Clinical trial NCT04050865
Conditions: Allergic Conjunctivitis
Sponsor: Ocular Therapeutix, Inc.
Start date: 2019-08-05; Completion date: 2020-02-28
Enrollment: 96 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the study is to evaluate the efficacy and safety of OTX-DP as a dexamethasone ophthalmic insert when placed in the canaliculus of the eyelid for the treatment of the signs and symptoms of allergic conjunctivitis.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Dexamethasone, 0.4mg intervention 2: Placebo plug with no drug
Intervention descriptions: intervention 1: Ophthalmic Insert intervention 2: Ophthalmic Insert

Protocol documents:
Prot_000.pdf: 
A Multi-Center, Randomized, Double-Masked, Vehicle Controlled Phase 3 Study Evaluating the 
Efficacy and Safety of OTX-DP for the Treatment of Allergic Conjunctivitis Using a Modified 
Conjunctival Allergen Challenge Model (Ora-CAC®) 
 
 
Investigational Protocol CLN-Protocol-0052 
 
Revision 002 
29-October-2019 
 
 
 
Sponsor: 
Ocular Therapeutix, Inc. 
15 Crosby Drive 
Bedford, MA 01730 
 
 
 
 
 
 
 
 
 
 
 
 
This protocol contains confidential, proprietary information which is the property of Ocular 
Therapeutix, Inc. Neither this document, nor the information contained herein, should be disclosed or 
reproduced without the prior written authorization of Ocular Therapeutix, Inc. 
 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 2 of 61 
 
A Multi-Center, Randomized, Double-Masked, Vehicle Controlled Phase 3 Study Evaluating the 
Efficacy and Safety of OTX-DP for the Treatment of Allergic Conjunctivitis Using a Modified 
Conjunctival Allergen Challenge Model (Ora-CAC®) 
I hereby agree to participate in the clinical investigation of OTX-DP sponsored by Ocular Therapeutix, 
Inc. (hereinafter “Study Sponsor”). I agree to conduct this investigation in accordance with the agreement, 
the investigational plan, and applicable regulations. I agree to protect the rights, safety, and welfare of 
subjects under my care; I agree to adhere to the guidelines outlined in 21 CFR Part 312, other applicable 
United States Food and Drug Administration (FDA) regulations, and conditions of approval imposed by 
the reviewing IRB and the FDA. I agree to supervise all uses of the intracanalicular insert and to ensure 
appropriate informed consent is obtained from all subjects prior to inclusion in this study. 
I understand that this investigation will be monitored by the Study Sponsor and/or 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 FDA to verify compliance with applicable federal regulations related 
to clinical research on human subjects. 
I am aware that the Study Sponsor reserves the right to discontinue this investigation at any time. In the 
event that I decide to discontinue my participation as an Investigator in this study, I will notify the Study 
Sponsor 30 days prior of my intent to discontinue. I understand that I am obligated to complete the follow 
up of the subjects already participating in the investigation. 
Any data generated as a result of this investigation will be the exclusive property of the Study Sponsor 
who retains all rights of publication. I understand that the Study Sponsor encourages me to pursue 
independent publications related to my experience with this intracanalicular insert with the understanding 
that the Study Sponsor reserves the right of prior review and approval of these publications. 
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 insert 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, and IRB/IEC or 
the FDA. 
I understand that this investigation, protocol and results are confidential, and I agree not to disclose any 
such information to any person other than a representative of Study Sponsor without the prior written 
consent of the Study Sponsor. 
 
Accepted by: 
 
 
Principal Investigator Signature 
Date 
Printed Name 
 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 3 of 61 
 
PROTOCOL REVISION HISTORY 
 
Date 
Revision 
Description of 
Modifications 
Rationale for Modification 
26-March-2019 
001 
Original Issue 
N/A 
29-OCT-2019 
002 
Removed requirement for 
punctum size between 0.4 
mm and 0.9mm (formerly 
exclusion criterion #17) 
Now that the product is available 
commercially, Ocular has experience 
placing the insert in various sizes. The 
dilated punctum size is the relevant 
criterion for study entry 
Defined the standard for re-
screening subjects 
To clarify that subjects who meet the 
current eligibility criteria can be re-
screened  
Stated when to capture slit 
lamp findings in Medical 
History  
To remain consistent with the definition 
of an adverse event 
Clarified example of 
laboratory adverse event  
To remain consistent with the definition 
of an adverse event 
Fixed minor typos and 
inconsistencies  
Correction of minor clerical errors  


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 4 of 61 
 
TABLE OF CONTENTS 
 
1. 
ABBREVIATIONS ............................................................................................................. 8 
2. 
SYNOPSIS ........................................................................................................................... 9 
3. 
PRINCIPAL CONTACTS ................................................................................................. 16 
4. 
INTRODUCTION ............................................................................................................. 16 
4.1. 
Background and Rationale ................................................................................................. 16 
4.2. 
Prior Experience with OTX-DP Inserts ............................................................................. 16 
4.3. 
Description of Treatment ................................................................................................... 18 
4.3.2. 
Safety of OTX-DP ............................................................................................................. 19 
4.4. 
Intended Indication ............................................................................................................ 19 
4.5. 
Risk/Benefits ...................................................................................................................... 19 
4.5.1. 
Potential Benefits ............................................................................................................... 19 
4.5.2. 
Potential Risks .................................................................................................................... 19 
5. 
STUDY OBJECTIVES AND DESIGN............................................................................. 20 
5.1. 
Study Objectives ................................................................................................................ 20 
5.2. 
Clinical Hypothesis ............................................................................................................ 21 
5.3. 
Efficacy and Safety Parameters ......................................................................................... 21 
5.3.1. 
Primary Efficacy Evaluations ............................................................................................ 21 
5.3.2. 
Secondary Efficacy Evaluations ........................................................................................ 21 
5.3.3. 
Safety Evaluations .............................................................................................................. 22 
5.4. 
Training of Investigators .................................................................................................... 22 
5.5. 
Subject Selection ................................................................................................................ 22 
5.5.1. 
Study Population ................................................................................................................ 22 
5.5.2. 
Inclusion Criteria ................................................................................................................ 22 
5.5.3. 
Exclusion Criteria .............................................................................................................. 23 
6. 
STUDY DATA COLLECTION ........................................................................................ 25 
6.1. 
Study Schematic ................................................................................................................. 25 
6.2. 
Data Collection .................................................................................................................. 25 
6.3. 
Subject Enrollment ............................................................................................................. 25 
6.4. 
Masking .............................................................................................................................. 25 
6.5. 
Data Collection .................................................................................................................. 25 
7. 
STUDY OBSERVATIONS AND PROCEDURES .......................................................... 25 
7.1. 
Subject Screening and Informed Consent .......................................................................... 25 
7.2. 
Screen Failures ................................................................................................................... 26 


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7.3. 
Subject Withdrawal ............................................................................................................ 26 
7.4. 
Product Quality Complaints ............................................................................................... 26 
7.5. 
Treatment of OTX-DP or PV ............................................................................................. 26 
7.6. 
Concomitant Medications .................................................................................................. 26 
7.7. 
Rescue Therapy .................................................................................................................. 27 
7.8. 
Early Loss of Insert and Patient Follow-up........................................................................ 27 
8. 
STUDY ASSESSMENTS .................................................................................................. 27 
8.1. 
Visit 1 - Screening (Day -45 to -6) .................................................................................... 27 
8.2. 
Visit 2 (Day -5+1 day) CAC screening / titration .............................................................. 28 
8.3. 
Visit 3a (Day -4+1 day) CAC confirmation #1) ................................................................ 29 
8.4. 
Visit 3b (Day -4+1 day; 8 hours post V3a) CAC confirmation #2 .................................... 30 
8.5. 
Visit 4a (Day -3+1 day; 24±6 hours post V3a) CAC confirmation #3 .............................. 30 
8.6. 
Visit 4b (Day 1): Randomization/Insertion of OTX-DP or PV ......................................... 31 
8.7. 
Visit 5 (Day 7; 6 days post-insertion) CAC #1 .................................................................. 31 
8.8. 
Visit 6a (Day 8; 7 days post-insertion) CAC re-challenge #2 ............................................ 31 
8.9. 
Visit 6b (Day 8; 8 hours from Visit 6a) CAC re-challenge #3 ........................................... 32 
8.10. 
Visit 7 (Day 14; 13 days post-insertion) CAC re-challenge #1 ......................................... 32 
8.11. 
Visit 8a (Day 15; 14 days post-insertion) CAC re-challenge #2 ........................................ 33 
8.12. 
Visit 8b (Day 15; 8 hours from Visit 8a) CAC re-challenge #3......................................... 33 
8.13. 
Visit 9 (Day 30+3): Study Exit .......................................................................................... 34 
8.14. 
Early Discontinued Subjects .............................................................................................. 34 
8.15. 
Unscheduled Visits ............................................................................................................ 34 
9. 
ADVERSE EVENTS ......................................................................................................... 35 
9.1. 
Definition of an Adverse Event.......................................................................................... 35 
9.2. 
Definition of a Serious Adverse Event (SAE) ................................................................... 36 
9.3. 
Disease-Related Events or Outcomes Not Qualifying as AE/SAEs .................................. 36 
9.4. 
Monitoring and Recording of AEs and SAEs .................................................................... 36 
9.4.1. 
Adverse Events .................................................................................................................. 36 
9.4.2. 
Serious Adverse Events ..................................................................................................... 36 
9.4.3. 
All Events ........................................................................................................................... 36 
9.5. 
Immediate Reporting of Serious Adverse Events and Pregnancies ................................... 37 
9.6. 
Death .................................................................................................................................. 37 
9.7. 
Evaluating AEs and SAEs .................................................................................................. 37 
9.7.1. 
Severity .............................................................................................................................. 37 


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CONFIDENTIAL 
 
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9.7.2. 
Relationship to OTX-DP or PV or procedure .................................................................... 38 
9.7.3. 
Expectedness of Events ...................................................................................................... 38 
9.8. 
Pre-scheduled or Elective Procedures or Routinely Scheduled Treatments ...................... 38 
9.9. 
Procedures for Handling Special Situations ....................................................................... 38 
9.9.1. 
Pregnancy ........................................................................................................................... 38 
9.9.2. 
Unmasking for Medical Emergencies ................................................................................ 38 
9.9.3. 
Regulatory Reporting ......................................................................................................... 39 
10. 
STATISTICAL ANALYSIS .............................................................................................. 39 
10.1. 
Study Populations............................................................................................................... 39 
10.1.1. 
Intent-to-Treat Population .................................................................................................. 39 
10.1.2. 
Per-Protocol Population ..................................................................................................... 39 
10.1.3. 
Safety Population ............................................................................................................... 40 
10.2. 
Primary Efficacy Variables ................................................................................................ 40 
10.3. 
Secondary Efficacy Variables ............................................................................................ 40 
10.4. 
Statistical Hypotheses ........................................................................................................ 41 
10.5. 
Adjustment for Multiplicity ............................................................................................... 41 
10.6. 
Sample Size ........................................................................................................................ 41 
10.7. 
General Imputation Methods.............................................................................................. 41 
10.8. 
Primary Efficacy Analyses ................................................................................................. 42 
10.9. 
Secondary Efficacy Analyses ............................................................................................. 42 
10.10. 
Demographics and Baseline Data ...................................................................................... 43 
10.11. 
Safety Analyses .................................................................................................................. 43 
11. 
GENERAL INFORMATION ............................................................................................ 43 
11.1. 
Study Termination .............................................................................................................. 43 
11.2. 
Monitoring ......................................................................................................................... 43 
11.3. 
Retention of Documentation .............................................................................................. 44 
11.4. 
Other Study Supplies ......................................................................................................... 44 
11.5. 
Photos and Videos .............................................................................................................. 44 
12. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS AND ADMINISTRATIVE ISSUES .............................................. 45 
12.1. 
Protection of Human Subjects ............................................................................................ 45 
12.2. 
Compliance with Informed Consent Regulations .............................................................. 45 
12.3. 
Compliance with IRB/IEC Regulations ............................................................................. 45 
12.4. 
Subject Confidentiality ...................................................................................................... 45 
13. 
STORAGE AND ACCOUNTABILITY OF OTX-DP AND PV ...................................... 46 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
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Rev 002: 29-October 2019 
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13.1. 
Product Storage .................................................................................................................. 46 
13.2. 
Product Accountability ...................................................................................................... 46 
13.3. 
Product Return and Disposal .............................................................................................. 46 
14. 
APPENDICES ................................................................................................................... 46 
APPENDIX A. TIME AND EVENT SCHEDULE ........................................................................... 47 
APPENDIX B. PREGNANCY TESTING ......................................................................................... 49 
APPENDIX C. VISUAL ACUITY PROCEDURES (ETDRS CHART) .......................................... 50 
APPENDIX D. SLIT LAMP BIOMICROSCOPY PROCEDURES ................................................. 52 
APPENDIX E. PROCEDURE FOR EVALUATING IOP ................................................................ 53 
APPENDIX F. DILATED FUNDOSCOPY ...................................................................................... 54 
APPENDIX G. INSERTION AND VISUALIZATION INSTRUCTIONS ......................................... 55 
APPENDIX H. INSERT REMOVAL INSTRUCTIONS..................................................................... 57 
APPENDIX I. APPENDIX I. ALLERGEN CHALLENGE SCALES- OCULAR SYMPTOMS .... 58 
APPENDIX J. ALLERGEN CHALLENGE SCALES- NASAL SYMPTOMS ............................... 59 
APPENDIX K. INVESTIGATOR-EVALUATED SIGNS (OCULAR) .............................................. 60 
15. 
REFERENCES................................................................................................................... 61 
 
 
LIST OF FIGURES 
Figure 1 
Placement of Intracanalicular Insert in the Canaliculus..................................................... 18 
Figure 2 
Reporting Information for SAEs and Pregnancies ............................................................. 37 
Figure 3 
Placement of OTX-DP or PV in the Canaliculus ............................................................... 56 
 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 8 of 61 
 
1. 
ABBREVIATIONS 
 
Abbreviation 
Meaning 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
API 
Active pharmaceutical ingredient 
BCVA 
Best corrected visual acuity 
BOCF 
Baseline Observation Carried Forward 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
eCRF 
electronic Case report form 
CV 
Curriculum vitae 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GC 
Glucocorticoid 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IOL 
Intraocular Lens 
IOP 
Intraocular pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent To Treat 
LASIK 
laser in situ keratomileusis 
LOCF 
Last Observation Carried Forward 
logMAR 
logarithm of the minimum angle of resolution 
LS 
Least Square 
MCMC 
Markov Chain Monte Carlo 
mmHg 
Millimeters of Mercury 
NCS 
Not clinically significant 
NSAID 
Nonsteroidal anti-inflammatory drug 
PEG 
Polyethylene glycol 
PP 
Per Protocol 
OD 
Right eye 
Ora-CAC® 
Conjunctival allergen challenge 
OS 
Left eye 
OTC 
Over the counter 
OU 
Both eyes 
PV 
Placebo Vehicle 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
US 
United States 
WCO 
Worst Case Observation 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 9 of 61 
 
2. 
SYNOPSIS 
 
Study Title 
A Multi-Center, Randomized, Double-Masked, Vehicle Controlled Phase 
3 Study Evaluating the Efficacy and Safety of OTX-DP for the Treatment 
of Allergic Conjunctivitis Using a Modified Conjunctival Allergen 
Challenge Model (Ora-CAC®) 
Investigational Product 
OTX-DP (dexamethasone ophthalmic insert, 0.4mg) or PV (Placebo 
Vehicle) 
Phase of Clinical Study 
Phase 3 
Number of Sites 
Approximately 4 investigative sites in the United States 
Study Objective 
To evaluate the efficacy and safety of OTX-DP as a dexamethasone 
ophthalmic insert when placed in the canaliculus of the eyelid for the 
treatment of the signs and symptoms of allergic conjunctivitis. 
Product Description 
OTX-DP is a resorbable hydrogel intracanalicular insert containing an 
anti-inflammatory glucocorticoid agonist. The insert is designed to be 
placed into the punctum and is retained in the canaliculus for the entire 
drug delivery duration. Over time, the insert softens and liquefies via 
hydrolysis, resulting in clearance through the nasolacrimal duct. 
Each OTX-DP ophthalmic insert contains 0.4mg dexamethasone and a 
polyethylene glycol (PEG) based hydrogel conjugated with fluorescein. 
The fluorescent PEG allows the insert to be visualized by the physician 
utilizing a blue light source and yellow filter. 
The Placebo Vehicle (PV) is the same fluorescent PEG hydrogel insert as 
OTX-DP, except that it does not contain dexamethasone. 
Number of Subjects 
Planned 
Approximately 80 subjects will be enrolled into this clinical trial. 
Approximately 10 additional subjects will be enrolled to make up for any 
subjects who did not complete Visit 6b CAC procedures. 
Study Population 
Subjects of at least 18 years of age of either sex and of any race who meet 
all of the inclusion criteria and none of the exclusion criteria. 
Study Design and 
Overview 
This is a prospective, multi-center, randomized, double-masked, vehicle-
controlled study to evaluate the efficacy and safety of OTX- DP compared 
to PV for the treatment of the signs and symptoms of allergic 
conjunctivitis. 
The modified Ora-CAC® model used in the current study has been 
developed to study the interactions between the early and late phases of 
the allergic response in the eye, and to evaluate the effects of 
pharmaceutical intervention. The modified CAC model utilizes 3 
challenges conducted over a 2-day interval to evaluate the effectiveness of 
a test agent to: 1) prevent an acute ocular allergic reaction (the initial 
CAC), and 2) evaluate the test agent’s ability to prevent an acute ocular 
allergic reaction in the presence of subclinical late phase inflammation 
(the latter re-challenge CACs). 
 
The modified CAC model provides the opportunity to investigate the 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 10 of 61 
 
effects of the underlying inflammatory reaction on the ability of the tissues 
to mount a robust acute response to a subsequent allergen challenge. The 
modified CAC model also provides a means to investigate the 
mechanism(s) of action of anti-inflammatory agents in the treatment of 
allergic reactions. 
This study consists of 13 office visits over a period of approximately 5 to 
11 weeks. 
Qualifying subjects will be randomized 1:1 at Visit 4b (Day 1) to receive 
one of the following treatment arms bilaterally: 
 
OTX-DP (N=40 subjects) or 
 
PV (N=40 subjects) 
 
In the OTX-DP arm, subjects will receive bilateral OTX-DP 
(dexamethasone ophthalmic insert, 0.4mg) inserts. 
 
Randomization is at a 1:1 ratio (active:vehicle) 
Summary of Visit 
Schedule 
 Visit 1 (Day -45 to Day -6): Screening Visit 
 Visit 2 (Day -5+1 day): CAC screening / titration 
 Visit 3a (Day -4+1 day): CAC confirmation #1 
 Visit 3b (Day -4+1 day; 8 hours post V3a): CAC confirmation #2 
 Visit 4a (Day -3 +1 day; 24±6 hours post V3a): CAC confirmation #3 
 
Subjects will be asked to return to the office 2-3 days from the time 
of their Baseline CAC (Visit 4a) for IP Insertion (Visit 4b/Day 1) 
 
 Visit 4b (Day 1): Enrollment/Randomization/Insertion of OTX- DP or 
PV 
 
 Visit 5 (Day 7; 6 days post-insertion) CAC #1 
 Visit 6a (Day 8; 7 days post-insertion) CAC re-challenge #2 
 Visit 6b (Day 8; 7 days post-insertion; 8 hours from Visit 6a) CAC re-
challenge #3 
 
The Visit 6b (Day 8) measures OTX-DP efficacy 7 days post- 
insertion. 
 
 Visit 7 (Day 14; 13 days post-insertion) CAC re-challenge #1 
 Visit 8a (Day 15; 14 days post-insertion) CAC re-challenge #2 Visit 
8b (Day 15; 14 days post-insertion; 8 hours from Visit 8a) CAC re-
challenge #3 
 Visit 9 (Day 30+3): Study Exit 
Primary Efficacy 
Evaluations 
The primary endpoint is: 
Ocular itching evaluated by the subject on Visit 6b (Day 8; 7 days post-
insertion; 8 hours from Visit 6a) at 3(±1), 5(±1), and 7(±1) minutes post-
CAC (0-4 scale, allowing half unit increments) 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
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Secondary Efficacy 
Evaluations 
Key secondary outcomes are the measures of ocular itching at the 
following visits at 3(±1), 5(±1), and 7(±1) minutes post-CAC: 
 Visit 6a (Day 8; 7 days post-insertion) 
 Visit 5 (Day 7; 6 days post-insertion) 
 Visit 8b (Day 15; 14 days post-insertion; 8 hours from Visit 8a) 
 Visit 8a (Day 15; 14 days post-insertion) 
 Visit 7 (Day 14; 13 days post-insertion) 
 
Other secondary efficacy measures are ocular itching at Visits 5, 6a, 6b, 7, 
8a, and 8b at the 10(±1) minutes post-CAC and the following assessments 
made at Visits 5, 6a, 6b, 7, 8a, and 8b at 7(±1), 15(±1), and 20(±3) minutes 
post-CAC: 
 Conjunctival redness evaluated by the investigator (0-4 scale, 
allowing half unit increments) 
 Ciliary and episcleral redness evaluated by the investigator (0-4 
scale, allowing half unit increments) 
 Chemosis evaluated by the investigator (0-4 scale, allowing half 
unit increments) 
 Eyelid swelling evaluated by the subject (0-3 scale, NOT allowing 
half unit increments) 
 Tearing/watery eyes evaluated by the subject (0-4 scale, NOT 
allowing half unit increments) 
 Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal 
congestion evaluated by the subject (0-4 scale, NOT allowing half-
unit increments) 
Nasal symptom composite score based on the assessments of rhinorrhea, 
nasal pruritus, ear or palate pruritus, and nasal congestion (analyzed as a 
qualitative measure determined as the presence or absence of at least one 
nasal symptom [present/absent], and as a quantitative measure calculated 
as the sum of the four component symptom scores [ranging from 0 to 16]) 
Safety Evaluations 
 Adverse Events (AEs) (reported, elicited, and observed)
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart
 Slit-lamp biomicroscopy, including punctum exam
 Intraocular Pressure (IOP)
 
Dilated Fundoscopy Examination

Inclusion Criteria 
Each subject must: 
1. be at least 18 years of age of either sex and any race; 
2. provide written informed consent and sign the HIPAA form; 
3. be willing and able to follow all instructions and attend all study visits; 
4. be able and willing to avoid all disallowed medication for the 
appropriate washout period and during the study (see exclusion 6 in 
Section 5.5.3) 
5. be able and willing to discontinue wearing contact lenses for at least 72 
hours prior to Visit 2 and during the study period; 
6. have a BCVA of greater than or equal to 50 ETDRS letters (20/100 
Snellen equivalent or better) in each eye as measured at Visit 1; 
7. agree to have urine pregnancy testing (for women considered capable 


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of becoming pregnant, including all females who have experienced 
menarche and have not experienced menopause [as defined by 
amenorrhea for greater than 12 consecutive months] or have not 
undergone successful surgical sterilization [hysterectomy, bilateral 
tubal ligation, or bilateral oophorectomy]) performed at Visit 2 and at 
the exit visit; not be lactating; and agree to use a medically acceptable 
form of birth control throughout the clinical study duration; 
8. have a positive history of ocular allergies and a positive skin test 
reaction to a perennial allergen (cat dander, dog dander, dust mites, 
cockroaches) and a seasonal allergen (trees, grasses, and/or ragweed) 
as confirmed by the allergic skin test conducted at Visit 1 or given to 
the subject within 24 months of the subject’s Visit 2; 
9. have a positive bilateral CAC reaction (defined as ≥ 2 itching and ≥2 
conjunctival redness) within 10 (±2) minutes of instillation of the last 
titration of allergen at Visit 2; 
10. have an average of ≥ 3 itching and ≥2.5 conjunctival redness for both 
eyes after the first three post-CAC assessment time points at Visit 4a 
Exclusion Criteria 
Each subject must not: 
1) have known contraindications or sensitivities to the use of any of the 
medications required by the protocol; 
2) have any ocular condition that, in the opinion of the investigator, could 
affect the subject’s safety or study parameters (including but not 
limited to narrow angle glaucoma, clinically significant blepharitis, 
follicular conjunctivitis, iritis, pterygium or a diagnosis of dry eye); 
3) have had a history of refractive surgery (including LASIK procedures) 
within the past 2 years; 
4) have a known history of retinal detachment, diabetic retinopathy, or 
active retinal disease; 
5) have the presence of an active ocular infection (bacterial, viral or 
fungal), a current diagnosis or history of Herpes Simplex Keratitis, or 
a positive history of an ocular herpetic infection at any visit; 
6) use any of the following disallowed medications* during the period 
indicated prior to Visit 2 and during the study: 
7 Days 
 
systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell 
stabilizer drug combinations, H1 antihistamine- vasoconstrictor 
drug combinations; 
 
decongestants; 
 
monoamine oxidase inhibitors; 
 
all other topical ophthalmic preparations (including artificial tears); 
 
lid scrubs; 
 
prostaglandins or prostaglandin derivatives; 
 
ocular, topical, or systemic nonsteroidal anti-inflammatory drugs 
(NSAIDs); 
*Baby aspirin (81 mg) is allowed as long as a stable dose has been 
maintained for at least 30 days prior to Visit 2 and will continue to be 
maintained for the duration of the study. 
14 Days 
 
inhaled, ocular or topical corticosteroids or mast cell stabilizers; 
 


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45 Days 
 
depot-corticosteroids; 
2 months 
 
immunotherapeutic agents (treatment must have been maintained 
steadily for at least 2 months; neither the immunotherapeutic agent nor 
its dosage may change during the clinical study) 
7) have a congenital or ocular anomaly (including punctal or lid 
ectropion, entropion, trichiasis, or supernumerary puncta) or anomalies 
of the punctum (including lack of good punctal apposition in both 
eyes); 
8) have a diagnosis of any significant uncontrolled illness; 
9) history of alcohol or drug abuse in the past year; 
10) known history of moderate to severe allergic asthmatic reactions to 
any of the study allergens; 
11) have planned surgery (ocular or systemic) during the trial period or 
within 30 days after; 
12) have used an investigational drug or medical device within 30 days of 
the study or be concurrently enrolled in another investigational product 
trial; 
13) be a female who is currently pregnant, planning a pregnancy, or 
lactating; 
14) have a score of >0 for ocular itching and/or >1 for conjunctival 
redness prior to the challenge in either eye at Visit 2; 
15) have an intraocular pressure that is less than 5 mmHg or greater than 
22 mmHg or any type of glaucoma at Visit 2; 
16) have had a history of an IOP increase as a result of steroid treatment; 
17) have an unsuccessful transient punctum dilation to 0.7 mm prior to 
insertion of OTX-DP or PV; 
18) be an employee of the site that is directly involved in the management, 
administration, or support of the study, or are an immediate family 
member of the same. 
General Statistical 
Methods and Types of 
Analysis 
In general, quantitative/continuous data will be summarized using 
descriptive statistics (n, mean, standard deviation, median, minimum, and 
maximum). Qualitative/categorical data will be summarized using 
frequencies and percentages. 
Efficacy analyses will be conducted on the intent-to-treat (ITT) population 
using multiple imputation using Markov Chain Monte Carlo (MCMC) for 
missing and incomplete efficacy data. The ITT population is defined as all 
randomized subjects. All data will be included in the ITT population and 
will be analyzed as randomized. The average of each subject’s eyes at 
each time point within each visit will be used for efficacy analyses. 
 
Sensitivity analysis on the primary endpoint will be performed on the Per-
Protocol (PP) population defined as all subjects who complete the study 
through Visit 6b (Day 8) without major protocol violations. The PP 
population will be analyzed as treated using observed data only. 
 
Safety analyses will be conducted on the safety population defined as all 


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randomized subjects who received the IP. The safety population will be 
analyzed as treated. 
Sample Size: 
Approximately 80 subjects will be randomized at Visit 4b in a 1:1 ratio 
across the two treatment arms (40 OTX-DP; 40 PV). Up to approximately 
10 additional subjects may be enrolled to make up for any subjects who 
did not complete Visit 6b CAC procedures. 
A total of 40 subjects in each treatment arm will provide 97.0%, 99.8%, 
and 99.9% power to demonstrate a statistically significant difference in 
ocular itching between OTX-DP and PV treated subjects at each of the 3, 
5, and 7 minute post-CAC time points of Visit 6b, respectively, assuming 
a treatment difference of 0.87 units 3 minutes post-CAC, 1.08 units at 5 
minutes post-CAC, and 1.13 units at 7 minutes post-CAC; a standard 
deviation of 1.0 unit at all time points; and a two-sided Type I error of 
0.05. 
Assuming independence between time points, 40 subjects per group will 
have at least 96.7% power to demonstrate a statistically significant 
difference over all post-CAC time points at Visit 6b for ocular itching 
between OTX-DP and PV treated subjects. 
Additionally, 40 subjects in each treatment arm will have at least 55.9% 
probability of showing a point estimate treatment difference for ocular 
itching between OTX-DP and PV treated subjects of at least 1.0 unit for a 
majority of the post-CAC time points and 0.5 units for all of the post-CAC 
time points at Visit 6b, using the same assumptions previously stated. 
 
Primary Hypothesis: 
 
Statistical hypotheses for the primary efficacy endpoint of ocular itching at 
Visit 6b are as follows: 
H10: There is no difference in mean ocular itching scores between 
OTX-DP and PV treated subjects for at least 1 of the 3 time points 
during Visit 6b. 
 
H1a: There is a difference in mean ocular itching scores between 
OTX-DP and PV treated subjects for all 3 time points during Visit 
6b. 
Primary and Key Secondary Analyses: 
The primary efficacy variable is ocular itching measured at Visit 6b (Day 
8; 7 days post-insertion; 8 hours from Visit 6a) measured at 3(±1), 5(±1), 
and 7(±1) minutes post-CAC. 
The key secondary variables are ocular itching measured at Visit 5 (Day 7; 
6 days post-insertion), Visit 6a (Day 8; 7 days post- insertion), Visit 7 
(Day 14; 13 days post-insertion), Visit 8a (Day 15; 14 days post-
insertion), and Visit 8b (Day 15; 14 days post- insertion; 8 hours from 
Visit 8a) measured at 3(±1), 5(±1), and 7(±1) minutes post-CAC. The 


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average of each subject’s eyes at each post-CAC time point will be used as 
the unit of analysis. The primary efficacy analyses will be conducted on 
the intent-to-treat (ITT) population with multiple imputation using Markov 
Chain Monte Carlo (MCMC) for missing data. 
 
Analysis of covariance (ANCOVA) models will be run at each post- CAC 
time point of a given visit to estimate least square (LS) treatment means. 
These models will include the time appropriate post-CAC® scores at Visit 
4a as a baseline covariate for adjustment and treatment group as the sole 
factor. LS means will be used to make treatment comparisons. Statistical 
significance of treatment differences will be determined using a two-sided 
significance level of α =0.05. 
 
Two-sample t-tests will be used as unadjusted sensitivity analyses at each 
post-CAC time point, as well as non-parametric Wilcoxon rank sum tests. 
Sensitivity analyses will be conducted on the ITT population with last 
observation carried forward (LOCF), worst case observation (WCO), and 
baseline observation carried forward (BOCF) for missing data, as well as 
using observed data only for the ITT and PP populations. 
 
Other Secondary Analyses: 
The remaining secondary variables including ocular itching (at later time 
points), conjunctival, episcleral, and ciliary redness; eyelid swelling; 
tearing/watery eyes; rhinorrhea; nasal pruritus; ear or palate pruritus; and 
nasal congestion will be analyzed in a manner similar to the primary and 
key secondary variables using ANCOVA models by time point. The 
secondary analyses will be conducted using observed data only on the ITT 
and PP populations. 


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3. 
PRINCIPAL CONTACTS 
Please refer to Study Contact List. 
4. 
INTRODUCTION 
4.1. 
Background and Rationale 
Ocular Therapeutix, Inc. is a biopharmaceutical company specifically focused on developing novel 
delivery systems for therapeutic products in order to address unmet and/or underserved medical 
needs. Ocular Therapeutix was founded to further develop its proprietary polyethylene glycol (PEG) 
hydrogel technology in various applications. Ocular Therapeutix has developed a resorbable 
intracanalicular hydrogel insert that serves as the platform for multiple drug delivery products and is 
being developed to deliver various APIs that are already approved by the Food and Drug 
Administration (FDA). The insert is designed to be placed into the punctum and is retained in the 
canaliculus for the intended drug delivery duration. Over time, the insert softens and liquefies via 
hydrolysis, resulting in clearance through the nasolacrimal duct. One of these inserts, known 
commercially as DEXTENZA®, a dexamethasone ophthalmic insert (OTX-DP) was approved by the 
FDA on November 30, 2018 for the treatment of pain following ophthalmic surgery. 
Based on its design, OTX-DP provides potential benefits in that it requires only a single application 
by the physician, thereby eliminating the potential for patient non-compliance and also provides 
consistent delivery of medication to the ocular surface over the intended duration of treatment. In 
addition, the fluorescent PEG hydrogel allows for physician and subject visualization of OTX-DP. 
Further, the drug inserts do not contain antimicrobial preservatives, thus providing an additional 
safety benefit. 
4.2. 
Prior Experience with OTX-DP Inserts 
Glucocorticoids (GCs) are among the most effective and widely prescribed therapies in the treatment 
of acute and chronic inflammatory diseases, including ocular inflammation, and are particularly 
effective in treating later phase ocular conjunctivitis reactions (Choi et al, 2008). GCs such as 
dexamethasone do not affect immune cell membranes or histamine release mechanisms (Leonardi et 
al, 2012). They are, however, potent and efficacious anti-inflammatory agents which exert their 
therapeutic effects by binding to the glucocorticoid receptor leading to modulation of gene expression 
through down regulation of transcriptional regulators (Rhen et all, 2005). They may also modulate the 
mast cell response by inhibiting cytokine production, recruitment, and activation of inflammatory 
cells (Rhen et all, 2005). As a consequence of their anti-inflammatory properties, ophthalmic steroids 
are commonly used in the treatment of acute ocular conditions such as conjunctivitis, uveitis, allergy, 
dry eye, diabetic macular edema, and postoperative inflammation in cataract patients. Administration 
of these anti-inflammatory agents has been shown to decrease allergic signs and symptoms, not only 
at 5-6 hours post challenge, but also at shorter times generally considered to represent an acute 
response time frame (Leonardi et al, 2002). In fact, one study suggests that treatment with a low-dose 
steroid (desonide) can inhibit or attenuate the allergic reaction phase that initiates the transition from 
early acute to the chronic inflammatory response (Leonardi et al, 2002). Consequently, when mast-
cell stabilizers and antihistamines fail to control the allergic response, less potent topical ophthalmic 
GCs such as loteprednol, rimexolone, and fluorometholone are used first, with dexamethasone 
prescribed later, at the lowest dose and for the shortest duration of time, in cases that are severe and/or 
unresponsive to other forms of treatment (Rizzo et al, 2006). 
Use of GCs can be limited, however, by their potential (especially after long-term systemic treatment) 


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to induce a number of severe and sometimes irreversible side effects, such as osteoporosis, diabetes, 
Cushing’s syndrome, glaucoma, and muscle wasting (Schäcke et al, 2002, Rizzo et al, 2006). For local 
ocular administration, GCs exhibit a variety of effect/side effect rations, with the primary adverse 
events (AEs) of concern being elevation of intraocular pressure (IOP), cataract formation, and 
increased vulnerability to superinfection (Wang et al, 2009, Kersey et al, 2006, Rizzo et al, 2006). All 
currently marketed ophthalmic steroids carry the warning that use for longer than 14 days should only 
be carried out under close physician supervision, and it is generally recommended that the dose be 
tapered slowly over several days (Rizzo et al, 2006). 
Dexamethasone, one of the most powerful GCs, is already marketed in the US as a sterile ophthalmic 
solution for the treatment of “steroid responsive inflammatory conditions of the palpebral and bulbar 
conjunctiva, cornea, and anterior segment of the globe, such as allergic conjunctivitis…”. While 
dexamethasone and other GCs are presumed to be the most clinically effective in the treatment of 
late-phase inflammatory allergic reactions, their well known safety limitations for long-term use 
prohibit wide-spread adoption of this treatment. 
Use of the OTX-DP seasonally creates a low, tapered, consistent dose of dexamethasone, possibly 
minimizing or possibly eliminating negative side effects of general topical ophthalmic GC use, while 
retaining its anti-inflammatory effects that may be particularly beneficial in the treatment of late-
phase ocular allergy. 
One Phase 2, multicenter, prospective, randomized, double-masked vehicle controlled study in 68 
subjects was completed utilizing the modified Ora-CAC® model. The study evaluated the safety and 
efficacy of OTX-DP as a sustained release drug depot for the treatment of the signs and symptoms of 
chronic allergic conjunctivitis.  At 2 weeks, 4 weeks and 6 weeks after insertion of the OTX-DP, 
subjects underwent a series of 4 CACs over a period of 48 hours followed by clinical evaluation of the 
signs and symptoms of chronic allergic conjunctivitis. The co-primary efficacy endpoints were ocular 
itching and conjunctival redness at 14 days after 
OTX-DP insertion. OTX-DP was shown to be efficacious. OTX-DP treated subjects had significantly 
lower ocular itching and conjunctival redness scores at all time points following repeated challenge at 
14 days post insertion. The effect was long lasting with a duration of action of at least 6 weeks 
following plug insertion. The majority of adverse events (AEs) were mild, and evenly distributed 
between the OTX-DP group (14 AEs in 11 subjects) and the vehicle group (12 AEs in 10 subjects). 
A Phase 3, multicenter, prospective, randomized, double-masked vehicle controlled study in 72 
subjects was completed utilizing the modified Ora-CAC® model. The study evaluated the safety and 
efficacy of OTX-DP as a sustained release drug depot for the treatment of the signs and symptoms of 
chronic allergic conjunctivitis. At 1, 2 and 4 weeks after insertion of the OTX-DP, subjects underwent 
a series of 4 CACs over a period of 48 hours followed by clinical evaluation of the signs and 
symptoms of chronic allergic conjunctivitis. The primary efficacy endpoints were ocular itching and 
conjunctival redness at 7 days after OTX-DP insertion. OTX-DP was shown to be efficacious. OTX-
DP treated subjects had lower conjunctival redness and significantly lower ocular itching scores at all 
time points following repeated challenge at 7 days post insertion. The effect was long lasting with a 
duration of action of at least 4 weeks following plug insertion. The majority of adverse events (AEs) 
were mild or moderate, and evenly distributed between the OTX-DP group (4 AEs in 3 subjects) and 
the vehicle group (7 AEs in 4 subjects). 
A second Phase 3, multicenter, randomized, double-masked, vehicle controlled study in 83 subjects 
was completed utilizing the modified Ora-CAC® model. The study evaluated the safety and efficacy 
of OTX-DP as a sustained release drug depot for the treatment of the signs and symptoms of chronic 
allergic conjunctivitis. At 1, 2 and 4 weeks after insertion of the OTX-DP, subjects underwent a series 


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of 4 CACs over a period of 48 hours followed by clinical evaluation of the signs and symptoms of 
chronic allergic conjunctivitis. The primary efficacy endpoint was ocular itching at 7 days after OTX-
DP insertion. OTX-DP was not shown to be efficacious as treatment group differences were not 
statistically significant at the Day 7 primary endpoint. Six subjects in the OTX-DP group experienced 
seven AEs and 11 subjects in the PV group experienced a total of 17 AEs. 
OTX-DP is designed to overcome potential patient non-compliance due to the repeated dosing 
regimens associated with topical ophthalmic solutions, and to improve the delivery such that the drug 
level is maintained over the treatment period. The efficacy and safety of OTX-DP compared to PV for 
the treatment of ocular inflammation and pain in subjects undergoing cataract surgery with 
implantation of an intraocular lens (IOL) have been recently evaluated in three Phase 3 studies 
involving 541 OTX-DP treated subjects. The most common ocular adverse reactions that occurred in 
patients treated with OTX-DP were: anterior chamber inflammation including iritis and iridocyclitis 
(10%); intraocular pressure increased (6%); visual acuity reduced (2%); eye pain (1%); cystoid 
macular edema (1%); and corneal edema (1%).The most common non-ocular adverse reaction that 
occurred in patients treated with OTX-DP was headache (1%). 
 
4.3. 
Description of Treatment 
OTX-DP (dexamethasone ophthalmic insert, 0.4mg) is a resorbable hydrogel intracanalicular insert 
consisting of two main components: dexamethasone and a polyethylene glycol (PEG)- based hydrogel 
conjugated with fluorescein. 
The hydrogel intracanalicular insert is designed to be placed in the canaliculus and swell on contact 
with moisture to occlude the lumen, securing it in place. Once the OTX-DP or PV swells to fill the 
canaliculus, it is designed to hydrolyze and be resorbed. 
OTX-DP or PV is provided to the Investigator as a terminally-sterilized dried product. The product is 
packaged in a hermetically sealed foil pouch to maintain stability and sterility over time. It is placed 
into the punctum (Figure 1) by the Investigator using forceps. The instructions for the insertion 
procedure are described in Appendix G. 
 
Figure 1 
Placement of Intracanalicular Insert in the Canaliculus 
 
 


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4.3.1. 
Placebo Vehicle 
The control, PV, is the same fluorescent PEG hydrogel as OTX-DP, except that it does not contain 
drug. 
 
4.3.2. 
Safety of OTX-DP 
Additional details as to the physical, chemical and pharmaceutical properties and product description 
are provided in the Investigator’s Brochure (IB). Packaging configuration is also provided in the IB. 
 
4.4. 
Intended Indication 
OTX-DP is being studied for the intended use in the treatment of ocular itching associated with 
allergic conjunctivitis. 
 
4.5. 
Risk/Benefits 
The potential risks and benefits associated with the use of the OTX-DP or PV are described below. 
 
4.5.1. 
Potential Benefits 
The benefits of OTX-DP are not yet known, but are thought to be: 
 Reduction of signs and symptoms associated with allergic conjunctivitis. 
 Improved treatment outcome through eliminating subject non-compliance with the use of 
daily drops. 
 Improved treatment outcome through the delivery of therapeutic levels of dexamethasone 
continuously for the intended duration of therapy and the elimination of preservatives 
commonly found in ophthalmic preparations. 
 
4.5.2. 
Potential Risks 
In general, the following risks could occur from the insertion and use of the OTX-DP or PV: 
 Ocular pain and discomfort 
 Conjunctivitis 
 Blepharitis 
 Epiphora 
 Ocular pruritus 
 Perforation of or trauma to the punctum and/or surrounding tissues; or punctoplasty 
 Allergic reaction 
 Impaired visual acuity 
 Chemosis 
 Inflammatory reaction 
 Canaliculitis 
 Dacrocystitis 


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 Tearing with mucopurulent discharge 
 Stenosis (narrowing/closing) of the punctum 
 IOP elevation 
 Cataract formation 
 Increased risk of infection 
 Infection that if severe could lead temporary or permanent impairment of sight 
 Inability to remove the OTX-DP or PV 
5. 
STUDY OBJECTIVES AND DESIGN 
This is a prospective, multi-center, randomized, double-masked, vehicle-controlled study to evaluate 
the efficacy and safety of OTX-DP compared to PV for the treatment of the signs and symptoms of 
allergic conjunctivitis. 
The modified Ora-CAC® model used in the current study has been developed to study the interactions 
between the early and late phases of the allergic response in the eye, and to evaluate the effects of 
pharmaceutical intervention. The modified CAC model utilizes 3 challenges conducted over a 2-day 
interval to evaluate the effectiveness of a test agent to: 1) prevent an acute ocular allergic reaction (the 
initial CAC), and 2) evaluate the test agent’s ability to prevent an acute ocular allergic reaction in the 
presence of subclinical late phase inflammation (the latter re-challenge CACs). 
The modified CAC model provides the opportunity to investigate the effects of the underlying 
inflammatory reaction on the ability of the tissues to mount a robust acute response to a subsequent 
allergen challenge. The modified CAC model also provides a means to investigate the mechanism(s) 
of action of anti-inflammatory agents in the treatment of allergic reactions. 
This study will comprise of 13 office visits over a period of approximately 5 to 11 weeks. Visits 2, 3a, 
3b, and 4a will be used to select a subject population that responds reproducibly to the 3 CACs 
administered over a 2-day interval used in the modified Ora-CAC model to induce the underlying 
inflammatory component characteristic of chronic allergic conjunctivitis. Subjects who meet the entry 
criteria for itching and redness response to the CAC at Visits 2, 3a, 3b, and 4a will be randomized at a 
1:1 ratio (active:vehicle) at Visit 4b (Day 1) to receive one of the following treatment arms bilaterally: 
 OTX-DP (N=40 subjects) or 
 PV (N=40 subjects) 
In the OTX-DP arm, subjects will receive bilateral OTX-DP (dexamethasone ophthalmic insert, 
0.4mg) inserts. 
The series of CACs and re-challenge CACs during Visits 5, 6a, and 6b will be used for the primary 
efficacy measures at Visit 6b and will assess the effectiveness of the OTX-DP (beginning at 5 days 
post-insertion, with the primary endpoint at 7 days post-insertion). Subjects will return to the office 
for Visits 7, 8a, and 8b for another series of CAC and re-challenge CACs and will return again for 
Visit 9 (Day 30+3) for the removal of OTX-DP or PV, if still present, and for final safety evaluations. 
5.1. 
Study Objectives 
To evaluate the efficacy and safety of OTX-DP as a dexamethasone ophthalmic insert when placed in 
the canaliculus of the eyelid for the treatment of the signs and symptoms of allergic conjunctivitis. 


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5.2. 
Clinical Hypothesis 
Statistical hypotheses for the primary efficacy endpoint of ocular itching at Visit 6b are as follows: 
H10: There is no difference in mean ocular itching scores between OTX-DP and PV treated 
subjects for at least 1 of the 3 time points during Visit 6b. 
H1a: There is a difference in mean ocular itching scores between OTX-DP and PV treated 
subjects for all 3 time points during Visit 6b. 
Similar hypotheses will be tested for the key secondary efficacy endpoints of ocular itching at Visits 
5, 6a, 7, 8a, 8b. Statistical significance will be determined using a two-sided significance level of 
0.05. 
 
5.3. 
Efficacy and Safety Parameters 
5.3.1. 
Primary Efficacy Evaluations 
The primary endpoint is: 
 Ocular itching evaluated by the subject on Visit 6b (Day 8; 7 days post-insertion; 8 hours 
from Visit 6a) at 3(±1), 5(±1), and 7(±1) minutes post-CAC (0-4 scale, allowing half unit 
increments) 
5.3.2. 
Secondary Efficacy Evaluations 
Key secondary outcomes are the measures of ocular itching at the following visits at 3(±1), 5(±1), and 
7(±1) minutes post-CAC: 
 Visit 6a (Day 8; 7 days post-insertion) 
 Visit 5 (Day 7; 6 days post-insertion) 
 Visit 8b (Day 15; 14 days post-insertion; 8 hours from Visit 8a) 
 Visit 8a (Day 15; 14 days post-insertion) 
 Visit 7 (Day 14; 13 days post-insertion) 
Other secondary efficacy measures are ocular itching at Visits 5, 6a, 6b, 7, 8a, and 8b at the 10(±1) 
minutes post-CAC and the following assessments made at Visits 5, 6a, 6b, 7, 8a, and 8b at 7(±1), 
15(±1), and 20(±3) minutes post-CAC: 
 Conjunctival redness evaluated by the investigator (0-4 scale, allowing half unit 
increments) 
 Ciliary and episcleral redness evaluated by the investigator (0-4 scale, allowing half unit 
increments) 
 Chemosis evaluated by the investigator (0-4 scale, allowing half unit increments) 
 Eyelid swelling evaluated by the subject (0-3 scale, NOT allowing half unit increments) 
 Tearing/watery eyes evaluated by the subject (0-4 scale, NOT allowing half unit 
increments) 
 Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated by the 
subject (0-4 scale, NOT allowing half-unit increments) 


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 Nasal symptom composite score based on the assessments of rhinorrhea, nasal pruritus, ear 
or palate pruritus, and nasal congestion (analyzed as a qualitative measure determined as 
the presence or absence of at least one nasal symptom [present/absent], and as a 
quantitative measure calculated as the sum of the four component symptom scores 
[ranging from 0 to 16]) 
 
5.3.3. 
Safety Evaluations 
 Adverse Events (AEs) (reported, elicited, and observed) 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart 
 Slit-lamp biomicroscopy, including punctum exam 
 Intraocular Pressure (IOP) 
 Dilated Fundoscopy Examination 
5.4. 
Training of Investigators 
Only ophthalmologists or optometrists who are experienced with punctal plug insertion will be 
considered for participation as Principal Investigators or Sub-Investigators in this study. All 
investigators who will use the OTX-DP or PV will undergo training on instructions for the insertion 
procedure which can be found in Appendix G. 
5.5. 
Subject Selection 
5.5.1. 
Study Population 
Subjects of at least 18 years of age of either sex and of any race, who meet all of the inclusion criteria 
and none of the exclusion criteria. 
 
5.5.2. 
Inclusion Criteria 
Each subject must: 
1. be at least 18 years of age of either sex and any race; 
2. provide written informed consent and sign the HIPAA form; 
3. be willing and able to follow all instructions and attend all study visits; 
4. be able and willing to avoid all disallowed medication for the appropriate washout period and 
during the study (see exclusion 6 in Section 5.5.3). 
5. be able and willing to discontinue wearing contact lenses for at least 72 hours prior to Visit 2 
and during the study period; 
6. have a BCVA of greater than or equal to 50 ETDRS letters (20/100 Snellen equivalent or 
better) in each eye as measured at Visit 1; 
7. agree to have urine pregnancy testing (for women considered capable of becoming pregnant, 
including all females who have experienced menarche and have not experienced menopause [as 
defined by amenorrhea for greater than 12 consecutive months] or have not undergone successful 
surgical sterilization [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy]) performed at 
Visit 2 and at the exit visit; not be lactating; and agree to use a medically acceptable form of birth 
control throughout the clinical study duration; 


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8. have a positive history of ocular allergies and a positive skin test reaction to a perennial 
allergen (cat dander, dog dander, dust mites, cockroaches) and a seasonal allergen (trees, 
grasses, and/or ragweed) as confirmed by the allergic skin test conducted at Visit 1 or given to 
the subject within 24 months of the subject’s Visit 2; 
9. have a positive bilateral CAC reaction (defined as ≥ 2 itching and ≥2 conjunctival 
redness) within 10 (±2) minutes of instillation of the last titration of allergen at Visit 2; 
10. have an average of ≥ 3 itching and ≥2.5 conjunctival redness for both eyes after the first 
three post-CAC assessment time points at Visit 4a. 
 
5.5.3. 
Exclusion Criteria 
Each subject must not: 
1. have known contraindications or sensitivities to the use of any of the medications required by 
the protocol; 
2. have any ocular condition that, in the opinion of the investigator, could affect the subject’s 
safety or study parameters (including but not limited to narrow angle glaucoma, clinically 
significant blepharitis, follicular conjunctivitis, iritis, pterygium or a diagnosis of dry eye); 
3. have had a history of refractive surgery (including LASIK procedures) within the past 2 years; 
4. have a known history of retinal detachment, diabetic retinopathy, or active retinal disease; 
5. have the presence of an active ocular infection (bacterial, viral or fungal), a current diagnosis 
or history of Herpes Simplex Keratitis, or a positive history of an ocular herpetic infection at 
any visit; 
6. use any of the following disallowed medications* during the period indicated prior to Visit 2 
and during the study: 
7 Days 
 systemic or ocular H1 antihistamine, H1 antihistamine/mast-cell stabilizer drug 
combinations, H1 antihistamine- vasoconstrictor drug combinations; 
 decongestants; 
 monoamine oxidase inhibitors; 
 all other topical ophthalmic preparations (including artificial tears); 
 lid scrubs; 
 prostaglandins or prostaglandin derivatives; 
 ocular, topical, or systemic nonsteroidal anti-inflammatory drugs (NSAIDs); 
*Baby aspirin (81 mg) is allowed as long as a stable dose has been maintained for at least 30 
days prior to Visit 2 and will continue to be maintained for the duration of the study. 
14 Days 
 inhaled, ocular or topical corticosteroids or mast cell stabilizers; 
45 Days 
 depot-corticosteroids; 


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2 Months 
 immunotherapeutic agents (treatment must have been maintained steadily for at least 2 
months; neither the immunotherapeutic agent nor its dosage may change during the clinical 
study) 
7. have a congenital or ocular anomaly (including punctal or lid ectropion, entropion, trichiasis, 
or supernumerary puncta) or anomalies of the punctum (including lack of good punctal 
apposition in both eyes); 
8. have a diagnosis of any significant uncontrolled illness; 
9. history of alcohol or drug abuse in the past year; 
10. known history of moderate to severe allergic asthmatic reactions to any of the study allergens; 
11. have planned surgery (ocular or systemic) during the trial period or within 30 days after; 
12. have used an investigational drug or medical device within 30 days of the study or be 
concurrently enrolled in another investigational product trial; 
13. be a female who is currently pregnant, planning a pregnancy, or lactating; 
14. have a score of >0 for ocular itching and/or >1 for conjunctival redness prior to the challenge 
in either eye at Visit 2; 
15. have an intraocular pressure that is less than 5 mmHg or greater than 22 mmHg or any type of 
glaucoma at Visit 2; 
16. have had a history of an IOP increase as a result of steroid treatment; 
17. have an unsuccessful transient punctum dilation to 0.7 mm prior to insertion of OTX-DP or 
PV; 
18. be an employee of the site that is directly involved in the management, administration, or 
support of the study, or are an immediate family member of the same. 


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6. 
STUDY DATA COLLECTION 
6.1. 
Study Schematic 
The study Time and Event Schedule is presented in Appendix A. 
 
6.2. 
Data Collection 
Data collected from all study procedures and assessments will be collected and documented on the 
appropriate electronic Case Report Form (eCRF) for the study. 
6.3. 
Subject Enrollment 
All subjects screened for the study who sign a consent form will be assigned a 5-digit Screening number 
which will be entered in the Screening and Enrollment Log. Screening numbers will be assigned in 
sequential order beginning with SXX001 where XX is a 2-digit site number. 
Once a subject meets all qualification criteria, they will be randomly assigned to masked treatment 
using a 1:1 (OTX-DP: PV) assignment ratio. Subjects will be randomized on Visit 4b (Day 1) by 
assignment of the lowest 4-digit randomization number available at the investigative site, starting with 
RXX01, where XX is a 2-digit site number. No product numbers will be skipped or omitted. The 
investigational product will be inserted per the procedures outlined in Appendix G. 
6.4. 
Masking 
The Sponsor, Investigator and the subject will be masked to the treatment assignment throughout the 
subject’s participation in the study. OTX-DP and PV are identical in appearance and will be supplied 
in identical packages so they cannot be distinguished by the user. If it is medically necessary to 
identify the product used, the Investigator will follow procedures outlined in Section 9.9.2. 
6.5. 
Data Collection 
Data collected from all study procedures and assessments will be collected and documented on the 
appropriate electronic Case Report Form (eCRF) for the study. 
7. 
STUDY OBSERVATIONS AND PROCEDURES 
7.1. 
Subject Screening and Informed Consent 
Prior to a subject’s participation in the study (i.e., changes in a subject’s medical treatment and/or 
study related procedures), the study will be discussed with each subject, and subjects wishing to 
participate must give written informed consent using an informed consent form (ICF). The ICF must 
be the most recent version that has received approval/favorable review by a properly constituted 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
Failure to obtain a signed ICF renders the subject ineligible for the study. Subjects must be willing to 
remain in the clinic for all CAC titrations and procedures and be willing to return to the clinic for 
study Visits 2, 3a, 3b, 4a, 4b, 5, 6a, 6b, 7, 8a, 8b, and 9, as required. 
Prior to the completion of the Screening Phase (Visit 1-4a), if it is determined a subject did not in fact 
meet eligibility criteria, the subject may be brought back at a later date to re-attempt the screening 
process. 
Subjects can be re-screened a maximum of three times. 


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7.2. 
Screen Failures 
A screen-fail will be defined as screened subjects who do not meet the inclusion/exclusion criteria 
prior to randomization at Visit 4b (Day 1). 
 
7.3. 
Subject Withdrawal 
Subjects may be discontinued prior to their completion of the study due to: 
 adverse events 
 protocol violations 
 administrative reasons (eg, inability to continue, lost to follow up) 
 sponsor termination of study 
 other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made to Ora and/or 
study sponsor and will be clearly documented on the eCRF. 
 
7.4. 
Product Quality Complaints 
All product quality complaints of the OTX-DP or PV will be documented on the appropriate eCRF 
and reported to Ocular Therapeutix or designee within 24 hours. Ocular Therapeutix will advise 
whether the investigational product(s) is still suitable for use or, should be returned to the Sponsor for 
additional analysis and investigation. The product quality complaint will be included in the final 
analysis. 
7.5. 
Treatment of OTX-DP or PV 
Qualifying subjects will be randomized at Visit 4b (Day 1) to receive one of the following treatment 
arms bilaterally: 
 OTX-DP (N=40 subjects) or 
 PV (N=40 subjects) 
In the OTX-DP arm, subjects will receive OTX-DP (dexamethasone, 0.4 mg) until insert absorption 
or removal (if needed), whichever comes first. 
Randomization is at a 1:1 ratio (active:vehicle). 
7.6. 
Concomitant Medications 
A concomitant medication is any drug or substance administered from Visit 1 (Screening) through the 
last study visit, Visit 9 (Day 30). The generic name of the drug or substance, the dose, the route of 
administration, the duration of treatment (including the start and stop dates), the frequency, the 
indication, and whether or not the medication was taken due to an AE will be recorded for each drug 
or substance. 
Subjects should be instructed not to start taking any new medications, including nonprescription drugs 
and herbal preparations, unless they have received permission from the Investigator. The use of any 
concurrent medication, prescription or over-the-counter (OTC), is to be recorded on the subject’s 


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source document and corresponding eCRF along with the reason the medication was taken. 
Concurrent enrollment in another investigational product study is not permitted. 
 
7.7. 
Rescue Therapy 
Cold compress should first be used in the management of allergic symptoms. Subjects may be 
prescribed anti-inflammatory or anti-allergy medication at the Investigator’s discretion. If prescribed 
such anti-inflammatory or anti-allergy medication, the insert will not be removed and subjects will be 
followed for safety only. 
Currently marketed over-the-counter anti-allergy eye drops (i.e., anti-histamine/ vasoconstrictor 
combination products such as Visine®-A®) may be administered to subjects at the end of the subject’s 
last visit, after all evaluations are completed. 
 
7.8. 
Early Loss of Insert and Patient Follow-up 
If at any point post-insertion, the subject is experiencing discomfort or an undesirable reaction due to 
OTX-DP or PV, it may be removed per the instructions in Appendix H, and the subject should be exited 
(discontinued) at that time. 
If only 1 insert is present at any visit prior to a subject’s Exit Visit (Visit 9), that subject should 
continue in the study for safety. These subjects will not undergo the conjunctival allergen challenge 
and will therefore return for Visit 9. At this visit, the following procedures will be performed: 
 Update of Medical/Medication History 
 Assessment of Adverse Events 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart 
 Slit Lamp Examination, including punctum exam 
 Visualization of OTX-DP or PV 
 IOP Measurement 
 Dilated Fundoscopy Examination 
Intracanalicular inserts that are no longer present or removed at any point in the study will not be 
replaced. 
8. 
STUDY ASSESSMENTS 
At the screening visits (Visits 1, 2, 3a, 3b, and 4a), the subject’s eligibility for study participation will 
be determined by checking all inclusion and exclusion criteria as specified in Section 5.5. If a subject 
fails one of the inclusion or exclusion criteria the subject will be a screening failure and no further 
assessments will be done. 
Details of the procedures for these assessments can be found in the Appendices and both eyes should 
be evaluated at every visit. 
 
8.1. 
Visit 1 - Screening (Day -45 to -6) 
 Informed Consent/HIPAA: Prior to any changes in a subject’s medical treatment and/or 
study visit procedures, the study will be discussed with each subject and subjects wishing 
to participate must give written informed consent and sign a HIPAA authorization form. 


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 Demographic data: Demographic data will be recorded. 
 Allergic Skin Test (if applicable): A diagnostic test for allergic disease (skin test) will be 
performed according to Ora, Inc. SOPs if there is no documented skin test within the past 
24 months. Subjects may receive either anti-itch cream or calamine lotion (depending on 
the washout) after the skin test has been completed. 
 Medical/medication/ocular and non-ocular history: Collect and record all medical history, 
any medications and any underlying condition(s). Current underlying conditions, including 
those that began within the last sixty days, which may have been resolved before screening 
must be recorded. Record any medications the subject is taking, as well as those the subject 
may have taken but discontinued within the sixty days prior to Visit 2. 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart: Subjects must have a BCVA 
of greater than or equal to 50 ETDRS letters (20/100 Snellen equivalent or better). See 
Appendix C. 
 Review of Inclusion/Exclusion Criteria: Confirm with subjects if washout from any current 
medications and instruct them to follow the appropriate washout time periods (refer to 
Section 5.5) 
 
8.2. 
Visit 2 (Day -5+1 day) CAC screening / titration 
 Update of Medical/Medication History 
 Urine Pregnancy Test (for females of childbearing potential): Women of childbearing 
potential must have a negative urine pregnancy test to continue in the study and must agree 
to use an adequate method of contraception for the duration of the study in order to be enrolled. 
See Appendix B. 
 Note: If a female has a positive pregnancy test during the study, then the investigator 
will notify the pharmacovigilance team immediately (See Section 9.5). The investigator 
shall request from the subject and/or the subject’s physician copies of all related 
medical reports during the pregnancy and shall document the outcome of the 
pregnancy. The investigator will retain these reports together with the subject’s source 
documents and will provide a copy of all documentation to the pharmacovigilance 
team and Sponsor as required. 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: The investigator 
and the subject will assess initial ocular and nasal allergic signs and symptoms using the 
Ora-CAC® scales (see Appendix I, Appendix J and Appendix K). Subjects exhibiting signs 
and/or symptoms of allergic conjunctivitis (defined as >1 redness in conjunctival bed or 
the presence of any itching in either eye) will be excluded. 
 Slit Lamp Biomicroscopy: A slit-lamp exam, including punctum exam, will be performed 
in both eyes to exclude subjects with disallowed ocular conditions (see Appendix D). 
Findings of abnormality which are not exclusionary should be recorded as Medical 
History. 
 Review of Inclusion/Exclusion Criteria 
 Titration Conjunctival Allergen Challenge: A conjunctival allergen challenge (CAC) will 
be performed bilaterally with a perennial or seasonal allergen (serially diluted in buffered 


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saline and administered via a micropipette). One drop of a solubilized allergen to which 
the subject is sensitized, at the weakest dilution, will be instilled bilaterally into the 
conjunctival cul-de-sac. 
 If the subject fails to react within 10 (±2) minutes, increasingly concentrated doses may be 
instilled bilaterally at approximately ten-minute intervals until a positive reaction is 
elicited. If increasing doses are required (i.e., for insufficient bilateral itching as assessed 
by the subject and/or redness as evaluated by the Investigator), doses may be skipped. If a 
positive CAC reaction is not elicited with the first allergen, other allergens to which the 
subject is sensitized may be used starting at the lowest dose. 
 A positive CAC at Visit 2 is defined as a score of > 2 for redness in the conjunctival vessel 
bed of each eye and > 2 for itching in both eyes within 10 (±2) minutes of receiving that 
dose of allergen. Any subject who fails to test positively will be excluded from the study. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Upon completion 
of the CAC, subjects will receive ocular examination by the investigator to evaluate all 
investigator evaluated efficacy variables and confirm the subject’s qualification. Subjects 
will be asked to assess their ocular and nasal symptoms. 
 IOP Measurement: For subjects eliciting a positive post-CAC reaction, intraocular 
pressure (IOP) will be measured in each eye by contact tonometry. This assessment will be 
considered baseline. See Appendix E. 
 Dilated Fundoscopy Examination: For subjects eliciting a positive post-CAC reaction, a 
dilated fundoscopy examination will be performed by the Investigator to evaluate the 
presence or absence of clinically significant fundus abnormalities and vitreous pathology. 
All findings should be recorded as Medical History. This assessment will be considered 
baseline. See Appendix F. 
8.3. 
Visit 3a (Day -4+1 day) CAC confirmation #1) 
 Update of Medical/Medication History 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: The investigator 
and the subject will assess pre-CAC ocular and nasal allergic signs and symptoms using 
the Ora-CAC® scales (see Appendix I, Appendix J and Appendix K). 
 Slit Lamp Biomicroscopy: A slit lamp exam, including punctum exam, will be performed 
to exclude subjects with disallowed ocular conditions (see Appendix D). Findings of 
abnormality which are not exclusionary should be recorded as Medical History. 
 Review of Inclusion/Exclusion Criteria 
 Confirmation Conjunctival Allergen Challenge: For each qualified subject, one drop of the 
allergen solution, of the same dose that elicited a positive reaction at Visit 2, will be 
administered bilaterally. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), and 7(±1) minutes following allergen 
challenge. Assessments of redness and chemosis will be graded by the investigator and 
assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms will be made by 
the subject at 7(±1), 15(±1) and 20(±3) minutes post- challenge (see Appendix I, 
Appendix J and Appendix K). 


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8.4. 
Visit 3b (Day -4+1 day; 8 hours post V3a) CAC confirmation #2 
 Update of Medical/Medication History 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam: A slit-lamp exam, including punctum 
exam, will be performed in both eyes to exclude subjects with disallowed ocular 
conditions. Findings of abnormality which are not exclusionary should be recorded as 
Medical History. See Appendix D. 
 Review of Inclusion/Exclusion Criteria 
 Confirmation Conjunctival Allergen Challenge: For each qualified subject, one drop of the 
allergen solution, of the same dose that elicited a positive reaction at Visit 2, will be 
administered bilaterally. Challenge will occur 8 hours +1 hour following the Visit 3a 
challenge. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), and 7(±1) minutes following allergen 
challenge. Assessments of redness and chemosis will be graded by the investigator and 
assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms will be made by 
the subject at 7(±1), 15(±1) and 20(±3) minutes post- challenge (see Appendix I, 
Appendix J and Appendix K). 
8.5. 
Visit 4a (Day -3+1 day; 24±6 hours post V3a) CAC confirmation #3 
 Update of Medical/Medication History 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam: A slit-lamp exam, including punctum 
exam, will be performed in both eyes to exclude subjects with disallowed ocular 
conditions. Findings of abnormality which are not exclusionary should be recorded as 
Medical History. See Appendix D. 
 Review Inclusion and Exclusion Criteria 
 Baseline Conjunctival Allergen Challenge: For each qualified subject, one drop of the 
allergen solution, of the same dose that elicited a positive reaction at Visit 2, will be 
administered bilaterally. Challenge will occur 24±6 hours following the Visit 3a challenge. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±3) minutes post- challenge (see 
Appendix I, Appendix J and Appendix K). 
 If the subject fails to react positively (i.e., an average of ≥ 3 itching and ≥2.5 conjunctival 
redness) in both eyes after the first three post-CAC assessment time points, he/she will be 
excluded from the study. 
 Review Inclusion and Exclusion Criteria 


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8.6. 
Visit 4b (Day 1): Randomization/Insertion of OTX-DP or PV 
 Update of Medical/Medication History 
 Enrollment and Randomization: Subjects who meet entry criteria and qualify to continue 
in the study will be enrolled and randomly assigned to undergo the insertion of either 
OTX-DP or PV. Subjects will be assigned the lowest 4-digit randomization number 
available, starting with RXX01, where XX is a 2-digit site number. No randomization 
numbers will be skipped or omitted. 
 Insertion of OTX-DP or PV: The Investigator will either insert OTX-DP or PV bilaterally 
based on the randomization schedule and according to the procedures outlined in 
Appendix G. The time of insertion will be recorded. 
 Visualization of OTX-DP or PV: The Investigator will visualize correct placement of the 
intracanalicular inserts according to the procedures outlined in Appendix G. 
 Adverse Event Query: Adverse Events will be monitored after the initial attempt of 
insertion of OTX-DP or PV. All adverse events will be promptly reviewed by the 
investigator for accuracy and completeness. All adverse events will be documented on the 
appropriate eCRF. 
8.7. 
Visit 5 (Day 7; 6 days post-insertion) CAC #1 
 Update of Medical/Medication History 
 Adverse Event Query 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam. See Appendix D. 
 Visualization of OTX-DP or PV 
 Conjunctival Allergen Challenge: Each subject will receive one drop of the allergen 
solution bilaterally of the same allergen and dose that elicited a positive reaction at Visit 2. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±3) minutes post- challenge (see 
Appendix I, Appendix J and Appendix K). 
 
8.8. 
Visit 6a (Day 8; 7 days post-insertion) CAC re-challenge #2 
 Update of Medical/Medication History 
 Adverse Event Query 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam. See Appendix D. 


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 Visualization of Intracanalicular Inserts. See Appendix G. 
 Conjunctival Allergen Challenge: Each subject will receive one drop of the allergen 
solution bilaterally of the same allergen and dose that elicited a positive reaction at Visit 2. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±3) minutes post- challenge (see 
Appendix I, Appendix J and Appendix K). 
8.9. 
Visit 6b (Day 8; 8 hours from Visit 6a) CAC re-challenge #3 
 Update of Medical/Medication History 
 Adverse Event Query 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam. See Appendix D. 
 Visualization of Intracanalicular Inserts. See Appendix G. 
 Conjunctival Allergen Challenge: Each subject will receive one drop of the allergen 
solution bilaterally of the same allergen and dose that elicited a positive reaction at Visit 2. 
Challenge will occur 8 hours +1 hour following the Visit 6a challenge. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±3) minutes post- challenge (see 
Appendix I, Appendix J and Appendix K). 
 IOP Measurement. See Appendix E. 
8.10. 
Visit 7 (Day 14; 13 days post-insertion) CAC re-challenge #1 
 Update of Medical/Medication History 
 Adverse Event Query 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam. See Appendix D. 
 Visualization of OTX-DP or PV. See Appendix G. 
 Conjunctival Allergen Challenge: Each subject will receive one drop of the allergen 
solution bilaterally of the same allergen and dose that elicited a positive reaction at Visit 2. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 


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investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±3) minutes post- challenge (see 
Appendix I, Appendix J and Appendix K). 
8.11. 
Visit 8a (Day 15; 14 days post-insertion) CAC re-challenge #2 
 Update of Medical/Medication History 
 Adverse Event Query 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam. See Appendix D. 
 Visualization of Intracanalicular Inserts. See Appendix G. 
 Conjunctival Allergen Challenge: Each subject will receive one drop of the allergen 
solution bilaterally of the same allergen and dose that elicited a positive reaction at Visit 2. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±3) minutes post- challenge (see 
Appendix I, Appendix J and Appendix K). 
 
8.12. 
Visit 8b (Day 15; 8 hours from Visit 8a) CAC re-challenge #3 
 Update of Medical/Medication History 
 Adverse Event Query 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 
Pre-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment 
 Slit Lamp Biomicroscopy including punctum exam. See Appendix D. 
 Visualization of Intracanalicular Inserts. See Appendix G. 
 Conjunctival Allergen Challenge: Each subject will receive one drop of the allergen 
solution bilaterally of the same allergen and dose that elicited a positive reaction at Visit 2. 
Challenge will occur 8 hours +1 hour following the Visit 8a challenge. 
 Post-CAC Ocular and Nasal Allergic Signs and Symptoms Assessment: Assessment of 
itching will be made by the subject at 3(±1), 5(±1), 7(±1), and 10(±1) minutes following 
allergen challenge. Assessments of redness and chemosis will be graded by the 
investigator and assessments of eyelid swelling, tearing/watery eyes, and nasal symptoms 
will be made by the subject at 7(±1), 15(±1), and 20(±3) minutes post- challenge (see 
Appendix I, Appendix J and Appendix K). 
 IOP Measurement. See Appendix E. 


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8.13. 
Visit 9 (Day 30+3): Study Exit 
 Update of Medical/Medication History 
 Adverse Event Query 
 Urine Pregnancy Test: This will be given to all women of childbearing potential. See 
Appendix B. 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart. See Appendix C. 
 Slit Lamp Biomicroscopy including punctum exam. See Appendix D. 
 Visualization of Intracanalicular Inserts. See Appendix G. 
 IOP Measurement. See Appendix E. 
 Dilated Fundoscopy. See Appendix F. 
 Intracanalicular Inserts Removal: If the intracanalicular inserts are still present at this 
visit, and the subject is experiencing any symptoms related to the inserts, the Investigator 
will remove the insert(s) according to the procedures outlined in Appendix H. 
Asymptomatic subjects may leave the office at the completion of visit assessments without 
removal of inserts. 
 Relief Drop Instillation: Subjects may receive a dose of a currently marketed, topical 
ophthalmic anti-allergic agent (i.e., anti-histamine/vasoconstrictor combination products 
like Visine®-A®) as they leave the office to relieve any immediate discomfort caused by 
the allergic reaction. 
 Study Exit 
8.14. 
Early Discontinued Subjects 
Subjects may voluntarily withdraw from the study at any time. Subjects who withdraw consent or are 
withdrawn per investigator discretion will be considered early discontinued subjects and should 
complete the exit visit assessments required at Visit 9. 
8.15. 
Unscheduled Visits 
For unscheduled visits, the reason for the visit should be clearly documented on the appropriate 
eCRF, including findings from all evaluations that are completed. 
These visits may be performed in order to ensure subject safety. All information gathered at 
unscheduled visits should be recorded on the Unscheduled Visit pages of the source document and 
corresponding eCRF for randomized subjects. 
Evaluations that may be conducted at an Unscheduled Visit (as appropriate, depending on the reason 
for the visit), include: 
 Assessment of Adverse Events 
 Assessment of Concomitant Medications 
 Best Corrected Visual Acuity (BCVA) using an ETDRS chart 
 Urine Pregnancy Test (for females of childbearing potential) 
 Slit lamp Biomicroscopy including punctum examination 


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 Visualization of Intracanalicular Inserts 
 IOP Measurement 
 Dilated Fundoscopy 
If a randomized subject does not attend their scheduled visit, eCRF pages for missed visits will be 
skipped. All efforts should be made to schedule the subject for an Exit Visit (Visit 9) to complete exit 
procedures. 
Inserts that are no longer present or removed at any point in the study will not be replaced. 
9. 
ADVERSE EVENTS 
The investigator and study staff are responsible for detecting and recording AEs and SAEs, during 
scheduled safety evaluations and whenever such information is brought to their attention. This section 
of the protocol provides definitions and detailed procedures to be followed. 
During each visit, the Investigator will question the subject about adverse events using an open 
question taking care not to influence the subject’s answers, e.g. "have you noticed any change in your 
health?” 
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If an 
AE occurs, the first concern should be for the safety of the subject. If necessary, appropriate medical 
intervention should be provided. 
At the signing of the ICF, each subject must be given the names and telephone numbers of study site 
staff for reporting AEs and medical emergencies. 
9.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered 
a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product. Examples of an AE include: 
 Exacerbation of a pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
 New conditions detected or diagnosed after investigational product administration even 
though it may have been present prior to the start of the study. 
 Signs, symptoms of a drug interaction 
 Signs, symptoms of a suspected overdose of either investigational product or a concurrent 
medication (overdose per se should not be reported as an AE/SAE). 
 A laboratory abnormality occurring after the administration of the IP that results in subject 
withdrawal from the study or medical treatment or further follow-up. 
Any medical events experienced pre-treatment, resulting from protocol-mandated procedures (i.e., invasive 
procedures, modification of subject’s previous therapeutic regimen) should be captured as medical history. 


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9.2. 
Definition of a Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 The term “life-threatening” refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
 Requires in-patient hospitalization or prolongation of existing hospitalization. 
Hospitalizations for elective surgeries do not constitute an SAE. 
 Results in persistent or significant disability/incapacity. 
 Is a congenital abnormality/birth defect. 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered SAEs, such as important medical events that might not be immediately life- threatening or 
result in death or hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. 
 
9.3. 
Disease-Related Events or Outcomes Not Qualifying as AE/SAEs 
Not applicable 
 
9.4. 
Monitoring and Recording of AEs and SAEs 
9.4.1. 
Adverse Events 
Any AE experienced by the subject from Visit 4b (Randomization/Insertion) through Visit 9 (30 day 
follow-up visit) is to be recorded in the eCRF, regardless of the severity of the event or its relationship 
to study treatment. 
Any AEs already documented at a previous assessment and designated as ongoing, should be 
reviewed at subsequent visits as necessary. If these have resolved, this should be documented. 
Changes in intensity or frequency of AEs should be recorded as separate events (i.e., a new record 
started). 
 
9.4.2. 
Serious Adverse Events 
Any SAE experienced by the subject from Visit 4b (Randomization/Insertion) through Visit 9 (30 day 
follow-up visit) is to be recorded on an SAE Form, regardless of the severity of the event or its 
relationship to study treatment. 
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
 
9.4.3. 
All Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 9.2. 
 The severity of the event as defined in Section 9.7.1. 
 The relationship of the event to study treatment as defined in Section 9.7.2. 


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9.5. 
Immediate Reporting of Serious Adverse Events and Pregnancies 
In order to adhere to all applicable laws and regulations for reporting an SAE or pregnancy, the study 
site must formally notify the pharmacovigilance team within 24 hours of the study site staff becoming 
aware of the SAE or pregnancy. It is the Investigator’s responsibility to ensure that the SAE or 
pregnancy reporting information is emailed or faxed as described in Figure 2. It may be necessary for 
the pharmacovigilance team to directly communicate with the Investigator if additional information is 
required. 
After the initial SAE report, the investigator is required to proactively follow each subject and provide 
further information to the pharmacovigilance team on the subject’s condition within 24 hours. New or 
updated information will be recorded on the SAE reporting form. The updated SAE reporting form 
should be sent to the pharmacovigilance team within 24 hours as described in Figure 2. 
All additional follow-up evaluations must be reported to the pharmacovigilance team. Such data 
should be sent by fax or email (Figure 2) within 10 calendar days. All SAEs will be followed until the 
Investigator and Ocular Therapeutix agree that the event is satisfactorily resolved. 
9.6. 
Death 
The death must be recorded on the appropriate eCRF. All causes of death must be reported as SAEs. The 
Investigator should make every effort to obtain and send death certificates and autopsy reports to the 
pharmacovigilance team. 
 
Figure 2 
Reporting Information for SAEs and Pregnancies 
 
9.7. 
Evaluating AEs and SAEs 
9.7.1. 
Severity 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
 Mild 
Event is noticeable to the subject, but is easily tolerated and  
 
 
does not interfere with the subject’s daily activities 
 Moderate Event is bothersome, possibly requiring additional therapy, and 
 
 
may interfere with the subject’s daily activities 
 Severe 
Event is intolerable, necessitates additional therapy or 
 
 
alteration of therapy, and interferes with the subject’s daily activities 
For AEs that change in intensity, the start and stop date of each intensity should be recorded. 
An AE that is assessed as severe should not be confused with a SAE. An event is defined as ‘serious’ 
when it meets one of the pre-defined outcomes as described in Section 9.2 “Definition of a SAE.” 
To report initial or follow up SAE or Pregnancy information email or fax a copy of the SAE or 
Pregnancy report form to the following: 
ProPharma Group 
Email: clinicalsafety@propharmagroup.com 
Fax: +1-866-681-1063 


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9.7.2. 
Relationship to OTX-DP or PV or procedure 
The following definitions should be considered when evaluating the relationship of AEs and SAEs to the 
study treatment: 
UNRELATED 
This category applies to those (S)AEs which, after careful consideration, are 
clearly and incontrovertibly due to extraneous causes (disease, environment, 
etc.); there is no reasonable probability that the (S)AE may have been caused 
by the insertion procedure or the intracanalicular insert. If the investigator 
determines that the AE is unlikely to be related to the study drug, then this 
would be the appropriate category. 
 
RELATED 
The following criteria should be applied in considering inclusion of an (S)AE 
in this category: 
1. 
It bears a reasonable temporal relationship to the insertion procedure 
or the presence of the intracanalicular insert 
2. 
It could not be reasonably explained by the known characteristics of 
the subject’s clinical state, environmental or toxic factors or other 
factors (e.g., disease under study, concurrent disease(s) and 
concomitant medications) and modes of therapy administered to the 
subject 
3. 
It disappears or decreases on removal of the intracanalicular insert 
4. 
It follows a known pattern of response to the insertion procedure or 
the intracanalicular insert 
9.7.3. 
Expectedness of Events 
Expectedness of all AEs will be determined according to the Investigator’s Brochure (IB); as 
determined by Ocular Therapeutix, Inc. 
 
9.8. 
Pre-scheduled or Elective Procedures or Routinely Scheduled 
Treatments 
A pre-scheduled or elective procedure or routinely scheduled treatment will not be allowed during the 
study period. 
 
9.9. 
Procedures for Handling Special Situations 
9.9.1. 
Pregnancy 
Females should not become pregnant during the study period. If this occurs the subject should notify 
the Investigator immediately. The Investigator must report the pregnancy as outlined in Section 9.5. 
In addition, the Investigator or study site staff must report the outcome of the pregnancy to the 
pharmacovigilance team. 
 
9.9.2. 
Unmasking for Medical Emergencies 
In the case of a medical emergency or occurrence of an SAE, the randomization code may be un- 
masked and made available to the Investigator, Sponsor, and/or other study personnel involved in the 
conduct of the study. In the absence of medical need, the randomization code will not be available to 
the above individuals until after the study is completed and the database is locked. 


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In the event of a medical need, the Investigator will treat each subject, as medically required. If the 
Investigator feels it is necessary to unmask a subject’s treatment assignment after an emergency, the 
Investigator may call the Medical Monitor and notify the Sponsor. The treatment assignment will be 
revealed on a subject-by-subject basis with the approval of the Medical Monitor and Sponsor, this 
leaving the masking of the remaining subjects intact. 
The site will receive one emergency unmasking envelope for every product received and the 
envelopes should be stored in a secured location. The envelopes and product will both be labeled with 
the same randomization number. The envelopes are sealed and contain the unmasked treatment 
information for the corresponding study product. 
Ocular Therapeutix will make the final determination if the unmasking request will be granted. Once 
the unmasking request is granted the investigator or designee should identify and retrieve the 
emergency unmasking envelope for the given subject. The emergency unmasking envelope should be 
opened by the designated site personnel. The investigator must also indicate in source documents and 
in the eCRF that the mask was broken and provide the date, time, and reason for breaking the mask. 
Any AE or SAE associated with breaking the mask must be recorded and reported as specified in this 
protocol. 
Subjects will have the investigational product removed immediately if treatment assignment is 
unmasked. 
 
9.9.3. 
Regulatory Reporting 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Ocular Therapeutix to be associated to the study treatment administered. 
Ocular Therapeutix will report SUSARs to the appropriate authorities within the required regulatory 
timeframes. Reports of SUSARs will be made to IRBs, and Investigators, as needed. 
10. 
STATISTICAL ANALYSIS 
In general, quantitative/continuous data will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum), and qualitative/categorical data will be 
summarized using frequencies and percentages. 
 
10.1. 
Study Populations 
10.1.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population consists of all subjects who are randomized. All data will be 
included and no subjects will be excluded because of protocol violations. The ITT population will be 
analyzed as randomized and will be used for the efficacy analyses. 
10.1.2. 
Per-Protocol Population 
The Per-Protocol (PP) population is a subset of the ITT population and includes the subjects who 
completed the study through Visit 6b (Day 8; 7 days post-insertion; 8 hours from Visit 6a) with no 
major protocol violations that would impact the efficacy of the drug. This population will be analyzed 
as treated using observed data only for confirmatory analyses. 
 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
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10.1.3. 
Safety Population 
The Safety population includes all randomized subjects who received the IP. The safety population 
will be analyzed as treated and will be used for the safety analyses. No data will be excluded for any 
reason. 
 
10.2. 
Primary Efficacy Variables 
The primary efficacy variable is: 
 Ocular itching evaluated by the subject on Visit 6b (Day 8; 7 days post-insertion; 8 hours 
from Visit 6a) at 3(±1), 5(±1), and 7(±1) minutes post-CAC (0-4 scale, allowing half unit 
increments) 
10.3. 
Secondary Efficacy Variables 
Key secondary outcomes are the measures of ocular itching at 3(±1), 5(±1), and 7(±1) minutes post-
CAC at the following visits: 
 Visit 6a (Day 8; 7 days post-insertion) 
 Visit 5 (Day 7; 6 days post-insertion) 
 Visit 8b (Day 15; 14 days post-insertion; 8 hours from Visit 8a) 
 Visit 8a (Day 15; 14 days post-insertion) 
 Visit 7 (Day 14; 13 days post-insertion) 
Other secondary efficacy measures are ocular itching at Visits 5, 6a, 6b, 7, 8a, and 8b at the 10(±1) 
minutes post-CAC and the following assessments made at Visits 5, 6a, 6b, 7, 8a, and 8b at 7(±1), 
15(±1), and 20(±3) minutes post-CAC: 
 Conjunctival redness evaluated by the investigator (0-4 scale, allowing half unit 
increments) 
 Ciliary and episcleral redness evaluated by the investigator (0-4 scale, allowing half unit 
increments) 
 Chemosis evaluated by the investigator (0-4 scale, allowing half unit increments) 
 Eyelid swelling evaluated by the subject (0-3 scale, NOT allowing half unit increments) 
 Tearing/watery eyes evaluated by the subject (0-4 scale, NOT allowing half unit 
increments) 
 Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated by the 
subject (0-4 scale, NOT allowing half-unit increments) 
 Nasal symptom composite score based on the assessments of rhinorrhea, nasal pruritus, ear 
or palate pruritus, and nasal congestion (analyzed as a qualitative measure determined as 
the presence or absence of at least one nasal symptom [present/absent], and as a 
quantitative measure calculated as the sum of the four component symptom scores 
[ranging from 0 to 16]) 


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10.4. 
Statistical Hypotheses 
Statistical hypotheses for the primary efficacy endpoint of ocular itching at Visit 6b are as follows: 
H10: There is no difference in mean ocular itching scores between OTX-DP and PV treated 
subjects for at least 1 of the 3 time points during Visit 6b. 
H1a: There is a difference in mean ocular itching scores between OTX-DP and PV treated 
subjects for all 3 time points during Visit 6b. 
Similar hypotheses will be tested for the key secondary efficacy endpoints of ocular itching at Visits 
5, 6a, 7, 8a, 8b. Statistical significance will be determined using a two-sided significance level of 
0.05. 
10.5. 
Adjustment for Multiplicity 
All six sets of hypotheses described in the previous section will be tested in a hierarchical order, 
testing the primary hypotheses first (corresponding to Visit 6b), and then proceeding with the key 
secondary efficacy hypotheses in the order presented below. 
1. Visit 6b 
2. Visit 6a 
3. Visit 5 
4. Visit 8b 
5. Visit 8a 
6. Visit 7 
If at any point in the hierarchical order statistical significance is not demonstrated, testing will stop, 
and the remaining tests will be deemed not statistically significant. 
There will be no adjustment necessary for testing multiple time points within a visit, as statistical 
significance at all three post-CAC® time points are required for a visit to be deemed statistically 
significant. 
10.6. 
Sample Size 
Approximately 80 subjects will be randomized at Visit 4b in a 1:1 ratio across the two treatment arms 
(40 OTX-DP; 40 PV). Up to approximately 10 additional subjects may be enrolled to make up for any 
subjects who did not complete Visit 6b CAC procedures. 
A total of 40 subjects in each treatment arm will provide 97.0%, 99.8%, and 99.9% power to 
demonstrate a statistically significant difference in ocular itching between OTX-DP and PV treated 
subjects at each of the 3, 5, and 7 minute post-CAC time points of Visit 6b, respectively, assuming a 
treatment difference of 0.87 units at 3 minutes post-CAC, 1.08 units at 5 minutes post-CAC, and 1.13 
units at 7 minutes post-CAC; a standard deviation of 1.0 unit at all time points; and a two-sided Type 
I error of 0.05. 
Assuming independence between time points, 40 subjects per group will have at least 96.7% power to 
demonstrate a statistically significant difference over all three primary post-CAC time points at Visit 
6b for ocular itching between OTX-DP and PV treated subjects. 
10.7. 
General Imputation Methods 
Missing data for the primary efficacy variable will be imputed using Markov Chain Monte Carlo 
(MCMC) multiple imputation techniques on the ITT population, producing twenty “complete” 
(imputed) datasets which will then be analyzed separately. Results from the separate analyses on the 
twenty “complete” datasets will be combined for presentation through the use of SAS PROC 


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CONFIDENTIAL 
 
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Page 42 of 61 
 
MIANALYZE. A separate imputation model will be fit for each time point. The model will include 
variables for treatment, baseline measure, and response measure. 
For sensitivity analysis, the ITT population will also be analyzed using the following: 
 Observed data only 
 Last observation carried forward (LOCF) 
 Worst case observation (WCO) 
 Baseline observation carried forward (BOCF) 
For the LOCF imputation, only post-challenge observations within the same visit will be carried 
forward. Therefore, there must be post-challenge values available at post-baseline visits to implement 
LOCF, as pre-challenge values will not be carried forward to post-challenge values and the prior visit 
values will not be carried forward to the following visit values. Missing values post-challenge will be 
carried forward from the last observed time point within the same visit, i.e., a missing 5-minute 
observation at Visit 5b will be imputed from the 3-minute observation from Visit 5b, etc. 
For the WCO imputation, missing data due to a subject being prescribed anti-inflammatory or anti-
allergy medication will be imputed using the worst possible outcome (maximum observed value) 
from the subject’s treatment group, starting at the first time point at which a subject takes an anti-
inflammatory or anti-allergy medication. 
For the BOCF imputation, missing data post-baseline will be imputed with the corresponding time 
point baseline data from Visit 4a. 
 
10.8. 
Primary Efficacy Analyses 
The primary efficacy endpoint is ocular itching assessed at 3(±1), 5(±1), 7(±1) minutes post- CAC® 
(0-4 scale, allowing half unit increments) at Visit 6b (Day 8; 7 days post-insertion; 8 hours from Visit 
6a). The average of each subject’s eyes at each post-CAC® time point will be used as the unit of 
analysis for ocular itching. Ocular itching will be analyzed using an ANCOVA model for each post-
CAC® time point at Visit 6b, with the time appropriate post- CAC® scores at Visit 4a as a covariate 
and treatment group as the sole factor (OTX-DP compared to PV). Two-sample t-tests will be used as 
unadjusted sensitivity analyses at each 
post-CAC® time point, as well as a non-parametric Wilcoxon rank sum tests (OTX-DP compared to 
PV). At each post-CAC® time point, a two-sided significance level of α = 0.05 will be used to 
determine statistical significance of treatment differences. 
The primary efficacy analyses will be conducted on the intent-to-treat (ITT) population using the 
multiple imputation MCMC method for missing data as described previously. Sensitivity or 
supportive analyses will be performed on the ITT population using observed data only and the LOCF, 
BOCF and WCO methods. The PP population will also be analyzed using observed data only as a 
sensitivity analysis. 
10.9. 
Secondary Efficacy Analyses 
Analyses will be performed on quantitative secondary endpoints in a manner similar to the primary 
endpoint. Qualitative measures will be analyzed using a Fisher’s exact test or Chi- Square test as 
appropriate (OTX-DP compared to PV). Secondary endpoints include ocular itching (except at Visit 
6b at 3(±1), 5(±1), and 7(±1) minutes post-CAC), conjunctival redness, episcleral and ciliary redness, 
chemosis, eyelid swelling, tearing/watery eyes, rhinorrhea, nasal pruritus, ear or palate pruritus, nasal 
congestion, and a composite score (analyzed as a qualitative measure determined as the presence or 
absence of at least one nasal symptom [present/absent], and as a quantitative measure calculated as 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 43 of 61 
 
the sum of the four component symptom scores [ranging from 0 to 16]). The secondary endpoints will 
be analyzed for the ITT population with observed data only and for the PP population with observed 
data only. 
In addition, quantitative analyses will include ANCOVA models which will be run at each visit, with 
treatment, time point, and time appropriate baseline as covariates for adjustment (accounting for 
repeated measurements). Least Square Means (LS Means) for each treatment, the corresponding 95% 
confidence intervals (CIs), and the estimated treatment difference between OTX-DP and PV will be 
calculated from these ANCOVA models. 
10.10. 
Demographics and Baseline Data 
The demographic and baseline medical history data will be summarized descriptively. For 
quantitative variables, the summaries will include the number of observations, mean, standard 
deviation, median, minimum, and maximum. Qualitative variables will be summarized using counts 
and percentages. 
10.11. 
Safety Analyses 
Incidence of adverse events will be tabulated by MedDRA System Organ Class and preferred term 
within each system organ class. Slit lamp biomicroscopy, dilated fundoscopy examination, visual 
acuity, and IOP will be summarized descriptively using quantitative and qualitative summary 
statistics as appropriate. 
11. 
GENERAL INFORMATION 
11.1. 
Study Termination 
Ocular Therapeutix reserves the right to discontinue the study at any stage, with suitable written 
notice to the Investigator and the IRB/IEC and other regulatory authorities as appropriate. 
Similarly, the Investigator may withdraw from participation in the study after providing written 
notification to Ocular Therapeutix within 30 days of their intent to withdraw. However, Ocular 
Therapeutix and the Investigator will be bound by their obligation to complete the follow-up of 
subjects already treated in the clinical study. The subjects must be followed according to the clinical 
protocol and information obtained during subject follow-up shall be reported on eCRFs. 
All Serious AEs will be evaluated and if the Sponsor determines that unreasonable risk to the subject 
is possible, the study will be terminated, and all regulatory authorities and the participating 
Investigator(s) will be notified. Termination shall occur no later than 5 working days after the Sponsor 
makes this determination and no later than 15 working days after the Sponsor first provides notice of 
the effect. 
A terminated study may not be resumed without the local IRB/IEC or regulatory authority approval, 
as required. 
 
11.2. 
Monitoring 
The Investigator and the investigating center will permit authorized clinical research personnel and 
clinical study monitors assigned by Ocular Therapeutix to source verify completed eCRFs, and review 
IRB/IEC decisions, and Investigator and clinical site records at regular intervals throughout the study. 
Additionally, subject charts and clinical records will be requested and reviewed so that protocol 
adherence and source documentation can be verified. In instances where data protection regulations 
and/or institution policies prohibit the direct examination of records by the study Sponsor or 


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CONFIDENTIAL 
 
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designee(s), the Investigator will cooperate in a system of source data verification with the Sponsor. 
Further details of the study monitoring procedures will be outlined in a Monitoring Plan. 
If the monitor discovers that the Investigator is not complying with the signed Investigator 
Agreement, the protocol, or other applicable regulations, or any conditions of approval imposed by 
the reviewing IRB/IEC, the monitor will report to the Sponsor and take such steps necessary to 
promptly secure compliance. If compliance cannot be secured, investigational product shipments to 
the Investigator may be discontinued and the Investigator’s participation in the clinical study may be 
terminated. The monitor shall also require such an Investigator to dispose of or return the unused 
product, unless this action would jeopardize the rights, safety or welfare of a subject. 
11.3. 
Retention of Documentation 
The Investigator will maintain all study related documentation including all correspondence, records 
of financial interest, individual subject records, informed consent forms, all drug product 
accountability records, the protocol with any/all amendments, all correspondence with and approval 
from the IRB/IEC, the clinical study agreement, and copies of eCRFs data for 2 years after the latter 
of the following dates: 
1. The date a marketing application is approved for the drug for the indication for which it is being 
studied, or 
20. The date that the records are no longer required for purposes of supporting an application to a 
regulatory agency. 
The files may be discarded only upon notification from Ocular Therapeutix. To avoid error, the 
Investigator should contact Ocular Therapeutix before the destruction of any records and reports 
pertaining to the study to ensure they no longer need to be retained. 
 
11.4. 
Other Study Supplies 
Clarity HCG (RAC Medical Boca Raton, FL) will be used for pregnancy tests. Ora, Inc. will supply 
these pregnancy kits. 
The allergens used for the skin test and conjunctival allergen challenge (cat dander, dog dander, dust 
mites, cockroach, grasses, ragweed, and trees) will be supplied by and reconstituted by Ora, Inc. 
Relief drops will be supplied by Ora, Inc. 
 
11.5. 
Photos and Videos 
The Investigator may be asked to record before, during, and/or after IP insertion, visualization, and/or 
removal procedures and to collect photographs of the eye. The videos and photographs should be 
identified only using the subject number and subject initials and should not contain any identifiers 
such as the subject’s name or birth date. The video and photographs will be used for training, 
advertising or in scientific conferences, journals or magazines. 


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12. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS AND ADMINISTRATIVE ISSUES 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) Guidelines, and consistent with the 1996 version 
of the Declaration of Helsinki. 
12.1. 
Protection of Human Subjects 
The protection of human subjects will follow the regulations of the United States and will be the 
responsibility of the Principal Investigator. 
 
12.2. 
Compliance with Informed Consent Regulations 
An IRB/IEC approved consent form, signed and dated by both the subject and the delegated study staff 
presenting the consent, is required from each subject prior to enrollment into the study, and before any 
study specific procedures are initiated. 
If at any point during the subject’s participation in the study the Informed Consent Form requires 
revision (e.g., due to a protocol amendment or significant new safety information) it is the 
Investigator’s responsibility to ensure that the revised ICF is reviewed by Ocular Therapeutix and 
approved by the IRB/IEC. The updated IRB/IEC approved Informed Consent Form must be presented 
to the subject, and signed and dated by both the subject, and the study staff presenting the consent as 
per IRB/IEC requirements. 
 
12.3. 
Compliance with IRB/IEC Regulations 
The Investigator must obtain approval from the appropriate IRB/IEC prior to initiating the study and 
continuing review approval per IRB/IEC policy. 
12.4. 
Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the Investigator and his/her staff with adequate precautions as to ensure the 
confidentiality of the data in accordance with local, state and federal laws and regulations. 
Monitors, auditors and other authorized representatives of Ocular Therapeutix, the IRB/IEC 
approving this study, and other regulatory agencies, as appropriate, will be granted direct access to the 
study subjects’ original medical and study records for verification of the data and/or clinical trial 
procedures. 


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13. 
STORAGE AND ACCOUNTABILITY OF OTX-DP AND PV 
13.1. 
Product Storage 
OTX-DP and PV inserts must be stored in a secure area accessible only to the Investigator and his/her 
designee(s) and must be stored refrigerated between 2ºC and 8ºC. Brief excursions up to 25±2°C are 
permitted; temperature excursions should be reported to Ocular Therapeutix to determine product 
suitability for use. 
 
13.2. 
Product Accountability 
The intracanalicular insert is to be administered only by qualified Investigators in accordance with the 
protocol, and only to subjects enrolled in the study. 
13.3. 
Product Return and Disposal 
After product accountability has been verified by the monitor, unused intracanalicular inserts can be 
destroyed by following the site’s established written destruction procedures. If the site does not have 
written destruction procedures the unused product will be returned to Ocular Therapeutix at the 
completion of the study or upon request by the Sponsor. The return details will be documented on the 
accountability form. 
14. 
APPENDICES 
Appendix A – TIME AND EVENT SCHEDULE  
Appendix B – PREGNANCY TESTING 
Appendix C – VISUAL ACUITY PROCEDURES (ETDRS CHART)  
Appendix D – SLIT LAMP BIOMICROSCOPY PROCEDURES  
Appendix E – PROCEDURE FOR EVALUATING IOP 
Appendix F – DILATED FUNDOSCOPY 
Appendix G – INSERTION AND VISUALIZATION INSTRUCTIONS  
Appendix H – INSERT REMOVAL INSTRUCTIONS 
Appendix I – ALLERGEN CHALLENGE SCALES – OCULAR SYMPTOMS  
Appendix J – ALLERGEN CHALLENGE SCALES – NASAL SYMPTOMS  
Appendix K – INVESTIGATOR-EVALUATED SIGNS (OCULAR) 
 


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APPENDIX A. TIME AND EVENT SCHEDULE 
 
 
Visit 
Visit Window 
V1 
V2 
V3a 
V3b1 
V4a2 
V4b 
V5 
V6a 
V6b1 
V7 
V8a 
V8b1 
V9 
 
-45 to -6 
 
-5+1 
 
-4+1 
 
(V3a+8hrs) 
 
(V3a+24±6 
hrs) 
(2-3 
days 
post 
V3a) 
 
7 
 
8 
 
(V6a+8hrs) 
 
14 
 
15 
 
(V8a+8hrs) 
 
30+3 
Visit Day 
(Number of days post 
insertion) 
 
6 
 
7 
7 
13 
14 
14 
29-32 
PROCEDURE 
 
 
General Assessments 
 
 
Informed Consent & HIPAA 
X 
 
 
Demographic Data 
X 
 
 
Medical & Medication 
History 
X 
 
 
Update Medical & 
Medication History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Allergic Skin Test 
X 
 
 
Urine Pregnancy Test3 
X 
 
 
X 
Randomization 
X 
 
 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Allergen Challenge 
 
 
CAC 
X4 
X5 
X5 
X5 
X 
X6 
X6 
X6 
X6 
X6 
Signs and Symptoms 
Assessments7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Visual/Systems Exams 
 
 
Best Corrected Visual Acuity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Biomicroscopy 
including punctum exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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CONFIDENTIAL 
 
CLN-Protocol-0052 
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Page 48 of 61 
 
Visit 
Visit Window 
V1 
V2 
V3a 
V3b1 
V4a2 
V4b 
V5 
V6a 
V6b1 
V7 
V8a 
V8b1 
V9 
 
-45 to -6 
 
-5+1 
 
-4+1 
 
(V3a+8hrs) 
 
(V3a+24±6 
hrs) 
(2-3 
days 
post 
V3a) 
 
7 
 
8 
 
(V6a+8hrs) 
 
14 
 
15 
 
(V8a+8hrs) 
 
30+3 
Visit Day 
(Number of days post 
insertion) 
 
6 
 
7 
7 
13 
14 
14 
29-32 
Intracanalicular Insert 
Visualization 
X 
X 
X 
X 
X 
X 
X 
X 
IOP 8 
X 
 
 
X 
X 
X 
Dilated Fundoscopy 
Examination 
X 
 
 
X 
Study Therapy 
 
 
Digital Photographs/Videos9 
X 
X 
X 
X 
X 
X 
X 
X 
IP Insertion 
X 
 
 
Removal of Inserts 
 
 
X10 
Exit from Study 
 
 
X 
 
1 Visits 3b, 6b, and 8b to occur 8 hours + 1 hour after Visits 3a, 6a, and 8a respectively. 
2 Visit 4a to occur 24±6 hours after Visit 3a. 
3 At Visits 2 and 9, for all women of childbearing potential. 
4 Titration CAC 
5   Confirmatory CAC 
6   Re-challenge CAC 
7 Ocular (itching; conjunctival, episcleral, and ciliary redness; chemosis; eyelid swelling; tearing/watery eyes) and Nasal (pruritis; rhinorrhea; ear or palate 
pruritis; congestion) pre- and post- CAC 
8 Measured following the last CAC assessments when all other evaluations are complete 
9 Digital photographs and/or videos may be taken of each subject’s eyes before, during, and/or after IP insertion, visualization, and/or removal. 
10If the inserts are still present, and the subject is experiencing symptoms related to the inserts, the Investigator will remove them according to the removal 
procedures. Inserts do not need to be removed for asymptomatic subjects. 
 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 49 of 61 
 
 
 
APPENDIX B. PREGNANCY TESTING 
Female subjects of childbearing potential will have a urine pregnancy test read at the site at Visit 2 and 
Visit 9 (or Exit Visit). Pregnancy tests (Clarity HCG urine test strips, RAC Medical Boca Raton, FL) 
will be used. 
 


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Page 50 of 61 
 
APPENDIX C. VISUAL ACUITY PROCEDURES (ETDRS CHART) 
Visual acuity should be evaluated at the beginning of each study visit. Every effort should be made to 
have the same BCVA assessor throughout the study period. Visual acuity testing should be done 
starting with most recent correction. 
BCVA should be measured using a backlit ETDRS chart such as Precision Vision’s or equivalent. It is 
recommended that the site use a backlit, wall-mounted or caster stand ETDRS distance eye chart with a 
luminance of 85cd/m2 set at 4 meters from the subject. A trial lens frame, or phoropter, set at 12.0 mm 
vertex distance should be used to obtain manifest refraction measurements. If possible, final refinement 
of sphere should be done at 4 meters with a trial lens set. 
EYE CHARTS 
All distance visual acuity measurement should be made using an Illuminator Box (or equivalent) set at 
4 meters from the subject. Any subject unable to read at least 20 or more letters on the ETDRS chart at 
4 meters should be tested at 1 meter according to the instructions provided for 1 meter testing. The 
fluorescent tubes in the light box should be checked periodically for proper functioning. 
A maximum effort should be made to identify each letter on the chart. When the subject says he or she 
cannot read a letter, he or she should be encouraged to guess. If the subject identifies a letter as one of 
two letters, he or she should be asked to choose one letter and, if necessary, to guess. When it becomes 
evident that no further meaningful readings can be made, despite encouragement to read or guess, the 
examiner should stop the test for that eye. However, all letters on the last line should be attempted as 
letter difficulties vary, and the last may be the only one read correctly. The number of letters missed or 
read incorrectly should be noted. 
LogMAR VISUAL ACUITY CALCULATIONS 
The last line in which a letter is read correctly will be taken as the base logMAR reading. To this value 
will be added the number "N × 0.02" where 'N' represents the total number of letters missed up to and 
included in the last line read. This total sum represents the logMAR visual acuity for that eye. 
For example: subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 line. 
 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 
as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
 
BCVA examination should begin with the right eye (OD). The procedure should be repeated for the 
left eye (OS). 
The subject must sit for the 1-meter test. The avoidance of any head movement forward or backward is 
particularly important during this test. 
 


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APPENDIX D. SLIT LAMP BIOMICROSCOPY PROCEDURES 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal findings 
will be categorized as clinically significant (findings that may interfere with study parameters or 
otherwise confound the data as determined by the investigator) or not clinically significant (NCS). 
For any finding of “abnormal clinically significant”, the Investigator will provide any relevant 
explanation/comment on the case report form. The following will be examined: 
 Eyelids including all four punctum and surrounding area 
 Conjunctiva 
 Sclera 
 Cornea 
 Anterior chamber 
 Iris 
 Lens 
External magnification and biomicroscopy will be performed using a slit-lamp. Magnification will 
be consistent with standard clinical practice. The subject will be seated. 
 
 


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APPENDIX E. PROCEDURE FOR EVALUATING IOP 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the examiner and the 
results will be recorded in mmHg. A single measurement is made to obtain a determination of IOP. 
Reasonable efforts should be made to use the same tonometer employing the investigator’s standard 
technique throughout the study. In addition, all reasonable efforts will be made to have the same 
examiner obtain all IOP measurements for a given subject. 
 


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CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 54 of 61 
 
APPENDIX F. DILATED FUNDOSCOPY 
Dilated fundoscopy exams will be performed using direct and indirect ophthalmoscopy. The 
investigator will make observations of the vitreous, retina, macula, choroid and optic nerve. 
Observations will be graded as Normal or Abnormal. Abnormal findings that are clinically significant 
(as determined by the investigator that may interfere with trial parameters or otherwise confound the 
data) and those that are not clinically significant will be described. An indirect fundoscopy 
examination should be performed if retinal disease is detected. It is recommended that tropicamide 1% 
ophthalmic solution be used to dilate subjects. The use of cyclopentolate 1% ophthalmic solution is 
recommended as secondary dilating medication, should the need arise. 


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APPENDIX G. INSERTION AND VISUALIZATION INSTRUCTIONS 
For qualifying subjects, the Investigator will conduct an insertion of either the OTX-DP or PV as per 
the randomization list at Visit 4b (Day 1). The area of the punctum should be anesthetized with either a 
topical anesthetic instilled into the conjunctival sac or an anesthetic soaked, cotton- tipped Weck-Cel™ 
spear or equivalent held against the punctum for 30 seconds. 
The size of the punctum will be assessed utilizing a standard punctum size gauge. If the punctum is 
less than 0.7 mm wide, it should be dilated using a standard punctum dilator tool. 
To insert the OTX-DP or PV: 
Using forceps, grasp the OTX-DP or PV and insert it into the punctum as per the instructions in the 
Prescribing Information: 
Do not use if pouch has been damaged or opened. Do not re-sterilize. 
21. Carefully remove foam carrier and transfer to a clean and dry area. 
22. If necessary, dilate the punctum with an ophthalmic dilator. Care should be taken not to 
perforate the canaliculus during dilation or insertion of OTX-DP or PV. If perforation occurs, 
do not insert OTX-DP or PV. 
23. After drying the punctal area, using blunt (non-toothed) forceps, grasp OTX-DP or PV and 
insert into the lower lacrimal canaliculus. OTX-DP or PV should be placed just below the 
punctal opening. Excessive squeezing of OTX-DP or PV may cause deformation. 
24. To aid in the hydration of OTX-DP or PV, 1 to 2 drops of balanced salt solution can be instilled 
into the punctum. OTX-DP or PV hydrates quickly upon contact with moisture. If OTX-DP or 
PV begins to hydrate before fully inserted, discard the product and use a new OTX-DP or PV. 
OTX-DP or PV can be visualized when illuminated by a blue light source (e.g., slit lamp or hand held 
blue light) with yellow filter. 
Note: If protrusion or partial extrusion occurs, the intracanalicular insert may be repositioned. 
The intracanalicular inserts should rest within the canaliculus just beyond the punctal opening as 
shown Figure 3 After insertion and exposure with tear film, the inserts will rapidly hydrate and expand 
to fill the vertical portion of the canalicular cavity. 


Ocular Therapeutix, Inc. 
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CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 56 of 61 
 
Figure 3 
Placement of OTX-DP or PV in the Canaliculus 
 
 
OTX-DP or PV Presence by Visual Technique 
The Investigator will assess the presence of the insert at Visits 4b, 5, 6a, 6b, 7, 8a, 8b, and 9 by using a 
slit lamp with a blue light and yellow filter. 
 


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Rev 002: 29-October 2019 
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APPENDIX H. INSERT REMOVAL INSTRUCTIONS 
The intracanalicular inserts can be removed either via application of manual pressure or saline 
irrigation, as described below. 
Application of Manual Pressure 
1. Apply topical anesthesia 
2. Identify the insert visually through the punctum tissue. 
3. Dilate the punctum and canaliculus (if necessary) 
4. Place the blunt end of an instrument, e.g. punctum dilator or equivalent, next to the distal end of 
the insert. 
5. Apply gentle pressure by pressing on the instrument in an outward motion towards the 
punctum, until the insert is expressed out of the punctum. 
Saline Irrigation 
1. Ensure the punctum and canaliculus is sufficiently dilated. 
2. Fill a sterile syringe and fixed cannula with sterile saline. 
3. Insert the cannula into the vertical canaliculus. 
4. Insert until it stops, and simultaneously rotate the syringe horizontally. 
5. Press slowly on the syringe plunger to flush the insert. 
6. In order to help assess whether the flush is complete, it may be helpful to ask the subject to 
report when they taste saline or feel it in their nose. 


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APPENDIX I. 
APPENDIX I. ALLERGEN CHALLENGE SCALES- OCULAR 
SYMPTOMS 
Subject-Evaluated Ocular Symptoms 
 
Ora CalibraTM Conjunctival Allergen Challenge Ocular Itching Scale 
Itching: 
0 = None 
0.5 = An intermittent tickle sensation possibly localized in the corner of the eye 
1.0 = An intermittent tickle sensation involving more than just the corner of the eye 
1.5 = An intermittent all-over tickling sensation 
2.0 = A mild continuous itch (can be localized) without desire to rub 
2.5 = A moderate, diffuse continuous itch with desire to rub 
3.0 = A severe itch with desire to rub 
3.5 = A severe itch improved with minimal rubbing 
4.0 = An incapacitating itch with an irresistible urge to rub 
 
0.5 unit increments ARE allowed 
 
Ora CalibraTM Conjunctival Allergen Challenge Eyelid Swelling Scale 
Eyelid Swelling: 
0 = None 
1.0 = Mild – Detectable swelling of lower and/or upper lid 
2.0 = Moderate – Definite swelling of lower and/or upper lid 
3.0 = Severe – Swelling of lower and/or upper lid to the point that there is a decrease in the space 
between your upper and lower lids 
 
0.5 unit increments ARE NOT allowed 
 
Ora CalibraTM Conjunctival Allergen Challenge Tearing/Watery Eyes Scale 
Tearing/Watery Eyes: 
0 = None/Normal 
1 = Mild – A noticeably increased moistening of your eye 
2 = Moderate – Your eye feels “full” of water; your lashes feel a little wet 
3 = Severe – Feels like tears might drip down your face; very wet lashes 
4 = Very Severe – Tears are dripping down your face 
 
0.5 increments ARE NOT allowed 
 
Ora proprietary scales – Not for distribution without permission 
 
 
 


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Rev 002: 29-October 2019 
Page 59 of 61 
 
APPENDIX J. ALLERGEN CHALLENGE SCALES- NASAL SYMPTOMS 
Subject-Evaluated Nasal Symptoms Ora CalibraTM Rhinorrhea Scale 
Rhinorrhea (Runny Nose): 
0= None 
1= Mild (sensation of nasal mucus flowing down nasal passage; no discharge present) 
2= Moderate (may be associated with post nasal drip; nasal mucus flow more pronounced; will need 
to blow nose soon) 
3= Moderate/Severe (nasal mucus discharge requiring occasional wiping with Kleenex) 
4= Severe (uncontrolled nasal discharge; requiring frequent wiping and blowing nose) 
 
0.5 unit increments ARE NOT allowed. 
 
Ora CalibraTM Nasal Pruritus Scale 
Nasal Pruritus (Itchy Nose): 
0= None 
1= Mild (An intermittent tickle sensation) 
2= Moderate (A mild continuous itch) 
3= Moderate/Severe (A severe itch with desire to rub) 
4= Severe (Incapacitating itch with an irresistible urge to rub) 
 
0.5 unit increments ARE NOT allowed. 
 
Ora CalibraTM Ear or Palate Pruritus Scale 
Ear or Palate Pruritus (Itchy Ear or Palate): 
0= None 
1= Mild (An intermittent tickle sensation) 
2= Moderate (A mild continuous itch) 
3= Moderate/Severe (A severe itch with desire to rub) 
4= Severe (Incapacitating itch with an irresistible urge to rub) 
 
0.5 unit increments ARE NOT allowed. 
Ora CalibraTM Nasal Congestion Scale 
Nasal Congestion: 
0= None (No breathing difficulty) 
1= Mild (Some sensation of blockage) 
2= Moderate (Partial Blockage) 
3= Moderate/Severe (Significant blockage but can still breathe through nose) 
4= Severe (Cannot breathe through nose at all) 
 
0.5 unit increments ARE NOT allowed. 
 
 
Ora proprietary scales – Not for distribution without permission 
 


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CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 60 of 61 
 
APPENDIX K. INVESTIGATOR-EVALUATED SIGNS (OCULAR) 
 
Ora CalibraTM Ocular Hyperemia Scale 
Regional Redness: Hyperemia (ciliary, conjunctival, and episcleral). All evaluated separately by 
an Investigator with the slit lamp 
0 = None 
1 = Mild – Slightly dilated blood vessels; color of vessels is typically pink; can be quadrantal 2 = 
Moderate – More apparent dilation of blood vessels; vessel color is more intense (redder); involves 
the majority of the vessel bed 
3 = Severe – Numerous and obvious dilated blood vessels; in the absence of chemosis the color is deep 
red, may be less red or pink in presence of chemosis, is not quadrantic 
4 = Extremely Severe – Large, numerous, dilated blood vessels characterized by unusually severe 
deep red color, regardless of grade of chemosis, which involves the entire vessel bed 
 
0.5 unit increments ARE allowed 
 
Ora CalibraTM Chemosis Scale 
Chemosis: 
0 = None 
1.0 = Detectable only by slit lamp beam; definite separation of conjunctiva from sclera 
2.0 = Visible in normal room light; more diffuse edema 
3.0 = Conjunctival billowing at the limbus; very diffuse and noticeable 
4.0 = Severe overall billowing of conjunctiva 
 
0.5 unit increments ARE allowed 
 
 
 
Ora Proprietary Scales – Not for distribution without permission 


Ocular Therapeutix, Inc. 
CONFIDENTIAL 
 
CLN-Protocol-0052 
Rev 002: 29-October 2019 
Page 61 of 61 
 
15. 
REFERENCES 
 
Choi, S. H. and L. Bielory (2008). Late-phase reaction in ocular allergy. Curr Opin Allergy Clin 
Immunol 8(5): 438-444. 
 
Heike Schäcke, Wolf-Dietrich Döcke, Khusru Asadullah, Mechanisms involved in the side effects of 
glucocorticoids, Pharmacology & Therapeutics, Volume 96, Issue 1, October 2002, Pages 23-43, ISSN 
0163-7258, http://dx.doi.org/10.1016/S0163-7258(02)00297-8. 
 
Kersey, J. P. and D. C. Broadway (2006). Corticosteroid-induced glaucoma: a review of the literature. 
Eye (Lond) 20(4): 407-416. 
 
Leonardi A, Bogacka E, Fauquert JL, Kowalski ML, Groblewska A, Jedrzejczak-Czechowicz M, Doan 
S, Marmouz F, Demoly P, Delgado L. Ocular allergy: recognizing and diagnosing hypersensitivity 
disorders of the ocular surface. Allergy 2012; 67: 1327–1337. 
 
Leonardi, A., V. Papa, G. Milazzo and A. G. Secchi (2002). Efficacy and safety of desonide phosphate 
for the treatment of allergic conjunctivitis. Cornea 21(5): 476-481. 
 
Rhen, T. and J. A. Cidlowski (2005). Antiinflammatory action of glucocorticoids--new mechanisms for 
old drugs. N Engl J Med 353(16): 1711-1723. 
 
Rizzo, G. and S. Fiorucci (2006). PPARs and other nuclear receptors in inflammation. Curr Opin 
Pharmacol 6(4): 421-427. 
 
Wang, J. J., E. Rochtchina, A. G. Tan, R. G. Cumming, S. R. Leeder and P. Mitchell (2009). Use of 
inhaled and oral corticosteroids and the long-term risk of cataract. Ophthalmology 116(4): 652-657. 

SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN  
A Multi-Center, Randomized, Double-Masked, Vehicle Controlled Phase 
3 Study Evaluating the Efficacy and Safety of OTX-DP for the Treatment 
of Allergic Conjunctivitis Using a Modified Conjunctival Allergen 
Challenge Model (Ora-CAC®) 
 
 
 
Sponsor:   
 
Ocular Therapeutix, Inc. 
 
 
 
 
 
 
Protocol Number: 
CLN-Protocol-0052 
 
 
Author:   
 
Xiao Wang 
 
 
 
Biostatistician 
Statistics & Data Corporation 
 
Date:    
 
27 MAR 2020 
Version:  
 
1.0 
 


31 March 2020
3/31/2020
02-Apr-2020
01-APR-2020
01-A


Protocol CLN-Protocol-0052 SAP, Version 1.0 
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Table of Contents 
1. 
Introduction............................................................................................................................... 6 
2. 
Study Objectives ...................................................................................................................... 6 
2.1 Study Variables ........................................................................................................................ 6 
2.2 Primary Variables ..................................................................................................................... 6 
2.3 Secondary Variables ................................................................................................................ 6 
2.4 Safety Variables ....................................................................................................................... 7 
2.5 Statistical Hypotheses .............................................................................................................. 7 
3. 
Study Design and Procedures ................................................................................................. 7 
3.1 General Study Design .............................................................................................................. 7 
3.2 Schedule of Visits and Assessments ....................................................................................... 9 
4. 
Study Treatments ................................................................................................................... 11 
4.1 Method of Assigning Subjects to Treatment Groups ............................................................. 11 
4.2 Masking and Unmasking ........................................................................................................ 11 
5. 
Sample Size and Power Considerations ................................................................................ 12 
6. 
Data Preparation .................................................................................................................... 12 
6.1 Input Data ............................................................................................................................... 12 
6.2 Output Data ............................................................................................................................ 12 
7. 
Analysis Populations .............................................................................................................. 13 
7.1 Intent-to-Treat......................................................................................................................... 13 
7.2 Per Protocol............................................................................................................................ 13 
7.3 Safety ..................................................................................................................................... 13 
8. 
General Statistical Considerations ......................................................................................... 13 
8.1 Unit of Analysis....................................................................................................................... 13 
8.2 Missing or Inconclusive Data Handling .................................................................................. 13 
8.2.1 
Imputation of Primary and Key Secondary Efficacy Variables ....................................... 13 
8.2.2 
Imputation of Dates ........................................................................................................ 14 
8.3 Definition of Baseline ............................................................................................................. 15 
8.4 Data Analysis Conventions .................................................................................................... 15 
8.5 Adjustments for Multiplicity ..................................................................................................... 16 
9. 
Disposition of Subjects ........................................................................................................... 16 
9.1 Demographic Variables .......................................................................................................... 17 
9.2 Pretreatment Variables .......................................................................................................... 17 
10. 
Medical History and Concomitant Medications ...................................................................... 17 
10.1 Medical History ....................................................................................................................... 17 
10.2 Prior and Concomitant Medications ....................................................................................... 17 
11. 
Study Therapy Variables ........................................................................................................ 18 


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12. 
Efficacy Analyses ................................................................................................................... 18 
12.1 Primary Analysis .................................................................................................................... 18 
12.2 Secondary Analyses .............................................................................................................. 22 
12.2.1 
Key Secondary Analyses ........................................................................................... 22 
12.2.2 
Other Secondary Analyses ........................................................................................ 22 
13. 
Safety Analyses ..................................................................................................................... 23 
13.1 Adverse Events ...................................................................................................................... 23 
13.2 Best Corrected Visual Acuity  ................................................................................................. 25 
13.3 Slit-Lamp Biomicroscopy and Punctum Examination ............................................................ 25 
13.4 Intraocular Pressure (IOP) ..................................................................................................... 25 
13.5 Dilated Fundoscopy Examination........................................................................................... 25 
14. 
Interim Analyses ..................................................................................................................... 26 
15. 
Changes from Protocol-Stated Analyses ............................................................................... 26 
16. 
References .............................................................................. Error! Bookmark not defined. 
17. 
Revision History ..................................................................................................................... 26 
18. 
Tables ..................................................................................................................................... 26 
19. 
Listings ................................................................................................................................... 28 
20. 
Figures ................................................................................................................................... 29 
21. 
Appendix A ............................................................................................................................. 30 
 
 
 


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List of Abbreviations 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity 
BOCF 
Baseline Observation Carried Forward 
CAC 
Conjunctival Allergen Challenge 
CI 
Confidence Interval 
CS 
Clinically Significant 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Transfer 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
LS Means 
Least Squares Means 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
OD 
Oculus dexter (Right Eye) 
OS 
Oculus sinister (Left Eye) 
OTX-DP 
Dexamethasone Ophthalmic Insert 0.4 mg 
OU 
Oculus uterque (Both Eyes) 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
PV 
Placebo Vehicle 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics & Data Corporation 
SDTM 
Study Data Tabulation Model 
SE 
Standard Error 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WCO 
Worst Case Observation 
WHO 
World Health Organization 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol CLN-Protocol-0052, Revision 002 dated 29OCT2019. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline entitled Guidance for Industry: Structure 
and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical analysis 
methods described in the clinical protocol. If additional analyses are required to supplement the planned 
analyses described in this SAP, they may be completed and will be identified in the clinical study report. 
2. Study Objectives 
The objective of this study is to evaluate the efficacy and safety of dexamethasone ophthalmic insert 0.4 
mg (OTX-DP) when placed in the canaliculus of the eyelid for the treatment of the signs and symptoms of 
allergic conjunctivitis. 
2.1 
Study Variables 
2.2 
Primary Variables 
The primary efficacy variable is: 
• 
Ocular itching evaluated by the subject on Visit 6b (Day 8; 7 days post-insertion; 8 hours from Visit 
6a) at 3(±1), 5(±1), and 7(±1) minutes post conjunctival allergen challenge (CAC) (0-4 scale, 
allowing half unit increments). 
2.3 
Secondary Variables 
The key secondary efficacy variables include the following: 
• 
Ocular itching at the following visits at 3(±1), 5(±1), and 7(±1) minutes post-CAC: 
o 
Visit 6a (Day 8; 7 days post-insertion) 
o 
Visit 5 (Day 7; 6 days post-insertion) 
o 
Visit 8b (Day 15; 14 days post-insertion; 8 hours from Visit 8a) 
o 
Visit 8a (Day 15; 14 days post-insertion) 
o 
Visit 7 (Day 14; 13 days post-insertion) 
Other secondary efficacy measures are ocular itching at Visits 5, 6a, 6b, 7, 8a, and 8b at 10(±1) minutes 
post-CAC, and the following assessments made at Visits 5, 6a, 6b, 7, 8a, and 8b at 7(±1), 15(±1), and 
20(±3) minutes post-CAC: 


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• 
Conjunctival redness evaluated by the Investigator (0-4 scale, allowing half unit increments) 
• 
Ciliary and episcleral redness evaluated by the Investigator (0-4 scale, allowing half unit 
increments) 
• 
Chemosis evaluated by the Investigator (0-4 scale, allowing half unit increments) 
• 
Eyelid swelling evaluated by the subject (0-3 scale, NOT allowing half unit increments) 
• 
Tearing/watery eyes evaluated by the subject (0-4 scale, NOT allowing half unit increments) 
• 
Rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion evaluated by the subject 
(0-4 scale, NOT allowing half-unit increments) 
• 
Nasal symptom composite score based on the assessments of rhinorrhea, nasal pruritus, ear or 
palate pruritus, and nasal congestion (analyzed as a qualitative measure determined as the 
presence or absence of at least one nasal symptom [present/absent], and as a quantitative 
measure calculated as the sum of the four component symptom scores [ranging from 0 to 16]) 
2.4 
Safety Variables 
The safety variables include the following: 
• 
Adverse Events (AEs) (reported, elicited, and observed) 
• 
Best Corrected Visual Acuity (BCVA) using an Early Treatment of Diabetic Retinopathy Study 
(ETDRS) chart 
• 
Slit-lamp biomicroscopy, including punctum exam 
• 
Intraocular Pressure (IOP) 
• 
Dilated Fundoscopy Examination 
2.5 
Statistical Hypotheses 
The null and alternative hypotheses, based on the primary efficacy variable, are as follows: 
H10: There is no difference in mean ocular itching scores at Visit 6b (Day 8) between OTX-DP and 
placebo vehicle (PV) treated subjects for at least 1 of the 3 time points during Visit 6b. 
H1a: There is a difference in mean ocular itching scores at Visit 6b (Day 8) between OTX-DP and PV 
treated subjects for all 3 time points during Visit 6b. 
Similar hypotheses will be tested for the key secondary efficacy endpoints of ocular itching at Visits 5, 6a, 
7, 8a, 8b. Statistical significance will be determined using a two-sided significance level of 0.05. 
3. Study Design and Procedures 
3.1 
General Study Design 
This study will comprise of 13 office visits over a period of approximately 5 to 11 weeks. Visits 2, 3a, 3b, 
and 4a will be used to select a subject population that responds reproducibly to the CAC before being 
randomized at Visit 4b.  


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The series of CACs and re-challenge CACs during Visits 5, 6a, and 6b will be used for the primary efficacy 
measures at Visit 6b. Subjects will return to the office for Visits 7, 8a, and 8b for another series of CAC and 
re-challenge CACs and will return again for Visit 9 (Day 30+3) for the removal of OTX-DP or PV, if still 
present and the subject is experiencing any symptoms related to the inserts, and for final safety evaluations. 
Study visits will be referred to in all tables and listings as the scheduled visit and the planned study day 
corresponding to the visit to enable reviewers to understand the assessment timing without referring to the 
protocol visit schedule. Table 1 shows the scheduled study visits, their planned study day (note that there 
is no Day 0 and that Day 1 corresponds to the day of randomization), and the acceptable visit window for 
each study visit: 
Table 1. Study Visit Windows 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1 
Day -45 
+39 Days 
Visit 2 
Day -5 
+ 1 Day 
Visit 3a 
Day -4 
+ 1 Day 
Visit 3b 
Day -4 (8 hours post Visit 3a) 
+1 Day 
Visit 4a 
Day -3 (24 +/- 6 hours post Visit 3a) 
+1 Day 
Visit 4b 
Day 1 
2-3 Days Post Visit 3a 
Visit 5 
 Day 7 (6 days post-insertion) 
N/A 
Visit 6a 
Day 8 (7 days post-insertion) 
N/A 
Visit 6b 
Day 8 (7 days post-insertion; 8 hours post Visit 6a) 
N/A 
Visit 7 
Day 14 (13 days post-insertion) 
N/A 
Visit 8a 
Day 15 (14 days post-insertion) 
N/A 
Visit 8b 
Day 15 (14 days post-insertion; 8 hours post Visit 8a) 
N/A 
Visit 9 
Day 30 
+3 Days 


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3.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments is provided Table 2. 
Table 2. Schedule of Visits and Assessments 
Visit 
V1 
V2 
V3a 
V3b1 
V4a2 
V4b 
V5 
V6a 
V6b1 
V7 
V8a 
V8b1 
V9 
Visit Window 
 
-45 to  
-6 
-5+1 
-4+1 
(V3a+8hrs) 
(V3a+24 
±6 hrs) 
(2-3 days 
post V3a) 
7 
8 
(V6a+8hrs) 
14 
15 
(V8a+8hrs) 
30+3 
Visit Day  
(Number of days post insertion)  
 
 
 
 
 
 
6 
7 
7 
13 
14 
14 
29-32 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent & HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Update Medical & Medication 
History 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Allergic Skin Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test3  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
AE Assessment 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Allergen Challenge 
 
 
 
 
 
 
 
 
 
 
 
 
 
CAC 
 
X4 
X5 
X5 
X5 
 
X 
X6 
X6 
X6 
X6 
X6 
 
Signs and Symptoms 
Assessments7 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Visual/Systems Exams 
 
 
 
 
 
 
 
 
 
 
 
 
 
Best Corrected Visual Acuity  
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Biomicroscopy 
including punctum exam 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Intracanalicular Insert 
Visualization 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
IOP8 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Dilated Fundoscopy 
Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Study Therapy  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visit 
V1 
V2 
V3a 
V3b1 
V4a2 
V4b 
V5 
V6a 
V6b1 
V7 
V8a 
V8b1 
V9 
Visit Window 
 
-45 to  
-6 
-5+1 
-4+1 
(V3a+8hrs) 
(V3a+24 
±6 hrs) 
(2-3 days 
post V3a) 
7 
8 
(V6a+8hrs) 
14 
15 
(V8a+8hrs) 
30+3 
Visit Day  
(Number of days post insertion)  
 
 
 
 
 
 
6 
7 
7 
13 
14 
14 
29-32 
PROCEDURE 
 
 
 
 
 
 
 
 
 
 
 
 
 
Digital Photographs/Videos9 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
IP Insertion 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Removal of Inserts 
 
 
 
 
 
 
 
 
 
 
 
 
 
X10 
Exit from Study 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1  Visits 3b, 6b, and 8b to occur 8 hours + 1 hour after Visits 3a, 6a, and 8a respectively.  
2  Visit 4a to occur 24±6 hours after Visit 3a.  
3  At Visits 2 and 9, for all women of childbearing potential.  
4  Titration CAC 
5  Confirmatory CAC 
6  Re-challenge CAC 
7  Ocular (itching; conjunctival, episcleral, and ciliary redness; chemosis; eyelid swelling; tearing/watery eyes) and Nasal (pruritis; rhinorrhea; ear or 
palate pruritis; congestion) pre- and post- CAC 
8  Measured following the last CAC assessments when all other evaluations are complete 
9  Digital photographs and/or videos may be taken of each subject’s eyes before, during, and/or after IP insertion, visualization, and/or removal. 
10 If the inserts are still present, and the subject is experiencing symptoms related to the inserts, the Investigator will remove them according to the 
removal procedures.  Inserts do not need to be removed for asymptomatic subjects.   


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4. Study Treatments 
4.1 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet the entry criteria for itching and redness response to the CAC at Visits 2, 3a, 3b, and 
4a will be randomized at a 1:1 ratio (active:vehicle) at Visit 4b (Day 1) to receive one of the following 
treatment arms bilaterally: 
• 
OTX-DP (N=40 subjects) or 
• 
PV (N=40 subjects) 
4.2 
Masking and Unmasking 
In the case of a medical emergency or occurrence of a serious adverse event (SAE), the randomization 
code may be unmasked and made available to the Investigator, Sponsor, and/or other study personnel 
involved in the conduct of the study. In the absence of medical need, the randomization code will not be 
available to the above individuals until after the study is completed and the database is locked. 
In the event of a medical need, the Investigator will treat each subject, as medically required. If the 
Investigator feels it is necessary to unmask a subject’s treatment assignment after an emergency situation, 
the Investigator may call the Medical Monitor and notify the Sponsor. The treatment assignment will be 
revealed on a subject-by-subject basis with the approval of the Medical Monitor and Sponsor, leaving the 
masking of the remaining subjects intact.  
The site will receive one emergency unmasking envelope for every product received and the envelopes 
should be stored in a secured location. The envelopes and product will both be labeled with the same 
randomization number. The envelopes are sealed and contain the unmasked treatment information for the 
corresponding study product. 
Ocular Therapeutix will make the final determination if the unmasking request will be granted. Once the 
unmasking request is granted the Investigator or designee should identify and retrieve the emergency 
unmasking envelope for the given subject. The emergency unmasking envelope should be opened by the 
designated site personnel. The Investigator must also indicate in source documents and in the electronic 
case report form (eCRF) that the mask was broken and provide the date, time, and reason for breaking the 
mask. Any AE or SAE associated with breaking the mask must be recorded and reported as specified in 
this protocol. 
Subjects will have the investigational product (IP) removed immediately if treatment assignment is 
unmasked. 


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5. Sample Size and Power Considerations 
Approximately 80 subjects will be randomized at Visit 4b in a 1:1 ratio across the two treatment arms (40 
OTX-DP; 40 PV). Up to approximately 10 additional subjects may be enrolled to make up for any subjects 
who did not complete Visit 6b CAC procedures. 
A total of 40 subjects in each treatment arm will provide 97.0%, 99.8%, and 99.9% power to demonstrate 
a statistically significant difference in ocular itching between OTX-DP and PV treated subjects at each of 
the 3-, 5-, and 7-minute post-CAC time points of Visit 6b, respectively, assuming a treatment difference of 
0.87 units at 3 minutes post-CAC, 1.08 units at 5 minutes post-CAC, and 1.13 units at 7 minutes post-CAC; 
a standard deviation of 1.0 unit at all time points; and a two-sided Type I error of 0.05. 
Assuming independence between time points, 40 subjects per group will have at least 96.7% power to 
demonstrate a statistically significant difference over all three primary post-CAC time points at Visit 6b for 
ocular itching between OTX-DP and PV treated subjects. 
6. Data Preparation 
6.1 
Input Data 
Study data will be recorded on the eCRFs supplied by Statistics & Data Corporation (SDC) using IBM 
clinical,  version 2019.4.0.1. When all prerequisites for database lock have been met, the database will be 
locked. Following database lock, approval will be obtained from the Sponsor to unmask the study. Any 
changes to the database after data have been locked can only be made with the approval of the Sponsor 
in consultation with SDC.  
Final analysis will be carried out after the following have occurred: 
• 
Protocol deviations have been identified and status defined (major/minor deviations). 
• 
Analysis populations have been determined. 
• 
Database lock has occurred. 
• 
Randomized treatment codes have been unmasked. 
6.2 
Output Data 
Data from IBM clinical will be transferred to SDC Biostatistics and incorporated into standard formats 
following the Study Data Tabulation Model (SDTM). Data will then be mapped to analysis datasets using 
the Analysis Data Model (ADaM).  Both SDTM- and ADaM-formatted data will be used to create the subject 
listings, while all tables and figures will be based on the ADaM-formatted data. 
SDTM will follow the SDTM version 1.4 model and will be implemented using the SDTM Implementation 
Guide version 3.2 and the SDTM Controlled Terminology version 2016-06-24. ADaM data will follow the 
ADaM version 2.1 model and will be implemented using the ADaM Implementation Guide version 1.3. Both 
SDTM and ADaM will be validated using Pinnacle 21 version 2.2. Any discrepancies in the validation will 
be noted in reviewer’s guides accompanying the final data transfers. 


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Define.xml will be created for SDTM and ADaM using the Define-XML version 2.0 model. 
7. Analysis Populations 
7.1 
Intent-to-Treat 
The Intent-to-Treat (ITT) population consists of all subjects who are randomized. All data will be included 
and no subjects will be excluded because of protocol violations. The ITT population will be analyzed as 
randomized and will be used for the efficacy analyses. 
7.2 
Per Protocol 
The Per-Protocol (PP) population is a subset of the ITT population and includes the subjects who completed 
the study through Visit 6b (Day 8; 7 days post-insertion; 8 hours from Visit 6a) with no major protocol 
violations that would impact the efficacy of the drug. Protocol deviations will be assessed and decisions 
regarding subject evaluability will be made prior to database lock and unmasking. This population will be 
analyzed as treated using observed data only for confirmatory analyses. 
7.3 
Safety 
The Safety population includes all randomized subjects who received the IP. The Safety population will be 
analyzed as treated and will be used for the safety analyses. No data will be excluded for any reason. 
8. General Statistical Considerations 
8.1 
Unit of Analysis 
The subject will be considered the unit of analysis for all efficacy variables (e.g., itching, redness). In cases 
where data are collected for each eye, the average of both eyes of each subject will be used for statistical 
summaries and analyses. Medical history, concomitant medications, and AEs will also be collected and 
presented at the subject level. 
The eye will be considered the unit analysis for all safety variables (e.g., BCVA, IOP).  
8.2 
Missing or Inconclusive Data Handling 
8.2.1 
Imputation of Primary and Key Secondary Efficacy Variables 
The impact of missing data on the primary and key secondary efficacy endpoints will be explored using the 
following variety of missing data handling techniques: 
• 
Markov chain Monte Carlo (MCMC) multiple imputations 
• 
Last observation carried forward (LOCF) 
• 
Baseline observation carried forward (BOCF) 
• 
Worst case observation (WCO) 


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Details related to the MCMC multiple imputation procedures are included in Section 12.1 as this imputation 
method will be used for the primary efficacy analysis. The screening visits (Visit 1, Visit 2, Visit 3a, Visit 3b 
and Visit 4a) will not be imputed nor summarized in the MCMC tables. 
For the LOCF imputation, only post-challenge observations within the same visit will be carried forward. 
For example, there must be a 3-minute, post-CAC value at each visit available to implement LOCF at that 
visit. However, in the case that the 3-minute, post-CAC value is missing, only the subsequent non-missing 
assessments will be used in the analysis. The screening visits (Visit 1, Visit 2, Visit 3a, Visit 3b and Visit 
4a) will not be imputed nor summarized in the LOCF table.  
For the BOCF imputation, missing data post-baseline will be imputed with the time appropriate baseline 
data from Visit 4a. For example, if a subject’s 3-minute, post-CAC value is missing at Visit 6b, then that 
subject’s 3-minute, post-CAC value from Visit 4a will be used in its place. The screening visits (Visit 1, Visit 
2, Visit 3a, Visit 3b and Visit 4a) will not be imputed nor summarized in the BOCF table. 
For the WCO imputation, missing data due to a subject being prescribed anti-inflammatory or anti-allergy 
(rescue) medication will be imputed using the worst possible outcome (maximum observed value) from the 
subject’s treatment group at the given visit and time point, starting at the first time point at which a subject 
takes an anti-inflammatory or anti-allergy medication. No other missing data will be imputed.Specific anti-
inflammatory and anti-allergy medications triggering the WCO imputation will be identified prior to database 
lock by the study team. The screening visits (Visit 1, Visit 2, Visit 3a, Visit 3b and Visit 4a) will not be imputed 
nor summarized in the WCO table. 
8.2.2 
Imputation of Dates 
Partial or missing dates will be imputed where complete dates are required to flag data as treatment-
emergent or concomitant with treatment. Partial/missing start and end dates for AEs and concomitant 
medications will be imputed as follows: 
Partial/missing start date:  
• 
Dates with missing day only will be imputed as the 1st of the month unless the month and year are 
the same as the month and year of the first dose of study medication, in which case the missing 
day will be imputed as the first dose day of study medication.  
• 
Dates with both day and month missing will be imputed as 1 Jan unless the year is same as the 
year of first dose of study medication, in which case missing day and month will be imputed as the 
first dose day and month of study medication. 
• 
Completely missing dates will be imputed as the first dose date of study medication unless the end 
date is on or before the first dose date of study medication, in which case the missing date will be 
imputed as 1 Jan of the same year as the end date. 
Partial/missing end date:  


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• 
Dates with missing day only will be imputed as the last day of the month unless the month and year 
are the same as the month and year of the last dose of study medication, in which case missing 
day will be imputed as the last dose day of study medication.  
• 
Dates with both day and month missing will be imputed as 31 Dec unless the year is the same as 
the year of the last dose of study medication, in which case missing day and month will be imputed 
as the last dose day and month of study medication.  
• 
If the ongoing flag is missing or “Yes” then the date will not be imputed unless death date is 
available, in which case the missing date will be imputed as the death date. If ongoing is “No” then 
the missing end date will be imputed as the last dose date. 
• 
If the imputed date is after the date of death, then the end date will be set equal to the date of 
death.  
The original dates will be displayed in data listings and the imputed dates will be used in derivations only 
(study day, treatment-emergence status, etc.). 
8.3 
Definition of Baseline 
For all efficacy variables , baseline will refer to the time specific measure at Visit 4a (e.g., ocular itching at 
3 minutes post-CAC at Visit 4a will be the baseline for ocular itching at 3 minutes post-CAC at Visits 6b, 
6a, 5, 8b, 8a, and 7).  
For all safety variables, baseline is defined as the last measurement prior to the first dose of study 
medication.  
8.4 
Data Analysis Conventions 
Final data analysis will be performed by SDC after the study is completed and the database has been 
locked and released for unmasking. Statistical programming and analyses will be performed using SAS® 
version 9.4 or higher. Output will be provided in rich text format (RTF) for tables and portable document 
format (PDF) for tables, listings, and figures using landscape orientation. All study data will be listed by 
subject, treatment, and visit (as applicable) based on all randomized subjects unless otherwise specified. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported with 
the same precision as the raw values; means and medians will be presented to one additional decimal 
place than reported in the raw values. Standard deviations will be presented to two additional decimal 
places than reported in the raw values. Summaries for discrete variables will include counts and 
percentages. All percentages will be rounded to one decimal place (i.e., XX.X%). Differences between 
active treatment groups and placebo will be calculated as active minus placebo and change from baseline 
will be calculated as follow-up visit minus baseline.  


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All statistical tests will be two-sided with a significance level of 0.05 (α = 0.05) unless otherwise specified. 
Confidence intervals (CIs) for differences between treatment groups will be two-sided at 95% confidence. 
All p-values will be rounded to 4 decimal places; p-values less than 0.0001 will be presented as “<0.0001”; 
p-values greater than 0.9999 will be presented as “>0.9999.” 
Unless otherwise specified, summaries will be presented by treatment group and, where appropriate, visit. 
Listings will be sorted by treatment group, subject number, visit/time point, and parameter as applicable. 
Unscheduled visits will not be included in summaries presented by visit (i.e. unscheduled visits will not be 
mapped to the nearest scheduled visit window and will not be included in the by-visit summaries). Early 
termination visits will be summarized together with Visit 9 (Day 30; Study Exit). Scheduled visits that are 
outside of the corresponding visit window will still be included in the applicable summary; however, such 
instances may be deemed to be a major protocol deviation resulting in an exclusion from the Per-Protocol 
population analyses. Listings will include data collected at all visits, including unscheduled visits. 
8.5 
Adjustments for Multiplicity 
All six sets of hypotheses described in Section 2.5 will be tested in a hierarchical order, testing the primary 
hypotheses first (corresponding to Visit 6b), and then proceeding with the key secondary efficacy 
hypotheses in the order presented below. 
1. Visit 6b 
2. Visit 6a 
3. Visit 5 
4. Visit 8b 
5. Visit 8a 
6. Visit 7 
If at any point in the hierarchical order, statistical significance is not demonstrated, testing will stop, and the 
remaining tests will be deemed not statistically significant. 
There will be no adjustment necessary for testing multiple time points within a visit, as statistical significance 
at all three post-CAC time points is required for a visit to be deemed statistically significant. 
9. Disposition of Subjects 
Analysis populations, study completion, and withdrawal from the study will be summarized for the ITT 
population. The summary table will include the numbers of subjects randomized and included in the analysis 
populations by randomized treatment group for the ITT population and by actual treatment group for the 
PP and Safety populations. The summary table will also include the numbers of subjects who completed 
the study. The reasons for withdrawal will be summarized for the applicable subjects. Reasons for 
withdrawal will include AE, protocol deviation, lost to follow-up, consent withdrawn, Sponsor termination of 
study, Investigator decision, unsuccessful insertion, other.  


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Disposition data for all subjects in the ITT population will be presented in a listing. Protocol deviations for 
the ITT population will also be presented in a listing. 
9.1 
Demographic Variables 
Subject demographic characteristics (age, sex, ethnicity, race, and iris color) will be summarized and 
presented by treatment group. These summaries will be based on the ITT population. Percentages will be 
based on the total number of subjects in each treatment group except for iris color, which will be based on 
the total number of eyes in each treatment group. 
Age will be reported in years and calculated using the following formula: 
Age = (Informed Consent Date – Date of Birth) / 365.25, truncated as an integer 
A subject listing that includes all demographic variables will be provided. 
9.2 
Pretreatment Variables 
At Visit 1 (Day -45) a diagnostic test for allergic disease (skin test) will be performed on subjects without a 
documented skin test within the past 24 months and the pre- and post-dilation punctum size of each eye 
will also be assessed. Results from both assessments will be presented in subject listings. 
10. Medical History and Concomitant Medications 
10.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA), version 20.0.  
Non-ocular medical history will be summarized for the ITT population using discrete summary statistics and 
presented by treatment group at the subject level by System Organ Class (SOC) and Preferred Term (PT). 
Ocular medical history will be similarly summarized at the subject level. If a subject reports the same PT 
multiple times within the same SOC, that PT will only be reported once within that SOC. As with the PT, if 
a subject reports multiple conditions within the same SOC, that SOC will only be reported once. 
Percentages will be based on the number of subjects in each treatment group. In the summary, SOC will 
be listed in order of descending frequency for all subjects; PTs will be listed in order of descending 
frequency for all subjects within each SOC. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
10.2 
Prior and Concomitant Medications 
A concomitant medication is any drug or substance administered from Visit 1 (Day -45) through the last 
study visit, Visit 9 (Day 30). A prior medication is any drug or substance administered prior to Visit 1 (Day -
45). The generic name of the drug or substance, the dose, the route of administration, the duration of 
treatment (including the start and stop dates), the frequency, the indication, and whether or not the 
medication was taken due to an AE will be recorded for each drug or substance. 


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Prior and concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary 
(Enhanced B2, March 2017) and summarized to the therapeutic drug class (ATC 4 classification) and 
preferred name. If the ATC 4 classification is not provided, then the next lowest classification that is provided 
in the coding dictionary will be used. The preferred name will be defined as the active ingredient; if the 
active ingredient is not provided or includes more than two ingredients (e.g., multivitamins), then the drug 
name will be summarized as the preferred name.  
Prior and concomitant medications will be summarized for the ITT population using discrete summary 
statistics and presented by treatment group, separated out by ocular and non-ocular medications. 
Percentages will be based on the number of subjects in each treatment group. Subjects may have more 
than one medication per ATC text. At each level of subject summarization, a subject will be counted once if 
he/she reports one or more medications. In the summary, ATC classification will be listed in order of 
descending frequency for all subjects; preferred name will be listed in order of descending frequency for all 
subjects within each ATC. 
Listings of prior and concomitant medications will be generated separately for ocular and non-ocular data. 
11. Study Therapy Variables 
Punctum size (pre- and post-dilation) and exposure to IP will be summarized using quantitative descriptive 
statistics. A subject will be considered exposed to study drug as long as at least one eye has a successful 
insertion. Exposure to IP will be calculated as: End Date – Date of Insertion + 1, where the end date is 
defined as the earliest date at which the insert is not visible in both eyes, the insert is removed from both 
eyes, or study exit date. 
Ease of punctum insertion (easy/moderate/difficult), visualization (easy/moderate/difficult), and removal 
(minimal, moderate, extensive manipulation) will be presented in subject listings and summarized using 
counts and percentages. Percentages will be based on the total number of subjects in treatment group for 
the Safety population. 
Punctum size, punctum insertion, visualization, and removal will all be presented in separate listings using 
the ITT population. Procedural exclusion criteria related to the punctum assessments will be presented in 
the same listing as study inclusion and exclusion criteria. 
Data related to the CAC procedure (CAC time, qualifying allergen and dose) will be presented in a listing. 
12. Efficacy Analyses 
12.1 
Primary Analysis 
The primary efficacy variable is ocular itching evaluated by the subject at 3(±1), 5(±1), and 7(±1) minutes 
post-CAC at Visit 6b (Day 8; 8 hours from Visit 6a). Ocular itching will be evaluated using the following Ora 
CalibraTM CAC Ocular Itching Scale as defined in Appendix A. 


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The average of each subject’s eyes’ itching score at each post-CAC time point will be used as the unit of 
analysis for ocular itching. 
The primary analysis of ocular itching will be performed on the ITT population with MCMC multiple 
imputation methodology for missing data using an ANCOVA model for each post-CAC time point at Visit 
6b, with the time appropriate post-CAC itching scores at Visit 4a as a covariate and treatment group as the 
sole factor.  
For multiple imputations using MCMC, twenty “complete” (imputed) datasets will be produced and analyzed. 
Results from the analyses on the twenty “complete” datasets will be combined for presentation using SAS 
PROC MIANALYZE.  
A separate imputation model will be fit for each visit and time point. The imputation model will include 
variables for treatment, baseline measure (the time appropriate post-CAC scores at Visit 4a), and response 
measure. 
The following SAS code will be used to produce twenty “complete” datasets: 
PROC MI DATA = INDATA SEED = 59411 NIMPUTE = 20 OUT = 
OUTDATA1 MINIMUM=. 0 0 MAXIMUM=. 4 4 ROUND =. 0.25 0.25; 
BY VISIT TIME; 
MCMC INITIAL = EM; 
VAR TREATMENT BASELINE SCORE; 
RUN; 
 
where 
- INDATA is the name of the input dataset; 
- OUTDATA1 is the name of the output dataset; 
- TREATMENT is the name of the treatment group variable in numeric format; 
- BASELINE is the time appropriate post-CAC scores at Visit 4a; and 
- SCORE is the average (of right eye [OD] and left eye [OS] for each subject) ocular itching score. 
 
After obtaining twenty “complete” datasets, the following SAS code will be employed to run the 
analysis of covariance (ANCOVA) models by time point on each dataset: 
 
ODS OUTPUT SOLUTIONF = MIXPARMS LSMEANS = LS DIFFS = DIFF; 
PROC MIXED DATA = OUTDATA1; 
BY VISIT TIME _IMPUTATION_; 
CLASS TREATMENT; 
MODEL SCORE = BASELINE TREATMENT / SOLUTION; 
LSMEANS TREATMENT / PDIFF CL; 
RUN; 
 
where 
- SUBJID is the subject ID number; 


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- BASELINE is the time appropriate post-CAC scores at Visit 4a;  
- VISIT is the visit; and 
- TIME is the time point. 
 
The following SAS code will then be used to combine results across imputations for the treatment 
means and differences respectively: 
 
ODS OUTPUT PARAMETERESTIMATES = PE1; 
PROC MIANALYZE DATA = LS; 
BY VISIT TIME TREATMENT; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
RUN; 
 
ODS OUTPUT PARAMETERESTIMATES = PE2; 
PROC MIANALYZE DATA = DIFF; 
BY VISIT TIME TREATMENT; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
RUN; 
where the statement WHERE _TREATMENT=2 identifies the differences for active minus vehicle. The 
detailed code will be determined based on the final data.  
Least squares means (LS Means) for each treatment, LS Means treatment differences and corresponding 
95% CIs as estimated by the ANCOVA model will be provided. 
In addition, ANCOVA models accounting for repeated measures will be run at Visit 6b as another supportive 
analysis. This ANCOVA model will include the time appropriate post-CAC itching scores at Visit 4a as a 
covariate and treatment group and time point as factors. The LS Means for each treatment, the LS Means 
treatment difference between OTX-DP and PV, and the corresponding 95% CIs will be calculated from 
these ANCOVA models. SAS pseudo-code for the ANCOVA model accounting for repeated measures at 
Visit 6 for multiply imputed data follows (Note: the same imputation routine described above [PROC MI → 
PROC MIXED → PROC MIANALYZE] will be employed using the below PROC MIXED pseudo-code): 
PROC MIXED DATA=INDATA; 
BY VISIT _IMPUTATION_; 
CLASS SUBJID TREATMENT TIME; 
MODEL SCORE = TREATMENT TIME BASELINE; 
REPEATED TIME / SUBJECT=SUBJID TYPE=UN; 
LSMEANS TREATMENT / PDIFF CL; 
RUN; 
where INDATA is the name of the input dataset sorted by VISIT, _IMPUTATION_, SUBJID and 
TIME.  


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An unstructured variance-covariance matrix will be used for the above repeated measures model. If the 
model does not converge using the unstructured matrix, the first order autoregressive structure and the 
compound symmetry structure will be employed, in that order. 
Two-sample t-tests will also be used as unadjusted sensitivity analyses at each post-CAC time point, as 
well as non-parametric Wilcoxon rank sum tests for comparing OTX-DP and PV. Mean treatment 
differences, 95% CIs for each of the means, and 95% CIs for the mean differences will be presented for 
each post-CAC time point.  
The following SAS code will be used for the t-test: 
PROC TTEST DATA=INDATA; 
BY VISIT TIME _IMPUTATION_; 
CLASS TREATMENT; 
VAR SCORE; 
ODS OUTPUT STATISTICS = OUTPUTDF; 
RUN; 
 
PROC MIANALYZE DATA = OUTPUTDF; 
BY VISIT TIME CLASS; 
MODELEFFECTS MEAN; 
STDERR STDERR; 
RUN; 
 
The following SAS code will be used for the Wilcoxon rank sum test: 
ODS OUTPUT WILCOXONSCORES = WILCOXON (WHERE=(CLASS=:"1")); 
PROC NPAR1WAY DATA = INDATA WILCOXON;  
    BY VISIT TIME _IMPUTATION_; 
    CLASS TREATMENT;  
    VAR SCORE;  
RUN; 
 
DATA WILCOXON; 
  SET WILCOXON; 
  BY VISIT TIME; 
  MEAN = (SUMOFSCORES - EXPECTEDSUM)/N; 
  STDERR = STDDEVOFSUM/N; 
RUN; 
 
PROC MIANALYZE DATA = WILCOXON ALPHA = 0.05; 
BY VISIT TIME; 
MODELEFFECTS MEAN; 
STDERR STDERR; 
RUN; 
The ordering of the above code should be adjusted accordingly for the real data, to make sure the tests are 
performed to compare the treatment group vs. the placebo group.   


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Sensitivity or supportive analyses will be performed on the ITT population using LOCF, BOCF, and WCO 
imputations as well as observed data only (see Section 8.2.1 for additional data imputation details). The 
primary analysis will also be repeated on the PP population with observed data only. 
A line graph will be produced to show mean (+/- standard error [SE]) ocular itching score by treatment group 
(OTX-DP, PV), visit (Visit 6b, Visit 8b), and time point (3, 5, and 7 minutes post-CAC). Mean change from 
baseline (+/- SE) for each treatment arm will be presented in a similar figure. Both figures will be presented 
separately for the ITT population using observed data only. 
A listing of ocular itching scores for all subjects will also be provided. 
12.2 
Secondary Analyses 
12.2.1 Key Secondary Analyses 
The key secondary efficacy variables include ocular itching at 3(±1), 5(±1), and 7(±1) minutes post-CAC at 
visits 5 (Day 7), 6a (Day 8), 7 (Day 14), 8a (Day 15), and 8b (Day 15; 8 hours from Visit 8a).  
Ocular itching scores for these time points and visits will be analyzed in a manner similar to the primary 
analyses using the same analysis populations and imputation methodologies for missing data. All ocular 
itching scores (including both key secondary and other secondary timepoints) will be included in the listing 
for primary efficacy ocular itching scores. 
12.2.2 Other Secondary Analyses 
Other secondary efficacy variables include ocular itching at 10(±1) minutes post-CAC at visits 5 (Day 7), 
6a (Day 8), 7 (Day 14), 8a (Day 15), and 8b (Day 15; 8 hours from Visit 8a), and conjunctival redness, 
episcleral and ciliary redness, chemosis, eyelid swelling, tearing/watery eyes, rhinorrhea, nasal pruritus, 
ear or palate pruritus, and nasal congestion assessed at Visits 5 (Day 7), 6a (Day 8), 6b (Day 8; 8 hours 
from Visit 6a), 7 (Day 14), 8a (Day 15), and 8b (Day 15; 8 hours from Visit 8a) at 7(±1), 15(±1), and 
20(±3) minutes post-CAC. Scoring scales for each assessment are presented in Appendix A. 
These secondary quantitative endpoints will be analyzed in a manner similar to the primary endpoint using 
the ITT and PP populations with observed data only. Note that ocular itching at 10(±1) minutes post-CAC 
will be analyzed together with the primary efficacy ocular itching scores (including imputing missing values) 
even though it is considered a secondary variable. 
Additionally, a composite score of the presence or absence of at least one nasal symptom will be derived 
for each subject based on rhinorrhea, nasal pruritus, ear or palate pruritus, and nasal congestion scores. 
The composite score is “Present” if at least one nasal symptom is > 0, “Absent” if all symptoms are equal 
to zero, and missing if any symptoms are missing and the recorded symptoms are all equal to zero.  
The nasal composite scores will be summarized using counts and percentages for each response category 
(present, absent, missing). Nasal composite scores will be analyzed using Fisher’s exact tests and 
Cochran-Mantel-Haenszel tests (controlling for time-appropriate Visit 4a post-CAC nasal composite scores 


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and including just the “Present” and “Absent” categories)  at each time point for each of Visits 5 (Day 7) 
through 8b (Day 15).  
Nasal composite scores will also be summarized as a quantitative measure calculated as the sum of the 
four component symptom scores (ranging from 0 to 16). If any of the four component symptom scores is 
missing, then the quantitative composite score will be missing. Quantitative nasal composite scores will be 
summarized using quantitative descriptive statistics. A two-sample test will be used to compare treatment 
groups at each timepoint for each of Visits 5 (Day 7) through 8b (Day 15). 
All secondary efficacy endpoints will be presented in separate listings. 
13. Safety Analyses 
All safety analyses will be conducted using the Safety population. No inferential testing will be done for 
safety variables. 
13.1 
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with the treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an IP, whether or not related to the IP. Treatment-emergent 
adverse events (TEAE) are defined as AEs that occur after the first use of IP.  Per the protocol, only AEs 
that begin or worsen after insertion of the IP will be captured in the database for this study; therefore, TEAEs 
and AEs are equivalent in this study and will be denoted as AEs.  
All AEs will be assigned a severity grade of mild, moderate, or severe based on the following definitions: 
• Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the subject’s 
daily activities. 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with the 
subject’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and interferes 
with the subject’s daily activities. 
An AE is considered serious if, in the view of either the Investigator or Sponsor, it results in any of the 
following outcomes: 
• Death 
• A life-threatening AE 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• A congenital anomaly/birth defect 


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Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Documentation of AEs will include onset date, resolution date, location (OD, OS, both eyes [OU], non-
ocular), severity, action(s) taken, IP relationship, outcome, seriousness, reason for seriousness, 
expectedness, action taken with IP, and a description/narrative of the AE. All AEs will be coded using 
MedDRA classifications with reference to SOCs and PTs (MedDRA, version 20.0). 
An overall summary table of AEs will be presented to report the number of AEs and the numbers and 
percentage of subjects who experienced at least one AE in the following categories: 
• 
AEs 
• 
Ocular AEs 
• 
Non-Ocular AEs 
• 
SAEs 
• 
AEs by Severity 
• 
AEs Leading to Subject Withdrawal 
• 
AEs Resulting in Death 
Additional AE summary tables will be presented by treatment and for all subjects showing the number of 
AEs and the number and percentage of subjects who experienced at least one AE. These summaries will 
be presented at the subject level by SOC and PT.  If a subject reports mutliple AEs coded the same SOC 
and/or PT , that SOC and/or PT will only be reported once. For AE summaries by severity or relationship 
to IP, if a subject reports multiple AEs coded to the same PT within a given SOC, the subject will be counted 
once under the maximum (worst) severity or relationship to IP as applicable.  In the summaries, SOC will 
be listed in order of descending frequency for all subjects; PTs will be listed in order of descending 
frequency for all subjects within each SOC. These summary tables will be presented for ocular and non-
ocular AEs separately and include the following: 
• 
All AEs 
• 
All AEs suspected to be related to the IP 
• 
All SAEs suspected to be related to the IP 
• 
All AEs by Relationship to IP 
• 
All AEs by Severity 
Subject listings will be provided for all AEs, SAEs, AEs leading to death, and AEs leading to study treatment 
discontinuation. 


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13.2 
Best Corrected Visual Acuity  
The logarithm of the minimum angle of resolution (logMAR) visual acuity will be assessed at each visit 
except for Visit 4b (Day 1) using an ETDRS chart set at 4 meters from the subject. Any subject unable to 
read at least 20 or more letters on the ETDRS chart at 4 meters will be tested at 1 meter. The assessment 
is performed pre-CAC for visits when the CAC is administered. 
The observed visual acuity (at 4 meters) and change from baseline will be summarized for each eye using 
continuous descriptive statistics by visit and treatment group for the Safety population. The number and 
percentage of subjects in each treatment group with a decrease of 10 or more letters (0.2 logMAR) from 
baseline will also be summarized. 
A subject listing of visual acuity (including any 1-meter assessments) will also be produced. 
13.3 
Slit-Lamp Biomicroscopy and Punctum Examination 
A slit-lamp biomicroscopy and punctum examination of the eyelid, punctal appearance, lid apposition, 
conjunctiva, sclera, anterior chamber, cornea, iris/pupil, and lens will be performed on each eye at each 
visit except for Visit 1 (Day -45) and Visit 4b (Day 1). The assessment is performed pre-CAC for visits when 
the CAC is administered. The results will be graded as normal, abnormal not clinically significant (NCS), or 
abnormal clinically significant (CS). The results will be summarized for the Safety population using counts 
and percentages for each treatment group at each visit for each eye. Percentages will be based on the 
number of subjects in each treatment group with responses. 
A subject listing of the slit-lamp biomicroscopy parameters will also be produced. 
13.4 
Intraocular Pressure (IOP) 
Intraocular pressure will be assessed post-CAC by contact tonometry in each eye at Visits 2 (Day -5), 6b 
(Day 8), 8b (Day 15; 8 hours post Visit 8a), 9 (Day 30). The assessment is performed post-CAC for visits 
when the CAC is administered. Results will be taken from a single measurement and will be recorded in 
mmHg. 
The observed IOP and change from baseline will be summarized using continuous descriptive statistics by 
visit, treatment group, and eye for the Safety population. The number of instances where IOP ≥ 30 mmHg 
and increases 10 mmHg over baseline will also be summarized using counts and percentages.  
A subject listing of IOP will also be produced.  
13.5 
Dilated Fundoscopy Examination 
A dilated fundoscopy examination of the vitreous, optic nerve, macula, retina, and choroid will be performed 
at Visit 2 (Day -5) post-CAC and Visit 9 (Day 30). The assessment is performed post-CAC for visits when 
the CAC is administered. The results will be graded as normal, abnormal NCS, or abnormal CS.  


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The results will be summarized using counts and percentages for each treatment group and for the Safety 
population at each visit for each eye. The number and percentage of subjects showing a worsening from 
baseline will be presented for the following categories: 
• 
Normal to Abnormal (NCS) 
• 
Normal to Abnormal (CS) 
• 
Abnormal (NCS) to Abnormal (CS) 
Percentages will be based on the number of subjects in each treatment group with responses.  
A subject listing of the dilated fundoscopy parameters will also be produced. 
14. Interim Analyses 
No interim analysis is planned. 
15. Changes from Protocol-Stated Analyses 
There are no changes from the protocol-stated analyses. 
16. Revision History 
Documentation of revision to the SAP will commence after approval of the final version 1.0. 
17. Tables 
Tables that will be included in the topline delivery are shown in boldface font.  
Table Number 
Title 
Population 
14.1.1 
Subject Disposition 
ITT Population 
14.1.2 
Demographics 
ITT Population 
14.1.3.1 
Ocular Medical History 
ITT Population 
14.1.3.2 
Non-Ocular Medical History 
ITT Population 
14.1.4.1 
Ocular Prior and Concomitant 
Medications 
ITT Population 
14.1.4.2 
Non-Ocular Prior and Concomitant 
Medications 
ITT Population 
14.1.5.1 
Test Article Insertion and Removal 
Safety Population 
14.1.5.2 
Test Article Visualization 
Safety Population 
14.1.5.3 
Punctum Size Assessment 
Safety Population 
14.1.5.4 
Exposure to Test Article 
Safety Population 
14.2.1.1 
Ocular Itching – Primary Timepoints 
ITT Population with Multiple Imputation 
(MCMC) 
14.2.1.2 
Ocular Itching 
ITT Population with Multiple Imputation 
(MCMC) 
14.2.1.3 
Ocular Itching 
ITT Population with LOCF 
14.2.1.4 
Ocular Itching 
ITT Population with BOCF 
14.2.1.5 
Ocular Itching 
ITT Population with WCO 
14.2.1.6 
Ocular Itching 
ITT Population with Observed Data Only 


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14.2.1.7 
Ocular Itching 
PP Population with Observed Data Only 
14.2.2.1 
Conjunctival Redness 
ITT Population with Observed Data Only 
14.2.2.2 
Conjunctival Redness 
PP Population with Observed Data Only 
14.2.3.1 
Ciliary Redness 
ITT Population with Observed Data Only 
14.2.3.2 
Ciliary Redness 
PP Population with Observed Data Only 
14.2.4.1 
Episcleral Redness 
ITT Population with Observed Data Only 
14.2.4.2 
Episcleral Redness 
PP Population with Observed Data Only 
14.2.5.1 
Chemosis 
ITT Population with Observed Data Only 
14.2.5.2 
Chemosis 
PP Population with Observed Data Only 
14.2.6.1 
Eyelid Swelling 
ITT Population with Observed Data Only 
14.2.6.2 
Eyelid Swelling 
PP Population with Observed Data Only 
14.2.7.1 
Tearing/Watery Eyes 
ITT Population with Observed Data Only 
14.2.7.2 
Tearing/Watery Eyes 
PP Population with Observed Data Only 
14.2.8.1 
Rhinorrhea 
ITT Population with Observed Data Only 
14.2.8.2 
Rhinorrhea 
PP Population with Observed Data Only 
14.2.9.1 
Nasal Pruritus 
ITT Population with Observed Data Only 
14.2.9.2 
Nasal Pruritus 
PP Population with Observed Data Only 
14.2.10.1 
Ear or Palate Pruritus 
ITT Population with Observed Data Only 
14.2.10.2 
Ear or Palate Pruritus 
PP Population with Observed Data Only 
14.2.11.1 
Nasal Congestion 
ITT Population with Observed Data Only 
14.2.11.2 
Nasal Congestion 
PP Population with Observed Data Only 
14.2.12.1 
Nasal Composite Score – Qualitative 
ITT Population with Observed Data Only 
14.2.12.2 
Nasal Composite Score – Qualitative 
PP Population with Observed Data Only 
14.2.12.3 
Nasal Composite Score – Quantitative 
ITT Population with Observed Data Only 
14.2.12.4 
Nasal Composite Score – Quantitative 
PP Population with Observed Data Only 
14.3.1.1 
Overall Adverse Event Summary 
Safety Population 
14.3.1.2 
All Ocular Adverse Events 
Safety Population 
14.3.1.3 
All Non-Ocular Adverse Events 
Safety Population 
14.3.1.4 
All Ocular Adverse Events Suspected 
to be Related to Investigational 
Product 
Safety Population 
14.3.1.5 
All Non-Ocular Adverse Events 
Suspected to be Related to 
Investigational Product 
Safety Population 
14.3.1.6 
All Ocular Serious Adverse Events 
Suspected to be Related to 
Investigational Product 
Safety Population 
14.3.1.7 
All Non-Ocular Serious Adverse Events 
Suspected to be Related to 
Investigational Product 
Safety Population 
14.3.1.8 
All Ocular Adverse Events by Severity 
Safety Population 
14.3.1.9 
All Non-Ocular Adverse Events by 
Severity 
Safety Population 


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14.3.1.10 
All Ocular Adverse Events by 
Relationship to IP 
Safety Population 
14.3.1.11 
All Non-Ocular Adverse Events by 
Relationship to IP 
Safety Population 
14.3.2 
Visual Acuity (logMAR) 
Safety Population 
14.3.3 
Slit-Lamp Biomicroscopy and Punctum 
Examination 
Safety Population 
14.3.4 
Intraocular Pressure (mmHg) 
Safety Population 
14.3.5 
Dilated Fundus Examination 
Safety Population 
 
18. Listings 
Listing Number 
Title 
Population 
16.1.7 
Randomization Schedule 
ITT Population 
16.2.1 
Subject Disposition 
ITT Population 
16.2.2.1 
Protocol Deviations 
ITT Population 
16.2.2.2 
Inclusion, Exclusion, and Procedural Exclusion Criteria 
All Subjects 
16.2.3 
Subjects Excluded from the Per Protocol Population 
ITT Population 
16.2.4.1 
Demographics 
ITT Population 
16.2.4.2 
Ocular Medical History 
ITT Population 
16.2.4.3 
Non-Ocular Medical History 
ITT Population 
16.2.4.4 
Prior and Concomitant Ocular Medications 
ITT Population 
16.2.4.5 
Prior and Concomitant Non-Ocular Medications 
ITT Population 
16.2.4.6 
Allergic Skin Test 
ITT Population 
16.2.4.7 
Punctum Size Assessment 
ITT Population 
16.2.5.1 
Test Article Insertion 
ITT Population 
16.2.5.2 
Test Article Visualization 
ITT Population 
16.2.5.3 
Test Article Removal 
ITT Population 
16.2.5.4 
Relief Medication Instillation 
ITT Population 
16.2.5.6 
Conjunctival Allergen Challenge 
ITT Population 
16.2.6.1 
Ocular Itching 
ITT Population 
16.2.6.2 
Conjunctival Redness 
ITT Population 
16.2.6.3 
Ciliary Redness 
ITT Population 
16.2.6.4 
Episcleral Redness 
ITT Population 
16.2.6.5 
Chemosis 
ITT Population 
16.2.6.6 
Eyelid Swelling 
ITT Population 
16.2.6.7 
Tearing 
ITT Population 
16.2.6.8 
Nasal Symptoms 
ITT Population 
16.2.7.1 
Adverse Events 
ITT Population 
16.2.7.2 
Serious Adverse Events – Part 1 
ITT Population 
16.2.7.2 
Serious Adverse Events – Part 2 
ITT Population 


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16.2.7.3 
Adverse Events Leading to Death 
ITT Population 
16.2.7.4 
Adverse Events Leading to Study Treatment 
Discontinuation 
ITT Population 
16.2.8.1 
Pregnancy Test Results for Female Subjects of 
Childbearing Potential 
ITT Population 
16.2.8.2 
Visual Acuity (logMAR) 
ITT Population 
16.2.8.3 
Slit-Lamp Biomicroscopy and Punctum Examination 
ITT Population 
16.2.8.4 
Intraocular Pressure (mmHg) 
ITT Population 
16.2.8.5 
Dilated Fundus Examination 
ITT Population 
16.2.8.7 
Comments 
ITT Population 
16.2.8.8 
Digital Photographs/Videos 
ITT Population 
 
19. Figures 
Figure Number 
Title 
Population 
14.2.1.1 
Mean +/- SE Ocular Itching 
ITT Population with Multiple Imputation 
(MCMC) 
14.2.1.2 
Change from Baseline in Ocular Itching 
(Mean +/- SE) 
ITT Population with Multiple Imputation 
(MCMC) 
14.2.1.3 
Mean +/- SE Ocular Itching 
ITT Population with Observed Data Only 
14.2.1.4 
Change from Baseline in Ocular Itching 
(Mean +/- SE) 
ITT Population with Observed Data Only 


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20. Appendix A 
Ora CalibraTM Conjunctival Allergen Challenge Ocular Itching Scale 
 
Itching: 
 
0 = None 
0.5 = An intermittent tickle sensation possibly localized in the corner of the eye 
1.0 = An intermittent tickle sensation involving more than just the corner of the eye 
1.5 = An intermittent all-over tickling sensation 
2.0 = A mild continuous itch (can be localized) without desire to rub 
2.5 = A moderate, diffuse continuous itch with desire to rub 
3.0 = A severe itch with desire to rub 
3.5 = A severe itch improved with minimal rubbing 
4.0 = An incapacitating itch with an irresistible urge to rub 
0.5 unit increments ARE allowed 
 
 
Ora CalibraTM Conjunctival Allergen Challenge Eyelid Swelling Scale 
 
Eyelid Swelling: 
 
   0 = None 
1.0 = Mild – Detectable swelling of lower and/or upper lid 
2.0 = Moderate – Definite swelling of lower and/or upper lid 
3.0 = Severe – Swelling of lower and/or upper lid to the point that there is a decrease in the     space 
between your upper and lower lids 
0.5 unit increments are NOT allowed 
 
 
Ora CalibraTM Conjunctival Allergen Challenge Tearing/Watery Eyes Scale 
 
Tearing/Watery Eyes: 
 
0 = None/Normal 
1 = Mild – A noticeably increased moistening of your eye 
2 = Moderate – Your eye feels “full” of water; your lashes feel a little wet 
3 = Severe – Feels like tears might drip down your face; very wet lashes 
4 = Very Severe – Tears are dripping down your face 
0.5 increments are NOT allowed 
 
 
 
 
 
 
 
Ora proprietary scales – Not for distribution without permission


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Subject-Evaluated Nasal Symptoms 
 
Ora CalibraTM Rhinorrhea Scale 
Rhinorrhea (Runny Nose): 
 
0= None 
1= Mild (sensation of nasal mucus flowing down nasal passage; no discharge present) 
2= Moderate (may be associated with post nasal drip; nasal mucus flow more pronounced; will need to 
blow nose soon) 
3= Moderate/Severe (nasal mucus discharge requiring occasional wiping with Kleenex) 
4= Severe (uncontrolled nasal discharge; requiring frequent wiping and blowing nose) 
0.5 unit increments ARE NOT allowed. 
 
Ora CalibraTM Nasal Pruritus Scale 
Nasal Pruritus (Itchy Nose): 
0= None 
1= Mild (An intermittent tickle sensation) 
2= Moderate (A mild continuous itch) 
3= Moderate/Severe (A severe itch with desire to rub) 
4= Severe (Incapacitating itch with an irresistible urge to rub) 
0.5 unit increments ARE NOT allowed. 
 
Ora CalibraTM Ear or Palate Pruritus Scale 
Ear or Palate Pruritus (Itchy Ear or Palate): 
0= None 
1= Mild (An intermittent tickle sensation) 
2= Moderate (A mild continuous itch) 
3= Moderate/Severe (A severe itch with desire to rub) 
4= Severe (Incapacitating itch with an irresistible urge to rub) 
0.5 unit increments ARE NOT allowed. 
 
 
 
 
 
 
 
 
 
Ora Proprietary Scales – Not for distribution without permission 


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Ora CalibraTM Nasal Congestion Scale 
Nasal Congestion: 
0= None (No breathing difficulty) 
1= Mild (Some sensation of blockage) 
2= Moderate (Partial Blockage) 
3= Moderate/Severe (Significant blockage but can still breathe through nose) 
4= Severe (Cannot breathe through nose at all) 
 0.5 unit increments ARE NOT allowed. 
 
Investigator-Evaluated Signs (Ocular) 
Ora CalibraTM Ocular Hyperemia Scale 
Regional Redness: 
Hyperemia (ciliary, conjunctival, and episcleral).  All evaluated separately by 
an Investigator with the slit lamp 
 
0 = None 
1 = Mild – Slightly dilated blood vessels; color of vessels is typically pink; can be quadrantal 
2 = Moderate – More apparent dilation of blood vessels; vessel color is more intense (redder); involves 
the majority of the vessel bed 
3 = Severe – Numerous and obvious dilated blood vessels; in the absence of chemosis the color is deep 
red, may be less red or pink in presence of chemosis, is not quadrantic 
4 = Extremely Severe – Large, numerous, dilated blood vessels characterized by unusually severe deep 
red color, regardless of grade of chemosis, which involves the entire vessel bed 
0.5 unit increments ARE allowed 
 
Ora CalibraTM Chemosis Scale 
Chemosis: 
0 = None 
1.0 = Detectable only by slit lamp beam; definite separation of conjunctiva from sclera 
2.0 = Visible in normal room light; more diffuse edema 
3.0 = Conjunctival billowing at the limbus; very diffuse and noticeable 
4.0 = Severe overall billowing of conjunctiva 
0.5 unit increments ARE allowed 
 
 
 
 
 
 
Ora Proprietary Scales – Nor for distribution without permission