1. Study Design 
22 

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1. Background and Purpose 
1.1 Background 
Chronic rhinosinusitis (CRS) is a common condition defined by symptomatic inflammation of 
the paranasal sinuses lasting longer than 12 weeks. CRS affects approximately 10.9% of the 
European population1 and 4.9% of the United States (US) population2 and is the 5th most 
common condition in people under age 65 in the US.3 CRS affects 6.95% of the population in 
south Korea4 and is common in mainland China with an estimated prevalence of 8%, affecting 
approximately 107 million individuals.5 CRS results in 18 million annual office visits,6 and the 
economic implications are high in both the US7 and Europe.8 Common symptoms of CRS 
include nasal blockage/obstruction/congestion, facial pressure or pain, nasal discharge, and sense 
of smell dysfunction.9,10 The underlying cause of CRS-related symptoms is inflammation of 
mucosal tissue, often leading to impairment of mucociliary clearance. 
Currently there is no FDA-approved medical therapy for CRS without nasal polyps. A clinically 
proven anti-inflammatory treatment delivered directly to the sinonasal mucosal tissue that can 
reach deep in the nasal passageway and is not dependent upon patient compliance is needed as a 
treatment option to offer CRS patients. 
Lyra Therapeutics, Inc. (Lyra) is developing the LYR-210 System, comprised of an implantable 
anti-inflammatory drug matrix (LYR-210 drug matrix) preloaded in a single-use applicator. The 
LYR-210 System is being studied in adult CRS patients who have failed previous medical 
management. The LYR-210 drug matrix is a miniaturized local drug implant designed to fit 
within the confined space of a patient’s middle meatus. The LYR-210 drug matrix is comprised 
of the synthetic corticosteroid mometasone furoate (MF), embedded in a bioabsorbable polymer 
matrix that allows for gradual, sustained, and targeted release of MF for up to 24 weeks from a 
single administration. Therefore, the primary mode of action of the LYR-210 System is 
pharmacological (anti-inflammatory). The LYR-210 drug matrix is designed to dynamically 
adapt and conform to the irregular shape of the sinonasal passageway and maintain contact with 
the mucosa through the duration of drug delivery. LYR-210 drug matrices are intended to be 
administered bilaterally into the middle meatus by an otolaryngologist in the physician’s office 
under endoscopic visualization using the provided single-use applicator. Administration of LYR-
210 drug matrices is performed with topical anesthesia using minimally invasive techniques. 
Two dose strengths of LYR-210 (2500 ug and 7500 ug) were developed and evaluated in the 
early phase clinical studies; Lyra intends to proceed with the 7500 ug dose of LYR-210 for 
future development. At this dose, LYR-210 is designed to deliver a total dose of 15 000 µg of 
MF for up to 24 weeks with an average daily dose of 89 µg of MF per human patient 
(approximately 45 µg of MF per nostril). When treatment is complete, the LYR-210 drug 
matrices are removed using standard tools during an office visit. 

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1.2 Investigator information/report of prior investigations 
Lyra’s nonclinical rabbit matrices, representative of human matrices, were tested in the maxillary 
sinuses of New Zealand white (NWZ) rabbits and demonstrated local and systemic safety. The 
human cadaver study demonstrated ease of placement and satisfactory anatomic conformation of 
the LYR-210 drug matrix in the middle meatus. 
Three clinical studies have been completed that evaluated the safety, tolerability, 
pharmacokinetics, and efficacy of the LYR-210 System in adult CRS patients. These studies 
have demonstrated the LYR-210 drug matrix to be safe with no treatment- or procedure-related 
serious adverse events (SAEs) reported to date. MF was detectable in the plasma of patients 
receiving the LYR-210 (7500 ug) drug matrices and systemic bioavailability of MF was within 
the limits of approved inhaled MF formulations for chronic use in adults and children. The LYR-
210 matrix (7500 ug) dose also showed statistically significant symptom improvement compared 
to control in patients with CRS who had previously failed medical management. These study 
results support the safety of the LYR-210 System and its further evaluation in pivotal clinical 
trials. 
For simplicity in this document, the product (matrix and/or system) is generally referred to as 
LYR-210. 
1.3 Purpose 
The purpose of this study is to evaluate the efficacy and safety of the LYR-210 compared with a 
sham procedure control for treatment in adults with CRS.  
2. Study Objectives and Endpoints 
2.1 Study objectives 
2.1.1 Primary objective 
The primary objective is to evaluate the efficacy of LYR-210, compared with a sham procedure 
control, in improving the 3 cardinal symptoms of CRS in CRS participants without nasal polyps, 
who had previously failed medical management. The 3CS are nasal blockage/obstruction/ 
congestion, anterior/posterior nasal discharge, and facial pain/pressure. 
2.1.2 Secondary objective 
The secondary objectives are to: 
1. Evaluate the efficacy of LYR-210, compared with a sham procedure, in improving the 3 
cardinal symptoms of CRS in CRS participants without nasal polyps or with nasal polyps of 
grade 1, who had previously failed medical management. 
2. Evaluate the efficacy of LYR-210, compared with sham control, in improving the individual 
CRS symptoms, CRS-related quality of life, the extent of inflammation in the ethmoid 
sinuses, and the need for rescue treatment in CRS participants without nasal polyps or with 
nasal polyps of Grade 1, who had previously failed medical management. 

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2.2 Study endpoints 
2.2.1 Primary estimand/Primary efficacy endpoint 
The primary estimand is a composite strategy. The attributes of the primary estimand are 
provided below in Table 1. 
Table 1. Attributes of the Primary Estimand 
Attribute 
Specification 
Treatment 
LYR-210 7500 µg drug matrix over a 20-week period or sham procedure, with daily saline 
nasal irrigation 
Population 
Adults with CRS who do not have nasal polyps, have failed medical management 
(including treatment with intranasal corticosteroid sprays [INCS]), and have not had 
endoscopic sinus surgery (ESS) 
Variable (Primary Endpoint) 
The primary endpoint is change from baseline (CFBL) in the 7-day average composite 
score of the 3 cardinal symptoms (3CS) of nasal blockage/obstruction/congestion, 
anterior/posterior nasal discharge, and facial pain/pressure at Week 24 in participants 
without nasal polyps. 
The daily composite score is the sum of the 3 daily cardinal symptom scores. If less than 4 
daily scores are available for a week, the 3CS score will be considered missing for the 
week. 
Intercurrent Events 
(1) Rescue with systemic corticosteroids (SCS) or ESS:  a composite variable strategy will 
be implemented where the 3CS score post SCS use or ESS will be censored and imputed 
with the participant’s worst observed score.  
(2) Decongestants use or INCS use or early termination of study treatment due to any 
reasons (e.g., spontaneous bilateral matrix dislodgement of LYR-210): a treatment policy 
strategy will be adopted in which the 3CS scores reported by the participants will be used 
regardless of whether the intercurrent event occurs. 
(3) Infection with COVID-19: a hypothetical strategy will be used in which the 3CS score 
reported by the participants post the intercurrent event will be censored as if the COVID-19 
infection did not occur. 
Population-level Summary for 
the Variable 
Difference in the mean change from baseline in the 3CS score at Week 24 
See Section 9 (Statistical Considerations) for the primary analysis method. 
2.2.2 Key secondary efficacy endpoints 
If the primary efficacy endpoint is met, the statistical significances of the key secondary 
endpoints will be evaluated, each at a 2-sided significance level of 0.05, using the hierarchical 
method in the following order: 
1. CFBL in the 7-day average composite score of 3CS at Week 24. 
2. CFBL in the 22-item Sino-Nasal Outcome Test (SNOT-22) total score at Week 24. 
3. CFBL in the percent opacification of the bilateral anterior and posterior ethmoids at 
Week 20, as determined by 3-D volumetric CT analysis. 
4. Rescue treatment requirement through Week 24. (This endpoint will be descriptively 
summarized in this study and the statistical testing will be conducted on pooled data from 
this [ENLIGHTEN 2] study and the ENLIGHTEN 1 study). 

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With this method, statistical significance cannot be achieved for a key secondary endpoint unless 
statistical significance is achieved for all key secondary endpoints already tested. This approach 
ensures that the overall study-wise type-1 error rate is controlled at 0.05 for the comparisons 
between treatment and control on the primary and all key secondary endpoints. 
The key secondary and secondary endpoints will be analyzed for all participants. 
2.2.3 Additional secondary endpoints 
Additional secondary endpoints include:  
1. CFBL in 3CS score at Weeks 2, 4, 8, 12, 16, and 20 
2. CFBL in the symptom score for individual cardinal symptoms of nasal 
blockage/obstruction/congestion, anterior/posterior nasal discharge, and facial 
pain/pressure at Weeks 2, 4, 8, 12, 16, 20 and 24 
3. CFBL in loss of smell score at Weeks 4, 8, 12, 16, 20, and 24, for all participants and for 
participants with baseline score ≥2 
4. Improvement of ≥1 point, ≥2 points, and ≥3 points from baseline in 3CS score at Week 
24 
5. CFBL in SNOT-22 total score at Weeks 4, 8, 12, 16, and 20 
6. CFBL in SNOT-22 subdomain scores at Weeks 4, 8, 12, 16, 20, and 24 
7. Improvement of ≥8.9 and ≥12 from baseline in SNOT-22 total score at Week 24 
8. CFBL in the Zinreich score of the bilateral anterior and posterior ethmoids at Week 20 
9. Time to first rescue treatment requirement through Week 24 
10. Sinonasal surgery requirement through Week 24 
11. Rescue medication use through Week 24 
12. Total systemic corticosteroid (SCS) dose prescribed through Week 24 
13. Number of days on SCS through Week 24 
14. Acute exacerbation of CRS (AECRS), defined as a sudden worsening of CRS symptoms 
resulting in escalation of treatment by the Investigator, through Week 24,  
15. Conversion to a nonsurgical candidate through Week 24 
16. CFBL in 36-Item short form health survey, version 2 (SF-36v2) physical health, mental 
health, and domain scores at Week 24 
17. CFBL in EuroQoL 5-dimension, 5-level (EQ-5D-5L) score at Week 24 
18. Improvement of ≥1 category and ≥2 categories in the severity of CRS-related symptoms, 
as indicated by the PGIS at Week 24 
19. Overall change of ‘very much better” or much better’ in the CRS-related symptom 
severity, as indicated by the PGIC at Week 24 
20. CFBL in Medical Outcomes Study Sleep Scale (MOS Sleep-R) score at Week 24 
21. CFBL in Work Productivity and Activity Impairment-Specific Health Problem (WPAI-
SHP), version 2.0 at Weeks 4, 12, and 24 
22. CFBL in Fordyce Emotions Questionnaire (FEQ) at Weeks 4, 8, 12, 16, 20, and 24 

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2.2.4 Safety endpoints 
Safety endpoints include:  
1. Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse 
events (TESAEs) through Week 24. 
2. Abnormal (clinically significant) laboratory values (hematology and chemistry) through 
Week 24. 
3. Newly identified adverse endoscopic findings in middle meatus including epistaxis, 
mucosal erosion or ulceration, and perforation through Week 24. 
4. Clinically significant increase of IOP through Week 24. 
5. Newly identified or worsened cataract in 1 or both eyes by slit-lamp examination through 
Week 24. 
3. Investigational Plan 
3.1 Study design 
This global, multicenter study will be conducted in a randomized, controlled, parallel-group, 
blinded fashion in approximately 180 symptomatic adult CRS participants who have failed 
previous medical management. Participants enrolled in the study will include participants who 
have accessible and intact middle meatus. The efficacy and safety of LYR-210 matrix (7500 µg) 
versus a control group receiving a sham procedure will be assessed on a background therapy of 
daily saline irrigation. Participants will be randomized 2:1 to either treatment with LYR-210 or 
to control.  
The study will consist of 2 stages:  
• Screening and run-in stage: 2-4 weeks before randomization and treatment procedure 
• Treatment stage (LYR-210 or control): randomization and treatment procedure through 
24 weeks  
The study design is depicted in Figure 1.  
 
Figure 1. Study Design 

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3.1.1 Study Design Rationale 
The proposed study aims at evaluating the efficacy of LYR-210 in the treatment of CRS in 
participants who have previously failed medical management, including INCS. Since participants 
must have already failed INCS and given that INCS do not have an approved indication for use 
in CRS without nasal polyps, use of INCS during the study is prohibited. Participants will use 
daily saline irrigation as background therapy.   
The safety and efficacy of LYR-210 in treating CRS will be evaluated against a control group 
receiving sham procedure. 
 
 
 Furthermore, a drug-free matrix is likely 
to induce a foreign-body inflammatory reaction and potentially exacerbate the CRS symptoms.11  
Inclusion of a sham procedure as a control is necessary for maintaining patient blinding and to 
ensure unbiased completion of the Patient Reported Outcome questionnaires as the primary and 
secondary efficacy endpoints of the study. Participants will be randomized 2:1 to either treatment 
with LYR-210 or to sham control. Since the participants must have previously failed medical 
management before entering the study, the impact of participants randomized to the sham control 
arm should be minimal. In addition, the protocol allows rescue treatment for any participant that 
experiences a worsening of CRS. 
3.2 Study size and duration 
Approximately 180 participants are planned to be enrolled in this study. 

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The total duration of study participation for all enrolled and treated participants is expected to be 
approximately 7 months (including the Screening/Run-in and Treatment stages). The end of the 
study (EOS) is defined as the date of the last EOS visit of the last participant of the study. 
3.3 Study population 
The study population will consist of approximately 180 adult participants with symptomatic CRS 
without nasal polyps or with grade 1 nasal polyps, who have failed previous medical 
management. Enrollment of participants with nasal polyps of grade 1 will be limited to 
approximately 30 participants. 
3.3.1 Inclusion criteria 
A participant must meet all the following criteria to be eligible for this study: 
1. Age ≥18. 
2. Diagnosed as having CRS, defined by duration of 12 weeks or longer with 2 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 
3. Bilateral ethmoid disease, defined as each side of anterior and/or posterior ethmoid 
sinus is ≥5% opacified upon the screening computed tomography (CT), as determined 
by the Central Imaging Core Lab/ Central Reviewer. 
4. Mean 3CS score over the preceding 7 days ≥5 (0-3 scale for each of the symptoms) 
determined within 7 days of Day 1 (the determination for eligibility can be made on 
any day from Day -7 through Day 1).  
5. Undergone at least 2 trials of medical treatments in the past, 1 of which must include 
intranasal corticosteroid sprays (INCS) for a minimum of 4 weeks with written 
medical record  or confirmed via patient report and documented in the medical report 
record and are no longer using INCS at Screening. 
6. 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. 
7. Agrees to comply with all study requirements.  
8. If currently on a waiting list for sinonasal surgery, is willing to be removed from the 
waiting list or have a preplanned surgery date cancelled for the duration of the study. 
[Note: this does not preclude a participant from receiving or being recommended for 
sinonasal surgery as rescue treatment during the study]. 
3.3.2 Exclusion criteria 
A participant who meets any of the following criteria will be excluded from this study: 
1. Inability to tolerate topical anesthesia or endoscopic procedure. 

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2. Previous ethmoidectomy, or surgery of the middle meatus and/or middle turbinate 
preventing proper placement and retention of LYR-210. NOTE: any previous 
ethmoidectomy is exclusionary. 
3. Previous nasal surgery or polypectomy within 3 months of Screening visit. 
4. Presence of nasal polyps grade 2 or higher (ie, polyps extending outside the middle 
meatus) on either side. 
5. Seasonal allergic rhinitis (SAR) with symptoms and/or, based on time of year, would 
anticipate onset of symptoms within 24 weeks of randomization. NOTE: mild SAR 
symptoms, as assessed by the Investigator, are not exclusionary. 
6. Perennial rhinitis with symptoms that are well controlled by regular use of intranasal 
corticosteroids. 
7. Severe asthma or experienced 1 or more exacerbations of asthma requiring SCS use 
within the 6 months prior to the Screening visit. Participants 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. 
8. Endoscopic exclusion criteria at Screening or Day 1 visit:  
a) Obstruction of middle meatus or degenerated middle turbinate preventing proper 
placement and retention of LYR-210. 
b) Evidence of mucosal erosion or ulceration. 
c) Acute nasal/sinus infection or purulence.  
d) Evidence of nasal septal perforation. 
9. Screening CT exclusion criteria: 
a) Anatomic variation that, in the opinion of the investigator, would adversely 
impact placement of LYR-210. 
b) Structural, noninflammatory related CRS (eg, large concha bullosa preventing 
proper matrix placement, tumor). 
c) Sinus disease extended into orbital or intracranial space. 
d) Evidence of mycetoma/fungal ball, allergic fungal rhinosinusitis. 
e) Sinus mucocele 
10. History or clinical evidence or suspicion of invasive fungal sinusitis, allergic fungal 
rhinosinusitis, atrophic rhinitis, or odontogenic sinusitis. 
11. Known history of hypersensitivity or intolerance to corticosteroids. 
12. Oral steroid or monoclonal antibody (Xolair, Nucala, Dupixent, etc.) dependent 
condition, including biologics use within 3 months of screening and systemic steroid 
use within 1 month of screening. NOTE: monoclonal antibodies for this exclusion are 
limited to those that target T2 inflammatory pathway and/or are known to impact 
CRS-related inflammation and symptoms. 
13. SCS administered within 1 month prior to Screening visit. 
14. Known history of hypothalamic pituitary adrenal axial dysfunction. 
15. Previous pituitary or adrenal surgery. 

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16. 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. 
17. Acute exacerbation of nasal allergy or CRS, upper respiratory tract infection (URTI), 
or common cold within 4 weeks of the Screening visit or during the screening/run-in 
period. The infection/exacerbation must be resolved, and antibiotic or other 
medication use must be discontinued prior to screening. 
18. Dental procedure/implant on maxillary dentition within 4 weeks of the Screening 
visit. 
19. Past or present acute or chronic intracranial or orbital complications of CRS (eg, brain 
abscess, related problems with eyes or central nervous system). 
20. History or diagnosis (in either eye) of glaucoma or ocular hypertension (IOP >21 mm 
Hg). 
21. 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. 
22. Loss of functional vision in 1 or both eyes. 
23. Diagnosed with ongoing rhinitis medicamentosa. 
24. Known history of immune dysfunction including immune deficiency (IgG subclass 
deficiency or IgA deficiency) or autoimmune disease (eg, Wegener’s granulomatosis, 
sarcoidosis) that requires immunotherapy. NOTE: Autoimmune conditions that do not 
require immunomodulatory therapy are not exclusionary. 
25. Currently positive for COVID-19 or residual sinonasal symptoms from a previous 
COVID-19 infection within the past 6 months. 
26. Past, present, or planned organ transplant or chemotherapy with immunosuppression 
within the past 5 years. 
27. History or diagnosis of ciliary dysfunction (eg, cystic fibrosis, primary ciliary 
dyskinesia [Kartagener syndrome]).  
28. Past or present systemic vasculitis (eg, granulomatosis with polyangiitis). 
29. Evidence of disease or condition expected to compromise survival or ability to 
complete follow-up assessments. 
30. 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 
participants of reproductive potential must agree to use highly effective methods of 
birth control, throughout the study. (See Appendix 14.3 for further information on 
contraception and pregnancy.) 
31. Previously received an experimental treatment in another clinical study within 5 half-
lives or 30 days (whichever is longer) of Screening visit or prior participation in 
another LYR-210 clinical trial.  

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32. Currently participating in another drug or device study.  
33. Determined by the investigator as not suitable to be enrolled for reasons not already 
specified if the health of the participant or the validity of the study outcomes may be 
compromised. 
3.4 Concomitant medications 
Participants 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 run-in and treatment stages to avoid confounding the 
efficacy or safety assessments of LYR-210. Effective treatment will not be withheld from study 
participants solely for entering the study. 
3.4.1 Permitted medications 
At the discretion of the investigator, the following concomitant medications may be used in 
accordance with the restrictions described for each treatment: 
• All participants will be provided with saline and instructions for daily intranasal saline 
irrigation as background treatment starting from screening through Week 24/EOS. 
• If acute sinus infection is suspected at any time during the study, treatment with 
antibiotics or macrolides (for a maximum of 14 days) will be allowed after a clinic visit 
and according to the investigator’s judgment. 
• For severe acute nasal blockage lasting a minimum of 3 consecutive days: a course of 
oxymetazoline nasal decongestant 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 CT assessments. 
• Nonsedating oral antihistamine including second (eg, loratadine, cetirizine), third (eg, 
fexofenadine), and fourth generation or equivalent. 
• Participants who have been on a stable regimen of inhaled corticosteroids or leukotriene 
receptor antagonist 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 2020 Global 
Initiative for Asthma Management and Prevention.12  
• Perennial allergic rhinitis (PAR) participants who have been on a stable regimen of a 
nonsedating oral or intranasal antihistamine including second (eg, loratadine, cetirizine, 
azelastine), third (eg, fexofenadine), and fourth generation or equivalent for a minimum 
of 3 months prior to the Screening visit should remain on the same dosage throughout the 
study. 
3.4.2 Prohibited medications 
Use of the following medications is prohibited for the duration of the study:  
• Oral/ocular/intramuscular/intravenous/intranasal corticosteroids (except for systemic 
corticosteroids permitted as rescue medication for CRS or sino-nasal symptoms only and 

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stable low or medium dose of inhaled corticosteroids for underlying respiratory diseases, 
eg, COPD, asthma). 
• Certain anti-allergy medications, including: first generation antihistamines (eg, 
diphenhydramine, dimenhydrinate, chlorpheniramine); leukotriene receptor antagonists 
(except for a stable regimen for asthma or another non-CRS indication), nasal cromolyn 
sodium or sodium cromoglycate, nedocromil sodium, atropine, ipratropium bromide, or 
guaifenesin. 
• Oral or intranasal decongestants (except for short course of intranasal decongestants 
permitted for severe acute nasal blockage or administration during endoscopic, insertion 
and removal procedures). 
• Inhaled anticholinergic medications (except for a stable regimen defined as no changes in 
the 3 months prior to screening and throughout study participation). 
• Any potent cytochrome P-450 3A4 (CYP3A4) inhibitors (eg, ketoconazole and ritonavir). 
• Any monoclonal antibody. 
• Any allergen immunotherapy (except for a stable dose and regimen defined as no 
changes in the 3 months prior to screening and throughout study participation). 
• Oral antifungal medication. 
Participants who received prohibited medications will be considered to have a protocol deviation 
and may require withdrawal from the study.  
3.4.3 Rescue medications and treatment 
Rescue treatment is defined as, after randomization, participant receives SCS and/or is 
recommended for sinonasal surgery to relieve CRS symptoms. 
The following rescue medication is recommended for worsening or uncontrolled severe CRS 
symptoms that results in the participant contacting the investigator who determines an initiation 
of rescue treatment is necessary any time during the study:  
• A course of systemic corticosteroids. Typical indications include persistent sinus 
infection after an initial course of antibiotics while starting another course of antibiotics, 
uncontrolled sinus inflammation, or a flare-up of asthma. The dose, duration of use, and 
rationale for the use of oral or systemic corticosteroid must be recorded. (NOTE: 
oral/systemic corticosteroids for rescue are not provided by the study sponsor.  The 
Investigator may prescribe, per their clinical judgement, any brand of systemic or oral 
corticosteroid that is authorized for use within their respective country.) 
• Sinonasal surgery as rescue treatment according to the investigator’s recommendation. 
The type and rationale for sinonasal surgery must be recorded. 
3.5 Methods and procedures 
The study-required activities and assessments are detailed below and are presented in tabular 
form in Appendix 14.1. 

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3.5.1 Eligibility assessment 
Participants are considered eligible for this study if they meet all the inclusion criteria and none 
of the exclusion criteria as defined in Section 3.3. The principal investigator or sub-investigator 
at each investigational site will determine participant eligibility based on the inclusion/exclusion 
criteria.  
3.5.2 Screening visit and run-in stage 
After providing written informed consent, participants who are qualified to participate in this 
study, have failed previous medical management and are no longer on oral or intranasal 
corticosteroids will have an initial Screening visit. Assessments at Screening will include 
demographics and medical history, a limited physical examination (head, neck, ear, nose, and 
throat) with vital signs, hematology and chemistry tests, SNOT-22 questionnaire, serum 
pregnancy test for women of childbearing potential, COVID-19 test, sinus CT (or within 1 month 
of Screening), nasal endoscopy, ocular examination (visual acuity [VA], IOP, and slit lamp), 
eligibility assessment, and concomitant medications/procedures. 
Immediately following the initial Screening visit, participants will undergo a run-in period of 2-4 
weeks. During this run-in period, if a patient requires rescue medication, he/she will not be 
enrolled into the study. In the event of difficulties in scheduling Day 1 visit (randomization), the 
run-in period can be extended up to day 35 with sponsor/medical monitor approval. If a 
participant fails the initial screening, they are permitted to be rescreened one time under a new 
participant ID.   
Participants who fail screening due to administrative reasons (eg, visit window) or abnormal lab 
value(s) may be allowed to repeat certain screening assessment(s) and re-establish eligibility. To 
minimize patient burden, the sinus CT, ocular exam and /or endoscopy do not need to be 
repeated for rescreened participants if done within the preceding month. Medical Monitor 
approval is required in such cases. Documentation of the decision and Medical Monitor approval 
will be filed in the participant’s file.  
Participants will be provided with saline and instructions for daily intranasal saline irrigation 
starting from the Screening visit throughout the study. Participants will be instructed to stop use 
of saline rinse approximately 24 hours prior to the scheduled sinus CT. Daily saline irrigation 
should then continue following the sinus CT. Daily saline irrigation procedures should adhere to 
the Investigator’s prescribing information and local standards, as applicable. Beginning at least 
14 days prior to LYR-210 administration/sham procedure on Treatment Day (Day 1), 
participants will record daily scores for each of the 4 cardinal symptoms (4CS) of CRS (nasal 
blockage/obstruction/ congestion, nasal discharge, facial pain/pressure, reduction/loss of sense of 
smell) on the electronic patient-reported outcomes (ePRO) questionnaire. 
3.5.3 Day 1 visit, pretreatment 
On Day 1, before the LYR-210/sham insertion procedure, participants will undergo the following 
assessments: urine pregnancy test for women of childbearing potential, COVID-19 test, 

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eligibility assessment, nasal endoscopy, baseline ePRO questionnaires (4CS, SNOT-22, PGIS, 
WPAI-SHP, FEQ, SF-36v2, EQ-5D-5L, MOS Sleep R), current medication listing, and AE 
reporting.  
3.5.4 Randomization and blinding 
On Day 1, after confirmation of eligibility and baseline assessments, and before any treatment, 
participants will be randomized in a 2:1 ratio to receive LYR-210 treatment or control (sham 
procedure) with stratification based on region (North America vs Europe) and nasal polyp status 
(yes vs no). Randomization will be conducted using Interactive Response Technology (IRT) and 
treatment will be assigned according to a randomization scheme generated by an 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 of the 
database. 
To maintain the participant blind to treatment assignment, each participant will wear an eye 
mask (ie, blindfold) and headphones at the time of the LYR-210 administration/sham procedure. 
Except for the cases of spontaneous matrix dislodgement, participants should remain blinded to 
their treatment assignment (LYR-210 or control) until the study is completed. Participants will 
complete blinding questionnaires at Week 4 and Week 24.  
The Sponsor will be blinded to participants’ study treatment assignments until database lock for 
the study. 
Due to the nature of the procedure, the treating investigator/surgeon will not be blinded to the 
treatment assignment. Efforts will be made to keep the study coordinator and other study staff 
blinded. A Site Blinding Plan will be implemented at each site to document the site-specific 
blinded and unblinded role. 
Breaking the blind to the participant 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 to properly treat the participant. If breaking the blind is required because of a 
medical emergency, decision to unblind lies solely with the investigator. In all cases where the 
blind is broken to the participant, the investigator must record the date and reason for breaking 
the blind. The unblinding should be noted in the participant’s eCRF. 
3.5.5 Treatment procedure (active and sham) 
On Day 1, after completing all required pretreatment assessments and randomization, 
participants will receive local anesthetic in the middle meatus and undergo a baseline nasal 
endoscopic assessment in preparation for the insertion procedure.  
Participants who are assigned to the active treatment arm will have the LYR-210 administered 
bilaterally into the middle meatus according to the Sponsor’s instructions for use. Participants 
who are assigned to the control arm, will undergo mock administration (ie, sham procedure) 
consisting of bilateral insertion of an unloaded applicator (without LYR-210 loaded) into the 

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middle meatus until the applicator tip touches the ethmoid bulla for a minimum of 20 seconds, 
followed by withdrawal of the applicator. 
After the procedure, all participants will be instructed to continue daily saline irrigation and 
completion of daily 4CS ePRO. 
The investigator will be allowed up to 2 attempts at LYR-210 administration or at the sham 
procedure per side. A treatment attempt is defined as an applicator of a LYR-210 or sham article 
is inserted to a participant’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 participant, the investigator will remove 
any LYR-210 already administered and treat the participant with any appropriate therapy, if 
necessary. The participant will be considered a treatment administration failure. Treatment 
administration failure participants will be followed within 7 (±2) days by telephone for AE and 
concomitant medication assessments. Treatment administration failure participants may be 
replaced to ensure adequate study enrollment. 
3.5.6 Telephone/virtual visits 
Participants will receive telephone/virtual follow-ups at Weeks 4 and 12 to record AEs and 
concomitant medications/procedures that they have had since their last follow-up assessment. 
Participants will also complete 4CS, SNOT-22, FEQ, and WPAI-SHP at these visits and women 
of childbearing potential will undergo a urine home pregnancy test. 
3.5.7 Clinic follow-up visits 
All participants will return to clinic for the scheduled follow up assessments at Weeks 8, 16, 20, 
and 24. Assessments at these visits include a urine pregnancy test for women of childbearing 
potential, COVID-19 test, nasal endoscopy, 4CS, SNOT-22, FEQ, concomitant medications/ 
procedures, and AEs. PGIS will also be assessed at Week 8 and 16 visits. Ocular examinations 
are required at Weeks 8 and 16.  
At the Week 20 visit, after the visit assessments, all participants will undergo a LYR-210 
removal or sham removal procedure. Participants who receive LYR-210 will have bilateral 
matrix removal using standard surgical tools. Control participants will undergo a sham removal 
procedure to remain blinded. 
If spontaneous dislodgement of LYR-210 occurs before the scheduled Week 20 visit in 
participants who receive LYR-210, participants are required to call the study clinic immediately 
to report the event. If a participant experiences dislodgement of 1 LYR-210 matrix, the 
participant will continue in the treatment phase. Any participant who undergoes a dual 
dislodgement is required to complete the assessments scheduled for the Week 20/ET visit, and 
subsequently the Week 24/End of Study (EOS) visit within 25-31 days of the ET visit.  
Opacification of ethmoid sinuses will be assessed by CT scans obtained during screening (or 
using a historical CT scan taken within 1 month of screening) and within 7-14 days after Week 
20/ET visit, unless medically contraindicated. Participants will be instructed to stop use of saline 

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rinse approximately 24 hours prior to the scheduled sinus CT. Daily saline irrigation should then 
continue following the sinus CT. If a participant is experiencing or recovering from a cold, acute 
exacerbation of nasal allergy, or URTI at the timing of follow up CT, the CT should be 
performed 4 weeks after resolution of the AE. If a participant requires SCS or sinonasal surgery 
as rescue treatment, the follow-up CT should be performed before receiving the rescue treatment.  
3.5.8 End of study (Week 24) 
All participants will undergo a Week 24 visit. If medically warranted per the treating physician’s 
discretion (for example, needing sinonasal surgery as rescue treatment), early matrix removal 
may be performed at an unscheduled early treatment termination (ET) visit. Any participant 
who undergoes an ET visit is required to complete the assessments scheduled for the Week 
20/ET visit, and subsequently the Week 24/ EOS visit within 25-31 days of the ET visit. ET 
participants are encouraged to continue completing ePRO assessments through the Week 
24/EOS visit. 
Week 24/EOS assessments include a urine pregnancy test for women of childbearing potential, 
COVID-19 test, hematology and chemistry tests, nasal endoscopy, ocular examination (IOP and 
slit lamp), all ePRO (4CS, SNOT-22, WPAI-SHP, FEQ, SF-36v2, EQ-5D-5L, PGIS. PGIC, 
MOS Sleep R), concomitant medications/procedures, and AEs. Participants enrolled in Germany 
will also undergo physical exam and vital signs at Week 24 /EOS. All participants will complete 
the End of Treatment (EOT) and blinding questionnaires at this visit. 
At the conclusion of their study participation, participants will be followed per the local standard 
of care.   
3.6 Data collection  
Study data will be collected according to good clinical practices (GCP). Data will be entered into 
the study database by investigational site staff using the Medpace ClinTrak® EDC system. The 
data will be reviewed by Lyra Therapeutics staff, or designee, and any queries will be submitted 
to the investigational site for clarification. Patient-reported outcome questionnaires will be 
entered into an ePRO device (eg, electronic tablet), smartphone application, or computer URL 
directly by study participants. 
3.7 Study assessments, endpoints, and activities 
The study assessments are described below. Frequency of each assessment is found in the 
Schedule of Assessments (Appendix 14.1). 
3.7.1 CRS Cardinal Symptoms ePRO 
Enrolled participants will be asked to complete a daily ePRO questionnaire to assess the severity 
of the 4 individual cardinal symptoms of CRS (nasal blockage/obstruction/congestion, facial 
pain/pressure, anterior/posterior nasal discharge, and reduction/loss of smell).9,10 Each symptom 
is scored on a 0-3 scale as follows: 0 = none, 1 = mild, 2 = moderate, and 3 = severe.  
In addition, the 4CS ePRO will capture use of daily saline irrigation by the participants.  

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3.7.2 SNOT-22 questionnaire 
The SNOT-22 questionnaire is a 22-item disease-specific quality of life instrument validated for 
use in CRS.13 Each symptom is scored on a 6-point scale as follows: 0 = no problem, 1 = very 
mild problem, 2 = mild or slight problem, 3 = moderate problem, 4 = severe problem, 5 = 
problem as bad as it can be. The total SNOT-22 score is the sum of the 22 items and can range 
from 0 to 110 with higher scores indicating worse symptoms. The MCID for the total SNOT-22 
score has been determined to be 8.9 units. Additionally, the SNOT-22 scores can be divided into 
subcategories of rhinologic symptoms, extra-nasal rhinologic symptoms, ear/facial symptoms, 
psychological dysfunction, and sleep dysfunction14.  
3.7.3 Patient Global Impression of Severity (PGIS) 
Participants will be asked a single question to rate their severity of CRS-related symptoms over 
the past 7 days on a 5-point ordinal scale: none, mild, moderate, severe, very severe.  
3.7.4 Patient Global Impression of Change (PGIC) 
The PGIC is a self-assessment of the participant’s overall change in CRS-related symptom 
severity compared to pretreatment. The PGIC 7-point scale range is as follows: very much better, 
much better, a little better, no change, a little worse, much worse, very much worse. 
3.7.5 Work Productivity and Activity Impairment (WPAI-SHP) questionnaire 
The WPAI-SHP is a questionnaire to measure the effect of a specific health problem on the 
participant’s work productivity and normal daily activities.15 Employed participants report 
absenteeism, (time absent from work) and presenteeism (time at work but not fully productive), 
which are calculated to a work productivity index. All participants report time away from normal 
activities. 
3.7.6 General quality of life questionnaires (SF-36v2, EQ-5D-5L) 
Participants will complete 2 general quality of life questionnaires, the SF-36v2 and EQ-5D-5L.  
The SF-36v2 health survey captures participants’ perceptions of their health and well-being in 8 
dimensions: physical functioning, physical limitations, emotional limitations, social functioning, 
bodily pain, general health, and mental health.16 The items of the SF-36v2 are transformed and 
summed to a norm-based scale (mean=50, SD=10) for each physical and mental component 
domain in which higher scores indicate a better health-related quality of life status. 
The EQ-5D-5L descriptive system comprises the following 5 dimensions, each describing a 
different aspect of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/ 
depression.17 Each dimension has 5 response levels of severity: no problems, slight problems, 
moderate problems, severe problems, ‘unable to’/extreme problems. In addition, the EQ-VAS 
records the overall current health on a vertical visual analogue scale, where the anchors are 
labelled ‘the best health you can imagine’ and ‘the worst health you can imagine’. 

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3.7.7 Sleep questionnaire (MOS Sleep-R) 
MOS Sleep-R is a 12-item instrument with a 4-week recall designed to measure key aspects of 
sleep, such as disturbance, adequacy, somnolence, and quantity.18 The score ranges from 0 to 
100, lower scores indicating better sleep and higher scores indicating worse sleep. The scale 
yields a sleep problem index and scores on the following 6 subscales: sleep disturbance, snoring, 
shortness of breath or headache, sleep adequacy, sleep somnolence, and sleep quantity. 
3.7.8 Happiness questionnaire (FEQ) 
The Fordyce Emotions Questionnaire (FEQ)19 asks participants to rate how happy or unhappy 
they are on a 0 (extremely unhappy) to 10 (extremely happy) scale. They also report the 
percentages of time that they feel happy, unhappy, and neutral.  
3.7.9 End-of-treatment questionnaire 
The EOT questionnaire is a Sponsor-specific questionnaire designed to evaluate participants’ 
experience with the study treatments. 
3.7.10 Blinding questionnaire 
To assess the adequacy of the blinding procedures, participants will complete a participant 
blinding questionnaire at various timepoints in the study. The participant blinding questionnaire 
is a 5-category response scale: 1 = I strongly believe I received the new treatment (LYR-210), 2 
= I somewhat believe I received the new treatment (LYR-210), 3 = I don’t know which treatment 
I received, 4 = I somewhat believe I received the placebo (the sham procedure), 5 = I strongly 
believe I received the placebo (the sham procedure). 
3.7.11 Nasal endoscopy  
Nasal endoscopies will be performed to evaluate presence/absence of and grade of nasal polyps 
and to document presence of epistaxis, mucosal erosion or ulceration, perforation, and any other 
local adverse effects. The endoscopic assessment of nasal polyps for eligibility will be conducted at 
Screening. A central reviewer will evaluate the screening endoscopy to determine presence/ absence 
of polyps and polyp grading (see Appendix 14.2 for the nasal polyp grading scale), if applicable. 
The central assessment will be used for randomization stratification. Participants are required to 
wear a blindfold and headphones during any endoscopy examination to maintain their blind to 
treatment assignment. All nasal endoscopies will be recorded and uploaded to the Central 
Imaging Core Lab’s repository. Nasal endoscopies will also be reviewed at the Central Imaging 
Core Lab for evaluation of presence of epistaxis, mucosal erosion or ulceration, perforation, and 
any other local adverse effects. 
3.7.12 SCS rescue 
Systemic corticosteroids (SCS) for rescue treatment of CRS or for another reason that are 
prescribed to the participant are to be recorded in the eCRF. If possible, an endoscopy should be 
performed before starting treatment with SCS. The participant should continue with the study 
treatment and follow-up visits per protocol. The investigator (or designee) will record the dates 
and dosing information (dosage form, daily dose, duration, name of drug) on the appropriate 

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page(s) of the eCRF. Indication for SCS use will also be captured by selecting 1 or more of the 
following categories: 
1. CRS 
2. Asthma 
3. Other respiratory or ENT disease (specify) 
4. Other reason (specify). 
A course of SCS is considered continuous if treatment is separated by less than 7 days. 
3.7.13 Sinonasal surgery (actual or planned) for CRS 
For participants who have a surgery or have a scheduled date for sinonasal surgery as rescue for 
CRS, the reason (worsening signs and/or symptoms during the study), the date the surgery was 
indicated, expected or actual surgery date, and the type and outcome of surgery will be recorded 
in the eCRF. Types of sinonasal surgery include, but are not limited to, functional endoscopic 
sinus surgery (FESS), balloon sinuplasty, turbinate reduction, septoplasty or polypectomy, or any 
endoscopic procedure that results in sinonasal tissue removal.  
If the surgery is to be performed during the study treatment period, the study treatment will be 
discontinued and all procedures/assessments for the ET and EOS visits will be completed prior to 
the surgery. The participant will be discontinued from the study.  
3.7.14 Sinus CT scoring 
Opacification of the ethmoid sinuses will be assessed using CT images. Two scoring 
methodologies will be employed to assess sinus opacification – Zinreich modified Lund-Mackay 
and 3-D volumetric analysis. The Zinreich modified Lund-Mackay scoring system uses a 0-5 
scale for scoring each sinus.20 The scoring is based on the percentage of sinus 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. The left and right sides are graded, and the sum is the total score 
out of maximum of 20. 3-D volumetric scoring will involve evaluations of each slice of 3-D 
coronal CT sequences and summing of all the slices to create a volumetric score ranging from 
0% to 100%. Sinus CT opacification scoring will be performed by Medical Metrics Inc. imaging 
core lab. 
3.7.15 Conversion to nonsurgical candidacy 
Participants will be deemed as having converted to a nonsurgical candidate if they do not 
undergo sinonasal surgery (planned or actual) during the treatment stage and if they meet the 
following criteria at Week 24: 
• 
3CS score ≤4, or 
• 
No disease in ethmoid sinuses on CT (Zinreich score=0) 
3.7.16 Physical examination  
A limited physical examination including a careful assessment of the head, eyes, ears, nose and 
throat will be performed per the Schedule of Assessments (Appendix 14.1). Height (cm), weight 
(kg) and body mass index (BMI) will be measured at Screening. 

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3.7.17 Vital signs  
Vital sign measurements will include seated blood pressure (systolic and diastolic, mm Hg), and 
pulse rate (beats per minute), body temperature (°C) tested per local practice, and respiration rate 
(breaths per minute). All measurements will be obtained after the participant has been resting for 
at least 5 minutes.  
3.7.18 Ocular examination  
Ophthalmologic assessments will include measurement of corrected VA, IOP, and a slit-lamp 
examination of the anterior segment of the eyes to identify new or worsening cataract 
development. The cataract assessment will be conducted according to the Simplified Cataract 
Grading System authored by the World Health Organization Cataract Grading Group.21 
Participants will be dilated with mydriatics following the WHO guidance for cataract 
assessment. IOP may be measured using Goldmann applanation tonometer, noncontact 
tonometer, or tono-pen; however, it is recommended that the same method be used for 
consistency across serial assessments on a given participant. A clinically significant increase of 
IOP is defined as IOP in 1 or both eyes >23 mm Hg or an increase of IOP from baseline in 1 or 
both eyes ≥10 mm Hg. Assessments will be conducted by an ophthalmologist/optometrist who is 
blinded to the participant’s treatment assignment. 
3.7.19 Laboratory Evaluations 
Hematology assessments will include a leukocyte count with differential (neutrophils, 
eosinophils, lymphocytes, monocytes, and basophils), erythrocytes, hematocrit, hemoglobin, and 
platelet count. 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 at the central lab, 
.  
Pregnancy testing is required for all female participants of childbearing potential. It will include 
a serum pregnancy test at Screening and a urine pregnancy test at all subsequent visits. 
All biological samples will be collected and analyzed per protocol and no samples will be stored 
for future research not outlined in this study protocol. 
4. Risk/Benefit Analysis 
4.1 Benefits 
Participation in this study is voluntary. The enrolled participants are adults with CRS who have 
failed previous medical management and have limited treatment options. Anticipated benefits 
over existing medical therapies for participants in this study are increased control of and local 
delivery of a known effective anti-inflammatory corticosteroid drug (MF) to a targeted area that 
is difficult to reach by intranasal sprays for an extended duration of time without the need for 

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Skin complications (acne) 
Susceptibility to infection 
Swallowing or aspiration of implant or 
fragments 
Weight gain (obesity) 
 
 
 
CRS is primarily a quality-of-life disease (as opposed to a life-threatening disease).29 The 
extensive clinical and nonclinical data from existing marketed medical devices and MF 
containing pharmaceutical products support the safety of the LYR-210 drug matrices. In 
addition, data from nonclinical studies with the Lyra’s rabbit matrix and the clinical studies of 
the LYR-210 drug matrices support product safety. Therefore, fatal and life-threatening 
‘suspected’ SAEs are not expected as a result of the use of the LYR-210 drug matrices. 
4.3 Risk mitigation 
The protocol has been developed to minimize the risks for the participant in several ways. 
Sample size was calculated to expose the smallest number of participants while still being able to 
adequately test the study hypothesis. The procedure will be performed by practicing 
otolaryngologists experienced in endoscopic procedures and trained on the administration and 
removal of the LYR-210. Investigators are expected to comply with the Sponsor’s IFU for the 
LYR-210.  
The safety of MF, the active ingredient in LYR-210, has been demonstrated across a range of 
commercially approved nasal and inhaled dosage forms for the treatment of allergic rhinitis, 
asthma, nasal polyps after ethmoid surgery, or to maintain patency after sinus surgery. The 
bioabsorbable polymers in the LYR-210 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.30  
The participant selection criteria have been designed to minimize risk by excluding participants 
who have comorbidities or conditions that may put the participant at higher risk for LYR-210 
placement. Because there are no clinical data on the LYR-210 System in pregnant women, 
women of childbearing potential will be required to take a serum pregnancy test at the initial 
Screening visit and a urine pregnancy test at all subsequent visits during the treatment phase. If 
the participant shows a positive pregnancy test after randomization, please refer to Section 7.8 
(Exposure in Utero). Concomitant medications/procedures that could increase risk and confound 
study results are not permitted during the study. Participants will be tested for COVID-19 at 
Screening and at each clinic visit. Participants testing positive at Screening will be excluded; 
participants testing positive during the study will be followed remotely until they are able to 
resume office visits. Finally, the participants will be closely monitored by frequent follow-up 
visits during the study. 
Because the LYR-210 System is investigational, there may be other side effects that cannot be 
predicted or foreseen. Unknown side-effects could be potentially serious and long lasting, 

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permanent, or even fatal. It is the conclusion of this risk analysis that potential benefits to 
participants in the clinical study outweigh the identified risks. Participants will be informed of 
these risks and the potential benefits through the informed consent process as a condition of 
study enrollment. 
5. Investigational Product Information 
5.1 Investigational product description 
The LYR-210 System is a combination product comprised of a single-use applicator, preloaded 
with an anti-inflammatory drug matrix. LYR-210 contains mometasone furoate (MF), an active 
ingredient in multiple FDA-approved products indicated for therapeutic and prophylactic 
management of seasonal and perennial allergic rhinitis (AR), nasal polyps, a phenotype of CRS 
disease, and asthma. LYR-210 is designed to gradually soften over time and is made of 
bioabsorbable polymers that have been used as components of approved pharmaceutical drugs 
and/or medical devices. 
Each LYR-210 contains a total MF dose of 7500 µg. LYR-210 is intended to be administered 
bilaterally into the middle meatus by an otolaryngologist under endoscopic visualization using 
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 is designed to deliver a total dose of 15,000 µg MF over the 24 
weeks, or an average daily dose of 89 µg MF per human participant (or approximately 45 µg MF 
per nostril).   
LYR-210 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 matrix is comprised of a base structure and a drug formulation layer. 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 layer 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. 
5.2 Investigational product management 
The Sponsor will supply quantities of LYR-210 and the sham procedure articles sufficient to 
allow completion of the study. The investigator or designee must maintain accurate records to 
document the disposition of all products received by the clinical site. Required information 
includes the kit numbers received, date received, date used, product description, and a participant 
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 all study procedures are complete, any unused investigational product 
will be returned to Sponsor or discarded per Sponsor’s 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. 
5.3 Product return 
All drug matrices administered to a participant are to be removed, as indicated in the Schedule of 
Assessments (Appendix 14.1). All study product that are not administered into a participant 
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.  
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.  
5.4 Packaging, labeling, and storage 
The investigational products (LYR-210 and Sham) will be packaged and labeled, as required by 
regional legislation and industry guidelines. The LYR-210 System and the Sham product are 
individually packaged in a foil pouch which is sterilized and placed within a shelf carton.  
The investigational products should be kept in a locked storage and stored in the original 
packaging to protect from moisture and light and at controlled room temperature (15 °C to 25 °C 
[59 °F to 77 °F]), with excursions permitted up to 30 °C (86 °F, inclusive). 
The Sponsor or designee will ship study products to the sites as needed. Specific instructions for 
ordering product will be provided to the sites. Traceability of LYR-210 or the sham procedure 
articles will be achieved by assigning each matrix and applicator a unique kit number. 
6. Monitoring Procedures 
Sponsor personnel or qualified designees will monitor the clinical study in a manner consistent 
with 21 CFR 312, Subpart D, Responsibilities of Sponsor and Investigators, and other applicable 
local or national regulations. Specific monitor contact information will be provided separately 
from the protocol. 
6.1 Investigational site monitoring 
An appropriate representative of the Sponsor or designee (study monitor) will verify participant 
data and ensure compliance with GCP, clinical protocol, and other study requirements, according 
to the guidelines set forth in the monitoring standard operating procedures (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 prespecified monitoring plan that is in compliance with 
applicable SOPs. Upon reasonable notice, the investigator and institution agree to provide the 
Sponsor representatives or designees and applicable regulatory authorities with direct access to 

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source documents relevant to the study for Sponsor quality assurance audits or inspections by the 
regulatory authorities. 
Completed CRFs will be verified by the study 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, participant CRFs, 
participant medical records and other study-related documents, as required. 
All CRFs will be reviewed for completeness and clarity. Missing or unclear data will be 
investigated by the study 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 AEs are observed and reported.  
6.2 Investigators 
The Sponsor will select investigators with appropriate training and experience to participate in 
this clinical study. 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 trial master file (TMF). 
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, IB, CRF 
completion, GCP, and clinical study personnel responsibilities. All training will be documented 
prior to engaging in study-related activities. 
The co-lead investigators for the study are:  
7. Adverse Event Definitions and Reporting 
7.1 Adverse events and treatment-emergent adverse events 
An AE is any untoward medical occurrence (signs, symptoms, abnormal laboratory findings) in a 
participant regardless of relationship to the investigational product or procedure. Each AE is 
either expected or unexpected as described below. The site is required to report AEs that occur 
during the study. These events shall also be classified according to the suspected causality by the 
study investigator.  

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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 
participant. Appropriate medical intervention will be undertaken. Any AE observed by the 
investigator or reported by the participants, whether or not ascribed to the investigational 
procedure or product, will be recorded on the participant’s AE case report form (CRF). A new 
AE CRF will be used for each AE. All on-going AEs that result in early termination (ET) from 
the study or are deemed to be study product- or procedure-related by the site investigator will be 
followed 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 product, action(s) taken, seriousness, and outcome of any sign 
or symptom observed by the physician or reported by the participant upon indirect questioning. 
A treatment emergent AE (TEAE) is an AE that occurs or worsens on or after initiation of the 
LYR-210 administration/sham procedure. 
7.2 Serious adverse events 
An AE or adverse reaction is considered a serious adverse event (SAE) if, in the view of either 
the investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening AE (Note: an AE or adverse reaction is considered “life-threatening” 
if, in view of either the investigator or Sponsor, its occurrence places the participant at 
immediate risk of death. It does not include an event that, had it occurred in a more 
severe form, might have caused death.) 
• Requires hospitalization or prolongation of existing hospitalizations (Note: any hospital 
admission with at least 1 overnight stay will be considered an inpatient hospitalization. 
An emergency room or urgent care visit without hospital admission will not be recorded 
as an SAE under this criterion, nor will hospitalization for a procedure scheduled or 
planned before signing of informed consent, or elective treatment of a pre-existing 
condition that did not worsen from baseline. However, unexpected complications and/or 
prolongation of hospitalization that occur during elective surgery should be recorded as 
AEs and assessed for seriousness. Admission to the hospital for social or situational 
reasons, eg, no place to stay, live too far away to come for hospital visits, respite care, 
will not be considered inpatient hospitalization.)  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• An important medical event (Note: important medical events that do not meet any of the 
above criteria may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the participant and may require medical or surgical 
intervention to prevent one of the outcomes listed above [eg, anaphylaxis]).  

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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 participant (Section 7.4). Any treatment-related SAE (Section 7.3) will be 
followed until resolution of the event, or until the participant withdraws from the study. 
7.3 Relationship to investigational product or study procedure 
The relationship between an AE and the LYR-210 study drug product or LYR-210 
administration/sham procedure (within 24 hours) will be determined by the investigator based on 
his or her clinical judgment and the following definitions: 
• Definitely related: The AE follows a reasonable temporal sequence from administration 
of the investigational product or the study procedure and the AE follows a known or 
expected response pattern to the investigational product or study procedure. 
• Probably related: The AE follows a reasonable temporal sequence from administration 
of the investigational product or the study procedure and is unlikely to have been 
produced by other factors (eg, disease, concomitant medications). 
• Possibly related: The AE follows a reasonable temporal sequence from administration of 
the investigational product or the study procedure and the AE follows a known or 
expected response pattern to the investigational product or study procedure but could 
readily have been produced by several other factors. 
• Unlikely related: The AE is temporally distant from administration of the investigational 
product or the study procedure that makes a relationship improbable and the AE could 
readily have been produced by several other factors. 
• Not related: An AE for which sufficient information exists to indicate that the etiology is 
unrelated to the investigational product or study procedure. One or more of the following 
variables apply: 
o The AE does not follow a reasonable temporal sequence following administration 
of the investigational product or study procedure 
o The AE is readily explained by the participant’s clinical state or other therapies 
The following factors should be considered when evaluating relatedness: 
• The temporal sequence from study drug administration – the event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases – each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other 
disease the participant may have. 
• Concomitant drug – the other drugs the participant is taking or the treatment the 
participant receives should be examined to determine whether any of them might be 
recognized to cause the event in question. 
• Known response pattern for this class of study drug – clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect. 

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• Exposure to physical and/or mental stresses – the exposure to stress might induce adverse 
changes in the participant and provide a logical and better explanation for the event. 
• The pharmacology and pharmacokinetics of the study drug – the known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should 
be considered. 
7.4 Severity of adverse events 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the investigator or reported to him/her by the participant. 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: 
• Mild: Event is noticeable to the participant but is easily tolerated and does not interfere 
with the participant’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere 
with the participant’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the participant’s daily activities. 
7.5 Expectedness of serious adverse events 
The expectedness of a product or procedure-related SAE should be determined by the Sponsor 
based upon existing safety information about the investigational product or study procedure 
using these explanations: 
• Unexpected: An SAE that is not listed in the study protocol, investigator’s brochure (IB), 
or prescribing information for the registered formulation of MF or is not listed at the 
specificity or severity that has been observed. 
• Expected: An SAE that is listed in the IB or prescribing information for the registered 
formulation of MF or is listed at the specificity and severity that has been observed. 
7.6 Reporting adverse events 
AEs are to be collected from the time a participant signs the informed consent form (ICF) until 
the completion of all follow-up visits. At each office or telephone/virtual visit during the study, 
AEs that have occurred since the previous office visit must be recorded. All participants 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 this study, regardless of severity or relationship to the study 
procedure or investigational product, will be recorded on the appropriate CRF. 
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. 

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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 (ie, clinically significant) CFBL for that individual participant. If this 
laboratory test result is determined to be a clinically significant abnormal CFBL for that 
participant, the value will be considered to constitute an AE. 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
throughout the study. 
7.7 Reporting serious adverse events 
7.7.1 Initial reports 
All SAEs occurring from the time of informed consent until the completion of all follow-up 
visits must be reported to the Sponsor or designee within 24 hours of the knowledge of the 
occurrence. After the completion of each follow-up visit, any SAE that the investigator considers 
related to study drug must be reported to the Sponsor or designee. 
To report the SAE, the investigator or designee must complete the AE form with the SAE 
information electronically in the electronic data capture (EDC) system for the study. When the 
form is completed, safety personnel will be notified electronically by the EDC system and will 
retrieve the form. If the event meets seriousness criteria and it is not possible to access the EDC 
system, the investigator or designee should send an email to the safety contact (as indicated by 
the Sponsor) and fax/email the completed paper SAE form to the safety contact within 24 hours 
of awareness. When the EDC system becomes available, the SAE information must be entered as 
soon as possible. 
7.7.2 Follow-up reports 
For participants with an SAE, the investigator must continue to follow the participant until the 
SAE has subsided or until the condition becomes chronic in nature, stabilizes (in the case of 
persistent impairment), or the participant dies. 
Within 24 hours of receipt of follow-up information, the investigator or designee must update the 
SAE form electronically in the EDC system for the study and submit any supporting 
documentation (eg, patient discharge summary or autopsy reports) to the safety contact by fax or 
email. If it is not possible to access the EDC system, refer to the procedures outlined above for 
initial reporting of SAEs. 

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7.8 Exposure in utero 
If a participant becomes pregnant during the treatment phase, the matrix will be removed (or 
sham removal) and the participant will continue study follow-up through Week 24. However, the 
investigator must continue to follow the participant until the completion of the pregnancy, 
including the outcome and the condition of the newborn at 8 weeks postpartum (if applicable).  
A pregnancy is not considered to be an AE or SAE; however, it must be reported within 24 hours 
of knowledge of the event. Sponsor or designee will then provide the Exposure In Utero (EIU) 
form to the investigator/site for completion and return.  
The pregnancy should be followed until the outcome of the pregnancy, whenever possible. Once 
the outcome of the pregnancy is known, the EIU form should be completed and faxed/emailed to 
Sponsor or designee. If the outcome of the pregnancy meets the criteria for immediate 
classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the investigator should follow the procedures for reporting an 
SAE. 
7.9 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, including the Eudravigilance database, in accordance with applicable local 
guidelines. 
The SUSARs meet all the following criteria: 
• Suspected adverse reaction  
• Serious  
• Unexpected  
• 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 
participants. Device deficiency reporting will be performed if applicable per regulations.  
7.10 Safety monitoring 
Participants will be closely monitored throughout the trial with high priority for participant 
safety. The Sponsor will establish a 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. 
Participant 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 nonserious AEs, various data 

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listings, lab results, vital signs, and other clinical data. Reviews of blinded aggregate data as well 
as individual participant data may be undertaken to identify outliers and trends that may impact 
safety of the participant and consistency of data. 
7.11 Stopping rules for individual participants 
Dosing for an individual participant will be stopped and drug matrices removed if the Sponsor 
and/or Investigator determine that either of the following have occurred in that participant: 
• An unexpected product-related SAE per causality and SAE definitions in Sections 7.2 
and 7.4 that warrants matrix removal. 
• Development of cataract where other potential factors (such as age) are not likely to have 
played a role or persistent clinically significant increase in IOP that, in the opinion of the 
Sponsor or Investigator, represent a safety concern. 
• If a participant becomes pregnant during the treatment phase, the matrix will be removed 
(or sham removal) 
8. Protocol Deviations 
The investigator agrees to conduct the study according to the clinical protocol, local regulatory 
authority regulations, GCP, and any conditions of approval imposed by their IRB/EC and agrees 
that all persons delegated to perform study procedures will do so as well.  
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 participant 
who does not meet all the inclusion/exclusion criteria specified in the protocol, use of prohibited 
medications or therapies, visits performed outside of the protocol-specified visit window and 
missed study assessments or visits. All protocol deviations should be documented and explained. 
Major/CSR reportable protocol violations are defined as those that could impact the performance 
evaluation such as enrollment of an ineligible participant, missing key data, administration of an 
unauthorized treatment. All participants with protocol deviations will continue to be followed for 
safety and performance assessments unless the Sponsor determines that the participant should be 
discontinued from the study. 
An investigator is not permitted to deviate from the protocol unless there are concerns of 
participant’s safety. Under emergency circumstances, deviations from the protocol to protect the 
rights, safety, and well-being of human participants may proceed, but such deviations must be 
documented and reported to the Sponsor and the IRB/EC (as required) as soon as possible and 
within 24 hours. 
If an investigator is found to be repeatedly noncompliant with the Clinical Trial Research 
Agreement (CTRA), study protocol, or any other conditions of the clinical study, the Sponsor at 
their sole discretion, will either undertake remedial measures to secure compliance or terminate 
the investigator's participation in the study. 

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9. Statistical Considerations 
9.1 Study hypothesis 
For the primary efficacy endpoint, the null and alternative hypotheses to be tested are: 
H0: μL = μC 
vs 
H1: μL ≠ μC  
where μL and μC are true mean CFBL in 3CS at Week 24 for participants without nasal polyps 
receiving the LYR-210 (7500 µg) treatment and the control (sham) treatment, respectively.  
9.2 Sample size estimation 
Per the null and alternative hypotheses described above, 2:1 randomization (LYR-210:control), 
in the participants without polyps, the residual standard deviation (SD) from the ANCOVA 
model (adjusted for baseline severity and using worst possible score imputation for treatment 
with SCS or sinonasal surgery [actual or planned]) is 2.08 and an observed mean difference of 
1.61 (3.89 unit decrease from baseline for treated and 2.28 unit difference from baseline for 
control). The observed effect size is therefore 0.77 SD units. With a sample size of 150 
participants (n=50 control and n=100 LYR-210), alpha = 0.05, and power of 0.95, we will be 
able to detect an effect size of 0.63, which represents a mean difference of 1.31. This effect size 
is 18% smaller than the observed difference in the Phase 2 study (1.61 versus 1.31 3CS mean 
change scores). For the first key secondary endpoint (an analysis of the primary endpoint in all 
participants; n=60 control and n=120 LYR-210), the study will have 95% power to detect an 
effect size of 0.57, which represents a mean difference of 1.19.   
9.3 Statistical analysis 
This section provides a summary of the statistical methods. Detailed specifications of the 
statistical methods will be described in the SAP. 
9.3.1 Analysis sets 
• Safety analysis set: all randomized participants who successfully received the study 
treatment (LYR-210 or control) on Day 1. Participants will be analyzed according to the 
treatment received. This is the primary analysis set for assessment of safety. 
• Intention-to-treat (ITT) analysis set: all randomized participants who successfully 
received the study treatment (LYR-210 or control) on Day 1. The primary analysis will 
be conducted for ITT Analysis Set without nasal polyp while the remaining efficacy 
analyses will be conducted for ITT Analysis Set. Participants will be analyzed according 
to the treatment they were assigned to at randomization. 
• Per-protocol (PP) analysis set: all randomized participants who successfully received the 
study treatment on Day 1, have post-Day 1 efficacy assessments, and are without any 
matrix dislodgement before Week 13 or important protocol deviations that might affect 
the accuracy and/or reliability of efficacy assessments.  

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9.3.2 Analysis methods 
Data collected in this study will be presented using listings, summary tables, and figures. 
Continuous data will be summarized by treatment group using the following descriptive 
statistics: the number of observations (n), mean, SD, median, minimum, and maximum. 
Categorical data will be summarized by treatment group as number and percentage of 
participants in each category. Individual participant’s data will be presented in listings. 
For cardinal symptoms (3CS and individual symptoms), the baseline score is the average of 
nonmissing daily scores over the 7-day period prior to and including Day 1. For other efficacy 
and safety assessments, the baseline value is the last nonmissing value prior to treatment 
administration. 
Unless otherwise specified, all hypothesis tests will be conducted at a 2-sided significance level 
of 0.05 and all confidence intervals will be constructed 2-sided with a confidence level of 95%. 
The primary analysis method for the primary endpoint will be mixed models repeated measures 
analysis of covariance (MMRM) with treatment group, and week as factors, with baseline 
measurement as covariate, an interaction of treatment by week and an interaction of baseline 
measurement by week. The primary analysis will be conducted according to the primary 
estimand that is specified in Table 1. Sensitivity analysis will be conducted to assess the impact 
of the missing at random assumption in the MMRM. Additionally, supplement analyses will be 
conducted to assess the robustness of the primary analysis according to the prespecified plan in 
the SAP. The LS mean change for each treatment group, the LS mean difference between 
treatment groups, as well as the corresponding 95% confidence intervals and p-values will be 
reported.  
Changes from baseline to continuous endpoints will be analyzed using an MMRM or ANCOVA 
as appropriate which will be prespecified in the SAP. 
Time-to-event endpoints will be analyzed using the Kaplan-Meier (K-M) method. The K-M 
curves will be compared between treatment groups using the log-rank test. 
Responder endpoints (eg, improvement of ≥8.9 in SNOT-22 and improvement of ≥1 point, ≥2 
points, ≥3 points in 3CS) will be analyzed using the CMH test controlling for geographic region 
and nasal polyp status. Participants who receive SCS for any reason and/or are indicated for 
sinonasal surgery will be considered nonresponders for time points after SCS use or surgery. 
Unless otherwise specified, participants with missing data will be included as nonresponders. 
9.3.3 Methods for handling missing data 
All efforts will be made to minimize missing data. Participants who discontinued treatment early 
are encouraged to continue completing ePRO assessments through Week 24. Data collected after 
treatment discontinuation will be included in the analysis. Details will be specified in the SAP. 

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9.3.4 Participant disposition and demographic characteristics 
Participant disposition, including analysis set assignment and reason for discontinuation, will be 
summarized for all randomized participants. Demographics, other baseline characteristics, and 
study drug exposure will be summarized for the ITT set and safety analysis set if these two sets  
are different.  
9.3.5 Safety analyses 
Safety will be assessed through adverse events (AEs) and changes in laboratory tests and nasal 
endoscopy assessment. AEs will be coded by using the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary.  
The number and percentage of participants with incidence of the safety endpoints will be 
presented by treatment group, where participants 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.  
9.3.6 Efficacy analyses 
Hypothesis testing for all efficacy endpoints will be conducted on the ITT population. The study 
level type-1 error for the family of primary and key secondary efficacy hypotheses will be 
controlled at alpha of 0.05. Unless otherwise noted, all analyses of efficacy outcome measures 
will be adjusted for baseline score, geographic region, and nasal polyp status. Adjustment by 
additional covariates, if any, will be described in the SAP. 
All efficacy analyses will be carried out after the last participant completes the blinded Week 24 
visit or withdraws prematurely before Week 24, and all data from the 24-week study period have 
been entered into the study database, cleaned, verified, and locked. 
9.3.7 Interim analyses 
No interim analysis is planned to be performed.  
10. Administrative Information 
10.1 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 Harmonisation (ICH) 
GCP, Regulation EU # 536/2014, United States Food and Drug Administration (US FDA) 
Guidelines, and all applicable regulatory requirements. The Sponsor will not commence the 
clinical study until all required approval is obtained from the relevant IRB/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. 

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10.2 Protocol amendments 
The clinical protocol, eCRFs, ICF and other participant information, or other clinical 
investigation documents may be amended as needed throughout the clinical investigation, and a 
justification statement shall be included with each amended section of a document. The 
amendments to the protocol and the participants’ ICF (if required) will be provided to and 
approved by, the local regulatory authorities and IRB/ECs, as required. For nonsubstantial 
changes (eg, minor logistical or administrative changes, change of monitor[s], telephone 
numbers, renewal of insurance) not affecting the rights, safety, and well-being of human 
participants, or not related to the clinical investigation objectives or endpoints, a simple 
notification to the IRB/EC and, where appropriate, local regulatory authority can be sufficient. 
The version number and date of amendments will be documented. 
10.3 Data quality assurance 
The investigator/designee(s) will maintain accurate source documentation as part of participant 
case histories. Electronic data capture (EDC) will be utilized for collecting participant data in the 
clinical database. Each site is required to have a computer and internet connection available for 
entry of clinical data in to the eCRF. 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 delegated clinical research 
organization (CRO) personnel 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 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 SOPs. 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 provider’s 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. 
10.4 Investigational site selection 
The study will be conducted at up to 60 investigational sites worldwide. The primary regions of 
investigation are the United States and Europe. Sites will be evaluated to ensure they have the 
capacity and capability to obtain informed consent and comply with all protocol requirements. 
The investigators and investigational site personnel are required to comply with the principles of 
GCP and all local and national regulations. 

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10.5 Training 
The Sponsor will select investigators with appropriate training and experience to participate in 
this clinical study. 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 TMF.  
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, IB, CRF 
completion, GCP, and clinical study personnel responsibilities. All training will be documented 
prior to engaging in study-related activities. 
10.6 Informed consent process 
The investigators have both an ethical and legal responsibility to ensure that each participant 
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 participant. The participant will be informed that, should an 
unexpected adverse product-related or study procedure-related AE occur, which presents an 
unreasonable risk to participating participants, he/she will be notified.  
The participant will be informed that the information obtained during the study will be used to 
evaluate the safety and performance of the investigational product. The participant will be 
informed that his/her medical records are available for review by representatives of the Sponsor 
or designee, the IRB/EC, and the appropriate regulatory authority, as necessary. However, 
his/her confidentiality will be maintained at all times and personal information will not publicly 
available. As part of the informed consent process, the investigator will obtain participants’ 
permission for the Sponsor personnel or designees, IRB/EC, and regulatory authority to review, 
in confidence, any pertinent records relating to the participants in this clinical investigation. The 
participant 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. 
A sample participant ICF template with standard wording suggested for this study will be 
provided to each investigator. A copy of the ICF from each site must be forwarded to the 
Sponsor for review and approval to assure compliance with the ICH requirements prior to 
submitting it to the IRB/EC. 
The IEB/EC-approved written consent form is to be reviewed with the participant by the 
investigator or designee and will be signed by each participant prior to enrolling in the study. 
The investigator or designee is responsible for maintaining each participant’s ICF in the study 
file and providing each participant with a copy of their signed ICF. 

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If new information becomes available that can significantly affect a participant’s future health 
and medical care, that information shall be provided to the affected participant in written form. If 
relevant, all affected participants will be asked to confirm their continuing informed consent in 
writing. 
10.7 Confidentiality and Data Protection 
The conduct of this study and the processing of any personal data collected from each participant 
(or from a subject’s healthcare professional or other relevant third-party sources) by the Sponsor 
or its designee, the site and the Investigator for use in the study will fully adhere to the 
requirements set out in applicable data protection and medical privacy laws or regulations, 
including, without limitation, the GDPR EU 2016/679, its subsequent amendments and any 
additional national laws on Data Protection.   
All study data will be stored and archived in line with national and local laws and regulations on 
the protection of personal data including the General Data Protection Regulation (GDPR) EU 
2016/679.  
The Sponsor or its designee shall ensure that at all times it has an appropriate legal basis for 
processing personal data under applicable data protection law. The Sponsor and its vendors have 
implemented and maintain a number of measures, including but not limited to appropriate 
database security, appropriate and restricted user access, pseudonymisation and encryption of 
personal data, as appropriate to maintain the confidentiality of personal data.  
The investigator has a responsibility to ensure that participant anonymity is protected and 
maintained. He or she must also ensure that the participants’ 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. Site-based organizational and technical 
arrangements to avoid unauthorized access vary by site but all include access-controlled/access-
limited document control and technical solutions (i.e., including passwords and security control 
measures) to protect study-specific data, both in paper and electronic format. 
Participation in the study will be treated as confidential and participants will not be referred to by 
name in any report of the study. Participant 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 participant identification code will be used that allows 
identification of all data reported for each participant. The investigators shall provide coded data 
to the Sponsor or its designee, which does not reveal the patient’s name and full date of birth. All 
personal information shall be replaced with a unique participant code before any information 
leaves the investigator’s sites. The identity of the participants will not be disclosed in any study 
records and participants’ data will be described using the unique participant identifier. 
Participant data will be processed electronically to determine the outcome of this study and will 
be provided to health authorities as applicable. 

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Participants 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 (eg, in the case of an 
audit performed by a regulatory authority) provided the data are treated confidentially and that 
the participant’s privacy is guaranteed. Participants will be advised that their data may be 
transferred to other countries. 
The Investigator shall report any data breaches that might occur to the Sponsor or its designee, 
without undue delay. The Sponsor has implemented a process to address Data Breaches that 
complies with the requirements of applicable laws and regulations including the GDPR.  If 
applicable, the authorities and the data subjects shall be notified of a data breach, within the 
required timeframes of the applicable laws and regulations, including those of the GDPR. In case 
of the occurrence of a data breach, the Sponsor will immediately apply relevant measures to 
mitigate the risks to data subjects. Any data breach presenting risks to the rights and freedoms of 
data subjects will be reported to the relevant supervisory data protection authority, as applicable. 
10.8 Institutional Review Board/Ethics Committee 
The clinical protocol and ICF must have the approval of a properly constituted IRB/EC 
responsible for approving clinical studies prior to commencing the study at that site. Any 
additional approval requirement(s) of the IRB/EC will be followed. Any advertisements used to 
recruit participants or any participant-facing documents will also be reviewed and approved by 
the IRB/EC before use. 
No investigative procedures other than those defined in this clinical protocol will be undertaken 
on the enrolled participants without the written agreement of the IEB/EC and Sponsor. Each site 
principal investigator will advise their IRB/EC of the progress of this clinical investigation on a 
regular basis, according to IRB/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 designee will submit reports as required by IRB/ECs and local and national 
regulations. These reports may include SAEs, withdrawal of IRB/EC or regulatory authority’s 
approval, annual progress reports, recall information, and final reports. 
10.9 Investigator responsibilities 
The investigator for each investigational site is responsible for ensuring the study is conducted 
according to: 
• All signed agreements 
• The study protocol 
• IRB/EC guidelines 
• Applicable local and federal regulations 
The investigator for each site may not begin enrollment until the Sponsor has provided written 
approval to do so. The Sponsor will not provide approval until they have received and approved 

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(when necessary) all required documents, including the IRB/EC approvals of the investigational 
plan and ICF. 
It is acceptable for the investigator to delegate one or more of the above functions to a 
subinvestigator or trained study coordinator; however, the investigator remains responsible for 
the proper conduct of the clinical investigation, including obtaining informed consent, collecting 
all required data, and submitting accurate and complete eCRFs. 
The study is not transferable to other sites/facilities attended by the investigator unless 
preapproval is obtained from the applicable IRB/EC and the Sponsor. 
10.10 Sponsor responsibilities 
The Sponsor’s responsibilities for this study are to: 
• Select all clinical investigators, investigational sites, and other consultants, including 
study monitors, who participate in the study 
• Provide sufficient training to participating investigational sites to support study activities 
according to the agreements executed with the sites 
• Provide financial support to each site according to the agreements executed with each site 
• Follow/promote all regulatory standards according to local/federal regulations for the 
investigational sites, core laboratories, and other participants, and ensure regular 
investigational site monitoring to assure compliance with the regulations 
• Retain ownership of all clinical data generated in this study and control the use of the 
data for appropriate purposes only 
• Review and approve publication of study results in the literature 
• Ensure timely and appropriate study registration and results posting in a public clinical 
trial database (eg, www.clinicaltrials.gov), if applicable 
10.11 Early study termination 
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 discovery of an unexpected, serious, or unacceptable risk to the study participants 
• A decision by the Sponsor to suspend or discontinue testing, evaluation, or development 
of the investigational product 
• Failure of the investigator to enroll participants into the study at an acceptable rate 
• Failure of the investigator to comply with pertinent regulations of IRB/EC or appropriate 
regulatory authority 
• Failure of the investigator to comply with the protocol 
• Submission of knowingly false information from the research facility to the Sponsor, the 
study monitor, IRB/EC, or regulatory authority 

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• Insufficient adherence to protocol requirements consistent with the US Code of Federal 
Regulations (CFR) 21 CFR 312, European Medical Device Regulation (EU MDR) 
2017/745, European Directive 2001/83/EC, or other relevant national regulations, as 
appropriate. 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
ICH E6(R2) on GCP as well as 21 CFR 312.56b, the EU MDR 2017/745, 2011/83/EC, and other 
relevant national regulations, as appropriate, which require the 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 participants 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 IRB/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. 
11. Reports and Records 
11.1 Records 
Each investigator will maintain all records pertaining to this clinical study as required by local 
regulations, the relevant IRB/EC, and the institution. The investigator will maintain all study-
related documentation, including all correspondence, records of financial interest, individual 
participant records, ICFs, 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 CRFs. 
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, 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 CTRA, 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. 

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11.2 Reporting requirements 
Investigators are responsible for the following reporting requirements to the applicable IRB/EC 
and the Sponsor: 
• Reporting failure to obtain informed consent before study procedures  
• Progress reports 
• Protocol deviations due to emergency or participant safety 
In addition to this list, each individual IRB/EC may add additional reporting requirements. The 
principal investigator at each investigational site is responsible for ensuring any additional local 
IRB/EC reporting requirements are met, if applicable. 
Investigators are also responsible for the following reporting requirements to the Sponsor: 
• Withdrawal of IRB/EC approval 
• Participant withdrawal 
The Sponsor will be responsible for reporting any investigational product recalls to the IRB/EC 
within 30 days of the request. Additionally, the Sponsor will develop a final study report upon 
study completion or termination. The Sponsor will also be responsible for registration and 
posting results on www.clinicaltrials.gov. 
12. Publications 
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 IRB/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 study. An 
investigator may only publish data generated by this clinical study in accordance with the terms 
of the CTRA. 
Results of the study will be posted by the Sponsor on a publicly available clinical study 
registration website(s) (eg, www.clinicaltrials.gov) in accordance with the applicable regulations.  

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14. Appendices 
14.1 
14.2 
14.3 
14.4 
14.5 
14.6 
14.7 
14.8 
14.9 
14.10 
14.11 
14.12 
14.13 
14.14 
14.15 
 
 
Appendices 14.1-14.15 have been redacted