Safety and Efficacy of KPI-121 1% Ophthalmic Suspension Versus Prednisolone Acetate Ophthalmic Suspension 1% for the Treatment of Inflammation Following Cataract Surgery in Children 0 to 3 Years of Age
Phase: PHASE3
Conditions: Ocular Inflammation
Sponsor: Kala Pharmaceuticals, Inc.

NCT03596723  
 
Study ID:  
KPI-121-C-010  
 
Study Title:  
Safety and Efficacy of KPI-121 1% Ophthalmic Suspension Versus Prednisolone 
Acetate Ophthalmic Suspension 1% for the Treatment of Inflammation Following 
Cataract Surgery in Children 0 to 3 Years of Age   
 
Date:  
11 Jul 2018 

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CONFIDENTIAL
KALA PHARMACEUTICALS, INC.
Clinical Protocol KPI-121-C-010
Project:
KPI-121
Compound Number/Name:
KPI-121 1%
Protocol Number:
KPI-121-C-010
Protocol Title:
Safety and Efficacy of KPI-121 1% Ophthalmic 
Suspension versus Prednisolone Acetate 
Ophthalmic Suspension 1% for the Treatment of
Inflammation Following Cataract Surgery in 
Children 0 to 3 Years of Age
Sponsor:
Kala Pharmaceuticals, Inc.
100 Beaver St, Suite 201
Waltham, MA 02453
Medical Monitor:
Issue Date:
Original:  14 Nov 2017
Amendment 1: 19 Dec 2017
Amendment 2: 16 Mar 2018
Amendment 3: 11 Jul 2018
Approved by:
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KALA PHARMACEUTICALS, INC.
Clinical Protocol KPI-121-C-010
Investigator Signature Page
Project:
KPI-121
Compound Number/Name:
KPI-121 1%
Protocol Number:
KPI-121-C-010
Protocol Title:
Safety and Efficacy of KPI-121 1% Ophthalmic 
Suspension versus Prednisolone Acetate Ophthalmic 
Suspension 1% for the Treatment of Inflammation 
Following Cataract Surgery in Children 0 to 3 Years 
of Age
Sponsor:
Kala Pharmaceuticals, Inc.
100 Beaver St, Suite 201
Waltham, MA 02453
Issue Date:
Original: 14 Nov 2017
Amendment 1: 19 Dec 2017
Amendment 2: 16 Mar 2018
Amendment 3: 11 Jul 2018
For Serious Adverse Event Reporting:
For Serious Adverse Event Questions:
Investigator Name (printed or typed):
________________________________________________
Investigator's Signature:
_______________________________________________ ______________
Date
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SYNOPSIS 
Study Title:
Safety and Efficacy of KPI-121 1% Ophthalmic Suspension versus 
Prednisolone Acetate Ophthalmic Suspension 1% for the Treatment 
of Inflammation Following Cataract Surgery in Children 0 to 3 
Years of Age
Objectives:
To compare the safety and efficacy of KPI-121 1% ophthalmic
suspension (KPI-121 1%) dosed twice daily versus prednisolone
acetate ophthalmic suspension 1% (prednisolone acetate 1%) dosed
four times daily in children 0 to 3 years of age following cataract
surgery.
Study Population: 
The study population will consist of pediatric subjects from 0 
through 3 years of age who have undergone routine, uncomplicated 
cataract surgery.
Number of 
Subjects:
Approximately 120 subjects who are candidates for cataract surgery 
will be screened. One study eye from approximately 60 subjects
will be randomized.
Investigational 
Products:
KPI-121 1% and vehicle or prednisolone acetate 1% will be 
supplied as investigational product.
Route and Duration 
of Administration:
Subjects will be randomized to either:
x
1-2 drops of KPI-121 1% and vehicle dosed two times per day
each for a total of four times per day (QID) instilled in the 
study eye for 29 days ± 2 days post-surgery, starting at the first 
post-operative assessment. This may be followed by treatment 
or taper using a commercially available product as determined 
by the Investigator.
OR
x
1-2 drops of prednisolone acetate 1% dosed QID instilled in 
the study eye for 29 days ± 2 days post-surgery, at the first 
post-operative assessment. This may be followed by treatment 
or taper using a commercially available product as determined 
by the Investigator.
Study Design:  
This is a Phase 3B, multicenter, double-masked, randomized, 
parallel-group, active-controlled study designed to evaluate the 
safety and efficacy of KPI-121 1% versus prednisolone acetate 1%
in controlling postoperative inflammation in children 0 to 3 years of 
age who have undergone cataract surgery. Approximately 120 
subjects who are candidates for cataract surgery will be screened.
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Subjects who meet all eligibility criteria and undergo routine, 
uncomplicated, cataract surgery will be randomized into this study 
at approximately 20 centers located in the United States (US). 
Subjects will be randomized into one of two study groups in an 
approximate 1:1 ratio. Subjects will be randomized to either:
o
BOTH KPI-121 1% ophthalmic suspension AND
KPI-121 vehicle dosed BID each for 29 days ± 2
OR
o
Prednisolone acetate ophthalmic suspension 1% 
dosed QID for 29 days ± 2 days.  
Dosing with investigational product will be initiated at the first 
post-operative assessment and will be instilled as one to two drops
in the surgery eye according to the assigned dosing regimen for 29
± 2 days. This may be followed by treatment or taper using a 
commercially available product as determined by the Investigator.
This study will include 6 clinic visits as well as the surgery visit
over 35 to 53 days total study duration. Visit 1 (Screening) will 
occur between 14 and 1 day(s) prior to surgery. Subjects who meet
preoperative screening inclusion/exclusion criteria will be entered 
into the study. On the day of surgery, subjects will undergo routine 
cataract surgery according to the Investigator’s normal procedures.
At the first post-surgery assessment, which may be later on the
same day of surgery or the following day, eligibility regarding 
inclusion and exclusion criteria will be confirmed and subjects will 
be randomized to one of the two treatment arms. The first dose of 
investigational product will be administered in the clinic, and
parents/guardians will be instructed how to dose and record 
investigational product use. This will be considered Day 1 (Visit 2).
Following randomization, subjects’ parents/caregivers will be 
instructed to return to the clinic to be evaluated on Day 8 ± 2 days
(Visit 3), Day 15 ± 2 days (Visit 4), Day 29 ± 2 days (Visit 5), and 
Day 36 ± 2 days (Visit 6). Additional investigational product will 
be dispensed at Visit 4. Investigational product will be discontinued 
at Visit 5. Used investigational product kits will be collected by the 
study staff at Visits 4 and 5. At Visit 5 further treatment or taper
with a commercially available product may be given as determined 
by the Investigator. Additionally, a phone contact will be made 
between Visits 4 and 5 (Day 21-23) to assess subject progress.
Subjects will return for a Follow-Up/Safety Visit on Day 36 ± 2
days (Visit 6).
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Assessments in this study will include (when obtainable):
x
Medical History Review
x
Age Appropriate Visual Acuity (VA)
x
Signs of anterior chamber ocular inflammation – cell and 
flare grading, corneal clarity, conjunctival injection, 
chemosis, hypopyon as well as vitritis and wound integrity 
x
Symptoms of anterior ocular inflammation – photophobia and 
lacrimation
x
Intraocular Pressure (IOP) Measurement 
x
Dilated Ophthalmoscopy
x
Modified Global Assessment of Postoperative Inflammation
x
Rescue Therapy Assessment
x
Assessment of Concomitant Medication Use 
x
Assessment of Adverse Events (AEs)
x
Dosing Compliance Assessment/Dosing Diary Review
Efficacy 
Evaluation:
Primary Efficacy Evaluation:
1. The proportion of study eyes with anterior chamber cell
grade = 0 at Visit 4 (Day 15 ± 2 days) without receiving rescue 
medication prior to Visit 4 as compared between the KPI-121
1% dose BID and the prednisolone acetate 1% dosed QID 
treatment arms.
Secondary Efficacy Evaluation:
1. The proportion of study eyes with a Modified Global Overall 
Assessment of Postoperative Inflammation Score = 0 at Visit 4
(Day 15 ± 2 days) without receiving rescue medication prior to 
Visit 4 as compared between the KPI-121 1% BID and the 
prednisolone acetate 1% QID treatment arms.
Statistical Analysis:
The efficacy and safety analyses will be based on a single study eye 
for each subject.  Each subject’s study eye will be defined as the 
surgery eye. All statistical analyses will be performed using 
Statistical Analysis System (SAS) software. 
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The primary analysis population will be the Intent-to-Treat (ITT) 
population, defined as all subjects randomized and with at least one 
post-baseline assessment. A subset of efficacy analyses, the Per 
Protocol (PP) population, will be repeated using data from those 
subjects who were randomized, completed 15 days ± 2 days of 
investigational product use, had complete data at Visit 4 (Day 15 ± 
2 days), and did not have significant protocol deviations. Rescued 
subjects will be included in the PP population if they did not have
significant protocol deviations: however, these subjects will be 
considered treatment failures.
No inferential statistical analyses are planned. Data will be 
summarized using descriptive statistics only. Assessment of 
efficacy will be based primarily on the number and percentage of 
subjects in each treatment group with an anterior chamber cell grade 
of 0 at Visit 4 (Day 15 ± 2 days) with no need for rescue medication 
through Visit 4 and, secondarily, on the Modified Global Overall 
Assessment of Postoperative Inflammation score of 0 at Visit 4
(Day 15 ± 2 days) without receiving rescue medication prior to Visit 
4.
The individual components of the Global Assessment score will 
also be evaluated (i.e., number and percentage of subjects in each 
treatment group in each score category at each visit). 
Safety Evaluations:
Assessment of AEs
Change from baseline to each post-surgery visit in ocular signs:
x
Visual Acuity
x
IOP Measurement
x
Dilated Ophthalmoscopy (at Visits 1 and 5 only)
Assessment of safety will be based on the assessment of AEs. To 
allow for at least a 95% chance of detecting an AE with a 10% 
incidence rate, a minimum sample size of 30 subjects per group 
(KPI-121 1% or prednisolone acetate 1%) is required.
Eligibility Criteria:
Inclusion Criteria:
At Visit 1, individuals of either gender and any race will be eligible 
for study participation if they:
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1. Have informed consent and Health Insurance Portability and 
Accountability Act (HIPAA) authorization provided by parent 
or guardian prior to any study-related procedures.
2. Are 0-3 years of age (have not had their 4th birthday) as of the 
date of surgery.
3.
Are candidates for routine, uncomplicated, cataract surgery 
a.
With or without capsulotomy and vitrectomy 
b. With or without posterior chamber intraocular lens 
(IOL) implantation
c.
But not combined with any other surgery. 
4.
Have a unilateral cataract or have bilateral cataracts and are 
candidates for surgery:
a.
On the first eye, and surgery on the second eye is not 
planned until after the subject completes participation in 
the study OR
b. On the second eye, and surgery on the first eye was 
uncomplicated,any post-operative inflammation has 
resolved and anterior chamber cell and flare grades both 
= 0.
Exclusion Criteria:
In order for subjects to be eligible at Visit 1 they may not:
1. Have a post-traumatic cataract. 
2. Have suspected permanent low vision or blindness in the 
fellow non-study eye. 
3. Have active uveitis in either eye. 
4. Have an ocular neoplasm in either eye. 
5. Have the presence of any active or suspected viral, bacterial, or 
fungal disease in the either eye. 
6. Have a history of glaucoma, ocular hypertension, steroid-
induced IOP rise or have an IOP >21 mmHg in either eye at the 
screening or randomization visit(s).
7. Require the use of any topical ophthalmic medication in the 
study eye within 2 days prior to surgery and for the duration of 
the study, except for drops that are needed to examine the eye 
or to prepare for and undergo surgery as well as post-operative 
antibiotic drops. NOTE: Besifloxacin Ophthalmic Suspension 
is not permitted within 2 days prior to surgery or for the 
duration of the study.
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8. Require the use of systemic or ocular non-steroidal anti-
inflammatory drugs within 2 days prior to surgery and for the 
duration of the study.
9. Require treatment with systemic, inhaled, or ocular 
corticosteroids within 14 days prior to surgery and for the 
duration of the study with the exception of intraoperative 
ocular corticosteroids.
10. Require a change in use of nutraceuticals or multivitamins 
within 2 days prior to surgery and for the duration of the study.
11. Have known hypersensitivity or contraindication to the 
investigational product(s) or their components.
12. Have a diagnosis of:
a) Severe/serious ocular condition that in the judgment of the 
Investigator could confound study assessments or limit 
compliance.
b) Severe/serious systemic disease or uncontrolled medical 
condition that in the judgment of the Investigator could 
confound study assessments or limit compliance.
13. Have been exposed to an investigational product within 30 
days prior to surgery.
Randomization Criteria:
To qualify for randomization at Visit 2 (1st post-surgery assessment
which may be later on the day of surgery or the following day), a
subject must:
1. Have undergone routine, uncomplicated, cataract surgery, with 
or without capsulotomy and/or anterior vitrectomy and with or 
without posterior chamber IOL implantation.
2. Continue to meet inclusion/exclusion criteria with respect to 
current ocular and medical conditions and medications.
3. Continue to have IOP < 21 mmHg in both eyes.
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...................... 14 
1. 
INTRODUCTION............................................................................ 15 
1.1. 
DESCRIPTION OF INVESTIGATIONAL PRODUCT................................... 15 
1.2. 
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE
SELECTION......................................................................................... 16 
1.3. 
GCP COMPLIANCE............................................................................. 16 
1.4. 
POPULATION TO BE STUDIED ............................................................. 16 
2. 
TRIAL OBJECTIVES AND PURPOSE.......................................... 17 
2.1. 
OBJECTIVE......................................................................................... 17 
3. 
TRIAL DESIGN............................................................................... 18 
3.1. 
PRIMARY EFFICACY EVALUATION..................................................... 18 
3.2. 
SECONDARY EFFICACY EVALUATION................................................ 18 
3.3. 
SAFETY ENDPOINTS........................................................................... 18 
3.4. 
DESCRIPTION OF TRIAL DESIGN......................................................... 18 
3.4.1. 
Investigational Product ..................................................................... 20 
3.4.2. 
Methods to Minimize Bias................................................................ 23 
4. 
SELECTION OF SUBJECTS .......................................................... 24 
4.1. 
SUBJECT INCLUSION CRITERIA .......................................................... 24 
4.2. 
SUBJECT EXCLUSION CRITERIA ......................................................... 24 
4.3. 
RANDOMIZATION CRITERIA............................................................... 25 
5. 
PROCEDURES ................................................................................ 26 
5.1. 
VISIT DESCRIPTIONS.......................................................................... 26 
5.1.1. 
Visit 1:  Screening Visit (Day -14 to Day -1)................................... 26 
5.1.2. 
Surgery.............................................................................................. 27 
5.1.3. 
Visit 2:  First Post-Operative Assessment Visit (This may be later on 
the day of surgery or the following day. This will be considered Day 
1)....................................................................................................... 27 
5.1.4. 
Visit 3:  Study Visit (Day 8 ± 2 days) .............................................. 28 
5.1.5. 
Visit 4:  Study Visit (Day 15 ± 2 days) ............................................ 29 
5.1.6. 
Mid-Visit Phone Contact (Day 21 - 23) ........................................... 30 
5.1.7. 
Visit 5:  End of Investigational Product Use (Day 29 ± 2 days) ...... 30 
5.1.8. 
Visit 6:  Follow-Up Visit (Day 36 ± 2 days) .................................... 31 
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5.1.9. 
Unscheduled Visit............................................................................. 31 
5.1.10. 
Early Termination Visit .................................................................... 31 
5.2. 
SUBJECT WITHDRAWAL AND/OR DISCONTINUATION......................... 32 
5.3. 
COLLECTION OF DATA....................................................................... 33 
5.4. 
RESCUE MEDICATION USE................................................................. 33 
6. 
TREATMENT OF SUBJECTS........................................................ 34 
6.1. 
INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED......................... 34 
6.2. 
CONCOMITANT MEDICATIONS........................................................... 34 
6.2.1. 
Permitted Medications...................................................................... 34 
6.2.2. 
Medications Not Permitted............................................................... 35 
6.3. 
INVESTIGATIONAL PRODUCT USE COMPLIANCE................................ 35 
6.4. 
DRUG ACCOUNTABILITY ................................................................... 35 
6.5. 
MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING 
THE CODE .......................................................................................... 36 
7. 
ASSESSMENT OF EFFICACY ...................................................... 38 
7.1. 
EFFICACY PARAMETERS .................................................................... 38 
8. 
ASSESSMENT OF SAFETY........................................................... 39 
8.1. 
SAFETY PARAMETERS........................................................................ 39 
8.2. 
ADVERSE EVENT DEFINITIONS .......................................................... 39 
8.3. 
PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR................. 41 
8.4. 
SERIOUS ADVERSE EVENT REPORTING BY THE INVESTIGATOR ......... 42 
9. 
STATISTICS .................................................................................... 44 
9.1. 
STATISTICAL METHODS..................................................................... 44 
9.1.1. 
Subject Disposition, Demographic and Background Characteristics44 
9.1.2. 
Evaluation of Efficacy...................................................................... 44 
9.1.3. 
Analysis of Safety............................................................................. 46 
9.2. 
SAMPLE SIZE ESTIMATION................................................................. 46 
9.3. 
LEVEL OF SIGNIFICANCE.................................................................... 46 
9.4. 
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS 
DATA................................................................................................. 46 
9.5. 
PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL 
PLAN.................................................................................................. 46 
9.6. 
SUBJECTS TO BE INCLUDED IN THE ANALYSIS ................................... 46 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS............... 48 
11. 
QUALITY CONTROL..................................................................... 49 
12. 
ETHICS ............................................................................................ 50 
12.1. 
Institutional Review Board............................................................... 50 
12.2. 
Informed Consent Requirements ...................................................... 50 
13. 
DATA HANDLING AND RECORDKEEPING............................. 51 
13.1. 
Data Quality Control and Reporting................................................. 51 
13.2. 
Records Retention............................................................................. 51 
14. 
PUBLICATION POLICY ................................................................ 52 
15. 
REFERENCES ................................................................................. 53 
16. 
APPENDICES .................................................................................. 54 
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LIST OF TABLES
TABLE 1: 
COMPOSITION OF KPI-121 1.0% (W/V) INVESTIGATIONAL PRODUCT 21 
TABLE 2: 
Composition of KPI-121 Vehicle..................................................... 21
 
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LIST OF FIGURES
Figure 1: 
Study Schematic ............................................................................... 20 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
AE
Adverse Event
AR
Adverse Reaction
BID
Twice Daily
qC
Degrees Celsius
CRF
Case Report Form
CRO
Contract Research Organization
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
qF
Degrees Fahrenheit
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Conference on Harmonization
ID
Identification
IOL
Intraocular Lens
IOP
Intraocular Pressure
IRB
Institutional Review Board
ITT
Intent-to-Treat
LE
Loteprednol etabonate
LDPE
Low-Density Polyethylene
MedDRA
Medical Dictionary for Regulatory Activities 
mL
Milliliter
mmHg
Millimeter of Mercury
PDF
Portable Document Format
pH
PP
Potential of Hydrogen
Per Protocol
QID
Four Times Daily
SAE
Serious Adverse Event
SAR
Suspected Adverse Reaction
SAS
Statistical Analysis System
SOPs
Standard Operating Procedures
US
United States of America
USP
United States Pharmacopeia
VA
Visual Acuity
w/v
Weight to Volume
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1.
INTRODUCTION
The most frequent surgery in ophthalmology is cataract extraction and intraocular lens
(IOL) implantation in adult patients with age-related cataracts. Most controlled clinical
trials evaluating the anti-inflammatoryactivity of topical corticosteroids have been
conducted in this patient population and have demonstrated efficacy in the treatment of 
both inflammation and pain following cataract surgery.
Children also experience cataracts, which are often treated via surgery, although the
incidence is significantly less than in adults. Pediatric cataract is a major cause of 
preventable childhood blindness, affecting approximately 200,000 children worldwide,
with an estimated prevalence ranging from three to six per 10,000 live births (Foster, 
Gilbert, & Rahi, 1997; Holmes, Leske, Burke, & Hodge, 2003; Stayte, Reeves, &
Wortham, 1993).  Pediatric cataracts are characterized as congenital if present within the
first year of life, developmental if present after infancy, or traumatic if caused by injury.
As in adults, the most common treatment for cataract in the pediatric population is
cataract extraction. Pediatric cataract surgery has historically been associated with a
high incidence of postoperative inflammation, which is most commonly treated with
topical corticosteroids (Sharma, Pushker, Dada, Vajpayee, & Dada, 1999; Zwaan,
Mullaney, Awad, Al-Mesfer, & Wheeler, 1998). Although improvements in surgical
techniques and IOL design have improved outcomes in pediatric cataract surgery, 
postoperative inflammation is still a concern for these patients (Medsinge & Nischal,
2015). Topical corticosteroids are generally considered to have significant anti-
inflammatory activity in pediatric patients, despite a dearth of controlled studies in this
population. In the American Academy of Ophthalmology Pediatric Ophthalmology
Education Center’s publication ‘Pediatric Cataracts: Overview’ the following is stated: 
“Prednisolone eye drops are the mainstay of treatment to control severe inflammation,
which is generally inevitable” (Wilson, 2016).
1.1.
DESCRIPTION OF INVESTIGATIONAL PRODUCT
KPI-121 1% contains submicron particles of loteprednol etabonate (LE) suspended in a 
formulation consisting of excipients that have been used in other FDA-approved 
ophthalmic products.  Each mL of KPI-121 1% ophthalmic suspension contains 10 mg 
loteprednol etabonate as the active ingredient.
Kala Pharmaceuticals, Inc. is 
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developing this novel loteprednol etabonate formulation for the treatment of 
postoperative anterior segment inflammation and pain.
KPI-121 vehicle has the same excipient composition as KPI-121 1% ophthalmic 
suspension with the exception of the active drug, LE.
Pred Forte® (prednisolone acetate ophthalmic suspension, USP) 1%, an approved
glucocorticoid product, will be purchased and supplied to sites as the active comparator
product. Pred Forte® contains prednisolone acetate (microfine suspension) 1% as the 
active ingredient. Inactive ingredients are benzalkonium chloride (as preservative); boric 
acid; edetate disodium; hypromellose; polysorbate 80; purified water; sodium bisulfite; 
sodium chloride; and sodium citrate. The pH during its shelf life ranges from 5.0 - 6.0.
For additional details on toxicology studies and the respective safety profiles, see the 
KPI-121 Investigator’s Brochure and the Pred Forte® package insert.
1.2.
JUSTIFICATION FOR ROUTE OF ADMINISTRATION AND DOSE SELECTION
KPI-121 1% and prednisolone acetate 1% will be administered as topical ophthalmic 
suspensions. Direct instillation into the eye 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. KPI-121 1% dosed BID has been shown to be safe and effective in adults (Kim, 
Gupta, Holland and Brazzell, 2018). Prednisolone acetate 1% dosed QID has been shown 
to be safe and effective in both adults and children (Wilson, 2016).
1.3.
GCP COMPLIANCE
This clinical trial will be conducted in compliance with the protocol, International 
Conference on Harmonization (ICH) guidelines, Good Clinical Practices (GCP) 
guidelines and other applicable regulatory requirements.
1.4.
POPULATION TO BE STUDIED
Approximately 120 subjects, from 0 - 3 years of age, who are candidates for cataract 
surgery will be screened. The surgical/study eye from approximately 60 subjects who 
have undergone routine, uncomplicated, cataract surgery, with or without capsulotomy 
and vitrectomy and with or without posterior chamber intraocular lens (IOL) 
implantation, but not combined with any other surgery, will be randomized and evaluated 
at approximately 20 centers located in the US.
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2.
TRIAL OBJECTIVES AND PURPOSE
2.1.
OBJECTIVE
The primary objective of this study is to investigate the safety and efficacy of 
KPI-121 1% ophthalmic suspension given BID compared to prednisolone acetate
ophthalmic suspension 1% given QID in pediatric subjects who have undergone routine, 
uncomplicated cataract surgery.
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3.
TRIAL DESIGN
3.1.
PRIMARY EFFICACY EVALUATION
The primary efficacy evaluation is the proportion of study eyes with anterior chamber 
cell grade = 0 at Visit 4 (Day 15 ± 2 days) without receiving rescue medication prior to 
Visit 4 as compared between the KPI-121 1% dosed BID and the prednisolone acetate
1% dosed QID treatment arms.
3.2.
SECONDARY EFFICACY EVALUATION
The secondary efficacy evaluation is the proportion of study eyes with a Modified Global 
Overall Assessment of Postoperative Inflammation Score = 0 at Visit 4 (Day 15 ± 2 days)
without receiving rescue medication prior to Visit 4 as compared between the KPI-121
1% BID and the prednisolone acetate 1% QID treatment arms.
3.3.
SAFETY ENDPOINTS
Safety evaluations will include:
x
Assessment of AEs
x
Visual Acuity
x
IOP Measurement
x
Dilated Ophthalmoscopy (assessed at visits 1 and 5 only)
Ocular assessments will be summarized at each post-surgery and compared between the 
KPI-121 1% dosed BID and the prednisolone acetate 1% dosed QID treatment arms.
3.4.
DESCRIPTION OF TRIAL DESIGN
This is a Phase 3B, multicenter, double-masked, randomized, parallel-group, active-
controlled study designed to evaluate the safety and efficacy of KPI-121 1% versus
prednisolone acetate 1% in pediatric subjects who undergo cataract surgery.
Approximately 120 subjects, from 0 - 3 years of age, who are candidates for cataract 
surgery will be screened. Approximately 60 subjects, after undergoing routine, 
uncomplicated, cataract surgery, will be randomized into this study at approximately 20
centers located in the US.  
Subjects who meet all eligibility criteria will be randomized to one of two treatment arms
in an approximate 1:1 ratio: 
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x
KPI-121 1% BID AND vehicle BID, to support the masking of the 
investigational product
x
Prednisolone acetate 1% QID
Dosing of investigational product will be initiated at the first post-surgery assessment, 
Visit 2 (Day 1), instilled as 1-2 drops in the study eye. The first dose of investigational 
product will be administered by the subject’s parent/caregiver under the supervision of a 
dedicated dosing coordinator who is otherwise uninvolved in the assessment or 
evaluation of the subject.
This study will include up to 6 clinic study visits and a phone contact and 35 to 53 days
total study duration. Visit 1 (Screening) will occur between 14 and 1 day(s) prior to 
surgery and subjects who meet preoperative screening inclusion/exclusion criteria will be 
entered into the study. On the day of Surgery, subjects will undergo routine cataract 
surgery according to the Investigator’s normal procedures. The first post-surgery
assessment, which may be later on the same day of surgery or the following day will be 
considered Visit 2 (Day 1). At this visit, subjects who continue to meet the eligibility 
criteria will be randomized to one of the two study groups and will initiate dosing with 
investigational product. Following randomization, the subject’s parent/caregiver will be 
instructed to instill investigational product in the study eye four times a day (QID) for 29
days ± 2 days up until Visit 5. The subject will return to the clinic to be evaluated at Visit 
3 (Day 8 ± 2 days), Visit 4 (Day 15 ± 2 days) and Visit 5 (Day 29 ± 2 days/End of 
Investigational Product Use Visit). A phone contact will be made between Visits 4 and 5 
(Day 21 -23) to assess subject progress.
Investigational product will be discontinued and collected at Visit 5. This may be 
followed by treatment or taper using a commercially available product as determined by 
the Investigator. Subjects will return for a follow up visit, Visit 6 (Day 36 ± 2 days) then 
will be released from the study. 
A summary of events is provided in Appendix 1. Assessments in this study will include
(when obtainable):
x
Medical History Review
x
Visual Acuity, (Snellen, Optotype recognition, Central/Steady/Maintained 
with Fix and Follow or Fix and Follow alone per the subject’s age and as 
determined by the Investigator and used for all study visits for the subject)
(Appendix 2)
x
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon, as well as vitritis and 
wound integrity, (Slit lamp biomicroscopy, ophthalmoscopy or light 
examination depending on subject’s tolerance.  The method used for these 
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assessments will be determined by Investigator and used for all study 
visits for the subject) (Appendix 3)
x
Symptoms of anterior ocular inflammation – photophobia and lacrimation
x
IOP Measurement (Appendix 4)
x
Dilated Ophthalmoscopy (Appendix 5)
x
Modified Global Overall Assessment of Postoperative Inflammation 
(Appendix 6)
x
Rescue Therapy Assessment
x
Concomitant Medication Use Assessment 
x
Assessment of Adverse Events
x
Dosing Compliance Assessment/Dosing Diary Review (Appendix 7)
A study schematic follows (Figure 1).
FIGURE 1: STUDY SCHEMATIC
Screening
 
Surgery 
Treatment
KPI-121 1% Ophthalmic Suspension + KPI-121 vehicle
(30 Subjects)
Follow-Up
Treatment
Prednisolone Acetate 1% Ophthalmic Suspension 
(30 Subjects)
Visit 1 
Cataract 
Surgery
Visit 2
Day 1
(day of surgery 
or following 
day)
Visit 3
Day 8 r 2
days
Visit 4
Day 15 r 2
days
Phone
Contact
Day 21-23
days
Visit 5
Day 29 r 2
days
Visit 6
Day 36 r
2 days
-14 to -1
days prior 
to surgery 
Randomization
Treatment
Treatment
Treatment
End of IP 
Use
Off Study
No
Dosing 
No
Dosing
First use of IP 
QID Dosing
QID Dosing
QID Dosing
QID Dosing
Last Dosing
No 
Dosing
3.4.1.
Investigational Product
KPI-121 1% ophthalmic suspension is a sterile, aqueous, submicron suspension of 
loteprednol etabonate (LE). Each mL of KPI-121 1% ophthalmic suspension contains 
10 mg of LE as the active ingredient.  
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KPI-121 1% ophthalmic suspension will be supplied in a white, low-density polyethylene 
(LDPE) bottle with a controlled-drop, linear low-density polyethylene tip and a pink,
high-density polyethylene cap. The dropper bottle also has a white LDPE tamper-evident 
overcap which, when removed, exposes the pink screw cap for opening the bottle and 
dispensing the product.  KPI-121 1% is supplied as a minimum fill of 2.8 mL in a 5-mL
bottle.
KPI-121 vehicle will be supplied in the same type of bottle/tip/cap configuration and will 
contain all components at the concentrations used in the KPI-121 1% ophthalmic 
suspension with the exception of the active component, LE.
TABLE 1:
COMPOSITION OF KPI-121 1.0% (W/V) INVESTIGATIONAL PRODUCT
Ingredient
Function
Concentration
(% w/v)
Loteprednol etabonate
Active pharmaceutical ingredient
1.0
TABLE 2:
COMPOSITION OF KPI-121 VEHICLE
Ingredient
Function
Concentration (% 
w/v)
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Pred Forte® (prednisolone acetate ophthalmic suspension, USP) 1% contains the active 
ingredient prednisolone acetate (microfine suspension) 1%. Other ingredients include 
benzalkonium chloride as a preservative; boric acid; edetate disodium; hypromellose; 
polysorbate 80; purified water; sodium bisulfite; sodium chloride; and sodium citrate. 
The exact concentrations of excipients are unpublished. The pH during its shelf life 
ranges from 5.0 - 6.0.
Pred Forte® (prednisolone acetate ophthalmic suspension, USP) 1% will be supplied as 1
ml of sterile aqueous suspension in opaque white 5 mL LDPE plastic dropper bottles with 
white, high impact polystyrene caps. The commercial bottle label will be over-wrapped to 
cover the commercial label, and then a masked clinical trial label will be applied to the 
overwrap. masked clinical trial label. 
Subjects’ parents/caregivers will be instructed to shake the investigational product bottle
well before every use.
The randomized investigational product kits to be dispensed will consist of a box with 
four dropper bottles, labeled Bottle 1 through Bottle 4.
At Visit 2, eligible subjects’ parents/caregivers will receive an investigational product kit
containing four bottles. Parents/caregivers will be instructed to dose with 1-2 drops of 
Bottle 1 in the morning, followed by 1-2 drops of Bottle 2 at midday, 1-2 drops of Bottle 
3 in the afternoon, and 1-2 drops of Bottle 4 at bedtime. This treatment schedule will be 
followed for 29 days ± 2 days. All bottles should be stored upright and shaken well
before dosing.
Subjects randomized to KPI-121 1% will receive investigational product kits containing 
both KPI-121 1% (Bottles 1 and 4) and vehicle (Bottles 2 and 3). Thus, the treatment 
schedule will result in QID dosing with 2 of the doses KPI-121 1% and 2 of the doses 
vehicle.
Subjects randomized to prednisolone acetate 1% will receive kits with 4 bottles of 
prednisolone acetate 1%, for QID dosing.
Subject’s parent/caregiver will return their kits (and bottles) and receive a new kit 
containing the same product at Visit 4 to ensure sufficient investigational product through 
Visit 5. At Visit 5 they will return their second kit and end investigational product use. 
Completion of investigational product use may be followed by treatment or taper with a 
commercially available product as determined by the Investigator.
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All kit labels and dropper bottle labels will contain the following information: sponsor 
name, protocol and kit number, storage temperature, and required statement(s) per the 
appropriate regulatory agency. The dropper bottle labels will also be printed with the 
bottle number (e.g., Bottle 1, Bottle 2, etc.).
Subjects’ parents/caregivers will be instructed to shake the investigational product bottle
well prior to administering each dose.  When subjects receive the first dose administered 
in the clinic, the dose will count as one of the daily doses. Parents/caregivers will then 
administer the additional doses of investigational product later that day, according to the 
dosing schedule and instructions provided by the dosing coordinator.
The Investigator will store all investigational product upright in a secure area, with 
limited access, at controlled room temperature (15-25qC/59 -77qF). Parents/caregivers 
will be instructed to store the investigational product upright at room temperature.
3.4.2.
Methods to Minimize Bias
To minimize bias, the following measures will be taken:
x
Investigational product assignment (KPI-121 1% ophthalmic suspension
or prednisolone acetate ophthalmic suspension 1%) will be randomized 
and masked to the sponsor, subjects, and investigative staff with the 
exception of a dedicated dosing coordinator. The dedicated dosing 
coordinator will manage drug dispensing and return, parent/caregiver 
instruction and initial dosing and will review the dosing diary. Since the 
KPI-121 1% ophthalmic suspension is only dosed BID, it will be 
supplemented with BID dosing of vehicle to support the masking.
x
The randomization schedule will be generated by the randomization 
statistician (who is not on the project team) or designee and maintained via 
the electronic data capture system (EDC) used for the trial.
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4.
SELECTION OF SUBJECTS
4.1.
SUBJECT INCLUSION CRITERIA
At Visit 1, individuals of either gender and any race will be eligible for study 
participation if they:
1. Have informed consent and Health Insurance Portability and 
Accountability Act (HIPAA) authorization provided by a parent or 
guardian prior to any study-related procedures.
2. Are 0-3 years of age (have not had their 4th birthday) as of the date of 
surgery.
3.
Are candidates for routine, uncomplicated, cataract surgery 
a.
With or without capsulotomy and vitrectomy 
b. With or without posterior chamber intraocular lens (IOL) 
implantation
c.
But not combined with any other surgery.
4. Have a unilateral cataract or have bilateral cataracts and are candidates for 
surgery:
a.
On the first eye, and surgery on the second eye is not planned until 
after the subject completes participation in the study OR 
b. On the second eye, and surgery on the first eye was uncomplicated,
any post-operative inflammation has resolved and anterior 
chamber cell and flare grades both = 0.
4.2.
SUBJECT EXCLUSION CRITERIA
In order for subjects to be eligible at Visit 1 they may not:
1. Have a post-traumatic cataract. 
2. Have suspected permanent low vision or blindness in the fellow non-study 
eye. 
3. Have active uveitis in either eye. 
4. Have an ocular neoplasm in either eye. 
5. Have the presence of any active or suspected viral, bacterial, or fungal 
disease in either eye. 
6. Have a history of glaucoma, ocular hypertension, steroid-induced IOP rise 
or have an IOP >21 mmHg in either eye at the screening or randomization 
visit(s).
7. Require the use of any topical ophthalmic medication in the study eye 
within 2 days prior to surgery and for the duration of the study, except for 
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drops that are needed to examine the eye or to prepare for and undergo 
surgery as well as post-operative antibiotic drops. NOTE: Besifloxacin 
Ophthalmic Suspension is not permitted within 2 days prior to surgery or 
for the duration of the study.
8. Require the use of systemic or ocular non-steroidal anti-inflammatory 
drugs within 2 days prior to surgery and for the duration of the study.
9. Require treatment with systemic, inhaled or ocular corticosteroids within 
14 days prior to surgery and for the duration of the study with the 
exception of intraoperative ocular corticosteroids.
10. Require a change in use of nutraceuticals or multivitamins within 2 days 
prior to surgery and for the duration of the study.
11. Have known hypersensitivity or contraindication to the investigational 
product(s) or their components.
12. Have a diagnosis of:
a.
Severe/serious ocular condition that in the judgment of the 
Investigator could confound study assessments or limit 
compliance. 
b. Severe/serious systemic disease or uncontrolled medical condition 
that in the judgment of the Investigator could confound study 
assessments or limit compliance.
13. Have been exposed to an investigational product within 30 days prior to 
surgery.
4.3.
RANDOMIZATION CRITERIA
To qualify for randomization at Visit 2 (1st post-surgery assessment which may be later 
on the day of surgery or the following day), a subject must:
1. Have undergone routine, uncomplicated, cataract surgery, with or without 
capsulotomy and/or anterior vitrectomy and with or without posterior 
chamber IOL implantation and not combined with any other surgery.
2. Continue to meet inclusion/exclusion criteria with respect to current ocular 
and medical conditions and medications.
3. Continue to have IOP < 21 mmHg in both eyes.
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5.
PROCEDURES
Written informed consent and HIPAA authorization will be obtained from each subject’s
parent/guardian prior to any study procedures being performed.
5.1.
VISIT DESCRIPTIONS
5.1.1.
Visit 1:  Screening Visit (Day -14 to Day -1)
The screening visit will occur no more than 14 days and no less than one (1) day prior to 
Surgery. After obtaining written informed consent and HIPAA authorization, site staff 
will perform/assess the following in the order suggested below:
x
Assign each screened subject a Subject Identification (ID) number 
consisting of a three-digit Investigator number plus a four-digit number 
starting with number 1001. The Subject ID will be used as the primary 
subject identifier for the duration of the study.
x
Collect the following information and perform the following assessments
(when obtainable) (NOTE: All ocular assessments must be performed in 
both eyes):
o
Non-ocular and ocular medical history
o
Medications taken during the 30 days prior to screening and 
concomitant medication usage 
o
Visual acuity (Snellen, Optotype recognition,
Central/Steady/Maintained with Fix and Follow or Fix and Follow 
alone per the subject’s age and as determined by the Investigator and 
used for all study visits for the subject)
o
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as vitritis 
and wound integrity (Slit lamp biomicroscopy, ophthalmoscopy or 
light examination depending on subject’s tolerance.  The method used 
for these assessments will be determined by Investigator and used for 
all study visits for the subject)
o
Symptoms of anterior ocular inflammation - photophobia and 
lacrimation
o
IOP measurement
o
Dilated Ophthalmoscopy
o
Inclusion/exclusion criteria evaluation
x
Ensure subjects to return for surgery in no more than 14 days.
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5.1.2.
Surgery
Pre-surgical Procedures:
Cataract surgery will occur no more than 14 days and no less than 1 day after Visit 1 and 
the following will be performed:
x
Routine pre-surgical care and procedures as determined by the 
Investigator
Surgical Procedure 
The surgeon will perform his or her routine cataract surgical procedures.
Post-Surgical Procedures 
x
Routine post-surgical care and instructions will be provided by the 
Investigator.
x
Medications routinely administered prior to, during and immediately 
following cataract surgery will be collected as a summary document and 
included as a source document but not listed in the EDC. Only non-routine
medications will be collected as concomitant medications in the subject’s 
source document and eCRF.
5.1.3.
Visit 2: First Post-Operative Assessment Visit (This may be later on the 
day of surgery or the following day. This will be considered Day 1)
The following assessments/evaluations will be performed (NOTE: All ocular 
assessments must be performed in both eyes):
x
Review use of any concomitant medications since Visit 1
x
Assess occurrence of any additional medical or ophthalmic history since 
Visit 1
x
Perform (when obtainable):
o
Visual acuity assessed using the same method used at the screening 
visit
o
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as vitritis 
and wound integrity assessed using the same method used at the 
screening visit
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o
Symptom assessment of anterior ocular inflammation – photophobia 
and lacrimation 
o
IOP measurement
x
Subjects whose surgery is confirmed to have been routine and who 
continue to meet inclusion/exclusion criteria with respect to current ocular 
and medical conditions and medications, including having intraocular 
pressures < 21 mmHg in both eyes, will be randomized to receive either 
KPI-121 1% ophthalmic suspension dosed BID AND vehicle dosed BID 
or prednisolone acetate ophthalmic suspension 1% dosed QID.  
x
Randomization will be performed through the EDC system.
Initiation of Dosing
x
Dispense the investigational product kit according to the randomization 
results. 
x
The dedicated dosing coordinator will review the investigational product 
kit, bottles, dosing times and proper method for instillation including but 
not limited to shaking investigational product bottle prior to each 
instillation with the parent/guardian and provide written instructions.
x
Provide the Dosing Diary and review instructions for completion.
x
The parent/guardian will administer the first dose of double-masked 
investigational product, in the study eye in the clinic under the supervision 
of a designated dosing coordinator.  
x
Study staff will assess the occurrence of any AEs after investigational 
product administration. NOTE: Signs and symptoms of inflammation 
typically seen after uncomplicated, cataract surgery will not be classified 
as AEs, but rather the condition under study.
x
Schedule the subject to return to the clinic on Day 8 ± 2 days for Visit 3.
x
Ask parent/guardian to bring the Dosing Diary with them to the next clinic 
visit.
5.1.4.
Visit 3:  Study Visit (Day 8 ± 2 days)
The following assessments/evaluations will be performed (NOTE: All ocular 
assessments must be performed in both eyes):
x
Review use of any concomitant medications since the last visit
x
Assess occurrence of any AEs since the last visit
x
Perform (when obtainable):
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o
Visual acuity assessed using the same method used at the screening 
visit
o
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as vitritis 
and wound integrity assessed using the same method used at the 
screening visit
o
Symptom assessment of anterior ocular inflammation – photophobia 
and lacrimation
o
IOP measurement
o
Modified Global Overall Assessment of Postoperative Inflammation
x
Review dosing compliance/Dosing Diary.
x
Instruct parents/caregivers to continue investigational product and return 
for Visit 4 on Day 15 ± 2 days. Remind them to bring the investigational 
product kit and Daily Dosing Diary with them.
5.1.5.
Visit 4:  Study Visit (Day 15 ± 2 days)
The following assessments/evaluations will be performed (NOTE: All ocular 
assessments must be performed in both eyes):
x
Review use of any concomitant medications since the last visit
x
Assess occurrence of any AEs since the last visit
x
Perform (when obtainable):
o
Visual acuity assessed using the same method used at the screening 
visit
o
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as and 
vitritis and wound integrity assessed using the same method used at 
the screening visit
o
Symptom assessment of anterior ocular inflammation – photophobia 
and lacrimation
o
IOP measurement
o
Modified Global Overall Assessment of Postoperative Inflammation
x
Review dosing compliance/Dosing Diary.
x
Collect initial investigational product Kit and dispense second Kit.
x
Instruct parents/caregivers to return for Visit 5 on Day 29 ± 2 days.
Remind them to bring the investigational product Kit and Dosing Diary 
with them.
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5.1.6.
Mid-Visit Phone Contact (Day 21 - 23)
A phone contact will be made between Visits 4 and 5 (Day 21 -23) to assess subject
progress, including but not limited to: continued dosing, adverse events, parent/caregiver 
questions, concerns and comments.
5.1.7.
Visit 5:  End of Investigational Product Use (Day 29 ± 2 days)
The following assessments/evaluations will be performed (NOTE: All ocular 
assessments must be performed in both eyes):
x
Review use of any concomitant medications since the last visit
x
Assess occurrence of any AEs since the last visit
x
Collect investigational product Kit
x
Collect diary
x
Perform (when obtainable):
o
Visual acuity assessed using the same method used at the screening 
visit
o
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as and 
vitritis and wound integrity assessed using the same method used at 
the screening visit
o
Symptoms of anterior ocular inflammation - photophobia and 
lacrimation
o
IOP measurement
o
Dilated ophthalmoscopy
o
Modified Global Overall Assessment of Postoperative Inflammation
Completion of investigational product at Visit 5 may be followed by treatment or taper
using a commercially available product as determined by the Investigator. Regardless of 
treatment and after cessation of investigational product, parents/caregivers will be 
instructed to return for follow-up on Day 36 ± 2 days for Visit 6.
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5.1.8.
Visit 6:  Follow-Up Visit (Day 36 ± 2 days)
The following assessments/evaluations will be performed (NOTE: All ocular 
assessments must be performed in both eyes):
x
Use of any concomitant medications since the last visit
x
Occurrence of any AEs since the last visit
x
Perform (when obtainable):
o
Visual acuity assessed using the same method used at the screening 
visit
o
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as vitritis 
and wound integrity assessed using the same method as used at the 
screening visit
o
Symptom assessment of anterior ocular inflammation - photophobia 
and lacrimation
o
IOP measurement
o
Modified Global Overall Assessment of Postoperative Inflammation
5.1.9.
Unscheduled Visit
Any visits or procedures performed beyond those specified within the protocol must be 
documented in the Unscheduled Visit pages of the eCRF. Unscheduled visits may include 
but are not limited to reporting adverse events (AEs), changes in concomitant 
medications, or ophthalmic assessments as deemed appropriate by an appropriately 
qualified physician.  If the subject is discontinuing study participation at the unscheduled 
visit, the Early Termination eCRFs should be completed rather than the Unscheduled 
Visit eCRFs.
5.1.10.
Early Termination Visit
In the event of study termination prior to Visit 6 but following Visit 2, every attempt will 
be made to ensure that the following will be performed/assessed (when obtainable) 
(NOTE: All ocular assessments must be performed in both eyes.):
x
Review use of any concomitant medications since the last visit
x
Assess occurrence of any AEs since the last visit
x
Collect used and unused investigational product and dosing diary
x
Perform (when obtainable):
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o
Visual acuity assessed using the same method used at the screening 
visit
o
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as and 
vitritis and wound integrity assessed using the same method used at 
the screening visit
o
Symptom assessment of anterior ocular inflammation – photophobia 
and lacrimation
o
IOP measurement
o
Dilated ophthalmoscopy
o
Modified Global Overall Assessment of Postoperative Inflammation
5.2.
SUBJECT WITHDRAWAL AND/OR DISCONTINUATION 
Any parent/guardian who wishes to discontinue their child’s investigational product use 
or withdraw their child from participation in the study for any reason is entitled to do so 
without obligation.  The Investigator may also discontinue any subject from 
investigational product use or from study participation, if deemed necessary. 
Investigational product use may be discontinued, and any subject may be discontinued 
from study participation at any time during the study at the discretion of the Investigator 
or the sponsor for any reason including but not limited to:
1. Occurrence of any medical condition or circumstance that exposes the 
subject to substantial risk and/or does not allow the subject to adhere to 
the requirements of the protocol.
2. Any SAE, clinically significant AE, severe, intercurrent illness, or other 
medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the subject.
3. Parent’s/guardian’s decision to withdraw.
4. Parent’s/caregiver’s failure to comply with protocol requirements or study 
related procedures.
5. Termination of the study by the Sponsor, FDA, or other regulatory 
authorities.
In the event study discontinuation of a randomized subject is necessary, the Investigator 
should make every attempt possible to have the subject complete the Early Termination
assessments.  The Investigator should make every attempt to follow all serious adverse 
events (SAEs) to resolution.  The reason for premature discontinuation should be 
recorded in the subject’s chart.
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Subjects who withdraw from the trial will not be replaced.
Additionally, the trial or parts of the trial may be discontinued by the sponsor or at the 
recommendation of the Investigator after consultation with Kala Pharmaceuticals, Inc.  
This may be based on a significant number of AEs of a similar nature that warrant such 
action.
5.3.
COLLECTION OF DATA
Source documentation for data collected in this study will be maintained at the investigative 
site.  The CRF will be electronic (eCRF) and data will be electronically entered from the 
source documentation into the eCRF. After study completion, an archival copy [e.g., 
portable document format (PDF)] of the eCRF data will be retained by the site.
5.4.
RESCUE MEDICATION USE
Any subjects not responding adequately to the investigational product 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 investigational product and continue study participation 
through Visit 6.
Rescued subjects will be considered treatment failures, and the need for rescue therapy 
will not be considered an AE. Rescued subjects should not be withdrawn from the study, 
but rather followed through the end of the study/Visit 6.
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6.
TREATMENT OF SUBJECTS
6.1.
INVESTIGATIONAL PRODUCTS TO BE ADMINISTERED
KPI-121 1% and vehicle or prednisolone acetate 1% will be supplied as investigational 
product.  One Kit of randomized investigational product containing four dropper bottles 
will be allocated to each subject at Visit 2.
The investigational product will be stored at the site upright in a secure area, with limited 
access, at 15-25qC/59-77qF.
Parents/caregivers will be asked to administer investigational product four times daily
during the treatment phase. Instillation of the four doses should be spaced throughout the 
day at the approximate time points of: morning (Bottle 1), midday (Bottle 2), afternoon
(Bottle 3), and bedtime (Bottle 4). Prior to each instillation of investigational product, the 
parent/caregiver will be instructed to shake the investigational product bottle well. The 
parent/caregiver will record the time of administration and number of drops administered 
for each dose of investigational product in the Daily Dosing Diary (Appendix 7).
Additional investigational product will be dispensed at Visit 4 and discontinued at Visit 
5.  Used investigational product kits will be collected by the study staff at Visits 4 and 5.  
Compliance with instillation of investigational product will be assessed at each clinic 
visit and reviewed with the parent/caregiver if poor compliance is noted.
6.2.
CONCOMITANT MEDICATIONS
With the exception of peri-operative standard of care medications, all medication that the 
subject has taken 30 days prior to Visit 1 and through Visit 6 or discontinuation from the 
study will be recorded in the subject’s chart/source documents and the eCRF. The 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 ocular antibiotics at the discretion of the Investigator is 
allowed (with the exception of besifloxacin). Medications routinely administered (and 
not explicitly prohibited in this protocol) as part of an uncomplicated cataract surgery 
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procedure are allowed. These medications will be collected in a summary source 
document and will not be captured within the eCRF. If there is a change from the 
standard of care as documented in the source document, the medication will be added to 
the eCRF.  Further, the routine medications administered as part of routine cataract 
surgery are not expected to be associated with treatment for AEs unless otherwise 
indicated. NOTE:  Any medication administered as part of the routine surgery that is 
ongoing subsequent to the surgical procedure should be captured in the eCRF as a 
concomitant medication.
6.2.2.
Medications Not Permitted
Use of the following medications is not allowed during the study and for the timeframes 
specified:
Within 30 days prior to surgery and for the duration of the study:
x
Other investigational products.
Within 14 days prior to surgery and for the duration of the study:
x
The use of systemic, inhaled or ocular corticosteroids with the exception of 
intraoperative ocular corticosteroids.
Within 2 days prior to surgery and for the duration of the study:
x
The use of any topical ophthalmic medication in the study eye, except for drops 
that are needed to examine the eye or to prepare for and undergo surgery,
including post-operative antibiotic drops. NOTE: besifloxacin ophthalmic 
suspension is not permitted.
x
The use of systemic or ocular non-steroidal anti-inflammatory drugs.
x
Change in use of nutraceuticals or multivitamins.
6.3.
INVESTIGATIONAL PRODUCT USE COMPLIANCE
Compliance will be assessed using the dosing information recorded in the Daily Dosing 
Diary completed by the parent/caregiver.
6.4.
DRUG ACCOUNTABILITY
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The sponsor’s study monitors or designees will conduct accountability of investigational
product (KPI-121 1%, vehicle, and prednisolone acetate 1%). Accountability will be 
ascertained by performing reconciliation between the amount of investigational product
sent to the site and the amount of used and unused investigational product at the time of 
reconciliation.
Investigational product will be shipped to the investigational sites under sealed 
conditions.  Investigational product shipment records will be verified by comparing the 
shipment inventory sheet to the actual quantity of drug received (i.e., kit level 
accounting) at the site. Accurate records of receipt and disposition of the investigational
product (e.g., dates, subject number, kit number dispensed, and kits and bottles returned) 
must be maintained by the Investigator or his/her designee. Investigational product will 
be stored upright in a secure area, with limited access, at 15-25qC/59-77qF.
At the end of the study, all investigational product (KPI-121 1%, vehicle and 
prednisolone acetate 1%), including all used and unused bottles and kits, will be returned 
to the drug packaging vendor in accordance with sponsor or designee’s standard 
operating procedures (SOPs), following approval by the Sponsor. All returns of
investigational product will be documented. The study monitor or designee will verify 
drug accountability. All drug accounting procedures must be completed before the study 
is considered complete.
6.5.
MAINTENANCE OF RANDOMIZATION AND PROCEDURE FOR BREAKING THE 
CODE
The sponsor, the project teams at the designated Contract Research Organizations 
(CROs), and investigative staff responsible for assessments of study endpoints will be 
masked to investigational product assignments. 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 1%, immediate emergency unmasking is not 
necessary. If the Investigator feels it is necessary to unmask a subject’s assignment after 
an emergency situation, the Investigator may call the medical monitor and notify the 
sponsor. The investigational product assignment will be revealed on a subject-by-subject
basis with the approval of the medical monitor and sponsor, thus leaving the masking of 
the remaining subjects intact.
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A randomization code for assignment of subjects to treatment arms will be computer-
generated by Kala Pharmaceuticals, Inc. or its designee. 
Randomization team members, specifically the designated dosing coordinator(s), will 
work independently of other team members at the site. Study personnel, study subjects, 
the sponsor, and project teams at the CROs involved in the study will be masked to 
investigational product assignments.
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7.
ASSESSMENT OF EFFICACY
7.1.
EFFICACY PARAMETERS
Efficacy Assessments include the following:
x
Signs of anterior ocular inflammation – cell and flare grading, corneal 
clarity, conjunctival injection, chemosis, hypopyon as well as vitritis and 
wound integrity 
x
Investigator assessment of symptoms of anterior ocular inflammation –
photophobia and lacrimation
x
Modified Global Overall Assessment of Postoperative Inflammation
x
Use of rescue therapy
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8.
ASSESSMENT OF SAFETY
8.1.
SAFETY PARAMETERS
Safety assessments include the following:
x
Assessments of AEs
x
Visual Acuity
x
IOP Measurement 
x
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.
Life-threatening: An AE or SAR is considered “life-threatening” if, in the view of either 
the Investigator or sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
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A SERIOUS ADVERSE EVENT (SAE) is any AE or suspected adverse reaction 
occurring at any dose that: 
x
Results in death.
x
Is life-threatening.
x
Results in a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions.
x
Requires inpatient hospitalization.
x
Prolongs inpatient hospitalization.
x
Is a congenital anomaly/birth defect.
x
Is a significant medical event (i.e., one that may jeopardize the subject or 
may require intervention to prevent one or more of the other outcomes 
listed above).
A NON-SERIOUS ADVERSE EVENT is any AE that does not meet the definitions for 
SAEs as described above. 
Each AE will be classified as SERIOUS or NON-SERIOUS using the definitions 
provided above.
The SEVERITY of each AE will be classified as MILD, MODERATE, or SEVERE.
The Investigator will review each event and assess its RELATIONSHIP to use of 
investigational product (unrelated, unlikely, possibly, probably, definitely). The AE will 
be assessed using the following definitions:
Unrelated:

Event or intercurrent illness due wholly to factors other than investigational 
product use.
Unlikely:

Poor temporal relationship with investigational product use.

Event easily explained by subject’s clinical state or other factors.
Possible:

Reasonable temporal relationship with investigational product use.

Event could be explained by subject’s clinical state or other factors. 
Probable:

Reasonable temporal relationship with investigational product use.
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
Likely to be known reaction to agent or chemical group or predicted by 
known pharmacology.

Event cannot easily be explained by subject’s clinical state or other factors.
Definitely:

Distinct temporal relationship with investigational product use.

Known reaction to agent or chemical group, or predicted by known 
pharmacology.

Event cannot be explained by subject’s clinical state or other factors. 
(NOTE: Expected changes such as the presence of inflammation resulting from routine 
uncomplicated cataract surgery will not be captured as AEs.)
8.3.
PROCEDURES FOR AE REPORTING BY THE INVESTIGATOR
AEs will be monitored throughout the study. AE reporting will start with the first dose of 
investigational product. AEs will be reported through the conclusion of Visit 6. AEs will 
be recorded on the CRF with the date and time of onset, date and time of resolution, 
severity, seriousness, causality (relationship to use of investigational product), treatment 
required, and the outcome. To elicit AEs, simple questions with minimal suggestions or 
implications should be used as the initial questions at all evaluation points during the 
trial.  For example:
x
How has your child felt since their last visit?
x
Has your child had any health problems since your last visit?
The severity of each AE should be categorized as mild, moderate, or severe.
The causality of use of investigational product in relation to the AE will be assessed by 
the Principal Investigator after careful medical consideration and categorized as 
unrelated, unlikely, possible, probable, or definite.
If an AE occurs, the Investigator will institute support and/or treat as deemed appropriate.  
If an AE is unresolved at the time of the last 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 
SAEs to resolution.
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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 staff's’ attention.  In the event of an SAE, the Investigator or site 
designee must fax the Kala Clinical Study Serious Adverse Event Form within 24 hours 
of becoming aware of the event to Drug Safety Navigator at Fax: 1-877-684-9387. It is 
also the responsibility of the Investigator to report all SAEs reported at their site to their 
Institutional Review Board (IRB), as required.  The Investigator should make every 
attempt to follow all SAEs to resolution.
The following information should be provided when an SAE is reported to the sponsor or 
designee:
1. Protocol Number
1. Site Number
2. Subject Number
3. Subject Demographic information, including:
x
Date of Birth
x
Sex
x
Race
4. Investigational product start date
5. Date of last dose of investigational product 
6. Date investigational product reinitiated (if investigational product interrupted) 
7. SAE information, including:
x
SAE term (diagnosis only; if known or serious signs/symptoms)
x
Description of SAE/narrative
x
Date/time of onset
x
Severity
x
Outcome
x
Date/time of resolution or death (if duration < 24 hours)
x
Relationship to investigational product
x
Action taken with investigational product
8. Criteria for classifying the event as serious, including whether the SAE:  
x
Resulted in death.
x
Was life-threatening.
x
Required inpatient hospitalization.
x
Prolonged inpatient hospitalization.
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x
Resulted in a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.
x
Was a congenital anomaly/birth defect.
x
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 investigational product
12. Copy of AE page from the eCRF
NOTE: If an SAE occurs in any study involving KPI-121 1% ophthalmic suspension that 
is unexpected and is determined to be related or possibly related to investigational 
product, all sites will be notified by the sponsor and each site should report it to its IRB.  
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9.
STATISTICS
9.1.
STATISTICAL METHODS
Continuous measures (e.g., age) will be summarized descriptively by the mean, standard 
deviation, median, minimum and maximum values. Categorical measures will be 
summarized by the number and percent of subjects.
9.1.1.
Subject Disposition, Demographic and Background Characteristics
Subject disposition, demographic characteristics, and background variables will be 
summarized by study group.  
9.1.2.
Evaluation of Efficacy
The efficacy and safety evaluations will be based on a single study eye, defined as the 
surgery eye, for each subject. 
The primary analysis population will be the Intent-to-Treat (ITT) population, defined as 
all subjects randomized and with at least one post-baseline assessment. A subset of 
efficacy analyses will be repeated using data from those subjects who were randomized, 
completed 15 days ± 2 days of investigational product use, had complete data at Visit 4
(Day 15 ± 2 days), and did not have significant protocol deviations, the Per Protocol (PP)
population. Rescued subjects will be included in the PP population if they did not have 
significant protocol deviations, however, these subjects will be considered treatment 
failures.
No inferential statistical analyses are planned. Data will be summarized using descriptive 
statistics only. Assessment of efficacy will be based primarily on the number and 
percentage of subjects in each treatment group with an anterior chamber cell grade of 0 at 
Visit 4 (Day 15 ± 2 days) with no need for rescue medication through Visit 4 and,
secondarily, on the Modified Global Overall Assessment of Postoperative Inflammation 
score of 0 at Visit 4 (Day 15 ± 2 days) without receiving rescue medication prior to Visit 
4.
The individual components of the Global Assessment score will also be evaluated (i.e., 
number and percentage of subjects in each treatment group in each score category at each 
visit).
The following scoring scale for anterior chamber cells will be used:
0 = No cells seen
1 = 1 - 5 cells
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2 = 6 - 15 cells
3 = 16 - 30 cells
4 = greater than 30 cells
The following signs and symptoms scoring scales for inflammation will be used:
SIGNS
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Anterior Chamber Cells
0 cells
1 - 5 cells
6 - 15 cells
16 - 30 cells
> 30 cells
Anterior Chamber Flare
Absent
Mild 
(trace to 
clearly 
noticeable, 
visible)
Moderate 
(without 
plastic aqueous 
humor)
Marked 
(with plastic 
aqueous 
humor)
Severe
(with fibrin 
deposits and/or 
clots)
Corneal Clarity
Absent
Mild
Moderate
Severe
Conjunctival Injection
Absent
Mild
Moderate
Severe
Chemosis
Absent
Mild
Moderate
Severe
Hypopyon
Absent
Mild
Moderate
Severe
Vitritis
Absent
Mild
Moderate
Severe
Wound Integrity
Absent
Mild
Moderate
Severe
SYMPTOMS
Grade 0
Grade 1
Grade 2
Grade 3
Photophobia
Absent
Mild
Moderate
Severe
Lacrimation
Absent
Mild
Moderate
Severe
Modified Global Overall Assessment of Postoperative Inflammation
Based on the signs and symptoms scoring above the following overall categorization of 
inflammation will be assessed:
0
Clear 
1
Improving satisfactorily 
2
Not improving or worsening; allow rescue therapy
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9.1.3.
Analysis of Safety
Analysis of safety data will be presented for all subjects in the Safety population (i.e., all 
subjects receiving randomized investigational product). AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA, version 21.0) 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 investigational product. Ophthalmoscopy findings 
will be summarized descriptively. IOP measurements, Visual Acuity and Dilated 
Ophthalmoscopy assessments will be summarized as safety outcomes.
9.2.
SAMPLE SIZE ESTIMATION
Assessment of safety will be based on the assessment of AEs. To allow for at least a 95% 
chance of detecting an AE with a 10% incidence rate, a minimum sample size of 
30 subjects per group (KPI-121 1% or prednisolone acetate 1%) is required. All 
statistical analyses will be performed using Statistical Analysis System (SAS) software. 
9.3.
LEVEL OF SIGNIFICANCE
Only descriptive analyses are planned.
9.4.
PROCEDURE FOR ACCOUNTING FOR MISSING, UNUSED, OR SPURIOUS DATA
If more than 5% of data points are missing at the primary analysis time point (Day 15) in 
any treatment group, a tipping point analysis will be employed to assess the sensitivity of 
the results to the distribution of the allocation of treatment success and failure to the 
missing data points.
9.5.
PROCEDURE FOR REPORTING DEVIATIONS FROM THE STATISTICAL PLAN
Any deviations from the statistical analysis plan will be described and a justification 
given in the final clinical study report.
9.6.
SUBJECTS TO BE INCLUDED IN THE ANALYSIS
The primary analysis population will be the Intent-to-Treat (ITT) population, defined as 
all randomized subjects with at least one post-randomization assessment. A subset of 
efficacy analyses will be repeated using data from those subjects who were randomized, 
completed 15 days ± 2 days of investigational product use, had complete data at Visit 4
(Day 15 ± 2 days), and did not have significant protocol deviations, the Per Protocol (PP)
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population. Rescued subjects will be included in the PP population if they did not have 
significant protocol deviations.
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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 designees
to inspect all CRFs; subject records (source documents); signed informed consent forms; 
HIPAA authorizations; records of investigational product receipt, storage, and 
disposition; and regulatory files related to the trial.
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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 trial.  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 will be submitted to 
the IRB.  Written IRB approval must adequately identify the protocol and informed 
consent form.  Copies of all approved materials, all correspondence with the IRB, and 
written approval from the IRB must be made available to the sponsor (or designated 
monitor).
Any modification of study procedures or amendments to the protocol must be approved 
by the IRB prior to implementation.  In the event that a modification or amendment is 
considered by the Investigator to be immediately necessary to ensure subject safety, the 
Investigator will promptly notify his or her IRB and the sponsor.
Investigators will report all SAEs reported at their site to their IRB, as appropriate.  
12.2.
Informed Consent Requirements
Written informed consent will be obtained from each subject’s parent/guardian prior to
their child undergoing any study-related procedures (prior to or upon Visit 1- Screening).  
A copy of the signed and dated informed consent document will be given to each 
parent/guardian.  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 parent/guardian can call 24 hours a day if they have medical concerns. 
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13.
DATA HANDLING AND RECORDKEEPING
All procedures for the handling and analysis of data will be conducted using GCP and 
will meet ICH guidelines and US FDA regulations for the handling and analysis of data 
for clinical trials.
13.1.
Data Quality Control and Reporting
After data have been entered into the study database, a system of computerized data 
validation checks will be implemented and applied to the database.  Query reports 
pertaining to data omissions and discrepancies will be forwarded to the clinical 
Investigator and monitor(s) for resolution.  The study database will be updated in 
accordance with the resolved query reports.  All changes to the study database will be 
documented.
13.2.
Records Retention
The study center will retain all records related to the study in accordance with local and 
ICH GCP guidelines.
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14.
PUBLICATION POLICY
The institution and Investigators participating in this trial shall have no right to publish or 
present the results of this study without the prior written consent of the sponsor.
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15.
REFERENCES
Foster A, Gilbert C, Rahi J. (1997). Epidemiology of cataract in childhood: A global 
perspective. Journal of Cataract & Refractive Surgery, 23, 601–604.
http://doi.org/10.1016/S0886-3350(97)80040-5.
Holmes JM, Leske DA, Burke JP, Hodge DO. (2003). Birth prevalence of visually 
significant infantile cataract in a defined U.S. population. Ophthalmic Epidemiology, 
10(2), 67–74. http://doi.org/10.1076/opep.10.2.67.13894.
Kim T, Gupta PK, Holland EJ, Brazzell K. (2018) Safety and Efficacy of Twice Daily 
Administration of KPI-121 1% for Ocular Inflammation and Pain Following Cataract 
Surgery. Presented at: American Society of Cataract and Refractive Surgery (ASCRS) 
2018 Annual Meeting, ASCRS Paper Sessions; April 16, 2018; Washington DC, USA.
Medsinge A, Nischal KK. (2015). Pediatric cataract: challenges and future directions.
Clinical Ophthalmology (Auckland, N.Z.), 9, 77–90.
http://doi.org/10.2147/OPTH.S59009.
Sharma, N, Pushker, N, Dada, T, Vajpayee, RB, Dada, VK. (1999). Complications of 
pediatric cataract surgery and intraocular lens implantation. Journal of Cataract & 
Refractive Surgery, 25(12), 1585–1588. http://doi.org/10.1016/S0886-3350(99)00296-5.
Stayte M, Reeves B, Wortham C. (1993). Ocular and vision defects in preschool children.
British Journal of Ophthalmology, 77(4), 228–232. http://doi.org/10.1136/bjo.77.4.228
Wilson ME. (2016). Pediatric Cataracts: Overview - American Academy of 
Ophthalmology. Retrieved May 20, 2016, from http://www.aao.org/pediatric-center-
detail/pediatric-cataracts- overview.
Wilson ME, O’Halloran H, VanderVeen D, Roarty J, Plager DA, Markwardt K, Gedif K, 
Lambert SR. Difluprednate versus prednisolone acetate for inflammation following 
cataract surgery in pediatric patients: a randomized safety and efficacy study Eye (Lond). 
2016 Sep; 30(9): 1187–1194.
Zwaan J, Mullaney PB, Awad A, Al-Mesfer S, Wheeler DT. (1998). Pediatric intraocular 
lens implantation: Surgical results and complications in more than 300 patients. 
Ophthalmology, 105(1), 112–119. http://doi.org/10.1016/S0161-6420(98)91568-8.
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16.
APPENDICES
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APPENDIX 1: SUMMARY OF EVENTS
Procedures
Visit 1
Visit 2
Visit 3
Visit 4
Phone
Visit 5
Visit 6
Screening
Surgery
Day
Study Visit 
Randomization, 
1st Treatment
Study Visit 
Study Visit
Contact
End of 
Investigational
Product Use Visit
Follow-Up 
Visit
-14 to -1 days
to Surgery
Day 1
(May be day of surgery 
or following day)
Day 8 
(± 2 days)
Day 15 
(± 2 days)
Day 21 - 23
Day 29
(± 2 days)
Day 36
(± 2 days)
Informed Consent, HIPAA Authorization 
X
Medical/Ophthalmic History
X
X
Concomitant Medication Review
X
X
X
X
X
X
Age appropriate Visual Acuity
X
X
X
X
X
X
Sign Assessment a
X
X
X
X
X
X
Symptom Assessment
X
X
X
X
X
X
IOP Measurement
X
X
X
X
X
X
Dilated Ophthalmoscopy
X
X
Modified Global Overall Assessment        
of Postoperative Inflammation
X
X
X
X
Inclusion/Exclusion
X
X
Surgery
X
Randomization
X
Dispense Investigational Product
X
X
Investigational Product Administration 
in Clinic
X
AE Assessment
Xb
X
X
X
X
X
Dosing Compliance Assessment
X
X
X
Collect Investigational Product
Xc
Xd
a By Slit lamp biomicroscopy, ophthalmoscopy or light exam as necessary, bAssessment of AEs starting with first Investigational Product instillation, cCollect first kit, dCollect second kit
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APPENDIX 2: VISUAL ACUITY
Visual acuity (VA) will be assessed using Snellen, Optotype recognition (HOTV or Lea 
Optotypes), Central/Steady/Maintained with Fix and Follow or Fix and Follow alone per the 
subject’s age and as determined by the Investigator. The same method will be used consistently 
for each subject.
VA will be assessed at all study visits (when obtainable).
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APPENDIX 3: ASSESSMENT OF SIGNS OF ANTERIOR OCULAR INFLAMMATION  
Signs of anterior ocular inflammation will be assessed by slit lamp biomicroscopy,
ophthalmoscopy or light examination depending on subject’s tolerance and as determined by the 
Investigator. It is recommended that a table-top slit lamp be used if at all possible. The use of a
portable slit lamp, ophthalmoscope or muscle light (transilluminator) should be reserved for 
subjects who cannot comply with the table-top slit lamp exam.
The same method will be used consistently for each subject (when possible).
The signs of anterior ocular inflammation will be performed at every study visit (when 
obtainable).
The following signs will be assessed:
Anterior Chamber Cells
0 = No cells seen
1 = 1 - 5 cells
2 = 6 - 15 cells
3 = 16 - 30 cells
4 = greater than 30 cells
Anterior Chamber 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)
Corneal Clarity
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
Conjunctival Injection
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
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Chemosis
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
Hypopyon
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
Vitritis
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
Wound Integrity (not assessed at Visit 1)
0 = Absent
1 = Mild
2 = Moderate
3 = Severe
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APPENDIX 4: IOP MEASUREMENT
IOP measurements will be performed utilizing an Icare rebound tonometer, or similar tonometer 
according to the Investigator’s standard procedure. All pressures will be recorded in mmHg.  
IOP will be assessed at all study visits (when obtainable, except at Visit 2 when this assessment 
is required). If unable to obtain a valid measurement by tonometer at Visit 2, assessment by other 
means, as determined by the investigator, will be accepted.
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APPENDIX 5: DILATED OPHTHALMOSCOPY
Dilated ophthalmoscopy will include assessment of vitreous clarity, optic disc, vessels, retina, 
choroid, macula and periphery. Indirect ophthalmoscopy will be used. 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.
Dilated Ophthalmoscopy will be performed at Visit 1 and Visit 5 (when obtainable).
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APPENDIX 6: MODIFIED GLOBAL OVERALL ASSESSMENT OF POSTOPERATIVE INFLAMMATION
SIGNS AND SYMPTOMS OF ANTERIOR OCULAR INFLAMMATION
Signs and symptoms of anterior ocular inflammation will be viewed as a composite to determine 
the Modified Global Overall Assessment of Postoperative Inflammation.
SIGNS
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Anterior Chamber Cells
0 cells
1 - 5 cells
6 - 15 cells
16 - 30 cells
> 30 cells
Anterior Chamber Flare
Absent
Mild 
(trace to 
clearly 
noticeable, 
visible)
Moderate 
(without 
plastic aqueous 
humor)
Marked 
(with plastic 
aqueous 
humor)
Severe
(with fibrin 
deposits and/or 
clots) 
Corneal Clarity
Absent
Mild
Moderate
Severe
Conjunctival Injection
Absent
Mild
Moderate
Severe
Chemosis
Absent
Mild
Moderate
Severe
Hypopyon
Absent
Mild
Moderate
Severe
Vitritis
Absent
Mild
Moderate
Severe
Wound Integrity
Absent
Mild
Moderate
Severe
SYMPTOMS
Grade 0
Grade 1
Grade 2
Grade 3
Photophobia
Absent
Mild
Moderate
Severe
Lacrimation
Absent
Mild
Moderate
Severe
MODIFIED GLOBAL OVERALL ASSESSMENT OF POSTOPERATIVE INFLAMMATION
Overall Assessment Score 
0
Clear 
1
Improving satisfactorily 
2
Not improving or worsening; allow rescue therapy
Overall Assessment Score will be assessed at Visits 3 - 6.
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APPENDIX 7: DAILY Dosing Diary
Parents/caregivers will be provided a Daily Dosing Diary and asked to record the following 
information related to administration of study drug:
x
Date
x
Time of administration of each dose
x
Number of drops
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