Conditions: Dry Eye Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 69
Healthy volunteers: no

Brief summary:
In subjects with Dry Eye Syndrome:

The primary objective of this study is to compare the safety and tolerability of TOP1630 Ophthalmic Solution to placebo.

The secondary objectives are to compare the efficacy of TOP1630 Ophthalmic Solution to placebo for the treatment of the signs and symptoms of dry eye syndrome.

Detailed description:
This study is designed to assess the safety, tolerability and efficacy of TOP1630 ophthalmic solution in subjects with Dry Eye Syndrome.

Eligible subjects will be randomized double masked to either TOP1630 or placebo.

Part 1 (time frame 12 days) comprises assessment of safety, tolerability and ocular comfort.

Part 2 (time frame 35 days) comprises assessment of safety, tolerability and efficacy

Arms:
arm 1: TOP1630 Ophthalmic Solution arm 2: Placebo (Vehicle) Ophthalmic Solution

Interventions: intervention 1: TOP1630 Ophthalmic Solution intervention 2: Placebo to TOP1630 Ophthalmic Solution
Intervention descriptions: intervention 1: Bilateral ocular drug administration intervention 2: Bilateral ocular drug administration

Protocol document:
Prot_002.pdf: 






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Clinical Trial Protocol # TOP1630-TV-04 
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SYNOPSIS 
 
 
Protocol Title: 
A Single-Center, Randomized, Double Masked, 
Placebo Controlled Clinical Study to Assess the 
Safety and Efficacy of TOP1630 Ophthalmic 
Solution Compared to Placebo in Subjects with Dry 
Eye Syndrome 
Protocol Number: 
TOP1630-TV-04 
Study Drug: 
1) 0.01% TOP1630 Ophthalmic Solution 
2) 0.1% TOP1630 Ophthalmic Solution 
3) Placebo (Vehicle solution with no TOP1630) 
Study Phase: 
2 
Study Objective: 
In subjects with dry eye syndrome: 
The primary objective of this study is to compare the 
safety and tolerability of TOP1630 Ophthalmic 
Solution to placebo. 
The secondary objectives are to compare the 
efficacy of TOP1630 Ophthalmic Solution to 
placebo for the treatment of the signs and symptoms 
of dry eye syndrome. 
Overall Study Design 
Structure: 
Double-masked, randomized, single-center study 
Duration: 
An individual subject’s participation time for the 
Comfort Assessment is expected to be 
approximately 12 days. 
An individual subject’s participation in the Safety 
and Efficacy Assessment is expected to be 
approximately 5 weeks (35 days). 
Controls: 
Placebo Ophthalmic Solution (Vehicle) 
Dosage/Dose Regimen: 
For the Comfort Assessment, 8 eligible subjects will 
be randomized to either active drug (TOP1630) or 
placebo (in the ratio of 3 active: 1 placebo) and the 
same subjects will be cycled through each dose 
cohort as described below unless a study stopping 
criterion is met in which case a lower dose regimen 
may be used for subsequent cohorts: 
Placebo or 0.01% TOP1630 bilaterally TID at Visit 
1, followed by a rest day, followed by a day with a 
single dose of placebo or 0.1% TOP1630 bilaterally, 
followed by a rest day, and then a day of TID dosing 
with placebo or 0.1% TOP1630 bilaterally, followed 


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by a rest day. Unless stopping criteria are 
implemented, subjects will proceed to receiving 4 
consecutive days dosing of placebo or 0.1% 
TOP1630 TID (as described in Summary of Visit 
Schedule). 
For the Safety and Efficacy Assessment, eligible 
subjects will be randomized to one of the treatments 
below (in the ratio of 1 active: 1 placebo) to be 
administered bilaterally TID for 28 days (from Visit 
2b to Visit 4b). 
1) TOP1630 Ophthalmic Solution 
2) Placebo (Vehicle with no TOP1630) 
TOP1630 dose selection will be based upon the 
evaluation of emergent (blinded) data from the 
Comfort Assessment and will not exceed the highest 
dose tested in that part of the study. 
During a 7 day study run-in period prior to 
randomization, all subjects will receive Placebo 
Ophthalmic Solution (Vehicle) bilaterally at the 
same dosing frequency as TOP1630. 
Summary of Visit Schedule: 
Comfort Assessment 
8 visits over the course of 12 days 
Visit 1a = Day 1, 0.01% TOP1630 or Placebo TID; 
Comfort Assessment 
Visit 2a = Day 2, Physician Assessment 
Visit 3a = Day 3, 0.1 % TOP1630 or Placebo QD, 
Comfort Assessment 
Visit 4a = Day 4, Physician Assessment 
Visit 5a = Day 5, 0.1 % TOP1630 or Placebo TID; 
Comfort Assessment 
Visit 6a = Day 6, Physician Assessment 
Visit 7a = Day 8, 0.1% TOP1630 or Placebo TID, 
Comfort Assessment followed by dosing daily with 
0.1% TOP1630 or Placebo TID at home for Day 9 , 
Day 10 and Day 11 
Visit 8a = Day 12, Physician Assessment 
Safety and Efficacy Assessment 
4 visits over the course of approximately 5 weeks 
Visit 1b = Day -7 ± 1 day, CAE Screening 
Visit 2b = Day 1, CAE Confirmation / Baseline 


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Visit 3b = Day 15 ± 1 day, 2-Week Follow-Up / 
CAE Test 
Visit 4b = Day 29 ± 2 days, 4-Week Follow-Up / 
CAE Test / Exit 
Measures Taken to Reduce 
Bias: 
This is a randomized treatment assignment, double 
masked study. 
Study Population 
Characteristics 
Number of Subjects: 
Total 68 
6 active and 2 placebo in the Comfort Assessment 
30 active and 30 placebo in the Safety and Efficacy 
Assessment 
Condition/Disease: 
Dry Eye Syndrome 
Inclusion Criteria: 
Subjects must meet all of the following requirements 
to be eligible for enrollment into the study. Subjects 
who participate in the Comfort Assessment will not 
be permitted to participate in the Safety and Efficacy 
Assessment. 
For the Comfort Assessment: 
1) Be at least 18 years of age; 
2) Provide written informed consent; 
3) Have a patient reported history of dry eye for at 
least 6 months prior to Visit 1a; 
4) Have a history of use or desire to use eye drops 
for dry eye symptoms for at least 6 months prior 
to Visit 1a; 
For the Safety and Efficacy Assessment: 
All of the above criteria (at Visit 1b), and: 
5) Report a score of ≥ 2 in at least one symptom of 
the Ora Calibra® Ocular Discomfort & 4- 
Symptom Questionnaire at Visits 1b and 2b; 
6) Report an OSDI score ≥ 18 at Visits 1b and 2b; 
7) Have a conjunctival redness score of ≥ 1 
according to the Ora Calibra® scale in at least 
one eye at Visits 1b and 2b; 
8) Have a tear film break-up time (TFBUT) >1 and 
< 7 seconds in at least one eye at Visit 1b and 
2b; 
9) Have a Schirmer’s Test score of ≤ 10 mm and ≥ 
1 mm in at least one eye at Visits 1b and 2b; 
10) Have a corneal fluorescein staining score of ≥ 2 


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according to the Ora Calibra® scale in at least 
one region (e.g. inferior, superior, or central) in 
at least one eye at Visits 1b and 2b; 
11) Have a total lissamine green conjunctival score 
of ≥ 2, based on the sum of the temporal and 
nasal regions of the conjunctiva according to the 
Ora Calibra® scale in at least one eye at Visits 
1b and 2b; 
12) Demonstrate a response to the CAE® at Visits 1b 
and 2b as defined by: 
a. Having at least a ≥ 1 point increase in 
fluorescein staining in the inferior region 
in at least one eye following CAE 
exposure on the Ora Calibra® scale; and 
b. Reporting an Ocular Discomfort score ≥ 
3 at 2 or more consecutive time points in 
at least one eye during CAE exposure on 
the Ora Calibra® scale (if a subject has an 
Ocular Discomfort rating of 3 at time = 0 
for an eye, s/he must report an Ocular 
Discomfort rating of 4 for two 
consecutive measurements for that eye). 
13) Have at least one eye (the same eye) satisfy all 
criteria for 7, 8, 9, 10, 11, and 12 above; 
14) At Visit 2b, subjects must have at least 5 days’ 
worth of diary symptom data and deemed by the 
PI to be at least 80% compliant with vehicle eye 
drops. 
Exclusion Criteria: 
Subjects may not participate in the study (Comfort 
Assessment as well as the Safety and Efficacy 
Assessment) if any of the following criteria are met: 
1) Unable or unwilling to follow instructions, 
including participation in all study assessments 
and visits; 
2) Have any clinically significant slit lamp findings 
at Visit 1(1a or 1b) that may include active 
blepharitis, meibomian gland dysfunction 
(MGD), lid margin inflammation or active 
ocular allergies that require therapeutic 
treatment, and/or in the opinion of the 
investigator may interfere with study parameters; 
3) Be diagnosed with an ongoing ocular infection 
(bacterial, viral, or fungal), or active ocular 
inflammation at Visit 1 (1a or 1b); 
4) Have any significant ocular lesion that could 


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interfere with assessment of safety or efficacy or 
prevent study conduct in the opinion of the PI; 
5) Have worn contact lenses within 14 days of Visit 
1 (1a or 1b) or anticipate using contact lenses 
during the study; 
6) Have used any eye drops within 2 hours of Visit 
1 (1a or 1b); 
7) Have previously had laser-assisted in situ 
keratomileusis (LASIK) surgery within the last 
12 months or any other ocular surgeries within 
the last 6 months; 
8) Have used Restasis® or Xiidra™ within 90 days 
of Visit 1 (1a or 1b); 
9) Have used topical ocular steroids within 30 days 
of Visit 1 (1a or 1b); 
10) Have any planned ocular and/or lid surgeries 
over the study period; 
11) Have temporary punctal plugs at Visit 1 that 
have not been stable within 45 days of Visit 1 
(1a or 1b) or anticipate having temporary punctal 
plugs inserted during the study; 
12) Have had punctal occlusion (not including 
punctal plugs) within 6 months of Visit 1(1a or 
1b); 
13) Be currently taking any topical ophthalmic 
prescription (including medications for 
glaucoma) or over-the-counter (OTC) solutions, 
artificial tears, gels or scrubs, and cannot 
discontinue these medications for the duration of 
the trial (excluding medications allowed for the 
conduct of the study) or have used any of these 
medications in the previous 24 hours prior to 
visit 1 (1a or 1b); 
14) Have corrected visual acuity greater than or 
equal to logMAR+0.7 as assessed by Early 
Treatment of Diabetic Retinopathy Study 
(ETDRS) scale in both eyes at Visit 1 (1a or 1b); 
15) Have an uncontrolled systemic disease; 
16) Be a woman who is pregnant, nursing or 
planning a pregnancy; 
17) Be unwilling to submit a urine pregnancy test at 
Visit 1 (1a or 1b) and Visit 8a or 4b) (or early 
termination visit) if of childbearing potential. 
Non-childbearing potential is defined as a 
woman who is permanently sterilized (e.g. has 


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had a hysterectomy or tubal ligation), or is post- 
menopausal (without menses for 12 consecutive 
months); 
18) Be a woman of childbearing potential who is not 
using an acceptable means of birth control; 
acceptable methods of contraception include: 
hormonal – oral, implantable, injectable, or 
transdermal contraceptives; mechanical – 
spermicide in conjunction with a barrier such as 
a diaphragm or condom; IUD; or surgical 
sterilization of partner. For non-sexually active 
females, abstinence may be regarded as an 
adequate method of birth control; however, if the 
subject becomes sexually active during the 
study, she must agree to use adequate birth 
control as defined above for the remainder of the 
study; 
19) Have a known allergy and/or sensitivity to the 
test article or its components; 
20) Have a condition or be in a situation which the 
investigator feels may put the subject at 
significant risk, may confound the study results, 
or may interfere significantly with the subject’s 
participation in the study; 
21) Be currently enrolled in an investigational drug 
or device study or have used an investigational 
drug or device within 30 days of Visit 1 (1a or 
1b). Subjects that were enrolled in the Comfort 
Assessment will be excluded from participating 
in the Safety and Efficacy Assessment; 
22) Be currently using any medication known to 
cause ocular drying that is not used on a stable 
dosing regimen for at least 30 days prior to Visit 
1 (1a or 1b); antihistamines are not allowed at 
any time during the study. 
Study Formulations: 
• 0.01% TOP1630 Ophthalmic Solution 
• 0.1% TOP1630 Ophthalmic Solution 
• Placebo (Vehicle minus active) 
Evaluation Criteria 


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Safety Measures: 
For the Comfort Assessment: 
• Visual acuity (ETDRS) 
• Slit-lamp biomicroscopy 
• Adverse event query 
• Vital Signs 
• Drop Comfort Assessment 
• Intraocular pressure (non-contact) at all 
Visits. 
For the Safety and Efficacy Assessment: 
• Visual acuity (ETDRS) 
• Slit-lamp biomicroscopy 
• Corneal Sensitivity 
• Adverse event query 
• Undilated Fundoscopy 
• Vital Signs 
• Drop Comfort Assessment 
• Intraocular pressure (non-contact) 
Stopping criteria will be utilized in the Comfort 
Assessment to ensure that an appropriate dose 
can be carried forward into the Safety and 
Efficacy Assessment. This may include use of a 
lower dose regimen in the multiple dose 
assessment of comfort. Stopping criteria will 
also be utilized during the conduct of the Safety 
and Efficacy Assessment. 
Exploratory Efficacy 
Measures: 
• Corneal fluorescein staining using the Ora 
Calibra® Scale and NEI Scale 
• Conjunctival lissamine green staining using 
the Ora Calibra® Scale and NEI Scale 
• Visual Analogue Scale (VAS) for symptoms 
(Pre-CAE®) 
• Tear film break-up time (TFBUT) 
• Conjunctival redness the Ora Calibra® scale 
• Schirmer Test at Visits 2b, 3b, and 4b 
• Ora Calibra® Ocular Discomfort & 4- 
Symptom Questionnaire 
• OSDI© 
• Ora Calibra® Lid Margin Redness 
• Ora Calibra® Posterior Lid Edge Evaluation 
• OPI 2.0 
• Ora Calibra® Ocular Discomfort Scale 
Other: 
Biomarker assessment by Impression Cytology 
(OPIA Eyeprim™) 


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General Statistical Methods and Types of Analyses 
Analysis Populations: 
• Modified Intent-to-Treat Population – The modified intent-to-treat (mITT) 
population includes all randomized subjects with at least one post visit 2 
study assessment. Efficacy analysis will be performed on the mITT 
population. Subjects in the mITT population will be analyzed as 
randomized. 
 
• Per Protocol Population – The per protocol (PP) population includes 
subjects in the mITT population who do not have significant protocol 
deviations and who complete the study. Protocol deviations will be assessed 
prior to database lock and unmasking. Subjects in the PP population will be 
analyzed as treated. 
 
• Safety Population – The safety population includes all subjects who have 
received at least one dose of the investigational product. Subjects in the 
Safety population will be analyzed as treated. 
 
Summaries of the comfort data from the Comfort Assessment will be performed on 
the safety population from that Assessment. The statistical analysis of safety data 
will be performed for the safety population, separately for the Comfort Assessment 
and the Safety and Efficacy Assessment. The analysis of baseline and all efficacy 
data in the Safety and Efficacy Assessment will be performed for the mITT 
population. The efficacy analyses may also be performed on the PP population as 
sensitivity analyses. 
 
Sample Size: 
 
The study is not powered to show statistical differences for any of the efficacy 
endpoints. The sample size was determined based on prior clinical trial experience 
in subjects with dry eye syndrome and is deemed to be sufficient to evaluate the 
safety and tolerability of TOP1630 Ophthalmic Solution in this population and to 
gather efficacy data that will aid in powering future clinical trials. 
 
With a sample size of 60 subjects in the Safety and Efficacy Assessment, the study 
will have 79% probability of detecting AEs occurring at a rate of 5% or more in 
either treatment arm. 
 
Multiplicity Consideration: 
There will be no adjustments for multiple endpoints or multiple treatment 
comparisons for this early phase, exploratory study. 
 
Safety Variables: 


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Adverse events will be coded using the MedDRA dictionary. 
Frequencies and percentages of subjects with treatment-emergent adverse events 
(TEAEs), serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An AE is treatment emergent if it occurs or worsens 
after the first dose of study treatment. Furthermore, frequencies will be given of 
subjects with TEAEs by system organ class and preferred term; by system organ 
class, preferred term and maximal severity; by system organ class and preferred 
term for treatment-related AEs; by system organ class, preferred term for SAEs; 
and by system organ class, preferred term, and time of onset. Separate summaries 
will be provided for ocular specific and all AEs (including systemic). 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, corneal 
sensitivity, undilated fundoscopy, intraocular pressure (non-contact), and vital signs 
will be summarized by treatment group and visit using descriptive statistics. 
Changes or shifts from baseline will also be summarized where appropriate. For 
assessments performed by eye, study eye and fellow eye will be summarized 
separately. In addition, shifts from baseline to worst on-treatment value for ocular 
safety assessments will be summarized. 
Safety summaries will be provided for the comfort and safety and efficacy portions 
of the study separately. 


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TABLE OF CONTENTS 
SYNOPSIS ..........................................................................................................................4 
TABLE OF CONTENTS.................................................................................................13 
LIST OF ABBREVIATIONS .........................................................................................16 
1 
INTRODUCTION...................................................................................................18 
2 
STUDY OBJECTIVES ...........................................................................................18 
3 
CLINICAL HYPOTHESES ..................................................................................19 
4 
OVERALL STUDY DESIGN ................................................................................19 
5 
STUDY POPULATION .........................................................................................21 
5.1 
Number of Subjects (approximate) .............................................................21 
5.2 
Study population characteristics .................................................................22 
5.3 
Withdrawal Criteria and Study Stopping Criteria ...................................24 
6 
STUDY PARAMETERS ........................................................................................26 
6.1 
Safety Measures ............................................................................................26 
6.2 
Exploratory Efficacy Measures ...................................................................26 
6.3 
Biomarkers ....................................................................................................26 
7 
STUDY MATERIALS ............................................................................................26 
7.1 
Study Drug(s) ................................................................................................26 
7.1.1 
Formulations .....................................................................................26 
7.1.2 
Dispensation Schedule ......................................................................27 
7.1.3 
Instructions for Use ...........................................................................28 
7.2 
Other Study Supplies ...................................................................................28 
8 
STUDY METHODS AND PROCEDURES .........................................................28 
8.1 
Subject Entry Procedures ............................................................................28 
8.1.1 
Informed Consent ..............................................................................28 
8.1.2 
Washout Intervals .............................................................................28 
8.1.3 
Procedures for Final Study Entry ......................................................28 
8.1.4 
Methods for Assignment to Treatment Groups .................................29 
8.2 
Concurrent Therapies ..................................................................................29 
8.2.1 
Prohibited Medications/Treatments ..................................................29 
8.2.2 
Escape Medications ..........................................................................29 
8.2.3 
Special Diet or Activities ..................................................................29 
8.3 
Examination Procedures ..............................................................................30 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ..........................................................................................30 
8.4 
Schedule of Visits and Measurements ........................................................39 
8.4.1 
Scheduled Visits ................................................................................39 
8.4.2 
Unscheduled Visits ...........................................................................39 
8.5 
Compliance with Protocol ............................................................................40 
8.6 
Subject Disposition .......................................................................................41 
8.6.1 
Completed Subjects ..........................................................................41 
8.6.2 
Discontinuation and Stopping Criteria ..............................................41 
8.7 
Study Termination .......................................................................................41 
8.8 
Study Duration .............................................................................................41 
8.9 
Monitoring and Quality Assurance ............................................................41 


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9 
ADVERSE EVENTS ..............................................................................................41 
9.1 
Adverse Event ...............................................................................................41 
9.1.1 
Severity .............................................................................................42 
9.1.2 
Relationship to Study Drug ...............................................................42 
9.1.3 
Expectedness .....................................................................................43 
9.2 
Serious Adverse Events ................................................................................43 
9.3 
Procedures for Reporting Adverse Events .................................................44 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................44 
9.3.2 
Reporting a Serious Adverse Event ..................................................44 
9.4 
Procedures for Unmasking of Study Drug .................................................45 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events 46 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ................46 
10.1 Analysis Populations ....................................................................................46 
10.2 Statistical Hypotheses ...................................................................................47 
10.3 Sample Size ...................................................................................................47 
10.4 Statistical Analysis ........................................................................................48 
10.4.1 General Considerations .....................................................................48 
10.4.2 Unit of Analysis ................................................................................48 
10.4.3 Missing Data .....................................................................................49 
10.4.4 Multiplicity Consideration ................................................................49 
10.4.5 Safety Variables ................................................................................49 
10.4.6 Tolerability Analyses ........................................................................49 
10.4.7 Exploratory Efficacy Analyses .........................................................50 
10.4.8 Interim Analyses ...............................................................................50 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ................................50 
11.1 Protection of Human Subjects .....................................................................51 
11.1.1 Subject Informed Consent .................................................................51 
11.1.2 Institutional Review Board (IRB) Approval .....................................51 
11.2 Ethical Conduct of the Study .......................................................................51 
11.3 Subject Confidentiality ................................................................................51 
11.4 Documentation ..............................................................................................52 
11.4.1 Retention of Documentation .............................................................52 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Study Drug ....................................................................................................52 
11.5.1 Labeling/Packaging...........................................................................52 
11.5.2 Storage of Study Drug.......................................................................53 
11.5.3 Accountability of Study Drug ...........................................................53 
11.5.4 Return or Disposal of Study Drug.....................................................53 
11.6 Recording of Data on Source Documents and Electronic Case Reports 
Forms (eCRFs) ..............................................................................................53 
11.7 Handling of Biological Specimens ...............................................................54 
11.8 Publications ...................................................................................................54 
12 
REFERENCES ........................................................................................................55 
13 
APPENDICES .........................................................................................................56 
Appendix 1: Schedule of Visits and Measurements ...................................................56 


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Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ...........59 
Appendix 3: Amendment Summary of Changes ...........................................................88 
Appendix 4: Sponsor and Ora Approvals ..................................................................98 
Appendix 5: Investigator’s Signature .........................................................................99 


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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ANCOVA 
analysis of covariance 
BCVA 
best-corrected visual acuity 
CAE® 
controlled adverse environment 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRF 
case report form 
DES 
Dry Eye Syndrome 
DHHS 
Department of Health and Human Services 
eCRF 
electronic case report form 
EKG 
Electrocardiograph 
ERC 
ethical review committee 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IRB 
institutional/independent review board 
ITT 
intent-to-treat 
IUD 
intra uterine device 
IWRS 
interactive web response system 
KCS 
keratoconjunctivitis sicca 
Kg 
Kilogram 
LASIK 
laser in situ keratomileusis 
LOCF 
last observation carried forward 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGD 
meibomian gland dysfunction 
Mg 
Milligram 
mL 
Milliliter 
Mm 
Millimeter 
NEI 
National Eye Institute 
µg 
microgram 
µL 
microliter 
µm 
Micrometer 
mmHg 
millimeters of mercury 
OD 
right eye 


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OPI 
ocular protection index 
OS 
left eye 
OSDI© 
ocular surface disease index 
OU 
both eyes 
OTC 
over-the-counter 
PMNs 
polymorphonuclear leucocytes 
PP 
per protocol 
TID 
three times a day (6 hour intervals in morning, 
afternoon, and evening) 
SAE 
serious adverse event 
TFBUT/TBUT 
tear film break-up time 
TEAEs 
treatment emergent adverse events 
VA 
visual acuity 


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1 INTRODUCTION 
Dry eye syndrome (DES) is a common disorder affecting an estimated 25-30 million 
people in the United States, with prevalence estimates varying widely from 7.8% to 
almost 34%1,2. Dry eye incidence rises sharply with age, and women are more affected 
than men, purportedly due to the pathophysiological role of androgens and the complex 
nexus of the endocrine-immunological systems. The Dry Eye Workshop (DEWS) has 
redefined dry eye as “a multifactorial disease of the tears and ocular surface that results in 
symptoms of discomfort, visual disturbance, and tear film instability with potential 
damage to the ocular surface, accompanied by increased osmolarity of the tear film and 
inflammation of the ocular surface”3. 
Approaches to treatment vary; however, disease modification usually has targeted the 
inflammatory aspects of the disease. The only currently approved therapies for dry eye 
are cyclosporine ophthalmic emulsion (Restasis®) and lifitigrast ophthalmic solution 
(Xiidra™). Despite a commonly reported side effect of burning/stinging while using these 
drops, Restasis® is widely prescribed and used for the treatment of DES4. Xiidra™ has 
recently been approved and is also associated with burning and stinging following 
application5. A well-tolerated drug that reduces the inflammatory response in DES would 
be a major step forward from current treatment options. 
 
TopiVert’s narrow spectrum kinase inhibitors (NSKIs) promise to deliver long-term 
efficacy, improving both signs and symptoms of dry eye syndrome by effectively treating 
the underlying inflammation. Specifically, they target several important kinases (p38- 
alpha, syk and src family kinases src and lck) involved in the inflammatory 
cascade. TopiVert has demonstrated these kinases are up regulated in dry eye syndrome 
and inhibition leads to synergistic anti-inflammatory effects on key cell signaling 
pathways involved in inflammation. TOP1630 has been specifically designed to act 
locally at surface of the eye, with little or no systemic absorption, minimizing any 
untoward effects of the drug in the rest of the body. Thus TOP1630 has the potential to 
deliver a very favorable efficacy and safety profile for the sustained treatment of DES. 
 
This study is the first in man for administration with TOP1630. Please refer to the 
Investigator’s Brochure for further information on TOP1630. 
 
2 STUDY OBJECTIVES 
In subjects with dry eye syndrome: 
 
The primary objective of this study is to compare the safety and tolerability of TOP1630 
Ophthalmic Solution to placebo. 
 
The secondary objectives are to compare the efficacy of TOP1630 Ophthalmic Solution 
to placebo for the treatment of the signs and symptoms of dry eye syndrome. 








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randomized subjects. Subjects will be randomized in a 1:1 ratio (30 subjects in the 
TOP1630 arm and 30 in the placebo arm). 
 
5.2 Study population characteristics 
Inclusion Criteria 
 
Subjects must meet all of the following requirements to be eligible for enrollment into the 
study: 
 
For the Comfort Assessment: 
 
1. Be at least 18 years of age; 
2. Provide written informed consent; 
3. Have a patient reported history of dry eye for at least 6 months prior to Visit 
1a; 
4. Have a history of use or desire to use eye drops for dry eye symptoms for at 
least 6 months prior to Visit 1a; 
 
For the Safety and Efficacy Assessment: 
 
All of the above criteria (at Visit 1b), and: 
5. Report a score of ≥ 2 in at least one symptom of the Ora Calibra® 
Ocular Discomfort & 4-Symptom Questionnaire at Visits 1b and 2b; 
6. Report an OSDI© score ≥ 18 at Visits 1b and 2b; 
7. Have a conjunctival redness score of ≥ 1 according to the Ora Calibra® scale 
in at least one eye at Visits 1b and 2b; 
8. Have a tear film break-up time (TFBUT) >1 and < 7 seconds in at least one 
eye at Visit 1b and 2b; 
9. Have a Schirmer’s Test score of ≤ 10 mm and ≥ 1 mm in at least one eye at 
Visits 1b and 2b; 
10. Have a corneal fluorescein staining score of ≥ 2 according to the Ora Calibra® 
scale in at least one region (e.g. inferior, superior, or central) in at least one 
eye at Visits 1b and 2b; 
11. Have a total lissamine green conjunctival score of ≥ 2, based on the sum of the 
temporal and nasal regions of the conjunctiva according to the Ora Calibra® 
scale in at least one eye at Visits 1b and 2b; 
12. Demonstrate a response to the CAE® at Visits 1b and 2b as defined by: 
a. Having at least a ≥ 1 point increase in fluorescein staining in the 
inferior region in at least one eye following CAE® exposure on the Ora 
Calibra® scale; and 
b. Reporting an Ocular Discomfort score ≥ 3 at 2 or more consecutive 
time points in at least one eye during CAE® exposure on the Ora 
Calibra® scale (if a subject has an Ocular Discomfort rating of 3 at 
time = 0 for an eye, s/he must report an Ocular Discomfort rating of 4 
for two consecutive measurements for that eye). 


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13. Have at least one eye (the same eye) satisfy all criteria for 7, 8, 9, 10, 11, and 
12 above; 
14. At Visit 2b, subjects must have at least 5 days’ worth of diary symptom data 
and deemed by the PI to be 80% compliant with vehicle eye drops. 
 
Exclusion Criteria 
Subjects may not participate in the study (Comfort Assessment as well as the Safety 
and Efficacy Assessment) if any of the following criteria are met: 
1. Unable or unwilling to follow instructions, including participation in all study 
assessments and visits; 
2. Have any clinically significant slit lamp findings at Visit 1 (1a or 1b) that may 
include active blepharitis, meibomian gland dysfunction (MGD), lid margin 
inflammation or active ocular allergies that require therapeutic treatment, 
and/or in the opinion of the investigator may interfere with study parameters; 
3. Be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal), or 
active ocular inflammation at Visit 1 (1a or 1b); 
4. Have any significant ocular lesion that could interfere with assessment of 
safety or efficacy or prevent study conduct in the opinion of the PI; 
5. Have worn contact lenses within 14 days of Visit 1 (1a or 1b) or anticipate 
using contact lenses during the study; 
6. Have used any eye drops within 2 hours of Visit 1 (1a or 1b); 
7. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery 
within the last 12 months or any other ocular surgeries within the last 6 
months; 
8. Have used Restasis® or Xiidra™ within 90 days of Visit 1 (1a or 1b); 
9. Have used topical ocular steroids within 30 days of Visit 1 (1a or 1b); 
10. Have any planned ocular and/or lid surgeries over the study period; 
11. Have temporary punctal plugs at Visit 1 that have not been stable within 45 
days of Visit 1 (1a or 1b) or anticipate having temporary punctal plugs 
inserted during the study; 
12. Have had punctal occlusion (not including punctal plugs) within 6 months of 
Visit 1(1a or 1b); 
13. Be currently taking any topical ophthalmic prescription (including 
medications for glaucoma) or over-the-counter (OTC) solutions, artificial 
tears, gels or scrubs, and cannot discontinue these medications for the duration 
of the trial (excluding medications allowed for the conduct of the study) or 
have used any of these medications in the previous 24 hours prior to visit 1 
(1a or 1b); 
14. Have corrected visual acuity greater than or equal to logMAR+0.7 as assessed 
by Early Treatment of Diabetic Retinopathy Study (ETDRS) scale in both 
eyes at Visit 1 (1a or 1b); 
15. Have an uncontrolled systemic disease; 
16. Be a woman who is pregnant, nursing or planning a pregnancy; 
17. Be unwilling to submit a urine pregnancy test at Visit 1 (1a or 1b) and Visit 8a 
or 4b (or early termination visit) if of childbearing potential. 
Non- 


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childbearing potential is defined as a woman who is permanently sterilized 
(e.g. has had a hysterectomy or tubal ligation), or is post-menopausal (without 
menses for 12 consecutive months); 
18. Be a woman of childbearing potential who is not using an acceptable means of 
birth control; acceptable methods of contraception include: hormonal – oral, 
implantable, injectable, or transdermal contraceptives; mechanical – 
spermicide in conjunction with a barrier such as a diaphragm or condom; 
IUD; or surgical sterilization of partner. For non-sexually active females, 
abstinence may be regarded as an adequate method of birth control; however, 
if the subject becomes sexually active during the study, she must agree to use 
adequate birth control as defined above for the remainder of the study; 
19. Have a known allergy and/or sensitivity to the test article or its components; 
20. Have a condition or be in a situation which the investigator feels may put the 
subject at significant risk, may confound the study results, or may interfere 
significantly with the subject’s participation in the study; 
21. Be currently enrolled in an investigational drug or device study or have used 
an investigational drug or device within 30 days of Visit 1 (1a or 1b). Subjects 
that were enrolled in the Comfort Assessment will be excluded from 
participating in the Safety and Efficacy Assessment; 
22. Be currently using any medication known to cause ocular drying that is not 
used on a stable dosing regimen for at least 30 days prior to Visit 1 (1a or 1b); 
antihistamines are not allowed at any time during the study. 
 
5.3 Withdrawal Criteria and Study Stopping Criteria 
Subjects may withdraw consent from study participation at any time. 
 
If at any time during the study the investigator determines that a subject’s safety is or 
has been compromised, the subject may be withdrawn from the study. 
 
Subjects may be discontinued prior to their completion of the study due to the 
following safety stopping criteria being met for any subject: 
• Persistent loss of 3 or more lines of visual acuity not explained by 
the condition under investigation and confirmed upon repeat 
testing 
• Development of persistent corneal opacities or severe keratitis 
• Persistent ocular irritation or redness not explained by condition 
• IOP increase of 12 or more confirmed upon repeat testing 
• Sight threatening adverse events such as corneal melting or corneal 
ulceration; 
• Any other possibly related adverse events 
Other reasons for discontinuation: 
• Protocol violations 


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• Administrative reasons (e.g., inability to continue, lost to follow 
up) 
• Subject choice (e.g. withdrawal of consent) 
• Non compliance 
• Any valid medical reason at discretion of investigator (see section 
8.6.2) 
• Other 
Notification of a subject discontinuation and the reason for discontinuation will be 
made to Ora and/or study Sponsor and will be clearly documented in the eCRF. 
 
Discontinued subjects will not be replaced. 
 
Study Stopping Criteria 
 
Comfort Assessment 
 
The Comfort Assessment will be considered for stopping should 3 or more 
subjects experience any of the following: 
 
• discontinue dosing due to persistent irritation deemed not to be due 
to underlying disease activity 
• suffer persistent loss of 3 or more lines of visual acuity not 
explained by the condition under investigation and confirmed upon 
repeat testing 
• develop persistent corneal opacities or severe keratitis 
• suffer an IOP increase of 12 or more confirmed upon repeat testing 
• subjects undergo sight threatening adverse events such as corneal 
melting or corneal ulceration 
 
If the study is stopped for any of the above reasons, a lower dose may be 
considered for completion of the remainder of the study if deemed appropriate by 
the Sponsor and PI. 
 
Safety and Efficacy Assessment  
 
The Safety and Efficacy Assessment will be considered for stopping should more 
than 10 subjects discontinue dosing due to any of the following: 
 
• persistent irritation deemed not to be due to underlying disease 
activity 
• persistent loss of 3 or more lines of visual acuity not explained by 
the condition under investigation and confirmed upon repeat 
testing 
• persistent corneal opacities or severe keratitis 
• an IOP increase of 12 or more confirmed upon repeat testing 


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• other sight threatening adverse events such as corneal melting or 
corneal ulceration 
 
6 STUDY PARAMETERS 
6.1 Safety Measures 
• Visual acuity (ETDRS) 
• Slit-lamp biomicroscopy 
• Corneal sensitivity (Pre-CAE®) 
• Adverse event query 
• Undilated fundoscopy 
• Vital signs at all visits 
• Drop comfort assessment 
• Intraocular pressure (non-contact) 
 
6.2 Exploratory Efficacy Measures 
• Corneal fluorescein staining on the Ora Calibra® and NEI scales 
• Conjunctival lissamine green staining on the Ora Calibra® and NEI scales 
• Visual Analogue Scale (VAS) (Pre-CAE®) 
• Tear film break-up time 
• Conjunctival redness the Ora Calibra® scale 
• Schirmer Test at Visits 2b, 3b, and 4b 
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
• OSDI© 
• Ora Calibra® Lid Margin Redness 
• Ora Calibra® Posterior Lid Edge Evaluation 
• OPI 2.0 
• Ora Calibra® Ocular Discomfort Scale 
6.3 Biomarkers 
• Impression Cytology (OPIA Eyeprim™). 
 
7 STUDY MATERIALS 
7.1 Study Drug(s) 
7.1.1 Formulations 
Comfort Assessment 
 
• 0.01% TOP1630 Ophthalmic Solution 


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• 0.1% TOP1630 Ophthalmic Solution 
• Placebo Ophthalmic Solution (Vehicle with no TOP1630) 
Run-In 
• Placebo Ophthalmic Solution (Vehicle with no TOP1630) 
Safety and Efficacy Assessment 
• TOP1630 Ophthalmic Solution (dose determined by outcome of 
Comfort Assessment) 
• Placebo Ophthalmic Solution (Vehicle with no TOP1630) 
7.1.2 Dispensation Schedule 
Comfort Assessment 
• At Visit 1a, qualified subjects will be randomized and receive their 
assigned study drug Comfort Kit. They will administer the first three 
doses of placebo or 0.01% TOP1630 in office. 
• At Visit 3a, subjects will administer a single dose of placebo or 0.1% 
TOP1630 from their assigned study drug Comfort Kit. Unless stopping 
criteria (as outlined in Section 5.3) are met, the remaining doses for 
each subject for the remainder of the Comfort Assessment will be at 
the 0.1% concentration of TOP1630 or placebo. If stopping criteria are 
met after the introduction of the 0.1% TOP1630, the Comfort 
Assessment study may proceed with the subjects’ dosing with the 
lower concentration 0.01% TOP1630 (or placebo). 
• At Visit 5a, subjects will dose TID in office with placebo or 0.1% 
TOP1630 from their assigned study drug Comfort Kit. 
• At Visit 7a, a Take Home Kit from their assigned study drug Comfort 
Kit will be dispensed to subjects for at-home dosing TID with placebo 
or 0.1% TOP1630 from days 8 through 11 (4 days TID). 
• At Visit 8a all study drug will be collected. 
Safety and Efficacy Assessment 
• At the end of Visit 1b, qualified subjects will receive a kit of run-in 
(Placebo) for one week, dosing TID until Visit 2b. Subject will be 
instructed to dose in 6-hour intervals in the morning, afternoon, and in 
the evening before bed. 
• The run-in kit will be collected at the beginning of Visit 2b and 
accountability will be performed by a study technician. 
• At the end of Visit 2b, qualified subjects will be randomized and the 
first dose of study drug will be administered in office, and subjects will 
take remaining doses at home. 


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• At the end of Visit 2b, subjects will be given two kits of 24 bottles 
each of TOP1630 Ophthalmic Solution or placebo for TID dosing. 
• At Visit 3b, subjects will receive two new kits of the same test article 
they were previously randomized to (at Visit 2b) for TID dosing. 
• At Visits 3b and 4b, remaining/unused study drug will be collected 
from subjects for drug accountability. 
• Subjects will be instructed to not use run-in (at Visit 2b) or study drug 
on the day of visits (Visit 3b and 4b) prior to the visit. 
 
7.1.3 
Instructions for Use 
Subjects will be instructed to dose by instilling 1 drop in each eye TID in 
approximately 6 hour intervals (morning, afternoon, and in the evening 
before bed). Subjects will be instructed to use a second drop only if the 
first drop does not fully coat the eye. Subjects will be given detailed 
instructions on study drug administration, accountability, and storage at 
each visit. 
 
7.2 Other Study Supplies 
Urine pregnancy tests, Schirmer’s test strips, sodium fluorescein, lissamine 
green/strips, Fluress, Eyeprim™ (impression cytology). 
 
8 STUDY METHODS AND PROCEDURES 
8.1 Subject Entry Procedures 
8.1.1 
Informed Consent 
Prior to a subject’s participation in the trial (i.e., prior to changes in a 
subject’s medical treatment and/or prior to study related procedures), the 
study will be discussed with each subject, and subjects wishing to 
participate must give written informed consent using an informed consent 
form (ICF). The informed consent form must be the most recent version 
that has received approval/favorable review by a properly constituted 
Institutional Review Board (IRB). 
8.1.2 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the 
Exclusion Criteria (Section 5.2). 
8.1.3 Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusion criteria. 


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8.1.4 Methods for Assignment to Treatment Groups: 
For the Comfort Assessment, prior to initiation of the study (at Visit 1a), 
each subject who qualifies for entry will be assigned a screening number. 
All screening numbers will be assigned in strict numerical sequence at a 
site and no numbers will be skipped or omitted. If all inclusion and 
exclusion criteria are met, each qualifying subject will then be assigned a 
randomization number at Visit 1a. 
For the Safety and Efficacy Assessment, prior to initiation of study run-in 
(at Visit 1b), each subject who qualifies for entry will be assigned a 
screening number. All screening numbers will be assigned in strict 
numerical sequence at a site and no numbers will be skipped or omitted. 
If all inclusion and exclusion criteria are met at Visits 1b and 2b, each 
qualifying subject will then be assigned a randomization number at the 
end of Visit 2b. 
The Sponsor, Investigator, study staff and subject will be masked to the 
subject’s treatment arm during the randomization process and throughout 
the study. 
 
8.2 Concurrent Therapies 
The use of any concurrent medication, prescription or over-the-counter, is to be 
recorded on the subject’s source document and corresponding electronic case report 
form (eCRF) along with the reason the medication was taken. 
Concurrent enrollment in another investigational drug or device study is not 
permitted. Subjects who were enrolled in the Comfort Assessment portion of the 
study will not be permitted to participate in the Safety and Efficacy Assessment. 
8.2.1 Prohibited Medications/Treatments 
Disallowed medications/treatments during the study are outlined in the 
Exclusion Criteria (Section 5.2). 
8.2.2 Escape Medications 
No escape medications are allowed for this study. 
8.2.3 Special Diet or Activities 
Subjects will only be permitted to leave the clinic space under supervision 
by a staff member during Visits 1a and 5a. 
Subjects will be instructed not to smoke (cigarettes, e-cigarettes, etc) for 
the duration of each of their clinic visits. 


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8.3 Examination Procedures 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
The following procedures will be performed (see Appendix 2 for 
description): 
For the Comfort Assessment:   
Visit 1a (Day 1): 0.01% TOP1630 
• Informed consent / HIPAA 
• Demographic data and medical / medication history 
• Urine pregnancy test (for females of childbearing potential) 
• Baseline visual acuity 
• Vital Signs (Pulse, Blood Pressure, and O2 Saturation) 
• Baseline slit lamp biomicroscopy 
• Baseline intraocular pressure (non-contact) 
• Review of Qualification Criteria 
• Adverse Event Query 
• Randomization & Assignment of study drug kit according to 
randomization 
• 0.01% TOP1630 or Placebo Morning Dose 
• Comfort assessment 
• 0.01% TOP1630 or Placebo Afternoon Dose 
• Comfort assessment 
• 0.01% TOP1630 or Placebo Evening Dose 
• Comfort assessment 
• Visual acuity 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact) 
• Adverse Event Query 
Visit 2a (Day 2 [24 +/- 3 hrs from Visit 1a first dose]): Physician 
Assessment 
 
• Medical/Medication History Update 
• Adverse Event Query 
• Visual acuity 
• Vital Signs 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact) 
Visit 3a (Day 3): 0.1% TOP1630, QD 
 
• Medical/Medication History Update 
• Adverse Event Query 


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• Visual acuity 
• Vital Signs 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact) 
• 0.1% TOP1630 or Placebo Dose 
• Comfort Assessment 
Visit 4a (Day 4) [24 +/- 3 hrs from Visit 3a dose]): Physician Assessment 
 
• Medical/Medication History Update 
• Adverse Event Query 
• Visual acuity 
• Vital Signs 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact). 
Visit 5a (Day 5): 0.1% TOP1630, TID 
 
• Medical/Medication History Update 
• Adverse Event Query 
• Visual acuity 
• Vital Signs 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact) 
• 0.1% TOP1630 or Placebo Morning Dose 
• Comfort assessment 
• 0.1% TOP1630 or Placebo Afternoon Dose 
• Comfort assessment 
• 0.1% TOP1630 or Placebo Evening Dose 
• Comfort assessment 
• Visual acuity 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact) 
• Adverse Event Query 
Visit 6a (Day 6 [24 +/- 3 hrs Visit 5a first dose]): Physician Assessment 
 
• Medical/Medication History Update 
• Adverse Event Query 
• Visual acuity 
• Vital Signs 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact). 
Visit 7a (Day 8): 0.1% TOP1630, TID 


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• Medical/Medication History Update 
• Adverse Event Query 
• Visual acuity 
• Vital Signs 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact) 
• Subject doses TOP1630 or Placebo at home TID 
• Comfort assessment at Home 
• Dispensation of study drug kit according to randomization for TID 
dosing until Visit 8a 
• Dispensation of comfort assessment questionnaire 
At home dosing of TOP1630 TID on days 9, 10, and 11. No site Visits. 
 
Visit 8a (Day 12): Assessment and Exit 
 
• Return study drug kit and comfort assessment questionnaires 
• Medical/Medication History Update 
• Adverse Event Query 
• Visual acuity 
• Vital Signs 
• Slit lamp biomicroscopy 
• Intraocular pressure (non-contact) 
• Urine pregnancy test (for females of childbearing potential) 
• Study exit 
 
For the Safety and Efficacy Assessment: 
Visit 1b (Day -7 ±1): Screening 
Pre-CAE® Procedures 
• Informed consent / HIPAA 
• Demographic data and medical / medication history 
• Urine pregnancy test (for females of childbearing potential) 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
• Ocular Surface Disease Index© (OSDI©) 
• 7 question Visual Analogue Scale (VAS) for symptoms of DES 
• Visual acuity 
• Vital Signs 


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• Review of qualification criteria 
• Slit-lamp biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• Ora Calibra® Lid Margin Redness 
• Ora Calibra® Posterior Lid Edge Evaluation 
• Tear Film Break-up Time (TFBUT) 
• Fluorescein staining – Ora Calibra® and NEI scale 
• Lissamine Green staining – Ora Calibra® and NEI scale 
• Corneal sensitivity 
• Unanesthetized Schirmer’s Test, to be performed at least 15 minutes 
after Lissamine Green staining 
• Adverse Event Query 
• 90-minute CAE® exposure 
o Ora Calibra® Ocular Discomfort upon entering the CAE® 
and every 5 minutes thereafter 
Post- CAE® Procedures 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
• Slit-lamp biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• TFBUT 
• Fluorescein staining – Ora Calibra® and NEI scale 
• Lissamine Green staining – Ora Calibra® and NEI scale 
• Intraocular pressure (non-contact) 
• Undilated fundoscopy 
• Review of qualification criteria 
• Adverse event query 
• Dispensation of run-in (RUN-IN) for TID dosing until Visit 2b; 
o Subjects will be instructed to dose in each eye three times daily 
(morning, afternoon, and in the evening before bed); 
• Dispensation of diaries and subject instructions; 


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o Subjects will be instructed to complete their diary and dose in 
each eye in the afternoon and before bed on the evening of 
Visit 1b 
o Subjects will be instructed to complete diary symptoms TID 
prior to drop instillation in the morning, afternoon, and evening 
before bed until Visit 2b 
o Subjects will be instructed to complete their diary on the 
morning of their next visit (Visit 2b) 
o Subjects will be instructed to not dose with run-in placebo on 
the morning of their next visit (Visit 2b) 
• Qualified subjects will be scheduled for Visit 2b. 
Visit 2b (Day 1): Confirmation/Baseline 
 
Pre-CAE® Procedures 
• Collection and review of run-in (RUN-IN) and subject diaries 
• Subject will be asked if he/she dosed with run-in on the morning of the 
visit; if the subject indicates he/she dosed that morning, he/she should 
wait at least 4 hours from the time of dosing before efficacy 
assessments are performed 
• Medical/medication history update 
• Adverse event query 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
• OSDI© 
• 7 question Visual Analogue Scale (VAS) for symptoms of DES 
• Visual Acuity 
• Vital Signs 
• Review of qualification criteria 
• Slit-lamp Biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• Ora Calibra® Lid Margin Redness 
• Ora Calibra® Posterior Lid Edge Evaluation 
• Ora Calibra® OPI 2.0 
• TFBUT 


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• Fluorescein staining – Ora Calibra® and NEI Scale 
• Lissamine Green staining – Ora Calibra® and NEI Scale 
• Unanesthetized Schirmer’s Test - to be performed at least 15 minutes 
after Lissamine Green staining 
• 90-minute CAE® exposure; 
o Ora Calibra™ Ocular Discomfort upon entering the CAE® and 
every 5 minutes thereafter; 
Post- CAE® Procedures 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom questionnaire 
• Slit-lamp biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• TFBUT 
• Fluorescein staining – Ora Calibra® and NEI scale 
• Lissamine Green staining – Ora Calibra® and NEI scale 
• Adverse Event Query 
• Review of qualification criteria 
• Randomization & Dispensation of study drug kit according to 
randomization for TID dosing until Visit 3b 
• Subject self-administers first dose of study drug, OU 
• Ora Calibra® Drop Comfort and Questionnaire 
• Wait at least 15 minutes from in office dose to Impression Cytology 
• Impression cytology (OPIA Eyeprim™) – to be performed on the 
“worst eye” as defined in Section 10.4.2. Anesthetic may be used at 
the discretion of the Investigator 
• Subjects will be instructed to dose in each eye three times daily 
(morning, afternoon, and in the evening before bed) 
• Dispensation of diaries: 
o Subjects will be instructed to complete diary symptoms TID 
prior to drop instillation in the morning, afternoon, and in the 
evening before bed until Visit 3b; 
o Subjects will be instructed to complete their diary TID to 
account for each dose of study drug taken; 


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o Subjects will be instructed to complete their diary and dose in 
each eye in the afternoon and before bed on the evening of 
Visit 2b; 
o Subjects will be instructed to complete their diary on the 
morning of their next visit (Visit 3b); 
o Subjects will be instructed to not dose with study drug on the 
morning of their next visit (Visit 3b); 
• Subject will remain at the site for at least 30 minutes after instillation 
of study drug 
• Qualified subjects will be scheduled for Visit 3b. 
 
Visit 3b (Day 15 ± 1): 2-Week Follow-Up 
Pre-CAE® Procedures 
 
• Collection and review of study drug and subject diaries 
• Subject will be asked if he/she dosed with study drug on the morning 
of the visit; if the subject indicates he/she dosed that morning, he/she 
should wait at least 4 hours from the time of dosing before efficacy 
assessments are performed 
• Medical / medication history update 
• Adverse event query 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
• OSDI© 
• 7 question Visual Analogue Scale (VAS) for symptoms of DES 
• Visual Acuity 
• Vital Signs 
• Slit-lamp biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• Ora Calibra® Lid Margin Redness; 
• Ora Calibra® Posterior Lid Edge Evaluation; 
• TFBUT 
• Fluorescein staining – Ora Calibra® and NEI scale 
• Lissamine Green staining – Ora Calibra® and NEI scale 


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• Unanesthetized Schirmer’s Test - to be performed at least 15 minutes 
after Lissamine Green staining 
• 90-minute CAE® exposure; 
o Ora Calibra® Ocular Discomfort upon entering the CAE® 
and every 5 minutes thereafter; 
Post-CAE® Procedures 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom questionnaire 
• Slit-lamp biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• TFBUT 
• Fluorescein staining – Ora Calibra®; and NEI Scale 
• Lissamine Green staining – Ora Calibra®; and NEI Scale 
• Adverse Event Query 
• Dispensation of study drug kit according to randomization for TID 
dosing until Visit 4b 
• Subject self-administers dose of study drug, OU 
• Ora Calibra® Drop Comfort and Questionnaire 
• Subjects will be instructed to dose in each eye three times daily 
(morning, afternoon, and in the evening before bed) 
• Dispensation of diaries: 
o Subjects will be instructed to complete diary symptoms TID in 
the morning, afternoon, and the evening before bed prior to 
drop instillation until Visit 4b; 
o Subjects will be instructed to complete their diary TID to 
account for each dose of study drug taken; 
o Subjects will be instructed to complete their diary and dose in 
each eye in the afternoon and before bed on the evening of 
Visit 3b; 
o Subjects will be instructed to complete their diary on the 
morning of their next visit (Visit 4b); 
o Subjects will be instructed to not dose with study drug on the 
morning of their next visit (Visit 4b); 
• Subjects will be scheduled for Visit 4b. 


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Visit 4b (Day 29 ± 2): 4-Week Follow-Up and Study Exit 
 
Pre-CAE® Procedures 
• Collection and review of study drug and subject diaries 
• Subject will be asked if he/she dosed with study drug on the morning 
of the visit; if the subject indicates he/she dosed that morning, he/she 
should wait at least 4 hours from the time of dosing before efficacy 
assessments are performed 
• Medical / medication history update 
• Adverse event query 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
• OSDI© 
• 7 question Visual Analogue Scale (VAS) for symptoms of DES 
• Visual Acuity 
• Vital Signs 
• Urine pregnancy test (for females of childbearing potential) 
• Slit-lamp Biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• Ora Calibra® Lid Margin Redness 
• Ora Calibra® Posterior Lid Edge Evaluation 
• Ora Calibra® OPI 2.0 
• TFBUT 
• Fluorescein staining – Ora Calibra® and NEI scale 
• Lissamine Green staining – Ora Calibra® and NEI scale 
• Corneal Sensitivity 
• Unanesthetized Schirmer’s Test, to be performed at least 15 minutes 
after Lissamine Green staining 
• 90-minute CAE® exposure; 
o Ora Calibra® Ocular Discomfort upon entering the CAE® 
and every 5 minutes thereafter; 
Post-CAE® Procedures 
• Ora Calibra® Ocular Discomfort 
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 


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• Slit-lamp biomicroscopy 
• Ora Calibra® Conjunctival Redness 
• TFBUT 
• Fluorescein staining – Ora Calibra® and NEI scale 
• Lissamine Green staining – Ora Calibra® and NEI scale 
• Impression cytology (OPIA Eyeprim™) to be performed on the “worst 
eye” as defined in Section 10.4.2. Anesthetic may be used at the 
discretion of the Investigator 
• Intraocular pressure (non-contact) 
• Undilated Fundoscopy 
• Adverse event query 
• Study exit. 
Early Termination/Discontinuation 
 
If a subject is discontinued from the study prior to Visit 8a or 4b, then all 
safety evaluations that were to be performed at the Visit should be 
performed on the day of discontinuation (early termination) or at the 
discretion of the investigator. 
 
Adverse Events (both elicited and observed) and SAEs will be monitored 
throughout the study. The investigator will promptly review all adverse 
events (both elicited and observed) for accuracy and completeness. All 
adverse events will be documented on the appropriate source document 
and case report form. 
 
If a female reports a pregnancy or has a positive pregnancy test during the 
study the investigator will notify Ora immediately. The investigator shall 
request from the subject and/or the subject’s physician copies of all related 
medical reports during the pregnancy and shall document the outcome of 
the pregnancy. The investigator will retain these reports together with the 
subject’s source documents and will provide a copy of all documentation 
to Ora. 
 
8.4 Schedule of Visits and Measurements 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All 
procedures performed at an unscheduled visit will be recorded in the 


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source documents and on the Unscheduled Visit eCRF pages. Any 
procedure indicated in the eCRF that is not performed should be indicated 
as “Not done.” 
 
Evaluations that may be conducted at an Unscheduled Visit include: 
 
• Visual Acuity; 
• Slit-lamp Biomicroscopy; 
• Intraocular pressure (non-contact); 
• Pregnancy Test; 
• Undilated Fundoscopy; 
• Assessment of Adverse Events; 
• Assessment of concomitant medications and/or treatments; and 
• Any other assessments needed in the judgment of the investigator. 
 
 
8.5 Compliance with Protocol 
Subjects will be instructed on proper use of the subject daily diary and proper 
instillation and storage of study drug at the end of Visit 1a and 7a (in the Comfort 
Assessment) and Visits 1b, 2b, and 3b (in the Safety and Efficacy Assessment) and 
given written instructions. In the Comfort Assessment, used and unused study drug 
bottles will be collected at Visit 8a. In the Safety and Efficacy Assessment, the 
subject daily diaries and used and unused study drug bottles will be collected at each 
visit from Visit 2b up to and including Visit 4b to assess dosing and symptom 
assessment compliance. Dosing compliance will be based on the used and unused 
bottle count. If the subject is less than 80% or more than 114% compliant with dosing 
based on the expected number of used bottles, then the subject will be deemed non- 
compliant and a deviation should be recorded. 
 
In the Safety and Efficacy study, subjects must have at least 5 days’ worth of diary 
symptom data and deemed by the Investigator to be at least 80% compliant with 
dosing during the placebo run-in to be able to continue in the study. In the subject 
daily diary, if more than 20% of applicable Dose Taken boxes are checked “no”, left 
blank, or missing for a diary period, a subject will be deemed non-compliant and a 
diary deviation will be recorded. If more than 20% of the total diary symptom 
assessments for that dosing period are missed, these subjects will be deemed non- 
compliant and a diary symptom assessment deviation will be recorded. These 
guidelines will be used by the Investigator for determining the subject’s necessary 
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8.6 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study 
and has undertaken all study assessments applicable for study completion. 
8.6.2 Discontinuation and Stopping Criteria  
Refer to Section 5.3 for withdrawal and stopping criteria. 
 
8.7 Study Termination 
The study may be stopped at any time by the investigator, the sponsor, and/or Ora 
with appropriate notification. 
 
8.8 Study Duration 
An individual subject’s participation time for the Comfort Assessment is expected to 
be approximately 12 days. 
 
An individual subject’s participation in the Safety and Efficacy Assessment is 
expected to be approximately 5 weeks (35 days). 
 
8.9 Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to 
review protocol compliance, assess study drug accountability, subject safety, and 
ensure the study is being conducted according to the pertinent regulatory 
requirements. The review of the subjects’ medical records will be performed in a 
manner that adequately maintains subject confidentiality. Further details of the study 
monitoring will be outlined in a monitoring plan. 
 
Regulatory authorities of domestic and foreign agencies, Ora, Inc. quality assurance 
personnel and may carry out on-site inspections and/or audits, which may include 
source data checks. Therefore direct access to the original source data will be required 
for inspections and/or audits. All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that 
local, state, and federal laws apply. 
 
9 ADVERSE EVENTS 
9.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence associated with the 
use of a drug in humans, whether or not the event is considered drug-related. An 
adverse event can therefore be any unfavorable and unintended sign (e.g., an 
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dosing with the study drug, without any judgment about causality. Any pre-existing 
medical condition that worsens after administration of the study drug will also be 
considered a new adverse event. 
 
Collection of Adverse Events will begin at the time of informed consent. 
 
If there is a worsening of a medical condition that was present prior to the 
administration of the informed consent, this should also be considered a new adverse 
event and reported. Any medical condition present prior to the administration of the 
study drug that remains unchanged or improved should not be recorded as an adverse 
event at subsequent visits. 
 
Study drug includes the investigational drug under evaluation, placebo, or any other 
medications required by the protocol given during any stage of the study. 
 
Documentation regarding the adverse event should be made as to the nature, date of 
onset, end date, severity, relationship to study drug, action(s) taken, seriousness, and 
outcome of any sign or symptom observed by the physician or reported by the subject 
upon indirect questioning. 
 
9.1.1 Severity 
Severity of an adverse event is defined as a qualitative assessment of the 
degree of intensity of an adverse event as determined by the investigator 
or reported to him/her by the patient/subject. The assessment of severity 
is made irrespective of relationship to study drug or seriousness of the 
event and should be evaluated according to the following scale: 
 
• Mild: Event is noticeable to the subject, but is easily tolerated and 
does not interfere with the subject’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional 
therapy, and may interfere with the subject’s daily activities. 
• Severe:Event is intolerable, necessitates additional therapy or 
alteration of therapy, and interferes with the subject’s daily 
activities. 
 
9.1.2 Relationship to Study Drug 
The relationship of each AE to the investigational product should be 
determined by the investigator using these explanations: 
• Definite: When there are good reason and sufficient 
documentation to demonstrate a direct causal relationship 
between investigational product and AE; 
• Probable: When there are good reasons and sufficient 
documentation to assume a causal relationship in the sense of 
plausible, conceivable, likely but not necessarily highly probable. 


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• Possible: When there is sufficient information to accept the 
possibility of a causal relationship in the sense of not impossible 
and not unlikely, although the connection is uncertain or doubtful, 
for example; due to missing data or insufficient evidence. 
• None: When there is sufficient information to accept a lack of a 
causal relationship, in the sense of impossible and improbable. 
• Unclassified: When the causal relationship is not assessable for 
whatever reason due to insufficient evidence, conflicting data or 
poor documentation. 
9.1.3 Expectedness 
The expectedness of an adverse event should be determined based upon 
existing safety information about the study drug using these explanations: 
• Unexpected: An adverse event that is not listed in the 
Investigator’s brochure or is not listed at the specificity or severity 
that has been observed. 
• Expected: An adverse event that is listed in the Investigator’s 
brochure at the specificity and severity that has been observed. 
• Not Applicable: Any adverse event that is unrelated to the study 
drug. 
 
Adverse events that are mentioned in the Investigator’s brochure as 
occurring with a class of drugs or as anticipated from the pharmacological 
properties of the drug, but are not specifically mentioned as occurring with 
the particular drug under investigation are to be considered unexpected. 
The investigator should initially classify the expectedness of an adverse 
event, but the final classification is subject to the Medical Monitor’s 
determination. 
 
9.2 Serious Adverse Events 
An adverse event is considered serious if, in the view of either the investigator or 
sponsor, it results in any of the following outcomes: 
 
• Death; 
• A life-threatening adverse event; 
Note: An adverse event is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an adverse event that, had it 
occurred in a more severe form, might have caused death. 
 
• Inpatient hospitalization or prolongation of existing hospitalization; 


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Note: The term “inpatient hospitalization” refers to any inpatient admission 
(even if less than 24 hours). For chronic or long-term inpatients, inpatient 
admission includes transfer within the hospital to an acute/intensive care 
inpatient unit. Inpatient hospitalization does not include: emergency room 
visits; outpatient/same-day/ambulatory procedures; observation/short stay 
units; rehabilitation facilities; hospice facilities; nursing homes; or clinical 
research/phase 1 units. 
 
Note: The term “prolongation of existing hospitalization” refers to any 
extension of an inpatient hospitalization beyond the stay anticipated or 
required for the reason for the initial admission as determined by the 
investigator or treating physician. 
 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
 
Note: A serious adverse event specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic 
nerve). 
 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, are not life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
 
9.3 Procedures for Reporting Adverse Events 
All adverse events and their outcomes must be reported to Ora, the study sponsor, and 
the IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities and recorded on the appropriate eCRF. 
 
9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All adverse events that are ‘suspected’ and ‘unexpected’ are to be reported 
to Ora, the study sponsor and the IRB/IEC as required by the IRB/IEC, 
federal, state, or local regulations and governing health authorities. 
 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all serious adverse events, regardless of 
relationship to the study drug, must be reported to the medical monitor 
within 24 hours of becoming aware of the event. All information relevant 
to the serious adverse event must be recorded on the appropriate case 
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information requested by Ora and/or the sponsor in addition to that 
information reported on the case report form. All subjects experiencing a 
serious adverse event must be followed up and the outcome reported. 
 
In the event of a serious adverse event, the investigator must notify Ora 
and the sponsor within 24 hours; obtain and maintain in his/her files all 
pertinent medical records, information, and medical judgments from 
colleagues who assisted in the treatment and follow-up of the subject; 
provide Ora and the study sponsor with a complete case history, which 
includes a statement as to whether the event was or was not suspected to 
be related to the use of the study drug; Site should inform the IRB of the 
adverse event according to the IRB guidelines for reporting serious 
adverse events. 
 
The Investigator will follow unresolved AEs to resolution until the subject 
is lost to follow-up or until the AE is otherwise classified. Resolution 
means the subject has returned to baseline state of health or the 
Investigator does not expect any further improvement or worsening of the 
AE (ongoing and stable). If the subject is lost to follow-up, the 
Investigator should make 3 reasonable attempts to contact the subject via 
telephone, and then a letter via certified mail. 
 
Contact information for reporting Serious Adverse Events: 
 
Name: 
Title: 
Company: 
Office Telephone: 
 
Project Manager, Dry Eye 
Ora, Inc. 
978-685-8900 x 9568 
Alternative Telephone: 
978-482-6817 
Office Facsimile: 
Name: 
Title: 
Office Telephone: 
Mobile Phone: 
Office Facsimile: 
978-689-0020 
 
Medical Monitor 
617-573-5575 
401-935-9662 
617-573- 4324 
 
9.4 Procedures for Unmasking of Study Drug 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment arm has been assigned to a 
subject. When possible (i.e., in non-emergency situations), Ora and/or the study 


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sponsor should be notified before unmasking study drug. Subjects will also be 
unmasked for treatment-related SAEs or pregnancies in a similar manner. 
The Investigator should complete the appropriate forms (per the Safety Plan) and, when 
possible, discuss with Ora, the Medical Monitor, and TopiVert Pharma, Ltd whether 
unmasking is required. The Investigator can unmask study drug assigned to a subject 
using the black blinding laminate label that was placed in the Source Document from 
the subject’s study drug kit by removing the protective plastic over it and then 
scratching it off. Documentation must be completed by the unmasking Investigator and 
filed in the subject’s study file. The subject’s study file must include documentation for 
the unmasking reason and date along with the signature and name of the person who 
unmasked the subject. A copy of the appropriate forms must be provided to Ora for the 
Trial Master File. Unmasked subjects will be discontinued from the study. 
9.5 Type and Duration of the Follow-up of Subjects after Adverse 
Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the Investigator does not expect any further 
improvement or worsening of the AE. If the subject is lost to follow-up, the 
Investigator should make reasonable attempts to contact the subject via telephone, 
post, or certified mail. All follow-up will be documented in the subject’s source 
document. Non-serious AEs identified on the last scheduled contact must be recorded 
on the AE eCRF with the status noted. 
If the Investigator becomes aware of any new information regarding an existing SAE 
(i.e., resolution, change in condition, or new treatment), a new SAE/Unanticipated 
Report Form must be completed and faxed to Ora within 24 hours of the site’s 
awareness of the new information. The original SAE form is not to be altered. The 
report should describe whether the event has resolved or continues and how the event 
was treated. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
The following analysis populations will be considered: 
•
Modified Intent-to-Treat Population – The modified intent-to-treat (mITT)
population includes all randomized subjects with one post baseline efficacy
assessment. Efficacy analysis will be performed on the mITT population.
Subjects in the mITT population will be analyzed as randomized.


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•
Per Protocol Population – The per protocol (PP) population includes subjects
in the mITT population who do not have significant protocol deviations and
who complete the study. Protocol deviations will be assessed prior to database
lock and unmasking. Subjects in the PP population will be analyzed as treated.
•
Safety Population – The safety population includes all subjects who have
received at least one dose of the investigational product. Subjects in the Safety
population will be analyzed as treated.
Summaries of the comfort data from the Comfort Assessment portion of the study 
will be performed on the safety population from that Assessment. The statistical 
analysis of safety data will be performed for the safety population, separately for the 
Comfort Assessment and the Safety and Efficacy Assessment of the study. The 
analysis of baseline and all efficacy data in the Safety and Efficacy Assessment of the 
study will be performed for the mITT population. 
The efficacy analyses may also 
be performed on the PP population as sensitivity analyses. 
10.2 
Statistical Hypotheses 
Although the primary objectives of the study are to evaluate safety and tolerability, 
exploratory hypothesis testing will be performed for efficacy endpoints. For each 
efficacy endpoint and time point, the statistical hypotheses are as follows: 
H0: There is no difference between the TOP1630 Ophthalmic Solution treatment 
group and placebo for the respective endpoint. 
H1: There is a difference between the TOP1630 Ophthalmic Solution treatment group 
and placebo for the respective endpoint. A difference in favor of TOP1630 
Ophthalmic Solutions will be considered a success for that endpoint. 
10.3 
Sample Size 
The study is not powered to show statistical differences for any of the efficacy 
endpoints. The sample size was determined based on prior clinical trial experience in 
subjects with dry eye syndrome and is deemed to be robust sufficient to evaluate the 
safety and tolerability of TOP1630 Ophthalmic Solution in this population and to 
gather efficacy data that will aid in powering future clinical trials. 
With a sample size of 60 subjects in the Safety and Efficacy Assessment, the study 
will have 79% probability of detecting AEs occurring at a rate of 5% or more in either 
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10.4.3 Missing Data 
The efficacy analyses will be performed using observed data. 
In 
addition, for key endpoints of corneal staining and ocular discomfort, 
missing data will be imputed using the following methods: 
 
• Using the last observation carried forward (LOCF) imputation 
method for missing values 
• Using multiple imputation methods to account for missing data 
10.4.4 Multiplicity Consideration 
There will be no adjustments for multiple endpoints or multiple treatment 
comparisons for this early phase, exploratory study. 
 
10.4.5 Safety Variables 
Adverse events will be coded using the MedDRA dictionary. 
 
Frequencies and percentages of subjects with treatment-emergent adverse 
events (TEAEs), serious TEAEs, and TEAEs causing premature 
discontinuation will be provided by treatment group. An AE is treatment 
emergent if it occurs or worsens after the first dose of study treatment. 
Furthermore, frequencies will be given of subjects with TEAEs by system 
organ class and preferred term; by system organ class, preferred term and 
maximal severity; by system organ class and preferred term for treatment- 
related AEs; by system organ class, preferred term for SAEs; and by 
system organ class, preferred term, and time of onset. Separate summaries 
will be provided for ocular specific and all AEs (including systemic). 
 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, 
corneal sensitivity, undilated fundoscopy, intraocular pressure (non- 
contact), and vital signs will be summarized by treatment group, visit, and 
time point (where relevant) using descriptive statistics. Changes or shifts 
from baseline will also be summarized where appropriate. For assessments 
performed by eye, study eye and fellow eye will be summarized 
separately. In addition, shifts from baseline to worst on-treatment value for 
ocular safety assessments will be summarized. 
 
10.4.6 Tolerability Analyses 
Drop Comfort Assessment results, completed by the subject, and 
physician assessment results will be summarized descriptively using 
counts and percentages with each response. In addition, scores will be 
summarized continuously using number of subjects (n), mean, median, 
standard deviation, minimum and maximum. Tolerability endpoints will 
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Assessment separately, as well as combining the like treatment arms from 
both study Assessments. 
 
10.4.7 Exploratory Efficacy Analyses 
The continuous and ordinal secondary efficacy variables collected at each 
visit will be summarized descriptively (n, mean, standard deviation, 
median, minimum and maximum), and analyzed with two-sample t-tests 
comparing the active treatment groups to placebo. All visit-based data will 
be analyzed at each visit as well as change from baseline. A Wilcoxon 
rank sum test and an ANCOVA model adjusting for baseline will also be 
assessed where appropriate. Corneal fluorescein staining by region and 
total (Ora and NEI scales), lissamine green staining by region, tear film 
break-up time, conjunctival redness, unanesthetized Schirmer’s test, ocular 
symptoms (Ora Calibra® scales and VAS), OSDI©, ocular discomfort and 
changes from baseline in these measures will be analyzed by visit and time 
point, where applicable (i.e., pre- and post-CAE®), using two-sample t- 
tests and Wilcoxon rank sum tests. Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values. For the 
measures of symptoms during CAE®, the ANCOVA models will also 
include the pre-CAE® measure as a covariate. Drop comfort will be 
summarized descriptively. Symptoms recorded on the daily diary will be 
analyzed using repeated measure ANCOVA models, where baseline 
scores are calculated as the average scores in the run-in period and post- 
baseline scores are calculated as weekly morning, afternoon, evening, and 
daily averages. 
 
A full statistical analysis plan (SAP) will be finalized before database lock 
and unmasking. 
 
10.4.8 Interim Analyses 
No interim analyses are planned; however, assessments from the Comfort 
Assessment will be analyzed in a blinded manner to ensure study stopping 
criteria have not been met and to confirm the dose for the 4 week Safety 
and Efficacy Assessment. If study stopping criteria have been met, 
unblinding may be needed to fully assess the data prior to dose selection. 
 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, Good Clinical Practices 
(GCPs), including the International Conference on Harmonization (ICH) Guidelines, and 
in general, consistent with the Declaration of Helsinki. In addition, all applicable local, 


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state, and federal requirements relevant to the use of study drugs in the countries involved 
will be adhered to. 
 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific 
procedures are initiated. Signed and dated written informed consent must 
be obtained from each subject and/or from the subject’s parent or legal 
guardian prior to enrollment into the study. If the subject is under the legal 
age of consent, the consent form must be signed by a legal guardian or as 
required by state and/or local laws and regulations. 
 
All informed consent/assent forms must be approved for use by the 
sponsor and receive approval/favorable opinion from an IRB/IEC prior to 
their use. If the consent form requires revision (e.g., due to a protocol 
amendment or significant new safety information), it is the investigator’s 
responsibility to ensure that the amended informed consent is reviewed 
and approved by Ora prior to submission to the governing IRB/IEC and 
that it is read, signed and dated by all subjects subsequently enrolled in the 
study as well as those currently enrolled in the study. 
 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with Institutional Review 
Board regulations (U.S. 21 CFR Part 56.103). The investigator must 
obtain appropriate IRB approval before initiating the study and re- 
approval at least annually. 
 
Only an IRB/ERC approved version of the informed consent form will be 
used. 
 
11.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 
11.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions 
as to ensure that the confidentiality of the data in accordance with local, state, and 
federal laws and regulations. 
 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the 
IRB/IEC approving this study, the FDA, the DHHS, other domestic government 
agencies, and other foreign regulatory agencies will be granted direct access to the 


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study subject’s original medical and study records for verification of the data and/or 
clinical trial procedures. Access to this information will be permitted to the 
aforementioned individuals to the extent permitted by law. 
 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but 
the subject’s identity will not be disclosed in these documents. 
 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic 
charts, the investigator’s study subject files, as well as the results of diagnostic tests 
such as X-rays, laboratory tests, and EKGs. The investigator’s copy of the Case 
Report Forms serves as the investigator’s record of a subject’s study-related data. 
 
11.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of 
the distribution and use of all study drug and copies of case report forms 
should be maintained on file for at least two years after the last approval of 
a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or until at least 
two years have elapsed since the formal discontinuation of clinical 
development of the study drug. These documents will be retained for a 
longer period if required by the applicable regulatory requirements or by 
an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer 
need to be retained. 
 
If the responsible investigator retires, relocates, or for other reasons 
withdraws from the responsibility of keeping study records, custody must 
be transferred to a person who will accept the responsibility. The sponsor 
must be notified in writing of the name and address of the new custodian. 
 
11.5 Labeling, Packaging, Storage, Accountability, and Return or 
Disposal of Study Drug 
11.5.1 Labeling/Packaging 
Investigational drug will be packaged and labeled into clinical kits. 
 
For the Comfort Assessment, subjects will receive one Subject Comfort 
Kit containing all of the drug needed for dosing. Within the kit will be 3 
bottles labeled “Visit 1a”, one bottle labeled “Visit 3a”, and 3 bottles 
labeled “Visit 5a”. In addition, there will be a Take-Home kit which will 
contain 15 bottles, enough for 4 days of dosing plus 3 reserve bottles. 


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For the Safety and Efficacy Assessment, 24 bottles will be packaged in 
one week clinical kits. One bottle contains enough supply for one dose. 
The extra bottles in the kit will not be used and will be returned to the 
clinical site at the next visit. Subjects will receive 2 kits at each visit 2b 
and 3b. 
 
Further information on the labeling and packaging of study drug can be 
found in the study Dispensation and Collection Plan. 
 
11.5.2 Storage of Study Drug 
The study drugs must be stored in a secure area accessible only to the 
investigator and his/her designee(s). Study drug(s) must be refrigerated (2- 
8°C, Do Not Freeze), protected from light, and secured at the 
investigational site in a locked refrigerator/room. 
 
11.5.3 Accountability of Study Drug 
The study drugs are to only be prescribed by the principal investigator or 
his/her named sub investigator(s), and is to only be used in accordance 
with this protocol. The study drugs must only be distributed to subjects 
properly qualified under this protocol to receive study drug. 
The 
investigator must keep an accurate accounting of the study drugs by 
maintaining a detailed inventory. This includes the amount of study drugs 
received by the site, amount dispensed to subjects, amount returned to the 
site by the subjects, and the amount returned to the Sponsor upon the 
completion of the study. 
 
11.5.4 Return or Disposal of Study Drug 
All study drugs will be returned to the sponsor or their designee for 
destruction. 
 
11.6 Recording of Data on Source Documents and Electronic Case 
Reports Forms (eCRFs) 
All subject data will be captured in the subject source documents which will be 
transcribed in the eCRFs. The investigator is responsible for ensuring that study data 
is completely and accurately recorded on each subject’s eCRF, source documents, 
and all study-related materials. All study data should also be attributable, legible, 
contemporaneous, and original. Recorded datum should only be corrected in a 
manner that does not obliterate, destroy, or render illegible the previous entry (e.g., by 
drawing a single line through the incorrect entry and writing the revision next to the 
corrected data). An individual who has corrected a data entry should make clear who 
made the correction and when, by adding to the correction his/her initials as well as 
the date of the correction. 


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Data entry of all enrolled and randomized subjects will use software that conforms to 
21 CFR Part 11 requirements, and will be performed only by staff who have been 
trained on the system and have access to the system. Data will not be entered for 
screen failure subjects. An audit trail will be maintained within the electronic system 
to capture all changes made within the eCRF database. After the end of the study and 
database lock, compact discs (CDs) containing copies of all applicable subjects’ 
eCRFs will be provided to each Investigator Site to be maintained on file by the 
Investigator. 
 
11.7 Handling of Biological Specimens 
Impression cytology samples will be collected from the worst eye at Visits 2b and 4b. 
Samples will be stored at the site and then submitted to the sponsor upon request for 
processing, storage and analysis. Details of sample collection, handling, storage, and 
shipping procedures are found in a study procedure manual. 
 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. 
The study sponsor and Ora will have the final decision regarding the manuscript and 
publication. 


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12 REFERENCES 
1. 
Panel. AAoOCED. Preferred Practice Pattern (R) Guidelines. Dry Eye 
Syndrome2013. 
2. 
The epidemiology of dry eye disease: report of the Epidemiology Subcommittee 
of the International Dry Eye WorkShop (2007). The ocular surface 2007;5:93-107. 
3. 
The definition and classification of dry eye disease: report of the Definition and 
Classification Subcommittee of the International Dry Eye WorkShop (2007). The ocular 
surface 2007;5:75-92. 
4. 
Mah F, Milner M, Yiu S, Donnenfeld E, Conway TM, Hollander DA. PERSIST: 
Physician's Evaluation of Restasis((R)) Satisfaction in Second Trial of topical 
cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review. Clinical 
ophthalmology 2012;6:1971-6. 
5. 
Tauber J, Karpecki P, Latkany R, et al. Lifitegrast Ophthalmic Solution 5.0% 
versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III 
OPUS-2 Study. Ophthalmology 2015;122:2423-31. 






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Fluorescein Staining-Ora 
Calibra® and NEI Scale 
X 
X 
X 
X 
X 
X 
X 
X 
Lissamine Green Staining- 
Ora Calibra® and NEI Scale 
X 
X 
X 
X 
X 
X 
X 
X 
Corneal Sensitivity 
(Cochet-Bonnet) 
X 
X 
OPI 2.0 
X 
X 
Unanesthetized Schirmer’s 
Test 
X 
X 
X 
X 
CAE® Exposure 
X 
X 
X 
X 
CAE® Discomfort – Ora 
Calibra® Ocular 
Discomfort Scale 
X 
X 
X 
X 
Intraocular pressure (non- 
contact) 
X 
X 
Undilated Fundus Exam 
X 
X 
Run-in Placebo & Diary 
Dispensation 
X 
Randomization 
X 
Subject self-instillation of 
study drug 
X 
X 
Ora Calibra® Drop Comfort 
Assessment 
X 
X 
Study Drug Dispensation 
X 
X 
Diary Dispensation 
X 
X 
X 
Exit Subject from Study 
X 
1For females of childbearing potential. 


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Appendix 2: Examination Procedures, Tests, Equipment, and 
Techniques 
The following examination procedures, tests, equipment and techniques are listed in this 
Appendix: 
Visual Acuity Procedures.................................................................................................. 60 
Collection of Vital Signs ................................................................................................... 62 
Slit-lamp Biomicroscopy .................................................................................................. 63 
Ora Calibra® Ocular Discomfort Scale ............................................................................. 64 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire ....................................... 65 
Ocular Surface and Disease Index (OSDI) © ..................................................................... 66 
Ora Calibra® Conjunctival Redness Scale ........................................................................ 68 
Ora Calibra® Lid Margin Redness .................................................................................... 69 
Ora Calibra® Posterior Lid Edge Evaluation: ................................................................... 70 
Tear Film Break-Up Time (TFBUT) ................................................................................ 71 
Fluorescein Staining .......................................................................................................... 72 
Ora Calibra® Corneal and Conjunctival Staining Scale .................................................... 73 
Fluorescein Staining – NEI/Industry Workshop Scale ..................................................... 74 
Lissamine Green Staining ................................................................................................. 75 
Lissamine Green Staining – NEI/Industry Workshop Scale ............................................. 76 
Ora Calibra® Corneal and Conjunctival Staining Scale .................................................... 77 
Ora Calibra® Ocular Protection Index (OPI) 2.0 System .................................................. 78 
Visual Analogue Scale ...................................................................................................... 79 
Unanesthetized Schirmer’s Test........................................................................................ 80 
Procedure for Evaluating Intraocular Pressure ................................................................. 81 
Investigator’s standard technique will be used throughout the study Procedure for 
Evaluating Corneal Sensitivity ......................................................................................... 82 
Impression Cytology Sampling (OPIA Eyeprim™ Device) ............................................. 83 
Procedure for Conducting Undilated Fundoscopy ............................................................ 84 
Drop Comfort Assessments .............................................................................................. 85 
At Home Ora Calibra® Drop Comfort Assessment........................................................... 86 
Subject Diary .................................................................................................................... 87 


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Visual Acuity Procedures 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
LogMAR Visual Acuity (VA) must be assessed using an ETDRS chart. The procedure 
used will be consistent with the recommendations provided for using the ETDRS eye 
chart. Visual Acuity should be evaluated at the beginning of each visit in the study (i.e., 
prior to slit-lamp examination). Subjects should use most recent correction to attain their 
best- corrected visual acuity (BCVA). 
 
Equipment 
The visual acuity chart to be used is the ETDRS chart. If smaller reproduction (18" by 
18", e.g., from Prevent Blindness) wall charts are used, the subject viewing distance 
should be exactly 10 feet (or as specified by the manufacturer). In ALL cases, for 
purposes of standardizing the testing conditions during the study, all sites must use only 
ETDRS Series 2000 Chart 1 & 2, and the right eye (OD) should be tested first. For 
reflectance (wall) charts, the chart should be placed frontally and well illuminated. 
 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. 
The subject should attempt to read each letter, line-by-line, left to right, beginning with 
line 1 at the top of the chart. The subject should be told that the chart has letters only, no 
numbers. If the subject reads a number, he/she should be reminded that the chart contains 
no numbers, and the examiner should then request a letter in lieu of the number. The 
subject should be asked to read slowly, so as to achieve the best identification of each 
letter. He/she is not to proceed to the next letter until he/she has given a definite response. 
 
If the subject changes a response (e.g., 'that was a "C" not an "O"') before he/she has read 
aloud the next letter, then the change must be accepted. If the subject changes a response 
having read the next letter, then the change is not accepted. The examiner should never 
point to the chart or to specific letters on the chart during the test. 
 
A maximum effort should be made to identify each letter on the chart. When the subject 
says he/she cannot read a letter, he/she should be encouraged to guess. If the subject 
identifies a letter as one of two letters, he/she should be asked to choose one letter and, if 
necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that 
eye. However, all letters on the last line should be attempted as letter difficulties vary and 
the last may be the only one read correctly. The number of letters missed or read 
incorrectly should be noted. 
 
LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
To this value will be added the number "N x 0.02" where 'N' represents the total number 


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of letters missed up to and including in the last line read. This total sum represents the 
logMAR visual acuity for that eye. 
 
For Example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on 
the 0.1 line. 
 
Base logMAR 
= 0.1 
N (total number of letters incorrect on 
line 0.2 as well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
 
Repeat the procedure for the left eye (OS). 
 
In order to provide standardized and well-controlled assessments of visual acuity during 
the study, all visual acuity assessments at a single site must be consistently done using the 
same lighting conditions and same correction if possible during the entire study. If the 
same correction cannot be used (i.e., a subject forgets his/her glasses), the reason for the 
change in correction should be documented. 
 
Note: A clinically significant visual acuity decrease (defined as an increase of 0.22 or 
greater in logMAR score) from baseline will be considered an Adverse Event. 


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Collection of Vital Signs 
 
 
Each subject will have vital signs assessments (resting blood pressure, pulse and 
Oxygen saturation (SpO2)) conducted at each study visit for both the Comfort and 
Safety and Efficacy Assessment. Vital signs are to be conducted by qualified site staff 
member delegated by the Principal Investigator. 
 
Systolic/ Diastolic Blood Pressure (mmHg) 
 
Systolic and diastolic blood pressure should be measured in the same arm, when 
possible, each time using a sphygmomanometer for subjects who have been in a 
resting state (seated upright) at least 5 minutes. Blood pressure will be recorded in 
mm Hg. 
 
Pulse (bpm) 
 
Pulse will be measured for subjects who have been in a resting state (seated) for at 
least 5 minutes. Pulse will be measured using the Pulse Oximeter, and recorded in 
beats per minute. 
 
Oxygen Saturation (Sp O2 %) 
SpO2 will be measured for subjects who have been in a resting state (seated) for at 
least 5 minutes using the Pulse Oximeter and recorded as a percentage. 


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Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be performed during the study. Observations will be graded 
as Normal or Abnormal. Abnormal findings, which are clinically significant, will be 
described. The following will be examined at each visit: 
 
• Cornea 
• Conjunctiva 
• Anterior Chamber 
• Iris 
• Lens 
• Lid 
External magnification and biomicroscopy will be performed using a slit-lamp. 
Magnification will be consistent with standard clinical practice. The subject will be 
seated. 


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Ora Calibra® Ocular Discomfort Scale 
 
 
 
 
 
 
 


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Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Ocular Surface and Disease Index (OSDI) © 


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Ora Calibra® Conjunctival Redness Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Ora Calibra® Lid Margin Redness 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance documents. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Ora Calibra® Posterior Lid Edge Evaluation: 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
 
 
 


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Tear Film Break-Up Time (TFBUT) 
The examiner will instill 5 L of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye. To thoroughly mix the fluorescein with 
the tear film, the subject will be instructed to blink several times. In order to achieve 
maximum fluorescence, the examiner should wait approximately 30 seconds after 
instillation before evaluating TFBUT. 
 
With the aid of a slit-lamp, the examiner will monitor the integrity of the tear film, noting 
the time it takes to form micelles from the time that the eye is opened. TFBUT will be 
measured in seconds using a stopwatch and a digital image recording system for the right 
eye followed by the left eye. A Wratten #12 yellow filter will be used to enhance the 
ability to grade TFBUT. 
 
 
 
 


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Fluorescein Staining 
The examiner will instill 5 L of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye. In order to achieve maximum 
fluorescence, the examiner should wait approximately 3-5 minutes after instillation 
before evaluating fluorescein staining. A Wratten #12 yellow filter will be used to 
enhance the ability to grade fluorescein staining. The staining will be graded with the Ora 
Calibra® Corneal and Conjunctival Staining Scale. Digital images of fluorescein staining 
may be taken for digital analysis. 




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Fluorescein Staining – NEI/Industry Workshop Scale 
Diagram of the division of the corneal surface for measuring fluorescein uptake. A 
standardized grading system of 0-3 is used for each of the five areas on each cornea. 
Grade 0 will be specified when no staining is present. The maximum score is 15. 
Score each of 5 areas on the cornea of each eye. 


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Lissamine Green Staining 
The Investigator will instill 10 L of lissamine green solution into the inferior 
conjunctival cul-de-sac and wait approximately 30 seconds before evaluating staining. 
Lissamine may also be applied using lissamine strips. The subject will be instructed to 
blink several times to distribute the lissamine green. The staining will be graded with the 
Ora Calibra® Corneal and Conjunctival Staining Scale. Digital images of lissamine green 
staining may be taken for digital analysis. 


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Lissamine Green Staining – NEI/Industry Workshop Scale 
The nasal and temporal conjunctivae are divided into three segments as diagrammed. 
Score each of the six areas of the conjunctiva of each eye. 
1 – Temporal 
2 – Superior Temporal 
3 – Inferior Temporal 
4 – Superior Nasal 
5 – Inferior Nasal 
6 – Nasal 
Right Eye 
Left 
Eye 
A standardized grading system of 0 - 3 is used for each of the six areas on each 
conjunctiva. Grade 0 will be specified when no staining is present. The maximum score is 
18.




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Ora Calibra® Ocular Protection Index (OPI) 2.0 System 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Visual Analogue Scale 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to 
study drug instillation) at all visits. The assessment period will include the previous week 
as well. 
 
The subject will be asked to rate each ocular symptom due to ocular dryness by placing a 
vertical mark on the horizontal line to indicate the level of discomfort. 0% corresponds to 
“no discomfort” and 100% corresponds to “maximal discomfort.” 
 
Burning/Stinging 
0% 
50% 
100% 
|  
| 
Itching 
0% 
50% 
100% 
|  
| 
Foreign body 
sensation 
0% 
50% 
100% 
|  
| 
Blurred Vision 
0% 
50% 
100% 
|  
| 
Eye Dryness 
0% 
50% 
100% 
|  
| 
Photophobia 
0% 
50% 
100% 
|  
| 
Pain 
0% 
50% 
100% 
|  
| 


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Unanesthetized Schirmer’s Test 
Schirmer Tear Test will be performed according to the following procedure: 
 
• Using a sterile Tear Flo Schirmer test strip (Rose Enterprises), a bend in the strip 
will be made in line with the notch in the strip 
• The subject will be instructed to gaze up and in 
• The Schirmer test strip will be placed in the lower temporal lid margin of each 
eye such that the strip fits tightly. Subjects will be instructed to close their eyes 
• After 5 minutes have elapsed, the Schirmer strip will be removed. The length of 
the moistened area will be recorded (mm) for each eye 


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Procedure for Evaluating Intraocular Pressure 
IOP will be measured in each eye by non-contact tonometry by the investigator or 
qualified technician and the results will be recorded in mmHg. 


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Investigator’s standard technique will be used throughout the study Procedure for 
Evaluating Corneal Sensitivity 
The aesthesiometer (Cochet–Bonnet) is a nylon thread contained in a pen–like case that 
can be extended specific distances from the tip of the case. The following steps will be 
followed by the examiner for evaluating corneal sensitivity: 
 
1. Remove Cochet–Bonnet from box 
2. Extend the filament to 60 mm (the filament should not have bends in it – if it does, 
the readings will be incorrect and the filament should not be used) 
3. The examiner will inform the subject that a thin delicate plastic filament will be used 
to test their corneal sensitivity and that they will feel the sensation similar to a strand 
of hair on their eye. (If the subject is hesitant, a spot on the subject’s hand will be 
cleaned with an alcohol pad and the filament touched to the hand to demonstrate the 
painless contact) 
4. The examiner will instruct the subject to say “Yes” when they feel sensation on their 
eyeball 
5. The examiner will place their free hand on the cheek below the eye being measured to 
stabilize subject’s head position 
6. The examiner will position their hand with the device such that the filament is normal 
(90 degree angle with corneal surface). The device should be between the examiner’s 
index, middle finger, and thumb. 
7. The examiner will extend fingers such that the filament applies gentle pressure on the 
central corneal surface. The examiner will then ask subject if they can perceive the 
filament touching the central corneal surface. 
a. If the subject responds “Yes”, the examiner will ensure the response is valid by 
performing a sham (not touching the cornea) application and also confirm that 
response was not due to eyelids touching the filament. 
b. If the subject responds “No”, then the filament is shortened the length by 5mm 
and reapplied to the cornea 
c. If the subject responds “Yes”, record length; if the subject responds “No”, go to 
step b. 
8. Step 7 is repeated three times. 
9. The filament is retracted such that only 10 mm are exposed 
10. The tip is wiped with an alcohol pad gently ENSURING that it does NOT bend the 
filament 
11. The alcohol is allowed to dry before reusing device (alcohol can cause corneal 
abrasions) 


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Impression Cytology Sampling (OPIA Eyeprim™ Device) 


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Procedure for Conducting Undilated Fundoscopy 
A non-contact undilated fundoscopy exam will be performed. Observations will be 
graded as Normal or Abnormal. Abnormal findings will be described. The following will 
be examined: 
 
• Vitreous 
• Retina 
• Macula 
• Choroid 
• Optic Nerve 




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At Home Ora Calibra® Drop Comfort Assessment 
Subjects will be instructed to dose with study drug TID at home between Visits 7a – 
8a and complete the drop comfort assessment for each eye after each dose 


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Subject Diary 
Subjects will be instructed to complete diary TID prior to each dose. Subjects will also 
indicate if their dose was taken. 


TOP1630 Ophthalmic Solution 
Clinical Trial Protocol # TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Confidential 
Page 88 of 99 
 
 
Appendix 3: Amendment Summary of Changes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






TOP1630 Ophthalmic Solution 
Clinical Trial Protocol # TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Confidential 
Page 91 of 99 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




TOP1630 Ophthalmic Solution 
Clinical Trial Protocol # TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Confidential 
Page 93 of 99 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


TOP1630 Ophthalmic Solution 
Clinical Trial Protocol # TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Confidential 
Page 94 of 99 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


TOP1630 Ophthalmic Solution 
Clinical Trial Protocol # TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Confidential 
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TOP1630 Ophthalmic Solution 
Clinical Trial Protocol # TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Confidential 
Page 97 of 99 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 98 of 99 
Confidential 
TOP1630 Ophthalmic Solution 
Clinical Trial Protocol I/. TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment I - Version 2.0 Final 20Jan20l 7 
Appendix 4: 
Sponsor and Ora Approvals 
Protocol Title: 
 A Single-Center, Randomized, Double Masked, Placebo Controlled 
Clinical Study to Assess the Safety and Efficacy ofTOP1630 
Ophthalmic Solution Compared to Placebo in Subjects with Dry Eye 
Syndrome 
Protocol Number: 
TOP1630-TV-04 
Amendment 1 Date: 
20 JAN 2017 
This clinical study protocol was subject to critical review and has been approved by the sponsor. 
The following personnel contributed to writing and/or approving this protocol. 


Page 98 of 99 
Confidential 
 
 


Page 98 of99 
Confidential 
TOPl630 Ophthalmic Solution 
Clinical Trial Protocol# TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Appendix 4: Sponsor and Ora Approvals 
Protocol Title: 
 A Single -C enter, Randomized , Double Masked, Placebo Controlled 
Clinical Study to Assess the Safety and Efficacy ofTOP1630 
Ophthalmic Solution Compared to Placebo in Subjects with Dry Eye 
Syndrome 
Protocol Number: 
TOP1630-TV-04 
Amendment 1 Date: 
20 JAN 2017 
This clinical study protocol was subject to critical review and has been approved by the sponsor. 
The following personnel contributed to writing and/or approving this protocol. 


TOPl630 Ophthalmic Solution 
Clinical Trial Protocol# TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
Page 98 of99 
Confidential 
Appendix 4: Sponsor and Ora Approvals 
Protocol Title: 
 A Single-Center, Randomized, Double Masked, Placebo Controlled 
Clinical Study to Assess the Safety and Efficacy ofTOP1630 
Ophthalmic Solution Compared to Placebo in Subjects with Dry Eye 
Syndrome 
Protocol Number: 
TOP1630-TV-04 
Amendment 1 Date: 
20 JAN 2017 
This clinical study protocol was subject to critical review and has been approved by the sponsor. 
The following personnel contributed to writing and/or approving this protocol. 


Page 99 of99 
Confidential 
TOP1630 Ophthalmic Solution 
Clinical Trial Protocol # TOP1630-TV-04 
Sponsor: TopiVert Pharma Ltd. 
Amendment 1 - Version 2.0 Final 20Jan2017 
 
 
 
 
Appendix 5: Investigator’s Signature 
 
Protocol Title: 
A Single-Center, Randomized, Double Masked, Placebo Controlled 
Clinical Study to Assess the Safety and Efficacy of TOP1630 
Ophthalmic Solution Compared to Placebo in Subjects with Dry Eye 
Syndrome 
Protocol Number: 
TOP1630-TV-04 
Amendment 1 Date: 
20 JAN 2017 
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. 
I agree to 
maintain all information supplied by Ora and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
 
FORM.152.03 Updated 30-Aug-2016 
STATISTICAL ANALYSIS PLAN 
A Single-Center, Randomized, Double Masked, Placebo Controlled Clinical 
Study to Assess the Safety and Efficacy of TOP1630 Ophthalmic Solution 
Compared to Placebo in Subjects with Dry Eye Syndrome 
 
 
 
Sponsor:   
 
TopiVert Pharma Ltd 
 
 
 
 
 
 
 
Protocol Number: 
TOP1630-TV-04 
 
 
Author:   
 
Amy Huang, PhD 
 
 
 
Sr. Biostatistician 
Statistics & Data Corporation 
 
Date:    
 
15 May 2017 
Version:  
 
Final 1.0 
 
 
 
 
 
 


 
 
 
Page 2 of 34 
Protocol Title 
A Single-Center, Randomized, Double Masked, Placebo Controlled Clinical Study to Assess the 
Safety and Efficacy of TOP1630 Ophthalmic Solution Compared to Placebo in Subjects with Dry 
Eye Syndrome 
 
Protocol Number: 
TOP1630-TV-04 
Version:  
 
Final 1.0  
Date:    
 
15 May 2017 
 
Statistical Analysis Plan Approval 
 
Prepared by: 
 
 
 
 
 
 
 
 
 
 
 
Amy Huang, PhD 
 
 
 
 
Date 
 
 
Sr. Biostatistician 
 
 
Statistics & Data Corporation 
 
Reviewed by:  
 
 
 
 
          
___________ 
 
 
Susan L. Potts, MS 
 
 
 
 
Date 
 
 
Sr. Principal Biostatistician 
 
 
Statistics & Data Corporation 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
George Ousler  
 
 
  
 
Date 
Vice President, Dry Eye 
 
 
Ora, Inc. 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
Ajay Duggal, MB ChB MRCP Dip Pharm Med          Date 
                          Chief Medical Officer  
 
 
TopiVert 
 
Approved by:  
 
 
 
 
 
 
 
 
 
 
Mike Taylor, PhD 
 
 
 
  
Date 
                          Head of Clinical Development  
 
 
TopiVert 


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Table of Contents 
1. 
Introduction ............................................................................................................................ 7 
2. 
Study Objectives .................................................................................................................... 7 
3. 
Study Variables ...................................................................................................................... 7 
3.1 Safety Variables ..................................................................................................................... 7 
3.2 Exploratory Efficacy Variables ............................................................................................... 7 
3.3 Biomarkers ............................................................................................................................. 8 
3.4 Statistical Hypotheses ............................................................................................................ 8 
4. 
Study Design and Procedures ............................................................................................... 8 
4.1 General Study Design ............................................................................................................ 8 
4.2 Schedule of Visits and Assessments ..................................................................................... 9 
5. 
Study Treatments ................................................................................................................. 12 
5.1 Method of Assigning Subjects to Treatment Groups ............................................................ 12 
5.2 Masking and Unmasking ...................................................................................................... 12 
6. 
Sample Size and Power Considerations .............................................................................. 13 
7. 
Data Preparation .................................................................................................................. 13 
8. 
Analysis Populations ............................................................................................................ 14 
8.1 Modified Intent-to-Treat ........................................................................................................ 14 
8.2 Per Protocol ......................................................................................................................... 14 
8.3 Safety ................................................................................................................................... 14 
9. 
General Statistical Considerations ....................................................................................... 14 
9.1 Unit of Analysis .................................................................................................................... 14 
9.2 Missing or Inconclusive Data Handling ................................................................................ 14 
9.3 Definition of Baseline ........................................................................................................... 15 
9.4 Data Analysis Conventions .................................................................................................. 15 
9.5 Adjustments for Multiplicity ................................................................................................... 16 
10. 
Disposition of Subjects ......................................................................................................... 16 
11. 
Demographic and Baseline Variables .................................................................................. 16 
11.1 Demographic Variables ........................................................................................................ 16 
11.2 Baseline Variables ............................................................................................................... 17 
Baseline worst dry eye symptoms, duration of dry eye syndrome and OSDI© will be summarized and 
listed. ........................................................................................................................................... 17 
12. 
Medical History and Concomitant Medications .................................................................... 17 
12.1 Medical History .................................................................................................................... 17 
12.2 Prior and Concomitant Medications ..................................................................................... 17 


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13. 
Dosing Compliance and Treatment Exposure...................................................................... 17 
13.1 Dosing Compliance .............................................................................................................. 17 
13.2 Treatment Exposure............................................................................................................. 18 
14. 
Safety Analyses ................................................................................................................... 18 
14.1 Adverse Events .................................................................................................................... 19 
14.2 Visual Acuity (ETDRS) ......................................................................................................... 20 
14.3 Slit-Lamp Biomicroscopy Examination ................................................................................. 20 
14.4 Corneal Sensitivity (Cochet-Bonnet) .................................................................................... 20 
14.5 Undilated Fundoscopy ......................................................................................................... 20 
14.6 Intraocular Pressure (IOP) ................................................................................................... 21 
15. 
Tolerability Analyses ............................................................................................................ 21 
16. 
Exploratory Efficacy Analyses .............................................................................................. 21 
16.1 Corneal Fluorescein Staining ............................................................................................... 22 
16.2 Ocular Discomfort ................................................................................................................ 25 
16.3 Lissamine Green Staining .................................................................................................... 25 
16.4 Tear Film Break-Up Time ..................................................................................................... 26 
16.5 Conjunctival Redness .......................................................................................................... 26 
16.6 Lid Margin Redness ............................................................................................................. 27 
16.7 Posterior Lid Edge Evaluation .............................................................................................. 27 
16.8 Unanesthetized Schirmer’s Test .......................................................................................... 27 
16.9 Ocular Surface Disease Index® (OSDI®) .............................................................................. 28 
16.10 
Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire ................................. 28 
16.11 
Ocular Symptoms of Dry Eye Syndrome – Visual Analog Scale (VAS) ....................... 29 
16.12 
Ocular Discomfort Using the Ora Calibra® Scale......................................................... 29 
16.13 
Ocular Protection Index (OPI) 2.0 ................................................................................ 30 
16.14 
Daily Diary .................................................................................................................... 31 
17. 
Interim Analyses .................................................................................................................. 31 
18. 
Changes from Protocol-Stated Analyses ............................................................................. 31 
19. 
References........................................................................................................................... 31 
20. 
Revision History ................................................................................................................... 31 
21. 
Tables .................................................................................................................................. 31 
22. 
Listings ................................................................................................................................. 33 
23. 
Figures ................................................................................................................................. 34 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
AICc 
Akaike information criterion with a correction for finite sample sizes 
ANCOVA 
Analysis of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best-corrected Visual Acuity 
CAE® 
Controlled Adverse Environment 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Compound Symmetry 
CSR 
Clinical Study Report 
DDE 
Drug Dictionary Enhanced 
DES 
Dry Eye Syndrome 
DHHS 
Department of Health and Human Services 
DVM 
Data Validation Manual 
eCRF 
Electronic Case Report Form 
EKG 
Electrocardiograph 
ERC 
Ethical Review Committee 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Information Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional/independent Review Board 
mITT 
modified intent-to-treat   
IUD 
Intra Uterine Device 
IWRS 
Interactive Web Response System 
KCS 
Keratoconjunctivitis Sicca 
Kg 
Kilogram 
LASIK 
Laser in Situ Keratomileusis 
LOCF 
Last Observation Carried Forward 
LS 
Least Squares 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MGD 
Meibomian Gland Dysfunction 
Mg 
Milligram 
mL 
Milliliter 
Mm 
Millimeter 
NEI 
National Eye Institute 
µg  
Microgram  
µL  
Microliter  
µm 
Micrometer 
mmHg 
Millimeters of Mercury 
OD 
Right Eye 
OPI 
Ocular Protection Index 
OS 
Left Eye 
OSDI© 
Ocular Surface Disease Index 
OU 
Both Eyes 
OTC 
Over-the-counter 
PMNs 
Polymorphonuclear Leucocytes 
PP 
Per Protocol 
PT 
Preferred Term 
TID 
Three Times a Day  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDC 
Statistics and Data Corporation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TFBUT/TBUT 
Tear Film Break-up Time 
TEAE 
Treatment Emergent Adverse Event 
VA 
Visual Acuity 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
 
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol TOP1630-TV-04, version 2.0 dated 20Jan2017. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports (CSR). 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated.  This SAP provides details of the specific statistical methods that 
will be used.  The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol.  If additional analyses are required to supplement 
the planned analyses described in this SAP they may be completed and will be identified in the CSR. 
2. Study Objectives 
The primary objective of this study is to compare the safety and tolerability of TOP1630 Ophthalmic 
Solution to placebo. The secondary objectives are to compare the efficacy of TOP1630 Ophthalmic 
Solution to placebo for the treatment of the signs and symptoms of dry eye syndrome.  
3. Study Variables 
3.1 
Safety Variables 
The safety variables are the following: 
• 
Visual acuity (VA) (ETDRS)  
• 
Slit-lamp biomicroscopy  
• 
Corneal sensitivity [Pre- (Controlled Adverse Environment) CAE®] 
• 
Adverse event (AE) query  
• 
Undilated fundoscopy  
• 
Vital signs at all visits  
• 
Drop comfort assessment  
• 
Intraocular pressure (IOP) (non-contact)  
3.2 
Exploratory Efficacy Variables 
• 
Corneal fluorescein staining on the Ora Calibra® and National Eye Institute (NEI) scales 
• 
Conjunctival lissamine green staining on the Ora Calibra® and NEI scales 
• 
Visual Analogue Scale (VAS) (Pre-CAE®) 
• 
Tear film break-up time (TFBUT) 
• 
Conjunctival redness the Ora Calibra® scale  
• 
Schirmer Test at Visits 2b, 3b, and 4b  
• 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  


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• 
Ocular Surface Disease Index (OSDI©) 
• 
Ora Calibra® Lid Margin Redness 
• 
Ora Calibra® Posterior Lid Edge Evaluation 
• 
Ocular Protection Index (OPI) 2.0 
• 
Ora Calibra® Ocular Discomfort Scale 
3.3 
Biomarkers 
• 
 Impression Cytology (OPIA Eyeprim™). 
3.4 
Statistical Hypotheses 
The null and alternative hypotheses, based on the exploratory efficacy variables, are as follows: 
H0: There is no difference between the TOP1630 Ophthalmic Solution treatment group and 
placebo for the respective endpoint. 
H1: There is a difference between the TOP1630 Ophthalmic Solution treatment group and 
placebo for the respective endpoint. A difference in favor of TOP1630 Ophthalmic 
Solutions will be considered a success for that endpoint. 
All hypothesis testing will be two-sided with a type I error rate (α) of 0.10. There will be no adjustments 
for multiple endpoints or multiple treatment comparisons for this early phase, exploratory study.  
Specifics of the statistical tests are provided in Section 14.  
4. Study Design and Procedures 
4.1 
General Study Design 
This is a Phase 2, single-center, randomized, double-masked, placebo controlled clinical study to assess 
the safety and tolerability of TOP1630 ophthalmic solution, and the efficacy of TOP1630 ophthalmic 
solution compared to placebo in subjects with dry eye syndrome. This study consists of two 
assessments, the Comfort Assessment and the Safety and Efficacy Assessment.  The goal of this SAP 
is to describe the statistical methodologies that will be applied to the Safety and Efficacy Assessment 
component of the study; therefore, the Comfort Assessment is not included. 
For the Safety and Efficacy Assessment, approximately 150 subjects will be screened to enroll 
approximately 60 randomized subjects. The Safety and Efficacy Assessment will consist of two periods: 
a 7-day run-in period, during which subjects will instill placebo Ophthalmic Solution (Vehicle) bilaterally 
TID and a 28-day treatment period, during which subjects will instill randomized study medication TID 
in both eyes. Subjects will be randomized in a 1:1 ratio (30 subjects in the TOP1630 arm and 30 in the 
placebo arm) with 4 visits over the course of approximately 5 weeks (including 1 week run-in). 


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  At Visit 1b (Day -7 ±1), Subjects will be challenged for 90 minutes in the CAE® model and will be 
assessed for eligibility.  At Visit 2b (Day 1), subjects will be reassessed for eligibility, re-challenged for 
90 minutes in the CAE® model and have baseline measures assessed.  Eligible subjects will be 
randomized to receive either active drug (TOP1630) or placebo (in the ratio of 1 active: 1 placebo)..  
Randomized subjects will then begin using study drug bilaterally TID for approximately 4 weeks.  At 
Visit 3b (Day 15 ± 1) and Visit 4b (Day 29 ± 2), subjects will be challenged for 90 minutes in the CAE® 
model. 
Study visits will be referred to in all tables and listings as the expected study day corresponding to the 
visit to enable reviewers to understand the assessment timing without referring to the protocol visit 
schedule.  The following tables show the scheduled study visits, their planned study day, and the 
acceptable visit window for each study visit for the Comfort Assessment and the Safety and Efficacy 
Assessment. 
For Comfort Assessment: 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1a 
Day 1 
N/A 
Visit 2a 
Day 2 
N/A 
Visit 3a 
Day 3 
N/A 
Visit 4a 
Day 4 
N/A 
Visit 5a 
Day 5 
N/A 
Visit 6a 
Day 6 
N/A 
Visit 7a 
Day 8 
N/A 
Visit 8a 
Day 12 
N/A 
 
For Safety and Efficacy Assessment: 
Scheduled Visit 
Planned Study Day 
Visit Window 
Visit 1b 
Day -7  
± 1 
Visit 2b 
Day 1 
- 
Visit 3b 
Day 15  
± 1 
Visit 4b 
Day 29  
± 2 
 
4.2 
Schedule of Visits and Assessments 
The schedule of visits and assessments for the Safety and Efficacy Assessment: 


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Procedure 
 
Visit 1b 
Day -7 ± 1 
 
 
Visit 2b 
Day 1 
 
 
Visit 3b 
Day15 ± 1 
 
 
Visit 4b 
Day 29 ±2 
 
 
Pre  
CAE® 
Post  
CAE® 
Pre 
CAE® 
Post 
CAE® 
Pre 
CAE® 
Post  
CAE® 
Pre 
CAE® 
Post  
CAE® 
Informed Consent / HIPAA 
X 
 
 
 
 
 
 
 
Medical / Medication History and 
Demographic 
X 
 
 
 
 
 
 
 
Run-in Placebo Collection 
 
 
X 
 
 
 
 
 
Study Drug Collection 
 
 
 
 
X 
 
X 
 
Diary Collection 
 
 
X 
 
X 
 
X 
 
Medical / Medication History Update 
 
 
X 
 
X 
 
X 
 
Adverse Event Query 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
X1 
 
 
 
 
 
X1 
 
Ocular Discomfort – Ora, Calibra® / 
Dry Eye Symptoms  
X 
X 
X 
X 
X 
X 
X 
X 
OSDI© Questionnaire 
X 
 
X 
 
X 
 
X 
 
Visual Acuity (ETDRS) 
X 
 
X 
 
X 
 
X 
 
Vital Signs 
X 
 
X 
 
X 
 
X 
 
Review of Qualification Criteria 
X 
X 
X 
X 
 
 
 
 
Slit-lamp Biomicroscopy 
X 
X 
X 
X 
X 
X 
X 
X 
VAS Symptom Assessment 
X 
 
X 
 
X 
 
X 
 
Impression Cytology (EyePrim) 
 
 
 
X 
 
 
 
X 
Conjunctival Redness, Ora Calibra® 
Scale 
X 
X 
X 
X 
X 
X 
X 
X 
Lid Margin Redness, Ora Calibra® 
Scale   
X 
 
X 
 
X 
 
X 
 
Posterior Lid Edge Evaluation, Ora 
Calibra® Scale 
X 
 
X 
 
X 
 
X 
 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
X 
Fluorescein Staining-Ora Calibra® 
and NEI Scale 
X 
X 
X 
X 
X 
X 
X 
X 
Lissamine Green Staining-Ora 
Calibra® and NEI Scale 
X 
X 
X 
X 
X 
X 
X 
X 
Corneal Sensitivity (Cochet-Bonnet) 
X 
 
 
 
 
 
X 
 
OPI 2.0 
 
 
X 
 
 
 
X 
 
Unanesthetized Schirmer’s Test 
X 
 
X 
 
X 
 
X 
 
CAE® Exposure 
X 
X 
X 
X 
CAE® Discomfort – Ora Calibra® 
Ocular Discomfort Scale 
X 
X 
X 
X 
Intraocular pressure (non-contact) 
 
X 
 
 
 
 
 
X 
Undilated Fundus Exam 
 
X 
 
 
 
 
 
X 


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Run-in Placebo & Diary Dispensation 
 
X 
 
 
 
 
 
 
Randomization  
 
 
 
X 
 
 
 
 
Subject self-instillation of study drug 
 
 
 
X 
 
X 
 
 
Ora Calibra® Drop Comfort 
Assessment 
 
 
 
X 
 
X 
 
 
Study Drug Dispensation 
 
 
 
X 
 
X 
 
 
Diary Dispensation 
 
X 
 
X 
 
X 
 
 
Exit Subject from Study 
 
 
 
 
 
 
 
X 
1For females of childbearing potential. 


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5. Study Treatments 
The investigational treatment for this study is TOP1630 Ophthalmic Solution.  The control is Placebo 
Ophthalmic Solution (Vehicle with no TOP1630). 
5.1 
Method of Assigning Subjects to Treatment Groups 
Prior to initiation of study run-in (at Visit 1b), each subject who qualifies for entry will be assigned a 
screening number.  All screening numbers will be assigned in strict numerical sequence at a site and 
no numbers will be skipped or omitted.  If all inclusion and exclusion criteria are met at Visits 1b and 
2b, each qualifying subject will then be assigned a randomization number at the end of Visit 2b.  
Subjects who meets all qualification criteria will be randomly assigned to masked treatment using a 1:1 
(approximately 30 subjects in the TOP1630 arm and approximately 30 in the placebo arm) assignment 
ratio. Subjects will be randomized by assignment of the next 4-digit randomization number available 
(3001-3100). No randomization numbers will be skipped or omitted. An independent randomization 
specialist who is not otherwise involved in the trial will generate the randomization code utilized at site. 
The unique randomization list will assign masked study kit numbers to be dispensed to each enrolled 
subject.  At the end of Visit 1b, qualified subjects will receive a kit of run-in (Placebo) for one week, 
dosing TID until Visit 2b. At the end of Visit 2b and 3b, subjects will be given two kits of 24 bottles each 
of TOP1630 Ophthalmic Solution or placebo for TID dosing. At Visits 3b and 4b, remaining/unused 
study drug will be collected from subjects for drug accountability.    
5.2 
Masking and Unmasking 
This is a double-masked study. Subjects, investigators and site staff, the sponsor and Ora/Statistics & 
Data Corporation (SDC) staff are masked to the treatment group assignments during the randomization 
process and for the duration of the study.   
Under normal circumstances, the mask should not be broken. When medically necessary, an 
investigator may need to determine what treatment has been assigned to a subject. The investigator will 
contact Ora/Sponsor with the details of the emergency unmasking request. Ora/Sponsor will make the 
final determination if the unmasking request will be granted. If granted, the investigator will complete 
unmasking via the “scratch-off” label affixed to the subject’s source documents. If the unmasking label 
is not available, unmasking information may be provided by the Unmasked designees (Zoe Falk at Ora 
or Jen Ohme at SDC). The investigator must also indicate in source documents and in the eCRF that 
the mask was broken and provide the date, time, and reason for breaking the mask.  Subjects should 
have their study drug discontinued immediately if treatment assignment is unmasked. 


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The overall randomization code will be broken only for reporting purposes.  This will occur once all final 
clinical data have been entered into the database, data queries have been resolved, and assignment of 
subjects to the analysis populations has been completed. The database will be kept masked until after 
the database lock has occurred. 
6. Sample Size and Power Considerations 
The study is not powered to show statistical differences for any of the efficacy endpoints. The sample 
size was determined based on prior clinical trial experience in subjects with dry eye syndrome and is 
deemed to be robust sufficient to evaluate the safety and tolerability of TOP1630 Ophthalmic Solution 
in this population and to gather efficacy data that will aid in powering future clinical trials. 
With a sample size of 60 subjects in the Safety and Efficacy Assessment, the study will have 79% 
probability of detecting AEs occurring at a rate of 5% or more in either treatment arm.  
7. Data Preparation 
Data management procedures, including database design, selection of the data dictionary, and coding 
of all AEs and medications, will be performed by SDC. All reported study data will be recorded on the 
electronic Case Report Forms (eCRF) supplied by SDC using iMedNet™.  Clinical personnel at the 
study center and Ora, Inc. are responsible for ensuring that the protocol is followed and that the eCRFs 
are properly completed.  
After data are entered into the clinical study database, electronic edit checks will be performed, including 
checks for missing data, out of range values, discrepancies within and across visits, and cross checks 
between different data tables. All data validation specifications and procedures are detailed in the Data 
Validation Manual (DVM). When the database has been declared to be complete and accurate, the 
database will be locked and treatment codes unmasked. Any changes to the database after that time 
can only be made with the approval of the Sponsor in consultation with Ora, Inc. and SDC.  
All analyses outlined in this document will be performed after: 
• 
All data management requirements are met according to SDC’s Standard Operating Procedures 
(SOP), including performance of edit and validation checks, documentation and resolution of 
data queries, and database lock with written authorization provided by appropriate SDC and 
Ora/Sponsor personnel; 
• 
All protocol deviations have been classified as major or minor and the Per Protocol population 
has been determined; and 
• 
The treatment codes have been unmasked. 


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8. Analysis Populations 
8.1 
Modified Intent-to-Treat 
The modified Intent-to-Treat (mITT) population includes all randomized subjects with one post 
baseline efficacy assessment. Efficacy analysis will be performed on the mITT population. Subjects in 
the mITT population will be analyzed as randomized. 
8.2 
Per Protocol 
The PP population includes subjects in the mITT population who do not have significant protocol 
deviations and who complete the study. Protocol deviations will be assessed  and determined prior to 
database lock and unmasking. Subjects in the PP population will be analyzed as treated. 
8.3 
Safety 
The Safety population includes all subjects who have received at least one dose of the investigational 
product. The Safety population will be analyzed as treated and will be used for the safety analyses. No 
data will be excluded for any reason. 
Summaries of the comfort data from the Comfort Assessment will be performed on the Safety population 
from that Assessment. The statistical analysis of safety data will be performed for the Safety population, 
separately for the Comfort Assessment and the Safety and Efficacy Assessment. The analysis of 
baseline and all efficacy data in the Safety and Efficacy Assessment will be performed for the mITT 
population. The efficacy analyses may also be performed on the PP population as sensitivity analyses. 
9. General Statistical Considerations 
9.1 
Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit of analysis will be the 
“worst eye” as defined by the following: 
Worst Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria. In the case that both 
eyes are eligible for analysis, the study eye will be the eye with worse (higher) increase in total corneal 
staining change from pre-CAE® to post-CAE® at Visit 2b on the Ora Calibra® scale. If the increase in 
total corneal staining is the same in both eyes, then the study eye will be the eye with the largest increase 
in ocular discomfort from pre-CAE® to post-CAE® at Visit 2b. If the ocular discomfort symptom increase 
is the same in both eyes, then the right eye will be selected as the worst eye. 
9.2 
Missing or Inconclusive Data Handling 
The efficacy analyses will be performed using observed data.  In addition, for key endpoints of corneal 
staining and ocular discomfort, missing data will be imputed using the following methods: 


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• 
Using the last observation carried forward (LOCF) imputation method for missing values 
• 
Using multiple imputation methods to account for missing data       
9.3 
Definition of Baseline 
Baseline measures are defined as the last measure prior to the initiation of study treatment, usually at 
Visit 2b. If a measure is taken both pre-CAE® and post-CAE®, the baseline will be the time point matched 
value at Visit 2b. For measures from daily subject diaries, baseline is defined as the average of all 
available days’ readings during the run-in period, where daily scores are first obtained by averaging the 
AM and PM scores for that day, as applicable. For changes from pre-CAE® to post-CAE® post first 
treatment, the change from pre-CAE® to post-CAE® at Visit 2b will be considered the baseline value. For 
purposes of analysis, only subjects with at least 5 days of data in the run-in period will be included in 
change from baseline summaries and analyses. 
9.4 
Data Analysis Conventions 
All data analysis will be performed by SDC after the study is completed and the database has been 
locked and released for unmasking.  Statistical programming and analyses will be performed using SAS 
Version 9.4.   
Quantitative variables will be summarized using descriptive statistics including the number of 
observations (n), mean, standard deviation (SD), median, minimum, and maximum values. Means, 
medians, and confidence intervals (CI) will be reported to two decimal places and SDs to three.  
Summaries for discrete variables will include frequency counts and percentages.  All percentages will 
be rounded to one decimal place (i.e., XX.X%).  Differences between the active treatment group and 
placebo will be calculated as Active minus Placebo and change from baseline will be calculated as 
follow-up visit minus baseline. 
All efficacy analyses will be 2-sided at a significance level of 0.10. CIs for differences between treatment 
groups will be two-sided at 90% confidence.  All p-values will be rounded to four decimal places; p-
values less than 0.0001 will be presented as “<0.0001”; p-values greater than 0.9999 will be presented 
as “>0.9999”. 
All summaries will be presented by treatment group. Summaries of data from the Comfort Assessment 
and Safety and Efficacy Assessment of the study will be summarized separately. Summaries will be 
provided for demographics, baseline medical history, concurrent therapies, and subject disposition. 
For the purpose of summarization, the following will be coded to the Medical Dictionary for Regulatory 
Activities (MedDRA) and World Health Organization (WHO) Drug Dictionary Enhanced (DDE), as 
appropriate: medical history, concurrent therapies, and AEs. 


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9.5 
Adjustments for Multiplicity 
There will be no adjustments for multiple endpoints or multiple treatment comparisons for this early 
phase, exploratory study. 
10. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study.  Subjects who are not discontinued 
from the study will be considered study completers.  Disposition will be summarized by treatment group 
and for all subjects. 
The number and percentage of subjects discontinued from the study and the reasons for study 
discontinuation will be summarized by treatment group for all randomized subjects.  The reasons for 
study discontinuation that will be summarized include: AEs, protocol violations, administrative reasons, 
sponsor termination of study, subject choice, and other.  A subject listing will be provided that includes 
the date of and reason for premature study discontinuation. 
The number and percentage of subjects with protocol deviations will be summarized by treatment group 
for all randomized subjects.  A subject listing will be provided that includes the date of the deviation, the 
deviation description and the classification of whether the deviation was judged to be major or minor. 
In addition, subject listings will be provided that include informed consent date, inclusion and exclusion 
criteria violations, and exclusions from the PP population. 
11. Demographic and Baseline Variables 
11.1 
Demographic Variables 
The demographic variables collected in this study include age, gender, race, ethnicity and iris color.  
Subjects who record more than one race will be grouped into a single category denoted as multi-racial.  
Age (years) will be summarized, overall and by treatment, using continuous descriptive statistics.  Age 
will also be categorized as follows:  <65 years and ≥65 years.  Age will be reported in years and 
calculated using the following formula: 
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
The number and percentage of subjects will be presented, overall and by treatment, for age category, 
gender, race, ethnicity and iris color.  Percentages will be based on the total number of subjects in each 
treatment group except for iris color, which will be based on the total number of eyes in each treatment 
group.  A subject listing that includes all demographic variables will be provided. 


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11.2 
Baseline Variables  
Baseline worst dry eye symptoms, duration of dry eye syndrome and OSDI© will be summarized and 
listed. 
12.       Medical History and Concomitant Medications 
12.1 
Medical History 
Medical history will be summarized using discrete summary statistics and presented by treatment group 
at the subject and event level by system organ class (SOC) and preferred term (PT).  If a subject reports 
the same PT multiple times within the same SOC, that PT will only be reported once within that SOC. 
As with the PT, if a subject reports multiple conditions within the same SOC, then that SOC will only be 
reported once.  Separate tables will be created for ocular and non-ocular medical history.  Medical 
history will be coded using MedDRA, version 20.0.  The summaries will be based on the mITT 
population. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
12.2 
Prior and Concomitant Medications 
At the first screening visit, subjects will be asked what medications they are taking, as well as those the 
subject may have taken prior to Visit 1b.  At each study visit, subjects will be asked what concomitant 
medications they are currently taking or if there have been any changes to their medication since their 
first visit. 
All prior and concomitant ocular and non-ocular medications will be listed using the mITT population 
including generic name, route of administration, start date, stop date, dosage, and indication.  Prior and 
concomitant medications will be coded using the WHO DDE version B2, September 2016, to the 
appropriate Anatomical Therapeutic Chemical (ATC) classification and WHO generic term. 
Counts and percentages of ocular and non-ocular concomitant medications will be summarized 
separately using WHO Drug ATC classification and preferred name.  Summaries will be displayed by 
treatment group and for all subjects.  Subjects with multiple medications in the same ATC class or 
preferred name will be counted only once for that respective ATC class or preferred name.   
13. Dosing Compliance and Treatment Exposure 
13.1 
Dosing Compliance 
Dosing compliance (% compliance) will be assessed by calculating the number of actual doses received 
and comparing that to the number of expected doses as follows: 
Compliance (%) = 
Number of Actual Doses Received 


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Number of Expected Doses 
x 100% 
The number of actual doses received will be calculated from the used and unused bottles recorded in 
the eCRF.  The number of expected doses that will be used for calculating compliance will be 
calculated as {3x [date of last dose – date of Visit 2 (Day 1)]} +3 for all subjects, regardless of study 
completion status. 
A categorical dosing compliance variable will also be derived as non-compliant (<80%), compliant 
(≥80% and ≤114%) and over compliant (>114%).  
Treatment compliance (%) will be summarized for the Safety population using continuous descriptive 
statistics.  The compliance categories defined above will be summarized with counts and percentages.   
A subject listing of compliance will also be produced. 
13.2 
Treatment Exposure 
For the Safety and Efficacy Assessment, extent of exposure will be calculated in days using the 
following: 
Extent of Exposure (days) = [Date of last dose – Date of Visit 2b (Day 1)] + 1 
Extent of treatment exposure (days) for each subject exposed to study drug will be summarized with 
continuous descriptive statistics for each treatment group, using the Safety population. A subject listing 
of treatment exposure will also be produced. 
14. Safety Analyses 
Frequencies and percentages of subjects with treatment-emergent adverse events (TEAEs), serious 
TEAEs, and TEAEs causing discontinuation will be provided by treatment group.  An AE is treatment 
emergent if it occurs or worsens after the first dose of study treatment. Furthermore, frequencies will be 
given of subjects with TEAEs by SOC and PT; by SOC, PT and maximal severity; by SOC and PT for 
treatment-related AEs; by SOC, PT for SAEs; and by SOC, PT, and time of onset. Separate summaries 
will be provided for ocular specific and all AEs (including systemic). 
Other safety endpoints including VA, slit-lamp biomicroscopy, corneal sensitivity, undilated fundoscopy, 
IOP (non-contact), and vital signs will be summarized by treatment group, visit, and time point (where 
relevant) using descriptive statistics. Changes or shifts from baseline will also be summarized where 
appropriate. For assessments performed by eye, study eye and fellow eye will be summarized 
separately. In addition, shifts from baseline to worst on-treatment value for ocular safety assessments 
will be summarized. 


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Safety variables will be summarized as appropriate.  All safety analyses will be performed on the Safety 
population.  No statistical inferential testing will be performed for safety variables. 
14.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an investigational 
product (IP) in humans, whether or not considered IP-related. TEAEs are defined as AEs that occur 
after the first use of IP.  Per the protocol, only AEs that begin or worsen after receipt of the first dose of 
IP will be captured in the database for this study; therefore, TEAEs and AEs are equivalent in this study 
and will be denoted as AEs.  All AEs will be assigned a severity grade of mild, moderate, or severe. 
Their relationship to IP will be classified as suspected (definite, probable or possible) or not suspected 
(not related).  The expectedness of an AE will be classified as unexpected, expected or not applicable.  
Documentation of AEs will include onset date, severity, action(s) taken, IP relationship, expectedness, 
outcome, resolution date, and seriousness.  All AEs will be coded using MedDRA classifications with 
reference to SOCs and PTs (MedDRA version 20.0). 
An adverse event is considered serious if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: 
• 
Death; 
• 
A life-threatening AE; 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions; 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed above. 
An overall tabular summary of AEs will be presented that includes the number of events and the number 
and percentage of subjects who experienced at least one event, by treatment group and overall.  This 
summary will also include breakdowns of AEs further categorized as ocular or non-ocular, SAEs, AEs 
by maximal severity, AEs leading to subject withdrawal and AEs resulting in death.  Additional 
summaries of AEs will be provided showing the number and percentage of subjects who experienced 
at least one AE, separately for ocular and non-ocular AEs.  Ocular and non-ocular AEs will be 
summarized separately using discrete summary statistics and presented by treatment group at the 
subject and event level by SOC and PT using the Safety population.  If a subject reports the same PT 
multiple times within the same SOC, that PT will only be reported once within that SOC.  As with the PT, 


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if a subject reports multiple conditions within the same SOC, that SOC will only be reported once.  The 
occurrence of AEs suspected to be related to IP will also be tabulated by SOC and PT, separately for 
ocular and non-ocular events.  SAEs will also be summarized separately for ocular and non-ocular 
events.  All AEs will be presented in a listing. 
14.2 
Visual Acuity (ETDRS) 
VA will be measured at the beginning of every study visit. VA (logMAR) will be summarized at each visit 
using quantitative summary statistics for both eyes combined by treatment.  Qualitative summaries for 
worsening of acuity of 10 letters or greater from the previous visit will also be tabulated.  VA results will 
be presented in a data listing.   
14.3 
Slit-Lamp Biomicroscopy Examination 
Slit-lamp biomicroscopy examinations will be conducted on both eyes at all scheduled visits, Pre- and 
Post-CAE®.  The slit lamp findings will include examinations of the cornea, conjunctiva, anterior 
chamber, iris, lens and lid.  Each parameter will be graded as normal or abnormal.  Abnormal findings 
will be further classified as not clinically significant (NCS) or clinically significant (CS).  
Slit lamp findings will be summarized by treatment group and visit, for the worst eye and fellow 
eye separately, using qualitative summary statistics (frequency counts and percentages).  
Percentages will be based on the number of subjects with non-missing values for the treatment group 
at a given visit.  
A shift table will show changes from baseline (Visit 2b (Day 1), Pre-CAE®) to all observations at 
later study visits and time points.  The data for slit lamp biomicroscopy will be presented in a listing. 
14.4 
Corneal Sensitivity (Cochet-Bonnet) 
Corneal Sensitivity will be performed at Visits 1b (Day -7 ± 1) Pre CAE® and 4b (Day 29 ± 2) Pre CAE®.  
Corneal sensitivity will be summarized for both eyes combined by visit and treatment group using 
quantitative summary statistics.  Results will be listed for both eyes at each visit. 
14.5 
Undilated Fundoscopy  
Undilated fundoscopy examinations will be conducted on both eyes at Visit 1b (Day -7 ± 1) Post-
CAE® and Visit 4b (Day 29 ± 2) Post-CAE®.  The fundus pathology findings will include examinations 
of the vitreous, retina, macula, choroid, and optic nerve, and be recorded as normal, abnormal (NCS), 
or abnormal (CS). Summaries of undilated fundoscopy findings will be presented by treatment and visit, 
for the worst eye and fellow eye separately, using frequency counts and percentages.  Percentages will 
be based on the number of subjects with non-missing values for the treatment group at a given visit. 


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A shift table will show changes from baseline (Visit 1b (Day -7 ± 1), Post-CAE® to Visit 4b (Day 29 ± 2), 
Post-CAE®) on the above variables.  The data for undilated fundoscopy will be presented in a listing. 
14.6 
Intraocular Pressure (IOP) 
IOP will be measured at Visits 1b (post-CAE®) and 4b (post-CAE®).  IOP will be summarized for both 
eyes combined by visit and treatment group using quantitative summary statistics.  At Visit 4b, an IOP 
of ≥21 mmHg AND ≥10 mmHg over baseline (Visit 1b) will be considered an AE, and presented in the 
tabular summary.  Results will be listed for both eyes at each visit. 
15. Tolerability Analyses 
Two tools will be used to assess drop comfort, each of which will be assessed at Visit 2b (Day 1) and 
Visit 3b (Day 15 ± 1), following the first dose of study drug.  
• 
Ora Calibra® Drop Comfort Scale will be used to assess drop comfort for each eye separately 
upon instillation and at 1 and 2 minutes Post-instillation.  The scale ranges from 0 to 10, with 0 
indicating very comfortable and 10 indicating very uncomfortable.  The worst eye from each 
subject will be used for this analysis.  Drop comfort will be summarized using quantitative 
summary statistics.  Statistical comparisons will employ two-sample t-tests as the primary 
method of analysis.   
• 
Ora Calibra® Drop Comfort Questionnaire will be used to assess drop comfort 3 minutes Post-
instillation.  Subjects will be asked to choose three words (among 12) that best describe how 
the eye drops feel in both eyes.  The positive responses are comfortable, cool, refreshing, 
smooth and soothing.  The negative responses include burning, filmy, stinging, sticky, thick, 
gritty and irritating.  Subjects may also select “other” and write in a response of their choosing, 
which may be either a positive or a negative response.  This analysis will be at the subject level.  
Drop Comfort Questionnaire responses will be summarized using qualitative summary statistics.  
Subjects with at least one negative response will also be summarized. 
16. Exploratory Efficacy Analyses 
The continuous and ordinal secondary efficacy variables collected at each visit will be summarized 
descriptively (n, mean, SD, median, minimum and maximum), and analyzed with two-sample t-tests 
comparing the active treatment groups to placebo. All visit-based data will be analyzed at each visit as 
well as change from baseline. A Wilcoxon rank sum test and an ANCOVA model adjusting for baseline 
will also be assessed where appropriate. Corneal fluorescein staining by region and total (Ora and NEI 
scales), lissamine green staining by region, TFBUT, conjunctival redness, unanesthetized Schirmer’s 
test, ocular symptoms (Ora Calibra® scales and VAS), OSDI©, ocular discomfort and changes from 
baseline in these measures will be analyzed by visit and time point, where applicable (i.e., pre- and post-


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CAE®), using two-sample t-tests and Wilcoxon rank sum tests. Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values. For the measures of symptoms during 
CAE®, the ANCOVA models will also include the pre-CAE® measure as a covariate. Symptoms recorded 
on the daily diary will be analyzed using repeated measure ANCOVA models, where baseline scores 
are calculated as the average scores in the run-in period and post-baseline scores are calculated as 
weekly morning, afternoon, evening, and daily averages.  
The efficacy analyses will be performed using observed data.  In addition, for key endpoints of corneal 
fluorescein staining using the Ora Calibra scale and ocular discomfort, missing data will be imputed 
using LOCF and multiple imputation methods to assess robustness of the results.  The PP population 
with observed data will also be analyzed as an additional sensitivity analysis. 
Adjustments for multiplicity will not be employed in this exploratory Phase 2 study. 
16.1 
Corneal Fluorescein Staining  
Corneal fluorescein staining (Ora Calibra® and NEI scales) will be performed pre-CAE® and post-CAE® 
for both eyes at Visit 1b (Day -7 ± 1), Visit 2b (Day 1, prior to treatment), Visit 3b (Day 15 ± 1) and Visit 
4b (Day 29 ± 2).  The 5-unit scale for evaluation of staining in each of the regions (inferior, superior, 
central, temporal and nasal) is given by the following [half (0.5) grade increments may be used]: 0 = 
none, 1 = trace, 2 = mild, 3 = moderate and 4 = severe, as measured on the Ora Calibra® scale.  The 
maximum score is 20 for total staining using the Ora Calibra® scale.  A standardized grading system of 
0-3 is used for each of the five regions of the ocular surface as measured on the NEI scale. Grade 0 will 
be specified when no staining is present. The maximum score is 15 for total staining using the NEI scale. 
The worst eye (defined in Section 9.1) will be used for these analyses.   
Corneal fluorescein staining by region, the corneal sum, the conjunctival sum and total staining (Ora 
and NEI scales) will be analyzed by visit and time point, where applicable (i.e., pre- and post-CAE® as 
well as the change from pre- to post-CAE®), using two-sample t-tests and Wilcoxon rank sum tests. 
Changes from baseline will be analyzed similarly and will also be analyzed using an ANCOVA model, 
which is described in detail below.   
Total staining is derived from summing the scores from all five regions.  The corneal sum is the total 
from the superior, central and inferior regions and the conjunctival sum is the total from the nasal and 
temporal regions.   
An analysis of covariance (ANCOVA) model will also be used to compare the changes from baseline for 
corneal fluorescein staining in each region, as well as the corneal, conjunctival and total staining scores, 
as measured on the Ora Calibra® and NEI scales, between TOP1630 Ophthalmic Solution and Placebo.  


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The ANCOVA model will include terms for treatment as the main effect and baseline corneal fluorescein 
staining as a covariate.  
Comparisons will use two-tailed, alpha=0.10 t-tests on the least squares (LS) means from the ANCOVA.  
LS Means for each treatment, the estimated treatment difference and the 90% CI for the difference will 
be calculated based on the ANCOVA model.  An example of SAS® code implementation is as follows:  
PROC MIXED DATA=ITT; 
  CLASS TREATMENT; 
  MODEL ΔCORNEAL FLUORESCEIN STAINING = TREATMENT BASELINE; 
  LSMEANS TREATMENT / CL PDIFF; 
RUN; 
where 
- 
treatment is the treatment group;  
- 
Δcorneal fluorescein staining is the corneal fluorescein staining score change from baseline 
in the study eye [note that this analysis will be carried out separately for each visit and time 
point (pre-CAE, post-CAE and change from pre-CAE to post-CAE) and region as well as for 
the corneal, conjunctival and total staining scores)]; and 
- 
baseline is the Visit 2b corneal fluorescein staining score for the relevant time point and 
region. 
For corneal fluorescein staining using the Ora Calibra® scale, missing data will be imputed using LOCF 
and multiple imputation methods as sensitivity analyses for the mITT Population.  For LOCF, the 
individual Visit 4b (Day 29 ± 2) pre- and post-CAE® values will be imputed from the individual non-
missing Visit 3b (Day 15 ± 1) pre- and post-CAE® values for each region prior to calculating the corneal, 
conjunctival and total staining scores.  Additionally, these imputations will be carried out prior to 
calculating any pre- to post-CAE® changes. If the individual pre- or post-CAE® values are missing at 
Visit 3b (Day 15 ± 1), no data will be imputed as pre-randomization values will not be used to impute 
post-randomization values. 
The Markov Chain Monte Carlo (MCMC) multiple imputation methodology will also be employed to 
impute missing data in the mITT population for the Ora Calibra® scale.  For MCMC, the imputations will 
be performed for each individual region, visit and time point prior to calculating the corneal, conjunctival 
and total staining scores or any changes from pre- to post-CAE®.  The MCMC method will be performed 
using the SAS procedure PROC MI by applying the following SAS code:  
PROC MI DATA = INDATA SEED = 1435892 OUT = OUTDATA1; 
   MCMC INITIAL = EM; 
   VAR TREATMENT VISIT TIME SCORE; 
RUN; 
where 


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- 
indata is the name of the input dataset; 
- 
outdata1 is the name of the output dataset; 
- 
treatment is the name of the treatment group variable in numeric format; 
- 
visit is the visit; 
- 
time is the time point; and 
- 
score is the score for corneal fluorescein staining. 
After obtaining twenty complete data sets, the following SAS code will be used to run the TTEST 
procedure on each data set: Then, the SAS procedure MIANALYZE will be used to analyze the results 
from the twenty complete data sets to generate a combined inference.  The following SAS code will be 
used: 
The SAS code for two-sample t-tests with multiple imputation data is as follows: 
ODS OUTPUT STATISTICS = OUTDATA2; 
PROC TTEST DATA = OUTDATA1; 
     CLASS TREATMENT; 
     VAR SCORE; 
     BY _IMPUTATION_ VISIT TIME; 
RUN; 
 
ODS OUTPUT PARAMETERESTIMATES = OUTDATA3; 
PROC MIANALYZE DATA = OUTDATA2; 
   MODELEFFECTS MEAN; 
   STDERR STDERR; 
   BY VISIT TIME; 
RUN; 
For the change from baseline analyses, an ANCOVA model will be run on the 20 individual datasets 
created from the above PROC MI procedure.  The following SAS code will be used to run the ANCOVA 
model on each data set: Then, the SAS procedure MIANALYZE will be used to analyze the results from 
the twenty complete data sets to generate a combined inference.  The following SAS code will be used: 
ODS OUTPUT STATISTICS=OUTDATA2; 
PROC MIXED DATA=OUTDATA1; 
    CLASS TREATMENT SITE; 
    MODEL Δ_STAIN_CHANGE = BASELINE TREATMENT; 
    LSMEANS TREATMENT / CL PDIFF; 
    BY VISIT TIME _IMPUTATION_; 
RUN; 
 
ODS OUTPUT PARAMETERESTIMATES=OUTDATA3; 
PROC MIANALYZE DATA=OUTDATA2; 
    CLASS TREATMENT; 
    MODELEFFECTS INTERCEPT BASELINE TREATMENT; 
    BY VISIT TIME; 
RUN; 
where 
- 
TREATMENT is the name of the treatment group variable in numeric format; 


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- 
BASELINE is the fluorescein staining score in the study eye at Visit 2b (Day 1); 
- 
VISIT is the visit; 
- 
TIME is the time point;  
- 
Δ_STAIN_CHANGE is the fluorescein staining score in the study eye at the follow-up visit – 
BASELINE; 
- 
OUTDATA2 is the name of the output dataset that contains the statistical results from the 
ANCOVA model that is run on each of the twenty imputation datasets for each region, visit 
and time point; and 
- 
OUTDATA3 is the name of the output dataset that contains all the information needed for the 
table. 
16.2 
Ocular Discomfort  
Ocular discomfort will be assessed pre-CAE® and post-CAE® for both eyes at Visit 1b (Day -7 ± 1), 
Visit 2b (Day 1, prior to treatment), Visit 3b (Day 15 ± 1) and Visit 4b (Day 29 ± 2).  The 5-unit scale for 
subject evaluation of ocular discomfort is given by the following: 0 = no discomfort, 1 = intermittent 
awareness, 2 = constant awareness, 3 = intermittent discomfort and 4 = constant discomfort, as 
measured on the Ora Calibra® Ocular Discomfort Scale.  The worst eye (defined in Section 9.1) will be 
used for this analysis. Missing data will be imputed using LOCF and multiple imputation methods similar 
to those defined for corneal fluorescein staining. 
Ocular discomfort will be analyzed by visit and time point, where applicable (i.e., pre- and post-CAE® as 
well as the pre- to post-CAE change), using two-sample t-tests and Wilcoxon rank sum tests. 
Change from baseline for ocular discomfort will be analyzed similarly to the change from baseline for 
corneal fluorescein staining. An ANCOVA model will be used to compare the change from baseline for 
ocular discomfort, as measured on the Ora Calibra® Ocular Discomfort scale, between TOP1630 
Ophthalmic Solution and Placebo. The ANCOVA model will include treatment as the main effect term 
and baseline ocular discomfort at Day 1 (Visit 2b) as a covariate.   
16.3 
Lissamine Green Staining 
Lissamine green staining will be graded with the Ora Calibra® and NEI scales. The Ora Calibra® Scale 
will grade the cornea and conjunctiva by five regions: inferior, superior, central, temporal and nasal and 
ranges from 0 to 4 (half grade increments may be used) where 0 = none, 1 = trace, 2 = mild, 3 = 
moderate and 4 = severe.  The maximum score for total staining using the Ora Calibra® scale is 20.  
The NEI Scale will grade the conjunctiva by six regions: temporal, superior temporal, inferior temporal, 
superior nasal, inferior nasal and nasal. A standardized grading system of 0 to 3 is used for each of the 


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six areas of the conjunctiva. Grade 0 will be specified when no staining is present. The maximum score 
using the NEI scale is 18. The worst eye from each subject will be used for these analyses.  
Lissamine green staining by region, the corneal sum (Ora scale only), the conjunctival sum (equal to 
total staining using the NEI scale) and total staining (Ora scale only) will be analyzed by visit and time 
point using the mITT Population with observed data, where applicable (i.e., pre- and post-CAE® as well 
as the change from pre- to post-CAE®), using two-sample t-tests and Wilcoxon rank sum tests. Changes 
from baseline will be analyzed similarly.  Changes from baseline will also be analyzed using ANCOVA 
models adjusting for baseline values, similar to those described for corneal fluorescein staining. 
Total staining is derived from summing the scores from all five regions using the Ora scale.  The corneal 
sum is the total from the superior, central and inferior regions using the Ora scale and the conjunctival 
sum is the total from the nasal and temporal regions using the Ora scale and is calculated as the total 
of all 6 regions using the NEI scale.  Note that the conjunctival sum and total staining are equivalent 
when using the NEI scale. 
16.4 
Tear Film Break-Up Time 
TFBUT will be measured in seconds at all scheduled visits, pre- and post-CAE®, on both eyes.  For 
each eye, two measurements will be taken and averaged unless the two measurements are >2 seconds 
apart and are each <10 seconds, in which case, a third measurement would be taken and the two closest 
of the three will be averaged and used for analyses.  If the differences between two sequential pairs of 
measurements are the same, e.g., 3, 6, 9 seconds, then the median of the three readings will be used 
for analysis.  The worst eye from each subject will be used for this analysis. 
TFBUT will be summarized by visit and time point (pre- and post-CAE®) for the mITT Population using 
quantitative summary statistics.  Change from pre- to post-CAE® within each visit as well as change 
from baseline will also be summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis. A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis. Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values. 
16.5 
Conjunctival Redness  
Conjunctival redness will be assessed at all scheduled visits, pre- and post-CAE®, on both eyes.  The 
grading will range from 0 to 4 (half grade increments may be used) where grade 0 = none, 1 = trace, 2 
= mild, 3 = moderate and 4 = severe.  The worst eye from each subject will be used for this analysis. 


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Conjunctival redness will be summarized for the mITT Population with observed data by visit and time 
point (pre- and post-CAE®) using quantitative summary statistics.  Change from pre- to post-CAE® 
within each visit as well as change from baseline will also be summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis. Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values. 
16.6 
Lid Margin Redness 
Lid margin redness will be assessed at all scheduled visits, pre-CAE®, on both eyes.  The grading will 
range from 0 to 4 (half grade increments may be used) where grade 0 = none, 1 = trace, 2 = mild, 3 = 
moderate and 4 = severe.  The worst eye from each subject will be used for this analysis. 
Lid margin redness will be summarized for the mITT Population with observed data by visit using 
quantitative summary statistics.  Change from baseline will also be summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis. Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values.  
16.7 
Posterior Lid Edge Evaluation 
Posterior Lid Edge Evaluation will be assessed at all scheduled visits, pre-CAE®, on both eyes.  The 
grading will range from 0 to 3 (half grade increments may be used) where grade 0 = none, 1 = slight, 2 
= moderate and 3 = severe.  The worst eye from each subject will be used for this analysis. 
Posterior Lid Edge Evaluation will be summarized for the mITT Population with observed data by visit 
using quantitative summary statistics.  Change from baseline will also be summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis. Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values. 
16.8 
Unanesthetized Schirmer’s Test  
Unanesthetized Schirmer’s Test will be assessed on both eyes at all scheduled visits only at pre-CAE®.  
The Schirmer’s test strip will be placed in the lower temporal lid margin of each eye.  After 5 minutes, 
the test strip will be removed and the length of the moistened area will be recorded in millimeters (mm) 
for each eye.  Lower values indicate less tears produced in the eye.  The worst eye from each subject 
will be used for this analysis. 


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Unanesthetized Schirmer’s Test will be summarized for the mITT Population with observed data by visit 
using quantitative summary statistics.  Change from baseline will be also summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis. A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis. Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values. 
16.9 
Ocular Surface Disease Index® (OSDI®) 
The OSDI will be assessed at the subject level at all scheduled visits only at pre-CAE®.  Subjects will 
be asked 12 questions at each visit.  Each question will be graded on a 0 to 4 scale, where 0 = none of 
the time, 1 = some of the time, 2 = half of the time, 3 = most of the time and 4 = all of the time.  The sum 
of the scores from all questions answered will be calculated.  The total OSDI score will be calculated 
using the formula: OSDI = (Sum of scores) x 25 / (# of questions answered), with the answer of N/A 
excluded.  The OSDI is on a scale of 0 to 100, with higher scores representing greater disability. 
Each individual response and the total OSDI score will be presented separately by visit using 
quantitative summary statistics for the mITT Population with observed data.  Change from baseline will 
also be summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis. 
16.10 
Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire 
Ocular discomfort and dry eye symptoms will be assessed at all scheduled visits, pre- and post-CAE® 
at the subject level in regard to how both eyes feel.  The Ora Calibra® Ocular Discomfort & 4-Symptom 
Questionnaire will be used, which includes rating of the severity of 5 symptoms: ocular discomfort, 
burning, dryness, grittiness and stinging.  Each symptom rating ranges from 0 to 5, where 0 = none and 
5 = worst. 
Ocular discomfort and dry eye symptoms will be summarized for the mITT Population with observed 
data by visit and time point (pre- and post-CAE®) using quantitative summary statistics.  Change from 
pre- to post-CAE® within each visit as well as change from baseline will be also summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis.  Changes from baseline will also be 
analyzed using ANCOVA models adjusting for baseline values. 


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16.11 
Ocular Symptoms of Dry Eye Syndrome – Visual Analog Scale (VAS) 
Ocular symptoms of dry eye syndrome will be assessed at all scheduled visits, pre-CAE® at the subject 
level in regard to how both eyes feel.  The ocular symptoms of dry eye syndrome visual analog scale 
will be used, which includes rating of the severity of 7 symptoms: burning/stinging, itching, foreign body 
sensation, blurred vision, eye dryness, photophobia and pain.  Each symptom is rated on a visual analog 
scale that ranges from 0 to 100 millimeters. 
Ocular symptoms of dry eye syndrome will be summarized for the mITT Population with observed data 
by visit using quantitative summary statistics.  Change from baseline will be also summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  Changes from 
baseline will also be analyzed using ANCOVA models adjusting for baseline values. 
16.12 
Ocular Discomfort Using the Ora Calibra® Scale 
Ocular discomfort scores will be subjectively graded by the subjects using the Ora Calibra® Ocular 
Discomfort Scale at all scheduled visits, pre- and post-CAE® and during CAE® exposure (immediately 
upon entering the chamber and every 5 minutes thereafter for the duration of the 90 minute exposure). 
The ocular discomfort scale ranges from 0 to 4 where 0 = no discomfort, 1 = intermittent awareness, 2 
= constant awareness, 3 = intermittent discomfort and 4 = constant discomfort.  Both eyes will be rated 
separately and the worst eye from each subject will be used for this analysis. 
16.12.1 ORA CALIBRA® OCULAR DISCOMFORT SCALE PRE-AND POST- CAE® 
Ocular discomfort scores will be summarized for the mITT Population with observed data by visit and 
time point using quantitative summary statistics.  Change from pre- to post-CAE® within each visit as 
well as change from baseline will also be summarized.  
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  A Wilcoxon 
rank sum test will also be assessed as a sensitivity analysis. 
16.12.2 ORA CALIBRA® OCULAR DISCOMFORT SCALE DURING CAE® 
Ocular discomfort scores during CAE® will be summarized by visit and time point using quantitative 
summary statistics.  The change from pre-CAE® will be the change from 0 minute to 90 minutes within 
the same visit and will also be summarized. 
The overall ocular discomfort during CAE® will be compared between TOP1630 ophthalmic solution 
and placebo using a mixed-effects model to account for the correlations among the repeated 
measurements for the same eye.  This analysis will be performed for each visit separately and include 
treatment and time (nominal time will be used) as fixed effects, subject as a random effect and the 
baseline (0 minute) ocular discomfort score as a random covariate.  An unstructured covariance matrix 


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will be used to model the covariance among repeated measures; however, if the model fails to converge 
using this covariance structure, either TOEPLITZ or CS (compound symmetry) will be implemented, 
according to the Akaike information criterion with a correction for finite sample sizes (AICc).  The method 
= ML option will be used as the estimation method for the covariance parameters and the DDFM = 
KENWARDROGER option will be used for the denominator degrees of freedom.  The overall treatment 
difference and the corresponding p-value will be estimated based on this mixed-effect model.  The 
following SAS code will be used: 
ods output LSMeans = outdata1 Diffs = outdata2; 
proc mixed data = indata method = ml; 
   by visit; 
   class subjid treatment time; 
   model score = treatment | time baseline; 
   repeated time / type = COV subject = subjid; 
   lsmeans treatment / pdiff cl; 
run; 
where 
- 
subjid is the name of the subject ID; 
- 
visit is the visit number; 
- 
treatment is the name of the treatment group; 
- 
time is the nominal time of the measurement; 
- 
score is the ocular discomfort score; 
- 
baseline is the baseline (0 minute) ocular discomfort score; and 
- 
COV is the appropriate variance-covariance structure. 
16.13 
Ocular Protection Index (OPI) 2.0 
Ocular protection index (OPI) will be assessed at Visits 2b and 4b, Pre-CAE®, on both eyes using the 
Ora Calibra™ OPI 2.0 System.  OPI will be expressed as a percentage of the area of tear film break up 
in the eye and ranges from 0 to 100%.  Inter blink interval (IBI) will also be measured by the Ora Calibra™ 
2.0 System, as a measure of the average time between blinks, in seconds.  The Ora Calibra™ OPI 
System will monitor each subject over a one-minute time frame.  The worst eye from each subject will 
be used for this analysis. 
The OPI and IBI will be summarized by visit using quantitative summary statistics.  Change from baseline 
will also be summarized. 
Statistical comparisons will employ two-sample t-tests as the primary method of analysis.  An ANCOVA 
model adjusting for baseline will also be assessed as a sensitivity analysis. 


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16.14 
Daily Diary 
Each day during the at-home dosing period (including the run-in period), subjects will grade the severity 
of their dry eye symptoms in their diary in the morning, afternoon and evening prior to each dose.  
Subjects will rate the severity of each of the following symptoms, with regard to how both their eyes feel: 
ocular discomfort, burning, dryness, grittiness and stinging.  Each symptom rating ranges from 0 to 5, 
with 0 indicating no symptom and 5 indicating the worst symptom.  The daily averages, per symptom, 
will be calculated for each day by averaging the morning, afternoon and evening assessments. 
The worst symptom for each subject will be identified as the symptom with the highest daily average 
score during the run-in period (Days -7 to -1) as recorded in the subject diary. First daily averages, per 
symptom, from morning, afternoon and evening diary entries will be calculated. Then the daily averages 
will be averaged for each symptom across the days in the run-in period. The highest average symptom 
from the run-in period is denoted as the worst symptom for each subject.  
The individual symptoms will be analyzed using a two-sample t-test to compare the two treatment 
groups.  This analysis will be completed separately for the morning, afternoon and evening scores as 
well as the daily average score.  Additionally, the average score for each time point (morning, afternoon, 
evening and daily average) will also be analyzed separately using a Wilcoxon rank sum test and an 
ANCOVA model adjusting for baseline, where baseline scores are calculated as the average scores in 
the run-in period and post-baseline scores are calculated as weekly morning, afternoon, evening, and 
daily averages.  
17. Interim Analyses 
No interim analyses are planned for this study. 
18. Changes from Protocol-Stated Analyses 
There are no changes from the protocol-stated analyses. 
19. References 
Not applicable 
20. Revision History 
Documentation of revision to the SAP will commence after approval of the Final version 1.0. 
21. Tables 
Tables that will be included in the topline delivery are shown in boldface font. 
Table Number 
Title 
Population 
14.1.1 
Subject Disposition 
All Randomized Subjects 
14.1.2.1 
Demographics 
mITT Population 
14.1.2.2 
Demographics 
PP Population 


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Table Number 
Title 
Population 
14.1.3 
Baseline Characteristics 
mITT Population 
14.1.4.1 
Ocular Medical History 
mITT Population 
14.1.4.2 
Non-Ocular Medical History 
mITT Population 
14.1.5.1 
Ocular Concomitant Medications 
mITT Population 
14.1.5.2 
Non-Ocular Concomitant Medications 
mITT Population 
Exploratory Efficacy Analyses 
14.2.1.1 
Corneal Fluorescein Staining (Ora Calibra® Scale) 
mITT Population 
14.2.1.2 
Corneal Fluorescein Staining  (Ora Calibra® Scale) 
mITT Population with LOCF 
14.2.1.3 
Corneal Fluorescein Staining  (Ora Calibra® Scale) 
mITT Population with MCMC 
14.2.1.4 
Corneal Fluorescein Staining  (Ora Calibra® Scale) 
PP Population 
14.2.2 
Corneal Fluorescein Staining (NEI Scale) 
mITT Population 
14.2.3.1 
Ocular Discomfort 
mITT Population 
14.2.3.2 
Ocular Discomfort 
mITT Population with LOCF 
14.2.3.3 
Ocular Discomfort 
mITT Population with MCMC 
14.2.3.4 
Ocular Discomfort 
PP Population 
14.2.4 
Lissamine Green Staining (Ora Calibra® Scale) 
mITT Population  
14.2.5 
Lissamine Green Staining (NEI Scale) 
mITT Population  
14.2.6 
Tear Film Break-up Time (TFBUT) 
mITT Population  
14.2.7 
Conjunctival Redness 
mITT Population  
14.2.8 
Lid Margin Redness 
mITT Population  
14.2.9 
Posterior Lid Edge Evaluation 
mITT Population  
14.2.10 
Unanesthetized Schirmer’s Test 
mITT Population  
14.2.11 
Ora Calibra®  Drop Comfort Scale 
mITT Population  
14.2.12 
Ora Calibra®  Drop Comfort Questionnaire 
mITT Population  
14.2.13 
Ocular Surface Disease Index (Pre-CAE®) 
mITT Population  
14.2.14 
Ora Calibra®  Ocular Discomfort & 4-Symptom 
Questionnaire 
mITT Population  
14.2.15 
Ocular Symptoms – Visual Analog Scale (VAS) 
mITT Population  
14.2.16 
Ora Calibra®  Ocular Discomfort Scale during CAE® 
mITT Population  
14.2.17 
Diary Assessments 
mITT Population  
14.2.18 
Ocular Protection Index (OPI) 2.0 
mITT Population 
Safety Analyses 
14.3.1.1 
Overall Adverse Event Summary 
Safety Population 
14.3.1.2 
All Ocular Adverse Events 
Safety Population 
14.3.1.3 
All Non-Ocular Adverse Events 
Safety Population 
14.3.1.4 
All Ocular Adverse Events Suspected to be Related to 
Investigational Product 
Safety Population 
14.3.1.5 
All Non-Ocular Adverse Events Suspected to be Related to 
Investigational Product 
Safety Population 
14.3.1.6 
All Ocular Serious Adverse Events 
Safety Population 
14.3.1.7 
All Non-Ocular Serious Adverse Events 
Safety Population 
14.3.2 
Visual Acuity (logMAR) 
Safety Population 
14.3.3.1 
Slit Lamp Biomicroscopy 
Safety Population 
14.3.3.2 
Slit Lamp Biomicroscopy – Shift Table 
Safety Population 
14.3.4 
Intraocular Pressure (mmHg) 
Safety Population 
14.3.5.1 
Undilated Fundoscopy 
Safety Population 
14.3.5.2 
Undilated Fundoscopy – Shift Table 
Safety Population 
14.3.6 
Corneal Sensitivity (Cochet-Bonnet) 
Safety Population 


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Table Number 
Title 
Population 
14.3.7 
Compliance with Study Drug 
mITT Population 
14.3.8 
Exposure to Study Drug 
mITT Population 
14.3.9 
Vital Signs 
Safety Population 
22. Listings 
Listing 
Number 
Title 
POPULATION 
16.1.7 
Randomization Schedule 
All Randomized Subjects 
16.2.1 
Subject Disposition 
All Randomized Subjects 
16.2.2.1 
Protocol Deviations  
All Randomized Subjects 
16.2.2.2 
Inclusion and Exclusion Criteria 
All Randomized Subjects 
16.2.3 
Subjects Excluded from the Per Protocol Population 
All Randomized Subjects 
16.2.4.1 
Demographics 
All Randomized Subjects 
16.2.4.2 
Baseline Characteristics 
All Randomized Subjects 
16.2.4.3 
Ocular Medical History 
All Randomized Subjects 
16.2.4.4 
Non-Ocular Medical History 
All Randomized Subjects 
16.2.4.5 
Prior and Concomitant Ocular Medications 
All Randomized Subjects 
16.2.4.6 
Prior and Concomitant Non-Ocular Medications 
All Randomized Subjects 
16.2.5.1 
In-Office Study Medication Instillation 
All Randomized Subjects 
16.2.5.2 
At-Home Study Medication Instillation (Diary) 
All Randomized Subjects 
16.2.5.3 
Study Drug Exposure and Dosing Compliance 
All Randomized Subjects 
16.2.6.1.1 
Corneal fluorescein staining (Ora Calibra® Scale) 
All Randomized Subjects 
16.2.6.1.2 
Corneal fluorescein staining (NEI Scale)  
All Randomized Subjects 
16.2.6.2 
Ocular Discomfort 
All Randomized Subjects 
16.2.6.3.1 
Lissamine Green Staining (Ora Calibra® Scale) 
All Randomized Subjects 
16.2.6.3.2 
Lissamine Green Staining (NEI Scale) 
All Randomized Subjects 
16.2.6.4 
Tear Film Break-up Time (TFBUT) 
All Randomized Subjects 
16.2.6.5 
Conjunctival Redness 
All Randomized Subjects 
16.2.6.6 
Unanesthetized Schirmer’s Test (Post-CAE) 
All Randomized Subjects 
16.2.6.7.1 
Ora Calibra®  Drop Comfort Scale 
All Randomized Subjects 
16.2.6.7.2 
Ora Calibra®  Drop Comfort Questionnaire 
All Randomized Subjects 
16.2.6.8 
Ocular Surface Disease Index (OSDI, Pre-CAE®) 
All Randomized Subjects 
16.2.6.9.1  
Ora Calibra®  Ocular Discomfort & 4-Symptom Questionnaire 
All Randomized Subjects 
16.2.6.9.2 
Ocular Symptoms of Dry Eye Syndrome – Visual Analog Scale 
(VAS) 
All Randomized Subjects 
16.2.6.10 
Ora Calibra®  Ocular Discomfort Scale During CAE® Exposure 
All Randomized Subjects 
16.2.6.11 
Diary Assessments 
All Randomized Subjects 
16.2.6.12 
Lid Margin Redness (Pre-CAE®) 
All Randomized Subjects 
16.2.6.13 
Posterior Lid Edge Evaluation (Pre-CAE®) 
All Randomized Subjects 
16.2.6.14 
Ocular Protection Index (OPI) 2.0 (Pre-CAE®) 
All Randomized Subjects 
16.2.6.15 
Impression Cytology (OPIA EyeprimTM) 
All Randomized Subjects 
16.2.7.1 
All Adverse Events 
Safety Population 
16.2.7.2 
Serious Adverse Events 
Safety Population 
16.2.7.3 
Adverse Events Leading to Treatment Discontinuation 
Safety Population 
16.2.7.4 
Deaths 
Safety Population 
16.2.8.1 
Visual Acuity (logMAR) 
Safety Population 
16.2.8.2 
Slit Lamp Biomicroscopy 
Safety Population 
16.2.8.3 
Intraocular Pressure (Post-CAE) 
Safety Population 


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Listing 
Number 
Title 
POPULATION 
16.2.8.4 
Undilated Fundoscopy (Post-CAE) 
Safety Population 
16.2.8.5 
Corneal Sensitivity (Cochet-Bonnet) (Pre-CAE) 
Safety Population 
16.2.8.6 
Urine Pregnancy Test Results 
Safety Population 
16.2.8.7 
Vital Signs 
Safety Population 
23. Figures 
Figures that will be included in the topline delivery are shown in boldface font. 
Figure Number Figure Title 
Population 
Figure 14.2.3.1 Total Corneal Fluorescein Staining as Measured by the Ora Calibra® 
Scale at Each Visit - Worst Eye (Pre-CAE® to Post-CAE® Change) 
mITT Population 
Figure 14.2.3.2 
Total Corneal Fluorescein Staining as Measured by the Ora Calibra® Scale at 
Each Visit - Worst Eye (Pre-CAE® to Post-CAE® Change from Baseline) 
mITT Population 
Figure 14.2.3.3 Ocular Discomfort as Measured by the Ora Calibra® Scale at Each Visit 
(Pre-CAE® to Post-CAE® Change) 
mITT Population 
Figure 14.2.3.4 
Ocular Discomfort as Measured by the Ora Calibra® Scale at Each Visit (Pre-
CAE® to Post-CAE® Change from Baseline) 
mITT Population 
Figure 14.2.3.5 
Ocular Symptoms of Dry Eye Syndrome – Visual Analog Scale (VAS) at Each 
Visit (Change from Baseline Pre-CAE®)    
mITT Population 
Figure 14.2.3.6 
Corneal Fluorescein Staining (NEI Scale) at Each Visit (Change from Baseline 
Pre-CAE®)    
mITT Population 
Figure 14.2.3.7 
Lissamine Green Staining (NEI Scale)at Each Visit (Change from Baseline Pre-
CAE®) 
mITT Population