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 
Amendment 2 
 26 July 2019 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
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: 
138738 
Indication: 
Dry eye disease 
Investigators: 
Multi-Center 
Sponsor: 
Kowa Research Institute, Inc. (KRI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
Original Protocol: 14 September 2018 
Amendment 1: 
13 June 2019 
Amendment 2: 
26 July 2019 
 
 
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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Clinical Trial Protocol No.: K-161-2.01US 
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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 subjects will receive Placebo 

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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 
 Follow-up Phone Call = Day 36 ± 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: 

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

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. 

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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 
 
 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 
comparisons of the following associated with 
taking the 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  

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 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©  
Safety Measures: 
 
 
  
 
  
 Adverse event query  
 
  
 
 
 
 
 
 

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 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 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: 

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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: 
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. The primary analyses will 
use the ITT population. 
For the primary endpoints multiple imputation with a control-based pattern 
mixture model will be used.  

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Secondary Efficacy Analyses 
Secondary and exploratory efficacy 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 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.  
For the two important secondary endpoints, other secondary, and exploratory 
endpoints, multiple imputation with a control-based pattern mixture model will be 
used.   
 
 
 
 
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.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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Other analyses may be conducted and the details will be included in a separate 
statistical analysis plan. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
SYNOPSIS............................................................................................................ 3 
TABLE OF CONTENTS.................................................................................... 14 
LIST OF ABBREVIATIONS ...................................................................................... 18 
1 
INTRODUCTION .............................................................................................. 20 
 
Drug Profile from Non-clinical Studies ................................................... 20 
2 
STUDY OBJECTIVES ....................................................................................... 21 
3 
CLINICAL HYPOTHESES ............................................................................... 21 
4 
OVERALL STUDY DESIGN ............................................................................ 21 
5 
STUDY POPULATION ..................................................................................... 22 
 
Number of Subjects (approximate) .......................................................... 22 
 
Study Population Characteristics .............................................................. 22 
 
Inclusion Criteria ...................................................................................... 22 
 
Exclusion Criteria ..................................................................................... 24 
 
Withdrawal Criteria (if applicable) .......................................................... 25 
6 
STUDY PARAMETERS .................................................................................... 26 
 
Efficacy Endpoints ................................................................................... 26 
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 
 
Other Measures ......................................................................................... 27 
 
Clinical Laboratory Measurements .......................................................... 29 
7 
STUDY MATERIALS ....................................................................................... 29 
 
Study Treatments ...................................................................................... 29 
7.1.1 
Masking................................................................................. 29 
7.1.2 
Description of and Justification for the Route of 
Administration, Dosage, Dosage Regimen, and Treatment 
Period. ................................................................................... 29 
7.1.3 
Instructions for Use and Administration ............................... 30 
 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ............................................................................. 30 

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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 ...................... 31 
 
Other Study Supplies ................................................................................ 31 
8 
STUDY METHODS AND PROCEDURES ...................................................... 31 
 
Subject Entry Procedures ......................................................................... 31 
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 
8.2.1 
Prohibited Medications/Treatments ...................................... 32 
8.2.2 
Escape Medications .............................................................. 32 
8.2.3 
Special Diet or Activities ...................................................... 32 
 
Schedule of Visits, Measurements and Dosing ........................................ 40 
8.4.1 
Scheduled Visits.................................................................... 40 
8.4.2 
Unscheduled Visits ............................................................... 40 
 
Compliance with Protocol ........................................................................ 41 
 
Subject Disposition ................................................................................... 41 
8.6.1 
Completed Subjects .............................................................. 41 
8.6.2 
Discontinued Subjects ........................................................... 41 
 
Study Termination .................................................................................... 41 
 
Study Duration ......................................................................................... 42 
 
Monitoring and Quality Assurance .......................................................... 42 

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9 
ADVERSE EVENTS .......................................................................................... 42 
 
Adverse Event .......................................................................................... 42 
9.1.1 
Severity ................................................................................. 43 
9.1.2 
Relationship to Investigational Product ................................ 43 
9.1.3 
Expectedness ......................................................................... 44 
 
Serious Adverse Events ............................................................................ 44 
 
Procedures for Reporting Serious Adverse Events .................................. 45 
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 
 
Type and Duration of the Follow-up of Subjects after Adverse Events .. 46 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES ............... 47 
 Analysis Populations ................................................................................ 47 
 Statistical Hypotheses ............................................................................... 47 
 Sample Size .............................................................................................. 48 
 Statistical Analysis ................................................................................... 48 
10.4.1 General Considerations ......................................................... 48 
10.4.2 Unit of Analysis .................................................................... 48 
10.4.3 Missing Data ......................................................................... 49 
10.4.4 Multiplicity Consideration .................................................... 49 
10.4.5 Efficacy Analyses ................................................................. 50 
10.4.6 Safety Variables .................................................................... 50 
10.4.7 Exploratory Safety Analyses................................................. 51 
 
 
 
 
 
10.4.11 Interim Analyses ................................................................... 51 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES .............................. 52 
 Protection of Human Subjects .................................................................. 52 
11.1.1 Subject Informed Consent..................................................... 52 
11.1.2 Institutional Review Board (IRB) Approval ......................... 52 
 Ethical Conduct of the Study .................................................................... 52 
 Subject Confidentiality ............................................................................. 52 
 Documentation ......................................................................................... 53 

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11.4.1 Retention of Documentation ................................................. 53 
 Recording of Data on Source Documents and Case Reports Forms 
(CRFs) ...................................................................................................... 53 
 Publications .............................................................................................. 53 
12 
REFERENCES ................................................................................................... 54 
13 
APPENDICES .................................................................................................... 55 
Appendix 1: Schedule of Visits and Measurements .................................................... 55 
Appendix 2: Examination Procedures, Tests, & Evaluations ...................................... 57 
Appendix 3: Protocol Amendment Summary .............................................................. 71 
 
Appendix 5: Investigator’s Signature .......................................................................... 73 
 
 

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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 

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MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
ODS 
Ocular Discomfort Score 
OSDI 
Ocular Surface Disease Index 
OTC 
Over the counter 
PP 
Per protocol 
SAE 
Serious adverse event 
SOP 
Standard operating procedure 
TFBUT 
Tear film break-up time 
WHO 
World Health Organization 
 
 

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1 INTRODUCTION 
Dry eye disease (DED) 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 (AEs); 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 
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 (
 
). Tofacitinib, a 
 
, 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. 
 
 
 
 
 
 
 
This will be the first clinical study of K-161 Ophthalmic Solution. 

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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 Health Insurance Portability 
and Accountability Act (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. 
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 

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Post-CAE ocular discomfort on the Ora Calibra® scale. Subjects will self-administer 
drops either 
 or 
 
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 subject visits and examinations will be consistent throughout the study. 
5 STUDY POPULATION 
 Number of Subjects (approximate) 
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 
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 
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 
Each subject must not: 
1. Have any clinically significant ocular condition 
 
 
 
 
 
 
2. Have a history of 
 
corneal refractive surgery, and/or any other ocular surgical procedure 
 
 within 12 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 Withdrawal Criteria (if applicable) 
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 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. 

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6 STUDY PARAMETERS 
 Efficacy Endpoints 
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 comparisons of the following associated with 
taking the 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 
 Ora Calibra® Ocular Discomfort Scale  
 Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire  
 Visual Analog Scale (VAS)   
 Burning/ Stinging 
 Itching 
 Foreign Body Sensation 

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 Blurred Vision 
 Eye Dryness 
 Photophobia 
 Pain 
 OSDI©  
6.1.4 
 
 
 
 
 
 
 
 
 
 
 Safety Measures 
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 
The other measures being evaluated are: 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 

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 Clinical Laboratory Measurements 
The following assessments are being conducted: 
Hematology: 
 
 
   
Clinical chemistry: 
 
 
 
 
 
   
Urinalysis: 
 
 
7 STUDY MATERIALS 
 Study Treatments 
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. 

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7.1.3 Instructions for Use and Administration 
Subjects who were randomized to 
 arm will be instructed to administer study drug 
 Subjects who were randomized to 
 arm will be 
instructed to administer study drug 
 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 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. 
 Labeling, Packaging, Storage, Accountability, and Return or 
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 
 Dosing: For the treatment period, 9
 
 to 
provide a sufficient supply of randomized study drug. 
 Dosing: For the treatment period, 
 
 to provide a 
sufficient supply of randomized study drug. 
 
7.2.2 Storage of Investigational Product 
The IPs must be stored in a secure area accessible only to the investigator and his/her 
designees. K-161 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 product label.  
7.2.3 Accountability of Investigational Product 
The IP is to only be prescribed by the PI 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 as described in this protocol to receive IP. 

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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 PI. 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. Requests for 
the return of IP must be specified in writing. 
 Other Study Supplies 
Other study supplies include 
 Schirmer’s test strips, tear 
meniscometry strips, sodium fluorescein, lissamine green, 
 
tear osmolarity cards, 
 
 
8 STUDY METHODS AND PROCEDURES 
 Subject Entry Procedures 
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 ICF. The ICF 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. 

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For the non-Japanese subjects, randomization will be further stratified by the 
following factors and cut-offs:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
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 
8.3.1 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. 

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8.3.2 Visit 1: Day –14 ± 2 – CAE Screening  
All subjects will undergo the following screening assessments: 
  
 Informed Consent/HIPAA  
 
 
 
 
 
 
 
 
 
  
 Ora Calibra® Ocular Discomfort Scale  
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
 OSDI© Questionnaire 
 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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 Dispensation of run-in (Vehicle) for 
 dosing until Visit 2 
 
 
 
 
 
 
 
 
 
 
 
 Subject Instructions Dispensation 
 
 
 
 
 
 
 AE Query 
 Subjects will be scheduled for Visit 2. 
8.3.3 Visit 2: Day 1 – CAE Confirmation and Baseline 
  
 Run-in Collection 
 
 
 Medical/medication history update 
 AE query 
 
 
 Ora Calibra® Ocular Discomfort Scale  
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
 OSDI© Questionnaire 
 Visual Analog Scale (VAS) 
 
 
 
  
 Conjunctival Redness 
 Blink Rate 
 Tear Osmolarity 
 
 
 TFBUT 

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 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 
 
  
 Randomization  
 Study Drug Kit Dispensation: 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. 
Subjects will receive their assigned study drug kit with sufficient supply to last 
until Visit 3.  
 
 
  
 
 
 
 
 
 
 Subject Instructions Dispensation  
 
 
 
 
 
 

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 AE Query 
 Subjects will be scheduled for Visit 3. 
8.3.4 Visit 3: Day 8 ±1  
 Study Drug Collection by unmasked staff member 
 Medical/medication history update 
 AE Query 
 Ora Calibra® Ocular Discomfort Scale  
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
 OSDI© Questionnaire 
 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 Kit 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. 
 Subject Instructions Dispensation  
 
 
 
 
 
 

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8.3.5 Visit 4: Day 15 ± 2  
 
 Study Drug Collection by unmasked staff member 
 Medical/medication history update 
 AE query 
 Ora Calibra® Ocular Discomfort Scale  
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
 OSDI© Questionnaire 
 Visual Analog Scale (VAS) 
 
 
 
  
 Conjunctival Redness 
 Blink Rate 
 Tear Osmolarity 
 TFBUT 

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 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 
 Study Drug Kit 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. 
 Subject Instructions Dispensation  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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 AE Query 
 Subjects will be scheduled for Visit 5. 
8.3.6 Visit 5: Day 29 ± 2 
 
 Study Drug Collection by unmasked staff member 
 Medical/medication history update 
 AE query 
 
 
 
  
 Ora Calibra® Ocular Discomfort Scale  
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire  
 OSDI© Questionnaire 
 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 
 
 
 
 
 
 
 AE Query 
8.3.7 Follow-up phone call Day 36 ± 2 
 Follow-up phone call (about 7 days after the final day of randomized study 
drug treatment) 
 AE query 
 Study exit 
 
Early Termination/Discontinuation  
If a subject is discontinued from the study prior to Visit 5 (Day 29 ± 2), then all safety 
evaluations and 
 evaluations for Visit 5 (Day 29 ± 2) should be performed 
on the day of discontinuation (early termination) or at the discretion of the 
investigator.  
AEs (both elicited and observed) and SAEs will be monitored throughout the study. 
The investigator will promptly review all AEs (both elicited and observed) for 
accuracy and completeness. All AEs will be documented on the appropriate source 
document and case report form. 
 
 
 
 
 
 
 
 Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the 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: 
 
 

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 Assessment of AEs 
 
 
 
 
 Compliance with Protocol 
Subjects will be given written instructions; instructed on proper instillation; and 
instructed on proper storage of the IP at the end of Visits 1, 2, 3, and 4. The subject 
used/unused 
 will be collected at each visit from Visit 2 up to and 
including Visit 5 to assess dosing compliance. Dosing compliance will be based on 
 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 source 
document. The investigator will use these guidelines to determine subject study 
compliance and deviation compliance.  
 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
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 
reported to 
 and/or the Sponsor and clearly documented on the electronic case 
report form (eCRF). 
 Study Termination 
The study may be stopped at any time by the investigator, Sponsor, and/or 
 with 
prior notification. 

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 Study Duration 
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 
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 (QA) 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 
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 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 will be noted as one comprehensive event. 
Documentation regarding the AE will include the nature, date of onset, end date, 
severity, relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the investigator 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. 

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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 by the subject. The assessment of 
severity is made irrespective of relationship to the IP or seriousness of the event and 
will 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 will 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)  
 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 

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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 will 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. 
The investigator will initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
 Serious Adverse Events 
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 

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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 
All SAEs and their outcomes, regardless of causality or expectedness, must be 
reported to 
 and the Sponsor as required by the IRB/Independent Ethics 
Committee(IEC), federal, state, or local regulations and governing health authorities 
and recorded on the appropriate CRF. Adverse events will be collected from the time 
of the signing of the ICF 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 will notify 
 and the Sponsor immediately 
using the contact information below; obtain and maintain 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 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/IEC of the SAE within their 
guidelines for reporting SAEs. 
 
 

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Contact information for reporting SAEs: 
 Procedures for Unmasking (if applicable) 
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 Sponsor will 
be notified before unmasking the investigator. 
 and/or the Sponsor must be 
informed immediately about any unmasking event. 
If the investigator identifies a medical need that requires unmasking the treatment 
assignment of a subject, 
 and/or the medical monitor will be contacted prior to 
unmasking the identity of the IP, if possible. 
 will ask the staff to complete and 
send them the Unmasking Request Form. 
 will notify the Sponsor and jointly 
determine if the unmasking request should be granted. In addition, 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 will be provided on the Unmasking Request Form. The investigator will 
unmask the subject using the interactive web response system (IWRS), complete the 
Unmasking Memo form, include it in the subject’s study file and make a copy for the 
trial master file (TMF). For each unmasked request, the reason, date, signature, and 
name of the person unmasking the subject must be noted in the subject’s study file.  
Unmasked subjects will be discontinued from the study and followed for safety 
monitoring, until resolution of the AE or study completion, whichever occurs last. 
 Type and Duration of the Follow-up of Subjects after Adverse 
Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up, or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the investigator does not expect any further 

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improvement or worsening of the AE. If the subject is lost to follow-up, the 
investigator will make 3 reasonable attempts to contact the subject via telephone, 
USPS, or certified mail. All follow-up will be documented in the subject’s source 
document. Non-serious AEs identified during 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 will include a description of the event, treatment, and whether it was resolved 
or continues. 
10 STATISTICAL HYPOTHESES AND METHODS OF 
ANALYSES 
 Analysis Populations 
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 
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.   
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. 

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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  
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 (SD) for change from baseline in post-CAE inferior corneal 
fluorescein staining ranges between 0.68 and 0.81 units. Assuming a common SD 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 SD for change from baseline scores in the post-CAE ODS at Day 29 is 
assumed a common SD 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 
10.4.1 General Considerations 
Quantitative variables will be summarized descriptively using number of subjects (n), 
mean, SD, 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 using the 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. 
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 

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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 
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 
 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) 

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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. 
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. 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 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.  
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 

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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.  
 
 
 
 
 
 
10.4.7 
 
 
 
 
10.4.8 
 
 
 
 
 
 
Other analyses may be conducted and the details will be included in a separate 
statistical analysis plan. 
10.4.9 
 
 
 
 
10.4.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10.4.11 Interim Analyses 
There will be no interim analyses in this study. 

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11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, 
ETHICAL CONSIDERATIONS, AND ADMINISTRATIVE 
ISSUES 
This study will be conducted in compliance with the protocol, current versions of the 
FDA Good Clinical Practice (GCP) regulations, the International Council for the 
Harmonisation of Technical Requirements for Human Use (ICH) GCP guidance, and 
in general, consistent with the Declaration of Helsinki. In addition, all applicable 
local, state, and federal requirements relevant to the use of IP will be met. 
 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures are 
initiated. Signed and dated written informed consent must be obtained from each 
subject and/or from the subject’s parent or legal guardian prior to enrollment into the 
study. The subject must also be given a copy of the signed ICF. 
All informed consent forms must be approved for use by the Sponsor and receive 
approval/favorable opinion from an IRB/IEC prior to their use. If the ICF requires 
revision (e.g., due to a protocol amendment or significant new safety information), it 
is the PI’s responsibility to ensure that the amended form is reviewed and approved by 
 prior to submission to the governing IRB/IEC and that it is read, signed and dated 
by all subjects currently and subsequently 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 the Sponsor and 
provided in writing by 
 and/or the Sponsor prior to the consent process. 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB/IEC regulations (e.g., US FDA 
21 Code of Federal Regulations Part 56.103). The PI must obtain appropriate 
IRB/IEC approval before initiating the study and re-approval at least annually. 
Only an IRB/IEC approved version of the ICF will be used. 
 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
will be maintained by the PI and site 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. 

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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 
Source documents may include a subject’s medical records, hospital charts, clinic 
charts, the study subject files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms. The site’s copy of the CRFs serves as the 
PI’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 must 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 PI when these documents 
no longer need to be retained. 
If the PI retires, relocates, or for other reasons withdraws from the responsibility of 
keeping study records, the custody of site study data must be transferred to a person 
who will accept the responsibility. The Sponsor must be notified in writing of the 
name and address of the new custodian. 
 Recording of Data on Source Documents and Case Reports 
Forms (CRFs) 
The PI 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, accurate, complete, 
and original. Recorded data must 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. The  
individual correcting the entry must initial and date it.   
Data entries for all randomized subjects will use software that conforms to 21 CFR 
Part 11 requirements, and will be performed only by staff who have access and have 
been trained on the system. Screen failure data will also be entered in the eCRF. 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 PI. 
 Publications 
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 
 
 
Exit Subject from Study 
 
 
 
 
 
 
 
 
 
X 
   
 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 57 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 58 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 59 
 
 
 
 
   
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 60 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 61 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 62 
 
 
 
 
 
 
   
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 63 
 
 
 
  
 
 
  
 
  
 
 
 
 
    
 
 
 
 
   
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 64 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 65 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 66 
 
 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 67 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 68 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 69 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 70 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 71 
 
APPENDIX 3: PROTOCOL AMENDMENT SUMMARY 
Not Applicable. 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 72 
 
APPENDIX 4: SPONSOR AND 
 APPROVALS 
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/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 / 
 
Amendment 2 Final Date:  
26Jul2019 
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. 

K-161 
Sponsor: Kowa Research Institute (KRI) 
Clinical Trial Protocol No.: K-161-2.01US 
Amendment 2 26Jul2019 
Confidential 
 
 
Page 73 
 
APPENDIX 5: INVESTIGATOR’S SIGNATURE 
 
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/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 / 
 
Amendment 2 Final Date:  
26Jul2019 
I agree to implement and conduct the study diligently and in strict compliance with 
the protocol, Declaration of Helsinki, Health Insurance Portability and Accountability 
Act, Good Clinical Practice, 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 / Independent Ethics  
Committee or another group, it will be submitted with a designation that it is 
confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to 
all aspects. 
 
 
 
Signed: 
 
 
Date:_______________ 
 
 
 
   dd mm yyyy