Clinical trial NCT02914509
Conditions: Open Angle Glaucoma Ocular Hypertension
Sponsor: Ocular Therapeutix, Inc.
Start date: 2016-11-07; Completion date: 2019-03-30
Enrollment: 565 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the study is to evaluate 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

Detailed description:
This was a prospective, multicenter, randomized, parallel-arm, double masked, placebo vehicle (PV) controlled study conducted 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 received either OTX-TP or PV to evaluate the safety and efficacy of OTX-TP.

Arms: arm 1: OTX-TP (sustained release travoprost) Intracanalicular Depot arm 2: PV (Placebo Vehicle) Intracanalicular Depot
Interventions: intervention 1: Travoprost intervention 2: Placebo Vehicle
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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. 
 
 
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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.


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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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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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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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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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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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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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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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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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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 
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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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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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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. 
 
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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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Rev E: May 2, 2017 
 
 
 
 
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 


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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. 
 

SAP_001.pdf: 
Protocol OTX-16-002 SAP, Version 1.0 
 
02Jan2018 
Confidential & Proprietary 
Page 1 of 42 
STATISTICAL ANALYSIS PLAN 
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 
Sponsor:   
 
Ocular Therapeutix, Inc 
 
 
 
34 Crosby Drive, Suite 105 
 
 
 
Bedford, MA 01730 USA 
 
 
Protocol Number: 
OTX-16-002
 
 
Author:   
 
Elizabeth Kumm 
 
 
 
Principal Biostatistician 
Statistics & Data Corporation 
 
Date:    
 
02Jan2018 
Version:  
 
Final Version 1.0 
 
 
 
 
 
 
 
 
 




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List of Abbreviations 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical Classification 
BCVA 
Best Corrected Visual Acuity 
BOCF 
Baseline Time-consistent Observation Carried Forward 
CI 
Confidence intervals 
C/D 
Cup to Disc 
CS 
Clinically Significant 
CSR 
Clinical Study Report 
DM 
Data Management 
eCRF 
Electronic Case Report Form 
ICH 
International Conference on Harmonisation 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
NCS 
Not Clinically Significant 
OTX 
Ocular Therapeutix, Inc 
OTX-TP 
Sustained Release Travoprost Intracanalicular Depot 
PDF 
Portable Document Format 
PLA 
poly (-lactic-acid) 
PP 
Per Protocol 
PT 
Preferred Term 
PV 
Placebo Vehicle Intracanalicular Depot 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
WHO DDE 
World Health Organization Drug Dictionary Enhanced 


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
1.
Introduction .............................................................................................................................. 7
2.
Study Objectives ...................................................................................................................... 7
3.
Study Variables ........................................................................................................................ 7
Primary Variable ............................................................................................................................... 7
Secondary Variables ........................................................................................................................ 7
Other Variables ................................................................................................................................ 7
Safety Variables ............................................................................................................................... 8
Statistical Hypotheses ...................................................................................................................... 8
4.
Study Design and Procedures ................................................................................................. 8
General Study Design ...................................................................................................................... 8
Schedule of Visits and Assessments ............................................................................................. 10
5.
Study Treatments ................................................................................................................... 14
Method of Assigning Subjects to Treatment Groups ..................................................................... 14
Masking and Unmasking ................................................................................................................ 15
6.
Sample Size and Power Considerations ............................................................................... 15
7.
Data Preparation .................................................................................................................... 15
8.
Analysis Populations .............................................................................................................. 16
Full Analysis Set............................................................................................................................. 16
Per Protocol Population ................................................................................................................. 16
Safety Population ........................................................................................................................... 17
9.
General Statistical Considerations ......................................................................................... 17
Unit of Analysis .............................................................................................................................. 17
Missing Data and Imputation Methods .......................................................................................... 17
Definition of Baseline ..................................................................................................................... 18
Data Analysis Conventions ............................................................................................................ 18
Adjustments for Multiplicity ............................................................................................................ 19
Unscheduled Visits ........................................................................................................................ 19
10.
Disposition of Subjects ........................................................................................................... 19
11.
Demographic and Pretreatment Variables ............................................................................. 20
Demographic Variables .................................................................................................................. 20
Pretreatment Variables .................................................................................................................. 20
Punctum Size Assessment Prior to Insertion ................................................................................. 21
12.
Medical History and Concomitant Medications ...................................................................... 21
Medical History ............................................................................................................................... 21


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Concomitant Medications ............................................................................................................... 21
13.
Dosing Compliance and Treatment Exposure ....................................................................... 22
Intracanalicular Depot Visualization by the Investigator ................................................................ 22
Intracanalicular Depot Removal ..................................................................................................... 22
Number of Replacements .............................................................................................................. 23
Treatment Exposure ...................................................................................................................... 23
14.
Efficacy Analyses ................................................................................................................... 23
Primary Analysis ............................................................................................................................ 23
Secondary Analysis ....................................................................................................................... 29
Additional Analyses ........................................................................................................................ 29
14.1.1
Additional Efficacy Analyses ....................................................................................... 29
14.1.2
Punctum Examination ................................................................................................. 29
14.1.3
Insertion Results and Ease of Insertion ....................................................................... 29
14.1.4
Ocular Complaints ....................................................................................................... 30
Graphical Outputs .......................................................................................................................... 30
15.
Safety Analyses ..................................................................................................................... 30
Ocular and Non-Ocular Adverse Events ........................................................................................ 30
Severity .......................................................................................................................................... 33
Relationship to OTX-TP or PV ....................................................................................................... 33
Expected AEs ................................................................................................................................. 34
AE Summaries ............................................................................................................................... 35
Best Corrected Visual Acuity (BCVA) ............................................................................................ 36
Slit Lamp Biomicroscopy Examination ........................................................................................... 36
Dilated Fundoscopy Examination .................................................................................................. 37
Ocular Hyperemia .......................................................................................................................... 37
Ocular Comfort Assessment .......................................................................................................... 37
Observed IOP Results ................................................................................................................... 37
16.
Interim Analyses .................................................................................................................... 38
17.
Pharmacokinetic Analyses ..................................................................................................... 38
18.
Pharmacodynamic Analyses ................................................................................................. 38
19.
Quality of Life ......................................................................................................................... 38
20.
Changes from Protocol-Stated Analyses ............................................................................... 38
21.
References ............................................................................................................................. 39
22.
Revision History ..................................................................................................................... 39
23.
Tables .................................................................................................................................... 39
24.
Listings ................................................................................................................................... 41


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25.
Figures ................................................................................................................................... 42
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol OTX-16-002, Revision E dated 02May2017 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated.  This SAP provides details of the specific statistical methods that 
will be used.  The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol.  If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR. 
2. Study Objectives 
The objective of this study is to evaluate the safety and intraocular pressure (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. 
3. Study Variables 
Primary Variable 
The primary efficacy variable is mean IOP at the following time points: 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits. 
Secondary Variables 
The secondary efficacy variables include the following: 
x 
Mean change from baseline IOP at the following time points: 8AM, 10AM, and 4PM at the 2 
Week, 6 Week, and 12 Week Visits. 
x 
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 Variables 
Additional variables on which data will be collected include the following: 
x 
Ocular complaints 
x 
Visualization of intracanalicular depot by the Investigator at each time point 
x 
Ease of insertion of intracanalicular depot 
x 
Number of intracanalicular depots required in each eye for the 12 week period per subject. 


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Safety Variables 
The safety variables include the following: 
x 
BCVA 
x 
Slit lamp biomicroscopy 
x 
Assessment and grade of ocular hyperemia (at slit lamp) 
x 
Subject ocular comfort assessment 
x 
Dilated fundus exam 
x 
Adverse events 
Statistical Hypotheses 
The null and alternative hypotheses, based on the primary variables, are as follows: 
x 
H0: The difference between study eyes that received sustained release travoprost (OTX-TP) 
and study eyes that received Placebo Vehicle (PV) (calculated as 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. 
x 
H1: The difference between study eyes that received OTX-TP and study eyes that received PV 
(calculated as 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. 
4. Study Design and Procedures 
General Study Design 
This is a prospective, multicenter, randomized, parallel-arm, double masked, placebo vehicle controlled 
Phase 3a 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 
intracanalicular depot (OTX-TP) or PV intracanalicular depot (PV), 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. 
At the Baseline Visit 2/Insertion Visit, 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.  If insertion 
is unsuccessful in the second 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 


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discretion for the eye that did not receive a depot. The subject 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 (490) who received a depot bilaterally are followed through the 12 Week Visit for efficacy and 
safety. If neither insertion is successful the End of Study eCRF will be completed for the subject and the 
subject will be exited from the study.  Unsuccessful punctal dilation of either eye (if needed) or if the 
punctum of either eye is too small to allow transient dilation to 0.7 mm prior for insertion of OTX-TP or 
PV is considered a Procedural Exclusion Criterion and the subject will be exited as a screen failure. 
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 be considered an efficacy failure.  and will be followed through the remainder of the study 
for safety. If still present, the intracanalicular depot will not be removed. IOP measurements taken 
through the remainder of the study will be excluded from the efficacy analyses. 
For any subject, if at any point the intracanalicular depot is removed bilaterally by the Investigator for an 
adverse event or 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. 
Intracanalicular depots that are removed due to subject withdrawal or an undesired reaction at any point 
in the study will not be replaced. 
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 depot replacements will be tracked and documented on the appropriate 
electronic Case Report Form (eCRF). 
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. Depots replaced between the 6 Week Visit and the 12 Week Visit will not be 


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removed at the 12 Week Visit.  The first attempt to remove these depots will be at the 20 Week Visit. 
The number of depot replacements will be tracked and documented on the appropriate eCRF. 
12 Week Visit: 
If the intracanalicular depot(s) is/are still present at the 12 Week Visit, the Investigator will attempt to 
remove the depot(s). 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 are 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 subject may be prescribed IOP-lowering drops if necessary at the 12 Week Visit at the 
Investigator’s discretion. 
20 Week Visit: 
At the 20 Week Visit, the Investigator will attempt removal of the 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. 
The subject may be prescribed IOP-lowering drops if necessary at the 20 Week Visit at the Investigator’s 
discretion. 
Schedule of Visits and Assessments 
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.  


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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 
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
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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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
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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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 
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
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.
 


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5. Study Treatments 
There are two study treatments, OTX-TP intracanalicular depot and PV intracanalicular depot, which 
are explained below. 
OTX-TP 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 OTX-PV 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. 
Placebo Vehicle Intracanalicular Depot 
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. 
Method of Assigning Subjects to Treatment Groups 
Prior to the initiation of the study, a treatment randomization scheme will be generated using a 3:2 ratio 
(Active Treatment to Placebo Control) approximately 330 subjects in the OTX-TP arm and 220 in the 
PV arm. The study will be supplemented with additional subjects for whom bilateral depot insertion is 
successful in order to ensure that at least 490 subjects who receive a depot bilaterally are followed 
through the 12 Week Visit for safety and efficacy. 
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. Both eyes will be 
provided with the same assigned treatment, OTX-TP or PV. Randomization will be stratified by 
investigational site (i.e., one randomization schema per study site) and previous ocular anti-hypertensive 
therapy with three stratum levels below: 
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). 
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). 
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. 


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A site may randomize up to a maximum of 55 subjects. 
The randomization number will be an alpha-numeric code using the following scheme: RnnX-nnn with 
R in the first place followed by the 2-digit site ID and one letter X corresponding to the stratum (A, B or 
C). Then a hyphen will separate the first alpha-numeric section and be followed by a three-digit number 
increasing in sequential order within each site and starting with 001. 
Masking and Unmasking 
The Investigator and the subject will be masked to the treatment assignment throughout the duration of 
therapy. The sponsor and study team (with the exception of the Investigators/investigative site staff)  will 
be unmasked at the time of the interim analysis (i.e., the final analysis of the primary endpoint). 
OTX-TP and the PV are identical in appearance, and will be supplied in identical packages so they 
cannot be distinguished by the user. If it is medically necessary to identify the product used, the 
Investigator will 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. 
6. Sample Size and Power Considerations 
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. 
7. Data Preparation 
All reported study data will be recorded on eCRFs using the iMedNet electronic data capture (EDC) 
system. All authorized personnel will have access to the EDC system; however, only the site study 
personnel assigned to have the role of a Research Coordinator will have data entry user rights. 
Ocular Therapeutix (OTX) is responsible for validating the OTX-16-002 study database, maintaining the 
study data, and cleaning and reviewing the data prior to database lock. OTX data management will 
prepare the edit check specifications document as well as the Business Logic Documents for review 
and approval. These documents are maintained in the trial master file. After data are entered into the 
clinical study database, electronic edit checks and data review will be performed. When the database 
has been declared to be complete, the following activities will take place to prepare for database lock: 


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x 
All clinical data are entered, source verified, and approved in the clinical database 
x 
All discrepancies are resolved and applied to the database 
x 
Dictionary coding (by SDC) is complete and Final AE Coding Approval Form is signed 
x 
SAE reconciliation is complete 
x 
Any DMP amendments are signed by the appropriate team members 
Additionally, for the final database lock and analysis, all analyses outlined in this document will be 
carried out only after the following have occurred: 
x 
Protocol deviations have been identified and status defined (major/important vs minor 
deviations) 
x 
Analysis populations have been determined 
x 
Randomized treatment codes have been unmasked 
In the event that the database must be unlocked, unlocking procedures fall under OTX processes and 
operating procedures. 
For the interim analysis, the database will not be locked but relevant enrollment, randomization 
demographics, baseline characteristics, protocol deviation, and efficacy eCRFs for IOP data will be 
marked as DM reviewed, ensuring the data are complete and clean with no outstanding queries.  
Datasets will be downloaded and exported using the Datasets on Demand functionality. At the time of 
interim and final analyses, OTX DM will communicate timing of the dataset downloads and release to 
Statistics & Data Corporation (SDC). 
8. Analysis Populations 
Subjects will be considered enrolled once they have signed informed consent. Once randomized and 
treated, subjects will fall into at least one of the following analysis populations. 
Full Analysis Set  
The Full Analysis Set  (FAS) population will include all randomized subjects with depots inserted in both 
eyes. Analysis on the data for the primary study eye in the FAS 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 Population 
The Per Protocol (PP) population will include all FAS 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 


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prior to the data cut-off date for the interim analysis. The primary efficacy analysis will be conducted 
using the PP population as a sensitivity analysis of the primary outcome. 
Safety Population 
The Safety population will include all subjects who received any investigational study treatment (OTX-
TP or PV). Analyses performed on the Safety population will be according to the treatment the subjects 
actually received. All safety analyses will be based on the Safety population. 
9. General Statistical Considerations 
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. 
Missing Data and Imputation Methods 
The primary analyses of efficacy data (IOP) will employ multiple imputation (MI) methods using the 
Markov Chain Monte Carlo (MCMC) approach to impute missing data and using the 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 as rescue therapy. 
Sensitivity analyses, to determine robustness of results, will be performed using the MCMC approach 
to impute non-monotone missing information and pattern mixture models control-based pattern 
imputation for monotone missing information (including data for subjects who drop out prior to the 12 
Week Visit 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, baseline time-consistent observation carried forward (BOCF) to impute both missing 
data and data after a subject’s primary study eye is prescribed IOP-lowering drops and using observed 
data only (excluding data after a subject’s primary study eye is prescribed IOP-lowering drops as rescue 
therapy). Additionally, sensitivity analyses will be performed on the PP population using observed data 
only (excluding data after a subject’s primary study eye is prescribed IOP-lowering drops as rescue 
therapy). 


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For time-consistent imputations, IOP values missing at an 8AM time point will only be imputed with the 
IOP value from a previous 8AM time point (last or baseline). Imputations at 10AM and 4PM will be 
performed similarly. 
Definition of Baseline 
For IOP, the baseline measure will be defined as the last non-missing time-consistent measure prior to 
initiation of investigational treatment and after washout of previous IOP medication. In most cases this 
will be the measure of IOP at Baseline Visit 2. For all other variables, baseline will be defined as the last 
non-missing measure prior to initiation of investigational treatment. Change from baseline will be 
calculated as follow-up visit – baseline visit. 
Data Analysis Conventions 
An interim analysis is planned after all subjects attend 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) Protocol deviations will be assigned major/minor status to determine the Per Protocol 
population prior to the data cutoff date for the interim 
3) No alpha adjustments for multiplicity will be made 
At this interim analysis, the study team with the exception of the Investigator/investigative site staff and 
the subjects will be unmasked. 
All data analysis will be performed by SDC at the interim and after the study is completed and the 
database has been locked.  Statistical programming and analyses will be performed using SAS® Version 
9.4 or higher.  Output will be provided in RTF format for tables and PDF format for tables, listings, and 
figures using landscape orientation.  All study data will be listed by subject, actual treatment, and visit 
(as applicable) based on all randomized subjects unless otherwise specified. 
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported 
with the same precision as the raw values; means, standard deviations and medians will be presented 
to one additional decimal place than reported in the raw values. Summaries for discrete variables will 
include frequency counts 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. 
All statistical tests will be two-sided with a significance level of 0.05 (Į = 0.05) unless otherwise specified.  
Confidence intervals (CI) for differences between treatment groups will be two-sided at 95% confidence.  


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All p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as  
“< 0.0001”; p-values greater than 0.9999 will be presented as “> 0.9999”. 
All efficacy summaries will be presented for the primary study eye. Additional efficacy analyses will be 
reported for secondary study eyes. Ocular AEs will be summarized at the eye level for any treated eye 
and subject level, and non-ocular AEs by subject level. All other safety variables will be assessed by 
primary study eye and secondary study eye, separately. 
Adjustments for Multiplicity 
In order to maintain the overall Type I error for the primary analyses, all 9 time points must show 
statistical significance for the study to be successful: 8AM, 10AM, and 4PM at the 2 Week, 6 Week, and 
12 Week Visits.  No other adjustments for multiplicity are necessary as there are no other sources of 
multiplicity for the primary analyses. 
Unscheduled Visits 
For Unscheduled Visits, the reason for the visit should be clearly documented on the appropriate eCRF, 
including findings from all evaluations that are completed. 
Data from unscheduled visits up to the 12 Week Visit will be integrated into subject listings and summary 
tables.  If unscheduled data is available within window of a scheduled Visit with missing data, the 
unscheduled data will be used.  If more than one set of unscheduled data falls within a window for an 
efficacy assessment, the earliest unscheduled visit in that visit window will be used. If more than one 
set of unscheduled data falls within a window for a safety assessment, the worst case observation will 
be used. 
10. Disposition of Subjects 
Subject disposition of all enrolled subjects will be presented in terms of the numbers and percentages 
of subjects who were screened, randomized, completed the study, discontinued from the study and /or 
experienced protocol deviations.  Number of subjects exiting the study prior to Week 12, at Week 12, at 
Week 20 and beyond Week 20 will also be summarized.  Subjects who are not discontinued from the 
study will be considered study completers.  Disposition will be summarized by treatment group and for 
all subjects. Reasons for subject discontinuation at various decision time points will be summarized. 
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 but will be entered 
in the EDC system with the reason for screen failure delineated. The total number of screened subjects 
with the number and percentage of screen failure subjects will be presented.  The reasons for screen 
failure will be displayed with the percentages calculated using total number of screen failures as the 
denominator. 


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The number of subjects in each of the analysis populations (FAS, PP and Safety) will be displayed by 
treatment and percentages will be calculated using randomized subjects as the denominator. A subject 
listing of analysis populations will be provided including reasons for exclusion from the PP and/or Safety 
populations.  In addition, a subject listing of randomization, including randomization strata assignment, 
will be provided. 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
group for all randomized subjects.  The protocol deviations will be summarized by deviation codes. 
A subject listing will be provided that includes the date of the deviation, the deviation description and the 
classification of whether the deviation was judged to be major or minor. 
In addition, subject listings will be provided that include informed consent date, and inclusion and 
exclusion criteria violations. Procedural exclusion criteria will be presented in the same listing as study 
inclusion and exclusion criteria. 
11. Demographic and Pretreatment Variables 
Demographic Variables 
The demographic variables collected at Screening in this study include date of birth, sex, race, ethnicity, 
height, weight and iris color.  Subjects who record more than one race will be grouped into a single 
category denoted as multi-racial. Demographic variables will be summarized for the FAS population
Age at informed consent (years), height, weight and BMI will be summarized, overall and by treatment, 
using continuous descriptive statistics.  Age will also be categorized as follows:  < 65 years and  65 
years.  Age will be reported in years and calculated using the following formula: 
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
BMI is calculated using the following formula: 
BMI (kg/m2) = (Weight (lb)/[Height (in)*Height (in)])*703 rounded to the nearest tenth. 
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
sex, race, ethnicity and iris color. 
A subject listing that includes all demographic variables will be provided. Note that iris color will be 
reassessed at the 12 Week Visit and these results will be listed along with a flag indicating any changes 
from baseline. 
Pretreatment Variables 
Female subjects of child-bearing potential will have urine pregnancy test at the Screening Visit.  A 
subject listing of child-bearing status and pregnancy test results will be provided. 


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Summary statistics will be provided for the baseline characteristic variables, which include mean IOP 
for both the primary study eye and the secondary study eye at screening (pre-washout) and at Baseline 
Visit 2, mean deviation in visual fields (dB), central corneal thickness (ȝm), and cup to disc ratio.  Counts 
and frequencies for current diagnosis of OHT or OAG, and gonioscopy results (including the following 
categories: Grade 4 [45° to 35° angle wide open], Grade 3 [35° to 20° angle wide open], Grade 2 [20° 
angle narrow], Grade 1 [10° angle extremely narrow], and Slit [0° angle narrowed to slit] will also be 
provided. 
A subject listing that includes all pretreatment variables will be provided. 
Punctum Size Assessment Prior to Insertion 
Punctum size will also be assessed prior to insertion of the depot. At the 4PM time point on Baseline 
Visit 2 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. Punctum size, both prior to and after dilation, will be recorded and provided in a 
subject listing. 
12. Medical History and Concomitant Medications 
Medical History 
Medical history will be collected at the Screening Visit and coded using MedDRA 20.0. 
Non-ocular and ocular medical history will be summarized for the Safety Population using discrete 
summary statistics and presented by treatment group at the subject level by System Organ Class (SOC) 
and Preferred Term (PT) using the FAS.  If a subject reports the same PT multiple times within the same 
SOC, that PT will only be reported once within that SOC.  As with PT, if a subject reports multiple 
conditions within the same SOC, that SOC will only be reported once. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
Concomitant Medications 
Starting at the Screening Visit through the end of the study, 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. The use of any herbal or vitamin 


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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. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary Enhanced 
(WHO DDE) March 2017 and summarized to the therapeutic drug class (Anatomical Therapeutic 
Chemical (ATC) 4 classification) and preferred name (generic drug name). 
Concomitant medications are defined as those medications listed as having been taken 1) prior to 
initiation of study drug administration and continuing for any period of time following the first 
administration of study drug or 2) at any time following the first administration of study drug. 
Ocular and non-ocular concomitant medications will be summarized using the FAS.  Medications will be 
tabulated for each treatment group using frequencies and percentages.  At each level of subject 
summarization, a subject will be counted once if he/she reports 1 or more medications.  Percentages 
will be based on the number of subjects in each treatment group.  Listings of concomitant medications 
will be generated separately for ocular and non-ocular data. Additionally, a table summarizing the subset 
of IOP-lowering medications and a summary table of IOP-lowering medication by visit will be produced. 
IOP-lowering medications will be designated on the listing of ocular medications using the eCRF 
indication “Lack of IOP control”. 
13. Dosing Compliance and Treatment Exposure 
Dosing compliance and treatment exposure will be assessed using visualization of the intracanalicular 
depot by the investigator, intracanalicular depot removal and the number of intracanalicular depots 
required in each eye for the 12 week period per subject.  These analyses will be performed on the Safety 
Population. No statistical inference testing will be performed. 
Intracanalicular Depot Visualization by the Investigator 
The intracanalicular depot will be assessed for presence and ease of visualization at the time of insertion 
time point as well as the 8AM time point at each post-baseline visit. The number of subjects with a 
intracanalicular depot present will be summarized by visit and treatment, and this number will be used 
as the denominator for the ease of visualization responses. Ease of visualization will be recorded as 
Easy, Moderate, or Difficult by the investigator.  Responses will be summarized by count and percentage 
at each visit by treatment group.  A subject listing, reported separately by primary and secondary study 
eyes, will also be provided. 
Intracanalicular Depot Removal 
When an intracanalicular depot is removed the reason for removal (removed per protocol, AE, other), 
the success of the removal (yes vs no), the ease of removal (easy, moderate, difficult) and the method 
of removal (saline irrigation, application of manual pressure) will be recorded. The responses will be 


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summarized by count and percentage at each visit by treatment group.  A subject listing, reported 
separately by primary and secondary study eyes, will also be provided. 
Number of Replacements 
The number of intracanalicular depots required in each eye for the 12 week period per subject will be 
reported and listed. For subjects with confirmed depots beyond 12 weeks, summaries will also be 
provided indicating the length of the depot being present in the canaliculus and the number of depots 
required and the number of patency checks performed. 
Treatment Exposure 
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using 
the following: 
Total Exposure (days) =  
(Date of last investigator visualization of a depot in either eye [that is not subsequently replaced] – 
Date of first insertion of a depot in either eye) + 1 
Date of first insertion of depot in either eye will in most cases be Baseline Visit 2 [Day 1].  Extent of 
treatment exposure for subjects who were lost to follow-up will be calculated in days using the 
following: 
Total Exposure (days) = (Date of last recorded visit – Date of first insertion of a depot in either eye) + 1 
Total treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group and for all subjects, using the Safety 
population. A subject listing of treatment exposure will also be produced. 
14. Efficacy Analyses 
Primary Analysis 
The primary analysis of the primary efficacy outcome will employ a linear model of IOP in the primary 
study eye of subjects in the FAS. The response variable will be IOP at the given visit (2 Week, 6 Week, 
and 12 Week) and time point (8AM, 10AM, and 4PM), time point specific baseline IOP will be used as 
a covariate, and treatment will be the main effect factor.  Each time point within each visit will be modeled 
separately. 
IOP refers to the single result from the following procedure.  IOP will be assessed by two qualified 
independent study site personnel at each visit and time point using a Goldmann applanation tonometer 
affixed to a slit lamp with the subject seated.  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. Averages of readings are calculated within the clinical database. 


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For the primary analysis, MI methods will use the MCMC approach for any data missing from these 
visits/time points, after LOCF has been used to impute data for time points after the subject’s primary 
study eye is prescribed IOP-lowering drops. Example MCMC imputation code which will be implemented 
after IOP after LOCF has been applied (SAS version 9.4) is shown here: 
PROC MI DATA = indata SEED = 7436892 OUT = outdata NIMPUTE=20; 
BY TMPTN; 
MCMC INITIAL = EM; 
VAR trt baseline WV2 WV4 WV6 WV8 WV10 WV12; 
RUN; 
where 
- indata is the name of the input dataset; 
- outdata is the name of the output dataset; 
- nimpute is the number of imputations; 
- tmptn is the time point of assessment, 8AM, 10AM, or 4PM; 
- trt is the name of the treatment group variable in numeric format; 
- baseline is the average IOP at baseline for the ith time point  
- WV2 is the IOP value for the 2 Week visit; 
- WV4 is the IOP value for the 4 Week visit; 
- WV6 is the IOP value for the 6 Week visit; 
- WV8 is the IOP value for the 8 Week visit; 
- WV10 is the IOP value for the 10 Week visit; 
- WV12 is the IOP value for the 12 Week visit. 
 
Twenty complete data sets for each time point will be generated from the above code. The data will be 
transposed to have a vertical structure with one record per subject, imputation, visit, and time point. 
Each complete data set will be used to compute the mean IOP and analyze using the linear model with 
time point specific baseline IOP used as a covariate, and treatment as the main effect factor. Then, the 
SAS procedure MIANALYZE will be used to analyze the results from the 20 complete data sets to 
generate a combined inference. The following SAS code will be used: 
ODS OUTPUT LSMEANS = outdataB; 
PROC MIXED DATA = outdataA; 
CLASS trt; 
MODEL IOP=trt baseline; 
BY visitn tmptn _IMPUTATION_; 
LSMEANS trt/PDIFF CL; 
RUN; 


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where 
- IOP is the IOP for each visit and time point; 
- visitn is the visit number variable in numeric format; 
- tmptn is the time point variable in numeric format; 
- baseline is the average IOP at baseline, matched by time point; 
- trt is the name of the treatment group variable in numeric format; 
- outdataA is the transposed dataset containing the 20 “complete” datasets from the imputation. 
 
ODS OUTPUT PARAMETERESTIMATES = outdataC; 
PROC MIANALYZE DATA = outdataB; 
MODELEFFECTS ESTIMATE; 
STDERR; 
BY visitn tmptn; 
RUN; 
where 
- outdataB is the name of the output dataset that contains the statistical results of the difference 
between treatment groups from the MIXED procedure that is run on each of the twenty 
imputation datasets; 
- outdataC is the name of the output dataset that contains all the information needed for the 
table. 
After imputation the least squares mean differences (OTX-TP minus 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. 
Two-sample t-test p-values and two-sided 95% CI’s will also be computed around the difference (OTX-
TP minus PV) in IOP between treatment groups at each time point and visit for the primary analysis data 
(FAS employing MI methods using MCMC 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). The 
following SAS code will be used for the t-test: 
ODS OUTPUT STATISTICS = outdataB; 
PROC TTEST DATA = outdataA; 
CLASS trt; 
VAR IOP; 
BY visitn tmptn _Imputation_; 


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RUN; 
- IOP is the IOP for each visit and time point; 
- visitn is the visit number variable in numeric format; 
- tmptn is the time point variable in numeric format; 
- baseline is the average IOP at baseline, matched by time point; 
- trt is the name of the treatment group variable in numeric format; 
- outdataA is the transposed dataset containing the 20 “complete” datasets from the imputation. 
Then, as with the PROC MIXED results, the SAS procedure MIANALYZE will be used to analyze the 
results from the 20 complete data sets to generate a combined inference. 
ODS OUTPUT PARAMETERESTIMATES = outdataC; 
PROC MIANALYZE DATA = outdataB; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
BY visitn tmptn; 
RUN; 
where 
- outdataB is the name of the output dataset that contains the statistical results of the difference 
between treatment groups from the MIXED procedure that is run on each of the twenty 
imputation datasets; 
- outdataC is the name of the output dataset that contains all the information needed for the 
table. 
Sensitivity analyses for the primary efficacy endpoint include both linear models of IOP and 2-sample t-
tests presented on the FAS  population using (1) MI approach using MCMC to impute non-monotone 
missing information and a pattern mixture model control-based pattern imputation for monotone missing 
information to impute both missing data and data after a subject’s primary study eye is prescribed IOP-
lowering drops as rescue therapy, (2) using LOCF to impute both missing data and data after a subject’s 
primary study eye is prescribed IOP-lowering drops as rescue therapy, (3) using BOCF to impute both 
missing data and data after a subject’s primary study eye is prescribed IOP-lowering drops as rescue 
therapy, and these analyses using observed data only (excluding data after a primary study eye is 
prescribed rescue therapy) for the (4) FAS  and (5) per protocol populations. 
For multiple imputations using a control-based pattern-mixture model, a process will be used that is 
similar to multiple imputations using MCMC. Twenty “complete” (imputed) datasets will be produced and 
analyzed. Results from the analyses on the twenty “complete” datasets will be combined for presentation 
through the use of SAS PROC MIANALYZE. Time point specific baseline IOP will be used as a 
covariate, and treatment will be the main effect factor. A separate model will be fit for each visit/time 
point combination. Monotone missing information refers to data missing from any visits beyond a 


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subject’s final visit (at which IOP is assessed) up to and including the 12 Week Visit.  Non-monotone 
missing information refers to data from missed visits between any two visits at which IOP is assessed. 
First LOCF will be used to impute data for time points after a subject’s primary study eye is prescribed 
IOP-lowering drops. Then MCMC will be employed to impute any non-monotone missing information 
using the code: 
PROC MI DATA = indata SEED = 3335891 OUT = mondata NIMPUTE=1; 
BY TMPTN; 
MCMC INITIAL = EM IMPUTE = MONOTONE; 
VAR trt baseline WV2 WV4 WV6 WV8 WV10 WV12; 
RUN; 
where 
- indatai is the name of the input dataset for the ith time point (i in {8, 10, 4} for 2, 6 and 12 Week 
visits, i = 8 for 4,8 and 10 Week visits); 
- mondatai is the name of the output dataset for the ith time point; 
- nimpute is the number of imputations; 
- trt is the name of the treatment group variable in numeric format; 
- baseline is the average IOP at baseline for the ith time point  
- WV2 is the IOP value for the 2 Week visit; 
- WV4 is the IOP value for the 4 Week visit; 
- WV6 is the IOP value for the 6 Week visit; 
- WV8 is the IOP value for the 8 Week visit; 
- WV10 is the IOP value for the 10 Week visit; 
- WV12 is the IOP value for the 12 Week visit. 
Then the following SAS code will be used to produce twenty “complete” datasets for each time point, 
imputing monotone missing data using a control-based pattern mixture model: 
PROC MI DATA = mondatai SEED = 48670 NIMPUTE = 20 OUT = outdatai 
MINIMUM = .  .  0 MAXIMUM =.  .   70 ROUND = .  .  0.25; 
BY visitn tmptn; 
CLASS trt; 
MONOTONE REG(WV2_8 WV4_8 WV6_8 WV8_8 WV10_8 WV12_8 = baseline / 
details); 
MNAR model(WV2_8 WV4_8 WV6_8 WV8_8 WV10_8 WV12_8/ MODELOBS = 
(TREATMENT=”2”)); 
VAR trt baseline WV2_8 WV4_8 WV6_8 WV8_8 WV10_8 WV12_8; 
RUN; 


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After obtaining twenty complete datasets, the data from the two MI procedures will be combined and will 
then be transposed to have a vertical structure with one record per subject, imputation, visit, and time 
point. SAS code similar to what is previously described for multiple imputations in the primary analysis 
will then be employed to run the model on each dataset and combine results across imputations. 
In the case that there is no missing data for a given visit and time point, observed data will be analyzed.  
Analyses on observed data and without MI methods will use the following statistical models: 
ODS OUTPUT LSMEANS = outdata; 
PROC MIXED DATA = indata; 
CLASS trt; 
MODEL IOP=trt baseline; 
BY visitn tmptn  
LSMEANS trt/PDIFF CL; 
RUN; 
where 
- IOP is the IOP for each visit and time point; 
- visitn is the visit number variable in numeric format; 
- tmptn is the time point variable in numeric format; 
- baseline is the average IOP at baseline, matched by time point; 
- trt is the name of the treatment group variable in numeric format; 
- indata is the dataset containing only observed data. 
and 
ODS OUTPUT STATISTICS = outdata; 
PROC TTEST DATA = indata; 
CLASS trt; 
VAR IOP; 
BY visitn tmptn; 
RUN; 
- IOP is the IOP for each visit and time point; 
- visitn is the visit number variable in numeric format; 
- tmptn is the time point variable in numeric format; 
- baseline is the average IOP at baseline, matched by time point; 
- trt is the name of the treatment group variable in numeric format; 
- indata is the dataset containing only observed data. 


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Secondary Analysis 
Mean change from baseline IOP and mean percent change from baseline IOP will be analyzed similarly 
to the primary endpoint analysis, including all sensitivity analyses. As described above, these analyses 
involve linear models of the response variables on the FAS  population using various combinations of 
imputation methods [(a) MCMC for missing data, LOCF for timepoints after rescue therapy has been 
initiated; (b) MCMC for non-monotone missing, pattern mixture models for monotone missing; (c) LOCF 
for both missing and “rescue” time points; and (d) BOCF for both missing and “rescue” time points] as 
well as inference on observed data confined to the FAS and Per Protocol populations. 
Additional Analyses 
14.1.1 ADDITIONAL EFFICACY ANALYSES
IOP measures, mean change from baseline, and mean percent change from baseline IOP measures 
from non-primary visits (4 Week, 8 Week, 10 Week Visits) will be also analyzed similarly to the primary 
endpoint analysis. 
Additionally, to further understand efficacy within each previous ocular anti-hypertensive therapy 
category, the primary analysis strategy (linear model of IOP Markov Chain Monte Carlo (MCMC) 
approach to impute missing data and using the 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 as 
rescue therapy) will be completed separately for the subgroups (i.e. stratum) of subjects within each 
previous ocular anti-hypertensive therapy category. The FAS will be used for these subgroup analyses. 
All analyses will be presented in summary tables by treatment group.  Subject level listings will also 
show IOP by treatment, time point and visit where appropriate. 
14.1.2 PUNCTUM EXAMINATION
At Screening, prior to insertion at Baseline Visit 2, and at the 8AM time point of each subsequent post-
baseline visit investigators will assess punctal appearance, lid apposition, tear meniscus recording 
results as normal, abnormal NCS or abnormal CS for each eye.  The responses will be summarized by 
count and percentage at each visit by treatment group and for all subjects. Shifts from Baseline to the 
evaluation visit will also be presented as frequencies and percentages. A subject listing, reported 
separately by primary and secondary study eyes, will also be provided. 
14.1.3 INSERTION RESULTS AND EASE OF INSERTION
The results of insertion will be summarized for insertion location (superior vs inferior punctum), success 
of insertion (yes vs no), ease of insertion (easy, moderate, difficult), the number of packages opened, 
number of depots used to attempt insertion in each eye and the reason(s) depots were not utilized 
(swelling of depot prior to insertion, depot not present in foam package, depot dropped prior to insertion, 
failed insertion in initial punctum, or other).  Product malfunctions during the insertion will also be 


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recorded. Summaries based on the Safety Population will be presented for Baseline Visit 2 and any 
Replacement or Re-insertion visits, and Replacement/Re-insertion visits within the initial 12 Week period 
by treatment group and overall.  Summaries will be separated by primary and secondary study eyes. A 
subject listing, reported separately by primary and secondary study eyes, will also be provided. 
14.1.4 OCULAR COMPLAINTS
In order to assess tolerability, ocular complaints are evaluated after insertion at Baseline Visit 2, and at 
the 8AM time point of each subsequent post-baseline visit. Complaint categories include Excessive 
Tearing, Foreign Body Sensation, Itching, Stinging/Burning, and Other Ocular Complaints. Within each 
category, a subject is required to answer yes or no as to whether the issue occurred, and the investigator 
responds as to whether or not the issue was within clinical expectations as well as whether or not any 
action was taken. 
Counts and percentages of study eyes and subjects experiencing each complaint category will be 
summarized by visit and treatment group using the number of assessments performed within each 
treatment group as the denominator. For expectedness and actions, counts and frequencies of yes and 
no responses will also be summarized, using the number of subjects having the complaint category as 
the denominator. Summaries at the study eye level will be split up by primary and secondary study eyes. 
For subject level summaries, the worse result between the two eyes will be summarized (ie, a response 
of yes to the ocular complaint). A subject listing, reported separately by primary and secondary study 
eyes, will also be provided. 
Graphical Outputs 
In addition to the tabular output, graphs will be provided of the mean (averaged over subjects) and  
standard error of IOP values for the primary study eye and changes from baseline values by treatment, 
visit and time point in the FAS with imputed data per the primary endpoint imputation strategy. In 
addition, figures will be created showing the difference between OTX-TP and PV mean IOP values along 
with their 95% CIs for each visit and time point using the FAS with imputed data per the primary endpoint 
imputation strategy and for observed data. Reference lines will be included at ±1 mmHg and ±1.5 mmHg. 
Figures using observed data for the PP population will also be presented. 
15. Safety Analyses 
Ocular and Non-Ocular Adverse Events 
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. 


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Documentation regarding the adverse event will 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. All AEs will be 
coded using the MedDRA version 16.1. 
AEs will be reported from the point subjects sign informed consent.  The AE and treatment emergent 
adverse event (TEAE) reporting period ends upon study exit for new AEs. Existing AEs and TEAEs will 
be followed until: 
x 
Resolution (return to baseline status or to ‘normal’) 
o 
AEs may be determined to have resolved (completely) or resolved with sequelae. 
x 
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. 
x 
Stabilization of the event has occurred (no worsening expected by the investigator) 
Adverse Event (or Adverse Experience, AE) 
An AE 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 AE 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 TEAOE) 
An adverse ocular event will be considered a treatment emergent AE if it occurs or worsens (based on 
severity: mild, moderate or severe) on or after the initiation of the intracanalicular depot insertion. 
Treatment Emergent Adverse Event (or TEAE) 
Treatment-emergent adverse events (TEAEs) are defined as any event that occurs or worsens on or 
after the initiation of the intracanalicular depot insertion, whether ocular or non-ocular in nature. Adverse 
events recorded in the eCRF which began prior to treatment will not be included in the summary tables 
but will be included in the AE data listings. 
Adverse Reaction (or Related Adverse Event or Adverse Effect) 


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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. 
Anticipated (as specified in the protocol) adverse ocular events that may be associated with OTX-TP or 
PV include, but are not necessarily limited to: 
x 
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 
x 
Prostaglandin Associated Orbitopathy 
x 
Iris discoloration 
x 
Blepharitis 
x 
Worsening in BCVA defined as  3 lines (15letters) 
x 
Subconjunctival hemorrhage 
x 
Cataract 
x 
Macular edema 
x 
Conjunctivitis 
x 
Keratitis 
x 
Perforation of or trauma to the punctum and/or surrounding tissues 
x 
Allergic reaction 
x 
Chemosis 
x 
Inflammatory reaction 
x 
Epiphora, defined as clinically significant excessive tearing outside of normal limits 
x 
Dacryocystitis 
x 
Tearing with mucopurulent discharge 
x 
Stenosis of the punctum 
x 
Infection* 
*Note: In the unlikely event of infection, the organism will be identified. 
Serious Adverse Event (Serious Adverse Experience) 
A serious adverse event (SAE) (experience) or reaction is any untoward medical occurrence that: 
x 
results in death 


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x 
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.) 
x 
requires inpatient hospitalization or prolongation of existing hospitalization 
x 
results in persistent or significant disability/incapacity 
x 
is a congenital anomaly/birth defect 
x 
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. 
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the Investigator or reported to him/her by the 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.1 
1The 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.) 
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 AE 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.) 


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RELATIONSHIP 
SUSPECTED 
The following criteria should be applied in considering inclusion of an AE 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. 
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 AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the study drug and the AE. 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. 
For TEAEs not suspected to be related to study product, a most likely cause will be selected from the 
following categories: Concomitant Medication(s), Pre-existing Condition(s), Insertion Process, Other. 
Expected AEs 
The expectedness of an AE should be determined based upon existing safety information about the 
study drug using these explanations: 
x 
Unexpected: 
An AE 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. 
x 
Expected: 
An AE that is listed in the Investigator’s brochure at the specificity and severity 
that has been observed. 


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AEs 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. 
The Investigator should initially classify the expectedness of an adverse event, but the final classification 
is subject to the Medical Monitor’s determination. 
AE Summaries 
All AEs and TEAEs will be coded using MedDRA 20.0.  AEs will be summarized in listings and tables 
for overall and ocular TEAEs by treatment group. 
An overall summary will be presented that includes the number of AEs, TEAEs and the number and 
percentage of subjects who experienced at least one AE or TEAE, by treatment group and for all 
subjects. This summary will also include breakdowns of TEAEs further categorized as ocular (primary 
study eye and secondary study eye separately) or non-ocular, serious AEs (SAEs), ocular TEAEs by 
maximum severity, non-ocular TEAEs by maximum severity, related TEAEs, TEAEs leading to early 
discontinuation, and deaths. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE and will be presented by SOC and PT. Non-ocular TEAEs will be 
summarized using discrete summary statistics and presented by treatment group at the subject and 
event level by SOC and PT. Ocular TEAEs will be similarly summarized at the subject level for both 
eyes and for primary study and secondary study eyes separately If a subject reports the same PT 
multiple times within the same SOC, that PT will only be reported once within that SOC. As with the PT, 
if a subject reports multiple conditions within the same SOC, that SOC will only be reported once. In the 
summary, SOC will be listed in ascending alphabetical order; PTs will be listed in order of descending 
frequency for all subjects within each SOC. 
Separate summaries will be provided for the following categories of AEs: 
x 
Ocular TEAEs in the primary study eye 
x 
Ocular TEAEs in the secondary study eye 
x 
Non-ocular TEAEs 
x 
Expected TEAEs 
x 
Unexpected TEAEs 
x 
Treatment related ocular TEAEs 
x 
Treatment related non-ocular TEAEs 
x 
Serious AEs 
x 
TEAEs by Maximum Severity 
x 
Non-related TEAEs by Most Likely Cause 


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x 
Non-related SAEs by Most Likely Cause 
All TEAEs, SAEs and TEAEs leading to early discontinuation will be presented in subject listing 
separately for ocular and non-ocular events. 
Best Corrected Visual Acuity (BCVA) 
The logarithm of the minimum angle of resolution (logMAR) visual acuity is assessed at each visit using 
an EDTRS chart at a viewing distance of 4 meters.  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. Subjects are required to read the chart from the top to the bottom until 2 letters are misread on 
the line. 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, then 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 the ability to count fingers or see hand motion or light perception as appropriate. 
BCVA will be measured at screening, at 8AM on Baseline Visit 2 and as well as the 8AM time point at 
each post-baseline visit. The baseline measurement will be the last assessment prior to insertion of the 
depot. 
The observed and change from baseline BCVA will be summarized for the primary study eye and 
secondary study eye using continuous descriptive statistics by visit for each treatment group and for all 
actively treated subjects.  Additionally, discrete summaries of the worst change from baseline will be 
presented for both the primary study eye and the secondary study eye with the following groupings 
based on the logMAR scores: 0 or less, >0 to +0.09, +0.10 to +0.19, +0.20 to 0.29, +0.30 or more. 
Visual acuity scores will also be presented in data listings. Subjects who lost three or more lines 
(equivalent to change from baseline of 0.30 logMAR or more) will be presented in an additional listing.  
This additional listing will also include subjects for whom vision worsened to the extent that the subject’s 
vision is measured by finger count, hand motion or light perception. 
Slit Lamp Biomicroscopy Examination 
A slit lamp biomicroscopy examination of the eyelid, conjunctiva, iris, cornea, anterior chamber, lens, 
and vitreous will be performed at each visit (except the Run-in Visits for Stratum B subjects) at the 8AM 
time point.  The results will be graded as normal, abnormal NCS or abnormal CS. 
The results will be summarized using counts and percentages for each treatment group and for all 
actively treated subjects at each visit for each eye (primary study eye and secondary study eye).  
Percentages will be based on the number of subjects in each treatment group with responses.  Shift 


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tables for the slit lamp biomicroscopy parameters will also be provided comparing each follow-up visit 
to baseline.  A subject listing of the slit lamp biomicroscopy parameters will also be produced. 
Dilated Fundoscopy Examination 
A dilated fundoscopy examination of the macula, peripheral retina, and optic nerve will be performed at 
Screening, and the 12 Week Visit.  The results will be graded as normal, abnormal NCS or abnormal 
CS.  The cup to disc (C/D) ratio will also be measured. Explanation/comment should be provided on the 
case report form for any abnormal findings. 
The results will be summarized using counts and percentages for each treatment group and for all 
actively treated subjects at each visit for each eye (primary study eye and secondary study eye).  
Percentages will be based on the number of subjects in each treatment group with responses.  For the 
cup to disc ratio, a continuous summary, including change from baseline, will be provided for each eye.  
Shift tables for the dilated fundoscopy parameters will also be provided comparing the 12 Week Visit 
results for each subject to the Screening results.  A subject listing of the dilated fundoscopy parameters 
(including C/D ratio) will also be produced. 
Ocular Hyperemia 
Ocular hyperemia will be graded every visit at 8AM (except the 1st baseline measurement, Visit 1)  on 
the following scale: 0 (None), 1 (Mild), 2 (Moderate), 3 (Severe), and 0.5 increments may be used if the 
subject’s hyperemia is between two grades. Frequencies and percentages will be summarized for each 
visit and treatment group. Shifts from baseline to post-baseline visits will be summarized categorically 
as  0 (no change or decrease), +0.5, +1, +1.5, +2, +2.5, +3. 
A subject listing of ocular hyperemia will also be produced. 
Ocular Comfort Assessment 
The subject comfort level will be assessed prior to insertion of the OTX-TP or PV, and again at each 
post-baseline visit. 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?”
Descriptive summary statistics of the comfort scores will be presented for each day which the question 
is asked. Changes from baseline will also be calculated and summarized alongside the observed values. 
Subject comfort scores will be listed, along with the Investigator’s response to the expectedness of the 
score and any action taken to alleviate discomfort. 
Observed IOP Results 
A summary and listing of observed IOP data with no imputation, based on the Safety Population, will 
also be provided. 


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16. Interim Analyses 
An interim analysis is planned after all subjects attend 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) Protocol deviations will be assigned major/minor status to determine the Per Protocol 
population prior to the data cutoff date for the interim 
At this interim analysis, the study team will be unmasked and the Investigator/investigative site staff and 
the subjects will remain masked. 
Once all subjects have completed the study (all intracanalicular depot removed or absence confirmed) 
the final safety data summaries will be created. 
17. Pharmacokinetic Analyses 
No pharmacokinetic data will be collected for this study. 
18. Pharmacodynamic Analyses 
No pharmacodynamic data will be collected for this study. 
19. Quality of Life 
No Quality of Life data will be collected for this study. 
20. Changes from Protocol-Stated Analyses 
This SAP differs from the protocol-stated analysis in three respects: 
(1) The statement, “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” in the 
protocol has been changed to “The Full Analysis Set (FAS) will include all randomized subjects 
with depots inserted in both eyes. Analysis on the data for the primary study eye in the FAS 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. 
(2) No subject visualization of depots are required. 
(3) The protocol (5.6) states, “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.”  Due to the logistics involved and the potential for 
bias, the sponsor has determined that investigators and investigative site staff will not be 
unmasked until the end of the study. 


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Any changes to the planned analyses after the interim analysis and unblinding will be described in the 
clinical study report. 
21. References 
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry: 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and Drug 
Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. (E9) 
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry: 
Structure and Content of Clinical Study Reports. Department of Health and Human Services: Food and 
Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320. (E3) 
22. Revision History 
Documentation of revision to the SAP will commence after approval of the Final version 1.0. 
23. Tables 
Tables that will be included in the topline delivery are shown in boldface font.  Tables that will be included 
in the interim analysis are shown in italicized font. 
Table Number 
Title 
Population 
Table 14.1.1 
Subject Disposition 
All Enrolled Subjects 
Table 14.1.2 
Major Protocol Deviations 
Full Analysis Set  
Table 14.1.3 
Demographic and Baseline Characteristics 
Full Analysis Set  
Table 14.1.4 
Baseline Disease Characteristics 
Full Analysis Set  
Table 14.1.5.1 
Non-Ocular Medical History 
Safety Population 
Table 14.1.5.2 
Ocular Medical History 
Safety Population 
Table 14.1.6.1 
Non-Ocular Concomitant Medications 
Safety Population 
Table 14.1.6.2 
Ocular Concomitant Medications 
Safety Population 
Table 14.1.6.3 
IOP-Lowering Ocular Medications 
Safety Population 
Table 14.1.6.4 
Rescue Medication Use (IOP-Lowering Drops) by Visit 
Full Analysis Set 
Table 14.2.1.1 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point 
MCMC Analysis – Primary Time Points 
Full Analysis Set  
Table 14.2.1.2 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point 
MCMC Analysis – Non-Primary Time Points 
Full Analysis Set  
Table 14.2.1.3 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point 
Pattern Mixture Analysis 
Full Analysis Set  
Table 14.2.1.4 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point 
LOCF Analysis 
Full Analysis Set  
Table 14.2.1.5 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point 
BOCF Analysis 
Full Analysis Set  
Table 14.2.1.6 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point 
Observed Data Analysis 
Full Analysis Set  


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Table Number 
Title 
Population 
Table 14.2.1.7 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point 
Observed Data Analysis 
Per Protocol Population 
Table 14.2.1.8 
Mean Observed, Change, and Percent Change from 
Baseline in Secondary Study Eye IOP by Time Point 
Observed Data Analysis 
Full Analysis Set  
Table 14.2.1.9 
Mean Observed, Change, and Percent Change from 
Baseline in Secondary Study Eye IOP by Time Point 
Observed Data Analysis 
Per Protocol Population 
Table 14.2.2.1 
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point and 
Strata
MCMC Analysis 
Full Analysis Set  
Table 14.2.4.1 
Insertion Results and Ease of Insertion 
Safety Population 
Table 14.2.4.2 
Summary of Replacements 
Safety Population 
Table 14.2.4.3 
Removal of Intracanalicular Depot 
Safety Population 
Table 14.2.5 
Ocular Complaints by Study Eye 
Safety Population 
Table 14.2.6 
Investigator Visualization of Intracanalicular Depot and 
Patency Check (Post Insertion Visit) 
Safety Population 
Table 14.2.7 
Punctum Examination Results 
Safety Population 
Table 14.3.1 
Study Treatment Exposure 
Safety Population 
Table 14.3.2.1 
Overall Summary of Adverse Events 
Safety Population 
Table 14.3.2.2.1 
Non-Ocular Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.2.2 
Ocular Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.2.3 
Primary Study Eye Ocular Treatment Emergent Adverse 
Events by System Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.2.4 
Secondary Study Eye Ocular Treatment Emergent 
Adverse Events by System Organ Class and Preferred 
Term 
Safety Population 
Table 14.3.2.2.5 
Treatment Related Ocular Treatment Emergent Adverse 
Events by System Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.2.6 
Treatment Related Non-Ocular Treatment Emergent 
Adverse Events by System Organ Class and Preferred 
Term 
Safety Population 
Table 14.3.2.2.7 
Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
Table 14.3.2.2.8 
Treatment Emergent Adverse Events Leading to Subject 
Withdrawal by System Organ Class and Preferred Term 
Safety Population 
Table 14.3.2.3 
Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity 
Safety Population 
Table 14.3.2.4 
Non-Related Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Most Likely 
Cause 
Safety Population 
Table 14.3.3.1 
Best Corrected Visual Acuity by Time Point and Eye 
Safety Population 
Table 14.3.3.2 
Worst Change from Baseline in Best Corrected Visual 
Acuity by Time Point and Eye 
Safety Population 
Table 14.3.4.1 
Slit Lamp Biomicroscopy by Visit and Eye 
Safety Population 
Table 14.3.4.2 
Shifts from Baseline in Slit Lamp Biomicroscopy by Visit 
and Eye 
Safety Population 
Table 14.3.5.1 
Dilated Fundoscopy Examination by Visit and Eye 
Safety Population 
Table 14.3.5.2 
Shifts from Screening to 12 Week Visit in Dilated 
Fundoscopy Examination by Visit and Eye 
Safety Population 


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Table Number 
Title 
Population 
 
Table 14.3.6 
Mean Observed and Change from Baseline in Primary 
Study Eye IOP by Time Point 
Safety Population 
Table 14.3.7.1 
Slit Lamp Ocular Hyperemia by Visit and Eye 
Safety Population 
Table 14.3.7.2 
Shifts from Baseline to Each Post-Baseline Visit in Ocular 
Hyperemia by Visit and Eye 
Safety Population 
Table 14.3.8 
Mean Observed and Change from Baseline in Subject 
Ocular Comfort Assessment by Visit and Eye 
Safety Population 
24. Listings 
Listings that will be included in the interim analysis are shown in italicized font. 
Table Number 
Title 
Population 
Listing 16.1.7 
Randomization Schedule 
All Enrolled Subjects 
Listing 16.2.1 
Subject Disposition 
All Enrolled Subjects 
Listing 16.2.2.1 
Protocol Deviations 
All Randomized 
Subjects 
Listing 16.2.2.2 
Inclusion, Exclusion, and Procedural Exclusion Criteria 
All Enrolled Subjects 
Listing 16.2.3 
Subjects Excluded from the Per Protocol Population 
All Randomized 
Subjects 
Listing 16.2.4.1 
Demographics 
All Randomized 
Subjects 
Listing 16.2.4.2 
Baseline Characteristics: 
Study Condition, Gonioscopy, Punctum Size, Cup to Disc Ratio 
and Intraocular Pressure 
Full Analysis Set  
Listing 16.2.4.3 
Pre-Treatment Perimetry 
All Randomized 
Subjects 
Listing 16.2.4.4 
Pre-Treatment Pachymetry 
All Randomized 
Subjects 
Listing 16.2.4.5 
Non-Ocular Medical History 
Safety Population 
Listing 16.2.4.6 
Ocular Medical History 
Safety Population 
Listing 16.2.4.7 
Prior and Concomitant Non-Ocular Medications 
Safety Population 
Listing 16.2.4.8 
Prior and Concomitant Ocular Medications 
Safety Population 
Listing 16.2.4.9 
Pregnancy Test Results 
Safety Population 
Listing 16.2.5.2 
Insertion of Intracanalicular Depot 
All Randomized 
Subjects 
Listing 16.2.5.3 
Investigator Intracanalicular Depot Visualization and Patency 
Check 
Safety Population 
Listing 16.2.5.4 
Removal of Intracanalicular Depot 
Safety Population 
Listing 16.2.6.1 
Intraocular Pressure 
Full Analysis Set  
Listing 16.2.6.2 
Ocular Complaints 
Safety Population 
Listing 16.2.8.1 
Ocular Adverse Events 
Safety Population 
Listing 16.2.8.2 
Serious Ocular Adverse Events 
Safety Population 
Listing 16.2.8.3 
Ocular Adverse Events Leading to Subject Withdrawal 
Safety Population 
Listing 16.2.8.4 
Non-Ocular Adverse Events 
Safety Population 
Listing 16.2.8.5 
Serious Non-Ocular Adverse Events 
Safety Population 
Listing 16.2.8.6 
Non-Ocular Adverse Events Leading to Subject Withdrawal 
Safety Population 
Listing 16.2.9.1 
Best Corrected Visual Acuity (logMAR Scale) 
Safety Population 
Listing 16.2.9.2 
Visual Acuity (logMAR) for Subjects Who Lost Three or More 
Lines 
Safety Population 
Listing 16.2.9.3 
Slit Lamp Biomicroscopy 
Safety Population 
Listing 16.2.9.4 
Dilated Fundus Examination and Cup to Disc Ratio 
Safety Population 


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Table Number 
Title 
Population 
Listing 16.2.9.5 
Punctum Examination Results 
Safety Population 
Listing 16.2.9.6 
Punctum Size at Insertion 
All Randomized 
Subjects 
Listing 16.2.9.7 
Slit Lamp Ocular Hyperemia and Ocular Comfort Assessment 
Safety Population 
25. Figures 
All figures will be produced as final for the interim analysis. 
Figure Number 
Title 
Population 
Figure 14.2.1 
Mean Primary Study Eye IOP by Time Point and Treatment 
(MCMC) 
Full Analysis Set  
Figure 14.2.2 
Mean Primary Study Eye IOP by Time Point and Treatment  
Per Protocol Population 
Figure 14.2.3 
Mean Change from Baseline in Primary Study Eye IOP by Time 
Point and Treatment (MCMC) 
Full Analysis Set  
Figure 14.2.4 
Mean Change from Baseline in Primary Study Eye IOP by Time 
Point and Treatment 
Per Protocol Population 
Figure 14.2.5 
Mean Difference in Primary Study Eye IOP by Time Point 
(MCMC) 
Full Analysis Set  
Figure 14.2.6 
Mean Difference in Primary Study Eye IOP by Time Point  
Per Protocol Population 
Figure 14.2.7 
Mean Primary Study Eye IOP by Time Point and Treatment 
(Observed Data) 
Full Analysis Set  
Figure 14.2.8 
Mean Change from Baseline in Primary Study Eye IOP by Time 
Point and Treatment (Observed Data) 
Full Analysis Set  
Figure 14.2.9 
Mean Difference in Primary Study Eye IOP by Time Point 
(Observed Data) 
Full Analysis Set  
 


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STATISTICAL ANALYSIS PLAN
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
Sponsor:
Ocular Therapeutix, Inc
34 Crosby Drive, Suite 105
Bedford, MA 01730 USA
Protocol Number:
OTX-16-002
Author:  
Elizabeth Kumm
Principal Biostatistician
Statistics & Data Corporation
Date:  
27 February 2019
Version: 
Version 2.0




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List of Abbreviations
AE
Adverse Event
ANCOVA
Analysis of Covariance
ATC
Anatomical Therapeutic Chemical Classification
BCVA
Best Corrected Visual Acuity
BOCF
Baseline Time-Consistent Observation Carried Forward
CI
Confidence intervals
C/D
Cup to Disc
CS
Clinically Significant
CSR
Clinical Study Report
dB
Decibel
DMP
Data Management Plan
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
ICH
International Conference on Harmonisation
IOP
Intraocular Pressure
ITT
Intent-to-Treat
LOCF
Last Observation Carried Forward
logMAR
Logarithm of the Minimum Angle of Resolution
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
NCS
Not Clinically Significant
OTX
Ocular Therapeutix, Inc
OTX-TP
Sustained Release Travoprost Intracanalicular Depot
PDF
Portable Document Format
PP
Per Protocol
PT
Preferred Term
PV
Placebo Vehicle Intracanalicular Depot
RTF
Rich Text Format
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SDC
Statistics and Data Corporation, Incorporated
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
WHO DDE
World Health Organization Drug Dictionary Enhanced


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Table of Contents 
1. 
Introduction ..............................................................................................................................7 
2. 
Study Objectives ......................................................................................................................7 
3. 
Study Variables........................................................................................................................7 
Primary Variable............................................................................................................................... 7 
Secondary Variables........................................................................................................................ 7 
Other Variables ................................................................................................................................ 7 
Safety Variables............................................................................................................................... 8 
Statistical Hypotheses...................................................................................................................... 8 
4. 
Study Design and Procedures .................................................................................................8 
General Study Design...................................................................................................................... 8 
Schedule of Visits and Assessments.............................................................................................10 
5. 
Study Treatments...................................................................................................................15 
Method of Assigning Subjects to Treatment Groups ..................................................................... 15 
Masking and Unmasking................................................................................................................ 16 
6. 
Sample Size and Power Considerations ...............................................................................16 
7. 
Data Preparation....................................................................................................................16 
8. 
Analysis Populations..............................................................................................................17 
Full Analysis Set............................................................................................................................. 17 
Per Protocol Population ................................................................................................................. 17 
Safety Population........................................................................................................................... 17 
9. 
General Statistical Considerations.........................................................................................18 
Unit of Analysis .............................................................................................................................. 18 
Missing Data and Imputation Methods .......................................................................................... 18 
Definition of Baseline ..................................................................................................................... 19 
Data Analysis Conventions ............................................................................................................ 19 
Adjustments for Multiplicity ............................................................................................................ 19 
Unscheduled Visits ........................................................................................................................ 20 
10. 
Disposition of Subjects...........................................................................................................20 
11. 
Demographic and Pretreatment Variables.............................................................................21 
Demographic Variables.................................................................................................................. 21 
Pretreatment Variables .................................................................................................................. 21 
Punctum Size Assessment Prior to Insertion................................................................................. 22 
12. 
Medical History and Concomitant Medications......................................................................22 
Medical History............................................................................................................................... 22 


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Concomitant Medications............................................................................................................... 22 
Dosing Compliance and Treatment Exposure............................................................................... 23 
Intracanalicular Depot Visualization by the Investigator ................................................................ 23 
Intracanalicular Depot Removal..................................................................................................... 23 
Number of Replacements .............................................................................................................. 23 
Treatment Exposure ...................................................................................................................... 24 
13. 
Efficacy Analyses...................................................................................................................24 
Primary Analysis ............................................................................................................................ 24 
Secondary Analysis ....................................................................................................................... 29 
Additional Analyses........................................................................................................................ 30 
13.1.1 
Additional Efficacy Analyses .......................................................................................30 
13.1.2 
Punctum Examination .................................................................................................30 
13.1.3 
Insertion Results and Ease of Insertion.......................................................................30 
13.1.4 
Ocular Complaints.......................................................................................................30 
Graphical Outputs .......................................................................................................................... 31 
14. 
Safety Analyses .....................................................................................................................31 
Ocular and Non-Ocular Adverse Events........................................................................................ 31 
Severity .......................................................................................................................................... 34 
Relationship to OTX-TP or PV....................................................................................................... 34 
Expected AEs................................................................................................................................. 35 
AE Summaries ............................................................................................................................... 35 
Best Corrected Visual Acuity (BCVA) ............................................................................................37 
Slit Lamp Biomicroscopy Examination........................................................................................... 37 
Dilated Fundoscopy Examination .................................................................................................. 38 
Ocular Hyperemia .......................................................................................................................... 38 
Ocular Comfort Assessment.......................................................................................................... 38 
Observed IOP Results ................................................................................................................... 39 
15. 
Interim Analyses ....................................................................................................................39 
16. 
Pharmacokinetic Analyses.....................................................................................................39 
17. 
Pharmacodynamic Analyses .................................................................................................39 
18. 
Quality of Life .........................................................................................................................39 
19. 
Changes from Protocol-Stated Analyses...............................................................................39 
20. 
References.............................................................................................................................40 
21. 
Revision History.....................................................................................................................40 
22. 
Tables ....................................................................................................................................42 
23. 
Listings...................................................................................................................................44 


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24. 
Figures ...................................................................................................................................45 


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1.
Introduction
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol OTX-16-002, Revision E dated 02May2017
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR).
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol. If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR.
2.
Study Objectives
The objective of this study is to evaluate the safety and intraocular pressure (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.
3.
Study Variables
Primary Variable
The primary efficacy variable is mean IOP at the following time points: 8AM, 10AM, and 4PM at the 2
Week, 6 Week, and 12 Week Visits.
Secondary Variables
The secondary efficacy variables include the following:
x
Mean change from baseline IOP at the following time points: 8AM, 10AM, and 4PM at the 2
Week, 6 Week, and 12 Week Visits.
x
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 Variables
Additional variables on which data will be collected include the following:
x
Ocular complaints
x
Visualization of intracanalicular depot by the Investigator at each time point
x
Ease of insertion of intracanalicular depot
x
Number of intracanalicular depots required in each eye for the 12 week period per subject.


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Safety Variables
The safety variables include the following:
x
BCVA
x
Slit lamp biomicroscopy
x
Assessment and grade of ocular hyperemia (at slit lamp)
x
Subject ocular comfort assessment
x
Dilated fundus exam
x
Adverse events
Statistical Hypotheses
The null and alternative hypotheses, based on the primary variables, are as follows:
x
H0: The difference between study eyes that received sustained release travoprost (OTX-TP)
and study eyes that received Placebo Vehicle (PV) (calculated as 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 
9LVLWVLVPP+JIRUDWOHDVWone time point over all visits.
x
H1: The difference between study eyes that received OTX-TP and study eyes that received PV 
(calculated as 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.
4.
Study Design and Procedures
General Study Design
This is a prospective, multicenter, randomized, parallel-arm, double masked, placebo vehicle controlled
Phase 3a 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 
intracanalicular depot (OTX-TP) or PV intracanalicular depot (PV), 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.
At the Baseline Visit 2/Insertion Visit, 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. If insertion 
is unsuccessful in the second 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 


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discretion for the eye that did not receive a depot. The subject 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 (490) who received a depot bilaterally are followed through the 12 Week Visit for efficacy and 
safety. If neither insertion is successful the End of Study eCRF will be completed for the subject and the 
subject will be exited from the study. Unsuccessful punctal dilation of either eye (if needed) or if the 
punctum of either eye is too small to allow transient dilation to 0.7 mm prior for insertion of OTX-TP or 
PV is considered a Procedural Exclusion Criterion and the subject will be exited as a screen failure.
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 be considered an efficacy failure and will be followed through the remainder of the study for 
safety. If still present, the intracanalicular depot will not be removed. IOP measurements taken through 
the remainder of the study will be excluded from the efficacy analyses.
For any subject, if at any point the intracanalicular depot is removed bilaterally by the Investigator for an 
adverse event or 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.
Intracanalicular depots that are removed due to subject withdrawal or an undesired reaction at any point 
in the study will not be replaced.
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 depot replacements will be tracked and documented on the appropriate
electronic Case Report Form (eCRF).
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. Depots replaced between the 6 Week Visit and the 12 Week Visit will not be 


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removed at the 12 Week Visit. The first attempt to remove these depots will be at the 20 Week Visit. 
The number of depot replacements will be tracked and documented on the appropriate eCRF.
12 Week Visit:
If the intracanalicular depot(s) is/are still present at the 12 Week Visit, the Investigator will attempt to 
remove the depot(s). 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 are 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 subject may be prescribed IOP-lowering drops if necessary at the 12 Week Visit at the 
Investigator’s discretion.
20 Week Visit:
At the 20 Week Visit, the Investigator will attempt removal of the 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.
The subject may be prescribed IOP-lowering drops if necessary at the 20 Week Visit at the Investigator’s 
discretion.
Schedule of Visits and Assessments
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. 


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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 
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
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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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
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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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
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
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.


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5.
Study Treatments
There are two study treatments, OTX-TP intracanalicular depot and PV intracanalicular depot, which 
are explained below.
OTX-TP 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 OTX-PV 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.
Placebo Vehicle Intracanalicular Depot
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.
Method of Assigning Subjects to Treatment Groups
Prior to the initiation of the study, a treatment randomization scheme will be generated using a 3:2 ratio 
(Active Treatment to Placebo Control) approximately 330 subjects in the OTX-TP arm and 220 in the 
PV arm. The study will be supplemented with additional subjects for whom bilateral depot insertion is 
successful in order to ensure that at least 490 subjects who receive a depot bilaterally are followed 
through the 12 Week Visit for safety and efficacy.
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 subject’s previous ocular anti-hypertensive therapy category. Both eyes will be 
provided with the same assigned treatment, OTX-TP or PV. Randomization will be stratified by 
investigational site (i.e., one randomization schema per study site) and previous ocular anti-hypertensive 
therapy with three stratum levels below:
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).
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).
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.


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A site may randomize up to a maximum of 55 subjects.
The randomization number will be an alpha-numeric code using the following scheme: RnnX-nnn with
R in the first place followed by the 2-digit site ID and one letter X corresponding to the stratum (A, B or 
C). Then a hyphen will separate the first alpha-numeric section and be followed by a three-digit number 
increasing in sequential order within each site and starting with 001.
Masking and Unmasking
The Investigator and the subject will be masked to the treatment assignment throughout the duration of 
therapy.
OTX-TP and the PV are identical in appearance, and will be supplied in identical packages so they 
cannot be distinguished by the user. If it is medically necessary to identify the product used, the 
Investigator will 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.
6.
Sample Size and Power Considerations
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.
7.
Data Preparation
All reported study data will be recorded on eCRFs using the iMedNet electronic data capture (EDC) 
system. All authorized personnel will have access to the EDC system; however, only the site study 
personnel assigned to have the role of a Research Coordinator will have data entry user rights.
Ocular Therapeutix (OTX) is responsible for validating the OTX-16-002 study database, maintaining the 
study data, and cleaning and reviewing the data prior to database lock. OTX data management will 
prepare the edit check specifications document as well as the Business Logic Documents for review 
and approval. These documents are maintained in the trial master file. After data are entered into the 
clinical study database, electronic edit checks and data review will be performed. When the database 
has been declared to be complete, the following activities will take place to prepare for database lock:
x
All clinical data are entered, source verified, and approved in the clinical database


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x
All discrepancies are resolved and applied to the database
x
Dictionary coding (by SDC) is complete and Final AE Coding Approval Form is signed
x
SAE reconciliation is complete
x
Any DMP amendments are signed by the appropriate team members
Additionally, for the final database lock and analysis, all analyses outlined in this document will be 
carried out only after the following have occurred:
x
Protocol deviations have been identified and status defined (major/important vs minor 
deviations)
x
Analysis populations have been determined
x
Randomized treatment codes have been unmasked
In the event that the database must be unlocked, unlocking procedures fall under OTX processes and 
operating procedures.
8.
Analysis Populations
Subjects will be considered enrolled once they have signed informed consent. Once randomized and 
treated, subjects will fall into at least one of the following analysis populations.
Full Analysis Set
The Full Analysis Set (FAS) population will include all randomized subjects with depots inserted in both 
eyes. Analysis on the data for the primary study eye in the FAS 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 Population
The Per Protocol (PP) population will include all FAS 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 the database lock. The primary efficacy analysis will be conducted using the PP population as a 
sensitivity analysis of the primary outcome.
Safety Population
The Safety population will include all subjects who received any investigational study treatment (OTX-
TP or PV). Analyses performed on the Safety population will be according to the treatment the subjects 
actually received. All safety analyses will be based on the Safety population.


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9.
General Statistical Considerations
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 and treated, 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, treated, 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. If both eyes are eligible but only one eye receives a depot, the 
eye with the depot inserted will be considered the primary study eye (for safety evaluations), and no 
secondary eye will be designated for this subject.
Ocular adverse events will be presented at the eye and subject level and non-ocular adverse events will 
be presented at the subject level.
Missing Data and Imputation Methods
The primary analyses of efficacy data (IOP) will employ multiple imputation (MI) methods using the 
Markov Chain Monte Carlo (MCMC) approach to impute missing data and using the 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 as rescue therapy.
Sensitivity analyses, to determine robustness of results, will be performed using the MCMC approach 
to impute non-monotone missing information and pattern mixture models control-based pattern 
imputation for monotone missing information (including data for subjects who drop out prior to the 12 
Week Visit 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, baseline time-consistent observation carried forward (BOCF) to impute both missing 
data and data after a subject’s primary study eye is prescribed IOP-lowering drops and using observed 
data only (excluding data after a subject’s primary study eye is prescribed IOP-lowering drops as rescue 
therapy). Additionally, sensitivity analyses will be performed on the PP population using observed data 
only (excluding data after a subject’s primary study eye is prescribed IOP-lowering drops as rescue 
therapy).
For time-consistent imputations, IOP values missing at an 8AM time point will only be imputed with the 
IOP value from a previous 8AM time point (last or baseline). Imputations at 10AM and 4PM will be 
performed similarly.


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Definition of Baseline
For IOP, the baseline measure will be defined as the last non-missing time-consistent measure prior to 
initiation of investigational treatment and after washout of previous IOP medication. In most cases this 
will be the measure of IOP at Baseline Visit 2. For all other variables, baseline will be defined as the last 
non-missing measure prior to initiation of investigational treatment. Change from baseline will be 
calculated as follow-up visit – baseline visit.
Data Analysis Conventions
All data analysis will be performed by SDC after the study is completed and the database has been 
locked. Statistical programming and analyses will be performed using SAS® Version 9.4 or higher.  
Output will be provided in RTF format for tables and PDF format for tables, listings, and figures using 
landscape orientation. All study data will be listed by subject, actual treatment, and visit (as applicable)
based on all randomized subjects unless otherwise specified.
Summaries for continuous and ordinal variables will include the number of observations (n), arithmetic 
mean, standard deviation (SD), median, minimum, and maximum. Minima and maxima will be reported 
with the same precision as the raw values; means, standard deviations and medians will be presented 
to one additional decimal place than reported in the raw values. (Height and weight which are collected 
in inches and pounds are converted to metric units and presented with 2 decimal places.) Summaries 
for discrete variables will include frequency counts 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.
All statistical tests will be two-VLGHGZLWKDVLJQLILFDQFHOHYHORIĮ  unless otherwise specified.
Confidence intervals (CI) for differences between treatment groups will be two-sided at 95% confidence. 
All p-values will be rounded to four decimal places; p-values less than 0.0001 will be presented as 
“< 0.0001”; p-values greater than 0.9999 will be presented as “> 0.9999”.
All efficacy summaries will be presented for the primary study eye. Additional efficacy analyses will be 
reported for secondary study eyes. Ocular AEs will be summarized at the eye level for any treated eye 
and subject level, and non-ocular AEs by subject level. All other safety variables will be assessed by 
primary study eye and secondary study eye, separately.
Adjustments for Multiplicity
In order to maintain the overall Type I error for the primary analyses, all 9 time points must show 
statistical significance for the study to be successful: 8AM, 10AM, and 4PM at the 2 Week, 6 Week, and 
12 Week Visits. No other adjustments for multiplicity are necessary as there are no other sources of 
multiplicity for the primary analyses.


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Unscheduled Visits
For Unscheduled Visits, the reason for the visit should be clearly documented on the appropriate eCRF, 
including findings from all evaluations that are completed.
Data from unscheduled visits up to the 12 Week Visit will be integrated into subject listings and summary 
tables. All unscheduled data is presented in listings. Tables will incorporate unscheduled data according 
to the following rules. If unscheduled data is available within window of a scheduled Visit with missing 
data, the unscheduled data will be used. If scheduled Visit data is not missing, unscheduled data will 
not be used. If more than one set of unscheduled data falls within a window for an efficacy assessment, 
the earliest unscheduled visit in that visit window will be used. If more than one set of unscheduled data 
falls within a window for a safety assessment, the worst case observation will be used. “Within window” 
is calculated based on Visit name rather than Visit date.
10. Disposition of Subjects
Subject disposition of all enrolled subjects will be presented in terms of the numbers and percentages 
of subjects who were screened, screened but not randomized, randomized, completed the study, 
discontinued from the study and/or experienced protocol deviations. Number of subjects exiting the 
study prior to Week 12, at Week 12, at Week 20 and beyond Week 20 will also be summarized. Subjects
who are not discontinued from the study will be considered study completers. Disposition will be 
summarized by treatment group and for all subjects. Reasons for subject discontinuation at various 
decision time points will be summarized.
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 but will be entered 
in the EDC system with the reason for screen failure delineated. The total number of screened subjects 
with the number and percentage of screen failure subjects will be presented. The reasons for screen 
failure will be displayed with the percentages calculated using total number of screen failures as the 
denominator.
The number of subjects in each of the analysis populations (FAS, PP and Safety) will be displayed by 
treatment and percentages will be calculated using randomized subjects as the denominator. A subject 
listing of analysis populations will be provided including reasons for exclusion from the PP and/or Safety 
populations. In addition, a subject listing of stratum assignment, randomization, including site records of 
whether randomization and kit choice were correct, and a listing of all subject visit dates, including 
reasons for unscheduled visits, will be provided.
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
group for all randomized subjects. The protocol deviations will be summarized by deviation codes.


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A subject listing will be provided that includes the date of the deviation, the deviation description and the 
classification of whether the deviation was judged to be major or minor.
In addition, subject listings will be provided that include informed consent date, and inclusion and 
exclusion criteria violations. Procedural exclusion criteria will be presented in the same listing as study 
inclusion and exclusion criteria.
11. Demographic and Pretreatment Variables
Demographic Variables
The demographic variables collected at Screening in this study include date of birth, sex, race, ethnicity, 
height, weight and iris color. Subjects who record more than one race will be grouped into a single 
category denoted as multi-racial. Demographic variables will be summarized for the FAS population.
Age at informed consent (years), height, weight and BMI will be summarized, overall and by treatment, 
using continuous descriptive statistics. Age will also be categorized as follows:  < \HDUVDQG 65
years. Age will be reported in years and calculated using the following formula:
Age = (informed consent date – date of birth) / 365.25 truncated as an integer
BMI is calculated in the database.
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
sex, race, ethnicity and iris color.
A subject listing that includes all demographic variables will be provided. Note that iris color will be 
reassessed at the 12 Week Visit (or the Early Termination Visit if subject discontinues the study prior to 
the 12 Week Visit) and these results will be listed along with a flag indicating any changes from baseline.
Pretreatment Variables
Female subjects of child-bearing potential will have urine pregnancy test at the Screening Visit.  A
subject listing of child-bearing status and pregnancy test results will be provided.
Summary statistics will be provided for the baseline characteristic variables, which include mean IOP
for both the primary study eye and the secondary study eye at screening (pre-washout) and at Baseline 
Visit 2, mean deviation in visual fields (dB), central corneal thickneVVȝPDQGFXSWRGLVFUDWLRCounts 
and frequencies for current diagnosis of OHT or OAG, and gonioscopy results (including the following 
categories: Grade 4 [45° to 35° angle wide open], Grade 3 [35° to 20° angle wide open], Grade 2 [20° 
DQJOHQDUURZ@*UDGH>DQJOHH[WUHPHO\QDUURZ@DQG6OLW>DQJOHQDUURZHGWRVOLW@ will also be 
provided.
A subject listing that includes all pretreatment variables will be provided.


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Punctum Size Assessment Prior to Insertion
Punctum size will also be assessed prior to insertion of the depot. At the 4PM time point on Baseline 
Visit 2 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. Punctum size, both prior to and after dilation, will be recorded and provided in a 
subject listing.
12. Medical History and Concomitant Medications
Medical History
Medical history will be collected at the Screening Visit and coded using MedDRA 20.0.
Non-ocular and ocular medical history will be summarized for the Safety Population using discrete 
summary statistics and presented by treatment group at the subject level by System Organ Class (SOC) 
and Preferred Term (PT). If a subject reports the same PT multiple times within the same SOC, that PT 
will only be reported once within that SOC. As with PT, if a subject reports multiple conditions within the 
same SOC, that SOC will only be reported once.
Listings of medical history will be generated separately for ocular and non-ocular data.
Concomitant Medications
Starting at the Screening Visit through the end of the study, 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. 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.
Concomitant medications will be coded using the World Health Organization Drug Dictionary Enhanced
(WHO DDE) March 2017 and summarized to the therapeutic drug class (Anatomical Therapeutic 
Chemical (ATC) 4 classification) and preferred name (generic drug name).
Concomitant medications are defined as those medications listed as having been taken 1) prior to
initiation of study drug administration and continuing for any period of time following the first 
administration of study drug or 2) at any time following the first administration of study drug.


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Ocular and non-ocular concomitant medications will be summarized using the Safety Population.
Medications will be tabulated for each treatment group using frequencies and percentages. At each level 
of subject summarization, a subject will be counted once if he/she reports 1 or more medications. 
Percentages will be based on the number of subjects in each treatment group. Listings of concomitant 
medications will be generated separately for ocular and non-ocular data. Additionally, a table 
summarizing the subset of IOP-lowering medications used in the primary study eye and a summary 
table of IOP-lowering medication used in the primary study eye by visit will be produced, as well as a 
listing of FAS subjects with IOP-lowering medications with start dates after Baseline Visit 2 and prior to 
12 Week Visit. IOP-lowering medications (rescue medications) are determined by the eCRF indication 
“Lack of IOP control” in the primary study eye.
Dosing Compliance and Treatment Exposure
Dosing compliance and treatment exposure will be assessed using visualization of the intracanalicular
depot by the investigator, intracanalicular depot removal and the number of intracanalicular depots 
required in each eye for the 12 week period per subject. These analyses will be performed on the Safety 
Population. No statistical inference testing will be performed.
Intracanalicular Depot Visualization by the Investigator
The intracanalicular depot will be assessed for presence and ease of visualization at the time of insertion 
time point as well as the 8AM time point at each post-baseline visit. The number of subjects with a 
intracanalicular depot present will be summarized by visit and treatment, and this number will be used 
as the denominator for the ease of visualization responses. Ease of visualization will be recorded as 
Easy, Moderate, or Difficult by the investigator. Responses will be summarized by count and percentage 
at each visit by treatment group. A subject listing, reported separately by right and left eyes, will also 
be provided.
Intracanalicular Depot Removal
When an intracanalicular depot is removed the reason for removal (removed per protocol, AE, other), 
the success of the removal (yes vs no), the ease of removal (easy, moderate, difficult) and the method 
of removal (saline irrigation, application of manual pressure) will be recorded. The responses will be 
summarized by count and percentage at each visit by treatment group. A subject listing, reported 
separately by right and left eyes, will also be provided.
Number of Replacements
The number of intracanalicular depots required in each eye for the 12 week period per subject will be 
reported and listed. For subjects with confirmed depots beyond 12 weeks, summaries will also be 
provided indicating the length of the depot being present in the canaliculus and the number of depots 
required and the number of patency checks performed.


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Treatment Exposure
Extent of treatment exposure for completed or discontinued subjects will be calculated in days using 
the following:
Total Exposure (days) = 
(Date of last investigator visualization of a depot in either eye [that is not subsequently replaced] –
Date of first insertion of a depot in either eye) + 1
Date of first insertion of depot in either eye will in most cases be Baseline Visit 2 [Day 1].  Extent of 
treatment exposure for subjects who were lost to follow-up will be calculated in days using the 
following:
Total Exposure (days) = (Date of last recorded visit – Date of first insertion of a depot in either eye) + 1
Total treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group and for all subjects, using the Safety 
population. A subject listing of treatment exposure will also be produced.
13. Efficacy Analyses
Primary Analysis
The primary analysis of the primary efficacy outcome will employ a linear model of IOP in the primary
study eye of subjects in the FAS. The response variable will be IOP at the given visit (2 Week, 6 Week, 
and 12 Week) and time point (8AM, 10AM, and 4PM), time point specific baseline IOP will be used as 
a covariate, and treatment will be the main effect factor. Each time point within each visit will be modeled 
separately.
IOP refers to the single result from the following procedure. IOP will be assessed by two qualified 
independent study site personnel at each visit and time point using a Goldmann applanation tonometer 
affixed to a slit lamp with the subject seated. 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. Averages of readings are calculated within the clinical database.
For the primary analysis, MI methods will use the MCMC approach for any data missing from these 
visits/time points, after LOCF has been used to impute data for time points after the subject’s primary 
study eye is prescribed IOP-lowering drops. Example MCMC imputation code which will be implemented  
after LOCF has been applied (SAS® version 9.4) is shown here:
PROC MI DATA = indata SEED = 7436892 OUT = outdata NIMPUTE=20;
BY TMPTN;
MCMC INITIAL = EM;
VAR trt baseline WV2 WV4 WV6 WV8 WV10 WV12;


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RUN;
where
- indata is the name of the input dataset;
- outdata is the name of the output dataset;
- nimpute is the number of imputations;
- tmptn is the time point of assessment, 8AM, 10AM, or 4PM;
- trt is the name of the treatment group variable in numeric format;
- baseline is the average IOP at baseline
- WV2 is the IOP value for the 2 Week visit;
- WV4 is the IOP value for the 4 Week visit;
- WV6 is the IOP value for the 6 Week visit;
- WV8 is the IOP value for the 8 Week visit;
- WV10 is the IOP value for the 10 Week visit;
- WV12 is the IOP value for the 12 Week visit.
Twenty complete data sets for each time point will be generated from the above code. The data will be 
transposed to have a vertical structure with one record per subject, imputation, visit, and time point. 
Each complete data set will be used to compute the mean IOP and analyze using the linear model with 
time point specific baseline IOP used as a covariate, and treatment as the main effect factor. A separate 
model will be fit for each visit/time point combination. Then, the SAS® procedure MIANALYZE will be 
used to analyze the results from the 20 complete data sets to generate a combined inference. The 
following SAS® code will be used:
ODS OUTPUT LSMEANS = outdataB;
PROC MIXED DATA = outdataA;
CLASS trt;
MODEL IOP = trt baseline;
BY visitn tmptn _IMPUTATION_;
LSMEANS trt/PDIFF CL;
RUN;
where
- IOP is the IOP for each visit and time point;
- visitn is the visit number variable in numeric format;
- tmptn is the time point variable in numeric format;
- baseline is the average IOP at baseline, matched by time point;
- trt is the name of the treatment group variable in numeric format;
- outdataA is the transposed dataset containing the 20 “complete” datasets from the imputation.


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ODS OUTPUT PARAMETERESTIMATES = outdataC;
PROC MIANALYZE DATA = outdataB;
MODELEFFECTS ESTIMATE;
STDERR STDERR;
BY visitn tmptn;
RUN;
where
- outdataB is the name of the output dataset that contains the statistical results of the difference 
between treatment groups from the MIXED procedure that is run on each of the twenty
imputation datasets;
- outdataC is the name of the output dataset that contains all the information needed for the 
table.
After imputation the least squares mean differences (OTX-TP minus 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.
Two-sample t-test p-values and two-sided 95% CI’s will also be computed around the difference (OTX-
TP minus PV) in IOP between treatment groups at each time point and visit for the primary analysis data 
(FAS employing MI methods using MCMC 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). The 
following SAS® code will be used for the t-test:
ODS OUTPUT STATISTICS = outdataB;
PROC TTEST DATA = outdataA;
CLASS trt;
VAR IOP;
BY visitn tmptn _Imputation_;
RUN;
- IOP is the IOP for each visit and time point;
- visitn is the visit number variable in numeric format;
- tmptn is the time point variable in numeric format;
- baseline is the average IOP at baseline, matched by time point;
- trt is the name of the treatment group variable in numeric format;
- outdataA is the transposed dataset containing the 20 “complete” datasets from the imputation.


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Then, as with the PROC MIXED results, the SAS® procedure MIANALYZE will be used to analyze the 
results from the 20 complete data sets to generate a combined inference.
ODS OUTPUT PARAMETERESTIMATES = outdataC;
PROC MIANALYZE DATA = outdataB;
MODELEFFECTS ESTIMATE;
STDERR STDERR;
BY visitn tmptn;
RUN;
where
- outdataB is the name of the output dataset that contains the statistical results of the difference 
between treatment groups from the MIXED procedure that is run on each of the twenty
imputation datasets;
- outdataC is the name of the output dataset that contains all the information needed for the 
table.
Sensitivity analyses for the primary efficacy endpoint include both linear models of IOP and 2-sample t-
tests presented on the FAS population using (1) MI approach using MCMC to impute non-monotone 
missing information and a pattern mixture model control-based pattern imputation for monotone missing 
information to impute both missing data and data after a subject’s primary study eye is prescribed IOP-
lowering drops as rescue therapy, (2) using LOCF to impute both missing data and data after a subject’s 
primary study eye is prescribed IOP-lowering drops as rescue therapy, (3) using BOCF to impute both 
missing data and data after a subject’s primary study eye is prescribed IOP-lowering drops as rescue 
therapy, and these analyses using observed data only (excluding data after a primary study eye is 
prescribed rescue therapy) for the (4) FAS and (5) per protocol populations.
For multiple imputations using a control-based pattern-mixture model, a process will be used that is
similar to multiple imputations using MCMC. Twenty “complete” (imputed) datasets will be produced and 
analyzed. Results from the analyses on the twenty “complete” datasets will be combined for presentation 
through the use of SAS® PROC MIANALYZE. Time point specific baseline IOP will be used as a 
covariate, and treatment will be the main effect factor. A separate model will be fit for each visit/time 
point combination. Monotone missing information refers to data missing from any visits beyond a 
subject’s final visit (at which IOP is assessed) up to and including the 12 Week Visit. Non-monotone 
missing information refers to data from missed visits between any two visits at which IOP is assessed. 
First LOCF will be used to impute data for time points after a subject’s primary study eye is prescribed 
IOP-lowering drops. Then MCMC will be employed to impute any non-monotone missing information
using the code:
PROC MI DATA = indata SEED = 3335891 OUT = mondata NIMPUTE=1;
BY TMPTN;


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MCMC INITIAL = EM IMPUTE = MONOTONE;
VAR trt baseline WV2 WV4 WV6 WV8 WV10 WV12;
RUN;
where
- indata is the name of the input dataset;
- mondata is the name of the output dataset;
- nimpute is the number of imputations;
- trt is the name of the treatment group variable in numeric format;
- baseline is the average IOP at baseline;
- WV2 is the IOP value for the 2 Week visit;
- WV4 is the IOP value for the 4 Week visit;
- WV6 is the IOP value for the 6 Week visit;
- WV8 is the IOP value for the 8 Week visit;
- WV10 is the IOP value for the 10 Week visit;
- WV12 is the IOP value for the 12 Week visit.
Then the following SAS® code will be used to produce twenty “complete” datasets for each time point,
imputing monotone missing data using a control-based pattern mixture model:
PROC MI DATA = mondata SEED = 48670 NIMPUTE = 20 OUT = outdata
MINIMUM = .  .  0 MAXIMUM =.  .  70 ROUND = .  .  0.25;
BY visitn tmptn;
CLASS trt;
MONOTONE REG(WV2_8 WV4_8 WV6_8 WV8_8 WV10_8 WV12_8 = baseline /
details);
MNAR model(WV2_8 WV4_8 WV6_8 WV8_8 WV10_8 WV12_8/ MODELOBS =
(TREATMENT=”2”));
VAR trt baseline WV2_8 WV4_8 WV6_8 WV8_8 WV10_8 WV12_8;
RUN;
After obtaining twenty complete datasets, the data from the two MI procedures will be combined and will 
then be transposed to have a vertical structure with one record per subject, imputation, visit, and time 
point. SAS® code similar to what is previously described for multiple imputations in the primary analysis
will then be employed to run the model on each dataset and combine results across imputations.
In the case that there is no missing data for a given visit and time point, observed data will be analyzed.
Analyses on observed data and without MI methods will use the following statistical models:
ODS OUTPUT LSMEANS = outdata;
PROC MIXED DATA = indata;


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CLASS trt;
MODEL IOP=trt baseline;
BY visitn tmptn
LSMEANS trt/PDIFF CL;
RUN;
where
- IOP is the IOP for each visit and time point;
- visitn is the visit number variable in numeric format;
- tmptn is the time point variable in numeric format;
- baseline is the average IOP at baseline, matched by time point;
- trt is the name of the treatment group variable in numeric format;
- indata is the dataset containing only observed data.
and
ODS OUTPUT STATISTICS = outdata;
PROC TTEST DATA = indata;
CLASS trt;
VAR IOP;
BY visitn tmptn;
RUN;
- IOP is the IOP for each visit and time point;
- visitn is the visit number variable in numeric format;
- tmptn is the time point variable in numeric format;
- baseline is the average IOP at baseline, matched by time point;
- trt is the name of the treatment group variable in numeric format;
- indata is the dataset containing only observed data.
Secondary Analysis
Mean change from baseline IOP and mean percent change from baseline IOP will be analyzed similarly 
to the primary endpoint analysis, including all sensitivity analyses. (If a subject is missing a baseline IOP 
value, or if Baseline Visit 2: 4PM IOP is measured after insertion, change from baseline and percent 
change from baseline are not calculated.) As described above, these analyses involve linear models of 
the response variables on the FAS population using various combinations of imputation methods [(a) 
MCMC for missing data, LOCF for timepoints after rescue therapy has been initiated; (b) MCMC for non-
monotone missing, pattern mixture models for monotone missing; (c) LOCF for both missing and 
“rescue” time points; and (d) BOCF for both missing and “rescue” time points] as well as inference on 
observed data confined to the FAS and Per Protocol populations.


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Additional Analyses
13.1.1
ADDITIONAL EFFICACY ANALYSES
IOP measures, mean change from baseline, and mean percent change from baseline IOP measures 
from non-primary visits (4 Week, 8 Week, 10 Week Visits) will be also analyzed similarly to the primary 
endpoint analysis.
Additionally, to further understand efficacy within each previous ocular anti-hypertensive therapy 
category, the primary analysis strategy (linear model of IOP Markov Chain Monte Carlo (MCMC) 
approach to impute missing data and using the 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 as 
rescue therapy) will be completed separately for the subgroups (i.e. stratum) of subjects within each 
previous ocular anti-hypertensive therapy category. The FAS will be used for these subgroup analyses.
All analyses will be presented in summary tables by treatment group. Subject level listings will also show 
IOP by treatment, time point and visit where appropriate.
13.1.2
PUNCTUM EXAMINATION
At Screening, prior to insertion at Baseline Visit 2, and at the 8AM time point of each subsequent post-
baseline visit investigators will assess punctal appearance, lid apposition, tear meniscus recording 
results as normal, abnormal NCS or abnormal CS for each eye. The responses will be summarized by 
count and percentage at each visit by treatment group and for all subjects. Shifts from Baseline to the 
evaluation visit will also be presented as frequencies and percentages. A subject listing, reported 
separately by right and left eyes, will also be provided.
13.1.3
INSERTION RESULTS AND EASE OF INSERTION
The results of insertion will be summarized for insertion location (superior vs inferior punctum), success 
of insertion (yes vs no), ease of insertion (easy, moderate, difficult), the number of packages opened, 
number of depots used to attempt insertion in each eye and the reason(s) depots were not utilized 
(swelling of depot prior to insertion, depot not present in foam package, depot dropped prior to insertion, 
failed insertion in initial punctum, or other). Product malfunctions during the insertion will also be 
recorded. Summaries based on the Safety Population will be presented for Baseline Visit 2 and any 
Replacement or Re-insertion visits, and Replacement/Re-insertion visits within the initial 12 Week period 
by treatment group and overall. Summaries will be separated by primary and secondary study eyes. A 
subject listing, reported separately by primary and secondary study eyes, will also be provided.
13.1.4
OCULAR COMPLAINTS
In order to assess tolerability, ocular complaints are evaluated after insertion at Baseline Visit 2, and at 
the 8AM time point of each subsequent post-baseline visit. Complaint categories include Excessive 
Tearing, Foreign Body Sensation, Itching, Stinging/Burning, and Other Ocular Complaints. Within each 


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category, a subject is required to answer yes or no as to whether the issue occurred, and the investigator 
responds as to whether or not the issue was within clinical expectations as well as whether or not any 
action was taken.
Counts and percentages of study eyes and subjects experiencing each complaint category will be 
summarized by visit and treatment group using the number of assessments performed within each 
treatment group as the denominator. For expectedness and actions, counts and frequencies of yes and 
no responses will also be summarized, using the number of subjects having the complaint category as
the denominator. Summaries at the study eye level will be split up by primary and secondary study eyes. 
For subject level summaries, the worse result between the two eyes will be summarized (ie, a response 
of yes to the ocular complaint). A subject listing, reported separately by primary and secondary study 
eyes, will also be provided.
Graphical Outputs
In addition to the tabular output, graphs will be provided of the mean (averaged over subjects) and 
standard error of IOP values for the primary study eye and changes from baseline values by treatment,
visit and time point in the FAS with imputed data per the primary endpoint imputation strategy. In 
addition, figures will be created showing the difference between OTX-TP and PV mean IOP values along 
with their 95% CIs for each visit and time point using the FAS with imputed data per the primary endpoint 
imputation strategy and for observed data. Reference lines will be included at ±1 mmHg and ±1.5 mmHg.
Figures using observed data for the PP population will also be presented.
14. Safety Analyses
Ocular and Non-Ocular Adverse Events
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.
Documentation regarding the adverse event will 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. All AEs will be 
coded using the MedDRA version 16.1.
AEs will be reported from the point subjects sign informed consent. The AE and treatment emergent 
adverse event (TEAE) reporting period ends upon study exit for new AEs. Existing AEs and TEAEs will 
be followed until:
x
Resolution (return to baseline status or to ‘normal’)


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o
AEs may be determined to have resolved (completely) or resolved with sequelae.
x
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.
x
Stabilization of the event has occurred (no worsening expected by the investigator)
Adverse Event (or Adverse Experience, AE)
An AE 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 AE 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 TEAOE)
An adverse ocular event will be considered a treatment emergent AE if it occurs or worsens (based on 
severity: mild, moderate or severe) on or after the initiation of the intracanalicular depot insertion.
Treatment Emergent Adverse Event (or TEAE)
Treatment-emergent adverse events (TEAEs) are defined as any event that occurs or worsens on or 
after the initiation of the intracanalicular depot insertion, whether ocular or non-ocular in nature. Adverse 
events recorded in the eCRF which began prior to treatment will not be included in the summary tables 
but will be included in the AE data listings.
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.
Anticipated (as specified in the protocol) adverse ocular events that may be associated with OTX-TP or 
PV include, but are not necessarily limited to:


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x
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
x
Prostaglandin Associated Orbitopathy
x
Iris discoloration
x
Blepharitis
x
Worsening in BCVA deILQHGDVOLQHVOHWWHUV
x
Subconjunctival hemorrhage
x
Cataract
x
Macular edema
x
Conjunctivitis
x
Keratitis
x
Perforation of or trauma to the punctum and/or surrounding tissues
x
Allergic reaction
x
Chemosis
x
Inflammatory reaction
x
Epiphora, defined as clinically significant excessive tearing outside of normal limits
x
Dacryocystitis
x
Tearing with mucopurulent discharge
x
Stenosis of the punctum
x
Infection*
*Note: In the unlikely event of infection, the organism will be identified.
Serious Adverse Event (Serious Adverse Experience)
A serious adverse event (SAE) (experience) or reaction is any untoward medical occurrence that:
x
results in death
x
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.)
x
requires inpatient hospitalization or prolongation of existing hospitalization
x
results in persistent or significant disability/incapacity
x
is a congenital anomaly/birth defect
x
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 


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one of the other outcomes listed in the definition above. These should also usually be considered 
serious.
Severity
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an AE as 
determined by the Investigator or reported to him/her by the 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.1
1The 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.)
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 AE 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 AE 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.


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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 AE. “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the study drug and the AE. 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.
For TEAEs not suspected to be related to study product, a most likely cause will be selected from the 
following categories: Concomitant Medication(s), Pre-existing Condition(s), Insertion Process, Other.
Expected AEs
The expectedness of an AE should be determined based upon existing safety information about the 
study drug using these explanations:
x
Unexpected:
An AE 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.
x
Expected:
An AE that is listed in the Investigator’s brochure at the specificity and severity 
that has been observed.
AEs 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.
The Investigator should initially classify the expectedness of an adverse event, but the final classification 
is subject to the Medical Monitor’s determination.
AE Summaries
All AEs and TEAEs will be coded using MedDRA 20.0.  AEs will be summarized in listings and tables 
for overall and ocular TEAEs by treatment group.


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An overall summary will be presented that includes the number of AEs, TEAEs and the number and 
percentage of subjects who experienced at least one AE or TEAE, by treatment group and for all 
subjects. This summary will also include breakdowns of TEAEs further categorized as ocular (primary 
study eye and secondary study eye separately) or non-ocular, serious AEs (SAEs), ocular TEAEs by 
maximum severity, non-ocular TEAEs by maximum severity, related TEAEs, TEAEs leading to subject 
withdrawal , and deaths.
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE and will be presented by SOC and PT. Non-ocular TEAEs will be 
summarized using discrete summary statistics and presented by treatment group at the subject and 
event level by SOC and PT. Ocular TEAEs will be similarly summarized at the subject level for both 
eyes and for primary study and secondary study eyes separately. If a subject reports the same PT 
multiple times within the same SOC, that PT will only be reported once within that SOC. As with the PT, 
if a subject reports multiple conditions within the same SOC, that SOC will only be reported once. In the 
summary, SOC will be listed in ascending alphabetical order; PTs will be listed in order of descending 
frequency for all subjects within each SOC.
Separate summaries will be provided for the following categories of AEs:
x
Ocular TEAEs in the primary study eye
x
Ocular TEAEs in the secondary study eye
x
Non-ocular TEAEs
x
Expected TEAEs
x
Unexpected TEAEs
x
Treatment related ocular TEAEs
x
Treatment related non-ocular TEAEs
x
Serious AEs
x
TEAEs by Maximum Severity
x
Non-related TEAEs by Most Likely Cause
x
Non-related SAEs by Most Likely Cause
x
Ocular TEAEs of Special Interest
The following Preferred Terms are considered TEAEs of Special Interest:
x
Conjunctival hyperaemia
x
Ocular hyperaemia
x
Iritis
x
Cystoid macular oedema
x
Eye colour change


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x
Madarosis
x
Eyelash discolouration
x
Eyelash hyperpigmentation
x
Eyelash injury
x
Growth of eyelashes
All TEAEs, SAEs and TEAEs leading to subject withdrawal from the study will be presented in subject 
listings separately for ocular and non-ocular events.
Best Corrected Visual Acuity (BCVA)
The logarithm of the minimum angle of resolution (logMAR) visual acuity is assessed at each visit using 
an EDTRS chart at a viewing distance of 4 meters. 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. Subjects are required to read the chart from the top to the bottom until 2 letters are misread on 
the line. 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, then 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 the ability to count fingers or see hand motion or light perception as appropriate.
BCVA will be measured at screening, at 8AM on Baseline Visit 2 and as well as the 8AM time point at 
each post-baseline visit. The baseline measurement will be the last assessment prior to insertion of the 
depot.
The observed and change from baseline BCVA will be summarized for the primary study eye and 
secondary study eye using continuous descriptive statistics by visit for each treatment group and for all 
actively treated subjects. Additionally, discrete summaries of the worst change from baseline will be 
presented for both the primary study eye and the secondary study eye with the following groupings 
based on the logMAR scores: 0 or less, >0 to +0.09, +0.10 to +0.19, +0.20 to 0.29, +0.30 or more.
Visual acuity scores will also be presented in data listings. Subjects who lost three or more lines 
(equivalent to change from baseline of 0.30 logMAR or more) will be presented in an additional listing.
This additional listing will also include subjects for whom vision worsened to the extent that the subject’s 
vision is measured by finger count, hand motion or light perception.
Slit Lamp Biomicroscopy Examination
A slit lamp biomicroscopy examination of the eyelid, conjunctiva, iris, cornea, anterior chamber, lens, 
and vitreous will be performed at each visit (except the Run-in Visits for Stratum B subjects) at the 8AM 
time point. The results will be graded as normal, abnormal NCS or abnormal CS.


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The results will be summarized using counts and percentages for each treatment group and for all 
actively treated subjects at each visit for each eye (primary study eye and secondary study eye). 
Percentages will be based on the number of subjects in each treatment group with responses. Shift 
tables for the slit lamp biomicroscopy parameters will also be provided comparing each follow-up visit 
to baseline. A subject listing of the slit lamp biomicroscopy parameters will also be produced.
Dilated Fundoscopy Examination
A dilated fundoscopy examination of the macula, peripheral retina, and optic nerve will be performed at 
Screening, and the 12 Week Visit. The results will be graded as normal, abnormal NCS or abnormal 
CS. The cup to disc (C/D) ratio will also be measured. Explanation/comment should be provided on the 
case report form for any abnormal findings.
The results will be summarized using counts and percentages for each treatment group and for all 
actively treated subjects at each visit for each eye (primary study eye and secondary study eye). 
Percentages will be based on the number of subjects in each treatment group with responses.  For the 
cup to disc ratio, a continuous summary, including change from baseline, will be provided for each eye. 
Shift tables for the dilated fundoscopy parameters will also be provided comparing the 12 Week Visit
results for each subject to the Screening results. A subject listing of the dilated fundoscopy parameters 
(including C/D ratio) will also be produced.
Ocular Hyperemia
Ocular hyperemia will be graded every visit at 8AM (except the 1st baseline measurement, Visit 1) on 
the following scale: 0 (None), 1 (Mild), 2 (Moderate), 3 (Severe), and 0.5 increments may be used if the 
subject’s hyperemia is between two grades. Frequencies and percentages will be summarized for each 
visit and treatment group. Shifts from baseline to post-baseline visits will be summarized categorically 
DV 0 (no change or decrease), +0.5, +1, +1.5, +2, +2.5, +3.
A subject listing of ocular hyperemia will also be produced.
Ocular Comfort Assessment
The subject comfort level will be assessed prior to insertion of the OTX-TP or PV, and again at each 
post-baseline visit. 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?”
Descriptive summary statistics of the comfort scores will be presented for each day which the question 
is asked. Changes from baseline will also be calculated and summarized alongside the observed values. 
Subject comfort scores will be listed, along with the Investigator’s response to the expectedness of the 
score and any action taken to alleviate discomfort.


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Observed IOP Results
A summary and listing of observed IOP data with no imputation, based on the Safety Population, will 
also be provided.
15. Interim Analyses
There are no planned interim analyses.
16. Pharmacokinetic Analyses
No pharmacokinetic data will be collected for this study.
17. Pharmacodynamic Analyses
No pharmacodynamic data will be collected for this study.
18. Quality of Life
No Quality of Life data will be collected for this study.
19. Changes from Protocol-Stated Analyses
This SAP differs from the protocol-stated analysis in three respects:
(1) The statement, “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” in the 
protocol has been changed to “The Full Analysis Set (FAS) will include all randomized subjects 
with depots inserted in both eyes. Analysis on the data for the primary study eye in the FAS 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.” The rationale behind 
this change is that the protocol allows for subjects with successful insertion of a depot in only 
one eye to be treated with IOP-lowering drops, which may have a systemic effect on both eyes
or lead to bilateral treatment with IOP-lowering drops.
(2) No subject visualization of depots is required.
(3) The protocol (5.6) states, “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.” Due to the logistics involved and the potential for 
bias, the sponsor has determined that investigators and investigative site staff will not be 
unmasked until the end of the study.
(4) An interim analysis as the primary efficacy analysis was planned as part of the protocol. As the 
study proceeded, the sponsor determined that the interim would not be necessary as accrual 
had been sufficient to shorten the time between the interim and final analyses.


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Any changes to the planned analyses after unmasking and the final analysis will be described in the 
clinical study report.
20. References
US Federal Register. (1998) International Conference on Harmonization; Guidance for Industry: 
Statistical Principles for Clinical Trials. Department of Health and Human Services: Food and Drug 
Administration. Federal Register, Vol. 63, No. 179, September 16, 1998, page 49583. (E9)
US Federal Register. (1996) International Conference on Harmonization; Guidance for Industry: 
Structure and Content of Clinical Study Reports. Department of Health and Human Services: Food and 
Drug Administration. Federal Register Vol. 61, July 17, 1996, page 37320. (E3)
21. Revision History
Final version 1.0 of this SAP was signed on 02Jan2018. Changes for Version 2.0 are detailed here.
Summary of Changes
Section #
Description of Change
Rationale
Abbreviations
FAS added.
Previously omitted in error.
Section 5 “Masking and Unmasking” 
subsection
References to interim analysis were 
removed.
Sponsor determined that interim analysis 
was not needed.  
Section 7 “Data Preparation”
References to interim analysis were 
removed.
Sponsor determined that interim analysis 
was not needed.  
Section 8 “Per Protocol Population” 
subsection
References to interim analysis were 
removed.
Sponsor determined that interim analysis 
was not needed.  
Section 9 “Data Analysis Conventions” 
subsection
References to interim analysis were 
removed, and precision for height and 
weight presentation was clarified.
Sponsor determined that interim analysis 
was not needed.  Details on decimal 
precision were finalized.
Section 9 “Unit of Analysis“ subsection
Clarification was made regarding the 
focus on bilaterally treated subjects and 
the classification of primary study eye.
Previous text was incomplete.
Section 
9 
“Unscheduled 
Visits”
subsection
Clarification was made regarding the 
used of unscheduled visit data.
Previous text was incomplete.
Section 10 “Subject Disposition”
Descriptions of additional CRF data to be 
provided in listings was included.
Review of CRFs indicated additional data 
would be available.


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Section 11 “Demographic Variables” 
subsection
Data on iris color collected at the Early 
Termination Visit was added.
Previously omitted in error.
Section 12 “Medical History” subsection
Typographical and grammatical errors 
have been corrected.
Originally in error.
Section 12 “Concomitant Medications” 
subsection
Criteria for IOP-lowering medications and 
TLFs 
presenting 
these 
data 
have 
clarified.
Final 
decision 
on 
IOP-lowering 
medications became available.
Section 
13 
“Intracanalicular 
Depot 
Visualization 
by 
the 
Investigator” 
subsection
References have been changed from 
primary eye/secondary eye to right 
eye/left eye
Descriptions 
of 
Screening/Baseline 
assessment listings had previously been 
described using primary/secondary eye.  
However, since the CRFs collected these 
data with respect to right and left eyes and  
primary eye was not determined until 
Baseline Visit 2, these were changed to 
right eye/left eye. 
Section 
13 
“Intracanalicular 
Depot 
Removal” subsection
References have been changed from 
primary eye/secondary eye to right 
eye/left eye
Descriptions 
of 
Screening/Baseline 
assessment listings had previously been 
described using primary/secondary eye.  
However, since the CRFs collected these 
data with respect to right and left eyes and  
primary eye was not determined until 
Baseline Visit 2, these were changed to 
right eye/left eye. 
Section 
14 
“Primary 
Analysis” 
subsection 
Typographical and grammatical errors 
have been corrected.
Originally in error.
Section 14.1.2 “Punctum Examination”
References have been changed from 
primary eye/secondary eye to right 
eye/left eye
Descriptions 
of 
Screening/Baseline 
assessment listings had previously been 
described using primary/secondary eye.  
However, since the CRFs collected these 
data with respect to right and left eyes and  
primary eye was not determined until 
Baseline Visit 2, these were changed to 
right eye/left eye. 
Section 15 “AE Summaries” subsection
Typographical and grammatical errors 
have been corrected.
Originally in error.


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Section 12 “Concomitant Medications” 
subsection
The 
population 
reference 
for 
the 
summary of ocular
and non-ocular 
concomitant 
medications 
has 
been 
corrected from FAS to Safety Population
Originally in error.
Section 15 “AE Summaries” subsection
Terminology has been changed to 
“subject withdrawal”
To match CRF language.
Section 15 “AE Summaries” subsection
AEs of special interest were defined and 
a summary of AEs of special interest was 
added.
Sponsor request
Section 16 “Interim Analysis”
References to interim analysis were 
removed.
Sponsor determined that interim analysis 
was not needed.  
Section 20 “Changes from Protocol-
Stated Analyses”
A rationale was added for using FAS 
rather than ITT for primary analysis.
Further explanation was required.
Headers of Sections 23-25
References to interim analysis were 
removed.
Sponsor determined that interim analysis 
was not needed.  
Titles of TLFs.
Typographical and grammatical errors 
have been corrected.
Originally in error.
Section 23 “Tables”
14.1.1, 14.1.6.3, 14.1.6.4 and 14.2.4.2 
were added to the top line delivery
Sponsor’s request
Section 23 “Tables”
A table for ocular TEAEs of special 
interest was added.
Sponsor’s request
Section 24 “Listings”
A visit date listing was added.
Sponsor’s request
Section 24 “Listings”
A rescue medication listing was added.
Sponsor’s request
Section 25 “Figures”
Three figures were added.
Completing references from the SAP text
22. Tables
Tables that will be included in the topline delivery are shown in boldface font.
Table Number
Title
Population
Table 14.1.1
Subject Disposition
All Enrolled Subjects
Table 14.1.2
Major Protocol Deviations
Full Analysis Set
Table 14.1.3
Demographic and Baseline Characteristics
Full Analysis Set


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Table Number
Title
Population
Table 14.1.4
Baseline Disease Characteristics
Full Analysis Set
Table 14.1.5.1
Non-Ocular Medical History
Safety Population
Table 14.1.5.2
Ocular Medical History
Safety Population
Table 14.1.6.1
Non-Ocular Concomitant Medications
Safety Population
Table 14.1.6.2
Ocular Concomitant Medications
Safety Population
Table 14.1.6.3
IOP-Lowering Ocular Medications
Safety Population
Table 14.1.6.4
Rescue Medication Use (IOP-Lowering Drops) by Visit
Full Analysis Set
Table 14.2.1.1
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point
MCMC Analysis – Primary Time Points
Full Analysis Set
Table 14.2.1.2
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point
MCMC Analysis – Non-Primary Time Points
Full Analysis Set
Table 14.2.1.3
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point
Pattern Mixture Analysis
Full Analysis Set
Table 14.2.1.4
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point
LOCF Analysis
Full Analysis Set
Table 14.2.1.5
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point
BOCF Analysis
Full Analysis Set
Table 14.2.1.6
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point
Observed Data Analysis
Full Analysis Set
Table 14.2.1.7
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point
Observed Data Analysis
Per Protocol Population
Table 14.2.1.8
Mean Observed, Change, and Percent Change from 
Baseline in Secondary Study Eye IOP by Time Point
Observed Data Analysis
Full Analysis Set 
Table 14.2.1.9
Mean Observed, Change, and Percent Change from 
Baseline in Secondary Study Eye IOP by Time Point
Observed Data Analysis
Per Protocol Population
Table 14.2.2.1
Mean Observed, Change, and Percent Change from 
Baseline in Primary Study Eye IOP by Time Point and 
Strata
MCMC Analysis
Full Analysis Set
Table 14.2.4.1
Insertion Results and Ease of Insertion
Safety Population
Table 14.2.4.2
Summary of Replacements
Safety Population
Table 14.2.4.3
Removal of Intracanalicular Depot
Safety Population
Table 14.2.5
Ocular Complaints by Study Eye
Safety Population
Table 14.2.6
Investigator Visualization of Intracanalicular Depot
Safety Population
Table 14.2.7
Punctum Examination Results
Safety Population
Table 14.3.1
Study Treatment Exposure
Safety Population
Table 14.3.2.1
Overall Summary of Adverse Events
Safety Population
Table 14.3.2.2.1
Non-Ocular Treatment Emergent Adverse Events by 
System Organ Class and Preferred Term
Safety Population
Table 14.3.2.2.2
Ocular Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term
Safety Population
Table 14.3.2.2.3
Primary Study Eye Ocular Treatment Emergent Adverse 
Events by System Organ Class and Preferred Term
Safety Population


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Table Number
Title
Population
Table 14.3.2.2.4
Secondary Study Eye Ocular Treatment Emergent 
Adverse Events by System Organ Class and Preferred 
Term
Safety Population
Table 14.3.2.2.5
Treatment Related Ocular Treatment Emergent Adverse 
Events by System Organ Class and Preferred Term
Safety Population
Table 14.3.2.2.6
Treatment Related Non-Ocular Treatment Emergent 
Adverse Events by System Organ Class and Preferred 
Term
Safety Population
Table 14.3.2.2.7
Serious Adverse Events by System Organ Class and 
Preferred Term
Safety Population
Table 14.3.2.2.8
Treatment Emergent Adverse Events Leading to Subject 
Withdrawal by System Organ Class and Preferred Term
Safety Population
Table 14.3.2.2.9
Ocular Treatment Emergent Adverse Events of Special 
Interest by System Organ Class and Preferred Term
Safety Population
Table 14.3.2.3
Treatment Emergent Adverse Events by System Organ 
Class, Preferred Term, and Maximum Severity
Safety Population
Table 14.3.2.4
Non-Related Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Most Likely 
Cause
Safety Population
Table 14.3.3.1
Best Corrected Visual Acuity by Time Point and Eye
Safety Population
Table 14.3.3.2
Change from Baseline Category in Best Corrected Visual 
Acuity by Time Point and Eye
Safety Population
Table 14.3.4.1
Slit Lamp Biomicroscopy by Visit and Eye
Safety Population
Table 14.3.4.2
Shifts from Baseline in Slit Lamp Biomicroscopy by Visit 
and Eye
Safety Population
Table 14.3.5.1
Dilated Fundoscopy Examination by Visit and Eye
Safety Population
Table 14.3.5.2
Shifts from Screening to 12 Week Visit in Dilated 
Fundoscopy Examination by Visit and Eye
Safety Population
Table 14.3.6
Mean Observed and Change from Baseline in IOP by Time 
Point and Eye
Safety Population
Table 14.3.7.1
Slit Lamp Ocular Hyperemia by Visit and Eye
Safety Population
Table 14.3.7.2
Shifts from Baseline to Each Post-Baseline Visit in Ocular 
Hyperemia by Visit and Eye
Safety Population
Table 14.3.8
Mean Observed and Change from Baseline in Subject 
Ocular Comfort Assessment by Visit and Eye
Safety Population
23. Listings
Listing Number
Title
Population
Listing 16.1.7
Randomization Schedule
All Enrolled Subjects
Listing 16.2.1
Subject Disposition
All Enrolled Subjects
Listing 16.2.2.1
Protocol Deviations
All Randomized 
Subjects
Listing 16.2.2.2
Inclusion, Exclusion, and Procedural Exclusion Criteria
All Enrolled Subjects
Listing 16.2.2.3
Subjects Excluded from the Per Protocol Population
All Randomized
Subjects
Listing 16.2.3
Visit Dates
All Randomized 
Subjects
Listing 16.2.4.1
Demographics
All Randomized 
Subjects
Listing 16.2.4.2
Baseline Characteristics:
Current Diagnosis, Gonioscopy, Punctum Size, Cup to Disc 
Ratio, and Intraocular Pressure
Full Analysis Set
Listing 16.2.4.3
Pre-Treatment Perimetry
All Randomized 
Subjects


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Listing Number
Title
Population
Listing 16.2.4.4
Pre-Treatment Pachymetry
All Randomized 
Subjects
Listing 16.2.4.5
Non-Ocular Medical History
Safety Population
Listing 16.2.4.6
Ocular Medical History
Safety Population
Listing 16.2.4.7
Prior and Concomitant Non-Ocular Medications
Safety Population
Listing 16.2.4.8
Prior and Concomitant Ocular Medications
Safety Population
Listing 16.2.4.9
Pregnancy Test Results
Safety Population
Listing 16.2.5.2
Insertion of Intracanalicular Depot
All Randomized 
Subjects
Listing 16.2.5.3
Investigator Intracanalicular Depot Visualization and Patency 
Check
Safety Population
Listing 16.2.5.4
Removal of Intracanalicular Depot
Safety Population
Listing 16.2.6.1
Intraocular Pressure
Safety Population
Listing 16.2.6.2
Ocular Complaints
Safety Population
Listing 16.2.8.1
Ocular Adverse Events
Safety Population
Listing 16.2.8.2
Serious Ocular Adverse Events
Safety Population
Listing 16.2.8.3
Ocular Adverse Events Leading to Subject Withdrawal
Safety Population
Listing 16.2.8.4
Non-Ocular Adverse Events
Safety Population
Listing 16.2.8.5
Serious Non-Ocular Adverse Events
Safety Population
Listing 16.2.8.6
Non-Ocular Adverse Events Leading to Subject Withdrawal
Safety Population
Listing 16.2.9.1
Best Corrected Visual Acuity (logMAR Scale)
Safety Population
Listing 16.2.9.2
Visual Acuity (logMAR) for Subjects Who Lost Three or More 
Lines
Safety Population
Listing 16.2.9.3
Slit Lamp Biomicroscopy
Safety Population
Listing 16.2.9.4
Dilated Fundus Examination and Cup to Disc Ratio
Safety Population
Listing 16.2.9.5
Punctum Examination Results
Safety Population
Listing 16.2.9.6
Punctum Size at Insertion
All Randomized 
Subjects
Listing 16.2.9.7
Slit Lamp Ocular Hyperemia and Ocular Comfort Assessment
Safety Population
Listing 16.2.9.8
Rescue (IOP-Lowering) Ocular Medications
Full Analysis Set
24. Figures
Figure Number
Title
Population
Figure 14.2.1
LSMeans for Primary Study Eye IOP by Time Point and 
Treatment (MCMC)
Full Analysis Set
Figure 14.2.2
LSMeans for Primary Study Eye IOP by Time Point and 
Treatment (MCMC)
Per Protocol Population
Figure 14.2.3
LSMeans Change from Baseline in Primary Study Eye IOP by 
Time Point and Treatment (MCMC)
Full Analysis Set
Figure 14.2.4
LSMeans Change from Baseline in Primary Study Eye IOP by 
Time Point and Treatment (MCMC)
Per Protocol Population
Figure 14.2.5
LSMeans Difference in Primary Study Eye IOP by Time Point
(MCMC)
Full Analysis Set
Figure 14.2.6
LSMeans Difference in Primary Study Eye IOP by Time Point
(MCMC)
Per Protocol Population
Figure 14.2.7
LSMeans for Primary Study Eye IOP by Time Point and 
Treatment (Observed Data)
Full Analysis Set
Figure 14.2.8
LSMeans for Primary Study Eye IOP by Time Point and 
Treatment (Observed Data)
Per Protocol Population
Figure 14.2.9
LSMeans Change from Baseline in Primary Study Eye IOP by 
Time Point and Treatment (Observed Data)
Full Analysis Set 


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Figure Number
Title
Population
Figure 14.2.10
LSMeans Change from Baseline in Primary Study Eye IOP by 
Time Point and Treatment (Observed Data)
Per Protocol Population
Figure 14.2.11
LSMeans Difference in Primary Study Eye IOP by Time Point 
(Observed Data)
Full Analysis Set 
Figure 14.2.12
LSMeans Difference in Primary Study Eye IOP by Time Point 
(Observed Data)
Per Protocol Population