Clinical trial NCT02845674
Conditions: Keratoconjunctivitis Sicca
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2016-07-29; Completion date: 2017-08-15
Enrollment: 258 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a safety extension enrolling subjects participating in Study OTX-101-2016-001 (NCT02688556)

Detailed description:

Arms: arm 1: 0.09% cyclosporine nanomicellar solution
Interventions: intervention 1: OTX-101 0.09%
Intervention descriptions: intervention 1: 0.09% cyclosporine nanomicellar solution

Protocol documents:
Prot_000.pdf: 
OTX-101 
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CLINICAL TRIAL PROTOCOL OTX-101-2016-002 
An Open-Label Extension of a Randomized, Multicenter, 
Double-Masked, Vehicle-Controlled Study of the Safety and 
Efficacy of OTX-101 in the Treatment of 
Keratoconjunctivitis Sicca 
 
Study Phase: 
Phase 3 
Product Name: 
OTX-101 Ophthalmic Solution 
Indication: 
Treatment of keratoconjunctivitis sicca 
Sponsor: 
Ocular Technologies SARL 
 
 
 
 
Medical Monitor: 
Robert David, MD 
Original Protocol: 
6 July 2016  
Amendment 1: 
23 March 2017 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
 
The information contained in this document is confidential and proprietary property of 
Ocular Technologies SARL Neither this document nor the information contained herein may 
be divulged, transmitted, reproduced, published, or otherwise used by others without the 
express written permission of Ocular Technologies SARL 




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INVESTIGATOR’S AGREEMENT 
 
Study Title: 
An Open-Label Extension of a Randomized, Multicenter, Double-
Masked, Vehicle-Controlled Study of the Safety and Efficacy of OTX-
101 in the Treatment of Keratoconjunctivitis Sicca 
Study Number: 
OTX-101-2016-002 
Original Protocol: 
6 July 2016 
Amendment 1: 
23 March 2017 
 
I have received and read the OTX-101-2016-002 protocol. The signature below constitutes the 
approval of this protocol and the attachments, and provides the necessary assurances that this 
trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and in compliance with ICH guidelines, and all applicable United 
States federal regulations and local legal and regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Project manager 
 
 
 
 
 
 
Medical monitor 
 
 
 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: Ocular Technologies SARL  
Name of Investigational Product: OTX-101 0.09% 
Name of Active Ingredient: Cyclosporine  
Title of Study: An Open-Label Extension of a Randomized, Multicenter, Double-Masked, Vehicle-
Controlled Study of the Safety and Efficacy of OTX-101 in the Treatment of Keratoconjunctivitis 
Sicca  
Studied Period (Years): 1 
Estimated date first patient enrolled: August 2016 
Estimated date last patient completed: September 2017 
Phase of Development: 3 
Objective: The objective of this study is to evaluate the long-term safety of OTX-101 0.09% 
ophthalmic solution in the treatment of keratoconjunctivitis sicca (KCS). 
Methodology: This is an open-label extension of OTX-101-2016-001, a randomized, multicenter, 
double-masked, vehicle-controlled study in which subjects were randomized to 1 of 2 treatment arms 
and treated for 12 weeks as follows: 
• 
OTX-101 0.09% (N = 
 subjects) 
• 
Vehicle (N = 
 subjects) 
Subjects successfully completing Study OTX-101-2016-001 may be eligible to enroll in this 40 to 52 
week open label extension study in which all subjects will receive OTX-101 0.09% therapy. Subjects 
may also use unpreserved artificial tears, as needed. Subjects assigned to OTX-101 0.09% in Study 
OTX-101-2016-001 will participate for 40 weeks. Subjects assigned to vehicle in Study OTX-101-
2016-001 are eligible to participate for 52 weeks. Both subject sets will total 52 weeks of 
participation receiving OTX-101 0.09%. 
Subjects may enroll in Study OTX-101-2016-002 for up to 14 days following completion of Visit 5 of 
Study OTX-101-2016-001. At Visit 5a, sites will obtain signed informed consent and dispense study 
medication. If Visit 5a is not conducted on the same day as Visit 5 of Study OTX-101-2016-001, any 
female subject of childbearing potential must also have a negative urine pregnancy test. Study “Day” 
approximately reflects the cumulative number of days of exposure to study drug since the baseline visit 
of Protocol OTX-101-2016-001, regardless of actual calendar time elapsed. 
Subjects will self-administer study medication topically to both eyes BID for 40 to 52 weeks depending 
on their treatment assignment in Study OTX-101-2016-001. Safety evaluations for all subjects will be 
conducted at study visits on Days 182, 273 and 364; the window for Visits 6 (Day 182) and Visit 7 
(Day 273) will be ± 7 days; the window for Visit 8 (Day 364) will be +14 days for those subjects 
assigned to OTX-101 0.09% in Study OTX-101-2016-001. (± 14 days for subjects assigned to vehicle 
in Study OTX-101-2016-001, participating for 52 weeks in Study OTX-101-2016-002). Subjects 
assigned to vehicle in Study OTX-101-2016-001, participating for 52 weeks in Study OTX-101-2016-
002, will also be evaluated at Visit 9 (Day 448), which will have a visit window of +14 days.  Both 
eyes will be assessed at each visit. Adverse events and concomitant medications will be documented 
from signing of informed consent to the subject’s final visit. 


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Number of Subjects (Planned): Approximately 
 subjects are to be enrolled in the Study OTX-
101-2016-001 (approximately 
 treatment arm) at approximately 50 clinical sites. 
Approximately 
 subjects successfully completing that study may be eligible to enter into this 
extension study. 
Diagnosis and Main Criteria For Inclusion: 
Inclusion Criteria 
1. Successful completion of participation in Protocol OTX-101-2016-001. 
2. All subjects must provide signed written consent prior to participation in any study related 
procedures. 
3. Female subjects of childbearing potential must have a negative urine pregnancy test at 
Visit 5 (Day 84) of Protocol OTX-101-2016-001 or at Visit 5a of Protocol OTX-101-2016-
002, if conducted at a later date. Women of childbearing potential (i.e., women who are not 
either postmenopausal for one year or surgically sterile) and men who have partners of 
childbearing potential must use an acceptable form of contraception throughout the study. 
4. Corrected Snellen visual acuity (VA) of better than 20/200 in both eyes at Visit 5 (Day 84) 
of Protocol OTX-101-2016-001  
Exclusion Criteria 
1. Subjects reporting an Adverse Event that has not resolved by Visit 5 of Protocol OTX-101-
2016-001 may be excluded if, in the judgment of the Principal Investigator and Medical 
Monitor, it would not be in the subject’s best interest to continue treatment with study 
drug. 
2. Use of Restasis or any topical cyclosporine preparation following Visit 5 of Protocol OTX-
101-2016-001.  
3. Use of any prescription topical ophthalmic medications (including antiglaucoma 
medications) other than the assigned study medication during the study period. 
Unpreserved artificial tears are permitted.  
4. Current active eye disease other than KCS (i.e., any disease for which topical or systemic 
ophthalmic medication is necessary). 
5. History of herpes keratitis. 
6. Unstable macular disease (e.g., age-related macular degeneration, diabetic maculopathy). 
Stable macular disease is defined as no reduction in central VA since the screening visit of 
Study OTX-101-2016-001. 
7. Diagnosis of chronic uveitis. 
8. Corneal transplant following Visit 5 of Protocol OTX-101-2016-001. 
9. Corneal refractive surgery following Visit 5 of Protocol OTX-101-2016-001. 
10. Non-laser glaucoma surgery following Visit 5 of Protocol OTX-101-2016-001. 
11. Lagophthalmos or clinically significant eyelid margin irregularity of the study eye whether 
congenital or acquired.  


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Exclusion Criteria (continued): 
12. Presence of conjunctivochalasis (i.e., mechanical blockage of the lower lid punctum by 
redundant conjunctiva). 
13. Presence of pterygium in either eye. 
14. Unwilling to discontinue use of contact lenses during the duration of the study. 
15. Preplanned elective surgery or hospitalization during the study period. 
16. HIV-positive. 
17. Unable to reliably report symptoms and history. 
18. Has a severe/serious ocular condition, or any other unstable medical condition that, in the 
Investigator’s opinion, may preclude study treatment or follow-up.  
19. Women who are pregnant or breastfeeding. 
Investigational Product, Dosage, and Mode of Administration: OTX-101 0.09%, 1 drop in both 
eyes BID 
Reference Therapy, Dosage, and Mode of Administration: N/A 
Duration of Treatment: 40 - 52 weeks  
Study Procedures: Ophthalmic examinations must be conducted in the order listed in the Schedule of 
Procedures. 
Visit 5a 
The site will obtain signed informed consent, inclusion/exclusion criteria, and dispense study 
medication. If Visit 5a is not conducted on the same day as Visit 5 of Protocol OTX-101-2016-001, the 
site will also update concomitant medications and conduct a urine pregnancy test for female subjects of 
childbearing potential.  
Visits 6 and 7 (Days 182 and 273)  
The site will update concomitant medications, conduct a urine pregnancy test for female subjects of 
childbearing potential, conduct ophthalmic examinations as specified, document any AEs, and dispense 
study medication. 
Visit 8 (Day 364): Final Treatment Visit for Subjects assigned to OTX-101 0.09% in Study OTX-
101-2016-001 
The site will update concomitant medications, conduct a urine pregnancy test for female subjects of 
childbearing potential, conduct ophthalmic examinations as specified and document any AEs. Study 
medication will be dispensed to those subjects continuing in the study for an additional 12 weeks. 
Visit 9 (Day 448): Final Treatment Visit for Subjects assigned to vehicle in Study OTX-101-2016-
001 
The site will update concomitant medications, conduct a urine pregnancy test for female subjects of 
childbearing potential, conduct ophthalmic examinations as specified and document any AEs. 
Clinical site personnel will document all received and returned study medication at each visit. Study 
medication accountability will be conducted by the monitor at each applicable monitoring visit. 
If a study subject is discontinued from study medication before Visit 8 or Visit 9, as appropriate, every 
effort should be made to perform all Visit 8 or Visit 9 procedures during the visit when the subject is 
discontinued. 
 


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Efficacy Assessments:  
None 
Safety Assessments: 
Safety assessments will include corrected Snellen VA, slit lamp examination, IOP, dilated 
fundoscopy/ophthalmoscopy and collection of AEs and concomitant medications  
Criteria for Evaluation: 
• 
The safety of OTX-101 0.09% as determined by ocular and non ocular AEs 
Statistical Methods: 
Analysis Population: 
• 
Safety: The safety population will include all patients who have received at least one dose of 
the study medication. 
Statistical Analyses: 
Descriptive statistics will be used to summarize continuous outcomes (number of subjects, mean, 
standard deviation or standard error of the mean, median, maximum, and minimum) and categorical 
variables (frequency and percentage) at each assessment time point. All summary tables will be 
supported with individual subject data listings. 
 


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Table 2: 
Schedule of Procedures 
 
Procedures 
Visit 5a 
Visit 6  
Phone 
Contact 
Visit 7 
Phone 
Contact 
Visit 8 
Phone 
Contact 
Visit 9 
Early 
Day of Study a 
Days since Visit 5a 
84 
- 
182 ± 7 
98 
227 ± 7 
143 
273 ± 7 
189 
318 ± 7 
234 
364 + 14 i 
280 
409 ± 7 
325 
448 + 14 
364 
Discontinuation 
Informed consent j 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Concomitant medication history/review 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test c 
Xb 
X 
 
X 
 
X 
 
X 
X 
Corrected Snellen Visual Acuity 
 
X 
 
X 
 
X 
 
X 
X 
Slit lamp examination 
 
X 
 
X 
 
X 
 
X 
X 
Ophthalmoscopy/dilated fundoscopy 
 
 
 
 
 
Xg 
 
Xg 
X 
IOP d 
 
X 
 
X 
 
X 
 
X 
X 
Study medication distribution 
X 
X 
 
X 
 
Xh 
 
 
 
Adverse event assessment e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study medication accountability f 
 
X 
 
X 
 
X 
 
X 
X 
a “Day” approximately reflects the cumulative number of days in study (Protocol OTX-101-2016-001 and OTX-101-2016-002), regardless of actual calendar 
time elapsed.  And ‘Day of Study’ is used along with Visit, throughout this protocol – e.g., Visit 6 (Day 182), etc. 
b Performed if Visit 5a is not conducted on the same calendar day as Visit 5 of Protocol OTX-101-2016-001. 
c Women of childbearing potential only. 
d Measure IOP using Goldmann applanation tonometry. 
e Collection of AEs extends from signing of informed consent until the last study visit. 
f Clinical site personnel will document all received and returned medication at Days 182, 273, 364 and 448. Study medication accountability will be performed 
by the monitor at each applicable monitoring visit. 
g Examination is required only at the subject’s final visit, 
h Medication is dispensed if the subject is participating for an additional 12 weeks 
i 364 ± 14 days if the subject is participating for an additional 12 weeks 
j Updated ICF due to Amendment #1 to be signed by all participating subjects for Protocol OTX-101-2016-002 Amendment #1 


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2. 
TABLE OF CONTENTS AND LIST OF TABLES 
TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
4. 
INTRODUCTION ......................................................................................................16 
4.1. 
Background .................................................................................................................16 
4.2. 
Rationale for the Use of OTX-101 Ophthalmic Solution in the Treatment of 
KCS.............................................................................................................................17 
4.3. 
Description of the Investigational Product: OTX-101 Ophthalmic Solution .............17 
4.4. 
Clinical Studies ...........................................................................................................18 
4.5. 
Justification of Route, Dose, Regimen, and Treatment Period ...................................19 
4.6. 
Good Clinical Practice Statement ...............................................................................19 
4.7. 
Population to Be Studied ............................................................................................19 
5. 
STUDY OBJECTIVES ..............................................................................................20 
5.1. 
Primary Objective .......................................................................................................20 
6. 
INVESTIGATIONAL PLAN .....................................................................................21 
6.1. 
Overall Study Design ..................................................................................................21 
6.2. 
Number of Subjects ....................................................................................................21 
6.3. 
Treatment Assignment ................................................................................................21 
6.4. 
Criteria for Study Termination ...................................................................................21 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................22 
7.1. 
Subject Inclusion Criteria ...........................................................................................22 
7.2. 
Subject Exclusion Criteria ..........................................................................................22 
7.3. 
Subject Withdrawal Criteria .......................................................................................23 
8. 
STUDY TREATMENTS............................................................................................24 
8.1. 
Description of Study Medications ..............................................................................24 
8.1.1. 
Investigational Product ...............................................................................................24 


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8.1.2. 
Reference Therapy ......................................................................................................24 
8.1.3. 
Rescue Therapy ..........................................................................................................24 
8.2. 
Randomization and Masking ......................................................................................24 
8.2.1. 
Unmasking During the Study Period ..........................................................................24 
8.3. 
Concomitant Medications ...........................................................................................24 
8.3.1. 
Permitted Medications and Treatments ......................................................................24 
8.3.2. 
Prohibited Medications and Treatments .....................................................................25 
8.4. 
Treatment Compliance ................................................................................................25 
8.5. 
Study Medication Materials and Management ...........................................................25 
8.5.1. 
Packaging and Labeling ..............................................................................................25 
8.5.2. 
Storage, Administration, and Dispensing ...................................................................25 
8.5.2.1. 
Storage ........................................................................................................................25 
8.5.2.2. 
Administration ............................................................................................................25 
8.5.2.3. 
Dispensing ..................................................................................................................26 
8.5.3. 
Study Medication Accountability ...............................................................................26 
9. 
STUDY ASSESSMENTS ..........................................................................................28 
9.1. 
Background Characteristics ........................................................................................28 
9.1.1. 
Medical/Ocular History ..............................................................................................28 
9.1.2. 
Concomitant Medications ...........................................................................................28 
9.2. 
Urine Pregnancy Test .................................................................................................28 
9.3. 
Efficacy Assessments .................................................................................................28 
9.4. 
Safety Assessments .....................................................................................................28 
9.4.1. 
Corrected Snellen Visual Acuity ................................................................................28 
9.4.2. 
Slit Lamp Examination ...............................................................................................29 
9.4.3. 
Intraocular Pressure ....................................................................................................29 
9.4.4. 
Ophthalmoscopy/Dilated Fundus Examination ..........................................................29 
9.5. 
Adverse and Serious Adverse Events .........................................................................29 
9.5.1. 
Definition of Adverse Events .....................................................................................29 
9.5.1.1. 
Serious Adverse Event ................................................................................................29 
9.6. 
Relationship to Study Medication ..............................................................................30 
9.7. 
Recording Adverse Events .........................................................................................30 
9.8. 
Reporting Adverse Events ..........................................................................................31 


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10. 
STUDY ACTIVITIES ................................................................................................33 
10.1. 
Visit 5a ........................................................................................................................33 
10.2. 
Treatment Visits ..........................................................................................................33 
10.2.1. 
Visit 6 (Day 182), Visit 7 (Day 273) and Visit 8 (Day 364)* .....................................33 
10.3. 
Final Study Visit: Visit 8 (Day 364) or Visit 9 (Day 448) .........................................34 
10.4. 
Telephone Contact ......................................................................................................34 
10.5. 
Early Discontinuation Visit ........................................................................................34 
11. 
STATISTICS ..............................................................................................................35 
11.1. 
General Considerations ...............................................................................................35 
11.2. 
Definition of Baseline Measurements ........................................................................35 
11.3. 
Handling of Missing Data ...........................................................................................35 
11.4. 
Determination of Sample Size ....................................................................................35 
11.5. 
Analysis Populations ..................................................................................................35 
11.5.1. 
Safety Analysis Populations .......................................................................................35 
11.5.1.1. 
One Year Safety Population .......................................................................................36 
11.6. 
Demographics and Baseline Characteristics ...............................................................36 
11.7. 
Efficacy Analysis ........................................................................................................36 
11.7.1. 
Hypothesis Testing .....................................................................................................36 
11.8. 
Safety Analyses ..........................................................................................................36 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................37 
13. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................38 
13.1. 
Institutional Review Board Approval .........................................................................38 
13.2. 
Ethical Conduct of the Study ......................................................................................38 
13.3. 
Subject Information and Consent ...............................................................................38 
13.4. 
Subject Confidentiality and Confidentiality of Data ..................................................39 
13.5. 
Study Monitoring ........................................................................................................39 
13.6. 
Case Report Forms and Study Records ......................................................................39 
13.7. 
Protocol Violations/Deviations ...................................................................................40 
13.8. 
Access to Source Documentation ...............................................................................40 
13.9. 
Data Generation and Analysis ....................................................................................40 
13.10. 
Retention of Data ........................................................................................................40 
13.11. 
Publication and Disclosure Policy ..............................................................................41 


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14. 
LIST OF REFERENCES ............................................................................................42 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................4 
Table 2: 
Schedule of Procedures .................................................................................................9 
Table 3: 
Abbreviations ..............................................................................................................14 
  


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table 2: 
Abbreviations 
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
BID 
twice daily 
DSEK 
Descemet’s stripping endothelial keratoplasty  
FDA 
Food and Drug Administration 
eCRF 
electronic case report form 
EDC 
electronic document capture 
ERG 
electroretinography 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HLA-DR 
human leukocyte antigen-DR 
HPRT-1 
hypoxanthine phosphoribosyltransferase 1  
IB 
Investigator’s Brochure 
ICH 
International Conference of Harmonisation 
IFN-γ 
interferon gamma 
IL 
interleukin 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LASIK 
laser-assisted in situ keratomileusis  
LFU 
lacrimal function unit 
LOCF 
last observation carried forward 
LRI 
limbal relaxing incision 
KCS 
keratoconjunctivitis sicca 
MAR 
missing at random 
MMP 
matrix metalloproteinase 
NZW 
New Zealand white (rabbit) 
OTC 
over-the-counter 
PRK 
photorefractive keratectomy 


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Abbreviation or Specialist Term 
Explanation 
QID 
four times daily 
SAE 
serious adverse event 
SOP 
standard operating procedures 
US 
United States 
VA 
visual acuity 


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4. 
INTRODUCTION 
4.1. 
Background  
Keratoconjunctivitis sicca (KCS) is a common multifactorial ophthalmologic disorder of the 
tears and ocular surface characterized by symptoms of burning, stinging, itching, grittiness, 
scratchiness, foreign body sensation, dryness, stickiness, and tired eye sensation. The onset of 
symptoms is usually gradual, bilateral, and chronic. Symptoms typically become more 
bothersome later in the day and are intensified by various environmental factors. 
The prevalence of KCS varies but it has been estimated to affect up to 35% of the population, 
although this number may be underreported and may be increasing especially in the older 
population (International Dry Eye Workshop, 2007). 
Keratoconjunctivitis sicca is generally caused by a disturbance of the lacrimal function unit 
(LFU), an integrated system comprising the lacrimal glands, ocular surface and lids, and the 
sensory and motor nerves that connects them. The LFU controls and regulates the major 
components of the tear film and responds to the various intrinsic and extrinsic environmental 
factors that a person encounters. 
The overall function of the LFU is to preserve the integrity of the tear film, the transparency of 
the cornea, and the quality of the image projected onto the retina. Damage to any component of 
the LFU can result in KCS, but the main mechanism for KCS is driven by tear hyperosmolarity, 
tear film instability, and inflammation.  
Activation of innate and adaptive immune systems by tear hyperosmolarity and desiccation leads 
to increased production of inflammatory mediators that can disrupt corneal barrier function 
(interleukin [IL]-17, matrix metalloproteinase [MMP]-3 and MMP-9), sensitize corneal and ocular 
surface nerve endings (IL-1β and IL-6), cause epithelial cell death (apoptosis, interferon gamma 
[IFN-γ]) and loss of mucus producing goblet cells (IFN-γ), and cause infiltration of T cells in the 
conjunctival tissue that further destabilizes the tear film and leads to more severe ocular surface 
disease (
). Increased 
human leukocyte antigen-DR (HLA-DR) expression by the conjunctival epithelium has been 
observed as a universal feature of KCS. The effectiveness of cyclosporine in the treatment of 
KCS may be due to its effects on the pathogenesis of this disease.  
In the United States, Restasis®, a 0.05% ophthalmic emulsion of cyclosporine, is the only 
approved prescription product for patients with KCS. Restasis is indicated for the increase in tear 
production in patients whose tear production is presumed to be suppressed due to ocular 
inflammation associated with KCS (Restasis Prescribing Information, 2013). This product has 
been shown to be effective in a relatively small percentage (15%) of patients, and, as a 
consequence, there is an unmet medical need for alternative drug treatments for the treatment of 
KCS. To meet this unmet medical need, Ocular Technologies SARL is developing OTX-101, a 
new nanomicellar formulation of cyclosporine for the treatment of KCS. 


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4.2. 
Rationale for the Use of OTX-101 Ophthalmic Solution in the 
Treatment of KCS 
OTX-101 is being investigated as a treatment for KCS. Cyclosporine has immunomodulatory 
and anti-inflammatory properties that are of presumed benefit for the treatment of KCS. 
Cyclosporine acts by binding calcineurin, an intracellular protein that ultimately controls 
transcription factors required for cytokine production and T-lymphocyte maturation, and also 
inhibits mitochondria-mediated apoptosis (
 
). By suppressing the immune-based inflammation of the ocular surface, treatment with 
cyclosporine allows the lacrimal glands to produce tears, potentiating the return of a more stable 
tear film and normal ocular surface. 
Cyclosporine applied topically to the eye at concentrations of 0.05%, 0.1%, 0.2%, and 0.4% has 
previously been evaluated in various nonclinical and clinical studies for systemic and ocular 
effects. Additionally, Restasis® was approved in 2002 based on studies submitted to the Agency 
in support of New Drug Applications (NDAs) #050790 and #021023. Restasis studies showed 
significant improvement in Schirmer’s test wetting 
 in 
 of patients in the treatment 
group compared with 5% of patients in the vehicle group (P ≤ 0.05).  
OTX-101, an aqueous nanomicellar solution of cyclosporine, is being developed in the 
expectation that it will be efficacious and well tolerated in the treatment of KCS.  
4.3. 
Description of the Investigational Product: OTX-101 Ophthalmic 
Solution 
The investigational drug product in this study, OTX-101, is an aqueous nanomicellar formulation 
of cyclosporine for topical ophthalmic use.  
The nonclinical toxicology program for OTX-101 currently includes 5 studies. The ocular 
tolerability of OTX-101 administered 4 times daily (QID) was evaluated in 5 repeat-dose studies 
conducted in NZW rabbits: (1) a pilot 5-day ocular tolerability and tissue distribution study with 
OTX-101 0.1% , (2) a pilot 6-day ocular tolerability study with OTX-101 0.05%, (3) a pilot 
7-day ocular toxicity and toxicokinetic study with OTX-101 0.05% and 0.1% compared to 
Restasis, (4) a GLP 28-day ocular toxicity and toxicokinetic study with a 14-day recovery period 
evaluating OTX-101 at 0.01%, 0.05%, or 0.1% concentrations and (5) a GLP 13-week ocular 
toxicity and toxicokinetic study with a 28-day recovery period evaluating OTX-101 at 0.01%, 
0.05%, or 0.1% concentrations. Results demonstrated that OTX-101 dosed QID at concentrations 
as high as 0.1% for up to 13 weeks was safe and well tolerated, producing no clinical 
observations, no changes in intraocular pressure and retinal function, and no histopathology 
findings.  
Following single-dose or repeat-dose administration of OTX-101 there was significant 
cyclosporine ocular tissue exposure but minimal systemic exposure. The highest exposure to 
cyclosporine was in the tears and eyelid, followed by the cornea and conjunctiva. Ocular 
cyclosporine exposure was higher with OTX-101 at either 0.1% or 0.05% concentrations than it 
was with Restasis. Following repeat dosing, the 0.05% OTX-101 nanomicellar formulation of 
cyclosporine produces approximately 1.3 to 2.5 times the tissue levels of Restasis (0.05% 
cyclosporine) in the cornea, conjunctiva, sclera, aqueous humor, and iris/ciliary body. The 0.1% 


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nanomicellar formulation of cyclosporine appears to produce approximately 1.8 to 4.5 times the 
tissue levels of Restasis.  
With respect to systemic exposure, maximum concentration (Cmax) for whole blood 
concentrations of cyclosporine was estimated to be 1.4 ng/mL following a single dose of the 
OTX-101 nanomicellar 0.1% formulation and 6.2 ng/mL following the final dose for QID dosing 
of OTX-101 0.1% at 2-hour intervals for 7 days. 
For further background, including further information regarding the nonclinical studies related to 
OTX-101, and clinical and nonclinical studies related to cyclosporine, please consult the 
Investigator’s Brochure (IB). 
4.4. 
Clinical Studies 
One clinical trial of OTX-101 has been completed. Study OTX-101-2014-001 was a Phase 2b 
dose-ranging, parallel-group, vehicle-controlled, double-masked trial of 12 weeks conducted in 
455 subjects with KCS. The efficacy and safety of 2 concentrations of OTX-101 (
 and 
%) were compared with vehicle in subjects aged 22 to 91 years with dry eye disease as 
confirmed by study evaluations of signs and symptoms. Following a 2-week run-in period during 
which all subjects received vehicle BID, qualified subjects were randomized to OTX-101 
%, 
OTX-101 
%, or vehicle in a 
 ratio and treated BID for 12 weeks. 
Both concentrations of OTX-101 demonstrated large, statistically significant differences from 
vehicle in mean change from baseline at 12 weeks for the first co-primary endpoint, lissamine 
green conjunctival staining, as well as for total corneal fluorescein staining, central corneal 
staining, and Schirmer’s tear test (categorized) (Sponsor, data on file). Of note, a dose response 
trend was observed in central corneal staining, with OTX-101 
 achieving a statistically 
significant difference from vehicle (P < .01). Neither active dose demonstrated a difference from 
vehicle in the second co-primary endpoint, global symptom score (Symptom Assessment iN Dry 
Eye [SANDE]). 
 In addition to an analysis of mean change from baseline, the Schirmer’s tear test data were also 
analyzed with respect to the proportions of subjects demonstrating an increase from baseline at 
12 weeks of
 A dose response trend across some variables was observed, with rates of 
 for OTX-101
, respectively. The 
difference in rates between OTX-101 
 and vehicle was statistically significant 
(P < .01). Similar results were obtained when a post hoc analysis was performed on the subset of 
subjects with baseline Schirmer’s scores in the range of 
 comprising 
 of the 
study population (n
). Rates of 
 were observed for OTX-101 
 
, respectively. The 
difference in rates between OTX-101 
and 
 was also statistically significant (P < .05). 
The most common ocular AEs (≥ 3 subjects) were instillation site pain (15.1%), eye irritation, 
and increased lacrimation (2.0% each) in the OTX-101 0.09% group; instillation site pain 
(13.2%), eye pruritus, and vitreous detachment (2.0% each) in the OTX-101 0.05% group; and 
instillation site pain (3.3%), eye pruritus, and blurred vision (2.6% each) in the vehicle group. 
Ocular AEs in all 3 treatment groups were predominantly mild to moderate and resolved without 
treatment (no action necessary regarding study drug). The most common non-ocular AEs 
(≥ 3 subjects) were upper respiratory tract infection in the OTX-101 0.09% group (2.0%), 


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bronchitis and sinusitis in the OTX-101 0.05% group (2.0% each), and nasopharyngitis in the 
vehicle group (2.6%). 
The majority of AEs were mild to moderate in intensity. Severe ocular events were reported for 2 
subjects in the OTX-101 0.09% group (instillation site pain), for 3 subjects in the OTX-101 
0.05% group (instillation site pain [n=2], eye irritation [n=1]) and 1 subject in the vehicle group 
(eye pain). All of these events resolved, and none led to discontinuation of study drug.  
Events considered to be related to study drug were observed in the OTX-101 0.09% group in 
19.7% of subjects, in the OTX-101 0.05% group in 15.9% of subjects, and in the vehicle group 
in 7.9% of subjects. Related events were predominantly ocular, mild to moderate in intensity, 
and resolved without treatment. Study drug-related AEs led to discontinuation of study drug for 
8 subjects, 3 in the OTX-101 0.09% group (hypersensitivity, instillation site pain, and eye 
irritation), 4 in the OTX-101 0.05% group (eye pruritus, conjunctival hyperemia, and instillation 
site pain [n=2]), and 1 in the vehicle group (reduced visual acuity and instillation site reaction 
reported for the same subject). 
4.5. 
Justification of Route, Dose, Regimen, and Treatment Period 
Cyclosporine ophthalmic emulsion 0.05% (Restasis®) instilled topically twice daily (BID) is 
approved by the United States (US) Food and Drug Administration (FDA) to increase tear 
production in patients whose tear production is presumed to be suppressed due to ocular 
inflammation associated with KCS. 
Although both concentrations of OTX-101 demonstrated efficacy for multiple signs of KCS in 
Study OTX-101-2014-001, only OTX-101 0.09% BID will be compared to vehicle in the OTX-
101-2016-001 Phase 3 study due to the dose-responses observed for several efficacy parameters. 
Given the absence of dose-limiting safety and tolerability issues observed in that study, it was 
judged unnecessary to include a lower concentration. 
This 40 week extension study will enroll subjects successfully completing Study OTX-101-
2016-001. Study OTX-101-2016-002 is intended to obtain long-term patient safety data.   
4.6. 
Good Clinical Practice Statement 
This study will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and in compliance with International Conference of 
Harmonisation (ICH) guidelines, and all applicable US federal regulations and local legal and 
regulatory requirements. 
4.7. 
Population to Be Studied 
Study subjects will be male or female, 18 years of age and older, with a patient-reported history 
of KCS for a period of at least 6 months and a clinical diagnosis of bilateral KCS supported by 
OTX-101-2016-001 study assessments. 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
The primary objective of this study is to evaluate the long-term safety of OTX-101 0.09% in 
subjects with KCS. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This will be an extension of OTX-101-2016-001, a randomized, multicenter, double-masked, 
vehicle-controlled study that enrolled male and female subjects, 18 years of age and older, with a 
patient-reported history of KCS for a period of at least 6 months, a clinical diagnosis of bilateral 
KCS supported by OTX-101-2016-001 study assessments, and corrected Snellen VA of better 
than 20/200 in both eyes at Screening and at Baseline.  
Subjects who complete Visit 5 (Day 84) of Study OTX-101-2016-001 may be eligible to enroll 
in protocol OTX-101-2016-002 within 14 days at the discretion of the Principal Investigator and 
Sponsor.  Subjects who provide written informed consent at Visit 5a and meet the 
inclusion/exclusion criteria requirements will be enrolled in the study and receive study 
medication (OTX-101 0.09%). All subjects will participate for at least 40 weeks. Subjects who 
were randomized to the vehicle arm in Study OTX-101-2016-001 may have the opportunity to 
participate for additional 12 weeks, total of 52 weeks. 
Subjects will self-administer study medication topically to both eyes BID from Visit 5a to Visit 8 
(Day 364) or Visit 9 (Day 448). Safety evaluations will be conducted at all study visits. The 
window for Visits 6 and 7 will be ± 7 days. The window for Visit 8 will be +14 days for those 
subjects assigned to OTX-101 0.09% in Study OTX-101-2016-001 (± 14 days for subjects 
assigned to vehicle in Study OTX-101-2016-001, participating for 52 weeks in Study OTX-101-
2016-002), and Visit 9 will be +14 days. Both eyes will be assessed at each visit. Adverse events 
and concomitant medications will be documented from signing of informed consent at each 
study visit. 
6.2. 
  Number of Subjects 
A total of approximately 
subjects will be enrolled in Protocol OTX-101-2016-001 
(approximately 
 
 at approximately 50 clinical sites. Subjects 
who successfully complete that study may be eligible to participate at the discretion of the 
Principal Investigator and the Sponsor with the goal of enrolling approximately 
subjects in 
Protocol OTX-101-2016-002. 
6.3. 
Treatment Assignment 
The treatment assignments will be: 
• OTX-101 0.09%  
6.4. 
Criteria for Study Termination 
The study may be terminated at any time by the Sponsor following appropriate notification. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
The subject will be included if he/she meets the following inclusion criteria: 
1. Successful completion of participation in Protocol OTX-101-2016-001. 
2. All subjects must provide signed written consent prior to participation in any study 
related procedures. 
3. Female subjects of childbearing potential must have a negative urine pregnancy test at 
Visit 5 (Day 84) of Protocol OTX-101-2016-001 or at Visit 5a of Protocol OTX-101-
2016-002, if conducted at a later date. Women of childbearing potential (i.e., women who 
are not either postmenopausal for one year or surgically sterile) and men who have 
partners of childbearing potential must use an acceptable form of contraception 
throughout the study.  
4. Corrected Snellen visual acuity (VA) of better than 20/200 in both eyes at Visit 5 (Day 
84) of Protocol OTX-101-2016-001. 
7.2. 
Subject Exclusion Criteria 
The subject will be included in the study if they meet the inclusion criteria listed in Section 7.1 
and do not meet the exclusion criteria listed below. 
1. Subjects reporting an Adverse Event that has not resolved by Visit 5 of Protocol OTX-
101-2016-001 may be excluded if, in the judgment of the Principal Investigator and 
Medical Monitor, it would not be in the subject’s best interest to continue treatment with 
study drug. 
2. Use of Restasis or any topical cyclosporine preparation following Visit 5 of Protocol 
OTX-101-2016-001. 
3. Use of any prescription topical ophthalmic medications (including antiglaucoma 
medications) other than the assigned study medication during the study period. 
Unpreserved artificial tears are permitted.  
4. Current active eye disease other than KCS (i.e., any disease for which topical or systemic 
ophthalmic medication is necessary). 
5. History of herpes keratitis. 
6. Unstable macular disease (e.g., age-related macular degeneration, diabetic maculopathy). 
Stable macular disease is defined as no reduction in central VA since the screening visit 
of Study OTX-101-2016-001. 
7. Diagnosis of chronic uveitis.  
8. Corneal transplant following Visit 5 of Study OTX-101-2016-001. 


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9. Corneal refractive surgery following Visit 5 of Study OTX-101-2016-001.  
10. Non-laser glaucoma surgery following Visit 5 of Study OTX-101-2016-001. 
11. Lagophthalmos or clinically significant eyelid margin irregularity of the study eye 
whether congenital or acquired.  
12. Presence of conjunctivochalasis (i.e., mechanical blockage of the lower lid punctum by 
redundant conjunctiva). 
13. Presence of pterygium in either eye. 
14. Unwilling to discontinue use of contact lenses during the duration of the study. 
15. Preplanned elective surgery or hospitalization during the study period. 
16. HIV-positive. 
17. Unable to reliably report symptoms and history. 
18. Has a severe/serious ocular condition, or any other unstable medical condition that, in the 
Investigator’s opinion, may preclude study treatment or follow-up.  
19. Women who are pregnant or breastfeeding.  
 
7.3. 
Subject Withdrawal Criteria 
The following are the criteria for considering withdrawal from the study: 
• Withdrawal of patient consent. 
• Subject lost to follow-up. 
• The subject has a clinically significant adverse event (AE) or serious adverse event 
(SAE) that would not be consistent with continuation in the study, as determined by 
the Investigator in discussion with the Medical Monitor. 
• Pregnancy. 
If a subject withdraws or is withdrawn from the study, the principal reason for withdrawal will 
be recorded on the electronic case report form (eCRF). If a study subject is discontinued from 
study medication before the final scheduled visit, all procedures scheduled for that visit should 
be conducted at the time the subject is discontinued. 


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8. 
STUDY TREATMENTS 
8.1. 
Description of Study Medications 
8.1.1. 
Investigational Product 
OTX-101 is an aqueous nanomicellar formulation of cyclosporine for topical ophthalmic use. It 
is supplied in unit dose vials. The subject will self-administer one full drop to both eyes BID. If a 
full drop is not instilled into the eye, the subject will wait approximately 10-15 seconds and 
administer a second drop. 
8.1.2. 
Reference Therapy 
Not applicable 
8.1.3. 
Rescue Therapy 
Subjects are permitted the ad libitum use of unpreserved artificial tears 
8.2. 
Randomization and Masking 
All subjects will receive OTX-101 0.09%. A supply of study medication from the assigned kit 
will be dispensed to the subject at the end of the Visit 5a, at Visit 6 (Day 182) and at Visit 7 (Day 
273). An additional box of medication will be dispensed at Visit 8 (Day 364) to those subjects 
who are scheduled to remain in the study until Visit 9 (Day 448).  
8.2.1. 
Unmasking During the Study Period 
Not applicable. 
8.3. 
Concomitant Medications 
8.3.1. 
Permitted Medications and Treatments 
Therapy considered necessary for the subject’s welfare that will not interfere with the evaluation 
of the study medication may be given at the discretion of the Investigator and in consultation 
with the Medical Monitor. If there is any question as to whether the medication may interfere, 
the Investigator should contact the Medical Monitor or Sponsor.  
Oral omega-3 fatty acids are permitted if the dosage has been stable for 3 months and the subject 
stays on the same dose until the end of the study. The subject should not begin oral omega-3 
fatty acids during the study. Whenever possible, medications should be administered in dosages 
that remain constant throughout the study duration. All concomitant medications will be 
recorded in the eCRF. 
Preservative-free artificial tears may be used ad libitum. 


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8.3.2. 
Prohibited Medications and Treatments 
The Medical Monitor should be notified before prohibited medication or therapy is administered, 
unless the safety of the subject requires immediate action. The decision to administer a 
prohibited medication or therapy should be done with the safety of the subject as the primary 
consideration.  
Prohibited ocular medications and therapies during the study include any prescription or 
over-the-counter topical ophthalmic medications other than the assigned study medication 
(unpreserved artificial tears are permitted) and ocular surgery/ocular laser treatment of any kind.  
8.4. 
Treatment Compliance 
Treatment compliance will be monitored by study medication accountability. Throughout the 
treatment phase, the amount of opened and unopened medication returned at each post-baseline 
visit will be documented by study site personnel. 
8.5. 
Study Medication Materials and Management 
8.5.1. 
Packaging and Labeling 
Study medication will be packaged and labeled at a central packaging facility. Each subject kit 
will consist of a single Main Box which is to remain at the clinical site.  
Each Main Box will contain 3 smaller boxes, each of which contains 210 unit dose vials (105 
days supply). The smaller boxes will be sealed and labeled to include the kit number and the visit 
number at which it is to be dispensed directly to the subjects. Other label information will 
include patient instructions and safety information. 
Clinical sites are to dispense study medication from the kit assigned to the subject at Visit 5a, 
Visit 6 (Day 182) and Visit 7 (Day 273). 
An additional box of medication will be dispensed at Visit 8 (Day 364) to those subjects 
scheduled to continue treatment until Visit 9 (Day 448). Each box contains 210 unit dose vials 
(105 days supply). 
8.5.2. 
Storage, Administration, and Dispensing 
8.5.2.1. 
Storage 
Study medication must be stored as indicated on the package label: “Store at 
 
(
)” in a secured area. A temperature log will be maintained at each clinical site. Subjects 
should be instructed to store study medication at home at room temperature. After opening a 
pouch, the remaining vials should be stored in the pouch until used. Subjects will retain all 
opened and unopened study medication materials (unit dose vials, foil pouches, boxes) to return 
to the site. 
8.5.2.2. 
Administration 
Subjects will self-administer study medication topically to both eyes BID for 40 or 52 weeks. 
The subject should be in a seated position and should tilt his or her head backward for 


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administration of the study medication. The vial of study medication should be held at an almost 
vertical position above the eye while the lower eyelid is pulled down gently, and one full drop is 
placed into the conjunctival cul-de-sac of each eye from the same vial. (Note: if a full drop is not 
instilled into the eye, the subject should wait approximately 10-15 seconds and administer a 
second drop.) The tip of the vial should not touch the eye. After instilling a drop in each eye, the 
remaining contents of the vial should be emptied and the vial should be stored in the foil pouch 
and placed back in the box. 
Twice each day, approximately 12 hours apart, the subject will open a new unit dose vial and 
administer 1 full drop to each eye, store the used vial in the foil pouch, and place it back in the 
box for return to the clinical site. At each post-baseline visit, the box, complete with used 
vials/pouches and any unopened study medication will be returned to the clinical site where the 
used and unopened medication will be documented and the next designated box will be 
dispensed to the subject.  
8.5.2.3. 
Dispensing 
At Visit 5a, the kit labeled with that visit will be removed from the Main Box at the site and 
dispensed to the subject with instructions to return the box along with used and unused study 
medication at Visit 6. The two remaining kits will remain in the Main Box at the site. 
At Visit 6 (Day 182), the kit returned by the subject will be taken by the site, sealed, and placed 
back into the Main Box and the site will dispense the kit labeled Visit 6 to the subject with 
instructions to return the box along used and unused study medication at Visit 7. 
At Visit 7 (Day 273), the kit returned by the subject will be taken by the site, sealed, and placed 
back into the Main Box and the site will dispense the kit labeled Visit 7 to the patient with 
instructions to return the box along with used and unused study medication at Visit 8. 
At Visit 8 (Day 364), the kit returned by the subject will be taken by the site, sealed, and placed 
back into the Main Box ready for the CRA to perform drug accountability and reconciliation. An 
additional box of drug will be dispensed to those subjects scheduled to continue treatment until 
Visit 9 (Day 448). 
At Visit 9 (Day 448), the box returned by the subject will be taken by the site, sealed and 
retained for the CRA to perform drug accountability and reconciliation. 
After site close out, the site or CRA will ship all materials back to the supplier. 
8.5.3. 
Study Medication Accountability 
The Investigator or designee (e.g., study coordinator or pharmacist) will maintain a full 
accountability record for the study medication and will be responsible for recording the receipt, 
dispensing, and return of all supplies of the study medication using the inventories supplied by 
the Sponsor. Clinical site personnel will document all received and returned study medication at 
each post-baseline visit. Study drug accountability will be conducted by the monitor at each 
applicable monitoring visit. 
As described in Section 
 the subject will return all opened vials/pouches as well as any 
unopened study medication at each post-baseline visit. The monitor will review dispensing and 


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drug accountability records during site visits and at the completion of the study and note any 
discrepancies. 
All investigational study medication must be stored in a secure facility, with access limited to the 
Investigator and authorized staff. 


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9. 
STUDY ASSESSMENTS 
Prior to entry into the study or initiation of any study-related procedures, the subject must read, 
sign, and date the current Institutional Review Board (IRB)-approved version of the informed 
consent form. A full discussion of informed consent is presented in Section 13.3. 
9.1. 
Background Characteristics 
9.1.1. 
Medical/Ocular History 
If Visit 5a does not occur on the date of Visit 5, the subject should be queried regarding relevant 
events that may have occurred in the interim. 
9.1.2. 
Concomitant Medications 
If Visit 5a does not occur on the date of Visit 5, the subject’s concomitant medication list should 
be updated, if necessary. 
9.2. 
Urine Pregnancy Test 
A urine pregnancy test will be performed at each visit for women of childbearing potential only. 
9.3. 
Efficacy Assessments  
Efficacy assessments will not be performed in this safety study as the absence of a comparator 
group and the subject selection process would obviate the possibility of obtaining interpretable 
efficacy data. Investigators should nevertheless perform any assessments consistent with the 
standard of care in their practice.  
9.4. 
Safety Assessments 
Safety will be assessed at each visit by corrected Snellen VA, slit lamp examination, IOP, AE 
documentation, and concomitant medication review. Ophthalmoscopy/dilated fundus 
examination will be performed at the subject’s last visit; i.e., Visit 8 (Day 364) or Visit 9 (Day 
448).  
9.4.1. 
Corrected Snellen Visual Acuity  
Corrected Snellen VA measurement will be performed at each study visit with the Snellen eye 
chart using the subject’s current corrective lens prescription. Subjects must read ≥ 50% of the 
letters on a single line to accept that VA line. The refraction used at the screening visit of 
Protocol OTX-101-2016-001 should be used for all subsequent VA assessments for the duration 
of the study. The subject must wear the same glasses, if applicable, at each visit. If the glasses 
are not available, the eyeglass prescription should be placed in a trial frame and used in place of 
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9.4.2. 
Slit Lamp Examination 
A routine slit lamp examination will be performed to evaluate the anterior segment of the eye, 
including lids, cornea, conjunctiva, anterior chamber, iris, and lens. Abnormalities will be 
documented.  
9.4.3. 
Intraocular Pressure 
Intraocular pressure will be measured via Goldmann applanation tonometry using the clinical 
site’s standard procedures. Intraocular pressure in a given subject should be recorded using the 
same tonometer and the same observer each time, if possible. The IOP values will be recorded in 
the eCRF. 
9.4.4. 
Ophthalmoscopy/Dilated Fundus Examination 
Direct ophthalmoscopy with dilation will include assessment of the optic nerve head for pallor 
and cupping. A dilated fundus examination consisting of the vitreous, optic nerve, macula, and 
peripheral retina will be conducted. Abnormalities will be documented. 
9.5. 
Adverse and Serious Adverse Events 
9.5.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
study medication (pharmaceutical/biological product) that does not necessarily have a causal 
relationship to this medication. An AE can, therefore, be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of the study medication, whether or not related to the study medication. Study medication 
includes the investigational drug under evaluation and the comparator product or vehicle placebo 
that is given during any phase of the study. 
Medical conditions/diseases present before signing the informed consent form are only 
considered AEs if they worsen after the informed consent form is signed. Abnormal test results 
constitute AEs only if they induce clinical signs or symptoms, are considered clinically 
significant, or require additional therapy or a change in therapy. 
At each study visit the subject will be asked how he/she has been feeling. All AEs whether 
observed by the Investigator or spontaneously reported by the subject will be documented in the 
subject's chart and the AE eCRF. 
Adverse events also may be detected when they are volunteered by the subject between visits or 
through study assessments. 
9.5.1.1. 
Serious Adverse Event  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 


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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. 
• Results in persistent or significant disability/incapacity (excluding 
progression/outcome of the disease under study), 
• Is a congenital anomaly/birth defect, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Is medically significant; i.e., defined as an event that jeopardizes the health of the 
subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Treatment on an outpatient emergency basis that does not result in hospital admission with an 
overnight stay is not considered an SAE. 
All SAEs that are ongoing at the time of completion or discontinuation from the study will be 
followed until stabilization or resolution of the event. 
9.6. 
Relationship to Study Medication 
The relationship of AEs to the study medication should be assessed by the Investigator using the 
definitions below. 
Not suspected: The temporal relationship of the event to the study medication makes a causal 
relationship unlikely, or, other drugs, therapeutic interventions or underlying conditions provide 
a sufficient explanation for the observed event. 
Suspected: The temporal relationship of the event to the study medication makes a causal 
relationship possible or other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the study medication and the occurrence of the AE, then the AE should be 
considered “suspected.” 
If the relationship between the AE/SAE and the study medication is determined by the Sponsor 
to be “suspected,” the event will be considered to be related to the study medication for the 
purposes of expedited regulatory reporting. 
9.7. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open-ended 
question from the study personnel or revealed by observation, regardless of severity or potential 
association with the study medication or study procedures, will be recorded in the eCRF. All 
AEs that occur after a subject has signed the informed consent form until the final study visit 
should be collected and recorded on the AE eCRF page. Adverse events will be followed until 
the event is resolved or stabilized, and SAEs that are ongoing at the time of completion or 
discontinuation from the study will be followed until resolution. 


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The AE term should be reported in standard medical terminology when possible. For each AE, 
the Investigator will evaluate and report the following: 
• Onset (date); 
• Resolution (date); 
• Severity grade (mild, moderate, severe); 
• Relationship to study medication (not suspected, suspected); 
• Action taken (none, study medication temporarily interrupted, study medication 
permanently discontinued, concomitant medication taken, hospitalization/prolonged 
hospitalization, other); 
• Serious outcome (yes/no). 
The severity grade should be determined by the Investigator using the definitions below: 
• Mild: Discomfort noticed but no disruption of normal daily activity  
• Moderate: Discomfort sufficient to cause interference with normal daily activity  
• Severe: Incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
(as defined directly above) whereas seriousness is defined by the criteria under Section 9.5.1.1. 
An AE of severe intensity may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the pregnancy form, as well as in 
the eCRF. The Sponsor or its designee must also be notified. Pregnancy in itself is not regarded 
as an AE unless there is a suspicion that the study medication may have interfered with the 
effectiveness of a contraceptive medication. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth, or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
9.8. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from the time the subject has signed the 
informed consent until the final study visit, following the end of treatment exposure. Any SAEs 
“suspected” to be related to the study medication and discovered by the Investigator at any time 
after the study should be reported.  
Any SAE that occurs must be reported to the Medical Monitor within 24 hours of its occurrence 
or within 24 hours of learning of its occurrence. Recurrent episodes, complications, or 
progression of the initial SAE must be reported to the Medical Monitor as follow-up to the 
original episode within 24 hours of the Investigator receiving the information. Information about 
all SAEs will be collected and recorded on the SAE form. All pertinent medical records and 
information collected during the treatment and follow-up of the subject should be maintained at 
the clinical site with a copy emailed or faxed to the Sponsor or its designee. The Investigator 
must assess the SAE relationship and complete the SAE form. The Sponsor or its designee may 


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request additional information. Follow-up information (e.g., discharge summary) will be retained 
in the subject’s chart and a copy will be faxed or emailed to the Sponsor or its designee. 
In addition, all SAEs should be recorded on the Adverse Event eCRF page with the serious 
question marked “Yes.” 
It is the Investigator’s responsibility to notify the approving IRB of any SAEs in accordance with 
IRB and regulatory requirements. 
All subjects who experience an SAE should be followed clinically and undergo the appropriate 
diagnostic evaluations until stabilization or resolution of the event. 
All SAEs will be reported to the US FDA on the appropriate schedule depending if the event is 
drug related or not drug related, expected or unexpected (based on the available information in 
the IB). 
Any death occurring during the study period should be reported as an SAE and the SAE form 
must be forwarded to the Medical Monitor within 24 hours of learning of its occurrence. A death 
that occurs after completion of the study does not require completion of the SAE form. 
The Medical Monitor will review and evaluate accumulating safety data from the entire clinical 
trial database to identify new safety signals or increased frequency of events. This will include a 
complete review of all SAEs and all follow-up documentation whether relationship to treatment 
is considered “not suspected” or “suspected”. 


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10. 
STUDY ACTIVITIES 
Error! Reference source not found. provides a tabular summary of all scheduled visits and 
procedures to be performed during the clinical study.  
NOTE: Ophthalmic assessments must be conducted in the order listed in the Schedule of 
Procedures. 
10.1. 
Visit 5a  
Subjects will provide written informed consent and then will be evaluated with respect to the 
inclusion/exclusion criteria. Assessments conducted at Visit 5 of Study OTX-101-2016-001 are 
not repeated.  
If Visit 5a is not conducted on the same day as Visit 5 of Study OTX-101-2016-001, the 
following procedures will be conducted.  
• AE assessment 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
Subjects who meet all inclusion/exclusion criteria will be assigned a kit of study medication and 
are again instructed in topical ocular drop administration procedures.  
• Dispense study medication 
10.2. 
Treatment Visits 
10.2.1. 
Visit 6 (Day 182), Visit 7 (Day 273) and Visit 8 (Day 364)* 
Procedures performed on Days 128 (± 7 days), 273 (± 7 days) and 364* (± 14 days) will include 
the following:  
• AE assessment 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• Corrected Snellen VA  
• Slit lamp examination 
• IOP 
• Collect and document used and unopened study medication materials 
• Dispense study medication 
 *  If not the final visit 


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10.3. 
Final Study Visit: Visit 8 (Day 364) or Visit 9 (Day 448) 
Procedures performed at the subject’s final visit; i.e., Day 364 (+14 days) or Day 448 (+14 days), 
depending on their treatment assignment in Study OTX-101-2016-001, will include the 
following:  
• Collect and document used and unopened study medication materials 
• AE assessment 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• Corrected Snellen VA 
• Slit lamp examination 
• IOP 
• Ophthalmoscopy/dilated fundus examination 
10.4. 
Telephone Contact 
The subject will be contacted by telephone approximately midway between scheduled visits (i.e., 
Days 227, 318 and 409) to assess the following: 
• AE assessment 
• Concomitant medication review 
10.5. 
Early Discontinuation Visit 
If the subject is discontinuing the study early, procedures performed will include the following: 
• Collect and document all used and unopened study medication materials, if available; 
otherwise arrange for the subject to return them  
• AE assessment 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• Corrected Snellen VA  
• Slit lamp examination 
• IOP 
• Ophthalmoscopy/dilated fundus examination 


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11. 
STATISTICS 
11.1. 
General Considerations 
This is an extension of Protocol OTX-101-2016-001 that will evaluate the safety of 
OTX-101 0.09% ophthalmic solution in subjects with KCS when dosed twice per day for one 
year. 
Subjects in Protocol OTX-101-2016-001 were randomly assigned to OTX-101 0.09% or its 
vehicle in a 1:1 ratio.  However, all subjects enrolling in this extension study will be assigned to 
OTX-101 0.09%. 
A biostatistician will perform statistical analyses as agreed with the Sponsor according to the 
Statistical Analysis Plan. Any additional or supplemental data analysis performed independently 
by an Investigator shall be submitted to the Sponsor for review. 
No efficacy analyses will be performed. Safety analyses will be performed using the safety 
analysis population. Definitions for all of the analysis populations can be found in Section 11.5. 
11.2. 
Definition of Baseline Measurements 
Baseline measurements will be the last measurement for the corresponding variable prior to the 
first randomized dose on Day 0 of Protocol OTX-101-2016-001. 
11.3. 
Handling of Missing Data 
No missing efficacy data will be imputed. The reasons for missing data will be recorded. 
11.4. 
Determination of Sample Size 
In accordance with the ICH E1A Guidance, safety data for a minimum of 100 subjects treated for 
one year is recommended for inclusion in applications for marketing approval. The masking of 
subject treatment assignments in Study OTX-101-2016-001 will be maintained until the database 
for that study has been locked, so qualified subjects receiving OTX-101 0.09% or vehicle may be 
enrolled in Study OTX-101-2016-002. Approximately 
 subjects will enroll in Study OTX-
101-2016-002 of which it is anticipated that at least 
 will have been randomly assigned to 
OTX-101 0.09% in Study OTX-101-2016-001. 
11.5. 
Analysis Populations 
Two populations will be used for analysis. 
11.5.1. 
Safety Analysis Populations 
The safety population will include all patients enrolled in Study OTX-101-2016-002 who have 
received at least one dose of the study medication.  


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11.5.1.1. One Year Safety Population 
Certain analyses will include only those subjects with a total of 1 year of exposure to active drug 
in Studies OTX-101-2016-001 and OTX-101-2016-002. The combined safety data from both 
protocols will be analyzed for this population. 
11.6. 
Demographics and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for the safety analysis 
populations. Summary tables will be supported with individual subject data listings. 
11.7. 
Efficacy Analysis 
Not applicable 
11.7.1. 
Hypothesis Testing 
Not Applicable 
11.8. 
Safety Analyses 
Safety and tolerability data will be presented in tables of descriptive statistics and frequency 
distribution. All summary tables will be supported with individual subject data listings. For all 
subjects enrolled in Study OTX-101-2016-002, the safety data recorded during Study OTX-101-
2016-001 will be merged to produce a dataset encompassing one year of exposure to treatment. 
AEs that occurred during the run-in period on vehicle of Protocol OTX-101-2016-001 will be 
summarized separately from AEs that occur from the first dose of double-masked treatment on 
Day 0 of that protocol to the Day 364 or Day 448 visit of Protocol OTX-101-2016-002. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor and/or its contracted agents will utilize standard operating procedures (SOPs) 
designed to ensure that research procedures and documentation are consistently 
conducted/prepared to the highest quality standards. These SOPs also require compliance with 
FDA regulations and the ICH Good Clinical Practice (GCP) guidance. 
The study will be monitored by the Sponsor or its designee to verify that the rights and well-
being of human subjects are being protected, the reported data are accurate, complete, and 
verifiable, and that the conduct of the study is in compliance with the currently approved 
protocol, with ICH GCP, and with the applicable regulatory requirements. 
To insure compliance with GCP and all applicable regulatory requirements, the Sponsor or its 
agent may conduct a quality assurance audit at any time during or after completion of a study. 
The Investigator will be given adequate notice if he/she is selected for an audit. The audit will 
include, but is not limited to: a review of all informed consent forms, medical records, and 
regulatory documentation; an assessment of study conduct and protocol compliance; and a 
review of the study medication receipt, storage, and administration. At the conclusion of an 
audit, the auditor will conduct a brief meeting with the Investigator to review the findings of the 
audit. 


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13. 
ADMINISTRATIVE CONSIDERATIONS 
13.1. 
Institutional Review Board Approval 
The IRB must review, approve, and provide continuing review of the clinical study protocol, 
protocol amendments, the informed consent documents, subject recruitment advertisements, and 
any other written information to be provided to the subjects. Initial IRB approval is an 
affirmative decision that the clinical study has been reviewed and may be conducted at the 
clinical site within the constraints set forth by the IRB, the institution, GCP, and applicable 
regulatory requirements. A copy of the IRB approval letter for the protocol, the informed 
consent, the intended advertising, and any written material to be provided to the subject must be 
submitted to the Sponsor or its designee prior to release of investigational supplies to the clinical 
site. Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB according to local regulations and guidelines. The IRB must be notified of completion or 
termination of the study. The clinical site must maintain an accurate and complete record of all 
reports, documents, and other submissions made to the IRB concerning this protocol.  
13.2. 
Ethical Conduct of the Study 
This clinical study will be conducted in accordance with the protocol, including all statements 
regarding confidentiality, and in compliance with ICH guidelines, and all applicable US federal 
regulations and local legal and regulatory requirements.  
13.3. 
Subject Information and Consent 
A sample informed consent form containing the required elements of informed consent will be 
provided by the Sponsor or its designee. Any changes made to this sample must be approved by 
the Sponsor prior to submission to the IRB. After approval by the Sponsor, the informed consent 
form must be submitted to and approved by the IRB. The informed consent form must be written 
in a language in which the subject is fluent. Regulations require that foreign language informed 
consent forms be submitted to the IRB for approval. The foreign language translation is required 
to contain a statement of certification of the translation. 
It is the responsibility of the Investigator to inform each subject, prior to the screening 
evaluation, of the purpose of this clinical trial, including possible risks and benefits, and to 
document the informed consent process in the subject’s research chart and medical record, if 
applicable. Prior to entry into the study or initiation of any study-related procedures, the subject 
must read, sign, and date the current IRB-approved version of the informed consent form. The 
original informed consent form is to be retained by the clinical site, and a copy is to be given to 
the subject. 


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13.4. 
Subject Confidentiality and Confidentiality of Data 
Data generated for the study should be stored in a limited-access file area and be accessible only 
to representatives of the clinical site, the Sponsor and its authorized agents, the IRB, and FDA 
and relevant regulatory agencies. Medical information resulting from a subject’s participation in 
this study may be given to the subject’s personal physician or to the appropriate medical 
personnel responsible for the subject’s welfare. No information that can be related to a specific 
individual subject will be released or used in any fashion without the signed written consent of 
that subject. All reports and communications relating to study subjects will identify subjects only 
by initials and subject identification number. Complete subject identification will be kept by the 
Investigator for purposes of long-term follow-up, if needed. This information will be treated with 
strict adherence to professional standards of confidentiality. 
13.5. 
Study Monitoring 
The study will be monitored by the Sponsor or its designee in accordance with current GCP. The 
study monitor(s) are responsible for monitoring whether the study is conducted according to 
applicable Clinical Research SOPs, the protocol, and other written instructions and regulatory 
guidelines. Monitoring visits may occur as required and could include a study initiation visit, a 
monitoring visit(s), and a study close-out visit. Training will be provided for key investigative 
personnel in all aspects of study conduct. The Investigator will be responsible for making sure 
that clinical site personnel are provided adequate training on conducting their designated tasks. 
This study will utilize electronic document capture (EDC). During this centralized monitoring, 
data are reviewed by the monitors as entered by the site, and the monitors will flag any 
abnormalities, trends, or safety signals for Medical Monitor review and monitor follow-up 
onsite, if necessary. 
During visits to the clinical site, the monitor may review the source documents, eCRFs, signed 
informed consent forms, study medication storage conditions, and the reporting procedures for 
AEs and SAEs. All data generated during this study and the medical records/documents from 
which they originated are subject to inspection by the Sponsor and/or its designee, the FDA, and 
other regulatory agencies. The Investigator must notify the Sponsor promptly of any inspections 
scheduled by regulatory authorities. 
Upon completion of the study, the clinical monitor will conduct a final visit (close-out) to the 
site. The objectives of this visit are to ascertain that all regulatory records and reports are 
complete, verify that the study medication and other supplies have been accounted for, perform 
final study medication accountability (see Section 8.5.3) and ensure that the Investigators are 
aware of their responsibilities once the study ends.  
13.6. 
Case Report Forms and Study Records 
The eCRF exists within an EDC system with controlled access managed by the Sponsor or its 
authorized representatives for this study. Study personnel will be appropriately trained in the use 
of eCRFs and application of electronic signatures before the start of the study and prior to being 
given access to the EDC system. Original data and any changes of data will be recorded using 
the EDC system, with all changes tracked by the system and recorded in an electronic audit trail. 


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The Investigator will attest that the information contained in the eCRFs is true by providing 
electronic signature within the EDC system prior to database lock. After database lock, the 
Investigator will receive a copy of the subject data (e.g., CD-ROM, or other appropriate media) 
for archiving at the study site. 
At all times, the Investigator has final responsibility for the accuracy and authenticity of all 
clinical data.  
13.7. 
Protocol Violations/Deviations 
The Investigator should not deviate from the requirements of this protocol without prior written 
approval of the Medical Monitor, with the exception of a medical emergency.  
Protocol deviations should be reported to the IRB in accordance with IRB guidelines. 
All changes to the protocol will be made by the Sponsor or designee as an approved amendment 
to the protocol, submitted to the FDA, and approved by the IRB prior to implementation. 
13.8. 
Access to Source Documentation 
A trial-related monitoring audit, review by the IRB, and/or regulatory inspection may be 
conducted at any time during or after completion of a study (Section 12). The Investigator must 
provide direct access to study documentation. The audit may include, but is not limited to, a 
review of all informed consent forms; a review of medical records; a review of regulatory 
documentation; an assessment of study conduct and protocol compliance; and a review of the 
study medication receipt, storage, and administration. 
13.9. 
Data Generation and Analysis 
Management of data and the production of the clinical study report will be the responsibility of 
the Sponsor or its designee. 
During the course of the trial, data queries will be generated for data items that are potentially 
erroneous and require appropriate clarification or correction. Such clarifications and corrections 
will be discussed with, and approved by, clinical site personnel and appropriately documented. 
Prior to database lock, data listings will be generated and anomalous values investigated. 
13.10. 
Retention of Data 
Investigators should retain study-related records at the site until informed by the Sponsor. The 
Investigator will not discard any records without notifying the Sponsor. If the Principal 
Investigator moves from the current clinical site, the Sponsor should be notified of the name of 
the person who will assume responsibility for maintenance of the records at the clinical site or 
the new address at which the records will be stored. The Investigator will notify the Sponsor as 
soon as possible in the event of accidental loss or destruction of any study documentation. 
If it becomes necessary for the Sponsor, its designee, or the FDA or relevant regulatory 
authorities to review any documentation relating to the study, the Investigator must permit access 
to such records.  


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13.11. 
Publication and Disclosure Policy 
All information concerning OTX-101 ophthalmic solution and the operations of the Sponsor, 
such as patent applications, formulas, manufacturing processes, basic scientific data, or 
formulation information not previously published, are considered CONFIDENTIAL and shall 
remain the sole property of the Sponsor.  The Investigator agrees to use this information solely 
for the purposes of accomplishing this study and agrees not to use it for any other purposes 
without the written consent of the Sponsor. 
The publication policy is addressed in a separate agreement. 
At the conclusion of the study, after the data are analyzed, a final study report will be prepared. 
The Sponsor will provide the Investigators with a summary of the results. 


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14. 
LIST OF REFERENCES 
 
 
 
C.T. Development America, Inc. Topical ocular tolerability/safety and tissue distribution of 
cyclosporine following topical administration of cyclosporine (0.1% in HCO-40) 4 times a day 
for 5 days in New Zealand White rabbits. CTD1205. 16 June 2013. 
 
 
International Dry Eye Workshop. The epidemiology of dry eye disease; report of the 
Epidemiology Subcommittee of the International Dry Eye Workshop. Ocul Surf. 2007 
Apr;5(2):93-107. 
 
 
 
 
 
  
Schaumberg DA, Gulati A, Mathers WD, Clinch T, Lemp MA, Nelson JD, et al. Development 
and validation of a short global dry eye symptom index. Ocul Surf. 2007 Jan;5(1):50-7. 
 
 
 
 
 

SAP_001.pdf: 




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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2
 
TABLE OF CONTENTS 
.................................................................................................................3
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
..................................................5 
1. 
INTRODUCTION
 ........................................................................................................6 
2. 
STUDY DESCRIPTION 
..............................................................................................7 
2.1. 
Primary Objective 
.........................................................................................................7 
2.2. 
Study Design 
.................................................................................................................7 
2.3. 
Inclusion Criteria 
..........................................................................................................7 
2.4. 
Exclusion Criteria 
.........................................................................................................8 
2.5. 
Permitted Medications and Treatments 
........................................................................9 
2.6. 
Prohibited Medications and Treatments 
.......................................................................9
 
2.7. 
Treatment Compliance 
..................................................................................................9 
3. 
STUDY ASSESSMENTS 
..........................................................................................10 
3.1. 
Background Characteristics 
........................................................................................10 
3.1.1. 
Medical/Ocular History 
..............................................................................................10 
3.1.2. 
Concomitant Medications 
...........................................................................................10 
3.2. 
Urine Pregnancy Test .................................................................................................10 
3.3. 
Efficacy Assessments .................................................................................................10 
3.4. 
Safety Assessments 
.....................................................................................................10 
3.4.1. 
Corrected Snellen Visual Acuity 
................................................................................10 
3.4.2. 
Slit Lamp Examination 
...............................................................................................11 
3.4.3. 
Intraocular Pressure 
....................................................................................................11 
3.4.4. 
Ophthalmoscopy/Dilated Fundus Examination 
..........................................................11 
3.5. 
Adverse and Serious Adverse Events 
.........................................................................11 
3.5.1. 
Definition of Adverse Events .....................................................................................11 
3.5.2. 
Serious Adverse Event 
................................................................................................11 
3.5.3. 
Relationship to Study Medication ..............................................................................12 
3.5.4. 
Recording Adverse Events .........................................................................................12 
4. 
SAMPLE SIZE AND POWER CONSIDERATIONS
 ...............................................14 
5. 
ANALYSIS POPULATIONS 
....................................................................................15 


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5.1. 
Safety Analysis Populations 
.......................................................................................15 
6. 
HANDLING OF MISSING DATA 
............................................................................16 
7. 
STATISTICAL ANALYSIS 
......................................................................................17 
7.1. 
Subject Disposition 
.....................................................................................................17 
7.2. 
Demographic and Baseline Characteristics 
................................................................18 
7.3. 
Concomitant Medications 
...........................................................................................18 
7.4. 
Ocular and Other Medical History .............................................................................18 
7.5. 
Treatment Compliance and Exposure 
.........................................................................18 
7.6. 
Adverse Events 
...........................................................................................................18 
7.7. 
Visual Acuity 
..............................................................................................................19 
7.8. 
Intraocular Pressure 
....................................................................................................19 
7.9. 
Ophthalmoscopy/Dilated Fundoscopy 
........................................................................19 
7.10. 
Slit Lamp Examination 
...............................................................................................19 
8. 
CHANGES  FROM THE PROTOCOL 
.....................................................................20 
9. 
INTERIM ANALYSIS 
...............................................................................................21 
10. 
TABLES AND LISTINGS 
.........................................................................................22 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
Abbreviation or Specialist Term  Explanation 
AE
 adverse
 
event
 
BID
 twice
 
daily
 
DOB 
date of birth 
FDA 
Food and Drug Administration 
eCRF 
electronic case report form 
HLA-DR 
human leukocyte antigen-DR 
ICH 
International Council for Harmonisation 
IFN- interferon
 gamma
 
IL
 interleukin
 
IOP
 intraocular
 
pressure
 
IRB
 Institutional
 
Review
 
Board
 
LFU 
lacrimal function unit 
KCS
 keratoconjunctivitis
 
sicca
 
MMP
 matrix
 
metalloproteinase
 
NDA 
New Drug Application 
PT
 Preferred
 
Term
 
SAE 
serious adverse event 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
VA
 visual
 
acuity
 
 


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1. 
INTRODUCTION 
Keratoconjunctivitis sicca (KCS) is a common multifactorial ophthalmologic disorder of 
the tears and ocular surface characterized by symptoms of burning, stinging, itching, 
grittiness, scratchiness, foreign body sensation, dryness, stickiness, and tired eye 
sensation. The onset of symptoms is usually gradual, bilateral, and chronic. Symptoms 
typically become more bothersome later in the day and are intensified by various 
environmental factors. 
The prevalence of KCS varies but it has been estimated to affect up to 35% of the 
population, although this number may be underreported and may be increasing, 
especially in the older population (International Dry Eye Workshop, 2007). 
KCS is generally caused by a disturbance of the lacrimal function unit (LFU), an 
integrated system comprising the lacrimal glands, ocular surface and lids, and the sensory 
and motor nerves that connect them. The LFU controls and regulates the major 
components of the tear film and responds to the various intrinsic and extrinsic 
environmental factors that a person encounters. 
The overall function of the LFU is to preserve the integrity of the tear film, the 
transparency of the cornea, and the quality of the image projected onto the retina. 
Damage to any component of the LFU can result in KCS, but the main mechanism for 
KCS is driven by tear hyperosmolarity, tear film instability, and inflammation.  
Activation of innate and adaptive immune systems by tear hyperosmolarity and 
desiccation leads to increased production of inflammatory mediators that can (1) disrupt 
corneal barrier function (interleukin [IL] 17, matrix metalloproteinase [MMP]-3 and 
MMP-9), (2) sensitize corneal and ocular surface nerve endings (IL-1  and IL-6), (3) 
cause epithelial cell death (apoptosis, interferon gamma [IFN-]) and loss of mucus-
producing goblet cells (IFN-), and (4) cause infiltration of T cells in the conjunctival 
tissue that further destabilizes the tear film and leads to more severe ocular surface 
disease (
). Increased human 
leukocyte antigen-DR (HLA-DR) expression by the conjunctival epithelium has been 
observed as a universal feature of KCS. The effectiveness of cyclosporine in the 
treatment of KCS may be due to its effects on the pathogenesis of this disease.  
In the United States, Restasis®, a 0.05% ophthalmic emulsion of cyclosporine, is the 
only approved prescription product for patients with KCS. Restasis is indicated for the 
increase in tear production in patients whose tear production is presumed to be 
suppressed due to ocular inflammation associated with KCS (Restasis Prescribing 
Information, 2014). This product has been shown to be effective in a relatively small 
percentage (15%) of patients, and, as a consequence, there is an unmet medical need for 
alternative drug therapies for the treatment of KCS. To meet this unmet medical need, 
Sun Pharma Global (FZE), the Sponsor is developing OTX-101, a new nanomicellar 
formulation of cyclosporine for the treatment of KCS. 


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2. 
STUDY DESCRIPTION 
2.1. 
Primary Objective 
The objective of this study is to evaluate the long-term safety of OTX-101 0.09% 
compared with vehicle in the treatment of KCS. 
2.2. 
Study Design 
This will be an extension of OTX-101-2016-001, a randomized, multicenter, double-
masked, vehicle-controlled study that enrolled male and female subjects, 18 years of age 
and older, with a patient-reported history of KCS for a period of at least 6 months, a 
clinical diagnosis of bilateral KCS supported by OTX-101-2016-001 study assessments, 
and corrected Snellen visual acuity (VA) of better than 20/200 in both eyes at Screening 
and at Baseline.  
Subjects who complete Visit 5 (Day 84) of Study OTX-101-2016-001 may be eligible to 
enroll in protocol OTX-101-2016-002 within 14 days at the discretion of the Principal 
Investigator and Sponsor.  Subjects who provide written informed consent at Visit 5a and 
meet the inclusion/exclusion criteria requirements will be enrolled in the study and 
receive study medication (OTX-101 0.09%). All subjects will participate for at least 
40 weeks.  Subjects who were randomized to the vehicle arm in Study OTX-101-2016-
001 may have the opportunity to participate for an additional 12 weeks, and a total of 
52 weeks. 
Subjects will self-administer study medication topically to both eyes twice daily (BID) 
from Visit 5a to Visit 8 (Day 364) or Visit 9 (Day 448). Safety evaluations will be 
conducted at all study visits. The window for Visits 6 and 7 will be ± 7 days. The window 
for Visit 8 will be +14 days for those subjects assigned to OTX-101 0.09% in Study 
OTX-101-2016-001 (± 14 days for subjects assigned to vehicle in Study OTX-101-2016-
001, participating for 52 weeks in Study OTX-101-2016-002), and for Visit 9 the window 
will be +14 days. Both eyes will be assessed at each visit. Adverse events (AEs) and 
concomitant medications will be documented at each study visit from signing of informed 
consent to Day 364. 
A total of approximately 700 subjects will be enrolled in Protocol OTX-101-2016-001 
(approximately 350 subjects in each treatment arm) at approximately 50 clinical sites. 
Subjects who successfully complete that study may be eligible to participate at the 
discretion of the Principal Investigator and the Sponsor with the goal of enrolling 
approximately 300 subjects in Protocol OTX-101-2016-002. 
Treatment Assignment 
All subjects will receive:  OTX-101 0.09% 
2.3. 
Inclusion Criteria 
1. Successful completion of participation in Protocol OTX-101-2016-001. 


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2. All subjects must provide signed written consent prior to participation in any 
study-related procedures. 
3. Female subjects of childbearing potential must have a negative urine pregnancy 
test at Visit 5 (Day 84) of Protocol OTX-101-2016-001 or at Visit 5a of Protocol 
OTX-101-2016-002, if conducted at a later date. Women of childbearing potential 
(i.e., women who are not either postmenopausal for one year or surgically sterile) 
and men who have partners of childbearing potential must use an acceptable form 
of contraception throughout the study.  
4. Corrected Snellen VA of better than 20/200 in both eyes at Visit 5 (Day 84) of 
Protocol OTX-101-2016-001. 
2.4. 
Exclusion Criteria 
1. Any AE reported in Protocol OTX-101-2016-001 that has not resolved. 
5. Use of Restasis or any topical cyclosporine preparation following Visit 5 of 
Protocol OTX-101-2016-001. 
6. Use of any prescription topical ophthalmic medications (including antiglaucoma 
medications) other than the assigned study medication during the study period. 
Unpreserved artificial tears are permitted.  
7. Current active eye disease other than KCS (i.e., any disease for which topical or 
systemic ophthalmic medication is necessary). 
8. History of herpes keratitis. 
9. Unstable macular disease (e.g., age-related macular degeneration, diabetic 
maculopathy). Stable macular disease is defined as no reduction in central VA 
since the screening visit of Study OTX-101-2016-001. 
10. Diagnosis of chronic uveitis.  
11. Corneal transplant following Visit 5 of Study OTX-101-2016-001. 
12. Corneal refractive surgery following Visit 5 of Study OTX-101-2016-001.  
13. Non-laser glaucoma surgery following Visit 5 of Study OTX-101-2016-001. 
14. Lagophthalmos or clinically significant eyelid margin irregularity of the study eye 
whether congenital or acquired.  
15. Presence of conjunctivochalasis (i.e., mechanical blockage of the lower lid 
punctum by redundant conjunctiva). 
16. Presence of pterygium in either eye. 
17. Unwilling to discontinue use of contact lenses during the duration of the study. 
18. Preplanned elective surgery or hospitalization during the study period. 
19. HIV-positive. 
20. Unable to reliably report symptoms and history. 


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21. Has a severe/serious ocular condition, or any other unstable medical condition 
that, in the Investigator’s opinion, may preclude study treatment or follow-up.  
22. Women who are pregnant or breastfeeding. 
2.5. 
Permitted Medications and Treatments 
Oral omega-3 fatty acids are permitted if the dosage has been stable for 3 months and the 
subject stays on the same dose until the end of the study. The subject should not begin 
oral omega-3 fatty acids during the study. Whenever possible, medications should be 
administered in dosages that remain constant throughout the study duration. All 
concomitant medications will be recorded in the electronic case report form (eCRF). 
Preservative-free artificial tears may be used ad libitum (as desired). 
2.6. 
Prohibited Medications and Treatments 
Prohibited ocular medications and therapies during the study include any prescription or 
over-the-counter topical ophthalmic medications other than the assigned study 
medication (unpreserved artificial tears are permitted) and ocular surgery/ocular laser 
treatment of any kind. 
2.7. 
Treatment Compliance 
Treatment compliance will be monitored by study medication accountability. Throughout 
the treatment phase, the amount of opened and unopened medication returned at each 
post-baseline visit will be documented by study site personnel. 


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3. 
STUDY ASSESSMENTS 
Prior to entry into the study or initiation of any study-related procedures, the subject must 
read, sign, and date the current Institutional Review Board (IRB)-approved version of the 
informed consent form.  
3.1. 
Background Characteristics 
3.1.1. 
Medical/Ocular History 
If Visit 5a does not occur on the date of Visit 5, the subject should be queried regarding 
relevant events that may have occurred in the interim. 
3.1.2. 
Concomitant Medications 
If Visit 5a does not occur on the date of Visit 5, the subject’s concomitant medication list 
should be updated, if necessary. 
3.2. 
Urine Pregnancy Test 
A urine pregnancy test will be performed at each visit for women of childbearing 
potential only. 
3.3. 
Efficacy Assessments  
Efficacy assessments will not be performed in this safety study as the absence of a 
comparator group and the subject selection process would obviate the possibility of 
obtaining interpretable efficacy data. Investigators should nevertheless perform any 
assessments consistent with the standard of care in their practice.  
3.4. 
Safety Assessments 
Safety will be assessed at each visit by corrected Snellen VA, slit lamp examination, 
intraocular pressure (IOP), AE documentation, and concomitant medication review. 
Ophthalmoscopy/dilated fundus examination will be performed at the subject’s last visit, 
i.e., Visit 8 (Day 364) or Visit 9 (Day 448).  
3.4.1. 
Corrected Snellen Visual Acuity  
Corrected Snellen VA measurement will be performed at each study visit with the 
Snellen eye chart using the subject’s current corrective lens prescription. Subjects must 
read  50% of the letters on a single line to accept that VA line. The refraction used at the 
screening visit of Protocol OTX-101-2016-001 should be used for all subsequent VA 
assessments for the duration of the study. The subject must wear the same glasses, if 
applicable, at each visit. If the glasses are not available, the eyeglass prescription should 
be placed in a trial frame and used in place of the unavailable glasses. 


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3.4.2. 
Slit Lamp Examination 
A routine slit lamp examination will be performed to evaluate the anterior segment of the 
eye, including lids, cornea, conjunctiva, anterior chamber, iris, and lens. Abnormalities 
will be documented.  
3.4.3. 
Intraocular Pressure 
Intraocular pressure will be measured via Goldmann applanation tonometry using the 
clinical site’s standard procedures.
 Intraocular pressure in a given subject should be 
recorded using the same tonometer and the same observer each time, if possible. The IOP 
values will be recorded in the eCRF. 
3.4.4. 
Ophthalmoscopy/Dilated Fundus Examination 
Direct ophthalmoscopy with dilation will include assessment of the optic nerve head for 
pallor and cupping. A dilated fundus examination consisting of the vitreous, optic nerve, 
macula, and peripheral retina will be conducted. Abnormalities will be documented. 
3.5. 
Adverse and Serious Adverse Events 
3.5.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study subject 
administered a study medication (pharmaceutical/biological product) that does not 
necessarily have a causal relationship to this medication. An AE can, therefore, be any 
unfavorable and unintended sign (including abnormal laboratory findings), symptom, or 
disease temporally associated with the use of the study medication, whether or not related 
to the study medication. Study medication includes the investigational drug under 
evaluation and the comparator product or vehicle placebo that is given during any phase 
of the study. 
Medical conditions/diseases present before signing the informed consent form are only 
considered AEs if they worsen after the informed consent form is signed. Abnormal test 
results constitute AEs only if they induce clinical signs or symptoms, are considered 
clinically significant, or require additional therapy or a change in therapy. 
At each study visit the subject will be asked how he/she has been feeling. All AEs 
whether observed by the Investigator or spontaneously reported by the subject will be 
documented in the subject
's chart and the AE eCRF. 
Adverse events also may be detected when they are volunteered by the subject between 
visits or through study assessments. 
3.5.2. 
Serious Adverse Event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 


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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. 
 Results in persistent or significant disability/incapacity (excluding 
progression/outcome of the disease under study), 
 Is a congenital anomaly/birth defect, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
or 
 Is medically significant; i.e., defined as an event that jeopardizes the health of 
the subject or may require medical or surgical intervention to prevent one of 
the outcomes listed above. 
Treatment on an outpatient emergency basis that does not result in hospital admission 
with an overnight stay is not considered an SAE. 
All SAEs that are ongoing at the time of completion or discontinuation from the study 
will be followed until stabilization or resolution of the event. 
3.5.3. 
Relationship to Study Medication 
The relationship of AEs to the study medication should be assessed by the Investigator 
using the definitions below. 
Not suspected: The temporal relationship of the event to the study medication makes a 
causal relationship unlikely, or, other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 
Suspected: The temporal relationship of the event to the study medication makes a 
causal relationship possible or other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-
effect relationship between the study medication and the occurrence of the AE, then the 
AE should be considered “suspected.” 
If the relationship between the AE/SAE and the study medication is determined by the 
Sponsor to be “suspected,” the event will be considered to be related to the study 
medication for the purposes of expedited regulatory reporting. 
3.5.4. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open-
ended question from the study personnel or revealed by observation, regardless of 
severity or potential association with the study medication or study procedures, will be 
recorded in the eCRF. All AEs that occur after a subject has signed the informed consent 
form until the final study visit should be collected and recorded on the AE eCRF page. 
Adverse events will be followed until the event is resolved or stabilized, and SAEs that 


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are ongoing at the time of completion or discontinuation from the study will be followed 
until resolution. 
The AE term should be reported in standard medical terminology when possible. For 
each AE, the Investigator will evaluate and report the following: 
 Onset (date); 
 Resolution (date); 
 Severity grade (mild, moderate, severe); 
 Relationship to study medication (not suspected, suspected); 
 Action taken (none, study medication temporarily interrupted, study 
medication permanently discontinued, concomitant medication taken, 
hospitalization/prolonged hospitalization, other); 
 Serious outcome (yes/no). 
The severity grade should be determined by the Investigator using the definitions below: 
 Mild: Discomfort noticed but no disruption of normal daily activity  
 Moderate: Discomfort sufficient to cause interference with normal daily 
activity  
 Severe: Incapacitating, with inability to perform normal activities 
 
 
 


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4. 
SAMPLE SIZE AND POWER CONSIDERATIONS 
In accordance with the International Council for Harmonisation (ICH) E1A Guidance, 
safety data for a minimum of 100 subjects treated for one year is recommended for 
inclusion in applications for marketing approval. The masking of subject treatment 
assignments in Study OTX-101-2016-001 will be maintained until the database for that 
study has been locked, so qualified subjects receiving OTX-101 0.09% or vehicle may be 
enrolled in Study OTX-101-2016-002. Approximately 300 subjects will enroll in Study 
OTX-101-2016-002 of which it is anticipated that at least 150 will have been randomly 
assigned to OTX-101 0.09% in Study OTX-101-2016-001. 


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5. 
ANALYSIS POPULATIONS 
Three populations will be used for analysis. 
5.1. 
Safety Analysis Populations 
The safety population will include all patients who were enrolled in Study OTX-101-
2016-002 and received at least one dose of the study medication.  
Summaries will be presented by the following groups of subjects: 
1. subjects assigned to the OTX-101 0.09% arm in Study OTX-101-2016-001; i.e., 
those subjects with 12 months exposure to active drug.
 
2. subjects assigned to the Vehicle arm in Study OTX-101-2016-001; i.e., those 
subjects with at least 9 months of exposure to active drug. 
 


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6. 
HANDLING OF MISSING DATA 
No missing data will be imputed. The reasons for missing data will be recorded. 
 


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7. 
STATISTICAL ANALYSIS 
All statistical analyses and reporting will be performed using the SAS® System Version 
9.3 or later.  
Unless otherwise specified, continuous variables will be summarized with descriptive 
statistics (n, mean, median, standard deviation, standard error, minimum, and maximum), 
and categorical variables will be summarized with counts and percentages. 
Definition of Baseline:  
Baseline measurements will be the last measurement for the corresponding variable prior 
to the first dose of OTX-101 0.09%.  For those initially randomized to OTX-101 0.09%, 
baseline would be the day of randomization (Day 0).  For those initially randomized to 
Vehicle, baseline would be the day of the first dose of OTX-101 0.09% in the extension 
phase. 
Out of Window and Unscheduled Visits: 
Data will be presented according to the assigned visit in the database. 
7.1. 
Subject Disposition 
Subject disposition, including the number of subjects entering the extension phase and 
completing the extension phase will be tabulated. The percentage of subjects treated and 
completing the study will be based on the total number entering the extension phase. A 
subject data listing will be provided. 
The total number and percentage of subjects included in each of the analysis datasets will 
be summarized with percentages based on the total number of subjects entering the 
extension phase. A subject data listing will be provided. 
Discontinuations and the reasons for discontinuation from the study will be summarized 
for all subjects. Summaries will include the number and percentage of subjects.  Reasons 
for discontinuation following the receipt of study drug will include the following: 
 Withdrawal by Subject 
 Lost to Follow-up 
 Adverse Event 
 Pregnancy 
 Death 
 Physician Decision 
 Protocol Deviation 
 Other 
A subject data listing will be provided. 


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7.2. 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for the safety 
population.  Summary tables will be supported with individual subject data listings. 
Continuous variables such as age will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum), and categorical variables 
such as gender, race, ethnicity, and iris color will be summarized using counts and 
percentages of subjects.  
Age will be determined as the whole integer number of years from the date of birth 
(DOB) to the date of the screening visit, i.e., the truncated integer difference between the 
DOB and Visit 1. 
7.3. 
Concomitant Medications 
A subject data listing will be provided.  Medications used prior to the first dose of OTX-
101 0.09%, but stopped prior to first dose will be indicated separately from those used 
concomitantly with OTX-101 0.09% on the listing.  
7.4. 
Ocular and Other Medical History 
A subject data listing will be provided. 
7.5. 
Treatment Compliance and Exposure 
The % compliance on OTX-101 0.9% will be summarized over all visits by the 
categories of <70% and 70%. 
Duration of drug exposure will be calculated for each subject as the last date of dosing 
minus the first date of dosing + 1. The number and percentage of subjects will be 
summarized according to the following duration-of-exposure categories: ‘< 3 mon (90 
days), ‘3 to < 6 mon’, ‘6 mon to < 9 mon’, ‘9 to < 12 mon’, and ‘12 mon (360 days)’. A 
subject data listing will be provided. 
7.6. 
Adverse Events 
A treatment-emergent adverse event (TEAE) is one that was experienced on or after the 
day of first dose of OTX-101 0.09% in Study OTX-101-2016-002; or if experienced prior 
to first dose, worsened after first dose. 
An overall summary will be presented which gives the number and percentage of subjects 
within each cohort that experienced a TEAE, experienced any treatment-related TEAE, 
permanently discontinued treatment due to a TEAE, experienced a treatment emergent 
SAE, and that died. 
In summary tables, AEs occurring in both eyes will be summarized once at the greater 
intensity and relationship to study drug.  
Events that are possibly or probably related will be counted as an event related to study 
drug.  


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The number and percentage of subjects experiencing one or more events within a 
Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and 
Preferred Term (PT) class without regard to intensity, relationship, or seriousness will be 
tabulated by cohort. In addition, tables will display events by SOC, PT, and maximum 
intensity or closest relationship to treatment. 
The number of deaths and SAEs will also be presented, and AEs leading to premature 
discontinuation from the study will be listed and tabulated. 
A glossary listing that shows the verbatim terms assigned to each SOC and PT will be 
provided.  
A listing of TEAEs by cohort ordered by subject, SOC, PT, and onset date will be 
provided. 
A listing of serious TEAEs by cohort ordered by subject, SOC, PT, and onset date will be 
provided. 
7.7. 
Visual Acuity 
Descriptive statistics of the observed and change from baseline Snellen VA expressed as 
equivalent logMAR will be tabulated for each eye by visit (see definition of baseline in 
Section 7) and cohort. Only the results from visits during the extension plus the 
appropriate baseline visit will be presented.  A subject data listing will be provided.  
7.8. 
Intraocular Pressure 
Descriptive statistics of the observed and change from baseline IOP will be tabulated for 
each eye by visit and cohort. Only the results from visits during the extension plus the 
appropriate baseline visit will be presented.  A subject data listing will be provided. 
7.9. 
Ophthalmoscopy/Dilated Fundoscopy 
The observations of ocular ophthalmoscopy and dilated fundoscopy will be summarized 
in frequency tables based on the ordinal or categorical scales for each measure for each 
eye by time point and cohort. Only the results from visits during the extension will be 
presented.  A subject data listing will be provided. 
7.10. 
Slit Lamp Examination  
The observations of slit lamp examination will be summarized in frequency tables based 
on the ordinal or categorical scales for each measure for each eye by time point and 
cohort. Only the results from visits during the extension will be presented.  A subject data 
listing will be provided. 
 


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8. 
CHANGES  FROM THE PROTOCOL 
None. 


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9. 
INTERIM ANALYSIS 
At the pre-New Drug Application (NDA) meeting with the Division of Transplantation 
and Ophthalmology Products (24 April 2017), it was recommended for the evaluation of 
longer-term exposure to OTX-101 0.09% that data from  100 subjects who were 
enrolled in OTX-101-2016-002 and had completed 6 months of exposure to study drug 
be submitted at the time of the NDA filing.  
Of the 258 subjects who were enrolled in Study OTX-101-2016-002 and exposed to 
OTX-101 0.09%, a subset of 165 subjects had  6 months of total OTX-101 exposure 
from their combined participation in Study OTX-101-2016-001 and Study  
OTX-101-2016-002 and for whom  6 months of data were monitored and cleaned as of 
the data cutoff (DCO) of 12 May 2017.  This subset also included data from subjects who 
prematurely discontinued from Study OTX-101-2016-002. 
Safety data from this subset were presented in the Summary of Clinical Safety (Module 
2.7.4) and Integrated Summary of Safety (Module 5.3.5.3) in the NDA. 


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10. 
TABLES AND LISTINGS  
List of Tables 
14.1.1    Study Performance - Safety Population 
14.1.2    Subject Disposition - Safety Population 
14.1.3    Visit Participation - Safety Population 
14.1.4    Demographics – Safety Population 
14.1.5    Inclusion and Exclusion Criteria - Safety Population 
14.1.6    Compliance - Safety Population 
14.1.7    Protocol Deviations – Safety Population 
 
14.3.1.1  Treatment Emergent Adverse Events:  Overall Summary - Safety Population 
14.3.1.2  Summary of Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term - Safety Population 
14.3.1.3  Summary of Treatment-Emergent Adverse Events by Closest Relationship to 
Study Drug - Safety Population  
14.3.1.4  Summary of Treatment-Emergent Adverse Events by Maximum Intensity - 
Safety Population 
14.3.1.5  Summary of Treatment-Emergent Adverse Events Leading to Permanent 
Withdrawal of Study Medication by System Organ Class and Preferred Term - 
Safety Population 
14.3.1.6  Treatment-Emergent  
Adverse  
Event / MedDRA Glossary 
14.3.2  
Listing of Serious Treatment Emergent Adverse Events - Safety Population 
14.3.3  
Adverse Event Narratives 
14.3.4  
Snellen Visual Acuity - By Eye - Safety Population 
14.3.5  
Intraocular Pressure - By Eye - Safety Population 
14.3.6  
Slit Lamp Examination - By Eye - Safety Population 
14.3.7  
Dilated Fundoscopy - By Eye - Safety Population 
14.3.8  
Exposure – Safety Population 


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List of Listings 
 
Listing 16.2.1 Disposition 
Listing 16.2.2 Protocol Deviations 
Listing 16.2.3 Inclusion and Exclusion Criteria 
 
Listing 16.2.4.1 Demographics  
Listing 16.2.4.2.1 Non-Ocular Medical History 
Listing 16.2.4.2.2 Ocular Medical History 
Listing 16.2.4.3.1 Prior Ocular Medications  
Listing 16.2.4.3.2 Concomitant Ocular Medications  
Listing 16.2.4.3.3 Prior Non-Ocular Medications  
Listing 16.2.4.3.4 Concomitant Non-Ocular Medications 
 
Listing 16.2.5 Dosing Days and Compliance  
 
Listing 16.2.7 Treatment Emergent Adverse Events 
 
Listing 16.2.8.1 Snellen Visual Acuity 
Listing 16.2.8.2 Intraocular Pressure 
Listing 16.2.8.3 Slit Lamp Examination 
Listing 16.2.8.4 Dilated Fundoscopy 
Listing 16.2.8.5 Urine Pregnancy Test 
 


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Table 1:  
Schedule of Procedures 
Procedures 
Visit 5a  Visit 6  
Phone 
Contact 
Visit 7 
Phone 
Contact 
Visit 8 
Phone 
Contact 
Visit 9 
Early 
Day of Study a 
Days since Visit 5a 
84 
- 
182 ± 7 
98 
227 ± 7 
143 
273 ± 7 
189 
318 ± 7 
234 
364 + 14 i 
280 
409 ± 7 
325 
448 + 14 
364 
Discontinuation 
Informed consent 
j 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion
 
criteria
  
X
 
 
 
 
 
 
 
 
 
 
Concomitant medication history/review  
Xb  X
 X
 X
 X
 X
 X
 X
  X
 
Urine pregnancy test c 
Xb X
 
 X
 
 X
 
 X
  X
 
Corrected
 
Snellen
 
Visual
 
Acuity
 
 
  X
 
 X
 
 X
 
 X
  X
 
Slit
 
lamp
 
examination
 
  X
 
 X
 
 X
 
 X
  X
 
Ophthalmoscopy/dilated fundoscopy  
  
  
  
  
  
Xg 
 
X
g X
 
IOP 
d 
  X
 
 X
 
 X
 
 X
  X
 
Study medication distribution 
X  
X  
  
X  
  
Xh 
 
 
 
 
 
Adverse event assessment e 
X
  X
 X
 X
 X
 X
 X
 X
  X
 
Study medication accountability f 
  X
 
 X
 
 X
 
 X
  X
 
a “Day” approximately reflects the cumulative number of days in study (Protocol OTX-101-2016-001 and OTX-101-2016-002), regardless of actual calendar time elapsed.  And 
‘Day of Study’ is used along with Visit, throughout this protocol – e.g., Visit 6 (Day 182), etc. 
b  Performed if Visit 5a is not conducted on the same calendar day as Visit 5 of Protocol OTX-101-2016-001. 
c  Women of childbearing potential only. 
d  Measure IOP using Goldmann applanation tonometry. 
e Collection of AEs extends from signing of informed consent until the last study visit. 
f  Clinical site personnel will document all received and returned medication at Days 182, 273, 364 and 448. Study medication accountability will be performed by the monitor at 
each applicable monitoring visit. 
g Examination is required only at the subject’s final visit, 
h Medication is dispensed if the subject is participating for an additional 12 weeks 
i 364 ± 14 days if the subject is participating for an additional 12 weeks 
j Updated ICF due to Amendment #1 to be signed by all participating subjects for Protocol OTX-101-2016-002 Amendment #1