Conditions: Post Surgical Ocular Inflammation and Pain
Keywords: postsurgical postoperative ocular cataract inflammation pain corticosteroid
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 520
Healthy volunteers: no

Brief summary:
The primary objective of the study is to investigate the efficacy and safety of KPI-121 1.0% ophthalmic suspension compared to placebo in subjects who have undergone cataract surgery.

Detailed description:
This is a Phase III, multicenter, double-masked, randomized, placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of KPI-121 1.0% ophthalmic suspension versus placebo in subjects who require treatment of postoperative anterior ocular inflammation.

Arms:
arm 1: dosed BID arm 2: dosed BID

Interventions: intervention 1: KPI-121 1% Ophthalmic Suspension dosed BID intervention 2: Vehicle of KPI-121 Ophthalmic Suspension dosed BID
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_002.pdf: 
NCT02793817  
 
Study ID:  
KPI-121-C-005  
 
Study Title:  
A Phase 3, Double-Masked, Randomized, Controlled Study to Evaluate the Safety 
and Efficacy of KPI-121 1.0% Ophthalmic Suspension in Subjects with Postsurgical 
Inflammation and Pain 
 
Date:  
24 Feb 2017 




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KALA PHARMACEUTICALS, INC. 
Clinical Protocol KPI-121-C-005  
Investigator Signature Page 
Project: 
KPI-121 
 
Compound Number/Name: 
KPI-121  
 
Protocol Number: 
KPI-121-C-005  
 
Protocol Title: 
A Phase 3, Double-Masked, Randomized, Controlled 
Study to Evaluate the Safety and Efficacy of KPI-121 
1.0% Ophthalmic Suspension in Subjects with 
Postsurgical Inflammation and Pain 
 
Sponsor: 
Kala Pharmaceuticals, Inc. 
 
100 Beaver St, Suite 201 
 
Waltham, MA 02453 
 
Issue Date: 
Original: 03 Feb 2016 
 
Amendment 01:  03 May 2016 
Amendment 02:  13 Jul 2016 
Amendment 03:  23 Aug 2016 
Amendment 04:  31 Jan 2017 
Amendment 05:  24 Feb 2017 
 
 
Contact for Serious Adverse Events:  
 
 
  
 
 
     
  
 
 
 
  
 
   
 
  
 
 
 
Investigator Name (printed or typed): 
 
________________________________________________ 
 
Investigator's Signature: 
 
_______________________________________________ ______________  
 
Date  
 


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SYNOPSIS  
Study Title: 
KPI-121-C-005:  A Phase 3, Double-Masked, Randomized, 
Controlled Study to Evaluate the Safety and Efficacy of KPI-121 
1.0% Ophthalmic Suspension in Subjects with Postsurgical 
Inflammation and Pain 
Objectives: 
The primary objective of the study is to investigate the efficacy and 
safety of KPI-121 1.0% ophthalmic suspension compared to 
placebo in subjects who have undergone cataract surgery.   
Study Population:  
The study population will consist of subjects who have undergone 
routine uncomplicated cataract surgery and experience ocular 
inflammation postoperatively.    
Number of 
Subjects: 
Approximately 720 subjects who are candidates for cataract surgery 
will be screened. One study eye from approximately 500 subjects 
will be randomized.  
Investigational 
Products: 
KPI-121 1.0% ophthalmic suspension or placebo will be supplied as 
investigational product. 
Route and Duration 
of Administration: 
1 to 2 drops of investigational product will be instilled in the study 
eye two times per day (BID) for 14 ± 1 days. 
Study Design:   
 
This is a Phase 3, multicenter, double-masked, randomized, 
placebo-controlled, parallel-group study designed to evaluate the 
efficacy and safety of KPI-121 1.0% ophthalmic suspension versus 
placebo in subjects who require treatment of postoperative anterior 
ocular inflammation. Approximately 720 subjects who are 
candidates for cataract surgery will be screened and approximately 
500 subjects who, after undergoing routine, uncomplicated cataract 
surgery, present at Visit 3 (Day 1) with ≥ 2 anterior chamber cells in 
the study eye will be randomized in this study at approximately 35 
centers located in the United States (US). Subjects who experience 
postoperative inflammation on the first day following routine, 
uncomplicated, cataract surgery and who meet all other eligibility 
criteria will be randomized to one of two study groups in an 
approximate 1:1 ratio to KPI-121 1.0% ophthalmic suspension 
dosed BID or placebo dosed BID. Investigational product or 
placebo will be initiated on the day following surgery and instilled 
as one to two drops in the study eye BID for 14 ± 1 days.   
 


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This study will include up to 7 clinic visits (including the surgery 
day) over 18 to 33 days total study duration. Visit 1 (Screening) will 
occur between 14 to 1 day(s) prior to surgery, and subjects who 
meet preoperative screening inclusion/exclusion criteria will be 
entered into the study. At Visit 2 (Surgery/Day 0) subjects will 
undergo routine cataract surgery according to the Investigator’s 
normal procedures.  Visit 3 (Randomization/Day 1) will occur on 
the day following surgery. Subjects who meet the qualifying 
postoperative randomization criteria will be eligible for 
randomization to one of the two study groups and will initiate 
investigational product on that day. Following randomization, 
subjects will be instructed to return to the clinic to be evaluated at 
Visit 4 (Day 4 ± 1 day), Visit 5 (Day 8 ± 1 day), and Visit 6 (Day 15 
± 1 day). The last dose of investigational product will be 
administered upon completion of 14 days of evaluation.  Following 
the End of Investigational Product Use Visit (Visit 6; Day 15 ± 1 
day), subjects will be asked to return to the clinic on Day 18 ± 1 day 
for Visit 7 (Follow-Up) and will be released from the study.  
 
Assessments in this study will include: 
 
 
Subject-Rated Ocular Pain assessment 
 
Snellen Distance Visual Acuity (VA) by Pinhole Method  
 
Slit Lamp Biomicroscopy: 
o Signs of anterior ocular inflammation (cell and flare 
grading) 
o Palpebral conjunctival erythema, corneal edema, 
hyphema, ciliary flush, bulbar conjunctival injection  
 
Intraocular Pressure (IOP) Measurement 
 
Dilated Ophthalmoscopy  
 
Rescue Therapy Assessment 
 
Concomitant Medication Use Assessment  
 
Assessments of Adverse Events (AEs) 
Efficacy 
Endpoint 
Primary Efficacy Endpoints: 
 
The primary endpoints of this study will be evaluated using 
hierarchical statistical testing in the following sequence:  
 
1. Proportion of study eyes with complete resolution of anterior 


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chamber cells (grade = 0) at Visit 5 (Day 8 ± 1 day) maintained 
through Visit 6 (Day 15 ± 1 day) without receiving rescue 
medication prior to Visit 6 (Day 15 ± 1 day) as compared 
between KPI-121 1.0% ophthalmic suspension dosed BID and 
placebo dosed BID. 
2. Proportion of study eyes with complete resolution of ocular pain 
(grade = 0) at Visit 5 (Day 8 ± 1 day) maintained through Visit 
6 (Day 15 ± 1 day) without receiving rescue medication prior to 
Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% 
ophthalmic suspension dosed BID and placebo dosed BID. 
 
Secondary Efficacy Endpoints: 
 
1. Proportion of study eyes with complete resolution of ocular pain 
(grade = 0) at Visit 4 (Day 4 ± 1 day) maintained through Visit 
6 (Day 15 ± 1 day) without receiving rescue medication prior to 
Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% 
ophthalmic suspension dosed BID and placebo dosed BID.  This 
endpoint will be tested at  = 0.0167. 
2. Proportion of study eyes with complete resolution of anterior 
chamber flare (grade = 0) at Visit 4 (Day 4 ± 1 day) maintained 
through Visit 6 (Day 15 ± 1 day) without receiving rescue 
medication prior to Visit 6 (Day 15 ± 1 day) as compared 
between KPI-121 1.0% ophthalmic suspension dosed BID and 
placebo dosed BID.  This endpoint will be tested at  = 0.0167. 
3. Change from baseline in mean anterior chamber cell count at 
Visit 4 (Day 4 ± 1 day) as compared between KPI-121 1.0% 
ophthalmic suspension dosed BID and placebo dosed BID.  This 
endpoint will be tested at  = 0.0167.  
Safety Endpoints 
Assessment of AEs 
Snellen Distance VA by Pinhole Method  
Slit Lamp Biomicroscopy 
IOP measurement 
Dilated Ophthalmoscopy 
Change from baseline to each post-surgery visit in ocular signs: 
 Palpebral conjunctival erythema 
 Corneal edema 
 Hyphema 
 Ciliary flush 


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 Bulbar conjunctival injection 
Eligibility Criteria: 
Inclusion Criteria: 
 
At Visit 1, 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. 
4. Are candidates for routine, uncomplicated cataract surgery 
[e.g., phacoemulsification with posterior chamber intraocular 
lens (IOL) implantation, not combined with any other surgery]. 
5. In the Investigator’s opinion, have potential postoperative 
Snellen Distance VA by pinhole method of at least 20/200 in 
the study eye. 
6. Are women of child bearing potential (WOCBP) who are not 
pregnant or lactating and not sexually active (i.e., abstinent) for 
14 days prior to Visit 1 and are 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 one of the following acceptable methods of birth control 
for the times specified:  
a. Intrauterine device (IUD) in place for at least three 
months prior to Visit 1 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 three 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 


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following last administration of the investigational 
product, whichever period of time is longer. 
c. Stable hormonal contraceptive for at least  
three 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.  
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 for at least six 
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.  
7. Are postmenopausal women who have had no menstrual cycle 
for at least one year prior to Visit 1 or are women who have 
undergone one 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 they may not: 
1. 
Require concurrent ocular therapy (either eye) with 
nonsteroidal anti-inflammatory drugs (NSAIDs), mast cell 
stabilizers, antihistamines, or decongestants within 2 days prior 
to surgery and for the duration of the study. 
2. 
Require treatment with systemic NSAIDs, with the exception 
of ≤ 81 mg/day of acetylsalicylic acid (ASA or aspirin), within 
2 days prior to surgery and for the duration of the study. 


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3. 
Require treatment with systemic (except stable maintenance 
dose of inhaled or intranasal corticosteroids) or ocular (either 
eye) corticosteroids (other than investigational product) within 
14 days prior to cataract surgery and for the duration of the 
study. 
4. 
Require concurrent systemic or ocular therapy with 
immunosuppressants (with the exception of oral corticosteroids 
less than prednisone 11 mg/day or equivalent) within 30 days 
prior to surgery and for the duration of the study. 
5. 
Require change in treatment with anticholinergics or oral 
corticosteroids (dose must be less than prednisone 11 mg/day 
or equivalent) within six months prior to Visit 1. 
6. 
Require change in stable treatment with antidepressants within 
6 months prior to Visit 1. 
7. 
Require change in use of nutraceuticals or multivitamins 
during trial participation. 
8. 
Have known hypersensitivity or contraindication to the 
investigational product(s) or their components. 
9. 
Use any topical ophthalmic medications including glaucoma 
medications, all eye drops (except antibiotic eye drops 
considered to be included in post cataract surgery standard of 
care treatment), all gels or artificial tears within 2 days prior to 
surgery and for the duration of the study.  Note:  Besifloxacin 
Ophthalmic Suspension is not permitted within 2 days prior to 
surgery or for the duration of the study. 
10.  Use any topical eyelash growth medications within 7 days 
prior to surgery and for the duration of the study. 
11. Have history of glaucoma, IOP >21 mmHg at the screening or 
randomization visit(s), or are being treated for glaucoma in 
either eye. 
12. Wear contact lenses for 4 weeks prior to Visit 1 and throughout 
the study. 
13. Be monocular or have Snellen Distance VA by pinhole method 
of 20/200 or worse in the non-study eye. 
14. Have had penetrating intraocular surgery in the study eye 
within 3 months or within two weeks in the fellow eye.   
15. Have had corneal refractive surgery or corneal transplantation 
(full thickness, anterior, or posterior) within the past year or 
are unstable and/or require medication. 
16. Have a diagnosis of: 


KPI-121-C-005 CLINICAL PROTOCOL INCORPORATING AMENDMENT 05 FINAL 
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a. 
Ongoing ocular infection. 
b. 
Severe/serious ocular condition that in the judgment of the 
Investigator could confound study assessments or limit 
compliance. 
c. 
Severe/serious systemic disease or uncontrolled medical 
condition that in the judgment of the Investigator could 
confound study assessments or limit compliance. 
17. Have been exposed to an investigational drug within 30 days 
prior to screening or up to 18 days following surgery. 
18. 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. 
19. Have a known history of alcohol and/or drug abuse. 
20. 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.  
 
Randomization Criteria: 
 
To qualify for randomization at Visit 3 (Postoperative Day 1), a 
subject must: 
 
1. Have undergone routine, uncomplicated cataract surgery (e.g., 
phacoemulsification with posterior chamber IOL implantation, 
not combined with any other surgery). 
2. Have ≥ Grade 2 anterior chamber cells. 
3. Continue to meet inclusion/exclusion criteria with respect to 
current ocular and medical conditions (Sections 4.1 and 4.2), 
and must not have taken prohibited medications (Section 
6.2.2). 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 15 
1. 
INTRODUCTION ................................................................................... 17 
1.1. 
DESCRIPTION OF INVESTIGATIONAL PRODUCT .......................................... 18 
1.2. 
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION .. 19 
1.3. 
GCP COMPLIANCE .................................................................................... 19 
1.4. 
POPULATION TO BE STUDIED..................................................................... 19 
2. 
TRIAL OBJECTIVES AND PURPOSE ................................................. 20 
2.1. 
OBJECTIVE ................................................................................................ 20 
3. 
TRIAL DESIGN ...................................................................................... 21 
3.1. 
PRIMARY EFFICACY ENDPOINTS ............................................................... 21 
3.2. 
SECONDARY EFFICACY ENDPOINTS .......................................................... 21 
3.3. 
SAFETY ENDPOINTS .................................................................................. 21 
3.4. 
DESCRIPTION OF TRIAL DESIGN ................................................................ 22 
3.4.1. 
Investigational Product ............................................................................ 24 
3.4.2. 
Methods to Minimize Bias ....................................................................... 26 
4. 
SELECTION OF SUBJECTS.................................................................. 27 
4.1. 
SUBJECT INCLUSION CRITERIA .................................................................. 27 
4.2. 
SUBJECT EXCLUSION CRITERIA ................................................................ 28 
4.3. 
RANDOMIZATION CRITERIA ...................................................................... 30 
5. 
PROCEDURES........................................................................................ 31 
5.1. 
VISIT DESCRIPTIONS ................................................................................. 31 
5.1.1. 
Visit 1:  Screening Visit (Day -14 to Day -1) .......................................... 31 
5.1.2. 
Visit 2:  Surgery Visit (Day 0) ................................................................. 31 
5.1.3. 
Visit 3:  Randomization Visit (Day 1) ..................................................... 32 
5.1.4. 
Visit 4:  Study Visit (Day 4 ± 1 day) ....................................................... 33 
5.1.5. 
Visit 5:  Study Visit (Day 8 ± 1 day) ....................................................... 34 
5.1.6. 
Visit 6:  End of Investigational Product Use (Day 15 ± 1 day) ............... 34 
5.1.7. 
Visit 7:  Follow-Up Visit (Days 18 ± 1 day) ........................................... 35 
5.1.8. 
Early Termination Visit ........................................................................... 35 
5.2. 
SUBJECT WITHDRAWAL AND/OR DISCONTINUATION ................................ 36 
5.3. 
COLLECTION OF DATA .............................................................................. 37 


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5.3.1. 
Unscheduled Visit .................................................................................... 37 
5.4. 
RESCUE MEDICATION USE ........................................................................ 37 
6. 
TREATMENT OF SUBJECTS ............................................................... 38 
6.1. 
INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED ................................ 38 
6.2. 
CONCOMITANT MEDICATIONS .................................................................. 38 
6.2.1. 
Permitted Medications ............................................................................. 38 
6.2.2. 
Medications Not Permitted ...................................................................... 39 
6.3. 
STUDY PRODUCT USE COMPLIANCE ......................................................... 40 
6.4. 
DRUG ACCOUNTABILITY ........................................................................... 40 
6.5. 
MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING THE 
CODE ........................................................................................................ 40 
7. 
ASSESSMENT OF EFFICACY ............................................................. 42 
8. 
ASSESSMENT OF SAFETY .................................................................. 43 
8.1. 
SAFETY PARAMETERS ............................................................................... 43 
8.2. 
ADVERSE EVENT DEFINITIONS.................................................................. 43 
8.3. 
PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR ........................ 45 
8.4. 
SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR ................. 45 
9. 
STATISTICS ........................................................................................... 48 
9.1. 
STATISTICAL METHODS ............................................................................ 48 
9.1.1. 
Subject Disposition, Demographic and Background Characteristics ...... 48 
9.1.2. 
Analysis of Efficacy ................................................................................. 48 
9.1.3. 
Analysis of Safety .................................................................................... 49 
9.2. 
SAMPLE SIZE ESTIMATION ........................................................................ 49 
9.3. 
LEVEL OF SIGNIFICANCE ........................................................................... 50 
9.4. 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS 
DATA ........................................................................................................ 50 
9.5. 
PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL PLAN 50 
9.6. 
SUBJECTS TO BE INCLUDED IN THE ANALYSIS ........................................... 50 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................... 51 
11. 
QUALITY CONTROL ............................................................................ 52 
12. 
ETHICS.................................................................................................... 53 
12.1. 
Institutional Review Board ...................................................................... 53 
12.2. 
Informed Consent Requirements ............................................................. 53 


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13. 
DATA HANDLING AND RECORDKEEPING .................................... 54 
13.1. 
Data Quality Control and Reporting ........................................................ 54 
13.2. 
Records Retention .................................................................................... 54 
14. 
PUBLICATION POLICY ....................................................................... 55 
15. 
REFERENCES ........................................................................................ 56 
16. 
APPENDICES ......................................................................................... 57 
 


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LIST OF TABLES 
 
TABLE 1: 
COMPOSITION OF KPI-121 1.0% (W/V) INVESTIGATIONAL PRODUCT ........ 25 
TABLE 2: 
COMPOSITION OF PLACEBO ....................................................................... 25 


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LIST OF FIGURES 
FIGURE 1: STUDY SCHEMATIC ................................................................................... 24 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
Adverse Event 
ASA 
Acetylsalicylic Acid 
BID 
Twice Daily 
C 
Degrees Celsius 
CME 
Cystoid Macular Edema 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
EE 
Efficacy Evaluable 
eCRF 
Electronic Case Report Form 
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 
IOL 
Intraocular Lens 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IUD 
Intrauterine device 
KPI 
Kala Pharmaceuticals, Inc. 
LE 
Loteprednol etabonate 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg  
Milligram 
mL  
Milliliter 
mm 
Millimeter 
mmHg 
Millimeter of Mercury 
MAR 
Missing at random 
MPP 
Mucus Penetrating Particles 
NDA 
New Drug Application 
NSAIDs 
Non-steroidal Anti-inflammatory Drugs 
OTC 
Over the Counter 
PDF 
Portable Document Format 
pH 
Potential Hydrogen 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SLT 
Selected Laser Trabeculoplasty 
TNF 
Tumor Necrosis Factor 


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UPT  
Urine Pregnancy Test 
US 
United States of America 
VA 
Visual Acuity 
WOCBP 
Women of Child Bearing Potential 
w/v 
Weight to Volume 


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1. 
INTRODUCTION 
 
Intraocular inflammation is an anticipated sequela of intraocular surgery such as cataract 
removal and intraocular lens (IOL) placement. In general, trauma to the internal structures of 
the eye is accompanied by the production of prostaglandins and other vasoactive moieties, an 
increase in blood flow to the affected area, and extravasations of protein and cellular blood 
elements. Postoperative inflammation is manifested principally as bulbar erythema, corneal 
edema, ciliary flush and aqueous cells and flare.   
 
If left untreated, inflammation generally resolves within 2 to 4 weeks after surgery; however 
20% to 80% of patients present with anterior chamber cells and/or flare 2 weeks after cataract 
surgery and IOL placement. Since untreated intraocular inflammation following cataract 
surgery may lead to complications such as cystoid macular edema (CME) (Apple et al., 1992; 
Tennant, 1978 ), treatment with anti-inflammatory agents such as glucocorticosteroids is 
employed to reduce pain and discomfort, and to facilitate recovery of the blood-aqueous 
barrier. When administered at the time of surgery and during the immediate postoperative 
period, glucocorticosteroids can reverse the clinical and non-clinical manifestations of 
inflammation (Leopold, 1985). In the United States (US), topical glucocorticosteroids are 
routinely prescribed for at least 2 weeks following cataract surgery, with longer treatment 
prescribed in cases of severe or unremitting inflammation.   
 
Loteprednol etabonate (LE) is an ester corticosteroid that is rapidly metabolized to inactive 
metabolites, and has been reported to have fewer side effects than traditional 
glucocorticosteroids. Loteprednol etabonate was approved by Food and Drug Administration 
(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 
postoperative ocular inflammation. Despite its attractive pharmacologic activity, wherein the 
drug is active at the site of administration but is rapidly metabolized to an inactive compound 
following absorption, Lotemax requires frequent dosing (four times per day) which may 
reduce patient compliance.  
 
Kala Pharmaceuticals, Inc. has developed an improved formulation of loteprednol etabonate, 
designated as 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 loteprednol etabonate formulated with excipients present in other FDA-approved 
ophthalmic investigational 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 


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24 FEB 2017 
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pharmacokinetic profile has the potential to reduce either dosing strength or frequency of 
loteprednol etabonate as compared to Lotemax.  
 
Kala Pharmaceuticals, Inc. intends to develop KPI-121 for the treatment of postoperative 
inflammation and pain following ocular surgery.  
 
1.1. 
DESCRIPTION OF INVESTIGATIONAL PRODUCT 
 
KPI-121 contains submicron particles of loteprednol etabonate suspended in a formulation 
consisting of excipients that have been used in other FDA-approved ophthalmic products.  
Kala is developing this improved loteprednol etabonate formulation for the treatment of 
postoperative anterior segment inflammation and pain. 
 
KPI-121 is a sterile, aqueous submicron suspension of loteprednol etabonate and will be filled 
in a white, low-density polyethylene plastic bottle with a translucent, controlled-drop 
polypropylene tip,  a pink polypropylene cap and a white polyethylene tamper-evident 
overcap. The bottle will be a 5 mL dropper bottle with a nominal fill of 3.2 mL. 
 
For this trial, KPI-121 investigational product will be supplied as 1.0% ophthalmic 
suspension.  Each mL of KPI-121 1.0% ophthalmic suspension contains 10 mg loteprednol 
etabonate as the active ingredient.  Inactive ingredients in KPI-121 investigational product are 
 
  
 as 
preservative.  KPI-121 1.0% ophthalmic suspension is essentially isotonic and is buffered to 
maintain a power of hydrogen (pH) of 5.0 – 7.0. 
 
The placebo control has the same excipient composition as KPI-121 1.0%  ophthalmic 
suspension but does not contain loteprednol etabonate. The placebo control contains 
 
  
 as 
preservative. The placebo control is essentially isotonic and buffered to maintain pH 5.0 – 7.0.  
It is a sterile, aqueous solution supplied in the same white, low-density polyethylene plastic 
bottle with the same translucent, controlled-drop polypropylene tip, pink polypropylene cap 
and white polyethylene tamper-evident overcap as KPI-121 1% ophthalmic suspension 
investigational product. 
 
 
 


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1.2. 
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION 
 
KPI-121 1.0% will be administered as a topical ophthalmic suspension.  
 
Subjects are expected to self-administer one to two drops of either KPI-121 1.0% ophthalmic 
suspension or placebo control BID. 
 
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 
effect and tolerability for 14 days of KPI-121 1.0% ophthalmic suspension dosed BID.  
 
For additional details on the toxicology studies and the respective safety multiples, see the 
Investigator’s Brochure.  
 
1.3. 
GCP COMPLIANCE  
 
This clinical trial will be conducted in compliance with the protocol, International Conference 
on Harmonization (ICH) guidelines, Good Clinical Practices (GCP) guidelines and other 
applicable regulatory requirements. 
 
 
1.4. 
POPULATION TO BE STUDIED 
 
Approximately 720 subjects who are candidates for cataract surgery will be screened. One 
study eye from approximately 500 subjects who have undergone routine, uncomplicated 
cataract surgery and have ≥ 2 anterior chamber cells in the study eye at Visit 3 (Day 1) will be 
evaluated at approximately 35 centers located in the US. 


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2. 
TRIAL OBJECTIVES AND PURPOSE 
2.1. 
OBJECTIVE 
 
The primary objective of this study is to investigate the safety and efficacy of KPI-121 1.0% 
ophthalmic suspension compared to placebo in subjects who have undergone cataract surgery.    
 


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3. 
TRIAL DESIGN 
3.1. 
PRIMARY EFFICACY ENDPOINTS 
 
The primary endpoints of this study will be evaluated using hierarchical statistical testing in 
the following sequence:  
 
1. Proportion of study eyes with complete resolution of anterior chamber cells (grade = 0) at 
Visit 5 (Day 8 ± 1 day) maintained through Visit 6 (Day 15 ± 1 day) without receiving 
rescue medication prior to Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% 
ophthalmic suspension dosed BID and placebo dosed BID. 
 
2. Proportion of study eyes with complete resolution of pain (grade = 0) at Visit 5 (Day 8 ± 1 
day) maintained through Visit 6 (Day 15 ± 1 day) without receiving rescue medication 
prior to Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% ophthalmic 
suspension dosed BID and placebo dosed BID. 
 
3.2. 
SECONDARY EFFICACY ENDPOINTS 
 
1. Proportion of study eyes with complete resolution of ocular pain (grade = 0) at Visit 4 
(Day 4 ± 1 day) maintained through Visit 6 (Day 15 ± 1 day) without receiving rescue 
medication prior to Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% 
ophthalmic suspension dosed BID and placebo dosed BID.  This endpoint will be tested at 
 = 0.0167. 
2. Proportion of study eyes with complete resolution of anterior chamber flare (grade = 0) at 
Visit 4 (Day 4 ± 1 day) maintained through Visit 6 (Day 15 ± 1 day) without receiving 
rescue medication prior to Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% 
ophthalmic suspension dosed BID and placebo dosed BID.  This endpoint will be tested at 
 = 0.0167. 
3. Change from baseline in mean anterior chamber cell count at Visit 4 (Day 4 ± 1 day) as 
compared between KPI-121 1.0% ophthalmic suspension dosed BID and placebo dosed 
BID.  This endpoint will be tested at  = 0.0167. 
 
3.3. 
SAFETY ENDPOINTS 
 
 Assessment of AEs 
 Snellen Distance VA by pinhole method  
 Slit Lamp Biomicroscopy  
 IOP Measurement 
 Dilated Ophthalmoscopy 
 Change from baseline to each post-surgery visit in ocular signs: 


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o Palpebral conjunctival erythema 
o Corneal edema 
o Hyphema 
o Ciliary flush 
o Bulbar conjunctival injection 
 
3.4. 
DESCRIPTION OF TRIAL DESIGN 
 
This is a Phase 3, multicenter, double-masked, randomized, placebo-controlled, parallel-group 
study designed to evaluate the safety and efficacy of KPI-121 1.0% ophthalmic suspension 
versus placebo in subjects who require treatment of postoperative anterior ocular 
inflammation. Approximately 720 subjects who are candidates for cataract surgery will be 
screened and approximately 500 subjects who, after undergoing routine, uncomplicated 
cataract surgery, present at Visit 3 (Day 1) with ≥ 2 anterior chamber cells in the study eye 
will be randomized in this study at approximately 35 centers located in the US.   
 
Subjects who experience postoperative inflammation on the first day following routine, 
uncomplicated, cataract surgery and who meet all other eligibility criteria will be randomized 
to one of two study groups in an approximate 1:1 ratio:  
 
 KPI-121 1.0% ophthalmic suspension, BID   
 Placebo, BID  
 
Dosing of investigational product will be initiated on the day following surgery, instilled as 1-
2 drops in the study eye BID for 14 ± 1 days. The first dose of investigational product will be 
administered by the subject under the supervision of a designated study team member who is 
otherwise uninvolved in the assessment or evaluation of the subject.  Except for this 
investigational product administration, no other information or discussion regarding the 
subject’s assigned investigational product will be exchanged, in order to maintain the masking 
for this trial. 
 
This study will include up to 7 clinic visits (including the surgery day) over 18 to 33 days 
total study duration. Visit 1 (Screening) will occur between 14 to 1 day(s) prior to surgery and 
subjects who meet preoperative screening inclusion/exclusion criteria will be entered into the 
study. At Visit 2 (Surgery/Day 0), subjects will undergo routine cataract surgery according to 
the Investigator’s normal procedures. Visit 3 (Randomization/Day 1) will occur on the day 
following surgery. Subjects who meet the qualifying postoperative randomization criteria will 
be eligible for randomization to one of the two study groups and will initiate dosing with 
investigational product on that day. Following randomization, subjects will be instructed to 
instill investigational product in the study eye two times a day (BID) for 14 ± 1 days, up until 


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Visit 6, and return to the clinic to be evaluated at Visit 4 (Day 4 ± 1 day), Visit 5 (Day 8 ± 1 
day), and Visit 6 (Day 15 ± 1 day/ End of Investigational Product Use Visit). Subjects will be 
asked to return to the clinic for Visit 7 (Day 18 ± 1 day) for follow-up and then will be 
released from the study.  
 
 
 


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A summary of events is provided in Appendix 1.  Procedures and assessments in this study 
will include:  
 
 Routine uncomplicated cataract surgery 
 Subject-Rated Ocular Pain Assessment (Appendix 2) 
 Snellen Distance VA by Pinhole Method (Appendix 3) 
 Slit Lamp Biomicroscopy (Appendix 4): 
o Signs of anterior ocular inflammation (cell and flare grading) 
o Palpebral conjunctival erythema, corneal edema, hyphema, ciliary flush, 
bulbar conjunctival injection  
 IOP Measurement (Appendix 5) 
 Dilated Ophthalmoscopy (Appendix 6) 
 Rescue Therapy Assessment 
 Concomitant Medication Use Assessment  
 Dosing Compliance Assessment 
 Assessments of AEs 
 
A study schematic follows (Figure 1). 
 
                 Screening 
              (All Subjects) 
KPI-121 1.0% Ophthalmic 
Suspension BID 
(175 Subjects) 
KPI-121 Placebo BID 
(175 Subjects) 
 
    
-14 to - 1 Days prior to Day 0 
Day 0 Day 1 
Day 4 ± 1 Day 8 ± 1 
Day 15 ± 1 
Day 18 ± 1 
  Visit 1 
 Visit 2 Visit 3 
 Visit 4 
Visit 5 
Visit 6 
Visit 7 
 
 
Screening  
 
Surgery 
Random- Study Visit 
Study Visit  
End of Use Visit  Follow-Up 
 
 
 
ization 
 
FIGURE 1: STUDY SCHEMATIC 
 
3.4.1. 
Investigational Product 
 
KPI-121 1.0% w/v will be supplied as a suspension in opaque dropper bottles.  KPI-121 1.0% 
ophthalmic suspension is a sterile, aqueous, submicron suspension of LE and will be supplied 
in a 5 mL, white, low-density polyethylene plastic dropper bottle with a translucent, 


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controlled-drop polypropylene tip, a pink polypropylene cap and a white polyethylene 
tamper-evident overcap. Each bottle contains 3.2 mL (nominal fill) of investigational product. 
 
Subjects randomized to the placebo control arm will receive the same bottles containing all 
components at the concentrations used in the KPI-121 1.0% ophthalmic suspension with the 
exception of the active component, LE.   
 
Subjects will be instructed to shake the investigational product bottle prior to each instillation.   
  
TABLE 1: 
COMPOSITION OF KPI-121 1.0% (W/V) INVESTIGATIONAL PRODUCT 
Ingredient 
Function 
Concentration 
(% w/v) 
Loteprednol etabonate 
Active pharmaceutical 
ingredient 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE 2: 
COMPOSITION OF PLACEBO  
Ingredient 
Function 
Concentration 
(% w/v) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The randomized investigational product kit consists of a box with two dropper bottles of 
investigational product.  At Visit 3, eligible subjects will receive one bottle of investigational 
product.  The second bottle will be retained at the site and provided to the subject in the event 


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the subject needs additional investigational product during the treatment period.  Both the box 
label and dropper bottle labels will contain the following information: sponsor name, protocol 
and randomization number, storage temperature and required statement(s) per the appropriate 
regulatory agency.   
 
The investigational product will be stored in a secure area with limited access at 15-25C/59 -
77F with upper limit excursions to 30C /86F allowed.   Subjects will be instructed to shake 
the investigational product bottle prior to administering each dose.  On days when subjects 
receive the first dose in the clinic (Visit 3), the in-clinic dose will count as one of their two 
(BID) daily doses. Subjects will then self-administer an additional dose of investigational 
product later that day. Visit 3 should be scheduled in the morning to allow subjects to receive 
a full day of BID dosing. 
 
On all other study evaluation days, subjects will be asked to instill one “Morning Dose” and 
one “Evening Dose” approximately 12 hours following the previous dose.  
 
3.4.2. 
Methods to Minimize Bias 
 
To minimize bias, the following measures will be taken: 
 
 Investigational product assignment (KPI-121 1.0% ophthalmic suspension 
versus placebo) will be randomized and masked to the sponsor, subjects, and 
select investigative staff.   
 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 CRITERIA 
 
At Visit 1, 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. 
4. Are candidates for routine, uncomplicated cataract surgery (e.g., 
phacoemulsification with posterior chamber IOL implantation, not combined 
with any other surgery). 
5. In the Investigator’s opinion, have potential postoperative Snellen Distance 
VA by pinhole method of at least 20/200 in the study eye. 
6. 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 
one of the following acceptable methods of birth control for the times 
specified:  
a. IUD in place for at least three months prior to Visit 1 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 three 
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 last administration of the investigational product, 
whichever period of time is longer. 
c. Stable hormonal contraceptive for at least three 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.  
NOTE: For Depo-Provera injection contraceptives, the statement 
regarding first menstrual cycle following administration of the 


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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 six 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. 
7. Are postmenopausal women who have had no menstrual cycle for at least one 
year prior to Visit 1 or are women who have undergone one 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 
 
4.2. 
SUBJECT EXCLUSION CRITERIA 
 
In order for subjects to be eligible at Visit 1 they may not: 
 
1. Require concurrent ocular therapy (either eye) with nonsteroidal anti-
inflammatory drugs (NSAIDs), mast cell stabilizers, antihistamines, or 
decongestants within 2 days prior to surgery and for the duration of the study. 
2. Require treatment with systemic NSAIDs, with the exception of ≤ 81 mg/day 
of acetylsalicylic acid (ASA or aspirin), within 2 days prior to surgery and for 
the duration of the study. 
3. Require treatment with systemic (except stable maintenance dose of inhaled or 
intranasal corticosteroids) or ocular (either eye) corticosteroids (other than 
investigational product) within 14 days prior to cataract surgery and for the 
duration of the study. 
4. Require concurrent systemic or ocular therapy with immunosuppressants (with 
the exception of oral corticosteroids less than prednisone 11 mg/day or 
equivalent) within 30 days prior to surgery and for the duration of the study. 
5. Require change in treatment with anticholinergics or oral corticosteroids (dose 
must be less than prednisone 11 mg/day or equivalent) within six months prior 
to Visit 1. 
6. Require change in stable treatment with antidepressants within 6 months prior 
to Visit 1. 
7. Require change in use of nutraceuticals or multivitamins during trial 
participation. 


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8. Have known hypersensitivity or contraindication to the investigational 
product(s) or their components. 
9. Use any topical ophthalmic medications including glaucoma medications, all 
eye drops (except antibiotic eye drops considered to be included in post 
cataract surgery standard of care treatment), all gels or artificial tears within 2 
days prior to surgery and for the duration of the study.   
NOTE:  Besifloxacin Ophthalmic Suspension is not permitted within 2 days 
prior to surgery or for the duration of the study. 
10. Use any topical eyelash growth medications within 7 days prior to surgery and 
for the duration of the study. 
11. Have history of glaucoma, IOP >21 mmHg at the screening or randomization 
visit(s), or are being treated for glaucoma in either eye. 
12. Wear contact lenses for 4 weeks prior to Visit 1 and throughout the study. 
13. Be monocular or have Snellen Distance VA by pinhole method of 20/200 or 
worse in the non-study eye. 
14. Have had penetrating intraocular surgery in the study eye within 3 months or 
within two weeks in the fellow eye.   
15. Have had corneal refractive surgery or corneal transplantation (full thickness, 
anterior, or posterior) within the past year or are unstable and/or require 
medication. 
16. Have a diagnosis of: 
a. Ongoing ocular infection. 
b. Severe/serious ocular condition that in the judgment of the Investigator 
could confound study assessments or limit compliance. 
c. Severe/serious systemic disease or uncontrolled medical condition that in 
the judgment of the Investigator could confound study assessments or limit 
compliance. 
17. Have been exposed to an investigational drug within 30 days prior to screening 
or up to 18 days following surgery. 
18. 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. 
19. Have a known history of alcohol and/or drug abuse. 
20. 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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4.3. 
RANDOMIZATION CRITERIA 
 
To qualify for randomization at Visit 3 (Postoperative Day 1), a subject must: 
 
1. Have undergone routine, uncomplicated cataract surgery (e.g., 
phacoemulsification with posterior chamber IOL implantation, not combined 
with any other surgery). 
2. Have ≥ Grade 2 anterior chamber cells. 
3. Continue to meet inclusion/exclusion criteria with respect to current ocular and 
medical conditions (Section 4.1 and Section 4.2), and must not have taken 
prohibited medications (Section 6.2.2). 
 


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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 DESCRIPTIONS 
5.1.1. 
Visit 1:  Screening Visit (Day -14 to Day -1) 
 
The screening visit will occur no more than 14 days and no less than one (1) day prior to Visit 
2/Surgery. After obtaining written informed consent and HIPAA authorization, site staff will 
perform/assess the following in the order suggested below:  
 
 Assign each subject screened a Subject Identification (ID) consisting of a 
three-digit Investigator number plus a three-digit number starting with number 
501. The Subject ID will be used as the primary subject identifier for the 
duration of the study. 
 Perform the following assessments/collect the following information (NOTE:  
All ocular assessments must be performed in both eyes): 
o Non-ocular and ocular medical history 
o Concomitant medication usage and medications taken during the 30 days 
prior to screening will be captured in the case report form (CRF) 
o Inclusion/exclusion criteria  
o Urine pregnancy test (UPT) for women of childbearing potential 
o Snellen Distance VA by pinhole method 
o Slit Lamp Biomicroscopy: 
 Signs of anterior ocular inflammation (cell and flare grading) 
 Palpebral conjunctival erythema, corneal edema, hyphema, ciliary 
flush, bulbar conjunctival injection  
o IOP Measurement 
o Dilated Ophthalmoscopy 
 Schedule subjects to return for surgery (Visit 2) in no more than 14 ± 1 day. 
 
5.1.2. 
Visit 2:  Surgery Visit (Day 0) 
 
Pre-surgical Procedures: 
 
This visit will occur no more than 15 days and no less than 1 day after Visit 1 and the 
following will be performed/assessed: 
 
 Use of any concomitant medications since the last visit 


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 Occurrence of any AEs since the last visit 
 Routine pre-surgical care and procedures as determined by the Investigator 
 
Surgical Procedure  
 
The surgeon will perform his or her routine cataract surgical procedure. The surgeon’s usual 
pre-operative sterile scrub and draping procedures should be performed. 
 
Post-Surgical Procedures  
 
 Assess the occurrence of any AEs.   
NOTE:  Changes that are expected due to uncomplicated cataract surgery will 
not be classified as AEs. 
 Provide instructions regarding routine post-surgical care and instructions. 
 Medications routinely administered prior to and following cataract surgery will 
be collected in the source documents. These medications will be indicated for 
routine cataract surgery and are not expected to be associated with treatment 
for AEs unless otherwise indicated. 
 Schedule the subject to return to the clinic on the following day (Day 1) for 
Visit 3. 
 
5.1.3. 
Visit 3:  Randomization Visit (Day 1) 
 
The randomization visit will occur 1 day after Visit 2/Surgery Visit. This visit should be 
scheduled in the morning (if possible) to allow for administration of two doses of 
investigational product during the day for eligible subjects.   
 
Eligible subjects who meet the randomization criteria (Section 4.3) will continue in the study.   
 
The following will be performed/assessed (NOTE:  All ocular assessments must be 
performed in both eyes):  
 
 Obtain Subject-Rated Ocular Pain Assessment 
 Review use of any concomitant medications since the last visit 
 Assess occurrence of any AEs since the last visit (NOTE: Expected changes or 
the presence of inflammation resulting from routine uncomplicated cataract 
surgery will not be captured as AEs.) 
 Perform: 
o Snellen Distance VA by pinhole method 
o Slit Lamp Biomicroscopy  


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 Signs of anterior ocular inflammation (cell and flare grading) 
 Palpebral conjunctival erythema, corneal edema, hyphema, ciliary 
flush, bulbar conjunctival injection 
o IOP Measurement 
 
Upon verification of study eligibility (Section 4.3), eligible subjects will be randomized to 
receive either KPI-121 1.0% ophthalmic suspension dosed BID or placebo dosed BID.  The 
following will be performed for all randomized subjects:  
 
 Administer the first dose of double-masked investigational product in the clinic 
under the supervision of designated study personnel.   
 Prior to administration of investigational product, remind the subjects 
regarding the proper method for instillation including but not limited to 
shaking investigational product bottle prior to each instillation.  
 Since subjects will receive one dose of investigational product in the clinic, 
instruct the subject to self-administer one additional dose of investigational 
product on the first day.   
 Assess the occurrence of any AEs after investigational product administration 
 Dispense investigational product kits and instructions for administration  
 Schedule subjects to return for Visit 4 on Day 4 ± 1 day. 
 
5.1.4. 
Visit 4:  Study Visit (Day 4 ± 1 day) 
 
This visit will occur on Day 4 ± 1 day and the following evaluations will be 
performed/assessed (NOTE:  All ocular assessments must be performed in both eyes.):  
 
 Obtain Subject-Rated Ocular Pain Assessment 
 Review use of any concomitant medications since the last visit 
 Assess occurrence of any AEs since the last visit 
 Perform: 
o Snellen Distance VA by pinhole method 
o Slit Lamp Biomicroscopy  
 Signs of anterior ocular inflammation (cell and flare grading) 
 Palpebral conjunctival erythema, corneal edema, hyphema, ciliary 
flush, bulbar conjunctival injection 
o IOP Measurement 
 Review dosing compliance. If needed, the second bottle of investigational 
product will be dispensed to the subject. 
 Instruct subjects to continue investigational product and return for Visit 5 on 
Day 8 ± 1 day. 


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5.1.5. 
Visit 5:  Study Visit (Day 8 ± 1 day) 
 
This visit will occur on Day 8 ± 1 day and the following evaluations will be 
performed/assessed (NOTE:  All ocular assessments must be performed in both eyes):  
 
 Obtain Subject-Rated Ocular Pain Assessment 
 Review use of any concomitant medications since the last visit 
 Assess occurrence of any AEs since the last visit 
 Perform: 
o Snellen Distance VA by pinhole method 
o Slit Lamp Biomicroscopy  
 Signs of anterior ocular inflammation (cell and flare grading) 
 Palpebral conjunctival erythema, corneal edema, hyphema, ciliary 
flush, bulbar conjunctival injection 
o IOP Measurement 
 Review dosing compliance.  If needed, the second bottle of investigational 
product will be dispensed to the subject. 
 Instruct subjects to continue investigational product and return for Visit 6 on 
Day 15 ± 1 day.   
 
5.1.6. 
Visit 6:  End of Investigational Product Use (Day 15 ± 1 day) 
 
The end of investigational product use visit will occur on Day 15 ± 1 day and the following 
will be performed/assessed (NOTE:  All ocular assessments must be performed in both 
eyes.):  
 
 Obtain Subject-Rated Ocular Pain Assessment 
 Review use of any concomitant medications since the last visit 
 Assess occurrence of any AEs since the last visit 
 Collect of used and unused investigational product 
 Perform: 
o UPT 
o Snellen Distance VA by pinhole method 
o Slit Lamp Biomicroscopy  
 Signs of anterior ocular inflammation (cell and flare grading) 
 Palpebral conjunctival erythema, corneal edema, hyphema, ciliary 
flush, bulbar conjunctival injection 
o IOP Measurement 
o Dilated Ophthalmoscopy 
 Review dosing compliance. 


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At the end of Visit 6, subjects with inflammation that has not resolved will be treated 
according to the Investigator's discretion.  Regardless of treatment and after cessation of 
experimental medication, all subjects will be asked to return for follow-up on Days 18 ± 1 day 
for Visit 7. 
 
5.1.7. 
Visit 7:  Follow-Up Visit (Days 18 ± 1 day) 
 
This follow-up visit will occur on Day 18 ± 1 day and the following will be 
performed/assessed (NOTE:  All ocular assessments must be performed in both eyes.):  
 
 Obtain Subject-Rated Ocular Pain Assessment 
 Use of any concomitant medications since the last visit 
 Occurrence of any AEs since the last visit 
 Perform: 
o Snellen Distance VA by pinhole method 
o Slit Lamp Biomicroscopy  
 Signs of anterior ocular inflammation (cell and flare grading) 
 Palpebral conjunctival erythema, corneal edema, hyphema, ciliary 
flush, bulbar conjunctival injection 
o IOP Measurement 
 
5.1.8. 
Early Termination Visit 
 
In the event of termination prior to Visit 6 but following Visit 3, every attempt will be made 
to ensure that the following will be performed/assessed (NOTE:  All ocular assessments must 
be performed in both eyes.):  
 
 Obtain Subject-Rated Ocular Pain Assessment 
 Review use of any concomitant medications since the last visit 
 Assess occurrence of any AEs since the last visit 
 Collect of used and unused investigational product and assessment of 
compliance via the daily dosing information recorded by the subject. 
 Perform: 
o UPT 
o Snellen Distance VA by pinhole method 
o Slit Lamp Biomicroscopy  
 Signs of anterior ocular inflammation (cell and flare grading) 
 Palpebral conjunctival erythema, corneal edema, hyphema, ciliary 
flush, bulbar conjunctival injection 


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o IOP Measurement 
o Dilated Ophthalmoscopy 
 
5.2. 
SUBJECT WITHDRAWAL AND/OR DISCONTINUATION  
 
Any subject who wishes to discontinue investigational product use or withdraw from 
participation in the study for any reason is entitled to do so without obligation.  The 
Investigator may also discontinue any subject from investigational product use or from study 
participation, if deemed necessary.  
 
Investigational product use may be discontinued and any subject may be discontinued from 
study participation at any time during the study at the discretion of the Investigator or the 
sponsor for any reason including but not limited to: 
 
1. Occurrence of any medical condition or circumstance that exposes the subject 
to substantial risk and/or does not allow the subject to adhere to the 
requirements of the protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent 
illness, or other medical condition that indicates to the Investigator that 
continued participation is not in the best interest of the subject. 
3. Subject's decision to withdraw. 
4. Any woman who becomes pregnant while participating in the study.  
Information on the pregnancy and outcome will be requested.   
5. Subject’s failure to comply with protocol requirements or study related 
procedures. 
6. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 
 
In the event study discontinuation of a randomized subject is necessary, the Investigator 
should make every attempt to have the 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. 
 


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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.    
 
5.3. 
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 (e.g., subject diary), 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. 
 
5.3.1. 
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. 
 
5.4. 
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 7.  
 
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. 
 
 
 


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6. 
TREATMENT OF SUBJECTS 
6.1. 
INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED 
 
KPI-121 1.0% ophthalmic suspension or placebo solution will be supplied as study product.  
One kit of randomized study product containing two dropper bottles will be allocated to each 
subject at Visit 3. Only one bottle will be dispensed to the subject at Visit 3. The second bottle 
will be retained at the site and provided to the subject if needed during the treatment period. 
The study product will be stored at the site in a secure area with limited access at 15-25C/59-
77F with upper limit excursions to 30C /86F allowed. 
 
Subjects will be asked to administer study product twice each day. Prior to each instillation of 
study product, subject will be instructed to shake the study product bottle. The subjects will 
record daily the time of administration of each dose of study product in the Dosing Diary 
(Appendix 7).  
 
Compliance with instillation of study product will be reviewed and assessed at each clinic 
visit. 
 
6.2. 
CONCOMITANT MEDICATIONS 
 
With the exception of pre- and post-operative standard of care medications, all medication 
that the subject has taken 30 days prior to Visit 1 and through Visit 7 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.  
Concomitant treatment with antibiotics at the discretion of the Investigator is allowed (with 
the exception of besifloxacin).  Medications routinely administered and not explicitly 
prohibited in this protocol used as part of an uncomplicated cataract surgery procedure are 
allowed. These medications will be collected in the source documentation and are not 
captured within the eCRF unless there is a change to the standard of care as documented in 
the source document.  Further, the routine medications administered as part of routine cataract 
surgery are not expected to be associated with treatment for AEs unless otherwise indicated.  
Note:  Any medication administered as part of the routine surgery that is ongoing subsequent 
to the surgical procedure, should be captured in the eCRF as a concomitant medication. 
 
 


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6.2.2. 
Medications Not Permitted 
 
Use of the following medications is not allowed during the study and for the timeframes 
specified: 
 
Within 2 days prior to surgery (Visit 2) and for the duration of the study: 
 
 Ocular NSAIDs 
 Systemic NSAIDs with the exception of ≤81 mg/day of acetylsalicylic acid (ASA or 
aspirin) 
 Ocular mast cell stabilizers 
 Ocular antihistamines 
 Ocular decongestants  
 All eye drops (except antibiotic eye drops considered to be included in post cataract 
surgery standard of care treatment). Note:  Besifloxacin Ophthalmic Suspension is not 
permitted within 2 days prior to the surgery or for the duration of the study. 
 Glaucoma medications 
 All topical ophthalmic gels or artificial tears 
 
Within 7 days prior to surgery (Visit 2) and for the duration of the study: 
 
 Topical eyelash growth medications  
 
Within 14 days prior to surgery (Visit 2) and for the duration of the study: 
 
 Systemic or ocular corticosteroids other than study product (except stable maintenance 
dose of inhaled or intranasal corticosteroids) 
 
Within 30 days prior to surgery (Visit 2) and for the duration of the study: 
 
 Ocular immunosuppressants (e.g., Restasis®) 
 Systemic immunosuppressants (with the exception of oral corticosteroids less than 
prednisone 11 mg/day or equivalent) 
 Other investigational products 
 
Within 6 months prior to the screening visit (Visit 1), alterations to the dose of the following 
are disallowed: 
 
 Anticholinergics 
 Antidepressants 


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 Oral corticosteroids (dose must be less than prednisone 11 mg/day or equivalent)  
 
NOTE: Dose must remain stable throughout the course of the study 
 
If using nutraceuticals or multivitamins, subjects may not alter their stable dose throughout 
the study. 
 
6.3. 
STUDY PRODUCT USE COMPLIANCE 
 
Compliance will be assessed by comparing study product accountability records with the 
dosing information recorded daily by the subject. The site will document this comparison 
along with verification of the numbers of used and unused study 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 study product (KPI-121 or 
placebo). Accountability will be ascertained by performing reconciliation between the amount 
of drug sent to the site and the amount unused at the time of reconciliation. 
 
Clinical trial materials will be shipped to the investigational sites under sealed conditions.  
Study 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 study product (e.g., dates, quantity, subject number, dose dispensed, returned) must be 
maintained by the Investigator or his/her designee. Study product will be stored in a secure 
area with limited access at 15-25C/59-77F with upper limit excursions to 30C /86F 
allowed.  
 
At the end of the study, all study materials, including any unused study product (KPI-121 
study product or placebo), as well as original containers (even if empty), will be returned to 
the drug packaging vendor in accordance with sponsor or designee’s standard operations 
procedures (SOPs), following approval by the Sponsor. All returns of study 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 study 
product assignments. In case of medical emergency, or occurrence of an SAE, the 


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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 study 
product assignment will be revealed on a subject-by-subject basis with the approval of the 
medical monitor and sponsor, thus leaving the masking of the remaining subjects intact. 
 
A randomization code will be computer-generated by Kala Pharmaceuticals, Inc. or its 
designee.  
 
Randomization team members will work independently of other team members at the CRO. 
Study personnel, study subjects, the sponsor, and project teams at the CROs involved in the 
study will be masked to study product assignments. 
 


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7. 
ASSESSMENT OF EFFICACY 
 
Efficacy Assessments include the following: 
 
 Slit Lamp Biomicroscopy examination of the following ocular signs of 
inflammation: 
o Signs of anterior ocular inflammation (i.e., cells; 0-4 Scale and flare; 0-4 
Scale) 
 Subject-Rated Ocular Pain Assessment (0-5 Scale) 
 Rescue therapy 
 


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8. 
ASSESSMENT OF SAFETY 
8.1. 
SAFETY PARAMETERS 
 
Safety parameters include: 
 Assessments of AEs 
 Snellen Distance VA by Pinhole Method 
 Slit Lamp Biomicroscopy including assessment of the following signs of 
inflammation: Palpebral conjunctival erythema, corneal edema, hyphema, 
ciliary flush, bulbar conjunctival injection  
 IOP Measurement  
 Dilated Ophthalmoscopy  
 
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: 
 Date of Birth 
 Sex 
 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: 
 SAE term (diagnosis only; if known or serious signs/symptoms) 
 Description of SAE/narrative 
 Date/time of onset 
 Severity 
 Outcome 
 Date/time of resolution or death (if duration < 24 hours) 
 Relationship to investigational product 
 Action taken with investigational product 
8. Criteria for classifying the event as serious, including whether the SAE:   
 Resulted in death. 
 Was life-threatening 
 Required inpatient hospitalization. 
 Prolonged inpatient hospitalization. 
 Resulted in a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 
 Was a congenital anomaly/birth defect 
 Important medical events that may not result in death, were not life-
threatening, or did not require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or 
at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.  
 
 


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9. Concomitant medications 
10. Relevant history 
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 1.0% 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 repeated using data from those 
subjects who were randomized, completed 14 days of study product use, had complete data at 
Visit 5 (Day 8 ± 1 day) and did not have significant protocol deviations, the Efficacy 
Evaluable (EE) population. Rescued subjects will be included in the EE population if they did 
not have significant protocol deviations. 
 
The primary analysis of all ophthalmic efficacy measures will be based on a single study eye 
for each subject.  Each subject’s study eye will be defined as the surgery eye.  The set of 
primary endpoints, using hierarchical statistical testing, is (1) proportion of study eyes with 
complete resolution of anterior chamber cells (grade = 0) at postoperative Visit 5 (Day 8 ± 1 
day) maintained through Visit 6 (Day 15 ± 1 day) without receiving rescue medication prior 
to Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% ophthalmic suspension and 
placebo, and (2) proportion of study eyes with complete resolution of pain (grade = 0) at 
postoperative Visit 5 (Day 8 ±1 day) maintained through Visit 6 (Day 15 ± 1 day) without 
receiving rescue medication prior to Visit 6 (Day 15 ± 1 day) as compared between KPI-121 
1.0% ophthalmic suspension and placebo. 
 
The following scoring scale for anterior chamber cells will be used: 
0 = No cells seen 
1 = 1 - 5 cells 
2 = 6 - 15 cells 
3 = 16 - 30 cells 
4 = greater than 30 cells 
 
 
 


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The following scoring scale for ocular pain will be used: 
0 = None 
1 = Minimal 
2 = Mild 
3 = Moderate 
4 = Moderately Severe 
5 = Severe 
 
Using the hierarchical testing scheme, the first test will be the proportion of study eyes with 
complete resolution of anterior chamber cells (grade = 0) at Visit 5 (Day 8 ± 1 day) 
maintained through Visit 6 (Day 15 ± 1 day) without receiving rescue medication prior to 
Visit 6 (Day 15 ± 1 day) as compared between KPI-121 1.0% ophthalmic suspension dosed 
BID and placebo dosed BID using the 2 statistic. 
 
If this test is statistically significant at the two-sided  = 0.05 level in favor of the KPI-121 
1.0% ophthalmic suspension group, then the difference in the proportion of study eyes with 
complete resolution of pain (grade = 0) at Visit 5 (Day 8 ± 1 day) maintained through Visit 6 
(Day 15 ± 1 day) without receiving rescue medication prior to Visit 6 (Day 15 ± 1 day) as 
compared between KPI-121 1.0% ophthalmic suspension dosed BID and placebo dosed BID 
will be tested using the same statistic.  
 
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 study 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 
intensity and relationship to the study product. Ophthalmoscopy findings will be summarized 
descriptively.  IOP measurements, Snellen Distance VA by pinhole method and Slit Lamp 
Biomicroscopy will be summarized as safety outcomes.   
 
9.2. 
SAMPLE SIZE ESTIMATION 
 
A two group 2 test with a 0.05 two-sided significance level will have 99% power to detect 
the difference between a proportion with complete resolution of anterior chamber cells in the 
active group of 0.31 and the placebo group proportion of 0.15 when the sample size in each 
group is 250.  The power is the same for the complete resolution of pain endpoint. 
 
 


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9.3. 
LEVEL OF SIGNIFICANCE 
 
The primary assessment will be evaluated using a 5% level of significance using the 
hierarchical testing described in Section 9.1.2 Analysis of Efficacy.   
 
All other reported p-values will be considered descriptive and hypothesis generating. 
 
9.4. 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA 
 
If more than 5% of data points are missing at the primary analysis time point (Day 8) in any 
treatment group, a tipping point analysis will be employed to assess the sensitivity of the 
results to the distribution of the allocation of treatment success and failure to the missing data 
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. 
 
9.6. 
SUBJECTS TO BE INCLUDED IN THE ANALYSIS 
 
Efficacy analysis will be performed for all randomized subjects, the Intent-to-Treat (ITT) 
population. A subset of the efficacy analysis will be repeated using data from those subjects 
who were randomized, completed 14-days of study product use, had complete data at Visit 5 
(Day 8 ± 1 day) and did not have significant protocol deviations, the Efficacy Evaluable (EE) 
population. Rescued subjects will be included in the EE population if they did not have 
significant protocol deviations. AEs and other safety parameters will be analyzed for all 
randomized subjects receiving randomized study product (Safety population). 
 


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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.  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 will 
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   
 
Apple DJ, Solomon KD, Tetz MR, Assia EI, Holland EY, Legler UF, Kostick AM. Posterior 
capsule opacification. Survey of ophthalmology. 1992;37:73–116. 
 
Leopold IH. Nonsteroidal and steroidal anti-inflammatory agents. In: Sears M, Tarkkanen A, 
editors. Surgical Pharmacology of the Eye. New York, NY: Raven Press; 1985:83–133 
 
Tennant JL. Cystoid maculopathy: 125 prostaglandins in ophthalmology. In: Emery JM, 
editor. Current Concepts in Cataract Surgery: Selected proceedings of the fifth biennial 
cataract surgical congress, Section 3. St. Louis, MO: CV Mosby; 1978:360–362. 


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CONFIDENTIAL 
16. 
APPENDICES 
 
 
 


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APPENDIX 1: SUMMARY OF EVENTS 
Procedures 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Screening 
Surgery 
Randomization 
Study Visit  
Study Visit 
End of  
Study Product 
Use Visit 
Follow-Up 
-14 to -1 
days 
Day 0 
 
Day 1 
Day 4  
(±1 day) 
Day 8  
(± 1 day) 
 Day 15  
(± 1 day) 
Day 18  
(± 1 day) 
Informed Consent, HIPAA Authorization 
and Medical/Ophthalmic History 
X 
 
 
 
 
 
 
Subject-Rated Ocular Pain Assessment 
 
 
X 
X 
X 
X 
X 
Concomitant Medication Query 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testa 
X 
 
 
 
 
X 
 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
AE Assessment 
 
Xb 
X 
X 
X 
X 
X 
Surgery  
 
X 
 
 
 
 
 
Snellen Distance Pinhole Visual Acuity  
X 
 
X 
X 
X 
X 
X 
Slit Lamp Biomicroscopy 
X 
 
X 
X 
X 
X 
X 
IOP Measurement 
X 
 
X 
X 
X 
X 
X 
Dilated Ophthalmoscopy 
X 
 
 
 
 
X 
 
Randomization 
 
 
X 
 
 
 
 
Study Product Administration in Clinic 
 
 
X 
 
 
 
 
Dispense Study Product 
 
 
X 
 
 
 
 
Collect Study Product 
 
 
 
 
 
X 
 
Dosing Compliance Assessment 
 
 
 
X 
X 
X 
 
aWomen of childbearing potential only; bAssessments of AEs pre-surgery and post-surgery 
 


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APPENDIX 2:  SUBJECT-RATED OCULAR PAIN ASSESSMENT 
 
In the clinic, subjects will be handed a laminated card on which is printed the Subject-Rated 
Ocular Pain Assessment.  Each subject will be asked to subjectively rate their pain at Visit 3 
to 7 based on this scale.  This information will be provided to study personnel to enter into the 
subject’s source documentation. The grading scale for pain to be used will be as follows: 
 
0 = None:   
 
 
 
Absence of positive sensation. 
 
1 = Minimal:   
 
 
Presence of mild sensation or discomfort typical of postoperative 
 
 
 
 
 
 
surgery (e.g., diffuse or focal foreign body sensation, mild transient 
 
 
 
 
 
 
burning or  stinging, etc.) 
 
2 = Mild:   
 
 
 
Mild, tolerable aching of the eye. 
 
3 = Moderate:  
 
 
Moderate or more prolonged aching sufficient to require the use of  
 
 
 
 
 
 
over the counter (OTC) analgesics (e.g. acetaminophen). 
 
4 = Moderately Severe:  More prolonged aching requiring the use of an OTC analgesic  
 
 
 
 
 
 
 
other than acetaminophen. 
 
5 = Severe:  
 
 
 
Intense ocular, periocular or radiating pain (e.g. constant or nearly  
 
 
 
 
 
 
constant sharp stabbing pain, throbbing or aching, etc.) requiring  
 
 
 
 
 
 
prescription analgesics. 
 
 
 


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APPENDIX 3:  SNELLEN DISTANCE PINHOLE VISUAL ACUITY 
 
VA measurement will be performed with the Snellen eye chart using pinhole at a distance of 
20 feet (6 meters). VA will be assessed at all study visits except the surgery visit (Visit 2). 
 
 


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APPENDIX 4: SLIT LAMP BIOMICROSCOPY  
 
The biomicroscopy exam will be performed at every visit (except Visit 2/Surgery) with the 
slit lamp using a beam of 1.0 mm height and 1.0 mm width with the beam at maximum 
luminance and using the high powered lens if using Haag-Streit model slit lamp.  If alternate 
model used, site to assure a 1.0 mm by 1.0 mm window with high magnification is achieved. 
 
This procedure will be the same for all subjects observed at the Investigator’s site.   
 
Anterior Chamber 
 
 
Cells 
 
  
0 = No cells seen 
1 = 1 - 5 cells 
2 = 6 - 15 cells 
3 = 16 - 30 cells 
4 = greater than 30 cells 
 
 
Flare 
 
  
0 = None 
1 = Mild (trace to clearly noticeable, visible) 
2 = Moderate (without plastic aqueous humor) 
3 = Marked (with plastic aqueous humor) 
4 = Severe (with fibrin deposits and/or clots) 
 
 
Hyphema: 
 
0 = Absent 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
 
 


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Conjunctiva 
 
Bulbar Conjunctival Injection 
 
0 = Absent 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
Palpebral Conjunctival Erythema  
   0 = Absent 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
Cornea 
 
 
Edema 
 
0 = Absent 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
Sclera 
 
Ciliary Flush 
 
0 = Absent 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
 


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APPENDIX 5: 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 all study visits except the surgery visit (Visit 2).   
 
 


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APPENDIX 6: 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. For each subject, the 
Investigator will determine whether direct or indirect ophthalmoscopy will be used.  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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APPENDIX 7: DOSING DIARY 
 
Subjects will be asked to record each day the following information related to administration 
of study drug: 
 
 Date 
 Time of Administration