A Prospective, Multicenter, Randomized, Parallel-Arm, Double Masked, Vehicle Controlled Phase 3A Study Evaluating the Safety and Efficacy of OTX-TP in the Treatment of Subjects With Open-Angle Glaucoma or Ocular Hypertension
Phase: PHASE3
Conditions: Open Angle Glaucoma, Ocular Hypertension
Sponsor: Ocular Therapeutix, Inc.

A Prospective, Multicenter, Randomized, Parallel-Arm, Double Masked, Vehicle 
Controlled Phase 3a Study Evaluating the Safety and Efficacy of OTX-TP in the 
Treatment of Subjects with Open-Angle Glaucoma or Ocular Hypertension 
 
 
 
Investigational Protocol 
OTX-16-002 
 
Revision E: May 2, 2017 
 
 
 
 
Sponsor: 
Ocular Therapeutix, Inc. 
34 Crosby Drive, Suite 105 
Bedford, MA 01730 USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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. 

Ocular Therapeutix, Inc. 
 
 
CONFIDENTIAL 
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Page 2 of 75 
Rev E: May 2, 2017 
A Prospective, Multicenter, Randomized, Parallel-Arm, Double Masked, Vehicle 
Controlled Phase 3a Study Evaluating the Safety and Efficacy of OTX-TP in the 
Treatment of Subjects with Open-Angle Glaucoma or Ocular Hypertension  
I hereby agree to participate in the clinical investigation of OTX-TP sponsored by Ocular Therapeutix, Inc. 
(hereinafter “Study Sponsor”).  I agree to conduct this investigation in accordance with the agreement, the 
investigational plan, and applicable regulations.  I agree to protect the rights, safety, and welfare of subjects 
under my care; I agree to adhere to the guidelines outlined in 21 CFR Part 312, other applicable United 
States Food and Drug Administration (FDA) regulations, and conditions of approval imposed by the 
reviewing IRB and the FDA.  I agree to supervise all use of the intracanalicular depot and to ensure 
appropriate informed consent is obtained from all subjects prior to inclusion in this study. 
I understand that this investigation will be monitored by the Study Sponsor and/or a designee employed by 
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 
Clinical Affairs at Ocular Therapeutix (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 Study Sponsor encourages me to pursue independent 
publications related to my experience with this intracanalicular depot 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 intracanalicular depot 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 
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 Study Sponsor or FDA without the prior 
written consent of the Study Sponsor. 
Accepted by: 
________________________________________________________________________________________ 
Principal Investigator Signature 
Date 
 
 
Printed Name 
 
_________________________________________________________________________________________ 
Sub-Investigator Signature 
Date 
 
 
Printed Name 
 
_________________________________________________________________________________________ 
Sub-Investigator Signature 
Date 
 
 
Printed Name 
*Note: Please add sub-Investigator signatures on an additional page, if needed.

Ocular Therapeutix, Inc. 
 
 
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TABLE OF CONTENTS 
PROTOCOL REVISION HISTORY ..............................................................................................7 
1. 
SYNOPSIS ...................................................................................................................9 
2. 
PRINCIPAL CONTACTS..........................................................................................26 
3. 
INTRODUCTION ......................................................................................................27 
3.1. 
Background and Rationale ..........................................................................................27 
3.2. 
Report of Prior Investigations .....................................................................................29 
3.2.1. 
Prior Experience with Travoprost ...............................................................................30 
3.3. 
Description of Intracanalicular depot .........................................................................30 
3.3.1. 
OTX-TP (sustained release travoprost) Intracanalicular Depot .................................30 
3.3.2. 
Placebo Vehicle Intracanalicular depot (PV) .............................................................31 
3.4. 
Intended Use ...............................................................................................................31 
3.5. 
Study Design and Duration .........................................................................................31 
3.5.1. 
Control of Bias ............................................................................................................34 
4. 
STUDY DESIGN .......................................................................................................35 
4.1. 
Study Objective ..........................................................................................................35 
4.2. 
Study Endpoints ..........................................................................................................35 
4.2.1. 
Endpoints ....................................................................................................................35 
4.2.2. 
Other Data to be Collected .........................................................................................35 
4.2.3. 
Safety Evaluations ......................................................................................................35 
4.3. 
Selection and Training of Investigators ......................................................................36 
4.4. 
Subject Selection ........................................................................................................36 
4.4.1. 
Pre-Procedure Inclusion Criteria ................................................................................36 
4.4.2. 
Pre-Procedural Exclusion Criteria ..............................................................................37 
4.4.3. 
Procedural Exclusion Criteria .....................................................................................39 
4.5. 
Study Procedures and Data Collection .......................................................................39 
4.5.1. 
Study Schedule ...........................................................................................................39 
4.5.2. 
Data Collection ...........................................................................................................43 
4.5.3. 
Subject Enrollment .....................................................................................................43 
4.5.4. 
Informed Consent .......................................................................................................43 
4.5.5. 
Randomization ............................................................................................................44 
4.5.6. 
Masking ......................................................................................................................44 
4.5.7. 
Study Assessments......................................................................................................44 

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4.5.7.1. 
Screening Visit ............................................................................................................44 
4.5.7.2. 
Run-in Visits 1 and 2 ..................................................................................................45 
4.5.7.3. 
IOP Confirmation Visit (only applicable for subjects exiting from a prior 
ophthalmic investigational research study) ................................................................45 
4.5.7.4. 
Baseline Visit 1 ...........................................................................................................46 
4.5.7.5. 
Baseline Visit 2/Insertion Visit: Day 1 .......................................................................46 
4.5.7.6. 
Point of Randomization ..............................................................................................47 
4.5.7.7. 
Concurrent Medications ..............................................................................................48 
4.5.7.8. 
Prohibited Medications/Treatments ............................................................................49 
4.5.7.9. 
Follow-up Assessments ..............................................................................................49 
4.6. 
Intracanalicular Depot Removal .................................................................................52 
4.7. 
Potential Risks and Benefits .......................................................................................52 
4.7.1. 
Risks Associated with OTX-TP Intracanalicular Deport or PV .................................52 
4.7.2. 
Minimization of Risks ................................................................................................53 
4.7.3. 
Potential Benefits ........................................................................................................54 
4.8. 
Product Malfunctions ..................................................................................................54 
4.9. 
Subject Withdrawal ....................................................................................................54 
5. 
ADVERSE EVENTS (AES) ......................................................................................55 
5.1. 
Definitions ..................................................................................................................55 
5.2. 
Severity .......................................................................................................................56 
5.3. 
Relationship to OTX-TP or PV ..................................................................................57 
5.4. 
Expectedness ...............................................................................................................57 
5.5. 
Procedures for Reporting Adverse Events ..................................................................58 
5.5.1. 
Specific Anticipated Adverse Ocular Events .............................................................58 
5.6. 
Procedures for Unmasking .........................................................................................59 
5.7. 
Type and Duration of the Follow-up of Subjects after Adverse Events .....................59 
6. 
STATISTICAL ANALYSIS ......................................................................................60 
6.1. 
Study Populations .......................................................................................................60 
6.2. 
Unit of Analysis ..........................................................................................................60 
6.3. 
Imputation Methods ....................................................................................................60 
6.4. 
Hypotheses ..................................................................................................................61 
6.5. 
Efficacy Variables ......................................................................................................61 
6.5.1. 
Primary .......................................................................................................................61 

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6.5.2. 
Secondary ...................................................................................................................61 
6.6. 
Safety Variables ..........................................................................................................61 
6.7. 
Sample Size ................................................................................................................61 
6.8. 
Interim Analyses .........................................................................................................62 
6.9. 
Methods of Analyses ..................................................................................................62 
6.10. 
Demographic and Baseline Medical History ..............................................................62 
6.11. 
Efficacy Analyses .......................................................................................................62 
6.12. 
Other Analyses ............................................................................................................63 
6.13. 
Safety Analyses ..........................................................................................................63 
7. 
GENERAL INFORMATION .....................................................................................65 
7.1. 
Study Termination ......................................................................................................65 
7.2. 
Monitoring ..................................................................................................................65 
7.3. 
Retention of Documentation .......................................................................................65 
7.4. 
Photos and Videos ......................................................................................................66 
8. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS AND ADMINISTRATIVE ISSUES ......................................67 
8.1. 
Protection of Human Subjects ....................................................................................67 
8.1.1. 
Compliance with Informed Consent Regulations .......................................................67 
8.1.2. 
Compliance with Institutional Review Board Regulations ........................................67 
8.2. 
Subject Confidentiality ...............................................................................................67 
9. 
LABELING, PACKAGING, STORAGE AND ACCOUNTABILITY OF 
INTRACANALICULAR DEPOT ..............................................................................68 
9.1. 
Labeling/Packaging ....................................................................................................68 
9.2. 
Product Storage ...........................................................................................................68 
9.3. 
Product Accountability ...............................................................................................68 
9.3.1. 
Product Return or Disposal .........................................................................................68 
10. 
APPENDICES ............................................................................................................69 
APPENDIX A. INSTRUCTIONS FOR DETERMINING ELIGIBILITY OF 
SUBJECTS EXITING FROM PRIOR OPHTHALMIC 
INVESTIGATIONAL RESEARCH STUDIES .........................................................70 
APPENDIX B. RECOMMENDED PROCEDURES FOR STUDY EXAMINATIONS ..........71 
A.  Best Corrected Visual Acuity ..................................................................................................71 
B.  Slit Lamp Biomicroscopy Examination ...................................................................................71 
C.  Ocular Hyperemia Grading ......................................................................................................72 

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D.  Pachymetry...............................................................................................................................72 
E.  IOP Measurement .....................................................................................................................73 
F.  Dilated Fundus Exam ...............................................................................................................73 
G.  Gonioscopy ..............................................................................................................................74 
H.  Automated Perimetry ...............................................................................................................74 
I.  Punctum Examination................................................................................................................74 
APPENDIX C. INSTRUCTIONS FOR REMOVAL OF THE 
INTRACANALICULAR DEPOT ..............................................................................75 
LIST OF TABLES 
Table 1: 
Study Schedule for subjects on prostaglandin treatment at the time of the 
Screening Visit (Stratum A) .......................................................................................40 
Table 2: 
 Study Schedule for subjects who are treatment-naïve at the time of the 
Screening Visit (Stratum B) ........................................................................................41 
Table 3: 
Study Schedule for Subjects who have exited from a prior ophthalmic 
investigational research study within 8 weeks of the Screening Visit and 
have written approval from the Medical Monitor to be allowed to participate 
in the current study without additional exposure to prostaglandin (Stratum 
C)* ..............................................................................................................................42 
 LIST OF FIGURES 
Figure 1: 
Placement of Intracanalicular depot in the Inferior Canaliculus ................................48 
Figure 2: 
Scale for Grading Ocular Hyperemia .........................................................................72 
 

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PROTOCOL REVISION HISTORY 
Date 
Revision Description of Modifications 
Rationale for Modification 
 
A 
Initial Release 
N/A 
Sep. 30, 2016 
B 
Slit Lamp exam requirement changed to 8:00 
am only for diurnal visits 
PM slit lamp not medically necessary 
BCVA at Baseline Visit 2 
Omitted mistakenly in prior version 
Clarified Visit Names (15 Day visit to 2 week 
visit, etc.) 
To match industry standard, and to 
provide greater clarity for Investigational 
Sites 
Clarified exclusion of systemic beta blockers 
To allow for inclusion of subjects on 
stable dose beta blockers 
Clarified Inclusion Criterion #5, Exclusion 
Criterion #2, and Exclusion Criterion #31 
Clarified language 
Fixed minor typos and protocol 
inconsistencies (e.g., added Iris color to 
Screening Visit on page 35) 
Correction of minor clerical errors 
Clarified washout window for patients taking 
prostaglandins, and widened the window 
between Baseline Visit 1 and Baseline Visit 
2. 
To provide greater flexibility in visit 
scheduling for Investigational Sites 
Changed length of time IOP must be 
controlled from 3 months to 2 months 
Based on Investigator and medical 
advisor feedback, restriction was tighter 
than medically necessary 
Made mandatory the visual field assessment 
at Baseline 
Aid Investigator decision regarding 
selection of appropriate subjects 
Removed ability to enroll patients currently 
being treated with Beta Blockers, clarified 
Inclusion Criterion #3, and clarified 
Exclusion Criterion #1. 
To ensure enrollment of only subjects 
who are known to respond to topical 
prostaglandins 
Clarified Inclusion Criterion #4 
To further ensure IOP at enrollment is 
stable 
Moved Exclusion Criterion #28 up to #3 
(which, therefore, effected the numbering of 
the other criteria) 
To emphasize the importance of the 
criterion 
Clarified/Updated description of naïve 
subjects:  Meaning, requirements, timeline, 
etc. 
To ensure enrollment of only subjects 
who are known to respond to topical 
prostaglandin  
Clarified instructions for IOP measurement 
technique and number of readings required. 
To ensure clarity of instructions provided 
to Investigational Sites 
Updated Baseline Visit 1 to remove diurnal 
IOP measurement requirement. 
Not medically necessary, wash out will 
be confirmed with diurnal BL2 values. 
Moved Hyperemia Assessment, and Subject 
Comfort Assessment to Baseline Visit 2, 
from Baseline Visit 1 
To move the majority of exams to 
Baseline Visit 2, and ease subject burden. 
Added Slit Lamp Exam to Baseline Visit 2 
To ensure most current Slit Lamp 
information available for eligibility 
verification 
Added AE Assessment text to Screening, 
Run-in Visits, and Baseline Visit 1 and 2. 
Inadvertently omitted in prior revision. 
Added ability to perform IOP on a different 
screening day. 
To allow flexibility in visit scheduling. 
Added Interim Analysis. 
To allow for getting efficacy results 
sooner once all subjects complete 
efficacy visits without having to wait for 
the completion of safety follow-ups. 

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Date 
Revision Description of Modifications 
Rationale for Modification 
Oct., 28 2016 
C 
Added sub-strata to randomize subjects 
within sites based on previous medication 
regimen at the time of Screening. 
To further ensure balanced  
randomization based upon recent IOP 
reduction therapy 
Added Instructions for determining eligibility 
and randomization of subjects exiting from 
prior ophthalmic investigational research 
studies (Appendix A ) 
To provide more guidance for enrolling 
subjects exiting from prior ophthalmic 
investigational research studies as 
additional randomization schema are 
more detailed 
Added description of PEG tip 
Inadvertent exclusion from previous 
revisions 
Fixed minor typos and protocol 
inconsistencies 
Correction of minor clerical errors 
Nov., 18 
2016 
D 
Removed “Baseline Visit 1” from Inclusion 
Criterion 4 in both the protocol synopsis and 
in Section 4.4.1  
Inadvertently remained after previous 
revision. 
Fixed minor typos and protocol 
inconsistencies 
Correction of minor clerical errors 
Added additional clarity to Pachymetry 
performed at Screening in the protocol 
synopsis. 
To ensure the same clear guidance is 
provided both times Screening 
Pachymetry is discussed.  
Clarified time requirement for reporting of 
serious events. 
To ensure clarity for Investigational 
Sites. 
May 2, 2017 
E 
Clarified safety exam performance 
requirements 
To ensure clarity for schedule of  exams 
that must be performed by Investigational 
Sites. 
Clarify when infections should be cultured 
To ensure clarity for Investigational 
Sites. 
Define “history” in Exclusion Criteria 1 
To ensure clarity for Investigational 
Sites. 
Made consistent which assessments must be 
performed at each visit 
Correction of minor clerical errors 
Update required timing for automated 
perimetry 
To allow sites a larger window for 
performance of automated perimetry. 
Clarified Inclusion 3, Exclusion 3, and 
Exclusion 31 in regards to Stratum C subjects 
To provide clarity on Inclusion/Exclusion 
Criteria for Stratum C Subjects. 
Updated Sponsor contact information 
Based on staffing changes. 
Updated prohibited medication section. 
To remove inconsistent language around 
medication usage. 

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1. 
SYNOPSIS  
Study Title: 
 A Prospective, Multicenter, Randomized, Parallel-Arm, Double 
Masked, Vehicle Controlled Phase 3a Study Evaluating the 
Safety and Efficacy of OTX-TP in the Treatment of Subjects 
with Open-Angle Glaucoma or Ocular Hypertension 
Test Article: 
Test Article: OTX-TP (sustained release travoprost) 
Intracanalicular Depot 
Control: PV (Placebo Vehicle) Intracanalicular Depot 
Phase of Clinical Study: 
3a 
Study Objective: 
To evaluate the safety and IOP lowering efficacy of OTX-TP, a 
sustained release travoprost drug product, placed in the 
canaliculus of the eyelid in the treatment of subjects with open-
angle glaucoma or ocular hypertension. 
Product Description: 
The OTX-TP drug product is a dried polyethylene glycol (PEG) 
based, rod-shaped hydrogel intracanalicular depot designed to be 
placed in the superior or inferior canaliculus. The hydrogel 
swells on contact with moisture to occlude the lumen, thus 
holding the intracanalicular depot in place.  Once OTX-TP 
swells to fill the canaliculus, it is contained in the canaliculus 
until the hydrogel is resorbed. Embedded in the hydrogel 
intracanalicular depot are bioabsorbable poly (lactic acid) (PLA) 
microparticles containing encapsulated travoprost. OTX-TP 
contains conjugated fluorescein to serve as a visualization aid for 
the Investigator through the use of a blue light source and yellow 
filter to confirm product presence. The intracanalicular depot 
also has an inert PEG tip to aid in insertion. 
The PV used as the study control is the same fluorescein-
conjugated PEG hydrogel intracanalicular depot with inert PEG 
tip as OTX-TP, except that it does not contain travoprost.  
Travoprost is a synthetic prostaglandin F2α analogue used for 
reducing elevated intraocular pressure in subjects with open-
angle glaucoma or ocular hypertension. Travoprost is the active 
pharmaceutical ingredient in Travatan®, Travatan Z® and Izba™ 
(Alcon Laboratories Inc., Fort Worth, TX) which have been 
approved by the US FDA under application numbers 021257, 
021994, and 204822, respectively.   
OTX-TP is an extended release drug delivery depot designed to 
release travoprost over a period of up to 12 weeks.  

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As both the hydrogel and PLA microparticles degrade by 
hydrolysis, both OTX-TP and PV soften, liquefy and are cleared 
through the nasolacrimal duct.   
Intended Use: 
OTX-TP (sustained release travoprost) Intracanalicular Depot is 
intended for the reduction of elevated intraocular pressure in 
subjects with open-angle glaucoma (OAG) or ocular 
hypertension (OH).  
Study Design: 
 
This is a prospective, multicenter, randomized, parallel-arm, 
double masked, placebo vehicle controlled trial to evaluate the 
safety and IOP-lowering efficacy of OTX-TP, a sustained 
release drug product placed in the canaliculus of the eye in 
subjects with open-angle glaucoma or ocular hypertension.  A 
total of up to 550 subjects (1100 eyes) with a clinical diagnosis 
of open-angle glaucoma or ocular hypertension in both eyes will 
be receive either OTX-TP or PV in this trial to evaluate the 
safety and efficacy of the OTX-TP drug product.   
The subjects enrolled in this parallel arm study will be 
randomized to receive either OTX-TP (sustained release 
travoprost) Intracanalicular Depot or PV (placebo vehicle) 
intracanalicular depot, respectively.  Subjects randomized to the 
treatment group will receive OTX-TP in either the superior or 
inferior canaliculus of each affected eye on Day 1.  Subjects 
randomized to the control group will receive PV in either the 
superior or inferior canaliculus of each affected eye on Day 1.   
Subject randomization is 3:2 with a total of approximately 330 
subjects in the OTX-TP arm and 220 in the PV arm. 

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Randomization will be stratified by investigational site and 
previous ocular anti-hypertensive therapy with 3 levels: 
Stratum A: Subjects who were on prostaglandin treatment at the 
time of the Screening Visit and have shown an adequate IOP rise 
after a 6-week washout (interval from Screening to Baseline 
Visit 1 is 6 weeks).  This may include subjects exiting from a 
prior ophthalmic investigational research study based on criteria 
specified in  
Appendix A . 
Stratum B: Subjects who were treatment-naïve at Screening and 
have shown an adequate prostaglandin response after a 2-week 
run-in period on prostaglandin treatment followed by a 6-week 
washout (interval from Screening to Baseline Visit 1 is 8 weeks). 
This may include subjects exiting from a prior ophthalmic 
investigational research study based on criteria specified in 
Appendix A . 
Stratum C: Subjects who have recently exited from a prior 
ophthalmic investigational research study and have written 
approval from the Medical Monitor to be allowed to participate 
in the current study without additional exposure to prostaglandin 
(Refer to Appendix A ). 
Once it is determined that the subject continues to meet 
eligibility for the study at Baseline Visit 2, the subject will be 
randomized into the study corresponding to the subject’s 
previous ocular anti-hypertensive therapy category and both eyes 
will be provided with the same assigned treatment, OTX-TP or 
PV. 
Both eyes will receive either OTX-TP or PV, but only the eye 
with the higher IOP at 8:00AM at Baseline Visit 2 that meets all 
enrollment criteria will be considered as the study eye and 
included in the primary efficacy analysis.  If both eyes are 
eligible and have the same IOP at 8AM on Baseline Visit 2 (Day 
1), the right eye will be the study eye and the left eye will be 
considered the secondary study eye. All eyes will be included in 
the safety analysis. 
Subjects currently being treated with a prostaglandin analogue at 
the time of the Screening Visit will undergo a 6 week (- 2 days/+ 
3 days) washout period starting at the Screening Visit and prior 
to Baseline Visit 1.  The Baseline Visit 2/Insertion Visit, Day 1 
will be conducted two to four days after the Baseline Visit 1.  
IOP measurements at the baseline visits will confirm that the 
washout period was sufficient.   

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Subjects not currently treated with a prostaglandin analogue will 
undergo a 2 week run-in starting at the Screening Visit, to 
confirm they are a prostaglandin responder. At least two IOP 
measurements will be taken over a two week period (Run-in 
Visit 1 at 2 days [+ 3 days] post-initiation of prostaglandin 
therapy; and Run-in Visit 2 at 11 days [+ 3 days] post-initiation 
of prostaglandin therapy). The Run-in IOP measurements will be 
conducted at 8 AM +/- 1 hour, to confirm the response to 
prostaglandin therapy. Once the response is confirmed, the 
subjects will undergo a 6 week (- 2 days/+ 3 days) washout 
period prior to Baseline Visit 1. The Baseline Visit 2/Insertion 
Visit, Day 1, will be conducted two to four days after the 
Baseline Visit 1. The IOP measurement at Baseline Visit 2 must 
demonstrate a ≥ 5 mmHg increase from Run-in Visit 2. IOP 
measurements at the baseline visits will confirm that the washout 
period was sufficient.  
Subjects who have exited from another ophthalmic 
investigational research study within the last 8 weeks will be 
started on a 6 week prior trial recovery period and stop all 
glaucoma/OHT meds, after completing Informed Consent and 
the Screening Visit. They will then be discussed with the 
Medical Monitor, in order to obtain written approval to be 
allowed to participate in the current study. The approval will be 
captured on the appropriate eCRF. Timing and requirements for 
the period between Screening and Baseline Visit 1 will vary, 
please refer to Appendix A  for additional specifications.  
At Baseline Visit 2/Insertion Visit (Day 1), if insertion is 
unsuccessful in one eye, the intracanalicular depot from the 
contralateral eye (if already inserted) will not be removed. The 
subject will be prescribed IOP-lowering drops at the 
Investigator’s discretion for the eye that did not receive a depot.  
These subjects will be followed for safety only, and the eye that 
received a depot will be included in the safety analysis. The 
study will be supplemented with additional subjects to account 
for these subjects in order to ensure that the necessary number of 
subjects who receive a depot bilaterally are followed through the 
12 Week Visit for efficacy and safety. 
All subjects will undergo follow-up visits at 2, 4, 6, 8, 10, and 12 
Weeks.  If at any visit, the investigator deems it necessary to 
initiate IOP-lowering drops as rescue therapy due to an increase 
in IOP, the subject will begin the IOP-lowering drops at the 
Investigator’s discretion and followed through the remainder of 
the study for safety. Sensitivity analyses, to determine 
robustness of results, will be performed using Monte Carlo 
Markov Chain approach to impute non-monotone missing 

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information and pattern mixture models control-based pattern 
imputation for monotone missing information (including 
subjects who drop out and data for time points after a subject’s 
primary study eye is prescribed IOP-lowering drops), LOCF to 
impute both missing data and data after a subject’s primary 
study eye is prescribed IOP-lowering drops, and baseline time-
consistent observation carried forward to impute both missing 
data and data after a subject’s primary study eye is prescribed 
IOP-lowering drops and observed data only.   
For subjects with Early Loss of Intracanalicular Depot Prior to 
the 6 Week Visit: 
At any visit prior to the 6 Week Visit, if the intracanalicular 
depot is not visualized in one or both eyes by the Investigator, 
the Investigator will insert a new intracanalicular depot in the 
respective eye(s) after confirming patency. For any depot 
replacements, IOP assessments should be completed prior to 
replacement. The subject will continue to return for follow-up 
visits per the study schedule through the 12 Week Visit. The 
number of replacements will be tracked and documented on the 
appropriate Case Report Form (CRF). 
If the intracanalicular depot is still present at the 12 Week Visit, 
the Investigator will attempt to remove it. If removal is 
successful bilaterally, the subject will be exited from the study 
upon confirmation of the bilateral absence of the intracanalicular 
depot. If the intracanalicular depot is not present bilaterally at 
the 12 Week Visit, the subject will be exited at the end of that 
visit.  
If removal is unsuccessful in one or both eyes at the 12 Week 
Visit, the subject will return at the 20 Week Visit. The 
Investigator will attempt removal of the intracanalicular depot(s) 
from the respective eye(s) at this visit. The subject may be 
prescribed IOP-lowering drops if necessary at the 12 Week Visit 
at the Investigator’s discretion. 
For subjects with Early Loss of Intracanalicular depot from 
the 6 Week Visit prior to the 12 Week Visit: 
At any visit from the 6 Week Visit prior to the 12 Week Visit, if 
the intracanalicular depot is not visualized in one or both eyes by 
the Investigator, the Investigator will insert a new 
intracanalicular depot in the respective eye(s) after confirming 
patency. For any depot replacements, IOP assessments should be 
completed prior to replacement. The subject will return for 
follow-up visits through the 12 Week Visit and then at the 20 

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Week Visit. The number of replacements will be tracked and 
documented on the appropriate CRF.  
At the 20 Week Visit, the Investigator will attempt removal of 
the intracanalicular depot, if still present. If removal at the 20 
Week Visit is successful bilaterally, the subject will be exited 
from the study upon confirmation of the bilateral absence of the 
intracanalicular depot.  
If removal at the 20 Week Visit is not successful in one or both 
eyes, the subject will be required to return to the clinic every 30 
(± 10) days until the intracanalicular depot is confirmed to be no 
longer present or removal of the intracanalicular depot is 
successful for the respective eye(s). Removal will be attempted 
at every visit until the intracanalicular depot is no longer present. 
If the intracanalicular depot is not present bilaterally at the 20 
Week Visit, the subject will be exited from the study at the end 
of that visit. The subject may be prescribed IOP-lowering drops 
if necessary at the 20 Week Visit at the Investigator’s discretion. 
The study will be conducted at approximately 50 qualified 
investigative sites in the United States following Institutional 
Review Board (IRB) approval. A site may randomize up to a 
maximum of 55 subjects. All subjects will be required to provide 
informed consent prior to study participation. 
Primary Endpoint: 
• 
Mean IOP at the following time points 8AM, 10AM, and 
4PM at the 2 Week, 6 Week, and 12 Week Visits. 
Secondary Endpoints: 
• 
Mean change from baseline IOP at the following time points 
8AM, 10AM, and 4PM at the 2 Week, 6 Week, and 12 Week 
Visits. 
• 
Mean percent change from baseline IOP at the following 
time points 8AM, 10AM, and 4PM at the 2 Week, 6 Week, 
and 12 Week Visits. 
Other Data to be Collected 
• 
Ocular complaints  
• 
Visualization of intracanalicular depot by the Investigator at 
each time point  
• 
Ease of insertion of intracanalicular depot 
• 
Number of intracanalicular depots required in each eye for 
the 12 week period per subject 
Safety Evaluations 
• Best corrected visual acuity (BCVA) 
• Slit lamp biomicroscopy 
• Assessment and grade of ocular hyperemia (at slit lamp) 
• Subject ocular comfort assessment 
• Dilated fundus exam 
• Adverse events  

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Rev E: May 2, 2017 
Inclusion Criteria: 
Subjects must meet all of the following criteria to be eligible: 
1. Greater than or equal to 18 years of age at Screening.  
2. Documented diagnosis of ocular hypertension with an open 
angle of Schaffer Grade 3 or greater or open-angle glaucoma 
without pseudoexfoliation or pigment dispersion or evidence 
of traumatic angle recession. 
3. IOP is currently controlled as assessed by the Investigator: 
• With a topical prostaglandin, and there has been no 
change in IOP lowering therapy over 8 weeks prior 
to Screening, or, 
• without IOP-lowering medication over 8 weeks prior 
to Screening and after a 2-week run-in period on 
prostaglandin therapy demonstrates an adequate 
response. 
Note:  For Subjects entering through Stratum C, a required 
Medical Monitor review will ensure subjects have: 
• demonstrated 8 weeks of stable treatment (or no 
treatment) for glaucoma and/or ocular hypertension 
prior to enrollment in the previous recent ophthalmic 
clinical trial(s).  
• documented history of an adequate prostaglandin 
response as described in the protocol, or will undergo 
a prostaglandin run-in trial as described in the 
protocol for patients who do not have such a history.  
4. Baseline IOP (following washout or run-in) in at least 1 eye 
(the same eye) of:  
• ≥ 24mmHg at Hour 0 (T0) at Baseline Visit 2 (Day 1)  
• ≥ 22mmHg at (T0+ 2h) and (T0 + 8h) at Baseline 
Visit 2 (Day 1)  
• At 8AM Baseline Visit 2 (Day 1), ≥ 5 mmHg 
increase from Screening for subjects previously on 
prostaglandins  
• At 8AM Baseline Visit 2 (Day 1), ≥ 5 mmHg 
increase from Run-in Visit 2 for subjects not 
previously on prostaglandins prior to the Screening 
Visit   
Note: the same eye must meet all  of the above listed IOP 
eligibility criteria 
5. IOP must be ≤ 34mmHg in each eye at all time points at 
the Baseline Visit 1 (Day -2 to -4) and Baseline Visit 2 
(Day 1).  

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6. Informed of the nature of the study and subject is able to 
comply with study requirements and visit schedule.  
7. Provided written informed consent, approved by the 
appropriate Institutional Review Board. 
Pre-Procedure Exclusion 
Criteria: 
Subjects who meet any of the following criteria are not eligible: 
1. A history, prior to Screening, of an inadequate response (< 
5mmHg decrease from prior to any treatment) or no response 
to topical prostaglandin for OAG/OH. 
2. For subjects on IOP-lowering medication(s): History of 
concurrent treatment with 3 or more IOP-lowering 
medications for longer than 2 weeks. Any combination 
medication will be considered as 2 medications. 
3. Currently (or within 8 weeks prior to Screening) on any 
ocular or systemic medication [i.e., carbonic anhydrase 
inhibitors, corticosteroids (including topical dermal steroids 
for the face), etc.] that may: 
• Have an effect on the subject's IOP or will require 
use of such ocular or systemic medications during the 
study period. 
• No topical ophthalmic medications other than 
prostaglandins allowed at the time of the screening 
visit. Systemic beta blockers will be allowed, but any 
initiation of or alterations in systemic regimen of 
beta-blocker containing medications from 8 weeks 
prior to screening through the final study visit is 
excluded. 
Subjects currently treated with topical prostaglandin 
analogues are required to undergo a washout period of 6 
weeks (- 2 days/+ 3 days). 
Note:  For Subjects entering through Stratum C, changes in 
ocular or systemic prior ophthalmic study medications, that 
may have an effect on the Subject’s IOP, will be allowed, but 
inclusion in the study will be based on a required Medical 
Monitor review. Stratum C subjects will also be allowed to 
screen for the study while on ophthalmic medications other 
than prostaglandins, however, these medications should be 
stopped at Screening, and a Prior Trial Recovery Period shall 
be started.   
4. A BCVA worse than 0.6 LogMAR (20/80 Snellen) in either 
eye as measured using an ETDRS chart. 
5. Punctum size smaller than 0.4 mm or greater than 0.9 mm in 
either eye as measured using a standard punctum gauge.  

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Rev E: May 2, 2017 
6. Known or suspected allergy and/or hypersensitivity to 
Travoprost or any prostaglandin, fluorescein, or to any 
component of the study products. 
7.  History of ocular trauma within the past 6 months in either 
eye. 
8. Evidence of angle recession by gonioscopy. 
9. Presence of any abnormality based upon the assessment by 
the Investigator preventing reliable applanation tonometry of 
either eye. 
10. Narrow or potentially occludable anterior chamber angle 
defined as an anterior chamber angle of less than or equal to 
Grade 2 (Schaffer classification) as measured by gonioscopy. 
11. Central corneal thickness < 480 µm or > 620 µm in either 
eye. 
12. Cup to disc ratio > 0.80 (horizontal or vertical measurement) 
in either eye. 
13. Functionally significant central visual field loss or 
documented significant progressive field loss within the last 
year in either eye based upon the assessment by the 
Investigator. 
14. History of complications, AEs, trauma or disease in the 
nasolacrimal area, whether or not it was due to punctal plug 
use, including but not limited to dacryocystitis, inflammation 
or canaliculitis in either eye. 
15. Structural lid abnormalities (i.e., ectropion, entropion) in 
either eye based upon the assessment by the Investigator. 
16. Active epiphora in either eye based upon the assessment by 
the Investigator. 
17. Presence of nasolacrimal duct obstruction in either eye based 
upon an assessment by the Investigator.  
18. Active lid disease in either eye (i.e., moderate or severe 
blepharitis, meibomitis) that requires medical treatment. 
19. History of ocular infection (bacterial, viral, or fungal) in 
either eye within the previous 3 months. 
20. History of any severe ocular pathology (including severe dry 
eye) in either eye. 
21. History of chronic/recurrent inflammatory eye disease (i.e., 
scleritis, uveitis, herpes keratitis) in either eye. 
22. Required use of any ocular topical medication(s), any over-
the counter drop(s), ointment(s), gel(s) or lid scrubs, other 
than the study ocular hypotensive medication(s) in either eye 
during the study period.  
Note: Use of artificial tears or ocular lubricants should be 
avoided but if necessary, intermittent use may be allowed 
up to twice a day. 
23. Any ophthalmic surgical procedures (e.g. glaucoma laser, 
minimally invasive glaucoma surgery, cataract, refractive) in 

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Rev E: May 2, 2017 
either eye within the last six months or will likely require 
ophthalmic surgery before completing the study. 
24. History of penetrating or lamellar keratoplasty in either eye 
(including endothelial keratoplasty). 
25. History of keratorefractive surgery in either eye (i.e., 
LASIK, PRK, RK, AK, LRI, Corneal inlay, intracorneal ring 
segment). 
26. Advanced diabetic retinopathy, branch retinal vein 
occlusion, or central retinal vein occlusion in either eye. 
27. History of macular edema in either eye. 
28. Any uncontrolled systemic or debilitating disease (e.g. 
cardiovascular disease, hypertension, diabetes, or cystic 
fibrosis) or a medical condition that may increase the risk 
associated with study participation or administration of study 
treatment or that may interfere with the interpretation of 
study results based upon the assessment of the Investigator 
(e.g., autoimmune disease if the subject is on chronic 
medications and has ocular involvement; host-versus-graft 
disease). 
29. Requiring contact lens use at any point during the study after 
the Screening Visit including on the day of the Baseline 
Visits. In addition, contact lens wear must be discontinued a 
minimum of 3 days prior to pachymetry for soft contact 
lenses and a minimum of 14 days prior to pachymetry for 
rigid gas permeable contact lenses. 
30. Currently pregnant or breast-feeding or who wishes to 
become pregnant during the length of study participation. 
31. Currently participating or has participated within the last 
30 days in any non-ophthalmic drug, device or other 
investigational research study prior to the start of this 
study.  
Note:  Previous participation in any ophthalmic 
investigational research study within 8 weeks will 
require written approval for enrollment from the 
Medical Monitor based on instructions provided in 
Appendix A. 
32. Investigator determines subject should not be included for 
reasons not already specified (e.g., systemic or other ocular 
disease/abnormality, not a candidate for topical 
prostaglandin, therapy, specifically travoprost) if the health 
of the subject or the validity of the study outcomes may be 
compromised by the subject’s enrollment. 
Procedural Exclusion 
Criterion 
1. Unsuccessful punctal dilation of either eye (if needed) or 
punctum of either eye is too small to allow transient dilation 
to 0.7 mm prior for insertion of OTX-TP or PV. 

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Rev E: May 2, 2017 
Screening Assessment  
(Visit timing will vary based 
on randomization stratum:  A, 
B, or C) 
This visit may be conducted 
over two days, separating the 
IOP Measurement, 
Automated perimetry, and/or 
pachymetry only. 
All IOP Measurements must 
be conducted within ± 60 
minutes of the required time, 
and must be conducted at 
approximately the same time 
at each of the follow-up visits. 
• 
Informed consent 
• 
Demographic data 
• 
Iris color 
• 
Medical and ophthalmic history 
• 
Medication history 
• 
Urine pregnancy test (if applicable): if female of 
childbearing potential, subject must utilize reliable 
contraceptive methods for the duration of the study as judged 
by the Investigator, and have a negative urine pregnancy test  
The following will be performed on both eyes:  
• 
Assessment of Best Corrected Visual Acuity (BCVA) 
• 
Automated perimetry 
• 
Pachymetry 
The average of the 3 measurements will be calculated to 
determine subject eligibility. Contact lens wear must be 
discontinued 3 days prior to pachymetry for soft contact 
lenses and 14 days prior to pachymetry for rigid gas 
permeable contact lenses. For contact lens wearers, the 
pachymetry assessment may be scheduled for a separate day 
from the Screening Visit based on the type of contact lens 
(i.e., 3 days after the Screening Visit for soft contact lenses 
and 14 days after the Screening Visit for rigid gas permeable 
contact lenses) 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Punctum exam (for normality of punctal appearance, lid 
apposition, and tear meniscus) 
• 
Punctum size assessment using a punctum gauging system 
provided by the Sponsor 
• 
IOP measurement (Goldmann applanation tonometry) at 
8AM ±60 minutes 
• 
Gonioscopy 
• 
Dilated fundus exam 
• 
Adverse event assessment 
At the end of the Screening Visit: 
• 
Subjects will be instructed to start washout, run-in, or prior 
trial recovery period based on prior prostaglandin therapy 
and/or prior participation in an ophthalmic investigational 
research study. Please refer to Appendix A  for subjects who 
need to start the prior trial recovery period. 

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Rev E: May 2, 2017 
Run-in Visit 1 and Run-in 
Visit 2 
(Run-in Visit 1 at 2 days  
[+ 3 days] post-initiation of 
prostaglandin therapy; and 
Run-in Visit 2 at 11 days [+ 3 
days] post-initiation of 
prostaglandin therapy) 
At 8AM (T0) 
• 
IOP measurement (Goldmann applanation tonometry) 
• 
Adverse event assessment 
Visits only applicable to Stratum B subjects. After 
prostaglandin response is confirmed, subjects will washout for 6 
Weeks (-2/+3 days). 
IOP Confirmation Visit 
(End of the 6 week prior trial 
recovery period [-2 days/+ 5 
days])  
At 8AM (T0) 
• 
IOP measurement (Goldmann applanation tonometry) 
• 
Adverse event assessment 
Visit only applicable to subjects exiting from a prior 
ophthalmic investigational research study.  
Baseline Visit 1 
(Visit timing will vary based 
on randomization stratum: A, 
B, or C) 
 
All IOP Measurements must 
be conducted within ± 60 
minutes of the required time, 
and must be conducted at 
approximately the same time 
at each of the follow-up visits. 
The following will be performed for both eyes on the day of the 
baseline visit:  
At 8AM (T0)  
• 
Medication and medical history update 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
IOP measurement 
• 
Adverse event assessment  
Baseline Visit 2/ Insertion 
Visit 
(Day 1) 
All IOP Measurements must 
be conducted within ± 60 
minutes of the required time, 
and must be conducted at 
approximately the same time 
at each of the follow-up visits. 
The following will be performed for both eyes on the day of the 
baseline visit:  
At 8AM (T0) 
• 
IOP measurement 
• 
Assessment of BCVA 
• 
Subject ocular comfort assessment 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
10AM (T0+2h) 
• 
IOP measurement 
4PM (T0+8h) 
• 
IOP measurement 
• 
Randomization 
• 
Punctum exam prior to insertion of OTX-TP or PV 
• 
Punctum size pre/post dilation 
• 
Insertion of intracanalicular depot into superior or inferior 
canaliculus of each eye for each subject 
At 8AM (T0), 10AM (T0+2h) and 4PM (T0+8h) 
• 
Adverse event assessment 

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OTX-16-002 
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Rev E: May 2, 2017 
4 Week (Day 29 ±3 days), 8 
Week (Day 57 ±3 days), and 
10 Week (Day 71 ±3 days) 
Visit 
All IOP Measurements must 
be conducted within ± 60 
minutes of the required time, 
and must be conducted at 
approximately the same time 
at each of the follow-up visits. 
The following will be performed on both eyes:  
At 8AM only 
• 
Medication and medical history update  
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by the 
Investigator  
• 
Punctum exam 
• 
IOP measurement 
• 
Adverse event assessment 
2 Week (Day 15 ±3 days), and 
6 Week (Day 43 ±3 days) Visit 
All IOP Measurements must 
be conducted within ± 60 
minutes of the required time, 
and must be conducted at 
approximately the same time 
at each of the follow-up visits. 
The following will be performed for both eyes:  
At 8AM (T0) 
• 
Medication and medical history update  
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by visual 
assessment  
• 
Punctum exam 
At 8AM (T0), 10AM (T0+2h) and 4PM (T0+8h) 
• 
IOP measurement 
• 
Adverse event assessment 
At any visit prior to the 6 Week Visit, if the intracanalicular 
depot is not visualized in one or both eyes by the Investigator, 
the Investigator will insert a new intracanalicular depot in the 
respective eye(s) after confirming patency. For any depot 
replacements, IOP assessments should be completed prior to 
replacement. The subject will continue to return for follow-up 
visits per the study schedule through the 12 Week Visit. The 
number of replacements will be tracked and documented on the 
appropriate Case Report Form (CRF). 
 
If the intracanalicular depot is still present in one or both eyes at 
the 12 Week Visit, the Investigator will attempt to remove the 
intracanalicular depot from the respective eye(s). If removal is 
successful bilaterally, the subject will be exited from the study. 
The subject may be prescribed IOP-lowering drops at the 
Investigator’s discretion. 
 

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Rev E: May 2, 2017 
If removal is unsuccessful in one or both eyes, the subject will 
return at the 20 Week Visit. The subject may be prescribed IOP-
lowering drops at the Investigator’s discretion. 
 
If the intracanalicular depot is not present bilaterally at the 12 
Week Visit, the subject will be exited at the end of that visit. The 
subject may be prescribed IOP-lowering drops at the 
Investigator’s discretion. 
 
At any visit from the 6 Week Visit prior to the 12 Week Visit, if 
the intracanalicular depot is not visualized in one or both eyes by 
the Investigator, the Investigator will insert a new 
intracanalicular depot in the respective eye (s) after confirming 
patency. For any depot replacements, IOP assessments should be 
completed prior to replacement. The subject will return for 
follow-up visits through the 12 Week Visit and then at the 20 
Week Visit. The number of replacements will be tracked and 
documented on the appropriate CRF. The removal of the 
replaced intracanalicular depot(s) will be conducted at the 20 
Week Visit. 

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Rev E: May 2, 2017 
12 Week (Day 85 ±3 days) 
Visit 
 
All IOP Measurements must 
be conducted within ± 60 
minutes of the required time, 
and must be conducted at 
approximately the same time 
at each of the follow-up visits. 
The following will be performed for both eyes:  
At 8AM(T0)  
• 
Medication and medical history update  
• 
Iris color 
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by visual 
assessment 
• 
Punctum exam 
At 8AM (T0), 10AM (T0+2h) and 4PM (T0+8h) 
• 
IOP measurement 
• 
Adverse event assessment 
At 4PM (T0+8hr) 
• 
Dilated fundus exam 
 
For subjects who received a replacement intracanalicular depot 
prior to the 6 Week Visit: 
If the intracanalicular depot is still present in one or both eyes at 
the 12 Week Visit, the Investigator will attempt to remove the 
intracanalicular depot from the respective eye(s). If removal is 
successful bilaterally, the subject will be exited from the study.  
If removal is unsuccessful in one or both eyes, the subject will 
return at the 20 Week Visit.  
If the intracanalicular depot is not present bilaterally at the 12 
Week Visit, the subject will be exited at the end of the visit.  
The subject may be prescribed IOP-lowering drops at the 
Investigator’s discretion. 
20 Week (141 ±7 Days) 
All IOP Measurements must 
be conducted within ± 60 
minutes of the required time, 
and must be conducted at 
approximately the same time 
at each of the follow-up visits. 
The following will be performed on both eyes (if necessary):  
At 8AM only 
• 
Medication and medical history update  
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by visual 
assessment 
• 
Punctum exam 
• 
IOP measurement 
• 
Adverse event assessment 

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CONFIDENTIAL 
OTX-16-002 
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Rev E: May 2, 2017 
For subjects who received a replacement intracanalicular depot 
starting at the 6 Week Visit and prior to the 12 Week Visit: 
If the intracanalicular depot is still present in one or both eyes at 
the 20 Week Visit, the Investigator will attempt to remove the 
intracanalicular depot from the respective eye(s). If removal is 
successful bilaterally, the subject will be exited from the study.  
If removal at the 20 Week Visit is not successful in one or both 
eyes, the subject will be required to return to the clinic every 30 
(± 10) days until the intracanalicular depot is confirmed to be no 
longer present. 
If the intracanalicular depot is not present bilaterally at the 20 
Week Visit, the subject will be exited at the end of the visit.  
The subject may be prescribed IOP-lowering drops at the 
Investigator’s discretion. 
Statistical Methods 
Hypotheses: 
H0: The difference between study eyes that received  OTX-TP 
and study eyes that received PV (OTX-TP minus PV), in mean 
IOP at the following time points: 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits, is ≥ 0 mmHg for at least 
one time point over all visits. 
H1: The difference between study eyes that received OTX-TP 
and study eyes that received PV (OTX-TP minus PV), in mean 
IOP at the following time points: 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits, is < 0 mmHg for all time 
points over all visits. 
Sample Size: 
Assuming a common standard deviation of 3.75 mmHg within a 
treatment group, a mean difference of 1.5 mmHg or greater 
between treatment groups at each of the 3 time points of each of 
the 3 visits, and a 3:2 randomization ratio, 294 subjects in the 
OTX-TP arm and 196 subjects in the PV arm yield >90% power 
to conclude superiority of OTX-TP to PV in mean IOP at all of 
the 9 time points using a 2-sided alpha = 0.05 and assuming 
independence among time points.  The power increases with 
increasing positive correlation among time points. 
To account for 10% of subjects discontinuing before the 12 
Week Visit, approximately 330 subjects will be randomized into 
the OTX-TP arm and 220 subjects will be randomized into the 
PV arm. 
 
Primary Analysis: 

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CONFIDENTIAL 
OTX-16-002 
Page 25 of 75 
Rev E: May 2, 2017 
The primary analysis of the primary efficacy outcome will 
employ a linear model with IOP at the given visit (2 Week, 6 
Week, and 12 Week) and time point (8AM, 10AM, and 4PM) as 
the response, time point specific baseline IOP as a covariate, and 
treatment as a main effect factor, using the intent to treat 
population with multiple imputation methods using Monte Carlo 
Markov Chain approach to impute missing data and using last 
time-consistent observation carried forward to impute data for 
time points after a subject’s study eye is prescribed IOP-
lowering drops.  Each time point within each visit will be 
modeled separately.  The least squares mean differences (test – 
control) between OTX-TP and PV will be presented along with 
2-sided 95% confidence intervals (CIs) around the difference 
and 2-sided p-values testing the difference equal to 0.  Inference 
will be made on the 2-sided p-value at a 2-sided alpha = 0.05 at 
each time point and visit.   
The study will be considered a success if the 2-sided p-value < 
0.05 and the point estimate of the difference is < 0 at all time 
points over the three visits. 
Sensitivity analyses, to determine robustness of results, will be 
performed using multiple imputation methods with pattern 
mixture models, last time-consistent observation carried forward 
(LOCF), and baseline time-consistent observation carried 
forward to impute missing values and observed data only.  
Additionally, sensitivity analyses will be performed on the per 
protocol population using observed data only. 
 
 
 

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Rev E: May 2, 2017 
2. 
PRINCIPAL CONTACTS 
 
Sponsor Contacts: 
 
Nicole Rissman 
Clinical Project Manager 
Phone:  (781) 850-6595 
Fax: (781) 357-4001 
Email: nrissman@ocutx.com  
Elizabeth Braun 
Clinical Project Manager 
Phone:  (781) 357-4038 
Fax:  (781) 357-4001 
Email:  ebraun@ocutx.com 
 
 
 
Data Management:  
 
Swati Sane 
Director, Data Management 
Phone:  (781) 357-4036 
Fax: (781) 357-4001 
Email: ssane@ocutx.com 
Medical Monitor: 
 
Lisa Feulner, M. D.  
Advanced Eye Care & Aesthetics,  
2227 Old Emmorton Rd., Suite 114 
Bel Air, MD 21015   
Phone:  410-569-7173 
Email: lisafeulner@yahoo.com  
 
 

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3. 
INTRODUCTION 
Ocular Therapeutix, Inc. (OTX) is a biopharmaceutical company focused on developing medical 
device and drug products to address unmet and underserved medical needs in ophthalmology. 
OTX was founded to further develop its proprietary polyethylene glycol (PEG) hydrogel 
technology in various ophthalmic applications. Ocular Therapeutix has designed a bioabsorbable 
intracanalicular depot as the platform for drug delivery products, which can be used to deliver 
various active pharmaceutical ingredients that have been included in other FDA-approved drug 
products.  The intracanalicular depot is designed to be inserted into the inferior or superior 
punctum and then be retained in the canaliculus for the entire duration in which the drug is being 
delivered.  Over this time and through hydrolysis, the intracanalicular depot softens, liquefies 
and is cleared through the nasolacrimal duct. Another similar hydrogel product, ReSure Sealant, 
manufactured by Ocular Therapeutix was FDA approved for ophthalmic use (reference PMA 
P130004) on January 8, 2014. 
3.1. 
Background and Rationale 
Glaucoma is a highly frequent chronic disease affecting more than 2 million people over 40 
years of age in the United States alone1.  It is defined as optic neuropathy leading to the loss of 
optic-nerve tissue and progressing into loss of vision.  In fact, it has been reported to be one of 
the leading causes of irreversible blindness. Open-angle glaucoma is the most common form of 
the disease2. 
Elevated fluid pressure within the eye (intraocular pressure, IOP), defined as pressures above the 
normal range of 10 to 21 mmHg4 is the main risk factor for glaucoma. People with elevated IOP 
levels without any optic nerve damage or visual field loss are diagnosed with ocular 
hypertension, as opposed to glaucoma. However, people with ocular hypertension are still at risk 
for progressive damage to the optic nerve. 
For both glaucoma and ocular hypertension, the critical factor for effective therapy is to lower 
the IOP. Laser treatments, surgery and various topical drugs have been shown to be effective 
treatments. Among the topical drugs are different classes such as beta-blockers, alpha-adrenergic 
agonists, carbonic anhydrase inhibitors and prostaglandin analogues4. 
Travoprost is a synthetic prostaglandin F 2α analogue. Its chemical name is (Z)-7- [(1 R ,2 R ,3 
R ,5 S )-3,5-dihydroxy-2-[(1 E ,3 R )-3-hydroxy-4-[(α,α,α-trifluoro-m–isopropyl-tolyl)oxy]-1-
butenyl]-cyclopentyl]-5-heptenoate.  It is a prostaglandin analogue that is enzymatically 
converted to a free acid form in human cornea. Travoprost free acid is a selective FP prostanoid 
receptor agonist which is believed to reduce IOP by increasing trabecular meshwork and  
uveoscleral outflow.  Travoprost is the active pharmaceutical ingredient in Travatan® ,Travatan Z 
®, and Izba™(Alcon Laboratories, Inc., Ft Worth, TX), which are all topical ophthalmic 
solutions for use to reduce elevated IOP.  Dosage is typically one drop daily of a 0.004% or 
0.003% solution.   
                                                 
 
1    Simmons, S. T, Glaucoma Today and Where We Are Going, Advanced Ocular Care, July/August 2010. 
2   Scientific Discussion for the approval of Travatan, European Medicines Agency 2004. 

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There are limitations associated with the application of commercially available topical travoprost 
drops: 
• 
Poor subject compliance3 
• 
Difficulty in administering drops 
• Limited accuracy of drops getting into the eye 
• Potential washout of drops  
• Conjunctival hyperemia 
• 
Prostaglandin associated periorbitopathy4 
With potential blindness being the long term effect of poorly managed glaucoma, subject 
compliance and proper instillation of eye drop medications become highly critical issues.  Studies 
have shown less than 50% of glaucoma subjects continue therapy and refill prescriptions as 
required5 6. Furthermore, a recent study of an elderly cataract population (similar in 
demographics to the glaucoma population) disclosed that over 90% of patients administered eye 
drops incorrectly.7 
To meet the clinical need for a safe and effective intracanalicular depot, the product should meet 
the following requirements: 
 
 
 
 
 
 
 
 
A 
bioabsorbable hydrogel intracanalicular depot has been developed by OTX as a platform for 
ophthalmic drug delivery.  OTX-TP (sustained release travoprost) Intracanalicular Depotis 
expected to have significant advantages over the commercially available eye drops treatments in 
that it:   
• Remains in the lacrimal canaliculus for desired duration of therapy, eliminating subject 
non-compliance.   
• Delivers therapeutic levels of travoprost continuously for the intended duration of 
therapy.  
                                                 
 
3  Francis, B. A, How Do You Ensure Patient Compliance with Glaucoma Therapy, Ophthalmology Web, July 8, 
2010. 
4 Peplinksi LS, Albani Smith K. Deepening of lid sulcus from topical bimatoprost therapy. Optom Vis Sci 
2004;81:574-7. 
5 Schwartz GF, Quigley HA.  Adherence and Persistence with Glaucoma Therapy.  Surv Ophthalmol.  53.1 (2008): 
57-68. 
6  Friedman, D. S. eta al., Using Pharmacy Claims Data to Study Adherence to Glaucoma Medications: 
Methodology and Findings of the Glaucoma and Adherence and    Persistency Study (GAPS), Investigative 
Ophthalmology &Visual Science, November 2007, Vol. 48, No. 11. 
7 An JA, KasnerO, SamekDA, Levesque V. Evaluation of eyedropadministration by inexperienced patients after 
cataract surgery. J Cataract Refract Surg2014; 40:1857-1861 
Easy to Insert 
Insertion times no longer than currently available commercial 
punctal plugs. 
Retention 
Remain in the lacrimal canaliculus for the desired duration of 
therapy. 
Extended 
Delivery 
An ideal product must deliver travoprost continuously for the 
intended course of therapy such that the subject continually receives 
treatment until the product is removed or replaced. 
Biocompatible 
Must be biocompatible, chemically inert, non-immunogenic, and 
synthetic (i.e. devoid of animal tissues). 

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The purpose of the Phase 3a clinical study described herein is to evaluate the safety and IOP-
lowering efficacy of OTX-TP when placed in the lacrimal canaliculus in subjects with open 
angle glaucoma or ocular hypertension.  OTX-TP will be compared to a placebo vehicle 
intracanalicular depot placed in the canaliculus of the eyelid.  In addition, the Investigator will 
confirm the presence of the intracanalicular depot during study follow up visits, and if the 
Investigator confirms the intracanalicular depot is no longer present at any time prior to the 12 
Week Visit, a new depot will be inserted. It is expected that this route of administration will 
maximize the consistency of dosing. 
3.2. 
Report of Prior Investigations 
Ocular Therapeutix has developed several types of PEG hydrogel intracanalicular depots that are 
similar to OTX-TP. These intracanalicular depots utilize the same bioabsorbable PEG hydrogel 
technology used in OTX-TP, but are loaded with different active pharmaceutical ingredients with 
various intended uses.  
OTX-TP has been evaluated for initial safety and feasibility in the treatment of elevated IOP 
associated with glaucoma in clinical trials conducted in Singapore and South Africa. A total of 
78 subjects were enrolled in these studies.  There were no serious adverse events reported and no 
safety concerns were raised. Initial efficacy was confirmed by what Ocular Therapeutix 
interpreted as clinically meaningful IOP reduction from baseline, thus warranting a larger study. 
OTX-TP Phase 2b, was a prospective, multicenter, randomized, double-masked, parallel arm 
study evaluating the safety and efficacy of OTX-TP for the reduction of elevated intraocular 
pressure in subjects with open-angle glaucoma or ocular hypertension.  The trial employed a 
“double dummy” design: Treatment A (OTX-TP and placebo eye drops) and Treatment B 
(timolol maleate ophthalmic solution plus placebo depot).  A total of 72 subjects were treated 
bilaterally; 33 in the OTX-TP group and 39 in the timolol group. The primary endpoint measures 
in the study were the difference between treatment groups in (1) mean change from baseline 
average diurnal IOP at the Day 60 Visit; (2) mean change from baseline average diurnal IOP at 
the Day 90 Visit; (3) mean change from baseline at each individual time point at the Day 60 and 
90 Visits; (4) mean IOP for the average diurnal IOP and each individual time point at the Day 60 
and 90 Visits; and (5) mean percent change from baseline for the average diurnal IOP and each 
individual time point at the Day 60 and 90 Visits. This results of this trial showed a slightly 
elevated IOP-lowering effect in the timolol group than in the OTX-TP group. 
Another Ocular Therapeutix drug product, DEXTENZA (sustained release dexamethasone) 
Intracanalicular Depot, has been clinically evaluated for the safety and efficacy compared to a 
Placebo Vehicle for the treatment of ocular inflammation and pain in subjects undergoing 
ophthalmic surgery in two prospective, multicenter, randomized, parallel-arm, double-masked, 
vehicle controlled Phase 3 studies.  
The first Phase 3 study enrolled 247 subjects and met both primary efficacy measures, achieving 
a statistically significant improvement in the reduction of inflammatory cells and pain. 33.1% of 
DEXTENZA treated subjects showed an absence of inflammatory cells in the anterior chamber 
of the eye on Day 14 following drug product insertion, compared to 14.5% of those receiving PV 
treatment (p=0.0018). In addition, 80.4% of subjects receiving DEXTENZA reported absence of 
pain in the study eye on Day 8 following insertion of the drug product, compared to 43.4% of 
those receiving PV treatment (p<0.00001). DEXTENZA was shown to be safe and efficacious in 
treating ocular pain in adult subjects having undergone cataract extraction with intraocular lens 
implantation. 

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The second Phase 3 study enrolled 241 subjects, met one of the primary efficacy measures 
achieving a statistically significant improvement in the reduction of pain, but failed to meet its 
primary efficacy endpoint of demonstrating superiority of DEXTENZA over PV in the reduction 
of anterior chamber cells of the eye on Day 14. 77.5% of DEXTENZA treated subjects showed 
an absence of pain in the study eye on Day 8 following drug product insertion, compared to 
58.8% of those receiving PV treatment (p=0.0025). However, 39.4% of subjects receiving 
DEXTENZA showed an absence of anterior chamber cells in the study eye on Day 14 following 
drug product insertion, compared to 31.3% of those receiving PV treatment (p=0.2182). The 
most frequent ocular AEs in the study eye were anterior chamber inflammation (characterized as 
anterior chamber inflammation, iritis or anterior chamber cell). 
OTX-MP, an intracanalicular depot delivering moxifloxacin, has been clinically evaluated by 
Ocular Therapeutix for initial safety and feasibility at one clinical site in Singapore. This 
prospective, single-arm feasibility clinical evaluation enrolled a total of 20 subjects (20 eyes).  
All subjects were adults undergoing clear corneal cataract surgery. There were no adverse events 
or serious adverse events reported.  Additionally, the safety assessments performed throughout 
the follow-up period did not raise any safety concerns. 
Ocular Therapeutix is conducting non-significant risk IDE medical device clinical trials in the 
United States to evaluate the PEG hydrogel intracanalicular depot for acute placement, retention, 
visualization and comfort as well as the safety of the intracanalicular depot replacement as would 
be required for ongoing delivery of treatment in a chronic disorder. This is a bioabsorbable 
hydrogel intracanalicular depot (i.e., the PV) that does not contain any active pharmaceutical 
ingredient. To date, no serious adverse events related to the PV have been reported, and no safety 
concerns have been raised. 
3.2.1. 
Prior Experience with Travoprost 
Travoprost, the active drug component of the OTX-TP, is a synthetic prostaglandin F2α analogue 
used for reducing elevated intraocular pressure in subjects with open angle glaucoma or ocular 
hypertension. Travoprost is the active pharmaceutical ingredient in Travatan®, Travatan Z® and 
Izba™ (Alcon Laboratories Inc., Fort Worth, TX) which have been approved by the US FDA 
under application numbers 021257, 021994 and 204822, respectively.  
3.3. 
Description of Intracanalicular depot  
3.3.1. 
OTX-TP (sustained release travoprost) Intracanalicular Depot 
The OTX-TP drug product is a fluorescent dried polyethylene glycol based, rod-shaped hydrogel 
intracanalicular depot designed to be placed in the superior or inferior canaliculus. The hydrogel 
swells on contact with moisture to occlude the lumen, thus holding the intracanalicular depot in 
place.  Once OTX-TP swells to fill the canaliculus, it is contained in the canaliculus until the 
hydrogel is resorbed. OTX-TP contains conjugated fluorescein to serve as a visualization aid 
through the use of a blue light source and yellow filter to confirm product presence.  
Embedded in OTX-TP are poly (-lactic- acid) (PLA) microparticles which contain encapsulated 
travoprost, the active pharmaceutical ingredient.  The microparticles are bioabsorbable particles 
designed to release travoprost in a controlled fashion over the intended duration of therapy. 
OTX-TP contains approximately 0.32 mg travoprost and is designed to provide a sustained 
release of therapeutic levels of travoprost for the reduction of elevated intraocular pressure. As 
OTX-TP hydrates in tear fluid and swells in volume, the microparticles will degrade by 
hydrolysis and the travoprost is slowly released over a period of up to approximately 90 days. 

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The OTX-TP also has an inert PEG tip to aid in insertion. This tip dissolves during insertion and 
placement to provide intracanalicular lubrication. 
OTX-TP is provided to the Investigator as a terminally-sterilized dried intracanalicular depot. 
The product is packaged in a hermetically sealed foil pouch to maintain stability and sterility 
over time. It is placed into the punctum by the Investigator using forceps.  
3.3.2. 
Placebo Vehicle Intracanalicular depot (PV) 
The PV consists of the same components as OTX-TP, except that it does not contain travoprost. 
The PV will be provided in the same packaging as OTX-TP to maintain masking for the clinical 
trial. 
3.4. 
Intended Use 
The intended use that will be utilized in this study is stated below. 
OTX-TP (sustained release travoprost) Intracanalicular Depot is intended for the reduction of 
elevated intraocular pressure in subjects with open-angle glaucoma (OAG) or ocular 
hypertension (OH). 
3.5. 
Study Design and Duration 
This is a prospective, multicenter, randomized, parallel-arm, double masked, placebo vehicle 
controlled trial to evaluate the safety and IOP-lowering efficacy of OTX-TP, a sustained release 
drug product placed in the canaliculus of the eyelid in subjects with open-angle glaucoma or 
ocular hypertension.  A total of up to 550 subjects (1100 eyes) with a clinical diagnosis of open-
angle glaucoma or ocular hypertension in both eyes will receive either OTX-TP or PV to 
evaluate the safety and efficacy of OTX-TP.   
The subjects enrolled in this parallel-arm study will be randomized to receive either OTX-TP 
(sustained release travoprost) Intracanalicular Depot or PV (placebo vehicle) intracanalicular 
depot, respectively.  Subjects randomized to the treatment group will receive OTX-TP in either 
the superior or inferior canaliculus of each affected eye on Day 1.  Subjects randomized to the 
control group will receive PV in either the superior or inferior canaliculus of each affected eye 
on Day 1.   
Subject randomization is 3:2 with a total of approximately 330 subjects in the OTX-TP arm and 
220 in the PV arm. Randomization will be stratified by investigational site and previous ocular 
anti-hypertensive therapy. 
Both eyes will receive either OTX-TP or PV, but only the eye with the higher IOP at 8:00AM at 
Baseline Visit 2 that meets all enrollment criteria will be considered as the study eye and 
included in the primary efficacy analysis.  If both eyes are eligible and have the same IOP at 
8AM on Baseline Visit 2 (Day 1), the right eye will be the study eye and the left eye will be 
considered the secondary study eye. All eyes will be included in the safety analysis. All eyes will 
be included in the safety analysis. 
Subjects currently being treated with a prostaglandin analogue at the time of the Screening Visit 
will undergo a 6 week (- 2 days/+ 3 days) washout period starting at the Screening Visit and 
prior to Baseline Visit 1.  The Baseline Visit 2/Insertion Visit, Day 1 will be conducted two to 
four days after the Baseline Visit 1.  IOP measurements at the baseline visits will confirm that 
the washout period was sufficient.   
Subjects not currently treated with a prostaglandin analogue will undergo a 2 week run-in 
starting at the Screening Visit to confirm that they are a prostaglandin responder. At least two 
IOP measurements will be taken over a two week period (Run-in Visit 1 at 2 days [+ 3 days] 

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post-initiation of prostaglandin therapy; and Run-in Visit 2 at 11 days [+ 3 days] post-initiation 
of prostaglandin therapy). The Run-in IOP measurements will be conducted at 8 AM +/- 1 hour, 
to confirm the response to prostaglandin therapy. Once the response is confirmed, the subjects 
will undergo a 6 week (- 2 days/+ 3 days) washout period prior to Baseline Visit 1. The Baseline 
Visit 2/Insertion Visit, Day 1 will be conducted two to four days after the Baseline Visit 1. The 
IOP measurement at Baseline Visit 2 must demonstrate a ≥ 5 mmHg increase from Run-in Visit 
2. IOP measurements at the baseline visits will confirm that the washout period was sufficient.   
Subjects who have exited from another ophthalmic investigational research study within the last 
8 weeks will be started on a 6 week prior trial recovery period and stop all glaucoma/OHT meds, 
after completing Informed Consent and the Screening Visit. They will then be discussed with the 
Medical Monitor, in order to obtain written approval to be allowed to participate in the current 
study. The approval will be captured on the appropriate eCRF. Timing and requirements for the 
period between Screening and Baseline Visit 1 will vary, please refer to Appendix A  for 
additional specifications.  
At Baseline Visit 2/Insertion Visit, if insertion is unsuccessful in one eye, the intracanalicular 
depot from the contralateral eye (if already inserted) will not be removed. The subject will be 
prescribed IOP-lowering drops at the Investigator’s discretion for the eye that did not receive a 
depot.  The subjects will be followed for safety only, and the eye that received a depot will be 
included in the safety analysis. The study will be supplemented with additional subjects to 
account for these subjects in order to ensure that the necessary number of subjects who received 
a depot bilaterally are followed through the 12 Week Visit for efficacy and safety. 
All subjects will undergo follow-up visits at 2, 4, 6, 8, 10, and 12 Weeks.  If at any visit, the 
Investigator deems it necessary to initiate IOP-lowering drops as rescue therapy due to an 
increase in IOP, the subject will begin IOP-lowering drops at the Investigator’s discretion and 
followed through the remainder of the study for safety. 
For subjects with Early Loss of Intracanalicular Depot Prior to the 6 Week Visit: 
At any visit prior to the 6 Week Visit, if the intracanalicular depot is not visualized in one 
or both eyes by the Investigator, the Investigator will insert a new intracanalicular depot 
in the respective eye(s) after confirming patency. For any depot replacements, IOP 
assessments should be completed prior to replacement. The subject will continue to 
return for follow-up visits per the study schedule through the 12 Week Visit. The number 
of replacements will be tracked and documented on the appropriate Case Report Form 
(CRF). 
If the intracanalicular depot is still present in one or both eyes at the 12 Week Visit, the 
Investigator will attempt to remove it (For removal methods, refer to Appendix C). If 
removal is successful bilaterally, the subject will be exited from the study upon 
confirmation of the bilateral absence of the intracanalicular depot. If the intracanalicular 
depot is not present bilaterally at the 12 Week Visit, the subject will be exited at the end 
of that visit.  
If removal is unsuccessful in one or both eyes at the 12 Week Visit, the subject will 
return at the 20 Week Visit. The Investigator will attempt removal of intracanalicular 
depot from the respective eye (s) at this visit. The subject may be prescribed IOP-
lowering drops if necessary at the 12 Week Visit at the Investigator’s discretion. 

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For subjects with Early Loss of Intracanalicular depot from the 6 Week Visit prior to the 12 
Week Visit: 
At any visit from the 6 Week Visit prior to the 12 Week Visit, if the intracanalicular 
depot is not visualized in one or both eyes by the Investigator, the Investigator will insert 
a new intracanalicular depot in the respective eye(s) after confirming patency. For any 
depot replacements, IOP assessments should be completed prior to replacement. The 
subject will return for follow-up visits through the 12 Week Visit and then at the 20 
Week Visit. The number of replacements will be tracked and documented on the 
appropriate CRF.  
At the 20 Week Visit, the Investigator will attempt removal of the replacement 
intracanalicular depot(s), if still present. If removal at the 20 Week Visit is successful 
bilaterally, the subject will be exited from the study upon confirmation of the bilateral 
absence of the intracanalicular depot.  
If removal at the 20 Week Visit is not successful in one or both eyes, the subject will be 
required to return to the clinic every 30 (± 10) days until the intracanalicular depot is 
confirmed to be no longer present or removal of the intracanalicular depot is successful 
for the respective eye(s). Removal will be attempted at every visit until the 
intracanalicular depot is no longer present. 
If the intracanalicular depot is not present bilaterally at the 20 Week Visit, the subject 
will be exited from the study at the end of that visit. The subject may be prescribed IOP-
lowering drops if necessary at the 20 Week Visit at the Investigator’s discretion. 

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Rescue Therapy for Subjects with unacceptable IOP increase after treatment: 
If at any visit prior to and including the 2 Week visit, the Investigator determines that the 
subject’s IOP is increasing to unacceptable levels, the Investigator will prescribe IOP 
lowering drops at his or her discretion and will confirm adequate IOP lowering response 
at the next visit.  The IOP lowering medication should be recorded on the appropriate 
CRF. The intracanalicular depot will not be removed, and the subject will be followed 
through the 12 Week Visit for the remaining scheduled study visits.  
Additionally, if at any point in the study, the Investigator determines that the IOP is not 
adequately controlled, IOP-lowering drops may be provided as rescue therapy at the 
Investigator’s discretion to ensure the subject’s safety. 
The study will be conducted at up to 50 qualified investigative sites in the United States 
following Institutional Review Board (IRB) approval. A site may randomize up to a maximum of 
55 subjects. All subjects will be required to provide informed consent prior to study 
participation. 
The anticipated duration of the clinical investigation is approximately 18 months. The expected 
duration of participation for each subject will vary depending on whether they have received 
previous treatment, and how long the intracanalicular depot is retained 
 
3.5.1. 
Control of Bias 
The following study design parameters will minimize bias:  
• 
The study design is a parallel-arm, prospective, placebo controlled study. 
• 
The study is double-masked. 
• 
The study will be conducted across multiple centers. 
• 
The study is randomized (3:2, treatment group to control group). 

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4. 
STUDY DESIGN 
4.1. 
Study Objective 
To evaluate the safety and IOP lowering efficacy of OTX-TP, a sustained release travoprost drug 
product, placed in the canaliculus of the eye in the treatment of subjects with open-angle 
glaucoma or ocular hypertension. 
4.2. 
Study Endpoints 
4.2.1. 
Endpoints 
The primary study endpoint measure to be evaluated is: 
• 
Mean IOP at the following time points 8AM, 10AM, and 4PM at the 2 Week, 6 Week, and 
12 Week Visits. 
The secondary endpoint measures to be evaluated are: 
• 
Mean change from baseline IOP at the following time points 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits. 
• 
Mean percent change from baseline IOP at the following time points 8AM, 10AM, and 4PM 
at the 2 Week, 6 Week, and 12 Week Visits. 
4.2.2. 
Other Data to be Collected 
Additionally, data will be collected for the following: 
• 
Ocular complaints  
• 
Visualization of intracanalicular depot by the Investigator at each time point  
• 
Ease of insertion of intracanalicular depot 
• 
Number of intracanalicular depots required in each eye for the 12 week period per subject 
4.2.3. 
Safety Evaluations 
The following safety evaluations will be completed: 
• Best corrected visual acuity (BCVA) 
• Slit lamp biomicroscopy 
• Assessment and grade of ocular hyperemia (at slit lamp) 
• Subject ocular comfort assessment (to be completed at all visits after/including Baseline visit 
2) 
• Dilated fundus exam (to be completed on at Screening and 12 week) 
• Adverse events 

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4.3. 
Selection and Training of Investigators 
Only ophthalmologists who are experienced with treating glaucoma or ocular hypertension will 
be considered for participation as Principal Investigators in this study.  Optometrists who are 
experienced with treating glaucoma or ocular hypertension will be considered for participation as 
Sub-Investigators. All investigators that will use the intracanalicular depot must be experienced 
in intracanalicular depot insertion and will undergo training per the OTX-TP instructions for use 
prior to initial use. 
4.4. 
Subject Selection 
4.4.1. 
Pre-Procedure Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible: 
1. Greater than or equal to 18 years of age at Screening.  
2. Documented diagnosis of ocular hypertension with an open angle of Schaffer Grade 3 or 
greater or open-angle glaucoma without pseudoexfoliation or pigment dispersion or 
evidence of traumatic angle recession. 
3. IOP is currently controlled as assessed by the Investigator: 
• With a topical prostaglandin, and there has been no change in IOP lowering 
therapy over 8 weeks prior to Screening, or, 
• without IOP-lowering medication over 8 weeks prior to Screening and after a 2-
week run-in period on prostaglandin therapy demonstrates an adequate response 
Note:  For Subjects entering through Stratum C, a required Medical Monitor review will 
ensure subjects have: 
• demonstrated 8 weeks of stable treatment (or no treatment) for glaucoma and/or 
ocular hypertension prior to enrollment in the previous recent ophthalmic clinical 
trial(s).  
• documented history of an adequate prostaglandin response as described in the 
protocol, or will undergo a prostaglandin run-in trial as described in the protocol for 
patients who do not have such a history.  
 
4. Baseline IOP (following washout or run-in) in at least 1 eye (the same eye) of: 
• ≥ 24mmHg at Hour 0 (T0) at Baseline Visit 2 (Day 1)  
• ≥ 22mmHg at (T0+ 2h) and (T0 + 8h) at Baseline Visit 2 (Day 1)  
• At 8AM Baseline Visit 2 (Day 1), ≥ 5 mmHg increase from Screening for subjects 
previously on prostaglandins  
• At 8AM Baseline Visit 2 (Day 1), ≥ 5 mmHg increase from Run-in Visit 2 for 
subjects not previously on prostaglandins prior to the Screening Visit   
Note: the same eye must meet all of the above listed IOP eligibility criteria 
5. IOP must be ≤ 34mmHg in each eye at all time points at the Baseline Visit 1 (Day -2 to -
4) and Baseline Visit 2 (Day 1).  
6. Informed of the nature of the study and subject is able to comply with study requirements 
and visit schedule.  
7. Provided written informed consent, approved by the appropriate Institutional Review 
Board. 

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4.4.2. 
Pre-Procedural Exclusion Criteria 
Subjects who meet any of the following criteria are not eligible: 
1. A history, prior to Screening, of an inadequate response (< 5mmHg decrease from prior to 
any treatment) or no response to topical prostaglandin for OAG/OH. 
2. For subjects on IOP-lowering medication(s): History of concurrent treatment with 3 or more 
IOP-lowering medications for longer than 2 weeks. Any combination medication will be 
considered as 2 medications. 
3.  Currently (or within 8 weeks prior to Screening) on any ocular or systemic medication [i.e., 
carbonic anhydrase inhibitors, corticosteroids (including topical dermal steroids for the face), 
etc.] that may: 
• Have an effect on the subject's IOP or will require use of such ocular or systemic 
medications during the study period. 
• No topical ophthalmic medications other than prostaglandins allowed at the time of 
the screening visit. Systemic beta blockers will be allowed, but any initiation of or 
alterations in systemic regimen of beta-blocker containing medications from 8 weeks 
prior to screening through the final study visit is excluded. 
Subjects currently treated with topical prostaglandin analogues are required to undergo a 
washout period of 6 weeks (- 2 days/+ 3 days).  
Note:  For Subjects entering through Stratum C, changes in ocular or systemic prior 
ophthalmic study medications, that may have an effect on the Subject’s IOP, will be allowed, 
but inclusion in the study will be based on a required Medical Monitor review. Stratum C 
subjects will also be allowed to screen for the study while on ophthalmic medications other 
than prostaglandins, however, these medications should be stopped at Screening, and a Prior 
Trial Recovery Period shall be started.   
4. A BCVA worse than 0.6 LogMAR (20/80 Snellen) in either eye as measured using an 
ETDRS chart. 
5. Punctum size smaller than 0.4 mm or greater than 0.9 mm in either eye as measured using a 
standard punctum gauge.  
6. Known or suspected allergy and/or hypersensitivity to Travoprost or any prostaglandin, 
fluorescein, or to any component of the study products. 
7.  History of ocular trauma within the past 6 months in either eye. 
8. Evidence of angle recession by gonioscopy. 
9. Presence of any abnormality based upon the assessment by the Investigator preventing 
reliable applanation tonometry of either eye. 
10. Narrow or potentially occludable anterior chamber angle defined as an anterior chamber 
angle of less than or equal to Grade 2 (Schaffer classification) as measured by gonioscopy 
11. Central corneal thickness < 480 µm or > 620 µm in either eye. 
12. Cup to disc ratio > 0.80 (horizontal or vertical measurement) in either eye. 
13. Functionally significant central visual field loss or documented significant progressive field 
loss within the last year in either eye based upon the assessment by the Investigator. 
14. History of complications, AEs, trauma or disease in the nasolacrimal area, whether or not it 
was due to punctal plug use, including but not limited to dacryocystitis, inflammation or 
canaliculitis in either eye. 
15. Structural lid abnormalities (i.e., ectropion, entropion) in either eye based upon the 
assessment by the Investigator. 

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16. Active epiphora based upon the assessment by the Investigator. 
17. Presence of nasolacrimal duct obstruction based upon an assessment by the Investigator.  
18. Active lid disease in either eye (i.e., moderate or severe blepharitis, meibomitis) that requires 
medical treatment. 
19. History of ocular infection (bacterial, viral, or fungal) in either eye within the previous 3 
months. 
20. History of any severe ocular pathology (including severe dry eye) in either eye. 
21. History of chronic/recurrent inflammatory eye disease (i.e., scleritis, uveitis, herpes keratitis) 
in either eye. 
22. Required use of any ocular topical medication(s), any over-the counter drop(s), ointment(s), 
gel(s) or lid scrubs, other than the study ocular hypotensive medication(s) in either eye 
during the study period.   
Note: Use of artificial tears or ocular lubricants should be avoided but if necessary, 
intermittent use may be allowed up to twice a day. 
23. Any ophthalmic surgical procedures (e.g. glaucoma laser, minimally invasive glaucoma 
surgery, cataract, refractive) in study eye within the last six months or will likely require 
ophthalmic surgery before completing the study. 
24. History of penetrating or lamellar keratoplasty in either eye (including endothelial 
keratoplasty). 
25. History of keratorefractive surgery in either eye (i.e., LASIK, PRK, RK, AK, LRI, Corneal 
inlay, intracorneal ring segment). 
26. Advanced diabetic retinopathy, branch retinal vein occlusion, or central retinal vein 
occlusion in either eye. 
27. History of macular edema in either eye. 
28. Any uncontrolled systemic or debilitating disease (e.g. cardiovascular disease, hypertension, 
diabetes, or cystic fibrosis) or a medical condition that may increase the risk associated with 
study participation or administration of study treatment or that may interfere with the 
interpretation of study results based upon the assessment of the Investigator (e.g., 
autoimmune disease if the subject is on chronic medications and has ocular involvement; 
host-versus-graft disease). 
29. Requiring contact lens use at any point during the study after the Screening Visit including 
on the day of the Baseline Visits. In addition, contact lens wear must be discontinued a 
minimum of 3 days prior to pachymetry for soft contact lenses and a minimum of 14 days 
prior to pachymetry for rigid gas permeable contact lenses. 
30. Currently pregnant or breast-feeding or who wishes to become pregnant during the length of 
study participation. 
31. Currently participating or has participated within the last 30 days in any non-ophthalmic 
drug, device or other investigational research study prior to the start of this study.  
Note:  Previous participation in any ophthalmic investigational research study within 
8 weeks will require written approval for enrollment from the Medical Monitor based 
on instructions provided in Appendix A . 
32. Investigator determines subject should not be included for reasons not already specified (e.g., 
systemic or other ocular disease/abnormality, not a candidate for topical prostaglandin, 
therapy, specifically travoprost) if the health of the subject or the validity of the study 
outcomes may be compromised by the subject’s enrollment. 

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4.4.3. 
Procedural Exclusion Criteria 
All subjects who meet the following procedural exclusion criteria are considered screen failures 
and are not eligible for enrollment into the study: 
1. Unsuccessful punctal dilation of either eyelid (if needed) or punctum of either eye is too 
small to allow transient dilation to 0.7 mm prior to insertion of OTX-TP or PV. 
4.5. 
Study Procedures and Data Collection 
4.5.1. 
Study Schedule 
The schematic of the study schedule is presented in Table 1, Table 2, and Table 3, respectively 
for: Stratum A, Stratum B, and Stratum C. For subjects exiting prior ophthalmic investigational 
research studies, please refer to Appendix A  to determine the appropriate randomization stratum 
and the respective study schedule.  Procedures for study assessments can be found in 
Appendix B .  
 

Ocular Therapeutix, Inc. 
 
CONFIDENTIAL 
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Rev E: May 2, 2017 
 
 
 
 
Page 40 of 75 
 
Table 1: 
Study Schedule for subjects on prostaglandin treatment at the time of the Screening Visit (Stratum A) 
 
 
 
 
Screening 
Baseline Visit 1 
Baseline Visit 2/ 
Insertion Visit 
Follow- Up Assessments 
Study Parameter 
 
 
6 weeks (- 2 days/ 
+3 days) after 
Screening  
Day 1 
(2 days [+2 days] after 
Baseline Visit 1) 
2 Week 
(Day 15 ±3 days) 
4 Week 
(Day 29 
±3 days) 
6 Week 
(Day 43 ±3 days) 
8 Week 
(Day 57 
±3 days) 
10 Week 
(Day 71 
±3 days) 
12 Week 
(Day 85 ±3 days) 
20 Week 
(Day 141 ± 
7 days) 
8AM  
8AM 
8AM 
10AM 
4PM 
8AM 
10AM 
4PM 
8AM 
8AM 
10AM 
4PM 
8AM 
8AM 
8AM 
10AM 
4PM 
8AM 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Iris Color 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Medical/Ophthalmic and 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
(if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Automated Perimetry  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gonioscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Fundus Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pachymetry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Punctum Size Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of BCVA 
X 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Slit Lamp Biomicroscopy 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Assess/Grade Hyperemia 
X 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Punctum Exam 
X 
 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
IOP Measurement 
X (8AM) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Ocular Comfort 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Randomize 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Punctum Size Pre/Post 
Dilation 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intracanalicular Depot 
Insertion 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intracanalicular Depot  
Presence 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Assessment of Ocular 
Complaints 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Medications 
X 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 

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Page 41 of 75 
Table 2: 
 
Study Schedule for subjects who are treatment-naïve at the time of the Screening Visit (Stratum B) 
 
Screening 
Run-in 
Baseline 
Visit 1 
Baseline Visit 2/ 
Insertion Visit 
Follow- Up Assessments 
Study Parameter 
 
 
 
 
Visit 1 
(Day 2  
+3 
days) 
Visit 2 
(Day 11  
+3 
days) 
 
8 Weeks (- 
2 days/ +3 
days)  after 
Screening 
 
Day 1 
(2 days [+2 days] after 
Baseline Visit 1) 
2 Week 
(Day 15 ±3 days) 
4 Week 
(Day 29 
±3 days) 
6 Week 
(Day 43 ±3 days) 
8 Week 
(Day 57 
±3 days) 
10 
Week 
(Day 71 
±3 days) 
12 Week 
(Day 85 ±3 days) 
20 
Week 
(Day 
141 ± 7 
days) 
8AM 
8AM 
8AM 
8AM 
8AM 
10AM 
4PM 
8AM 
10AM 
4PM 
8AM 
8AM 
10AM 
4PM 
8AM 
8AM 
8AM 
10AM 
4PM 
8AM 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Iris Color 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Medical/Ophthalmic and 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
(if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Automated Perimetry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gonioscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Fundus Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pachymetry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Punctum Size 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of BCVA 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Slit Lamp 
Biomicroscopy 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Assess/Grade Hyperemia 
X 
 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Punctum Exam 
X 
 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
IOP Measurement 
X (8AM) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Ocular Comfort 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Randomize 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Punctum Size Pre/Post 
Dilation 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intracanalicular Depot 
Insertion 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intracanalicular Depot  
Presence 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Assessment of Ocular 
Complaints 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Medications 
X 
 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 

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Page 42 of 75 
Table 3: 
Study Schedule for Subjects who have exited from a prior ophthalmic investigational research study within 8 
weeks of the Screening Visit and have written approval from the Medical Monitor to be allowed to participate in 
the current study without additional exposure to prostaglandin (Stratum C)* 
 
Screening 
IOP 
Confirmation 
Visit * 
Baseline Visit 1 
Baseline Visit 2/ 
Insertion Visit 
Follow- Up Assessments 
Study Parameter 
 
End of 6 week 
prior trial 
recovery 
period (- 2 
days/ +5 days)  
  
2 weeks (+3 
days) after IOP 
Confirmation 
Visit 
 
Day 1 
2 days (+2 days) after 
Baseline Visit 1 
2 Week 
(Day 15 ±3 days) 
4 Week 
(Day 29 
±3 days) 
6 Week 
(Day 43 ±3 days) 
8 Week 
(Day 57 
±3 days) 
10 
Week 
(Day 
71 ±3 
days) 
12 Week 
(Day 85 ±3 days) 
20 
Week 
(Day 
141 ± 
7 days) 
8AM  
8AM  
8AM 
8AM 
10AM 
4PM 
8AM 
10AM 
4PM 
8AM 
8AM 
10AM 
4PM 
8AM 
8AM 
8AM 
10AM 
4PM 
8AM 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Iris Color 
X  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Medical/Ophthalmic and 
Medication History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
(if applicable) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Automated Perimetry  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gonioscopy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dilated Fundus Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pachymetry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Punctum Size Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of BCVA 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Slit Lamp Biomicroscopy 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Assess/Grade Hyperemia 
X 
 
X 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Punctum Exam 
X 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
IOP Measurement 
X (8AM) 
X (8AM) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Ocular Comfort 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Randomize 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Punctum Size Pre/Post 
Dilation 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intracanalicular Depot 
Insertion 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intracanalicular Depot  
Presence 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Assessment of Ocular 
Complaints 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Medications 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
 
X 
X 
X 
 
 
X 
*For information on which study schedule should be followed after the IOP Confirmation Visit, please refer to Appendix A  to determine whether the subject is in Stratum A, B, or C 

Ocular Therapeutix, Inc. 
 
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4.5.2. 
Data Collection 
Data collected from all study procedures and assessments will be collected and documented on 
the appropriate Case Report Form (CRF) for the study.  All data should be entered in compliance 
with the latest version of the eCRF Completion Guidelines. 
4.5.3. 
Subject Enrollment 
Prior to enrollment in the study, subjects will be evaluated to determine potential eligibility. The 
subject’s willingness and ability to meet the follow-up requirements will be determined. If the 
subject desires to participate in the study, written informed consent will be obtained prior to 
performance of any study-specific examinations. Following all the baseline assessments, the 
subject will be assessed to determine if the eligibility criteria are met. If the subject meets the 
procedural eligibility requirement and agrees to participate, the subject will be randomized.  
A subject is considered enrolled in the study at the time the subject signs the Informed Consent 
Form.  Once a subject qualifies for the study and is randomized, they must be followed whether 
or not the subject received the study assigned treatment. In the event that after randomization the 
insertion of the intracanalicular depot is successful in the first eye, but unsuccessful in the second 
eye, the intracanalicular depot will not be removed from the first eye and the subject will be 
prescribed IOP-lowering drops at the Investigator’s discretion for the eye that did not receive the 
depot.  The subjects will be followed for safety only, and the eye that received the depot will be 
included in the safety analysis. The study will be supplemented with additional subjects in order 
to ensure that up to 495 subjects who receive a depot bilaterally are followed through the 12 
Week Visit for safety and efficacy. 
In the event that after randomization the insertion of the intracanalicular depot is unsuccessful in 
the first eye, the subject will be exited from the study. The study will be supplemented with 
additional subjects in order to ensure that up to 495 subjects who receive a depot bilaterally are 
followed through the 12 Week Visit for safety and efficacy. 
Subjects who are enrolled but determined to be ineligible during the screening assessment, run-in 
visits, IOP confirmation visit, or baseline visits prior to randomization will be considered screen 
failures, will be withdrawn from the study, and will not require additional study follow-up visits.  
These subjects should be entered in the EDC system per the latest version of the eCRF 
Completion Guidelines. 
For subjects who fail eligibility criteria at the Baseline Visit, the reason for the screen failure will 
be clearly delineated on the applicable eCRF.   
All subjects who receive a depot in the study will be required to adhere to the follow-up schedule 
outlined in this protocol.  Subjects withdrawing consent after insertion initiation will not be 
required to undergo follow-up after withdrawal; however, these subjects will still be considered 
part of the study cohort to which they were originally assigned. 
4.5.4. 
Informed Consent 
Once a study candidate’s eligibility has been determined and the Investigator agrees, a member 
of the research team will present the study to the subject. The background of the proposed study, 
the study procedures, follow up schedule, and the risks and potential benefits of the procedures 
and study will be explained to the subject. Prior to enrollment in the study, all subjects must 
review and complete an IRB approved Informed Consent Form (ICF). Failure to obtain a signed 
ICF renders the subject ineligible for the study.  Subjects must be willing to return to the clinic 

Ocular Therapeutix, Inc. 
 
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Rev E: May 2, 2017 
for study visits at 2, 4, 6, 8, 10, and 12 weeks after the insertion as required.  Additional visits 
may be required based on depot replacement.   
4.5.5. 
Randomization 
Prior to the initiation of the study, a treatment randomization scheme will be generated using a 
3:2 ratio (Active Treatment to Placebo Control).  Randomization will be stratified by 
investigational site (i.e., one randomization schema per study site) and previous ocular anti-
hypertensive therapy with 3 levels:  
Stratum A: Subjects who were on prostaglandin treatment at the time of the Screening 
Visit and have shown an adequate IOP rise after a 6-week washout (interval from 
Screening to Baseline Visit 1 is 6 weeks).  This may include subjects exiting from a prior 
ophthalmic investigational research study based on based on criteria specified in 
Appendix A . 
Stratum B: Subjects who were treatment-naïve at Screening and have shown an adequate 
prostaglandin response after a 2-week run-in period on prostaglandin treatment followed 
by a 6-week washout (interval from Screening to Baseline Visit 1 is 8 weeks). This may 
include subjects exiting from a prior ophthalmic investigational research study based on 
based on criteria specified in Appendix A . 
Stratum C: Subjects who have recently exited from a prior ophthalmic investigational 
research study and have written approval from the Medical Monitor to be allowed to 
participate in the current study without additional exposure to prostaglandin (Refer to 
Appendix A ). 
Once it is determined that the subject continues to meet eligibility for the study at Baseline Visit 
2, the subject will be randomized into the study through assigning the next sequential kit within 
the kits corresponding to the subjects previous ocular anti-hypertensive therapy category and 
both eyes will be provided with the same assigned treatment, OTX-TP or PV. 
4.5.6. 
Masking 
The Investigator and the subject will be masked to the treatment assignment throughout the 
duration of therapy.  At the conclusion of the study, the Principal Investigator will be unmasked 
to the treatment assignment of the subjects who received OTX-TP or PV. Subjects in both groups 
will be prescribed IOP-lowering drops based on the Investigator’s discretion.   
OTX-TP and the PV are identical in appearance, and will be supplied in identical packages so as 
they cannot be distinguished by the user.  If it is medically necessary to identify the product 
used, the Investigator will follow procedures outlined in Section 5.6.  
4.5.7. 
Study Assessments 
Please refer to Appendix B for procedures for conducting the study assessments (e.g. BCVA, slit 
lamp biomicroscopy, ocular hyperemia grading, pachymetry, IOP measurement, dilated fundus 
exam, gonioscopy, automated perimetry and punctum exam).  
4.5.7.1. 
Screening Visit 
The following procedures and assessments will be completed at least 6 weeks (-2/+3 days) prior 
to the Baseline Visit 1 for Stratum A, at least 8 weeks (-2/+3 days) prior to Baseline Visit 1 for 
Stratum B, and as instructed by Medical Monitor for Stratum C, to allow for adequate washout of 
potential subject’s current OAG/OHT medication(s):  
• Obtain informed consent  

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• Demographic information: age, gender, ethnicity, height, weight (height and weight may be 
self-reported by subject) 
• Iris color 
• Medical and ophthalmic history 
• Medication history 
• Urine pregnancy test (if applicable): If female of childbearing potential, subject must utilize 
reliable contraceptive methods for the duration of the study as judged by the Investigator, and 
have a negative urine pregnancy test. 
The following procedures and assessments will be performed for both eyes: 
• Best Corrected Visual Acuity  
• Automated perimetry  
• Slit lamp biomicroscopy 
• Assessment and grade of ocular hyperemia (at slit lamp) 
• Punctum exam (for normality of punctal appearance, lid apposition, and tear meniscus) 
• Punctum size assessment using a punctum gauging system provided by the Sponsor 
• IOP measurement (Goldmann applanation tonometry) at 8AM ±60 minutes 
• Pachymetry: The average of the 3 measurements will be calculated to determine subject 
eligibility. Contact lens wear must be discontinued 3 days prior to pachymetry for soft 
contact lenses and 14 days prior to pachymetry for rigid gas permeable contact lenses. For 
contact lens wearers, the pachymetry assessment may be scheduled for a separate day from 
the Screening Visit based on the type of contact lens (i.e., 3 days after the Screening Visit for 
soft contact lenses and 14 days for rigid gas permeable lenses).  
• Gonioscopy 
• Dilated fundus exam 
• Adverse event assessment 
• At the end of the Screening Visit: 
o Subjects will be instructed to start washout, run-in, or prior trial recovery period 
based on randomization stratum. Please refer to Appendix A  for subjects who need to 
start the prior trial recovery period. 
4.5.7.2. 
Run-in Visits 1 and 2 
For subjects in Stratum B, Run-in Visit 1 will be 2 days (+ 3 days) post-initiation of 
prostaglandin therapy for subjects; and Run-in Visit 2 will be 11 days (+ 3 days) post-initiation 
of prostaglandin therapy. 
The following will be performed for both eyes: 
At 8AM (T0) 
• 
IOP measurement (Goldmann applanation tonometry) 
• 
Adverse event assessment 
Run-in Visits are only applicable to Stratum B subjects. After prostaglandin response is 
confirmed, subjects will washout for 6 Weeks (-2/+3 days). 
4.5.7.3. 
IOP Confirmation Visit (only applicable for subjects exiting from a prior ophthalmic 
investigational research study) 
At the end of the 6 week prior trial recovery period (-2 days/+ 5 days), subjects will return for a 
visit to confirm adequacy of IOP, in that the subject continues to meet the IOP criteria. 

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Rev E: May 2, 2017 
The following will be performed for both eyes: 
At 8AM (T0) 
• 
IOP measurement (Goldmann applanation tonometry) 
• 
Adverse event assessment 
 
4.5.7.4. 
Baseline Visit 1 
For all subjects the following procedures and assessments will be performed for both eyes after 
completing appropriate washout, run-in and washout, or prior trial recovery period and IOP 
confirmation. Please refer to Appendix A  for subjects who have exited from a prior ophthalmic 
investigational research study.    
Note: All IOP measurements must be conducted within +/- 60 min of the required time, and must 
be conducted at approximately the same time at each of the follow-up visits.  
The following will be performed for both eyes:  
At 8AM (T0) 
• 
Medication and medical history update 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
IOP measurement 
• 
Adverse event assessment 
4.5.7.5. 
Baseline Visit 2/Insertion Visit: Day 1 
The following procedures and assessments will be performed for both eyes on the day of 
treatment:  
Note: All IOP measurements must be conducted within +/- 60 min of the required time, and must 
be conducted at approximately the same time at each of the follow-up visits.  
The following will be performed for both eyes on the day of treatment:  
At 8AM (T0) 
• 
IOP measurement 
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Subject ocular comfort assessment 
Subjects will be asked to grade their comfort level by asking them the following question:  
“On a scale of 0 to 10, 0 being very comfortable and 10 being very uncomfortable, how 
comfortable does your eye feel at this time?” 
10AM (T0+2h) 
• 
IOP measurement 
4PM (T0+8h) 
• 
IOP measurement 
• 
Randomization 
• 
Punctum exam prior to insertion of OTX-TP or PV 
• 
Punctum size pre/post dilation 

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• 
Insertion of intracanalicular depot into superior or inferior canaliculus of each eye for each 
subject 
At 8AM (T0), 10AM (T0+2h) and 4PM (T0+8h) 
• 
Adverse event assessment 
4.5.7.6. 
Point of Randomization  
At the conclusion of all assessments at the Baseline Visit 2, the Investigator will confirm that 
subject does not meet the protocol specified procedural exclusion criteria. If subject is still 
eligible, the Investigator will conduct the punctum size assessment.  
The Investigator will use a standard punctum gauge to assess the size of the punctum. If the 
punctum measures < 0.4 mm or > 0.9 mm, the subject will be screen failed and will not be 
randomized.  
The Investigator will utilize a commercially available dilator probe from standard practice or as 
provided by Sponsor  to dilate the punctum to 0.7 mm, as required for proper insertion of the 
intracanalicular depot. If the Investigator determines that the punctum cannot be dilated to 
approximately 0.7 mm, the subject will be screen failed and will not be randomized.  
If the subject remains eligible for the study, the Investigator will randomize the subject and insert 
OTX-TP or PV into the superior or inferior canaliculus of the subject’s eyes.  
4.5.7.6.1. Intracanalicular Depot Insertion 
Prior to insertion, it should be ensured that the area of the superior or inferior punctum including 
eyelids is clean using an eyelid wash, if necessary. The area should be anesthetized with either a 
topical anesthetic instilled into the conjunctival sac or an anesthetic soaked, cotton-tipped Weck-
Cel™ spear or equivalent held against the conjunctival side of the eye lid in the area of the 
punctum for approximately 30 seconds. The punctum will be dilated as necessary prior to 
insertion of the intracanalicular depot. The intracanalicular depot will then be inserted using 
forceps as per the instructions for use.  The intracanalicular depot should rest down within the 
canaliculus just below the punctal opening as shown in Figure 1.  
After insertion and exposure with tear film, the intracanalicular depot will rapidly hydrate and 
expand to fill the canaliculus; however, gentle irrigation of the eye with BSS solution or artificial 
tears may be used to ensure the intracanalicular depot is adequately hydrated. 
If protrusion or partial extrusion occurs, the intracanalicular depot may be removed and insertion 
may be reattempted using a new depot.  
Misalignment of the intracanalicular depot, failure to insert it into the canaliculus, or contact of 
the intracanalicular depot with other adnexa of the eye will result in discarding the 
intracanalicular depot, followed by replacement and re-attempt with a new, sterile 
intracanalicular depot. 
 

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Figure 1: 
Placement of Intracanalicular depot in the Inferior Canaliculus 
 
 
 
4.5.7.6.2. Observations to be Recorded 
The following observations for the insertion of the intracanalicular depot will be recorded: 
• 
Use of dilation 
• 
Ease of insertion of the intracanalicular depot: The Investigator will be asked to grade the 
level of ease of insertion of the intracanalicular depot as “easy”, “moderate” or “difficult”. 
4.5.7.6.3. Discharge Instructions 
Subjects should be instructed to refrain from rubbing his/her eyes and to contact their Study 
Doctor in the event that they experience excessive pain, excessive discomfort, loss of vision, or 
increasing redness of the eye. 
4.5.7.7. 
Concurrent Medications  
The use of any concurrent ophthalmic medications and systemic medications, prescription or 
over-the-counter, from up to 3 years prior to the Screening Visit, is to be recorded on the 
subject’s source document form and corresponding electronic case report form along with the 
reason the medication was taken, starting at the Screening Visit  through the end of the study. 
The use of any herbal or vitamin supplements and any dilation and other Standard of Care drops 
used for the ophthalmic assessments including IOP measurement and the insertion procedure will 
not be required to be recorded. 
 
 
 
 
 
 
 
 
 
 
 
Upper Punctum 
Nasolacrimal ducts 
Intracanalicular 
depot 
Eye 
Lower Punctum 

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4.5.7.8. 
Prohibited Medications/Treatments 
The following restrictions related to medications and treatments apply: 
• 
Topical or systemic ocular hypotensive medications may not be used for the duration of the 
study with the exception of the study treatment. The washout period for medications between 
the Screening and Baseline Visit 1 for subjects currently taking prostaglandin analogues for 
OAG/OHT, is 6 weeks (- 2 days/+ 3 days) 
• 
Systemic beta blockers will be allowed, but any initiation of or alterations in systemic 
regimen of beta-blocker containing medications from 8 weeks prior to screening through the 
final study visit is excluded. 
• 
Use of inhaled (using mouthpiece) and nasal corticosteroids and topical dermal steroids 
(except on the face) are allowed.  
• 
Any medication or substance administered by any route and used on a chronic basis that has 
not been on a stable dose for 8 weeks prior to Screening and may not be changed for the 
duration of the study. 
• 
Non-diagnostic topical ophthalmic solutions (other than the study treatment) may not be used 
from Baseline Visit 1 through the duration of the study. Note: Use of artificial tears or ocular 
lubricants should be avoided but if necessary, intermittent use may be allowed up to twice a 
day.  
• 
Contact lenses may not be used at any point during the study after the Screening Visit 
including on the day of the Baseline Visits. In addition, contact lens wear must be 
discontinued prior to pachymetry a minimum of 3 days for soft contact lenses, or 14 days for 
rigid gas permeable contact lenses. 
4.5.7.9. 
Follow-up Assessments 
4.5.7.9.1. 4 Week (Day 29± 3 days), 8 Week (Day 57 ± 3 days), and 10 Week (Day 71 ± 3 
days) Visits 
The following will be performed for both eyes:  
At 8AM only 
• 
Medication and medical history update  
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by the Investigator  
• 
Punctum exam 
• 
IOP measurement 
• 
Adverse event assessment 
*If the intracanalicular depot has to be removed for subject discomfort or an undesirable 
reaction, the investigator will prescribe IOP lowering medication at his/her discretion, and the 
subject will be exited from the study. 
4.5.7.9.2. 2 Week (Day 15 ± 3 days) and 6 Week (43 ± 3 days) Visits 
The following will be performed for both eyes:  

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At 8AM (T0) 
• 
Medication and medical history update  
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by visual assessment  
• 
Punctum exam 
At 8AM (T0), 10AM (T0+2h) and 4PM (T0+8h) 
• 
IOP measurement 
• 
Adverse event assessment 
 
At any visit prior to the 6 Week Visit, if the intracanalicular depot is not visualized in one or both 
eyes by the Investigator, the Investigator will insert a new intracanalicular depot in the respective 
eye(s) after confirming patency. For any depot replacements, IOP assessments should be 
completed prior to replacement. The subject will continue to return for follow-up visits per the 
study schedule through the 12 Week Visit. The number of replacements will be tracked and 
documented on the appropriate Case Report Form (CRF). 
 
If the intracanalicular depot is still present in one or both eyes at the 12 Week Visit, the 
Investigator will attempt to remove the intracanalicular depot from the respective eye(s). If 
removal is successful bilaterally, the subject will be exited from the study. The subject may be 
prescribed IOP-lowering drops at the Investigator’s discretion. 
 
If removal is unsuccessful in one or both eyes, the subject will return at the 20 Week Visit. The 
subject may be prescribed IOP-lowering drops at the Investigator’s discretion. 
 
If the intracanalicular depot is not present bilaterally at the 12 Week Visit, the subject will be 
exited at the end of that visit. The subject may be prescribed IOP-lowering drops at the 
Investigator’s discretion. 
 
At any visit from the 6 Week Visit prior to the 12 Week Visit, if the intracanalicular depot is not 
visualized in one or both eyes by the Investigator, the Investigator will insert a new 
intracanalicular depot in the respective eye(s) after confirming patency. For any depot 
replacements, IOP assessments should be completed prior to replacement. The subject will return 
for follow-up visits through the 12 Week Visit and then at the 20 Week Visit. The number of 
replacements will be tracked and documented on the appropriate CRF. The removal of the 
replaced intracanalicular depot will be conducted at the 20 Week Visit. 
4.5.7.9.3. 12 Week (Day 85 ± 3 days) Visit 
The following will be performed for both eyes:  
At 8AM (T0) 
• 
Medication and medical history update  
• 
Iris color 

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• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by visual assessment 
• 
Punctum exam 
At 8AM (T0), 10AM (T0+2h) and 4PM (T0+8h) 
• 
IOP measurement 
• 
Adverse event assessment 
At 4PM (T0+8hr) 
• 
Dilated fundus exam 
For subjects who received a replacement intracanalicular depot prior to the 6 Week Visit: 
If the intracanalicular depot is still present at the 12 Week Visit in one or both eyes, the 
Investigator will attempt to remove the intracanalicular depot from the respective eye(s). If 
removal is successful bilaterally, the subject will be exited from the study.  
If removal is unsuccessful in one or both eyes, the subject will return at the 20 Week Visit.  
If the intracanalicular depot is not present bilaterally at the 12 Week Visit, the subject will be 
exited at the end of the visit.  
The subject may be prescribed IOP-lowering drops at the Investigator’s discretion. 
4.5.7.9.4. 20 Week (Day 141 ± 7 days) Visit 
The following will be performed for both eyes:  
At 8AM only 
• 
Medication and medical history update  
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of intracanalicular depot presence by visual assessment 
• 
Punctum exam 
• 
IOP measurement 
• 
Dilated fundus exam 
• 
Adverse event assessment 
For subjects who received a replacement intracanalicular depot starting at the 6 Week Visit and 
prior to the 12 Week Visit: 
If the intracanalicular depot is still present in one or both eyes at the 20 Week Visit, the 
Investigator will attempt to remove the intracanalicular depot from the respective eye(s). If 
removal is successful bilaterally, the subject will be exited from the study.  
If removal at the 20 Week Visit is not successful in one or both eyes, the subject will be required 
to return to the clinic every 30 (± 10) days until the intracanalicular depot is confirmed to be no 
longer present. 

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If the intracanalicular depot is not present bilaterally at the 20 Week Visit, the subject will be 
exited at the end of the visit.  
The subject may be prescribed IOP-lowering drops at the Investigator’s discretion. 
4.5.7.9.5.  Unscheduled Visits 
For Unscheduled Visits, the reason for the visit should be clearly documented on the appropriate 
CRF, including findings from all evaluations that are completed.  The following evaluations 
must be completed. Ocular assessments are required to be conducted on both eyes.   
• 
Medication and Medical History Update 
• 
Subject ocular comfort assessment  
• 
Assessment of Ocular complaints  
• 
Assessment of BCVA 
• 
Slit Lamp biomicroscopy 
• 
Assessment and grade of ocular hyperemia (at slit lamp) 
• 
Confirmation of  intracanalicular depot presence by visual assessment 
• 
Punctum exam 
• 
IOP measurement 
• Adverse event assessment 
4.6. 
Intracanalicular Depot Removal 
For any subject, if at any point the intracanalicular depot is removed bilaterally by the 
Investigator for an adverse event, the subject will be exited from the study at the time of AE 
stabilization or resolution. If at any point for any subject the depot is removed bilaterally for 
subject discomfort, the subject will be exited from the study at that visit. If the intracanalicular 
depot needs to be removed from only one eye, the depot from the contralateral eye will not be 
removed and the subject will be followed per the study schedule for safety. 
Once OTX-TP has been removed, the subject may be prescribed IOP-lowering drops for the 
affected eye(s) at the Investigator’s discretion.  Intracanalicular depots that are removed due to 
subject withdrawal or an undesired reaction at any point in the study will not be replaced. 
4.7. 
Potential Risks and Benefits 
The potential risks and benefits associated with the use of OTX-TP Intracanalicular Depot are 
discussed in sections below.  
4.7.1. 
Risks Associated with OTX-TP Intracanalicular Deport or PV 
In general the following risks are associated with travoprost and/or could occur from the 
insertion and use of the intracanalicular depot:  
• 
Visual changes 
• 
Ocular pain and discomfort 
• 
Conjunctivitis 
• 
Keratitis 
• 
Dacryocystitis 
• 
Tearing with mucopurulent discharge 

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• 
Stenosis (narrowing/closing) of the punctum 
• 
Ocular hyperemia 
• 
Prostaglandin Associated Orbitopathy 
• 
Blepharitis 
• 
Epiphora 
• 
Dry eye 
• 
Iris discoloration 
• 
Ocular pruritus 
• 
Subconjunctival hemorrhage 
• 
Cataract 
• 
Macular edema 
• 
Infection that if severe could lead temporary or permanent impairment of sight 
• 
Perforation of or trauma to the punctum and/or surrounding tissues; or punctoplasty 
• 
Allergic reaction 
• 
Chemosis 
• 
Inflammatory reaction 
• 
Inability to remove the intracanalicular depot 
4.7.2. 
Minimization of Risks 
With any new product, there is always chance of developing complications.  Not all risks of 
using OTX-TP are known.  However, the risks associated with OTX-TP have been minimized by 
the use of iterative product design changes during the OTX-TP clinical development program as 
well as by formulating the intracanalicular depot with constituents that have a long history of 
safe use in ophthalmic drugs, medical devices and cosmetics. Furthermore, results of 
biocompatibility and preclinical testing when evaluated at a comparable dose, demonstrate OTX-
TP does not invoke an inflammatory or toxic response from ocular tissues. 
Subjects will be selected and enrolled using clearly defined inclusion and exclusion criteria to 
ensure that subjects with ocular or periocular anatomy and/or comorbidities that put them at 
higher risk for procedural complications are excluded. Appropriate therapeutic intervention 
following standard medical practices will be used in the event of medical complications 
including the use of rescue medication. If IOP is unreasonably high in the opinion of the 
Investigator, the protocol allows rescue medication to be administered to the subjects, at any 
point throughout the study. The specific medication regimen will be at the Principal 
Investigators’ discretion.  Safety checks will be conducted at every scheduled visit, however the 
investigator may initiate rescue therapy and any time during the study. 
This study will be monitored by the Sponsor and/or its CRO designates to ensure the 
identification, documentation and analysis of all adverse events, compliance with the protocol, 
the terms of the participating IRB’s to protect the safety and rights of all subjects, and applicable 
Federal regulations. To minimize safety risks to the subjects, only those investigators trained for 

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treating subjects with glaucoma or ocular hypertension will be considered for participation as 
investigators in this study. For all investigators who will use the intracanalicular depot, only 
those who are experienced in intracanalicular depot insertion will be considered and all 
investigators will be required to undergo training per the OTX-TP Instructions for Use by the 
Sponsor and/or its designates prior to initial use. 
4.7.3. 
Potential Benefits 
The benefits of OTX-TP are not yet known, but are thought to be the reduction of elevated 
intraocular pressure and improved treatment outcome through eliminating subject non-
compliance with the use of daily drops.   
4.8. 
Product Malfunctions 
All malfunctions of OTX-TP or PV will be documented on the appropriate eCRF and reported to 
Ocular Therapeutix within 24 hours. Ocular Therapeutix will advise whether the intracanalicular 
depot(s) should be returned for analysis. The incidence of malfunctions will be included in the 
final analysis. 
4.9. 
Subject Withdrawal 
For any subject who withdraws their consent following randomization, to the extent possible, the 
reason(s) for withdrawal will be documented on the End of Study eCRF. Subjects will be asked, 
but not required, to return for removal of the intracanalicular depot (if still present) prior to 
withdrawing from the study.  Every attempt will be made to contact subjects who are non-
compliant or lost to follow-up and such attempts will be documented in the subject’s study 
record.  

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5. 
ADVERSE EVENTS (AES) 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
events or untoward findings.  If adverse events occur, the first concern will be the safety and 
welfare of the subject.  Appropriate medical intervention will be undertaken.  Any adverse events 
observed by the Investigator or reported by the subjects, whether or not ascribed to the study 
treatment, will be recorded on the subject’s Adverse Event Case Report Form.  A new Adverse 
Event Case Report Form is used for each adverse event. 
Documentation regarding the adverse event should be made as to the nature, date of onset, end 
date, severity, and relationship to study drug, action(s) taken, seriousness, and outcome of any 
sign or symptom observed by the physician or reported by the subject upon indirect questioning.   
5.1. 
Definitions 
Adverse Event (or Adverse Experience, AE)  
An adverse event is any untoward medical occurrence, which does not necessarily have to have a 
causal relationship with the treatment. 
Adverse Ocular Event 
An adverse ocular event is an adverse event that affects ocular tissues, the nasolacrimal duct, 
sinuses or vision. All adverse ocular events are a subset of adverse events 
Note: Subjects will be queried for the presence or absence of the following ocular complaints: 
excessive tearing, foreign body sensation, stinging/burning, and itching. Positive responses to 
these standardized ocular complaint inquiries should be reported as ocular complaints and not 
adverse ocular events unless the complaint: meets the criteria of a specific event as listed, and/or 
is: outside of normal limits, associated with clinical sequelae (e.g., adverse slit lamp examination 
findings), and requires an intervention to be resolved. 
Treatment Emergent Adverse Ocular Event (or TEAE)  
An adverse ocular event will be considered a treatment-emergent AE if it occurs or worsens on 
or after the initiation of the intracanalicular depot insertion.  
Adverse Reaction (or Related Adverse Event or Adverse Effect) 
An adverse reaction is any noxious and unintended response to the treatment. 
Unexpected Adverse Reaction (Unanticipated Adverse Effect) 
An unexpected adverse reaction is an adverse reaction, the nature (including specificity and 
outcome) or severity of which is not consistent with the applicable product information. For this 
study, the study protocol; Investigator's Brochure; and prescribing information for the registered 
formulation of travoprost (Travatan®) will be used to assess events for unexpectedness. 

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Serious Adverse Event (Serious Adverse Experience) 
A serious adverse event (experience) or reaction is any untoward medical occurrence that: 
• results in death 
• is life-threatening 
(The term "life-threatening" in the definition of "serious" refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe.) 
• requires inpatient hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is sight threatening 
Medical and scientific judgment will be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious.8 
5.2. 
Severity 
Severity of an adverse event is defined as a qualitative assessment of the degree of intensity of an 
adverse event as determined by the Investigator or reported to him/her by the subject. The 
assessment of severity is made irrespective of relationship to study drug or seriousness of the 
event and should be evaluated according to the following scale: 
• 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. 
 
                                                 
 
8 The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or 
severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as 
severe headache). This is not the same as “serious”, which is based on the outcome or action criteria usually 
associated with events that pose a threat to life or functioning. Seriousness (not severity) and causality serve as a 
guide for defining regulatory reporting obligations. (Severity of all adverse events, ocular and non-ocular, will be 
reported according to the terminology defined in the protocol.) 

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5.3. 
Relationship to OTX-TP or PV 
The following table will be used by the investigator as a guide when assessing the causal 
relationship of an adverse event to the intracanalicular depot and the insertion procedure. 
NO RELATIONSHIP 
SUSPECTED 
This category applies to those adverse events which, after careful consideration, are 
clearly and incontrovertibly due to extraneous causes (disease, environment, etc.) 
RELATIONSHIP 
SUSPECTED 
 
The following criteria should be applied in considering inclusion of an adverse event 
in this category: 
1) It bears a reasonable temporal relationship to the insertion procedure or the 
presence of the intracanalicular depot. 
2)  It could not be reasonably explained by the known characteristics of the subject's 
clinical state, environmental or toxic factors or other modes of therapy 
administered to the subject. 
3)  It disappears or decreases on removal of the intracanalicular depot. 
4)  It follows a known pattern of response to the insertion procedure or the 
intracanalicular depot. 
UNABLE TO 
DETERMINE* 
The Investigator is unable to assess the relationship of the event to the insertion 
procedure or the intracanalicular depot. 
*Where the causal relationship of the AE to the insertion procedure or the intracanalicular depot has not been 
determined or is unknown, the AE will be treated as if a relationship is suspected for the purposes of regulatory 
reporting.  
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the study drug caused the adverse event. “Reasonable possibility” means there is evidence to 
suggest a causal relationship between the study drug and the adverse event. Types of evidence 
that would suggest a causal relationship between the study drug and the adverse event include: a 
single occurrence of an event that is uncommon and known to be strongly associated with drug 
exposure; one or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture); an aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events that 
commonly occur in the study population independent of drug therapy) that indicates those events 
occur more frequently in the drug treatment group than in a concurrent or historical control 
group. 
5.4. 
Expectedness 
The expectedness of an adverse event should be determined based upon existing safety 
information about the study drug using these explanations: 
• Unexpected: 
An adverse event or adverse reaction that is not listed in the study 
protocol, Investigator’s brochure, or  prescribing information for the 
registered formulation of travoprost (Travatan®) or is not listed at the 
specificity or severity that has been observed. 
• Expected: 
An adverse event that is listed in the Investigator’s brochure at the 
 
specificity and severity that has been observed. 
Adverse events that are mentioned in the Investigator’s Brochure as occurring with a class of 
drugs or as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation are to be considered 
unexpected. 

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The Investigator should initially classify the expectedness of an adverse event, but the final 
classification is subject to the Medical Monitor’s determination. 
5.5. 
Procedures for Reporting Adverse Events 
All adverse events that are “serious” and “unexpected” and related to the study drug are to be 
reported to Ocular Therapeutix and the IRB as required by the IRB, federal, state, or local 
regulations and governing health authorities.  All serious events, regardless of their expectedness 
or relatedness are to be reported to Ocular Therapeutix within 24 hours of site awareness. 
All adverse events observed during the course of this study from the point of consent, regardless 
of severity or relationship to the study product will be recorded on the appropriate case report 
form(s). To the extent possible, the event to be recorded and reported is the event diagnosis as 
opposed to event symptoms (e.g., symptoms of vision loss or diplopia associated with 
intraocular lens dislocation; the event should be documented as intraocular lens dislocation).  
Details and symptomology associated with the event may be reported in the narrative section of 
the Adverse Event Case Report Form.   
Any serious adverse experiences or any severe, sight-threatening adverse reactions, whether 
ascribed to the study treatment or not, will be communicated within 24 hours, by telephone, to 
Ocular Therapeutix, Inc. The Investigator must obtain and maintain in his/her files all pertinent 
medical records, information, and medical judgments from colleagues who assisted in the 
treatment and follow-up of the subject; provide OTX with a complete case history, which 
includes a statement as to whether the event was or was not suspected to be related to the use of 
the study drug; and inform the IRB of the adverse event within the IRB’s guidelines for reporting 
SAEs.  A written report detailing the event, signed by the Investigator, shall be submitted to the 
Sponsor within 5 working days.  All subjects experiencing an SAE must be followed up and the 
outcome reported.   
5.5.1. 
Specific Anticipated Adverse Ocular Events  
Anticipated adverse ocular events that may be associated with OTX-TP or PV include, but are 
not necessarily limited to: 
• Ocular hyperemia should be considered as an AE only if the subject complains of it or if 
the subject is discontinued because of ocular hyperemia 
• Prostaglandin Associated Orbitopathy 
• Iris discoloration 
• Blepharitis 
• Worsening in BCVA defined as ≥ 3 lines (≥15letters) 
• Subconjunctival hemorrhage 
• Cataract 
• Macular edema 
• Conjunctivitis 
• Keratitis 
• Perforation of or trauma to the punctum and/or surrounding tissues 
• Allergic reaction 
• Chemosis 

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• Inflammatory reaction 
• Epiphora, defined as clinically significant excessive tearing outside of normal limits 
• Dacryocystitis 
• Tearing with mucopurulent discharge 
• Stenosis of the punctum 
• Infection*  
*Note: In the case of a suspected infection, a culture should be performed and the organism identified, if possible. 
5.6. 
Procedures for Unmasking  
When medically necessary, the Investigator may need to determine the treatment that has been 
assigned to a subject. The Investigator will contact the Sponsor with the details of the emergency 
unmasking request. Ocular Therapeutix will make the final determination if the unmasking 
request will be granted. If granted, the Investigator will be permitted to use the unmasking 
instructions available on site. 
At the conclusion of the 12 Week visit, if both eyes no longer have the depot present or depots 
have been removed bilaterally, the Investigator may be unmasked to the treatment assignment of 
the subjects who were assigned to OTX-TP or PV as those subjects may require IOP-lowering 
drops.   
5.7. 
Type and Duration of the Follow-up of Subjects after Adverse Events 
Adverse Events (AEs) will be followed until:  
• 
Resolution (return to baseline status or to ‘normal’) 
o AEs may be determined to have resolved (completely) or resolved with sequelae. 
• Principal Investigator determines, for events that do not end (i.e., metastasis), the 
condition to be chronic. The event can be determined to be resolved or resolved with 
sequelae. 
• 
Stabilization of the event has occurred (no worsening expected by the investigator) 
Adverse events will be documented on the appropriate Case Report Form.  

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6. 
STATISTICAL ANALYSIS 
6.1. 
Study Populations 
Intent-to-Treat (ITT): The ITT population will include all randomized subjects with a primary 
study eye in which an intracanalicular depot was inserted. 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 related to study inclusion or exclusion criteria, conduct of the trial, subject 
management, or subject assessment will be identified prior to locking the study database. 
Safety:  The Safety population will include all subjects who received any investigation study 
medication (OTX-TP or PV). Analyses performed on the Safety population will be according to 
the treatment the subjects actually received. 
6.2. 
Unit of Analysis 
The unit of analysis in this study will be the primary study eye for all efficacy summaries and 
any eye that received a depot for ocular safety summaries. The primary study eye will be defined 
as the study eligible eye with ocular hypertension or open angle glaucoma that meets the IOP 
enrollment criteria and has an intracanalicular depot successfully inserted.  If a subject has both 
eyes eligible, then the primary study eye will be the eye with the highest IOP at 8AM on 
Baseline Visit 2 (Day 1) and the other eye will be considered to be the secondary study eye; if 
both eyes are eligible and have the same IOP at 8AM on Baseline Visit 2 (Day 1), the right eye 
will be the study eye and the left eye will be considered the secondary study eye.    Ocular 
adverse events will be presented at the eye and subject level and non-ocular adverse events will 
be presented at the subject level. 
6.3. 
Imputation Methods 
The primary analyses of efficacy data (IOP) will employ multiple imputation methods using 
Monte Carlo Markov Chain approach to impute missing data and using last time-consistent 
observation carried forward (LOCF) to impute data for time points after a subject’s primary 
study eye is prescribed IOP-lowering drops.  
Sensitivity analyses, to determine robustness of results, will be performed using Monte Carlo 
Markov Chain approach to impute non-monotone missing information and pattern mixture 
models control-based pattern imputation for monotone missing information (including subjects 
who drop out and data for time points after a subject’s primary study eye is prescribed IOP-
lowering drops), LOCF to impute both missing data and data after a subject’s primary study eye 
is prescribed IOP-lowering drops, and baseline time-consistent observation carried forward to 
impute both missing data and data after a subject’s primary study eye is prescribed IOP-lowering 
drops and observed data only.  Additionally, sensitivity analyses will be performed on the per 
protocol population using observed data only. 

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6.4. 
Hypotheses 
H0: The difference between study eyes that received OTX-TP and study eyes that received PV 
(OTX-TP minus PV), in mean IOP at the following time points: 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits, is ≥ 0 mmHg for at least one time point over all visits. 
H1: The difference between study eyes that received OTX-TP and study eyes that received PV 
(OTX-TP minus PV), in mean IOP at the following time points: 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits, is < 0 mmHg for all time points over all visits. 
6.5. 
Efficacy Variables 
6.5.1. 
Primary 
• Mean IOP at the following time points 8AM, 10AM, and 4PM at the 2 Week, 6 Week, and 
12 Week Visits.  
6.5.2. 
Secondary 
• Mean change from baseline IOP at the following time points 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits. 
• Mean percent change from baseline IOP at the following time points 8AM, 10AM, and 4PM 
at the 2 Week, 6 Week, and 12 Week Visits. 
6.6. 
Safety Variables 
The safety variables are: 
• Best corrected visual acuity (BCVA) 
• Slit lamp biomicroscopy 
• Assessment and grade of ocular hyperemia (at slit lamp) 
• Subject ocular comfort assessment 
• Dilated fundus exam 
• Adverse events 
6.7. 
Sample Size 
Assuming a common standard deviation of 3.75 mmHg within a treatment group, a mean 
difference of 1.5 mmHg or greater between treatment groups at each of the 3 time points of each 
of the 3 visits, and a 3:2 randomization ratio, 294 subjects in the OTX-TP arm subjects and 196 
subjects in the PV arm yield >90% power to conclude superiority of OTX-TP to PV in mean IOP 
at all of the 9 time points using a 2-sided alpha = 0.05 and assuming independence among time 
points.  The power increases with increasing positive correlation among time points. 
To account for 10% of subjects discontinuing before the 12 Week Visit, approximately 330 
subjects will be randomized into the OTX-TP arm and 220 subjects will be randomized into the 
PV arm. 

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6.8. 
Interim Analyses 
An interim analysis is planned after all subjects complete the 12 Week Visit.  As this interim 
analysis will be the final analysis for efficacy:  
1) All efficacy data will be cleaned and monitored prior to unmasking and conducting the 
interim analysis 
2) No alpha adjustments for multiplicity will be made.  
  
At this interim analysis, the study team will be unmasked with the exception of the 
Investigator/investigative site staff and the subject 
6.9. 
Methods of Analyses 
Summaries for continuous variables will include the sample size, mean, standard deviation, 
median, minimum, and maximum. Minima and maxima will be reported with the same precision 
as the raw values; means, standard deviations, and medians will be presented to one additional 
decimal place than reported in the raw values. Summaries for discrete variables will include 
frequencies and percentages. All percentages will be rounded to one decimal place (i.e., 
XX.X%). Differences between treatment groups will be calculated as OTX-TP minus PV and 
change from baseline will be calculated as follow-up visit minus baseline. The baseline visit will 
be defined as the last non-missing measure prior to initiation of investigational treatment.  For 
IOP the baseline time point will be defined as the last non-missing time equivalent measure prior 
to initiation of investigational treatment and after washout of previous IOP medication.  All 
efficacy summaries will be presented for the primary study eye.  Additional analyses may be 
reported for secondary study eyes. 
All summaries will be presented by treatment group and where appropriate by visit. 
6.10. 
Demographic and Baseline Medical History 
Subject demographics: gender, ethnicity, race, age category (< 65 years and ≥ 65 years), and iris 
color will be presented using discrete summary statistics. Age will also be presented using 
continuous summary statistics. 
Non-ocular and ocular medical history will be summarized by treatment group using discrete 
summaries. 
6.11. 
Efficacy Analyses 
The primary analysis of the primary efficacy outcome will employ a linear model with IOP at the 
given visit (2 Week, 6 Week, and 12 Week) and time point (8AM, 10AM, and 4PM) as the 
response, time point specific baseline IOP as a covariate, and treatment as a main effect factor, 
using the ITT population with multiple imputation methods using Monte Carlo Markov Chain 
approach to impute missing data and using LOCF to impute data for time points after a subject’s 
study eye is prescribed IOP-lowering drops.  Each time point within each visit will be modeled 
separately.  The least squares mean differences (test – control) between OTX-TP and PV will be 
presented along with 2-sided 95% confidence intervals (CIs) around the difference and 2-sided 
p-values testing the difference equal to 0.  Inference will be made on the 2-sided p-value at a 2-
sided alpha = 0.05 at each time point and visit.  The study will be considered a success if the 2-
sided p-value < 0.05 (demonstrating statistical superiority) and the point estimate of the 
difference is < 0 at all time points over the three visits. 

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Similar analyses will be conducted on the ITT data obtained after using each of the imputation 
methods as described in Section 7.3 to assess the sensitivity of results.   
Additional sensitivity analyses will be performed on the per protocol population using observed 
data only. 
Two-sample t-test p-values and two-sided 95% t-distribution CI’s will also be computed around 
the difference in mean IOP between treatment groups at each time point and visit for the primary 
analysis data (ITT population employing multiple imputation methods using Monte Carlo 
Markov Chain approach to impute missing data and using LOCF to impute data for time points 
after a subject’s study eye is prescribed IOP-lowering drops as rescue therapy).  Similar 
summaries will be presented on the ITT population using LOCF to impute both missing data and 
data after a subject’s primary study eye is prescribed IOP-lowering drops as rescue therapy and 
for the ITT and per protocol populations using observed data only. 
Mean change from baseline IOP will be analyzed similarly to the primary endpoint analysis, 
including all sensitivity analyses.   
Mean percent change from baseline IOP will be analyzed using two-sample t-tests and two-sided 
95% t-distribution CI’s for the primary analysis data (ITT population employing multiple 
imputation methods using Monte Carlo Markov Chain approach to impute missing data and 
using LOCF to impute data for time points after a subject’s study eye is prescribed IOP-lowering 
drops as rescue therapy).  Similar summaries will be presented on the ITT population using 
LOCF to impute both missing data and data after a subject’s primary study eye is prescribed 
IOP-lowering drops as rescue therapy and for the ITT and per protocol populations using 
observed data only.   
IOP measures and change from baseline IOP measures from non-primary visits will be analyzed 
and summarized similarly to the mean percent change from baseline IOP. 
Additionally, as secondary analyses to further understand efficacy within each previous ocular 
anti-hypertensive therapy category, the primary analysis strategy will be completed separately 
for the subgroups of subjects within each previous ocular anti-hypertensive therapy category. 
6.12. 
Other Analyses 
Visualization of the intracanalicular depot by the Investigator and by the subject will be 
summarized at each time point using discrete summary statistics. 
Ocular complaints will be summarized using discrete summary statistics at the eye level as well 
as at the subject level for all eyes that received a depot. 
6.13. 
Safety Analyses 
The primary safety analysis will summarize treatment emergent ocular AEs (TEAE) separately 
for primary study eyes and secondary study eyes using discrete summaries at the eye and event 
level by system organ class and preferred term for each treatment group. A TEAE will be 
defined as occurring on or after the day treatment is initiated. Treatment emergent non-ocular 
AEs will be summarized using discrete summaries at the subject and event level by system organ 
class and preferred term for each treatment group. Treatment related treatment emergent ocular 
and non-ocular AEs will be summarized similarly. Treatment emergent ocular and non-ocular 
AEs will also be summarized by severity. 
Slit lamp biomicroscopy and dilated fundoscopy measures will be summarized at each time point 
using discrete summary statistics. 

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Visual acuity data will be summarized at each time point using both continuous summaries, 
including change from baseline, and discrete summaries, including change from baseline in the 
number of lines and the proportion of subjects with a worsening of ≥ 3 lines from baseline. 
Ocular hyperemia and ocular comfort will be summarized at each time point using discrete 
summary statistics. 

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7. 
GENERAL INFORMATION 
7.1. 
Study Termination 
Ocular Therapeutix reserves the right to discontinue the study at any stage, with suitable written 
notice to the Investigator and the local research ethics committee or regulatory authority.  
Similarly, the Investigator may withdraw from the study subject to providing written notification 
to Ocular Therapeutix within 30 days of their intent to withdraw.  However, Ocular Therapeutix 
and the Investigator will be bound by their obligation to complete the follow up of subjects 
already randomized in the trial.  The subjects must be followed according to the clinical protocol 
and information obtained during subject follow-up shall be reported to Ocular Therapeutix on 
follow-up CRFs. 
All serious adverse events will be evaluated and if the Sponsor determines that unreasonable risk 
to the subject is possible, the study will be terminated, and all regulating authorities and 
participating Investigators will be notified.  Termination shall occur not later than 5 working 
days after the Sponsor makes this determination and not later than 15 working days after the 
Sponsor first received notice of the effect.   
A terminated investigation may not be resumed without the local research ethics committee or 
regulatory authority approval, as required. 
7.2. 
Monitoring 
The Investigator and the investigating center will permit authorized clinical research personnel 
and clinical monitors from Ocular Therapeutix and/or designee(s) employed by Ocular 
Therapeutix to review completed CRFs, IRB decisions, and Investigator and clinical site records 
at regular intervals throughout the study.  Additionally, subject charts and clinical records will be 
requested and reviewed so that protocol adherence and source documentation can be verified.  In 
instances where data protection regulations and/or hospital policies prohibit the direct 
examination of hospital records by the study Sponsor or designee(s), the Investigator will 
cooperate in a system of source data verification with the Sponsor.  Further details of the study 
monitoring will be outlined in a Monitoring Plan.   
If the monitor discovers that the Investigator is not complying with the signed Investigator 
Agreement, the investigational plan, or other applicable regulations, or any conditions of 
approval imposed by the reviewing IRB, the monitor will report to the Sponsor and take such 
steps necessary to promptly secure compliance.  If compliance cannot be secured, investigational 
product shipments to the Investigator may be discontinued and the Investigator’s participation in 
the investigation terminated.  The monitor shall also require such an Investigator to dispose of or 
return the product, unless this action would jeopardize the rights, safety, or welfare of a subject. 
7.3. 
Retention of Documentation 
The Investigator will maintain all study related documentation including all correspondence, 
records of financial interest, individual subject records, informed consent forms, all 
intracanalicular depot accountability records, the protocol with any/all amendments, all 
correspondence with and approval from the IRB, the budget agreement, the Investigator 
agreement, and copies of electronic case report forms for 2 years after the latter of the following 
two dates: 
a. The date on which the investigation is terminated or completed, or 
b. The date that the records are no longer required for purposes of supporting an application 
to a regulatory agency. 

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The files may be discarded only upon notification from OTX.  To avoid error, the Investigator 
should contact Ocular Therapeutix before the destruction of any records and reports pertaining to 
the study to ensure they no longer need to be retained.  In addition, in accordance with the 
Clinical Trial Agreement (CTA), Ocular Therapeutix should be contacted if the Investigator 
plans to leave the investigational site so that appropriate arrangements can be made for the 
transfer of the records to the appropriate designee at the study site.  
7.4. 
Photos and Videos  
The Investigator may be asked to record the insertion procedure and follow-up assessments, and 
to collect photographs of the eye. The videos and photographs should be identified only using the 
subject number and subject initials and should not contain any identifiers such as the subject’s 
name or birth date. The video and photographs will be used for training, advertising or in 
scientific conferences, journals or magazines.  

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8. 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE ISSUES 
The study will be conducted in compliance with the protocol, International Conference on 
Harmonization (ICH) Good Clinical Practices (GCP) Guidelines, and consistent with the 2013 
version of the Declaration of Helsinki. In addition, all applicable local, state and federal 
requirements relevant to the use of intracanalicular depots will be adhered to. 
8.1. 
Protection of Human Subjects 
8.1.1. 
Compliance with Informed Consent Regulations 
An IRB approved consent form, signed and dated by both the subject and the approved study 
staff presenting the consent, is required from each subject prior to enrollment into the study, and 
before any study specific procedures are initiated. 
If at any point during the subject’s participation in the study the Informed Consent Form requires 
revision (e.g., due to a protocol amendment or significant new safety information) it is the 
Investigator’s responsibility to ensure that the revised ICF is approved by Ocular Therapeutix 
and the IRB. The updated and IRB approved ICF must be presented to the subject, and signed 
and dated by both the subject, and the study staff presenting the consent as per IRB requirements.  
8.1.2. 
Compliance with Institutional Review Board Regulations 
The Investigator must obtain approval from appropriate the IRB prior to initiating the study and 
re-approval at least annually. 
8.2. 
Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study should be 
maintained by the Investigator and his/her staff with adequate precautions as to ensure the 
confidentiality of the data in accordance with local, state and federal laws and regulations. 
Monitors, auditors and other authorized representatives of Ocular Therapeutix, the IRB 
approving this study, the Food and Drug Administration, and other regulatory agencies, as 
appropriate, will be granted direct access to the study subjects’ original medical and study 
records for verification of the data and/or clinical trial procedures.  
A report of the results of this study may be published or sent to the appropriate health authorities 
in any country in which the intracanalicular depot may ultimately be marketed, but the subjects’ 
identity will not be disclosed in these documents. 

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9. 
LABELING, PACKAGING, STORAGE AND ACCOUNTABILITY 
OF INTRACANALICULAR DEPOT 
9.1. 
Labeling/Packaging 
OTX-TP and the PV will be identical in appearance and will be supplied in identical packaging. 
The packages will be labeled with a unique number based on the randomization scheme such that 
the identity of the intracanalicular depot cannot be identified by the study site.  
9.2. 
Product Storage  
OTX-TP and PV must be stored in a secure area accessible only to the Investigator and their 
designee(s) and in accordance with the conditions specified in the IFU (between 2ºC and 8ºC).   
9.3. 
Product Accountability  
The intracanalicular depot is to be administered only by the Principal Investigator or Sub-
Investigator, in accordance with the protocol, and only to subjects enrolled in the study.  
The Investigator must keep an accurate accounting of all OTX-TP and PV received from Ocular 
Therapeutix on the provided accountability forms. Accountability will include details of receipt 
of investigational product from the Sponsor, administration of the investigational product to 
study subjects, and return of investigational product. 
9.3.1. 
Product Return or Disposal 
All unused intracanalicular depots will be returned to the Ocular Therapeutix upon request by the 
Sponsor and documented on the accountability form.  All product shipment will be accompanied 
by a completed Ocular Therapeutix Product Return Log. 
 
 

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10. 
APPENDICES 
Appendix A : Instructions for Determining Eligibility of Subjects Exiting From Prior 
Ophthalmic Investigational Research Studies 
Appendix B : Procedures for Study Assessments 
Appendix C : Instructions for Removal of OTX-TP or PV 
 
 

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APPENDIX A. INSTRUCTIONS FOR DETERMINING ELIGIBILITY OF 
SUBJECTS EXITING FROM PRIOR OPHTHALMIC 
INVESTIGATIONAL RESEARCH STUDIES 
Please refer to the table below for determining eligibility and Visit Schedule for subjects who 
have exited an ophthalmic investigational research studies within 8 weeks of the Screening Visit. 
Please consult the Medical Monitor (MM) after obtaining informed consent.  Written approval 
from the Medical Monitor will be required for the subject to continue in the Study after the 
Screening Visit.  
Subject has just exited a study for any ophthalmic indication and may be interested in the Ocular Therapeutix (OTX) 
investigational research study  
 Complete Informed Consent and Screening Visit for OTX investigational research study 
 Begin 6 week prior trial recovery period and stop all glaucoma/ocular hypertension (OHT) medications 
Was this an investigational research study for ocular anti-hypertensive therapy? 
YES:  was subject stable and IOP controlled on ocular anti-
hypertensive medication for 8 weeks prior to start of non-
OTX ophthalmic investigational research study?  
NO:  i.e., investigational research study was for another ocular 
indication that is not excluded by protocol. Was subject stable 
and IOP controlled on ocular anti-hypertensive medication for 
8 weeks prior to start of non-OTX ophthalmic investigational 
research study? 
Is there history of monotherapy with a Prostaglandin 
Analogue (PGA) and a response? 
Is there history of monotherapy with a Prostaglandin 
Analogue (PGA) and a response?* 
YES: was there a 5 mm Hg or 
greater increase in IOP after 
PGA washout prior to or 
during non-OTX ophthalmic 
investigational research study?  
Documentation of Med 
History confirmed by MM? 
 
If Yes:  Proceed to 
IOP Confirmation 
Visit at the end of the 
6 week prior trial 
recovery period. (8 
AM IOP must be >24 
and <34 mm Hg).  
 
If Yes: 
return in 2 
weeks for 
Baseline 
Visit 1. 
(Stratum C). 
 
 
If No: Screen Failure 
NO: is subject PGA naïve 
or on therapy with a PGA 
plus a second agent at 
time of entry to non-OTX 
ophthalmic investigational 
research study? 
 
If Yes:  At the 
end of the 6 
week prior trial 
recovery period, 
perform IOP 
Confirmation 
Visit and start 2 
week run-in 
period with PGA.  
If adequate 
response at Run–
in Visits 1 and 2, 
then 6-week 
washout period 
and proceed to 
Baseline Visit 1 
(Stratum B). 
 
 
If No:  Screen Failure. 
YES: was there a 5 mm Hg or 
greater increase in IOP after 
PGA washout prior to or 
during non-OTX ophthalmic 
investigational research study? 
Documentation of Med 
History confirmed by MM? 
 
If Yes:  Proceed to 
IOP Confirmation 
Visit at the end of the 
6 week prior trial 
recovery period. (8 
AM IOP must be >24 
and <34 mm Hg). 
 
If Yes: 
return in 2 
weeks for 
Baseline 
Visit 1. 
(Stratum C). 
 
 
If No: Screen Failure 
NO: is subject PGA naïve or 
on therapy with a PGA plus a 
second agent at time of entry 
to prior non-OTX ophthalmic 
investigational research 
study? 
 
If Yes:  At the end 
of the 6 week prior 
trial recovery period, 
perform the IOP 
Confirmation Visit 
and start 2 week run-
in period with PGA.  
If adequate response 
at Run–in Visits 1 
and 2 is 
demonstrated, then 
start 6-week 
washout period and 
proceed to Baseline 
Visit 1 (Stratum B). 
 
 
 
If No:  Screen Failure. 
*If subject is exiting a prior non-OTX ophthalmic investigational research study for an allowed indication 
other than ocular anti-hypertensive therapy and has continued PGA monotherapy during the study, subject 
(again, with Medical Monitor approval) should discontinue PGA therapy and proceed to Baseline Visit 1 at the end 
of the 6 week prior trial recovery period (Stratum A). 

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APPENDIX B. RECOMMENDED PROCEDURES FOR STUDY 
EXAMINATIONS 
A.  Best Corrected Visual Acuity 
BCVA will be measured without refraction using a pinhole or while the subject is wearing his/her glasses, 
if the subject normally wears glasses or contact lenses.   
Visual acuity is to be measured using an ETDRS (i.e., logMAR) chart at a viewing distance of 4 
meters.    Subjects are required to read the chart from the top to the bottom until he or she can no 
longer make a meaningful attempt. The visual score is to be calculated based on an assigned 
value of 0.02 logMAR per letter.   
If visual acuity is so poor that the subject cannot read any of the largest letters at 4 meters, than acuity is 
to be measured at 2 meters and the appropriate conversions made.   
If visual acuity is so poor that the subject cannot read any of the largest letters at 2 meters, the subject 
should be checked for count fingers or hand motion acuity or light perception as appropriate. 
 
B.  Slit Lamp Biomicroscopy Examination 
The slit beam observations should be assessed in a dark room using the highest lamp voltage, an 
aperture of 0.3 mm, an illumination angle of 30 degrees and a magnification of 16X.   
The clinician will use a slit lamp, which is a table-mounted binocular microscope to assess the 
following as normal, abnormal clinically significant or abnormal not clinically significant: 
• Eyelids 
• Conjunctiva 
• Iris 
• Cornea 
• Anterior Chamber 
• Lens 
• Vitreous 
Explanation/comments should be provided on the case report form for any abnormal 
observations. 

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C.  Ocular Hyperemia Grading 
The following scale9 will be used to grade the ocular hyperemia: 
Figure 2: 
Scale for Grading Ocular Hyperemia 
 
0 = None             1 = Mild            2 = Moderate            3 = Severe 
Using the slit lamp biomicroscope, the subject’s eye(s) should be examined and compared to the 
images depicted in Figure 2. A grade (0-3) should be assigned and noted on the appropriate CRF 
based on the images. 0.5 increments may be used if the subject’s hyperemia is between 2 images. 
D.  Pachymetry 
The following procedure is recommended for conducting pachymetry: 
Central corneal thickness measurements of each eye will be made at the screening visit using an 
ultrasonic pachymeter. Measurements will be made after IOP is taken. For ultrasound probes, the 
Probe Quality Factor must be greater than or equal to 85% (if applicable). With the subject 
seated and visualizing a consistent fixation target, position the probe tip on the cornea, 
perpendicular to the corneal surface, on the visual axis (i.e., centered on the pupil). Once the 
probe tip is positioned properly, take a measurement. A total of 3 acceptable measurements, as 
described above, should be made for each eye, and the 3 measurements will be recorded in 
microns. The average of the 3 measurements will be calculated to determine subject eligibility. 
                                                 
 
9 Parrish, R. K.., Palmberg, P., and Sheu, W-P.  A Comparison of Latanoprost, Bimatoprost, and Travoprost in 
Patients With Elevated Intraocular Pressure: A 12-week, Randomized, Masked-evaluator Multicenter Study, Am J 
Ophthal., Vol. 135, No.5, p. 688-703, May 2003. 

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E.  IOP Measurement 
Goldmann tonometry as the international gold standard for tonometry is quite accurate and 
reproducible if proper technique is used.  When performing Goldmann tonometry the following 
procedures should be followed: 
1. 
Pre-tonometry procedures:  Set tonometer in the correct position and make sure the prism 
is in the horizontal position on the slit lamp. Set the tension at 1 mmHg.  Use Cobalt filter 
with slit beam open maximally with the angle between the illumination and the 
microscope at approximately 60 degrees. 
2. 
Instill one drop of a topical anesthetic and a moistened fluorescein strip may be lightly 
touched against the tarsal conjunctiva of the lower lid of each eye, taking care not to 
flood the ocular surface with fluorescein dye. Alternatively a drop of topical anesthetic-
fluorescein (e.g., Fluress) solution may be instilled into the lower conjunctival fornix of 
each eye, taking care not to flood the ocular surface with fluorescein dye.  Ask subject to 
blink a few times just prior to tonometry.   
3. 
Place subject in adjustable chair so chin can fit comfortably on the slit lamp chin rest and 
the forehead can be snug against the forehead bar. 
4. 
Apply tonometer to the subject’s eye while subject looks straight ahead and increase the 
force of applanation until the observer sees the inner portion of the two half fluorescein 
circles are touching. Record pressure on the case report form. 
IOP measurement will be masked based on the following procedure: 
Measurements will be taken by two qualified independent study site personnel using a Goldmann 
applanation tonometer affixed to a slit lamp with the subject seated.  One person will adjust the 
dial in masked fashion and a second person will read and record the value.  The subject and slit 
lamp should be adjusted so that the subject’s head is firmly positioned on the chin rest and 
against the forehead rest without leaning forward or straining.  Both eyes will be tested, with the 
right eye preceding the left eye.  Each IOP measurement is to be recorded. 
One person (“the measurer”) looks through the binocular viewer of the slit lamp at low power.  
The tension knob is pre-set at a low pressure value (4 to 6 mmHg).  The measurer follows the 
image of the fluorescein-stained semicircles while he/she slowly rotates the tension knob until 
the inner borders of the fluorescein rings touch each other at the midpoint of their pulsation in 
response to the cardiac cycle.  When this image is reached, the measurer takes his/her fingers off 
the tension knob and the second person (“the reader”) reads and records the IOP reading along 
with the date and time of day in the source document, thus maintaining a masked IOP reading. 
Two measurements should be performed, and if the IOP is within 1 mm Hg, the average of the 
first two measurements should be recorded.  If the IOP from the first two readings shows a 
greater than 1 mm Hg difference, a third reading should be taken and the average of all three 
readings recorded.   
F.  Dilated Fundus Exam 
Assessments should be conducted using indirect ophthalmoscopy. It is acceptable to perform the 
indirect ophthalmoscopy examination without scleral depression. Each of the following will be 
evaluated and documented as normal, abnormal clinically significant or abnormal not clinically 
significant: macula, peripheral retina and optic nerve.  The cup to disc (C/D) ratio will also be 
measured. Explanation/comment should be provided on the case report form for any abnormal 
pathology.   

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G.  Gonioscopy 
The following procedure is recommended for conducting gonioscopy: 
Clean and sterilize the front (curved) surface of the goniolens. Apply lubricating fluid to the front 
surface. Anaesthetize the subject's cornea with topical anesthetic. Prepare the slit lamp for 
viewing through the goniolens. Gently move the subject's eyelids away from the cornea. Slowly 
apply the goniolens to the ocular surface, forming suction. Fine-tune the slit lamp to optimize the 
view. The angle can now be viewed by rotating the lens gently through 360 degrees.  Grade the 
angle based on the Shaffer System as follows.  Subjects with a Grade 2 or lower should be 
excluded for angle closure glaucoma. 
Grade 4 - 45º to 35º angle Wide open 
Grade 3 - 35º to 20º angle Wide open 
Grade 2 - 20º angle Narrow 
Grade 1 - ≤ 10º angle Extremely narrow 
Slit - 0º angle Narrowed to slit 
H.  Automated Perimetry 
The following procedure is recommended for conducting automated perimetry. 
Measure the subject's pupils (to the nearest 0.5 mm). If they are less than 3 mm in diameter, dilate them 
with 2.5% phenylephrine drops, unless contraindicated. If the brow is heavy or the upper lid is drooping, 
tape accordingly. Visual field results must be reliable (i.e., 33% fixation losses, false positive or false 
negative errors) or the field should be repeated within two weeks. Visual field examinations will be 
performed using a Humphrey automated perimetry test (full threshold 24-2 program or SITA standard or 
FAST assessment). Preferred equipment is the Humphrey 700 HFA-2 series machines (e.g., 740 or 750). 
Visual fields will be reported as normal or abnormal and the mean deviation will also be recorded in 
decibels (dB). 
Begin by testing the right eye. Adjust the chin rest and the table height as needed to achieve proper 
alignment as well as to maintain the subject in a comfortable seated position throughout the test. It is 
permissible to encourage the subject occasionally if the subject seems to be fatigued or losing 
concentration, and to allow the subject to pause and rest if necessary. The subject should also be informed 
that a good time to blink is when the response button is pushed so as not to affect the results of the test.  
Repeat for the left eye. 
I.  Punctum Examination 
The punctum and surrounding area is to be examined and the following assessed: 
• Punctal appearance:  score as normal or abnormal 
• Lid apposition:  score as normal or abnormal 
• Tear meniscus:  score as normal or abnormal 
All abnormal findings will be graded as clinically significant or not clinically significant. 
Explanation/comments should be provided on the case report form for any abnormal 
observations. 

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APPENDIX C. INSTRUCTIONS FOR REMOVAL OF THE 
INTRACANALICULAR DEPOT  
The intracanalicular depot can be removed either via saline irrigation or application of manual 
pressure, as described below. 
Application of Manual Pressure 
1. Identify the intracanalicular depot visually 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 intracanalicular depot. 
3. Apply gentle pressure by pressing on the instrument in an outward motion towards the 
punctum, until the intracanalicular depot 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 canaliculus.  
4. Insert until it stops, and simultaneously rotate the syringe horizontally.  
5. Press slowly on the syringe plunger to flush the intracanalicular depot. 
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.