Conditions: Dry Eye Syndromes Keratoconjunctivitis Sicca
Keywords: Pain Corticosteroid Dry Eye Hyperemia Ocular Discomfort
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 150
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to determine the efficacy and safety of KPI-121 0.25% ophthalmic suspension compared to vehicle (placebo) in subjects who have a documented clinical diagnosis of dry eye disease. The product will be studied over 28 days, with 1-2 drops instilled in each eye four times daily (QID).

Detailed description:
This is a Phase II, 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 400 subjects will be screened and up to 150 subjects will be randomized at up to 12 centers located in the United States. 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 1-2 drops in each eye QID for up to 28 days or 2) vehicle administered as 1-2 drops in each eye QID for up to 28 days.

This study will include up to 6 clinic visits over 6 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 single-masked 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 to have a complete study evaluation at Study Visits 4 and 6 (Days 15 ± 1 day and 29 ± 1 day, respectively). Subjects will further be instructed to return to the clinic for diary collection and in-clinic symptom assessment only at Visits 3 and 5 (Days 8 ± 1 day and 22 ± 1 day, respectively). The last dose of investigational product and the final study visit will occur upon completion of 28 ± 1 days of exposure to investigational product. Subjects will be released from the study at the end of Visit 6 (Day 29 ± 1 day).

Arms:
arm 1: KPI-121 0.25% ophthalmic suspension dosed QID for 28 days in subjects with dry eye disease arm 2: Vehicle (placebo) dosed QID for 28 days in subjects with dry eye disease

Interventions: intervention 1: KPI-121 intervention 2: Placebo
Intervention descriptions: intervention 1: KPI-121 drug product will be supplied as 0.25% as a suspension in identically packaged opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate. intervention 2: Subjects randomized to placebo control arms will receive the same bottles containing all components at the concentrations used in the KPI-121 drug product with the exception of the active component, loteprednol etabonate.

Protocol document:
Prot_SAP_000.pdf: 
NCT02188160 
 
Study ID:  
KPI-121-C-002  
 
Study Title:  
A Phase 2, Double-Masked, Randomized, Controlled 
Study of KPI-121 0.25% Ophthalmic Suspension 
Compared to Vehicle in Subjects with Dry Eye Disease 
 
Date:  
26 Sep 2014 


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CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 2 OF 80 
26 SEP 2014 
CONFIDENTIAL 
KALA PHARMACEUTICALS, INC. 
Clinical Protocol KPI-121-C-002 
Investigator Signature Page 
Project: 
KPI-121 
 
Compound Number/Name: 
KPI-121  
 
Protocol Number: 
KPI-121-C-002  
 
Protocol Title: 
A Phase 2, 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:  22 May 2014 
 
Amendment 1:  10 Jun 2014 
 
Amendment 2:  02 Jul 2014 
 
Amendment 3:  21 Jul 2014 
 
Amendment 4:  07 Aug 2014 
 
Amendment 5:  12 Sep 2014 
 
Amendment 6:  26 Sep 2014 
 
 
  
Contact for Serious Adverse Events: 
 
 
  
     
  
 
 
  
 
  
 
 
Investigator Name (printed or typed): 
 
________________________________________________ 
 
Investigator's Signature: 
 
 
________________________________________________ 
______________  
 
 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 3 OF 80 
26 SEP 2014 
CONFIDENTIAL 
SYNOPSIS  
Study Title: 
KPI-121-C-002: A Phase 2, 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 
Up to 400 subjects who are diagnosed with dry eye disease 
will be screened.  Among those screened, approximately 150 
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 up to 28 days. 
Study Design:   
 
This is a Phase 2, 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 400 subjects will be screened and up to 150 
subjects will be randomized at up to 12 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 up to 28 days or 2) vehicle administered as 
1-2 drops in each eye QID for up to 28 days.   
 
Furthermore, subjects will be assigned to a study arm based 
on the stratification of: 
• Subject’s day prior to Visit 2 (Day 1) 
 
 score 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 4 OF 80 
26 SEP 2014 
CONFIDENTIAL 
 AND 
• Study eye baseline investigator-rated bulbar 
conjunctival hyperemia score 
 
 
This study will include up to 6 clinic visits over 6 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 single-masked 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 to have a complete study evaluation at Study Visits 4 
and 6 (Days 15 ± 1 day and 29 ± 1 day, respectively).  
Subjects will further be instructed to return to the clinic for 
diary collection and in-clinic symptom assessment only at 
Visits 3 and 5 (Days 8 ± 1 day and 22 ± 1 day, respectively).  
The last dose of investigational product and the final study 
visit will occur upon completion of 28 ± 1 days of exposure 
to investigational product.  Subjects will be released from the 
study at the end of Visit 6 (Day 29 ± 1 day). 
 
Assessments in this study will include: 
• Subject-rated assessment of ocular discomfort 
 
  
• 
 
• Investigator-rated assessment of bulbar conjunctival 
hyperemia 
• 
 
• Best corrected visual acuity (BCVA) 
• Slit lamp biomicroscopy 
• Corneal fluorescein staining 
• Unanesthetized Schirmer Test evaluation 
• Lissamine Green conjunctival staining 
• Intraocular pressure (IOP) measurement  


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 5 OF 80 
26 SEP 2014 
CONFIDENTIAL 
• Dilated ophthalmoscopy 
Efficacy Endpoints 
Primary Efficacy Endpoints: 
 
Comparison of mean bulbar conjunctival hyperemia 
 
 between the KPI-121 
0.25% ophthalmic suspension group and the vehicle group: 
• Visit 6 
 
Comparison of mean 
 Severity Assessment 
Scores between the KPI-121 0.25% ophthalmic suspension 
group and the vehicle group: 
• Visit 5 through the day before Visit 6 
 
Secondary Efficacy Endpoints: 
 
Comparison of mean corneal fluorescein staining between the 
KPI-121 0.25% ophthalmic suspension group and the vehicle 
group: 
• Visit 4 
• Visit 6 
 
Comparison of mean bulbar conjunctival hyperemia 
 
between the KPI-121 
0.25% ophthalmic suspension group and the vehicle group: 
• Visit 4 
 
Comparison of mean 
 Severity Assessment 
Scores between the KPI-121 0.25% ophthalmic suspension 
group and the vehicle group: 
• Visit 3 through the day before Visit 4 
 
Exploratory Efficacy Endpoints 
 
Comparison of mean difference within the KPI-121 0.25% 
ophthalmic suspension group and within the vehicle group 
for bulbar conjunctival hyperemia 
 
 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 6 OF 80 
26 SEP 2014 
CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Comparison of mean difference within the KPI-121 0.25% 
ophthalmic suspension group and within the vehicle group 
for 
 Severity Assessment Scores: 
• Visit 3 through the day before Visit 4 as compared to 
Days -7 to -1 
• Visit 5 through the day before Visit 6 as compared to 
Days -7 to -1. 
 
Comparison of mean 
 Frequency 
Assessment Scores between the KPI-121 0.25% ophthalmic 
suspension group and the vehicle group: 
• Visit 3 through the day before Visit 4 
• Visit 5 through the day before Visit 6 
 
Comparison of mean difference within the KPI-121 0.25% 
ophthalmic suspension group and within the vehicle group 
for 
 Frequency Assessment Scores: 
• Visit 3 through the day before Visit 4 as compared to 
Days -7 to -1 
• Visit 5 through the day before Visit 6 as compared to 
Days -7 to -1. 
 
Comparison of mean Subject-Rated Ocular Discomfort 
Severity Scores between the KPI-121 0.25% ophthalmic 
suspension group and the vehicle group: 
• Visit 4 
• Visit 6 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 7 OF 80 
26 SEP 2014 
CONFIDENTIAL 
Comparison of mean difference within the KPI-121 0.25% 
ophthalmic suspension group and within the vehicle group 
for Subject-Rated Ocular Discomfort Severity Scores: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 
Comparison of mean Subject-Rated Ocular Discomfort 
Frequency Scores between the KPI-121 0.25% ophthalmic 
suspension group and the vehicle group: 
• Visit 4 
• Visit 6 
 
Comparison of mean difference within the KPI-121 0.25% 
ophthalmic suspension group and within the vehicle group 
for Subject-Rated Ocular Discomfort Frequency Scores: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 
Comparison of mean difference within KPI-121 0.25% 
ophthalmic suspension group and within the vehicle group 
for corneal fluorescein staining: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 
Comparison of mean Lissamine Green conjunctival staining 
between the KPI-121 0.25% ophthalmic suspension group 
and the vehicle group: 
• Visit 4 
• Visit 6 
 
Comparison of mean difference within the KPI-121 0.25% 
ophthalmic suspension group and within the vehicle group 
for Lissamine Green conjunctival staining: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
Safety Endpoints 
• Assessment of adverse events (AEs) 
• Slit lamp biomicroscopy 
• IOP measurement 
• BCVA 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 8 OF 80 
26 SEP 2014 
CONFIDENTIAL 
• 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. 
 
 
 
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
 [National Eye Institute 
(NEI) scale] AND 
b. 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 
 
Severity Assessment at Visit 1 AND a score 
of 
 Severity 
 
 Visit 2 (Day 1) 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 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 9 OF 80 
26 SEP 2014 
CONFIDENTIAL 
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 6 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 6 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 6 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 6 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 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 10 OF 80 
26 SEP 2014 
CONFIDENTIAL 
surgically sterilized (i.e., vasectomized) 
partner at least 6 months prior to Visit 1 
through Visit 6 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 
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: 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 11 OF 80 
26 SEP 2014 
CONFIDENTIAL 
a. Topical cyclosporine (Restasis®) 
b. 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. Antidepressants 
c. Isotretinoin 
d. Oral corticosteroids 
e. Systemic immunosuppressive agents 
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, 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, using corrective 
lenses if necessary, 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 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 12 OF 80 
26 SEP 2014 
CONFIDENTIAL 
requiring penetrating intraocular surgery during the 
study. 
12. Have had eyelid surgery within 6 months prior to 
Visit 1 (Screening) or anticipate requiring eyelid 
surgery during the study. 
13. Have congenitally absent lacrimal glands or 
meibomian glands.   
14. Have had selective laser trabeculoplasty (SLT) within 
3 months prior to Visit 1 (Screening) or anticipate 
requiring SLT. 
15. 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. 
16. Have had corneal refractive surgery, glaucoma 
surgery, or corneal transplantation (full thickness, 
anterior or posterior) within 1 year prior to Visit 1 
(Screening) 
NOTE:  This exclusion also applies if surgery was 
performed greater than 1 year prior to Visit 1 but the 
Investigator considers the subject to be unstable 
and/or require medication. 
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 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 13 OF 80 
26 SEP 2014 
CONFIDENTIAL 
confluent staining more than 33% of area (focal 
confluent staining is acceptable), over 5 filaments or 
epithelial defects.Have active or have had an outbreak 
of herpetic keratitis within 1 year of Visit 1. 
19. 
 
 
 
 
 
 
 
 
 
 
 
20. 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. 
21. Have been exposed to an investigational drug within 
30 days prior to Visit 1. 
22. Be an employee of the site that is directly involved in 
the management, administration, or support of this 
study or be an immediate family member of the same. 
23. Have a documented history of alcohol and/or drug 
abuse. 
24. 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. 
 
 
 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 14 OF 80 
26 SEP 2014 
CONFIDENTIAL 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................................... 18 
1. INTRODUCTION ................................................................................................................. 20 
1.1. DESCRIPTION OF INVESTIGATIONAL PRODUCT ..................................................................... 21 
1.2. JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION ............................. 21 
1.3. GCP COMPLIANCE ............................................................................................................... 22 
1.4. POPULATION TO BE STUDIED ................................................................................................ 22 
2. TRIAL OBJECTIVES AND PURPOSE ............................................................................... 23 
2.1. OBJECTIVE ........................................................................................................................... 23 
3. TRIAL DESIGN .................................................................................................................... 24 
3.1. PRIMARY EFFICACY ENDPOINTS .......................................................................................... 24 
3.2. SECONDARY EFFICACY ENDPOINTS ..................................................................................... 24 
3.3. EXPLORATORY EFFICACY ENDPOINTS ................................................................................. 24 
3.4. SAFETY ENDPOINTS ............................................................................................................. 30 
3.5. DESCRIPTION OF TRIAL DESIGN ........................................................................................... 30 
3.5.1. Investigational product ..................................................................................................... 32 
3.5.2. Methods to Minimize Bias ............................................................................................... 34 
4. SELECTION OF SUBJECTS ................................................................................................ 35 
4.1. SUBJECT INCLUSION AND EXCLUSION CRITERIA .................................................................. 35 
5. PROCEDURES ...................................................................................................................... 39 
5.1. VISIT DESCRIPTION .............................................................................................................. 39 
5.1.1. Visit 1:  14 ± 1 Days Prior to Day 1 – Screening ............................................................. 39 
5.1.2. Visit 2:  Day 1 (Randomization) ...................................................................................... 40 
5.1.3. Visit 3: Day 8 ± 1 day – 
 ............................................................... 41 
5.1.4. Visit 4: Day 15 ± 1 day – Study Visit .............................................................................. 41 
5.1.5. Visit 5: Day 22 ± 1 day – 
 ............................................................. 42 
5.1.6. Visit 6: Day 29 ± 1 day – End of Study Visit .................................................................. 43 
5.1.7. Unscheduled Visit ............................................................................................................ 43 
5.1.8. Early Termination Visit ................................................................................................... 43 
5.2. RESCUE MEDICATION USE ................................................................................................... 44 
5.3. SUBJECT WITHDRAWAL AND/OR DISCONTINUATION ........................................................... 44 
5.4. COLLECTION OF DATA ......................................................................................................... 45 
6. TREATMENT OF SUBJECTS ............................................................................................. 46 
6.1. INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED ........................................................... 46 
6.2. CONCOMITANT MEDICATIONS ............................................................................................. 46 
6.2.1. Permitted Medications ..................................................................................................... 46 
6.2.2. Medications Not Permitted .............................................................................................. 46 
6.3. INVESTIGATIONAL PRODUCT USE COMPLIANCE ................................................................... 47 
6.4. DRUG ACCOUNTABILITY ...................................................................................................... 47 
6.5. MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING THE CODE .............. 48 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
PAGE 15 OF 80 
26 SEP 2014 
CONFIDENTIAL 
7. ASSESSMENT OF EFFICACY ............................................................................................ 50 
8. ASSESSMENT OF SAFETY ................................................................................................ 51 
8.1. SAFETY PARAMETERS .......................................................................................................... 51 
8.2. ADVERSE EVENT DEFINITIONS ............................................................................................. 51 
8.3. PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR ................................................... 53 
8.4. SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR ............................................ 53 
9. STATISTICS ......................................................................................................................... 56 
9.1. STATISTICAL METHODS ....................................................................................................... 56 
9.1.1. Subject Disposition, Demographic and Background Characteristics .............................. 56 
9.1.2. Analysis of Efficacy ......................................................................................................... 56 
9.1.3. Analysis of Safety ............................................................................................................ 56 
9.2. SAMPLE SIZE ESTIMATION ................................................................................................... 57 
9.3. LEVEL OF SIGNIFICANCE ...................................................................................................... 57 
9.4. PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA ...................... 57 
9.5. PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL PLAN ........................... 57 
10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................. 58 
11. QUALITY CONTROL ........................................................................................................ 59 
12. ETHICS ................................................................................................................................ 60 
12.1. Institutional Review Board ............................................................................................... 60 
12.2. Informed Consent Requirements ...................................................................................... 60 
13. DATA HANDLING AND RECORDKEEPING ................................................................ 61 
13.1. Data Quality Control and Reporting ................................................................................. 61 
13.2. Records Retention ............................................................................................................. 61 
14. PUBLICATION POLICY .................................................................................................... 62 
15. REFERENCES ..................................................................................................................... 63 
16. APPENDICES ..................................................................................................................... 64 
 


CLINICAL PROTOCOL KPI-121-C-002 FINAL 
 
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26 SEP 2014 
CONFIDENTIAL 
LIST OF TABLES 
 
Table 1: SUMMARY OF EFFICACY ENDPOINTS ............................................................................ 27 
Table 2: COMPOSITION OF KPI-121 0.25% (W/V) DRUG PRODUCT ............................................. 33 
Table 3:  COMPOSITION OF VEHICLE ........................................................................................... 33 


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LIST OF FIGURES 
FIGURE 1: STUDY SCHEMATIC ..................................................................................................... 32 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AR 
Adverse Reaction 
AE 
Adverse Event 
BCVA 
Best Corrected Visual Acuity 
BL 
Baseline 
°C 
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 
°F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonization 
ID 
Identification 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 
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 
 
 


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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 
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-002 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% ophthalmic suspension contains 0.25% (w/v) LE in an isotonic formulation 
that is buffered to maintain pH 5.0 – 7.0.  It is a sterile, aqueous submicron suspension of LE 
and is filled in a white, low-density polyethylene plastic dropper bottle with a white, 
controlled-drop polyethylene tip and a polypropylene cap. Each bottle contains 5.5 mL 
nominal fill volume. 
 
The vehicle control has the same composition as KPI-121 0.25% ophthalmic suspension but 
does not contain LE.  The vehicle is essentially isotonic and is buffered to maintain pH 5.0 – 
7.0.  It is a sterile, aqueous solution supplied in the same white, low-density polyethylene 
plastic dropper bottle with the same white, controlled-drop polyethylene tip and white 
polypropylene closure as KPI-121 0.25% ophthalmic suspension. 
 
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 28 
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 
 
Up to 400 subjects who are diagnosed with dry eye disease will be screened for this study.  
Approximately 150 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 
 
Comparison of mean bulbar conjunctival hyperemia 
 
 between the KPI-121 0.25% ophthalmic suspension group and the vehicle group: 
• Visit 6 
 
Comparison of mean 
 Severity Assessment Scores between the KPI-121 
0.25% ophthalmic suspension group and the vehicle group: 
• Visit 5 through the day before Visit 6 
 
3.2. 
SECONDARY EFFICACY ENDPOINTS 
 
Comparison of mean corneal fluorescein staining between the KPI-121 0.25% ophthalmic 
suspension group and the vehicle group: 
• Visit 4 
• Visit 6 
 
Comparison of mean bulbar conjunctival hyperemia 
 
 between the KPI-121 0.25% ophthalmic suspension group and the vehicle group: 
• Visit 4 
 
Comparison of mean 
 Severity Assessment Scores between the KPI-121 
0.25% ophthalmic suspension group and the vehicle group: 
• Visit 3 through the day before Visit 4 
 
3.3. 
EXPLORATORY EFFICACY ENDPOINTS 
 
Comparison of mean difference within the KPI-121 0.25% ophthalmic suspension group and 
within the vehicle group for bulbar conjunctival hyperemia 
 
 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 
 
 
 
 
 
 
 


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Comparison of mean difference within the KPI-121 0.25% ophthalmic suspension group and 
within the vehicle group for 
 Severity Assessment Scores: 
• Visit 3 through the day before Visit 4 as compared to Days -7 to -1 
• Visit 5 through the day before Visit 6 as compared to Days -7 to -1. 
 
Comparison of mean 
 Frequency Assessment Scores between the KPI-121 
0.25% ophthalmic suspension group and the vehicle group: 
• Visit 3 through the day before Visit 4 
• Visit 5 through the day before Visit 6 
 
Comparison of mean difference within the KPI-121 0.25% ophthalmic suspension group and 
within the vehicle group for 
 Frequency Assessment Scores: 
• Visit 3 through the day before Visit 4 as compared to Days -7 to -1 
• Visit 5 through the day before Visit 6 as compared to Days -7 to -1. 
 
Comparison of mean Subject-Rated Ocular Discomfort Severity Scores between the KPI-121 
0.25% ophthalmic suspension group and the vehicle group: 
• Visit 4 
• Visit 6 
 
Comparison of mean difference within the KPI-121 0.25% ophthalmic suspension group and 
within the vehicle group for Subject-Rated Ocular Discomfort Severity Scores: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 
Comparison of mean Subject-Rated Ocular Discomfort Frequency Scores between the KPI-
121 0.25% ophthalmic suspension group and the vehicle group: 
• Visit 4 
• Visit 6 
 
Comparison of mean difference within the KPI-121 0.25% ophthalmic suspension group and 
within the vehicle group for Subject-Rated Ocular Discomfort Frequency Scores: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 


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Comparison of mean difference within KPI-121 0.25% ophthalmic suspension group and 
within the vehicle group for corneal fluorescein staining: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 
Comparison of mean Lissamine Green conjunctival staining between the KPI-121 0.25% 
ophthalmic suspension group and the vehicle group: 
• Visit 4 
• Visit 6 
 
Comparison of mean difference within the KPI-121 0.25% ophthalmic suspension group and 
within the vehicle group for Lissamine Green conjunctival staining: 
• Visit 4 as compared to Visit 2 
• Visit 6 as compared to Visit 2 
 




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Evaluation 
Comparison 
Visit 
1° 
2° 
Exploratory 
 Frequency  
Mean values 
5 through day before 6 
 
 
X 
Frequency  
Mean change 
from BL 
3 through day before 4 vs. 
Day -7 through Day -1 
 
 
X 
 Frequency 
Mean change 
from BL 
5 through day before 6 vs. 
Day -7 through Day -1 
 
 
X 
Corneal Fluorescein Staining 
Mean values 
4 
 
X 
 
Corneal Fluorescein Staining 
Mean values 
6 
 
X 
 
Corneal Fluorescein Staining 
Mean change 
from BL 
4 vs. 2 
 
 
X 
Corneal Fluorescein Staining 
Mean change 
from BL 
6 vs. 2 
 
 
X 
Lissamine Green Staining 
Mean values 
4 
 
 
X 
Lissamine Green Staining 
Mean values 
6 
 
 
X 
Lissamine Green Staining 
Mean change 
from BL 
4 vs. 2 
 
 
X 
Lissamine Green Staining 
Mean change 
from BL 
6 vs. 2 
 
 
X 
Subject-Rated Ocular Discomfort Severity 
Scores 
Mean values 
4 
 
 
X 
Subject-Rated Ocular Discomfort Severity 
Scores 
Mean values 
6 
 
 
X 
Subject-Rated Ocular Discomfort Severity 
Scores 
Mean change 
from BL 
4 vs. 2 
 
 
X 
Subject-Rated Ocular Discomfort Severity 
Scores 
Mean change 
from BL 
6 vs. 2 
 
 
X 


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Evaluation 
Comparison 
Visit 
1° 
2° 
Exploratory 
Subject-Rated Ocular Discomfort Frequency 
Scores 
Mean values 
4 
 
 
X 
Subject-Rated Ocular Discomfort Frequency 
Scores 
Mean values 
6 
 
 
X 
Subject-Rated Ocular Discomfort Frequency 
Scores 
Mean change 
from BL 
4 vs. 2 
 
 
X 
Subject-Rated Ocular Discomfort Frequency 
Scores 
Mean change 
from BL 
6 vs. 2 
 
 
X 


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3.4. 
SAFETY ENDPOINTS 
 
• Assessment of AEs 
• Slit lamp biomicroscopy  
• IOP measurement 
• BCVA 
• Dilated Ophthalmoscopy 
 
3.5. 
DESCRIPTION OF TRIAL DESIGN 
 
This is a Phase 2, 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 6 clinic visits, including 2 weeks of single-masked vehicle run-in 
followed by up to 28 days of investigational product dosing (KPI-121 0.25% ophthalmic 
suspension or vehicle).   
 
Up to 400 subjects at up to 12 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 150 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. If both eyes 
qualify for the study with exactly the same values for ocular entry criteria, IWRS will choose 
the study eye as OD.  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:  
 
• Subject’s day prior to Visit 2 (Day 1) 
 score
 
 AND 
• Study eye baseline 
 bulbar conjunctival hyperemia score 
 
 
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, 


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Investigators, and study staff 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 Visits 4 and 6 (Day 15 ± 1 
day and Day 29 ± 1 day, respectively).  Subject will also return at Visits 3 and 5 (Days 8 ± 1 
day and 22 ± 1 day, respectively) to 
 
 assess concomitant medication use and adverse events.  Subjects will 
discontinue dosing and be released from the study at Visit 6 (Day 29 ± 1 day).  
 
A summary of events is provided in Appendix 1.  Assessments in this study will include:  
 
• Subject-rated ocular discomfort assessment (Appendix 2) 
• 
 assessment (Appendix 3) 
• Investigator-rated assessment of bulbar conjunctival hyperemia (Appendix 4) 
• Unanesthetized Schirmer Test (Appendix 5) 
• BCVA (Appendix 6) 
• Slit lamp biomicroscopy (Appendix 7) 
• Corneal fluorescein staining (Appendix 8) 
• Lissamine Green conjunctival staining (Appendix 9) 
• IOP measurement (Appendix 10) 
• Dilated ophthalmoscopy (Appendix 11) 
• 
 (Appendix 12) 
 
 
• Concomitant medication use assessment  
• Assessments of AEs 
 
 
 






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be returned to the site at Visit 6 (Day 29 ± 1 day).  The box labels and the dropper bottle 
labels will contain the following information: sponsor name, protocol number, randomization 
number, storage temperature, and required statement(s) per the appropriate regulatory agency.  
 
All investigational products will be stored in a secure area with limited access at controlled 
room temperature (15-25°C/59 -77°F).  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 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 who will be responsible for dispensing 
investigational product to subjects and instructing subjects regarding dosing of the 
investigational product.  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.   


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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. 
 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  6 NEI scale 
AND 
b. Bulbar conjunctival hyperemia at Visit 1 and Visit 2 of 
 as assessed using 
the CCLRU scale AND 
c. A score of 
 Severity Assessment at Visit 1 
AND a score of 
 Severity on the day prior to 
Visit 2 (Day 1) 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 6 
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 
6 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 6 or last administration of the 


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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 6 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 6 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 
 
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 


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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. Any form of topical 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. Antidepressants 
c. Isotretinoin 
d. Oral corticosteroids 
e. Systemic immunosuppressive agents 
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, 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, using corrective lenses if necessary, of +1.0 logMAR 
or worse as assessed by 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 eyelid surgery within 6 months prior to Visit 1 (Screening) or anticipate 
requiring eyelid surgery during the study. 
13. Have congenitally absent lacrimal glands or meibomian glands.   
14. Have had SLT within 3 months prior to Visit 1 (Screening) or anticipate requiring 
SLT . 
15. 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. 


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16. Have had corneal refractive surgery, glaucoma surgery, or corneal transplantation (full 
thickness, anterior or posterior) within 1 year prior to Visit 1 (Screening) 
NOTE:  This exclusion also applies if surgery was performed greater than 1 year prior 
to Visit 1 but the Investigator considers the subject to be unstable and/or require 
medication. 
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), over 5 filaments or epithelial defects. 
19. Have active or have had an outbreak of herpetic keratitis within 1 year of Visit 1. 
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 drug within 30 days prior to Visit 1. 
23. Be an employee of the site that is directly 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.    
 
• Non-ocular and ocular medical history 
• Concomitant medication usage and medications taken during the 6 months prior to 
screening  
• Inclusion/exclusion criteria  
• Urine pregnancy test (UPT) for women of childbearing potential 
• Subject-rated assessment of ocular discomfort 
• 
 assessment 
• BCVA   
• Investigator-rated assessment of bulbar conjunctival hyperemia 
• Slit Lamp Biomicroscopy 
• Corneal fluorescein staining 
• Lissamine Green conjunctival staining 
• Unanesthetized Schirmer Test evaluation 
• IOP measurement 
• Dilated Ophthalmoscopy 
• Single-masked, investigational product instillation 
• AE Assessment 
• Dispense single masked, investigational product and instructions for administration  
• 
 
 
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.   
 


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Instructions to subject: 
• Dose single-masked run-in investigational product as instructed 
• 
 
• 
 
• 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:  
 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• 
 
• Used and unused single-masked run-in investigational product collected, counted, and 
compliance assessed (via subject diary)  
• Subject-rated assessment of ocular discomfort 
• Investigator-rated assessment of bulbar conjunctival hyperemia 
• 
 
• BCVA 
• Slit Lamp Biomicroscopy 
• Corneal fluorescein staining 
• Lissamine Green conjunctival staining 
• IOP measurement 
• 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:  
• Instillation of randomized investigational product 
• AE Assessment 
• Dispensing of double-masked, investigational product (2 bottles) and instructions for 
administration 
• 
 
 
The first dose of double-masked investigational product will be administered in the clinic 
under the supervision of a designated dosing coordinator.  This dosing coordinator, who is not 


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responsible for study assessments, will also be required to dispense and retrieve 
investigational product to the subjects. 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: 
• Dose investigational product as instructed 
• 
 
• 
 
• Return for Visit 3 scheduled on Day 8 ± 1 day. 
 
5.1.3. 
Visit 3: Day 8 ± 1 day – Diary Collection Visit 
 
This visit will occur on Day 8 ± 1 day as calculated from Visit 2: Day 1, and the following 
evaluations will be performed:  
 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• 
 
• Subject-rated assessment of ocular discomfort 
 
Instructions to subject: 
• Dose investigational product as instructed 
• 
 
• 
 
• Return for Visit 4 scheduled on Day 15 ± 1 day. 
 
5.1.4. 
Visit 4: Day 15 ± 1 day – Study Visit 
 
This visit will occur on Day 15 ± 1 day as calculated from Visit 2: Day 1, and the following 
evaluations will be performed/assessed:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• 
 
• Used and unused double-masked investigational product collected, counted, and 
compliance assessed (via subject diary)  
• Subject-rated assessment of ocular discomfort 


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• Investigator-rated assessment of bulbar conjunctival hyperemia 
• 
 
• BCVA 
• Slit Lamp Biomicroscopy: 
• Corneal fluorescein staining 
• Lissamine Green conjunctival staining 
• IOP measurement 
• Subject will receive a re-supply of double-masked investigational product to last until 
Visit 6.   
 
Instructions to subject: 
• Dose investigational product as instructed 
• 
 
• 
 
• Return for Visit 5 scheduled on Day 22 ± 1 day. 
 
5.1.5. 
Visit 5: Day 22 ± 1 day – Diary Collection Visit 
 
This visit will occur on Day 22 ± 1 day as calculated from Visit 2: Day 1, and the following 
evaluations will be performed:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• 
 
• Subject-rated assessment of ocular discomfort 
 
Instructions to subject: 
• Dose investigational product as instructed 
• 
 
• 
 
• Return for Visit 6 scheduled on Day 29 ± 1 day 
 
 
 


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5.1.6. 
Visit 6: Day 29 ± 1 day – End of Study Visit 
 
The end-of-investigational-product-use visit will occur on Day 29 ± 1 day as calculated from 
Visit 2: Day 1, and the following will be performed/assessed:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• 
 
• Used and unused double-masked investigational product collected, counted, and 
compliance assessed (via subject diary)  
• Subject-rated assessment of ocular discomfort 
• Investigator-rated assessment of bulbar conjunctival hyperemia 
• 
 
• BCVA 
• Slit Lamp Biomicroscopy: 
• Corneal fluorescein staining 
• Lissamine Green conjunctival staining 
• IOP measurement 
• Dilated ophthalmoscopy 
• UPT 
• Release of subject from the study 
 
5.1.7. 
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 6 
should be completed rather than the eCRFs for an Unscheduled Visit. 
 
5.1.8. 
Early Termination Visit 
 
In the event of termination prior to Visit 6, every attempt will be made to ensure that all Visit 
6 assessments are performed.  If this is not feasible, at least the following should be 
performed/assessed:  
 
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• Used and unused investigational product collected and compliance 
 
 


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• 
 
• BCVA 
• Slit lamp biomicroscopy  
• IOP measurement 
 
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 6.  
Rescued subjects will be considered treatment failures, but 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.   
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. 
 


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In the event study discontinuation of a randomized subject is necessary, the Investigator 
should make every attempt to have subject complete Visit 6 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 2 bottles of single-masked 
investigational product (vehicle).  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 3 dropper bottles will be allocated to each 
subject at Visit 2.  At Visit 2 (Day 1/Randomization), subjects will receive 2 bottles of 
double-masked investigational product (KPI-121 0.25% ophthalmic suspension or vehicle).  
At Visit 4 (Day 15 ± 1 day), subjects will receive 1 additional bottle of double-masked 
investigational product from the kit allocated.  All bottles will be returned to the site at Visit 6 
(Day 29 ± 1 day).  The investigational product will be stored at the site in a secure area with 
limited access at controlled room temperature (15-25°C/59-77°F). 
 
Subjects will be asked to administer investigational product QID.  Prior to each instillation, 
subject will be instructed to shake investigational product bottle.  The subjects will record the 
time of administration of each dose of investigational product at the time of instillation 
(Appendix 12).  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 6 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 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: 
• Any topical ophthalmic medications including eyelash growth medications, eye drops, 
gels, or artificial tears  
• TNF-blocking agents (e.g. etanercept, adalimumab, infliximab) 
• Treatment for glaucoma 
 


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Within 30 days prior to screening (Visit 1) and for the duration of the study: 
• Ocular, inhaled, or intranasal corticosteroids 
• Ocular or oral non-steroidal anti-inflammatory drugs (NSAIDs) 
• Topical ocular antibiotics 
• Topical ocular antihistamines or mast cell stabilizers 
• Oral antihistamines 
• Topical or nasal vasoconstrictors 
• Other investigational products 
 
Within 60 days prior to screening (Visit 1) and for the duration of the study: 
• Topical cyclosporine (Restasis®) 
• Any form of topical LE 
 
Within 30 days prior to the screening visit (Visit 1) alteration to the dose or anticipated 
alterations to the dose of the following are disallowed: 
• Tetracycline compounds (tetracycline, doxycycline, or minocycline) 
• Omega-3 or Omega-6 supplements 
 
Within 6 months prior to the screening visit (Visit 1) alterations to the dose or anticipated 
alterations to the dose of the following are disallowed: 
• Anticholinergics 
• Antidepressants 
• Isotretinoin 
• Oral corticosteroids 
• Systemic immunosuppressive agents 
 
6.3. 
INVESTIGATIONAL PRODUCT USE COMPLIANCE 
 
Compliance will be assessed by comparing investigational product accountability records 
with the 
.  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. 
DRUG 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 


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performing reconciliation between the amount of drug 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 drug 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 at controlled room temperature (15-25°C/59-77°F) in an 
area limited to controlled access. 
 
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 drug accountability.  All drug accounting procedures must be completed before the 
study is considered complete. 
 
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. 
 


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A randomization code will be computer-generated by Kala Pharmaceuticals, Inc. or designee.  
Randomization team members will work independently of other team members 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: 
• Investigator-rated assessment of bulbar conjunctival hyperemia 
• 
 severity assessment  
• 
 frequency assessment  
• Subject-rated assessment of ocular discomfort severity 
• Subject-rated assessment of ocular discomfort frequency 
• 
 
• Corneal fluorescein staining 
• Lissamine green conjunctival staining 
 


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8. 
ASSESSMENT OF SAFETY 
8.1. 
SAFETY PARAMETERS 
 
Safety parameters include: 
• Assessments of AEs 
• BCVA 
• Slit lamp biomicroscopy  
• Dilated ophthalmoscopy  
• 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.  
 
 
 


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A SERIOUS ADVERSE EVENT (SAE) is any AE or suspected adverse reaction occurring 
at any dose that:  
 
• Results in death. 
• Is life-threatening. 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• Requires inpatient hospitalization. 
• Prolongs inpatient hospitalization. 
• Is a congenital anomaly/birth defect. 
• Is a significant medical event (i.e., one that may jeopardize the subject or may require 
intervention to prevent one or more of the other outcomes listed above). 
 
A NON-SERIOUS ADVERSE EVENT is any AE that does not meet the definitions for 
SAEs as described above.  
 
Each AE will be classified as SERIOUS or NON-SERIOUS using the definitions provided 
above. 
 
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: 
 
• Event occurring before dosing. 
• Event or intercurrent illness due wholly to factors other than investigational product 
use. 
 
Unlikely:  
• Poor temporal relationship with investigational product use. 
• Event easily explained by subject’s clinical state or other factors. 
 
Possible: 
 Reasonable temporal relationship with investigational product use. 
 Event could be explained by subject’s clinical state or other factors.  
 
Probable: 
 Reasonable temporal relationship with investigational product use. 


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 Likely to be known reaction to agent or chemical group, or predicted by known 
pharmacology. 
 Event cannot easily be explained by subject’s clinical state or other factors. 
 
Definite:  
• Distinct temporal relationship with investigational product use. 
• Known reaction to agent or chemical group, or predicted by known pharmacology. 
• Event cannot be explained by subject’s clinical state or other factors.  
 
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: 
 
• How have you felt since your last assessment? 
• Have you had any health problems since your last assessment? 
 
The severity of each AE should be categorized as mild, moderate, or severe. 
 
The causality of use of investigational product in relation to the AE will be assessed by the 
Principal Investigator after careful medical consideration and categorized as unrelated, 
unlikely, possible, probable, or definite. 
 
If an AE occurs, the Investigator will institute support and/or treat as deemed appropriate.   
If a non-SAE is unresolved at the time of the last day of the study, an effort will be made to 
follow up until the AE is resolved or stabilized, the subject is lost to follow-up, or there is 
some other resolution of the event.  The Investigator should make every attempt to follow 
SAEs to resolution. 
 
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.   


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The following information should be provided when an SAE is reported to the sponsor or 
designee: 
1. Protocol Number 
1. Site Number 
2. Subject Number 
3. Subject Demographic information, including: 
o Date of Birth 
o Sex 
o Race 
4. Investigational product start date 
5. Date of last dose of investigational product  
6. Date investigational product reinitiated (if investigational product interrupted)  
7. SAE information, including: 
o SAE term (diagnosis only; if known or serious signs/symptoms) 
o Description of SAE/narrative 
o Date/time of onset 
o Severity 
o Outcome 
o Date/time of resolution or death (if duration < 24 hours) 
o Relationship to investigational product 
o Action taken with investigational product 
8. Criteria for classifying the event as serious, including whether the SAE:   
o Resulted in death. 
o Was life-threatening 
o Required inpatient hospitalization. 
o Prolonged inpatient hospitalization. 
o Resulted in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
o Was a congenital anomaly/birth defect 
o Important medical events that may not result in death, were not life-threatening, 
or did not require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the 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.  
9. Concomitant medications 
10. Relevant history 


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11. Possible causes of SAE other than investigational product 
12. Copy of AE page from the CRF 
 
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. 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 co-primary endpoints are (1) the mean bulbar conjunctival hyperemia score at Visit 6; 
and (2) the mean 
 severity score averaged over the days from Visit 5 to the 
day before Visit 6. 
 
Secondary and exploratory efficacy endpoints will be evaluated as elaborated in Section 3. 
 
9.1.3. 
Analysis of Safety 
 
Analysis of safety data will be presented for all subjects in the Safety population (i.e., all 
subjects receiving randomized investigational product).  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.  Ophthalmoscopy findings 
will be summarized descriptively.  IOP measurements, BCVA and Biomicroscopy will be 
summarized as safety outcomes.   
 
 
 


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9.2. 
SAMPLE SIZE ESTIMATION 
 
A sample size of 71 in each group will have 90% power to detect an effect size of 
 using a 
2-group t-test with a 
2-sided significance level. 
 
9.3. 
LEVEL OF SIGNIFICANCE 
 
The primary assessment of the dose-response will be evaluated using a 5% level of 
significance.  Since both co-primary endpoints will be required to be significant at the 0.05 
level, there is no adjustment needed for multiple comparisons. 
 
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.  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).  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. Imputation will be carried out only 
on the co-primary endpoints and time points. 
 
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. 
4.  
 
 
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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Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Investigational product administration in-clinic 
Xb 
X 
 
 
 
 
Dispense investigational product 
Xb 
X 
 
X 
 
 
 
Xb 
X 
X 
X 
X 
 
Collect investigational product 
 
Xb 
 
 
 
X 
 
 
Xb 
X 
X 
X 
X 
aWomen of childbearing potential only;  bRun-In Product  


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APPENDIX 2: SUBJECT-RATED OCULAR DISCOMFORT ASSESSMENT 
 
Subjects will be asked to subjectively rate their ocular discomfort severity and frequency at 
Visits 1-6.  Investigator site designees will ask the subject the following question and record 
their answer in the eCRF.  This assessment is a general assessment of both eyes.  There will 
not be a question for each individual eye. 
 
Severity of Symptoms 
 
On average over the past day, how would you rate the severity of your ocular discomfort 
associated with dry eye (for example, dryness or irritation)? 
 
0 = None   
 
 
 
 
 
1 = Mild   
 
 
 
 
2 = Moderate   
 
 
 
 
 
3 = Severe  
 
 
 
 
 
 
 
 
 
4 = Very Severe 
 
Frequency of Symptoms 
 
On average over the past day, how often have you had this level of ocular discomfort 
associated with dry eye (for example, dryness or irritation)? 
 
0 = Never 
 
1 = Sometimes 
 
2 = Often 
 
3 = Constantly 
 
 
 
 
  
 
 


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APPENDIX 3: 
 ASSESSMENT  
 
Subjects will be asked to subjectively rate their ocular discomfort severity and frequency at 
Visit 1 for eligibility.  
 
  The total length of the line from 
 
 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. 
 
 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: 
 
 
 
 
 
 
 
 
 
       
 
 
 
 
 
 
 
 
   
 
 
 
          
 
 
 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, 4, and 6 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  
• While still in the plastic sheath, fold the notched end of the unanesthetized Schirmer 
Test strip at the apex of “v”.  Additionally, fold a partial second fold at the halfway 
point of the strip so that the strip does not lie directly in the subject’s line of sight. 
• Remove the right eye strip from the sheath. 
• Ask the subject to look up and gently draw the right lower lid in a downward and 
temporal direction.  
• Place the rounded end of the strip toward the temporal one-third of the lower eyelid.  
• Repeat this procedure in the left eye. 
• Darken the room, but ensure that the Large E or the ETDRS chart is visible. 
• Instruct the subject to relax and look at the chart while blinking normally or have 
subject gently close eyes. 
• Strips are removed after 5 minutes. 
• After removing the strips, with a sharp pencil draw a horizontal line across the leading 
edge of moisture and a second horizontal line across the lowest point of moisture. 
• Using a ruler and/or the millimeters recorded on the strips, measure a point halfway 
between the 2 lines and record this as the amount of wetting. 
• Retain Schirmer strips in source documentation. 
 
 
 
 
 
 
 


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APPENDIX 6: BEST-CORRECTED VISUAL ACUITY 
 
BCVA will be conducted at Visits 1, 2, 4 and 6.   
 
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, 4 and 6.  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 the 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. 
 
Character of Meibomian Gland Content (middle part of lower lid, n = 10) 
0 = 
Normal 
Clear liquid 
1 =  Mild 
Hazy, turbid liquid 
2 =  Moderate 
Turbid liquid with clumps 
3 =  Severe 
Solid (paste) 
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 
 


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Edema  
 
     
 0 = Normal, no swelling of the lid tissue 
 
 
 1 = Abnormal 
 
Conjunctiva 
Edema   
    
  0 = Normal, no swelling of the conjunctiva 
 
 
  1 = Abnormal 
 
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. 
 
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, 4, and 6.  Corneal staining assessment will be 
performed using methods developed by the NEI Dry Eye Workshop5,6. 
 
Evaluation Technique 
1. Place magnification at 16x  
2. Use a yellow barrier filter (Wratten or Tiffen #11 or #12)  
3. Place 5 µl of non-preserved, 2% fluorescein into eye using a 2-20μl micropipette fitted 
with a clean pipette tip. 
4. Gently touch the drop at the tip to the lower palpebral conjunctiva of the right eye.  
5. In order to thoroughly mix the fluorescein with the tear film, ask the subject to blink 
several times and move his/her eye around.  
6. Wait 2.5 minutes to assess cornea 
7. Measure staining under Cobalt blue light (465 nm to 490 nm) 
8. Compare staining with standard with scoring in each of 5 areas of the 5 corneal 
sections as described below: 
 
Scoring system 
1. Grade each of 5 sections of cornea (superior, inferior, nasal, temporal, central) 
2. Provide grades for each of the 5 sections: 
a. Grade by NEI scale (definition below) as 0, 1 (mild), 2 (moderate), 3 (severe) 
3. Total score is obtained by summing each of the 5 sections of the cornea 
a. NEI score will be from 0-15 
4. Definitions 
a. NEI Scoring System (0, 1, 2, 3) 
i. Grade 0 
No visible staining within the section of cornea being evaluated 
ii. Grade 1 
MILD 
Small amount of micropunctate staining within the section of cornea 
being evaluated 
iii. Grade 2 
MODERATE 
Medium amount of micropunctate staining within the section of cornea 
being evaluated or mild amount of macropunctate stain 
iv. Grade 3 
SEVERE 
Significant amount of micopunctate  or macropunctate staining within 
the section of cornea being evaluated 
 
 
 


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APPENDIX 9: LISSAMINE GREEN CONJUNCTIVAL STAINING 
 
Lissamine Green staining will be performed at Visit 1, 2, 4, and 6.   
 
The conjunctiva will be stained with non-preserved, 1% lissamine green. When conducting all 
assessments room temperature and humidity should be relatively consistent throughout each 
visit and throughout the study. 
 
• Without flushing the eye from the previous assessment, instill a 20 µl drop of lissamine 
green to the right eye using a micropipette, allowing a drop to form. 
• Gently touch the drop at the tip of the delivery dropper to the lower palpebral 
conjunctiva of the right eye.    
• In order to thoroughly coat the ocular surface with the lissamine, ask the subject to 
blink several times and move his/her eye around. 
• After 1 minute and before 4 minutes have elapsed, using white light of moderate 
intensity, grade the areas of the conjunctiva of the right eye with the 0-3 scale shown 
below. 
• Staining induced by Schirmer Test strip should be excluded. 
• Repeat this procedure for the left eye. 
 
 
 
 
 
 
 
 
 


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APPENDIX 10: 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, 4, and 6. 
 
 
 
 


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APPENDIX 11: 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 6 after to 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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