Clinical trial NCT02813265
Conditions: Dry Eye Syndromes Keratoconjunctivitis Sicca
Keywords: Ocular Discomfort Pain Corticosteroid Hyperemia Dry Eye
Sponsor: Kala Pharmaceuticals, Inc.
Start date: 2016-06-01; Completion date: 2017-10-01
Enrollment: 918 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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 0.25% Ophthalmic Suspension intervention 2: Vehicle of KPI-121 0.25% Ophthalmic Suspension
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
NCT02813265  
 
Study ID:  
KPI-121-C-006 (STRIDE 1)  
 
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   
Date:  
06 Jul 2017 




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KALA PHARMACEUTICALS, INC. 
Clinical Protocol KPI-121-C-006 
Investigator Signature Page 
Project: 
KPI-121 
Compound Number/Name: 
KPI-121  
Protocol Number: 
KPI-121-C-006  
Protocol 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 
Sponsor: 
Kala Pharmaceuticals, Inc. 
 
100 Beaver St., Suite 201 
 
Waltham, MA 02453 
Issue Date: 
Original:  24 May 2016 
 
Amendment 1:  21 Jul 2016 
 
Amendment 2:  23 Aug 2016 
 
Amendment 3:  14 Jun 2017 
 
Amendment 4: 06 Jul 2017 
Contact for Serious Adverse Events: 
 
 
  
 
     
  
 
 
  
   
 
  
 
 
Investigator Name (printed or typed): 
 
________________________________________________ 
 
Investigator's Signature: 
 
________________________________________________ 
______________  
 
 


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SYNOPSIS  
Study Title: 
KPI-121-C-006: A Phase 3, Double-Masked, Randomized, Controlled 
Study of KPI-121 0.25% Ophthalmic Suspension Compared to Vehicle in 
Subjects with Dry Eye Disease 
Objectives: 
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. 
Study 
Population:  
The study population will consist of subjects diagnosed with dry eye 
disease. 
Number of 
Subjects 
Approximately 2000 subjects who are diagnosed with dry eye disease will 
be screened.  From those screened, approximately 900 subjects will be 
randomized to KPI-121 0.25% ophthalmic suspension or vehicle. 
Investigational 
Products: 
KPI-121 0.25% ophthalmic suspension and vehicle will be supplied as 
investigational product. 
Route and 
Duration of 
Administration: 
1 to 2 drops of investigational product will be instilled in each eye four 
times per day (QID) for approximately 14 days. 
Study Design:   
 
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.   
Approximately 2000 subjects will be screened and approximately 900 
subjects will be randomized at approximately 60 centers located in the 
United States (US).   
Subjects will be randomized to 1 of 2 study arms in an approximate 1:1 
ratio.  The study arms are: 1) KPI-121 0.25% ophthalmic suspension 
administered as 1-2 drops in each eye QID for approximately 14 days and 
2) vehicle administered as 1-2 drops in each eye QID for approximately 
14 days.   


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Furthermore, subjects will be assigned to a study arm based on the 
stratification of: 
x Ocular discomfort severity scores 
 (low) and 
 (high) based on the subject’s scoring of 
ocular discomfort severity 
 prior to Visit 2 (Day 1) 
AND 
x Investigator-rated bulbar conjunctival hyperemia score of  (low) 
and 
 (high) in the eye with the higher score at Visit 2 (Day 1).  
Randomization in the ocular discomfort severity strata will be distributed 
between the high and low strata.  
 
 
 
 
 
 
 
 
  A 
distribution ratio will not be imposed on the investigator-rated bulbar 
conjunctival hyperemia strata.  
This study will include up to 4 clinic visits over 4 weeks. At Visit 1 
Screening (14 ± 1 days prior to Day 1), subjects who meet screening 
inclusion/exclusion criteria will begin a 2-week run-in period during 
which they will be treated with 1-2 drops of vehicle in each eye QID for 
14 ± 1 days.   
At Visit 2, Randomization (Day 1), subjects who continue to meet 
inclusion/exclusion criteria will be eligible for randomization to 1 of the 2 
arms of the study (i.e., KPI-121 0.25% ophthalmic suspension or vehicle).  
Following randomization, subjects will be instructed to return to the clinic 
for 
 in-clinic eye dryness assessment at Visit 3 (Day 8 
± 1 day) and to have a complete study evaluation at Study Visit 4 (Day 15 
± 1 day).  The last dose of investigational product and the final study visit 
will occur upon completion of 14 ± 1 days of exposure to investigational 
product.  Subjects will be released from the study at the end of Visit 4 
(Day 15 ± 1 day). 
 
 
 


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Assessments in this study will include: 
x Subject-rated assessment of ocular discomfort 
 
 utilizing 
 
 visual analog scales) 
x Subject-rated assessment of eye dryness (in office) 
x Investigator-rated assessment of bulbar conjunctival hyperemia 
x 
  
x Best corrected visual acuity (BCVA) 
x Slit lamp biomicroscopy 
x Corneal fluorescein staining 
x Unanesthetized Schirmer Test evaluation 
x Intraocular pressure (IOP) measurement  
x Dilated ophthalmoscopy 
Efficacy 
Endpoints 
All primary endpoint comparisons will be performed between KPI-121 
0.25% ophthalmic suspension group and the vehicle group using 
sequentially rejective multiple testing as described below 
Primary Efficacy Endpoints: 
The trial will have 4 primary endpoints: 
 
 
 
 
 
 
 
 Mean change from baseline bulbar conjunctival hyperemia 
in the ITT population for Visit 4 (Day 15 ± 1 day) compared to 
Visit 2 (Day 1) 
 
 
 
   


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 Mean change from baseline 
 staining in the 
ITT population for Visit 4 (Day 15 ± 1 day) compared to Visit 2 
(Day 1) in the study eye.   
 Mean change from baseline ocular discomfort 
severity in the ITT population 
 
 prior to Day 
15 compared 
 to Day 1.   
 Mean change from baseline ocular discomfort 
severity in the subgroup population 
 
 
 
 prior to Day 15 compared  
 to Day 1.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Secondary Efficacy Endpoints: 
Secondary efficacy endpoint comparisons will be performed between 
KPI-121 0.25% ophthalmic suspension group and the vehicle group 
 
if primary endpoints are rejected.  Secondary 
endpoints will be tested at D = 0.05: 
1. Mean change from baseline bulbar conjunctival hyperemia, in the 
subgroup population defined as those subjects with an initial 
ocular discomfort severity 
 prior to Visit 2 
(Day 1) for Visit 4 (Day 15 ± 1 day) compared to Visit 2 (Day 1) 
 
in the study eye at Visit 2 
 
   
2. Mean change from baseline ocular discomfort severity in the ITT 
population 
 
 prior to Day 8 compared 
 
 to Day 1.  
3. Mean change from baseline ocular discomfort severity, in the 
subgroup population 
 
 
 
 prior to Day 8 compared 
 
 to Day 1.   
4. Mean change from baseline ocular discomfort severity in the ITT 
population 
 
on Day 4 compared 
 to Day 1.  
5. Mean change from baseline ocular discomfort severity, in the 
subgroup population 
 
 
 
on Day 4 compared 
 to Day 1.   
 
 


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Exploratory Efficacy Endpoints: 
Exploratory efficacy endpoints will be evaluated.  The specific details of 
endpoint testing will be elaborated in the Statistical Analysis Plan (SAP). 
Meta-Analysis: 
The data from this trial may be used for a meta-analysis as described in a 
separate Meta-Analysis Statistical Analysis Plan. 
Safety Endpoints 
x Assessment of adverse events (AEs) 
x Slit lamp biomicroscopy 
x IOP measurement 
x BCVA 
x Dilated Ophthalmoscopy 
Eligibility 
Criteria: 
Inclusion Criteria: 
At Visit 1 (Screening) and Visit 2 (Randomization), individuals of either 
gender or any race will be eligible for study participation if they: 
1. Provide written informed consent and Health Insurance Portability 
and Accountability Act (HIPAA) authorization prior to any study-
related procedures. 
2. Are 18 years of age or older. 
3. Are willing and able to follow instructions and can be present for 
the required study visits for the duration of the study, including: 
a. Single-masked investigational product use compliance of 
at least 80% during the final week of the run-in phase 
AND 
b. 
ocular discomfort 
scoring of at least 80% in the final week of the run-in 
phase. 
4. Have a documented clinical diagnosis of dry eye disease in both 
eyes. 
5. Have ongoing dry eye disease as defined by the following criteria 
in the same eye or both eyes: 


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a. A corneal fluorescein staining score at Visit 1 and Visit 2 
of 
 [National Eye Institute (NEI) scale] AND 
b. Investigator-rated assessment of bulbar conjunctival 
hyperemia at Visit 1 and Visit 2 of 
 as assessed using 
the Cornea and Contact Lens Research Unit (CCLRU) 
scale AND 
c. A score of 
 on ocular discomfort severity at Visit 
1 AND a score of 
 on ocular discomfort severity 
 prior to Visit 2 (Day 1) as graded by the 
subject utilizing 
 visual analog scales 
AND 
d. An unanesthetized Schirmer Test score at Visit 1 of 
 
. 
6. Have normal lid anatomy. 
7. Are women of child bearing potential (WOCBP) who are not 
pregnant or lactating and not sexually active (i.e., abstinent) for 
14 days prior to Visit 1 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. Intrauterine device (IUD) in place for at least 3 months 
prior to Visit 1 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 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. 


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c. Stable hormonal contraceptive for at least 3 months prior 
to Visit 1 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 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) or are women who have undergone 1 of 
the following sterilization procedures at least 6 months prior to 
Visit 1: 
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 
(Randomization) 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 within 30 days prior 
to Screening (Visit 1) or for the duration of the study: 
a. Ocular, inhaled or intranasal corticosteroids 


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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 
3. Have used any of the following medications within 60 days prior 
to Screening (Visit 1) or for the duration of the study: 
x Topical cyclosporine (Restasis®) 
x Topical lifitegrast 
x Any form of topical loteprednol etabonate (LE) 
4. Have altered oral dosing of the following within 30 days prior to 
Screening (Visit 1) 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 Screening (Visit 1) 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. 


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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 
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 (Randomization). 
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 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: 


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a. Ongoing ocular infection  
b. Moderate to severe pinguecula or pterygia 
c. Stevens-Johnson Syndrome 
d. Significant conjunctival scarring 
e. Significant anterior blepharitis 
f. Severe/serious ocular condition that in the judgment of the 
investigator could confound study assessments or limit 
compliance. 
g. Severe/serious systemic disease or uncontrolled medical 
condition that in the judgment of the investigator could 
confound study assessments or limit compliance. 
18. Have Corneal Fluorescein Staining with diffuse confluent staining 
more than 33% of area (focal confluent staining is acceptable), or 
over 5 filaments or epithelial defects. 
19. Have a history of herpetic keratitis. 
20. 
 
 
 
 
 
 
 
 
 
21. Have a history of ocular allergies, which, in the judgment of the 
investigator, are likely to have an acute increase in severity due to 
the expected timing of exposure to the allergen to which the 
subject is sensitive.  Subjects sensitive to seasonal allergens that 
are not expected to be present during the study are permitted. 
22. Have been exposed to an investigational product within 30 days 
prior to Visit 1. 


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23. Be an employee of the practice that is involved in the 
management, administration, or support of this study or be an 
immediate family member of the same. 
24. Have a documented history of alcohol and/or drug abuse. 
25. In the opinion of the Investigator or study coordinator, be 
unwilling or unable to comply with the study protocol or unable to 
successfully instill eye drops. 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 19
1.
INTRODUCTION ................................................................................... 22
1.1.
Description of Investigational Product .................................................... 23
1.2.
Justification for Route of Administration and Dose Selection ................ 23
1.3.
GCP Compliance ..................................................................................... 24
1.4.
Population to be Studied .......................................................................... 24
2.
TRIAL OBJECTIVES AND PURPOSE ................................................. 25
2.1.
Objective .................................................................................................. 25
3.
TRIAL DESIGN ...................................................................................... 26
3.1.
Primary Efficacy Endpoints ..................................................................... 26
3.2.
Secondary Efficacy Endpoints ................................................................. 28
3.3.
Exploratory Efficacy Endpoints ............................................................... 28
3.4.
Safety Endpoints ...................................................................................... 28
3.5.
Description of Trial Design ..................................................................... 29
3.5.1.
Investigational product............................................................................. 31
3.5.2.
Methods to Minimize Bias ....................................................................... 33
3.6.
Meta-analysis ........................................................................................... 33
4.
SELECTION OF SUBJECTS.................................................................. 34
4.1.
Subject Inclusion and Exclusion Criteria ................................................. 34
5.
PROCEDURES........................................................................................ 40
5.1.
Visit Description ...................................................................................... 40
5.1.1.
Visit 1:  14 ± 1 Days Prior to Day 1 – Screening .................................... 40
5.1.2.
Visit 2:  Day 1 (Randomization) .............................................................. 41
5.1.3.
Visit 3: Day 8 ± 1 day – 
 Visit ...................................... 43
5.1.4.
Visit 4: Day 15 ± 1 day – End of Study Visit .......................................... 43
5.1.5.
Unscheduled Visit .................................................................................... 44
5.1.6.
Early Termination Visit ........................................................................... 44
5.2.
Rescue Medication Use............................................................................ 45
5.3.
Subject Withdrawal and/or Discontinuation ............................................ 45
5.4.
Collection of Data .................................................................................... 46
6.
TREATMENT OF SUBJECTS ............................................................... 47


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6.1.
Investigational Products to be Administered ........................................... 47
6.2.
Concomitant Medications ........................................................................ 47
6.2.1.
Permitted Medications ............................................................................. 47
6.2.2.
Medications Not Permitted ...................................................................... 47
6.3.
Investigational product Use Compliance ................................................. 49
6.4.
Investigational product Accountability .................................................... 49
6.5.
Maintenance of Randomization and Procedure for Breaking the Code .. 50
7.
ASSESSMENT OF EFFICACY ............................................................. 51
8.
ASSESSMENT OF SAFETY .................................................................. 52
8.1.
Safety Parameters..................................................................................... 52
8.2.
Adverse Event Definitions ....................................................................... 52
8.3.
Procedures for AE Reporting by the Investigator .................................... 54
8.4.
Serious Adverse Event Reporting by the Investigator ............................. 55
9.
STATISTICS ........................................................................................... 58
9.1.
Statistical Methods ................................................................................... 58
9.1.1.
Subject Disposition, Demographic and Background Characteristics ...... 58
9.1.2.
Analysis of Efficacy ................................................................................. 58
9.1.3.
Analysis of Safety .................................................................................... 60
9.2.
Sample Size Estimation ........................................................................... 61
9.3.
Level of Significance ............................................................................... 61
9.4.
Procedure for Accounting for Missing, Unused, or Spurious Data ......... 61
9.5.
Procedure for Reporting Deviations from the Statistical Plan ................. 62
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................... 63
11.
QUALITY CONTROL ............................................................................ 64
12.
ETHICS.................................................................................................... 65
12.1.
Institutional Review Board ...................................................................... 65
12.2.
Informed Consent Requirements ............................................................. 65
13.
DATA HANDLING AND RECORDKEEPING .................................... 66
13.1.
Data Quality Control and Reporting ........................................................ 66
13.2.
Records Retention .................................................................................... 66
14.
PUBLICATION POLICY ....................................................................... 67
15.
REFERENCES ........................................................................................ 68


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16.
APPENDICES ......................................................................................... 69
 
LIST OF TABLES 
TABLE 1:
COMPOSITION OF KPI-121 0.25% (W/V) INVESTIGATIONAL PRODUCT ...... 32
TABLE 2:
COMPOSITION OF PLACEBO (VEHICLE) ..................................................... 32
 
 
 
 


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LIST OF FIGURES 
FIGURE 1: SEQUENTIALLY REJECTIVE MULTIPLE TESTING PROCEDURE ......................................26
FIGURE 2: STUDY SCHEMATIC ......................................................................................................31
FIGURE 3: SEQUENTIALLY REJECTIVE MULTIPLE TESTING PROCEDURE ......................................59
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AR 
Adverse Reaction 
AE 
Adverse Event 
BCVA 
Best Corrected Visual Acuity 
BL 
Baseline 
qC 
Degrees Celsius 
CCLRU 
Cornea and Contact Lens Research Unit 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
EE 
Efficacy Evaluable 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
qF 
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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KCS 
Keratoconjunctivitis sicca 
KPI 
Kala Pharmaceuticals, Inc. 
L 
Liter 
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 
NSAID 
Non-steroidal anti-inflammatory drug 
PDF 
Portable Document Format 
QID 
Four Times Daily 
SAE 
Serious Adverse Event 
 
 
SAR 
Suspected Adverse Reaction 
SLT 
Selected Laser Trabeculoplasty 
SOP 
Standard Operating Procedure 
TNF 
Tumor Necrosis Factor 
UPT  
Urine Pregnancy Test 
US 
United States of America 


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WOCBP 
Women of Child Bearing Potential 
w/v 
Weight to Volume 


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1. 
INTRODUCTION 
Over 7 million people in the United States experience dry eye symptoms of some severity 
(DEWS Report, 2007).  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.  
Patients with dry eye disease may experience significant ocular discomfort and reduced visual 
function, thus resulting in a decreased quality of life or work productivity1. 
Current treatment of dry eye disease generally begins with artificial tear replacement and then 
expands to include topical anti-inflammatory therapy and punctal occlusion1.  Topical 
cyclosporine (Restasis®) is currently the only Food and Drug Administration (FDA) approved 
prescription medication for use in patients with dry eye disease.  Restasis® is indicated to 
increase tear production in patients whose tear production is presumed to be suppressed due to 
ocular inflammation associated with KCS, but a significant percentage of patients experience 
adverse reactions to the drug, including ocular irritation upon instillation, slow onset of 
response, and limited efficacy.   
Inflammation has a prominent role in the development and proliferation of dry eye disease2. 
Factors adversely affecting tear film stability and osmolarity can initiate an inflammatory 
cascade that leads to the development of a self-perpetuating inflammatory cycle2.  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 segment3.  
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.  
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.  


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Kala Pharmaceuticals, Inc. intends to develop KPI-121 for the treatment of dry eye disease.  
Study KPI-121-C-006 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.    
1.1. 
DESCRIPTION OF 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.  Kala is developing this improved LE formulation for the treatment of dry eye 
disease. 
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.  
1.2. 
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION 
KPI-121 will be administered as a topical ophthalmic suspension.  Subjects are expected to 
self-administer 1 to 2 drops of either KPI-121 0.25% ophthalmic suspension or vehicle QID. 
Direct instillation is the most efficient method for delivery to the ocular surface and is an 
accepted and widely used method for topical application to the eye. This study will examine 
safety and efficacy of KPI-121 0.25% ophthalmic suspension versus vehicle dosed QID for 14 
days in subjects with dry eye disease.  
For additional details on the toxicology studies and the respective safety multiples, see the 
Investigator’s Brochure.  
 
 
 


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1.3. 
GCP COMPLIANCE  
This clinical trial will be conducted in compliance with the protocol, International Conference 
on Harmonization (ICH) guidelines, Good Clinical Practices (GCP) guidelines and other 
applicable regulatory requirements. 
1.4. 
POPULATION TO BE STUDIED 
Approximately 2000 subjects who are diagnosed with dry eye disease will be screened for this 
study.  Approximately 900 subjects of these subjects will be randomized to either KPI-121 
0.25% ophthalmic suspension or vehicle. 


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2. 
TRIAL OBJECTIVES AND PURPOSE 
2.1. 
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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3. 
TRIAL DESIGN 
3.1. 
PRIMARY EFFICACY ENDPOINTS 
All primary endpoint comparisons will be performed between KPI-121 0.25% ophthalmic 
suspension group and the vehicle group using sequentially rejective multiple testing as 
described below. 
Primary Efficacy Endpoints: 
The trial will have 4 primary endpoints: 
 
 
 
 
 
 
FIGURE 1: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Mean change from baseline bulbar conjunctival hyperemia in the ITT 
population for Visit 4 (Day 15 ± 1 day) compared to Visit 2 (Day 1) 
 
 in the study eye at Visit 2 (Day 1) 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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 Mean change from baseline 
 staining in the ITT population for 
Visit 4 (Day 15 ± 1 day) compared to Visit 2 (Day 1) in the study eye.   
 Mean change from baseline ocular discomfort severity in the ITT 
population 
 
 prior to Day 15 compared 
 to Day 1.   
 Mean change from baseline ocular discomfort severity in the subgroup 
population 
 
 
 prior to Day 15 compared 
 
 to Day 1.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.2. 
SECONDARY EFFICACY ENDPOINTS 
Secondary efficacy endpoint comparisons will be performed between KPI-121 0.25% 
ophthalmic suspension group and the vehicle group following the testing of the primary 
endpoints and will be summarized using descriptive statistics: 
1. Mean change from baseline bulbar conjunctival hyperemia in the in the subgroup 
population 
 
 for Visit 4 (Day 15 ± 1 day) compared to Visit 
2 (Day 1) 
 bulbar conjunctival hyperemia in the 
study eye at Visit 2 
 
   
2. Mean change from baseline ocular discomfort severity in the ITT population 
 
 
prior to Day 8 compared 
 to Day 1.  
3. Mean change from baseline ocular discomfort severity in the subgroup population 
 
 
 Day 8 compared 
 
 to Day 1.   
4. Mean change from baseline ocular discomfort severity in the ITT population 
 
 Day 4 compared 
 
 to Day 1.  
5. Mean change from baseline ocular discomfort severity in the subgroup population 
 
 on 
Day 4 compared 
 to Day 1.   
3.3. 
EXPLORATORY EFFICACY ENDPOINTS 
Exploratory efficacy endpoint comparisons will be performed between KPI-121 0.25% 
ophthalmic suspension group and the vehicle group.  
3.4. 
SAFETY ENDPOINTS 
x Assessment of AEs 
x Slit lamp biomicroscopy  


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x IOP measurement 
x BCVA 
x Dilated Ophthalmoscopy 
3.5. 
DESCRIPTION OF TRIAL 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 run-in 
followed by up to 14 days of investigational product dosing (KPI-121 0.25% ophthalmic 
suspension or vehicle).   
Approximately 2000 subjects at approximately 60 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 run-in 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.   
The study eye will be selected based on the study qualification criteria 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 the following 2 stratification criteria:  
x Ocular discomfort severity scores 
 (low) and 
 
(high) based on the subject’s scoring of ocular discomfort severity 
 prior to 
Visit 2 (Day 1) AND 
x Investigator-rated bulbar conjunctival hyperemia score of  (low) and 
 (high) in the 
eye with the higher score at Visit 2 (Day 1).   
Randomization in the ocular discomfort severity strata will be distributed 
 
between the high and low strata.  
 
 
 
 
    
 


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  A 
distribution ratio will not be imposed on the investigator-rated bulbar conjunctival hyperemia 
strata. 
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.   
Subjects will return to the clinic for complete study evaluation at Visit 4 (Day 15 ± 1 day).  
Subject will also return at Visit 3 (Days 8 ± 1 day) to 
 
assess concomitant medication use and adverse events.  
Subjects will discontinue dosing and be released from the study at Visit 4 (Day 15 ± 1 day).  
A summary of events is provided in Appendix 1.  Assessments in this study will include:  
x Subject-rated assessment eye dryness (Appendix 2) 
x Subject-rated assessment of ocular discomfort 
 visual analog scales 
(Appendix 3) 
x Investigator-rated assessment of bulbar conjunctival hyperemia (Appendix 4)  
x Unanesthetized Schirmer Test (Appendix 5)  
x BCVA (Appendix 6)  
x Slit lamp biomicroscopy (Appendix 7)  
x Corneal fluorescein staining (Appendix 8)  
x IOP measurement (Appendix 9)  
x Dilated ophthalmoscopy  (Appendix 10)  
x 
  
x 
  
x Concomitant medication use assessment  
x Assessments of AEs 


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A study schematic follows (Figure 2). 
 
Run-In 
(All Subjects) 
KPI-121 0.25% Ophthalmic Suspension QID  
(450 Subjects) 
KPI-121 Vehicle QID  
(450 Subjects) 
 
14 ± 1 Days prior to Day 1 
Day 1 
 
Day 8 ± 1  
Day 15 ± 1 
  
  Visit 1 
 Visit 2 
  
Visit 3 
  
Visit 4  
 
 
Screening 
 Randomization   
 
 
 
Study Visit 
 
 
 
  
 
FIGURE 2: 
STUDY SCHEMATIC 
3.5.1. 
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.  Kala is developing this improved LE formulation for the treatment of dry eye 
disease. 
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.  
Subject will be instructed to shake the investigational product bottle prior to each instillation.   
y 8 ±
Day 1
y 15 ±


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TABLE 1: 
COMPOSITION OF KPI-121 0.25% (W/V) INVESTIGATIONAL PRODUCT 
Ingredient 
Function 
Concentration 
(% w/v) 
Loteprednol etabonate 
Active 
pharmaceutical 
ingredient 
0.25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE 2: 
COMPOSITION OF PLACEBO (VEHICLE) 
Ingredient 
Function 
Concentration 
(% w/v) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At Visit 1, eligible subjects will receive 1 bottle of single-masked, investigational product 
(vehicle) from a common site level supply.  The bottle labels for the single-masked period 
contain the following information:  sponsor name, protocol number, lot number, storage 
temperature, and required statement(s) per the appropriate regulatory agency.  A second bottle 
of vehicle may be provided to the subject from the common site level supply in the event the 
subject needs additional single-masked, investigational product during the run-in period. Run-
in product bottles will be returned to the site at Visit 2 (Day 1). 
The randomized, double-masked, investigational product kit consists of a box that contains 2 
dropper bottles of investigational product.  At Visit 2 (Day 1/Randomization), subjects will 
receive 1 bottle of double-masked investigational product (KPI-121 0.25% ophthalmic 
suspension or vehicle) from their assigned kit.  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.  Randomized investigational product bottles will be returned to 
the site at Visit 4 (Day 15 ± 1 day).  


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All investigational products will be stored in a secure area with limited access at 15-25qC/59 -
77qF with upper limit excursions to 30qC /86qF allowed.  Subjects will be instructed to shake 
the investigational product bottle prior to administering each dose. 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 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. 
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.”  
3.5.2. 
Methods to Minimize Bias 
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. 
3.6. 
  Meta-analysis 
The data for this trial may be used for a meta-analysis as described in a separate Meta-
Analysis Statistical Analysis Plan. 


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4. 
SELECTION OF SUBJECTS 
4.1. 
SUBJECT INCLUSION AND EXCLUSION CRITERIA 
4.1.1.  
Inclusion Criteria 
At Visit 1 (Screening) and Visit 2 (Randomization), individuals of either gender or any race 
will be eligible for study participation if they: 
1. Provide written informed consent and HIPAA authorization prior to any study-related 
procedures. 
2. Are 18 years of age or older. 
3. Are willing and able to follow instructions and can be present for the required study 
visits for the duration of the study, including: 
a. Single-masked investigational product use compliance of at least 80% during 
the final week of the run-in phase AND 
b. 
 ocular discomfort scoring of at least 80% in 
the final week of the run-in phase. 
4. Have a documented clinical diagnosis of dry eye disease in both eyes. 
5. Have ongoing dry eye disease as defined by the following criteria in the same eye or 
both eyes: 
a. A corneal fluorescein staining score at Visit 1 and Visit 2 of 
 NEI scale 
AND 
b. Investigator-rated assessment of bulbar  conjunctival hyperemia at Visit 1 and 
Visit 2 of 
 as assessed using the CCLRU scale AND 
c. A score of 
 on ocular discomfort severity at Visit 1 AND a score of  
 on ocular discomfort severity 
 prior to Visit 2 (Day 1) as 
graded by the subject utilizing 
 visual analog scales AND 
d. An unanesthetized Schirmer Test score at Visit 1 of 
 
6. Have normal lid anatomy. 
7. Are WOCBP who are not pregnant or lactating and not sexually active (i.e., abstinent) 
for 14 days prior to Visit 1 and willing to remain so through 30 days following Visit 4 


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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 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 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 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 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) or are women who have undergone 1 of the following sterilization procedures at 
least 6 months prior to Visit 1: 
a. Bilateral tubal ligation 
b. Hysterectomy 


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c. Hysterectomy with unilateral or bilateral oophorectomy. 
d. Bilateral oophorectomy 
4.1.2.  
Exclusion Criteria 
In order for subjects to be eligible at Visit 1 (Screening) and Visit 2 (Randomization) 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 within 30 days prior to Screening (Visit 
1) 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 
3. Have used any of the following medications within 60 days prior to Screening (Visit 
1) 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 Screening (Visit 1) 
or anticipate alteration of dosing during the study:  
a. Tetracycline compounds (e.g., tetracycline, doxycycline, or minocycline) 
b. Omega-3 or Omega-6 supplements 


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5. Have altered dosing of the following medications within 6 months prior to Screening 
(Visit 1) 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 
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 (Randomization). 
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 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. 


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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 
c. Stevens-Johnson Syndrome 
d. Significant conjunctival scarring 
e. Significant anterior blepharitis 
f. Severe/serious ocular condition that in the judgment of the investigator could 
confound study assessments or limit compliance. 
g. Severe/serious systemic disease or uncontrolled medical condition that in the 
judgment of the investigator could confound study assessments or limit 
compliance. 
18. Have Corneal Fluorescein Staining with diffuse confluent staining more than 33% of 
area (focal confluent staining is acceptable), or over 5 filaments or epithelial defects. 
19. Have a history of herpetic keratitis. 
20. 
 
 
 
 
 
 


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c. 
 
 
21. Have a history of ocular allergies, which, in the judgment of the investigator, are likely 
to have an acute increase in severity due to the expected timing of exposure to the 
allergen to which the subject is sensitive.  Subjects sensitive to seasonal allergens that 
are not expected to be present during the study are permitted. 
22. Have been exposed to an investigational product within 30 days prior to Visit 1. 
23. Be an employee of the practice that is involved in the management, administration, or 
support of this study or be an immediate family member of the same. 
24. Have a documented history of alcohol and/or drug abuse. 
25. In the opinion of the Investigator or study coordinator, be unwilling or unable to 
comply with the study protocol or unable to successfully instill eye drops. 
 


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5. 
PROCEDURES 
Written Informed Consent and HIPAA authorization will be obtained from all subjects prior 
to any study procedures being performed. 
5.1. 
VISIT DESCRIPTION 
5.1.1. 
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 3-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.    
x Subject-rated assessment of ocular discomfort as graded by the subject utilizing 
 
visual analog scales 
x Significant non-ocular and significant ocular medical history 
x Concomitant medication usage and medications taken during the 6 months prior to 
screening  
x Inclusion/exclusion criteria  
x Urine pregnancy test (UPT) for WOCBP 
x BCVA   
x Investigator-rated assessment of bulbar conjunctival hyperemia 
x Slit Lamp Biomicroscopy 
x Corneal fluorescein staining 
x Unanesthetized Schirmer Test evaluation 
x IOP measurement 
x Dilated Ophthalmoscopy 
x Single-masked, investigational product instillation 
x AE Assessment 


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x Dispense single masked, investigational product and instructions for administration  
x 
 
The first dose of single-masked investigational product will be taken in the clinic under the 
supervision of study personnel.  Prior to administration, subjects will be instructed regarding 
proper instillation of investigational product.  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: 
 
x Dose single-masked run-in investigational product as instructed 
x Complete dosing information 
 
x Complete ocular discomfort assessments 
 
x Return for Visit 2 scheduled in 14 ± 1 days. 
5.1.2. 
Visit 2:  Day 1 (Randomization) 
The randomization visit will occur 14 ± 1 days after Visit 1 (Screening). This visit 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 4) will continue in the 
study.  The following will be performed/assessed:  
x Subject-rated assessment of eye dryness 
x Use of any concomitant medications since the last visit 
x Occurrence of any AEs since the last visit 
x 
 
x Used and unused single-masked run-in investigational product collected, counted, and 
compliance assessed 
  
 
 


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x Investigator-rated assessment of bulbar conjunctival hyperemia 
x 
  
x BCVA 
x Slit Lamp Biomicroscopy 
x Corneal fluorescein staining 
x IOP measurement 
x Upon verification of study eligibility (Section 4), 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:  
x Instillation of randomized investigational product 
x AE Assessment 
x Dispensing of double-masked, investigational product (1 bottle) and instructions for 
administration 
x 
 
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. 
Instructions to subject: 
x Dose investigational product as instructed 
x Complete dosing information 
 


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x Complete ocular discomfort assessments 
 
x Return for Visit 3 scheduled on Day 8 ± 1 day. 
5.1.3. 
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:  
x Subject-rated assessment of eye dryness 
x Use of any concomitant medications since the last visit 
x Occurrence of any AEs since the last visit 
x 
 
Instructions to subject: 
x Dose investigational product as instructed 
x Complete dosing information 
 
x Complete ocular discomfort assessments 
 
x Return for Visit 4 scheduled on Day 15 ± 1 day. 
5.1.4. 
Visit 4: Day 15 ± 1 day – End of Study Visit 
The end-of-investigational-product-use visit will occur on Day 15 ± 1 day as calculated from 
Visit 2: Day 1, and the following will be performed/assessed:  
x Subject-rated assessment of eye dryness 
x Use of any concomitant medications since the last visit 
x Occurrence of any AEs since the last visit 
x 
 
x Used and unused double-masked investigational product collected, counted, and 
compliance assessed 
  
x Investigator-rated assessment of bulbar conjunctival hyperemia 


CLINICAL PROTOCOL KPI-121-C-006 
 
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x 
 
x BCVA 
x Slit Lamp Biomicroscopy 
x Corneal fluorescein staining 
x IOP measurement 
x Dilated ophthalmoscopy 
x UPT for WOCBP 
x Release of subject from the study 
5.1.5. 
Unscheduled Visit 
Any visits or procedures performed beyond those specified within the protocol must be 
documented in the Unscheduled Visit pages of the eCRF. Unscheduled visits may include but 
are not limited to reporting adverse events (AEs), changes in concomitant medications, or 
ophthalmic assessments as deemed appropriate by an appropriately qualified physician.  If the 
subject is discontinuing study participation at the unscheduled visit, the eCRFs for Visit 4 
should be completed rather than the eCRFs for an Unscheduled Visit. 
5.1.6. 
Early Termination Visit 
In the event of termination prior to Visit 4, every attempt will be made to ensure that all Visit 
4 assessments are performed.  If this is not feasible, at least the following should be 
performed/assessed:  
x Subject-rated assessment of eye dryness 
x Use of any concomitant medications since the last visit 
x Occurrence of any AEs since the last visit 
x Used and unused investigational product collected and compliance 
 
. 
x 
 
x BCVA 


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x Slit lamp biomicroscopy  
x IOP measurement 
x UPT for WOCBP 
5.2. 
RESCUE MEDICATION USE 
Any subjects not responding adequately to the study medication may be rescued and placed 
on alternate therapy at the Investigator's discretion at any time. The choice of rescue 
medication is at the Investigator's discretion. Any subject placed on rescue therapy will 
discontinue use of the study medication and continue study participation through Visit 4.  
The need for rescue therapy will not be considered an AE. Rescued subjects experiencing an 
AE at the time of rescue will be followed through stabilization or resolution of the AE or the 
end of the study (whichever comes last).  Rescued subjects should not be withdrawn from the 
study, but rather followed to resolution of signs and symptoms or until the Investigator has 
deemed the subject is stable. 
5.3. 
SUBJECT WITHDRAWAL AND/OR DISCONTINUATION  
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.   


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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.  If a non-
serious AE is unresolved at the time of the subject’s final study visit, 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 all 
serious adverse events (SAEs) to resolution.  The reason for premature discontinuation should 
be entered onto the Case Report Form (CRF) 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.    
5.4. 
COLLECTION OF DATA 
Source documentation for data collected in this study will be maintained at the investigative 
site.  In cases where no source will be used  
 it will be noted in the 
Investigator files.  The CRF will be electronic (eCRF) and data will be electronically entered 
from the source documentation into the eCRF.  After study completion, an archival copy [e.g., 
Portable Document Format (PDF)] of the eCRF data will be retained by the site. 


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6. 
TREATMENT OF SUBJECTS 
6.1. 
INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED 
All subjects meeting eligibility criteria at Visit 1 will receive 1 bottle of single-masked 
investigational product (vehicle).  A second bottle of vehicle may be provided to the subject 
in the event additional single-masked, investigational product is needed during the run-in 
period.  Run-in product bottles will be returned to the site at Visit 2 (Day 1). 
Subjects who continue to meet eligibility criteria at Visit 2 will be randomized to either KPI-
121 0.25% ophthalmic suspension or vehicle.  One kit of randomized investigational product 
containing 2 dropper bottles will be allocated to each subject at Visit 2.  At Visit 2 (Day 
1/Randomization), subjects will receive 1 bottle of double-masked investigational product 
(KPI-121 0.25% ophthalmic suspension or vehicle) from their assigned kit.  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.  Randomized investigational product 
bottles will be returned to the site at Visit 4 (Day 15 ± 1 day). The investigational product will 
be stored at the site in a secure area with limited access at 15-25qC/59-77qF with upper limit 
excursions to 30qC /86qF allowed. 
Subjects will be asked to administer investigational product QID.  Prior to each instillation, 
subject will be instructed to shake the investigational product bottle.  The subjects will record 
the time of administration of each dose of investigational product at the time of instillation 
(Appendix 11).  Compliance with instillation of investigational product will be reviewed and 
assessed at each clinic visit. 
6.2. 
CONCOMITANT MEDICATIONS 
All medications that the subject has taken 6 months prior to Visit 1 and through Visit 4 or 
discontinuation from the study will be recorded in the eCRF and the subject chart.  The 
generic name of the drug, dose, route of administration, duration of treatment (including start 
and stop dates), frequency, indication, and whether or not the medication was taken due to an 
AE or as a rescue medication will be recorded for each medication. 
6.2.1. 
Permitted Medications 
Medications not specifically excluded in Section 6.2.2 may be taken as necessary. 
6.2.2. 
Medications Not Permitted 
At Visit 1 (Screening) and for the duration of the study: 


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x Any topical ophthalmic medications including eyelash growth medications, eye drops, 
gels, ointments, or artificial tears  
x TNF-blocking agents (e.g. etanercept, adalimumab, infliximab) 
x Treatment for glaucoma 
Within 30 days prior to screening (Visit 1) and for the duration of the study: 
x Ocular, inhaled, or intranasal corticosteroids 
x Ocular or oral non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of 
≤ 81 mg/day of acetylsalicylic acid (ASA or aspirin) 
x Topical ocular antibiotics 
x Topical ocular antihistamines or mast cell stabilizers 
x Oral antihistamines 
x Topical or nasal vasoconstrictors 
x Other investigational products 
Within 60 days prior to screening (Visit 1) and for the duration of the study: 
x Topical cyclosporine (Restasis®) 
x Topical lifitegrast 
x 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: 
x Tetracycline compounds (tetracycline, doxycycline, or minocycline) 
x 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: 
x Anticholinergics 
x Anticonvulsants (e.g., topiramate) 


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x Antidepressants 
x Isotretinoin 
x 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. 
6.3. 
INVESTIGATIONAL PRODUCT USE COMPLIANCE 
Compliance will be assessed by comparing investigational product accountability records 
with the dosing information recorded daily by the subject.  The site will document this 
comparison along with verification of the numbers of used and unused investigational product 
bottles. The numbers of missed doses as assessed at each clinic visit should be documented in 
the eCRF.   
6.4. 
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.   
Investigational product will be stored in a secure area with limited access at 15-25qC/59-77qF 
with upper limit excursions to 30qC /86qF allowed. 
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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6.5. 
MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING THE CODE 
The sponsor, the project teams at the designated Contract Research Organizations (CROs), 
and investigative staff responsible for assessments of study endpoints will be masked to 
investigational product assignments.  A dosing coordinator, who is not responsible for study 
assessments, will be required to dispense and retrieve investigational product to the subjects. 
In case of medical emergency, or occurrence of an SAE, the randomization code may be 
unmasked and made available to the Investigator, sponsor, and/or other personnel involved in 
the monitoring or conduct of this study.  In the absence of medical need, the randomization 
code will not be available to the above individuals until after the study is completed and the 
database is locked.   
In the event of a medical need, the Investigator will treat each subject as needed.  Since there 
is no specific antidote to KPI-121, immediate emergency unmasking is not necessary.  If the 
Investigator feels it is necessary to unmask a subject’s assignment after an emergency 
situation, the Investigator may call the medical monitor and notify the sponsor.  The 
investigational product assignment will be revealed on a subject-by-subject basis with the 
approval of the medical monitor and sponsor, thus leaving the masking of the remaining 
subjects intact. 
A randomization code will be computer-generated by Kala Pharmaceuticals, Inc. or designee.  
Randomization team members will work independently of other team members at the CRO.  
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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7. 
ASSESSMENT OF EFFICACY 
Efficacy assessments include the following: 
x Bulbar conjunctival hyperemia 
 
x Corneal fluorescein staining 
x Subject-rated assessment of ocular discomfort severity  
x Subject-rated assessment of ocular discomfort frequency 
x Subject-rated assessment of eye dryness 
 


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8. 
ASSESSMENT OF SAFETY 
8.1. 
SAFETY PARAMETERS 
Safety parameters include: 
x Assessments of AEs 
x BCVA 
x Slit lamp biomicroscopy  
x Dilated ophthalmoscopy  
x IOP measurement  
8.2. 
ADVERSE EVENT DEFINITIONS 
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):  
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 patient 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.  
A SERIOUS ADVERSE EVENT (SAE) is any AE or suspected adverse reaction occurring 
at any dose that:  


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x Results in death. 
x Is life-threatening. 
x Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
x Requires inpatient hospitalization. 
x Prolongs inpatient hospitalization. 
x Is a congenital anomaly/birth defect. 
x 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. 
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: 
Unrelated: 
 
x Event occurring before dosing. 
x Event or intercurrent illness due wholly to factors other than investigational product 
use. 
Unlikely:  
x Poor temporal relationship with investigational product use. 
x Event easily explained by subject’s clinical state or other factors. 
 
 


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Possible: 
x Reasonable temporal relationship with investigational product use. 
x Event could be explained by subject’s clinical state or other factors. 
Probable: 
x Reasonable temporal relationship with investigational product use. 
x Likely to be known reaction to agent or chemical group, or predicted by known 
pharmacology. 
x Event cannot easily be explained by subject’s clinical state or other factors. 
Definite:  
x Distinct temporal relationship with investigational product use. 
x Known reaction to agent or chemical group, or predicted by known pharmacology. 
x Event cannot be explained by subject’s clinical state or other factors.  
8.3. 
PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR 
AEs will be monitored throughout the study and will be recorded on the CRF 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: 
x How have you felt since your last assessment? 
x 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. 
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 


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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. 
8.4. 
SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR 
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: 
 Date of Birth 
 Sex 
 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: 
 SAE term (diagnosis only; if known or serious signs/symptoms) 
 Description of SAE/narrative 
 Date/time of onset 


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 Severity 
 Outcome 
 Date/time of resolution or death (if duration < 24 hours) 
 Relationship to investigational product 
 Action taken with investigational product 
9. Criteria for classifying the event as serious, including whether the SAE:   
 Resulted in death. 
 Was life-threatening 
 Required inpatient hospitalization. 
 Prolonged inpatient hospitalization. 
 Resulted in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
 Was a congenital anomaly/birth defect 
 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 patient 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 inpatient 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 
13. Copy of AE page from the CRF 


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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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9. 
STATISTICS 
9.1. 
STATISTICAL METHODS 
Continuous measures (e.g., age) will be summarized descriptively by the mean, standard 
deviation, median, minimum and maximum values.  Categorical measures will be 
summarized by the number and percent of subjects. 
9.1.1. 
Subject Disposition, Demographic and Background Characteristics 
Subject disposition, demographic characteristics, and background variables will be 
summarized by study group.   
9.1.2. 
Analysis of Efficacy 
The primary analysis population will be the Intent-to-Treat (ITT) population, defined as all 
subjects randomized with at least one post-baseline (baseline = Visit 2) assessment. A subset 
of efficacy analyses will be examined for the Efficacy Evaluable (EE) population, the 
definition of which will be outlined in the Statistical Analysis Plan and finalized prior to 
unmasking of study data pursuant to clinical data review.  
The primary analysis of all ophthalmic efficacy measures will be based on the single study 
eye for each subject.   
The trial will have 4 primary endpoints: 
 
 
 
 
 
 
 
 


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FIGURE 3: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Mean change from baseline bulbar conjunctival hyperemia in the ITT 
population for Visit 4 (Day 15 ± 1 day) compared to Visit 2 (Day 1) 
 
 bulbar conjunctival hyperemia in the study eye at Visit 2 (Day 1) 
   
 Mean change from baseline 
 staining in the ITT population for 
Visit 4 (Day 15 ± 1 day) compared to Visit 2 (Day 1) in the study eye.   
 Mean change from baseline ocular discomfort severity in the ITT 
population 
 
 Day 15 compared 
 to Day 1.   
 Mean change from baseline ocular discomfort severity in the subgroup 
population 
 
 
 Day 15 compared 
 
 to Day 1.   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


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Secondary efficacy endpoints will be evaluated as elaborated in Section 3. 
The data for this trial may be used for a meta-analysis as described in a separate Meta-Analysis 
Statistical Analysis Plan. 
1.1.1. 
Analysis of Safety 
Analysis of safety data will be presented for all subjects in the Safety population (i.e., all 
randomized subjects receiving at least one dose of randomized investigational product and from 
whom at least one safety assessment is obtained after randomization).  AEs will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA, most current version) and categorized 
by system organ class using preferred terms.  AEs will be tabulated by study group with respect 
to their Severity and relationship to the investigational product.   


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Ophthalmoscopy findings will be summarized descriptively.  IOP measurements, BCVA and 
Biomicroscopy will be summarized as safety outcomes.   
9.2. 
SAMPLE SIZE ESTIMATION 
1.  Bulbar conjunctival hyperemia, Day 15, ITT: A sample size of 450 in each group will have 
> 99% power to detect an effect size of 
using a 2-group t-test with a 
 2-sided 
significance level. 
2. Ocular discomfort severity, Day 15, ITT:  A sample size of 450 in each group will have   > 
99% power to detect an effect size of 
 using a 2-group t-test with a 
 2-sided 
significance level. 
3. Ocular discomfort severity, Day 15, Subgroup 
: A sample size of 225 
in each group will have 95% power to detect an effect size of 
 using a 2-group t-test 
with a 
 2-sided significance level. 
4.  
 staining, Day 15, ITT:  A sample size of 450 in each group will 
have 74% power to detect an effect size of 
 using a 2-group t-test with a 
 2-sided 
significance level. 
9.3. 
LEVEL OF SIGNIFICANCE 
 
 
 
 
 
 Overall the Type I 
error rate is controlled at 0.05. 
All other reported p-values will be considered descriptive and hypothesis generating. 
9.4. 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA 
Any missing, unused, or spurious data will be noted in the final clinical study report.  If more 
than 5% of data are missing, multiple imputation will be employed to analyze incomplete data 
sets under the assumption that missing data are, at worst, characterized as missing at random 
(MAR).  Imputation will be carried out for the analysis of only the primary endpoints.  The 
reasons for missing data will be recorded and the impact of these reasons and any treatment 
group imbalance on the assumption of MAR will be evaluated. 


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9.5. 
PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL PLAN 
Any deviations from the statistical analysis plan will be described and a justification given in 
the final clinical study report. 
 


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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
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. 


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11. 
QUALITY CONTROL 
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. 


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12. 
ETHICS 
12.1. 
Institutional Review Board 
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.   
12.2. 
Informed Consent Requirements 
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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13. 
DATA HANDLING AND RECORDKEEPING 
All procedures for the handling and analysis of data will be conducted using GCP and meet 
ICH guidelines and US FDA regulations for the handling and analysis of data for clinical 
trials. 
13.1. 
Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database.  Query reports pertaining to data 
omissions and discrepancies will be forwarded to the clinical Investigator and monitor(s) for 
resolution.  The study database will be updated in accordance with the resolved query reports.  
All changes to the study database will be documented. 
13.2. 
Records Retention 
The study center will retain all records related to the study in accordance with local and ICH 
GCP guidelines. 
 


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14. 
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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15. 
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.  Stevenson W, Chauhan SK, Dana R. Dry eye disease: An immune-mediated ocular 
surface disorder. Arch Ophthalmol. 2012;130(1):90-100. 
doi:10.1001/archophthalmol.2011.364. 
3.  Lane SS, Holland EJ. Loteprednol etabonate 0.5% versus prednisolone acetate 1.0% for 
the treatment of inflammation after cataract surgery. J Cataract Refract Surg. 
2013;39(2):168-173. doi:10.1016/j.jcrs.2012.10.039. 
 
 
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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16. 
APPENDICES 
 
 
 


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APPENDIX 1: SUMMARY OF EVENTS 
Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Screening 
Randomization 
 
End of 
Study Visit 
14 r 1 Days Prior to 
Day 1 
Day 1 
Day 8  
(±1 day) 
Day 15 
(±1 day) 
Informed Consent, HIPAA Authorization and Significant Medical 
History 
X 
 
 
 
Subject-rated assessment of ocular discomfort 
 
X 
 
 
 
Subject-rated assessment of ocular discomfort 
 
 
Xc 
Xc 
Xc 
Subject-rated assessment of eye dryness 
 
 
X 
X 
X 
Concomitant medication query 
X 
X 
X 
X 
UPTa 
X 
 
 
X 
Inclusion/Exclusion 
X 
X 
 
 
AE Assessment 
X 
X 
X 
X 
Investigator-rated assessment of bulbar conjunctival hyperemia 
X 
X 
 
X 
 
 
X 
 
X 
BCVA 
X 
X 
 
X 
Slit lamp biomicroscopy 
X 
X 
 
X 
Corneal fluorescein staining 
X 
X 
 
X 
Unanesthetized Schirmer Test Assessment 
X 
 
 
 
IOP measurement 
X 
X 
 
X 
Dilated ophthalmoscopy 
X 
 
 
X 
Investigational product administration in-clinic 
Xb 
X 
 
 
Dispense investigational product 
Xb 
X 
 
 
 
Xb 
X 
X 
 
Collect investigational product 
 
Xb 
 
X 
 
 
Xb 
X 
X 
aWomen of childbearing potential only;  bRun-In Product  c
 


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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. 
 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 DISCOMFORT  
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 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: INVESTIGATOR-RATED ASSESSMENT OF BULBAR CONJUNCTIVAL HYPEREMIA 
Investigators will rate 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.  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  
x 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. 
x Remove the right eye strip from the sheath. 
x Ask the subject to look up and gently draw the right lower lid in a downward and 
temporal direction.  
x Place the rounded end of the strip toward the temporal one-third of the lower eyelid.  
x Repeat this procedure in the left eye. 
x Darken the room, but ensure that the Large E or the ETDRS chart is visible. 
x Instruct the subject to relax and look at the chart while blinking normally or have 
subject gently close eyes. 
x Strips are removed after 5 minutes. 
x After removing the strips, with a sharp pencil draw a horizontal line across the leading 
edge of moisture and a second horizontal line across the lowest point of moisture. 
x 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. 
x 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 Workshop5,6. 
Evaluation Technique  
NOTE:  All steps in this procedure should be completed for OD prior to repeating the 
procedure for OS using separate fluorescein strips for each eye. 
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 BioGlo 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 


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06 JUL 2017 
 
 
Medium amount of micropunctate staining within the section of cornea 
being evaluated or mild amount of macropunctate stain 
iv. Grade 3 
SEVERE 
Significant amount of micropunctate or macropunctate staining within 
the section of cornea being evaluated 
 
 
 
 
  
 
 
 
 
 
 
 


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06 JUL 2017 
 
 
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 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, the Investigator will determine 
whether or not the abnormality would exclude subject from study participation.   
 
 
 
 


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