Conditions: Kerato Conjunctivitis Sicca
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 901
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to determine the efficacy and safety of KPI-121 0.25% ophthalmic suspension compared to vehicle (placebo) in subjects who have a documented clinical diagnosis of dry eye disease. The product will be studied over 14 days, with 1-2 drops instilled in each eye four times daily (QID).

Detailed description:
This is a Phase 3, multi-center, double-masked, randomized, vehicle-controlled, parallel-group study designed to evaluate the safety and efficacy of KPI-121 0.25% ophthalmic suspension versus vehicle in subjects with dry eye disease.

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: KPI-121 Ophthalmic Suspension intervention 2: Vehicle
Intervention descriptions: intervention 1: KPI-121 Ophthalmic Suspension intervention 2: Vehicle for KPI-121 0.25% ophthalmic suspension

Protocol document:
Prot_SAP_000.pdf: 
NCT03616899 
Study ID:  
KPI-121-C-011  
 
Study Title:  
A Phase 3, Double-masked, Randomized, Controlled Study of KPI-121 0.25% 
Ophthalmic Suspension Compared to Vehicle In Subjects With Dry Eye Disease 
(STRIDE 3)   
Date:  
27 Mar 2019 


27Mar2019 
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KPI-121 
KPI-121-C-011 
A PHASE 3, DOUBLE-MASKED, RANDOMIZED, CONTROLLED STUDY 
OF KPI-121 0.25% OPHTHALMIC SUSPENSION COMPARED TO VEHICLE 
IN SUBJECTS WITH DRY EYE DISEASE (STRIDE 3) 
Sponsor: 
Kala Pharmaceuticals, Inc. 
 
490 Arsenal Way, Suite 120 
 
Watertown, MA 02472 
Medical Monitor: 
 
 
     
 
Issue Date: 
Original:  14 Jun 2018 
 
Version 1.1:  19Jun2018 
 
Version 1.2:  25 Jun 2018 
 
Amendment 01: 27 Mar 2019 
 
Approved:   
 
 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for KPI-121.  I have read Protocol KPI-121-
C-011 (STRIDE 3) dated 27Mar2019 and agree to conduct the study as outlined.  I agree to 
maintain the confidentiality of all information received or developed in connection with this 
protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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EMERGENCY CONTACTS 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact information 
Clinical Project Manager 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
Chief Medical Officer 
 
 
 
 
 
SAE Reporting 
 
 
 
 
 






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following administration of the investigational product, whichever period of time is 
longer. 
8. Are postmenopausal women [i.e., no menstrual cycle for at least one year prior to Visit 1 
(Screening)] or are women who have undergone 1 of the following sterilization procedures at 
least 6 months prior to Visit 1 (Screening): 
a. Bilateral tubal ligation 
b. Hysterectomy 
c. Hysterectomy with unilateral or bilateral oophorectomy 
d. Bilateral oophorectomy 
Exclusion Criteria: 
In order for subjects to be eligible at Visit 1 (Screening) and Visit 2 (Day 1) they may not: 
1. Have a known hypersensitivity or contraindication to the investigational product(s) or their 
components. 
2. Have used any of the following medications or had any of the following procedures within 30 
days prior to Visit 1 (Screening) or for the duration of the study: 
a. Ocular, inhaled or intranasal corticosteroids 
b. Ocular or oral non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of 
≤ 81 mg/day of acetylsalicylic acid (ASA or aspirin) 
c. Topical ocular antibiotics 
d. Topical ocular antihistamines or mast cell stabilizers 
e. Oral antihistamines 
f. Topical or nasal vasoconstrictors 
g. Autologous serum tear preparations 
h. Lipiflow treatment 
i. TruTear treatment 
j. Blephex treatment 
3. Have used any of the following medications within 60 days prior to Visit 1 (Screening) or for 
the duration of the study: 
• 
Topical cyclosporine (Restasis®) 
• 
Topical lifitegrast 
• 
Any form of topical loteprednol etabonate (LE) 
4. Have altered oral dosing of the following within 30 days prior to Visit 1 (Screening) or 
anticipate alteration of dosing during the study:  


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a. Tetracycline compounds (e.g., tetracycline, doxycycline, or minocycline) 
b. Omega-3 or Omega-6 supplements 
5. Have altered dosing of the following medications within 6 months prior to Visit 1 
(Screening) or anticipate alteration of dosing during the study: 
a. Anticholinergics 
b. Anticonvulsants (e.g., topiramate) 
c. Antidepressants 
d. Isotretinoin 
e. Systemic immunosuppressive agents including oral corticosteroids at a dose of 
prednisone < 11 mg/day or equivalent. 
NOTE:  Oral corticosteroid use at a dose of prednisone >11 mg/day or equivalent is 
excluded. 
6. Be unwilling to abstain from the use of any topical ophthalmic medications at Visit 1 
(Screening) and for the duration of the study, including: 
a. Eyelash growth medications, including both prescription and over-the-counter 
b. Eye drops, gels, ointments, or artificial tears  
7. Be unwilling to abstain from the use TNF-blocking agents (e.g. etanercept, adalimumab, 
infliximab) at Visit 1 (Screening) and for the duration of the study. 
8. Be currently receiving treatment for glaucoma at Visit 1 (Screening) or for the duration of 
the study and/or have history of or current glaucoma, or an IOP over 21mmHg at Visit 1 
(Screening) or Visit 2 (Day 1). 
9. Be unwilling to abstain from wearing contact lenses for 14 days prior to Visit 1 (Screening) 
and for the duration of the study. 
10. Be monocular or have a BCVA of +1.0 logMAR or worse as assessed by Early Treatment 
Diabetic Retinopathy Study (ETDRS). 
11. Have had penetrating intraocular surgery within 3 months prior to Visit 1 (Screening) or 
anticipate requiring penetrating intraocular surgery during the study. 
12. Have had corneal refractive surgery (e.g. Lasik) or corneal transplantation (full thickness, 
anterior or posterior). 
13. Have had eyelid surgery within 6 months prior to Visit 1 (Screening) or anticipate requiring 
eyelid surgery during the study. 
14. Have congenitally absent lacrimal glands or meibomian glands.   
15. Have had laser trabeculoplasty or anticipate requiring laser trabeculoplasty. 








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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............11 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
5. 
INTRODUCTION ......................................................................................................18 
6. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................20 
6.1. 
Primary Objective .......................................................................................................20 
7. 
INVESTIGATIONAL PLAN .....................................................................................21 
7.1. 
Overall Study Design ..................................................................................................21 
7.2. 
Number of Subjects ....................................................................................................22 
7.3. 
Treatment Assignment ................................................................................................22 
7.4. 
Visit Description .........................................................................................................23 
7.4.1. 
Visit 1:  14 ± 1 Days Prior to Day 1 – Screening .......................................................23 
7.4.2. 
Visit 2:  Day 1 – Randomization ................................................................................24 
7.4.3. 
Visit 3: Day 8 ± 1 day – 
 .........................................................26 
7.4.4. 
Visit 4: Day 15 + 2 days – End of Study Visit ...........................................................26 
7.4.5. 
Unscheduled Visit .......................................................................................................27 
7.4.6. 
Early Termination Visit ..............................................................................................27 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................29 
8.1. 
Subject Inclusion Criteria ...........................................................................................29 
8.2. 
Subject Exclusion Criteria ..........................................................................................31 
8.3. 
Subject Withdrawal and Study Termination Criteria .................................................34 
9. 
TREATMENT OF SUBJECTS ..................................................................................35 
9.1. 
Description of Investigational product .......................................................................35 
9.2. 
Concomitant Medications ...........................................................................................35 
9.3. 
Treatment Compliance ................................................................................................37 
9.4. 
Randomization and Masking ......................................................................................37 
10. 
INVESTIGATIONAL PRODUCT MATERIALS AND MANAGEMENT .............39 
10.1. 
Investigational product ...............................................................................................39 


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10.2. 
Investigational product Packaging and Labeling ........................................................39 
10.3. 
Investigational product Storage ..................................................................................39 
10.4. 
Investigational product Preparation ............................................................................39 
10.5. 
Administration ............................................................................................................40 
10.6. 
Investigational product Accountability .......................................................................40 
10.7. 
Investigational product Handling and Disposal ..........................................................40 
11. 
ASSESSMENT OF EFFICACY ................................................................................41 
12. 
ASSESSMENT OF SAFETY .....................................................................................42 
12.1. 
Safety Parameters .......................................................................................................42 
12.2. 
Adverse and Serious Adverse Events .........................................................................42 
12.2.1. 
Definition of Adverse Events .....................................................................................42 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................42 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................43 
12.3. 
Relationship to Investigational product ......................................................................43 
12.4. 
Recording Adverse Events .........................................................................................44 
12.5. 
Reporting Adverse Events ..........................................................................................45 
13. 
STATISTICS ..............................................................................................................48 
13.1. 
Subject Demographics, Disposition and Background variables .................................48 
13.2. 
Analysis of Efficacy ...................................................................................................48 
13.3. 
Analysis of Safety .......................................................................................................49 
13.4. 
Sample Size Estimation ..............................................................................................49 
13.5. 
Level of Significance ..................................................................................................50 
13.6. 
Procedure for Accounting for Missing, Unused or Spurious Data .............................50 
13.7. 
Procedure for Reporting Deviations from the Statistical Plan ....................................50 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................51 
14.1. 
Study Monitoring ........................................................................................................51 
14.2. 
Audits and Inspections ................................................................................................51 
14.3. 
Institutional Review Board (IRB) ...............................................................................51 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................52 
16. 
ETHICS ......................................................................................................................53 
16.1. 
Ethics Review .............................................................................................................53 
16.2. 
Ethical Conduct of the Study ......................................................................................53 
16.3. 
Written Informed Consent ..........................................................................................53 


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17. 
DATA HANDLING AND RECORDKEEPING .......................................................54 
17.1. 
Inspection of Records .................................................................................................54 
17.2. 
Retention of Records ..................................................................................................54 
18. 
PUBLICATION POLICY ..........................................................................................55 
19. 
LIST OF REFERENCES ............................................................................................56 
20. 
APPENDICES ............................................................................................................57 
 
 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................16 
TABLE 3: 
COMPOSITION OF KPI-121 0.25% (W/V) INVESTIGATIONAL PRODUCT ........................35 
TABLE 4: 
COMPOSITION OF PLACEBO (VEHICLE) ........................................................................35 
 


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LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................22 
 
  


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AR 
Adverse Reaction 
AE 
Adverse Event 
BCVA 
Best Corrected Visual Acuity 
°C 
Degrees Celsius 
CCLRU 
Cornea and Contact Lens Research Unit 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
ID 
Identification 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 


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Abbreviation or Specialist Term 
Explanation 
KCS 
Keratoconjunctivitis sicca 
KPI 
Kala Pharmaceuticals, Inc. 
LE 
Loteprednol etabonate 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL  
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of Mercury 
MPP 
Mucus Penetrating Particles 
NDA 
New Drug Application 
NEI 
National Eye Institute 
ODS 
Ocular Discomfort Severity 
QID 
Four Times Daily 
SAE 
Serious Adverse Event 
 
 
SAR 
Suspected Adverse Reaction 
SOP 
Standard Operating Procedure 
TNF 
Tumor Necrosis Factor 
UPT  
Urine Pregnancy Test 
US 
United States of America 
WOCBP 
Women of Child Bearing Potential 
w/v 
Weight to Volume 


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5. 
INTRODUCTION 
 
It is estimated that dry eye disease affects approximately 33 million people in the United States 
based on an estimated prevalence of 14.5% described in The Beaver Dam Offspring Study, a 
major epidemiological study published in 2014 in the American Journal of Ophthalmology 
(Paulsen, 2014). Dry eye disease, also called keratoconjunctivitis sicca (KCS) is characterized by 
several symptoms of ocular discomfort, including but not limited to dry eye sensation, foreign 
body sensation, irritation, burning, tearing, ocular pain, and itching. Subjects with dry eye 
disease may experience significant ocular discomfort and reduced visual function, thus resulting 
in a decreased quality of life or work productivity.  Current treatment of dry eye disease 
generally begins with artificial tear replacement and then expands to include topical anti-
inflammatory therapy and punctal occlusion.  Three anti-inflammatory therapies for dry eye 
disease are currently approved by the FDA, and all are intended to be long-term treatments for 
dry eye disease: cyclosporine ophthalmic solution (Restasis®, Allergan; CequaTM, Sun 
Ophthalmics) and lifitegrast (Xiidra®; Shire). Cyclosporine has shown effectiveness in increasing 
tear volume in dry eye patients; however, it is not effective in subjects with punctal plugs or 
those already being treated with anti-inflammatory ophthalmic solutions (DEWS Report, 2007), 
it produces adverse reactions in a significant percentage of patients (eg, ocular irritation upon 
instillation, slow onset of response, and limited efficacy), and it may take several weeks to 
produce a therapeutic effect and up to 6 months for maximal effectiveness (Pflugfelder, 2004). 
Lifitegrast inhibits an integrin, lymphocyte function-associated antigen 1 (LFA-1) from binding 
to intercellular adhesion molecule 1 (ICAM-1), which down-regulates inflammation mediated by 
T lymphocytes; however, the exact mechanism of action of lifitegrast in dry eye disease is not 
known. The most common side effects of lifitegrast reported in 5% to 25% of subjects are 
instillation site irritation, dysgeusia (unusual taste sensation), and reduced visual acuity (Xiidra 
package insert, 2016). 
Inflammation has a prominent role in the development and proliferation of dry eye disease.  
Factors adversely affecting tear film stability and osmolarity can initiate an inflammatory 
cascade that leads to the development of a self-perpetuating inflammatory cycle. Topical 
corticosteroids are used to treat an array of ocular conditions that have an inflammatory 
component and are generally indicated for treatment of steroid-responsive inflammatory 
conditions of the conjunctiva, cornea, and anterior segment. 
LE is an ester corticosteroid that is rapidly metabolized to inactive metabolites and has been 
reported to have fewer side effects than traditional glucocorticosteroids. LE was approved by 
FDA in 1998 under New Drug Application (NDA) 20-583 (Lotemax®; Bausch & Lomb). 
Lotemax has gained wide acceptance by ophthalmologists for use in the treatment of ocular 
inflammation. 


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Kala Pharmaceuticals, Inc. (KPI) has developed an improved formulation of LE, designated KPI-
121, using a proprietary technology known as Mucus Penetrating Particles (MPP). MPP 
technology utilizes submicron drug particles formulated to enhance penetration through the 
mucous layer of the tear film. KPI-121 is an aqueous suspension of submicron particles of LE 
formulated with excipients present in other FDA-approved ophthalmic drug products. Preclinical 
studies have shown improved pharmacokinetics for KPI-121 compared to Lotemax, with 
prolonged drug presence on the ocular surface and increased drug penetration into ocular tissues. 
This improved pharmacokinetic profile has the potential to reduce dosing strength of LE as 
compared to Lotemax. 
Kala Pharmaceuticals, Inc. intends to develop KPI-121 for the treatment of dry eye disease. In 
previously conducted clinical trials (one phase 2 and two phase 3), the safety profile of KPI-121 
in subjects with dry eye disease was shown to be favorable.  Study KPI-121-C-011 will evaluate 
the safety and efficacy of KPI-121 0.25% ophthalmic suspension in subjects with dry eye 
disease. Additional information about KPI-121, including nonclinical pharmacology study 
results, and potential risks and benefits to human subjects, are found in the Investigator’s 
Brochure. 


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6. 
TRIAL OBJECTIVES AND PURPOSE 
6.1. 
Primary Objective 
The primary objective of the study is to investigate the safety and efficacy of KPI-121 0.25% 
ophthalmic suspension compared to vehicle in subjects who have a documented clinical 
diagnosis of dry eye disease. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a Phase 3, multicenter, double-masked, randomized, vehicle-controlled, parallel-group 
study designed to evaluate the safety and efficacy of KPI-121 0.25% ophthalmic suspension in 
treating the signs and symptoms of dry eye disease.   
This study will include up to 4 clinic visits, including 2 weeks of single-masked vehicle in Stage 
1 followed by approximately 14 days of investigational product dosing (KPI-121 0.25% 
ophthalmic suspension or vehicle in Stage 2).   
Approximately 3200 subjects at approximately 80 centers located in the United States (US) will 
be screened at Visit 1 (Screening).  Subjects meeting eligibility criteria at this visit will enter a 
14-day Stage 1 period of QID dosing with single masked vehicle.  At Visit 2 (Day 
1/Randomization), approximately 900 subjects who continue to meet eligibility criteria will be 
randomized in an approximate 1:1 ratio to either KPI-121 0.25% ophthalmic suspension or 
vehicle dosed QID.  Subjects will be allocated in an approximate 1:1 ratio at each site. 
Study qualification criteria will be entered into the Interactive Web Response System (IWRS) for 
stratification at randomization.  Other randomization and stratification allocation criteria will be 
applied as elaborated in the data management plan.  Randomization numbers will be 
automatically assigned to each subject as they are entered into the IWRS based on stratification 
criteria.  
To minimize bias, investigational product allocation (KPI-121 0.25% ophthalmic suspension 
versus vehicle) will be randomized and masked to the Sponsor, subjects, and the investigative 
staff with the exception of a dosing coordinator.  The dosing coordinator will be responsible for 
dispensing and retrieving investigational product to/from subjects, instructing subjects regarding 
dosing of the investigational product, addressing study subjects’ questions regarding 
investigational product, 
. As a consequence of these 
interactions, the dosing coordinator has the potential for being unmasked to the study treatment 
for each subject.  The randomization schedule will be generated by the randomization statistician 
(who is not on the project team) or designee and maintained in a secure and limited-access 
location separate from the study Investigator and members of the project team. 
The “study eye” that is used for analyses will be determined according to the algorithm detailed 
in the final Statistical Analysis Plan. 
Subjects will return at Visit 3 (Days 8 ± 1 day) to 
 
evaluate ocular discomfort and assess concomitant medication use and adverse events.  Subjects 




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The IWRS will assign masked study kit numbers. Bottles of investigational product will be 
dispensed at designated visits based on the subject’s randomization. The Sponsor, Investigators, 
study staff, and subject will be masked during the randomization process and through the 
remainder of the study. 
7.4. 
Visit Description 
7.4.1. 
Visit 1:  14 ± 1 Days Prior to Day 1 – Screening 
After obtaining written informed consent and HIPAA authorization, site staff will perform/assess 
the following in the order suggested below.  Each subject that is screened will be assigned a 
Subject Identification (ID) consisting of a 5-digit Investigator number plus a 3-digit Subject 
number.  The Subject ID will be used as the primary subject identifier for the duration of the 
study.    
• Subject-rated assessment of ocular discomfort as graded by the subject 
 
 
• Significant non-ocular and significant ocular medical history 
• Concomitant medication usage and medications taken during the 6 months prior to 
screening  
• Inclusion/exclusion criteria  
• Urine pregnancy test (UPT) for WOCBP 
• BCVA   
• 
 assessment of bulbar conjunctival hyperemia 
• Slit Lamp Biomicroscopy 
• Corneal fluorescein staining 
• Unanesthetized Schirmer Test evaluation 
• IOP measurement 
• Dilated Ophthalmoscopy 
• Single-masked, investigational product instillation 
• AE Assessment 


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• Dispense single masked, investigational product and instructions for administration  
• The first dose of single-masked investigational product will be administered in the 
clinic under the supervision of a designated dosing coordinator.  This dosing 
coordinator, who is not responsible for study assessments, will also be required to 
dispense and retrieve investigational product to/from the subjects, provide instruction 
to the subjects regarding dosing of the investigational product, address study subjects’ 
questions regarding the investigational product, 
. Prior 
to administration of investigational product, subjects will be instructed regarding 
proper method for instillation of investigational product including but not limited to 
shaking investigational product bottle prior to each instillation.  Since subjects will 
receive 1 dose of investigational product in the clinic, they will self-administer at 
most 3 additional doses of investigational product on the first day. 
• 
 
Instructions to subject: 
 
• Dose single-masked Stage 1 investigational product as instructed 
• 
 
• 
 
• Return for Visit 2 scheduled in 14 ± 1 days. 
7.4.2. 
Visit 2:  Day 1 – Randomization 
The randomization visit will occur 14 ± 1 days after Visit 1 (Screening). This visit, the first visit 
of Stage 2, should be scheduled in the morning (if possible) to allow for administration of QID 
dosing of investigational product during the day for eligible subjects.   
Eligible subjects who continue to meet the eligibility criteria (Section 8) will continue in the 
study.  The site staff will perform/assess the following in the order suggested below:  
• Subject-rated assessment of eye dryness 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit and a status review of any ongoing AEs 
• 
 


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• Used and unused single-masked Stage 1 investigational product collected, counted, and 
compliance assessed 
  
• 
 assessment of bulbar conjunctival hyperemia 
• 
  
• BCVA 
• Slit Lamp Biomicroscopy 
• Corneal fluorescein staining 
• IOP measurement 
• Upon verification of study eligibility, randomization of appropriate subjects to receive 
QID dosing of either KPI-121 0.25% ophthalmic suspension or vehicle.   
The following will be performed for all randomized subjects:  
• Instillation of randomized investigational product 
• AE Assessment 
• Dispensing of double-masked, investigational product (1 bottle) and instructions for 
administration 
The first dose of double-masked investigational product will be administered in the clinic under 
the supervision of a designated dosing coordinator.  This dosing coordinator, who is not 
responsible for study assessments, will also be required to dispense and retrieve investigational 
product to/from the subjects, provide instruction to the subjects regarding dosing of the 
investigational product, address study subjects’ questions regarding the investigational product, 
. Prior to administration of investigational product, subjects will 
be instructed regarding proper method for instillation of their assigned investigational product 
including but not limited to shaking investigational product bottle prior to each instillation.  
Since subjects will receive 1 dose of investigational product in the clinic, they will self-
administer at most 3 additional doses of investigational product on the first day.  Any Stage 1 
doses taken on the morning of Visit 2 should be counted into the total 4 doses for the day. 
 
• 
 
Instructions to subject: 
• Dose investigational product as instructed 


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• Complete dosing information 
 
• Complete ocular discomfort assessments 
 
• Return for Visit 3 scheduled on Day 8 ± 1 day. 
7.4.3. 
Visit 3: Day 8 ± 1 day – 
 
This visit will occur on Day 8 ± 1 day as calculated from Visit 2: Day 1, and the following 
evaluations will be performed:  
• Subject-rated assessment of eye dryness 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit and a status review of any ongoing AEs 
• 
 
Instructions to subject: 
• Dose investigational product as instructed 
• 
 
• 
 
• Return for Visit 4 scheduled on Day 15 + 2 days. 
7.4.4. 
Visit 4: Day 15 + 2 days – End of Study Visit 
The end-of-investigational-product-use visit will occur on Day 15 +2 days as calculated from 
Visit 2: Day 1. The site staff will perform/assess the following in the order suggested below:  
• Subject-rated assessment of eye dryness 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit and a status review of any ongoing AEs 
• 
 
• Used and unused double-masked investigational product collected, counted, and 
compliance assessed 
  
• 
 assessment of bulbar conjunctival hyperemia 




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• IOP measurement 
• UPT for WOCBP 
 




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7. Are WOCBP who are not pregnant or lactating and not sexually active (i.e., 
abstinent) for 14 days prior to Visit 1 (Screening) and willing to remain so 
through 30 days following Visit 4 or the last administration of the investigational 
product or until completion of the subject’s first menstrual cycle following the last 
administration of the investigational product, whichever period of time is longer.  
Alternatively, WOCBP who are not abstinent must have been using 1 of the 
following acceptable methods of birth control for the times specified:  
a. IUD in place for at least 3 months prior to Visit 1 (Screening) and 
continuing through Visit 4 or last administration of investigational product 
or until completion of the subject’s first menstrual cycle following last 
administration of the investigational product, whichever period of time is 
longer. 
b. Barrier method (condom or diaphragm) with spermicide for at least 3 
months prior to Visit 1 (Screening) and continuing through Visit 4 or last 
administration of the investigational product or until completion of the 
subject’s first menstrual cycle following last administration of the 
investigational product, whichever period of time is longer. 
c. Stable hormonal contraceptive for at least 3 months prior to Visit 1 
(Screening) and continuing through Visit 4 or last administration of the 
investigational product or until completion of the subject’s first menstrual 
cycle following administration of the investigational product, whichever 
period of time is longer. 
NOTE: For Depo-Provera injection contraceptives, the statement 
regarding first menstrual cycle following administration of the 
investigational product is not applicable as females receiving this form of 
contraception will not have menses. 
d. In a monogamous relationship with a surgically sterilized (i.e., 
vasectomized) partner at least 6 months prior to Visit 1 (Screening) 
through Visit 4 or last administration of the investigational product or until 
completion of the subject’s first menstrual cycle following administration 
of the investigational product, whichever period of time is longer. 
8. Are postmenopausal women (i.e., no menstrual cycle for at least one year prior to 
Visit 1 (Screening)) or are women who have undergone 1 of the following 
sterilization procedures at least 6 months prior to Visit 1 (Screening): 
a. Bilateral tubal ligation 
b. Hysterectomy 
c. Hysterectomy with unilateral or bilateral oophorectomy. 
d. Bilateral oophorectomy 


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8.2. 
Subject Exclusion Criteria 
In order for subjects to be eligible at Visit 1 (Screening) and Visit 2 (Day 1) they may 
not: 
1. Have a known hypersensitivity or contraindication to the investigational 
product(s) or their components. 
2. Have used any of the following medications or had any of the following 
procedures within 30 days prior to Visit 1 (Screening) or for the duration of the 
study: 
a. Ocular, inhaled or intranasal corticosteroids 
b. Ocular or oral non-steroidal anti-inflammatory drugs (NSAIDs) with the 
exception of ≤ 81 mg/day of acetylsalicylic acid (ASA or aspirin) 
c. Topical ocular antibiotics 
d. Topical ocular antihistamines or mast cell stabilizers 
e. Oral antihistamines 
f. Topical or nasal vasoconstrictors 
g. Autologous serum tear preparations 
h. Lipiflow treatment 
i. TruTear treatment 
j. Blephex treatment 
3. Have used any of the following medications within 60 days prior to Visit 1 
(Screening) or for the duration of the study: 
a. Topical cyclosporine (Restasis®) 
b. Topical lifitegrast 
c. Any form of topical loteprednol etabonate (LE) 
4. Have altered oral dosing of the following within 30 days prior to Visit 1 
(Screening) or anticipate alteration of dosing during the study:  
a. Tetracycline compounds (e.g., tetracycline, doxycycline, or minocycline) 
b. Omega-3 or Omega-6 supplements 
5. Have altered dosing of the following medications within 6 months prior to Visit 1 
(Screening) or anticipate alteration of dosing during the study: 
a. Anticholinergics 
b. Anticonvulsants (e.g., topiramate) 
c. Antidepressants 


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d. Isotretinoin 
e. Systemic immunosuppressive agents including oral corticosteroids at a 
dose of prednisone < 11 mg/day or equivalent. 
NOTE:  Oral corticosteroid use at a dose of prednisone >11 mg/day or 
equivalent is excluded. 
6. Be unwilling to abstain from the use of any topical ophthalmic medications at 
Visit 1 (Screening) and for the duration of the study, including: 
a. Eyelash growth medications, including both prescription and over-the-counter 
b. Eye drops, gels, ointments, or artificial tears  
7. Be unwilling to abstain from the use TNF-blocking agents (e.g. etanercept, 
adalimumab, infliximab) at Visit 1 (Screening) and for the duration of the study. 
8. Be currently receiving treatment for glaucoma at Visit 1 (Screening) or for the 
duration of the study and/or have history of or current glaucoma, or an IOP over 
21mmHg at Visit 1 (Screening) or Visit 2 (Day 1). 
9. Be unwilling to abstain from wearing contact lenses for 14 days prior to Visit 1 
(Screening) and for the duration of the study. 
10. Be monocular or have a BCVA of +1.0 logMAR or worse as assessed by Early 
Treatment Diabetic Retinopathy Study (ETDRS). 
11. Have had penetrating intraocular surgery within 3 months prior to Visit 1 
(Screening) or anticipate requiring penetrating intraocular surgery during the 
study. 
12. Have had corneal refractive surgery (e.g. Lasik) or corneal transplantation (full 
thickness, anterior or posterior).  
13. Have had eyelid surgery within 6 months prior to Visit 1 (Screening) or 
anticipate requiring eyelid surgery during the study. 
14. Have congenitally absent lacrimal glands or meibomian glands.   
15. Have had laser trabeculoplasty or anticipate requiring laser trabeculoplasty. 
16. Have had cauterization of the punctum or have had punctal plugs (silicone or 
collagen) inserted or removed less than 3 months prior to Visit 1 (Screening) or 
planned during the study. 
NOTE:  If subject starts the study with punctal plugs, they must remain in place 
for the duration of the study and must be replaced if inadvertently removed. 
17. Have a diagnosis of: 
a. Ongoing ocular infection  
b. Moderate to severe pinguecula or pterygia 




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8.3. 
Subject Withdrawal and Study Termination Criteria 
Any subject who wishes to may withdraw from the investigational product use or from 
participation in the study of his or her own accord for any reason is entitled to do so 
without obligation.  The Investigator may also withdraw any subject from the 
investigational product use or from study participation, if deemed necessary.  
Investigational product use may be discontinued and any subject may be discontinued 
from study participation at any time during the study at the discretion of the Investigator 
or the Sponsor for any reason including but not limited to: 
1. Occurrence of any medical condition or circumstance that exposes the subject to 
substantial risk and/or does not allow the subject to adhere to the requirements of 
the protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the subject. 
3. Subject's decision to withdraw. 
4. Any woman who becomes pregnant while participating in the study.  Information 
on the pregnancy and outcome will be requested.   
5. Subject’s failure to comply with protocol requirements or study related 
procedures. 
6. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
In the event study discontinuation of a randomized subject is necessary, the Investigator 
should make every attempt to have subject complete Visit 4 assessments as possible. The 
reason for premature discontinuation should be entered onto the eCRF and recorded in 
the subject chart. 
Subjects who withdraw from the study will not be replaced. 
Additionally, the trial or parts of the trial may be discontinued by the Sponsor or at the 
recommendation of the Investigator after consultation with Kala Pharmaceuticals, Inc.  
This may be based on a significant number of AEs of a similar nature that warrant such 
action.    
 




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Medications and/or procedures not specifically excluded in the list below may be taken 
and/or conducted as necessary. 
At Visit 1 (Screening) and for the duration of the study: 
• Any topical ophthalmic medications including eyelash growth medications 
(including both prescription and over-the-counter), eye drops, gels, ointments, or 
artificial tears  
• TNF-blocking agents (e.g. etanercept, adalimumab, infliximab) 
• Treatment for glaucoma 
Within 30 days prior to Visit 1 (Screening) and for the duration of the study: 
• Ocular, inhaled, or intranasal corticosteroids 
• Ocular or oral non-steroidal anti-inflammatory drugs (NSAIDs) with the 
exception of ≤ 81 mg/day of acetylsalicylic acid (ASA or aspirin) 
• Topical ocular antibiotics 
• Topical ocular antihistamines or mast cell stabilizers 
• Oral antihistamines 
• Topical or nasal vasoconstrictors 
• Other investigational products 
• Autologous serum tear preparations 
Within 60 days prior to Visit 1 (Screening) and for the duration of the study: 
• Topical cyclosporine (Restasis®) 
• Topical lifitegrast 
• Any form of topical LE 
Within 30 days prior to the screening visit (Visit 1) alteration to the dose or anticipated 
alterations to the dose of the following are disallowed: 
• Tetracycline compounds (tetracycline, doxycycline, or minocycline) 
• Omega-3 or Omega-6 supplements 
Within 6 months prior to the screening visit (Visit 1) alterations to the dose or 
anticipated alterations to the dose of the following are disallowed: 
• Anticholinergics 
• Anticonvulsants (e.g., topiramate) 
• Antidepressants 
• Isotretinoin 




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A randomization code will be computer-generated by Kala Pharmaceuticals, Inc. or 
designee.  Randomization team members will work independently of other team 
members.  Study personnel involved in subject assessment (i.e., not the dosing 
coordinator), study subjects, the Sponsor, and project teams at the CROs involved in the 
study will be masked to investigational product assignments. 
 
 
 


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10. 
INVESTIGATIONAL PRODUCT MATERIALS AND 
MANAGEMENT 
10.1. 
Investigational product 
KPI-121 0.25% ophthalmic suspension contains submicron particles of LE suspended in 
a formulation consisting of excipients that have been used in other FDA-approved 
ophthalmic products.   
KPI-121 0.25% drug product will be supplied as a suspension in opaque dropper bottles.  
KPI-121 0.25% ophthalmic suspension is a sterile, aqueous, submicron suspension of LE 
and will be supplied in a 10 mL, white, low-density polyethylene dropper bottle with a 
translucent, controlled-drop linear low-density polyethylene tip, a pink high-density 
polyethylene cap, and a white, low-density polyethylene, tamper-evident overcap. Each 
bottle contains 8.2 mL (nominal fill) of drug product. 
Subjects randomized to the vehicle control arm will receive the same bottles containing 
all components at the concentrations used in the KPI-121 0.25% ophthalmic suspension 
with the exception of the active component, LE.  
10.2. 
Investigational product Packaging and Labeling 
The Stage 1 investigational product will be 1 bottle of single-masked, investigational 
product (vehicle) from a common site level supply which will be provided to the subject 
after qualifying for Stage 1.  The bottle labels for the single-masked period contain the 
following information:  Sponsor name, protocol number, lot number, unique identifying 
number, storage temperature, and required statement(s) per the FDA requirements. 
The randomized investigational product kit will consist of a box containing 2 dropper 
bottles of investigational product. At Day 1, eligible subjects will receive 1 bottle of 
investigational product. The second bottle will be retained at the site and provided to the 
subject in the event the subject needs additional investigational product during the 
treatment period. The box label and dropper bottle labels will contain the following 
information: Sponsor name, protocol and kit number, storage temperature, and required 
statement(s) per the FDA requirements. 
10.3. 
Investigational product Storage 
All investigational products will be stored at the site upright in a secure area, with limited 
access, at 15-25°C/59 -77°F.   
10.4. 
Investigational product Preparation 
Subjects will be instructed to shake the investigational product bottle for 2 to 3 seconds 
prior to each instillation.   


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10.5. 
Administration 
At Visits 1 and 2, when subjects receive the first dose in the clinic, that dose will count as 
1 of their 4 (QID) daily doses. Subjects will then self-administer at most 3 additional 
doses of investigational product during the remainder of that day to complete QID 
dosing.  All visits should be scheduled in the morning to allow subjects to receive a full 
day of QID dosing.  Any Stage 1 doses taken on the morning of Visit 2 should be counted 
into the total 4 doses for the day. 
Subjects will be asked to instill 1 dose upon awakening and then 3 subsequent doses 
approximately 4 hours after their previous dose.  The 4 doses will be described as 
“Morning Dose,” “Mid-Morning Dose,” “Afternoon Dose,” and “Evening Dose.”  
10.6. 
Investigational product Accountability 
Sponsor study monitors or designees will conduct accountability of investigational 
product (KPI-121 0.25% ophthalmic suspension or vehicle).  Accountability will be 
ascertained by performing reconciliation between the amount of investigational product 
sent to the site and the amount used and unused at the time of reconciliation. 
Clinical trial materials will be shipped to the investigational sites under sealed conditions.  
Investigational product shipment records will be verified by comparing the shipment 
inventory sheet to the actual quantity of investigational product received at the site.  
Accurate records of receipt and disposition of the investigational product (e.g., dates, 
quantity, subject number, dose dispensed, returned) must be maintained by the 
Investigator or his/her designee.   
10.7. 
Investigational product Handling and Disposal 
At the end of the study, all study materials, including any unused investigational products 
(KPI-121 0.25% ophthalmic suspension or vehicle), as well as original containers (even if 
empty), will be returned to the drug-packaging vendor in accordance with Sponsor or 
designee’s Standard Operating Procedures (SOPs), following approval by the Sponsor. 
All returns of investigational product will be documented.  The study monitor or designee 
will verify investigational product accountability.  All investigational product accounting 
procedures must be completed before the study is considered complete. 


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11. 
ASSESSMENT OF EFFICACY 
Efficacy assessments will be performed according to the schedule of events provided in Appendix 
1 and include: 
• 
Subject-rated assessment of ocular discomfort
 
 
 
• 
 bulbar conjunctival hyperemia 
• 
 
• 
corneal fluorescein staining 
• 
Subject-rated assessment of eye dryness 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
An ophthalmic examination will be performed at all study visits, except at Visit 3, 
according to the schedule of events provided in Appendix 1. Safety parameters include: 
• Assessments of AEs 
• BCVA 
• Slit lamp biomicroscopy  
• Dilated ophthalmoscopy  
• IOP measurement 
• Pregnancy screen (performed only at Visits 1 and 4 on WOCBP)* 
*All pregnancies are to be reported from the time informed consent is 
signed until Visit 4/End of study.  Any report of pregnancy for any subject must 
be reported within 24 hours of site awareness to Kala or its delegate using the 
Pregnancy Report Form. The Pregnancy form should be faxed to 
 
or emailed to 
 
Women who have a positive pregnancy test during the study will be withdrawn 
from the study treatment and, whenever possible, should complete all remaining 
study visits and assessments.  Every effort should be made to gather information 
regarding the pregnancy outcome and condition of the infant. It is the 
responsibility of the investigator to obtain this information within 30 calendar 
days after the initial notification and approximately 30 calendar days postpartum.  
Pregnancy complications such as spontaneous abortion/miscarriage, premature 
birth or congenital abnormality are considered SAEs. The SAE must be entered 
on the AE eCRF in EDC and the SAE fax cover letter completed then faxed to 1-
 or emailed to 
 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
12.2.1.1. Adverse Event (AE) 
Adverse Event (AE):  Any untoward medical occurrence associated with the use of an 
investigational product in humans, whether or not considered drug related.  
Adverse Reaction (AR): any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the drug caused the 
event.  
Suspected Adverse Reaction (SAR):  


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Any AE for which there is a reasonable possibility that the drug caused the AE. For the 
purposes of IND safety reporting, “reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the AE. A SAR implies a lesser 
degree of certainty about causality than adverse reaction, which means any AE caused by 
a drug.  
Unexpected:  An AE or SAR is considered “unexpected” if it is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or, if an Investigator’s Brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the 
current application.   
Life-threatening: An AE or SAR is considered “life-threatening” if, in the view of either 
the Investigator or Sponsor, its occurrence places the subject or subject at immediate risk 
of death. It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
12.2.1.2. Serious Adverse Event (SAE) 
A SERIOUS ADVERSE EVENT (SAE) is any AE or suspected adverse reaction 
occurring at any dose that:  
• Results in death. 
• Is life-threatening. 
• Results in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
• Requires in subject hospitalization. 
• Prolongs in subject hospitalization. 
• Is a congenital anomaly/birth defect. 
• Is a significant medical event (i.e., one that may jeopardize the subject or may 
require intervention to prevent one or more of the other outcomes listed above). 
A NON-SERIOUS ADVERSE EVENT is any AE that does not meet the definitions for 
SAEs as described above.  
Each AE will be classified as SERIOUS or NON-SERIOUS using the definitions 
provided above. 
12.3. 
Relationship to Investigational product 
The SEVERITY of each AE will be classified as MILD, MODERATE, or SEVERE.   
The Investigator will review each event and assess its RELATIONSHIP to use of 
investigational product (unrelated, unlikely, possibly, probably, definitely). The AE will 
be assessed using the following definitions: 


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Unrelated: 
 
• Event occurring before dosing. 
• Event or intercurrent illness due wholly to factors other than investigational 
product use. 
Unlikely:  
• Poor temporal relationship with investigational product use. 
• Event easily explained by subject’s clinical state or other factors. 
Possibly: 
• Reasonable temporal relationship with investigational product use. 
• Event could be explained by subject’s clinical state or other factors. 
Probably: 
• Reasonable temporal relationship with investigational product use. 
• Likely to be known reaction to agent or chemical group, or predicted by known 
pharmacology. 
• Event cannot easily be explained by subject’s clinical state or other factors. 
Definitely: 
• Distinct temporal relationship with investigational product use. 
• Known reaction to agent or chemical group, or predicted by known pharmacology. 
• Event cannot be explained by subject’s clinical state or other factors.  
12.4. 
Recording Adverse Events 
AEs will be monitored throughout the study (from the time of ICF signature through Visit 
4) and will be recorded on the eCRF with the date and time of onset, date and time of 
resolution, severity, seriousness, causality (relationship to use of investigational product), 
treatment required, and the outcome.   
To elicit AEs, simple questions with minimal suggestions or implications should be used 
as the initial questions at all evaluation points during the trial.  For example: 
How have you felt since your last assessment? 
Have you had any health problems since your last assessment? 
The severity of each AE should be categorized as mild, moderate, or severe. 
The causality of use of investigational product in relation to the AE will be assessed by 
the Principal Investigator after careful medical consideration and categorized as 
unrelated, unlikely, possible, probable, or definite. 


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If an AE occurs, the Investigator will institute support and/or treat as deemed appropriate.   
If a non-SAE is unresolved at the time of the last day of the study, an effort will be made 
to follow up until the AE is resolved or stabilized, the subject is lost to follow-up, or there 
is some other resolution of the event.  The Investigator should make every attempt to 
follow SAEs to resolution. 
12.5. 
Reporting Adverse Events 
Serious Adverse Event Reporting 
It is the responsibility of the Investigators or their designees to report any event of this 
nature to the Sponsor or a designee within 24 hours of the event being brought to the 
Investigators’ or their staffs’ attention.  It is also the responsibility of the Investigator to 
report all SAEs reported at their site to their Institutional Review Board (IRB), as 
required.  The Investigator should make every attempt to follow all SAEs to resolution.   
The following information should be provided when an SAE is reported to the Sponsor or 
designee: 
1. Protocol Number 
2. Site Number 
3. Subject Number 
4. Subject Demographic information, including: 
o Date of Birth 
o Sex 
o Race 
5. Investigational product start date 
6. Date of last dose of investigational product  
7. Date investigational product reinitiated (if investigational product interrupted)  
8. SAE information, including: 
o SAE term (diagnosis only; if known or serious signs/symptoms) 
o Description of SAE/narrative 


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o Date/time of onset 
o Severity 
o Outcome 
o Date/time of resolution or death (if duration < 24 hours) 
o Relationship to investigational product 
o Action taken with investigational product 
9. Criteria for classifying the event as serious, including whether the SAE:   
o Resulted in death. 
o Was life-threatening 
o Required inpatient hospitalization. 
o Prolonged inpatient hospitalization. 
o Resulted in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
o Was a congenital anomaly/birth defect. 
o Important medical events that may not result in death, were not life-
threatening, or did not require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the 
subject or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in subject hospitalization, or the development of drug dependency 
or drug abuse.  
10. Concomitant medications 
11. Relevant history 
12. Possible causes of SAE other than investigational product 


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13. Copy of AE page from the eCRF 
NOTE: If an SAE occurs in any study involving KPI-121 0.25% ophthalmic suspension 
that is unexpected and is determined to be related or possibly related to investigational 
product, all sites will be notified by the Sponsor and each site should report it to its IRB.   
 








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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
The progress of the study will be monitored by on-site, written, e-mail, and telephone 
communications between personnel at the study center and the Sponsor (or designated 
monitor).  The Investigator will allow Kala Pharmaceuticals, Inc. monitors or designee to 
inspect all CRFs; subject records (source documents); signed informed consent forms; 
HIPAA authorizations; records of investigational product receipt, storage, and 
disposition; and regulatory files related to the study. 
14.2. 
Audits and Inspections 
Authorized representatives of Kala Pharmaceuticals, Inc, a regulatory authority, an 
Independent Ethics Committee or an Institutional Review Board may visit the site to 
perform audits or inspections, including source data verification.  The purpose of a Kala 
Pharmaceuticals, Inc. audit or inspection is to systematically and independently examine 
all study-related activities and documents to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization, and any applicable regulatory requirements.  The investigator should 
contact Kala Pharmaceuticals, Inc immediately if contacted by a regulatory agency about 
an inspection. 
14.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB 
approval, and all materials approved by the IRB for this study including the subject 
consent form and recruitment materials must be maintained by the Investigator and made 
available for inspection. 
 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory 
requirements, Kala Pharmaceuticals, Inc. may conduct a quality assurance audit.  Please 
see Section 14.2 for more details regarding the audit process. 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
This protocol and the informed consent form must be approved by an appropriately 
constituted and qualified IRB and the approvals made available to the Sponsor or 
designee prior to the start of enrollment into the study based on these items.  Materials 
used to recruit subjects will be approved by the appropriate IRB and the approvals made 
available to the Sponsor or designee prior to their use. In addition, the Investigator’s 
Brochure should be submitted to the IRB.  Written IRB approval must adequately 
identify the protocol and informed consent form.  Copies of all approved materials, all 
correspondence with the IRB, and written approval from the IRB must be made available 
to the Sponsor (or designated monitor). 
Any modification of study procedures or amendments to the protocol must be approved 
by the IRB prior to implementation.  In the event that a modification or amendment is 
considered by the Investigator to be immediately necessary to ensure subject safety, the 
Investigator will promptly notify his or her IRB and the Sponsor. 
Investigators will report all SAEs reported at their site to their IRB, as appropriate.   
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in 
the Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and 
applicable regulatory requirements. 
16.3. 
Written Informed Consent 
Written informed consent will be obtained from each participant prior to any study-
related procedures being performed [prior to or upon Visit 1 (Screening)].  A copy of the 
signed and dated informed consent document will be given to each subject.  The original 
signed and dated informed consent document must be maintained in the study files at the 
investigative site and be available for Sponsor or designee review. 
Each informed consent will contain Investigator contact information with a telephone 
number the subject or the subject’s authorized representative can call 24 hours a day if 
they have medical concerns. 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
The Investigator will permit trial-related monitoring, audits, IRB review, and regulatory 
inspection(s) by providing direct access to source data and documents (such as tests 
performed as a requirement for participation in the study and other medical records 
required to confirm information contained in the case report form such as medical 
history) to the monitor. 
Electronic case report forms will be used to collect subject data during the course of the 
trial.  Electronic case report forms must be fully completed for each subject and signed by 
the Investigator upon completion. The Investigator or designated individual shall be 
responsible for recording trial data on the eCRFs.  Access to the eCRFs will be by means 
of a unique username and password through a secure web-browser.  Changes to the 
original data entries will trigger a reason for change dialogue box while the time, date and 
user making the change are automatically logged. 
The Investigator is required to sign the eCRF on the appropriate page(s) to verify that 
he/she has reviewed the recorded data. Completed eCRFs will be verified by the Sponsor 
study monitors or designees at regular intervals during the trial. The Investigator will 
allow the monitor and other external regulatory body to review and inspect the study 
files, the eCRFs, subject medical records and other trial related documents as required. 
17.2. 
Retention of Records 
The study center will retain all records related to the study in accordance with local and 
ICH GCP guidelines. Final signed eCRFs will be provided to the site at the end of the 
study for record retention. 


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18. 
PUBLICATION POLICY 
The institution and Investigators participating in this trial shall have no right to publish or 
present the results of this study without the prior written consent of the Sponsor. 


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19. 
LIST OF REFERENCES 
1. DEWS Report. The definition and classification of dry eye disease.; 2007:75-92. 
Available at: 
http://www.sciencedirect.com/science/article/pii/S1542012412700812. Accessed 
April 29, 2014. 
 
2. Paulsen, AJ, Cruickshanks, KJ, Fischer, ME, et al. Dry eye in the beaver dam 
offspring study: prevalence, risk factors, and health-related quality of life. Am J 
Ophthalmol. 2014;157(4):799-806.  doi:10.1016/j.ajo.2013.12.023. 
 
3. Pflugfelder, SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol. 2004; 
137(2):337-342.  doi:10.1016/j.ajo.2003.10.036. 
 
4. Xiidra® [package insert]. Lexington, MA: Shire Pharmaceuticals Inc; 2016. 
5. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical 
Trials in Dry Eyes. CLAO J Off Publ Contact Lens Assoc Ophthalmol Inc. 
1995;21(4):221-232. 
6. Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the 
context of other dry eye tests. Cornea. 2003;22(7):640-650. 
 


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20. 
APPENDICES 




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APPENDIX 2: SUBJECT-RATED ASSESSMENT OF EYE DRYNESS 
Subjects will be asked to subjectively rate their eye dryness at Visits 2-4. Subjects will be 
instructed to rate eye dryness using the scales shown below and entered on a source 
document.  The total length of the line from 
 to 
 is 100 mm.  
The length of the line between the 
 starting point and the first point where the 
subject’s mark crosses the line will be measured and recorded in millimeters. This assessment 
is a general assessment of both eyes.  There will not be a question for each individual eye. 
Instantaneous Evaluation of Eye Dryness 
Please place a single line across the line below to indicate the severity of your eye dryness  
: 
 
  
 
 
 
 
 
 
 
       
 
 
 
 
 
 
    
 
 
 
 
 
 
  
 
 


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APPENDIX 3: SUBJECT-RATED ASSESSMENT OF OCULAR DISCOMFORT4 
Subjects will be asked to subjectively rate their ocular discomfort severity and frequency 
during the course of this study.  
 
  This assessment will be collected at Visit 1 (Screening) for eligibility.  
Further, subjects will be instructed to rate their discomfort 
 using the scales shown 
below 
.  The total length of the lines from 
 to 
 and 
 to 
 are 100 mm.  The length of the line between the 
 on the severity scale or 
 on the frequency scale starting point and the first 
point where the subject’s mark crosses the line will be measured and recorded in millimeters. 
This assessment is a general assessment of both eyes.  There will not be a question for each 
individual eye. 
OCULAR DISCOMFORT SEVERITY ASSESSMENT 
Please place a single line across the line below to indicate how severe, 
 
you feel your eye discomfort (for example, dryness or irritation) was: 
 
 
 
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
   
 
 
OCULAR DISCOMFORT FREQUENCY ASSESSMENT 
Please place a single line across the line below to indicate how often, 
 
you feel your eye discomfort (for example, dryness or irritation) was: 
 
      
  
 
 
 
 
 
 
 
        
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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APPENDIX 4: I
 ASSESSMENT OF BULBAR CONJUNCTIVAL HYPEREMIA 
 bulbar conjunctival hyperemia at Visits 1, 2, and 4 using the CCLRU 
Grading Scale. 
 
 
(0) None 
(1) Very Slight 
(2) Slight 
(3) Moderate 
(4) Severe 
 


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APPENDIX 5: UNANESTHETIZED SCHIRMER TEST EVALUATION 
Unanesthetized Schirmer Test evaluation will be conducted at Visit 1 (Screening).  Identical 
Schirmer Test strips will be supplied to each site.  When conducting assessments room 
temperature and humidity should be relatively consistent throughout each visit and throughout 
the study.  Please make certain to allow at least 20 minutes between any corneal staining 
evaluations and the unanesthetized Schirmer Test. 
Unanesthetized Schirmer Test  
• While still in the plastic sheath, fold the rounded end of the unanesthetized Schirmer Test 
strip at the first line on the strip (closest to the rounded end). Additionally, fold a partial 
second fold at the halfway point of the strip so that the strip does not lie directly in the 
subject’s line of sight. 
• Remove the right eye strip from the sheath. 
• Ask the subject to look up and gently draw the right lower lid in a downward and temporal 
direction.  
• Place the rounded end of the strip toward the temporal one-third of the lower eyelid.  
• Repeat this procedure in the left eye. 
• Darken the room, but ensure that the Large E or the ETDRS chart is visible. 
• Instruct the subject to relax and look at the chart while blinking normally or have subject 
gently close eyes. 
• Strips are removed after 5 minutes. 
• After removing the strips, with a pen draw a horizontal line across the leading edge of 
moisture and a second horizontal line across the lowest point of moisture. 
• Using a ruler and/or the millimeters recorded on the strips, measure a point halfway 
between the 2 lines and record this as the amount of wetting. 
• Retain Schirmer strips in source documentation. 
 
 
 


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APPENDIX 6: BEST-CORRECTED VISUAL ACUITY 
BCVA will be conducted at Visits 1, 2, and 4.   
Visual acuity testing should precede any examination requiring contact with the eye or 
instillation of study dyes.  LogMAR visual acuity must be assessed using an ETDRS or modified 
ETDRS chart.  Visual acuity testing should be performed with best correction using subject’s 
own corrective lenses (spectacles only) or pinhole refraction. 
An ETDRS or modified ETDRS chart may be used.  If a Lighthouse chart is used (24.5” by 25”; 
either reflectance or retro-illuminated), the subject must view the chart from a distance of exactly 
4 meters (13.1 feet).  If smaller reproductions (18” by 18”, e.g., Prevent Blindness) are used, the 
subject viewing distance should be exactly 10 feet.  Reflectance wall charts should be frontally 
illuminated (60-watt bulb or a well-lit room). 
The subject should be positioned according to the elevation of the chart (either seated or 
standing) so that the chart is at a comfortable viewing angle.  The right eye should be tested first.  
The subject should attempt to read each letter, line-by-line, left to right, beginning with line 1 at 
the top of the chart.  The subject should be told that the chart has letters only, no numbers.  If the 
subject reads a number, he or she should be reminded that the chart contains no numbers, and the 
examiner should then request a letter instead of the number.  The subject should be asked to read 
slowly, about 1 letter per second, to achieve the best identification of each letter.  He/she is not to 
proceed to the next letter until he/she has given a definite response.  If the subject changes a 
response before he has read aloud the next letter, then the change must be accepted. 
Maximum effort should be made to identify each letter on the chart encouraging the subject to 
guess.  When it becomes evident that no further meaningful readings can be made, the examiner 
should stop the test.  The number of letters missed or read incorrectly should be noted. 
In order to provide standardized and well-controlled assessments of visual acuity during 
the study, consistently use the same lighting conditions during the entire study. 
Calculations: logMAR VA = Baseline value + (n X 0.02) 
where: 
the baseline value is the logMAR number of the last line read (at least 1 letter read 
correctly in this line), and 
“n” is the total number of letters missed up to and including the last line read, and  
“0.02” is the value for each letter 


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APPENDIX 7: SLIT LAMP BIOMICROSCOPY 
The biomicroscopy exam will be performed at Visits 1, 2, and 4.  It should be performed with the 
slit lamp using a beam of width and intensity to provide optimal evaluation of anterior segment. 
This procedure will be performed in the same manner for all subjects observed at the 
Investigator’s site.   
Lashes  
             0 = Normal 
 
 
 1 = Abnormal 
Eyelid 
Eyelid Margin Hyperemia (lower eyelid): 
 
 
 
0 = 
Normal 
Normal age-appropriate redness and vasculature. 
1 =  Mild 
Slightly dilated blood vessels; vessels colored pink; present in greater than 
25% of the lower eyelid margin 
2 =  Moderate 
More apparent dilation of blood vessels; vessel color red, present in greater 
than 25% of the lower eyelid margin. 
3 =  Severe 
Increased vascularity of the eyelid margin, numerous and obvious dilated 
blood vessels, deep red in color, present in greater than 25% of the lower 
eyelid margin. 
4 =  Very Severe 
Clearly increased vascularity of the eyelid margin; numerous dilated blood 
vessels deep red color, present in greater than 75% of the lower eyelid 
margin. 


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Character of Meibomian Gland Content (middle part of lower lid, n = 10) 
 
 
 
 
 
The most severe finding in any one meibomian gland should be recorded for this evaluation 
Expressibility of Meibomian Gland (middle part of lower lid, n = 10) 
0 = 
Normal 
9 – 10 glands expressible 
1 =  Mild 
6 – 8 glands expressible 
2 =  Moderate 
3 – 5 glands expressible 
3 =  Severe 
1 – 2 glands expressible 
Edema  
 
    
  0 = Normal, no swelling of the lid tissue 
 
 
  1 = Abnormal 
Conjunctiva 
Edema   
    
  0 = Normal, no swelling of the conjunctiva 
 
 
  1 = Abnormal 
 
 
0 = 
Normal 
Clear liquid 
1 =  Mild 
Hazy, turbid liquid 
2 =  Moderate 
Turbid liquid with clumps 
3 =  Severe 
Solid (paste) 


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Cornea 
Infiltrates 
 
 
 0 = Absent 
 
 
 1 = Present 
Endothelial Changes 
 
 
 0 = Normal, None 
 
 
 1 = Abnormal, pigment, keratoprecipitates, guttata 
 
Edema 
    
 0 = Normal None, transparent and clear 
 
 
 1 = Abnormal 
Anterior Chamber 
 
Cells 
 
  
 0 = Normal, No cells seen 
 
  
 1 = Abnormal (+ to +++ cells) 
 
Flare 
 
  
 0 = Normal, No Tyndall effect 
     
 1 = Abnormal, Tyndall beam in the anterior chamber 
Lens Pathology  
 0 = Normal; no opacity in the lens 
 1 = Abnormal; existing opacity in the lens; aphakic or pseudophakic eyes or other  
 
 
 
abnormal findings. 
 
 


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Sclera 
Injection 
 
 
0 = Normal, without any redness  
 
 
1 = Abnormal 
 


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APPENDIX 8:  CORNEAL FLUORESCEIN STAINING 
Corneal staining will be performed at Visit 1, 2, and 4.  Corneal staining assessment will be 
performed for both eyes using methods developed by the NEI Dry Eye Workshop5,6with separate 
strips used for each eye. 
Evaluation Technique  
1. Use a Wratten #12 barrier filter in the assessment of fluorescein staining to enhance the 
appearance of the fluorescein. 
2. Use sufficient unpreserved saline solution (study stock) to wet the entire area of 
fluorescein impregnation on a 1.0 mg strip.  If the strip becomes too saturated, please 
discard and begin again with a new strip. 
3. Within 15 seconds of wetting the strip, taking care not to touch the strip to the eye, instill 
the fluorescein sodium on the inferior palpebral conjunctiva. 
4. Instruct the subject to blink several times to distribute the fluorescein staining. 
5. Examine the cornea 2 minutes after instillation of fluorescein 
6. Use a cobalt blue illumination (465 nm to 490 nm) and a 3-mm-wide scanning beam in 
each eye.  
7. Compare corneal fluorescein staining in each eye with the standard by scoring each of the 
5 corneal sections as described below: 
Scoring system 
1. Grade each of 5 sections of cornea (superior, inferior, nasal, temporal, central) 
2. Provide grades for each of the 5 sections: 
a. Grade by NEI scale (definition below) as 0, 1 (mild), 2 (moderate), 3 (severe) 
3. Total score is obtained by summing each of the 5 sections of the cornea 
a. NEI score will be from 0-15 
4. Definitions 
a. NEI Scoring System (0, 1, 2, 3) 
i. Grade 0 
No visible staining within the section of cornea being evaluated 
ii. Grade 1 
MILD 
Small amount of micropunctate staining within the section of cornea being 
evaluated 
iii. Grade 2 
MODERATE 
Medium amount of micropunctate staining within the section of cornea 
being evaluated or mild amount of macropunctate stain 


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iv. Grade 3 
SEVERE 
Significant amount of micropunctate or macropunctate staining within the 
section of cornea being evaluated 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 9: IOP MEASUREMENT 
IOP measurements will be performed utilizing Goldmann applanation tonometery according to 
the Investigator’s standard procedure.  All pressure will be recorded in mmHg.  IOP assessments 
will occur at study Visits 1, 2, and 4. 
 
 
 
 
 
 
 
 


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APPENDIX 10: DILATED OPHTHALMOSCOPY 
Dilated ophthalmoscopy will include assessment of the optic nerve head for pallor and cupping 
(cup to disc ratio) and will be performed at Visit 1 (Screening) and Visit 4 after the 
administration of all other study assessments (except for symptom assessments).  After the 
ophthalmoscopy procedure, the Investigator will determine if findings are within normal limits 
or are abnormal.  For abnormal findings at Visit 1 (Screening), the Investigator will determine 
whether or not the abnormality would exclude subject from study participation.   
 
 
 
 


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