A Phase 3, Prospective, Double-masked, Randomized, Multi-center, Vehicle-controlled, Parallel-group, 12-week Administration and 40-week Extension Study Confirming the Efficacy and Safety of K-161 Ophthalmic Solution for the Treatment of Moderate to Severe Dry Eye Disease
Phase: PHASE3
Conditions: Dry Eye Disease
Sponsor: Kowa Research Institute, Inc.

NCT #: 
         NCT05403827

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K-161-3.01, Study Protocol 
 
K-161 
 
 
December 7, 2022 
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INVESTIGATOR’S STATEMENT 
I, the Investigator, understand that all information concerning the product supplied to me 
by Kowa Research Institute, Inc. (KRI) in connection with this study and not previously 
published is confidential information. This information includes the Investigator’s 
Brochure, protocol, case report forms, assay methods, technical methodology, and basic 
scientific data. 
I understand that any changes to the protocol must be approved in writing by KRI or 
representative 
and 
the 
Institutional 
Review 
Board/Independent 
Ethics 
Committee/Research Ethics Committee (IRB/IEC/REC) before implementation, except 
where necessary to eliminate apparent immediate hazards to the patients. 
I confirm that I will report all adverse events (AEs) following the regulations indicated in 
the protocol. 
I confirm that I will conduct this study in conformance with the ethical principles that have 
their origin in the Declaration of Helsinki, Health Insurance Portability and Accountability 
Act (HIPAA), as applicable, and, as applicable, the International Council for 
Harmonisation (ICH) tripartite guideline E6 (R2): Good Clinical Practice (GCP). I will 
also conduct this study, as applicable, in compliance with the requirements of the United 
States (US) Food and Drug Administration (FDA) as outlined in Title 21 of the Code of 
Federal Regulations (CFR) (Parts 11, 50, 54, 56, and 312) and all other applicable regional 
or local regulatory requirements. 
I confirm that I am informed of the need for record retention and that no data can be 
destroyed. 
By my signature below, I hereby attest that I have read, understood, and agree to abide by 
all conditions, instructions, and restrictions contained in this version of the protocol dated 
December 7, 2022. 
 
Investigator’s 
Signature: 
 
Date:  
 
 
 
 
 
mm/dd/yyyy 
Investigator’s 
Name: 
 
 
 
 
 
 
 

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K-161-3.01, Study Protocol 
 
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December 7, 2022 
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SIGNATURE PAGE 
Date  ____________________ 
mm/dd/yyyy 
Kowa Pharma Development Company 
 
 
  ___________________
mm/dd/yyyy 
Kowa Pharma Development Company 
_________________
 
mm/dd/yyyy 
Kowa Pharma Development Company 

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Criteria for Evaluation: 
Primary Efficacy Endpoints: 
The primary efficacy endpoint (symptom) is: 
• 
Change in EDS (VAS) from baseline to Day 85 
The primary efficacy endpoint (sign) is: 
• 
Change in conjunctival sum fluorescein staining score from baseline to Day 85 as assessed by 
expanded NEI scale 
 
Key Secondary Efficacy Endpoint: 
Change from baseline to Day 85 in: 
• 
Total eye fluorescein staining score as assessed by expanded NEI scale 
 
Secondary Efficacy Endpoints: 
Change from baseline to Day 85 in: 
• 
Corneal sum fluorescein staining score as assessed by expanded NEI scale 
• 
OSDI 
• 
Schirmer’s test (unanesthetized) 
• 
TFBUT 
 
Safety Endpoints: 
Safety assessments from baseline up to Day 85 
• 
Adverse events (AEs) 
 
 
 
 
 
 
 
 
• 
Systemic clinical evaluation  
• 
Clinical laboratory measurement 
 
 
 
 
 
Extension Endpoints: 
• 
Safety assessments, as described for up to Day 85, from baseline up to Day 365 
• 
Change in all efficacy and exploratory endpoints from baseline to Day 365 
 
Exploratory Endpoints: 
 
 
 
 
 
 
 
 
 
 
 

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December 7, 2022 
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who were assigned to K-161 
 and did not have an ICE, (3) patients who were assigned to 
vehicle and had an ICE, and (4) patients who were assigned to vehicle and did not have an ICE. 
 
Regarding EDS (VAS), a population mean in each pattern is assumed as follows: 
 
Assigned Treatment 
Intercurrent Event 
Not Occurred 
Occurred 
K-161 
 
(1) -10.0 
(2)   -3.6 
Vehicle 
(3)   -3.6 
(4)   -3.6 
 
A common variance, 431.2, and a common ICE occurrence rate, 8%, are assumed among the patterns. 
In order for EDS (VAS) to have at least 90% power when Holm’s method is applied, i.e., in order to have 
90% probability that EDS (VAS) is statistically significant when an alpha is set to 0.025 (two-sided), 
310 patients/arm will be needed. 
Targeted Estimand: 
The summary of the targeted estimand is as follows: 
Treatment Condition 
Treatment condition based on the assigned treatment group. 
Population 
DED patients based on the Inclusion and Exclusion criteria of the study. 
Variable 
Change from baseline to Day 85 in conjunctival sum fluorescein staining score and EDS (VAS) 
including measurements after intercurrent events (i.e., treatment policy strategy). Potential 
intercurrent events of the study are as follows: 
 Discontinuation of the study treatment due to an adverse event 
 Discontinuation of the study treatment due to lack of efficacy 
Population-level Summary 
Difference in means between the two treatment conditions. 
 
Primary Efficacy Analyses: 
The primary efficacy endpoints are change from baseline to Day 85 in conjunctival sum fluorescein 
staining score and EDS (VAS) on study eye, which are used regardless of whether or not the following 
ICEs occur: discontinuation of the study treatment due to an AE or lack of efficacy. Patients’ 
measurements will be made even after occurrence of those ICEs. For each of the primary endpoints, the 
Analysis of Covariance with baseline value, sex and treatment as covariates is used in order to make a 
comparison between the treatment groups. Least squares means will be calculated for the comparison. 
 
The data set to be used for the primary analyses is the FAS. 
 
Missing values will be imputed using the PMM with MI. Patterns to be used for the PMM are, as feasible, 
determined in each treatment group by whether or not patients had an ICE, or the type of ICEs if patients 
had an ICE. For example, if patients who discontinued the study treatment due to an AE had missing 
values, their missing values will be imputed from the patients who had the same ICE, i.e., discontinuation 
of the study treatment due to an AE. If enough patients to develop an imputation model in each pattern 
does not exist, the control-based mean imputation proposed by Mehrotra et al. (2017) will be applied 
instead of the PMM with MI. 
 

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8.2 
Prohibited Medication ....................................................................................................... 63 
8.3 
Permitted Medication and Rescue Therapy ...................................................................... 63 
 
AEs AND SAEs ............................................................................................................... 65 
9.1 
AEs ................................................................................................................................... 65 
 
AE Definition .................................................................................................................... 65 
 
Reporting of AEs .............................................................................................................. 65 
 
Follow-up of AEs .............................................................................................................. 67 
9.2 
SAEs ................................................................................................................................. 67 
 
SAE Definition ................................................................................................................. 67 
 Life-Threatening AEs ....................................................................................................... 68 
 Hospitalization .................................................................................................................. 68 
 
Reporting of SAEs ............................................................................................................ 68 
 
Serious Unexpected Suspected Adverse Reactions .......................................................... 69 
9.3 
 
9.4 
Patient Withdrawal and Drug Discontinuation ................................................................. 70 
 
STATISTICAL METHODS AND DATA ANALYSIS ............................................... 71 
10.1 
Sample Size Justification .................................................................................................. 71 
10.2 
Targeted Estimand ............................................................................................................ 71 
10.3 
Study Populations ............................................................................................................. 72 
10.4 
Analysis of Efficacy Parameters ....................................................................................... 72 
 Analysis of Secondary Efficacy Parameters ..................................................................... 73 
10.5 
Analysis of Safety Data .................................................................................................... 73 
10.6 
Analysis of Exploratory Endpoints ................................................................................... 74 
10.7 
Demographic/Baseline Information .................................................................................. 74 
10.8 
Interim Analysis ................................................................................................................ 74 
10.9 
Pharmacokinetic/Pharmacodynamic Analysis .................................................................. 74 
 
STUDY MANAGEMENT AND DATA COLLECTION ............................................ 75 
11.1 
Ethical Conduct of the Trial .............................................................................................. 75 
11.2 
IRB/IEC/REC ................................................................................................................... 75 
11.3 
Patient Informed Consent ................................................................................................. 75 
11.4 
Amendments to the Protocol ............................................................................................. 76 
11.5 
Study Initiation ................................................................................................................. 76 
11.6 
Study Monitoring .............................................................................................................. 77 
11.7 
Case Report Form ............................................................................................................. 77 
11.8 
Verification Procedures .................................................................................................... 77 
11.9 
Retention of Records ........................................................................................................ 78 
11.10 Insurance and Indemnity ................................................................................................... 78 
11.11 Audit and Inspection ......................................................................................................... 78 
 
USE OF INFORMATION ............................................................................................. 80 
12.1 
General Aspects ................................................................................................................ 80 
12.2 
Patient Confidentiality and Data Protection ..................................................................... 80 
12.3 
Final Report and Publication Policy ................................................................................. 80 
 
REFERENCES ................................................................................................................ 82 
 
 

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December 7, 2022 
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List of Tables 
 
Table 1 
Clinical Evaluation Schedule ..................................................................................... 23 
 
 
List of Figures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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OD 
oculus dexter; right eye  
OS 
oculus sinister; left eye 
OSDI 
ocular surface disease index 
OTC 
over-the-counter 
PI 
principal Investigator 
PMM 
pattern mixture model 
PPS 
per protocol set 
REC 
Research Ethics Committee 
SAE 
serious adverse event 
SUSAR 
serious unexpected suspected adverse reaction 
TEAE 
treatment-emergent adverse event 
TFBUT 
tear film break-up time 
 
 
US 
United States 
 
 
VAS 
visual analog scale 
 

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Table 1 
Clinical Evaluation Schedule 
ASSESSMENTS 
PERFORMED 
STUDY PERIOD 
Screening 
/Run-in 
Period 
Days of Dosing and Assessments 
Post-dose 
Assessments 
52-week Overall Period 
12-week Primary Period 
40-week Extension Period 
Visit 1 
Day -14 
(Day -21 
to -12) 
Visit 2 
Day 1 
(Baseline) 
Visit 3 
Day 15 
± 2 
(Remote)a 
Visit 4 
Day 29 
± 2 
Visit 5 
Day 57 
± 7 
Visit 6 
Day 85 
± 7 
Visit 7b 
Day 169 
± 7 
Visit 8b 
Day 253 
± 7 
Visit 9b 
Day 365 
± 7 
Visit 6.5b  
Day 99 ± 7c  
or 
Visit 10b 
Day 379 
± 7c 
Informed Consent/HIPAA 
X 
 
 
 
 
 
 
 
 
 
Medical/Medication/Ocular 
History and Demographics 
X 
 
 
 
 
 
 
 
 
 
Medical/Medication Update 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vehicle Run-In Dispensation 
X 
 
 
 
 
 
 
 
 
 
Vehicle Run-In Instillation 
X 
 
 
 
 
 
 
 
 
 
Vehicle Run-in Collection and 
Accountability 
 
X 
 
 
 
 
 
 
 
 
Determination/assignment of the 
study eye 
 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study Drug Dispensation 
 
X 
 
 
 
Xd 
Xd 
Xd 
 
 
Study Drug Instillation 
 
X 
 
X 
X 
Xd 
Xd 
Xd 
 
 
Study Drug Collection and 
Accountability 
 
 
 
Xe 
Xe 
X 
Xd 
Xd 
Xd 
 
Fluorescein Staining Scoring 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
VAS 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
TFBUT 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Schirmer’s Test 
X 
X 
 
X 
X 
X 
X 
X 
X 
 

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ASSESSMENTS 
PERFORMED 
STUDY PERIOD 
Screening 
/Run-in 
Period 
Days of Dosing and Assessments 
Post-dose 
Assessments 
52-week Overall Period 
12-week Primary Period 
40-week Extension Period 
Visit 1 
Day -14 
(Day -21 
to -12) 
Visit 2 
Day 1 
(Baseline) 
Visit 3 
Day 15 
± 2 
(Remote)a 
Visit 4 
Day 29 
± 2 
Visit 5 
Day 57 
± 7 
Visit 6 
Day 85 
± 7 
Visit 7b 
Day 169 
± 7 
Visit 8b 
Day 253 
± 7 
Visit 9b 
Day 365 
± 7 
Visit 6.5b  
Day 99 ± 7c  
or 
Visit 10b 
Day 379 
± 7c 
Adverse Event Collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Systemic Clinical Evaluation  
 
X 
 
 
 
X 
 
 
X 
 
Clinical Laboratory 
Measurement 
X 
 
 
 
 
X 
 
 
X 
 
Exit Patient from Study 
 
 
 
 
 
 
 
 
 
X 
 
 HIPAA=Health Insurance 
Portability and Accountability Act; OSDI=Ocular Surface Disease Index; TFBUT=tear film break-up time; VAS=Visual analog scale. 
Note: The visit schedule will always be calculated from randomization visit date (Visit 2). 
a. 
Visit 3 will be a remote visit. 
b. Only first 120 patients of each arm, approximate total 240 patients, will proceed to Visit 7 (Day 169) and following visits. Other patients will proceed to 
Visit 6.5 (Day 99) for post-dose assessments. 
c. 
Post-dose assessments will be performed at least 14 days after the last dose of study medication. 
d. Only patients in the Extension Period will be dispensed and instilled with the study drugs and will be examined for 
 

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a. Study medication should be stopped if the patient develops severe 
ocular/periocular infection disease. In case of a mild or moderate 
infectious event, the study medication can be continued at the 
Investigator’s discretion.  
3. Violation of the protocol inclusion or exclusion criteria is discovered, and if, in 
the opinion of the Investigator or the sponsor, the violation will significantly 
compromise data interpretation or safety 
4. The patient undergoes rescue ophthalmic surgery (Section 8.3) 
5. The female patient becomes pregnant during the study (Section 9.3) 
6. Lack of efficacy, as judged by the Investigator 
7. Lost to follow-up 
8. Site termination of the study by the site itself 
9. Sponsor termination of study 
10. Other 
Although a patient is not obligated to give his/her reason for discontinuing study drug, 
the Investigator will make a reasonable effort to obtain the reason while fully respecting 
the patient’s rights. The reason for discontinuation of study drug must be documented in 
the electronic case report form (eCRF). The clinical study report will include the 
reason(s) for discontinuation of study drug. 
4.4 
Withdrawal Criteria 
The patient has the right to withdraw from the study at any time and for any reason 
without prejudice to the patient’s future medical care. Nevertheless, every attempt will be 
made to prevent missing data and to obtain complete follow-up of all patients. 
Patients who meet study drug discontinuation criteria described in Section 4.3 will be 
discontinued from study drug; however, are not required to withdraw from the study 
unless the patient withdraws consent completely. As such, these patients will be 
encouraged to remain in the study and asked to attend all of the remaining study visits 
through Visit 6 (for the patients who are assigned into the 12-week Primary Period) or 
Visit 9 (for the patients who are assigned into the 52-week Overall Period) (Table 1). 
Patients who choose to withdraw from the study will be asked if they are prepared to 
complete a last visit. In this case, the same evaluations as the End of Treatment Period 
(Visit 6 or 9), or at least, the same evaluations as the Post-dose Assessment Visit (Visit 
6.5 or 10) should be performed. If a patient fails to actively maintain contact with the 
Investigator, reasonable efforts (telephone calls to family members or friends, email 
contacts, etc.) will be made in order to encourage the patient to complete the study visits. 
If the patient withdraws from the study, the reason should be captured. 
The patient will be withdrawn from the study if: 
1. The patient withdraws consent to attend the remaining study visits 

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2. Lost to follow-up 
3. Site termination of the study by the site itself 
4. Sponsor termination of study 
5. Other 
Although a patient is not obligated to give his/her reason for withdrawing from the study, 
the Investigator will make a reasonable effort to obtain the reason while fully respecting 
the patient’s rights. Unless revoked, further contact in the case of withdrawal from the 
study will occur consistent with methods listed in the informed consent form (ICF). The 
reason for withdrawal from the study must be documented in the eCRF. The clinical 
study report will include the reason(s) for withdrawal from the study. 
If a patient withdraws from the study due to an AE, the patient will be asked to return to 
the clinic for, at a minimum, the evaluations scheduled for post-dose assessments. If the 
AE has still not resolved, additional follow-up will be performed, as appropriate. Every 
effort will be made by the Investigator or delegate to contact the patient until the AE is 
resolved or stabilized, or the medical monitor and Investigator agree that further follow-
up is not necessary. If patients are lost to follow-up, the Investigator will make 3 
reasonable attempts to contact the patient via telephone, US postal service, or certified 
mail. All attempts to contact them must be made and documented in the study records.  
4.5 
Replacement, Rescreening, and Retesting 
 Replacement 
Patients who are screened for the study may be replaced if they never are randomly 
assigned study drug or are withdrawn from the study before they administer any study 
drug after randomization. The replacement patients will receive a new randomly assigned 
treatment and not the treatment assignment of the replaced patient. Patients who self-
administer any study drug after randomization and subsequently are withdrawn early 
from the study will not be replaced. 
 Rescreening 
Patients who fail to satisfy inclusion and exclusion criteria at screening (Visit 1 or 
Visit 2) may be rescreened 1 additional time at the discretion of the sponsor. Screen 
failures due to inclusion and/or exclusion criteria that could transiently change and do not 
compromise the patient’s safety as judged by the Investigator can be rescreened once. 
Patients who were re-screen failures under the previous version of this protocol 
(Amendment No. 1) can be re-screened one additional time for this amended protocol 
(Amendment No. 2), only if the eligibility criteria determining the original screen failures 
have been revised in this amendment (i.e. corneal sum fluorescein staining score and/or 
Schirmer score). All eligibility assessments will be repeated regardless of the reason for 
the screen failure(s) and new subject number will be assigned. Rescreening decision must 
be confirmed by the sponsor’s medical monitor. 

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 Retesting 
Clinical labs with clinically significant abnormalities (per the principal Investigator’s [PI] 
assessment) can be retested 1 time if there is a reasonable expectation that abnormality 
will resolve within the Screening Period (21 days at maximum). Unscheduled visits 
should be allowed within Screening Period. 

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5.4 
Data Monitoring Committee 
No data monitoring committee is planned for this study. 

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CONDUCT OF STUDY 
6.1 
Study Masking and Randomization 
All arms will be double-masked. The run-in drops will be single-masked for patients.  
Before the initiation of study run-in at Visit 1, each patient who provides written 
informed consent will be assigned a subject code. All subject codes will be assigned in 
strict numerical sequence at a site and no numbers will skipped or omitted. If a patient is 
retested on clinical labs, the same subject code will be used (Section 4.5.3). If a patient is 
rescreened, the patient will be assigned with a new subject code (Section 4.5.2). 
Patients who have signed informed consent and subsequently fail to satisfy inclusion and 
exclusion criteria are defined as screen failures. For all screen failures, the reason(s) for 
screen failure will be recorded on the patient’s source document and eCRF. 
Each patient who meets all the inclusion and none of the exclusion criteria at Visit 1 and 
Visit 2 will be randomized at the end of Visit 2 by using the IWRS. 
Subject codes and kit numbers will be assigned automatically to each patient as they are 
entered into the IWRS. All patients will be randomized into either vehicle or active 
treatment group at Visit 2 (Day 1) in a 1:1 ratio. 
 
The first approximately 240 (120/arm) randomized patients will be 
assigned into the 52-week Overall Period and the rest of study population (approximately 
380 [190/arm] patients) will be assigned into the 12-week Primary Period. 
The site staff will dispense the required kit(s). Both the subject codes and the dispensed 
study drug kit number(s) will be recorded on the patient’s source document and eCRF. 
Patients, sponsor, CRO, and site personnel will be masked to treatment assignment. 
After Visit 6 (Day 85), patients who are randomized to enter the 40-week Extension 
Period will proceed to Visit 7 (Day 169) until Visit 10 (Day 379). Other patients, who are 
randomized to enter the 12-week Primary Period only, will proceed to Visit 6.5 (Day 99) 
for post-dose assessments and will complete the study. 
Planned analyses at Day 85 including the primary analyses will be performed by an 
unmasked team not involved in the conduct of the study once all patient data until Day 85 
are obtained in a fashion to protect the masking of all patients who will be followed in the 
40-week Extension Period. The masked team will have access only to a summary of the 
results comparing the two arms so the same study team can continue to be masked while 
conducting the remaining part of the trial until the end of the 52-week Overall Period. 
The investigational sites will not be unmasked and will not have access to the summary 
of the results comparing the two arms. 
6.2 
Study Visits 
For each patient, a maximum of 10 scheduled visits will be performed: 
• Visit 1 at Day -14 (Day -21 to -12): Screening: The screening examination to 
determine patient eligibility can take place anytime within this time period. 

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• Visit 2 at Day 1: Baseline (12-21 days after Visit 1) 
• Visit 3 at Day 15 ± 2 days 
• Visit 4 at Day 29 ± 2 days 
• Visit 5 at Day 57 ± 7 days 
• Visit 6 at Day 85 ± 7 days 
For the patients who are assigned into the 12-week Primary Period 
• Visit 6.5 (post-dose) at Day 99 ± 7 days (at least 14 days after the last dose of 
study medication) 
For the patients who are assigned into the 52-week Overall Period (with the 40-week 
Extension Period): 
• Visit 7 at Day 169 ± 7 days 
• Visit 8 at Day 253 ± 7 days 
• Visit 9 at Day 365 ± 7 days 
• Visit 10 (post-dose) at Day 379 ± 7 days (at least 14 days after the last dose of 
study medication) 
The procedures and assessments to be performed at each visit are indicated in Table 1. 
6.3 
Compliance with The Protocol 
The Investigator must agree to implement the study protocol as written and adhere to the 
guidelines given in the Investigator’s Statement, which will be signed prior to the start of 
the study. The study will be performed in accordance with HIPAA, Declaration of 
Helsinki, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) 
guidelines, local laws, FDA GCP regulations (21 Code of Federal Regulations [CFR] 
Parts 11, 50, 54, 56, and 312), and other applicable guidance documents. 
If the Investigator considers enrolling a patient that does not meet all inclusion or 
exclusion criteria, an exemption must be requested from the sponsor’s medical monitor 
prior to patient enrollment. The justification for the exemption must be document by the 
Investigator. The approval or rejection of the exemption must be documented by the 
sponsor’s medical monitor prior to the patient’s enrollment or screen failure. 
Protocol non-compliance must be reported to the sponsor or its representatives. Each 
deviation and the reason for its occurrence must be documented. The sponsor retains the 
right to require the withdrawal of any patient who violates the protocol. 
6.4 
Termination of the Study 
If, in the opinion of the Investigator, the clinical observations in the study suggest that it 
may be unwise to continue, the study may be terminated after consultation with the 
sponsor. A written statement fully documenting the reason(s) for the termination will be 
provided to the sponsor. In addition, the sponsor may terminate the study at any time. 

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If it becomes apparent that patient enrollment is unsatisfactory with respect to quality or 
quantity, or data recording is inaccurate or incomplete on a chronic basis, the sponsor has 
the right to terminate the study and remove all study materials from the investigational 
site. A written statement will be provided to the Investigator, the Institutional Review 
Board/Independent Ethics Committee/Research Ethics Committee (IRB/IEC/REC), and 
regulatory authorities, if required. In the event of any serious or non-serious AEs having 
occurred at a site, all documentation relating to the event(s) must be obtained. 

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7.7 
Drug Accountability 
The study drug is to only be dispensed by the PI or his/her named sub-Investigator(s), and 
is to only be used in accordance with this protocol. The study drug must only be 
distributed to patients properly qualified as described in this protocol to receive study 
drug. 
The Investigator must keep an accurate account of the study drug received from the 
supplier. This includes the amount of study drug dispensed to patients, amount of study 
drug returned to the Investigator by the patients, and the amount returned or disposed 
upon the completion of the study. A detailed inventory must be completed for the study 
drug. 
7.8 
Procedure for Unmasking 
As needed, the randomization code may be broken by the Investigator to manage an 
urgent medical safety event. If possible, the medical monitor should be contacted to 
discuss the case before the code is broken. 
If it becomes necessary to unmask treatment information during the study, the reason for 
unmasking must be documented in the eCRF. If the medical monitor cannot be notified 
prior to unmasking, the Investigator must contact the medical monitor promptly and 
explain the reason for the premature unmasking (e.g., unmasking due to an SAE). 
Planned analyses at Day 85 including the primary analyses will be performed by 
unmasked team not involved in the conduct of the study once all patient data until Day 85 
are obtained in a fashion to protect the masking of the patients who will be followed in 
the 40-week Extension Period. 
 

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CONCOMITANT MEDICATION 
The Investigator must record the use of all concomitant medications and any historical 
use of 
 before Visit 1, both dispensed and OTC, in the eCRF along with the 
reason the medication was taken. This includes drugs used on a chronic and as-needed 
basis. Patients must be discouraged from starting any new medication, both dispensed 
and OTC, without consulting the Investigator, unless the new medication is required for 
emergency use. 
8.1 
General Considerations 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2 
Prohibited Medication 
Disallowed medications/treatments during the study are outlined in the exclusion criteria 
(Section 4.2). 
8.3 
Permitted Medication and Rescue Therapy 
Contact lenses are allowed only during the 40-week Extension Period (except for study 
visit days before all visit assessments are completed). Contact lenses should be removed 
prior to the administration of study drug and may be reinserted at least 15 minutes 
following administration. If a patient is using another prescription eye drop in 
combination with the study medication, the concomitant use of contact lenses is not 
recommended for the duration of such combination therapy. 
The following medications are permitted as long as the dosage is stable: 
• Systemic tetracycline compounds (e.g., tetracycline, doxycycline, or 
minocycline), macrolides (e.g., azithromycin): for at least 30 days prior to Visit 1 
and dose will remain stable until the end of the 12-week Primary Period 
• Any medication (topical and systemic) known to cause ocular drying, such as 
systemic anticholinergic medications (e.g., atropine, homatropine), 
antidepressants and antipsychotic agents, statins, diuretics, beta-blockers, 
NSAIDs: for at least 30 days prior to Visit 1 and dose will remain stable until the 
end of the 12-week Primary Period 
o Episodic use of anticholinergic drops for eye examination and episodic use 
of systemic NSAIDs are allowed during the study except for within 2 days 
prior to any study visit.  
• Omega-3 fatty acid supplements in doses above 3000 mg/day, oral hormonal 
contraceptives, hormone replacement therapy for menopause: for 12 weeks prior 
to Visit 1 and dose will remain stable until the end of the 12-week Primary Period. 
Omega-3 fatty acid supplements in doses equal to or below 3000 mg/day are 
permitted. 

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Any prohibited and restricted medications, devices, and procedures indicated for dry eye 
disease are permitted as “rescue therapy” after all assessments are completed at Visit 6  
(except for study visit days before all visit assessments are completed) (Table 1). 
Especially, 
 will be summarized as described in 
Section 5.2.10. All other prohibited medications, other than isotretinoin, systemic 
 
, and restricted medications, devices, and procedures are permitted as 
“permitted therapy” after all assessments are completed at Visit 6 (except for study visit 
days before all visit assessments are completed). If more than one topical ophthalmic 
medicinal product is being used, the medicinal products must be administered at least 15 
minutes apart. 
Any non-emergent ocular surgical procedure is prohibited until the end of the 12-week 
Primary Period. However, if the patient’s condition necessitates a surgical ocular 
procedure during the study, the patient may undergo rescue ophthalmic surgery. In this 
case, the use of study medication should be interrupted in the eye undergoing the 
procedure until resolution or stabilization of this condition and full recovery after surgery 
as determined by the Investigator. The decision to interrupt or restart the study 
medication for a specific ocular procedure/condition should be based on the best clinical 
judgment of the Investigator and preferably after consultation with the medical monitor. 

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AEs AND SAEs 
9.1 
AEs 
 AE Definition 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical 
product and which does not necessarily have a causal relationship with the 
pharmaceutical product. An AE can, therefore, be any unfavorable and unintended sign, 
symptom, or disease temporally associated with the use of a medicinal product, whether 
or not related to the medicinal product. Any worsening of the patient’s disease under 
study or other medical conditions will also be considered to be an AE, unless it is within 
the normal range of disease fluctuation for that patient. 
Clinically meaningful (for a given patient) changes in physical examination findings and 
abnormal objective test findings (e.g., clinical laboratory tests) are also recorded as AEs. 
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows: 
1. Test result is associated with accompanying symptoms, and/or; 
2. Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or; 
3. Test result leads to a change in study dosing or withdrawal from the study, 
significant additional concomitant drug treatment or other therapy, and/or; 
4. Test result leads to any of the outcomes included in the definition of an SAE 
(Section 9.2). 
Merely repeating a test, in the absence of any of the above conditions, does not meet 
condition number 2 above for reporting as an AE. 
Any abnormal test result that is determined to be an error does not require reporting as an 
AE. 
A treatment-emergent AE (TEAE) is defined as an AE that begins after the start of the 
double-masked study treatment or an event that begins before the start of the double-
masked study treatment and worsens in intensity after starting double-masked study 
treatment. 
 Reporting of AEs 
At each evaluation, the Investigator will determine whether any AEs have occurred. The 
patient will be questioned in a general way and no specific symptoms will be suggested. 
If any AEs have occurred, they will be recorded on the AE pages of the eCRF and in the 
patient’s medical record. If known, the diagnosis will be recorded, in preference to the 
listing of individual signs and symptoms. 
AE reporting begins when informed consent is obtained and ends at the conclusion of the 
study, unless an unresolved AE is still being followed. 

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The severity of the AE will be graded as follows: 
Mild 
The AE is easily tolerated and does not interfere with normal daily 
activities. 
Moderate 
The AE causes some interference with daily activities. 
Severe  
The AE causes all normal daily activities to be completely halted. 
 
The relationship of each AE to the study drug will be determined by the Investigator 
using these explanations: 
• Related: A reasonable possibility exists that the study drug caused the AE. A 
related AE can be further defined as follows: 
o Occurs within a reasonable temporal sequence to administration of study 
drug 
o Cannot be explained by concurrent disease or other drugs or chemicals 
o Improves or disappears on stopping or reducing study drug (de-challenge) 
o Reappears on repeated exposure to study drug (re-challenge) 
o 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 
o 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 study drug caused 
the AE. A not related AE can be further defined as follows: 
o Occurs with a temporal relationship to administration of study drug which 
makes a causal relationship improbable 
o Other drugs, chemicals or underlying disease provide plausible 
explanations of causality 
o Is known to be associated with the participant’s clinical condition, or with 
other medication taken by the participant 
 
The Investigator will record each action taken and outcome for each AE according to the 
following: 
Action taken 
• None 
• Treatment required 
• Hospitalization 
• Study drug interrupted 

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• Study drug discontinued 
• Patient withdrawn 
• Other (specify) 
Outcome 
• Recovered 
• Recovered with sequelae 
• Recovering 
• Ongoing 
• Death 
• Lost to follow-up 
Whether each AE is ocular or non-ocular will be determined by the Investigator for each 
AE and it will be recorded on the AE pages of the eCRF. 
 Follow-up of AEs 
If any AEs are present when a patient completes the study, or if a patient is withdrawn 
from the study, the patient will be re-evaluated. At the Investigator’s discretion, minor 
AEs can be re-evaluated via telephone and documented. If the AE is still not resolved, 
additional follow-up will be performed as appropriate. Every effort will be made by the 
Investigator or delegate to contact the patient until the AE is resolved or stabilized, or the 
medical monitor and Investigator agree that further follow-up is not necessary. The 
follow-up of AEs after post-dose assessments at Visits 6.5 or 10 will be documented in 
the patient’s medical records. 
9.2 
SAEs 
 SAE Definition 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening 
• Requires patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
Medical and scientific judgment will be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the patient or may require intervention to prevent one of the other outcomes listed in the 

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definition above. Events that require expedited reporting will also be considered to be 
SAEs. 
 
Life-Threatening AEs 
The term life-threatening in the definition of serious refers to an event in which the 
patient was at risk of death at the time of the event. It does not refer to an event which 
hypothetically might have caused death, if it were more severe. 
 
Hospitalization 
Hospitalization is defined as the patient being hospitalized overnight, or the patient’s 
hospital stay being prolonged for at least an additional overnight stay. Pre-planned 
hospital stays or hospital stays for non-medical social reasons are not applicable. Twenty-
three-hour hospitalizations for observation will be discussed with the medical monitor to 
determine whether they are appropriate for SAE reporting. 
 Reporting of SAEs 
All SAEs occurring from the time of informed consent until Visit 6.5 (patients enrolled in 
the Primary Period only) or Visit 10 (all other patients) must be reported to the CRO 
safety personnel within 24 hours of the knowledge of the occurrence (this refers to any 
AE that meets any of the aforementioned serious criteria). All SAEs that the Investigator 
considers related to study drug occurring after post-dose assessments at Visits 6.5 or 10 
must be reported to the CRO or the sponsor/designee. 
To report the SAE, the site staff will complete the SAE form electronically in the 
electronic data capture (EDC) system for the study. When the form is completed, the 
CRO safety personnel will be notified electronically and will retrieve the form. If the 
event meets serious criteria and it is not possible to access the EDC system, site staff will 
send a completed paper SAE form to
 within 24 hours of 
awareness. When the EDC system becomes available, the SAE information must be 
entered within 24 hours. 
 
 
  
 
  
 
  
 
 
The Investigator must continue to follow-up with the patient until the SAE has subsided 
or until the condition becomes chronic in nature, stabilizes (in the case of persistent 
impairment), or the patient dies. 
Within 24 hours of receipt of follow-up information, the Investigator must update the 
SAE form electronically in the EDC system for the study and submit any supporting 

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documentation (e.g., patient discharge summary or autopsy reports) to 
. If it is not possible to access the EDC system, refer to the 
procedures outlined above for initial reporting of SAEs. Written confirmation that any 
serious, unexpected, and related AEs have been submitted to the IRB/IEC/REC must be 
forwarded to the sponsor and kept in the Investigator files. 
 Serious Unexpected Suspected Adverse Reactions 
According to FDA CFR 312.32(a) and FDA Guidance “Safety Reporting Requirements 
for Investigational New Drugs (INDs) and BA/BE (Bioavailability/Bioequivalence) 
Studies” finalized December 2012, suspected adverse reaction means any AE for which 
there is a reasonable possibility that the medicinal product caused the AE. The phrase 
reasonable possibility means there is evidence to suggest a causal relationship between 
the AE and the medicinal product. 
The following are examples of types of evidence that would suggest a causal relationship 
between the drug and the AE (i.e., reasonable possibility): 
• A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
syndrome) 
• One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug 
(e.g., tendon rupture) 
Suspected adverse reactions are the subset of all AEs for which there is a reasonable 
possibility that the drug caused the event. 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. 
A suspected adverse reaction is considered unexpected if it is not listed in the Reference 
Safety Information in Section 6 of the K-161 Investigator’s Brochure or is not listed at 
the specificity or severity that has been described in the K-161 Investigator’s Brochure. 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or sponsor, it results in any of the following outcomes: Death, a 
life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect (Section 9.2.1). 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 patient or patient and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Any AE meeting the definitions of suspected adverse reaction, unexpected, and serious is 
considered a serious unexpected suspected adverse reaction (SUSAR). In accordance 
with the FDA Guidance “Safety Reporting Requirements for INDs and BA/BE Studies” 
finalized December 2012, the sponsor will unmask the study data for patients 

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 STATISTICAL METHODS AND DATA ANALYSIS 
10.1 
Sample Size Justification 
The parameters to be needed for the calculation of sample size were estimated from the 
previous Phase 2 study (K-161-2.01US). In order to take intercurrent events (ICEs) into 
account, 4 different patient patterns are considered: (1) patients who were assigned to 
K-161 
 and had an ICE, (2) patients who were assigned to K-161 
 
and did not have an ICE, (3) patients who were assigned to vehicle and had an ICE, and 
(4) patients who were assigned to vehicle and did not have an ICE. 
Regarding EDS (VAS), a population mean in each pattern is assumed as follows: 
Assigned Treatment 
Intercurrent Event 
Not Occurred 
Occurred 
K-161 
 
(1) -10.0 
(2)   -3.6 
Vehicle 
(3)   -3.6 
(4)   -3.6 
 
A common variance, 431.2, and a common ICE occurrence rate, 8%, are assumed among 
the patterns. In order for EDS (VAS) to have at least 90% power when Holm’s method is 
applied, i.e., in order to have 90% probability that EDS (VAS) is statistically significant 
when an alpha is set to 0.025 (two-sided), 310 patients/arm will be needed. 
10.2 
Targeted Estimand 
The summary of the targeted estimand is as follows: 
Treatment Condition 
Treatment condition based on the assigned treatment group. 
Population 
DED patients based on the Inclusion and Exclusion criteria of the study. 
Variable 
Change from baseline to Day 85 in conjunctival sum fluorescein staining score and 
EDS (VAS) including measurements after intercurrent events (i.e., treatment policy 
strategy). Potential intercurrent events of the study are as follows: 
 Discontinuation of the study treatment due to an adverse event 
 Discontinuation of the study treatment due to lack of efficacy 
Population-level Summary 
Difference in means between the two treatment conditions. 
 

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10.3 
Study Populations 
The following analysis populations will be considered: 
Full Analysis Set (FAS) in the 12-week Primary Period: will include all randomized 
patients who received at least 1 dose of study treatment. Patients will be analyzed 
according to their randomized treatment group, regardless of whether they adhere to their 
assigned treatment. The FAS will be used as the primary efficacy analyses. 
Per Protocol Set (PPS) in the 12-week Primary Period: will include all randomized 
patients without any major protocol deviations and have valid baseline and Day 85 
primary endpoint values. Major protocol deviations will be pre-specified prior to 
unmasking the study. PPS will be used to assess robustness of the primary analysis 
results. 
Safety Population in the 12-week Primary Period: will include all randomized patients 
who have received at least 1 dose of study treatment. 
FAS in the 52-week Overall Period: will include the randomized patients who are 
assigned into the 52-week Overall Period and received at least 1 dose of study treatment. 
Patients will be analyzed according to their randomized treatment group, regardless of 
whether they adhere to their assigned treatment. 
Safety Population in the 52-week Overall Period: will include randomized patients for the 
52-week Overall Period and who had at least 1 dose of study treatment. 
10.4 
Analysis of Efficacy Parameters 
The primary efficacy endpoints are change from baseline to Day 85 in conjunctival sum 
fluorescein staining score on study eye and EDS (VAS), which are used regardless of 
whether or not the following ICEs occur: discontinuation of the study treatment due to an 
AE or lack of efficacy. Patients’ measurements will be made even after occurrence of 
those ICEs. For each of the primary endpoints, the analysis of covariance with baseline 
value, sex and treatment as covariates is used in order to make a comparison between the 
treatment groups. Least squares means will be calculated for the comparison. 
The data set to be used for the primary analyses is the FAS. 
Missing values will be imputed using the pattern mixture model (PMM) with multiple 
imputation (MI). Patterns to be used for the PMM are, as feasible, determined in each 
treatment group by whether or not patients had an ICE, or the type of ICEs if patients had 
an ICE. For example, if patients who discontinued the study treatment due to an AE had 
missing values, their missing values will be imputed from the patients who had the same 
ICE, i.e., discontinuation of the study treatment due to an AE. If enough patients to 
develop an imputation model in each pattern do not exist, the control-based mean 
imputation proposed by Mehrotra (Mehrotra 2017) will be applied instead of the PMM 
with MI. 
If the MI is applied, multiple parameter estimates will be combined using Rubin’s rule 
(Rubin 1987). 

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With regard to multiplicity caused by the 2 primary endpoints, Holm’s method 
(Holm 1979) will be utilized. First, an endpoint with a smaller p-value will be tested at 
alpha=0.025 (two-sided). If the first test is significant, another endpoint will be tested at 
alpha=0.05 (two-sided). Otherwise, the second test will not be performed. 
Planned analyses at Day 85 including the primary analyses will be performed by 
unmasked team not involved in the conduct of the study once all patient data until Day 85 
are obtained in a fashion to protect the masking of the patients who will be followed in 
extension. Masked team will have access only to a summary of the results comparing the 
two arms so the same study team can continue to be masked while conducting the 
remaining part of the trial until the end of the 52-week Overall Period. The 
investigational sites will not be unmasked and will not have access to the summary of the 
results comparing the two arms.  
As a sensitivity analysis, a tipping point, at which the primary analysis result turns out to 
be not-significant, is examined in each ICE.  
Further details will be included in a separated statistical analysis plan.  
 Analysis of Secondary Efficacy Parameters 
The key secondary efficacy endpoint is change from baseline of total eye fluorescein 
staining score as assessed by expanded NEI scale for study eye will be analyzed in a 
similar manner as performed for primary endpoint. All other secondary endpoints will 
also be analyzed in a similar manner. 
The other secondary efficacy endpoints are ordered as follows: corneal sum fluorescein 
staining score as assessed by expanded NEI scale, OSDI, Schirmer’s test 
(unanesthetized), and TFBUT. 
Key secondary efficacy endpoint will be tested at alpha=0.05 (two-sided) if primary 
endpoints are both significant at alpha=0.05. 
The other secondary efficacy endpoints will be tested in order by fixed sequence method 
if the key secondary endpoint is significant. 
10.5 
Analysis of Safety Data 
AEs will be coded using the Medical Dictionary for Regulatory Activities dictionary (the 
most recent version, ver. 24.1 or later). Frequencies, percentages, severity, and 
relationship to study drug of patients with TEAEs, serious TEAEs, and TEAEs causing 
premature study withdrawal and study drug 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 of occurrence will be given of patients 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 additionally performed for ocular and non-ocular AEs. 

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 STUDY MANAGEMENT AND DATA COLLECTION 
11.1 
Ethical Conduct of the Trial 
The study will be performed in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki, the HIPAA, and the ICH harmonised tripartite 
guideline E6(R2): GCP. The study will also be performed in compliance with the 
requirements of the US FDA as outlined in Title 21 of the CFR (Parts 11, 50, 54, 56, and 
312) and all other applicable regional or local regulatory requirements. 
11.2 
IRB/IEC/REC 
The IRB/IEC/REC must be assembled according to the applicable state and federal 
requirements of each participating location, including ICH E6(R2) guidelines, and 
US FDA 21 CFR Part 56. 
It is the responsibility of the clinical site to submit the Protocol, Investigator’s Brochure, 
patient ICF, patient recruitment materials (if applicable), and other documentation as 
required by the IRB/IEC/REC for review and approval. A copy of the written approval 
must be provided to KRI. The documentation must clearly mention the 
approval/favorable opinion of the Protocol, the patient ICF, and patient recruitment 
materials (if applicable), including respective version dates. The written approval and a 
list of the voting members, their titles or occupations, and their institutional affiliations 
must be obtained from the IRB/IEC/REC and provided to KRI before the release of 
clinical study supplies to the clinical site and commencement of the study. If any member 
of the IRB/IEC/REC has direct participation in the study, written notification regarding 
his or her abstinence from voting must also be obtained. 
The clinical site must adhere to all requirements stipulated by the IRB/IEC/REC. This 
includes notification to the IRB/IEC/REC regarding the following: protocol amendments, 
updates to the patient ICF, recruitment materials intended for viewing by patients, IND 
safety reports, serious and unexpected AEs, reports and updates regarding the ongoing 
review of the study at intervals specified by the IRB/IEC/REC, and submission of final 
study reports and summaries to the IRB/IEC/REC. 
It is the responsibility of each investigational site to submit information to the appropriate 
IRB/IEC/REC for annual review and annual re-approval. 
11.3 
Patient Informed Consent 
Written consent must be obtained from the patient prior to any study-specific procedure 
or investigation. 
Prior to the implementation of study procedures, patients and persons conducting the 
consent discussion will be required to sign and date the IRB/IEC-approved ICF, and each 
patient will be given a copy. In addition, this information will be recorded in the patient’s 
medical record (i.e., source document). 

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The written consent document will embody the elements of informed consent as 
described in the HIPAA, World Medical Association Declaration of Helsinki, FDA 21 
CFR Part 50.25, ICH GCP, and in accordance with any local regulations. The 
Investigator is responsible for the preparation, content, and IRB/IEC/REC approval of the 
ICF. The ICF must be approved by the clinical site-designated IRB/IEC/REC and be 
acceptable to KRI or its designee prior to their use. 
The ICF must be written in a language fully comprehensible to the prospective patient. 
The written patient ICF will explain the objectives of the study and its potential risks and 
benefits. The information included on the ICF must be provided to the patient both 
verbally and in writing whenever possible and in a manner deemed appropriate by the 
IRB/IEC/REC. Patients must be given ample opportunity to read the information and 
inquire about details of the study. The Investigator must be satisfied that the patient has 
understood the information provided before written consent is obtained. If there is any 
doubt as to whether the patient has understood the written and verbal information, the 
patient must not be allowed to enter the study. 
If a patient agrees to participate, he or she will be asked to sign and date an ICF, the 
original copy of which will be kept by the Investigator. A copy of the signed ICF will be 
given to the patient. Information documenting the informed consent procedure will be 
recorded in the patient’s medical records (i.e., source document), and the original signed 
ICF must be made available to the study monitor for inspection. 
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by CRO and/or the sponsor and 
provided in writing by CRO and/or the sponsor prior to the consent process. 
All ICFs must be approved for use by the sponsor or designee and receive 
approval/favorable opinion from an IRB/IEC/REC 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 the 
sponsor prior to submission to the governing IRB/IEC/REC and that it is read, signed, 
and dated by all patients or their designees currently and subsequently enrolled in the 
study. 
11.4 
Amendments to the Protocol 
An amendment must be agreed to in writing by the sponsor, submitted to FDA as an IND 
application amendment, and submitted to and approved by the respective IRB/IEC/REC 
for each investigational site before it is implemented. Written approval of a protocol 
amendment is not required prior to implementation for changes to the protocol, which 
eliminate immediate hazard to the patient; however, approval must be obtained as soon as 
possible thereafter. Approved amendments must also be signed by the Investigator. 
11.5 
Study Initiation 
The Investigator must not enroll any patients prior to the completion of a formal meeting 
conducted by a representative of the sponsor. This meeting will include a detailed review 
of the study protocol and eCRFs. Study drug will not be supplied to an Investigator until 

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all the necessary pre-study requirements have been completed and essential signed 
documents are received by the sponsor or its representative. 
11.6 
Study Monitoring 
It is the responsibility of the Investigator to ensure that the study is conducted in 
accordance with the protocol, ICH/FDA GCPs, applicable regulatory requirements, 
HIPAA, and the current Declaration of Helsinki. Valid data are to be entered into the 
eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same 
time, the sponsor in the maintenance of accurate, complete, legible, well-organized, and 
easily retrievable data. The monitor will review the protocol with the Investigator. In 
addition, the monitor will explain the Investigator’s reporting responsibilities and all 
applicable regulations concerning the clinical evaluation of the study drug. 
The Investigator will permit the representatives of the sponsor to monitor the study as 
frequently as the sponsor deems is necessary to determine that data recording and 
protocol adherence are acceptable. The eCRFs and related source documents will be 
reviewed in detail by the monitor at each visit, in accordance with relevant standard 
operating procedures, ICH GCP guidance, and FDA GCP regulations. This includes 
results of tests performed as a requirement for participation in this study and any other 
medical records required to confirm information contained in the eCRFs, such as past 
medical history and secondary diagnoses. The Investigator and staff will be expected to 
cooperate with the monitor and provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will 
be documented at the investigational site by signature and date on the study-specific 
monitoring log. 
11.7 
Case Report Form 
All patient data generated during the study will be recorded on the eCRF. 
The Investigator will ensure that all data are entered promptly, legibly, completely, 
accurately and conform to source documents, in accordance with specific instructions 
accompanying the eCRFs, designed specifically for this study and supplied by the 
representatives of the sponsor for each patient. 
The representatives of the sponsor will only consider the eCRFs to be complete after they 
are reviewed and signed by the Investigator, indicating his/her assurance of the accuracy 
of all recorded data. It is expected that the Investigator and staff will cooperate with the 
monitoring team and provide missing data in a timely manner. 
11.8 
Verification Procedures 
In fulfillment of their obligations to the sponsor and to verify compliance with this 
protocol, ICH GCP guidance, and FDA GCP regulations, the Investigator will permit the 
representatives of the sponsor, the IRBs/IECs/RECs, the monitor, and regulatory 
authorities to have direct access to the patient’s medical records. 

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It is the Investigator’s obligation to ensure documentation of all relevant data in the 
patient’s medical record, eCRFs, and on study forms, when applicable, according to 
procedures provided in the protocol and/or supplemental instructions. 
The Investigator will maintain a Patient Identification Code List to enable unambiguous 
identification of the patients (patient names and corresponding subject codes). The 
Patient Identification Code List is an essential document and as such must be maintained 
according to the ICH GCP guidelines. 
11.9 
Retention of Records 
All documentation pertaining to the study will be retained by the sponsor in accordance 
with US FDA regulations and the ICH GCP guidance document. 
The representatives of the sponsor will provide each Investigator with a study file, which 
will be used to file the Investigator’s Brochure, protocol, drug accountability records, 
correspondence with the IRB/IEC and the sponsor, and other study-related documents. 
The Investigator agrees to keep records and those documents that include (but are not 
limited to) the identification of all participating patients, medical records, study-specific 
source documents, source worksheets, all original signed and dated ICFs, copies of all 
eCRFs, query responses, and detailed records of drug disposition, to enable evaluations 
or audits from regulatory authorities and the sponsor or its designees. 
The Investigator will retain records required to be maintained under federal regulations 
for a period of 2 years following the date a marketing application is approved for the drug 
for the indication for which it is being investigated; or, if no application is to be filed or if 
the application is not approved for such indication, until 2 years after the investigation is 
discontinued and FDA is notified. However, these documents will be retained for a 
longer period if required by the applicable regulatory requirement(s) or if needed by the 
sponsor. In addition, the Investigator must make provision for the patient’s medical 
records to be kept for the same period of time. 
Patients’ medical records and other original data will be archived in accordance with 
applicable regulations and requirements established by the investigational sites. 
11.10 Insurance and Indemnity 
The sponsor’s obligations regarding insurance and indemnification are described in other 
documents or agreements. 
11.11 Audit and Inspection 
The Investigator must permit study-related quality oversight monitoring, quality 
assurance audits, IRB/IEC/REC review, and regulatory agency inspections and provide 
direct access to source data documents. It is important that the Investigator(s) and their 
relevant personnel are available during the monitoring, audit, or inspection visits and that 
sufficient time is devoted to the process. 

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It is the responsibility of KRI to perform sponsor quality oversight, as part of the quality 
assurance and quality control programs. The purpose of a quality assurance audit, which 
is independent of and separate from routine monitoring or quality control functions, is to 
evaluate trial conduct and compliance with the protocol, the principles of ICH GCP, and 
other applicable regulatory requirements. 

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 USE OF INFORMATION 
12.1 
General Aspects 
All information concerning KRI, such as patent applications, formula, manufacturing 
processes, basic scientific data or formulation information supplied by KRI and not 
previously published, are considered confidential and will remain the sole property of 
KRI. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes without the written consent of KRI, except for official 
representatives, such as regulatory authorities. 
It is understood by the Investigator that the information developed in this clinical study, 
in connection with the development of K-161 will be used by KRI and, therefore, may be 
disclosed by KRI as required to other clinical Investigators, other pharmaceutical 
companies and to other government agencies. In order to allow for the use of the 
information derived from clinical studies, it is understood that there is an obligation to 
provide to KRI complete test results and all data compiled in this study. 
12.2 
Patient Confidentiality and Data Protection 
KRI and its designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, all data will be linked to the eCRF via 
a unique identification number and the patient's initials. The data will be masked 
correspondingly in all data analyses. 
However, in compliance with the guidelines and regulations of the US FDA concerning 
the acceptance of clinical studies in support of IND applications and the ICH GCP 
(whether performed in the US or elsewhere), and in fulfillment of its obligations to KRI 
to verify compliance with this protocol, KRI’s designee requires that the Investigator to 
permit its monitor, representatives from the FDA, KRI’s designated auditors, IRBs/IECs, 
and other governmental regulatory authorities to review the patient’s primary medical 
records (source data or documents) including, but not limited to laboratory test result 
reports, electrocardiogram reports, admission and discharge summaries for hospital 
admissions occurring during a patient’s study participation, and autopsy reports related to 
deaths occurring during the study. 
Should access to such medical records require a waiver or authorization separate from the 
statement of informed consent, the Investigator will obtain such permission in writing 
from the patient before the patient is entered into the study. 
12.3 
Final Report and Publication Policy 
All information regarding this study will be kept strictly confidential. All data derived 
from the study will be the property of KRI. The Investigator must undertake not to submit 
any part of the data from this study for publication without prior consent of KRI. KRI 
may disclose data derived from the study to other Investigators and drug regulatory 
authorities. 

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After completion of the study, and as agreed by the Investigator and KRI, the Investigator 
may send a draft manuscript to KRI to be reviewed in order to reach an agreement 
regarding publication. The Investigator must receive written approval from KRI before 
the final version of the manuscript is submitted for publication. 
At the conclusion of the study, after the data are analyzed, KRI or its designee will 
prepare a final clinical report. 

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Tauber J, Karpecki P, Latkany R, Luchs J, Martel J, Sall K, et al. Lifitegrast ophthalmic 
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