Conditions: Dry Eye Disease
Keywords: Cyclosporine Intracanalicular insert
Allocation: RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 153
Healthy volunteers: no

Brief summary:
To assess the safety, tolerability and efficacy of a single dose of OTX-CSI, a sustained release cyclosporine drug product, in subjects with dry eye disease.

Detailed description:
Randomized, multi-center, double-masked, vehicle-controlled, Phase 1/2 study to evaluate the safety, tolerability, and efficacy of OTX-CSI in subjects with dry eye disease. The subjects will be followed for approximately 16 weeks after product insertion

Arms:
arm 1: Formulation 2A-.36 mg arm 2: Formulation 1- .36 mg arm 3: Cohort 2:

Formulation 2B arm 4: Formulation 2A- .36 mg arm 5: Cohort 2:

Formulation 3

Interventions: intervention 1: OTX-CSI intervention 2: Placebo Vehicle
Intervention descriptions: intervention 1: OTX-CSI intracanalicular insert intervention 2: Hydrogel Vehicle intracanalicular insert

Protocol document:
Prot_000.pdf: 
Ocular Therapeutix, Inc. 
CLN-Protocol-0054 
 
 
 
 
A randomized, multi-center, double-masked, vehicle-controlled, 
Phase 1/2 study to evaluate the safety, tolerability, and efficacy of 
OTX-CSI (cyclosporine ophthalmic insert) for intracanalicular 
use for the treatment of subjects with dry eye disease (DED) 
 
Investigational Product 
CLN-Protocol-0054 
 
Version 05 
03 June 2021 
 
 
 
Sponsor 
Ocular Therapeutix, Inc. 
24 Crosby Drive 
Bedford, MA 01730 USA 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
This protocol contains confidential, proprietary information which is the property of Ocular Therapeutix, 
Inc. Neither this document, nor the information contained herein, should be disclosed or reproduced 
without prior authorization of Ocular Therapeutix, Inc. 
 
 


Ocular Therapeutix, Inc. 
CLN-Protocol-0054 
 
Version 05, 03 June 2021 
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Page 2 of 76 
 
 
A randomized, multi-center, double-masked, vehicle-controlled, Phase 1/2 study to evaluate the 
safety, tolerability, and efficacy of OTX-CSI (cyclosporine ophthalmic insert) for intracanalicular 
use for the treatment of subjects with dry eye disease (DED) 
I hereby agree to participate in the clinical investigation of OTX-CSI (cyclosporine ophthalmic insert) 
for intracanalicular use sponsored by Ocular Therapeutix, (hereinafter “Study Sponsor”). I agree to 
conduct this investigation in accordance with the agreement, the investigational plan, and applicable 
regulations. I agree to protect the rights, safety, and welfare of subjects under my care; I agree to adhere 
to the regulations outlined in 21 CFR Part 312, other applicable United States Food and Drug 
Administration (FDA) regulations, and conditions of approval imposed by the reviewing IRB and the 
FDA. I agree to supervise all use of the investigational product and to ensure appropriate informed 
consent is obtained from all subjects prior to inclusion in this study. 
I understand that this investigation will be monitored by the Study Sponsor and/or a designee of the 
Study Sponsor. This monitoring will involve periodic inspection of my investigational site and ongoing 
review of the data that is submitted by me to the Study Sponsor. I am also aware that I may be inspected 
by a representative of the FDA to verify compliance with applicable federal regulations related to 
clinical research on human subjects. I am aware that my contact for all matters related to this 
investigation is the Ocular Therapeutix Clinical Department at (781) 357-4000. 
I am aware that the Study Sponsor reserves the right to discontinue this investigation at any time. In the 
event that I decide to discontinue my participation as an Investigator in this study, I will notify the Study 
Sponsor 30 days prior of my intent to discontinue. I understand that I am obligated to complete the 
follow up of the subjects already participating in the investigation.  
Any data generated as a result of this investigation will be the exclusive property of the Study Sponsor 
who retains all rights of publication. I understand that the Study Sponsor encourages me to pursue 
independent publications related to my experience with this investigational product with the 
understanding that Study Sponsor reserves the right of prior review and approval of these publications. 
I agree to provide to the Study Sponsor my current curriculum vitae along with the current curriculum 
vitae of those physicians at this institution who will be using this investigational product or participating 
in this study as Sub-Investigators under my supervision. These CVs include education, training, and the 
extent and type of our relevant experience with pertinent dates and locations. I certify that I have not 
been involved in an investigation that was terminated for noncompliance at the insistence of a Study 
Sponsor, an IRB or the FDA. 
I understand that this investigation, protocol, and trial results are confidential, and I agree not to disclose 
any such information to any person other than a representative of the Study Sponsor or FDA without the 
prior written consent of the Study Sponsor. 
I will provide financial information, as indicated in 21 CFR Part 312.64(d) and 21 CFR Part 54. 
Accepted by: 
 
 
 
Principal Investigator Signature 
Date 
Printed Name 
 
          
 
 
 
 


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PROTOCOL REVISION HISTORY 
Date 
Version 
Description of 
Modifications 
Rationale for Modification 
02 December 2019 
01 
Original Issue 
N/A 
31 January 2020 
01 
Version 01 dated 02 December 
2019 was not initiated in the clinic 
1. Extended follow-up 
timeframe for Cohort 
1 subjects. 
2. Updated statistical 
section to include 
planned methods of 
analyses for the 
primary and 
secondary efficacy 
endpoints. 
3. Add language 
regarding replacement 
of inserts. 
1. To have Cohort 1 
subjects follow the 
same schedule as the 
Cohort 2 subjects.   
2. To specify planned 
analyses. 
3. To allow for 
reinsertion due to 
early loss of insert.   
7 July 2020 
02 
1. Updated Screening 
visit to include wait 
time for Schirmer test. 
2. Updated Appendices 
to refer to Lab Manual 
for Schirmer test and 
Tear Film PK.  
1. To ensure screening 
Schirmer is same as 
other visits.  
2. To ensure alignment 
within the protocol 
and across the 
protocol and other 
study documents. 
25 August 2020 
03 
1. Updated Section 7.4 
to note both eyes. 
2. Removed Impression 
Cytology assessment 
from the protocol. 
3. Added secondary 
efficacy endpoint for 
Schirmer Test. 
4. Moved TBUT from 
Week 16 visit to 
Week 12 visit. 
1. Any subject with an 
insert should be 
followed in the study. 
2. Decided to include 
Impression Cytology 
in another study. 
3. This efficacy endpoint 
should have been 
included previously.  
4. Correction needed to 
align with the 
associated exploratory 
endpoint. 


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Date 
Version 
Description of 
Modifications 
Rationale for Modification 
23 November 2020 
 
04 
 
 
1. Study Design, Sections 4.7 
and 6.1 changed to reflect 
increase in subject population 
from 105 to 140 cohort 2. 
2.Updated Section 7.4 to state 
that any subject with a 
successful unilateral insertion 
should return within three 
days to reattempt insertion in 
the unsuccessful eye.  
3. Inclusion #7 added to 
include post-menopausal 
women 
4. OTC decongestants added 
to Exclusion #14. 
5.Procedural Exclusion 
Criteria updated to specify 
that subjects with unilateral 
insertion will be followed 
throughout study. 
6.For Visit 1 procedures, 
Urine pregnancy test specifies 
it is for Women of Child      
Bearing Potential (WOCBP) 
only. 
7. Section 8.4.10 updated to 
state Replacement of inserts 
is not permitted for subjects 
enrolled in Cohort 2.   
 
1. Increase in subject 
population total.  
 
 
2. To specify that 
reinsertion should be 
attempted when 
possible. 
3. To specify post-
menopausal women 
can be included. 
4.To clarify that over-
the-counter 
decongestants as well 
as prescription ones 
are excluded. 
5. Clarification. 
6. Clarification. 
7. Clarification. 
 
03 Jun 2021 
05 
 
1. Removal of all ‘Rescue’ 
Language referring to 
Artificial Tears. 
2. Removal of sentence from 
Section 11.6 regarding 
subjects data after sustained 
usage of rescue medication. 
3. Addition of the word 
‘procedural’ to the body of 
the section named 
 
1. Artificial Tears are 
commonly used in Dry Eye 
Disease studies and not 
viewed in this study as a 
rescue therapy. 
2.  All data will be used. 
3.Clarification. 
 
 


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Date 
Version 
Description of 
Modifications 
Rationale for Modification 
‘Procedural Exclusion 
Criteria’. 
4. Addition of the phrase 
‘procedural screen failures’ to 
section 7.4. 
 
4.Clarification. 
 


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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 9 
2 
SYNOPSIS .............................................................................................................. 11 
3 
PRINCIPAL CONTACTS ..................................................................................... 19 
4 
BACKGROUND INFORMATION ....................................................................... 19 
4.1 
Dry Eye Disease (DED)........................................................................................... 19 
4.2 
Investigational Product Rationale.......................................................................... 19 
4.3 
Nonclinical Findings ............................................................................................... 20 
4.4 
Risk-Benefit Analysis ............................................................................................. 21 
4.5 
Dose and Administration Justification .................................................................. 22 
4.6 
Compliance ............................................................................................................. 24 
4.7 
Trial Population ...................................................................................................... 24 
5 
TRIAL OBJECTIVES ........................................................................................... 24 
6 
TRIAL DESIGN ..................................................................................................... 25 
6.1 
Description of Trial ................................................................................................ 25 
6.2 
Study Endpoints ..................................................................................................... 28 
6.2.1 
Safety Evaluations (Cohorts 1 and 2) .................................................................... 28 
6.2.2 
Efficacy Endpoints (Cohort 2 only): ...................................................................... 28 
6.2.2.1 
Primary Efficacy Endpoints .................................................................................... 28 
6.2.2.2 
Secondary Efficacy Endpoints ................................................................................. 28 
6.2.2.3 
Exploratory Efficacy Endpoints .............................................................................. 28 
6.2.3 
Supplementary Objectives ..................................................................................... 28 
6.3 
Randomization and Blinding ................................................................................. 29 
6.4 
Trial Treatment ...................................................................................................... 29 
6.5 
Trial Duration ......................................................................................................... 29 
6.6 
Trial Material Accountability ................................................................................ 29 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................... 30 
7.1 
Inclusion Criteria ................................................................................................... 30 
7.2 
Exclusion Criteria ................................................................................................... 31 
7.3 
Entry/Randomization Criteria: ............................................................................. 33 
7.4 
Procedural Exclusion Criteria ............................................................................... 33 
7.5 
Subject Recruitment and Screening ...................................................................... 34 
7.6 
Withdrawal Criteria ............................................................................................... 34 
7.6.1 
Withdrawal Methods .............................................................................................. 34 
7.6.2 
Collection of Data from Withdrawn Subjects ....................................................... 34 
7.6.3 
Subject Replacement .............................................................................................. 34 
8 
SUBJECT TREATMENT ...................................................................................... 34 
8.1 
Treatment Regimen ................................................................................................ 34 
8.2 
Prior and Concomitant Therapy............................................................................ 35 
8.3 
Study Assessments by Visit .................................................................................... 35 
8.3.1 
Visit 1 (14 days prior to Day 1) Screening/Baseline Visit ...................................... 35 
8.3.2 
Visit 2 Insertion/Day 1 ............................................................................................ 36 
8.3.3 
Visit 2B (Day 1 + 1 to 3 days) ................................................................................. 37 
8.3.4 
Follow-Up Visit 3 (Week 2 ±2 days) ....................................................................... 37 
8.3.5 
Follow-Up Visit 4 (Week 4 ±2 days) ....................................................................... 37 


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8.3.6 
Follow-Up Visit 5 (Week 6 ±3 days) ....................................................................... 38 
8.3.7 
Follow-Up Visit 6 (Week 9 ±3 days) ....................................................................... 38 
8.3.8 
Follow-Up Visit 7 (Week 12 ±3 days) ..................................................................... 39 
8.3.9 
Final Visit 8 (Week 16 ±3 days) .............................................................................. 39 
8.3.10 
30-day Follow-Up Visit (Week 20 ± 10 days) ......................................................... 39 
8.3.11 
Replacement of Inserts ........................................................................................... 40 
8.3.12 
Unscheduled Visit ................................................................................................... 40 
9 
ASSESSMENT OF EFFICACY ............................................................................ 40 
9.1 
Efficacy Parameters ............................................................................................... 40 
10 
ADVERSE EVENTS .............................................................................................. 41 
10.1 
Definition of an Adverse Event .............................................................................. 41 
10.2 
Definition of Serious Adverse Event ...................................................................... 42 
10.3 
Disease-Related Events or Outcomes Not Qualifying as AE/SAE’s ..................... 42 
10.4 
Monitoring and Recording of AEs and SAEs ........................................................ 42 
10.4.1 
Adverse Events ....................................................................................................... 42 
10.4.2 
Serious Adverse Events .......................................................................................... 42 
10.4.3 
All Events ................................................................................................................ 42 
10.5 
Immediate Reporting of Serious Adverse Events and Pregnancies ...................... 43 
10.6 
Death ....................................................................................................................... 43 
10.7 
Evaluating AEs and SAEs ...................................................................................... 43 
10.7.1 
Severity ................................................................................................................... 43 
10.7.2 
Relationship to OTX-CSI or Hydrogel Vehicle product or procedure ................ 44 
10.7.3 
Expectedness of Events ........................................................................................... 44 
10.8 
Pre-scheduled or elective Procedures or Routinely Scheduled Treatments ......... 44 
10.9 
Procedures for Handling Special Situations .......................................................... 44 
10.9.1 
Pregnancy ............................................................................................................... 44 
10.9.2 
Unmasking for Medical Emergencies .................................................................... 44 
10.9.3 
Regulatory Reporting ............................................................................................. 45 
11 
STATISTICAL METHODS AND DATA ANALYSIS ......................................... 45 
11.1 
Statistical Methods ................................................................................................. 45 
11.2 
Unit of Analysis....................................................................................................... 45 
11.3 
Sample Size Determination .................................................................................... 46 
11.4 
Statistical Significance ............................................................................................ 46 
11.5 
Trial Termination ................................................................................................... 46 
11.6 
Missing Data ........................................................................................................... 46 
11.7 
Efficacy Analyses .................................................................................................... 46 
11.8 
Exploratory Analyses ............................................................................................. 46 
11.9 
Reporting Deviations .............................................................................................. 46 
11.10 
Subject Population(s) for Analysis ......................................................................... 47 
12 
STUDY MANAGEMENT AND DATA COLLECTION ...................................... 47 
12.1 
Confidentiality ........................................................................................................ 47 
12.2 
Source Documents .................................................................................................. 47 
12.3 
Case Report Forms ................................................................................................. 47 
12.4 
Records Retention .................................................................................................. 48 
13 
STUDY MONITORING, AUDITING, AND INSPECTING ................................ 48 
13.1 
Study Monitoring Plan ........................................................................................... 48 


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14 
ETHICAL CONSIDERATIONS ........................................................................... 48 
15 
REFERENCES ....................................................................................................... 49 
 
 
TABLE OF TABLES 
Table 1 
Safety Margins for Ocular and Systemic Toxicity ................................................ 24 
Table 2 
Treatment Assignment Paradigm for Cohorts 1 and 2 ......................................... 25 
Table 3 
List of Prohibited Medications ............................................................................... 35 
 
 
TABLE OF FIGURES 
Figure 1 
Cohort 1 and Cohort 2 Study Schematic ............................................................... 27 
Figure 2 
Reporting Information for SAEs and Pregnancies ............................................... 43 
 
 
LIST OF APPENDICES 
Appendix 1 
Time and Events Schedule ...................................................................... 51 
Appendix 2 
Safety Review Group Charter ................................................................. 53 
Appendix 3 
VAS for Eye Dryness ............................................................................... 60 
Appendix 4 
OSDI ........................................................................................................ 61 
Appendix 5 
Standard Patient Evaluation of Eye Dryness (SPEED) Questionnaire . 63 
Appendix 6 
Corneal Fluorescein Staining (CFS) Procedure - Using NEI Scale ....... 64 
Appendix 7 
Conjunctival Lissamine Green Staining (LGS) Procedure - Using the NEI 
Scale ......................................................................................................... 65 
Appendix 8 
Best Corrected Visual Acuity .................................................................. 66 
Appendix 9 
Slit Lamp Biomicroscopy and External Eye Exam Procedures ............ 67 
Appendix 10 
PK Sample collection (Systemic and Tear Film Sample) ....................... 68 
Appendix 11 
Tear Film Break-Up Time ....................................................................... 69 
Appendix 12 
Schirmer Test (without anesthesia) ........................................................ 70 
Appendix 13 
OTX-CSI or HV Insert Placement .......................................................... 71 
Appendix 14 
OTX-CSI or HV Insert Ease of Visualization ........................................ 73 
Appendix 15 
OTX-CSI or HV Insert Removal Instructions ....................................... 74 
Appendix 16 
Daily Subject Diary (For Artificial Tear Use) ........................................ 75 
Appendix 17 
Marketed Cyclosporine ........................................................................... 76 
 


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1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Term 
Definition 
AE 
AT 
BCVA 
Adverse Event/Experience 
Artificial Tears 
Best Corrected Visual Acuity 
C 
CD 
Celsius 
Compact Disc 
CFB 
Change from Baseline 
CFR 
CFS 
CMO 
CRF 
Code of Federal Regulations 
Corneal Fluorescein Staining 
Chief Medical Officer 
Case Report Form 
CRO 
CsA 
Contract Research Organization 
Cyclosporine A 
CV 
Curriculum Vitae 
DED 
Dry Eye Disease 
DLT 
Dose-Limiting Toxicity 
e 
Electronic 
EDC 
ETDRS 
Electronic Data Capture 
Early Treatment of Diabetic Retinopathy Study 
FCS 
Fluorescein Corneal Scoring 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
HED 
HV 
Good Laboratory Practice 
Human Equivalent Dose 
Hydrogel Vehicle Insert 
ICH 
ICF 
ID 
International Council on Harmonization  
Informed Consent Form 
Subject Identification 
IEC 
Independent Ethics Committee 
IOP 
IP 
Intraocular Pressure 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
ITT 
IUD 
KCS 
LogMAR 
Interactive Response Technology 
Intent-to-Treat 
Intra-Uterine Device 
Keratoconjunctivitis Sicca 
Logarithm of the Minimum Angle of Resolution 
mg 
ml 
mm 
mmHg 
Milligram 
Milliliter 
Millimeter 
Millimeters of Mercury 
NDA 
NEI 
NOAEL 
New Drug Application 
National Eye Institute 
No Observed Adverse Event Level 
NSAID 
NSR 
PP 
PRN 
OD 
OS 
OSDI 
OTX 
OTX-CSI 
Nonsteroidal Anti-Inflammatory Drug 
Non-Significant Risk 
Per Protocol 
As Needed 
Right Eye 
Left eye 
Ocular Surface Disease Index 
Ocular Therapeutix 
Cyclosporine Ophthalmic Insert 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event/Experience 


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Term 
Definition 
SPEED 
SRG 
Standard Patient Evaluation of Eye Dryness 
Safety Review Group 
SUSAR 
TBUT 
tCFS 
μg 
Suspected Unexpected Serious Adverse Reactions 
Tear Film Break Up Time 
Total Corneal Fluorescein Staining 
Microgram 
UPT 
US 
VA 
VAS 
VKC 
WOCBP 
Urine Pregnancy Test 
United States 
Visual Acuity 
Visual Analog Scale 
Vernal Keratoconjunctivitis 
Women of Child-Bearing Potential 
 


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2 
SYNOPSIS 
Protocol Title 
A randomized, multi-center, double-masked, vehicle-controlled, Phase 1/2 
study to evaluate the safety, tolerability, and efficacy of OTX-CSI 
(cyclosporine ophthalmic insert) for intracanalicular use for the treatment of 
subjects with dry eye disease (DED) 
Protocol Number 
CLN-Protocol-0054 
Phase of Clinical 
Study 
1/2   
Investigational 
Products 
  
Formulation 
Number 
Name 
Approximate 
Persistence 
1 
OTX-CSI 0.36 mg Cyclosporine 
Ophthalmic Insert 
2 to 3 months 
2A 
OTX-CSI 0.36 mg Cyclosporine 
Ophthalmic Insert 
3 to 4 months 
2B 
Hydrogel Vehicle Insert 
3 to 4 months 
3 
Hydrogel Vehicle Insert 
1 week 
Study Objective 
To assess the safety, tolerability, and efficacy of OTX-CSI in subjects with 
DED. 
Safety Evaluations 
Primary: 
 Non-ocular and Ocular Adverse Events (AEs)  
Secondary: 
 Best-Corrected Visual Acuity (BCVA) 
 Slit Lamp Biomicroscopy (including punctum assessment) 
 Intraocular Pressure (IOP) 
 Fundus Examination 
 Artificial tear use during the study 
Efficacy Endpoints 
Primary: 
 Schirmer Test (without anesthesia) change from baseline (CFB) and 
absolute value at Week 12. 
Secondary: 
Signs: 
 Percent of subjects with ≥10 mm increase in Schirmer at Week 12. 
 Total Corneal Fluorescein Staining (tCFS) using NEI scale, CFB and 
absolute values at each post baseline study visit. 
 CFS sub-regions using NEI scale, CFB and absolute values at each 
post-baseline visit. 
 Conjunctival Lissamine Green Staining using NEI Scale, CFB and 
absolute values at each post-baseline visit. 


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Symptoms (subject-reported): 
 Eye Dryness Score (visual analogue scale [VAS]), CFB and absolute 
values at each post-baseline visit.  
 Ocular Surface Disease Index (OSDI©) questionnaire, CFB and 
absolute values at each post-baseline visit (total score, each of the 
three domains, and individual questions). 
 SPEED questionnaire (overall score and individual questions), CFB 
at each post-baseline visit. 
Exploratory: 
 Tear Film Break Up Time (TBUT), CFB at Week 12  
 Presence of OTX-CSI or HV insert at all post-baseline visits 
 Ease of insertion as assessed by the Investigator 
 Ease of visualization as assessed by the Investigator 
 
Pharmacokinetics 
(PK) Parameters 
 Systemic PK (at selected sites) 
 Tear Film PK (all sites) 
Number of 
Investigational Sites 
Approximately 15 sites in the United States (US) 
Number of Subjects 
Planned 
Approximately 145 subjects (290 eyes) will be enrolled in two cohorts. 
Study Population 
Subjects with signs and symptoms of DED. 
Study Design and 
Overview 
This is a randomized, multi-center, double-masked, vehicle-controlled, 
phase 1/2 clinical study designed to evaluate the safety, tolerability, and 
efficacy of OTX-CSI (cyclosporine ophthalmic insert) for intracanalicular 
use for the treatment of subjects with DED. Approximately 145 subjects 
(290 eyes) will be enrolled in this study at approximately 15 sites in the US. 
Subjects will be enrolled in two cohorts. Cohort 1 will be an open-label 
group consisting of approximately 5 subjects. Cohort 2 will be a 
randomized, double-masked group consisting of approximately 140 subjects 
(280 eyes)treated with 2 different hydrogel formulations of OTX-CSI and 2 
different formulations of hydrogel vehicle inserts (HV).  Both eyes will be 
treated with the same treatment/formulation.   
Cohort Number Number of 
Subjects 
Treatment 
Formulation Number 
1 
Open-label 
5 
OTX-CSI 
2A 
2 
Randomized, 
double-masked 
40 
OTX-CSI 
1 
40 
OTX-CSI 
2A 
40 
HV 
2B 
20 
HV 
3 
The recommendation to progress to Cohort 2 will be the responsibility of the 
Safety Review Group (SRG).  The SRG will review Cohort 1 data to 


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evaluate the safety of OTX-CSI Formulation 2A after all subjects have been 
followed for at least 2 weeks and will issue a recommendation on whether or 
not to open enrollment in Cohort 2.   
Once subject eligibility has been determined, OTX-CSI or HV insert, as 
applicable, will be placed bilaterally, into either the superior or inferior 
canaliculus (per investigator’s preference), during the Insertion/Day 1 
(Visit 2) for all subjects who meet the eligibility criteria. 
Cohort 1 
Subjects in Cohort 1 will undergo Screening 14 days prior to Insertion/Day 
1 (Visit 2) to determine eligibility and eligibility will be re-confirmed at 
Visit 2 (Insertion/Day 1).  The treatment follow-up visits will occur at Week 
2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 9 (Visit 6), Week 12 
(Visit 7), and Week 16 (Visit 8). All subjects in Cohort 1 will be followed 
until Week 16 (Visit 8), whether or not an insert is visualized.  
Cohort 2 
Subjects in Cohort 2 will undergo Screening 14 days prior to Insertion/Day 
1 (Visit 2) to determine eligibility.  At Visit 2 (Insertion/Day 1) eligibility 
will be confirmed and subjects who are eligible will be randomly assigned to 
one of four treatment groups (OTX-CSI Formulation 1, OTX-CSI 
Formulation 2A, HV Formulation 2B or HV Formulation 3) in a 2:2:2:1 
ratio.  Should only a unilateral insertion be possible, Visit 2B will occur 
within 3 days to attempt the insertion again. The treatment follow-up visits 
will occur at Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 9 
(Visit 6), Week 12 (Visit 7), and Week 16 (Visit 8).  All subjects in Cohort 2 
will be followed until Week 16 (Visit 8), whether or not an insert is 
visualized. 
For both cohorts, if an OTX-CSI or HV insert is visualized at Week 16 
(Visit 8), the subject will return to the clinic in 30 days (± 10 days; Visit 9) 
and will continue returning to the clinic every 30 days as needed, until an 
insert can no longer be visualized and the physician has determined that 
there is no evidence of biological activity.  Additionally, subjects may be 
exited any time at the investigator’s discretion.  If an OTX-CSI or HV insert 
cannot be visualized at Week 16 (Visit 8) and the physician has determined 
that there is no evidence of biological activity, the subject will exit the study. 
Inclusion Criteria 
Subjects will be eligible for study participation if they: 
1. Provide written informed consent prior to performing any study 
procedures and are willing to comply with study requirements and 
the study visit schedule. 
2. Are 18 years of age or older. 
3. Have a self-reported history or clinically confirmed diagnosis of 
DED by an eye care professional in both eyes for ≥6 months. 
4. Have ongoing DED, in the study eye at screening visit as defined by 
the following criteria: 


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a. VAS eye dryness severity score ≥ 30. 
And in the same qualifying eye or both eyes: 
            b.   Total Corneal Fluorescein Staining Score of ≥6 (NEI scale)   
and <15. 
           c.   Have a Schirmer score (unanesthetized) of >0 mm and ≤10 
mm wetting at 5 minutes. 
5. Have corrected visual acuity better than or equal to logarithm of the 
minimum angle of resolution (logMAR), +0.7 as assessed with 
Early Treatment of Diabetic Retinopathy Study (ETDRS) charts in 
both eyes. 
6. Are women of child-bearing potential (WOCBP) who are non-
pregnant, non-lactating, and sexually inactive (abstinent) for 14 days 
prior to screening. And are willing to remain so through the last 
study visit. Alternatively, WOCBP who are not abstinent must have 
been using one of the following acceptable methods of birth control 
for the times specified: 
a. Intra-uterine device (IUD) in place for at least 3 months prior 
to screening and the desire to continue this method through 
the last study visit. 
b. Barrier method (condom or diaphragm) with spermicide for 
at least 14 days prior to screening and the desire to continue 
this method through the last study visit. 
c. Stable hormonal contraceptive for at least 3 months prior to 
screening and the desire to continue this method through the 
last study visit. 
d. Surgical sterilization (vasectomy) of partner for at least 6 
months prior to Day 1. 
7. Are postmenopausal women [i.e., no menstrual cycle for at least one 
year prior to Visit 1 (Screening)] or are women who have undergone 
1 of the following sterilization procedures at least 6 months prior to 
Visit 1 (Screening): 
a. Bilateral tubal ligation 
b. Hysterectomy 
c. Hysterectomy with unilateral or bilateral oophorectomy 
d. Bilateral oophorectomy 
8. Agree to the removal of non-dissolvable punctal plugs 4 weeks prior 
to the insertion visit (Day 1, Visit 2).  Long-term dissolvable punctal 
plugs were not placed within 4 months prior to insertion visit (Day 
1, Visit 2) and short-term dissolvable punctual plugs were not 
placed within 6 weeks prior to insertion (Day 1, Visit 2). 
 


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Pre-Procedural 
Exclusion Criteria 
Subjects are not eligible for study participation if they: 
1. Have a known or suspected allergy to any component of the study 
product. 
2. Are unwilling to discontinue use of contact lenses for 4 weeks prior to 
the screening visit and throughout the study period. 
3. Have any active systemic disease and/or systemic infection (e.g., fever 
or current antibiotic use), or uncontrolled medical condition that in the 
judgment of the investigator could confound study assessments or limit 
compliance. 
4. Have a documented history of ocular allergies, which, in the judgment of 
the investigator, are likely to have an acute increase in severity during 
the duration of this trial. Subjects sensitive to seasonal allergens that are 
not expected to be present during the study are permitted. 
5. Have a history of neuropathic pain related to dry eye. 
6. Have corneal erosive disease (e.g., multiple filaments, recurrent erosion 
syndrome) or other conditions suggestive of extensive damage of the 
cornea. 
7. Have a history of glaucoma or ocular hypertension or have intraocular 
pressure (IOP) < 5 mmHg or > 24 mmHg or a history of elevated IOP 
within the past 6 months prior to the screening visit. 
8. Have abnormal lid anatomy that may confound study data, in the 
judgement of the investigator. 
9. Have a diagnosis of any of the following: 
a. 
Active ocular infection 
b. 
Uveitis 
c. 
Uncontrolled blepharitis (including severe MGD), in the 
judgement of the investigator 
d. 
Moderate to severe pinguecula or pterygia, in the judgement of 
the investigator 
e. 
Stevens-Johnson syndrome 
f. 
Mucous membrane pemphigoid 
g. 
Significant conjunctival scarring, in the judgement of the 
investigator 
h. 
Chemical burn 
i. 
Herpetic or neurotrophic keratitis 
j. 
Congenitally absent lacrimal gland or meibomian glands 
k. 
Nasolacrimal duct obstruction in either eye 


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10. Have had penetrating intraocular surgery in the past 6 months or require 
penetrating intraocular surgery during the study. 
11. Have had eyelid surgery within 6 months prior to the screening visit. 
12. Have had corneal laser refractive surgery, glaucoma surgery or corneal 
transplantation (full thickness, anterior or posterior). 
13. Have had cauterization of the punctum resulting in complete occlusion 
of the punctum. 
14. Have taken any of the following in either eye within 30 days prior to the 
screening visit: 
a. 
Topical ocular cyclosporine (e.g., Cequa®, Restasis®) 
b. 
Lifitegrast (Xiidra®) 
c. 
Autologous tears 
d. 
Topical ocular corticosteroids 
e. 
Topical ocular antibiotics 
f. 
Topical ocular NSAID 
g. 
Topical ocular antihistamines and/or mast cell stabilizers 
h. 
Topical or nasal vasoconstrictors 
i. 
Over The Counter (OTC) decongestants 
j. 
Intranasal Tear Neurostimulation 
15. Have taken any of the following in either eye prior to the screening visit: 
a. 
Periocular injection of any corticosteroid solution – 3 months 
b. 
Corticosteroid intra-vitreal depot injection– 3 months 
c. 
Ozurdex– 6 months 
d. 
Retisert– 40 months 
16. Have altered the dose of the following within 30 days prior to the 
screening visit (i.e., should keep dose stable throughout the study): 
a. 
Nutraceuticals or multivitamins 
b. 
Tetracycline compounds (tetracycline, doxycycline or 
minocycline) 
c. 
Inhaled, intramuscular or intra-articular corticosteroids (mouth or 
nasal spray form) 
17. Have altered the dose of the following within 6 months prior to the 
screening visit (i.e., should keep dose stable throughout the study): 
a. 
Systemic anticholinergics 
b. 
Antidepressants (with the exception of rare usage as a sleep aid) 


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c. 
Oral corticosteroids (e.g., prednisone. Prednisone dose must be 
less than 11 mg/day) 
18. Have taken isotretinoin (Accutane) or systemic immunosuppressive 
agents within 6 months prior to the screening visit. 
19. Are unwilling to withhold use of artificial tears (AT) for the duration of 
the trial. 
20. Have participated in any other investigational study within 30 days of 
the screening visit or plans to participate in any other investigational 
study during the follow-up period. 
21. Are an employee of the site or an immediate family member of the site. 
22. Are a current smoker (including marijuana, cigar, cigarette, and/or 
e-cigarettes). 
23. Have a known history of alcohol and/or drug abuse or are currently 
using illicit drugs or plan to use illicit drugs for the duration of the study. 
Recreational or medicinal marijuana allowed if oral consumption (no 
inhaled use). 
24. Are unwilling or unable to comply with the study protocol. 
25. The Investigator determines that the subject should not be included for 
reasons not already specified (e.g., systemic, behavioral, or other ocular 
disease/abnormality) if the health of the subject or the validity of the 
study outcomes may be compromised by the subject’s enrollment. 
Entry/Randomization 
Criteria 
To qualify for insertion at Day 1 (Visit 2), a subject must continue to meet 
all screening inclusion/exclusion criteria with the following 
exceptions/additions: 
1. VAS eye dryness severity score ≥25 
2. CFS total score ≥5 (NEI scale) and <15 in the same qualifying eye as 
Visit 1.  
3. Subject must not have taken prohibited medications and have completed 
the appropriate washout of prior medications, if necessary. 
4. Subjects who require AT use must not have administered >3 times/day 
for 3 consecutive days during the washout period. NOTE:  AT use is not 
permitted unless absolutely necessary.  If subject requires AT use and 
has administered >3 times/for 3 days during the Screening period, they 
are not eligible for randomization. 
Procedural Exclusion 
Criteria 
Subjects are considered procedural screen failures if the investigator is 
unsuccessful at placing the OTX Ophthalmic insert in both eyes (i.e. neither 
eye has an insert). Subjects will be followed per protocol if the investigator 
successfully places one insert. 
 
 


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Sample Size 
Considerations 
No formal sample size calculations were performed.  The proposed sample 
size will allow for initial estimates of efficacy as well as provide for 
sufficient safety information to be obtained, while still limiting the number 
of subjects exposed to the IP. 
Statistical Methods 
Summaries for continuous variables will include the sample size, mean, 
standard deviation, median, minimum and maximum.  Summaries for 
discrete variables will include frequencies and percentages.  The baseline 
visit will be defined as the last non-missing measure prior to initiation of IP.  
Differences between treatment groups will be calculated as OTX-CSI minus 
HV and change from baseline will be calculated as follow-up visit minus 
baseline visit values.   
Efficacy summaries will be presented for the primary study eye for Cohort 2 
only.  Cohort 1 will be included for all safety summaries and will include 
summaries of the secondary study eye.  Additional analyses may be 
presented for the secondary study eye.  All summaries will be presented by 
treatment group and visit, where appropriate.  In addition to looking at the 
individual formulations, the two formulations of OTX-CSI and HV will be 
combined and summarized. 
 
 


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3 
PRINCIPAL CONTACTS 
Please reference the CLN-Protocol-0054 Contact List. 
4 
BACKGROUND INFORMATION 
4.1 
Dry Eye Disease (DED) 
Dry eye disease (DED), also known as Keratoconjunctivitis Sicca (KCS), is one of the most common 
ophthalmic disorders presenting to the clinician (American Academy of Ophthalmology, 2018). It is 
estimated that more than 16 million United States (US) adults have been diagnosed with the disorder 
with 9 million being classified as moderate to severe (Farrand et al, 2017; Prevent Blindness, 2019). 
Prevalence of dry eye is higher among women than men (8.8% or approximately 11.1 million compared 
to 4.5% or 5.3 million, respectively) (Farrand et al, 2017).  Prevalence also increases with age with 2.7% 
of Americans age 18 to 34 years and 18.6% of Americans ≥75 years diagnosed with DED (Farrand et al, 
2017). 
DED is a multifactorial disorder of the tear film and ocular surface that results in eye discomfort (such 
as burning sensation, itching, redness, stinging, pain, and foreign body sensation), visual disturbances, 
tear film instability, and often ocular surface damage (Perry, 2008; Schultz, 2014). Inflammation of both 
the lacrimal gland and ocular surface has been shown to play a role in dry eye, resulting in a reduction in 
tear production (Salib et al, 2006; Sall et al, 2000; Stevenson et al, 2000; Willen et al, 2008). In animal 
models, T-cell-mediated inflammation was both a cause and result of dry eye (Niederkorn et al, 2006). 
In humans, dry eye was found to be associated with the presence of conjunctival T-cells and elevated 
levels of inflammatory cytokines in the tears compared with controls (Massingale et al, 2009; Lee et al, 
2013).  
4.2 
Investigational Product Rationale 
Cyclosporine for ophthalmic use was first approved in 1995 for the treatment of KCS in dogs. In 2003, it 
was approved for ophthalmic use in humans as Restasis® (cyclosporine ophthalmic emulsion 0.05%) and 
is indicated for increased tear production in patients whose tear production is presumed to be suppressed 
due to ocular inflammation associated with KCS (Restasis® NDA #021023). Cyclosporine A is a cyclic 
polypeptide immunosuppressive agent. Cyclosporine exerts its effect by lowering the activity of T-cells 
suppressing the associated immune response. Cyclosporine is thought to act as a partial 
immunomodulator. Topical cyclosporine eye drops were shown to decrease inflammatory mediators 
(Turner et al, 2000) and increase tear production (Stevenson et al, 2012). 
Commercial and marketed topical cyclosporine eye drops are sold around the world for the treatment of 
DED/KCS, Vernal Keratoconjunctivitis (VKC), and ocular inflammation (Appendix 17); however, there 
are limitations with the application of topical drops, which affect patient management. These limitations 
include difficulty with handling the bottle, limited instillation accuracy, potential washout of drops 
(Winfield, et al, 1990), and limited bioavailability of topical eye drops (Aldrich et al, 2013). In humans, 
the bioavailability from topical eye drops reaching the ocular tissues is less than 5% (Aldrich et al, 2013) 
which estimates to a bioavailable amount of less than 1.4 µg cyclosporine per day from Restasis® eye 
drops. Other limitations include the length of time (up to 6 months) for patients to be relieved from 
symptoms of DED and adverse reactions, such as ocular burning, associated with topical cyclosporine 
eye drops (Restasis® NDA #021023). 
In order to address the limitations of topical ophthalmic eye drops, Ocular Therapeutix has developed 
OTX-CSI (cyclosporine ophthalmic insert) for intracanalicular use. OTX-CSI combines the benefits of 
cyclosporine with punctal occlusion, an effective therapy for DED (McCabe, 2009). OTX-CSI contains 


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approximately 0.36 mg of cyclosporine and is designed to deliver therapeutic levels of cyclosporine onto 
the ocular surface for a duration of approximately 12 weeks. Continuous release of cyclosporine from 
the hydrogel inserts may result in higher daily concentrations of cyclosporine delivered to the ocular 
surface than is found with topical Restasis. In a beagle dog study, the average cyclosporine release rate 
from OTX-CSI was 3.5 μg/day, exceeding the estimated daily bioavailable dose from Restasis of <1.4 
µg cyclosporine per day. Tear fluid concentrations of cyclosporine measured in the beagle dog studies 
were typically 1 to 3 µg/mL. It is known that cyclosporine accumulates with repeat dosing in the cornea 
and lacrimal gland in animal studies (Acheampong et al, 1999), and this may be the case with sustained 
cyclosporine delivery from OTX-CSI. However, considering the low cyclosporine concentrations 
required at the ocular surface, OTX-CSI, offers promise as a potential sustained release treatment for 
patients with signs and symptoms of DED for approximately 12 weeks with a single insert.   
The two active formulations of OTX-CSI being studied in this clinical trial contain the same 
cyclosporine dose and release drug at the same daily rates but differ in their hydrogel composition. 
These two formulations are designed to have different breakdown periods of the hydrogel with one 
formulation designed to last approximately 2 to 3 months (Formulation 1) and the other approximately 3 
to 4 months (Formulation 2A). These formulations have been evaluated in prior human clinical trials 
conducted by the sponsor either with an active molecule or in a non-significant risk (NSR) study. The 
difference between these two OTX-CSI hydrogel formulations will be studied for retention and 
persistence in this Phase 1/2 clinical study.  
The two HV insert formulations being studied contain no active drug but differ in their hydrogel 
formulation. These two formulations are designed to have different hydrogel breakdown periods with 
one formulation designed to last approximately 1 week (Formulation 3) and the other approximately 3 to 
4 months (Formulation 2B). The difference between these two HV formulations will be studied in the 
clinical study as they provide for a short-acting and long-acting placebo. 
4.3 
Nonclinical Findings 
The safety, efficacy, and pharmacology of topical cyclosporine eye drops have been studied extensively 
by other Sponsors in animals (most notably rabbits and dogs). The study results have been extensively 
published in the scientific literature and in supporting regulatory submissions (Cequa NDA 210913, 
Restasis NDA 021023, Optimmune NADA 141 052). See Section 4 of the Investigator’s Brochure for 
more details. 
OTX-CSI has been assessed by Ocular Therapeutix in 2 non-GLP pharmacokinetic (PK) studies and 1 
GLP (Good Laboratory Practice) study to determine the PK of cyclosporine drug release from OTX-CSI 
into tear fluid over time. OTX-CSI was assessed in the GLP nonclinical study in a beagle dog model to 
determine its safety and toxicokinetics in a 90-day toxicology study with a 104-day recovery period 
compared to controls (hydrogel vehicle). The study designs are presented in Table 5 of Investigator’s 
Brochure. 
The average daily release rate of 3.5 µg/day released from OTX-CSI in the beagle dog PK study is 270-
fold less than demonstrated to be safe in 12-month repeat-dose toxicology study performed in support of 
Restasis (NDA 021023) and 68,000-fold less than the daily oral maintenance dose of cyclosporine used 
in transplantation therapy in patients.  
Ocular Therapeutix performed a GLP-compliant single-dose toxicity study for OTX-CSI (TP1408/CSI-
NC-Tox-2019-001 “Tox Study”) in beagle dogs, summarized in Table 5 of the Investigator’s Brochure. 
The two test article formulations (OTX-CSI-1A and OTX-CSI-2A) contained approximately 0.7 mg of 
cyclosporine, which approximates a 2X dose relative to the proposed clinical dose, and the vehicle 
hydrogels (HV-1B and HV-2B) contained no drug; both inserts (with and without active ingredient) 


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were manufactured in a similar fashion. The number 1 (OTX-CSI-1A; HV-1B) and number 2 (OTX-
CSI-2A; HV-2B) designated hydrogel formulations are designed to persist in vivo for approximately 2 
to 3 months, and 3 to 4 months, respectively. 
This study evaluated the potential ocular toxicity, ocular irritation, and systemic toxicity of the OTX-
CSI test articles and vehicle hydrogels following insertion over a 90-day period in 27 male and 27 
female beagle dogs. This study also evaluated the reversibility, persistence, and delayed occurrence of 
toxic effects after a 14-day recovery period.  
In summary, there was no evidence of systemic toxicity. No cyclosporine was observed in plasma. 
Cyclosporine concentrations in the tear fluid over the study duration demonstrated a sustained steady 
state release of cyclosporine for both formulations achieving average concentrations in the tear fluid 
ranging from 2.2 to 4.1 µg/mL over 90 days.  Monthly clinical ophthalmic examinations demonstrated 
no clinically relevant abnormalities for all eyes. Microscopic observations of relevant ocular tissues and 
surrounding adnexa was normal (score of 0) for all study groups with the single occurrence of an iris 
cyst deemed incidental. Findings of minimal to mild inflammation were due to localized tissue irritation 
at the site of the insert (punctal region) for both control and test article groups or frequent eyelid 
manipulation, as evidenced in the sham group and were not considered adverse. When present, any 
noted localized inflammation demonstrated reversal upon removal of the insert.  Histopathology 
findings were comparable between active and control groups. The presence of the control and test 
articles in the puncta was generally well tolerated. Please see the Investigator’s Brochure (section 4.4.3) 
for additional details. 
Relative to the proposed clinical dose of 0.36 mg per insert, this GLP toxicity study in male and female 
beagle dogs over 90-days assessed high cyclosporine doses of 0.70 mg (OTX-CSI-1A) and 0.68 mg 
(OTX-CSI-2A) in two hydrogel formulations. A maximum feasible dose in the test articles was 
formulated by increasing the percentage of drug in each insert and increasing the length from 2.7 mm 
(clinical formulation) to 3.5 mm (test articles). A maximum tolerated dose (MTD) was not established in 
this study despite exaggerated dosing, thereby supporting the use of a 0.36 mg cyclosporine dose in 
clinical studies. 
4.4 
Risk-Benefit Analysis 
OTX-CSI has the potential to deliver an efficacious cyclosporine dose to the ocular surface as a 
sustained release treatment for patients with signs and symptoms of DED; the dose selected is based on 
pre-clinical and clinical data. The risks associated with OTX-CSI have been minimized by formulating 
the ophthalmic insert with constituents that have a long history of use in medical devices and 
pharmaceuticals. Furthermore, results of biocompatibility and preclinical testing at a comparable dose, 
which will be used in the clinic, confirmed that OTX-CSI has no difference in inflammatory or toxic 
response of ocular tissues in the canine model compared with controls. 
The most common adverse events (AEs) associated with topical cyclosporine (see Appendix 1 
Cyclosporine Package Insert in the Investigator’s Brochure)   
• 
Ocular burning (17%) 
• 
Conjunctival hyperemia (1-5%) 
• 
Discharge (1-5%) 
• 
Epiphora (1-5%) 
• 
Eye pain (1-5%) 
• 
Foreign body sensation (1-5%) 
• 
Pruritus (1-5%) 
• 
Stinging (1-5%) 


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• 
Visual disturbance (most often blurring; 1-5%) 
The following adverse reactions have also been identified during post approval use of Restasis®: 
hypersensitivity (including eye swelling, urticaria, rare cases of severe angioedema, face swelling, 
tongue swelling, pharyngeal edema and dyspnea) and superficial injury of the eye (from the vial tip 
touching the eye during administration). Since these reactions are voluntarily reported by a population of 
an uncertain size, it is not always possible to reliably estimate their frequency or establish a causal 
relationship to drug exposure. 
The following AEs and/or risks have been observed with the insertion procedure: 
• 
Perforation of or trauma to the punctum and/or surrounding tissues 
• 
Punctoplasty 
• 
Tearing or epiphora 
• 
Eye inflammation 
• 
Allergic reaction 
• 
Dacrocystitis 
• 
Canaliculitis 
• 
Eye pain and discomfort, including foreign body sensation 
• 
Decreased/impaired visual acuity 
• 
Tearing with mucopurulent discharge 
• 
Stenosis 
• 
Inability to remove test article 
• 
Infection or intraocular infection that if severe could lead to temporary or permanent impairment 
of eyesight 
• 
Need for surgery on the lacrimal system 
Overall, the risk-benefit analysis supports the evaluation of OTX-CSI and HV inserts as planned for 
administration in this trial. 
4.5 
Dose and Administration Justification 
OTX-CSI planned clinical dose contains approximately 0.36 mg of cyclosporine designed to provide a 
sustained release of therapeutic levels of drug over approximately 12 weeks. Based on the size of the 
human canalicular system, this is the maximum dose that can be loaded into the insert without 
increasing the size of the insert. Using a lower or higher concentration of cyclosporine in the insert 
would not change the daily release of cyclosporine from the insert but would result in a shorter or longer 
duration of release, respectively, since low drug solubility (10 µg/mL) at physiological conditions and 
low tear fluid volume effectively regulates the rate of drug delivery to the ocular surface rather than 
concentration of cyclosporine in the implant.  
The purpose for studying the two active hydrogel formulations (Formulation 1 and Formulation 2A) in 
this clinical study is to ensure an adequate duration of hydrogel retention and persistence to allow drug 
delivery to the ocular surface for approximately 12 weeks prior to hydrogel degradation. Cyclosporine 
not released to the ocular surface and remaining within OTX-CSI will clear through the nasolacrimal 
duct when the insert softens and liquefies via hydrolysis.  
In humans, the bioavailability from topical Restasis eye drops reaching the ocular tissues is estimated to 
be less than 1.4 µg cyclosporine per day. Low cyclosporine concentrations (≥ 0.24 μg/mL) at the ocular 
surface are required for immunomodulation (Tang-Liu and Acheampong, 2005). The average daily 
cyclosporine release rate from OTX-CSI in the beagle PK study (see Table 8 in the Investigator’s 
Brochure) approximates 3.5 μg/day (range: 2.7 to 4.4 µg/day), so this daily dose should be sufficient for 
therapy in the treatment of DED. Assuming a maximum exposure of 4.4 µg cyclosporine/day/eye 


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delivered from OTX-CSI then this amount is approximately 218 times lower than the dose demonstrated 
to be safe in beagle dogs in the 12 month repeat-dose toxicology study performed in support of 
Restasis® (NDA 021023).  
Considering the highest daily cyclosporine release seen in the PK studies, the 4.4 µg/day release of 
cyclosporine from OTX-CSI (administered bilaterally) is approximately 68,000 times lower than the 
typical maintenance dose of 10 mg/kg/day in patients administered oral cyclosporine in transplantation 
treatment (Cequa NDA 210913). If all cyclosporine was released immediately following bilateral OTX-
CSI administration, then this would still be 750-fold less than the daily maintenance dose of oral 
cyclosporine. A rat carcinogenicity study was performed in support of Sandimmune (NDA 050573), and 
the NOAEL was 0.5 mg/kg/day. 
Because beagle dogs have an approximate 7-fold higher tear production rate than humans (7.8 vs 1.1 
µL/min, respectively; (Williams, 2005; Tomlinson, 2005), the total amount of cyclosporine released in 
humans could be less than 3.5 µg/day due to reduced tear fluid lavage at the interface of the hydrogel 
matrix. On the other hand, the cyclosporine concentrations on the human ocular surface may be 
expected to be higher due to less tear fluid dilution. Human PK studies with OTX-CSI will be conducted 
to confirm the actual daily cyclosporine release in humans.  
Ocular Therapeutix demonstrated ocular and systemic safety of bilateral administration of OTX-CSI in a 
single dose toxicity study in beagle dogs that were administered an exaggerated dose of 0.7 mg 
cyclosporine per eye, total of 1.4 mg per animal as summarized in Table 1. The inserts tested in the 
toxicity studies were much higher compared with the proposed clinical dose. Inserts in the GLP 
toxicology study were larger in size and greater in dose to achieve a maximal feasible dose of 
cyclosporine within the beagle canaliculus to attain a safety margin. A maximum feasible dose of 
approximately 0.7 mg cyclosporine per insert in the OTX-CSI assessed in the 90-day toxicity study in 
beagle dogs did not establish a maximum tolerated dose, thereby supporting the safe use of a 0.36 mg 
cyclosporine dose in clinical studies.   
No systemic drug levels were observed in the beagle dog toxicology study and these results are 
consistent with studies evaluating topical eye drops. Therefore, there is no systemic safety concerns 
beyond those established for the oral dosing formulations.  
Calculations of human equivalent dose (HED) of NOAELs and applications of safety factors used to 
calculate the ocular and systemic safety factors for the planned clinical dose of 0.36 mg/eye are 
presented in Table 1. Ocular HED is based on equivalence of eyes between humans and beagle dogs, 
and systemic HED is based on the dog to human conversion factor (1.8X) dose per unit weight per 
guidance (FDA, 2005). 
The dose of 0.36 mg cyclosporine in OTX-CSI to be evaluated in the proposed clinical trial is 
appropriate and safe for testing based on OTX-CSI nonclinical studies performed by Ocular Therapeutix 
and supported by cyclosporine topical eye drops and oral dosage form studies in support of regulatory 
submissions and reported in the literature. 
 


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Table 1 Safety Margins for Ocular and Systemic Toxicity 
NOAEL 
Study 
Dose per Eye 
Ocular Safety 
Factor for 0.36 
mg Human 
Dose per Eye 
Total 
Systemic Dose 
Systemic 
HED 
Systemic Safety 
Factor for 0.36 
mg Bilateral 
Human Dose 
“Tox Study” OTX-CSI 
90-Day Toxicity Study 
with a 14 Day 
Recovery Period in 
male and female dogs  
(TP1408/ CSI-NC-
Tox-2019-001) 
0.7 
mg/eye 
1.9×a 
0.18 
mg/kg 
0.10 mg/kgb 
8.3×c 
12-month repeat dose 
toxicology study in 
beagles from  
RESTASIS NDA 
021023 
0.96 mg/eye/day 
218×d 
NA 
NA 
NA 
Oral cyclosporine 
maintenance dose in 
transplantation therapy 
patients 
NA 
NA 
10 mg/kg/day 
NA 
68,000e 
a Ocular safety factor is a direct comparison between beagle and human eyes.  
b Systemic HED is derived by converting total systemic dose to mg/kg in beagles (8 kg) then dividing by a factor of 1.8 consistent with 
Example 3 in FDA Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in 
Adult Healthy Volunteers.  
c The systemic safety factor is the systemic HED (0.10 mg/kg) times human weight (60 kg) divided by the proposed clinical dose of 
0.36 mg administered bilaterally in patients. 
d Ocular safety factor is a direct comparison between daily cyclosporine exposure in beagle eyes from Restasis repeat-dose 12-month 
safety studies compared to maximal daily amounts (4.4 µg/day) released from OTX-CSI in PK studies. 
e Systemic safety factor is a direct comparison between daily cyclosporine dose used in transplantation therapy compared to maximal 
daily amounts (4.4 µg/day) released from OTX-CSI in beagle PK studies. 
4.6 
Compliance 
This trial will be conducted in compliance with the protocol, Good Clinical Practices (GCPs), including 
the International Council on Harmonization (ICH) Guidelines, and in general, consistent with the 
Declaration of Helsinki. In addition, all applicable local, state, and federal requirements relevant to the 
use of IPs in the countries involved will be adhered to. 
4.7 
Trial Population 
Cohort 1 will consist of approximately 5 subjects diagnosed with DED enrolled into an open-label active 
study arm.  In Cohort 2 approximately 140 subjects diagnosed with DED will be screened and randomly 
assigned to four treatment arms. 
5 
TRIAL OBJECTIVES 
The objectives of the trial with respect to Cohort 1 are to assess the safety and tolerability of OTX-CSI 
in subjects with DED.  The objectives of the trial with respect to Cohort 2 are to assess the safety, 
tolerability, and efficacy of OTX-CSI in subjects with DED. 


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6 
TRIAL DESIGN 
6.1 
Description of Trial 
This is a randomized, multi-center, double-masked, vehicle-controlled, phase 1/2 clinical study designed 
to evaluate the safety, tolerability, and efficacy of OTX-CSI (cyclosporine ophthalmic insert) for 
intracanalicular use for the treatment of subjects with DED.  Approximately 145 subjects (290 eyes) will 
be enrolled in this study at approximately 15 sites in the US.  Subjects will be enrolled in two cohorts. 
Cohort 1 will be an open-label group consisting of approximately 5 subjects.  Cohort 2 will be a 
randomized, double-masked group consisting of approximately 140 subjects treated with 2 different 
hydrogel formulations of OTX-CSI and 2 different formulations of HV.  Both eyes will be treated with 
the same treatment/formulation.  If both eyes qualify, the eye having the higher total corneal fluorescein 
staining score will be designated as the study eye and the other eye designated as the non-study eye.  If 
both eyes have the same total corneal fluorescein staining score, the study eye will be determined by the 
biostatistician prior to the analysis and will be detailed in the Statistical Analysis Plan.  If only one eye 
qualifies, that eye will be the study eye, but both eyes will still receive the same treatment/formulation.  
Table 2 reflects the treatment assignment paradigm for both Cohorts. 
Table 2 Treatment Assignment Paradigm for Cohorts 1 and 2 
Cohort Number 
Number of Subjects 
Treatment 
Formulation Number 
1 
Open-label 
5 
OTX-CSI 
2A 
2 
Randomized, 
double-masked 
40 
OTX-CSI 
1 
40 
OTX-CSI 
2A 
40 
HV 
2B 
20 
HV 
3 
 
The recommendation to progress to Cohort 2 will be the responsibility of the Safety Review Group 
(SRG) which will be minimally comprised by a Principal Investigator(s) in the study, the study Medical 
Monitor and the Chief Medical Officer (CMO) at Ocular Therapeutix, Inc.  The SRG (Appendix 2) may 
request the participation of an independent statistician and/or independent medical expert to assist in the 
assessment of the safety of the IP and the recommendation to progress.  The SRG will review the Cohort 
1 data to evaluate the safety of OTX-CSI Formulation 2A after all subjects have been followed for at 
least 2 weeks and will issue a recommendation whether or not to open enrollment in Cohort 2.  The SRG 
may further convene at any time during the study if necessary. 
Once subject eligibility has been determined, OTX-CSI or HV insert, as applicable, will be placed 
bilaterally, into either the superior or inferior canaliculus (per investigator’s preference), during the 
Insertion/Day 1 (Visit 2) for all subjects who meet the eligibility criteria. 
Cohort 1 
Subjects in Cohort 1 will undergo Screening 14 days prior to Insertion/Day 1 (Visit 2) to determine 
eligibility and eligibility will be re-confirmed at Visit 2 (Insertion/Day 1).  The treatment follow-up 
visits will occur at Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 9 (Visit 6), Week 12 
(Visit 7), and Week 16 (Visit 8). All subjects in Cohort 1 will be followed until Week 16 (Visit 8) 
whether or not an insert is visualized.  
Cohort 2 
Subjects in Cohort 2 will undergo Screening 14 days prior to Insertion/Day 1 (Visit 2) to determine 
eligibility.  At Visit 2 (Insertion/Day 1) eligibility will be confirmed and subjects who are eligible will 


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be randomly assigned to one of four treatment groups (OTX-CSI Formulation 1, OTX-CSI Formulation 
2A, HV Formulation 2B or HV Formulation 3) in a 2:2:2:1 ratio.  Should only a unilateral insertion be 
possible, Visit 2B will occur within 3 days to attempt the insertion again. The treatment follow-up visits 
will occur at Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 9 (Visit 6), Week 12 (Visit 7), 
and Week 16 (Visit 8).  All subjects in Cohort 2 will be followed until Week 16 (Visit 8) whether or not 
an insert is visualized. 
For both cohorts, if an OTX-CSI or HV insert is visualized in either eye or both eyes at Week 16 (Visit 
8) the subject will return to the clinic in 30 days (± 10 days; Visit 9) and will continue returning to the 
clinic every 30 days as needed until an insert can no longer be visualized and the physician has 
determined that there is no evidence of biological activity.  Additionally, subjects may be exited any 
time at the investigator’s discretion.  If an OTX-CSI or HV insert cannot be visualized at Week 16 (Visit 
8) and the physician has determined that there is no evidence of biological activity, the subject will exit 
the study. 
This study will be conducted per the schedule shown in Figure 1. 


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Figure 1 
Cohort 1 and Cohort 2 Study Schematic 
Cohort 1 
 
 
Cohort 2 
 


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6.2 
Study Endpoints 
6.2.1 
Safety Evaluations (Cohorts 1 and 2) 
Primary: 
• 
Non-ocular and Ocular Adverse Events (AEs) 
Secondary: 
• 
Best-Corrected Visual Acuity (BCVA) 
• 
Slit Lamp Biomicroscopy (including punctum assessment) 
• 
Intraocular Pressure (IOP) 
• 
Fundus Examination 
• 
Artificial tears use during the study 
6.2.2 
Efficacy Endpoints (Cohort 2 only): 
6.2.2.1 
Primary Efficacy Endpoints 
• 
Schirmer Test (without anesthesia) change from baseline (CFB) and absolute value at Week 12. 
6.2.2.2 
Secondary Efficacy Endpoints 
Signs: 
• 
Percent of subjects with ≥10 mm increase in Schirmer at Week 12. 
• 
Total Corneal Fluorescein Staining (tCFS) using NEI scale, CFB and absolute values at each 
post baseline study visit. 
• 
CFS sub-regions using NEI scale, CFB and absolute values at each post-baseline visit. 
• 
Conjunctival Lissamine Green Staining using NEI Scale, CFB and absolute values at each post-
baseline visit. 
Symptoms (subject-reported): 
• 
Eye Dryness Score (visual analogue scale [VAS]), CFB and absolute values at each post-baseline 
visit.  
• 
Ocular Surface Disease Index questionnaire (OSDI©) questionnaire, CFB and absolute values at 
each post-baseline visit (total score, each of the three domains, and the individual questions). 
• 
SPEED questionnaire (overall score and individual questions), CFB at each post-baseline visit. 
6.2.2.3 
Exploratory Efficacy Endpoints 
• 
Tear Film Break Up Time (TBUT), CFB at Week 12  
• 
Presence of OTX-CSI or HV insert at all post-baseline visits 
• 
Ease of insertion as assessed by the Investigator 
• 
Ease of visualization as assessed by the Investigator 
6.2.3 
Supplementary Objectives 
Systemic PK will be collected and analyzed from subjects at a subset of sites.  Tear Film PK will be 
collected and analyzed at all sites. 


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6.3 
Randomization and Blinding 
Cohort 1 will be open-label and treatment assignment will be known to the sponsor, investigator and 
subjects.  All 5 enrolled subjects in Cohort 1 will receive OTX-CSI Formulation 2A. 
Cohort 2 will be randomized to treatment assignment and double-masked.  If unmasking is required, the 
integrity of the study assessments and objectives will be maintained by limiting access to the unmasked 
data to the two individuals in the Safety Review Group (Sponsor Medical Monitor and Sponsor 
Statistician) who are not involved in the study conduct or directly by the investigator if required in an 
emergency. 
A randomization schedule will be computer-generated by a qualified biostatistician independent of the 
study conduct or project team and uploaded into the EDC system.  The EDC/IRT system will be used 
for randomization and unmasking. 
The HV and OTX-CSI inserts administered to subjects at randomization in the double-masked treatment 
phase will be comparable in appearance.  Study subjects and investigators and their staff will be masked 
to the identity of treatment until the final database is locked.  The Sponsor’s personnel involved with the 
conduct and monitoring of the study will remain masked until completion of the study and database 
lock. 
Appropriate precautions must be taken to prevent unauthorized access to the randomization scheme. 
Unless the subject’s safety requires otherwise and if time permits, the decision to unmask a treatment 
assignment is to be made jointly by the Investigator and Sponsor’s medical monitor.  
6.4 
Trial Treatment 
Formulation 1–   OTX-CSI 0.36 mg Cyclosporine Ophthalmic Insert 
Formulation 2A –  OTX-CSI 0.36 mg Cyclosporine Ophthalmic Insert  
Formulation 2B – Hydrogel Vehicle Insert 
Formulation 3 – Hydrogel Vehicle Insert 
6.5 
Trial Duration 
An individual subject’s participation in Cohort 1 and Cohort 2 will last approximately 18 weeks.  After 
the trial, subjects will be treated per the standard of care, at the discretion of their physician.  
Ongoing clinical investigational data will be reviewed by the Medical Monitor and/or the SRG. The 
clinical investigation may be suspended if the Medical Monitor and/or SRG, upon review and evaluation 
of the clinical data, finds the severity or incidence of adverse events or complications unacceptable for 
continuation of the investigation. 
6.6 
Trial Material Accountability 
All IP required for this study will be provided by Ocular Therapeutix, Inc., or its designee. The recipient 
will acknowledge receipt of study drug, indicating shipment content and condition. Damaged supplies 
may be replaced upon notification to Ocular Therapeutix, Inc., or its designee. Accurate records of all IP 
administered by study site should be maintained and recorded. A study monitor will periodically check 
the supplies of IP held at the site to verify accountability of all IP. All used and unused IP (non-
dispensed) will either be returned to Ocular Therapeutix, Inc., or its designee, or destroyed at the site 
upon written confirmation from Ocular Therapeutix, according to site procedures. The investigator must 
keep an accurate accounting of IP received from the supplier by maintaining a detailed inventory. This 
includes the amount of IP received by the site, amount administered to subjects, the amount destroyed 


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by the site and the amount returned to the sponsor or designee (as applicable), upon completion of the 
trial. All IP that is used during the course of the trial must be accounted for on a drug accountability 
form.  
Accurate records of receipt and disposition of the IP (e.g., dates, subject number, kits used, kits unused, 
etc.) must be maintained by designated site personnel. 
OTX-CSI and HV Inserts are sterile, ophthalmic inserts that are without antimicrobial preservatives. 
OTX-CSI and HV Inserts are provided in sterile, single use packages. The product is packaged in a 
hermetically sealed aluminum/polyester laminate pouch to maintain stability and sterility over time. The 
product is terminally sterilized and stored refrigerated. 
At the investigational site, IP must be kept in a safe storage area with limited access (e.g., in a 
refrigerator in a locked/limited access area). The refrigerator should be temperature monitored. IP 
should be stored at controlled refrigerated temperatures from 2°C to 8°C and protected from light.  
The IP must not be used outside of this clinical trial. The investigator or site personnel may not supply 
IP to other clinical sites, investigators, or subjects, or allow the IP to be used other than as directed by 
this protocol without prior authorization from Ocular Therapeutix, Inc. 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
The trial will include approximately 145 subjects from approximately 15 sites. 
7.1 
Inclusion Criteria 
Subjects will be eligible for study participation if they: 
1. 
Provide written informed consent prior to performing any study procedures and are willing to 
comply with study requirements and the study visit schedule. 
2. 
Are 18 years of age or older. 
3. 
Have a self-reported history or clinically confirmed diagnosis of DED by an eye care 
professional in both eyes for ≥6 months. 
4. 
Have ongoing DED, in the study eye at screening visit as defined by the following criteria: 
a. 
VAS eye dryness severity score of at least ≥30. 
In the same qualifying eye or both eyes: 
b 
A Total Corneal Fluorescein Staining Score of ≥6 (NEI scale) and <15.  
c. 
Have a Schirmer score (unanesthetized) of >0 mm and ≤10 mm wetting at 5 minutes. 
5. 
Have corrected visual acuity better than or equal to logarithm of the minimum angle of 
resolution (logMAR), +0.7 as assessed with Early Treatment of Diabetic Retinopathy Study 
(ETDRS) charts in both eyes. 
6. 
Are women of child-bearing potential (WOCBP) who are non-pregnant, non-lactating, and 
sexually inactive (abstinent) for 14 days prior to screening. And are willing to remain so 
through the last study visit. Alternatively, WOCBP who are not abstinent must have been 
using one of the following acceptable methods of birth control for the times specified: 
a. 
Intra-uterine device (IUD) in place for at least 3 months prior to screening and the desire 
to continue this method through the last study visit. 


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b. 
Barrier method (condom or diaphragm) with spermicide for at least 14 days prior to 
screening and the desire to continue this method through the last study visit. 
c. 
Stable hormonal contraceptive for at least 3 months prior to screening and the desire to 
continue this method through the last study visit. 
d. 
Surgical sterilization (vasectomy) of partner for at least 6 months prior to Day 1. 
7. 
Are postmenopausal women [i.e., no menstrual cycle for at least one year prior to Visit 1 
(Screening)] or are women who have undergone 1 of the following sterilization procedures at 
least 6 months prior to Visit 1 (Screening): 
a. 
Bilateral tubal ligation 
b. 
Hysterectomy 
c. 
Hysterectomy with unilateral or bilateral oophorectomy 
d. 
Bilateral oophorectomy 
8. 
Agree to the removal of non-dissolvable punctal plugs  4 weeks prior to the insertion visit 
(Day 1, Visit 2).  Long-term dissolvable punctal plugs  were not placed within 4 months prior 
to insertion visit (Day 1, Visit 2) and short-term dissolvable punctual plugs were not placed 
within 6 weeks prior to insertion (Day 1, Visit 2). 
7.2 
Exclusion Criteria 
Subjects are not eligible for study participation if they: 
1. 
Have a known or suspected allergy to any component of the study product. 
2. 
Are unwilling to discontinue use of contact lenses for 4 weeks prior to the screening visit and 
throughout the study period. 
3. 
Have any active systemic disease and/or systemic infection (e.g., fever or current antibiotic 
use), or uncontrolled medical condition that in the judgment of the investigator could 
confound study assessments or limit compliance. 
4. 
Have a documented history of ocular allergies, which, in the judgment of the investigator, are 
likely to have an acute increase in severity during the duration of this trial. Subjects sensitive 
to seasonal allergens that are not expected to be present during the study are permitted. 
5. 
Have a history of neuropathic pain related to dry eye. 
6. 
Have corneal erosive disease (e.g., multiple filaments, recurrent erosion syndrome) or other 
conditions suggestive of extensive damage of the cornea. 
7. 
Have a history of glaucoma or ocular hypertension or have intraocular pressure (IOP) < 5 
mmHg or > 24 mmHg or a history of elevated IOP within the past 6 months prior to the 
screening visit. 
8. 
Have abnormal lid anatomy that may confound study data, in the judgement of the 
investigator. 
9. 
Have a diagnosis of any of the following: 
a. 
Active ocular infection 
b. 
Uveitis 
c. 
Uncontrolled blepharitis (including severe MGD), in the judgement of the investigator 


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d. 
Moderate to severe pinguecula or pterygia, in the judgement of the investigator 
e. 
Stevens-Johnson syndrome 
f. 
Mucous membrane pemphigoid 
g. 
Significant conjunctival scarring, in the judgement of the investigator 
h. 
Chemical burn 
i. 
Herpetic or neurotrophic keratitis 
j. 
Congenitally absent lacrimal gland or meibomian glands 
k. 
Nasolacrimal duct obstruction in either eye 
10. Have had penetrating intraocular surgery in the past 6 months or require penetrating 
intraocular surgery during the study. 
11. Have had eyelid surgery within 6 months prior to the screening visit. 
12. Have had corneal laser refractive surgery, glaucoma surgery or corneal transplantation (full 
thickness, anterior or posterior). 
13. Have had cauterization of the punctum resulting in complete occlusion of the punctum. 
14. Have taken any of the following in either eye within 30 days prior to the screening visit: 
a. 
Topical ocular cyclosporine (e.g., Cequa®, Restasis®) 
b. 
Lifitegrast (Xiidra®) 
c. 
Autologous tears 
d. 
Topical ocular corticosteroids 
e. 
Topical ocular antibiotics 
f. 
Topical ocular NSAID 
g. 
Topical ocular antihistamines and/or mast cell stabilizers 
h. 
Topical or nasal vasoconstrictors 
i. 
Over The Counter (OTC) decongestants 
j. 
Intranasal Tear Neurostimulation 
15. Have taken any of the following in either eye prior to the screening visit: 
a. 
Periocular injection of any corticosteroid solution – 3 months 
b. 
Corticosteroid intra-vitreal depot injection– 3 months 
c. 
Ozurdex– 6 months 
d. 
Retisert– 40 months 
16. Have altered the dose of the following within 30 days prior to the screening visit (i.e., should 
keep dose stable throughout the study): 
a. 
Nutraceuticals or multivitamins 
b. 
Tetracycline compounds (tetracycline, doxycycline or minocycline) 
c. 
Inhaled, intramuscular or intra-articular corticosteroids (mouth or nasal spray form) 


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17. Have altered the dose of the following within 6 months prior to the screening visit (i.e., should 
keep dose stable throughout the study): 
a. 
Systemic anticholinergics 
b. 
Antidepressants (with the exception of rare usage as a sleep aid) 
c. 
Oral corticosteroids (e.g., prednisone. Prednisone dose must be less than 11 mg/day) 
18. Have taken isotretinoin (Accutane) or systemic immunosuppressive agents within 6 months 
prior to the screening visit. 
19. Are unwilling to withhold use of artificial tears (AT) for the duration of the trial.  
20. Have participated in any other investigational study within 30 days of the screening visit or 
plans to participate in any other investigational study during the follow-up period. 
21. Are an employee of the site or an immediate family member of an employee of the site. 
22. Are a current smoker (including marijuana, cigar, cigarette, and/or e-cigarettes). 
23. Have a known history of alcohol and/or drug abuse or are currently using illicit drugs or plan 
to use illicit drugs for the duration of the study. Recreational or medicinal marijuana allowed 
if oral consumption (no inhaled use). 
24. Are unwilling or unable to comply with the study protocol. 
25. The Investigator determines that the subject should not be included for reasons not already 
specified (e.g., systemic, behavioral, or other ocular disease/abnormality) if the health of the 
subject or the validity of the study outcomes may be compromised by the subject’s 
enrollment. 
7.3 
Entry/Randomization Criteria: 
To qualify for insertion at Day 1 (Visit 2), a subject must continue to meet all screening 
inclusion/exclusion criteria with the following exceptions/additions: 
1. 
VAS eye dryness severity score ≥25 
2. 
CFS total score ≥5 (NEI scale) and <15 in the same qualifying eye as Visit 1.  
3. 
Subject must not have taken prohibited medications and have completed the appropriate 
washout of prior medications, if necessary. 
4. 
Subjects who require AT use must not have administered >3 times/day for 3 consecutive days 
during the washout period (i.e. period between the screening and Day 1 visits.). 
NOTE:  AT use is not permitted unless absolutely necessary.  If subject requires AT use and 
has administered >3 times/for 3 days during the Screening period, they are not eligible for 
randomization. 
7.4 
Procedural Exclusion Criteria 
Subjects are considered procedural screen failures if the investigator is unsuccessful at placing the OTX 
Ophthalmic insert in both eyes (i.e. neither eye has an insert). Procedural screen failures will be exited 
from the study at that time and will be included in the disposition tables as ‘randomized, not treated’. 
Subjects will be followed per protocol if the investigator successfully places one insert.  
Note: A subject with a successful unilateral insertion should return within three days to re-attempt 
insertion in the unsuccessful eye.  


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7.5 
Subject Recruitment and Screening 
Each subject that is screened will be assigned a Subject Identification (ID) consisting of a 2-digit Site 
number plus a 3-digit Subject number. The Subject ID will be used as the primary subject identifier for 
the duration of the study.  For Cohort 2, once all inclusion and exclusion criteria are met at Visits 1 and 
2, each qualifying subject will be randomized via the IRT system and will be assigned a randomization 
number.   
The subject must sign the Informed Consent Form (ICF) before his or her participation in the study. A 
copy of the ICF must be provided to the subject or the subject's legal guardian. If applicable, it will be 
provided in a certified translation of the subject’s first or native language. The original signed ICF for 
each participating subject shall be filed with records kept by the investigator and must be available for 
verification by study monitors at any time, and a copy will be given to each subject.  
7.6 
Withdrawal Criteria 
Any subject who wishes to voluntarily discontinue study drug or withdraw from participation in the 
study for any reason is entitled to do so without obligation.   
IP may be discontinued (insert removed) and any subject may be discontinued from study participation 
at any time during the study at the discretion of the Investigator or the Sponsor for any reason.  
7.6.1 
Withdrawal Methods 
The Sponsor may terminate this study at any time. Reasons for termination may include but are not 
limited to, the following: 
• 
The incidence or severity of adverse events (AE) in this or other studies point to a potential 
health hazard for trial subjects. 
• 
Insufficient subject enrollment. 
• 
Any information becoming available during the study that substantially changes the expected 
benefit risk profile of the study treatments. 
7.6.2 
Collection of Data from Withdrawn Subjects 
In the event that study discontinuation of a randomized subject is necessary, the Investigator should 
make every attempt to have the subject complete Visit 8 assessments as soon as possible.  The reason for 
premature discontinuation should be recorded in the subject chart and entered in the eCRF. 
7.6.3 
Subject Replacement 
Subjects who withdraw from Cohort 1 will be replaced. Subjects who withdraw from Cohort 2 will not 
be replaced. 
8 
SUBJECT TREATMENT 
8.1 
Treatment Regimen 
OTX-CSI contains 0.36 mg of micronized cyclosporine in a resorbable hydrogel matrix.  It is intended 
to be inserted at Visit 2 and retained in the inferior or superior vertical canaliculus where it then provides 
sustained release of therapeutic levels of cyclosporine over approximately 12 weeks.   


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8.2 
Prior and Concomitant Therapy 
Only sponsor provided preservative free artificial tears may be used as needed (PRN), if absolutely 
needed, during the study. Use of AT will be discouraged, and subjects will be counseled to administer 
only if absolutely necessary.  Further, if used, subjects will be instructed not to administer AT with 2 
hours prior to any study visit. Preservative-free AT use will be recorded by subjects in a daily diary. All 
other tears substitutes are not permitted. 
Table 3 List of Prohibited Medications 
Medication 
Minimum Washout Period Prior to 
Screening (Visit 1) 
Topical ocular cyclosporine (e.g., Cequa®, Restasis®) 
30 days 
Lifitegrast (Xiidra®) 
30 days 
Autolgous tears 
30 days 
Topical ocular corticosteroids 
30 days 
Topical ocular antibiotics 
30 days 
Topical ocular NSAID 
30 days 
Topical ocular antihistamines and/or mast cell stabilizers 
30 days 
Topical or nasal vasoconstrictors 
30 days 
Intranasal Tear Neurostimulation 
30 days 
Periocular injection of any corticosteroid 
90 days 
Corticosteroid intra-vitreal depot injection 
90 days 
Ozurdex 
6 months 
Retisert 
40 months 
Isotretinoin 
6 months 
Systemic Immunosuppressants 
6 months 
 
8.3 
Study Assessments by Visit 
For every visit, perform study procedures as referenced in the Schedule of Events (Appendix 1) in the 
order specified below in both eyes.  Note:  Procedures will apply to both Cohort 1 and Cohort 2 unless 
otherwise indicated.  An asterisk (*) indicates the assessment may occur at any time during the visit.  
8.3.1 
Visit 1 (14 days prior to Day 1) Screening/Baseline Visit  
Note:  In rare cases, the Screening Visit can be split into 2 consecutive days. 
• 
Informed consent 
• 
Demographics * 
• 
Medical/ophthalmic history * 
• 
Record concomitant medications * 
• 
Urine pregnancy test * (may be performed at any time during the visit for WOCBP only) 
• 
VAS for Eye Dryness (Appendix 3) 
• 
OSDI (Appendix 4) 
• 
SPEED assessment (Appendix 5) 
• 
BCVA assessment (Appendix 8) 
• 
Slit lamp biomicroscopy (including punctum assessment) (Appendix 9) 
• 
TBUT (Appendix 11) 
• 
Corneal fluorescein staining (NEI scale) (Appendix 6) 
Conjunctival Lissamine Green Staining (NEI scale) (Appendix 7) 
• 
Schirmer Test (without anesthesia) (Appendix 12) 


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             Note: Wait 20 minutes prior to conducting Schirmer 
• 
IOP 
• 
Dilated fundus exam 
• 
Determine Eligibility 
• 
Dispense artificial tears (as needed) 
Note: Subjects will be provided with sponsor supplied Preservative Free Artificial Tear 
Substitutes but instructed to use only if necessary.  If used, instillation will be recorded in 
a daily diary.  Subjects will also be asked to withhold the tears within two hours of study 
visits. 
• 
Dispense Daily Subject Diary for Artificial Tears Use (as needed) (Appendix 16) 
Note: All ophthalmic assessments must be performed on both eyes. 
8.3.2 
Visit 2 Insertion/Day 1  
• 
Record concomitant medications * 
• 
Record AEs  
Note:  Any signs, symptoms or conditions captured prior to the insertion of IP, will be recorded 
as medical history. 
• 
Collect and review Subject Daily Diary for Artificial Tears Use (as needed) 
Note:  Subjects using AT > 3x/day for 3 consecutive days will be ineligible for randomization. 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
Note: Prior to insertion, a clinical determination of the absence of infection will be made based 
on the lack of erythema or discharge at the punctum. 
• 
Punctum Size Assessment  
• 
TBUT 
• 
Corneal fluorescein staining (NEI scale) 
• 
Conjunctival Lissamine Green Staining (NEI scale)  
Schirmer Test (without anesthesia) 
 Note: Wait 20 minutes prior to conducting Schirmer 
• 
IOP  
• 
Determine Eligibility for Insertion (Cohort 1 and 2) and Randomization (Cohort 2) 
• 
OTX-CSI or HV Insert Placement (Appendix 13) 
Note:  If placement is only successful in one eye, subjects should be asked to return within 0-3 
days to re-attempt insertion in the other eye.  
• 
Ease of Insertion Assessment 
• 
Systemic PK (at selected sites – to be collected 2 hours (±30 minutes) or 4 hours (±30 minutes) 
post-insertion) (Appendix 10) 
• 
Tear film PK (to be collected 1 hour (±30 minutes), 2 hours (±30 minutes) and 4 hours (±30 
minutes) post-insertion) 
• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
Note: All ophthalmic assessments must be performed on both eyes. 


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8.3.3 
Visit 2B (Day 1 + 1 to 3 days)  
This visit should be conducted for subjects with a successful unilateral insertion at Visit 2 (Day 1) to re-
attempt insertion in the other eye.  The following assessments should be performed at this visit: 
• 
OTX-CSI or HV Insert Placement (Appendix 13) 
• 
Ease of Insertion Assessment 
• 
Systemic PK (at selected sites – to be collected 2 hours (±30 minutes) or 4 hours (±30 minutes) 
post-insertion) (Appendix 10) 
• 
Tear film PK (to be collected 1 hour (±30 minutes), 2 hours (±30 minutes) and 4 hours (±30 
minutes) post-insertion) 
8.3.4 
Follow-Up Visit 3 (Week 2 ±2 days)  
• 
Record concomitant medications * 
• 
Record AEs * 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) * 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
OTX-CSI or HV Insert Presence by visual Assessment 
• 
Ease of Visualization by Investigator (Appendix 14) 
• 
Corneal fluorescein staining (NEI scale) 
• 
Conjunctival Lissamine Green Staining (NEI scale)  
• 
Systemic PK (at selected sites)  
      Note: Wait 20 minutes prior to conducting Schirmer/Tear Film PK 
• 
Schirmer Test (without anesthesia) and Tear Film PK  
• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
Note: All ophthalmic assessments must be performed on both eyes. 
8.3.5 
Follow-Up Visit 4 (Week 4 ±2 days) 
• 
Record concomitant medications * 
• 
Record AEs* 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) * 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
OTX-CSI or HV Insert Presence by visual Assessment 
• 
Ease of Visualization by Investigator 
• 
Corneal fluorescein staining (NEI scale) 
• 
Conjunctival Lissamine Green Staining (NEI scale) Schirmer Test (without anesthesia) and Tear 
Film PK  
Note: Wait 20 minutes prior to conducting Schirmer/Tear Film PK 


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• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
Note: All ophthalmic assessments must be performed on both eyes. 
8.3.6 
Follow-Up Visit 5 (Week 6 ±3 days) 
• 
Record concomitant medications * 
• 
Record AEs * 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) * 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
OTX-CSI or HV Insert Presence by visual Assessment 
• 
Ease of Visualization by Investigator 
• 
TBUT 
• 
Corneal fluorescein staining (NEI scale) 
Conjunctival Lissamine Green Staining (NEI scale)Schirmer Test (without anesthesia)/Tear Film 
PK  
Note: Wait 20 minutes prior to conducting Schirmer/Tear Film PK 
 
• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
Note: All ophthalmic assessments must be performed on both eyes. 
8.3.7 
Follow-Up Visit 6 (Week 9 ±3 days)  
• 
Record concomitant medications * 
• 
Record AEs * 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) * 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
OTX-CSI or HV Insert Presence by visual Assessment 
• 
Ease of Visualization by Investigator 
• 
Corneal fluorescein staining (NEI scale) 
• 
Conjunctival Lissamine Green Staining (NEI scale) 
• 
Schirmer Test (without anesthesia) and Tear Film PK 
 Note: Wait 20 minutes prior to conducting Schirmer/Tear Film PK 
• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
Note: All ophthalmic assessments must be performed on both eyes. 


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8.3.8 
Follow-Up Visit 7 (Week 12 ±3 days)  
• 
Record concomitant medications * 
• 
Record AEs * 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) * 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
OTX-CSI or HV Insert Presence by visual Assessment 
• 
Ease of Visualization by Investigator 
• 
TBUT 
• 
Corneal fluorescein staining (NEI scale) 
• 
Conjunctival Lissamine Green Staining (NEI scale)  
 Schirmer Test (without anesthesia) and Tear Film PK 
 Note: Wait 20 minutes prior to conducting Schirmer/Tear Film PK 
• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
Note: All ophthalmic assessments must be performed on both eyes. 
8.3.9 
Final Visit 8 (Week 16 ±3 days)  
• 
Record concomitant medications * 
• 
Record AEs * 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) * 
• 
Urine pregnancy test (WOCBP only) 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
OTX-CSI or HV Insert Presence by visual Assessment 
• 
Ease of Visualization by Investigator 
• 
Corneal fluorescein staining (NEI scale) 
• 
Conjunctival Lissamine Green Staining (NEI scale) 
• 
 Schirmer Test (without anesthesia) and Tear Film PK 
 Note: Wait 20 minutes prior to conducting Schirmer/Tear Film PK 
• 
Undilated Fundus Exam (*may be performed before or after IOP) 
• 
IOP 
• 
Punctum Size Assessment  
• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
Note: All ophthalmic assessments must be performed on both eyes. 
8.3.10 
30-day Follow-Up Visit (Week 20 ± 10 days) 
This visit will be conducted every 30 days (± 10 days) until an insert can no longer be visualized and the 
physician has determined that there is no evidence of biological activity.   


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• 
Record concomitant medications * 
• 
Record AEs * 
• 
Collect and review Subject Daily Diary for Artificial Tear Use (as needed) * 
• 
VAS for Eye Dryness 
• 
OSDI 
• 
SPEED assessment 
• 
BCVA assessment 
• 
Slit lamp biomicroscopy, including punctum assessment 
• 
OTX-CSI or HV Insert Presence by visual Assessment 
• 
Ease of Visualization by Investigator 
• 
Corneal fluorescein staining (NEI scale) 
 
Conjunctival Lissamine Green Staining (NEI scale) 
Schirmer Test (without anesthesia) and Tear Film PK 
 Note: Wait 20 minutes prior to conducting Schirmer/Tear Film PK 
• 
Dispense artificial tears (as needed) 
• 
Dispense Daily Subject Diary for Artificial Tear Use (as needed) 
 
Note: All ophthalmic assessments must be performed on both eyes. 
8.3.11 
Replacement of Inserts 
For Cohort 1 subjects only, within the first six weeks post treatment, if an insert is not visualized in one 
or both eyes by the Investigator, the Investigator should place a new insert in the respective eye(s) after 
confirming patency.  Refer to Appendix 13 for placement instructions. Replacement of inserts is not 
permitted for subjects enrolled in Cohort 2.   
8.3.12 
Unscheduled Visit 
An unscheduled visit may be performed during the course of the trial in order to ensure subject safety. 
All procedures performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit eCRF pages.  
Evaluations that may be conducted at an Unscheduled Visit may include: 
• 
Slit lamp biomicroscopy 
• 
BCVA assessment 
• 
IOP 
• 
Dilated or Undilated fundus exam 
• 
Urine pregnancy test (if applicable) 
• 
Assessment of AEs 
• 
Assessment of concomitant medications and/or treatments 
• 
Any other assessments needed in the judgment of the investigator 
9 
ASSESSMENT OF EFFICACY 
9.1 
Efficacy Parameters 
The efficacy assessments of the study are listed below and will be performed per the Schedule of Events 
in Appendix 1.  All clinical efficacy assessments should be performed in both eyes.  Efficacy 
assessments should be performed by the same person, e.g., FCS scoring for a given subject should be 
performed by the same person at each visit if possible.   


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The following efficacy measures will be assessed: 
Signs 
• 
Percent of subjects with ≥10 mm increase in Schirmer at Week 12. 
• 
Schirmer Test (without anesthesia) change from baseline (CFB) and absolute value at Week 12. 
• 
Total Corneal Fluorescein Staining (tCFS) using NEI scale, CFB and absolute values at each 
post baseline study visit. 
• 
CFS sub-regions using NEI scale, CFB and absolute values at each post-baseline visit. 
• 
Conjunctival Lissamine Green Staining using NEI Scale, CFB and absolute values at each post-
baseline visit. 
Symptoms (subject-reported) 
• 
Eye Dryness Score (visual analogue scale [VAS]), CFB and absolute values at each post-baseline 
visit.  
• 
Ocular Surface Disease Index questionnaire (OSDI©) questionnaire, CFB and absolute values at 
each post-baseline visit (total score and each of the three domains). 
• 
SPEED questionnaire, CFB at each post-baseline visit. 
Other Efficacy Evaluations 
• 
Tear Film Break Up Time (TBUT), CFB at Week 12. 
• 
Presence of OTX-CSI or HV insert at all post-baseline visits. 
• 
Ease of insertion as assessed by the Investigator. 
• 
Ease of visualization as assessed by the Investigator. 
10 
ADVERSE EVENTS 
The investigator and study staff are responsible for detecting and recording AEs and SAEs, during 
scheduled safety evaluations and whenever such information is brought to their attention. 
This section of the protocol provides definitions and detailed procedures to be followed. 
During each visit, the Investigator will question the subject about adverse events using an open question 
taking care not to influence the subject’s answers.  Throughout the course of the study, every effort must 
be made to remain alert to possible AEs. If an AE occurs, the first concern should be for the safety of the 
subject. If necessary, appropriate medical intervention should be provided.  At the signing of the ICF, 
each subject must be given the names and telephone numbers of study site staff for reporting AEs and 
medical emergencies. 
10.1 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. Examples of an AE include: 
• 
Exacerbation of a pre-existing condition including either an increase in frequency and/or 
intensity of the condition. 
• 
New conditions detected or diagnosed after IP administration even though it may have been 
present prior to the start of the study. 
• 
Signs, symptoms of a drug interaction. 


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• 
Signs, symptoms of a suspected overdose of either IP or a concurrent medication (overdose per 
se should not be reported as an AE/SAE). 
• 
A laboratory abnormality occurring after the start of the study (i.e., after insertion) that results in 
subject withdrawal from the study or medical treatment or further follow-up. 
10.2 
Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• 
Results in death. 
• 
Is life-threatening. 
Note: The term “life-threatening” refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe. 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. Hospitalizations 
for elective surgeries do not constitute an SAE. 
• 
Results in persistent or significant disability/incapacity. 
• 
Is a congenital abnormality/birth defect. 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered SAEs, such as important medical events that might not be immediately life threatening or 
result in death or hospitalization but might jeopardize the subject or might require intervention to 
prevent one of the other outcomes listed above. 
10.3 
Disease-Related Events or Outcomes Not Qualifying as AE/SAE’s 
Not applicable. 
10.4 
Monitoring and Recording of AEs and SAEs 
10.4.1 
Adverse Events 
Any AE experienced by the subject from Visit 2 (Insertion/Day 1) through Visit 9 (30-day follow-up 
visit) is to be recorded in the eCRF, regardless of the severity of the event or its relationship to study 
treatment.   
Any AEs already documented at a previous assessment and designated as ongoing, should be reviewed 
at subsequent visits, as necessary. If these have resolved, this should be documented.   
Changes in intensity or frequency of AEs should be recorded as separate events (i.e., a new record 
started). 
10.4.2 
Serious Adverse Events 
Any SAE experienced by the subject from Visit 2 (Insertion/Day 1) through Visit 9 (30-day follow-up 
visit) is to be recorded on an SAE Form, regardless of the severity of the event or its relationship to 
study treatment.  
Any SAE ongoing when the subject completes the study or discontinues from the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
10.4.3 
All Events 
All events must be assessed to determine the following: 
• 
If the event meets the criteria for an SAE as defined in Section 10.2. 


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• 
The severity of the event as defined in Section 10.7.1. 
• 
The relationship of the event to study treatment as defined in Section 10.7.2. 
10.5 
Immediate Reporting of Serious Adverse Events and Pregnancies 
In order to adhere to all applicable laws and regulations for reporting an SAE or pregnancy, the study 
site must formally notify the pharmacovigilance team within 24 hours of the study site staff becoming 
aware of the SAE or pregnancy. It is the Investigator’s responsibility to ensure that the SAE or 
pregnancy reporting information is emailed or faxed as described in Figure 2. It may be necessary for 
the pharmacovigilance team to directly communicate with the Investigator if additional information is 
required. 
After the initial SAE report, the investigator is required to proactively follow each subject and provide 
further information to the pharmacovigilance team on the subject’s condition within 24 hours. New or 
updated information will be recorded on the SAE reporting form. The updated SAE reporting form 
should be sent to the pharmacovigilance team within 24 hours as described in Figure 2. 
All additional follow-up evaluations must be reported to the pharmacovigilance team. Such data should 
be sent by fax or email (Figure 2) within 10 calendar days. All SAEs will be followed until the 
Investigator and Ocular Therapeutix agree that the event is satisfactorily resolved. 
10.6 
Death 
The death must be recorded on the appropriate eCRF. All causes of death must be reported as SAEs. The 
Investigator should make every effort to obtain and send death certificates and autopsy reports to the 
pharmacovigilance team. 
Figure 2 
Reporting Information for SAEs and Pregnancies 
To report initial or follow up SAE or Pregnancy information email or fax a copy of the SAE or 
Pregnancy report form to the following: 
ProPharma Group 
Email: clinicalsafety@propharmagroup.com 
Fax: +1-866-681-1063 
10.7 
Evaluating AEs and SAEs 
10.7.1 
Severity 
The following definitions should be considered when evaluating the severity of AEs and SAEs. 
Mild 
Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities. 
Moderate Event is bothersome, possibly requiring additional therapy, and may interfere with the 
subject’s daily activities. 
Severe 
Event is intolerable, necessitates additional therapy or alteration of therapy, and interferes 
with the subject’s daily activities. 
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An AE that is assessed as severe should not be confused with a SAE. An event is defined as ‘serious’ 
when it meets one of the pre-defined outcomes as described in Section 10.2 Definition of a SAE. 
10.7.2 
Relationship to OTX-CSI or Hydrogel Vehicle product or procedure 
The following definitions should be considered when evaluating the relationship of AEs and SAEs to the 
study treatment:  
Unrelated This category applies to those (S)AEs which, after careful consideration, are clearly and 
incontrovertibly due to extraneous causes (disease, environment, etc.); there is no 
reasonable probability that the (S)AE may have been caused by the insertion procedure 
or the ophthalmic insert. If the investigator determines that the AE is unlikely to be 
related to the study drug, then this would be the appropriate category. 
Related 
The following criteria should be applied in considering inclusion of an (S)AE in this 
category:   
i. 
It bears a reasonable temporal relationship to the insertion procedure or the 
presence of the ophthalmic insert  
ii. 
It could not be reasonably explained by the known characteristics of the subject’s 
clinical state, environmental or toxic factors or other factors (e.g., disease under 
study, concurrent disease(s) and concomitant medications) and modes of therapy 
administered to the subject  
iii. It disappears or decreases on removal of the ophthalmic insert  
iv. It follows a known pattern of response to the insertion procedure or the ophthalmic 
insert 
10.7.3 
Expectedness of Events 
Expectedness of all AEs will be determined according to the Investigator’s Brochure as determined by 
Ocular Therapeutix, Inc. 
10.8 
Pre-scheduled or elective Procedures or Routinely Scheduled Treatments 
A pre-scheduled or elective procedure or routinely scheduled treatment will not be allowed during the 
study period. 
10.9 
Procedures for Handling Special Situations 
10.9.1 
Pregnancy 
Females should not become pregnant during the study period. If this occurs the subject should notify the 
Investigator immediately. The Investigator must report the pregnancy as outlined in Section 10.5. In 
addition, the Investigator or study site staff must report the outcome of the pregnancy to the 
pharmacovigilance team. 
10.9.2 
Unmasking for Medical Emergencies 
In the case of a medical emergency or occurrence of an SAE, the randomization code may be unmasked 
and made available to the Investigator, Sponsor, and/or other study personnel involved in the conduct of 


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the study. In the absence of medical need, the randomization code will not be available to the above 
individuals until after the study is completed and the database is locked.  
In the event of a medical need, the Investigator will treat each subject, as medically required. If the 
Investigator feels it is necessary to unmask a subject’s treatment assignment after an emergency 
situation, the Investigator may call the Medical Monitor and notify the Sponsor. The treatment 
assignment will be revealed on a subject-by-subject basis with the approval of the Medical Monitor and 
Sponsor, thus leaving the masking of the remaining subjects intact. Ocular Therapeutix will make the 
final determination if the unmasking request will be granted. Once the unmasking request is granted the 
investigator or designee should use the IRT system to unmask the subject’s randomization code. The 
investigator must also indicate in source documents and in the eCRF that the mask was broken and 
provide the date, time, and reason for breaking the mask. Any AE or SAE associated with breaking the 
mask must be recorded and reported as specified in this protocol. 
Subjects will have the IP removed (Appendix 15) immediately if treatment assignment is unmasked. 
10.9.3 
Regulatory Reporting 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and judged 
by the Investigator or Ocular Therapeutix to be associated to the study treatment administered. Ocular 
Therapeutix will report SUSARs to the appropriate authorities within the required regulatory 
timeframes. Reports of SUSARs will be made to IRBs, and Investigators, as needed. 
11 
STATISTICAL METHODS AND DATA ANALYSIS 
11.1 
Statistical Methods 
Summaries for continuous variables will include the sample size, mean, standard deviation, median, 
minimum, and maximum.  Summaries for discrete variables will include frequencies and percentages.  
The baseline visit will be defined as the last non-missing measure prior to initiation of investigational 
treatment.  Differences between treatment groups will be calculated as OTX-CSI minus HV and change 
from baseline will be calculated as follow-up visit minus baseline visit values.   
11.2 
Unit of Analysis 
Both eyes will be treated with the same treatment/formulation.  If both eyes qualify, the eye having the 
higher total corneal fluorescein staining score will be designated as the study eye and the other eye 
designated as the non-study eye.  If both eyes have the same total corneal fluorescein staining score, the 
study eye will be determined by the biostatistician prior to the analysis and will be detailed in the 
Statistical Analysis Plan.  If only one eye qualifies, that eye will be the study eye, but both eyes will still 
receive the same treatment/formulation.   
The unit of analysis in this study will be the primary study eye for all efficacy summaries.  Efficacy 
summaries will be presented for the primary study eye for Cohort 2 only.  Cohort 1 will be included for 
all safety summaries and will include summaries of the secondary study eye.  Additional analyses may 
be presented for the secondary study eye.  All summaries will be presented by treatment group and visit, 
where appropriate.  In addition to looking at the individual formulations, the two formulations of OTX-
CSI and HV will be combined and summarized. 


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11.3 
Sample Size Determination 
No formal sample size calculations were performed.  The proposed sample size will allow for initial 
estimates of efficacy as well as provide for sufficient safety information to be obtained, while still 
limiting the number of subjects exposed to the IP. 
11.4 
Statistical Significance 
All statistical testing will be done at the two-sided alpha level of 0.05.  As this is a Phase 1/2 study, no 
adjustments to alpha will be made for testing of multiple endpoints. 
11.5 
Trial Termination 
Should it become apparent during the trial that there is a significant safety concern or there is an issue 
with enrollment, the trial may be terminated.  In addition, should information become known during the 
course of the trial that would negatively impact the trial, the trial may be terminated.  In addition, the 
FDA or another regulatory authority may terminate the trial. 
11.6 
Missing Data 
The primary analyses of efficacy data will use Markov Chain Monte Carlo (MCMC) multiple 
imputation methodology to impute missing data. Sensitivity analyses, to determine robustness of results, 
will be performed using last observation carried forward (LOCF) and observed data only. 
11.7 
Efficacy Analyses 
The primary efficacy endpoint analysis of Schirmer Test will use a linear model with fixed effects of 
baseline Schirmer Test value and treatment will be used to compare Schirmer Test change from baseline 
and absolute values with least square means comparing OTX-CSI treatment groups to HV treatment 
groups at each visit.  In addition to looking at the individual formulations, the two formulations of OTX-
CSI and HV will be combined and a linear model, two-sample t-test and Wilcoxon rank sum test will be 
performed at each visit. 
Secondary efficacy endpoint analyses of Total Corneal Fluorescein Staining (tCFS) using NEI scale, 
CFS sub-regions using NEI scale, Conjunctival Lissamine Green Staining using NEI scale, Eye Dryness 
Score (VAS) and Ocular Surface Disease Index questionnaire (total score, each of the three domains and 
the individual questions) will be analyzed similar to the Schirmer Test.  Speed measures (overall score 
and individual questions) will also be analyzed similarly, however only change from baseline will be 
presented. Percent of subjects with ≥10 mm increase in Schirmer at Week 12 will be analyzed using a 
chi-squared test. 
11.8 
Exploratory Analyses 
Tear Film Break Up Time at Week 12 will be analyzed similar to the Schirmer Test, however only 
observed data will be used.  Presence of insert, ease of insertion as assessed by the Investigator and ease 
of visualization as assessed by the Investigator at all post-baseline visits will be summarized using 
discrete statistics and will be tested between treatment groups (all treatment groups separately and 
combined) using the Pearson chi-squared statistic. 
11.9 
Reporting Deviations 
Should there be changes in any analyses described in the protocol, the statistical analysis plan will 
document them.  Should there be changes in any analyses described in the statistical analysis plan, the 
final clinical study report will describe them.  


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11.10 
Subject Population(s) for Analysis 
Intent-to-Treat (ITT): The ITT population will include all randomized subjects. Analysis on the ITT 
population will be used as the primary efficacy analysis and will be performed for all efficacy endpoints, 
analyzing subjects under the treatment to which they were randomized.   
Per Protocol (PP): The PP population will include all ITT subjects who do not deviate from the 
protocol in any way likely to seriously affect the efficacy outcomes of the study.  Analysis on the PP 
population will be used as secondary efficacy analysis and will be performed for select efficacy 
endpoints, analyzing subjects under the treatment actually received.  Important protocol deviations will 
be identified prior to locking the study database.  
Safety:  The Safety population will include all subjects who received IP (OTX-CSI or HV). Analyses 
performed on the Safety population will be according to the treatment the subject actually received. 
12 
STUDY MANAGEMENT AND DATA COLLECTION 
12.1 
Confidentiality 
All trial subject data collected and processed for the purposes of this trial should be maintained by the 
investigator and his/her staff with adequate precautions as to ensure that the confidentiality of the data is 
in accordance with local, state, and federal laws and regulations. 
Monitors, auditors, and other authorized representatives of CRO, drug safety, the sponsor, the IRB/IEC 
approving this trial, the FDA, the Department of Health and Human Services, other domestic 
government agencies, and other foreign regulatory agencies will be granted direct access to the trial 
subject’s original medical and trial records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to the aforementioned individuals to the extent permitted by 
law. 
A report of the results of this trial may be published or sent to the appropriate health authorities in any 
country in which the IP may ultimately be marketed, but the subject’s identity will not be disclosed in 
these documents. 
12.2 
Source Documents 
Source documents may include a subject’s medical records, hospital charts, clinic charts, the 
investigator’s trial subject files, as well as the results of diagnostic tests such as X-rays, laboratory tests, 
and EKGs. The investigator’s electronic copy of the eCRFs serves as the investigator’s record of a 
subject’s trial-related data. 
12.3 
Case Report Forms 
All subject data will be captured in the subject source documents which will be transcribed to the 
eCRFs. The investigator is responsible for ensuring that trial data is completely and accurately recorded 
on each subject’s eCRF, source documents, and all trial-related materials. All trial data should also be 
attributable, legible, contemporaneous, original, accurate and complete. Recorded data should only be 
corrected in a manner that does not obliterate, destroy, or render illegible the previous entry (e.g., by 
drawing a single line through the incorrect entry and writing the revision next to the corrected data). An 
individual who has corrected a data entry should make clear who made the correction and when, by 
adding to the correction his/her initials as well as the date of the correction. 
Data entry of all enrolled and randomized subjects will use software that conforms to 21 CFR Part 11 
requirements and will be performed only by staff that have been trained on the system and have access 


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to the system. Minimal data will be entered for screen failure subjects. An audit trail will be maintained 
within the electronic system to capture all changes made within the eCRF database. After the end of the 
trial and database lock, compact discs (CDs) containing copies of all applicable subjects’ eCRFs will be 
provided to each investigator site to be maintained on file by the investigator. 
12.4 
Records Retention 
All trial related correspondence, subject records, consent forms, record of the distribution and use of all 
IP and copies of case report forms should be maintained on file for at least two years after the last 
approval of a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region; or until at least two years have elapsed since the formal 
discontinuation of clinical development of the IP. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. The investigator must notify the sponsor prior to destroying trial documentation 
even after the above-mentioned time has passed. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping trial records, custody must be transferred to a person who will accept the responsibility. The 
sponsor must be notified in writing of the name and address of the new custodian. 
13 
STUDY MONITORING, AUDITING, AND INSPECTING 
13.1 
Study Monitoring Plan 
Each investigator must adhere to the protocol as detailed in this document and agrees that any changes 
to the protocol must be approved by Ocular Therapeutix, Inc., prior to seeking approval from the 
IRB/Ethics Committee.  Investigators’ proficiency in observing and scoring ophthalmic observations 
will be established and documented via review of academic training and experience, prior to examining 
subjects.  Each investigator will be responsible for enrolling only those subjects who have met protocol 
eligibility criteria. During study conduct, Ocular Therapeutix, Inc and/or its representative will conduct 
periodic monitoring visits to ensure that the protocol and Good Clinical Practice (GCP) are being 
followed. The monitors may review source documents to confirm that the data recorded on the 
electronic case report forms (eCRFs) are accurate.  Further details of the trial monitoring (including 
medical monitoring) will be outlined in a monitoring plan. 
The investigator and institution will allow Ocular Therapeutix, Inc., monitors or its representatives and 
appropriate regulatory authorities direct access to source documents and CRFs to perform this 
verification. Data Managers will also review data and may interact with site personnel for clarifications. 
It is important that the investigator(s) and their relevant personnel are available during the monitoring 
visits and possible audits or inspections and that sufficient time is devoted to the process. 
14 
ETHICAL CONSIDERATIONS 
This study will be conducted according to the standards of International Council on Harmonization, 
Good Clinical Practice Guideline, Research Ethics Committee regulations, any applicable government 
regulations, Trust and Research Office policies and procedures.  
This protocol, the ICF, relevant supporting information, and all types of subject recruitment or 
advertisement information must be submitted to the IRB/Ethics Committee for review and must be 
approved before the study is initiated. Any amendments to the protocol must also be approved by the 
IRB/Ethics Committee prior to implementing changes in the study. The investigator is responsible for 


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keeping the IRB/Ethics Committee apprised of the progress of the study, any SAEs, and any changes 
made to the protocol according to the requirements of the site’s IRB.  
15 
REFERENCES 
Acheampong, A.A., Shackleton, M., Tang-Liu, D.D.S., Ding, S., Stern, M.E. and Decker, R., 1999. 
Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle 
dogs. Current eye research, 18(2), pp.91-103. 
Aldrich, D.S., Bach, C.M., Brown, W., Chambers, W., Fleitman, J., Hunt, D., Marques, M.R., Mille, Y., 
Mitra, A.K., Platzer, S.M. and Tice, T., 2013. Ophthalmic preparations. US Pharmacopeia, 39(5), pp.1-
21. 
American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern® 
Guidelines. Dry Eye Syndrome. San Francisco, CA: American Academy of Ophthalmology; 2018. 
Available at www.aao.org/ppp. Accessed September 23, 2019. 
Cequa NDA 210913 
Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. 2017. Prevalence of Diagnosed Dry Eye 
Disease in the United States Among Adults Aged 18 Years and Older. Am J Ophthalmol. Oct;182:90-
98. 
Food Drug Administration (FDA). Guidance for Industry: Estimating the Maximum Safe Starting Dose 
in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. July 2005. Available at 
www.fda.gov/regulatory-information/search-fda-guidance-documents/estimating-maximum-safe-
starting-dose-initial-clinical-trials-therapeutics-adult-healthy-volunteers. Accessed September 23, 2019. 
Lee, S.Y., Han, S.J., Nam, S.M., Yoon, S.C., Ahn, J.M., Kim, T.I., Kim, E.K. and Seo, K.Y., 2013. 
Analysis of tear cytokines and clinical correlations in Sjögren syndrome dry eye patients and non–
Sjögren syndrome dry eye patients. American journal of ophthalmology, 156(2), pp.247-253. 
Massingale, M.L., Li, X., Vallabhajosyula, M., Chen, D., Wei, Y. and Asbell, P.A., 2009. Analysis of 
inflammatory cytokines in the tears of dry eye patients. Cornea, 28(9), pp.1023-1027. 
McCabe C. Plugs reduce dry-eye symptoms, improve vision. Review of Ophthalmology. 19 November 
2009. Available at www.reviewofophthalmology.com/article/plugs-reduce-dry-eye-symptoms-improve-
vision. Accessed September 29, 2019. 
Niederkorn, J.Y., Stern, M.E., Pflugfelder, S.C., De Paiva, C.S., Corrales, R.M., Gao, J. and Siemasko, 
K., 2006. Desiccating stress induces T cell-mediated Sjögren’s syndrome-like lacrimal 
keratoconjunctivitis. The Journal of Immunology, 176(7), pp.3950-3957. 
OPTIMMUNE label - https://vetlabel.com/lib/vet/meds/optimmune/  
OPTIMMUNE NADA 141052 
Perry HD. Dry eye disease: Pathophysiology, classification, and diagnosis. Am J Manag Care. 
2008;14:S79-S87. 
Prevent Blindness. Am I at risk for dry eye? 2019. Available at www.preventblindness.org/dry-eye. 
Assessed September 23, 2019. 
RESTASIS® NDA #021023 
Salib GM, McDonald MB, Smolek M. Safety and efficacy of cyclosporine 0.05% drops versus 
unpreserved artificial tears in dry-eye patients having laser in situ keratomileusis. J Cataract Refract 
Surg. 2006; 32(5):772–778. 


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Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and 
safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 study 
group. Ophthalmology. 2000; 107(4):631–639. 
Sandimmune NDA #050573 
Schultz C. Safety and efficacy of cyclosporine in the treatment of chronic dry eye. Ophthalmol Eye Dis. 
2014;6:37-42. 
Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporin A ophthalmic emulsion in the 
treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin A 
Phase 2 Study Group. Ophthalmology. 2000; 107(5):967–974. 
Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. 
Arch Ophthalmol. 2012;130(1):90-100. 
Tang-Liu DD-S, Acheampong A 2005. Ocular pharmacokinetics and safety of ciclosporin, a novel 
topical treatment for dry eye. Clin Pharmacokinet.44(3):247-261. 
Tomlinson A, Khanal S. Assessment of tear film dynamics: quantification approach. Ocul Surf. 
2005;3(2):81-95. 
Turner K, Pflugfelder SC, Ji Z, Feuer WJ, Stern M, Reis BL. Interleukin-6 levels in the conjunctival 
epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion. Cornea. 
2000; 19(4):492–496. 
Willen CM, McGwin G, Liu B, Owsley C, Rosenstiel C. Efficacy of cyclosporine 0.05% ophthalmic 
emulsion in contact lens wearers with dry eyes. Eye Contact Lens. 2008; 34(1):43–45. 
Williams DL. Analysis of tear uptake by the Schirmer tear test strip in the canine eye. Vet 
Ophthalmol.2005;8(5):325-30. 
Winfield AJ, Jessiman D, Williams A, Esakowitz L. A study of the causes of non-compliance by 
patients prescribed eyedrops. British Journal of Ophthalmology. 1990;74(8):477-480. 


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Appendix 1 
Time and Events Schedule  
See Section 8.3 for order of assessments. 
Study Parameter* 
Screening/ 
Baseline Visit 
Day -14  
Insertion Day 
Day 1 
Follow-
up  
Week 2 
±2 days 
Follow-up  
Week 4 
±2 days 
Follow-up  
Week 6 
±3 days 
Follow-up  
Week 9 
±3 days 
Follow-up 
Week 12 
±3 days 
Final Visit  
Week 168 
±3 days 
30-Day 
Follow-Up 
Visit9   
(± 10 days) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Determine Eligibility 
X 
X 
 
 
 
 
 
 
 
Demographic Information 
X 
 
 
 
 
 
 
 
 
Medical/Ophthalmic History 
X 
 
 
 
 
 
 
 
 
Record Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record Adverse Events10 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine Pregnancy Test1 
X 
 
 
 
 
 
 
X 
 
OSDI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VAS for Eye Dryness 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SPEED 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Corneal Fluorescein Staining Using the NEI 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conjunctival Lissamine Green Staining Using 
the NEI Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of BCVA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Slit Lamp Biomicroscopy (including punctum 
assessment) 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
OTX-CSI or HV Insert Presence by Visual 
Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
Ease of Visualization as assessed by 
Investigator 
 
 
X 
X 
X 
X 
X 
X 
X 
Systemic PK sample collection2 (at selected 
sites) 
 
X5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tear Film PK sample collection7  (at all sites) 
 
X6 
X 
X 
X 
X 
X 
X 
X 
Measurement of TBUT 
X 
X 
 
 
X 
 
X 
 
 
Schirmer Test (without anesthesia) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP Measurement 
X 
X 
 
 
 
 
 
X 
 
Fundus Exam3 
X 
 
 
 
 
 
 
X 
 


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Study Parameter* 
Screening/ 
Baseline Visit 
Day -14  
Insertion Day 
Day 1 
Follow-
up  
Week 2 
±2 days 
Follow-up  
Week 4 
±2 days 
Follow-up  
Week 6 
±3 days 
Follow-up  
Week 9 
±3 days 
Follow-up 
Week 12 
±3 days 
Final Visit  
Week 168 
±3 days 
30-Day 
Follow-Up 
Visit9   
(± 10 days) 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Punctum Size Assessment 
 
X 
 
 
 
 
 
X 
 
Randomization (Cohort 2) 
 
X 
 
 
 
 
 
 
 
OTX-CSI or HV Insert Placement 
 
         X11 & 12 
 
 
 
 
 
 
 
Ease of Insertion as assessed by the 
Investigator 
 
X 
 
 
 
 
 
 
 
Dispense Artificial Tears (as needed) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Daily Subject Diary for Artificial 
Tear Use  
(as needed) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect/review Daily Subject Diary for 
Artificial Tear Use (as needed) 
 
X 
X 
X 
X 
X 
X 
X 
X 
*All examinations need to be performed on both eyes. See Section 8.4 to confirm the order that the assessments should be performed.   
 
1 A negative UPT is required for women of childbearing potential to be included in the study. 
2   Select sites will collect Systemic PK.  All sites will collect Tear Film PK.   
3  Dilated fundus examination at screening; undilated fundus examination at Week 16. 
4  Prior to insertion, a clinical determination of the absence of infection will be made based on the lack of erythema or discharge at the punctum. 
5  Systemic PK sample on Day 1 will be collected after successful insertion at 2 hours (±30 minutes) or 4 hours (±30 minutes) post-insertion. 
6  Tear Film PK will be collected at 1 hour (±30 minutes), 2 hours (±30 minutes), and 4 hours (±30 minutes) post insertion on Day1. Tear Film PK should be collected using Schirmer 
strips. 
7  Tear Film PK will be collected using Schirmer Tests strips. These will be collected and sent to the central lab for analysis. See lab manual.   
8  Early termination subjects should complete assessments based on the final visit (Visit 8) schedule of assessments. 
9  Post week 16 visit will be conducted every 30 days (± 10 days) until an insert can no longer be visualized and the physician has determined that there is no evidence of biological 
activity. Additionally, subjects may be exited at the investigator’s discretion. 
10 Signs, symptoms, conditions occurring prior to insertion on Day 1 should be captured as medical history. 
11 For Cohort 1 subjects only, within the first six weeks post treatment, if an insert is not visualized in one or both eyes by the Investigator, the Investigator should place a new insert in the 
respective eye(s) after confirming patency.  Refer to Appendix 13 for placement instructions. Replacement of inserts for Cohort 2 subjects is not permitted. 
12 If placement is only successful in one eye, subjects should be asked to return within 1-3 days to attempt insertion in the other eye. The following items should be repeated at the return   
visit, Insert Placement, Ease of Insertion, Tear Film PK and AEs. 


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Appendix 2 
Safety Review Group Charter 
The recommendation to continue into Cohort 2 (double-masked, vehicle-controlled, portion of the study) will be the responsibility of a Safety 
Review Group constituted by the Principal Investigator(s) of the study, the Medical Monitor and the Chief Medical Officer at Ocular 
Therapeutix, Inc.  The SRG, may request the participation of an independent statistician and/or independent medical expert to assist in the 
assessment of the safety of the IP and the recommendation to progress.  
In order to maintain the integrity of the trial, unless it is absolutely necessary, the safety review should be conducted using masked subject-
specific information.  The Safety Review Group will convene after all subjects in Cohort 1 have been followed for at least 2 weeks (or at any 
time during the study if necessary) to evaluate the safety of the IP.  Upon review and evaluation, the SRG will issue a recommendation to 
Ocular Therapeutix, Inc.   
General guidelines for the recommendation to escalate to the next cohort: 
A recommendation to escalate to the next cohort may be issued if no more than 1 dose limiting toxicity (DLT) is found during or at the end of 
the cohort. 
Indicators of DLT in this study will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0, 
Published November 27, 2017).  
A DLT is defined as one of the following events at the specified toxicity level deemed by the Investigator to be related to OTX-CSI and based 
on CTCAE (version 5.0)1 
 Any Grade 3 or higher adverse event 
 Any Grade 2 or higher adverse event that in the judgment of the Investigator or Sponsor requires discontinuation of dosing 
 Any Grade 2 or higher adverse event that in the judgment of the Investigator or Sponsor requires further investigation before 
determining dose escalation. 
Events, including serious adverse events (SAEs), deemed by the Investigator to be related to the subject’s underlying medical condition, will 
not be considered DLTs and used for determination of dose escalation, e.g., hyperglycemic event.  
                                               
1 Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general 
guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or 
noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 


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Recommendations: 
The recommendations of the Safety Review Group to Ocular Therapeutix, Inc. may include:  
 Escalate to Cohort 2 
 Repeat Cohort 1 
 Amend the protocol 
 Stop the study 
If the safety data obtained in Cohort 1 warrants continuation of the study and initiation of Cohort 2, the Safety Review Group will issue a 
memorandum to Ocular Therapeutix, Inc. recommending continuing to Cohort 2.   
If a review of Cohort 2 data is required and upon the review of the masked safety information, the Safety Review Group requires unmasked 
information in order to ensure the safeguard of the interests of the study subjects, the unmasked information will be provided. Please refer to 
Section 10.9.2 for unmasking procedures. 
The Safety Review Group will make every effort to arrive to a recommendation by consensus. 
Ocular Therapeutix, Inc. representatives then will make a decision that is consistent primarily with the safeguard of the interests of the study 
subjects. 


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Appendix 3 
VAS for Eye Dryness  
The following procedures should be followed for conducting the study assessments. The Visual Analog 
Scale (VAS) should be performed prior to all other ocular assessments.  
To complete the VAS questionnaire, ask the subject to rate the severity and the frequency of symptom of 
eye dryness (0%-100%) by placing a vertical mark (ǀ) on the horizontal line to indicate the level of eye 
discomfort that they are experiencing in both eyes currently (i.e., right now) and how often the eye 
dryness is experienced.   
0% corresponds to: “no discomfort” 
100% corresponds to: “maximal (the most) discomfort” 
 
Eye Dryness  
Severity 
 
  0%                                                                                   100% 
|                                                                                                     |        
Eye Dryness Frequency 
 
  0%                                                                                   100%                   
|                                                                                                     |        
 


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Appendix 4 
OSDI 
 


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Appendix 5 
Standard Patient Evaluation of Eye Dryness (SPEED) Questionnaire 
The following procedure should be followed for conducting the study assessments.  
Report the type of SYMPTOMS you experience and when they occur: 
 
At This Visit 
Within Past 72 
Hours 
Within Past 3 
Months 
Symptoms 
Yes 
No 
Yes 
No 
Yes 
No 
Dryness, Grittiness, or Scratchiness 
 
 
 
 
 
 
Soreness or Irritation 
 
 
 
 
 
 
Burning or Watering 
 
 
 
 
 
 
Eye Fatigue 
 
 
 
 
 
 
 
 
 
 
 
 
 
Report the FREQUENCY of the above-checked symptoms as Never, Sometimes, Often, or Constant 
using the numbering system below: 
Symptoms 
0 
1 
2 
3 
0 = Never 
1 = Sometimes 
2 = Often 
3 = Constant 
Dryness, Grittiness, or Scratchiness 
 
 
 
 
Soreness or Irritation 
 
 
 
 
Burning or Watering 
 
 
 
 
Eye Fatigue 
 
 
 
 
 
 
 
 
 
 
Report the SEVERITY of your symptoms using the rating list: 
Symptoms 
0 
1 
2 
3 
4 
 
Dryness, Grittiness, or Scratchiness 
 
 
 
 
 
 
Soreness or Irritation 
 
 
 
 
 
 
Burning or Watering 
 
 
 
 
 
 
Eye Fatigue 
 
 
 
 
 
 
 
0 = No problems 
 
1 = Tolerable – not perfect but not uncomfortable 
 
2 = Uncomfortable – irritating but does not interfere with my day 
 
3 = Bothersome – irritating and interferes with my day 
 
4 = Intolerable – unable to perform my daily tasks 
 


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Appendix 6 
Corneal Fluorescein Staining (CFS) Procedure - Using NEI Scale 
The procedure for evaluating corneal staining should be completed after the Tear Film Breakup Time 
(TBUT).  If the CFS is done closely following the TBUT, then an additional application of fluorescein 
dye is not required.  If a long time has elapsed between the TBUT and the CFS then an additional 
application of fluorescein dye may be required. 
The process of completing the TBUT followed by the CFS may be completed right eye first followed by 
the left eye.  A second fluorescein strip to apply dye to the left eye is required with this technique.  If 
preferred, the TBUT followed by the CFS may be performed by alternating between the right and left 
eye. Starting first with the TBUT right eye, followed by TBUT left eye, then CFS right eye, then CFS 
left eye. Using this technique only one fluorescein strip is required to apply the dye to both the right and 
left eye. 
1. 
Wet a sponsor supplied Fluorescein strip with the sponsor supplied saline solution/eye wash.  
Use enough liquid to wet the end of the strip without liquid falling from the end of the strip. 
2. 
Ask the subject to look up and touch the moistened strip to the inferior palpebral conjunctiva 
without touching the strip to the bulbar conjunctiva. 
3. 
Ask the subject to blink several times to distribute the fluorescein dye. 
4. 
Wait between 2 to 3 minutes before evaluating the cornea for staining. 
5. 
Use the cobalt blue illumination and the Wratten yellow filter to assess the corneal staining. 
6. 
Record the staining for each of the 5 regions of the cornea, central, inferior, nasal, temporal, 
and superior using the NEI 0-3 scoring scale (see diagram).  The CFS total score will be the 
sum of the five areas (0 to 15). 
Grade each region, Central (1), Superior (2), Temporal (3), Nasal (4), Inferior (5), for each eye 
according to the following grading scale: 
0 = No Staining 
1 = Mild Staining 
2 = Moderate Staining 
3 = Severe Staining 
NEI Corneal Staining Grading - Scale 
OD 
      
 
 
  OS 
 
 


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Appendix 7 
Conjunctival Lissamine Green Staining (LGS) Procedure - Using the NEI Scale 
Using this technique only one lissamine strip is required to apply the dye to both the right and left eye. 
1. 
The goal is to moisten the strip without having a drop of dye ready to fall from the end of the 
strip.  Wet a sponsor supplied Lissamine strip with the sponsor supplied saline solution/eye 
wash.  If a drop of excess dye hangs from the end of the moistened strip, then shake off the 
excess over a paper towel. The moistened strip is now ready to use. 
2. 
Ask the subject to look up and touch the moistened strip to the inferior palpebral conjunctiva 
without touching the strip to the bulbar conjunctiva.  
3. 
Ask the subject to blink several times to distribute the lissamine dye. 
4. 
Wait between 1 to 4 minutes before evaluating the conjunctiva for staining. 
5. 
Use the moderate illumination to assess the conjunctival staining. 
6. 
Record the staining for each of the 6 regions of the conjunctiva. The temporal conjunctive is 
divided into 3 sections, zones 1, 2, and 3, temporal, superior temporal, inferior temporal, 
respectively. The nasal conjunctive is divided into 3 sections, zones 4, 5, and 6, superior 
nasal, inferior nasal, and nasal, respectively.  Grade the conjunctival staining using the NEI 0-
3 scoring scale (see diagram).  The LGS total score will be the sum of the six areas (0 to 18). 
7. 
The staining produced by an elevated pinguecula may not improve.  The staining associate 
with the pinguecula may be consistently excluded from the total Lissamine score. 
 
NEI Conjunctival Staining Grading – Lissamine: 
 
 


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Appendix 8 
Best Corrected Visual Acuity 
BCVA will be conducted at all Visits.   
Visual acuity testing should precede any examination requiring contact with the eye or instillation of 
study dyes.  LogMAR visual acuity must be assessed using an ETDRS or modified ETDRS chart.  
Visual acuity testing should be performed with best correction using subject’s own corrective lenses 
(spectacles only) or pinhole refraction. 
An ETDRS or modified ETDRS chart may be used.  If a Lighthouse chart is used (24.5” by 25”; either 
reflectance or retro-illuminated), the subject must view the chart from a distance of exactly 4 meters 
(13.1 feet).  If smaller reproductions (18” by 18”, e.g., Prevent Blindness) are used, the subject viewing 
distance should be exactly 10 feet.  Reflectance wall charts should be frontally illuminated (60-watt bulb 
or a well-lit room). 
The subject should be positioned according to the elevation of the chart (either seated or standing) so 
that the chart is at a comfortable viewing angle.  The right eye should be tested first.  The subject should 
attempt to read each letter, line-by-line, left to right, beginning with line 1 at the top of the chart.  The 
subject should be told that the chart has letters only, no numbers.  If the subject reads a number, he or 
she should be reminded that the chart contains no numbers, and the examiner should then request a letter 
instead of the number.  The subject should be asked to read slowly, about 1 letter per second, to achieve 
the best identification of each letter.  He/she is not to proceed to the next letter until he/she has given a 
definite response.  If the subject changes a response before he has read aloud the next letter, then the 
change must be accepted. 
Maximum effort should be made to identify each letter on the chart; the subject should be encouraged to 
guess.  When it becomes evident that no further meaningful readings can be made, the examiner should 
stop the test.  The number of letters missed or read incorrectly should be noted. 
In order to provide standardized and well-controlled assessments of visual acuity during the 
study, consistently use the same lighting conditions throughout the study. 
LogMAR Visual Acuity Calculations 
After each measurement of visual acuity, the visual acuity score for the visit is calculated. The last line 
in which a letter is read correctly will be taken as the base logMAR reading. To this value will be added 
the number "N x 0.02" where 'N' represents the total number of letters missed up to and included in the 
last line read. This total sum represents the logMAR visual acuity for that eye. 
For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 0.1 line. 
 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 and line 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
 


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


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Appendix 10 
PK Sample collection (Systemic and Tear Film Sample) 
Systemic PK 
Refer to laboratory manual for complete procedure. 
Tear Film PK Sample 
Tear fluid samples will be collected from both eyes at the same time.  
Refer to the lab procedure manual for the complete procedure. 


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Appendix 11 
Tear Film Break-Up Time 
The time required for the tear film to break up following a blink is called TBUT. It is a quantitative test 
for measurement of tear film stability. The normal time for tear film breakup is over 15 seconds. A 
fluorescein strip is moistened with saline and applied to the inferior cul-de-sac. After a couple of blinks, 
the tear film is examined using a broad-beam of slit lamp with a blue filter for the appearance of the first 
dry spots on the cornea. TBUT values of less than 5–10 seconds indicate tear instability and are 
observed in patients with mild to moderate dry eye disease. 


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Appendix 12 
Schirmer Test (without anesthesia) 
Please refer to Tear Film PK Sample collection in the Lab Manual for measurement technique. 
 


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Appendix 13 
OTX-CSI or HV Insert Placement 
The following is the suggested placement technique and it can be modified based on investigator’s 
medical judgment. 
1. Apply lateral pressure to elongate the canalicular system.  Pull the skin 
near the punctum down and temporally.  A technician may assist if 
needed.   
 
2. Dilate using the punctal dilator in towards the nose, ensuring the 
system is elongated.  Dilate through the punctum deeper into the 
canaliculus, dilate for depth, as well as width.  If desired, rotating the 
dilator in a spinning motion may help with the dilating process. 
 
3. Dry the surface around the punctal opening using an ophthalmic 
sponge.  More than one sponge may be necessary to ensure adequate 
drying of area.  A technician may assist if needed. 
 
4. Grasp the OTX-CSI or HV insert with forceps and insert at a slight 
angle towards the nose.  Aim for 70% of insertion within the first 
motion.  Use forceps to tap or push insert the remainder of the way in.  
The insert should sit slightly beneath the punctal opening.   
Note:  Excessive squeezing of an OTX-CSI or HV may cause 
deformation.  The product should be handled with care, so it maintains its 
original shape prior to insertion.  If the insert hydrates before placement 
slightly below the punctal opening (resembling a trumpet shape), it should 
be discarded and a new insert should be used.  If the insert hydrates before 
ideal positioning or if a portion of the insert is protruding and unable to be 
inserted, it should be removed, discarded and a new insert should be used. 
 
5. An OTX-CSI or HV insert can be visualized when illuminated by a 
blue light source (e.g., slit lamp or hand-held blue light) with yellow 
filter. 
 


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Version 05, 03 June 2021 
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Page 72 of 76 
 
Placement of OTX-CSI or HV insert in Canaliculus 
 
The investigator will grade the level of ease of insertion of the ophthalmic insert as “easy” (1), 
“moderate” (2) or “difficult” (3).   


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Appendix 14 
OTX-CSI or HV Insert Ease of Visualization 
The Investigator will assess the presence of an OTX-CSI or HV insert at each study visit, using a blue 
light and yellow filter. The Investigator will be asked to grade the level of ease of visualization of the 
punctum plug as “easy”, “moderate”, or “difficult”.  


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Confidential  
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Appendix 15 
OTX-CSI or HV Insert Removal Instructions 
An OTX-CSI or HV Insert can be removed either via application of manual pressure or saline irrigation, 
as described below. 
Application of Manual Pressure 
1. 
Identify the OTX-CSI or HV insert through the punctal tissue. 
2. 
Place the blunt end of an instrument (e.g., punctum dilator or equivalent) next to the distal end 
of the test article. 
3. 
Apply gentle pressure by pressing on the instrument in an outward motion towards the 
punctum until the test article is expressed out of the punctum. 
Saline Irrigation 
1. 
Ensure the punctum and canaliculus is sufficiently dilated.  
2. 
Fill a sterile syringe and fixed cannula with sterile saline.  
3. 
Insert the cannula into the vertical canaliculus.  
4. 
Insert until it stops and simultaneously rotate the syringe horizontally.  
5. 
Press slowly on the syringe plunger to flush the test article. 
6. 
In order to help assess whether the flush is complete, it may be helpful to ask the subject to 
report when they taste saline or feel it in their nose. 
The investigator will grade the level of ease of removal of the insert as “easy” (1), “moderate” (2) or 
“difficult” (3).  


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Appendix 16 
Daily Subject Diary (For Artificial Tear Use) 
If subjects are using artificial tears, they will be asked to complete a dosing diary for each 
administration.  The dosing diary will collect the following information with respect to artificial tear 
administration: 
Date 
Time 
Time 
Time 
Time 
Time 
Initials 
 DD/MMM/YYYY 
___ /____ / _____ 
HR/MIN 
AM/PM 
 
HR/MIN 
AM/PM 
HR/MIN 
AM/PM 
HR/MIN 
AM/PM 
HR/MIN 
AM/PM 
  


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Appendix 17 
Marketed Cyclosporine 
Product Name 
Company 
Indication 
Region 
Marketed since 
Cequa™ 
(0.9 mg/ml) 
Sun Ophthalmics 
DED (KCS with 
presumed 
suppression of 
tear production) 
US 
2018 
Restasis® 
(0.5 mg/ml) 
Allergan 
DED (KCS with 
presumed 
suppression of 
tear production) 
US, Canada, and 
33 other countries 
2003 
Ikervis® 
(1.0 mg/ml) 
Santen 
Pharmaceutical 
DED (Severe 
keratitis which 
has not improved 
with tear 
substitutes) 
Europe 
2015 
Papilock Mini® 
(1.0 mg/ml) 
Santen 
Pharmaceutical 
VKC 
Japan 
2005 
Modusik-A 
Ofteno® 
(1.0 mg/ml) 
Laboratorios 
Sophia 
KCS with a 
functional 
decrease of 
lacrimal glands 
Mexico, Chile 
Columbia, Peru, 
Ecuador, 
Argentina 
2003 
TJ Cyporin® 
(0.5 mg/ml) 
Taejoon Pharma 
Co, Ltd 
Ocular 
inflammation 
associated with 
KCS 
South Korea 
2003 
Lacrinmune®  
(0.5 mg/ml) 
Bausch & Lomb, 
Inc. 
KCS with a 
functional 
decrease of 
lacrimal glands 
Argentina 
NA 
Cyporin® 
(0.5 mg/ml) 
Aristopharma, Ltd Ocular 
inflammation 
associated with 
KCS 
Bangladesh, 
Myanmar 
NA 
Cyclorin® 
(0.5 mg/ml) 
Ibn Sina 
Pharmaceutical 
Industry, Ltd. 
Ocular 
inflammation 
associated with 
KCS 
Bangladesh 
NA 
Adapted from Lallemand et al., 2017 
 

SAP_001.pdf: 
     Statistical Analysis Plan 
Sponsor:  
Ocular Therapeutix, Inc. 
Protocol: 
CLN-Protocol-0054 
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 CRS-BS-TP-000005 V 1.0  
 
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A randomized, multi-center, double-masked, vehicle-controlled, Phase 1/2 study to evaluate the 
safety, tolerability, and efficacy of OTX-CSI (cyclosporine ophthalmic insert) for intracanalicular use 
for the treatment of subjects with dry eye disease (DED) 
 
Protocol Number: 
(Version Date) 
CLN-Protocol-0054 
Version 05 – 03 June 2021 
Name of Test Drug: 
OTX-CSI 0.36 mg Cyclosporine Ophthalmic Insert 
Phase: 
1/2 
Methodology: 
A randomized, multi-center, double-masked, vehicle-controlled 
Sponsor: 
Ocular Therapeutix, Inc. 
24 Crosby Drive 
Bedford, MA 01730 USA 
Sponsor Representative: 
Alet Van Beek 
Senior Director, Clinical Operations 
 
Document Date: 
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Document Version: 
1.0 
 
 
 






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TABLE OF CONTENTS  
 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS .................................................................. 11 
1.1. 
INTRODUCTION ............................................................................................................................. 11 
2. 
STUDY DESIGN ................................................................................................................... 13 
2.1. 
SYNOPSIS OF STUDY DESIGN......................................................................................................... 13 
2.2. 
OBJECTIVES OF STATISTICAL ANALYSIS ......................................................................................... 16 
2.3. 
RANDOMIZATION METHODOLOGY AND MASKING ...................................................................... 16 
2.4. 
STOPPING RULES AND UNMASKING ............................................................................................. 16 
2.5. 
STUDY PROCEDURES ..................................................................................................................... 16 
 
EFFICACY AND SAFETY VARIABLES ................................................................................................ 19 
2.6. 
19 
2.6.1. 
EFFICACY VARIABLES ................................................................................................... 19 
2.6.2. 
SAFETY VARIABLES ...................................................................................................... 20 
3. 
SUBJECT POPULATIONS ...................................................................................................... 21 
3.1. 
POPULATION DEFINITIONS ........................................................................................................... 21 
3.2. 
PROTOCOL DEVIATIONS ................................................................................................................ 21 
4. 
STATISTICAL METHODS ...................................................................................................... 22 
4.1. 
SAMPLE SIZE JUSTIFICATION ......................................................................................................... 22 
4.2. 
GENERAL STATISTICAL METHODS AND DATA HANDLING ............................................................ 22 
4.2.1. 
GENERAL METHODS .................................................................................................... 22 
4.2.2. 
UNIT OF ANALYSIS....................................................................................................... 23 
4.2.3. 
COMPUTING ENVIRONMENT ...................................................................................... 23 
4.2.4. 
METHODS OF POOLING DATA .................................................................................... 23 
4.2.5. 
ADJUSTMENTS FOR COVARIATES ............................................................................... 23 
4.2.6. 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................... 23 
4.2.7. 
SUBPOPULATIONS....................................................................................................... 24 
4.2.8. 
WITHDRAWALS, DROPOUTS, LOSS TO FOLLOW-UP, REPLACEMENT ......................... 24 
4.2.9. 
MISSING, UNUSED, AND SPURIOUS DATA .................................................................. 24 
4.2.10. 
VISIT WINDOWS .......................................................................................................... 25 
4.3. 
INTERIM ANALYSES ....................................................................................................................... 25 


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4.4. 
SUBJECT DISPOSITION ................................................................................................................... 26 
4.5. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................................................... 26 
4.5.1. 
BASELINE OCULAR ASSESSMENTS .............................................................................. 26 
4.5.2. 
OCULAR AND NON-OCULAR MEDICAL HISTORY ......................................................... 27 
4.6. 
TREATMENT EXPOSURE ................................................................................................................ 27 
4.7. 
EFFICACY EVALUATION ................................................................................................................. 28 
4.7.1. 
PRIMARY ANALYSES .................................................................................................... 28 
4.7.2. 
SENSITIVITY ANALYSES ................................................................................................ 29 
4.7.3. 
SECONDARY ANALYSES ............................................................................................... 29 
4.7.4. 
EXPLORATORY ANALYSES ............................................................................................ 30 
4.8. 
PHARMACOKINETIC EVALUATIONS .............................................................................................. 31 
4.9. 
SAFETY ANALYSES ......................................................................................................................... 31 
4.9.1. 
LABORATORY DATA..................................................................................................... 32 
4.9.2. 
VITAL SIGNS AND PHYSICAL EXAMINATIONS .............................................................. 33 
4.9.3. 
CONCOMITANT MEDICATIONS ................................................................................... 33 
5. 
CHANGES TO PLANNED ANALYSES ...................................................................................... 34 
6. 
REFERENCES ...................................................................................................................... 35 
7. 
CLINICAL STUDY REPORT APPENDICES ................................................................................ 36 
7.1. 
STATISTICAL TABLES TO BE GENERATED ....................................................................................... 36 
7.2. 
DATA LISTINGS TO BE GENERATED ............................................................................................... 42 
7.3. 
SAS CODES .................................................................................................................................... 45 
7.3.1. 
VARIABLES USED IN SAS CODES: ................................................................................. 45 
7.3.2. 
SAS CODES TO IMPUTE THE MISSING USING MCMC MI ............................................ 46 
7.3.3. 
SAS CODES TO IMPUTE THE MISSING USING FCS MI .................................................. 46 
7.3.4. 
SAS CODES TO RUN T-TEST ON MI DATA .................................................................... 46 
7.3.5. 
SAS CODES TO RUN ANCOVA (USING PROC MIXED) ON MI DATA ............................. 47 
7.3.6. 
SAS CODES TO GENERATE AND POOL PROPORTIONS USING MI DATA ...................... 48 
7.3.7. 
SAS CODES TO GENERATE AND POOL THE ODDS RATIO (OR) USING MI 
DATA ........................................................................................................................... 48 
7.3.8. 
SAS CODES TO OUTPUT 95% CI FOR PROPORTIONS USING CLOPPER-
PEARSON METHOD AND 95% CI FOR THE PROPORTION DIFFERENCE 


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USING CHAN AND ZHANG (1999) METHOD USING OBSERVED AND 
LOCF DATA .................................................................................................................. 49 
7.3.9. 
SAS CODES TO DESIGNATE STUDY EYE RANDOMLY IN A CASE BOTH 
EYES HAVE THE SAME TOTAL CORNEAL FLUORESCEIN STAINING SCORE .................. 49 
 
 
 
 
 
 
LIST OF IN-TEXT TABLES 
Table 
Page 
Table 1 
Table 1 Time and Events Schedule .................................................................................. 17 
 


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ABBREVIATIONS 
AE 
Adverse Event/Experience 
AT 
Artificial Tears 
BCVA 
Best Corrected Visual Acuity 
C 
Celsius 
CD 
Compact Disc 
CFB 
Change from Baseline 
CFR 
Code of Federal Regulations 
CFS 
Corneal Fluorescein Staining 
CMO 
Chief Medical Officer 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
CV 
Curriculum Vitae 
DED 
Dry Eye Disease 
DLT 
Dose-Limiting Toxicity 
e  
Electronic 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
F1 
Formulation 1 - OTX-CSI 0.36 mg Cyclosporine Ophthalmic Insert 


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F2A 
Formulation 2A - OTX-CSI 0.36 mg Cyclosporine Ophthalmic Insert 
F2B 
Formulation 2B (F2B) - Hydrogel Vehicle Insert 
F3 
Formulation 3 (F3) - Hydrogel Vehicle Insert 
FCS 
Fluorescein Corneal Scoring 
FCS MI 
Fully Conditional Specification multiple imputation 
FDA 
Food and Drug Administration 
GCB 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HED 
Human Equivalent Dose 
HV 
Hydrogel Vehicle Insert 
ICH 
International Council on Harmonization 
ICF 
Informed Consent Form 
ID 
Subject Identification 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
IUD 
Intra-Uterine Device 
KCS 
Keratoconjunctivitis Sicca 


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LogMAR 
Logarithm of the Minimum Angle of Resolution 
mg 
Milligram 
ml 
Milliliter 
mm 
Millimeter 
mmHg 
Millimeters of Mercury 
NDA 
New Drug Application 
NEI 
National Eye Institute 
NOAEL 
No Observed Adverse Event Level 
NSAID 
Nonsteroidal Anti-Inflammatory Drug 
NSR 
Non-Significant Risk 
PP 
Per Protocol 
PRN 
As Needed 
OD 
Right Eye 
OS 
Left eye 
OSDI 
Ocular Surface Disease Index 
OTX 
Ocular Therapeutix 
OTX-CSI 
Cyclosporine Ophthalmic Insert 
PK 
Pharmacokinetics 
SAE 
Serious Adverse Event/Experience 
SPEED 
Standard Patient Evaluation of Eye Dryness 
SRG 
Safety Review Group 


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SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBUT 
Tear Film Break Up Time 
tCFS 
Total Corneal Fluorescein Staining 
μg 
Microgram 
UPT 
Urine Pregnancy Test 
US 
United States 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
VKC 
Vernal Keratoconjunctivitis 
WOCBP 
Women of Child-Bearing Potential 


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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
Dry Eye Disease (DED) 
Dry eye disease (DED), also known as Keratoconjunctivitis Sicca (KCS), is one of the most 
common ophthalmic disorders presenting to the clinician (American Academy of 
Ophthalmology, 2018). Prevalence of dry eye is higher among women than men (Farrand et al, 
2017). Prevalence also increases with age with 2.7% of Americans age 18 to 34 years and 18.6% 
of Americans ≥75 years diagnosed with DED (Farrand et al, 2017). 
DED is a multifactorial disorder of the tear film and ocular surface that results in eye discomfort, 
visual disturbances, tear film instability, and often ocular surface damage (Perry, 2008; Schultz, 
2014). In humans, dry eye was found to be associated with the presence of conjunctival T-cells 
and elevated levels of inflammatory cytokines in the tears compared with controls (Massingale 
et al, 2009; Lee et al, 2013). 
Investigational Product Rationale 
In order to address the limitations of topical ophthalmic eye drops, Ocular Therapeutix has 
developed OTX-CSI (cyclosporine ophthalmic insert) for intracanalicular use. OTX-CSI combines 
the benefits of cyclosporine with punctal occlusion, an effective therapy for DED (McCabe, 
2009). OTX-CSI contains approximately 0.36 mg of cyclosporine and is designed to deliver 
therapeutic levels of cyclosporine onto the ocular surface for a duration of approximately 12 
weeks. Continuous release of cyclosporine from the hydrogel inserts may result in higher daily 
concentrations of cyclosporine delivered to the ocular surface than is found with topical 
Restasis.  
Considering the low cyclosporine concentrations required at the ocular surface, OTX-CSI, offers 
promise as a potential sustained release treatment for patients with signs and symptoms of DED 
for approximately 12 weeks with a single insert. 
The two active formulations of OTX-CSI being studied in this clinical trial contain the same 
cyclosporine dose and release drug at the same daily rates but differ in their hydrogel 
composition. These two formulations are designed to have different breakdown periods of the 
hydrogel with one formulation designed to last approximately 2 to 3 months (Formulation 1 (F1)) 
and the other approximately 3 to 4 months (Formulation 2A (F2A)). 
 
 


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The two HV insert formulations being studied contain no active drug but differ in their hydrogel 
formulation. These two formulations are designed to have different hydrogel breakdown 
periods with one formulation designed to last approximately 1 week (Formulation 3 (F3)) and 
the other approximately 3 to 4 months (Formulation 2B (F2B)). 
 


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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a randomized, multi-center, double-masked, vehicle-controlled, phase 1/2 clinical study 
designed to evaluate the safety, tolerability, and efficacy of OTX-CSI (cyclosporine ophthalmic 
insert) for intracanalicular use for the treatment of subjects with DED. Approximately 145 
subjects (290 eyes) will be enrolled in this study at approximately 15 sites in the US.  
Subjects will be enrolled in two cohorts. Cohort 1 will be an open-label group consisting of 
approximately 5 subjects. Cohort 2 will be a randomized, double-masked group consisting of 
approximately 140 subjects treated with 2 different hydrogel formulations of OTX-CSI and 2 
different formulations of hydrogel vehicle inserts (HV). Both eyes will be treated with the same 
treatment/formulation. 
 
Cohort Number  
Number of 
Subjects 
 
Treatment  
Formulation 
1 Open-label 
5 
OTX-CSI 
2A 
2 Randomized, double-masked 
40 
OTX-CSI 
1 
40 
OTX-CSI 
2A 
40 
HV 
2B 
20 
HV 
3 
 
Cohort 1 
Subjects in Cohort 1 will undergo Screening 14 days prior to Insertion/Day 1 (Visit 2) to 
determine eligibility and eligibility will be re-confirmed at Visit 2 (Insertion/Day 1). The 
treatment follow-up visits will occur at Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 
9 (Visit 6), Week 12 (Visit 7), and Week 16 (Visit 8). All subjects in Cohort 1 will be followed until 
Week 16 (Visit 8) whether or not an insert is visualized. 
 
Cohort 2 
Subjects in Cohort 2 will undergo Screening 14 days prior to Insertion/Day 1 (Visit 2) to 
determine eligibility. At Visit 2 (Insertion/Day 1) eligibility will be confirmed and subjects who 
are eligible will be randomly assigned to one of four treatment groups (OTX-CSI Formulation 1, 
OTX-CSI Formulation 2A, HV Formulation 2B or HV Formulation 3) in a 2:2:2:1 ratio. Should only 
a unilateral insertion be possible, Visit 2B will occur within 3 days to attempt the insertion again. 
The treatment follow-up visits will occur at Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), 


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Week 9 (Visit 6), Week 12 (Visit 7), and Week 16 (Visit 8). All subjects in Cohort 2 will be followed 
until Week 16 (Visit 8) whether or not an insert is visualized. 
For both cohorts, if an OTX-CSI or HV insert is visualized in either eye or both eyes at Week 16 
(Visit 8) the subject will return to the clinic in 30 days (± 10 days; Visit 9) and will continue 
returning to the clinic every 30 days as needed until an insert can no longer be visualized and 
the physician has determined that there is no evidence of biological activity. Additionally, 
subjects may be exited any time at the investigator’s discretion. If an OTX-CSI or HV insert cannot 
be visualized at Week 16 (Visit 8) and the physician has determined that there is no evidence of 
biological activity, the subject will exit the study. 
This study will be conducted per the schedule shown in Figure 1. 
 
 
 
 


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Figure 1 Cohort 1 and Cohort 2 Study Schematic 
 
 


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2.2. 
Objectives of Statistical Analysis 
The objectives of the trial with respect to Cohort 1 are to assess the safety and tolerability of 
OTX-CSI in subjects with DED. The objectives of the trial with respect to Cohort 2 are to assess 
the safety, tolerability, and efficacy of OTX-CSI in subjects with DED. 
2.3. 
Randomization Methodology and Masking  
Cohort 1 will be open-label and treatment assignment will be known to the sponsor, investigator 
and subjects. All 5 enrolled subjects in Cohort 1 will receive OTX-CSI Formulation 2A.  
Cohort 2 will be randomized to treatment assignment and double-masked.  
A randomization schedule will be computer-generated by a qualified biostatistician independent 
of the study conduct or project team and uploaded into the EDC system. The EDC/IRT system 
will be used for randomization and unmasking. At Visit 2 (Insertion/Day 1) eligibility will be 
confirmed and subjects who are eligible will be randomly assigned to one of four treatment 
groups (OTX-CSI Formulation 1, OTX-CSI Formulation 2A, HV Formulation 2B or HV Formulation 
3) in a 2:2:2:1 ratio. 
The HV and OTX-CSI inserts administered to subjects at randomization in the double-masked 
treatment phase will be comparable in appearance. Study subjects and investigators and their 
staff will be masked to the identity of treatment until the final database is locked. The Sponsor’s 
personnel involved with the conduct and monitoring of the study will remain masked until 
completion of the study and database lock. 
2.4. 
Stopping Rules and Unmasking 
Appropriate precautions must be taken to prevent unauthorized access to the randomization 
scheme. Unless the subject’s safety requires otherwise and if time permits, the decision to 
unmask a treatment assignment is to be made jointly by the Investigator and Sponsor’s medical 
monitor. 
If unmasking is required, the integrity of the study assessments and objectives will be maintained 
by limiting access to the unmasked data to the two individuals in the Safety Review Group 
(Sponsor Medical Monitor and Sponsor Statistician) who are not involved in the study conduct 
or directly by the investigator if required in an emergency. 
2.5. 
Study Procedures 
The Time and Events Schedule, as outlined in the study protocol, is provided in Table 1. 


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Table 1 Time and Events Schedule   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 1 Time and Events Schedule – continued  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2.6. 
Efficacy and Safety Variables 
2.6.1. 
Efficacy Variables 
2.6.1.1. 
Primary Efficacy Variable 
1- Schirmer Test (mm) and its change from baseline (CFB) at Week 12  
 
2.6.1.2. 
Secondary Efficacy Variables 
1- Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline at Week 12 
2- Eye Dryness Severity and Frequency Scores (VAS) and their CFB to each post-baseline 
visit. 
3- Schirmer Test (mm) and its change from baseline (CFB) to each post-baseline visit.   
4- Total Corneal Fluorescein Staining (tCFS) using National Eye Institute (NEI) scale and its 
CFB to each post-baseline visit. 
5- CFS sub-regions using NEI scale and its CFB to each post-baseline visit. 
6- Conjunctival Lissamine Green Staining using NEI scale and its CFB to each post-baseline 
visit. 
7- Ocular Surface Disease Index questionnaire (OSDI©) (total score, each of the three 
domains and the individual questions) and its CFB to each post-baseline visit. 
- 
OSDI total score will be calculated using below OSDI© formula:  
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 = (𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓 𝑎𝑎𝑎𝑎𝑎𝑎 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎) ×  25
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎
 
 
- 
OSDI score for each section (ABC) will be calculated using below formula: 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓 𝑒𝑒𝑒𝑒𝑒𝑒ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 (𝐴𝐴, 𝐵𝐵, 𝐶𝐶)
= (𝑆𝑆𝑆𝑆𝑆𝑆 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓 𝑎𝑎𝑎𝑎𝑎𝑎 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑓𝑓𝑓𝑓𝑓𝑓 𝑡𝑡ℎ𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠) ×  25
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑒𝑒𝑟𝑟 𝑜𝑜𝑜𝑜 𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞𝑞 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑎𝑎𝑎𝑎 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠
 
The OSDI is scored on a scale of 0 to 100, with higher scores representing greater 
disability.  
8- SPEED measures (overall score and individual questions) and its CFB to each post-
baseline visit.  
- 
SPEED overall score will be calculated as Sum of the questions in frequency and 
severity of symptoms. 


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The final score ranges from 0 to 28, with higher scores representing the severe dryness.   
 
2.6.2. 
Safety Variables 
The safety variables are as follows: 
1- Ocular and non-ocular adverse events 
2- Best Corrected Visual Acuity (BCVA): LogMAR Visual Acuity (VA) score at each visit and 
its CFB at each post-baseline visit 
3- Slit-Lamp biomicroscopy parameters by location (Eyelid Vascularity (vascular 
engorgement), Vascular, Engorgement of Eyelid Margin of upper and lower lid, Punctal 
Appearance, Lid Apposition, Lashes, Conjunctiva, Sclera, Cornea, Anterior Chamber, Iris, 
Pupil, Lens) by visit 
4- Intraocular Pressure (IOP) measurement (mmHg) and its CFB by visit 
5- Fundus Examination: Vitreous, Retina, Macula, Choroid, Optic nerve by visit 
6- Artificial tears use during the study: the use of Artificial tears since last visit at each post-
baseline visit. 


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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
1. Intent-to-Treat (ITT): The ITT population will include all randomized subjects.  
2. Modified Intent-to-Treat (mITT): the Modified ITT population is defined as all subjects 
in ITT who received the insert, investigational product (IP) (OTX-CSI or HV). The mITT 
population will be used as the primary efficacy analysis population and will be performed 
for all efficacy endpoints. 
3. Per Protocol (PP): includes all mITT subjects who do not have any major protocol 
deviation which is likely to seriously affect the safety and efficacy outcomes of the study 
and who do not report excessive artificial tear use defined as greater or equal to 60 drops 
between Week 9 (Visit 6) and Week 12 (Visit 7). Analysis on the PP population will be 
used as secondary efficacy analysis and will be performed for select efficacy endpoints, 
analyzing subjects under the treatment actually received. Important protocol deviations 
will be identified prior to locking the study database. 
4. Safety Set (SAF): includes all subjects who received investigational product (IP) (OTX-
CSI or HV) from Cohort 1 and Cohort 2. Analyses performed on the Safety population will 
be according to the treatment the subject actually received. 
5. Cohort 1 population: Cohort 1 population will include all subjects who received IP.  
Demographic and baseline characteristics, other ocular examination data, and safety 
data will be summarized.  
3.2. 
Protocol Deviations 
At the discretion of the sponsor, major protocol deviations as determined by a review of the 
data prior to unmasking of the study results and the conduct of statistical analyses may result in 
the removal of a subject’s data from the PP Population. This file will include a description of the 
protocol deviations, and classification of major or minor protocol deviations. It will be finalized 
prior to hard database lock and unmasking. Major protocol deviations will be summarized by 
treatment groups and overall. The data listing for all protocol violations will be also presented. 
 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
No formal sample size calculations were performed. The proposed sample size will allow for 
initial estimates of efficacy as well as provide for sufficient safety information to be obtained, 
while still limiting the number of subjects exposed to the IP. 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All output will be incorporated into Microsoft Excel or Word files, sorted, and labeled according 
to the International Council on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic 
and safety parameters. For categorical variables, summary tabulations of the number of missing, 
and number and percentage of each category of the parameter will be presented by treatment 
groups and visits (as applicable). For continuous variables, the n, mean, standard deviation, 
median, minimum, and maximum values will be presented.  
The baseline visit will be defined as the last non-missing measure prior to initiation of 
investigational treatment. Differences between treatment groups will be calculated as OTX-CSI 
minus HV, and change from baseline will be calculated as follow-up visit minus baseline visit 
values. 
All statistical testing will be done at the two-sided alpha level of 0.05. 
 
 


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4.2.2. 
Unit of Analysis 
Both eyes will be treated with the same treatment/formulation. If both eyes qualify, the eye 
having the higher total corneal fluorescein staining score will be designated as the study eye and 
the other eye designated as the non-study eye. If both eyes have the same total corneal 
fluorescein staining score, the study eye will be designated randomly, and the other eye 
designated as the non-study eye. If only one eye qualifies, that eye will be the study eye, but 
both eyes will still receive the same treatment/formulation. 
The unit of analysis in this study will be the study eye (primary study eye) for all efficacy 
summaries. Efficacy summaries will be presented for both study and non-study eyes for Cohort 
1 and Cohort 2. Cohort 1 will be included for all safety summaries and will include summaries of 
both study and non-study eyes. All primary, sensitivity, secondary, and exploratory endpoints 
will be analyzed for both study and non-study eyes, separately. All summaries will be presented 
by treatment groups and visits, where appropriate. In addition to summarizing the individual 
formulations, the two formulations of OTX CSI will be combined and summarized. 
 
4.2.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4), 
unless otherwise noted. Medical History and adverse events will be coding using Medical 
Dictionary for Regulatory Activities (MedDRA) version 24.0 - Mar 2021.  Concomitant 
medications will be coded using World Health Organization (WHO) DD B3 WHO Drug DDE – Sep 
2019.  
4.2.4. 
Methods of Pooling Data 
The two OTX formulations will be combined and summarized as well as individual formulations. 
4.2.5. 
Adjustments for Covariates 
The statistical modeling of change from baseline for each variable will be adjusted for its baseline 
value.  
4.2.6. 
Multiple Comparisons/Multiplicity 
As this is a Phase 1/2 study, no adjustments to alpha will be made for testing of multiple 
endpoints. 


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4.2.7. 
Subpopulations 
No analyses of subgroups of subjects are planned. 
4.2.8. 
Withdrawals, Dropouts, Loss to Follow-up, replacement  
Any subject who wishes to voluntarily discontinue study drug or withdraw from participation in 
the study for any reason is entitled to do so without obligation. 
IP may be discontinued (insert removed) and any subject may be discontinued from study 
participation at any time during the study at the discretion of the Investigator or the Sponsor for 
any reason. 
In the event that study discontinuation of a randomized subject is necessary, the Investigator 
should make every attempt to have the subject complete Visit 8 assessments as soon as possible. 
The reason for premature discontinuation should be recorded in the subject chart and entered 
in the eCRF. 
Subjects who withdraw from Cohort 1 will be replaced. Subjects who withdraw from Cohort 2 
will not be replaced. 
4.2.9. 
Missing, Unused, and Spurious Data 
If the start date of an AE is partially or completely missing, the date will be compared as far as 
possible with the date of the start of administration of study drug. The AE will be assumed to be 
treatment-emergent if it cannot be definitively shown that the AE did not occur or worsen during 
the treatment-emergent period (worst case approach). The imputed dates will only be used to 
classify events as treatment emergent and will only be used in the table analyses. Listings will 
display the available date data. 
The following general rules will be used: 
• If the start day is missing but the start month and year are complete, an AE will only be 
excluded as being treatment-emergent if the start month/year is before the month/year 
of study drug administration or if the date of resolution is before study drug 
administration.  
• If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment-emergent if start year is before the year of study drug 
administration or if the date of resolution is before study drug administration.  
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the date of resolution is before study drug administration. 


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4.2.9.1. 
Imputation Method for Efficacy Endpoints 
To impute missing, Markov Chain Monte Carlo (MCMC) multiple imputation (MI), Fully 
Conditional Specification multiple imputation (FCS MI) and last observation carried forward 
(LOCF) methods will be used.  
For MI, we will have below phases: 
1. Imputation Phase: in this phase, the missing data will be imputed using SAS PROC MI 
and a complete data set will be created. This process of imputation will be repeated 25 
times. Therefore, 25 compete datasets will be created. In this phase, treatment group, 
baseline value, and post-baseline visits from visit 3 to visit 8, respectively, will be included 
in multiple imputation model.  
2. Analysis Phase: each of the 25 complete data sets will be analyzed independently using 
desired statistical method (e.g. ANCOVA for primary efficacy analysis). 
3. Pooling Phase: in this phase the estimates obtained from each analyzed complete 
dataset from phase 2, will be combined using PROC MIANALYZE. 
The analysis of efficacy variables Schirmer Test, Eye Dryness Severity Score and Eye Dryness 
Frequency Score on mITT and PP populations will be performed by imputing missing data using 
MCMC MI methodology with repeated 25 times of imputation under the assumption of 
missingness at random. Last observation carried forward (LOCF) method and Fully Conditional 
Specification multiple imputation (FCS MI) with 200 burn-in iterations and 25 times of 
imputation under the assumption of missingness at random will be used for sensitivity analyses 
(Section 4.7.2).  LOCF method will be used for sensitivity analyses.  
4.2.10. 
Visit Windows 
Visit windows will be calculated based on the schedule of assessments in Table 1. Any visits or 
procedures performed outside the scheduled visits must be documented in the Unscheduled 
Visit page of the eCRF. Although there is a visit window around the expected visit date, nominal 
visits will be used for the per-visit analyses. 
4.3. 
Interim Analyses 
An interim analysis was not planned for this study. 


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4.4. 
Subject Disposition 
A summary of subject disposition will be tabulated, including the number screened and screened 
failure, and procedural screen failures will be presented. Subjects are considered procedural 
screen failures if the investigator is unsuccessful at placing the OTX-CSI or HV intracanalicular 
ophthalmic insert in both eyes (i.e. neither eye has an insert). The number and percentage of 
subjects included in each of the analysis populations (ITT, mITT, PP, SAFETY) will be presented 
by treatment groups and overall. Subject disposition events including randomization, treated, 
completed study, withdrawal prior to completing the study, and reasons for withdrawal will be 
summarized by treatment groups and overall. 
A by-subject listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
4.5. 
Demographic and Baseline Characteristics 
Baseline, demographic and medical history information will be summarized for the mITT and 
Cohort 1 populations, separately, using descriptive statistics. Demographic characteristic 
information will include Gender (Male, Female), Age (year), Ethnicity (Hispanic or Latino, Not 
Hispanic or Latino), and Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Unknown, Other). 
Demographic and Baseline data will be provided in data listings. 
4.5.1. 
Baseline Ocular Assessments 
The following baseline assessments will be presented using descriptive statistics for mITT and 
Cohort 1 populations, separately, by treatment group and overall. 
The assessments below will be presented at the eye level (study eye and non-study eye): 
1. Unanesthetized Schirmer’s Test 
2. Corneal Fluorescein Staining (tCFS)  
3. CFS sub-regions using NEI scale  
4. Conjunctival Lissamine Green Staining (CLGS)  
5. CLGS sub-regions 
6. Tear Film Break Up Time (TFBUT) 
7. Best Corrected Visual Acuity (BCVA) LogMAR Score 
8. IOP Measurement (mmHg) 


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The assessments below will be presented at the subject level: 
1. Eye Dryness Severity (VAS) Score  
2. Eye Dryness Frequency (VAS) Score 
3. OSDI total score (0-100) and the scores of three domains 
4. SPEED Total Score (0-28)  
 
4.5.2. 
Ocular and Non-Ocular Medical History 
Medical history, including ocular medical history, will be coded using the MedDRA Version 24.0 
- Mar 2021. Non-ocular medical history will be summarized in the mITT and Cohort 1 populations, 
separately, by system organ class (SOC) and preferred term (PT) by treatment group and overall. 
SOC will be sorted alphabetically. PT will be sorted by descending frequency overall within each 
SOC. Subjects with a particular medical history event or medical history class will be counted 
once at the PT level and once at the SOC level. Ocular medical history will be summarized at the 
eye and subject levels by treatment group and overall, for the mITT and Cohort 1 populations, 
separately, with separate summaries for the study eye and non-study eye. 
Data listings will be provided for medical history as well. 
4.6. 
Treatment Exposure  
Details of study drug administration, including duration of treatment will be tabulated and 
presented in the Safety population. The duration of exposure will be calculated in days as latest 
date investigator confirms insert is not present in either eye minus date of the earliest insertion 
in either eye plus 1 and summarized using descriptive statistics by treatment group and overall. 
Treatment exposure for subjects who discontinue the study prior to the insert no longer being 
present in both eyes, will be calculated in days as date of last insert visualization in either eye 
minus date of the earliest insertion in either eye plus 1. In addition, treatment exposure for 
subjects who discontinue the study prior to the insert no longer being present in both eyes will 
be set to the longest observed insert exposure in the applicable cohort as an additional analysis. 
All dosing information will be presented in a data listing. 


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4.7. 
Efficacy Evaluation 
The efficacy summaries and analyses will be presented for both study and non-study eyes for 
Cohort 2 only.  
The Primary efficacy analysis of the Schirmer test will be conducted using the mITT and PP 
populations. All the efficacy parameters, with the exception of categorical Schirmer test 
evaluation (i.e., ≥10 mm increase in Schirmer) and the categorical BCVA evaluation (i.e. Loss of 
3 lines of vision), will be analyzed as continuous variables. Their absolute values at each 
timepoint (Visit 1, Visit 2, Baseline, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, Visit 8, and 30-Day 
Follow-Up), and change from baseline to each post-baseline visit will be summarized using 
descriptive statistics (the number of subjects, mean, SD, median, minimum and maximum) by 
treatment group and overall. The number and percentage of subjects with ≥10 mm increase 
from baseline in Schirmer test and loss of 3 lines of vision based on BCVA at each post-baseline 
visit will be tabulated by treatment group and overall. The results for 30-Day Follow-Up visits 
will be reported only for observed data.  
4.7.1. 
Primary Analyses 
For the primary efficacy endpoint analyses of Schirmer Test change from baseline, the following 
modeling and analyses will be performed on MCMC MI of mITT population: 
A linear model with fixed effects of treatment (four individual formulations) and baseline 
Schirmer test value as covariate will be used to compare different formulations in terms of 
Schirmer Test change from baseline at Visit 7 (Week 12) and all other post-baseline visits (Visit 
3, Visit 4, Visit 5, Visit 6, and Visit 8). In the linear model, least square means treatment group 
comparison of CSI Formulation 1 to HV Formulation 2B, CSI Formulation 2A to HV Formulation 
2B, CSI Formulation 1 to HV Formulation 3, CSI Formulation 2A to HV Formulation 3, will be 
reported. This model will also be used to compare overall OTX-CSI (combined Formulation 1 and 
Formulation 2A using sample size weights of Formulation 1 and Formulation 2A as coefficients 
for the parameters in least square means treatment group comparison) to each HV Formulation 
(2B and 3).  Unadjusted treatment group analyses using two-sample t-test will be run on these 
treatment group combinations. 
These analyses will also be performed on the PP population. 
 


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4.7.2. 
Sensitivity Analyses 
To determine robustness of results, the sensitivity analyses will be performed for the primary 
efficacy endpoint, Schirmer test at visit 7 (week 12) and all other post-baseline visits (Visit 3, Visit 
4, Visit 5, Visit 6, and Visit 8), on the mITT and PP populations by using:  
1. last observation carried forward (LOCF)  
2. observed data only 
3. FCS MI. 
As sensitivity analyses, LOCF, observed data, and FCI MI will be analyzed in a manner similar to 
the primary efficacy variable (details in section 4.7.1). For the unadjusted treatment group 
comparisons analyses using LOCF and observed data, in addition to t-test, Wilcoxon rank sum 
test will be run on the treatment group combinations. 
4.7.3. 
Secondary Analyses 
1. To analyze the efficacy endpoint of percent of eyes with ≥10 mm Increase in Schirmer 
Test from Baseline at Visit 7 (Week 12) and other Post-Baseline Visits, the logistic 
regression or Fisher’s exact test will be used as described below: 
The two groups of Schirmer test (≥10 mm vs <10 mm) will be compared between 
treatment groups as CSI Formulation 1 to HV Formulation 2B, CSI Formulation 2A to HV 
Formulation 2B, CSI Formulation 1 to HV Formulation 3, CSI Formulation 2A to HV 
Formulation 3, will be reported. This model will also be used to compare overall OTX-CSI 
(combined Formulation 1 and Formulation 2A) to each HV Formulation (2B and 3) using 
the logistic regression. 
The above analyses will be performed on the change from baseline in Schirmer test (≥10 
mm vs <10 mm) derived based on the imputed Schirmer data using FCS MI (details in 
section 4.2.9.1) at visit 7 on the mITT and PP populations using the logistic regression and 
Odds Ratio (OR), 95% confidence interval for OR, and P-value for OR will be reported. In 
addition, sensitivity analyses will be done using LOCF and observed data and the two 
groups of Schirmer test (≥10 mm vs <10 mm) will be compared between treatment 
groups using the Fisher’s exact test on this endpoint. These analyses will also be 
performed on all post-baseline visits. 
2. To analyze the efficacy endpoints of Eye Dryness Severity and Eye Dryness Frequency, 
statistical modeling similar to the primary efficacy endpoint analysis (4.7.1) will be 
performed for each post-baseline visit (Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8) 


     Statistical Analysis Plan  
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using the MCMC MI imputed data on the mITT and PP populations.  In addition, 
sensitivity analyses done for the primary efficacy endpoint will also be performed on this 
endpoint. 
3. To analyze the efficacy endpoints of total Corneal Fluorescein Staining (tCFS) and its 
sub-region, statistical modeling similar to the primary efficacy endpoint analysis (4.7.1) 
will be performed for each post-baseline visit (Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and 
Visit 8) using the MCMC MI imputed data on the mITT and PP populations.  In addition, 
sensitivity analyses done for the primary efficacy endpoint will also be performed on this 
endpoint. 
The rest of secondary efficacy endpoint analysis of below parameters will be done similar to 
analysis of Schirmer test using observed data, for each post-baseline visit (Visit 3, Visit 4, Visit 5, 
Visit 6, Visit 7, Visit 8, and30-Day Follow-Up) on mITT and PP populations using observed data: 
1. Conjunctival Lissamine Green Staining using NEI scale 
2. Ocular Surface Disease Index questionnaire (OSDI©) (total score, each of the three 
domains and the individual questions)  
3. SPEED measures (overall score and individual questions) and its CFB 
 
 
4.7.4. 
Exploratory Analyses 
The exploratory analyses will be done on mITT populations for both study and non-study eye. 
The Tear Film Break Up Time at Week 12 and its CFB will be summarized using descriptive 
statistics (the number of subjects, mean, SD, median, minimum and maximum) by treatment 
group and overall. Tear Film Break Up Time at Week 12 will be analyzed similar to analysis of 
Schirmer test using observed data.  
Ease of insertion as assessed by the Investigator at Visit 2 or Visit 2B, presence of insert and ease 
of visualization as assessed by the Investigator at all post-baseline visits will be summarized using 
discrete statistics (number and percentage) and will be tested between treatment groups (CSI 
Formulation 1 to HV Formulation 2B, CSI Formulation 2A to HV Formulation 2B, CSI Formulation 
1 to HV Formulation 3, CSI Formulation 2A to HV Formulation 3, will be reported. This model will 
also be used to compare overall OTX-CSI (combined Formulation 1 and Formulation 2A) to each 
HV Formulation (2B and 3). To analyze ease of insertion as assessed by the Investigator and ease 
of visualization as assessed by the Investigator, Pearson Chi-squared test will be used.  To analyze 
presence of insert, Fisher’s exact Test will be used.  


     Statistical Analysis Plan  
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4.8. 
Pharmacokinetic Evaluations 
PK analysis will be described separately. 
4.9. 
Safety Analyses 
All safety analyses will be conducted on the Safety Population.   
Adverse Events 
Adverse events will be coded using the MedDRA Version 24.0 - Mar 2021 and displayed in tables 
and listings using System Organ Class (SOC) and Preferred Term (PT). 
Analyses of adverse events will be performed for those events that are considered treatment 
emergent adverse events (TEAE), where treatment emergent is defined as any adverse event 
with onset on or after the first dose of study medication through the end of the study or any 
event that was present at baseline but worsened in intensity or was considered drug-related by 
the investigator through the end of the study.   
The safety will be assessed by incidence of TEAEs, therefore, in any tabulation, a subject 
contributes only once to the count for a given adverse event (SOC or preferred term). An overall 
summary of TEAEs will be presented including the number of events and the number of the 
subjects with events along with percentages by treatment group and overall. The overall 
summary will include subjects with AE leading to death, subjects with TEAEs leading to insert 
removal and subjects with TEAEs leading to subject withdrawal.  In summary tables, SOC will be 
presented alphabetically and events within SOC will be presented by decreasing frequency count 
based on the total column.  
The frequency and percentage of subjects with any TEAEs and separately for ocular and non-
ocular TEAEs, with any ocular TEAEs by relationship to treatment (unrelated, related), with any 
ocular serious TEAEs by relationship to treatment (unrelated, related), with any TEAE by severity 
(mild, moderate, or severe), and with any serious adverse event (SAE) and separately for ocular 
and non-ocular events will be summarized by treatment group and overall.     
All adverse events will be listed in subject data listings. 
By-subject listings also will be provided for the following: subject deaths; serious adverse events; 
and adverse events leading to withdrawal.  
Non-AE Safety Analyses 
The following safety assessments will be summarized using descriptive statistics for Safety 
population by treatment group and overall. Assessments will be presented for study eye and 
non-study eye separately. 


     Statistical Analysis Plan  
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1- Best Corrected Visual Acuity (BCVA) 
LogMAR Visual Acuity (VA) score for each visit, its CFB, and loss of 3 Lines or more 
in BCVA LogMAR Score from Baseline at each post-baseline visit will be calculated 
and summarized using descriptive statistics. 
2- Slit-Lamp biomicroscopy  
The evaluation of normal, mild, moderate, severe, and very severe for each eye 
in Eyelid Vascularity (vascular engorgement) and Vascular Engorgement of Eyelid 
Margin of upper and lower lid, as well as normal, abnormal non-clinically 
significant, and abnormal clinically significant for each eye in Punctal Appearance, 
Lid Apposition, Lashes, Conjunctiva, Sclera, Cornea, Anterior Chamber, Iris, Pupil, 
and Lens will be tabulated for each visit by using the frequency and percentage. 
3- Intraocular Pressure (IOP) measurement (mmHg) 
Absolute value at baseline and visit 8 (week 16), its CFB, absolute IOP 
measurement ≥ 30 mmHg at each visit, and CFB in IOP > 5 mmHg as well as >10 
mmHg at Visit 8 will be summarized using descriptive statistics. 
4- Fundus Examination  
The evaluation of normal, abnormal non-clinically significant, and abnormal 
clinically significant for each eye in vitreous, retina, macula, choroid, and optic 
nerve exam will be tabulated for visit 1 and visit 8 by using the frequency and 
percentage. The absolute cup-to-disc ratio at baseline and Visit 8 (Week 16) and 
its CFB at Visit 8 (Week 16) will be presented using descriptive statistics.  
5- Artificial tears use during the study 
The use of artificial tears, based on the Daily Subject Diary, since last visit will be 
tabulated for each post-baseline visit by using frequency and percentage. 
Number of times AT used since last visit will be reported among all subjects who 
have any daily subject dairy data since the last visit using descriptive statistics.  
4.9.1. 
Laboratory Data 
Safety laboratory tests will not be collected. Urine pregnancy test results will be captured at Visit 
1 and Visit 8 (Week 16). Urine pregnancy test results will be provided in data listing. 


     Statistical Analysis Plan  
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4.9.2. 
Vital Signs and Physical Examinations 
Vital signs and physical examinations data will not be collected. 
4.9.3. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary, WHO DD B3 WHO Drug 
DDE – Sep 2019. Results will be tabulated by Anatomic Therapeutic Class (ATC) and preferred 
term. 
Concomitant medications will be defined as those medications that were initiated after study 
drug administration or those that were ongoing at the time of study drug administration. If the 
start date or stop date of a medication is partially missing, the date will be compared as far as 
possible with the date of the start of administration of study drug. The medication will be 
assumed to be prior medication if it cannot be definitively shown that the medication did not 
start or continue during the treatment period. 
Non-ocular prior and concomitant medications will be summarized by higher ATC level 3 
(therapeutic subgroup) and preferred term by treatment group and overall, in the Safety 
population.  ATC Level 3 terms will be sorted alphabetically. Preferred terms will be sorted by 
descending frequency overall within ATC Level 3 term. Subjects receiving a particular medication 
or medication of ATC Level 3 will be counted once at the preferred term level and once at ATC 
Level 3.  
Ocular prior and concomitant medications will be summarized at the eye level, separately for 
study and non-study eyes, and at the subject level (both eyes) by ATC Level 3 and preferred term 
by treatment group and overall, in the Safety population. 
All prior and concomitant medications information will be presented in the data listing. 
 


     Statistical Analysis Plan  
Sponsor:  
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Protocol: 
 
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5. 
CHANGES TO PLANNED ANALYSES 
The language in the SAP will supersede the language in the protocol should there be a 
discrepancy. 
The primary analysis will be repeated for all visits using observed data (without imputation) for 
both mITT and PP populations. These results will be provided in sensitivity analyses section. 
The difference between two OTX-CSI hydrogel formulations as well as the difference between 
two HV formulations will not be studied. HV formulations will not be combined. 
Wilcoxon rank sum test will be used only to analyze LOCF and observed data. 
For Eye Dryness Severity and Eye Dryness Frequency, as well total Corneal Fluorescein Staining 
(tCFS) and its sub-region the main analysis will be based on MCMC MI and sensitivity analyses 
will be done using LOCF, observed data, and FCS. 
For the first secondary efficacy endpoint analysis, for the main analysis, the two groups of 
change from baseline in Schirmer test (≥10 mm vs <10 mm) at visit 7 will be compared between 
treatment groups using the logistic regression and for the sensitivity analyses, the groups will be 
compared using LOCF and observed data by Fisher’s exact test;  Clopper-Pearson method will be 
used to calculate 95% confidence interval of the proportion of subject with change from baseline 
in Schirmer Test  ≥ 10 mm;  to calculate 95% confidence interval of the proportion difference, 
the Chan and Zhang (1999) method will be used.   
These analyses will also be performed on all post-baseline visits. 


     Statistical Analysis Plan  
Sponsor:  
Ocular Therapeutix, Inc. 
Protocol: 
 
CLN-Protocol-0054 
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01-OCT-2021 
 
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6. 
REFERENCES 
American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice 
Pattern® Guidelines. Dry Eye Syndrome. San Francisco, CA: American Academy of 
Ophthalmology; 2018. Available at www.aao.org/ppp. Accessed September 23, 2019. 
Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. 2017. Prevalence of Diagnosed Dry Eye 
Disease in the United States Among Adults Aged 18 Years and Older. Am J Ophthalmol. 
Oct;182:90- 98. 
Perry HD. Dry eye disease: Pathophysiology, classification, and diagnosis. Am J Manag Care. 
2008;14:S79-S87. 
Schultz C. Safety and efficacy of cyclosporine in the treatment of chronic dry eye. Ophthalmol 
Eye Dis. 2014;6:37-42. 
Massingale, M.L., Li, X., Vallabhajosyula, M., Chen, D., Wei, Y. and Asbell, P.A., 2009. Analysis of 
inflammatory cytokines in the tears of dry eye patients. Cornea, 28(9), pp.1023-1027. 
Lee, S.Y., Han, S.J., Nam, S.M., Yoon, S.C., Ahn, J.M., Kim, T.I., Kim, E.K. and Seo, K.Y., 2013. 
Analysis of tear cytokines and clinical correlations in Sjögren syndrome dry eye patients 
and non– Sjögren syndrome dry eye patients. American journal of ophthalmology, 156(2), 
pp.247-253. 
McCabe C. Plugs reduce dry-eye symptoms, improve vision. Review of Ophthalmology. 19 
November 2009. Available at www.reviewofophthalmology.com/article/plugs-reduce-dry-
eye-symptoms-improvevision. Accessed September 29, 2019. 


     Statistical Analysis Plan  
Sponsor:  
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Protocol: 
 
CLN-Protocol-0054 
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Document Date: 
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7. 
CLINICAL STUDY REPORT APPENDICES 
7.1. 
Statistical Tables to be Generated 
Table 14.1.1: Overall Disposition and Subject Accountability – All Subjects Screened 
Table 14.1.2: Overview of Analysis Sets 
Table 14.1.3: Major Protocol Deviations – mITT and Cohort 1 
Table 14.1.4: Demographic and Baseline Characteristics – mITT and Cohort 1 
Table 14.1.5: Ocular Characteristics at baseline - mITT and Cohort 1 
Table 14.1.6.1: Study Eye Ocular Medical History - mITT and Cohort 1 
Table 14.1.6.2: Non-Study Eye Ocular Medical History – mITT and Cohort 1 
Table 14.1.6.3: Non-ocular Medical History – mITT and Cohort 1 
Table 14.1.7.1: Study Eye Ocular Prior Medications – SAFETY 
Table 14.1.7.2: Non-Study Eye Ocular Prior Medications – SAFETY 
Table 14.1.7.3: Non-ocular Prior Medications – SAFETY 
Table 14.1.7.4: Study Eye Ocular Concomitant Medications – SAFETY 
Table 14.1.7.5: Non-Study Eye Ocular Concomitant Medications – SAFETY 
Table 14.1.7.6: Non-ocular Concomitant Medications – SAFETY 
Table 14.1.8: Treatment Exposure – SAFETY 
Table 14.2.1.1.1: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Schirmer Test (mm) on Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – mITT 
Table 14.2.1.1.2: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Schirmer Test (mm) on Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – PP 
Table 14.2.1.1.3: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Schirmer Test (mm) on Non-Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – mITT 
Table 14.2.1.1.4: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Schirmer Test (mm) on Non-Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – PP 


     Statistical Analysis Plan  
Sponsor:  
Ocular Therapeutix, Inc. 
Protocol: 
 
CLN-Protocol-0054 
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Table 14.2.2.1.1: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Schirmer Test (mm) on Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – mITT 
Table 14.2.2.1.2: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Schirmer Test (mm) on Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – PP 
Table 14.2.2.1.3: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Schirmer Test (mm) on Non-Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – mITT 
Table 14.2.2.1.4: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Schirmer Test (mm) on Non-Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits – PP 
Table 14.2.2.2.1: The Summary and Linear Model of Change from Baseline in Schirmer Test (mm) on Study Eye at 
Visit 7 (Week 12) and other Post-Baseline Visits – mITT (Observed data) 
Table 14.2.2.2.2: The Summary and Linear Model of Change from Baseline in Schirmer Test (mm) on Study Eye at 
Visit 7 (Week 12) and other Post-Baseline Visits – PP (Observed data) 
Table 14.2.2.2.3: The Summary and Linear Model of Change from Baseline in Schirmer Test (mm) on Non-Study Eye 
at Visit 7 (Week 12) and other Post-Baseline Visits – mITT (Observed data) 
Table 14.2.2.2.4: The Summary and Linear Model of Change from Baseline in Schirmer Test (mm) on Non-Study Eye 
at Visit 7 (Week 12) and other Post-Baseline Visits – PP (Observed data) 
Table 14.2.2.3.1: The Summary and Linear Model with Fully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Schirmer Test (mm) on Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits 
– mITT 
Table 14.2.2.3.2: The Summary and Linear Model withFully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Schirmer Test (mm) on Study Eye at Visit 7 (Week 12) and other Post-Baseline Visits 
– PP 
Table 14.2.2.3.3: The Summary and Linear Model withFully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Schirmer Test (mm) on Non-Study Eye at Visit 7 (Week 12) and other Post-Baseline 
Visits – mITT 
Table 14.2.2.3.4: The Summary and Linear Model withFully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Schirmer Test (mm) on Non-Study Eye at Visit 7 (Week 12) and other Post-Baseline 
Visits – PP 
Table 14.2.3.1.1:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Fully Conditional 
Specification (FCS) Multiple Imputation on Study Eye at visit 7 (Week 12) and other Post-Baseline Visits  –  
mITT 
Table 14.2.3.1.2:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Fully Conditional 
Specification (FCS) Multiple Imputation on Study Eye at visit 7 (Week 12) and other Post-Baseline Visits – PP 


     Statistical Analysis Plan  
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Ocular Therapeutix, Inc. 
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CLN-Protocol-0054 
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Table 14.2.3.1.3:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Fully Conditional 
Specification (FCS) Multiple Imputation on Non-Study Eye at visit 7 (Week 12) and other Post-Baseline Visits – 
mITT 
Table 14.2.3.1.4:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Fully Conditional 
Specification (FCS) Multiple Imputation on Non-Study Eye at visit 7 (Week 12) and other Post-Baseline Visits – 
PP 
Table 14.2.3.2.1:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Last Observation 
Carried Forward (LOCF) on Study Eye at visit 7 (Week 12) and other Post-Baseline Visits – mITT 
Table 14.2.3.2.2:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Last Observation 
Carried Forward (LOCF) on Study Eye at visit 7 (Week 12) and other Post-Baseline Visits – PP 
Table 14.2.3.2.3:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Last Observation 
Carried Forward (LOCF) on Non-Study Eye at visit 7 (Week 12) and other Post-Baseline Visits – mITT 
Table 14.2.3.2.4:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline Using Last Observation 
Carried Forward (LOCF) on Non-Study Eye at visit 7 (Week 12) and other Post-Baseline Visits – PP 
Table 14.2.3.3.1:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline on Study Eye at visit 7 
(Week 12) and other Post-Baseline Visits – mITT (Observed data) 
Table 14.2.3.3.2:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline on Study Eye at visit 7 
(Week 12) and other Post-Baseline Visits – PP (Observed data) 
Table 14.2.3.3.3:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline on Non-Study Eye at visit 7 
(Week 12) and other Post-Baseline Visits – mITT (Observed data) 
Table 14.2.3.3.4:  Percent of eyes with ≥10 mm Increase in Schirmer Test from Baseline on Non-Study Eye at visit 7 
(Week 12) and other Post-Baseline Visits – PP (Observed data) 
Table 14.2.3.4.1: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in Eye 
Dryness Severity and Frequency Scores (VAS) at each Post-Baseline Visits – mITT 
Table 14.2.3.4.2: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in Eye 
Dryness Severity and Frequency Scores (VAS) at each Post-Baseline Visits – PP 
Table 14.2.3.5.1: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Eye Dryness Severity and Frequency Scores (VAS) at each Post-Baseline Visits – mITT 
Table 14.2.3.5.2: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Eye Dryness Severity and Frequency Scores (VAS) at each Post-Baseline Visits – PP 
Table 14.2.3.6.1: The Summary and Linear Model of Change from Baseline in Eye Dryness Severity and Frequency 
Scores (VAS) at each Post-Baseline Visits – mITT (Observed data) 


     Statistical Analysis Plan  
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CLN-Protocol-0054 
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Table 14.2.3.6.2: The Summary and Linear Model of Change from Baseline in Eye Dryness Severity and Frequency 
Scores (VAS) at each Post-Baseline Visits – PP (Observed data) 
Table 14.2.3.7.1: The Summary and Linear Model with Fully Conditional Specification (FCS) Multiple Imputationof 
Change from Baseline in Eye Dryness Severity and Frequency Scores (VAS) at each Post-Baseline Visits – mITT 
Table 14.2.3.7.2: The Summary and Linear Model with Fully Conditional Specification (FCS) Multiple Imputationof 
Change from Baseline in Eye Dryness Severity and Frequency Scores (VAS) at each Post-Baseline Visits – PP 
Table 14.2.3.8.1: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Corneal Fluorescein Staining (CFS) and its Sub-Regions on Study Eye at each Post-Baseline Visits – mITT 
Table 14.2.3.8.2: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Corneal Fluorescein Staining (CFS) and its Sub-Regions on Study Eye at each Post-Baseline Visits – PP 
Table 14.2.3.8.3: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Corneal Fluorescein Staining (CFS) and its Sub-Regions on Non-Study Eye at each Post-Baseline Visits – mITT 
Table 14.2.3.8.4: The Summary and Linear Model with MCMC Multiple Imputation of Change from Baseline in 
Corneal Fluorescein Staining (CFS) and its Sub-Regions on Non-Study Eye at each Post-Baseline Visits – PP 
Table 14.2.3.9.1: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Study Eye at each Post-Baseline Visits – 
mITT 
Table 14.2.3.9.2: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Study Eye at each Post-Baseline Visits – 
PP 
Table 14.2.3.9.3: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Non-Study Eye at each Post-Baseline 
Visits – mITT 
Table 14.2.3.9.4: The Summary and Linear Model with Last Observation Carried Forward (LOCF) of Change from 
Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Non-Study Eye at each Post-Baseline 
Visits – PP 
Table 14.2.3.10.1: The Summary and Linear Model of Change from Baseline in Corneal Fluorescein Staining (CFS) 
and its Sub-Regions on Study Eye at each Post-Baseline Visits – mITT (Observed data) 
Table 14.2.3.10.2: The Summary and Linear Model of Change from Baseline in Corneal Fluorescein Staining (CFS) 
and its Sub-Regions on Study Eye at each Post-Baseline Visits – PP (Observed data) 
Table 14.2.3.10.3: The Summary and Linear Model of Change from Baseline in Corneal Fluorescein Staining (CFS) 
and its Sub-Regions on Non-Study Eye at each Post-Baseline Visits – mITT (Observed data) 
Table 14.2.3.10.4: The Summary and Linear Model of Change from Baseline in Corneal Fluorescein Staining (CFS) 
and its Sub-Regions on Non-Study Eye at each Post-Baseline Visits – PP (Observed data) 


     Statistical Analysis Plan  
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Table 14.2.3.11.1: The Summary and Linear Model with Fully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Study Eye at each Post-
Baseline Visits – mITT 
Table 14.2.3.11.2: The Summary and Linear Model with Fully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Study Eye at each Post-
Baseline Visits – PP 
Table 14.2.3.11.3: The Summary and Linear Model with Fully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Non-Study Eye at each 
Post-Baseline Visits – mITT 
Table 14.2.3.11.4: The Summary and Linear Model with Fully Conditional Specification (FCS) Multiple Imputation of 
Change from Baseline in Corneal Fluorescein Staining (CFS) and its Sub-Regions on Non-Study Eye at each 
Post-Baseline Visits – PP 
Table 14.2.3.12.1: The Summary and Linear Model of Change from Baseline in Total Conjunctival Lissamine Green 
Staining (CLGS) on Study Eye at each Post-Baseline Visits – mITT 
Table 14.2.3.12.2: The Summary and Linear Model of Change from Baseline in Total Conjunctival Lissamine Green 
Staining (CLGS) on Study Eye at each Post-Baseline Visits – PP 
Table 14.2.3.12.3: The Summary and Linear Model of Change from Baseline in Total Conjunctival Lissamine Green 
Staining (CLGS) on Non-Study Eye at each Post-Baseline Visits – mITT 
Table 14.2.3.12.4: The Summary and Linear Model of Change from Baseline in Total Conjunctival Lissamine Green 
Staining (CLGS) on Non-Study Eye at each Post-Baseline Visits – PP 
Table 14.2.3.13.1: The Summary of Ocular Surface Disease Index (OSDI) individual questions by Visit – mITT 
Table 14.2.3.13.2: The Summary of Ocular Surface Disease Index (OSDI) individual questions by Visit – PP 
Table 14.2.3.14.1: The Summary and Linear Model of Change from Baseline in Ocular Surface Disease Index (OSDI), 
its domains, and individual questions at each Post-Baseline Visits – mITT 
Table 14.2.3.14.2: The Summary and Linear Model of Change from Baseline in Ocular Surface Disease Index (OSDI), 
its domains, and individual questions at each Post-Baseline Visits – PP 
Table 14.2.3.15.1: The Summary of Individual Questions of First Section ofStandard Patient Evaluation of Eye 
Dryness (SPEED) (Symptoms You Experience And When They Occur) By Visit – mITT 
Table 14.2.3.15.2 The Summary of Individual Questions of First Section ofStandard Patient Evaluation of Eye 
Dryness (SPEED) (Symptoms You Experience And When They Occur) By Visit – PP 
Table 14.2.3.15.3: The Summary of Individual Questions of Second And Third Sections ofStandard Patient 
Evaluation of Eye Dryness (SPEED) (Frequency And Severity Of Symptoms) by Visit – mITT 


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Table 14.2.3.15.4 The Summary of Individual Questions of Second and Third Sections ofStandard Patient Evaluation 
of Eye Dryness (SPEED) (Frequency and Severity of Symptoms) by Visit – PP 
Table 14.2.3.16.1: The Summary and Linear Model of Change from Baseline inStandard Patient Evaluation of Eye 
Dryness (SPEED) total score and its individual questions at each Post-Baseline Visits – mITT 
Table 14.2.3.16.2: The Summary and Linear Model of Change from Baseline inStandard Patient Evaluation of Eye 
Dryness (SPEED) total score and its individual questions at each Post-Baseline Visits – PP 
Table 14.2.4.1.1: The Summary and Linear Model of Change from Baseline in TFBUT average on Study Eye at Visit 7 
(Week 12) – mITT 
Table 14.2.4.1.2: The Summary and Linear Model of Change from Baseline in TFBUT average on Non-Study Eye at 
Visit 7 (Week 12) – mITT 
Table 14.2.4.2.1: Ease of Insertion as Assessed by the Investigator on Study Eye at Visit 2 (or Visit 2B) – mITT 
Table 14.2.4.2.2: Ease of Insertion as Assessed by the Investigator on Non-Study Eye at Visit 2 (or Visit 2B) – mITT 
Table 14.2.4.3.1: The Presence of Insert on Study Eye at each Post-Baseline Visits – mITT 
Table 14.2.4.3.2: The Presence of Insert on Non-Study Eye at each Post Baseline-Visits – mITT 
Table 14.2.4.4.1: Ease of Visualization as Assessed by Investigator on Study Eye at each Post-Baseline Visits – mITT 
Table 14.2.4.4.2: Ease of Visualization as Assessed by Investigator on Non-Study Eye at each Post-Baseline Visits – 
mITT 
Table 14.3.1: Overview of Treatment-Emergent Adverse Events (TEAEs) – SAFETY 
Table 14.3.2.1: Ocular Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and Preferred Term – 
SAFETY 
Table 14.3.2.2: Non-Ocular Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and Preferred 
Term – SAFETY 
Table 14.3.2.3: Ocular Treatment-Emergent Adverse Events (TEAEs) by Preferred Term 
Table 14.3.2.4: Non-Ocular Treatment-Emergent Adverse Events (TEAEs) by Preferred Term 
Table 14.3.3.1: Ocular Serious Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and Preferred 
Term – SAFETY 
Table 14.3.3.2: Non-Ocular Serious Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term – SAFETY 
Table 14.3.4.1: Ocular Treatment-Emergent Adverse Events (TEAEs) Related to IP by System Organ Class and 
Preferred Term – SAFETY 


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Protocol: 
 
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Table 14.3.4.2 Non-Ocular Treatment-Emergent Adverse Events (TEAEs) Related to IP by System Organ Class and 
Preferred Term – SAFETY 
Table 14.3.4.3: Ocular Serious Treatment-Emergent Adverse Events (TEAEs) Related to IP by System Organ Class 
and Preferred Term – SAFETY 
Table 14.3.4.4: Non-Ocular Serious Treatment-Emergent Adverse Events (TEAEs) Related to IP by System Organ 
Class and Preferred Term – SAFETY 
Table 14.3.5.1: Maximum Severity of Ocular Treatment-Emergent Adverse Events (TEAEs) by System Organ Class 
and Preferred Term – SAFETY 
Table 14.3.5.2: Maximum Severity of Non-Ocular Treatment-Emergent Adverse Events (TEAEs) by System Organ 
Class and Preferred Term – SAFETY 
Table 14.3.6.1: Summary of Best Corrected Visual Acuity (BCVA) LogMAR VA Score and Change from Baseline on 
Study Eye by Visit – SAFETY 
Table 14.3.6.2: Summary of Best Corrected Visual Acuity (BCVA) LogMAR VA Score and Change from Baseline on 
Non-Study Eye by Visit – SAFETY 
Table 14.3.7.1: Summary of Intraocular Pressure (IOP) (mmHg), IOP ≥ 30 mmHg and Change from Baseline (CFB), 
CFB IOP >5 mmHg and >10 mmHg on Study Eye by Visit – SAFETY 
Table 14.3.7.2: Summary of Intraocular Pressure (IOP) (mmHg), IOP ≥ 30 mmHg and Change from Baseline (CFB), 
CFB IOP >5 mmHg and >10 mmHg on Non-Study Eye by Visit – SAFETY 
Table 14.3.8.1: Summary of Slit-Lamp Biomicroscopy Results on Study Eye by Location and Visit – SAFETY 
Table 14.3.8.2: Summary of Slit-Lamp Biomicroscopy Results on Non-Study Eye by Location and Visit – SAFETY 
Table 14.3.9.1: Summary of Fundus Examination Results on Study Eye by Visit – SAFETY 
Table 14.3.9.2: Summary of Fundus Examination Results on Non-Study Eye by Visit – SAFETY 
Table 14.3.10: Summary of Artificial Tear Use from Baseline by Visit – SAFETY 
7.2. 
Data Listings to be Generated 
–Listing 16.1.1.1: Subject Disposition – All Subjects Screened 
Listing 16.1.1.2: Eligibility – All Subjects 
Listing 16.1.1.3: Major Protocol Deviations – All Subjects Randomized 
Listing 16.1.1.4: Subjects Excluded from the Efficacy Analysis – All Subject Randomized 


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Listing 16.1.2: Demographic and Baseline Characteristics - mITT and Cohort 1 
Listing 16.1.3.1: Ocular Medical History - mITT and Cohort 1 
Listing 16.1.3.2: Non-Ocular Medical History - mITT and Cohort 1 
Listing 16.1.4: Treatment Exposure - SAFETY 
Listing 16.1.5: Schirmer’s Test without Anesthesia Result- mITT and Cohort 1 
Listing 16.1.6: CFS Assessment - mITT and Cohort 1 
Listing 16.1.7: CLGS Assessment - mITT and Cohort 1 
Listing 16.1.8: VAS of Eye Dryness Score - mITT and Cohort 1 
Listing 16.1.9: Ocular Surface Disease Index questionnaire (OSDI©) - mITT and Cohort 1 
Listing 16.1.10: Standardized Patient Evaluation of Eye Dryness (SPEED) - mITT and Cohort 1 
Listing 16.1.11: Tear Film Break Up Time (TBUT) - mITT and Cohort 1 
Listing 16.1.12: Insert Placement at Visit 2 or Visit 2B - mITT and Cohort 1 
Listing 16.1.13: Ease of insertion at Visit 2 or Visit 2B as assessed by the Investigator - mITT and Cohort 1 
Listing 16.1.14: Presence of OTX-CSI or HV by Visual Assessment - mITT and Cohort 1 
Listing 16.1.15: Ease of visualization as assessed by the Investigator - mITT and Cohort 1 
Listing 16.1.16.1: All Adverse Events - SAFETY 
Listing 16.1.16.2: Serious Adverse Events - SAFETY 
Listing 16.1.16.3: Adverse Events leading to Discontinuation of Treatment - SAFETY 
Listing 16.1.16.4: Subject Deaths - SAFETY 
Listing 16.1.17: Best Corrected Visual Acuity (BCVA) - SAFETY 
Listing 16.1.18: Slit-lamp Biomicroscopy and External Eye Exam - SAFETY 
Listing 16.1.19: Intraocular Pressure (IOP) Measurement - SAFETY 
Listing 16.1.20: Fundus Examination - SAFETY 
Listing 16.1.21: Use of Artificial Tears - SAFETY 


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Protocol: 
 
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Listing 16.1.22: Urine Pregnancy Test - SAFETY 
Listing 16.1.23: Concomitant Medications - SAFETY 
Listing 16.1.24: Prior Medications - SAFETY 
 
 
 
 


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7.3. 
SAS Codes 
7.3.1. 
variables used in SAS codes: 
TRPG1N 
Treatment groups with 4 groups  
TRPG1N_FG1  
TRPG1N_FG2 
TRPG1N_FG3 
Dummy variables based on TRPG1N 
AVAL2  
Value at visit 2 
AVAL4  
Value at visit 3 
AVAL5  
Value at visit 4 
AVAL6  
Value at visit 5 
AVAL7  
Value at visit 6 
AVAL8  
Value at visit 7 
CHG 
Change from baseline  
CRIT4 
Categorical Schirmer test (>=10 mm vs <10 mm) at visit 3 
CRIT5 
Categorical Schirmer test at visit 4 
CRIT6 
Categorical Schirmer test at visit 5 
CRIT7 
Categorical Schirmer test at visit 6 
CRIT8 
Categorical Schirmer test at visit 7 
CRIT9 
Categorical Schirmer test at visit 8 
SEFN 
Study eye flag 
 
 
 


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7.3.2. 
SAS codes to impute the missing using MCMC MI 
PROC MI DATA=pr1t SEED=738493 OUT=pr1mcmcmiy MINIMUM=0 MAXIMUM=35 ROUND=0.1 
NIMPUTE=25; 
/*The imputation will be done in eye level, SEFL is study eye flag*/ 
               where SEFL="Y"; 
  MCMC INITIAL=EM; 
  VAR TRPG1N_FG1 TRPG1N_FG2 TRPG1N_FG3 AVAL2 AVAL4 AVAL5 AVAL6 AVAL7 AVAL8 
AVAL9; 
RUN;  
 
7.3.3. 
SAS codes to impute the missing using FCS MI  
PROC MI DATA=pr1t SEED=918411 OUT=pr1fcsy MINIMUM=0 MAXIMUM=35 ROUND=0.1 
NIMPUTE=25; 
  where SEFL="Y"; 
  class TRPG1N CRIT4 CRIT5 CRIT6 CRIT7 CRIT8 CRIT9; 
  VAR TRPG1N AVAL2 AVAL4 AVAL5 AVAL6 AVAL7 AVAL8 AVAL9; 
/*This part imputes the continues Schirmer test */ 
  fcs nbiter=200 reg (AVAL2=TRPG1N ); 
  fcs nbiter=200 reg (AVAL4=TRPG1N AVAL2); 
  fcs nbiter=200 reg (AVAL5=TRPG1N AVAL2 AVAL4); 
  fcs nbiter=200 reg (AVAL6=TRPG1N AVAL2 AVAL4 AVAL5); 
  fcs nbiter=200 reg (AVAL7=TRPG1N AVAL2 AVAL4 AVAL5 AVAL6); 
  fcs nbiter=200 reg (AVAL8=TRPG1N AVAL2 AVAL4 AVAL5 AVAL6 AVAL7); 
  fcs nbiter=200 reg (AVAL9=TRPG1N AVAL2 AVAL4 AVAL5 AVAL6 AVAL7 AVAL8); 
RUN; 
 
7.3.4. 
SAS codes to run t-test on MI data  
ods output statistics=ttest1; 
proc ttest data=pr2; 
              by AVISITN IMPUT; 
where TRPG1N in (1 3); 
class TRPG1N ; 
var CHG; 
run; 
 
 


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data ttest2; 
set ttest1; 
if class="Diff (1-2)" and method ne "Pooled" then delete; 
run; 
 
ods output parameterestimates=pdiff_ttest; 
proc mianalyze data=ttest2; 
modeleffects mean; 
stderr stderr; 
by AVISITN CLASS; 
run; 
 
7.3.5. 
SAS codes to run ANCOVA (using PROC MIXED) on MI data  
ods output LSMESTIMATEs=LSMESTIMATEs; 
proc mixed data= pr2; 
 by AVISITN IMPUT; 
 CLASS TRPG1N (ref=last); 
 MODEL CHG=TRPG1N base; 
 lsmeans TRPG1N/ cl  pdiff; 
 LSMESTIMATE TRPG1N                              "1G1" 1 0 0 0, 
 
 
 
 
 
"2G2" 0 1 0 0, 
/* WF1 and WF2 are the sample size weighted coefficient for group 1 and 2 respectively*/  
 
 
 
 
 
"3G(1/2)" &WF1. &WF2A. 0 0, 
 
 
 
 
 
"4G3" 0 0 1 0, 
 
 
 
 
 
"5G4" 0 0 0 1, 
 
 
 
 
 
"6G1 vs G3" 1 0 -1 0 , 
 
 
 
 
 
"7G2 vs G3" 0 1 -1 0 , 
 
 
 
 
 
"8G1 vs G4" 1 0 0 -1, 
 
 
 
 
 
"91G2 vs G4" 0 1 0 -1, 
 
 
 
 
 
"92G(1/2) vs G3" &WF1. &WF2A.   -1 0 , 
 
 
 
 
 
"93G(1/2) vs G4" &WF1. &WF2A.   0 -1  / cl; 
run; 
 
proc sort data=LSMESTIMATEs; 
  by  AVISITN LABEL; 
run; 
 
 


     Statistical Analysis Plan  
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ods output ParameterEstimates=outlsmean; 
PROC MIANALYZE DATA=LSMESTIMATEs;  
  modeleffects estimate;  
  stderr stderr; 
  by  AVISITN LABEL; 
RUN; 
 
7.3.6. 
SAS codes to generate and pool proportions using MI data  
proc surveyfreq data= pr1fcsy; 
 
by avisitn imput; 
 
tables TRPG1*CRIT8 / row ; 
 
ods output CrossTabs=mi_perc_out; 
run; 
 
proc mianalyze data=mi_perc_out; 
 
by  TRPG1 CRIT8; 
 
modeleffects RowPercent; 
 
stderr  RowStdErr; 
 
ods output ParameterEstimates=pooled_percent; 
run; quit; 
 
 
7.3.7. 
SAS codes to generate and pool the Odds Ratio (OR) using MI data  
ods output ParameterEstimates =OR_out; 
proc surveylogistic data= pr1fcsy; 
              by avisitn imput; 
class TRPG1 / param = ref; 
model CRIT8 (desc) =TRPG1; 
where TRPG1N in (1 3); 
run; 
 
proc mianalyze data=OR_out; 
 
modeleffects Estimate  ; 
 
stderr  StdErr; 
 
ods output ParameterEstimates=pooled_OR; 
run; quit; 
 
 
 


     Statistical Analysis Plan  
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7.3.8. 
SAS codes to output 95% CI for proportions using Clopper-Pearson method and 
95% CI for the proportion difference using Chan and Zhang (1999) method using 
observed and LOCF data 
 
ods output RiskDiffCol1=RiskDiffCol1 FishersExact=FishersExact; 
proc freq data=adoe; 
 
table   TRPG1N* CRIT8 / fisher; 
 
exact riskdiff(method=score); 
run; 
 
 
7.3.9. 
SAS codes to designate study eye randomly in a case both eyes have the same 
total corneal fluorescein staining score 
***** 
1-    Create a SAS dataset RND1 with 1000 observations,  
2-    Create a variable named FOCID. The first 500 observation with value of "OD" (Right Eye) the last 
500 observation with value of "OS" (Left Eye) 
3-    Generate a random number using RANUNI (Uniform distribution) 
4-    Sort this dataset by random variable ****; 
data rnd1; 
do i=1 to 500; 
  FOCID="OD"; 
  rand=ranuni(54603); 
  output; 
end; 
do i=501 to 1000; 
  FOCID="OS"; 
  rand=ranuni(54603); 
  output; 
end; 
run; 
proc sort data=rnd1(drop=i); by rand; run; 
data rnd1; set rnd1; VSORT=_n_; run; 
proc sort data=rnd1; by VSORT; run; 
***** 
5-    Sort the subject by using 2 variables  
    a- date of randomization for randomized subjects / date of informed consent for open label subjects 
    b- random number 
    c- subject number  


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6-    Then merge this dataset with RND1 and then selected FOCID will be their study eye.*****; 
proc sort data=idsd.suppdm out=dm1(keep=USUBJID QVAL); 
where QNAM="RANDNUMB"; 
by USUBJID; 
run; 
proc sort data=idsd.ds out=dm2(keep=USUBJID DSSTDTC); 
where DSDECOD="RANDOMIZED" or (DSDECOD="INFORMED CONSENT OBTAINED" and USUBJID in 
("CLN-0054-02-02001" "CLN-0054-02-02002" "CLN-0054-02-02003" "CLN-0054-02-02004" "CLN-0054-
02-02005")); 
by USUBJID; 
run; 
data dm3; 
merge dm1 dm2; 
by USUBJID; 
run; 
proc sort data=dm3; 
by DSSTDTC QVAL USUBJID; 
run; 
data dm3; set dm3; VSORT=_n_; run; 
proc sort data=dm3; by VSORT; run; 
data rnd2; 
merge dm3(in=dm) rnd1;  
 by VSORT;  
 if dm then output; 
run; 
proc sort data=rnd2; by USUBJID FOCID; run;