Clinical trial NCT02163824
Conditions: Ocular Infections, Irritations and Inflammations
Keywords: postsurgical postoperative ocular cataract inflammation pain corticosteroid
Sponsor: Kala Pharmaceuticals, Inc.
Start date: 2014-05-01; Completion date: 2014-12-01
Enrollment: 380 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to determine the efficacy and safety of KPI-121 ophthalmic suspension compared to placebo in subjects who have undergone cataract surgery. The efficacy and safety of two different concentrations and two different dosing regimens of KPI-121 are also being assessed.

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

Approximately 500 subjects will be screened and up to 402 subjects with one study eye each will be randomized in this study at approximately 25 centers located in the United States. 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 four study groups (0.25% four times daily or 1.0% two times daily) or Placebo A four times daily or Placebo B two times daily. Drug product or placebo will be initiated on the day following surgery and instilled as one to two drops in the study eye according to the assigned dosing regimen for 14 days.

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.

Following randomization, subjects will be instructed to return to the clinic to be evaluated at Visit 4 (Day 3 +2 day), Visit 5 (Day 8 ±1 day), and Visit 6 (Day 15 ±1 day). The last dose of study product will be administered upon completion of 14 days of evaluation. Following the End of Study Product Use Visit (Visit 6; Day 15 ±1 day), subjects will be asked to return to the clinic on Day 17-19 for Visit 7 (Follow-Up) and will be released from the study.

Arms: arm 1: KPI-121 0.25% Ophthalmic Suspension dosed 4 times daily for 14 days after routine, uncomplicated surgery for cataract removal and intraocular lens implant. arm 2: KPI-121 1.0% Ophthalmic Suspension dosed 2 times daily for 14 days after routine, uncomplicated surgery for cataract removal and intraocular lens implant. arm 3: Vehicle of KPI-121 0.25% Ophthalmic Suspension dosed 4 times daily for 14 days after routine, uncomplicated surgery for cataract removal and intraocular lens implant. arm 4: Vehicle of KPI-121 1.0% Ophthalmic Suspension dosed 2 times daily for 14 days after routine, uncomplicated surgery for cataract removal and intraocular lens implant.
Interventions: intervention 1: KPI-121 0.25% intervention 2: KPI-121 1.0% intervention 3: Vehicle of KPI-121 0.25% intervention 4: Vehicle of KPI-121 1.0%
Intervention descriptions: intervention 1: KPI-121 drug product will be supplied as 0.25% as a suspension in identically packaged opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate. intervention 2: KPI-121 drug product will be supplied as 1.0% as a suspension in identically packaged opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, submicron suspension of loteprednol etabonate. intervention 3: Placebo control arms will receive the same bottles containing vehicle of KPI-121 including all components at the concentrations used in the KPI-121 drug product with the exception of the active component, loteprednol etabonate. intervention 4: Placebo control arms will receive the same bottles containing vehicle of KPI-121 including all components at the concentrations used in the KPI-121 drug product with the exception of the active component, loteprednol etabonate.

Protocol documents:
Prot_SAP_000.pdf: 
NCT02163824   
 
Study ID:  
KPI-121-C-001  
 
Study Title:  
A Phase III, Double-Masked, Randomized, Controlled Trial of KPI-121 in 
Postsurgical Inflammation 
 
Date:  
21 Jul 2014 


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CONFIDENTIAL 
KALA PHARMACEUTICALS, INC. 
Clinical Protocol KPI-121-C-001  
Incorporating Amendment 1, Clarification Letter 1, Amendment 2, and Amendment 3 
Project: 
KPI-121 
 
Compound Number/Name: 
KPI-121  
 
Protocol Number: 
KPI-121-C-001 
 
Protocol Title: 
A Phase III, Double-Masked, Randomized, Controlled 
 
Trial of KPI-121 in Postsurgical Inflammation 
 
Sponsor: 
Kala Pharmaceuticals, Inc. 
 
100 Beaver Street, Suite 201 
 
Waltham, MA 02453 
 
Medical Monitor: 
 
 
     
 
 
Issue Date: 
Original:  10 Dec 2013 
 
Amendment 1: 28 Mar 2014 
 
Clarification Letter 1 and Amendment 2: 18 Jun 2014 
 
Amendment 3:  21 Jul 2014 
Approved:   
21 Jul 2014 
 
 
 


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KALA PHARMACEUTICALS, INC. 
Clinical Protocol KPI-121-C-001  
Incorporating Amendment 1, Clarification Letter 1, Amendment 2, and Amendment 3 
Investigator Signature Page 
Project: 
KPI-121 
 
Compound Number/Name: 
KPI-121  
 
Protocol Number: 
KPI-121-C-001  
Protocol Title: 
A Phase III, Double-Masked, Randomized, Controlled 
Trial of KPI-121 in Postsurgical Inflammation 
 
Sponsor: 
Kala Pharmaceuticals, Inc. 
 
100 Beaver Street, Suite 201 
 
Waltham, MA 02453 
 
Issue Date: 
Original: 10 Dec 2013 
 
Amendment 1: 28 Mar 2014 
 
Clarification Letter 1 and Amendment 2: 18 Jun 2014 
 
Amendment 3:  21 Jul 2014 
Approved:   
21 Jul 2014 
 
Contact for Serious Adverse Events: 
 
 
  
     
  
 
 
  
 
  
 
 
Investigator Name (printed or typed): 
 
________________________________________________ 
 
Investigator's Signature: 
 
________________________________________________ 
______________ 
 
Date 
 


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SYNOPSIS  
Study Title: 
A Phase III, Double-Masked, Randomized, Controlled Trial 
of KPI-121 in Postsurgical Inflammation 
Objectives: 
The primary objective of the study is: 
• To investigate the efficacy and safety of KPI-121 
ophthalmic suspension compared to placebo in subjects 
who have undergone cataract surgery. 
The secondary objective of the study is: 
• To investigate the comparative efficacy and safety of 
two different concentrations and two different dosing 
regimens of KPI-121. 
Study Population:  
 
The study population will consist of subjects who have 
undergone routine uncomplicated cataract surgery and 
experience ocular inflammation postoperatively. 
Number of Subjects 
Up to 500 subjects who are candidates for cataract surgery 
will be screened. One study eye from approximately 402 
subjects will be randomized.  
Study Products: 
 
KPI-121 drug products (0.25% and 1.0%) or placebo 
solutions (A and B) will be supplied as study product. 
Route and Duration of 
Administration 
Study product will be instilled in the study eye only. Study 
groups include KPI-121 drug product 0.25% four times a day 
(QID), KPI-121 drug product 1.0% two times a day (BID), 
Placebo A QID and Placebo B BID. Study product will be 
administered for 14 days. 
Study Design:   
 
This is a Phase III, multicenter, double-masked, randomized, 
placebo-controlled, parallel-group study designed to evaluate 
the efficacy and safety of two doses and two dosing regimens 
of KPI-121 ophthalmic suspension versus placebo in subjects 
who require treatment of postoperative anterior ocular 
inflammation. Approximately 500 subjects will be screened 
and up to 402 subjects with one study eye each will be 
randomized in this study at approximately 25 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 four study 
groups in an approximate 2:2:1:1 ratio to one of two doses of 
KPI-121 drug product (0.25% QID or 1.0% BID) or Placebo 
A or B QID or BID. Drug product or placebo will be initiated 
on the day following surgery and instilled as one to two drops 


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in the study eye according to the assigned dosing regimen for 
14 days.   
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 four study groups and will 
initiate study 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 study product 
will be administered upon completion of 14 days of 
evaluation.  Following the End of Study Product Use Visit 
(Visit 6; Day 15 ±1 day), subjects will be asked to return to 
the clinic on Day 17-19 for Visit 7 (Follow-Up) and will be 
released from the study.  
Assessments in this study will include: 
• Subject-Rated Ocular Pain assessment (Appendix 2) 
• Snellen Distance Visual Acuity (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  
• Intraocular Pressure (IOP) Measurement (Appendix 5) 
• Dilated Ophthalmoscopy (Appendix 6) 
• Rescue Therapy Assessment 
• Concomitant Medication Use Assessment  
• Assessments of Adverse Events (AEs) 
 
 


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Efficacy Endpoints 
 
 
 
 
 
 
 
Primary Efficacy Endpoints: 
The primary endpoints of this study will be evaluated using 
hierarchical statistical testing in the following sequence: (1) 
the difference in the proportion of study eyes with complete 
resolution of anterior chamber cells (grade = 0) at 
postoperative Day 8 maintained through end of study and no 
need for rescue medication for KPI-121 0.25% QID 
compared to placebo; (2) the difference in the proportion of 
study eyes with complete resolution of anterior chamber cells 
(grade = 0) at postoperative Day 8 maintained through end of 
study and no need for rescue medication for KPI-121 1.0% 
BID compared to placebo; (3) the difference in the proportion 
of study eyes with complete resolution of pain (grade = 0) at 
postoperative Day 8 maintained through end of study and no 
need for rescue medication for KPI-121 1.0% BID compared 
to placebo; and (4) the difference in the proportion of study 
eyes with complete resolution of pain (grade = 0) at 
postoperative Day 8 maintained through end of study and no 
need for rescue medication for KPI-121 0.25% QID 
compared to placebo. 
Secondary Efficacy Endpoints: 
The proportion of study eyes with complete resolution (grade 
= 0) of anterior chamber cells (scale 0-4) and complete 
resolution (grade = 0) of pain (scale 0-5) at Day 8.   
The proportion of study eyes with complete resolution (grade 
= 0) of anterior chamber cells (scale 0-4) and complete 
resolution (grade = 0) of pain (scale 0-5) at Day 15. 
Mean grade of anterior chamber cells (scale 0-4) at Day 8. 
Mean pain grade (scale 0-5) at Day 8. 
Mean grade of anterior chamber cells (scale 0-4) at Day 15. 
Mean pain grade (scale 0-5) at Day 15. 
Safety Endpoints 
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 


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• Hyphema 
• Ciliary flush 
• 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 study product or 
until completion of the subject’s first menstrual cycle 
following the last administration of the study 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 study product or until 
completion of the subject’s first menstrual cycle 
following last administration of the study 
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 
study product or until completion of the subject’s 


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first menstrual cycle following last 
administration of the study 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 study product or until 
completion of the subject’s first menstrual cycle 
following administration of the study product, 
whichever period of time is longer.  
NOTE: For Depo-Provera injection 
contraceptives, the statement regarding first 
menstrual cycle following administration of 
the study 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 study product or until 
completion of the subject’s first menstrual cycle 
following administration of the study 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), for the duration of the study 
3. Require treatment with systemic (except stable 


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maintenance dose of inhaled or intranasal 
corticosteroids) or ocular (either eye) corticosteroids 
(other than study product) within 14 days prior to 
cataract surgery and for the duration of the study 
4. Require concurrent ocular therapy with 
immunosuppressants (e.g., Restasis®) within 30 days 
prior to surgery and for the duration of the study. 
5. Require change in treatment with anticholinergics, 
systemic immunosuppressive agents, oral steroids (dose 
must be less than 11 mg/day) 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 
study 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. 
10. Use any topical eyelash growth medications within 7 
days prior to surgery and for the duration of the study 
11. Use TNF-blocking agents (e.g., etanercept, adalimumab, 
infliximab) within 2 days prior to surgery and for the 
duration of the study  
12. Have history of glaucoma, IOP >21 mmHg at the 
screening or randomization visit(s), or are being treated 
for glaucoma in either eye. 
13. Wear contact lenses for 4 weeks prior to Visit 1 and 
throughout the study. 
14. Be monocular or have Snellen Distance VA by pinhole 
method of 20/200 or worse in the non-study eye. 
15. Have had penetrating intraocular surgery in the study 
eye within 3 months or within two weeks in the fellow 
eye.   
16. Have had selective laser trabeculoplasty (SLT) within 3 
months prior to surgery. 
17. Have had corneal refractive surgery, glaucoma surgery, 
or corneal transplantation (full thickness, anterior, or 
posterior) within the past year or are unstable and/or 


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require medication. 
18. 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. 
19. Have been exposed to an investigational drug within 30 
days prior to screening or up to 18 days following 
surgery. 
20. 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. 
21. Have a known history of alcohol and/or drug abuse. 
22. 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 ............................. 18 
1.3. GCP COMPLIANCE ............................................................................................................... 19 
1.4. POPULATION TO BE STUDIED ................................................................................................ 19 
2. TRIAL OBJECTIVES AND PURPOSE ............................................................................... 20 
2.1. PRIMARY OBJECTIVE ............................................................................................................ 20 
2.2. SECONDARY OBJECTIVES ..................................................................................................... 20 
3. TRIAL DESIGN .................................................................................................................... 21 
3.1. ENDPOINTS ........................................................................................................................... 21 
3.1.1. Efficacy Endpoints ........................................................................................................... 21 
3.1.2. Safety Endpoints .............................................................................................................. 21 
3.2. DESCRIPTION OF STUDY AND DURATION OF PARTICIPATION ............................................... 22 
3.2.1. Description of Trial Design .............................................................................................. 22 
3.2.2. Study Product ................................................................................................................... 25 
3.2.3. Methods to Minimize Bias ............................................................................................... 27 
4. SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................... 28 
4.1. SUBJECT INCLUSION CRITERIA ............................................................................................. 28 
4.2. SUBJECT EXCLUSION CRITERIA ............................................................................................ 29 
4.3. RANDOMIZATION CRITERIA ................................................................................................. 30 
4.4. SUBJECT WITHDRAWAL CRITERIA ....................................................................................... 30 
5. PROCEDURES ...................................................................................................................... 32 
5.1. VISIT DESCRIPTION .............................................................................................................. 32 
5.1.1. Visit 1:  Screening Visit  (Day -14 to Day -1) ................................................................. 32 
5.1.2. Visit 2:  Surgery Visit (Day 0) ......................................................................................... 32 
5.1.3. Visit 3:  Randomization Visit (Day 1) ............................................................................. 33 
5.1.4. Visit 4:  Study Visit (Day 4 ±1 day) ................................................................................ 34 
5.1.5. Visit 5:  Study Visit (Day 8 ±1 day) ................................................................................ 34 
5.1.6. Visit 6:  End of Study Product Use (Day 15 ±1 day) ....................................................... 35 
5.1.7. Visit 7:  Follow-Up Visit (Days 17-19) ........................................................................... 35 


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5.1.8. Early Termination Visit ................................................................................................... 36 
5.2. DISCONTINUATION CRITERIA ............................................................................................... 36 
5.3. COLLECTION OF DATA ......................................................................................................... 37 
6. TREATMENT OF SUBJECTS ............................................................................................. 38 
6.1. STUDY PRODUCTS TO BE ADMINISTERED ............................................................................. 38 
6.2. CONCOMITANT MEDICATIONS ............................................................................................. 38 
6.2.1. Permitted Medications ..................................................................................................... 38 
6.2.2. Medications Not Permitted .............................................................................................. 38 
6.3. STUDY PRODUCT USE COMPLIANCE .................................................................................... 39 
6.4. DRUG ACCOUNTABILITY ...................................................................................................... 39 
6.5. MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING THE CODE .............. 40 
7. ASSESSMENT OF EFFICACY ............................................................................................ 41 
8. ASSESSMENT OF SAFETY ................................................................................................ 42 
8.1. SAFETY PARAMETERS .......................................................................................................... 42 
8.2. ADVERSE EVENT DEFINITIONS ............................................................................................. 42 
8.3. PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR ................................................... 44 
8.4. SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR ............................................ 44 
8.5. RESCUE THERAPY ................................................................................................................ 47 
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 ................................................................................................... 50 
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: 
COMPOSITIONS OF KPI-121 DRUG PRODUCTS ............................................................ 25 
TABLE 2: 
COMPOSITION OF PLACEBO A AND PLACEBO B .......................................................... 26 


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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 
BID 
Acetylsalicylic Acid 
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 
FDA 
Degrees Fahrenheit 
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 
IUD 
KPI 
Intent-to-Treat 
Intrauterine device 
Kala Pharmaceuticals, Inc. 
LE 
Loteprednol etabonate 
MedDRA 
Medical Dictionary for Regulatory Activities  
mg  
Milligram 
mL  
mm 
mmHg 
Milliliter 
Millimeter 
Millimeter of Mercury 
MAR 
MPP 
Missing at random 
Mucus Penetrating Particles 
NDA 
New Drug Application 
NSAIDs 
Non-steroidal Anti-inflammatory Drugs 


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OTC 
PDF 
pH 
Over the Counter 
Portable Document Format 
Potential Hydrogen 
QID 
Four Times Daily 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SLT 
TNF 
Selected Laser Trabeculoplasty 
Tumor Necrosis Factor 
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 drug products. Preclinical studies have shown improved pharmacokinetics for 
KPI-121 compared to Lotemax, with prolonged drug presence on the ocular surface and 
increased drug penetration into ocular tissues. This improved pharmacokinetic profile has the 
potential to reduce 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. Study KPI-121-C-001 will help establish the 
optimal dosing strength and dosing frequency. 
 
 


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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 white, controlled-drop polyethylene 
tip and a polypropylene cap. The bottle will be a 7.5 mL dropper bottle; the fill volume will 
be determined after manufacturing trial runs, and will be in the range of 5.0 to 6.0 mL of 
product. 
For this trial, KPI-121 drug product will be supplied in two strengths: 0.25% and 1.0%.  Each 
milliliter of KPI-121 0.25% drug product contains 2.5 mg loteprednol etabonate as the active 
ingredient; each milliliter of KPI-121 1.0% drug product contains 10 mg loteprednol 
etabonate as the active ingredient.  Inactive ingredients in KPI-121 drug products ar
 
 
as preservative.  
KPI-121 suspensions are essentially isotonic and are buffered to maintain a power of 
hydrogen (pH) of 5.0 – 7.0. 
There are two placebo controls that have the same composition as KPI-121 drug products but 
do not contain loteprednol etabonate. Placebo A contains 
 
. Both placebo controls also contain
 
 as preservative. The placebo controls are 
essentially isotonic and are buffered to maintain pH 5.0 – 7.0.  They are sterile, aqueous 
solutions supplied in the same white, low-density polyethylene plastic bottle with the same 
white, controlled-drop polyethylene tip and white polypropylene closure as KPI-121 drug 
products. 
1.2. 
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION 
KPI-121 will be administered as a topical ophthalmic suspension. This clinical study will be 
used to determine the optimal dosing strength and dosing frequency for the commercial 
product.   
Subjects are expected to self-administer one to two drops of either KPI-121 drug product or 
placebo control according to the dosing schedule appropriate to the study group to which the 
subject is assigned. 
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 
dose effect and tolerability for 14 days across two dosing concentrations and two dosing 
regimens of KPI-121 drug products:  0.25% QID and 1.0% BID.  
For additional details on the toxicology studies and the respective safety multiples, see the 
Investigator’s Brochure.  


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1.3. 
GCP COMPLIANCE  
This clinical trial will be conducted in compliance with the protocol, International Conference 
on Harmonization (ICH) guidelines, Good Clinical Practices (GCP) guidelines and other 
applicable regulatory requirements. 
1.4. 
POPULATION TO BE STUDIED 
Up to 500 subjects who are candidates for cataract surgery will be screened. One study eye 
from approximately 402 subjects who have undergone routine uncomplicated cataract surgery 
and experience ocular inflammation postoperatively will be randomized.  


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2. 
TRIAL OBJECTIVES AND PURPOSE 
2.1. 
PRIMARY OBJECTIVE 
The primary objective of the study is: 
• To investigate the efficacy and safety of KPI-121 drug product compared to 
placebo in subjects who have undergone cataract surgery. 
2.2. 
SECONDARY OBJECTIVES 
The secondary objective of the study is: 
• To investigate the comparative efficacy and safety of two different concentrations 
and two different dosing regimens of KPI-121. 


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3. 
TRIAL DESIGN 
3.1. 
ENDPOINTS 
3.1.1. 
Efficacy Endpoints 
3.1.1.1. 
Primary Efficacy Endpoints 
The primary endpoints of this study will be evaluated using hierarchical statistical testing in 
the following sequence: 
(1) the difference in the proportion of study eyes with complete resolution of anterior 
chamber cells (grade = 0) at postoperative Day 8 maintained through end of study and 
no need for rescue medication for KPI-121 0.25% QID compared to placebo; 
 
(2) the difference in the proportion of study eyes with complete resolution of anterior 
chamber cells (grade = 0) at postoperative Day 8 maintained through end of study and 
no need for rescue medication for KPI-121 1.0% BID compared to placebo; 
 
(3) the difference in the proportion of study eyes with complete resolution of pain (grade 
= 0) at postoperative Day 8 maintained through end of study and no need for rescue 
medication for KPI-121 1.0% BID compared to placebo; and 
 
(4) the difference in the proportion of study eyes with complete resolution of pain (grade 
= 0) at postoperative Day 8 maintained through end of study and no need for rescue 
medication for KPI-121 0.25% QID compared to placebo. 
 
3.1.1.2. 
Secondary Efficacy Endpoints 
• The proportion of study eyes with complete resolution (grade=0) of anterior chamber 
cells (scale 0-4) and complete resolution (grade=0) of pain (scale 0-5) at Day 8.   
• The proportion of study eyes with complete resolution (grade=0) of anterior chamber 
cells (scale 0-4) and complete resolution (grade=0) of pain (scale 0-5) at Day 15. 
• Mean grade of anterior chamber cells (scale 0-4) at Day 8. 
• Mean pain grade (scale 0-5) at Day 8. 
• Mean grade of anterior chamber cells (scale 0-4) at Day 15. 
• Mean pain grade (scale 0-5) at Day 15. 
3.1.2. 
Safety Endpoints 
3.1.2.1. 
Safety Endpoints 
• Snellen Distance VA by pinhole method  
• Slit Lamp Biomicroscopy  
• IOP Measurement 


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• Dilated Ophthalmoscopy 
• Change from baseline to each post-surgery visit in ocular signs: 
• Palpebral conjunctival erythema 
• Corneal edema 
• Hyphema 
• Ciliary flush 
• Bulbar conjunctival injection  
3.2. 
DESCRIPTION OF STUDY AND DURATION OF PARTICIPATION 
3.2.1. 
Description of Trial Design 
This is a Phase III, multicenter, double-masked, randomized, placebo-controlled, parallel-
group study designed to evaluate the efficacy and safety of two doses and two dosing 
regimens of KPI-121 versus placebo in subjects who require treatment of postoperative 
anterior ocular inflammation. Approximately 500 subjects will be screened and up to 402 
subjects with one study eye each randomized in this study at approximately 25 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 four study groups in an approximate 2:2:1:1 ratio:  
• KPI-121 0.25% QID  
• KPI-121 1.0% BID   
• Placebo A QID  
• Placebo B BID  
Dosing of study product will be initiated on the day following surgery and instilled as one to 
two drops in the study eye according to the assigned dosing regimen for 14 days. The first 
dose of study 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 study product administration, no other information or discussion 
regarding the subject’s assigned study product or regimen 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 four study groups and will initiate study 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), and Visit 6 (Day 15 ±1). The last dose 
of study product will be administered upon completion of 14 days of evaluation. Following 


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the End of Study Product Use Visit (Visit 6), subjects will be asked to return to the clinic on 
Days 17-19 for Visit 7 for follow-up and then will be released from the study.  
A summary of events is provided in Appendix 1.  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 
 
 


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A study schematic follows (Figure 1). 
 
 
FIGURE 1: STUDY SCHEMATIC 
 
 


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3.2.2. 
Study Product 
KPI-121 drug product will be supplied in two strengths:  0.25% and 1.0% as a suspension in 
identically packaged opaque dropper bottles. KPI-121 drug product is a sterile, aqueous, 
submicron suspension of loteprednol etabonate and will be supplied in a 7.5 mL, white, low-
density polyethylene plastic bottle with a white, controlled-drop polyethylene tip and a white 
polypropylene cap. 
Subjects randomized to placebo control arms will receive the same bottles containing all 
components at the concentrations used in the KPI-121 drug product with the exception of the 
active component, loteprednol etabonate. Prior to each instillation of study product, subject 
will shake the study product bottle.   
 
TABLE 1: 
COMPOSITIONS OF KPI-121 DRUG PRODUCTS 
Ingredient 
Function 
0.25% 
Drug 
Product 
1.0% 
Drug  
Product 
Concentration (% w/v) 
Loteprednol etabonate 
Active pharmaceutical 
ingredient 
0.25 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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TABLE 2: 
COMPOSITION OF PLACEBO A AND PLACEBO B 
Ingredient 
Function 
Placebo A 
Placebo B 
Concentration (% w/v) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The study product kit consists of a box of randomized study product that contains two dropper 
bottles of study product. At Visit 3, eligible subjects will receive one bottle of study product.  
The second bottle will be retained at the site and provided to the subject, in the event the 
subject needs additional study product during the treatment period. The box label will contain 
the following information: sponsor name, protocol and medicinal number, storage 
temperature and required statement(s) per the appropriate regulatory agency. The dropper 
bottle contained within the box will be labeled with the following information: sponsor name, 
protocol number and medicinal number.   
The study product will be stored in a secure area with limited access at controlled room 
temperature (15-25°C/59 -77°F). Subjects will be instructed to shake the study 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) or four (QID) daily doses. 
Subjects will then self-administer either one (BID) or three (QID) additional doses of study 
product during the remainder of that day. Visit 3 should be scheduled in the morning to allow 
subjects to receive a full day of either BID or QID dosing. 
On all other study evaluation days, subjects in the BID group will be asked to instill one (1) 
“Morning Dose” and one (1) “Evening Dose” approximately 12 hours following the previous 
dose. Subjects in the QID group will be asked to instill one (1) dose upon awakening and then 
three (3) subsequent doses approximately four (4) hours after their previous dose. The four (4) 


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doses in the QID group will be described as “Morning Dose,” “Mid-Morning Dose,” 
“Afternoon Dose,” and “Evening Dose.”  
3.2.3. 
Methods to Minimize Bias 
To minimize bias, the following measures will be taken: 
Study product allocation (placebo versus drug product) 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 AND WITHDRAWAL 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 study product or until completion of the subject’s first 
menstrual cycle following the last administration of the study 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 study product or until completion of the subject’s first 
menstrual cycle following last administration of the study 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 study 
product or until completion of the subject’s first menstrual cycle following last 
administration of the study 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 study product or until completion of the 
subject’s first menstrual cycle following administration of the study product, 
whichever period of time is longer.  
NOTE: For Depo-Provera injection contraceptives, the statement regarding 
first menstrual cycle following administration of the study 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 study product or until completion of the subject’s first menstrual cycle 
following administration of the study product, whichever period of time is 
longer. 
 
 


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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), 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 study product) within 14 
days prior to cataract surgery and for the duration of the study 
4. Require concurrent ocular therapy with immunosuppressants (e.g., Restasis®) within 30 
days prior to surgery and for the duration of the study. 
5. Require change in treatment with anticholinergics, systemic immunosuppressive agents, 
oral steroids (dose must be less than 11 mg/day) 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 study 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. 
10. Use any topical eyelash growth medications within 7 days prior to surgery and for the 
duration of the study 
11. Use TNF-blocking agents (e.g., etanercept, adalimumab, infliximab) within two days 
prior to surgery and for the duration of the study  
12. Have history of glaucoma, IOP >21 mmHg at the screening or randomization visit(s), or 
are being treated for glaucoma in either eye. 
13. Wear contact lenses for 4 weeks prior to Visit 1 and throughout the study. 


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14. Be monocular or have Snellen Distance VA by pinhole method of 20/200 or worse in the 
non-study eye. 
15. Have had penetrating intraocular surgery in the study eye within 3 months or within two 
weeks in the fellow eye.   
16. Have had selective laser trabeculoplasty (SLT) within 3 months prior to surgery. 
17. Have had corneal refractive surgery, glaucoma surgery, or corneal transplantation (full 
thickness, anterior, or posterior) within the past year or are unstable and/or require 
medication. 
18. 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. 
19. Have been exposed to an investigational drug within 30 days prior to screening or up to 
18 days following surgery. 
20. 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. 
21. Have a known history of alcohol and/or drug abuse. 
22. 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.  
 
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). 
4.4. 
SUBJECT WITHDRAWAL CRITERIA 
Any subject who wishes to withdraw from the study on his or her own accord for any reason 
is entitled to do so without obligation. The Investigator may remove any subject from the 
study, if it is deemed necessary.  


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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 subject should remain in 
the study and continue to be evaluated at the regularly scheduled visits. In the event study 
discontinuation of a randomized subject is necessary, the Investigator should make every 
attempt to have subject complete Visit 6 assessments and/or follow through until Investigator 
deems the reason for study discontinuation has resolved, if applicable. If a non-serious 
adverse event (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. 
Subjects who withdraw from the study will not be replaced. 


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5. 
PROCEDURES 
Written Informed Consent and HIPAA authorization will be obtained from all subjects prior 
to any study procedures being performed. 
5.1. 
VISIT DESCRIPTION 
5.1.1. 
Visit 1:  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:  
• Each subject that is screened will be assigned a Subject Identification (ID) 
consisting of a three-digit Investigator number plus a three-digit number starting 
with number 001. The Subject ID will be used as the primary subject identifier for 
the duration of the study    
• Non-ocular and ocular medical history 
• Concomitant medication usage and medications taken during the 30 days prior to 
screening will be captured in the case report form (CRF) 
• Inclusion/exclusion criteria  
• Urine pregnancy test (UPT) for women of childbearing potential 
• Snellen Distance 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  
• IOP Measurement 
• Dilated Ophthalmoscopy 
Instructions to subject: 
• Subjects will be informed of the date and time for their cataract surgery 
• Subjects will be asked to return for Visit 2/Surgery as scheduled within 14 days 
5.1.2. 
Visit 2:  Surgery Visit (Day 0) 
Pre-surgical Procedures: 
This visit will occur no more than 14 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 
• Occurrence of any AEs since the last visit 
• Routine pre-surgical care and procedures as determined by the Investigator 


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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. 
• The subject will receive routine post-surgical care and instructions for the cataract 
surgery as determined by the Investigator. 
• Medications routinely administered prior to and following cataract surgery will be 
collected in the source and CRF. These medications will be indicated for routine 
cataract surgery and are not expected to be associated with treatment for AEs unless 
otherwise indicated. 
• The subject will be instructed 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 either BID or QID dosing 
of study 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:  
• Use of any concomitant medications since the last visit 
• 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.) 
• Subject-Rated Ocular Pain Assessment 
• Snellen Distance 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 
• IOP Measurement 
NOTE:  All ocular assessments must be performed in each eye. 
• Upon verification of study eligibility (Section 4.3), all eligible subjects will be 
randomized to receive four times per day dosing of either 0.25% KPI-121 drug 
product or Placebo A OR two times per day dosing of either 1.0% KPI-121 drug 


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product or Placebo B.  The following will be performed for all randomized 
subjects:  
o The first dose of double-masked study product will be administered in the 
clinic under the supervision of designated study personnel.  Prior to 
administration of study product, subjects will be reminded on the proper 
method for instillation including but not limited to shaking study product 
bottle prior to each instillation. Since subjects will receive one (1) dose of 
study product in the clinic, they will self-administer at most three (3) 
additional doses of study product on the first day if assigned to the QID 
groups or one (1) additional dose of study product if assigned to the BID 
dosing group.   
• Assess the occurrence of any AEs after study product administration 
• Study product kits and instructions for administration will be dispensed 
• Subjects will be scheduled 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 3 or 4 and the following evaluations will be performed/assessed:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• Subject-Rated Ocular Pain Assessment 
• Snellen Distance VA by pinhole method 
• Slit Lamp Biomicroscopy: 
o Signs of anterior ocular inflammation (i.e., cell and flare grading) 
o Palpebral conjunctival erythema, corneal edema, hyphema, ciliary flush, 
bulbar conjunctival injection 
• IOP Measurement 
• Dosing compliance will be reviewed and assessed. If needed, the second bottle of 
study product will be dispensed to the subject. 
• Subjects will be asked to return for Visit 5 on Day 8 ±1. 
5.1.5. 
Visit 5:  Study Visit (Day 8 ±1 day) 
This visit will occur on Day 8 ±1 and the following evaluations will be performed/assessed:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• Subject-Rated Ocular Pain Assessment 
• Snellen Distance VA by pinhole method 
• Slit Lamp Biomicroscopy: 


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o Signs of anterior ocular inflammation (i.e., cell and flare grading) 
o Palpebral conjunctival erythema, corneal edema, hyphema, ciliary flush, 
bulbar conjunctival injection 
• IOP Measurement 
• Dosing compliance will be reviewed and assessed.  If needed, the second bottle of 
study product will be dispensed to the subject. 
• Subjects will be asked to discontinue study product upon return for Visit 6 on Day 
15 ±1.   
5.1.6. 
Visit 6:  End of Study Product Use (Day 15 ±1 day) 
The end of study product use visit will occur on Day 15 ±1 and the following will be 
performed/assessed:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• Collect used and unused study product 
• UPT 
• Subject-Rated Ocular Pain Assessment 
• Snellen Distance VA by pinhole method 
• Slit Lamp Biomicroscopy  
o Signs of anterior ocular inflammation (i.e., cell and flare grading) 
o Palpebral conjunctival erythema, corneal edema, hyphema, ciliary flush, 
bulbar conjunctival injection 
• IOP Measurement 
• Dilated Ophthalmoscopy 
• Dosing compliance will be reviewed and assessed. 
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 17-19 for 
Visit 7. 
5.1.7. 
Visit 7:  Follow-Up Visit (Days 17-19) 
This follow-up visit will occur on Day 17 to 19 and the following will be performed/assessed:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• Subject-Rated Ocular Pain Assessment 
• Snellen Distance VA by pinhole method 


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• Slit Lamp Biomicroscopy  
o Signs of anterior ocular inflammation (i.e., cell and flare grading) 
o Palpebral conjunctival erythema, corneal edema, hyphema, ciliary flush, 
bulbar conjunctival injection  
• 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:  
• Use of any concomitant medications since the last visit 
• Occurrence of any AEs since the last visit 
• UPT 
• Used and unused study product collected and compliance assessed via the daily 
dosing information recorded by the subject. 
• Subject-Rated Ocular Pain Assessment 
• Snellen Distance VA by pinhole method 
• Slit Lamp Biomicroscopy  
o Signs of anterior ocular inflammation (i.e., cell and flare grading) 
o Palpebral conjunctival erythema, corneal edema, hyphema, ciliary flush, 
bulbar conjunctival injection 
• IOP Measurement 
• Dilated Ophthalmoscopy 
5.2. 
DISCONTINUATION CRITERIA 
Study product use may be discontinued and any subject may be withdrawn 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. Termination of the study by the Sponsor, FDA, or other regulatory authorities. 


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In the event that discontinuation of study product is necessary, the Investigator will make 
every attempt to complete all subsequent safety and efficacy assessments. The reason for 
premature discontinuation should be entered onto the CRF and recorded in the subject chart. 
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. 
 


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6. 
TREATMENT OF SUBJECTS 
6.1. 
STUDY PRODUCTS TO BE ADMINISTERED 
KPI-121 drug product (0.25% or 1.0%) 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 controlled 
room temperature (15-25°C/59-77°F). 
Subjects will be asked to administer study product either twice or four times each day 
depending on assignment. Prior to each instillation of study product, subject will be instructed 
to shake study product bottle. The subjects will record daily, the time of administration of 
each dose of study product (Appendix 7). Compliance with instillation of study product will 
be reviewed and assessed at each clinic visit. 
6.2. 
CONCOMITANT MEDICATIONS 
All medications 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. 
• Medications routinely administered and not explicitly prohibited in this protocol used 
prior to and following uncomplicated cataract surgery are allowed. These medications 
will be collected in the source and eCRF as indicated for routine cataract surgery and 
are not expected to be associated with treatment for AEs unless otherwise indicated. 
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) 
• Mast cell stabilizers 
• Antihistamines 
• Decongestants  


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• All eye drops (except antibiotic eye drops considered to be included in post cataract 
surgery standard of care treatment)  
• Glaucoma medications 
• All topical ophthalmic gels or artificial tears 
• TNF-blocking agents (e.g., etanercept, adalimumab, infliximab) 
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 immunosuppressant (e.g., Restasis®) 
• Other investigational products 
Within 6 months prior to the screening visit (Visit 1) alterations to the dose of the following 
are disallowed: 
• Anticholinergics 
• Antidepressants (stable dose of PRN treatment acceptable) 
• Systemic immunosuppressive agents 
• Oral steroids (dose must be less than 11 mg/day)  
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 


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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 at controlled 
room temperature (15-25°C/59-77°F) in an area limited with controlled access. 
At the end of the study, all study materials, including any unused study product (KPI-121 
drug 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 
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 D.A.T.A., Inc. or 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) 
• 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.  
NOTE: Events that are related and expected due to uncomplicated cataract surgery 
should not be classified as an AE. 
 
 


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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 study 
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 study product use. 
Unlikely:  
• Poor temporal relationship with study product use. 
• Event easily explained by subject’s clinical state or other factors. 
Possible: 
 Reasonable temporal relationship with study product use. 
 Event could be explained by subject’s clinical state or other factors.  
Probable: 
 Reasonable temporal relationship with study product use. 
 Likely to be known reaction to agent or chemical group, or predicted by known 
pharmacology. 
 Event cannot easily be explained by subject’s clinical state or other factors. 


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Definite:  
• Distinct temporal relationship with study 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 
Typically, the time that the informed consent is signed by the subject is designated as the start 
of safety data collection. 
If a subject will not formally enter a trial until several days or longer after the informed 
consent is signed, the day of randomization to treatment may be a more appropriate time to 
begin collecting safety information.  AEs occurring prior to randomization may be more 
appropriately considered medical history or pre-existing conditions. 
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, intensity, seriousness, causality (relationship to 
use of study 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 study 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. 
Expected changes resulting from routine uncomplicated cataract surgery will not be captured 
as AEs. Likewise, the presence of inflammation due to surgery is not an AE but rather the 
condition under investigation. 
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 


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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. Study product start date 
5. Date of last dose of study product  
6. Date study product reinitiated (if study 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 study product 
• Action taken with study 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 
 
 


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• Important medical events that may not result in death, were not life-threatening, or 
did not require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse.  
9. Concomitant medications 
10. Relevant history 
11. Possible causes of SAE other than study product 
12. Copy of AE page from the CRF 
NOTE: If an SAE occurs in any study involving KPI-121 that is unexpected and is 
determined to be related or possibly related to study product, all sites will be notified by the 
sponsor and each site should report it to their IRB.   
8.5. 
RESCUE THERAPY 
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). 
 


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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. 
If the two placebo groups demonstrate no statistically significant difference, they will be 
pooled for analysis. 
9.1.1. 
Subject Disposition, Demographic and Background Characteristics 
Subject disposition, demographic characteristics, and background variables will be 
summarized by study group.   
9.1.2. 
Analysis of Efficacy 
The primary analysis population will be the Intent-to-Treat (ITT) population, defined as all 
subjects randomized. A subset of efficacy analyses will be examined for the Efficacy 
Evaluable (EE) population defined as all subjects who were randomized, completed 14 days 
of study product use, had complete data at the Day 8 visit and 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) the difference in the 
proportion of study eyes with complete resolution of anterior chamber cells (grade = 0) at 
postoperative Day 8 maintained through end of study and no need for rescue medication for 
KPI-121 0.25% QID compared to placebo; (2) the difference in the proportion of study eyes 
with complete resolution of anterior chamber cells (grade = 0) at postoperative Day 8 
maintained through end of study and no need for rescue medication for KPI-121 1.0% BID 
compared to placebo;; (3) the difference in the proportion of study eyes with complete 
resolution of pain (grade = 0) at postoperative Day 8 maintained through end of study and no 
need for rescue medication for KPI-121 1.0% BID compared to placebo; and (4) the 
difference in the proportion of study eyes with complete resolution of pain (grade=0) at 
postoperative Day 8 maintained through end of study and no need for rescue medication for 
KPI-121 0.25% QID compared to 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 
 
If the two placebo groups demonstrate no statistically significant difference, they will be 
pooled for analysis. 
Using the hierarchical testing scheme, the first test will be the difference in the proportion of 
study eyes with complete resolution of anterior chamber cells (grade = 0) at postoperative 
Day 8 between the pooled placebo control group and the KPI-121 0.25% QID group using the 
chi-squared statistic. 
If this test is statistically significant at the two-sided alpha = 0.05 level in favor of the KPI-
121 0.25% QID group, then the difference in the proportion of study eyes with complete 
resolution of anterior chamber cells (grade = 0) at postoperative Day 8 between the pooled 
placebo control group and the KPI-121 1.0% BID group will be tested using the same 
statistic. 
If this test is statistically significant at the two-sided alpha = 0.05 level in favor of the KPI-
121 1.0% BID group, then the difference in the proportion of study eyes with complete 
resolution of pain (grade = 0) at postoperative Day 8 between the pooled placebo control 
group and the KPI-121 1.0% BID group will be tested using the same statistic. 
If this test is statistically significant at the two-sided alpha = 0.05 level in favor of the KPI-
121 1.0% BID group, then the difference in the proportion of study eyes with complete 
resolution of pain (grade = 0) at postoperative Day 8 between the pooled placebo control 
group and the KPI-121 0.25% QID group will be tested using the same statistic. 
Secondary endpoints will be the proportion of study eyes with complete resolution (grade = 0) 
of anterior chamber cells (scale 0-4) and complete resolution (grade = 0) of pain (scale 0-5) at 
Day 8 and at Day 15.  
Additional secondary endpoints are composite mean scores of anterior chamber cell and pain 
grades which will be summarized for each study group at each visit. 
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.   


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9.2. 
SAMPLE SIZE ESTIMATION 
A two group chi-squared test with a 0.05 two-sided significance level will have 91% power to 
detect the difference between a proportion of responders in either of the active dosing regimen 
groups of 0.31 and a combined placebo group proportion of 0.14 when the sample size in each 
group is 134. 
9.3. 
LEVEL OF SIGNIFICANCE 
The primary assessment of the dose-response with 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 
Any missing, unused, or spurious data will be noted in the final clinical study report.  Multiple 
imputation will be employed to analyze incomplete data sets under the assumption that 
missing data are, at worst, characterized as missing at random (MAR). The reasons for 
missing data will be recorded and the impact of these reasons and any treatment group 
imbalance on the assumption of MAR will be evaluated. 
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 ITT population) with at 
least one post-baseline (baseline = Visit 3) assessment. A subset of the efficacy analysis will 
be repeated using data from those subjects completing 14-days of study product use, fulfilling 
all study visits and achieving reasonable compliance with the study protocol (the EE 
population). 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 study product receipt, storage, disposition, and regulatory files 
related to the study. Monitors or designees will also assess the ongoing suitability of the 
investigative site throughout the study. 


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12. 
ETHICS 
12.1. 
Institutional Review Board 
This protocol and the informed consent form must be approved by an appropriately 
constituted and qualified IRB and the approvals made available to the sponsor or designee 
prior to the start of enrollment into the study based on these items. Materials used to recruit 
subjects will be approved by the appropriate IRB and the approvals made available to the 
sponsor or designee prior to their use. In addition, the Investigator’s Brochure should be 
submitted to the IRB. Written IRB approval must adequately identify the protocol and 
informed consent form. Copies of all approved materials, all correspondence with the IRB, 
and written approval from the IRB must be made available to the sponsor (or designated 
monitor). 
Any modification of study procedures or amendments to the protocol must be approved by the 
IRB prior to implementation. In the event that a modification or amendment is considered by 
the Investigator to be immediately necessary to ensure subject safety, the Investigator will 
promptly notify their 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 Good Clinical 
Practices (GCP) meeting 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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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) 
Days 17 - 19  
Informed Consent, HIPAA Authorization 
and Medical History 
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 
 
 
 
 
 
Subject-Rated Ocular Pain Assessment 
 
 
X 
X 
X 
X 
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 the Subject-Rated Ocular Pain Assessment to 
subjectively rate their pain at Visit 3 to 7. 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 
Conjunctiva 
Bulbar Conjunctival Injection 
 
0 = Absent 
 
1 = Mild 
 
2 = Moderate 
 
3 = Severe 
 
 


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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