Clinical trial NCT04747977
Conditions: Dry Eye
Keywords: dexamethasone ophthalmic insert
Sponsor: Ocular Therapeutix, Inc.
Start date: 2021-02-12; Completion date: 2021-09-22
Enrollment: 172 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess the efficacy and safety of OTX-DED for the short-term treatment of signs and symptoms of dry eye disease.

Detailed description:
Randomized, double-masked, vehicle-controlled, phase 2 study evaluating the efficacy and safety of OTX-DED (dexamethasone intracanalicular ophthalmic insert) for the short-term treatment of signs and symptoms of Dry Eye Disease (DED). The subjects will be followed for approximately 2-3 months from screening to the last visit.

Arms: arm 1: Approximately 50 subjects arm 2: Approximately 50 subjects arm 3: Approximately 50 subjects
Interventions: intervention 1: OTX-DED intervention 2: OTX-DED intervention 3: OTX-DED
Intervention descriptions: intervention 1: 0.2mg dexamethasone ophthalmic insert intervention 2: 0.3mg dexamethasone ophthalmic insert intervention 3: Hydrogel vehicle ophthalmic insert

Protocol documents:
Prot_000.pdf: 
Ocular Therapeutix, Inc. 
OTX-DED-2020-201 
 
Version 02, 15 December 2020 
Confidential  
Page 1 of 61 
 
 
A randomized, double-masked, vehicle-controlled, phase 2 study 
to evaluate the efficacy and safety of OTX-DED (dexamethasone 
intracanalicular ophthalmic insert) for the short-term treatment 
of signs and symptoms of dry eye disease (DED) 
 
Investigational Product 
OTX-DED 
 
Version 02 
15 December 2020 
 
 
 
Sponsor 
Ocular Therapeutix, Inc. 
24 Crosby Drive 
Bedford, MA 01730 USA 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
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 prior authorization of Ocular Therapeutix, Inc. 
 
 
 
 
 


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A randomized, double-masked, vehicle-controlled, phase 2 study to evaluate the efficacy and 
safety of OTX-DED (dexamethasone intracanalicular ophthalmic insert) for the short-term 
treatment of signs and symptoms of dry eye disease (DED) 
I hereby agree to participate in the clinical investigation of OTX-DED (dexamethasone ophthalmic 
insert) for intracanalicular use sponsored by Ocular Therapeutix, (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 regulations 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 use of the investigational product and to ensure appropriate informed 
consent is obtained from all subjects prior to inclusion in this study. 
I understand that this investigation will be monitored by the Study Sponsor and/or a designee of 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 my contact for all matters related to this 
investigation is the Ocular Therapeutix Clinical Department at (781) 357-4000. 
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 investigational product with the 
understanding that 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 along with the current curriculum 
vitae of those physicians at this institution who will be using this investigational product or participating 
in this study as Sub-Investigators under my supervision. These CVs include education, training, and the 
extent and type of our relevant experience with pertinent dates and locations. I certify that I have not 
been involved in an investigation that was terminated for noncompliance at the insistence of a Study 
Sponsor, an IRB or the FDA. 
I understand that this investigation, protocol, and trial results are confidential, and I agree not to disclose 
any such information to any person other than a representative of the Study Sponsor or FDA without the 
prior written consent of the Study Sponsor. 
I will provide financial information, as indicated in 21 CFR Part 312.64(d) and 21 CFR Part 54. 
Accepted by: 
 
 
 
Principal Investigator Signature 
Date 
Printed Name 
 
          
 
 


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PROTOCOL REVISION HISTORY 
Date 
Version 
Description of Modifications 
Rationale for Modification 
09 November 2020 
01 
Original Issue 
N/A 
15 December 2020 
02 
1. Entered correct name of 
KPI-121.  
2. Added CCLRU grading 
entry criterion to Visit 2 
list. 
3. Added unanesthetized 
Schirmer to Visit 2. 
4. Added unscheduled 
visit. 
1. Corrected typographical 
errors. 
2. Item was inadvertently 
omitted from initial 
version. 
3. Added to align with the 
endpoint. 
4. Item was inadvertently 
omitted from initial 
version.  
 


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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 7 
2 
SYNOPSIS ................................................................................................................ 8 
3 
PRINCIPAL CONTACTS ..................................................................................... 16 
4 
BACKGROUND INFORMATION ....................................................................... 16 
4.1 
Dry Eye Disease (DED) .......................................................................................... 16 
4.2 
Investigational Product Rationale ......................................................................... 17 
4.3 
Nonclinical Findings ............................................................................................... 18 
4.4 
Risk-Benefit Analysis ............................................................................................. 19 
4.5 
Dose and Administration Justification .................................................................. 20 
4.6 
Compliance ............................................................................................................. 21 
4.7 
Trial Population...................................................................................................... 21 
5 
TRIAL OBJECTIVES ........................................................................................... 21 
6 
TRIAL DESIGN ..................................................................................................... 22 
6.1 
Description of Trial ................................................................................................ 22 
6.2 
Study Endpoints ..................................................................................................... 23 
6.2.1 
Efficacy Endpoints ................................................................................................. 23 
6.2.2 
Primary Efficacy Endpoints ................................................................................... 23 
6.2.2.1 
Secondary Efficacy Endpoints ................................................................................. 23 
6.2.2.2 
Exploratory Efficacy Endpoints .............................................................................. 23 
6.2.3 
Safety Evaluations .................................................................................................. 23 
6.2.4 
Supplementary Objectives ..................................................................................... 23 
6.3 
Randomization and Masking ................................................................................. 24 
6.4 
Trial Treatment ...................................................................................................... 24 
6.5 
Trial Duration......................................................................................................... 24 
6.6 
Trial Material Accountability ................................................................................ 24 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................... 25 
7.1 
Inclusion Criteria ................................................................................................... 25 
7.2 
Exclusion Criteria................................................................................................... 26 
7.3 
Entry/Randomization Criteria: ............................................................................. 28 
7.4 
Procedural Exclusion Criteria ............................................................................... 28 
7.5 
Subject Recruitment and Screening ...................................................................... 28 
7.6 
Withdrawal Criteria ............................................................................................... 29 
7.6.1 
Withdrawal Methods .............................................................................................. 29 
7.6.2 
Collection of Data from Withdrawn Subjects ....................................................... 29 
7.6.3 
Subject Replacement .............................................................................................. 29 
8 
SUBJECT TREATMENT ...................................................................................... 29 
8.1 
Treatment Regimen ................................................................................................ 29 
8.2 
Prior and Concomitant Therapy ........................................................................... 29 
8.3 
Rescue Therapy ...................................................................................................... 30 
8.4 
Study Assessments by Visit .................................................................................... 30 
8.4.1 
Visit 1 (14 ±2 days prior to Day 1) Screening/Baseline Visit ................................. 30 
8.4.2 
Visit 2 Insertion/Day 1 ............................................................................................ 31 
8.4.3 
Visit 3 (Week 1 ±2 days) ......................................................................................... 32 
8.4.4 
Visit 4 (Week 2 ±2 days) ......................................................................................... 32 


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8.4.5 
Visit 5 (Week 3 ±2 days) ......................................................................................... 32 
8.4.6 
Visit 6 (Week 4 ±3 days) ......................................................................................... 33 
8.4.7 
Final Visit 7 (Week 8±10 days) .............................................................................. 33 
8.4.8 
Unscheduled Visits ................................................................................................. 33 
9 
ADVERSE EVENTS .............................................................................................. 34 
9.1 
Definition of an Adverse Event .............................................................................. 34 
9.2 
Definition of Serious Adverse Event ...................................................................... 34 
9.3 
Disease-Related Events or Outcomes Not Qualifying as AE/SAE’s ..................... 35 
9.4 
Monitoring and Recording of AEs and SAEs ........................................................ 35 
9.4.1 
Adverse Events ....................................................................................................... 35 
9.4.2 
Serious Adverse Events .......................................................................................... 35 
9.4.3 
All Events ................................................................................................................ 35 
9.5 
Immediate Reporting of Serious Adverse Events and Pregnancies ...................... 35 
9.6 
Death ....................................................................................................................... 36 
9.7 
Evaluating AEs and SAEs ...................................................................................... 36 
9.7.1 
Severity ................................................................................................................... 36 
9.7.2 
Relationship to OTX-DED or Hydrogel Vehicle product or procedure ............... 36 
9.7.3 
Expectedness of Events........................................................................................... 37 
9.8 
Pre-scheduled or elective Procedures or Routinely Scheduled Treatments ......... 37 
9.9 
Procedures for Handling Special Situations .......................................................... 37 
9.9.1 
Pregnancy ............................................................................................................... 37 
9.9.2 
Unmasking for Medical Emergencies .................................................................... 37 
9.9.3 
Regulatory Reporting ............................................................................................. 38 
10 
STATISTICAL METHODS AND DATA ANALYSIS ......................................... 38 
10.1 
Statistical Methods ................................................................................................. 38 
10.2 
Unit of Analysis ...................................................................................................... 38 
10.3 
Sample Size Determination .................................................................................... 38 
10.4 
Statistical Significance ............................................................................................ 38 
10.5 
Trial Termination ................................................................................................... 38 
10.6 
Missing Data ........................................................................................................... 39 
10.7 
Efficacy Analyses .................................................................................................... 39 
10.8 
Safety Analyses ....................................................................................................... 40 
10.9 
Reporting Deviations .............................................................................................. 40 
10.10 
Subject Population(s) for Analysis ......................................................................... 40 
11 
STUDY MANAGEMENT AND DATA COLLECTION...................................... 40 
11.1 
Confidentiality ........................................................................................................ 40 
11.2 
Source Documents .................................................................................................. 41 
11.3 
Case Report Forms ................................................................................................. 41 
11.4 
Records Retention .................................................................................................. 41 
12 
STUDY MONITORING, AUDITING, AND INSPECTING................................ 41 
12.1 
Study Monitoring Plan ........................................................................................... 41 
13 
ETHICAL CONSIDERATIONS ........................................................................... 42 
14 
REFERENCES ....................................................................................................... 42 
 
 


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TABLE OF TABLES 
Table 1 
Safety Margins for Ocular and Systemic Toxicity ................................................ 21 
Table 2 
Treatment Assignment Paradigm .......................................................................... 22 
Table 3 
List of Prohibited/Restricted Medications ............................................................. 30 
 
 
TABLE OF FIGURES 
Figure 1 
Dexamethasone Entrapped in the Hydrogel Intracanalicular Insert ................... 17 
Figure 2 
Study Schematic ..................................................................................................... 22 
Figure 3 
Reporting Information for SAEs and Pregnancies ............................................... 36 
 
 
LIST OF APPENDICES 
Appendix 1 
Time and Events Schedule ................................................................................... 44 
Appendix 2 
VAS for Eye Dryness ............................................................................................ 46 
Appendix 3 
OSDI ..................................................................................................................... 47 
Appendix 4 
Standard Patient Evaluation of Eye Dryness (SPEED) Questionnaire .............. 49 
Appendix 5 
Investigator Rated Conjunctival Hyperemia Grade ........................................... 50 
Appendix 6 
Bulbar Conjunctival Hyperemia Photography ................................................... 51 
Appendix 7 
Corneal Fluorescein Staining (CFS) Procedure - Using NEI Scale .................... 52 
Appendix 8 
Best Corrected Visual Acuity ............................................................................... 53 
Appendix 9 
Slit Lamp Biomicroscopy and External Eye Exam Procedures ......................... 55 
Appendix 10 
Tear Film PK Sample collection .......................................................................... 56 
Appendix 11 
OTX-DED or HV Insert Suggested Placement Technique ................................. 57 
Appendix 12 
OTX-DED or HV Insert Ease of Visualization.................................................... 59 
Appendix 13 
OTX-DED or HV Insert Removal Instructions ................................................... 60 
Appendix 14 
Daily Subject Diary (For Artificial Tear Use) ..................................................... 61 
 
 
 


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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AE 
AT 
BCVA 
Adverse Event/Experience 
Artificial Tears 
Best Corrected Visual Acuity 
C 
CD 
Celsius 
Compact Disc 
CCLRU 
Cornea and Contact Lens Research Unit 
CFB 
Change from Baseline 
CFR 
CFS 
CRF 
Code of Federal Regulations 
Corneal Fluorescein Staining 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Curriculum Vitae 
DED 
Dry Eye Disease 
e 
Electronic 
EDC 
ETDRS 
Electronic Data Capture 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Scoring 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HV 
Hydrogel Vehicle Insert 
ICH 
ICF 
ID 
International Council on Harmonization  
Informed Consent Form 
Subject Identification 
IEC 
Independent Ethics Committee 
IOP 
IP 
Intraocular Pressure 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
ITT 
IUD 
KCS 
LogMAR 
Interactive Response Technology 
Intent-to-Treat 
Intra-Uterine Device 
Keratoconjunctivitis Sicca 
Logarithm of the Minimum Angle of Resolution 
NDA 
NEI 
New Drug Application 
National Eye Institute 
NSAID 
PP 
OD 
OS 
OSDI 
OTX 
OTX-DED 
Nonsteroidal Anti-Inflammatory Drug 
Per Protocol 
Right Eye 
Left eye 
Ocular Surface Disease Index 
Ocular Therapeutix 
Dexamethasone Ophthalmic Insert 
PK 
Pharmacokinetics 
QD 
quaque die (one a day) 
SAE 
Serious Adverse Event/Experience 
SUSAR 
TBUT 
tCFS 
Suspected Unexpected Serious Adverse Reactions 
Tear Film Break Up Time 
Total Corneal Fluorescein Staining 
UPT 
US 
VA 
VAS 
WOCBP 
Urine Pregnancy Test 
United States 
Visual Acuity 
Visual Analog Scale 
Women of Childbearing Potential 


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2 
SYNOPSIS 
Protocol Title 
A randomized, double-masked, vehicle-controlled phase 2 study to 
evaluate the efficacy and safety of OTX-DED (dexamethasone 
intracanalicular ophthalmic insert) for the short-term treatment of signs 
and symptoms of dry eye disease (DED) 
Protocol Number 
OTX-DED-2020-201 
Phase of Clinical Study 
2   
Investigational Products 
Name 
Dry Dimensions 
Hydrated 
Dimensions 
OTX-DED 0.2mg 
Dexamethasone 
Ophthalmic Insert 
Diameter:  0.41-
0.49mm  
Length: 2.14-2.36 
mm 
Diameter:  1.35-
1.80mm Length:  
1.8mm 
OTX-DED 0.3mg 
Dexamethasone 
Ophthalmic Insert 
Diameter: 0.44-
0.55mm 
Length: 2.14-
2.36mm 
Diameter:  1.35-
1.80 mm; Length: 
1.8mm 
Hydrogel Vehicle 
(HV) 
Insert 
Diameter: 0.38mm 
Length: 2.25mm 
Diameter: 1.5 mm; 
Length: 1.8mm 
Study Objective 
To assess the efficacy and safety of OTX-DED for the short-term 
treatment of signs and symptoms of Dry Eye Disease. 
Efficacy Endpoints 
Primary: 
 Photographic assessment of bulbar conjunctival hyperemia change 
from baseline (CFB) at 15 days (evaluated via central reading 
center). 
Secondary:  
 Severity of Eye Dryness Score (visual analogue scale [VAS]) CFB 
at 15 days   
 Frequency of Eye Dryness (VAS) CFB at 15 days. 
 Severity of Eye Dryness Score (VAS), CFB and absolute values at 
each post-baseline visit. 
 Frequency Eye Dryness Score (VAS), CFB and absolute values at 
each post-baseline visit. 
 Investigator assessment of bulbar conjunctival hyperemia CFB at 
each post-baseline visit. 
 Total Corneal Fluorescein Staining (tCFS) [National Eye Institute 
(NEI) scale], CFB and absolute values at each post-baseline visit. 
 CFS sub-regions using NEI scale, CFB and absolute values at each 
post-baseline visit. 


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 Ocular Surface Disease Index questionnaire (OSDI©) 
questionnaire, CFB and absolute values at each post-baseline visit 
(total score, each of the three domains, and individual questions). 
 SPEED questionnaire (overall score and individual questions), 
CFB at each post-baseline visit. 
Exploratory: 
 Presence of OTX-DED or HV insert at all post-baseline visits 
 Ease of insertion as assessed by the Investigator 
 Ease of visualization as assessed by the Investigator 
 Schirmer Test without anesthesia CFB  
Safety Evaluations 
 Adverse Events (Ocular and Non-ocular)  
 Best-Corrected Visual Acuity (BCVA) 
 Slit Lamp Biomicroscopy (including punctum assessment) 
 Intraocular Pressure (IOP) 
 Fundus Examination 
 Rescue artificial tear use during the study 
Pharmacokinetics (PK) 
Parameters 
Tear Film PK 
Number of 
Investigational Sites 
Approximately 15 sites in the United States (US) 
Number of Subjects 
Planned 
Approximately 150 subjects (300 eyes) will be enrolled  
Study Population 
Subjects with signs and symptoms of DED. 
Study Design and 
Overview 
This is a randomized, double-masked, vehicle-controlled, phase 2 clinical 
study designed to evaluate the efficacy and safety, of OTX-DED for the 
short-term treatment of subjects with signs and symptoms of DED. 
Approximately 150 subjects (300 eyes) will be enrolled in this study at 
approximately 15 sites in the US. Subjects will be enrolled into one of 
three arms as noted in the table below.  
Arm 
Number of 
Subjects 
(Bilateral 
insertion) 
Duration 
of IP 
Release 
OTX-DED 0.2mg Dexamethasone 
Intracanalicular Ophthalmic Insert 
50 
2 weeks 
OTX-DED 0.3mg Dexamethasone 
Intracanalicular Ophthalmic Insert 
50 
3 weeks 
Hydrogel Vehicle Intracanalicular 
Insert 
50 
N/A 


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Subjects will undergo Screening within 14 ±2 days prior to Insertion/Day 
1 (Visit 2).  At Visit 2 (Insertion/Day 1) subjects confirmed to be eligible 
will be randomly assigned to one of three treatment groups (OTX-DED 
0.2 mg, OTX-DED 0.3 mg, or HV) in a 1:1:1 ratio.  OTX-DED or HV 
insert, as applicable, will be placed bilaterally, into either the superior or 
inferior canaliculus (per investigator’s preference).  The treatment follow-
up visits will occur at Week 1/Day 8 (Visit 3), Week 2/Day 15 (Visit 4), 
Week 3/Day 22 (Visit 5) and Week 4/day 29 (Visit 6).  All subjects will be 
followed until Week 8/Day 57 (Visit 7) to evaluate whether or not the 
insert is visualized.   
Inclusion Criteria 
Subjects will be eligible for study participation if they: 
1. Provide written informed consent prior to performing any study 
procedures and are willing to comply with study requirements and 
the study visit schedule. 
2. Are 18 years of age or older. 
3. Have a self-reported history or clinically confirmed diagnosis of 
DED by an eye care professional in both eyes for ≥6 months. 
4. Have ongoing DED, at screening visit as defined by the following 
criteria: 
a. VAS Eye Dryness severity score ≥ 40. 
And in the same qualifying eye or both eyes: 
b. Investigator assessment of bulbar conjunctival hyperemia 
grade ≥ 2 (CCLRU; 0 – 4 scale). 
c.  Unanesthetized Schirmer of > 0 and ≤ 10 mm. 
5. Have corrected visual acuity better than or equal to logarithm of 
the minimum angle of resolution (logMAR), +0.7 as assessed with 
Early Treatment of Diabetic Retinopathy Study (ETDRS) charts in 
both eyes. 
6. Are women of childbearing potential (WOCBP) who are non-
pregnant, non-lactating, and sexually inactive (abstinent) for 14 
days prior to screening and are willing to remain so through the 
last study visit. Alternatively, WOCBP who are not abstinent must 
have been using one of the following acceptable methods of birth 
control for the times specified: 
a. Intra-uterine device (IUD) in place for at least 3 months 
prior to screening and the desire to continue this method 
through the last study visit. 
b. Barrier method (condom or diaphragm) with spermicide for 
at least 14 days prior to screening and the desire to 
continue this method through the last study visit. 
c. Stable hormonal contraceptive for at least 3 months prior to 


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screening and the desire to continue this method through 
the last study visit. 
d. Surgical sterilization (vasectomy) of partner for at least 6 
months prior to Day 1. 
e. Alternatively, are post-menopausal women (i.e. no 
menstrual cycle for at least one year prior to Visit 
1/Screening) or are women who have undergone one of the 
following sterilization procedures at least 6 months prior to 
screening: 
i. Bilateral tubal ligation 
ii. Hysterectomy 
iii. Bilateral oophorectomy 
7. Agree to the removal of non-dissolvable punctal plugs 4 weeks 
prior to the insertion visit (Day 1, Visit 2) and long-term 
dissolvable punctal plugs were not placed within 4 months prior to 
insertion visit (Day 1, Visit 2) and short-term dissolvable punctual 
plugs were not be placed within 6 weeks prior to insertion (Day 1, 
Visit 2). 
8. Agree to restrict the use of artificial tears (AT) through Day 29 of 
the trial. 
Pre-Procedural Exclusion 
Criteria 
Subjects are not eligible for study participation if they: 
1. Have a known or suspected allergy to any component of the study 
product. 
2. Are unwilling to discontinue use of contact lenses for 4 weeks prior to 
the screening visit and throughout the study period. 
3. Have any active systemic disease and/or systemic infection (e.g., fever 
or current antibiotic use), or uncontrolled medical condition that in the 
judgment of the investigator could confound study assessments or 
limit compliance. 
4. Have a documented history of ocular allergies, which, in the judgment 
of the investigator, are likely to have an acute increase in severity 
during the duration of this trial. Subjects sensitive to seasonal 
allergens that are not expected to be present during the study are 
permitted. 
5. Have a history of neuropathic pain related to dry eye. 
6. Have corneal erosive disease (e.g., multiple filaments, recurrent 
erosion syndrome) or other conditions suggestive of extensive damage 
of the cornea. 
7. Have a history of glaucoma or ocular hypertension or have intraocular 
pressure (IOP) < 5 mmHg or > 24 mmHg or a history of elevated IOP 
within the past 6 months prior to the screening visit.  


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8. Have abnormal lid anatomy that may confound study data, in the 
judgement of the investigator. 
9. Have a diagnosis of any of the following: 
a. Active ocular infection 
b. In the judgement of the investigator uncontrolled anterior 
blepharitis or posterior blepharitis or blepharitis requiring the use 
of systemic or antibiotic therapy.   
c. Uveitis 
d.  Moderate to severe pinguecula or pterygia, in the judgement of the 
investigator 
e. Stevens-Johnson syndrome 
f. Mucous membrane pemphigoid 
g. Significant conjunctival scarring, in the judgement of the 
investigator 
h. Chemical burn 
i. Herpetic or neurotrophic keratitis 
j. Congenitally absent lacrimal gland or meibomian glands 
k. Nasolacrimal duct obstruction in either eye 
10. Have had penetrating intraocular surgery within 6 months or require 
penetrating intraocular surgery during the study, eyelid surgery within 
6 months, corneal laser refractive surgery within the last 1 year, 
cauterization of the punctum resulting in complete occlusion of both 
punctum in both eyes, glaucoma surgery or corneal transplantation 
(full thickness, anterior or posterior) 
11. Have taken any of the following in either eye within 30 days prior to 
the screening visit: 
a. Topical ocular corticosteroids 
b. Topical ocular antibiotics 
c. Topical ocular NSAID 
d. Topical ocular antihistamines and/or mast cell stabilizers 
e. Topical ocular or nasal vasoconstrictors 
f. Topical ocular cyclosporine (e.g., Cequa®, Restasis®) 
g. Lifitegrast (Xiidra®) 
h. Autologous tears  
i. Intranasal Tear Neurostimulation 
12. Have taken any of the following in either eye prior to the screening 
visit: 


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a. Periocular injection of any corticosteroid solution – 3 months 
b. Corticosteroid intra-vitreal depot injection– 3 months 
c. Ozurdex– 6 months 
d. Retisert– 40 months 
13. Have altered the dose of the following within 30 days prior to the 
screening visit (i.e., should keep dose stable throughout the study): 
a. Nutraceuticals or multivitamins 
b. Tetracycline compounds (tetracycline, doxycycline or 
minocycline) 
c. Inhaled, intramuscular or intra-articular corticosteroids (mouth or 
nasal spray form), or dermatological steroids (use is allowed if 
applied to <4 locations for < 4 continuous days). 
14. Have altered the dose of the following within 6 months prior to the 
screening visit (i.e., should keep dose stable throughout the study): 
a. Systemic anticholinergics 
b. Antidepressants (with the exception of rare usage as a sleep aid) 
c. Oral corticosteroids (e.g., prednisone. Prednisone dose must be less 
than 11 mg/day) 
15. Have taken isotretinoin (Accutane) or systemic immunosuppressive 
agents within 6 months prior to the screening visit. 
16. Have participated in any other investigational study within 30 days of 
the screening visit or plans to participate in any other investigational 
study during the follow-up period. 
17. Are an employee of the site or an immediate family member of an 
employee of the site. 
18. Are a current smoker (including marijuana, cigar, cigarette, and/or 
e-cigarettes). 
19. Have a known history of alcohol and/or drug abuse or are currently 
using illicit drugs or plan to use illicit drugs for the duration of the 
study. Recreational or medicinal marijuana allowed if oral 
consumption (no inhaled use). 
20. Are unwilling or unable to comply with the study protocol. 
21. The Investigator determines that the subject should not be included for 
reasons not already specified (e.g., systemic, behavioral, or other 
ocular disease/abnormality) if the health of the subject or the validity 
of the study outcomes may be compromised by the subject’s 
enrollment. 
Entry/Randomization 
Criteria 
To qualify for insertion at Day 1 (Visit 2), a subject must continue to meet 
all screening inclusion/exclusion criteria with the following 


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exceptions/additions: 
1. VAS Eye Dryness severity score ≥35. 
2. Investigator assessment of bulbar conjunctival hyperemia grade ≥ 2 
(CCLRU; 0 – 4 scale). 
3. Subjects must not have taken prohibited medications and have 
completed the appropriate washout of prior medications, if necessary.   
4. Subjects who require rescue AT must not have administered > 3 
time/day for 3 consecutive days during the washout period. NOTE:  
AT use is not permitted unless absolutely necessary as rescue therapy.  
If subject requires rescue AT and has administered >3 times/ for 3 
days during the Screening period, they are not eligible for 
randomization.  
Procedural Exclusion 
Criteria 
Subjects are considered procedural screen failures if the investigator is 
unsuccessful at placing the OTX-DED or HV Intracanalicular Ophthalmic 
insert in both eyes (i.e. neither eye has an insert). Subject will be followed 
per protocol if the investigator successfully places one insert.  
Rescue Therapy 
Preservative-free AT will be supplied by the sponsor and will be provided 
only as rescue therapy if absolutely required.  If AT is administered, 
subjects will be instructed not to administer AT within 2 hours prior to any 
study visit. Preservative-free AT use if needed will be recorded by 
subjects in a daily diary. 
Sample Size 
Considerations 
This study is not powered to show statistical significance but will provide 
initial estimates and trends of the endpoints for use in future trial designs.  
Statistical analyses will be descriptive. 
Statistical Methods 
Summaries for continuous variables will include the sample size, mean, 
standard deviation, median, minimum and maximum.  Summaries for 
discrete variables will include frequencies and percentages.  The baseline 
visit will be defined as the last non-missing measure prior to initiation of 
IP.  Differences between treatment groups will be calculated as OTX-DED 
minus HV and change from baseline will be calculated as follow-up visit 
minus baseline visit values.   
The study eye will be the eye with the higher grade from the photographic 
assessment of bulbar conjunctival hyperemia.  If both eyes have the same 
bulbar conjunctival hyperemia grades, the study eye will be determined by 
the biostatistician prior to the analysis and will be detailed in the Statistical 
Analysis Plan. 
Efficacy and safety summaries will be presented for the study eye.  Safety 
summaries of the non-study eye will also be included, and additional 
analyses may be presented for the non-study eye.  All summaries will be 
presented by treatment group and visit, where appropriate.   In addition to 
looking at the individual formulations, the two formulations of OTX-DED 
will be combined and summarized 


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Primary Hypothesis: 
Statistical hypothesis for the primary efficacy endpoint of photographic 
assessment of bulbar conjunctival hyperemia at 15 days is as follows: 
H10: There is no difference in mean change from baseline in photographic 
assessment of bulbar conjunctival hyperemia grades between OTX-DED 
and HV treated subjects at 15 days. 
H1a: There is a difference in mean change from baseline in photographic 
assessment of bulbar conjunctival hyperemia grades between OTX-DED 
and HV treated subjects at 15 days. 
 
Primary Efficacy Analyses: 
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. 
 
An analysis of covariance (ANCOVA) model will be run to estimate least 
square (LS) treatment means. This model will include the baseline value 
as a covariate for adjustment and treatment group as the sole 
factor. LS means will be used to make treatment comparisons using 
Dunnett's adjustment for multiple comparisons to a control. Statistical 
significance of treatment differences will be determined using a two-sided 
significance level of α =0.10. Two-sample t-tests will be used as an 
unadjusted sensitivity analysis, as well as non-parametric Wilcoxon rank 
sum tests. If both OTX-DED treatment groups have similar results, they 
will be combined and compared to HV using a two-sample t-test and 
Wilcoxon rank sum test.  Sensitivity analyses will be conducted on the 
ITT population with last observation carried forward (LOCF), as well as 
using observed data only for the ITT and per protocol (PP) populations. 
 
Secondary Efficacy Analyses: 
The secondary efficacy endpoints including change from baseline of: 
severity of eye dryness score at 15 days, frequency of eye dryness score at 
15 days, severity of eye dryness score at each post-baseline visit, 
frequency of eye dryness score at each post-baseline visit, investigator 
assessment of bulbar conjunctival hyperemia at each post-baseline visit, 
total corneal fluorescein staining (tCFS) at each post-baseline visit, CFS 
sub-regions at each post-baseline visit, Ocular Surface Disease Index 
questionnaire (OSDI©) at each post-baseline visit (total score, each of the 
three domains, and individual questions) and SPEED questionnaire 
(overall score and individual questions), CFB at each post-baseline visit 
will be analyzed in a manner similar to the primary efficacy variable 
using ANCOVA model. The secondary efficacy analyses of severity of 
eye dryness scores, frequency of eye dryness scores and photographic 
assessment of bulbar conjunctival hyperemia will be analyzed in a similar 
manner as the primary efficacy analyses.  The remaining secondary 
efficacy analyses will be conducted using observed data only on the ITT 
and PP populations. 
 


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3 
PRINCIPAL CONTACTS 
Please reference the OTX-DED-2020-201 Contact List. 
4 
BACKGROUND INFORMATION 
4.1 
Dry Eye Disease (DED) 
Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by 
symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully 
understood, it is recognized that inflammation has a prominent role in the development and propagation 
of this debilitating condition. Factors that adversely affect tear film stability and osmolarity can induce 
ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune 
responses. These immunoinflammatory responses lead to further ocular surface damage and the 
development of a self-perpetuating inflammatory cycle. 
DED flares are rapid-onset, inflammation driven responses to a variety of triggers that typically cannot 
be adequately managed with patients ongoing maintenance therapy – such as artificial tears and chronic 
prescribed therapies (ASCRS, 2019).  Ocular surface inflammation plays a key role in all types of DED 
and conjunctival hyperemia in DED is a good indicator of inflammation (Baudouin, 2018).  Acute DED 
flares are driven by both innate and adaptive immune responses (Perez et al., 2020) and corticosteroids 
targets both innate and adaptive immune response (Jones et al., 2017).  With that in mind, many 
different groups of patients with DED may benefit from a short-term treatment of corticosteroids. 
Patients on artificial tears and/or other palliative treatments who experience episodic flares, patients 
requiring induction therapy while initiating chronic treatment for dry eye, patients experiencing 
breakthrough flares who are on chronic treatment such as cyclosporine and lifitegrast, patients requiring 
treatment of dry eye before cataract and refractive surgery to improve outcomes/satisfaction and short-
term treatment of signs and symptoms of dry eye after cataract or refractive surgery.  
Furthermore, corticosteroids have a fast onset and effective treatment for both signs and symptoms of 
DED as they target inflammation driven by both innate and adaptive immune responses (Perez et al., 
2020).  Despite the efficacy of corticosteroids there is only one currently FDA approved (Kala 
Pharmaceuticals) for safe and efficacious short-term treatment of episodic DED. Steroid pre-treatment 
before initiating long term therapy for chronic DED can lead to faster resolution of signs and symptoms 
of DED and have been reported to reduce some side effects such as ocular burning from cyclosporine.  
In a multicenter randomized controlled clinical trial, the use of 0.5% loteprednol therapy two weeks 
before the initiation of long-term topical cyclosporine provided more rapid improvement in symptoms, 
corneal fluorescein staining, lissamine green staining and Schirmer score, than topical cyclosporine or 
artificial tears alone (Sheppard, et al., 2014).  Furthermore, induction therapy with loteprednol etabonate 
decreased the incidence of severe stinging and discontinuation of topical cyclosporine (Sheppard, et al., 
2014).  In another study, treatment with topical 1% methylprednisolone and cyclosporine for an initial 
three-week period provided faster symptom relief and improvement in ocular signs than topical 
cyclosporine alone (Byun et al., 2012). 
On 10/27/2020, EYSUVIS (KPI-121-loteprednol etabonate ophthalmic suspension) 0.25%, developed 
by Kala Pharmaceuticals was FDA approved. KPI-121 a preserved eyedrop delivered 4x/day for 2 
weeks was approved for the short term (up to 2 weeks) treatment of the signs and symptoms of dry eye 
disease (Kala Pharmaceuticals, 2020). 


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4.2 
Investigational Product Rationale 
Given limitations of topical ocular treatments and devices indicated for treatments of DED, there is a 
rational for novel therapies. Ocular Therapeutix has designed a resorbable intracanalicular insert as the 
platform for drug delivery products which can be used to deliver various active pharmaceutical 
ingredients approved by the Food and Drug Administration (FDA).  
OTX-DED is an intracanalicular insert that consists of two main components: dexamethasone and 
polyethylene glycol (PEG) based hydrogel conjugated with fluorescein.  OTX-DED contains 
approximately 0.2 mg or 0.3 mg of dexamethasone and is designed to provide a sustained and tapered 
release of dexamethasone for up to 14 and 21 days, respectively.  Over this time and through hydrolysis, 
OTX-DED softens, liquefies and is cleared through the nasolacrimal duct without the need for removal. 
The fluorescent PEG illuminates when excited with a blue light source to allow for visualization of 
product presence.  
 
Figure 1 
Dexamethasone Entrapped in the Hydrogel Intracanalicular Insert 
 
 
 


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The insert is designed to be placed in the inferior or superior punctum and is retained in the canaliculus 
for the entire duration in which the drug is being delivered. Over time the insert softens and liquefies via 
hydrolysis, resulting in clearance through the nasolacrimal duct.  
Anti-inflammatory effects of corticosteroids make them interesting development candidates for acute 
(short-term) DED. The drug and PEG-hydrogel technology used in OTX-DED is the same as that 
approved by the FDA in 2018 for DEXTENZA (dexamethasone ophthalmic insert) 0.4 mg for 
intracanalicular use but contains lower dexamethasone dose of 0.2 or 0.3 mg and shorter intended 
therapy.  Dexamethasone is already approved by FDA for treatment of steroid responsive inflammatory 
ocular conditions (MAXIDEX®, Alcon, Inc. NDA 013422, approved June 20, 1962).  OTX-DED 
combines the benefits of dexamethasone with punctal occlusion, which is an established effective 
therapy for DED (McCabe, 2009).  Recent clinical trials have demonstrated the efficacy using a topical 
corticosteroid treatment KPI-121 (loteprednol etabonate ophthalmic suspension) as a pharmacological 
treatment for acute episodes of DED. 
There is significant prior experience with the marketed product dexamethasone.  .OTX-DED offers 
several potential advantages over current therapies and/or standard of care regimens such as: tapered 
delivery of low doses of dexamethasone, single administration by a physician which provides for hands 
free drug delivery, contains no anti-microbial preservatives which may cause damage to the ocular 
surface and provides punctal occlusion  .  Moreover, OTX-DED is physician administered which 
eliminates the potential to abuse or misuse steroids and therefore eliminates long-term risks including 
glaucoma, cataract formation. 
4.3 
Nonclinical Findings 
The sustained and then tapered drug release rate from dexamethasone inserts (OTX-DED) is regulated 
by drug solubility in the hydrogel matrix and transfer at the interface in contact with the tear fluid 
lavage.  Nonclinical studies demonstrated that dexamethasone concentrations in the tear fluid and 
Name 
Dry Dimensions 
Hydrated Dimensions 
OTX-DED 0.2mg Dexamethasone 
Ophthalmic Insert 
Diameter:  0.41-0.49mm  
Length: 2.14-2.36 mm 
Diameter:  1.35-1.80mm  
Length:  1.8mm 
OTX-DED 0.3mg Dexamethasone 
Ophthalmic Insert 
Diameter: 0.44-0.55mm 
Length: 2.14-2.36mm 
Diameter:  1.35-1.80 mm 
 Length: 1.8mm 
Hydrogel Vehicle (HV) 
Insert 
Diameter: 0.38mm 
Length: 2.25mm 
Diameter: 1.5 mm 
Length: 1.8mm 


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aqueous humor of beagle dogs delivered from early development versions of dexamethasone inserts 
were similar to those achieved from Maxidex® (0.1% dexamethasone suspension) eye drops.   
Pharmacokinetic (PK) dosing studies of dexamethasone inserts performed in beagle dogs produced 
sustained AH and TF concentrations which then decreased and tapered to zero (complete release) over 
time.  The average amount of dexamethasone released from the dexamethasone insert in beagle dogs 
during the sustained release phase is approximately 0.20 mg per day.  The OTX-DED dexamethasone 
doses are proposed to contain either 0.2 or 0.3 mg and is designed to provide a sustained release of 
dexamethasone for up to 14 or 21 days, respectively.   
Dexamethasone inserts containing a maximum feasible dose of 0.737 mg dexamethasone, was evaluated 
in a GLP toxicology study in Beagle dogs. Daily clinical examinations, and histology performed at 36 
and 50 days following implantation was generally well tolerated.  Adverse findings included some mild 
and/or local ocular irritation.  Otherwise no significant ocular toxicity was detected.  Notably, there were 
no toxic effects observed on the posterior segment and no significant increases in IOP. No indication of 
systemic toxicity was observed, and absorption of the drug is negligible. 
Additional details about non-clinical findings can be found in the Investigator’s Brochure (IB).  
4.4 
Risk-Benefit Analysis 
OTX-DED has several potential advantages over topical corticosteroid drops, assuming such a treatment 
is approved for the signs and symptoms of dry eye disease, given that OTX-DED does not contain any 
anti-microbial preservatives, may treat the signs and symptoms of episodic dry eye with a single 
application that is relatively easy to insert, eliminates complexity with daily drops, and delivers 
therapeutic levels of dexamethasone continuously for the intended duration of therapy. OTX-DED 
combines two currently used therapies for DED (steroid and punctal plug occlusion).   
Based on several decades of use of topical ocular corticosteroids, risks have been identified with the use 
of dexamethasone, some of which have been observed in clinical trials with the higher dose 0.4 mg 
dexamethasone insert.   
The following AEs and/or risks have been observed with the administration of corticosteroids: 
1. 
IOP Increase/Glaucoma/Ocular hypertension 
2. 
Masking of infection or enhancing existing infections 
3. 
Delayed healing 
4. 
Cataracts 
The following AEs and/or risks have been observed with the insertion procedure of the intracanalicular 
insert: 
1. 
Eye pain and discomfort, including foreign body sensation 
2. 
Tearing or epiphora (with or without mucopurulent discharge) 
3. 
Stenosis 
4. 
Inability to remove test article 
5. 
Perforation of or trauma to the punctum and/or surrounding tissues 
6. 
Punctoplasty 
7. 
Eye inflammation 
8. 
Allergic reaction 
9. 
Dacrocystitis 
10. Canaliculitis 
11. Decreased/impaired visual acuity 
12.  Infection or intraocular infection that if severe could lead to temporary or permanent 
impairment of eyesight 


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13. Need for surgery on the lacrimal system 
Not all risks or problems of using OTX-DED are known. However, the risks associated with OTX-DED 
have been minimized by lowering the dose strength of the active ingredient dexamethasone and 
formulating the hydrogel intracanalicular insert with constituents that have a long history of safe use in 
ophthalmic drugs and medical devices. Furthermore, based on the results of a high dose (0.4 mg 
dexamethasone insert) in multiple Phase 2 and 3 studies and commercial experience with over 30,000 
inserts placed, biocompatibility and preclinical testing, the highest dose (0.4 mg dexamethasone) has 
generally been shown to be safe and well tolerated in the eye.  Moreover, OTX-DED is physician 
administered which eliminates the potential to abuse or misuse steroids and therefore eliminates long-
term risks including glaucoma, cataract formation.  
The risks described will be minimized via selection of experienced eye care professionals skilled in the 
use of intracanalicular inserts. All Investigators that will use the investigational product will undergo 
training per the product’s Instructions for Use (IFU). Subjects will be selected and enrolled using clearly 
defined inclusion and exclusion criteria to ensure that patients with conditions/comorbidities that put 
them at higher risk for procedural complications are excluded. Treatment and follow up of the subjects 
will be performed consistent with current medical practices. Furthermore, risks will be minimized by 
requiring subjects to report for routine clinic visits allowing for prospective diagnosis of potential 
complications. Participants will be given instructions on whom to contact in the event they have any 
questions or are experiencing any problems.  
4.5 
Dose and Administration Justification 
It is hypothesized that the efficacy of corticosteroid therapy may be enhanced by delivering a sustained 
low dose of dexamethasone compared to the typical eye drop.  OTX-DED contains either 0.2 or 0.3 mg 
of dexamethasone, which has been designed to deliver dexamethasone in a sustained fashion for up to 
14 – 21 days, respectively.   
Preclinical studies have demonstrated compelling pharmacokinetics for OTX-DED compared to 
topically administered corticosteroids.  There is a sustained presence of OTX-DED on the ocular 
surface.  Dexamethasone levels will remain sustained until the insert is sufficiently depleted of 
dexamethasone at the interface, which results in the gradual tapering effect observed in tear fluid seen in 
the pharmacokinetic profiles.  This pharmacokinetic profile may mark an efficacy improvement through 
steady and relatively low levels of drug delivered compared to the peak and trough model of topically 
administered corticosteroid eye drops.  
The drug and PEG-hydrogel technology used in OTX-DED is the same as that approved by the FDA in 
2018 for DEXTENZA (dexamethasone ophthalmic insert), 0.4 mg for intracanalicular use [NDA 
208742] but contains a lower dexamethasone dose of 0.2 or 0.3 mg and are of a shorter intended 
duration of therapy.  Clinical studies evaluating DEXTENZA (Phase 2: OTX-12-002; Phase 3: OTX-13-
002, OTX-14-003 and OTX-15-003) that were double-masked, vehicle-controlled trials for the treatment 
of pain and inflammation following ophthalmic surgery demonstrated safety and efficacy of 
dexamethasone inserts in these patients. 
Calculations of human equivalent dose (HED) of no observed adverse effect levels (NOAELs) and 
applications of safety factors used to calculate the ocular and systemic safety factors for the proposed 
clinical dose of 0.2 and 0.3 mg/eye are presented in Table 1.  Ocular HED is based on equivalence of 
eyes between humans and beagles, and systemic HED is based on dose per unit weight. 


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Table 1 Safety Margins for Ocular and Systemic Toxicity 
NOAEL 
Study 
Beagle 
Dose per 
Eye 
Ocular Safety 
Factora for 
0.2 mg and  
Human Dose per 
Eye 
Ocular 
Safety 
Factora for 
0.3 mg 
Human 
Dose per 
Eye 
Total 
Systemic 
Dose 
Systemic 
HEDb 
Systemic 
Safety 
Factor for 
Bilateral  
0.2 mg and  
Human 
Dosec 
Systemic 
Safety 
Factor for 
Bilateral  
0.3 mg 
Human 
Dosec 
35-Day Toxicity 
Study of the 
Dexamethasone 
Punctum Plug 
with a 2 Week 
Recovery Period  
(TP/TR0161) 
0.73 
mg/eye 
 
3.6 (0.2 mg dose) 
 
2.4 (0.3 mg 
dose) 
 1.46 mg 
5.41 mg 
13.5 (0.4 
mg dose) 
 
9.0 (0.6 mg 
dose 
a Ocular safety factor is a direct comparison between beagle and human eyes.  
b Systemic HED is derived by converting total systemic dose to mg/kg in beagles (9 kg) then dividing by a factor of 1.8 and 
multiplying by human weight (60 kg) consistent with Table 1 in FDA Guidance. [U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER)]. 
c The systemic safety factor is the systemic HED divided by the proposed doses of 0.2 and 0.3 mg. 
d The ocular and systemic safety factors may vary by up to 10% to allow for the drug content specification range consistent 
with the label claim. 
4.6 
Compliance 
This trial will be conducted in compliance with the protocol, Good Clinical Practices (GCPs), including 
the International Council on Harmonization (ICH) Guidelines, and in general, consistent with the 
Declaration of Helsinki. In addition, all applicable local, state, and federal requirements relevant to the 
use of IPs in the countries involved will be adhered to. 
4.7 
Trial Population 
Approximately 150 subjects diagnosed with DED will be screened and randomly assigned to one of 
three treatment arms. 
5 
TRIAL OBJECTIVES 
The objectives of the trial are to assess the efficacy and safety of OTX-DED for short term treatment of 
DED. 


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6 
TRIAL DESIGN 
6.1 
Description of Trial 
This is a randomized, multi-center, double-masked, vehicle-controlled, phase 2 clinical study designed 
to evaluate the efficacy and safety of OTX-DED (dexamethasone ophthalmic insert) for intracanalicular 
use for the short-term treatment of DED.  Approximately 150 subjects (300 eyes) will be enrolled in this 
study at approximately 15 sites in the US. Subjects will be a randomized to one of three treatment 
groups as noted in Table 2.  Both eyes will be treated with the same treatment.   
Table 2 
Treatment Assignment Paradigm  
Name 
Number of Subjects 
OTX-DED 0.2mg Dexamethasone Ophthalmic Insert 
50 
OTX-DED 0.3mg Dexamethasone Ophthalmic Insert 
50 
Hydrogel Vehicle (HV) Insert 
50 
 
Subjects will undergo Screening 14 days prior to Insertion/Day 1 (Visit 2).  At Visit 2 (Insertion/Day 1) 
eligibility will be confirmed and subjects who are eligible will be randomly assigned to one of three 
treatment groups (OTX-DED 0.2mg, OTX-DED 0.3mg, or HV in a 1:1:1 ratio.  The treatment follow-up 
visits will occur at Week 1 (Visit 3), Week 2 (Visit 4), Week 3 (Visit 5), Week 4 (Visit 6), and Week 8 
(Visit 7).   
This study will be conducted per the schedule shown in Figure 2. 
Figure 2 
Study Schematic 
  
 


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6.2 
Study Endpoints 
6.2.1 
Efficacy Endpoints  
6.2.2 
Primary Efficacy Endpoints 
 Photographic assessment of bulbar conjunctival hyperemia change from baseline (CFB) at 15 
days (evaluated via central reading center). 
6.2.2.1 
Secondary Efficacy Endpoints 
 Severity of Eye Dryness Score (visual analogue scale [VAS]) CFB at 15 days 
 Frequency of Eye Dryness (VAS) CFB at 15 days. 
 Severity of Eye Dryness Score (VAS), CFB and absolute values at each post-baseline visit. 
 Frequency Eye Dryness Score (VAS), CFB and absolute values at each post-baseline visit. 
 Investigator assessment of bulbar conjunctival hyperemia CFB at each post-baseline visit. 
 Total Corneal Fluorescein Staining (tCFS) [National Eye Institute (NEI) scale], CFB and 
absolute values at each post-baseline visit. 
 CFS sub-regions using NEI scale, CFB and absolute values at each post-baseline visit. 
 Ocular Surface Disease Index questionnaire (OSDI©) questionnaire, CFB and absolute values at 
each post-baseline visit (total score, each of the three domains, and individual questions). 
 SPEED questionnaire (overall score and individual questions), CFB at each post-baseline visit. 
6.2.2.2 
Exploratory Efficacy Endpoints 
 Presence of OTX-DED or HV insert at all post-baseline visits 
 Ease of insertion as assessed by the Investigator 
 Ease of visualization as assessed by the Investigator 
 Schirmer Test without anesthesia CFB 
6.2.3 
Safety Evaluations  
Primary: 
 Non-ocular and Ocular Adverse Events (AEs) 
Secondary: 
 Best Corrected Visual Acuity (BCVA) 
 Slit Lamp Biomicroscopy (including punctum assessment) 
 Intraocular Pressure (IOP) 
 Fundus Examination 
 Rescue artificial tear use during the study 
6.2.4 
Supplementary Objectives 
 Tear Film PK will be collected and analyzed at all sites. 


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6.3 
Randomization and Masking  
Subjects will be randomized to treatment assignment.  If unmasking is required, the integrity of the 
study assessments and objectives will be maintained by limiting access to the unmasked data. 
A randomization schedule will be computer-generated by a qualified biostatistician independent of the 
study conduct or project team and uploaded into the EDC system.  The EDC/IRT system will be used 
for randomization and unmasking. 
The OTX-DED and HV inserts administered to subjects at randomization in the double-masked 
treatment phase will be comparable in appearance.  Study subjects and investigators and their staff will 
be masked to the identity of treatment until the final database is locked.  The Sponsor’s personnel 
involved with the conduct and monitoring of the study will remain masked until completion of the study 
and database lock. 
Appropriate precautions must be taken to prevent unauthorized access to the randomization scheme. 
Unless the subject’s safety requires otherwise and if time permits, the decision to unmask a treatment 
assignment is to be made jointly by the Investigator and Sponsor’s medical monitor.  
6.4 
Trial Treatment 
• 
OTX-DED 0.2 mg Dexamethasone Ophthalmic Insert 
• 
OTX-DED 0.3 mg Dexamethasone Ophthalmic Insert  
• 
Hydrogel Vehicle Insert 
6.5 
Trial Duration 
An individual subject’s participation will last approximately 10 weeks.  After the trial, subjects will be 
treated per the standard of care, at the discretion of their physician.  
Ongoing clinical investigational data will be reviewed by the Medical Monitor. The clinical 
investigation may be suspended if the Medical Monitor, upon review and evaluation of the clinical data, 
finds the severity or incidence of adverse events or complications unacceptable for continuation of the 
investigation. 
6.6 
Trial Material Accountability 
All IP required for this study will be provided by Ocular Therapeutix, Inc., or its designee. The recipient 
will acknowledge receipt of study drug, indicating shipment content and condition. Damaged supplies 
may be replaced upon notification to Ocular Therapeutix, Inc., or its designee. Accurate records of all IP 
administered by study site should be maintained and recorded. A study monitor will periodically check 
the supplies of IP held at the site to verify accountability of all IP. All used and unused IP (non-
dispensed) will either be returned to Ocular Therapeutix, Inc., or its designee, or destroyed at the site 
upon written confirmation from Ocular Therapeutix, according to site procedures. The investigator must 
keep an accurate accounting of IP received from the supplier by maintaining a detailed inventory. This 
includes the amount of IP received by the site, amount administered to subjects, the amount destroyed 
by the site and the amount returned to the sponsor or designee (as applicable), upon completion of the 
trial. All IP that is used during the course of the trial must be accounted for on a drug accountability 
form.  
Accurate records of receipt and disposition of the IP (e.g. dates, subject number, kits used, kits unused, 
etc.) must be maintained by designated site personnel. 
OTX-DED and HV Inserts are sterile, ophthalmic inserts that are without antimicrobial preservatives. 
OTX-DED and HV Inserts are provided in sterile, single use packages. The product is packaged in a 


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hermetically sealed aluminum/polyester laminate pouch to maintain stability and sterility over time. The 
product is terminally sterilized and stored refrigerated. 
At the investigational site, IP must be kept in a safe storage area with limited access (e.g., in a 
refrigerator in a locked/limited access area). The refrigerator should be temperature monitored. IP 
should be stored at controlled refrigerated temperatures from 2°C to 8°C and protected from light.  
The IP must not be used outside of this clinical trial. The investigator or site personnel may not supply 
IP to other clinical sites, investigators, or subjects, or allow the IP to be used other than as directed by 
this protocol without prior authorization from Ocular Therapeutix, Inc. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The trial will include approximately 150 subjects (300 eyes) from approximately 15 sites. 
7.1 
Inclusion Criteria 
Subjects will be eligible for study participation if they: 
1. Provide written informed consent prior to performing any study procedures and are willing to 
comply with study requirements and the study visit schedule. 
2. Are 18 years of age or older. 
3. Have a self-reported history or clinically confirmed diagnosis of DED by an eye care 
professional in both eyes for ≥6 months. 
4. Have ongoing DED, at screening visit as defined by the following criteria: 
a. 
VAS Eye Dryness severity score ≥ 40. 
And in the same qualifying eye or both eyes: 
b. 
Investigator assessment of bulbar conjunctival hyperemia grade ≥ 2 (CCLRU; 0 – 4 
scale)  
c. 
 Unanesthetized Schirmer of >0 and <10mm. 
5. 
Have corrected visual acuity better than or equal to logarithm of the minimum angle of 
resolution (logMAR), +0.7 as assessed with Early Treatment of Diabetic Retinopathy Study 
(ETDRS) charts in both eyes. 
6. Are women of child-bearing potential (WOCBP) who are non-pregnant, non-lactating, and 
sexually inactive (abstinent) for 14 days prior to screening and are willing to remain so through 
the last study visit. Alternatively, WOCBP who are not abstinent must have been using one of 
the following acceptable methods of birth control for the times specified: 
a. Intra-uterine device (IUD) in place for at least 3 months prior to screening and the desire 
to continue this method through the last study visit. 
b. Barrier method (condom or diaphragm) with spermicide for at least 14 days prior to 
screening and the desire to continue this method through the last study visit. 
c. Stable hormonal contraceptive for at least 3 months prior to screening and the desire to 
continue this method through the last study visit. 
d. Surgical sterilization (vasectomy) of partner for at least 6 months prior to Day 1. 


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e. Alternatively, are post-menopausal women (i.e. no menstrual cycle for at least one year 
prior to Visit 1/Screening) or are women who have undergone one of the following 
sterilization procedures at least 6 months prior to screening: 
i. Bilateral tubal ligation 
ii. Hysterectomy 
iii. 
Bilateral oophorectomy 
7. 
Agree to the removal of non-dissolvable punctal plugs 4 weeks prior to the insertion visit 
(Day 1, Visit 2) and long-term dissolvable punctal plugs were not placed within 4 months 
prior to insertion visit (Day 1, Visit 2) and short-term dissolvable punctual plugs were not  
placed within 6 weeks prior to insertion (Day 1, Visit 2). 
8. 
Agree to restrict the use of artificial tears (AT) through Day 29 of the trial. 
7.2 
Exclusion Criteria 
Subjects are not eligible for study participation if they: 
1. 
Have a known or suspected allergy to any component of the study product. 
2. 
Are unwilling to discontinue use of contact lenses for 4 weeks prior to the screening visit and 
throughout the study period. 
3. 
Have any active systemic disease and/or systemic infection (e.g., fever or current antibiotic 
use), or uncontrolled medical condition that in the judgment of the investigator could 
confound study assessments or limit compliance. 
4. 
Have a documented history of ocular allergies, which, in the judgment of the investigator, are 
likely to have an acute increase in severity during the duration of this trial. Subjects sensitive 
to seasonal allergens that are not expected to be present during the study are permitted. 
5. 
Have a history of neuropathic pain related to dry eye. 
6. 
Have corneal erosive disease (e.g., multiple filaments, recurrent erosion syndrome) or other 
conditions suggestive of extensive damage of the cornea. 
7. 
Have a history of glaucoma or ocular hypertension or have intraocular pressure (IOP) < 5 
mmHg or > 24 mmHg or a history of elevated IOP within the past 6 months prior to the 
screening visit. 
8. 
Have abnormal lid anatomy that may confound study data, in the judgement of the 
investigator. 
9. 
Have a diagnosis of any of the following: 
a. 
Active ocular infection 
b. 
Uveitis 
c. 
In the judgement of the investigator uncontrolled anterior blepharitis or posterior 
blepharitis or blepharitis requiring the use of systemic or antibiotic therapy.   
d. 
Moderate to severe pinguecula or pterygia, in the judgement of the investigator 
e. 
Stevens-Johnson syndrome 
f. 
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g. 
Significant conjunctival scarring, in the judgement of the investigator 
h. 
Chemical burn 
i. 
Herpetic or neurotrophic keratitis 
j. 
Congenitally absent lacrimal gland or meibomian glands 
k. 
Nasolacrimal duct obstruction in either eye 
10. Have had penetrating intraocular surgery within 6 months or require penetrating intraocular 
surgery during the study, eyelid surgery within 6 months, corneal laser refractive surgery 
within the last 1 year, cauterization of the punctum resulting in complete occlusion of both 
punctum in both eyes, glaucoma surgery or corneal transplantation (full thickness, anterior or 
posterior) 
11. Have taken any of the following in either eye within 30 days prior to the screening visit: 
a. 
Topical ocular corticosteroids 
b. 
Topical ocular antibiotics 
c. 
Topical ocular NSAID 
d. 
Topical ocular antihistamines and/or mast cell stabilizers 
e. 
Topical ocular or nasal vasoconstrictors 
f. 
Topical ocular cyclosporine (e.g., Cequa®, Restasis®) 
g. 
Lifitegrast (Xiidra®) 
h. 
Autologous tears  
i. 
Intranasal Tear Neurostimulation 
12. Have taken any of the following in either eye prior to the screening visit: 
a. 
Periocular injection of any corticosteroid solution – 3 months 
b. 
Corticosteroid intravitreal depot injection– 3 months 
c. 
Ozurdex– 6 months 
d. 
Retisert– 40 months 
13. Have altered the dose of the following within 30 days prior to the screening visit (i.e., should 
keep dose stable throughout the study): 
a. 
Nutraceuticals or multivitamins 
b. 
Tetracycline compounds (tetracycline, doxycycline or minocycline) 
c. 
Inhaled, intramuscular or intra-articular corticosteroids (mouth or nasal spray form) or 
dermatological steroids (use is allowed if applied to < 4 locations for < 4 continuous 
days). 
14. Have altered the dose of the following within 6 months prior to the screening visit (i.e., should 
keep dose stable throughout the study): 
a. 
Systemic anticholinergics 
b. 
Antidepressants (with the exception of rare usage as a sleep aid) 


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c. 
Oral corticosteroids (e.g., prednisone. Prednisone dose must be less than 11 mg/day) 
15. Have taken isotretinoin (Accutane) or systemic immunosuppressive agents within 6 months 
prior to the screening visit. 
16. Have participated in any other investigational study within 30 days of the screening visit or 
plans to participate in any other investigational study during the follow-up period. 
17. Are an employee of the site or an immediate family member of an employee of the site. 
18. Are a current smoker (including marijuana, cigar, cigarette, and/or e-cigarettes). 
19. Have a known history of alcohol and/or drug abuse or are currently using illicit drugs or plan 
to use illicit drugs for the duration of the study. Recreational or medicinal marijuana allowed 
if oral consumption (no inhaled use). 
20. Are unwilling or unable to comply with the study protocol. 
21. The Investigator determines that the subject should not be included for reasons not already 
specified (e.g., systemic, behavioral, or other ocular disease/abnormality) if the health of the 
subject or the validity of the study outcomes may be compromised by the subject’s 
enrollment. 
7.3 
Entry/Randomization Criteria: 
To qualify for insertion at Day 1 (Visit 2), a subject must continue to meet all screening 
inclusion/exclusion criteria with the following exceptions/additions: 
1. VAS eye dryness severity score ≥ 35. 
2. Investigator assessment of bulbar conjunctival hyperemia grade ≥ 2 (CCLRU; 0 – 4 scale) 
3. Subject must not have taken prohibited medications and have completed the appropriate 
washout of prior medications, if necessary. 
4. Subjects who require rescue AT must not have administered >3 time/day for 3 consecutive 
days during the washout period 
Note:  AT use is not permitted unless absolutely necessary as rescue therapy.  If subject 
requires rescue AT and have administered >3 times/ for 3 days during the Screening 
period, they are not eligible for randomization. 
7.4 
Procedural Exclusion Criteria 
Subjects are considered procedural screen failures if the investigator is unsuccessful at placing the OTX-
DED or HV intracanalicular ophthalmic insert in both eyes (i.e. neither eye has an insert).  Subjects will 
be followed per protocol if the investigator successfully places one insert. 
7.5 
Subject Recruitment and Screening 
Each subject that is screened will be assigned a Subject Identification (ID) consisting of a 2-digit Site 
number plus a 3-digit Subject number. The Subject ID will be used as the primary subject identifier for 
the duration of the study.  Once all inclusion and exclusion criteria are met at Visits 1 and 2, each 
qualifying subject will be randomized via the IRT system and will be assigned a randomization number.   
The subject must sign the Informed Consent Form (ICF) before his or her participation in the study. A 
copy of the ICF must be provided to the subject or the subject's legal guardian. If applicable, it will be 
provided in a certified translation of the subject’s first or native language. The original signed ICF for 


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each participating subject shall be filed with records kept by the investigator and must be available for 
verification by study monitors at any time, and a copy will be given to each subject.  
7.6 
Withdrawal Criteria 
Any subject who wishes to voluntarily discontinue study drug or withdraw from participation in the 
study for any reason is entitled to do so without obligation.   
IP may be discontinued (insert removed [see Appendix 13]) and any subject may be discontinued from 
study participation at any time during the study at the discretion of the Investigator or the Sponsor for 
any reason.  
7.6.1 
Withdrawal Methods 
The Sponsor may terminate this study at any time. Reasons for termination may include but are not 
limited to, the following: 
• 
The incidence or severity of adverse events (AE) in this or other studies point to a potential 
health hazard for trial subjects. 
• 
Insufficient subject enrollment. 
• 
Any information becoming available during the study that substantially changes the expected 
benefit risk profile of the study treatments. 
7.6.2 
Collection of Data from Withdrawn Subjects 
In the event that study discontinuation of a randomized subject is necessary, the Investigator should 
make every attempt to have the subject complete Visit 7 assessments as soon as possible.  The reason for 
premature discontinuation should be recorded in the subject chart and entered in the eCRF. 
7.6.3 
Subject Replacement 
Subjects who withdraw will not be replaced.  
8 
SUBJECT TREATMENT 
8.1 
Treatment Regimen 
OTX-DED contains 0.2 mg or 0.3mg of micronized dexamethasone in a resorbable hydrogel matrix.  It 
is intended to be inserted at Visit 2 and retained in the inferior or superior vertical canaliculus where it 
then provides sustained release of therapeutic levels of dexamethasone over approximately 14 - 21 days.   
8.2 
Prior and Concomitant Therapy 
Only sponsor provided preservative free artificial tear use will be permitted as rescue therapy during the 
study.  All other tear substitutes are not permitted. 
 


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Table 3 List of Prohibited/Restricted Medications 
8.3 
Rescue Therapy 
Use of preservative-free artificial tears (AT) should be discouraged, and subjects should be counseled to 
administer only if absolutely necessary as rescue.  Further, if used, subjects will be instructed not to 
administer AT within 2 hours prior to any study visit.  Preservative-free AT will be provided by the 
sponsor and use will be recorded by subjects in a daily diary. 
8.4 
Study Assessments by Visit 
Perform study procedures as referenced in the Schedule of Events (Appendix 1) in the order specified 
below.  Note:  All subjects will have both eyes evaluated at all visits. 
8.4.1 
Visit 1 (14 ±2 days prior to Day 1) Screening/Baseline Visit  
Note:  The Screening Visit can be split into two (2) visits in rare cases, but both visits must be within the 
allowable window. 
• 
Informed consent 
• 
Demographics  
• 
Medical/ophthalmic history  
• 
Record concomitant medications  
• 
VAS Severity and Frequency for Eye Dryness (Appendix 2) 
• 
OSDI (Appendix 3)  
Minimum Washout Period Prior to Screening (Visit 1) 
30 days: 
Topical ocular cyclosporine (e.g., Cequa®, Restatsis®) 
Lifitegrast (Xiidra®) 
Autologous tears 
Topical ocular corticosteroids 
Topical ocular antibiotics 
Topical ocular NSAID 
Topical ocular antihistamines and/or mast cell stabilizers 
Topical ocular or nasal vasoconstrictors 
Intranasal Tear Neurostimulation 
Stable within 30 days of Visit 1 and stable throughout study: 
Nutraceuticals or multivitamins 
Tetracycline compounds (tetracycline, doxycycline or minocycline) 
Inhaled, intramuscular or intra-articular corticosteroids (mouth or nasal spray form) 
Stable within 6 months of Visit 1 and stable throughout study: 
Systemic anticholinergics 
Antidepressants (with the exception of rare usage as a sleep aid) 
Oral corticosteroids (e.g., prednisone, prednisone dose must be less than 11mg/day) 
90 days: 
Periocular injection of any corticosteroid 
Corticosteroid intra-vitreal depot injection 
6 months: 
Ozurdex 
Isotretinoin 
Systemic Immunosuppressants 
40 months: 
Retisert 


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• 
SPEED assessment (Appendix 4)  
• 
BCVA assessment (Appendix 8) 
• 
Slit lamp biomicroscopy (including punctum assessment) (Appendix 9) 
• 
Investigator Rated Assessment of Bulbar Conjunctival Hyperemia (Appendix 5)  
• 
CFS (Appendix 7)  
Note:  Wait 15 minutes prior to conducting unanesthetized Schirmer test 
• 
Unanesthetized Schirmer  
• 
IOP 
• 
Dilated fundus exam 
• 
Determine Eligibility 
• 
Dispense artificial tears (as needed and not to be administered within 2 hours of clinic visit.) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) (Appendix 14) 
8.4.2 
Visit 2 Insertion/Day 1  
• 
Record concomitant medications  
• 
Record AEs*  
Note:  Any signs, symptoms or conditions captured prior to the insertion of IP, will be recorded 
as medical history. 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (if applicable)   
Note:  Subjects using rescue AT > 3x/day for 3 consecutive days will be ineligible for 
randomization. 
• 
VAS Frequency and Severity for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
Conjunctival Hyperemia Photography (Appendix 6) 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum evaluation 
• 
Investigator Rated Assessment of Bulbar Conjunctival Hyperemia  
• 
CFS  
• 
IOP 
• 
Punctum Size Assessment 
• 
Urine pregnancy test (if applicable must be performed prior to treatment) 
• 
Determine Eligibility for Insertion  
• 
Randomization  
• 
OTX-DED or HV Insert Placement (Appendix 11)* 
Note:  If placement is only successful in one eye, the items with the asterisk should be performed 
on the same day. Subjects should be asked to return within 0-3 days to attempt insertion in the 
other eye. At the return visit, items with an asterisk should be performed on the second eye, and 
the AE review, Ease of Insertion Assessment and Tear film PK for the second eye should only be 
performed if the second eye has a successful insertion.   
• 
Ease of Insertion Assessment* 
• 
Tear film PK by Schirmer (to be collected 1 hour (±30 minutes), 2 hours (±30 minutes) and 4 
hours (±30 minutes) post-insertion)* (Appendix 10) 
• 
Dispense artificial tears (as needed and if used, not to be administered within 2 hours of the 
clinic visits) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 


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8.4.3 
Visit 3 (Week 1 ±2 days) 
• 
Record concomitant medications  
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) 
• 
Record AEs 
• 
VAS Frequency and Severity for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
Investigator Rated Conjunctival Hyperemia Grade 
• 
CFS 
• 
OTX-DED or HV Insert Presence by visual assessment 
• 
Ease of Visualization by Investigator (Appendix 12) 
• 
Tear Film PK by Schirmer 
• 
IOP 
• 
Dispense artificial tears and diary (as needed) 
8.4.4 
Visit 4 (Week 2 ±2 days) 
• 
Record concomitant medications  
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) 
• 
Record AEs 
• 
VAS Frequency and Severity for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
Conjunctival Hyperemia Photography 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
Investigator Rated Conjunctival Hyperemia Grade 
• 
CFS 
• 
OTX-DED or HV Insert Presence by visual assessment 
• 
Ease of Visualization by Investigator 
• 
Tear Film PK by Schirmer 
• 
IOP 
• 
Dispense artificial tears and diary (as needed) 
8.4.5 
Visit 5 (Week 3 ±2 days)  
• 
Record concomitant medications  
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) 
• 
Record AEs 
• 
VAS Frequency and Severity for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
Investigator Rated Conjunctival Hyperemia Grade 
• 
CFS 
• 
OTX-DED or HV Insert Presence by visual assessment 


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• 
Ease of Visualization by Investigator 
• 
Tear Film PK by Schirmer 
• 
IOP 
• 
Dispense artificial tears and diary (as needed) 
8.4.6 
Visit 6 (Week 4 ±3 days)  
• 
Record concomitant medications  
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) 
• 
Record AEs 
• 
OSDI 
• 
VAS Frequency and Severity for Eye Dryness 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
Investigator Rated Conjunctival Hyperemia Grade 
• 
CFS 
• 
OTX-DED or HV Insert Presence by visual assessment 
• 
Ease of Visualization by Investigator 
• 
Tear Film PK by Schirmer 
• 
IOP 
• 
Dispense artificial tears and diary (as needed) 
8.4.7 
Final Visit 7 (Week 8±10 days) 
• 
Record concomitant medications  
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) 
• 
Record AEs 
• 
Urine Pregnancy Test 
• 
VAS Frequency and Severity for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
Investigator Rated Conjunctival Hyperemia Grade 
• 
CFS 
• 
Undilated Fundus Exam  
• 
OTX-DED or HV Insert Presence by visual assessment 
• 
Ease of Visualization by Investigator 
• 
Tear Film PK by Schirmer 
• 
IOP 
• 
Punctum Size Assessment 
8.4.8 
Unscheduled Visits  
An unscheduled visit may be performed during the course of the trial in order to ensure subject safety. 
All procedures performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit eCRF pages. 
Evaluations that may be conducted at an Unscheduled Visit may include: 
• BCVA assessment 


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• Slit lamp biomicroscopy 
• IOP 
• Dilated or Undilated fundus exam 
• Urine pregnancy test (if applicable) 
• Assessment of AEs 
• Assessment of concomitant medications and/or treatments 
• Any other assessments needed in the judgment of the investigator 
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.  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 IP 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 IP or a concurrent medication (overdose per 
se should not be reported as an AE/SAE). 
• 
A laboratory abnormality occurring after the start of the study (i.e., after screening) that results in 
subject withdrawal from the study or medical treatment or further follow-up. 
9.2 
Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening 
Note: 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. 


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• 
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/SAE’s 
Not applicable. 
9.4 
Monitoring and Recording of AEs and SAEs 
9.4.1 
Adverse Events 
Any AE experienced by the subject from Visit 2 (Insertion/Day 1) through Visit 7 (Week 8) 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 2 (Insertion/Day 1) through Visit 7 (Week 8) 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. 
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 3. 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. 


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All additional follow-up evaluations must be reported to the pharmacovigilance team. Such data should 
be sent by fax or email (Figure 3) 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 3 
Reporting Information for SAEs and Pregnancies 
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 
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. 
9.7.2 
Relationship to OTX-DED or Hydrogel Vehicle product 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 ophthalmic 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 


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category:   
i. 
It bears a reasonable temporal relationship to the insertion procedure or the 
presence of the ophthalmic insert  
ii. 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  
iii. 
It disappears or decreases on removal of the ophthalmic insert  
iv. It follows a known pattern of response to the insertion procedure or the ophthalmic 
insert 
9.7.3 
Expectedness of Events 
Expectedness of all AEs will be determined according to the Investigator’s Brochure 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 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. 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 use the IRT system to unmask the subject’s randomization code. 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. 


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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 METHODS AND DATA ANALYSIS 
10.1 
Statistical Methods 
Summaries for continuous variables will include the sample size, mean, standard deviation, median, 
minimum and maximum.  Summaries for discrete variables will include frequencies and percentages.  
The baseline visit will be defined as the last non-missing measure prior to initiation of investigational 
treatment.  Differences between treatment groups will be calculated as OTX-DED minus HV and 
change from baseline will be calculated as follow-up visit minus baseline visit value.   
10.2 
Unit of Analysis 
Both eyes will be treated with the same treatment/formulation.  If both eyes qualify, the eye having the 
higher grade from the photographic assessment of conjunctival hyperemia will be designated as the 
study eye and the other eye designated as the non-study eye.  If both eyes have the same conjunctival 
hyperemia grade, the study eye will be determined by the biostatistician prior to the analysis and will be 
detailed in the Statistical Analysis Plan.  If only one eye qualifies, that eye will be the study eye, but 
both eyes will still receive the same treatment/formulation.   
Efficacy and safety summaries will be presented for the study eye.  Safety summaries of the non-study 
eye will also be included, and additional analyses may be presented for the non-study eye.  All 
summaries will be presented by treatment group and visit, where appropriate.  In addition to looking at 
the individual formulations, the two formulations of OTX-DED will be combined and summarized. 
10.3 
Sample Size Determination 
This study is not powered to show statistical significance but will provide initial estimates and trends of 
the endpoints for use in future trial designs.  The sample size will allow for safety information to be 
obtained, while still limiting the number of subjects exposed to the IP. Statistical analyses will be 
descriptive. 
10.4 
Statistical Significance 
All statistical testing will be done at the two-sided alpha level of 0.05.  As this is a Phase 2 study, no 
adjustments to alpha will be made for testing of multiple endpoints.  Statistical analyses will be 
descriptive. 
10.5 
Trial Termination 
Should it become apparent during the trial that there is a significant safety concern or there is an issue 
with enrollment, the trial may be terminated.  In addition, should information become known during the 
course of the trial that would negatively impact the trial, the trial may be terminated.  In addition, the 
FDA or another regulatory authority may terminate the trial. 


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10.6 
Missing Data 
The primary analyses of efficacy data will use Markov Chain Monte Carlo (MCMC) multiple 
imputation methodology to impute missing data. Sensitivity analyses, to determine robustness of results, 
will be performed using last observation carried forward (LOCF) and observed data only.  Subjects who 
receive sustained rescue medication will have their data after receiving rescue medicine set to missing 
and will be imputed as described above. 
10.7 
Efficacy Analyses 
Primary Hypothesis 
Statistical hypothesis for the primary efficacy endpoint of photographic assessment of bulbar 
conjunctival hyperemia grade at 15 days is as follows: 
H10: There is no difference in mean change from baseline in photographic assessment of bulbar 
conjunctival hyperemia grades between OTX-DED and HV treated subjects at 15 days. 
H1a: There is a difference in mean change from baseline in photographic assessment of bulbar 
conjunctival hyperemia grades between OTX-DED and HV treated subjects at 15 days. 
 
Primary Efficacy Analyses 
The primary efficacy analysis will be conducted on the intent-to-treat (ITT) population with multiple 
imputation using Markov Chain Monte Carlo (MCMC) for missing data. 
 
An analysis of covariance (ANCOVA) model will be run to estimate LS treatment means. This model 
will include the baseline value as a covariate for adjustment and treatment group as the sole 
factor. Least square means will be used to make treatment comparisons using Dunnett's adjustment for 
multiple comparisons to a control. 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 an unadjusted 
sensitivity analysis, as well as non-parametric Wilcoxon rank sum tests. If both OTX-DED treatment 
groups have similar results, they will be combined and compared to HV using a two-sample t-test and 
Wilcoxon rank sum test.  Sensitivity analyses will be conducted on the ITT population with last 
observation carried forward (LOCF), as well as using observed data only for the ITT and PP 
populations. 
 
Secondary Efficacy Analyses 
The secondary efficacy variables including change from baseline of: severity of eye dryness score at 15 
days, frequency of eye dryness score at 15 days, severity of eye dryness score at each post-baseline visit, 
frequency of eye dryness score at each post-baseline visit, investigator assessment of bulbar conjunctival 
hyperemia at each post-baseline visit, total corneal fluorescein staining (tCFS) at each post-baseline 
visit, CFS sub-regions at each post-baseline visit, Ocular Surface Disease Index questionnaire (OSDI©) 
at each post-baseline visit (total score, each of the three domains, and individual questions) and SPEED 
questionnaire (overall score and individual questions), CFB at each post-baseline visit will be analyzed 
in a manner similar to the primary efficacy variable using ANCOVA model. The secondary efficacy 
analyses of severity of eye dryness scores, frequency of eye dryness scores and photographic assessment 
of bulbar conjunctival hyperemia will be analyzed in a similar manner as the primary efficacy analyses.  
The remaining secondary efficacy analyses will be conducted using observed data only on the ITT and 
PP populations. 
 
Exploratory Efficacy Analyses 
Presence of insert, ease of insertion as assessed by the Investigator and ease of visualization as assessed 
by the Investigator at all post-baseline visits will be summarized using discrete statistics and will be 


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tested between treatment groups using the Pearson chi-squared statistic.  Change from baseline in 
Schirmer’s test will be analyzed using an ANCOVA model similar to the primary analysis, on observed 
data. 
 
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. 
10.8 
Safety Analyses 
Incidence of adverse events will be tabulated by MedDRA System Organ Class and preferred term 
within each system organ class for ocular and non-ocular events, visual acuity, slit lamp biomicroscopy, 
IOP, dilated fundoscopy examination, and rescue medication use will be summarized descriptively using 
quantitative and qualitative summary statistics as appropriate. 
10.9 
Reporting Deviations 
Should there be changes in any analyses described in the protocol, the statistical analysis plan will 
document them.  Should there be changes in any analyses described in the statistical analysis plan, the 
final clinical study report will describe them.  
10.10 
Subject Population(s) for Analysis 
Intent-to-Treat (ITT): The ITT population will include all randomized subjects. Analysis on the ITT 
population will be used as the primary efficacy analysis and will be performed for all efficacy endpoints, 
analyzing subjects under the treatment to which they were randomized.   
Per Protocol (PP): The PP population will include all ITT subjects who do not deviate from the 
protocol in any way likely to seriously affect the efficacy outcomes of the study.  Analysis on the PP 
population will be used as secondary efficacy analysis and will be performed for select efficacy 
endpoints, analyzing subjects under the treatment actually received.  Important protocol deviations will 
be identified prior to locking the study database.  
Safety:  The Safety population will include all subjects who received IP (OTX-DED or HV). Analyses 
performed on the Safety population will be according to the treatment the subject actually received. 
11 
STUDY MANAGEMENT AND DATA COLLECTION 
11.1 
Confidentiality 
All trial subject data collected and processed for the purposes of this trial should be maintained by the 
investigator and his/her staff with adequate precautions as to ensure that the confidentiality of the data is 
in accordance with local, state, and federal laws and regulations. 
Monitors, auditors and other authorized representatives of CRO drug safety, the sponsor, the IRB/IEC 
approving this trial, the FDA, the Department of Health and Human Services, other domestic 
government agencies, and other foreign regulatory agencies will be granted direct access to the trial 
subject’s original medical and trial records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to the aforementioned individuals to the extent permitted by 
law. 


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A report of the results of this trial may be published or sent to the appropriate health authorities in any 
country in which the IP may ultimately be marketed, but the subject’s identity will not be disclosed in 
these documents. 
11.2 
Source Documents 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
investigator’s trial subject files, as well as the results of diagnostic tests such as X-rays, laboratory tests, 
and EKGs. The investigator’s electronic copy of the eCRFs serves as the investigator’s record of a 
subject’s trial-related data. 
11.3 
Case Report Forms 
All subject data will be captured in the subject source documents which will be transcribed to the 
eCRFs. The investigator is responsible for ensuring that trial data is completely and accurately recorded 
on each subject’s eCRF, source documents, and all trial-related materials. All trial data should also be 
attributable, legible, contemporaneous, original, accurate and complete. Recorded data should only be 
corrected in a manner that does not obliterate, destroy, or render illegible the previous entry (eg, by 
drawing a single line through the incorrect entry and writing the revision next to the corrected data). An 
individual who has corrected a data entry should make clear who made the correction and when, by 
adding to the correction his/her initials as well as the date of the correction. 
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR Part 11 
requirements and will be performed only by staff that have been trained on the system and have access 
to the system. Minimal data will be entered for screen failure subjects. An audit trail will be maintained 
within the electronic system to capture all changes made within the eCRF database. After the end of the 
trial and database lock, compact discs (CDs) containing copies of all applicable subjects’ eCRFs will be 
provided to each investigator site to be maintained on file by the investigator. 
11.4 
Records Retention 
All trial related correspondence, subject records, consent forms, record of the distribution and use of all 
IP and copies of case report forms should be maintained on file for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region; or until at least two years have elapsed since the formal 
discontinuation of clinical development of the IP. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. The investigator must notify the sponsor prior to destroying trial documentation 
even after the above-mentioned time has passed. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping trial records, custody must be transferred to a person who will accept the responsibility. The 
sponsor must be notified in writing of the name and address of the new custodian. 
12 
STUDY MONITORING, AUDITING, AND INSPECTING 
12.1 
Study Monitoring Plan 
Each investigator must adhere to the protocol as detailed in this document and agrees that any changes 
to the protocol must be approved by Ocular Therapeutix, Inc., prior to seeking approval from the 
IRB/Ethics Committee.  Investigators’ proficiency in observing and scoring ophthalmic observations 
will be established and documented via review of academic training and experience, prior to examining 


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subjects.  Each investigator will be responsible for enrolling only those subjects who have met protocol 
eligibility criteria. During study conduct, Ocular Therapeutix, Inc and/or its representative will conduct 
periodic monitoring visits to ensure that the protocol and Good Clinical Practice (GCP) are being 
followed. The monitors may review source documents to confirm that the data recorded on the 
electronic case report forms (eCRFs) are accurate.  Further details of the trial monitoring (including 
medical monitoring) will be outlined in a monitoring plan. 
The investigator and institution will allow Ocular Therapeutix, Inc., monitors or its representatives and 
appropriate regulatory authorities direct access to source documents and CRFs to perform this 
verification. Data Managers will also review data and may interact with site personnel for clarifications. 
It is important that the investigator(s) and their relevant personnel are available during the monitoring 
visits and possible audits or inspections and that sufficient time is devoted to the process. 
13 
ETHICAL CONSIDERATIONS 
This study will be conducted according to the standards of International Council on Harmonization, 
Good Clinical Practice Guideline, Research Ethics Committee regulations, any applicable government 
regulations, Trust and Research Office policies and procedures.  
This protocol, the ICF, relevant supporting information, and all types of subject recruitment or 
advertisement information must be submitted to the IRB/Ethics Committee for review and must be 
approved before the study is initiated. Any amendments to the protocol must also be approved by the 
IRB/Ethics Committee prior to implementing changes in the study. The investigator is responsible for 
keeping the IRB/Ethics Committee apprised of the progress of the study, any SAEs, and any changes 
made to the protocol according to the requirements of the site’s IRB.  
14 
REFERENCES 
ASCRS EyeWorld. https://www.eyeworld.org/download/file/fid/453. Published May 2019. Accessed 
May 24, 2019. 
Baudouin C, Irkeç M, Messmer EM, et al. Clinical impact of inflammation in dry eye disease: 
proceedings of the ODISSEY group meeting. Acta Ophthalmol. 2018;96(2):111-119. 
doi:10.1111/aos.13436 
Byun Y, Kim T, Kwon SM, et al. Efficacy of combined 0.05% cyclosporine and 1% methylprednisolone 
treatment for chronic dry eye. Cornea. 2012;31(5):509-513. doi:10.1097/ICO.0b013e31818c69ef 
Cequa NDA 210913 
Food Drug Administration (FDA). Guidance for Industry: Estimating the Maximum Safe Starting Dose 
in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. July 2005. Available at 
www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-
starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers. Accessed September 23, 2019. 
Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. The Ocular 
Surface. 2017;15(3):575-628. doi:10.1016/j.jtos.2017.05.006 
McCabe C. Plugs reduce dry-eye symptoms, improve vision. Review of Ophthalmology. 19 November 
2009. Available at www.reviewofophthalmology.com/article/plugs-reduce-dry-eye-symptoms-improve-
vision. Accessed September 29, 2019. 
Perez VL, Stern ME, Pflugfelder SC, Experimental Eye Research 2020: Cornea Special Issue IV: 
Immunology, infection, neovascularization, and surgery submitted 


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Kala Pharmaceuticals, Inc. Presentations | Accessed October 1, 2020. 
https://investors.kalarx.com/presentations/ 
RESTASIS® NDA #021023 
Sheppard JD, Donnenfeld ED, Holland EJ, Slonim CB, Solomon R, Solomon KD, et al. Effect of 
loteprednol etabonate 0.5% on initiation of dry eye treatment with topical cyclosporine 0.05%. Eye 
Contact Lens 2014;40(5):289e96 


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Appendix 1 
Time and Events Schedule  
See Section 8.4 for order of assessments. 
Study Parameter 
Screening/ 
Baseline Visit  
Day -14 
(-16 to -12) 
Insertion  
Day 1 
Follow-up  
Day 8 
Week 1 
±2 days 
Follow-up  
Day 15 
Week 2 
±2 days 
Follow-up 
Day 22 
Week 3 
±2 days 
Follow-up  
Day 29 
Week 46 
±3 days 
Follow-Up  
Day 57 
 Week 8 
(± 10 days) 
Visit 
1 
2 
3 
4 
5 
6 
7 
Informed Consent 
X 
 
 
 
 
 
 
Determine Eligibility 
X 
X 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
 
 
 
 
 
 
Record Medications 
X 
X 
X 
X 
X 
X 
X 
Record Adverse Events3,7 
 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test1 
 
X 
 
 
 
 
X 
VAS for Eye Dryness  
X 
X 
X 
X 
X 
X 
X 
OSDI 
X 
X 
X 
X 
X 
X 
X 
SPEED 
X 
X 
X 
X 
X 
X 
X 
Conjunctival Hyperemia photography  
 
 X 
 
X 
 
 
 
Assessment of BCVA 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Biomicroscopy (including punctum assessment) 
X 
X 
X 
X 
X 
X 
X 
Investigator Rated Conjunctival Hyperemia grade 
X 
X 
X 
X 
X 
X 
X 
Corneal Fluorescein Staining Using the NEI Scale 
X 
X 
X 
X 
X 
X 
X 
OTX-DED or HV Insert Presence by Visual Assessment 
 
 
X 
X 
X 
X 
X 
Ease of Visualization as assessed by Investigator 
 
 
X 
X 
X 
X 
X 
Unanesthetized Schirmer Tear Test 
X 
 
 
 
 
 
 
Tear Film PK performed using Schirmer Strips3,4,5 
 
X 
X 
X 
X 
X 
X 
IOP Measurement 
X 
X 
X 
X 
X 
X 
X 
Fundus Exam2 
X 
 
 
 
 
 
X 
Punctum Size Assessment 
 
X 
 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
OTX-DED or HV Insert Placement3 
 
X 
 
 
 
 
 
Ease of Insertion as assessed by the Investigator3 
 
X 
 
 
 
 
 
Dispense Sponsor Supplied Artificial Tears (if needed) and Daily Diary 
X 
X 
X 
X 
X 
X 
 
Collect/review Daily Subject Diary for Artificial Tear Use (as needed) 
 
X 
X 
X 
X 
X 
X 
1 A negative UPT is required for women of childbearing age to be included in the study. 


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2   Dilated fundus examination at screening; undilated fundus examination at Week 8. 
3  Prior to insertion, a clinical determination of the absence of infection will be made based on the lack of erythema or discharge at the punctum. If placement is only successful in one eye, 
subjects should be asked to return within 1-3 days to attempt insertion in the other eye. The following items should be repeated at the return visit, Insert Placement, Ease of Insertion, 
Tear Film PK and AEs. 
4  Tear Film PK will be collected at 1 hour (±30 minutes), 2 hours (±30 minutes), and 4 hours (±30 minutes) post insertion on Day 1. Tear Film PK should be collected using Schirmer 
strips. 
5  Tear Film PK will be collected using Schirmer Tests strips. These will be collected and sent to the central lab for analysis. See lab manual.   
6  Early termination subjects should complete assessments based on the final visit (Visit 7) schedule of assessments. 
7  Signs, symptoms, conditions occurring prior to insertion on Day 1 should be captured as medical history. 
 


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Appendix 2 
VAS for Eye Dryness  
The following procedures should be followed for conducting the study assessments. The Visual Analog 
Scale (VAS).  
To complete the VAS questionnaire, ask the subject to rate the severity and the frequency of symptom of 
eye dryness (0-100) by placing a vertical mark (ǀ) on the horizontal line to indicate the level of eye 
discomfort that they are experiencing in both eyes currently (i.e., right now) and how often the eye 
dryness is experienced.   
0% corresponds to: “no discomfort” 
100% corresponds to: “maximal (the most) discomfort” 
 
Eye Dryness  
Severity 
 
  0%                                                                                   100% 
|                                                                                                     |        
Eye Dryness Frequency 
 
  0%                                                                                   100%                     
|                                                                                                     |        
 


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Appendix 3 
OSDI 
 


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Appendix 4 
Standard Patient Evaluation of Eye Dryness (SPEED) Questionnaire 
The following procedure should be followed for conducting the study assessments. The Standard Patient 
Evaluation of Eye Dryness (SPEED) should be performed prior to all other ocular assessments.  
Report the type of SYMPTOMS you experience and when they occur: 
 
At This Visit 
Within Past 72 
Hours 
Within Past 3 
Months 
Symptoms 
Yes 
No 
Yes 
No 
Yes 
No 
Dryness, Grittiness, or 
Scratchiness 
 
 
 
 
 
 
Soreness or Irritation 
 
 
 
 
 
 
Burning or Watering 
 
 
 
 
 
 
Eye Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report the FREQUENCY of the above-checked symptoms as Never, Sometimes, Often, or 
Constant using the numbering system below: 
Symptoms 
0 
1 
2 
3 
0 = Never 
1 = Sometimes 
2 = Often 
3 = Constant 
Dryness, Grittiness, or 
Scratchiness 
 
 
 
 
Soreness or Irritation 
 
 
 
 
Burning or Watering 
 
 
 
 
Eye Fatigue 
 
 
 
 
 
 
 
 
 
 
Report the SEVERITY of your symptoms using the rating list: 
Symptoms 
0 
1 
2 
3 
4 
 
Dryness, Grittiness, or 
Scratchiness 
 
 
 
 
 
 
Soreness or Irritation 
 
 
 
 
 
 
Burning or Watering 
 
 
 
 
 
 
Eye Fatigue 
 
 
 
 
 
 
 
0 = No problems 
 
1 = Tolerable – not perfect but not uncomfortable 
 
2 = Uncomfortable – irritating but does not interfere with my day 
 
3 = Bothersome – irritating and interferes with my day 
 
4 = Intolerable – unable to perform my daily tasks 
 


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Appendix 5 
Investigator Rated Conjunctival Hyperemia Grade 
Investigators will rate overall bulbar conjunctival hyperemia using the Cornea and Contact Lens 
Research Unit (CCLRU) Grading Scale. 
 
 
0 = None 
1 = Very Slight 
2 = Slight 
3 = Moderate 
4 = Severe 


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Appendix 6 
Bulbar Conjunctival Hyperemia Photography 
The Investigator will obtain photographs of each eye at baseline and Day 15. These will be 
sent to a central reading center for assessment of bulbar conjunctival hyperemia. Procedures 
will be elaborated in a Photography Manual of Operations. 


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Appendix 7 
Corneal Fluorescein Staining (CFS) Procedure - Using NEI Scale 
CFS may be completed right eye first followed by the left eye.  Using this technique only one 
fluorescein strip is required to apply the dye to both the right and left eye. 
1. 
Wet a sponsor supplied Fluorescein strip with the sponsor supplied saline solution/eye wash.  
Use enough liquid to wet the end of the strip without liquid falling from the end of the strip. 
2. 
Ask the subject to look up and touch the moistened strip to the inferior palpebral conjunctiva 
without touching the strip to the bulbar conjunctiva. 
3. 
Ask the subject to blink several times to distribute the fluorescein dye. 
4. 
Wait between 2 to 3 minutes before evaluating the cornea for staining. 
5. 
Use the cobalt blue illumination and the Wratten yellow filter to assess the corneal staining. 
6. 
Record the staining for each of the 5 regions of the cornea, central, inferior, nasal, temporal, 
and superior using the NEI 0-3 scoring scale (see diagram).  The CFS total score will be the 
sum of the five areas (0 to 15). 
Grade each region, Central (1), Superior (2), Temporal (3), Nasal (4), Inferior (5), for each eye 
according to the following grading scale: 
0 = No Staining 
1 = Mild Staining 
2 = Moderate Staining 
3 = Severe Staining 
NEI Corneal Staining Grading - Scale 
OD 
      
 
 
  OS 
 
 


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Appendix 8 
Best Corrected Visual Acuity 
BCVA will be conducted at all Visits.   
Visual acuity testing should precede any examination requiring contact with the eye or instillation of 
study dyes.  LogMAR visual acuity must be assessed using an ETDRS or modified ETDRS chart.  
Visual acuity testing should be performed with best correction using subject’s own corrective lenses 
(spectacles only) or pinhole refraction. 
An ETDRS or modified ETDRS chart may be used.  If a Lighthouse chart is used (24.5” by 25”; either 
reflectance or retro-illuminated), the subject must view the chart from a distance of exactly 4 meters 
(13.1 feet).  If smaller reproductions (18” by 18”, e.g., Prevent Blindness) are used, the subject viewing 
distance should be exactly 10 feet.  Reflectance wall charts should be frontally illuminated (60-watt bulb 
or a well-lit room). 
The subject should be positioned according to the elevation of the chart (either seated or standing) so 
that the chart is at a comfortable viewing angle.  The right eye should be tested first.  The subject should 
attempt to read each letter, line-by-line, left to right, beginning with line 1 at the top of the chart.  The 
subject should be told that the chart has letters only, no numbers.  If the subject reads a number, he or 
she should be reminded that the chart contains no numbers, and the examiner should then request a letter 
instead of the number.  The subject should be asked to read slowly, about 1 letter per second, to achieve 
the best identification of each letter.  He/she is not to proceed to the next letter until he/she has given a 
definite response.  If the subject changes a response before he has read aloud the next letter, then the 
change must be accepted. 
Maximum effort should be made to identify each letter on the chart; the subject should be encouraged to 
guess.  When it becomes evident that no further meaningful readings can be made, the examiner should 
stop the test.  The number of letters missed or read incorrectly should be noted. 
In order to provide standardized and well-controlled assessments of visual acuity during the 
study, consistently use the same lighting conditions throughout the study. 
LogMAR Visual Acuity Calculations 
After each measurement of visual acuity, the visual acuity score for the visit is calculated. 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 x 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 and line 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 


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Appendix 9 
Slit Lamp Biomicroscopy and External Eye Exam Procedures 
Biomicroscopy 
 
The physician will examine the following using their usual technique: 
 Eyelids (including punctum size) 
 Lashes 
 Conjunctiva 
 Sclera  
 Cornea 
 Anterior Chamber 
 Iris/pupil 
 Lens 
Except for Eyelids (Parameters below), findings will be reported as normal, abnormal non-clinically 
significant, or abnormal clinically significant. For any findings of “abnormal”, the Investigator will 
provide all relevant explanation/comment.  
 
Eyelid/Eyelid Margin Evaluations 
Eyelid Vascularity 
0 = Normal – Typical vascularity for patient age 
1 = Mild vascular engorgement – Slightly dilated and pink blood vessels involving up to 1/3 of the lid 
margin 
2 = Moderate vascular engorgement – Slightly more dilated pink/red blood vessels involving between 
1/3 and 2/3 of the lid margin 
3 = Severe vascular engorgement – Multiple significantly dilated red blood vessels involving between 
1/3 and 2/3 of the lid margin 
4 = Very Severe vascular engorgement – Multiple significantly dilated deep red blood vessels involving 
>2/3 of the lid margin 
 
Meibomian glands (Out of 10 glands evaluated for the lower and upper eyelids) 
1 = Normal: Clear orifices of meibomian glands 
2 = Mild: Less than 1/3 of orifices plugged 
3 = Moderate: Between 1/3 and 2/3 of orifices plugged 
4 = Severe: More than 2/3 of orifices plugged 
5 = Very severe: All orifices plugged 


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Appendix 10 
Tear Film PK Sample collection  
Refer to the lab procedure manual for the complete procedure. 


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Appendix 11 
OTX-DED or HV Insert Suggested Placement Technique 
The following is the suggested placement technique and it can be modified based on investigator’s 
medical judgment. 
1. Apply lateral pressure to elongate the canalicular system.  Pull the skin 
near the punctum down and temporally.  A technician may assist if 
needed.   
 
2. 
Dilate using the punctal dilator in towards the nose, ensuring 
the system is elongated.  Dilate through the punctum deeper into the 
canaliculus, dilate for depth, as well as width.  If desired, rotating the 
dilator in a spinning motion may help with the dilating process. 
 
3. Dry the surface around the punctal opening using an ophthalmic 
sponge.  More than one sponge may be necessary to ensure adequate 
drying of area.  A technician may assist if needed. 
 
4. Grasp OTX-DED or HV insert with forceps and insert at a slight angle 
towards the nose.  Aim for 70% of insertion within the first motion.  
Use forceps to tap or push insert the remainder of the way in.  The 
insert should sit slightly beneath the punctal opening.   
Note:  Excessive squeezing of OTX-DED or HV may cause deformation.  
The product should be handled with care, so it maintains its original shape 
prior to insertion.  If the insert hydrates before placement slightly below 
the punctal opening (resembling a trumpet shape), it should be discarded 
and a new insert should be used.  If the insert hydrates before ideal 
positioning or if a portion of the insert is protruding and unable to be 
inserted, it should be removed, discarded and a new insert should be used. 
(Note:  cutting of the exposed insert is NOT allowed.) 
 
5. OTX-DED or HV insert can be visualized when illuminated by a blue 
light source (e.g., slit lamp or hand-held blue light) with yellow filter. 
 


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Placement of OTX-DED or HV insert in Canaliculus 
 
The investigator will grade the level of ease of insertion of the ophthalmic insert as “easy” (1), 
“moderate” (2) or “difficult” (3).   


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Appendix 12 
OTX-DED or HV Insert Ease of Visualization 
The Investigator will assess the presence of OTX-DED or HV insert at each study visit, using a blue 
light and yellow filter. The Investigator will be asked to grade the level of ease of visualization of the 
punctum plug as “easy”, “moderate”, or “difficult”.  


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Appendix 13 
OTX-DED or HV Insert Removal Instructions 
OTX-DED or HV Insert can be removed either via application of manual pressure or saline irrigation, as 
described below. 
Application of Manual Pressure 
1. 
Identify the OTX-DED or HV insert through the punctal tissue. 
2. 
Place the blunt end of an instrument (e.g., punctum dilator or equivalent) next to the distal end 
of the test article. 
3. 
Apply gentle pressure by pressing on the instrument in an outward motion towards the 
punctum until the test article 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 test article. 
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. 
The investigator will grade the level of ease of removal of the insert as “easy” (1), “moderate” (2) or 
“difficult” (3).  


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Appendix 14 
Daily Subject Diary (For Artificial Tear Use) 
If subjects are using artificial tears as a rescue, they will be asked to complete a dosing diary for each 
administration.  The dosing diary will collect the following information with respect to artificial tear 
administration: 
Date 
Time 
Time 
Time 
Time 
Time 
Initials 
 DD/MMM/YYYY  
___ /____ / _____ 
HR/MIN 
AM/PM 
 
HR/MIN 
AM/PM 
HR/MIN 
AM/PM 
HR/MIN 
AM/PM 
HR/MIN 
AM/PM 
  
 

SAP_001.pdf: 
     Statistical Analysis Plan 
Sponsor:  
Ocular Therapeutix, Inc. 
Protocol: 
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Document Version No.: 
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 CRS-BS-TP-000005 V 1.0  
 
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A randomized, double-masked, vehicle-controlled, phase 2 study to evaluate 
the efficacy and safety of OTX-DED (dexamethasone intracanalicular 
ophthalmic insert) for the short-term treatment of signs and symptoms of dry 
eye disease (DED) 
 
Protocol Number: 
(Version Date) 
OTX-DED-2020-201  
(V04 16 June 2021) 
Name of Test Drug: 
OTX-DED  
Phase: 
 2  
Methodology: 
Randomized, double-masked, vehicle-controlled 
Sponsor: 
Ocular Therapeutix, Inc. 
24 Crosby Drive 
Bedford, MA 01730 USA 
Sponsor Representative: 
Alet Van Beek 
Senior Director, Clinical Operations 
 
Document Date: 
11NOV2021 
Document Version: 
1.0  
 
 






     Statistical Analysis Plan  
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unauthorized person. 
 
TABLE OF CONTENTS  
 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................................................. 10 
1.1. 
INTRODUCTION ............................................................................................................................. 10 
2. 
STUDY DESIGN ................................................................................................................... 11 
2.1. 
SYNOPSIS OF STUDY DESIGN......................................................................................................... 11 
2.2. 
OBJECTIVES OF STATISTICAL ANALYSIS ......................................................................................... 12 
2.3. 
RANDOMIZATION AND MASKING ................................................................................................. 12 
2.4. 
STOPPING RULES AND UNMASKING ............................................................................................. 13 
2.5. 
STUDY PROCEDURES ..................................................................................................................... 13 
2.6. 
EFFICACY, PHARMACOKINETIC, AND SAFETY VARIABLES ............................................................. 16 
2.6.1. 
EFFICACY VARIABLES ................................................................................................... 16 
2.6.2. 
SAFETY VARIABLES ...................................................................................................... 18 
3. 
SUBJECT POPULATIONS ...................................................................................................... 19 
3.1. 
POPULATION DEFINITIONS ........................................................................................................... 19 
3.2. 
PROTOCOL DEVIATIONS ................................................................................................................ 19 
4. 
STATISTICAL METHODS ...................................................................................................... 20 
4.1. 
SAMPLE SIZE JUSTIFICATION ......................................................................................................... 20 
4.2. 
GENERAL STATISTICAL METHODS AND DATA HANDLING ............................................................ 20 
4.2.1. 
GENERAL METHODS .................................................................................................... 20 
4.2.2. 
UNIT OF ANALYSIS....................................................................................................... 21 
4.2.3. 
COMPUTING ENVIRONMENT ...................................................................................... 21 
4.2.4. 
METHODS OF POOLING DATA .................................................................................... 21 
4.2.5. 
ADJUSTMENTS FOR COVARIATES ............................................................................... 22 
4.2.6. 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................... 22 
4.2.7. 
SUBPOPULATIONS....................................................................................................... 22 
4.2.8. 
WITHDRAWALS, DROPOUTS, LOSS TO FOLLOW-UP ................................................... 22 
4.2.9. 
MISSING, UNUSED, AND SPURIOUS DATA .................................................................. 22 


     Statistical Analysis Plan  
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4.2.10. 
VISIT WINDOWS .......................................................................................................... 24 
4.3. 
INTERIM ANALYSES ....................................................................................................................... 24 
4.4. 
SUBJECT DISPOSITION ................................................................................................................... 24 
4.5. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................... 24 
4.5.1. 
BASELINE OCULAR ASSESSMENTS .............................................................................. 25 
4.5.2. 
OCULAR AND NON-OCULAR MEDICAL HISTORY ......................................................... 25 
4.6. 
TREATMENT EXPOSURE ................................................................................................................ 25 
4.7. 
EFFICACY EVALUATION ................................................................................................................. 26 
4.7.1. 
PRIMARY ANALYSES .................................................................................................... 26 
4.7.2. 
SENSITIVITY ANALYSES ................................................................................................ 27 
4.7.3. 
SECONDARY ANALYSES ............................................................................................... 27 
4.7.4. 
EXPLORATORY ANALYSES ............................................................................................ 28 
4.8. 
PHARMACOKINETIC EVALUATIONS .............................................................................................. 28 
4.9. 
SAFETY ANALYSES ......................................................................................................................... 28 
4.9.1. 
ADVERSE EVENTS ........................................................................................................ 28 
4.9.2. 
NON-AE SAFETY ANALYSES ......................................................................................... 29 
4.9.3. 
LABORATORY DATA..................................................................................................... 30 
4.9.4. 
VITAL SIGNS AND PHYSICAL EXAMINATIONS .............................................................. 30 
4.9.5. 
CONCOMITANT MEDICATIONS ................................................................................... 30 
5. 
CHANGES TO PLANNED ANALYSES ...................................................................................... 32 
6. 
REFERENCES ...................................................................................................................... 33 
7. 
CLINICAL STUDY REPORT APPENDICES ................................................................................ 34 
7.1. 
SAS CODES .................................................................................................................................... 34 
7.1.1. 
SAS CODES TO IMPUTE THE MISSING USING MCMC MI ............................................ 34 
7.1.2. 
SAS CODES TO IMPUTE THE MISSING USING FCS MI .................................................. 34 
7.1.3. 
SAS CODES TO RUN ANCOVA (USING PROC MIXED) ON MI DATA ............................. 35 
7.1.4. 
SAS CODES TO RUN T-TEST ON MI DATA .................................................................... 35 
7.1.5. 
SAS CODES TO RUN ANCOVA (USING PROC MIXED) ON OBSERVED 
DATA AND LOCF .......................................................................................................... 35 


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7.1.6. 
SAS CODES TO OUTPUT 95% CI FOR PROPORTIONS USING CLOPPER-
PEARSON METHOD AND 95% CI FOR THE PROPORTION DIFFERENCE 
USING CHAN AND ZHANG (1999) METHOD USING OBSERVED AND 
LOCF DATA .................................................................................................................. 36 
 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Treatment Assignment Paradigm  ................................................................................... 11 
Table 2 
Schedule of Assessments ................................................................................................ 14  
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event/Experience 
AT 
Artificial Tears 
BCVA 
Best Corrected Visual Acuity 
C 
Celsius 
CD 
Compact Disc 
CCLRU 
Cornea and Contact Lens Research Unit 
CFB  
Change from Baseline 
CFR 
Code of Federal Regulations 
CFS 
Corneal Fluorescein Staining 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CV 
Curriculum Vitae 
DED 
Dry Eye Disease 
E 
Electronic 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Scoring 
FCS MI 
Fully Conditional Specification multiple imputation 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HV 
Hydrogel Vehicle Insert 
ICH 
International Council on Harmonization 
ICF 
Informed Consent Form 
ID 
Subject Identification 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 


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Abbreviation 
Definition 
IUD 
Intra-Uterine Device 
KCS 
Keratoconjunctivitis Sicca 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
NDA 
New Drug Application 
NEI 
National Eye Institute 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
PP 
Per Protocol 
OD 
Right Eye 
OS 
Left eye 
OSDI 
Ocular Surface Disease Index 
OTX 
Ocular Therapeutix 
OTX-DED 
Dexamethasone Ophthalmic Insert 
PK 
Pharmacokinetics 
QD 
quaque die (one a day) 
SAE 
Serious Adverse Event/Experience 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBUT 
Tear Film Break Up Time 
tCFS 
Total Corneal Fluorescein Staining 
UPT 
Urine Pregnancy Test 
US 
United States 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WOCBP 
Women of Childbearing Potential 


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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized 
by symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully 
understood, it is recognized that inflammation has a prominent role in the development and 
propagation of this debilitating condition. Factors that adversely affect tear film stability and 
osmolarity can induce ocular surface damage and initiate an inflammatory cascade that 
generates innate and adaptive immune responses. These immunoinflammatory responses lead 
to further ocular surface damage and the development of a self-perpetuating inflammatory 
cycle. 
DED flares are rapid-onset, inflammation driven responses to a variety of triggers that typically 
cannot be adequately managed with patients ongoing maintenance therapy – such as artificial 
tears and chronic prescribed therapies (ASCRS, 2019). Ocular surface inflammation plays a key 
role in all types of DED and conjunctival hyperemia in DED is a good indicator of inflammation 
(Baudouin, 2018). Acute DED flares are driven by both innate and adaptive immune responses 
(Perez et al., 2020) and corticosteroids targets both innate and adaptive immune response 
(Jones et al., 2017). 
Ocular Therapeutix has designed a resorbable intracanalicular insert as the platform for drug 
delivery products which can be used to deliver various active pharmaceutical ingredients 
approved by the Food and Drug Administration (FDA). 
OTX-DED is an intracanalicular insert that consists of two main components: dexamethasone 
and polyethylene glycol (PEG) based hydrogel conjugated with fluorescein. OTX-DED contains 
approximately 0.2 mg or 0.3 mg of dexamethasone and is designed to provide a sustained and 
tapered release of dexamethasone for up to 14 and 21 days, respectively. Over this time and 
through hydrolysis, OTX-DED softens, liquefies and is cleared through the nasolacrimal duct 
without the need for removal.  
 
 
 
 
 
 


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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a randomized, multi-center, double-masked, vehicle-controlled, phase 2 clinical study 
designed to evaluate the efficacy and safety of OTX-DED (dexamethasone ophthalmic insert) for 
intracanalicular use for the short-term treatment of DED. Approximately 150 subjects (300 eyes) 
will be enrolled in this study at approximately 15 sites in the US. Subjects will be a randomized 
to one of three treatment groups as noted in Table 2. Both eyes will be treated with the same 
treatment. 
 
Table 1 Treatment Assignment Paradigm 
Name Number of Subjects 
Number of Subjects 
OTX-DED 0.2mg Dexamethasone Ophthalmic Insert 
50 
OTX-DED 0.3mg Dexamethasone Ophthalmic Insert 
50 
Hydrogel Vehicle (HV) Insert 50 
50 
 
Subjects will undergo Screening 14 days prior to Insertion/Day 1 (Visit 2). At Visit 2 (Insertion/Day 
1) eligibility will be confirmed and subjects who are eligible will be randomly assigned to one of 
three treatment groups. The treatment follow-up visits will occur at Visit 3 (Day 8), Visit 4 (Day 
15), Visit 5 (Day 22), Visit 6 (Day 29), Visit 7 (Day 57). 
This study will be conducted per the schedule shown in Figure 1 
 
 
 


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Figure 1:  Study schematic 
 
2.2. 
Objectives of Statistical Analysis 
To assess the efficacy and safety of OTX-DED for the short-term treatment of signs and 
symptoms of Dry Eye Disease. 
2.3. 
Randomization and Masking 
Subjects will be randomized to treatment assignment.  
A randomization schedule will be computer-generated by a qualified biostatistician independent 
of the study conduct or project team and uploaded into the EDC system. The EDC/IRT system 
will be used for randomization and unmasking.  The OTX-DED and HV inserts administered to 
subjects at randomization in the double-masked treatment phase will be comparable in 
appearance. Eligible subjects will be randomly assigned to one of three treatment groups (OTX-
DED 0.2mg, OTX-DED 0.3mg, or HV) in a 1:1:1 ratio. 
Study subjects and investigators and their staff will be masked to the identity of treatment until 
the final database is locked. The Sponsor’s personnel involved with the conduct and monitoring 
of the study will remain masked until completion of the study and database lock.  


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2.4. 
Stopping Rules and Unmasking 
Should it become apparent during the trial that there is a significant safety concern or there is 
an issue with enrollment, the trial may be terminated. In addition, should information become 
known during the course of the trial that would negatively impact the trial, the trial may be 
terminated. In addition, the FDA or another regulatory authority may terminate the trial. 
Appropriate precautions must be taken to prevent unauthorized access to the randomization 
scheme. Unless the subject’s safety requires otherwise and if time permits, the decision to 
unmask a treatment assignment is to be made jointly by the Investigator and Sponsor’s medical 
monitor. 
If unmasking is required, the integrity of the study assessments and objectives will be maintained 
by limiting access to the unmasked data. 
2.5. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 
 
 
 
 


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Table 2 
Schedule of Assessments 
 


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1 A negative UPT is required for women of childbearing age to be included in the study. 
2 Dilated fundus examination at screening; undilated fundus examination at Week 8. 
3 Prior to insertion, a clinical determination of the absence of infection will be made based on the lack of erythema or discharge at the punctum. If placement is only successful 
in one eye, subjects should be asked to return within 1-3 days to attempt insertion in the other eye. The following items should be repeated at the return visit, Insert Placement, 
Ease of Insertion, Tear Film PK and AEs. 
4 Tear Film PK will be collected at 1 hour (±30 minutes), 2 hours (±30 minutes), and 4 hours (±30 minutes) post insertion on Day 1. Tear Film PK should be collected using 
Schirmer strips. 
5 Tear Film PK will be collected using Schirmer Tests strips. These will be collected and sent to the central lab for analysis. See lab manual. 
6 Early termination subjects should complete assessments based on the final visit (Visit 7) schedule of assessments. 
7 Signs, symptoms, conditions occurring prior to insertion on Day 1 should be captured as medical history. 
 
 
 
 
 
 
 
 
 
 


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2.6. 
Efficacy, Pharmacokinetic, and Safety Variables 
2.6.1. 
Efficacy Variables 
2.6.1.1. 
Primary Efficacy Variables 
1- Photographic assessment of bulbar conjunctival hyperemia (evaluated via central 
reading center) change from baseline (CFB) at Visit 4 (Day 15) in study eye. 
The primary analysis will be based on the change from baseline in worst zone of photographic 
assessment of bulbar conjunctival hyperemia at baseline in the study eye. The worst (highest 
grading score) zone will be determined among Nasal, Temporal, and Frontal zones of 
photographic assessment of bulbar conjunctival hyperemia; if there are equal scores in two or 
more zones, the worst zone will be selected in a preferential order with Nasal zone being the 
most preferred, followed by Temporal zone, and then by Frontal zone in study eye at baseline. 
Change from baseline in this same chosen zone at Visit 4 (Day 15) will be investigated.  
 
2.6.1.2. 
Secondary Efficacy Variables 
1- Severity of Eye Dryness Score (visual analogue scale [VAS]) and their CFB at Visit4  (Day 
15) and other post-baseline visits. 
2- Frequency Eye Dryness Score (visual analogue scale [VAS]) and their CFB at Visit4  (Day 
15) and other post-baseline visits. 
3- Investigator assessment of bulbar conjunctival hyperemia  and their CFB at Visit 4 (Day 
15) and other post-baseline visits,  
4- Absolute value of photographic assessment of bulbar conjunctival hyperemia (evaluated 
via central reading center) at Visit 4 (Day 15). 
For this analysis, similar to primary efficacy variable, the worst (highest grading score) zone will 
be determined among Nasal, Temporal, and Frontal zones of bulbar conjunctival hyperemia 
assessed by investigator; if equal scores in two or more zones, the worst zone will be selected in 
a preferential order with Nasal zone being the most preferred, followed by Temporal zone, and 
then by Frontal zone in study eye at baseline. Change from baseline in this same chosen zone at 
each post-baseline visit will be investigated. 
5- Total Corneal Fluorescein Staining (tCFS) using National Eye Institute (NEI) scale and its  
CFB to each post-baseline visit. 
6- CFS sub-regions using NEI scale and its CFB to each post-baseline visit. 


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7- Ocular Surface Disease Index questionnaire (OSDI©) questionnaire, CFB and absolute 
values at each post-baseline visit (total score, each of the three domains, and individual 
questions). 
- 
OSDI total score will be calculated using below OSDI© formula:  
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 = (𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓 𝑎𝑎𝑎𝑎𝑎𝑎 𝑞𝑞𝑞𝑞𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎) ×  25
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
 
 
- 
OSDI score for each section (ABC) will be calculated using below formula: 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓 𝑒𝑒𝑒𝑒𝑒𝑒ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 (𝐴𝐴, 𝐵𝐵, 𝐶𝐶)
= (𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓 𝑎𝑎𝑎𝑎𝑎𝑎 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓 𝑡𝑡ℎ𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠) ×  25
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
 
The OSDI is scored on a scale of 0 to 100, with higher scores representing greater. 
8- SPEED questionnaire (overall score and individual questions), CFB at each post-baseline 
visit. 
 
2.6.1.3. 
 Exploratory Efficacy Variables 
1- Presence of OTX-DED or HV insert at all post-baseline visits 
2- Ease of insertion as assessed by the Investigator 
3- Ease of visualization as assessed by the Investigator 
4- Schirmer Test without anesthesia CFB 
 
 


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2.6.2. Safety Variables 
1- Ocular and Non-Ocular Adverse Events  
2- Best Corrected Visual Acuity (BCVA): LogMAR Visual Acuity (VA) score at each visit and 
its CFB at each post-baseline visit. 
3- Slit Lamp biomicroscopy parameters by location (Eyelid Vascularity (vascular 
engorgement), Meibomian Glands (upper and lower lid orifice plugging), Punctal 
Appearance, Lid Apposition, Lashes, Cornea, Sclera, Conjunctiva, Anterior Chamber, Iris, 
Pupil, Lens) at baseline and at each post-baseline visit. 
4- Intraocular Pressure (IOP) measurement (mmHg) and CFB by visit. 
5- Fundus Examination: Vitreous, Retina, Macula, Choroid, Optic Nerve at baseline and at 
Visit 7 (Day 57). 
6- Artificial tear use during the study: the use of Artificial tears since last visit at each post-
baseline visit. 
 
 
 


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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
1. Intent-to-Treat (ITT): The ITT population will include all randomized subjects. Subjects 
who are randomized but not treated due to procedural screen failures will be included 
as part of ITT population.  
2. Modified Intent-to-Treat (mITT): The Modified ITT will include all subjects in ITT who 
received the insert in the study eye, investigational product (IP) (OTX-DED or HV). The 
mITT population will be used as the primary efficacy analysis population and will also be 
used for all efficacy endpoints.  Analyses performed on the mITT population will be 
according to the treatment the subject are randomized. 
3. Per Protocol (PP): The PP population will include all mITT subjects who do not have any 
major protocol deviation which is likely to seriously affect the safety and efficacy 
outcomes of the study and who do not report excessive artificial tear use defined as 
greater or equal to 30 drops between Insertion/Day 1 (Visit 2) and Week 2 (Visit 4). 
Analysis on the PP population will be used as secondary efficacy analysis and will be 
performed for select efficacy endpoints, analyzing subjects under the treatment actually 
received. Important protocol deviations will be identified prior to locking the study 
database. 
4. Safety: The Safety population will include all randomized subjects who received 
Investigational Product (IP) (OTX-DED or HV). Analyses performed on the Safety 
population will be according to the treatment the subject actually received. 
 
3.2. 
Protocol Deviations 
At the discretion of the sponsor, major protocol deviations as determined by a review of the 
data prior to unmasking of the study results and the conduct of statistical analyses may result in 
the removal of a subject’s data from the PP Population. This file will include a description of the 
protocol deviations, as well as classification of major or minor. It will be finalized prior to hard 
database lock and unmasking. Major protocol deviations will be summarized by treatment 
groups and overall. The data listing for all protocol violations will be also presented. 
 
 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
This study is not powered to show statistical significance but will provide initial estimates and 
trends of the endpoints for use in future trial designs. The sample size will allow for safety 
information to be obtained, while still limiting the number of subjects exposed to the IP. 
Statistical analyses will be descriptive. 
The trial will include approximately 150 subjects (300 eyes) from approximately 15 sites. 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All output will be incorporated into Microsoft Excel or Word files, sorted, and labeled according 
to the International Council on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
each category of the parameter will be presented by treatment groups and visits (as applicable). 
For continuous variables, the n, mean, standard deviation, median, minimum, and maximum 
values will be presented.  
The baseline visit will be defined as the last non-missing measure prior to initiation of IP. 
Differences between treatment groups will be calculated as OTX-DED minus HV and change from 
baseline will be calculated as follow up visit minus baseline visit values. In addition to looking at 
the individual formulations, the two formulations of OTX-DED will be combined and 
summarized.  
All statistical testing will be done at the two-sided alpha level of 0.05, with no adjustments due 
to multiple endpoints testing.  
 
 


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4.2.2. 
Unit of Analysis 
Both eyes will be treated with the same treatment/formulation. The study eye and non-study 
eye will be determined at the time of programing as follows. If both eyes qualify, the eye having 
the highest (worst) grading score among Nasal, Temporal, and Frontal zones from the 
photographic assessment of conjunctival hyperemia at baseline will be designated as the study 
eye and the other eye will be designated as the non-study eye.  If both eyes have the same 
photographic assessment conjunctival hyperemia the highest (worst) grade score, the right eye 
will be the study eye. If only one eye qualifies, that eye will be the study eye, but both eyes will 
still receive the same treatment/formulation and be included in the safety analysis. If only an 
insert is successfully placed in one eye, then that eye will be the study eye, if it qualifies for the 
study. 
The unit of analysis will be the study eye (primary study eye) with the worst zone chosen for 
bulbar conjunctival hyperemia summaries and analyses. If there are equal scores in two or more 
zones, the worst zone will be selected in a preferential order with Nasal zone being the most 
preferred, followed by Temporal zone, and then by Frontal zone. Efficacy summaries will be 
presented for both study and non-study eyes. Safety summaries will include summaries of both 
study and non-study eyes. All primary, sensitivity, secondary, and exploratory endpoints will be 
analyzed for both study and non-study eyes, separately. All summaries will be presented by 
treatment groups and visits, where appropriate. In addition to looking at the individual 
formulations, the two formulations of OTX-DED will be combined and summarized. 
 
4.2.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4), 
unless otherwise noted. Medical History and adverse events will be coding using Medical 
Dictionary for Regulatory Activities (MedDRA) version 24.0 - Mar 2021.  Concomitant 
medications will be coded using World Health Organization (WHO) DD B3 WHO Drug DDE – Sep 
2020.  
 
4.2.4. 
Methods of Pooling Data 
The two OTX-DED formulations will be presented separately as individual formulations and 
combined.   
 


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4.2.5. 
Adjustments for Covariates 
The baseline value will be included in the analysis of covariance (ANCOVA) model as a covariate 
for adjustment. 
 
4.2.6. 
Multiple Comparisons/Multiplicity 
To control the type I error for the hypothesis testing of the primary endpoint, least square means 
will be used to make treatment comparisons using Dunnett's adjustment for multiple 
comparisons to a control. 
As this is a Phase 2 study, no adjustments to alpha will be made for testing of multiple endpoints.  
4.2.7. 
Subpopulations 
No analyses of subgroups of subjects are planned. 
 
4.2.8. 
Withdrawals, Dropouts, Loss to Follow-up 
Any subject who wishes to voluntarily discontinue study drug or withdraw from participation in 
the study for any reason is entitled to do so without obligation. IP may be discontinued (insert 
removed) and any subject may be discontinued from study participation at any time during the 
study at the discretion of the Investigator or the Sponsor for any reason. 
In the event that study discontinuation of a randomized subject is necessary, the Investigator 
should make every attempt to have the subject complete Visit 7 assessments as soon as possible. 
The reason for premature discontinuation should be recorded in the subject chart and entered 
in the eCRF. 
Subjects who withdraw will not be replaced. 
 
4.2.9. 
Missing, Unused, and Spurious Data 
If the start date of an AE is partially or completely missing, the date will be compared as far as 
possible with the date of the start of administration of study drug. The AE will be assumed to be 
treatment-emergent if it cannot be definitively shown that the AE did not occur or worsen during 
the treatment-emergent period (worst case approach). The imputed dates will only be used to 
classify events as treatment emergent and will only be used in the table analyses. Listings will 
display the available date data. 
The following general rules will be used: 
• If the start day is missing but the start month and year are complete, an AE will only be 
excluded as being treatment-emergent if the start month/year is before the month/year 


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of study drug administration or if the date of resolution is before study drug 
administration.  
• If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment-emergent if start year is before the year of study drug 
administration or if the date of resolution is before study drug administration.  
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the date of resolution is before study drug administration. 
 
4.2.9.1. 
Imputation Method for Primary Efficacy Endpoints 
To impute missing, Markov Chain Monte Carlo (MCMC) multiple imputation (MI), Fully 
Conditional Specification multiple imputation (FCS MI) and LOCF methods will be used.  
For MI, we will have below phases: 
1. Imputation Phase: in this phase, the missing data will be imputed using SAS PROC MI 
and a complete data set will be created. This process of imputation will be repeated 25 
times. Therefore, 25 compete datasets will be created. In this phase, treatment group, 
baseline value, and post-baseline visits will be included in multiple imputation model. 
2. Analysis Phase: each of the 25 complete data sets will be analyzed independently using 
desired statistical method (e.g. ANCOVA for primary efficacy analysis). 
3. Pooling Phase: in this phase the estimates obtained from each analyzed complete 
dataset from phase 2, will be combined using PROC MIANALYZE. 
The primary analyses of efficacy data will use MCMC MI methodology to impute missing data. 
The expectation and maximization (EM) algorithm will be used to estimate the mean vector and 
the covariance assuming a missing at random (MAR) distribution. The MAR distribution assumes 
the probability that a value is missing does not depend on the true values of the missing items. 
The imputation phase will create 25 copies of the dataset which will contain different estimates 
of the missing values. The 25 complete datasets will then be analyzed to produce several sets of 
parameter estimates and standard errors, which will then be pooled to create a single set of 
results. 
Last observation carried forward (LOCF) method and Fully Conditional Specification multiple 
imputation (FCS MI) with 200 burn-in iterations and 25 times of imputation under the 
assumption of missingness at random will be used for sensitivity analyses (Section 4.7.2). 
 
 


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4.2.10. 
Visit Windows 
Visit windows will be calculated based on the Schedule of Assessments in Table 1. Any visits or 
procedures performed outside the scheduled visits will be documented in the Unscheduled Visit 
page of the eCRF. Although there is a visit window around the expected visit date, nominal visits 
will be used for the per-visit analyses. 
4.3. 
Interim Analyses 
An interim analysis was not planned for this study. 
4.4. 
Subject Disposition 
A summary of subject disposition will be tabulated, including the number screened, screened 
failure, and procedural screen failures will be presented. Subjects are considered procedural 
screen failures if the investigator is unsuccessful at placing the OTXDED or HV intracanalicular 
ophthalmic insert in both eyes (i.e. neither eye has an insert). Procedural screen failures will be 
exited from the study at that time,  and will be included in the disposition tables as ‘randomized, 
not treated’. Subjects will be followed per protocol if the investigator successfully places one 
insert. 
The number and percentage of subjects included in each of the analysis populations (ITT, mITT, 
PP, Safety) will be presented by treatment groups and overall. Subject disposition events 
including randomization, treated, completed study, withdrawal prior to completing the study, 
and reasons for withdrawal will be summarized by treatment groups and overall. 
A by-subject listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
4.5. 
Demographic and Baseline Characteristics 
Baseline and demographic information will be summarized for the mITT population using 
descriptive statistics. Demographic characteristic information will include Age (year), Age 
categories (<65, ≥65), Gender (Male, Female), Ethnicity (Hispanic or Latino, Not Hispanic or 
Latino), and Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Unknown, Other). 
Demographic and Baseline data will be provided in data listings. 
 
 


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4.5.1. 
Baseline Ocular Assessments 
The following baseline assessments will be presented using descriptive statistics for mITT 
population by treatment group and overall. 
The assessments below will be assessed: 
1. Bulbar conjunctival hyperemia (worst zone, Nasal, Temporal, Frontal, Total of 3 zones) 
2. Eye Dryness Severity (VAS) Score  
3. Eye Dryness Frequency (VAS) Score 
4. Investigator assessment of bulbar conjunctival hyperemia 
5. Corneal Fluorescein Staining (tCFS) by study eye 
6. CFS sub-regions using NEI scale by study eye 
7. OSDI total score (0-100) and the score of its three domains 
8. SPEED Total Score (0-28) 
9. Best Corrected Visual Acuity (BCVA) LogMAR Score 
10. IOP Measurement (mmHg) 
11. Unanesthetized Schirmer’s Test 
 
4.5.2. 
Ocular and Non-Ocular Medical History 
Medical history, including ocular medical history, will be coded using MedDRA Version 24.0 – 
Mar 2021. Non-ocular medical history will be summarized in the mITT population by system 
organ class (SOC) and preferred term (PT) by treatment group and overall. SOC will be sorted 
alphabetically. PT will be sorted by descending frequency overall within each SOC. Subjects with 
a particular medical history event or medical history class will be counted once at the PT level 
and once at the SOC level. Ocular medical history will be summarized at the eye and subject 
levels by treatment group and overall, for the mITT population with separate summaries for the 
study eye and non-study eye. 
Data listings will be provided for medical history as well. 
4.6. 
Treatment Exposure  
Details of study drug administration, including duration of treatment will be tabulated and 
presented for the  Safety population.  The duration of exposure will be calculated in days as 
latest date investigator confirms insert is not present in either eye minus date of the earliest 
insertion in either eye plus 1 and summarized using descriptive statistics by treatment group and 


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overall. Treatment exposure for subjects who discontinue the study prior to the insert no longer 
being present in both eyes, will be calculated in days as date of last insert visualization in either 
eye minus date of the earliest insertion in either eye plus 1. In addition, treatment exposure for 
subjects who discontinue the study prior to the insert no longer being present in both eyes will 
be set to the longest observed insert exposure as an additional analysis. 
All dosing information will be presented in a data listing. 
4.7. 
Efficacy Evaluation 
The efficacy summaries and analyses will be presented for both study and non-study eyes.  
The Primary efficacy analysis of the bulbar conjunctival hyperemia will be conducted using the 
mITT and PP populations.  
 
4.7.1. 
Primary Analyses 
For the primary efficacy endpoint analyses of change from baseline in photographic assessment 
of bulbar conjunctival hyperemia (evaluated by central reading center) worst zone in the study 
eye at Visit  4  (Day 15) (as defined in section 2.6.1.1), the following modeling and analyses will 
be performed on  mITT population, observed data: 
An analysis of covariance (ANCOVA) model will be run to estimate least square (LS) means 
treatment. This model will include the baseline value as a covariate for adjustment and 
treatment group as the sole factor. Least square means will be used to make treatment 
comparisons using Dunnett's adjustment for multiple comparisons to a control. Statistical 
significance of treatment differences will be determined using a two-sided significance level of 
α =0.05.  
In the ANCOVA model, LS means treatment group comparison of OTX-DED 0.2 mg to HV, OTX-
DED 0.3 mg to HV, and Overall OTX-DED (combined OTX-DED 0.2 mg and OTX-DED 0.3 mg using 
sample size weights of OTX-DED 0.2 mg and OTX-DED 0.3 mg groups as coefficients for the 
parameters) to HV will be reported. Unadjusted treatment group analyses using two-sample t-
test and Wilcoxon rank sum test will be run on these treatment group combinations.  
Each bulbar conjunctival hyperemia zone (Nasal, Temporal, and Frontal) and the Total of the 
three zones in study eye will be analyzed in a manner similar to the primary efficacy variable as 
described above.  
The same analyses will be done for the non-study eye. For non-study eye, the worst zone similar 
to worst zone in study eye (details in section 2.6.1.1) will be independently determined using 
photographic assessment bulbar conjunctival hyperemia in non-study eye at baseline. 


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The primary efficacy endpoints will also be analyzed on PP population.  
 
4.7.2. 
Sensitivity Analyses 
To determine robustness of results, the sensitivity analyses will be performed for the primary 
efficacy endpoint, bulbar conjunctival hyperemia at Visit   
4  (Day 15), on the mITT and PP 
populations by using:  
1. MCMC MI 
2. last observation carried forward (LOCF)  
3. FCS MI. 
As sensitivity analyses, LOCF will be analyzed in a manner similar to the primary efficacy variable 
(details in section 4.7.1). MCMC MI and FCS MI will be analyzed in a manner similar to the 
primary efficacy variable (details in section 4.7.1), however, for treatment comparisons, least 
square means will not be adjusted for multiple comparison and for the unadjusted treatment 
group comparisons, only t-test will be used. 
 
4.7.3. 
Secondary Analyses 
The below secondary efficacy endpoints will be analyzed in a manner similar to the primary 
efficacy variable using ANCOVA model of change from baseline using observed data: 
1. Severity of eye dryness score at Visit 4 (Day 15) and other post-baseline visits,  
2. Frequency of eye dryness score at Visit 4 (Day 15) and other post-baseline visits, 
3. Investigator assessment of bulbar conjunctival hyperemia in worst zone, Nasal, 
Temporal, Frontal zones, and Total at each post-baseline visit,  
4. Total corneal fluorescein staining (tCFS) and CFS sub-regions at each post-baseline visit.  
In addition, sensitivity analyses done for the primary efficacy endpoint (section 4.7.2) will also 
be performed on severity and frequency of eye dryness scores, investigator assessment of 
bulbar conjunctival hyperemia, tCFS, and CFS sub-regions endpoints. 
The below secondary efficacy endpoints will be analyzed using ANCOVA model of change from 
baseline at each post-baseline visit similar to primary efficacy endpoint analysis (section 4.7.1) 
using observed data: 
5. Ocular Surface Disease Index questionnaire (OSDI©) at each post-baseline visit (total 
score, each of the three domains, and individual questions) and  
6. SPEED questionnaire (overall score and individual questions), CFB at each post-baseline 
visit will be analyzed 


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All the secondary endpoints will be analyzed on mITT and PP populations; therefore, related 
summary tables will be reported for both mITT and PP populations.  
 
4.7.4. 
Exploratory Analyses 
Ease of insertion as assessed by the Investigator at Visit 2 or Visit 2B, presence of OTX-DED or 
HV insert and ease of visualization as assessed by the Investigator at all post-baseline visits will 
be summarized using discrete statistics (number and percentage) and will be tested between 
treatment groups (OTX-DED 0.2 mg to HV, OTX-DED 0.3 mg to HV, and Overall OTX-DED 
(combined OTX-DED 0.2 mg and OTX-DED 0.3 mg) to HV). To analyze ease of insertion as 
assessed by the Investigator and ease of visualization as assessed by the Investigator, the 
Pearson Chi-squared statistic will be used. To analyze presence of insert, Fisher’s exact Test will 
be used, and Clopper-Pearson method will be used to calculate 95% confidence interval of the 
proportion of subject with presence of insert; to calculate 95% confidence interval of the 
proportion difference, the Chan and Zhang (1999) method will be used. 
The Schirmer Test without anesthesia will be summarized using descriptive statistics by 
treatment group and overall and it will be analyzed using ANCOVA model of both change from 
baseline and absolute value at each post-baseline visit similar to primary efficacy endpoint 
analysis (section 4.7.1) using observed data.  
The exploratory analyses will be done on mITT populations 
 
4.8. 
Pharmacokinetic Evaluations 
PK analysis will be described separately. 
4.9. 
Safety Analyses 
All safety analyses will be conducted on the Safety population.   
 
4.9.1. 
Adverse Events 
Adverse events will be coded using MedDRA Version 24.0 – Mar 2021  and displayed in tables 
and listings using System Organ Class (SOC) and Preferred Term (PT). 
Analyses of adverse events will be performed for those events that are considered treatment 
emergent adverse events (TEAE), where treatment emergent is defined as any adverse event 


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with onset on or after the first dose of study medication through the end of the study or any 
event that was present at baseline but worsened in intensity or was considered drug-related by 
the investigator through the end of the study.   
The safety will be assessed by incidence of TEAEs, therefore, in any tabulation, a subject 
contributes only once to the count for a given adverse event (SOC or preferred term). An overall 
summary of TEAEs will be presented including the number of events and the number of the 
subjects with events along with percentages by treatment group and overall. The overall 
summary will include subjects with AE leading to death, subjects with TEAEs leading to insert 
removal and subjects with TEAEs leading to subject withdrawal. In summary tables, SOC will be 
presented alphabetically and events within SOC will be presented by decreasing frequency count 
based on the total column. 
 The frequency and percentage of subjects with any TEAE, any serious TEAE, any TEAEs by 
relationship to treatment (unrelated, related), any serious TEAEs by relationship to treatment 
(unrelated, related), any TEAE by severity (mild, moderate, or severe) will be summarized 
separately for ocular and non-ocular events by treatment group and overall. Separate 
summaries for ocular TEAEs and non-ocular TEAEs by preferred terms in decreasing frequency 
based on all subjects will be tabulated. 
All adverse events will be listed in subject data listings. 
By-subject listings also will be provided for the following: subject deaths; serious adverse events; 
and adverse events leading to withdrawal. 
 
4.9.2. 
Non-AE Safety Analyses 
The following safety assessments will be summarized using descriptive statistics for Safety 
population by treatment group and overall. Assessments will be presented for study eye and 
non-study eye separately. 
1. Best Corrected Visual Acuity (BCVA) 
LogMAR Visual Acuity (VA) score for each visit, its CFB, and loss 3 Lines or more in BCVA 
LogMAR Score from Baseline at each post-baseline visit will be calculated and 
summarized using descriptive statistics. 
2. Slit-Lamp biomicroscopy  
The evaluation of normal, mild, moderate, severe, and very severe for each eye in Eyelid 
Vascularity (vascular engorgement) and Meibomian Glands (upper and lower lid orifice 
plugging) , as well as normal, abnormal non-clinically significant, and abnormal clinically 
significant for each eye in Punctal Appearance, Lid Apposition, Lashes, Conjunctiva, 


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Sclera, Cornea, Anterior Chamber, Iris, Pupil, and Lens will be tabulated for each visit by 
using the frequency and percentage. 
3. Intraocular Pressure (IOP) measurement (mmHg) 
Absolute values and CFB of IOP at each post-baseline visit, absolute IOP measurement ≥ 
30 mmHg at each visit, and CFB in IOP > 5 mmHg as well as >10 mmHg at each post-
baseline visit will be summarized using descriptive statistics. 
4. Fundus Examination  
The evaluation of normal, abnormal non-clinically significant, and abnormal clinically 
significant for each eye in vitreous, retina, macula, choroid, and optic nerve exam will be 
tabulated for visit 1 and visit 7 by using the frequency and percentage. The absolute cup-
to-disc ratio at baseline and Visit 7 (Day 57) and its CFB at Visit 7 (Day 57) will be 
presented using descriptive statistics.  
5. Artificial tears use during the study 
The use of artificial tears, based on the Daily Subject Diary, since last visit will be 
tabulated for each post-baseline visit by using frequency and percentage. Number of 
times AT used since last visit will be reported among all subjects who have any daily 
subject dairy data since the last visit using descriptive statistics.  
 
4.9.3. 
Laboratory Data 
Safety laboratory tests will not be collected. Urine pregnancy test results will be captured at Visit 
2 (Day 1) and Visit 7 (Day 57). Urine pregnancy test results will be provided in data listing. 
 
4.9.4. 
Vital Signs and Physical Examinations 
Vital signs and physical examinations data will not be collected. 
 
4.9.5. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary, DD B3 WHO Drug DDE 
– Sep 2020. Results will be tabulated by Anatomic Therapeutic Class (ATC) and preferred term. 
Concomitant medications will be defined as those medications that were initiated after study 
drug administration or those that were ongoing at the time of study drug administration. If the 
start date or end date of a medication is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug. The medication will be 


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assumed to be prior medication if it cannot be definitively shown that the medication did not 
start or continue during the treatment period. 
Non-ocular prior and concomitant medications will be summarized by higher ATC level 3 
(therapeutic subgroup) and preferred term by treatment group and overall, in the Safety 
population.  ATC Level 3 terms will be sorted alphabetically. Preferred terms will be sorted by 
descending frequency overall within ATC Level 3 term. Subjects receiving a particular medication 
or medication of ATC Level 3 will be counted once at the preferred term level and once at ATC 
Level 3.  
Ocular prior and concomitant medications will be summarized at the eye level, separately for 
study and non-study eyes, and at the subject level (both eyes) by ATC Level 3 and preferred term 
by treatment group and overall, in the Safety population. 
All prior and concomitant medications information will be presented in the data listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
The primary, sensitivity, and secondary efficacy endpoints will be analyzed using both mITT and 
PP populations.  
Protocol pre-specified primary analysis is multiple imputation using MCMC with Dunnett’s 
adjustment.  Upon further technical research, multiple imputation using MCMC with Dunnett’s 
adjustment can’t be correctly implemented.  Due to the current limitation of multiple imputation 
with multiplicity correction, the primary analysis will be conducted using observed data with 
Dunnett’s adjustment.  
For sensitivity analyses, MCMC MI, LOCF, and FCS MI will be used. For analyses using MCMC MI 
and FCS MI, for treatment comparisons, least square means will not be adjusted for multiple 
comparison and for the unadjusted treatment group comparisons, only t-test will be used. 
For severity and frequency eye dryness (VAS), investigator assessment of bulbar conjunctival 
hyperemia, and tCFS and its sub-regions, the main analysis will be based on observed data and 
sensitivity analyses will be done using MCMC MI, LOCF, and FCS MI. 
For the presence of insert, the groups will be compared using observed data by Fisher’s exact 
test. Clopper-Pearson method will be used to calculate 95% confidence interval of the 
proportion of subject with presence of insert; to calculate 95% confidence interval of the 
proportion difference, the Chan and Zhang (1999) method will be used. 
 


     Statistical Analysis Plan  
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Protocol: 
 
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Document Date: 
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6. 
REFERENCES 
ASCRS EyeWorld. https://www.eyeworld.org/download/file/fid/453. Published May 2019. 
Accessed May 24, 2019. 
Baudouin C, Irkeç M, Messmer EM, et al. Clinical impact of inflammation in dry eye disease: 
proceedings of the ODISSEY group meeting. Acta Ophthalmol. 2018;96(2):111-119. 
doi:10.1111/aos.13436 
Byun Y, Kim T, Kwon SM, et al. Efficacy of combined 0.05% cyclosporine and 1% 
methylprednisolone treatment for chronic dry eye. Cornea. 2012;31(5):509-513. 
doi:10.1097/ICO.0b013e31818c69ef 
Cequa NDA 210913 Food Drug Administration (FDA). Guidance for Industry: Estimating the 
Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy 
Volunteers. July 2005. Available at www.fda.gov/regulatory-information/search-fda-
guidance-documents/estimating-maximum-safestarting- 
dose-initial-clinical-trials-
therapeutics-adult-healthy-volunteers. Accessed September 23, 2019. 
Jones L, Downie LE, Korb D, et al. TFOS DEWS II Management and Therapy Report. The Ocular 
Surface. 2017;15(3):575-628. doi:10.1016/j.jtos.2017.05.006 
McCabe C. Plugs reduce dry-eye symptoms, improve vision. Review of Ophthalmology. 19 
November 2009. Available at www.reviewofophthalmology.com/article/plugs-reduce-dry-eye-
symptoms-improvevision. Accessed September 29, 2019. 
Perez VL, Stern ME, Pflugfelder SC, Experimental Eye Research 2020: Cornea Special Issue IV: 
Immunology, infection, neovascularization, and surgery submitted  
Kala 
Pharmaceuticals, 
Inc. 
Presentations 
| 
Accessed 
October 
1, 
2020. 
https://investors.kalarx.com/presentations/ 
RESTASIS® NDA #021023 
Sheppard JD, Donnenfeld ED, Holland EJ, Slonim CB, Solomon R, Solomon KD, et al. Effect of 
loteprednol etabonate 0.5% on initiation of dry eye treatment with topical cyclosporine 
0.05%. Eye Contact Lens 2014;40(5):289e96


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Protocol: 
 
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Document Date: 
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7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
SAS Codes  
7.1.1. 
SAS codes to impute the missing using MCMC MI 
 
***** Bulbar Conjunctival Hyperemia multiple imputations *****; 
 
***** Photographic Assessments *****; 
 
PROC MI DATA=pr1t SEED=738493 OUT=pr1miyp MINIMUM=0 MAXIMUM=4 ROUND=1 NIMPUTE=25; 
 
  MCMC INITIAL=EM; 
 
  by PARAMN PARAMCD; 
 
  where SEFL="Y" and PARAMCD in ("BCHSCTP" "BCHSCFP" "BCHSCNP"); 
                                /* TRTPN_FG1 TRTPN_FG2 are dummy variables based on TRTPN*/ 
 
  VAR TRTPN_FG1 TRTPN_FG2 AVAL2 AVAL4; 
 
RUN; 
 
***** Investigator Assessments *****; 
 
PROC MI DATA=pr1t SEED=738493 OUT=pr1miyi MINIMUM=0 MAXIMUM=4 ROUND=1 NIMPUTE=25; 
 
  MCMC INITIAL=EM; 
 
  by PARAMN PARAMCD; 
 
  where SEFL="Y" and PARAMCD in ("BCHSCTI" "BCHSCFI" "BCHSCNI"); 
 
  VAR TRTPN_FG1 TRTPN_FG2 AVAL2 AVAL3 AVAL4 AVAL5 AVAL6 AVAL7; 
 
RUN; 
7.1.2. 
SAS codes to impute the missing using FCS MI 
 
***** Bulbar Conjunctival Hyperemia multiple imputations *****; 
 
***** Photographic Assessments *****; 
 
PROC MI DATA=pr1t SEED=918411 OUT=pr1fcsyp MINIMUM=0 MAXIMUM=4 ROUND=1 NIMPUTE=25; 
 
  by PARAMN PARAMCD; 
 
  where SEFL="Y" and PARAMCD in ("BCHSCTP" "BCHSCFP" "BCHSCNP"); 
 
  class TRTPN; 
 
  VAR TRTPN AVAL2 AVAL4; 
 
  fcs nbiter=200 reg (AVAL2=TRTPN); 
 
  fcs nbiter=200 reg (AVAL4=TRTPN AVAL2); 
 
RUN; 
 
***** Investigator Assessments *****; 
 
PROC MI DATA=pr1t SEED=918411 OUT=pr1fcsyi MINIMUM=0 MAXIMUM=4 ROUND=1 NIMPUTE=25; 
 
  by PARAMN PARAMCD; 
 
  where SEFL="Y" and PARAMCD in ("BCHSCTI" "BCHSCFI" "BCHSCNI"); 
 
  class TRTPN; 
 
  VAR TRTPN AVAL2 AVAL3 AVAL4 AVAL5 AVAL6 AVAL7; 
 
  fcs nbiter=200 reg (AVAL2=TRTPN); 
 
  fcs nbiter=200 reg (AVAL3=TRTPN AVAL2); 
 
  fcs nbiter=200 reg (AVAL4=TRTPN AVAL2 AVAL3); 
 
  fcs nbiter=200 reg (AVAL5=TRTPN AVAL2 AVAL3 AVAL4); 
 
  fcs nbiter=200 reg (AVAL6=TRTPN AVAL2 AVAL3 AVAL4 AVAL5); 
 
  fcs nbiter=200 reg (AVAL7=TRTPN AVAL2 AVAL3 AVAL4 AVAL5 AVAL6); 
 
RUN; 


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7.1.3. 
SAS codes to run ANCOVA (using PROC MIXED) on MI data 
 
 
*** MULTIPLE IMPUTATIONS ***; 
 
*** PROC MIXED ***; 
 
ods output LSMESTIMATEs=outlsmean0(rename=(label=PARAMETER)); 
 
proc mixed data=din; 
 
  by AVISIT PARAMN IMPUT; 
 
  CLASS TRTPN (ref=last); 
 
  MODEL CHG=TRTPN BASE; 
 
  LSMESTIMATE TRTPN   "OTX-DED 0.2MG" 1 0 0, 
 
                "OTX-DED 0.3MG" 0 1 0, 
 
 /* WG1 and WG2 are the sample size weighted coefficient for group 1 and 2 respectively*/ 
 
                "Overall OTX-DED" &WG1. &WG2. 0, 
 
                "HV" 0 0 1, 
 
                "OTX-DED 0.2MG vs HV" 1 0 -1 , 
 
                "OTX-DED 0.3MG vs HV" 0 1 -1,  
 
                "Overall OTX-DED vs HV" &WG1. &WG2. -1 / cl; 
 
run; 
 
 
ods output ParameterEstimates=outlsmean1; 
 
PROC MIANALYZE DATA=outlsmean0;  
 
  modeleffects estimate;  
 
  stderr stderr; 
 
  by avisit PARAMN PARAMETER; 
 
RUN; 
 
7.1.4. 
SAS codes to run t-test on MI data 
/* SAS code below for testing group 1 vs group 3*/ 
 
ods output statistics=ttest1; 
 
proc ttest data=din; 
 
where TRTPN in (1 3)   ; 
 
by AVISIT PARAMN IMPUT; 
 
class TRTPN; 
 
var CHG; 
 
run; 
 
 
ods output parameterestimates=pdiff; 
 
proc mianalyze data=ttest2; 
 
modeleffects mean; 
 
stderr stderr; 
 
by AVISIT PARAMN Class; 
 
run; 
 
7.1.5. 
SAS codes to run ANCOVA (using PROC MIXED) on Observed data and LOCF 
 
 


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*** PROC MIXED ***; 
 
ods output LSMESTIMATES=ls1(rename=(label=PARAMETER)) DIFFS=dun1; 
 
 
proc mixed data=din; 
 
 
by PARAMN AVISITN; 
 
 
CLASS TRTPN (ref=last); 
 
 
MODEL CHG=TRTPN BASE; 
 
 
lsmeans TRTPN / cl pdiff=control('3') adjust=Dunnett; 
 
 
LSMESTIMATE TRTPN  "OTX-DED 0.2MG" 1 0 0, 
                "OTX-DED 0.3MG" 0 1 0, 
                "Overall OTX-DED" &WG1. &WG2. 0, 
                "HV" 0 0 1, 
                "OTX-DED 0.2MG vs HV" 1 0 -1 , 
                "OTX-DED 0.3MG vs HV" 0 1 -1,  
                "Overall OTX-DED vs HV" &WG1. &WG2. -1 / cl; 
      run; 
 
7.1.6. 
SAS codes to output 95% CI for proportions using Clopper-Pearson method and 95% CI 
for the proportion difference using Chan and Zhang (1999) method using observed and 
LOCF data 
 
ods output RiskDiffCol1=freq1(where=(ROW in ("Row 1" "Row 2" "Difference"))) 
FishersExact=freq2(where=(NAME1="XP2_FISH")); 
 
proc freq data=din; 
 
 
where TRTPN in (1 3) and avisitn=4; 
 
 
table TRTPN*AVALN / norow nocol nopercent fisher; 
 
 
exact riskdiff(method=score); 
 
run;