A Study Assessing the Safety, Efficacy, and Optimum Dosage of K-161 in Subjects With Moderate to Severe Dry Eye Disease
Phase: PHASE2
Conditions: Dry Eye Disease
Sponsor: Kowa Research Institute, Inc.

K-161-2.01US 
 
 
A Phase 2, Prospective, Double-Masked, Randomized, Multi-Center, Vehicle-Controlled, 
Parallel-group, 4-week Administration Study Assessing the Safety, Efficacy, and 
Optimum Dosage of K-161 in non-Japanese and Japanese Adult Subjects with Moderate 
to Severe Dry Eye Disease Both in Environmental and Controlled Adverse Environmental 
(CAE®) Settings 
 
NCT #: 04084483 
Clinical Trial Protocol 
Ver. 1.0 
 14 September 2018 
 

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Clinical Trial Protocol: K-161-2.01US 
Protocol Title: 
A Phase 2, Prospective, Double-Masked, 
Randomized, Multi-Center, Vehicle-Controlled, 
Parallel-group, 4-week Administration Study 
Assessing the Safety, Efficacy, and Optimum 
Dosage of K-161 in non-Japanese and Japanese 
Adult Subjects with Moderate to Severe Dry Eye 
Disease Both in Environmental and Controlled 
Adverse Environmental (CAE®) Settings 
Protocol Number: 
K-161-2.01US 
Study Phase: 
2 
Investigational Product Name: K-161 
IND/IDE/PMA Number: 
N/A 
Indication: 
Dry eye disease 
Investigators: 
Multi-Center 
Sponsor: 
Kowa Research Institute, Inc. (KRI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Original Protocol: 
14 September 2018 
Amendment 1: 
- 
 
 
Confidentiality Statement 
 
This protocol contains confidential, proprietary information of 
. and/or Kowa 
Research Institute, Inc. Further dissemination, distribution or copying of this protocol or 
its contents is strictly prohibited. 
 

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SPONSOR PERSONNEL 
 
 
MEDICAL MONITOR 
 
 

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SYNOPSIS 
Protocol Title: 
A Phase 2, Prospective, Double-Masked, 
Randomized, Multi-Center, Vehicle-Controlled, 
Parallel-group, 4-week Administration Study 
Assessing the Safety, Efficacy, and Optimum 
Dosage of K-161 in non-Japanese and Japanese 
Adult Subjects with Moderate to Severe Dry Eye 
Disease Both in Environmental and Controlled 
Adverse Environmental (CAE) Settings 
Protocol Number: 
K-161-2.01US 
Investigational Product: 
1. K-161 Ophthalmic Solution 
2. Placebo Ophthalmic Solution (Vehicle) 
Study Phase: 
2 
Objective(s): 
The objective of the study is to assess the safety, 
efficacy, optimum dosage, and dosing regimen of K-
161 compared to its vehicle from Day 1 (baseline) to 
Day 29 in non-Japanese and Japanese adult subjects 
with moderate to severe dry eye disease both in 
environmental and CAE settings. 
Overall Study Design: 
Structure: 
Prospective, double-masked, randomized, multi-
center, vehicle-controlled, parallel-group study 
Duration: 
An individual subject’s participation is estimated to 
be approximately 6 weeks (42 days) with a follow-
up phone call. 
Controls: 
Placebo Ophthalmic Solution (Vehicle) 
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
Subjects eligible to be randomized will receive one 
of the following treatments to be administered 
bilaterally for 28 days (from Visit 2 to Visit 5). 
1) 
 K-161 Ophthalmic Solution; 
 
 
2) 
 K-161 Ophthalmic Solution; 
 
 
3) 
 K-161 Ophthalmic Solution; 
 
  
4) Placebo Ophthalmic Solution (Vehicle); 
 
 
During a 14-day study run-in period (for the purpose 
of subject selection) prior to randomization, all 

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subjects will receive Placebo Ophthalmic Solution 
(Vehicle) 
 
Summary of Visit Schedule: 
5 visits over the course of approximately 6 weeks 
with a follow-up phone call. 
• Visit 1 = Day -14 ± 2, CAE Screening  
• Visit 2 = Day 1, CAE Confirmation/ Baseline 
• Visit 3 = Day 8 ± 1 
• Visit 4 = Day 15 ± 2 
• Visit 5 = Day 29 ± 2 
Measures Taken to Reduce 
Bias: 
This is a double-masked, randomized treatment 
assignment study. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 600 subjects will be screened to 
enroll approximately 240 (60 per treatment arm*) 
subjects 
 
Condition/Disease: 
Dry Eye Disease (DED) 
Inclusion Criteria: 
Subjects who meet all of the following criteria will be eligible to participate in the 
study. 
Subjects must: 
1. Be at least 18 years of age at the time of informed consent visit 
2. Have a reported history of dry eye disease in both eyes 
 
 and a history of eye drop use for dry eye symptoms 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
  
  
 
 

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Exclusion Criteria: 
Subjects who meet any of the following criteria will not be eligible to participate in the 

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study. 
Subjects must not: 
1. Have any ocular condition 
 
 
2. Have a history of 
 
corneal refractive surgery within 12 months prior to Visit 1, and/or any other 
ocular surgical procedure 
 within 12 
months
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Evaluation Criteria: 
 
Efficacy Measures and 
Endpoints: 
Primary Efficacy Endpoints: 
The primary efficacy endpoint (sign) is: 
• Change in inferior corneal staining score 
from Day 1 (baseline) to Day 29 by 
comparing 
 K-161 
 to its 
vehicle 
 in CAE setting 
The primary efficacy endpoint (symptom) is: 
• Change in Ora Calibra® ODS from Day 1 
(baseline) to Day 29 by comparing 
 K-
161 
 to its vehicle 
 in 
CAE setting 
Important Secondary Efficacy Endpoints: 
The important secondary efficacy endpoints are: 
• Change in Schirmer’s Test value 
(unanesthetized) from Day 1 (baseline) to 
Day 29 by comparing 
 K-161 
 

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 to its vehicle 
 in 
environmental setting 
• Change in TFBUT from Day 1 (baseline) to 
Day 29 by comparing 
 K-161 
 
 to its vehicle 
 in CAE setting 
Secondary Efficacy Endpoints: 
The secondary efficacy endpoints are: 
• Fluorescein staining by region: central, 
superior, inferior, temporal, nasal and 
corneal sum as assessed by the Ora Calibra® 
Corneal and Conjunctival Staining Scale 
• Lissamine green staining by region: central, 
superior, inferior, temporal, nasal, and 
conjunctival sum as assessed by the Ora 
Calibra® Corneal and Conjunctival Staining 
Scale 
• Conjunctival Redness as assessed by the Ora 
Calibra® Scale 
• TFBUT  
• Tear Osmolarity 
• Schirmer’s Test (unanesthetized) 
• Blink Rate 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort and 4-
Symptom Questionnaire  
• Visual Analog Scale (VAS)   
 Burning/ Stinging 
 Itching 
 Foreign Body Sensation 
 Blurred Vision 
 Eye Dryness 
 Photophobia 
 Pain 
• OSDI©  
• Daily diary  

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Safety Measures: 
 
 
  
 
 
• Adverse event query  
 
  
 
 
 
 
• Maximum dose tolerability by comparing the 
 K-161 
 arm to the 
 and 
 K-161 
 arms 
Other: 
Analysis Populations 
• Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. The primary analysis will be performed on the ITT 
population. Subjects in the ITT population will be analyzed as randomized. 
• Per Protocol Population – The per protocol (PP) population includes subjects in 
the ITT population who do not have significant protocol deviations and who 
complete the study. Protocol deviations will be assessed prior to database lock 

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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. The safety population 
will be analyzed for all safety assessments. Subjects in the Safety population 
will be analyzed as treated.  
Sample Size 
This study is expected to enroll 240 subjects in a 1:1:1:1 ratio across four treatment 
arms, or 60 subjects per treatment arm. In addition, randomization will be stratified such 
that 
 will be randomized in each treatment arm.  
The standard deviation for change from baseline in post-CAE inferior corneal 
fluorescein staining ranges between 0.68 and 0.81 units. Assuming a common standard 
deviation of 0.77, a sample size of 60 subjects per group will have approximately 90% 
power to detect a difference of 0.46 units between the active treatment group and the 
vehicle group using a two-sample t-test at a two-sided significance level of 0.05. Again, 
it is assumed that adjusting for baseline and site will further reduce variability and 
provide >90% power. 
Likewise, the standard deviation for change from baseline scores in the post-CAE ODS 
at Day 29 is assumed a common standard deviation of 0.82, a sample size of 60 subjects 
per group will have approximately 90% power to detect a difference of 0.49 units 
between the active treatment group and the vehicle group using a two-sample t-test at a 
two-sided significance level of 0.05. It is assumed that adjusting for baseline and site 
will further reduce variability and provide >90% power. 
Multiplicity Consideration: 
Common factors for multiplicity are multiple arms and multiple endpoints. 
1) Multiple arms 
The primary treatment comparison will be between the 
 K-161 
 treatment arm 
and the vehicle 
 treatment arm. Other treatment comparisons will be considered 
secondary or exploratory.  
2) Multiple endpoints 
The primary and important secondary endpoints will be tested hierarchically to maintain 
the study-wise Type I error rate of 0.05. First, change from baseline in inferior corneal 
fluorescein staining will be tested at an alpha level of 0.05. The test for change from 
baseline scores in the ODS will be conducted at an alpha level of 0.05 only if the 
previous test demonstrates significance. The test for change from baseline in Schirmer’s 
test will be conducted at an alpha level of 0.05 only if the previous test demonstrates 
significance. The test for change from baseline in TFBUT will be conducted at an alpha 
level of 0.05 only if the previous test demonstrates significance. All other secondary and 
exploratory endpoints and treatment comparisons will be considered exploratory. 
The hierarchical testing order will be as follows: 
Primary comparisons: 

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1. Comparison of the change from baseline in post-CAE inferior corneal staining at 
Day 29 (
 K-161 
 vs vehicle) 
2. Comparison of the change from baseline in post-CAE ocular discomfort at Day 
29 (
 K-161 
 vs vehicle) 
Important Secondary comparisons: 
3. Comparison of the change from baseline in pre-CAE Schirmer’s test value at 
Day 29 (
 K-161 
 vs vehicle) 
4. Comparison of the change from baseline in post-CAE TFBUT at Day 29 (
 
K-161 
 vs vehicle) 
Thus, the study-wise Type I error rate will be maintained at 0.05 by considering only 
one dose of K-161 as the primary treatment comparison and using a hierarchical testing 
procedure. 
Primary Efficacy Analyses:  
The primary comparisons of change from baseline in post-CAE inferior corneal staining 
and ocular discomfort between the 
 K-161 
 group and the vehicle group at Day 
29, will be performed using analysis of covariance (ANCOVA) models. The respective 
baseline post-CAE score will be included as a covariate in each model and site will be 
included as a fixed effect. Treatment by baseline and treatment by site interactions will 
be explored in separate models and, if significant, analyses will be performed by 
baseline stratification and/or site, respectively, to further examine significant 
interactions. In addition, unadjusted two-sample t-tests and Wilcoxon rank-sum tests 
will be performed for each comparison as sensitivity analyses. The primary analyses 
will use the ITT population. 
For the primary endpoints multiple imputation with a control-based pattern mixture 
model will be used.  
Secondary Efficacy Analyses 
Secondary and exploratory endpoints will be analyzed similarly to the primary analyses 
on the ITT population. Continuous and ordinal variables collected at each visit will be 
summarized descriptively (n, mean, standard deviation, median, minimum and 
maximum), and analyzed with ANCOVA models and two-sample, two-sided t-tests 
comparing each K-161 
 group to the vehicle group. All visit-based data will be 
analyzed by visit and for each timepoint, if applicable, as well as the change from 
baseline.  
Data collected pre- and post-CAE will also be analyzed for the change from pre- to 
post-CAE within each visit. Data collected during the CAE will also be analyzed using 
repeated measures models including all of the time points from a CAE exposure. Daily 
subject diary symptom data will be analyzed using each weekly average score from the 
diaries, as well as using repeated measures models across the diary collection period. 
For the two important secondary endpoints, other secondary, and exploratory endpoints, 
multiple imputation with a control-based pattern mixture model will be used.   

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Safety Variables 
Adverse events (AEs) 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; 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 TEAEs; and by system organ class, preferred term, and study day of onset. 
Separate summaries will be performed for ocular and non-ocular AEs.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Other analyses may be conducted and the details will be included in a separate statistical 
analysis plan. 
 
 
 
 
 
 

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TABLE OF CONTENTS 
Clinical Trial Protocol: K-161-2.01US ................................................................................1 
SYNOPSIS ...........................................................................................................................3 
TABLE OF CONTENTS ...................................................................................................14 
LIST OF ABBREVIATIONS ............................................................................................18 
1 
INTRODUCTION ....................................................................................................20 
 
Drug Profile from Non-clinical Studies .........................................................20 
1.1
2 
STUDY OBJECTIVES .............................................................................................21 
3 
CLINICAL HYPOTHESES .....................................................................................21 
4 
OVERALL STUDY DESIGN ..................................................................................21 
5 
STUDY POPULATION ...........................................................................................22 
 
Number of Subjects (approximate) ................................................................22 
5.1
 
Study Population Characteristics ....................................................................22 
5.2
 
Inclusion Criteria ............................................................................................22 
5.3
 
Exclusion Criteria ...........................................................................................24 
5.4
 
Withdrawal Criteria (if applicable) ................................................................25 
5.5
6 
STUDY PARAMETERS ..........................................................................................26 
 
Efficacy Endpoints .........................................................................................26 
6.1
6.1.1 
Primary Efficacy Endpoints ..............................................................26 
6.1.2 
Important Secondary Efficacy Endpoints .........................................26 
6.1.3 
Secondary Efficacy Endpoints ..........................................................26 
6.1.4 
Exploratory Efficacy Endpoints ........................................................27 
 
Safety Measures .............................................................................................27 
6.2
 
Other Measures ...............................................................................................27 
6.3
 
 
 
 
 
 
 
Clinical Laboratory Measurements ................................................................28 
6.7
7 
STUDY MATERIALS .............................................................................................29 
 
Study Treatments ............................................................................................29 
7.1
7.1.1 
Masking.............................................................................................29 
7.1.2 
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period. ...........................29 

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7.1.3 
Instructions for Use and Administration ...........................................29 
 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
7.2
Investigational Product ...................................................................................30 
7.2.1 
Labeling/Packaging...........................................................................30 
7.2.2 
Storage of Investigational Product ....................................................30 
7.2.3 
Accountability of Investigational Product ........................................30 
7.2.4 
Return or Disposal of Investigational Product ..................................30 
 
Other Study Supplies ......................................................................................30 
7.3
8 
STUDY METHODS AND PROCEDURES ............................................................31 
 
Subject Entry Procedures ...............................................................................31 
8.1
8.1.1 
Overview ...........................................................................................31 
8.1.2 
Informed Consent..............................................................................31 
8.1.3 
Washout Intervals .............................................................................31 
8.1.4 
Procedures for Final Study Entry ......................................................31 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................31 
 
Concurrent Therapies .....................................................................................32 
8.2
8.2.1 
Prohibited Medications/Treatments ..................................................32 
8.2.2 
Escape Medications ..........................................................................32 
8.2.3 
Special Diet or Activities ..................................................................32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of Visits, Measurements and Dosing ..............................................39 
8.4
8.4.1 
Scheduled Visits................................................................................39 
8.4.2 
Unscheduled Visits ...........................................................................40 
 
Compliance with Protocol ..............................................................................40 
8.5
 
Subject Disposition .........................................................................................40 
8.6

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8.6.1 
Completed Subjects ..........................................................................40 
8.6.2 
Discontinued Subjects .......................................................................41 
 
Study Termination ..........................................................................................41 
8.7
 
Study Duration ...............................................................................................41 
8.8
 
Monitoring and Quality Assurance ................................................................41 
8.9
9 
ADVERSE EVENTS ................................................................................................41 
 
Adverse Event ................................................................................................41 
9.1
9.1.1 
Severity .............................................................................................42 
9.1.2 
Relationship to Investigational Product ............................................42 
9.1.3 
Expectedness .....................................................................................43 
 
Serious Adverse Events ..................................................................................44 
9.2
 
Procedures for Reporting Serious Adverse Events ........................................44 
9.3
9.3.1 
Reporting a Serious Unexpected Suspected Adverse Reaction ........45 
9.3.2 
Reporting a Serious Adverse Event ..................................................45 
 
Procedures for Unmasking (if applicable) ......................................................46 
9.4
 
Type and Duration of the Follow-up of Subjects after Adverse Events ........47 
9.5
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................47 
 Analysis Populations ......................................................................................47 
10.1
 Statistical Hypotheses .....................................................................................47 
10.2
 Sample Size ....................................................................................................48 
10.3
 Statistical Analysis .........................................................................................48 
10.4
10.4.1 General Considerations .....................................................................48 
10.4.2 Unit of Analysis ................................................................................49 
10.4.3 Missing Data .....................................................................................49 
10.4.4 Multiplicity Consideration ................................................................49 
10.4.5 Efficacy Analyses .............................................................................50 
10.4.6 Safety Variables ................................................................................51 
10.4.7 Exploratory Safety Analyses.............................................................51 
 
 
 
10.4.11 Interim Analyses ...............................................................................52 

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11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................52 
 Protection of Human Subjects ........................................................................52 
11.1
11.1.1 Subject Informed Consent.................................................................52 
11.1.2 Institutional Review Board (IRB) Approval .....................................53 
 Ethical Conduct of the Study ..........................................................................53 
11.2
 Subject Confidentiality ...................................................................................53 
11.3
 Documentation ...............................................................................................53 
11.4
11.4.1 Retention of Documentation .............................................................53 
 Recording of Data on Source Documents and Case Reports Forms (CRFs) .54 
11.5
 Publications ....................................................................................................54 
11.6
12 
REFERENCES .........................................................................................................55 
13 
APPENDICES ..........................................................................................................56 
Appendix 1: Schedule of Visits and Measurements ..........................................................56 
Appendix 2: Examination Procedures, Tests, & Evaluations ............................................58 
Appendix 3: Protocol Amendment Summary ....................................................................73 
 
Appendix 5: Investigator’s Signature ................................................................................75 
 
 

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LIST OF ABBREVIATIONS 
AE 
adverse event 
 
 
 
 
CAE 
controlled adverse environment 
CFR 
Code of Federal Regulations 
 
 
 
 
CRF 
case report form 
CRO 
contract research organization 
 
 
DED 
dry eye disease 
eCRF 
electronic case report form 
 
 
 
 
FDA 
Food and Drug Administration 
 
 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
 
 
 
 
IND 
investigational new drug application 
 
 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
IWRS 
interactive web response system 
 
 
LASIK 
laser in situ keratomileusis 
LOCF 
last observation carried forward 
 
 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 

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NCS 
not clinically significant 
ODS 
Ocular Discomfort Score 
OSDI 
Ocular Surface Disease Index 
 
 
PP 
per protocol 
 
 
SAE 
serious adverse event 
 
 
SOP 
standard operating procedure 
 
 
TFBUT 
tear film break-up time 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1 INTRODUCTION 
Dry eye disease is a multifactorial, progressive disorder of the ocular surface resulting 
from insufficient tear coverage of the surface of the eye in combination with ocular 
surface inflammation. Patients with DED often experience severe pain, visual 
impairment, tear film hyperosmolarity and instability, inflammation, and corneal 
wounding. While the prevalence of DED is difficult to report due to varying definitions 
and diagnostic criteria, the global prevalence of DED is estimated to be between 5% and 
50%, and increases with age (Bron et al. 2017). In the United States, it is estimated that 
as many as 3.2 million women and 1.7 million men over the age of 50 have DED, with a 
projected 40% increase in number of patients affected by 2030 (Schaumberg et al. 2002, 
Schaumberg et al. 2003, Schaumberg et al. 2009). 
Current treatment and management of DED consists primarily of tear supplementation 
with lubricants (artificial tears). While artificial tears improve symptoms associated with 
DED, they have no effect on resolving the underlying conditions that lead to 
inflammation of the ocular surface. Three currently available options for treating 
inflammation at the ocular surface are Restasis® (cyclosporine ophthalmic emulsion) 
CEQUA™ (cyclosporine ophthalmic solution), and Xiidra® (lifitegrast ophthalmic 
solution). It has been shown that only 15% of patients respond to Restasis® after 6 
months of treatment, as measured by Schirmer’s test, and many more report ocular side-
effects such as burning and stinging (Mah et al. 2012). Xiidra® has also been shown to be 
associated with ocular adverse events; in a clinical study of Xiidra® for subjects with 
DED, subjects reported increased ocular irritation upon instillation with Xiidra® 
compared to placebo (7.8% compared to 1.4% in the placebo group) (Tauber et al. 2015). 
Similarly, common adverse reactions reported after use of CEQUA include instillation 
site pain and conjunctival hyperemia (CEQUA 2018). Thus, there remains a medical need 
for more efficacious treatment options with a more favorable safety and comfort profile 
for patients with DED.  
 Drug Profile from Non-clinical Studies 
1.1
 a tyrosine kinase involved in 
cytokine signaling and activation of lymphocytes. 
 have been shown to 
have potent anti-inflammatory activity both in vitro and in vivo 
 
. 
 
 was shown to suppress ocular surface inflammation 
and corneal injury in a mouse model of dry eye disease (
). Because 
inflammation is a key component of DED, targeting the inflammatory pathway via 
 
 to reduce cytokine production and/or immune cell infiltration at the ocular 
surface may reduce the signs and symptoms of DED. 
 
 

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This will be the first clinical study of K-161 Ophthalmic Solution. 
2 STUDY OBJECTIVES 
Prior to any changes in a subject’s medical treatment and/or study visit procedures, the 
study will be discussed with each subject and subjects wishing to participate must give 
written informed consent (and/or assent) and sign a HIPAA form.  
The objectives of the study are to assess the safety, efficacy, optimum dosage, and dosing 
regimen of K-161 compared to its vehicle from Day 1 (baseline) to Day 29 in non-
Japanese and Japanese adult subjects with moderate to severe dry eye disease both in 
environmental and Controlled Adverse Environment (CAE) settings. 
3 CLINICAL HYPOTHESES 
The clinical hypotheses for this study is that 
 K-161 Ophthalmic Solution 
 
 (
 is superior to its vehicle (
 for the primary endpoints of signs and 
symptoms of dry eye, as follows:  
• Sign: Post-CAE inferior corneal fluorescein staining score on the Ora Calibra® 
scale, measured by mean change from baseline (Visit 2) to Visit 5 
• Symptom: Post-CAE ocular discomfort scale on the Ora Calibra® scale, measured 
by mean change from baseline (Visit 2) to Visit 5 
4 OVERALL STUDY DESIGN 
This is a Phase 2, multicenter, randomized, double-masked, vehicle-controlled, parallel-
group design with block enrollment. Subjects will be randomized to one of the following 
treatment groups at Visit 2:  
• 
 K-161; 
 (
 
 (N=~60) 
• 
 K-161; 
 
 (N=~60) 
• 
 K-161; 
 (
 
 (N=~60)  
• Placebo Ophthalmic Solution (Vehicle); 
 
 (N=~60) 
Approximately 240 subjects will be randomly assigned to one of the four treatment 
groups (1:1:1:1).
 
 Subjects, Sponsor, Contract research 
organization (CRO), and site personnel will be masked to treatment assignment. To 
ensure masking, a dedicated unmasked staff member/technician will be delegated to 
dispense and observe instillation of randomized study drug and collect randomized study 
drug from a subject for drug accountability. This person cannot perform any other study-
related procedures. Additionally, the informed consent form (ICF) will not indicate any 
relationship between dosing regimen and treatment. Subjects will be instructed not to 
discuss their assigned dosing regimen or perceived treatment effects with other study 
participants. 

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During the screening period, two 90-minute exposures to the CAE will be conducted to 
ascertain eligibility to enter the study. Subjects who qualify after the initial screening visit 
will enter the run-in phase, where they will self-administer vehicle 
 for 
approximately 14 days. Those who qualify at Visit 2 (Day 1) will be randomized to 
receive study drug in a double-masked fashion for 28 days. Randomization will be 
stratified on Visit 2 Post-CAE inferior fluorescein staining and Post-CAE ocular 
discomfort on the Ora Calibra® scale. Subjects will self-administer drops either 
 or 
 and will complete daily diary assessments as instructed. 
At Visit 4 (Day 15) and Visit 5 (Day 29), CAE exposure will occur, with pre-CAE, 
during CAE (symptoms only) and post-CAE assessments of ocular signs and symptoms. 
At Visit 3, no CAE exposure will occur but signs and symptoms will be assessed. Study 
drug will be discontinued at Visit 5. Subjects will exit from the study at this visit. The 
follow-up phone call will occur about 7 days after the final day of randomized study drug 
treatment. 
The timing of visit including each examinations should be consistent in each subject 
through the study phase. 
5 STUDY POPULATION 
 Number of Subjects (approximate) 
5.1
It is estimated that approximately 600 subjects will be screened to enroll approximately 
240 randomized subjects (60 in each group). 
 
Subjects will 
be randomized in a 1:1:1:1 ratio of  
• 
 K-161; 
 
• 
 K-161; 
 
• 
 K-161; 
     
• Placebo Ophthalmic Solution (Vehicle); 
  
 Study Population Characteristics 
5.2
All subjects must be at least 18 years of age, of either gender, and of any race, and must 
meet all inclusion criteria and none of the exclusion criteria. 
 Inclusion Criteria 
5.3
Each subject must: 
1. Be at least 18 years of age at the time of informed consent visit 
2. Have a reported history of dry eye disease in both eyes 
 
 and have a history of eye drop use for dry eye symptoms 
 
 
  
 

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 Exclusion Criteria 
5.4
Each subject may not: 
1. Have any ocular condition
 
 
 
 
2. Have a history of 
 
corneal refractive surgery within 12 months prior to Visit 1, and/or any other 
ocular surgical procedure 
 within 12 months 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 Withdrawal Criteria (if applicable) 
5.5
If at any time during the study the investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from the study. 
Subjects may withdraw consent from the study at any time. 
Sponsor and/or investigator may discontinue any subject for non-compliance or any valid 
medical reason (see Section 8.6.2). 
The subject has the right to withdraw from the study at any time. Nevertheless, in this 
study, every attempt will be made to prevent missing data and to obtain complete follow 
up of all subjects during the study period. Investigators will be trained to minimize full 
withdrawals from the study period wherever possible. Subjects who discontinue study 
drug during the study period are not required to withdraw from the study. These subjects 

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will be encouraged to remain in the study and asked to conduct the remaining study visits 
as outlined in the protocol through Visit 5. If a subject fails to actively maintain contact 
with the Investigator, reasonable efforts (telephone calls to family members or friends, e-
mail contacts, etc.) will be made in order to encourage the subject to complete the study 
visits. 
6 STUDY PARAMETERS 
 Efficacy Endpoints 
6.1
6.1.1 Primary Efficacy Endpoints 
The primary efficacy endpoint (sign) is: 
• Change in inferior corneal staining score from Day 1 (baseline) to Day 29 by 
comparing 
 K-161 
 to its vehicle 
 in CAE setting 
The primary efficacy endpoint (symptom) is: 
• Change in Ora Calibra® ODS from Day 1 (baseline) to Day 29 by comparing 
 K-161 
 to its vehicle 
 in CAE setting 
6.1.2 Important Secondary Efficacy Endpoints 
The important secondary endpoints are: 
• Change in Schirmer’s Test value (unanesthetized) from Day 1 (baseline) to Day 
29 by comparing 
 K-161 
 to its vehicle 
 in 
environmental setting 
• Change in TFBUT from Day 1 (baseline) to Day 29 by comparing 
 K-161 
 to its vehicle 
 in CAE setting 
6.1.3 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are compared between vehicle 
 and K-161 
 
(i.e., 
 K-161 
 and 
 K-161 
) for: 
• Fluorescein staining by region: central, superior, inferior, temporal, nasal and 
corneal sum as assessed by the Ora Calibra® Corneal and Conjunctival Staining 
Scale 
• Lissamine green staining by region: central, superior, inferior, temporal, nasal, 
and conjunctival sum as assessed by the Ora Calibra® Corneal and Conjunctival 
Staining Scale 
• Conjunctival Redness as assessed by the Ora Calibra® Scale 
• TFBUT  
• Tear Osmolarity 
• Schirmer’s Test (unanesthetized) 
• Blink Rate 

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• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire  
• Visual Analog Scale (VAS)   
 Burning/ Stinging 
 Itching 
 Foreign Body Sensation 
 Blurred Vision 
 Eye Dryness 
 Photophobia 
 Pain 
• OSDI©  
• Daily diary  
6.1.4 
 
 
 
 
 
 
 
 
 
 
 
 
 Safety Measures 
6.2
The safety measures being evaluated are: 
 
  
 
 
• 
AE query 
 
 
 
 
 
 
 
 
• 
Maximum dose tolerability by comparing the 
 K-161 
 arm to the 
 and 
 K-161 
 arms 
 Other Measures 
6.3
The other measures being evaluated are: 

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6.4
 
 
 
 
6.5
 
 
 
  
 
 
 
 
   
 
 
6.6
 
 
 
 
 Clinical Laboratory Measurements 
6.7
The following assessments are being conducted: 
Hematology: 
 
 
  
Clinical chemistry:
 
 
 

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Urinalysis: 
 
 
7 STUDY MATERIALS 
 Study Treatments 
7.1
7.1.1 Masking 
All arms will be double-masked. To ensure masking, an unmasked technician delegated 
by the Investigator will perform all study drug instruction, dispensation, collection and 
accountability. This technician cannot perform any other study visit procedures. Study 
Treatments/Formulations 
• 
 K-161; 
 
• 
 K-161; 
 
• 
 K-161; 
    
• Placebo Ophthalmic Solution (Vehicle); 
  
7.1.2 Description of and Justification for the Route of Administration, Dosage, 
Dosage Regimen, and Treatment Period. 
Topical ophthalmic dosing is the optimal route of administration for dry eye treatments. 
The dosage and dosage regimen were selected based on non-clinical studies. The 
proposed treatment period of 4 weeks is based on results from pre-clinical studies and on 
the anti-inflammatory mechanism of action of the drug. 
7.1.3 Instructions for Use and Administration 
Subjects who were randomized to 
 arm must administer study drug at 
 
. Subjects who were randomized to 
 arm must at 
 If missed, the subject must not administer the eye drop if the next dosing is in 
less than 2 hours. At Visits 2, 3, 4, and 5, all subjects must visit their study sites without 
administering any topical ophthalmic preparations, including study drug, and must not 
administer topical ophthalmic preparations until all examinations are finished. Subjects, 
Sponsor, CRO, and site personnel (with the exception of the following person) will be 
masked to treatment assignment. To ensure masking, a dedicated unmasked staff 
member/technician will be delegated to dispense and observe instillation of randomized 
study drug and collect randomized study drug from a subject for drug accountability. This 
person cannot perform any other study-related procedures. Additionally, the informed 
consent form (ICF) will not indicate any relationship between dosing regimen and 
treatment. Subjects will be instructed not to discuss their assigned dosing regimen or any 
perceived treatment effects with other study participants. 

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 Labeling, Packaging, Storage, Accountability, and Return or 
7.2
Disposal of Investigational Product 
7.2.1 Labeling/Packaging 
Investigational product (IP) will be packaged and labeled into clinical kits. 
Run-in Period 
For the run-in period,
 
 to provide a sufficient 
medication supply.  
Treatment Period 
 For the treatment period, 
 
 to provide a 
sufficient supply of randomized study drug. 
 For the treatment period, 
 
 to provide a 
sufficient supply of randomized study drug. 
7.2.2 Storage of Investigational Product 
The study drugs must be stored in a secure area accessible only to the investigator and 
his/her designees.K-161 drug product must be stored at controlled room temperature of 
20-25°C (68-77°F) with excursions permitted between 15°C and 30°C (59-86°F) as 
indicated on the drug label.  
7.2.3 Accountability of Investigational Product 
The IP is 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 IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed upon the completion of 
the study. A detailed inventory must be completed for the IP. Study drug accountability 
will be performed by an Unmasked Technician as delegated by the Investigator. To 
ensure masking, a dedicated unmasked staff member/technician will be delegated to 
dispense and collect randomized study drug from a subject for drug accountability. This 
person cannot perform any other study-related procedures. 
7.2.4 Return or Disposal of Investigational Product 
All IP (used or unused) will be returned to the sponsor or their designee. The return of IP 
will be specified in writing. 
 Other Study Supplies 
7.3
Other study supplies include 
 Schirmer’s test strips, Tear 
meniscometry strips, sodium fluorescein, lissamine green, 
 Tear 

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Osmolarity cards and
 
 
8 STUDY METHODS AND PROCEDURES 
 Subject Entry Procedures 
8.1
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2 and 5.3 will be considered for entry into 
this study. 
8.1.2 Informed Consent 
Prior to a subject’s participation in the study (i.e., changes in a subject’s medical 
treatment and/or 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. The informed consent form must be the most recent version that has 
received approval/favorable review by a properly constituted Institutional Review Board 
(IRB). 
8.1.3 Washout Intervals 
Prohibited medications, treatments, and activities are outlined in the exclusion criteria 
(Section 5.4). 
8.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion and none of the exclusion criteria (Section 5.3 and 5.4). 
8.1.5 Methods for Assignment to Treatment Groups: 
Before the initiation of study run-in at Visit 1, each subject who provides written 
informed consent will be assigned a screening number. All screening numbers will be 
assingned in strict numerical sequence at a site and no numbers will skipped or omitted. 
Each subject who meets all the inclusion and none of the exclusion criteria at Visit 1 and 
Visit 2 will be assigned a randomization number at the end of Visit 2. The Interactive 
Web Response System (IWRS) will be used to assign all randomization numbers. 
 
For the non-Japanese subjects, randomization will be further stratified by the following 
factors and cut-offs:  
 
 
 
 
 
 
 
 
 
 
 
 
 

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Randomization and kit numbers will be assigned automatically to each subject as they are 
entered into the IWRS.  
The site staff will dispense kit(s) required until the next visit. Both the randomization 
number and the dispensed study drug kit number(s) will be recorded on the subject’s 
source document and electronic case report form (eCRF). Subjects, Sponsor, CRO, and 
site personnel will be masked to treatment assignment. To ensure masking, a dedicated 
unmasked staff member/technician will be delegated to dispense and observe instillation 
of randomized study drug and collect randomized study drug from a subject for drug 
accountability. This person cannot perform any other study-related procedures. 
 Concurrent Therapies 
8.2
The use of any concurrent medication, prescription or OTC, is to be recorded on the 
subject’s source document and corresponding eCRF along with the reason the medication 
was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
Disallowed medications/treatments during the study are outlined in the Exclusion Criteria 
(Section 5.4).  
8.2.2 Escape Medications 
No escape medications are required for this study. 
8.2.3 Special Diet or Activities 
No special diets or activities are required for this study. 
 Examination Procedures 
8.3
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objectives 
Procedures listed below should be performed in the given order. See Appendix 1 for the 
Schedule of Visits and Measurements Appendix 2 for details on methodologies and 
grading systems. 
8.3.2 Visit 1: Day –14 ± 2 – CAE Screening  
All subjects will undergo the following screening assessments: 
  
• Informed Consent/HIPAA  
 
 
 
 
 
 

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• 
 
 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI© 
• Visual Analog Scale (VAS) 
 
 
 
  
• Conjunctival Redness 
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
 
 
 
 
 
 
 
 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Visual Analog Scale (VAS) 
 
 
• Conjunctival Redness 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
 
 
 
 
 
 
 
  

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• Run-in Instillation at the Study Site: All subjects having a positive response and 
meeting all other screening eligibility criteria at the end of Visit 1 will receive 
run-in drops for dosing.
 
 
• Ora Calibra® Drop Comfort Scale 
• 
Ora Calibra® Drop Comfort Questionnaire 
• Run-in (Vehicle) and Diary Dispensation: Prior to discharge from the study site 
on Day –14, subjects will be dispensed sufficient Run-in supply to last until Visit 
2 and will be educated in diary recording and self–administration of vehicle run-
in. 
 
 
  
• AE Query 
• Subjects will be scheduled for Visit 2. 
8.3.3 Visit 2: Day 1 – CAE Confirmation and Baseline 
  
• Study Diary/Run-in Collection 
 
 
• Medical/medication history update 
• AE query 
 
 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI© 
• Visual Analog Scale (VAS) 
 
 
 
  
• Conjunctival Redness 
• Blink Rate 
• Tear Osmolarity 
 
 
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  

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• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
 
 
 
 
 
 
 
 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Visual Analog Scale (VAS) 
 
 
 
 
• Conjunctival Redness 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
 
  
• Randomization  
• Study Drug Instillation at the Study Site: All subjects having a positive response 
and meeting all other screening eligibility criteria at the end of Visit 2 will be 
randomized to one of four treatment groups utilizing the IWRS system. 
 
  
• Ora Calibra® Drop Comfort Scale 
• Ora Calibra® Drop Comfort Questionnaire 
• Study Drug Diary/Study Drug Dispensation: Prior to discharge from the study site 
on Visit 2 (Day 1), randomized subjects will be educated in study drug diary 
recording and self–administration of study drug.
 
 
  
• AE Query 
• Subjects will be scheduled for Visit 3. 

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8.3.4 Visit 3: Day 8 ±1  
• Study Drug Diary/Study Drug Collection 
• Medical/medication history update 
• AE Query 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI© 
• Visual Analog Scale (VAS) 
 
 
 
  
• Conjunctival Redness 
• Blink Rate 
• Tear Osmolarity 
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
 Study Drug Diary/Study Drug Dispensation: Prior to discharge from the study site 
on Visit 3, subjects will be assigned a new study drug kit via the IWRS system for 
at-home dosing up to Visit 4. Subjects will again be educated in study drug diary 
recording and self–administration of study drug.
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 

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• 
 
 
• AE Query 
• Subjects will be scheduled for Visit 4. 
8.3.5 Visit 4: Day 15 ± 2  
 
• Study Drug Diary/Study Drug Collection 
• Medical/medication history update 
• AE query 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI© 
• Visual Analog Scale (VAS) 
 
 
 
  
• Conjunctival Redness 
• Blink Rate 
• Tear Osmolarity 
• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
 
 
 
 
 
 
 
 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Visual Analog Scale (VAS) 
 
 

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• Conjunctival Redness 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
 Study Drug Diary/Study Drug Dispensation: Prior to discharge from the study site 
on Visit 4, subjects will be assigned a new study drug kit via the IWRS system for 
at-home dosing up to Visit 5. Subjects will again be educated in study drug diary 
recording and self–administration of study drug.
 
 
• 
 
 
 
 
 
 
• AE Query 
• Subjects will be scheduled for Visit 5. 
8.3.6 Visit 5: Day 29 ± 2 
 
• Study Drug Diary/Study Drug Collection 
• Medical/medication history update 
• AE query 
 
 
 
  
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• OSDI© 
• Visual Analog Scale (VAS) 
 
 
 
  
• Conjunctival Redness 
• Blink Rate 
• Tear Osmolarity 
 
 

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• TFBUT 
• Fluorescein Staining  
• Lissamine Green Staining  
• At least 15-minute wait between lissamine green staining and Schirmer’s test 
• Schirmer’s test 
 
 
 
 
 
 
 
 
• Ora Calibra® Ocular Discomfort Scale  
• Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
• Visual Analog Scale (VAS) 
 
 
 
 
• Conjunctival Redness 
• TFBUT 
• Fluorescein Staining 
• Lissamine Green Staining 
 
 
 
 
 
 
• AE Query 
8.3.7 Follow-up phone call 
• Follow-up phone call (about 7 days after the final day of randomized study drug 
treatment) 
• AE query 
• Study exit 
 Schedule of Visits, Measurements and Dosing 
8.4
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 

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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 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: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• Assessment of AEs 
 
 
• Any other assessments needed in the judgment of the investigator. 
 Compliance with Protocol 
8.5
Subjects will be instructed on proper use of the subject daily diary and proper instillation 
and storage of study drug at the end of Visits 1, 2, 3, and 4, and given written 
instructions. The subject daily diaries, used and unused 
 will be 
collected at each visit from Visit 2 up to and including Visit 5 to assess dosing and 
symptom assessment compliance. Dosing compliance will be based on the used and 
. If the subject is less than 80% or more than 125% compliant with 
dosing based on 
 then the subject will be deemed 
non-compliant and a dosing deviation should be recorded.  
In the subject daily diary, if more than 20% of Dose 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 compliance for the study and for 
recording deviations from this compliance. 
 Subject Disposition 
8.6
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 

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8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• subject request/withdrawal 
• AEs 
• protocol violations 
• administrative reasons (e.g., inability to continue, lost to follow up) 
• sponsor termination of study 
• other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to 
 and/or sponsor and will be clearly documented on the eCRF. 
 Study Termination 
8.7
The study may be stopped at any time by the investigator, the sponsor, and/or 
 with 
appropriate notification. 
 Study Duration 
8.8
An individual subject’s participation will involve 5 visits over approximately a 6-week 
(~42 days) period (14 days pre-screening, 28 days of treatment) and a follow-up phone 
call. 
 Monitoring and Quality Assurance 
8.9
During the course of the study an 
 monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, 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, quality assurance and or its 
designees 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 
 Adverse Event 
9.1
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 

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unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise 
from any use of the IP (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the CRF. Any clinically relevant deterioration in clinical finding is considered 
an AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning. 
Exacerbation of conditions related to the signs and symptoms of DED will not be 
reported as an AE. 
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the subject. The 
assessment of severity is made irrespective of relationship to IP 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 Investigational Product 
The relationship of each AE to the IP should be determined by the investigator using 
these explanations: 
• Related: A reasonable possibility exists that the IP caused the AE. A related AE 
can be further defined as follows: 
 Occurs within a reasonable temporal sequence to administration of study drug  
 Cannot be explained by concurrent disease or other drugs or chemicals  
 Improves or disappears on stopping or reducing study drug (de-challenge)  
 Reappears on repeated exposure to study drug (re-challenge)  

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 Is an unusual event that is known to be associated with the drug or this class 
of compound, and cannot be explained by other therapy or the participant’s 
physical condition 
 Unlikely to be attributed to concurrent disease or other drugs or a clinically 
reasonable response on withdrawal (de-challenge) 
• Not Related: A reasonable possibility does not exist that the IP caused the AE. A 
not related AE can be further defined as follows: 
 Occurs with a temporal relationship to administration of study drug which 
makes a causal relationship improbable 
 Other drugs, chemicals or underlying disease provide plausible explanations 
of causality 
 Is known to be associated with the participant’s clinical condition, or with 
other medication taken by the participant 
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the IP caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. Types of evidence that would suggest a 
causal relationship between the IP and the AE event include: a single occurrence of an 
event that is uncommon and known to be strongly associated with IP exposure (e.g., 
angioedema, hepatic injury, Stevens-Johnson Syndrome); one or more occurrences of an 
event that is not commonly associated with IP exposure, but is otherwise uncommon in 
the population exposed to the IP (e.g., tendon rupture); an aggregate analysis of specific 
events observed in a clinical trial (such as known consequences of the underlying disease 
or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more 
frequently in the IP-treatment group than in a concurrent or historical control group. 
The investigator should initially classify the relatedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination unless revised by the 
Sponsor, which has the ultimate responsibility for judging relatedness. 
9.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
• Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
• Expected: An AE that is listed in the IB at the specificity and severity that has 
been observed. 
• Not applicable: An AE unrelated to the IP. 
AEs that are mentioned in the IB as occurring with a class of products or as anticipated 
from the pharmacological/mechanical (or other) properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation are to 
be considered unexpected. 

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The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
 Serious Adverse Events 
9.2
An AE is considered serious if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes: 
• Death; 
• Is life-threatening; 
Note: An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might 
have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even 
if less than 24 hours), unless the inpatient admission was pre-planned prior to the 
signing of the informed consent. 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 (SAE) 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, 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 in this definition. 
 Procedures for Reporting Serious Adverse Events 
9.3
All SAEs and their outcomes, regardless of causality or expectedness, must be reported to 
 and the sponsor as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities and recorded on the appropriate CRF. Adverse events will be 

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collected from the time of the signing of the Informed Consent until the follow-up phone 
call (about 7 days after the final day of randomized study drug treatment). 
9.3.1 Reporting a Serious Unexpected Suspected Adverse Reaction 
All SAEs that are both ‘suspected’ and ‘unexpected’ are also to be reported to the 
IRB/IEC and the regulatory authorities 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 SAEs, regardless of relationship to the IP, must be 
immediately reported. All information relevant to the SAE must be recorded on the 
appropriate CRFs. The investigator is obligated to pursue and obtain information 
requested by 
 and/or the sponsor in addition to that information reported on the CRF. 
All subjects experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify 
 and the sponsor immediately 
using the contact information below; 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 
 and the 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 IP; and inform the IRB of the SAE within their guidelines for 
reporting SAEs. 
 
 

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Contact information for reporting SAEs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Procedures for Unmasking (if applicable) 
9.4
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 group has been assigned to a subject. 
When possible (i.e., in non-emergent situations), 
 and/or the study sponsor should be 
notified before unmasking study drug. 
 and/or the study sponsor must be informed 
immediately about any unmasking event. 
If an investigator identifies a medical need for unmasking the treatment assignment of a 
subject, he/she should contact 
 and/or the medical monitor prior to unmasking the 
identity of the IP, if possible. 
 will ask the site to complete and send them the 
Unmasking Request Form. 
 will notify the sponsor, and jointly will determine if the 
unmasking request should be granted. They may consult the medical monitor as needed. 
The result of the request will be documented on the Unmasking Request Form. If 
approval is granted to unmask a subject, written permission via the Unmasking Request 
Form will be provided to the investigator. The investigator will unmask the subject using 
IWRS. The investigator will complete the Unmasking Memo form and include it in the 
subject’s study file and provide a copy for the TMF. For each unmasked request, the 
reason, date, signature, and name of the person who unmasked the subject must be noted 
in the subject’s study file.  
Unmasked subjects will be discontinued from the study. Unmasked subjects will be 
followed for safety monitoring until resolution of the adverse event or study completion, 
whichever occurs last. 

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 Type and Duration of the Follow-up of Subjects after Adverse 
9.5
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 3 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 
 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 
 Analysis Populations 
10.1
The following analysis populations will be considered: 
• Intent-to-Treat Population – The intent-to-treat (ITT) population includes all 
randomized subjects. Subjects in the ITT population will be analyzed as 
randomized. 
• Per-Protocol Population – The per-protocol (PP) population includes subjects in 
the ITT 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 randomized subjects who 
have received at least one dose of the investigational product. Subjects in the 
Safety population will be analyzed as treated.  
The statistical analysis of safety data will be performed for the safety population. The 
analysis of efficacy data will be performed for the ITT population and on the PP 
population as sensitivity analyses. 
 Statistical Hypotheses 
10.2
The following primary hypotheses will be tested against their respective two-sided 
alternative hypotheses in the order: 
H01:  There is no difference in the change from baseline in the post-CAE inferior corneal 
staining score after 28 days of treatment of 
 K-161 
 compared to vehicle.   
H02:  There is no difference in the change from baseline in the post-CAE ocular 
discomfort score after 28 days of treatment of 
 K-161 
 compared to vehicle.   

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Upon rejecting both H01 and H02, the secondary hypotheses will be tested as detailed in 
Section 10.4.4 in the following order  
H03:  There is no difference in the change from baseline in the pre-CAE Schirmer’s test 
value after 28 days of treatment of 
 K-161 
 compared to vehicle. 
H04:  There is no difference in the change from baseline in the post-CAE TFBUT after 
28 days of treatment of 
 K-161 
 compared to vehicle. 
These four hypotheses will be tested hierarchically, each at the alpha = 0.05 level to 
maintain a study-wise Type I error rate at 0.05. 
 Sample Size  
10.3
This study is expected to enroll 240 subjects in a 1:1:1:1 ratio across four treatment arms, 
or 60 subjects per treatment arm. In addition, randomization will be stratified such that 
will be randomized in each treatment arm.  
The standard deviation for change from baseline in post-CAE inferior corneal fluorescein 
staining ranges between 0.68 and 0.81 units. Assuming a common standard deviation of 
0.77, a sample size of 60 subjects per group will have approximately 90% power to detect 
a difference of 0.46 units between the active treatment group and the vehicle group using 
a two-sample t-test at a two-sided significance level of 0.05. Again, it is assumed that 
adjusting for baseline and site will further reduce variability and provide >90% power. 
Likewise, the standard deviation for change from baseline scores in the post-CAE ODS at 
Day 29 is assumed a common standard deviation of 0.82, a sample size of 60 subjects per 
group will have approximately 90% power to detect a difference of 0.49 units between 
the active treatment group and the vehicle group using a two-sample t-test at a two-sided 
significance level of 0.05. It is assumed that adjusting for baseline and site will further 
reduce variability and provide >90% power. 
 Statistical Analysis 
10.4
10.4.1 General Considerations 
Quantitative variables will be summarized descriptively using number of subjects (n), 
mean, standard deviation, median, minimum, and maximum. Qualitative variables will be 
summarized using counts and percentages. 
All summaries will be presented by treatment group. Summaries will be provided for 
demographics, baseline medical history, concurrent therapies, and subject disposition. 
For the purpose of summarization, medical history, concurrent therapies, and AEs will be 
coded to MedDRA and WHO Drug dictionaries, as appropriate.  
Change from pre-CAE to post-CAE will be calculated as post-CAE value minus pre-CAE 
value. Baseline measures are defined as the last non-missing measure prior to the 
initiation of randomized study treatment. Change from baseline will be calculated as 
follow-up visit value minus baseline value. Treatment comparisons between active and 
vehicle will be calculated as active minus vehicle. 

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All analyses will be 2-sided at a significance level of 0.05 unless otherwise specified. For 
all efficacy analyses, 95% confidence intervals on the difference between each dose of K-
161 and vehicle will be provided. 
10.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit of 
analysis will be the study eye, or the “worst eye,” as defined by the following:  
Worst Eye: Eyes are eligible for analysis if they meet all of the inclusion criteria. At least 
one eye (the right eye or the left eye) must meet all of the criterial. In the case that both 
eyes are eligible for analysis, the worst eye will be selected as the eye with the worst 
post-CAE inferior corneal staining at Visit 2. If the post-CAE inferior corneal staining at 
Visit 2 is the same in both eyes then the eye with the worst post-CAE ODS at Visit 2 will 
be worst eye. If the post-CAE inferior corneal staining and ocular discomfort are the 
same in both eyes then the right eye will be selected as the worst eye. 
10.4.3 Missing Data 
Missing data will be imputed using multiple imputation with a control-based pattern 
mixture model on the ITT population for the primary analyses, the important secondary, 
other secondary, and exploratory comparisons.   
Sensitivity analyses of the primary analyses and important secondary comparisons will 
include the following in order to provide a robust understanding of the impact of missing 
and spurious data:  
• Using complete case data (i.e. observed data only) on the ITT population 
• Using last observation carried forward (LOCF) on the ITT population 
• Multiple imputation under missing at random assumption with Markov Chain 
Monte Carlo (MCMC) techniques on the ITT population 
• Using complete case data on the PP population.  
No imputation will be used for safety endpoints. 
10.4.4 Multiplicity Consideration 
Common factors for multiplicity are multiple arms and multiple endpoints. 
1) Multiple arms 
The primary treatment comparison will be between the 
 K-161 
 treatment arm 
and the vehicle 
 treatment arm. 
 
  
2) Multiple endpoints 
The primary and important secondary endpoints will be tested hierarchically to maintain 
the study-wise Type I error rate of 0.05. First, change from baseline in inferior corneal 
fluorescein staining will be tested at an alpha level of 0.05. The test for change from 
baseline scores in the ODS will be conducted at an alpha level of 0.05 only if the 
previous test demonstrates significance. The test for change from baseline in Schirmer’s 
test will be conducted at an alpha level of 0.05 only if the previous test demonstrates 
significance. The test for change from baseline in TFBUT will be conducted at an alpha 

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level of 0.05 only if the previous test demonstrates significance. 
 
The hierarchical testing order will be as follows: 
Primary comparisons: 
1. Comparison of the change from baseline in post-CAE inferior corneal staining at 
Day 29 (
 K-161 
 
) 
2. Comparison of the change from baseline in post-CAE ocular discomfort at Day 29 
(
 K-161 
 
 
Important Secondary comparisons: 
3. Comparison of the change from baseline in pre-CAE Schirmer’s test value at Day 
29 (
 K-161 
) 
4. Comparison of the change from baseline in post-CAE TFBUT at Day 29 (
 
K-161 
) 
Thus, the study-wise Type I error rate will be maintained at 0.05 by considering only one 
dose of K-161 as the primary treatment comparison and using a hierarchical testing 
procedure. 
10.4.5 Efficacy Analyses 
Primary Efficacy Analyses 
The primary comparisons of change from baseline in post-CAE inferior corneal staining 
and ocular discomfort between the 
 K-161 
 group and the vehicle group at Day 
29, will be performed using analysis of covariance (ANCOVA) models. The respective 
baseline post-CAE score will be included as a covariate in each model and site will be 
included as a fixed effect. Treatment by baseline and treatment by site interactions will be 
explored in separate models and, if significant, analyses will be performed by baseline 
stratification and/or site, respectively, to further examine significant interactions. In 
addition, unadjusted two-sample t-tests and Wilcoxon rank-sum tests will be performed 
for each comparison as sensitivity analyses. The primary analyses will use the ITT 
population. 
For the primary endpoints, multiple imputation with MCMC techniques will be used. 
Imputation will be performed by treatment arm with imputation terms for baseline and 
Day 29 scores. 
Secondary Efficacy Analyses 
Secondary and exploratory endpoints will be analyzed similarly to the primary analyses 
on the ITT population. Continuous and ordinal variables collected at each visit will be 
summarized descriptively (n, mean, standard deviation, median, minimum and 
maximum), and analyzed with ANCOVA models and two-sample two-sided t-tests 
comparing each K-161 group to the vehicle group. All visit-based data will be analyzed 
by visit and for each timepoint, if applicable, as well as the change from baseline.  
Data collected pre- and post-CAE will also be analyzed for the change from pre- to post-
CAE within each visit. Data collected during the CAE will also be analyzed using 

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repeated measures models including all of the time points from a CAE exposure. Daily 
subject diary symptom data will be analyzed using each weekly average score from the 
diaries, as well as using repeated measures models across the diary collection period.   
For the two important secondary endpoints, other secondary, and exploratory endpoints, 
multiple imputation with MCMC techniques will be used. Imputation will be performed 
by treatment arm with imputation terms for baseline and Day 29 scores. 
 
 
 
10.4.6 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; 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 TEAEs; and by system organ class, preferred term, and study day of onset. 
Separate summaries will be performed for ocular and non-ocular AEs.  
 
 
 
 
 
 
 
 
 
 
 
 
Other analyses may be conducted and the details will be included in a separate statistical 
analysis plan. 
 
 
 

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10.4.11 Interim Analyses 
There will be no interim analyses in this study. 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonisation (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IP in the countries 
involved will be addressed. 
 Protection of Human Subjects 
11.1
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.  
All informed consent forms must be approved for use by the sponsor and receive 
approval/favorable opinion from an IRB 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 
 prior to submission to the governing IRB 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. 
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by 
 and/or sponsor and provided in 
writing by 
 and/or sponsor prior to the consent process. 

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11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB 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 approved version of the informed consent form will be used. 
 Ethical Conduct of the Study 
11.2
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
11.3
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 is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of 
 the sponsor, the IRB/IEC 
approving this study, the FDA, the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted 
direct access to the subject’s original medical and study records for verification of the 
data and/or clinical study 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 IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
 Documentation 
11.4
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 CRFs 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 IP, and copies of CRFs should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region; or until at 
least two years have elapsed since the formal discontinuation of clinical development of 
the IP. These documents will be retained for a longer period if required by the applicable 
regulatory requirements or by an agreement with the sponsor. It is the responsibility of 
the sponsor to inform the investigator/institution as to when these documents no longer 
need to be retained. 
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 

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accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
 Recording of Data on Source Documents and Case Reports Forms 
11.5
(CRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s CRF, source document, and all study-related material. 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. 
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 be entered in eCRF 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. 
 Publications 
11.6
All data derived from the study will be the property of the sponsor and must be kept 
strictly confidential. The investigator must not submit any of the data from this study for 
publication without prior consent of the sponsor. The sponsor will have the final decision 
regarding any manuscript and publication. 
 

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12 REFERENCES 
Bron, A. J., C. S. de Paiva, S. K. Chauhan, S. Bonini, E. E. Gabison, S. Jain, E. Knop, M. 
Markoulli, Y. Ogawa, V. Perez, Y. Uchino, N. Yokoi, D. Zoukhri and D. A. Sullivan 
(2017). "TFOS DEWS II pathophysiology report." Ocul Surf 15(3): 438-510. 
CEQUA (2018). "CEQUA (cyclosporine ophthalmic solution) 0.9% [drug label]. Sun 
Pharmaceuticals." 
Kudlacz, E., M. Conklyn, C. Andresen, C. Whitney-Pickett and P. Changelian (2008). 
"The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model 
of pulmonary eosinophilia." Eur J Pharmacol 582(1-3): 154-161. 
Mah, F., M. Milner, S. Yiu, E. Donnenfeld, T. M. Conway and D. A. Hollander (2012). 
"PERSIST: Physician's Evaluation of Restasis((R)) Satisfaction in Second Trial of topical 
cyclosporine ophthalmic emulsion 0.05% for dry eye: a retrospective review." Clin 
Ophthalmol 6: 1971-1976. 
 
 
 
 
 
Schaumberg, D. A., R. Dana, J. E. Buring and D. A. Sullivan (2009). "Prevalence of dry 
eye disease among US men: estimates from the Physicians' Health Studies." Arch 
Ophthalmol 127(6): 763-768. 
Schaumberg, D. A., D. A. Sullivan, J. E. Buring and M. R. Dana (2003). "Prevalence of 
dry eye syndrome among US women." Am J Ophthalmol 136(2): 318-326. 
Schaumberg, D. A., D. A. Sullivan and M. R. Dana (2002). "Epidemiology of dry eye 
syndrome." Adv Exp Med Biol 506(Pt B): 989-998. 
Stevenson, W., Z. Sadrai, J. Hua, S. Kodati, J. F. Huang, S. K. Chauhan and R. Dana 
(2014). "Effects of topical Janus kinase inhibition on ocular surface inflammation and 
immunity." Cornea 33(2): 177-183. 
Tauber, J., P. Karpecki, R. Latkany, J. Luchs, J. Martel, K. Sall, A. Raychaudhuri, V. 
Smith, C. P. Semba and O.-. Investigators (2015). "Lifitegrast Ophthalmic Solution 5.0% 
versus Placebo for Treatment of Dry Eye Disease: Results of the Randomized Phase III 
OPUS-2 Study." Ophthalmology 122(12): 2423-2431. 
 
 

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13 
APPENDICES 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
Procedure 
Visit 1 
Day -14 ± 2 
Visit 2 
Day 1 
Visit 3 
Day 8 
± 1 
Visit 4 
Day 15 ± 2 
Visit 5 
Day 29 ± 2 
Follow-up 
Phone Call 
(Day 36 ± 2) 
 
Pre  
CAE 
Post  
CAE 
Pre 
CAE 
Post 
CAE 
Non 
CAE 
Pre 
CAE 
Post 
CAE 
Pre 
CAE 
Post  
CAE 
 
Informed Consent / 
HIPAA 
X 
 
 
 
 
 
 
 
 
 
Medical / Medication 
History and Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical / Medication 
Update 
 
 
X 
 
X 
X 
 
X 
 
 
Adverse Event Query 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ora Calibra® Ocular 
Discomfort Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Ora Calibra® Ocular 
Discomfort & 4-Symptom 
Questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
OSDI© Questionnaire 
X 
 
X 
 
X 
X 
 
X 
 
 
Visual Analog Scale 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Conjunctival Redness 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Tear Osmolarity 
 
 
X 
 
X 
X 
 
X 
 
 
TFBUT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fluorescein Staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lissamine Green Staining 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Schirmer’s Test 
X 
 
X 
 
X 
X 
 
X 
 
 
Blink Rate 
 
 
X 
 
X 
X 
 
X 
 
 

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Procedure 
Visit 1 
Day -14 ± 2 
Visit 2 
Day 1 
Visit 3 
Day 8 
± 1 
Visit 4 
Day 15 ± 2 
Visit 5 
Day 29 ± 2 
Follow-up 
Phone Call 
(Day 36 ± 2) 
 
Pre  
CAE 
Post  
CAE 
Pre 
CAE 
Post 
CAE 
Non 
CAE 
Pre 
CAE 
Post 
CAE 
Pre 
CAE 
Post  
CAE 
 
Vehicle Run-In 
Dispensation 
 
X 
 
 
 
 
 
 
 
 
Vehicle Run-In Instillation 
 
X 
 
 
 
 
 
 
 
 
Vehicle Run-in Collection 
 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
 
X 
 
 
 
 
 
 
Study Drug Dispensation 
 
 
 
X 
X 
 
X 
 
 
 
Study Drug Collection 
 
 
 
 
X 
X 
 
X 
 
 
Diary Dispensation 
 
X 
 
X 
X 
 
X 
 
 
 
Diary Collection 
 
 
X 
 
X 
X 
 
X 
 
 
Exit Subject from Study 
 
 
 
 
 
 
 
 
 
X 
   
 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
 
Confidential 
 
 
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APPENDIX 3: PROTOCOL AMENDMENT SUMMARY 
Not Applicable. 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.0 I US 
APPENDIX 4: SPONSOR AND 
 APPROVALS 
Protocol Title: 
A Phase 2, Prospective, Double-Masked, 
Randorrized, Multi-Center, Vehicle-Controlled, 
Parallel-group, 4-week Administration Study 
Assessing the Safety, Efficacy, and Optimum Dosage 
ofK-161 in non-Japanese/Japanese Adult Subjects 
with Moderate to Severe Dry Eye Disease Both in 
Environmental and Controlled Adverse 
Environmental (CAE) Settings 
Protocol Number: K-161-2.01 US 
Final Date: 
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. 
Confidential 
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1\,-]61
Clinical Trial Protocol No.: K-161-2.0IUS
Sponsor: KOW3 Research lnstilUle (KRI)
APPENDIX 5: INVESTIGATOR'S
SIGNATURE
Pretocol Title:
A Phase 2. Prospective. Double-Masked.
Randomized.
Multi-Center.
Vehicle-Controlled.
Parallel-group.
4-week Administration
Study
Assessing the Safety. Efficacy. and Optimum
Dosage
of K-) 6) in non-Japanese/Japanese
Adult Subjects
with Moderate to Severe Dry Eye Disease Both in
Environmental
and Controlled Adverse
Environmental
(CAE) Settings
Protocol Number: K-161-2.0 IUS
Final Date:
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
and the sponsor in confidence and, when this
information
is submitted to an Institutional
Review Board (lRB). Ethical Review
Committee
(ERC) or another group. it win 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.
Confidential
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