Conditions: Cataract
Keywords: Pediatric cataract
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 107
Healthy volunteers: no

Brief summary:
The objective of this study is to compare the efficacy and safety for the treatment of postoperative inflammation following ocular surgery for childhood cataract.

Detailed description:
The objective of this study is to compare the efficacy and safety of topical Loteprednol Etabonate (LE), 0.5%, to Prednisolone Acetate 1%, for the treatment of postoperative inflammation following ocular surgery for childhood cataract.

Arms:
arm 1: Loteprednol etabonate 0.5% arm 2: Prednisolone acetate 1.0%

Interventions: intervention 1: Loteprednol etabonate intervention 2: Prednisolones acetate
Intervention descriptions: intervention 1: 1-2 Ophthalmic drops administered to study eye four times daily (QID) for 14 days post surgery. Tapered to twice daily (BID) for 7 days. Then once daily (QD) for 7 days. intervention 2: 1-2 Ophthalmic drops administered to study eye four times daily (QID) for 14 days post surgery. Tapered to twice daily (BID) for 7 days. Then once daily (QD) for 7 days.

Protocol document:
Prot_000.pdf: 




 
Page 2 of 3 
 
 
7 Giralda Farms, Suite 1001 
 
Madison, NJ  07940 
 
973.360.6300 
 
www.bausch.com 
 
 
 
TO: 
Protocol Distribution Log Listing for Bausch & Lomb Study 670 Protocol, 
Amendment 6, dated 22 May 2013 
FROM: 
Michael Zhang, Study Manager, Pharmaceuticals 
RE: 
Study # 670 Protocol, Amendment 6, dated, 22 May 2013, Administrative 
Changes, dated 19 Aug 2013 
The purpose of this letter is to inform you of minor clarifications or administrative changes 
to Bausch & Lomb Study 670, entitled “A Randomized, Multicenter, Double Masked, 
Parallel-Group Study Assessing the Safety and Efficacy of Loteprednol Etabonate 
Ophthalmic Gel, 0.5% versus Prednisolone Acetate Ophthalmic Suspension, 1% for the 
Treatment of Intraocular Inflammation Following Surgery for Childhood Cataract”.  These 
clarifications are administrative in nature. They do not meet the criteria for a protocol 
amendment as they have no impact on clinical decision-making procedures, a subject’s 
health, safety, or welfare, or study design.   
Page 
Section 
Description of Change or Clarification 
Rationale 
4 
Personnel 
and 
Facilities 
Change Scientific & Clinical Affairs/Medical Monitor 
from: 
“James Gow, MD 
Clinical Affairs 
Bausch & Lomb Incorporated 
50 Technology Drive 
Irvine, CA  92618-2301 
US 
Tel: + 1 949 788 5359 
Mobile: + 1 949 701 6398 
Email:  james.gow@bausch.com” 
To: 
“Jon I. Williams, PhD 
Director, Clinical Affairs 
Bausch & Lomb Incorporated 
50 Technology Drive 
Irvine, CA  92618 
US 
Tel: + 1 949 788 5334 
Mobile: + 1 949 345 5703 
Email: Jon.Williams@bausch.com” 
Administrative 
change. 


 
Page 3 of 3 
 
16 
 
38 
Synopsis – 
Hypothesis 
7.2 
Change from:  
“…where µLE and µPR are the mean grade of 
anterior chamber inflammation at Visit 4 
(Postoperative Day 7) for LE Ophthalmic Gel, 
0.5%...” 
To: 
“…where µLE and µPR are the mean grade of 
anterior chamber inflammation at Visit 5 
(Postoperative Day 14) for LE Ophthalmic Gel, 
0.5%...” 
Typographical 
error 
remaining 
from previous 
amendment. 
 
Note: The Statistical Analysis Plan (SAP) will be am ended prior to database lock to 
correct this error. Additionally, country-specific translations of the Study 670 s ynopsis 
and/or protocol may reflect correction of this error in the translated document. 


SOC, Am 6, 22 May 2013 
 
Page 1 
 
 
SUMMARY OF CHANGES 
STUDY #670 
A Randomized, Multicenter, Double Masked, Parallel-Group Study Assessing the Safety 
and Efficacy of Loteprednol Etabonate Ophthalmic Gel, 0.5% versus Prednisolone Acetate 
Ophthalmic Suspension, 1% for the Treatment of Intraocular Inflammation Following 
Surgery for Childhood Cataract 
AMENDMENT 6, 22 MAY 2013 
 
Deletions indicated by strikethrough; additions indicated by bold. 
Section 
Page 
Description of Change or Clarification 
Rationale 
As applicable 
As 
applicable 
Update to revision chronology and footers. 
Administrative change. 
As applicable 
As 
applicable 
Corrected grammatical and punctuation errors. 
Clarification. 
As applicable 
As 
applicable 
Changed Visit 6 from Postoperative Day 29 to Day 28. 
Changed per FDA 
Written Request. 
Sponsor Approval 
Page 
2 
Updated Biostatistics Sponsor Signatory as follows: 
“Tesfaye Liranso, PhD  
Principal Biostatistician 
Xiaohui Luo, PhD 
Director, Biostatistics” 
Administrative change. 
Investigator 
Statement of 
Approval 
3 
Changed instructions on page as follows: 
“Upon signing, provide a copy the original of this 
page to Bausch + Lomb and retain a copy for your 
files.” 
Clarification. 
Personnel and 
Facilities page 
4-5 
Updated study personnel information as follows: 
“Laura Trusso, MS  
Michael Zhang 
Study Manager 
Bausch & Lomb Incorporated 
1400 North Goodman Street 
Rochester, NY 14609 
7 Giralda Farms, Suite 1001 
Madison, NJ 07940 
US 
Tel: +1 585 338 5561 973 360 6448 
Mobile: +1 585 747 4187 973 610 3294 
Fax: +1 585 338 0788 585 338 0606 
Email: Laura_Trusso@bausch.com 
Michael.Zhang@bausch.com 
 
AP Sites: 
Paul Park 
Clinical Study Manager 
Bausch & Lomb (S) Pte Ltd 
Administrative change. 


SOC, Am 6, 22 May 2013 
 
Page 2 
Section 
Page 
Description of Change or Clarification 
Rationale 
151 Lorong Chuan #04-03A 
New Tech Park, Lobby C 
Singapore  556741 
Tel: +65 6490 5858 
Mobile: + 65 9230 3963 
Fax: +65 6286 4218 
Email: Paul.Park@bausch.com 
 
Sharon W. Adams 
Executive Director, Global Head of 
Pharmacovigilance  
Saberi Rana Ali, MBBS, MS (Ophth), MPH 
Associate Director, Global Safety and Vigilance  
Bausch & Lomb Incorporated 
8500 Hidden River Parkway 7 Giralda Farms, Suite 
1001 
Tampa, FL 33637 Madison, NJ 07940  
Tel: +1 813 866 2585 973 360 6478 
Fax: +1 813 975 7750 
Mobile: +1 813 240 5853 862 579 8366 
SAE Inbox: SAE@bausch.com 
 
AP Sites: 
Global Safety and Vigilance, Asia Pacific 
Bausch & Lomb Korea 
13F, KT&G Kosmo Daechi-Tower, 
#945-10 Daechi-dong, Gangnam-gu, 
Seoul 135-280, Korea 
Tel: + 82 70 7167 9784 
Mobile: + 82 10 9112 9784 
Fax: + 82 2 6442 1460 
Email: safety.asia@bausch.com 
 
Raphaele Siou-Mermet, MD, MS 
Manager, European Pharmaceutical Clinical Science 
Laboratoire Chauvin/Bausch & Lomb 
416 Rue Samuel Morse, CS 99535 
34961 Montpellier Cedex 2 
France 
James Gow, MD 
Clinical Affairs 
Bausch & Lomb Incorporated 
50 Technology Drive 
Irvine, CA  92618-2301 
US 
Tel: + 33 1 60 87 14 91 1 949 788 5359 
Fax: + 33 1 60 87 14 75  
Mobile: +33 6 19 53 06 90  1 949 701 6398 
Email: Raphaele.Siou-Mermet@bausch.com 
james.gow@bausch.com 
 
AP Sites: 
Zuellig Pharma Korea Clinical Trial 
2nd Floor 213-7 
Jangji-Ri, Dongtan-Myun 
Hwasung-City 
Gyunggi-Do 


SOC, Am 6, 22 May 2013 
 
Page 3 
Section 
Page 
Description of Change or Clarification 
Rationale 
445-812 
Korea”  
List of 
Abbreviations 
8 
Added the following entries: 
AP 
Asia Pacific 
Bausch + Lomb 
Bausch & Lomb Incorporated 
 
Clarification. 
Synopsis 
8 
Changed number of subjects and regions as follows: 
“Approximately 158 140 subjects at approximately 
30 investigative sites in the United States (US), and 
European Union (EU), and Asia Pacific (AP) will be 
enrolled in this study.” 
Updated sample size to 
align with statistical 
recommendations from 
FDA Written Request 
and administrative 
change to regions. 
Synopsis 
9 
Changed description of the phase of the study as follows: 
“Phase 3b 4” 
Updated to align with 
the FDA Written 
Request that the study 
be conducted as a 
Phase 4 
post-marketing 
commitment study to 
satisfy pediatric 
evaluation 
requriements.   
Synopsis 
3.1 (Study Design) 
3.4 (Study 
Duration) 
9 
18 
 
22 
Changed description of study duration as follows: 
“Study duration will be approximately 12-18 11-19 
weeks…” 
Updated to align with 
visit window changes 
in FDA Written 
Request. 
Synopsis 
3.1 (Description of 
Study Design 
Including Choice 
of Control Groups) 
9 
18 
Changed number of subjects and regions as follows: 
“Approximately 158 140 subjects will be enrolled in 
this double-masked, parallel-group, active-controlled 
study at approximately 30 investigative sites in the 
United States (US), and European Union (EU), and 
Asia Pacific (AP).  
A total of 158 140 subjects aged 0-11 years will be 
randomized in a 1:1 ratio to LE Ophthalmic Gel, 
0.5% or Prednisolone Acetate Ophthalmic 
Suspension, 1%. Of the 158 140 randomized 
subjects, at least 79 60 subjects (approximately 40 30 
subjects per treatment group) will be in the age range 
from 0-3 years. Prednisolone Acetate Ophthalmic 
Suspension, 1% was chosen as the active-control 
because it has a long history as the standard of care in 
the US.” 
Updated sample size to 
align with statistical 
recommendations from 
FDA Written Request 
and administrative 
change to regions. 
Synopsis 
3.1 (Description of 
Study Design 
Including Choice 
of Control Groups) 
9 
18-19 
Changed window of Visit 1 and Visit 6 as follows: 
“… Subjects will visit the clinic eight times. Visit 1 
will be the Screening Visit and will occur up to a 
maximum of 6 weeks 29 days prior to surgery.” 
Changed per FDA 
Written Request. 
Synopsis 
3.2.1.2 (Exclusion 
Criteria) 
11 
21 
Changed exclusion criterion #11 as follows: 
“Female subjects who have started menarche prior to 
Visit 1 (Screening) or during the study.” 
Clarification.  


SOC, Am 6, 22 May 2013 
 
Page 4 
Section 
Page 
Description of Change or Clarification 
Rationale 
Synopsis 
5.1.1 (Visit 1) 
11-12 
26-27 
Changed visit window and text for Visit 1 as follows: 
“Visit 1 (Screening, ≤ 42 Days Prior to Surgery  
Day -15 ±14 days) 
… 
•  obtain assent (when applicable), written informed 
consent (US, and EU, and AP) and HIPAA 
authorization (US only) 
… 
NOTE: Surgery will be scheduled to occur within 6 
weeks 29 days of the Screening Visit. Screening and 
surgery cannot take place on the same day.” 
Changed per FDA 
Written Request, 
clarification, and 
administrative change. 
Synopsis 
5.1.2 (Visit 2) 
12 
27 
Changed visit window for Visit 2 as follows: 
“Visit 2 (Surgery/Randomization, ≤ 42 Days of 
Screening Day 0 [within 29 days of screening])” 
Changed per FDA 
Written Request. 
Synopsis 
5.1.4 (Visit 4) 
13 
27 
Changed visit window for Visit 4 as follows: 
“Visit 4 (Postoperative Day 7, ±12 days)” 
Changed per FDA 
Written Request. 
Synopsis 
5.1.5 (Visit 5) 
14 
29 
Changed visit window for Visit 5 as follows: 
“Visit 5 (Postoperative Day 14, ±13 days)” 
Changed per FDA 
Written Request. 
Synopsis 
5.1.6 (Visit 6) 
14 
29 
Changed visit window for Visit 6 as follows: 
“Visit 6 (Postoperative Day 298, ±37 days; End of 
Treatment)” 
Changed per FDA 
Written Request. 
Synopsis 
5.1.7 (Visit 7) 
14 
30 
Changed visit window for Visit 7 as follows: 
“Visit 7 (Postoperative Day 42, ±37 days)” 
Changed per FDA 
Written Request. 
Synopsis 
5.1.8 (Visit 8) 
15 
30 
Changed visit window for Visit 8 as follows: 
“Visit 8 (Postoperative Day 90, ±314 days; Study 
Exit)” 
Changed per FDA 
Written Request. 
Synopsis 
7.1.1 (Primary 
Efficacy 
Endpoints) 
15 
37 
Changed primary efficacy endpoint from Visit 4 to 
Visit 5, as follows: 
“…mean grade of anterior chamber inflammation at 
Visit 4 (Postoperative Day 7) Visit 5 (Postoperative 
Day 14)” 
Changed per FDA 
Written Request. 
Synopsis 
7.1.2 (Secondary 
Efficacy 
Endpoints) 
15 
37 
Changed secondary efficacy endpoint from Visit 5 to 
Visit 4, as follows: 
“mean grade of anterior chamber inflammation at 
Visits 5 4 and 6 (Postoperative Days 147 and 298)” 
Changed to align with 
primary endpoint 
changes. 
Synopsis 
7.3 (Sample Size) 
16 
38 
Updated sample size calculation as follows: 
“A sample size of 124 subjects (62 subjects per 
treatment group) yields 80% power to detect non-
inferiority of LE Ophthalmic Gel, 0.5% to 
Prednisolone Acetate Ophthalmic Suspension, 1% 
using a non-inferiority upper limit of 0.50. This 
sample size assumes a common standard deviation of 
0.98 and an expected difference of 0 for the 
difference in means between treatment groups using 
anterior chamber inflammation at Visit 4 
(Postoperative Day 7). The standard deviation is 
obtained by pooling the standard deviations of the LE 
and vehicle arms from the integrated adult studies of 
LE Gel in post cataract surgery8,9.  The absolute 
upper limit of the 95% CI for the treatment effect 
from the pooled data was 0.57.  From a clinical 
1) Changed power 
calculation to be based 
on ITT population per 
FDA Draft Guidance 
for Industry, Non-
Inferiority Clinical 
Trials (March 2010).  
2) Assumption 
(standard deviation 
and non-inferiority 
margin) aligned with 
FDA Written Request. 


SOC, Am 6, 22 May 2013 
 
Page 5 
Section 
Page 
Description of Change or Clarification 
Rationale 
perspective and based on this upper limit of 0.57, a 
non-inferiority margin of 0.50 is selected. The 0.50 
unit is < 0.57 and represents clinically one half of the 
smallest increment on the grading scale of anterior 
chamber inflammation. These sample size 
calculations utilize a one-sided, level alpha = 0.025 
non-inferiority analysis. Of the 124 subjects 
randomized, at least 62 subjects will be in the age 
group 0-3 years. As the percentage of subjects with 
rescue medication was 8% at Day 8 in one adult 
study (highest value), it is estimated that in children, 
12% can require rescue medication. Assuming a 
subject dropout rate of 12% for rescue medication, it 
is necessary to enroll 141 subjects. Furthermore, 
assuming a 10% rate for major protocol violations, 
158 subjects (79 per treatment group) will be 
randomized to obtain 124 PP subjects at the 
completion of the study.  
A sample size of 120 subjects (60 subjects per 
treatment group) yields 98% power to detect non-
inferiority of LE Ophthalmic Gel, 0.5% to 
Prednisolone Acetate Ophthalmic Suspension, 
1%. This sample size assumes a common standard 
deviation of 0.47, a two-sided alpha=0.05, a non-
inferiority margin of 0.35 and an expected 
difference of 0 for the difference in means between 
treatment groups using anterior chamber 
inflammation at Visit 5 (Postoperative Day 14).  
Assuming a subject dropout rate (including the 
initiation of rescue medication) of 12%, 
approximately 140 subjects will be randomized of 
which at least 60 subjects will be in the age group 
0-3 years as per the FDA’s Written Request.” 
Synopsis 
7.2 (Hypothesis) 
16 
38 
Changed non-inferiority margin as follows: 
“Ho: µLE - µPR ≥ 0.50 0.35 
versus 
Ha: µLE -  µPR < 0.50 0.35” 
Changed per FDA 
Written Request. 
Synopsis 
16 
Changed primary efficacy endpoint listed in Primary 
Analysis as follows: 
“For the primary efficacy analysis, the mean grade of 
anterior chamber inflammation at Visit 4 5 
(Postoperative Day 7 14) will be calculated by 
treatment group, including a two-sided 95% CI about 
the difference between the means. If the upper limit 
of the 95% CI is less than 0.50 0.35, then non-
inferiority of LE Ophthalmic Gel, 0.5% to 
Prednisolone Acetate Ophthalmic Suspension, 1% 
will be claimed.” 
Changed per FDA 
Written Request. 
Synopsis 
16 
Changed description of Primary Analysis as follows: 
“The primary efficacy analysis will be based on the 
Per Protocol (PP) set ITT population. The primary 
analysis will be repeated for the ITT set using the PP 
population to supplement the PP ITT analysis. Any 
discrepancy between the 2 analyses will be 
explained.” 
Changed to follow 
FDA Draft Guidance 
for Industry, 
Non-Inferiority 
Clinical Trials (March 
2010). 


SOC, Am 6, 22 May 2013 
 
Page 6 
Section 
Page 
Description of Change or Clarification 
Rationale 
Synopsis 
16 
Changed endpoints listed in Secondary Efficacy Analysis 
as follows: 
“The secondary efficacy analyses will include be 
conducted based on all subjects in the ITT 
population as well as and the PP sets population. 
As a secondary analysis, the analysis of the mean 
grade of anterior chamber inflammation will be 
repeated as above for Visits 54 and 6 (Postoperative 
Days 147 and 298, respectively).” 
Clarification and 
changed to align with 
change in primary 
endpoint. 
Synopsis 
7.6.1 (Methods of 
Analysis) 
17 
40 
Added text to MedDRA dictionary description as 
follows: 
“All AEs will be coded using a MedDRA dictionary 
(the most current version available at the start of 
the study will be used).” 
Clarification. 
3.2 (Selection of 
Study Population) 
19 
Updated number of subjects as follows: 
“Approximately 158 140 subjects who have 
undergone routine, uncomplicated surgery for 
childhood cataract will be enrolled in this clinical 
investigation.”  
Changed to align with 
sample size changes. 
3.2.4 (Subject 
Discontinuation 
21 
Added the “onset of menarche during the study” as a 
reason that a subject must be discontinued prior to the 
final study visit.  
Added for subject 
safety based on the 
update to exclusion 
criterion #11.  
3.3 (Investigators) 
22 
Updated study regions as follows: 
“The study will be conducted at approximately 30 
investigative sites located in the US, and EU, and 
AP.” 
Administrative change. 
3.4 (Study 
Duration) 
22 
Updated description of study duration as follows: 
“Visit 1 will be the Screening Visit and will occur up 
to a maximum of 42 29 days prior to surgery.” 
Changed per FDA 
Written Request. 
3.5 (Treatments) 
22 
Changed treatment description as follows: 
“A total of 79 140 subjects will be randomized 
randomly assigned in a 1:1 ratio to receive either 
LE Ophthalmic Gel, 0.5% and 79 subjects will be 
randomized to receive or Prednisolone Acetate 
Ophthalmic Suspension, 1%.” 
Clarification and 
changed to align with 
sample size changes. 
4.5 (Packaging and 
Labeling) 
24 
Added Asia Pacific information as follows: 
“The medication will be identified as a new drug, 
limited by federal law, and EU Directive, and AP 
local regulation to investigational use, and 
appropriately labeled for investigational use for this 
age group.” 
Administrative change. 
4.10 (Selection of 
Dose) 
26 
Updated description of Lotemax as follows: 
“This regimen was selected for the study based on the 
dose regimen of the currently marketed Lotemax (LE 
Ophthalmic Suspension Gel, 0.5%) and is also the 
treatment recommended in the Package Insert (PI) and 
Summary of Product Characteristics (SmPC) of the 
comparator drug.” 
Administrative change.  


SOC, Am 6, 22 May 2013 
 
Page 7 
Section 
Page 
Description of Change or Clarification 
Rationale 
6.4 (Reporting 
SAEs and 
Follow-up) 
35-36 
Added Asia Pacific information as follows: 
“For US sites, these should be reported to Bausch + 
Lomb Global Safety & Vigilance; for EU sites, these 
should be reported to the EU Study Manager who 
will be responsible for forwarding to Bausch + Lomb 
Global Safety & Vigilance; for AP sites, these 
should be reported to Bausch + Lomb AP Global 
Safety & Vigilance (Seoul, Korea), who will be 
responsible for forwarding to Bausch + Lomb 
Global Safety & Vigilance (Madison, NJ, US). 
… 
For US sites, the events and endpoints will be 
reported in writing by the Investigator to Bausch + 
Lomb Global Safety & Vigilance; or, for the EU 
sites, the SAE form should be sent to the EU Study 
Manager who will be responsible for forwarding to 
Bausch + Lomb Global Safety & Vigilance;, for AP 
sites,  these should be reported to Bausch + Lomb 
AP Global Safety & Vigilance (Seoul, Korea), who 
will be responsible for forwarding to Bausch + 
Lomb Global Safety & Vigilance (Madison, NJ, 
US). 
… should also be reported to Bausch + Lomb Global 
Safety & Vigilance.” 
Administrative change 
and clarification. 


SOC, Am 6, 22 May 2013 
 
Page 8 
Section 
Page 
Description of Change or Clarification 
Rationale 
6.4 (Reporting 
SAEs and 
Follow-up) 
35-36 
Updated SAE contact information as follows: 
“US Sites: 
Sharon W. Adams 
Executive Director, Global Head of 
Pharmacovigilance  
Bausch & Lomb Incorporated 
8500 Hidden River Parkway 
Tampa, Florida 33637 
Saberi Rana Ali, MBBS, MS (Ophth), MPH 
Associate Director, Global Safety and Vigilance 
Bausch & Lomb Incorporated 
7 Giralda Farms, Suite 1001 
Madison, NJ 07940 
US 
Tel: +1 813 866 2585 
Fax: +1 813 975 7750 
Mobile: +1 813 240 5853 
Tel: +1 973 360 6478 
Fax: +1 813 975 7750 
Mobile: +1 862 579 8366 
SAE Inbox: SAE@bausch.com 
 
AP Sites: 
Bausch + Lomb Asia Pacific Global Safety and 
Vigilance 
Bausch & Lomb Korea 
13F, KT&G Kosmo Daechi-Tower, 
#945-10 Daechi-dong, Gangnam-gu, 
Seoul 135-280, Korea 
Tel: + 82 70 7167 9784 
Mobile: + 82 10 9112 9784 
Fax: + 82 2 6442 1460 
Email: safety.asia@bausch.com” 
Administrative change. 
6.6 (Medical 
Monitor) 
37 
Updated Medical Monitor information as follows: 
“Raphaele Siou-Mermet, MD, MS 
Manager, European Pharmaceutical Clinical Science 
Laboratoire Chauvin/Bausch & Lomb 
416 Rue Samuel Morse, CS 99535 
34961 Montpellier Cedex 2 
France 
James Gow, MD 
Clinical Affairs 
Bausch & Lomb Incorporated 
50 Technology Drive 
Irvine, CA  92618-2301 
US 
Tel: + 33 1 60 87 14 91 1 949 788 5359 
Fax: + 33 1 60 87 14 75 
Mobile: + 33 6 19 53 06 90 1 949 701 6398 
Email: Raphaele.Siou-Mermet@bausch.com 
james.gow@bausch.com” 
Administrative change. 


SOC, Am 6, 22 May 2013 
 
Page 9 
Section 
Page 
Description of Change or Clarification 
Rationale 
7.4 
(Randomization) 
39 
Updated the sample size as follows: 
“A total of 158 140 subjects from ages 0-11 will be 
randomized to receive LE Ophthalmic Gel, 0.5% or 
Prednisolone Acetate Ophthalmic Suspension, 1% in 
a 1:1 ratio. The subgroup age 0-3 years will consist 
of at least 60 subjects be randomized in 
approximately equal proportion.” 
Changed to align with 
sample size changes. 
7.5 Analysis Sets 
39 
Updated section as follows: 
“7.5  Analysis Sets Populations 
The analysis sets populations that will be used in this 
study are: 
• 
Intent-to-Treat (ITT) Set Population: includes 
all subjects who were randomized and have at least 
one post-treatment assessment. Analysis on the ITT 
set population will be used for secondary primary 
efficacy analyses and will be performed for all 
efficacy endpoints, analyzing subjects under the 
treatment to which they were randomized. Analysis 
on the primary endpoint on the ITT set will be used 
to supplement the Per Protocol analysis. 
• 
Per Protocol (PP) Set Population: includes all 
of the subjects in the ITT set population that 
remained in the study through Visit 4 Visit 5 
(Postoperative Day 7 14) and who did not deviate 
from the protocol in any way likely to seriously affect 
the primary outcome of the study.  Analyses on the 
PP set will be used for the primary efficacy analysis 
and will be performed for the primary and secondary 
efficacy endpoints, Analysis using the PP 
population will be used to supplement the ITT 
analysis, analyzing subjects according to the 
treatment received.” 
Clarification and 
changed to align with 
FDA Draft Guidance 
for Industry, 
Non-Inferiority 
Clinical Trials (March 
2010). 


SOC, Am 6, 22 May 2013 
 
Page 10 
Section 
Page 
Description of Change or Clarification 
Rationale 
7.6.1 Methods of 
Analysis 
39-40 
Updated the description of primary efficacy analysis as 
follows: 
“The primary efficacy analysis will be based on the 
Per Protocol (PP) set ITT population with missing 
data imputed using the last observation carried 
forward (LOCF) method and the primary endpoint 
mean grade of anterior chamber inflammation at Visit 
4 Visit 5 (Postoperative Day 7 14). The mean grade 
of anterior chamber inflammation at Visit 4 Visit 5 
(Postoperative Day 7 14) will be analyzed using an 
analysis of variance (ANOVA) model with treatment 
as a classification variable. 
…The null hypothesis will be rejected and non-
inferiority established if the upper limit of the 
confidence interval does not exceed 0.50 0.35. 
To supplement the primary analyses, the analyses 
above will be repeated for the PP population; no 
imputation will be conducted for missing data. 
Any discrepancy between the ITT and PP analyses 
will be explained. 
The last observation carried forward (LOCF) 
imputation method implements the idea that a 
subject’s anterior chamber inflammation is 
unchanged after dropout, an assumption that needs to 
be checked for plausibility. To this end, a sensitivity 
analysis of the primary endpoint using the ITT set 
will be performed. 
The secondary efficacy analyses will be conducted 
based on include all subjects in the ITT population 
as well as and the PP sets population. 
As a secondary analysis, the analysis of the mean 
grade of anterior chamber inflammation will be 
repeated as above for Visits 54 and 6 (Postoperative 
Days 147 and 298, respectively).” 
Changed to align with 
FDA Written Request, 
changed to follow 
FDA Draft Guidance 
for Industry, Non-
Inferiority Clinical 
Trials (March 2010), 
and clarification. 
 
7.6.3 Subject 
Disposition 
40-41 
Updated descriptions of study populations as follows: 
“• 
subjects randomized (ITT set population) 
• 
subjects treated (Safety set population) 
• 
subjects in the PP set population” 
Clarification. 
7.6.7 Missing Data 41 
Updated missing data description as follows: 
“Subjects with missing data or with rescue 
medication prior to Day 7 will be excluded from the 
primary PP analysis. For the primary efficacy 
endpoint analyzed using the ITT set population, 
missing data and data from subjects placed on rescue 
medication will be analyzed imputed using the 
LOCF methodology. For the secondary efficacy 
endpoints analyzed using the ITT set, missing data 
and data from subjects placed on rescue medication 
prior to the visit being summarized will be imputed 
as LOCF and will also be summarized as missing. 
For the PP analysis, missing data and data from 
subjects placed on rescue medication will not be 
imputed.” 
Clarification and 
changed to align with 
change in primary 
efficacy endpoint. 


SOC, Am 6, 22 May 2013 
 
Page 11 
Section 
Page 
Description of Change or Clarification 
Rationale 
8.2 Source 
Documentation 
42 
Added Asia Pacific information as follows: 
“…If an entry is found to be illegible or a mistake is 
found (eg, incorrect year was recorded), the subject’s 
parent/legal guardian should be instructed to edit the 
entry by drawing a single line through the original 
entry, entering the new information, and dating and 
initialing (US and AP only)/writing year of birth to 
acknowledge (EU only) the change.” 
Administrative change. 
8.6 IRB/EC 
Approval 
43 
Added Asia Pacific information as follows: 
“In the US and AP, the Investigator, or in the EU…  
… 
In addition, in the US and AP, the Investigator, or in 
the EU…” 
Administrative change. 
9.0 References 
45 
Deleted the following references: 
“10 National Research Council (2010). The 
Prevention and Treatment of Missing Data in Clinical 
Trials. Panel on Handling Missing Data in Clinical 
Trials. Committee on National Statistics, Division of 
Behavioral and Social Sciences and Education. 
Washington, DC: The National Academic Press. 
11 Ratitch, B., O’Kelly, M., Implementation of 
Pattern-Mixture Models Using Standard SAS/STAT 
Procedures, PharmaSUG2011 - Paper SP04. 
12 SAS Institute Inc. 2008. SAS/STAT ® 9.2 User’s 
Guide. Cary, NC: SAS Institute Inc.” 
Administrative change.  
Appendix A 
A-1 
Updated the following items in the Schedule of Visits 
and Parameters: 
“Visit 1 Screening -6 Weeks Day -15 (±14 days) 
Visit 4 Follow-up Day 7 (±12 days) 
Visit 5 Follow-up Day 14 (±13 days) 
Visit 6 Follow-up/End Treatment Day 298 (±37 days) 
Visit 7 Follow-up Day 42 (±37 days) 
Visit 8 Study Exit Day 90 (±314 days) 
2 Visit 2 must occur within 6 weeks 29 days of 
Visit 1. 
5 Fundoscopy will be performed bilaterally either at 
Visit 2 (surgery/randomization) or Visit 3 
(postoperative day 1), at Visit 5 (postoperative day 14 
±13 days), and at Visit 8 (postoperative day 90 ±314 
days).” 
Changed per FDA 
Written Request. 
 


TITLE PAGE 
 
 
 
A Randomized, Multicenter, Double Masked, Parallel-Group Study Assessing the 
Safety and Efficacy of Loteprednol Etabonate Ophthalmic Gel, 0.5% versus 
Prednisolone Acetate Ophthalmic Suspension, 1% for the Treatment of Intraocular 
Inflammation Following Surgery for Childhood Cataract 
 
PROTOCOL 
IND #102654 and EudraCT#2010-024388-41 
STUDY #670 
 
Sponsor: 
Bausch & Lomb Incorporated 
 
This clinical investigation is being conducted in accordance with 21CFR Parts 11, 50, 54, 56, and 312, 
42 USC 282(j), ICH GCPs, and applicable local regulations. 
 
Revision Chronology:  
Original 
- 
05 Jan 2011 
Amendment 1 
- 
26 May 2011 
Amendment 2 
- 
15 Nov 2011 
Amendment 3 
 
15 Dec 2011 
Amendment 4 
 
27 Mar 2012 
Amendment 5 
 
04 Jun 2012 
Amendment 6 
 
22 May 2013 
 
The confidential information in the following document is provided to you, as an Investigator or consultant, 
for review by you, your study personnel, and the applicable IRB/EC. By accepting this document, you 
agree that the information contained herein will not be disclosed to others without written authorization 
from Bausch & Lomb Incorporated, except to the extent necessary to obtain consent from those persons 
who participate in this study.  
 
All brand names/product names are trademarks of their respective owners.  






Study #670 - Protocol 
Amendment 6, 22 May 2013 
INVESTIGATOR STATEMENT OF APPROVAL 
 
A Randomized, Multicenter, Double Masked, Parallel-Group Study Assessing the 
Safety and Efficacy of Loteprednol Etabonate Ophthalmic Gel, 0.5% versus 
Prednisolone Acetate Ophthalmic Suspension, 1% for the Treatment of Intraocular 
Inflammation Following Surgery for Childhood Cataract 
 
PROTOCOL 
IND #102654 and EudraCT#2010-024388-41 
STUDY #670 
 
I have read the attached document, concur that it contains all information necessary to 
conduct the study, and agree to abide by all provisions set forth therein.  
I agree to conduct this study in accordance with 21CFR Parts 11, 50, 54, 56, and 312, 
42 USC 282(j), ICH GCPs, and applicable local regulations. I will not initiate the study 
until I have obtained written approval by the appropriate IRB/EC and have complied with 
all financial and administrative requirements of the governing body of the clinical 
institution and the Sponsor. I will obtain written informed consent (and, if applicable, 
assent for children) from each study subject prior to performing any study specific 
procedures.  
I understand that my signature on a case report form indicates that the data therein has 
been reviewed and accepted by me. 
I understand that this document and related information is subject to confidentiality terms 
found in my signed Confidentiality or Clinical Services Agreement. I agree to protect the 
confidentiality of my patients when allowing the Sponsor of this clinical investigation, 
and/or relevant regulatory authorities and IRB/ECs, direct access to my medical records 
for study subjects. 
 
 
 
 
 
Principal Investigator, Printed Name 
 
 
 
 
 
 
Principal Investigator, Signature 
 
Date 
 
Upon signing, provide the original of this page to Bausch + Lomb and retain a copy for your files.  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 4 
PERSONNEL AND FACILITIES 
 
NOTE: The information on this page is subject to change. All changes will be provided under separate 
cover. 
Sponsor  
Bausch & Lomb Incorporated  
Global Clinical Operations 
1400 North Goodman Street 
Rochester, NY 14609 
US 
 
Study Manager (Primary Study Contact)  
US Sites: 
Michael Zhang 
Study Manager 
Bausch & Lomb Incorporated 
7 Giralda Farms, Suite 1001 
Madison, NJ  07940 
US 
Tel: +1 973 360 6448 
Mobile: +1 973 610 3294 
Fax: +1 585 338 0606 
Email: Michael.Zhang@bausch.com  
 
EU Sites: 
Natasa Orlic-Pleyer, MD 
Clinical Study Manager 
Dr. Gerhard Mann chem.-pharm. Fabrik 
GmbH/Bausch & Lomb1 
Brunsbütteler Damm 165-173 
13581 Berlin  
Germany 
Tel. + 49 (0) 30 33093 -318 
Fax: + 49 (0) 30 33093 6699 
Email: natasa.orlic-pleyer@bausch.com  
            
AP Sites: 
Paul Park 
Clinical Study Manager 
Bausch & Lomb (S) Pte Ltd 
151 Lorong Chuan #04-03A 
New Tech Park, Lobby C 
Singapore  556741 
Tel: +65 6490 5858 
Mobile: + 65 9230 3963 
Fax: +65 6286 4218 
Email: Paul.Park@bausch.com 
Contact for Reporting Serious Adverse Events  
US Sites: 
Saberi Rana Ali, MBBS, MS (Ophth), MPH 
Associate Director, Global Safety and Vigilance 
Bausch & Lomb Incorporated 
7 Giralda Farms, Suite 1001  
Madison, NJ 07940  
Tel: +1 973 360 6478 
Fax: +1 813 975 7750 
Mobile: +1 862 579 8366 
SAE Inbox: SAE@bausch.com 
 
EU Sites: 
Natasa Orlic-Pleyer, MD (contact details above) 
 
AP Sites: 
Global Safety and Vigilance, Asia Pacific 
Bausch & Lomb Korea 
13F, KT&G Kosmo Daechi-Tower, 
#945-10 Daechi-dong, Gangnam-gu, 
Seoul 135-280, Korea 
Tel: + 82 70 7167 9784 
Mobile: + 82 10 9112 9784 
Fax: + 82 2 6442 1460 
Email: safety.asia@bausch.com 
 
Scientific & Clinical Affairs/Medical Monitor 
James Gow, MD 
Clinical Affairs 
Bausch & Lomb Incorporated 
50 Technology Drive 
Irvine, CA  92618-2301 
US 
Tel: + 1 949 788 5359 
Mobile: + 1 949 701 6398 
Email:  james.gow@bausch.com 
 
Return of Used and Unused Study Drug 
US Sites: 
Bausch & Lomb Incorporated  
Clinical Trial Materials Supply Chain, Area 19 
1400 North Goodman Street 
Rochester, New York 14609 US 
 
EU Sites: 
Almac Clinical Services 
9 Charlestown Road 
Seagoe Industrial Estate 
Craigavon 
BT63 5PW 
                                                 
1 Dr. Gerhard Mann chem.-pharm. Fabrik GmbH/Bausch & Lomb is an authorized affiliate of 
Bausch & Lomb Incorporated. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 5 
Northern Ireland 
 
AP Sites: 
Zuellig Pharma Korea Clinical Trial 
2nd Floor 213-7 
Jangji-Ri, Dongtan-Myun 
Hwasung-City 
Gyunggi-Do 
445-812 
Korea 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 6 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................................................ 1 
SPONSOR APPROVAL PAGE .................................................................................................................. 2 
INVESTIGATOR STATEMENT OF APPROVAL ................................................................................. 3 
PERSONNEL AND FACILITIES .............................................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................................. 6 
LIST OF ABBREVIATIONS ...................................................................................................................... 8 
SYNOPSIS .................................................................................................................................................... 9 
1.0 
INTRODUCTION ..........................................................................................................................18 
2.0 
OBJECTIVE ...................................................................................................................................18 
3.0 
STUDY DESIGN ............................................................................................................................18 
3.1 
DESCRIPTION OF STUDY DESIGN INCLUDING CHOICE OF CONTROL GROUPS................................18 
3.2 
SELECTION OF STUDY POPULATION ..............................................................................................19 
3.2.1 
Eligibility .................................................................................................................................19 
3.2.2 
Subject Completion .................................................................................................................21 
3.2.3 
Rescue Therapy .......................................................................................................................21 
3.2.4 
Subject Discontinuation ...........................................................................................................21 
3.2.5 
Lost to Follow-up ....................................................................................................................22 
3.3 
INVESTIGATORS ............................................................................................................................22 
3.4 
STUDY DURATION ........................................................................................................................22 
3.5 
TREATMENTS ................................................................................................................................23 
4.0 
STUDY MATERIALS ...................................................................................................................23 
4.1 
DESCRIPTION OF TEST ARTICLE ....................................................................................................23 
4.2 
DESCRIPTION OF COMPARATOR ....................................................................................................23 
4.3 
INSTRUCTIONS FOR USE AND ADMINISTRATION ...........................................................................23 
4.3.1 
Storage Requirements ..............................................................................................................23 
4.4 
OTHER MATERIALS.......................................................................................................................24 
4.5 
PACKAGING AND LABELING .........................................................................................................24 
4.6 
ACCOUNTABILITY .........................................................................................................................24 
4.7 
MASKING/UNMASKING .................................................................................................................25 
4.8 
METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................25 
4.8.1 
Treatment Allocation ...............................................................................................................25 
4.8.2 
Treatment Replacement ...........................................................................................................25 
4.9 
RISK ASSESSMENT ........................................................................................................................25 
4.10 
SELECTION OF DOSE .....................................................................................................................26 
5.0 
STUDY METHODS .......................................................................................................................26 
5.1 
STUDY VISITS ...............................................................................................................................26 
5.1.1 
Visit 1 (Screening, Day -15 ±14 days).....................................................................................26 
5.1.2 
Visit 2 (Surgery/Randomization, Day 0 [within 29 days of screening]) ..................................27 
5.1.3 
Visit 3 (Postoperative Day 1; First Calendar Day after Surgery) ............................................28 
5.1.4 
Visit 4 (Postoperative Day 7, ±2 days) ....................................................................................28 
5.1.5 
Visit 5 (Postoperative Day 14, ±3 days) ..................................................................................29 
5.1.6 
Visit 6 (Postoperative Day 28, ±7 days; End of Treatment) ....................................................29 
5.1.7 
Visit 7 (Postoperative Day 42, ±7 days) ..................................................................................30 
5.1.8 
Visit 8 (Postoperative Day 90, ±14 days; Study Exit) .............................................................30 
5.1.9 
Unscheduled Visits ..................................................................................................................30 
5.1.10 
Missed Visits .......................................................................................................................31 
5.2 
POST-STUDY FOLLOW-UP .............................................................................................................31 
5.3 
STUDY COMPLETION.....................................................................................................................31 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 7 
5.3.1 
Early Study Termination..........................................................................................................31 
5.4 
CONCOMITANT MEDICATIONS/THERAPY ......................................................................................31 
5.4.1 
Permitted Therapy ...................................................................................................................31 
5.4.2 
Disallowed Therapy .................................................................................................................32 
5.5 
TREATMENT COMPLIANCE ............................................................................................................33 
5.6 
PROTOCOL DEVIATIONS................................................................................................................33 
6.0 
ADVERSE EVENTS ......................................................................................................................33 
6.1 
DEFINITION OF ADVERSE EVENTS ................................................................................................33 
6.2 
DEFINITION OF SERIOUS ADVERSE EVENTS ..................................................................................33 
6.3 
REPORTING ADVERSE EVENTS AND FOLLOW-UP ..........................................................................34 
6.4 
REPORTING SERIOUS ADVERSE EVENTS AND FOLLOW-UP ............................................................35 
6.5 
SUBMITTING AN EXPEDITED SAFETY REPORT TO THE IRB (CENTRAL OR LOCAL) .......................36 
6.6 
MEDICAL MONITOR ......................................................................................................................37 
7.0 
STATISTICAL METHODS ..........................................................................................................37 
7.1 
STUDY ENDPOINTS .......................................................................................................................37 
7.1.1 
Primary Efficacy Endpoints .....................................................................................................37 
7.1.2 
Secondary Efficacy Endpoints .................................................................................................37 
7.1.3 
Safety Endpoints ......................................................................................................................38 
7.1.4 
Tolerability Endpoints .............................................................................................................38 
7.2 
HYPOTHESES ................................................................................................................................38 
7.3 
SAMPLE SIZE ................................................................................................................................38 
7.4 
RANDOMIZATION ..........................................................................................................................39 
7.5 
ANALYSIS POPULATIONS ..............................................................................................................39 
7.6 
STATISTICAL ANALYSIS ................................................................................................................39 
7.6.1 
Methods of Analysis ................................................................................................................39 
7.6.2 
Subject Demographics and Baseline Characteristics ...............................................................40 
7.6.3 
Subject Disposition ..................................................................................................................40 
7.6.4 
Protocol Deviations .................................................................................................................41 
7.6.5 
Treatment Compliance.............................................................................................................41 
7.6.6 
Treatment Exposure .................................................................................................................41 
7.6.7 
Missing Data ............................................................................................................................41 
8.0 
DATA QUALITY ASSURANCE ..................................................................................................41 
8.1 
STUDY MONITORING ....................................................................................................................41 
8.2 
SOURCE DOCUMENTATION ...........................................................................................................42 
8.3 
CASE REPORT FORMS AND DATA VERIFICATION ..........................................................................42 
8.4 
RECORDING OF DATA AND RETENTION OF DOCUMENTS ..............................................................43 
8.5 
AUDITING PROCEDURES ...............................................................................................................43 
8.6 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE APPROVAL ................................................43 
8.7 
PUBLICATION OF RESULTS ............................................................................................................44 
9.0 
REFERENCES ...............................................................................................................................45 
 
 
APPENDICES 
APPENDIX A: 
SCHEDULE OF VISITS AND PARAMETERS..................................................... A-1 
APPENDIX B: 
METHODS OF CLINICAL EVALUATION ...........................................................B-1 
 
 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 8 
LIST OF ABBREVIATIONS 
Abbreviation/Acronym 
Term 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ANOVA 
Analysis of Variance 
AP 
Asia Pacific 
BAK 
Benzalkonium Chloride  
Bausch + Lomb 
Bausch & Lomb Incorporated 
BID 
Twice a Day 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CFR 
Code of Federal Regulations 
dpt 
Diopter 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
EU 
European Union 
FDA 
United States Food and Drug Administration 
GCPs 
Good Clinical Practices 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
IOL 
Intraocular Lens 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
LDPE 
Low Density Polyethylene 
LE 
Loteprednol Etabonate 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MNAR 
Missing Not At Random 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
PI 
Package Insert 
PMM 
Pattern Mixture Model 
PP 
Per Protocol 
QD 
Once a Day 
QID 
Four Times a Day 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOP 
Standard Operating Procedure 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
US 
United States 
USC 
United States Code 
VA 
Visual Acuity 
NOTE: The first occurrence of some abbreviations is not spelled out in the document (eg, units of 
measure). 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 9 
SYNOPSIS 
Bausch + Lomb Study #670 
Title: 
A Randomized, Multicenter, Double Masked, Parallel-Group Study 
Assessing the Safety and Efficacy of Loteprednol Etabonate Ophthalmic 
Gel, 0.5% versus Prednisolone Acetate Ophthalmic Suspension, 1% for the 
Treatment of Intraocular Inflammation Following Surgery for Childhood 
Cataract 
Phase of study: 
Phase 4 
Number of study 
centers and subjects: 
Approximately 140 subjects at approximately 30 investigative sites in the 
United States (US), European Union (EU), and Asia Pacific (AP) will be 
enrolled in this study. 
Planned study period: 
Study duration will be approximately 11-19 weeks depending on the time 
between screening, the day of surgery, and the last study visit (Visit 8, 
Postoperative Day 90). The enrollment period is expected to be completed in 24 
months. 
Objective(s): 
The primary objective is to compare the efficacy and safety of Loteprednol 
Etabonate (LE) Ophthalmic Gel, 0.5% to Prednisolone Acetate Ophthalmic 
Suspension, 1% for the treatment of postoperative inflammation following 
ocular surgery for childhood cataract. 
Study design: 
Approximately 140 subjects will be enrolled in this double-masked, parallel-
group, active-controlled study at approximately 30 investigative sites in the 
United States (US), European Union (EU), and Asia Pacific (AP).  
A total of 140 subjects aged 0-11 years will be randomized in a 1:1 ratio to LE 
Ophthalmic Gel, 0.5% or Prednisolone Acetate Ophthalmic Suspension, 1%. Of 
the 140 randomized subjects, at least 60 subjects (approximately 30 subjects per 
treatment group) will be in the age range from 0-3 years. Prednisolone Acetate 
Ophthalmic Suspension, 1% was chosen as the active-control because it has a 
long history as the standard of care in the US. 
Study duration will be approximately 11-19 weeks from screening to the last 
visit (Visit 8, Postoperative Day 90). Subjects will visit the clinic eight times. 
Visit 1 will be the Screening Visit and will occur up to a maximum of 29 days 
prior to surgery. Visit 2 will be on the day of surgery. At the end of surgery on 
Visit 2, eligibility for randomization into the study will be assessed and, if 
appropriate, subjects will be randomized at this time. Randomized subjects will 
complete postoperative study Visits 3 through 8 (Postoperative Days 1, 7, 14, 
28, 42, and 90, respectively). 
Subject’s eyes meeting eligibility criteria at both Visit 1 (Screening) and Visit 2 
(Surgery/Randomization) will be randomized to receive study medication. If 
both eyes of a subject undergo routine, uncomplicated surgery at Visit 2 
(Surgery/Randomization) and meet eligibility criteria, the subject’s right eye 
will be considered the study eye. In the event that the subject requires surgery 
on the contralateral eye at any time during the study, the fellow eye will be 
treated with standard of care medication. 
The subject will receive the first dose of study drug by the unmasked designee 
at the end of the surgery. Either the unmasked designee or the subject’s 
parent/legal guardian will then administer 1 t o 2 drops of study drug to the 
lower cul-de-sac of the study eye once in the evening on the day of surgery and 
then four times a day (QID), at approximately four hour intervals, beginning on 
the morning after surgery. QID dosing will continue until postoperative day 14, 
including dosing at appropriate time intervals on the day of a visit. Treatment 
will be tapered from QID to twice a d ay (BID) during the interval between 
postoperative days 15 and 21. Treatment will be further tapered from 
postoperative day 22 until day 28 to once a day (QD) with the last dose being 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 10 
administered on the day prior to Visit 6 (Postoperative Day 28). 
Criteria for inclusion: 
This study will include subjects who meet the following criteria at Visit 1 
(Screening): 
1. Subjects who are male or female, 0 to 11 years of age, on the date the 
Informed Consent Form (ICF) is signed.  
2. Subjects who have the ability to understand and provide assent (when 
applicable) and whose parent/legally authorized representative has the 
ability to understand and provide written informed consent on the 
Institutional Review Board (IRB)/Ethics Committee (EC) approved ICF 
and provide authorization as appropriate for local privacy regulations. 
3. Subjects whose parent/legally authorized representative is able and willing 
to comply with all treatment and follow-up procedures. 
4. Subject is a can didate for routine, uncomplicated surgery for childhood 
cataract (aspiration, with or without posterior capsulotomy with or without 
anterior vitrectomy, and with or without posterior chamber intraocular lens 
(IOL) implantation, not combined with any other surgery and without the 
planned use of iris hooks and/or pupil stretching). 
This study will include subjects who meet the following criteria at Visit 2 
(Surgery/Randomization):  
1. Subjects who have undergone routine, uncomplicated surgery for 
childhood cataract (aspiration, with or without posterior capsulotomy, with 
or without anterior vitrectomy, and with or without posterior chamber IOL 
implantation, not combined with any other surgery). 
Criteria for exclusion:  
This study will exclude subjects who meet the following criteria: 
1. Subjects who have a severe/serious ocular condition, or any other unstable 
medical condition that, in the Investigator’s opinion, may preclude study 
treatment or follow-up, eg: 
− 
presence of any active or suspected viral, bacterial, or fungal disease in 
the study eye 
− 
subjects with post-traumatic cataract in the study eye 
− 
active uveitis in the study eye 
− 
ocular neoplasm in the study eye 
2. Subjects with glaucoma, ocular hypertension, or those receiving intraocular 
pressure (IOP) lowering therapy in either eye or systemically. 
3. Subjects with a history of steroid-induced IOP elevation in either eye. 
4. Subjects who have suspected permanent low vision or blindness (eg, legal 
definition of blindness: visual acuity [VA] of ≤ 20/200 or visual field of 
≤ 20 degrees) in the fellow non-study eye. (The study eye must not be the 
subject's only sighted eye.) 
5. Subjects who have had ocular surgery (including laser therapy) in the study 
eye 
within 
90 da
ys 
prior 
to 
randomization 
on 
Visit 
2 
(Surgery/Randomization). 
6. Subjects who are expected to require treatment with systemic or ocular 
(study eye) corticosteroids other than study drug during the 90 da ys 
following cataract surgery or have used any systemic or ocular 
corticosteroids (study eye) within 14 days prior to cataract surgery. (Ocular 
therapy with corticosteroids in the fellow eye is permitted.) 
7. Subjects who are expected to require concurrent systemic or ocular therapy 
(study eye) with nonsteroidal anti-inflammatory drugs (NSAIDs), or 
concurrent ocular therapy (either eye) with mast cell stabilizers, 
antihistamines, or decongestants during the 90 days following cataract 
surgery or have received any of the above medications within 2 days prior 
to surgery (intraoperative NSAIDs for mydriasis in the study eye are NOT 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 11 
permitted; ocular therapy with NSAIDs in the fellow eye is permitted).  
8. Subjects who are expected to require concurrent ocular (either eye,  
eg, Restasis) or systemic immunosuppressant therapy during the 90 days 
following 
cataract 
surgery 
or 
have 
used 
ocular 
(either 
eye) 
immunosuppressants within 30 da ys prior to surgery or systemic 
immunosuppressants within 10 months prior to surgery. 
9. Subject or subject’s breastfeeding mother or wet nurse who is expected to 
use corticosteroids (except corticosteroid inhalers and dermatological 
corticosteroids, as long as they are not used on the eyelids or surrounding 
area) or immunosuppressants during the 90 days following cataract 
surgery. 
10. Subjects who have a history or presence of chronic generalized systemic 
disease that the Investigator believes may either increase the risk to the 
subject or confound the results of the study (eg, Diabetes mellitus, human 
immunodeficiency virus [HIV], acquired immunodeficiency syndrome 
[AIDS]). 
11. Female subjects who have started menarche prior to Visit 1 (Screening). 
12. Subjects who have known hypersensitivity or other contraindication to the 
study drug(s) or any components in the drug formulation. 
13. Subjects who have participated in an investigational drug or device study 
within 30 days prior to Visit 1 (Screening). 
14. Subjects who were previously randomized in this study. 
Investigational 
product: 
Loteprednol Etabonate Ophthalmic Gel, 0.5%, contains the active ingredient 
loteprednol etabonate 0.5% and the preservative benzalkonium chloride (BAK), 
0.003%. It also contains the inactive ingredients glycerin, propylene glycol, 
sodium chloride, polycarbophil, sodium hydroxide, tyloxapol, edetate disodium 
dihydrate, boric acid, and water for injection. 
Comparator 
product(s):  
Prednisolone Acetate Ophthalmic Suspension, 1% contains the active ingredient 
prednisolone acetate 1% and the preservative BAK 0.004%. The inactive 
ingredients are comprised of: 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. 
Duration of treatment: 
The subject will receive the first dose of study drug by the unmasked designee 
at the end of the surgery. Either the unmasked designee or the subject’s 
parent/legal guardian will then administer 1 to 2 dr ops of study drug to the 
lower cul-de-sac of the study eye once in the evening on the day of surgery and 
then QID, at approximately four hour intervals, beginning on the morning after 
surgery. QID dosing will continue until postoperative day 14, including dosing 
at appropriate time intervals on the day of a visit. Treatment will be tapered 
from QID to BID during the interval between postoperative days 15 and 21. 
Treatment will be further tapered from postoperative day 22 until day 28 to QD 
with the last dose being administered on the day prior to Visit 6 (Postoperative 
Day 28). 
NOTE:  At the conclusion of surgery, each randomized subject will receive 
the first dose of study drug from the unmasked designee followed by 
an antibiotic of the Investigator’s choice and an eye patch. 
Study procedures: 
Visit 1 (Screening, Day -15 ±14 days) 
Visit 1 will proceed as follows: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
obtain assent (when applicable), written informed consent (US, EU, and 
AP) and HIPAA authorization (US only) 
• 
determine if the subject meets preliminary eligibility criteria: 
− 
documentation of demographic information 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 12 
− 
current and relevant medical and ophthalmic history 
− 
concomitant medications 
• 
if the subject meets the preliminary eligibility criteria, the following 
assessments will be performed: 
− 
ocular symptoms  
− 
pediatric visual acuity (VA) testing  
− 
biomicroscopy  
− 
IOP measurement  
NOTE:  Measurement of IOP must occur after the assessment of ocular 
symptoms, VA and biomicroscopy 
NOTE:  Surgery will be scheduled to occur within 29 days of the Screening 
Visit. Screening and surgery cannot take place on the same day. 
 
Visit 2 (Surgery/Randomization, Day 0 [within 29 days of Screening]) 
Visit 2 will proceed as follows: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
record adverse events (AEs) and changes in concomitant medications 
• 
pediatric VA assessment  
• 
biomicroscopy  
• 
IOP measurement  
• 
fundoscopy, if performed during surgery, if not, then perform at Visit 3 
• 
immediately following surgery, determine eligibility  
NOTE: Subjects who, in the Investigator's opinion, have surgical 
complications such that it is not in their best interest to continue in 
the study are considered screen failures and will not be randomized 
into the trial. 
 
If during the surgery it is determined that additional manipulations, 
such as pupil stretching or the use of iris hooks are required, it is left 
to the Investigator’s discretion whether or not it is safe to randomize 
the subject into the trial.  
 
At the conclusion of the surgery, no subconjunctival or intracameral 
steroid injections are permitted. If a steroid injection is deemed 
necessary by the Investigator, the subject cannot be randomized and 
is considered a screen failure. 
• 
randomize eligible subjects by assigning the next sequential subject kit box 
• 
the unmasked designee must weigh both bottles of study drug prior to 
dispensing  
• 
at the conclusion of surgery, the randomized subject will receive the first 
dose of study drug from the unmasked designee followed by an antibiotic 
of the Investigator’s choice and an eye patch  
• 
study drug will be dispensed to the subject’s parent/legal guardian by the 
unmasked designee 
• 
a study drug administration diary will be provided to the subject’s 
parent/legal guardian who will be instructed to record the time of each 
instillation and to bring the diary and study drug (both bottles) to each visit. 
The subject’s parent/legal guardian will be reminded that no other 
information should be recorded in the diary 
• 
the subject’s parent/legal guardian will be trained by site personnel with 
regard to the correct instillation of eye drops prior to administration of the 
initial dose at any time at Visit 1 or 2 without using the study drug, but 
prior to their first instillation of study drug outside of the office. The time 
and method is left to the Investigator’s discretion  


Study #670 - Protocol 
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• 
either the unmasked designee or the subject’s parent/legal guardian will 
administer approximately one to two drops of study drug into the lower 
cul-de-sac of the study eye in the evening, after removing the patch and 
before applying the shield, which will cover the study eye overnight 
• 
the subject’s parent/legal guardian will proceed with administration of the 
study drug on the morning of the first postoperative day with QID dosing at 
approximately four hour intervals, independently of when Visit 3 is 
scheduled to occur 
 
Visit 3 (Postoperative Day 1; First Calendar Day after Surgery) 
At Visit 3, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug  
• 
ocular symptoms  
• 
pediatric VA 
• 
biomicroscopy 
• 
IOP measurement  
NOTE:  Measurement of IOP must occur after the assessment of ocular 
symptoms, VA and biomicroscopy. 
NOTE:  If, at any time point after surgery, IOP is elevated, treatment or 
intervention is left to the Investigator's discretion and the subject is 
to continue the study. 
• 
fundoscopy, if not performed during surgery  
NOTE: Topical antibiotic drops should be administered at least 15 minutes 
AFTER study drug application. 
• 
review and collect study drug administration diary for compliance. Instruct 
subject’s parent/legal guardian to record time of each instillation on the 
diary and to bring the diary and study drug (both bottles) to their next visit. 
Remind subjects that no other information should be recorded in the diary 
• 
dispense new diary  
• 
the unmasked designee must redispense study drug 
• 
instruct subject’s parent/legal guardian to continue dosing the study drug 
QID, at approximately four hour intervals for the next 2 weeks 
 
Visit 4 (Postoperative Day 7, ±2 days) 
At Visit 4, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug  
• 
ocular symptoms  
• 
pediatric VA 
• 
biomicroscopy 
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular 
symptoms, VA and biomicroscopy 
• 
review study drug administration diary for compliance. Instruct subject’s 
parent/legal guardian to record time of each instillation in the diary and to 
bring the diary and study drug (both bottles) to their next visit. Remind 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 14 
subject’s parent/legal guardian that no other information should be 
recorded in the diary 
• 
dispense new diary  
• 
the unmasked designee must redispense study drug 
• 
remind subject’s parent/legal guardian that the dosing is QID for another 
week and then BID for one week 
 
Visit 5 (Postoperative Day 14, ±3 days) 
At Visit 5, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug  
• 
ocular symptoms  
• 
pediatric VA  
• 
biomicroscopy  
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular 
symptoms, VA and biomicroscopy 
• 
fundoscopy (it is at the Investigator’s discretion whether to perform 
fundoscopy with or without mydriasis) 
• 
review study drug administration diary for compliance. Instruct subject’s 
parent/legal guardian to record time of each instillation in the diary and to 
bring the diary and study drug (both bottles) to their next visit. Remind 
subject’s parent/legal guardian that no other information should be 
recorded in the diary 
• 
dispense new diary  
• 
the unmasked designee must redispense study drug 
• 
remind subject’s parent/legal guardian that the dosing is BID for the rest of 
the week and QD for the last week 
 
Visit 6 (Postoperative Day 28, ±7 days; End of Treatment) 
At Visit 6, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug and collect 
all used and unused study drug (both bottles) 
• 
collect diaries  
• 
ocular symptoms  
• 
pediatric VA  
• 
biomicroscopy 
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular 
symptoms, VA and biomicroscopy 
 
Visit 7 (Postoperative Day 42, ±7 days) 
At Visit 7, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 


Study #670 - Protocol 
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• 
AEs and changes in concomitant medications 
• 
ocular symptoms  
• 
pediatric VA 
• 
biomicroscopy 
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular 
symptoms, VA and biomicroscopy 
 
Visit 8 (Postoperative Day 90, ±14 days; Study Exit) 
At Visit 8, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
ocular symptoms  
• 
pediatric VA  
• 
biomicroscopy  
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular 
symptoms, VA and biomicroscopy 
• 
fundoscopy (it is at the Investigator’s discretion whether to perform 
fundoscopy with or without mydriasis) 
• 
subject exits from study 
Study endpoints:  
Primary Efficacy Endpoints 
• 
mean grade of anterior chamber inflammation at  Visit 5 (Postoperative 
Day 14). 
Secondary Efficacy Endpoints 
• 
mean grade of anterior chamber inflammation at Visits 4 and 6 
(Postoperative Days 7 and 28) 
• 
proportion of subjects with Grade 0, Grade 1, Grade 2, Grade 3, and Grade 
4 anterior chamber inflammation at each visit (Postoperative Days 7, 14, 
and 28)  
• 
presence/absence and total area, if present, of synechiae at each visit 
(Postoperative Days 7, 14, and 28) 
• 
presence/absence and total number, if present, of precipitates on the 
implant and cornea at each visit (Postoperative Days 7, 14, and 28) 
Safety Endpoints 
• 
incidence of overall and specific AEs 
• 
type and incidence of AEs at each visit  
• 
change in IOP from baseline (Visit 2, Surgery/Randomization) to each visit 
• 
greatest IOP change from baseline - including the measurement at Visit 3 
(Postoperative Day 1) 
• 
greatest IOP change from baseline - excluding the measurement at Visit 3 
(Postoperative Day 1) 
• 
ocular signs (biomicroscopic examination of the lids, conjunctiva, cornea, 
anterior chamber without pupil dilation) at each visit 
Tolerability Endpoint 
• 
ocular symptoms at each visit 
Statistical methods:  
Summaries for continuous variables will include the sample size, mean, 


Study #670 - Protocol 
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standard deviation (SD), median, minimum, and maximum. Summaries for 
discrete variables will include the tabulation of frequencies and percentages. 
Means and medians will be presented to one more decimal place than the 
recorded data. Standard deviations will be presented to two more decimal 
places than the recorded data. Minimum and maximum values will be presented 
using the same number of decimal places as the recorded data. Confidence 
intervals (CIs) will be presented using the same number of decimal places as the 
parameters (eg, mean). Percentages will be presented to one decimal place.  
 
Sample Size 
A sample size of 120 s ubjects (60 subjects per treatment group) yields 98% 
power to detect non-inferiority of LE Ophthalmic Gel, 0.5% to Prednisolone 
Acetate Ophthalmic Suspension, 1%. This sample size assumes a co mmon 
standard deviation of 0.47, a two-sided alpha=0.05, a non-inferiority margin of 
0.35 and an expected difference of 0 for the difference in means between 
treatment groups using anterior chamber inflammation at Visit 5 (Postoperative 
Day 14).  Assuming a subject dropout rate (including the initiation of rescue 
medication) of 12%, approximately 140 subjects will be randomized of which 
at least 60 subjects will be in the age group 0-3 years as per the FDA’s Written 
Request. 
 
Hypothesis 
Test for the non-inferiority of LE Ophthalmic Gel, 0.5% to Prednisolone 
Acetate Ophthalmic Suspension, 1% will be primarily based on the following 
one-sided null hypothesis (Ho) and alternative hypothesis (Ha): 
 
Ho: µLE - µPR ≥ 0.35     versus              Ha: µLE -  µPR < 0.35 
where µLE and µPR are the mean grade of anterior chamber inflammation at 
Visit 4 (Postoperative Day 7) for LE Ophthalmic Gel, 0.5% and Prednisolone 
Acetate Ophthalmic Suspension, 1% treatment group, respectively. 
 
Primary Analysis 
For the primary efficacy analysis, the mean grade of anterior chamber 
inflammation at Visit 5 (Postoperative Day 14) will be calculated by treatment 
group, including a two-sided 95% CI about the difference between the means. If 
the upper limit of the 95% CI is less than 0.35, then non-inferiority of LE 
Ophthalmic Gel, 0.5% to Prednisolone Acetate Ophthalmic Suspension, 1% 
will be claimed.  
The primary efficacy analysis will be based on the ITT population. The primary 
analysis will be repeated using the PP population to supplement the ITT 
analysis. Any discrepancy between the 2 analyses will be explained. 
 
Secondary Efficacy Analysis 
The secondary efficacy analyses will be conducted based on the ITT population 
as well as the PP population. 
As a secondary analysis, the analysis of the mean grade of anterior chamber 
inflammation will be repeated as above for Visits 4 and 6 (Postoperative Days 7 
and 28, respectively). 
Additional secondary analyses include:  
• 
the proportion of subjects with  a nterior chamber inflammation with 
Grade 0, Grade 1, Grade 2, Grade 3, and Grade 4 for each visit 
(Postoperative Days 7, 14, and 28) 
• 
the proportion of subjects with presence/absence and total area, if present, 
of synechiae for each visit (Postoperative Days 7, 14, and 28) 


Study #670 - Protocol 
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• 
the proportion of subjects with presence/absence and total number, if 
present, of precipitates on the implant and cornea at each visit 
(Postoperative Days 7, 14, and 28) 
For each of the above endpoints, treatment groups will be compared using the 
Pearson Chi-squared test or fisher’s exact test as appropriate. Differences 
between the proportions of treatment groups and 95% confidence interval about 
the differences will be presented. 
Subgroup analyses will be performed for anterior chamber inflammation, 
anterior chamber cells, and anterior chamber flare as appropriate by method of 
assessment (slit lamp versus penlight with handheld magnifying 20 diopter 
lens), country (region), age group, IOL implantation, and iris color. 
 
Safety Analysis 
All subjects in the safety set will be included in the safety analyses. Intraocular 
pressure will be summarized by visit using continuous summaries (including 
change from baseline and change from screening) for the following items: 
• 
change in IOP from baseline to each visit 
• 
greatest IOP change from baseline - including the one day postoperative 
measurement at Day 1 
• 
greatest IOP change from baseline - excluding the one day postoperative 
measurement at Day 1 
• 
ocular signs (biomicroscopic examination of the lids, conjunctiva, cornea, 
anterior chamber without pupil dilation) 
Treatment emergent systemic AEs will be summarized using discrete 
summaries at the subject and event level by system organ class and preferred 
term for each treatment group. Treatment emergent ocular AEs will be 
summarized for treated eyes and fellow eyes separately. Similarly, treatment 
emergent AEs will be summarized by severity and relationship separately. All 
AEs will be coded using a Med DRA dictionary (the most current version 
available at the start of the study will be used). 
 
Tolerability 
Ocular symptoms will be summarized using discrete summary statistics by visit 
and treatment group. These data will be summarized under the safety analyses.  
 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
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1.0 
INTRODUCTION  
Corticosteroids are potent, non-specific, anti-inflammatory drugs that inhibit a variety of 
chemotactic substances and factors that mediate capillary permeability, contraction of 
nonvascular smooth muscle, and vasodilation. In addition, corticosteroids suppress 
inflammation by inhibiting edema, fibrin deposition, migration of leukocytes, and 
phagocytic activity. 
Topical corticosteroids are useful in a variety of ophthalmic conditions and are generally 
indicated for treatment of steroid-responsive inflammatory conditions of the palpebral 
and bulbar conjunctiva, cornea, and anterior segment of the eye.1 Although 
corticosteroids are widely used as a topical agent for ocular inflammation, most possess a 
safety risk profile that limits their general utility. A common risk associated with 
corticosteroid therapy is an elevation of intraocular pressure (IOP).2,3 In addition, chronic 
use of topical corticosteroids may result in the development of cataracts.4 
Loteprednol etabonate (LE) is a novel compound designed as a unique C-20 ester 
corticosteroid5 that will undergo a predictable transformation to an inactive metabolite. 
The relatively rapid metabolism of LE to an inactive metabolite improves the safety 
profile of this corticosteroid. In clinical studies, LE Ophthalmic Suspension, 0.5% 
(Lotemax®) has been shown to have a decreased incidence of clinically significant IOP 
increase (ie, ≥10 mm Hg) compared to prednisolone acetate.6,7 This characteristic of LE 
makes it an optimal candidate for use in inflammatory ocular conditions.  
The pH of LE Ophthalmic Gel, 0.5% was adjusted to 6.0 - 6.5 making it closer to normal 
physiological pH of 7.4. Preservative effectiveness has been demonstrated in this new 
formulation using a reduced level of the preservative, benzalkonium chloride (BAK), 
than in the currently marketed product (ie, from 100ppm or 0.01% to 30 ppm or 0.003%), 
which may improve the tolerability of the gel. 
2.0 
OBJECTIVE 
The primary objective is to compare the efficacy and safety of Loteprednol Etabonate 
(LE) Ophthalmic Gel, 0.5% to Prednisolone Acetate Ophthalmic Suspension, 1% for the 
treatment of postoperative inflammation following ocular surgery for childhood cataract. 
3.0 
STUDY DESIGN 
3.1 
Description of Study Design Including Choice of Control Groups  
Approximately 140 subjects will be enrolled in this double-masked, parallel-group, 
active-controlled study at approximately 30 investigative sites in the United States (US), 
European Union (EU), and Asia Pacific (AP).  
A total of 140 subjects aged 0-11 years will be randomized in a 1:1 ratio to LE 
Ophthalmic Gel, 0.5% or Prednisolone Acetate Ophthalmic Suspension, 1%. Of the 140 
randomized subjects, at least 60 subjects (approximately 30 subjects per treatment group) 
will be in the age range from 0-3 years. Prednisolone Acetate Ophthalmic Suspension, 
1% was chosen as the active-control because it has a long history as the standard of care 
in the US. 
Study duration will be approximately 11-19 weeks from screening to the last visit (Visit 8, 
Postoperative Day 90). Subjects will visit the clinic eight times. Visit 1 will be the 


Study #670 - Protocol 
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Screening Visit and will occur up to a maximum of 29 days prior to surgery. Visit 2 will 
be on the day of surgery. At the end of surgery on Visit 2, eligibility for randomization 
into the study will be assessed and, if appropriate, subjects will be randomized at this 
time. Randomized subjects will complete postoperative study Visits 3 t hrough 8 
(Postoperative Days 1, 7, 14, 28, 42, and 90, respectively). 
Subject’s eyes meeting eligibility criteria at both Visit 1 (Screening) and Visit 2 
(Surgery/Randomization) will be randomized to receive study medication. If both eyes of 
a subject undergo routine, uncomplicated surgery at Visit 2 (Surgery/Randomization) and 
meet eligibility criteria, the subject’s right eye will be considered the study eye. In the 
event that the subject requires surgery on the contralateral eye at any time during the 
study, the fellow eye will be treated at the Investigator’s discretion with standard of care 
medication. 
The subject will receive the first dose of study drug by the unmasked designee at the end 
of the surgery. Either the unmasked designee or the subject’s parent/legal guardian will 
then administer 1 to 2 drops of study drug to the lower cul-de-sac of the study eye once in 
the evening on the day of surgery and then four times a day (QID), at approximately four 
hour intervals, beginning on the morning after surgery. QID dosing will continue until 
postoperative day 14, including dosing at appropriate time intervals on the day of a visit. 
Treatment will be tapered from QID to twice a day (BID) during the interval between 
postoperative days 15 and 21. Treatment will be further tapered from postoperative day 
22 until day 28 to once a day (QD) with the last dose being administered on the day prior 
to Visit 6 (Postoperative Day 28). 
3.2 
Selection of Study Population  
Approximately 140 subjects who have undergone routine, uncomplicated surgery for 
childhood cataract will be enrolled in this clinical investigation.  
3.2.1 
Eligibility 
3.2.1.1 
Inclusion Criteria 
This study will include subjects who meet the following criteria at Visit 1 (Screening):  
1. Subjects who are male or female, 0 t o 11 years of age, on t he date the Informed 
Consent Form (ICF) is signed.  
2. Subjects who have the ability to understand and provide assent (when applicable) and 
whose parent/legally authorized representative has the ability to understand and 
provide written informed consent on t he Institutional Review Board (IRB)/Ethics 
Committee (EC) approved ICF and provide authorization as appropriate for local 
privacy regulations. 
3. Subjects whose parent/legally authorized representative is able and willing to comply 
with all treatment and follow-up procedures. 
4. Subject is a candidate for routine, uncomplicated surgery for childhood cataract 
(aspiration, with or without posterior capsulotomy with or without anterior vitrectomy, 
and with or without posterior chamber intraocular lens (IOL) implantation, not 
combined with any other surgery and without the planned use of iris hooks and/or 
pupil stretching). 


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This study will include subjects who meet the following criteria at Visit 2 
(Surgery/Randomization):  
1. Subjects who have undergone routine, uncomplicated surgery for childhood cataract 
(aspiration, with or without posterior capsulotomy, with or without anterior 
vitrectomy, and with or without posterior chamber IOL implantation, not combined 
with any other surgery). 
3.2.1.2 
Exclusion Criteria 
This study will exclude subjects who meet the following criteria: 
1. Subjects who have a severe/serious ocular condition, or any other unstable medical 
condition that, in the Investigator’s opinion, may preclude study treatment or follow-
up, eg: 
− presence of any active or suspected viral, bacterial, or fungal disease in the study 
eye 
− subjects with post-traumatic cataract in the study eye 
− active uveitis in the study eye 
− ocular neoplasm in the study eye 
2. Subjects with glaucoma, ocular hypertension, or those receiving intraocular pressure 
(IOP) lowering therapy in either eye or systemically. 
3. Subjects with a history of steroid-induced IOP elevation in either eye. 
4. Subjects who have suspected permanent low vision or blindness (eg, legal definition 
of blindness: visual acuity [VA] of ≤ 20/200 or visual field of ≤ 20 degrees) in the 
fellow non-study eye. (The study eye must not be the subject's only sighted eye.) 
5. Subjects who have had ocular surgery (including laser therapy) in the study eye 
within 90 days prior to randomization on Visit 2 (Surgery/Randomization). 
6. Subjects who are expected to require treatment with systemic or ocular (study eye) 
corticosteroids other than study drug during the 90 days following cataract surgery or 
have used any systemic or ocular corticosteroids (study eye) within 14 days prior to 
cataract surgery. (Ocular therapy with corticosteroids in the fellow eye is permitted.) 
7. Subjects who are expected to require concurrent systemic or ocular therapy (study eye) 
with nonsteroidal anti-inflammatory drugs (NSAIDs), or concurrent ocular therapy 
(either eye) with mast cell stabilizers, antihistamines, or decongestants during the 
90 days following cataract surgery or have received any of the above medications 
within 2 days prior to surgery (intraoperative NSAIDs for mydriasis in the study eye 
are NOT permitted; ocular therapy with NSAIDs in the fellow eye is permitted).  
8. Subjects who are expected to require concurrent ocular (either eye, eg, Restasis) or 
systemic immunosuppressant therapy during the 90 days following cataract surgery or 
have used ocular (either eye) immunosuppressants within 30 days prior to surgery or 
systemic immunosuppressants within 10 months prior to surgery. 
9. Subject or subject’s breastfeeding mother or wet nurse who is expected to use 
corticosteroids (except corticosteroid inhalers and dermatological corticosteroids, as 


Study #670 - Protocol 
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Page 21 
long as they are not used on the eyelids or surrounding area) or immunosuppressants 
during the 90 days following cataract surgery. 
10. Subjects who have a history or presence of chronic generalized systemic disease that 
the Investigator believes may either increase the risk to the subject or confound the 
results of the study (eg, Diabetes mellitus, human immunodeficiency virus [HIV], 
acquired immunodeficiency syndrome [AIDS]). 
11. Female subjects who have started menarche prior to Visit 1 (Screening). 
12. Subjects who have known hypersensitivity or other contraindication to the study 
drug(s) or any components in the drug formulation. 
13. Subjects who have participated in an investigational drug or device study within  
30 days prior to Visit 1 (Screening). 
14. Subjects who were previously randomized in this study. 
3.2.2 
Subject Completion 
The subject has completed the study when Visit 8 ( Postoperative Day 90) has been 
completed and the subject has been exited. Subjects who require further follow-up for an 
AE will be followed according to Section 6.3 and 6.4. 
3.2.3 
Rescue Therapy 
Subjects will be assessed at Visits 3 through 6 (Postoperative Days 1, 7, 14, and 28) for 
rescue. A study eye with greater than anticipated inflammation at Visit 3 or, at the 
following visits, a worsening or no change of the grade of inflammation compared to the 
previous visit may be eligible for rescue therapy. In some cases a persistent or worsening 
inflammation may be due to a lack of compliance. This should be explored and rectified. 
If the Investigator deems rescue necessary, the choice of rescue therapy and dosing shall 
be determined by the Investigator. Subjects requiring rescue therapy for inflammation 
will stop treatment with study medication. The subject should be exited from the study 
and the reason selected for exit should be “rescue therapy” in the eCRF. This should not 
be reported as an AE unless determined to be an SAE.  
3.2.4 
Subject Discontinuation 
A subject MAY be discontinued (at the discretion of the Investigator, the Sponsor and/or 
the IRB/EC) prior to the final study visit for several reasons, including, but not limited to:  
• 
a serious adverse event (SAE) occurring during the course of the study, which 
precludes continued treatment or follow-up  
• 
the subject’s parent/legally authorized representative not following required study 
procedures 
A subject MUST be discontinued prior to the final study visit for any of the following 
reasons: 
• 
voluntary withdrawal 
• 
onset of menarche during the study 
• 
death 


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• 
Investigator decision that it is  not in the best medical interest of the subject to 
continue participation in the investigation 
• 
requires rescue medication 
Prior to discontinuing a subject, every effort should be made to contact the subject’s 
parent/legal guardian, schedule a final study visit, and obtain as much follow-up data as 
possible, and to retrieve all study materials. Adverse events will be followed as described 
in Section 6.3 and 6.4. Subject withdrawals will be documented clearly on t he source 
document and applicable electronic case report form (eCRF). The assessments scheduled 
for Visit 8 (Postoperative Day 90) should be performed at this early termination visit. 
Subject discontinuation will be documented clearly on the applicable eCRF. Any subject 
discontinued from the study after randomization will not be replaced. 
3.2.5 
Lost to Follow-up 
Subjects who do not return for scheduled follow-up Visits 3 through 8, as defined by the 
visit window and cannot be contacted via two telephone calls and one letter with delivery 
confirmation are considered lost to follow-up. All follow-up attempts will be documented 
and kept with the subject’s source documentation, and the applicable eCRFs will be 
completed. 
3.3 
Investigators 
The study will be conducted at approximately 30 investigative sites located in the US, EU, 
and AP.  
The study will be conducted by Investigators who are determined by Bausch + Lomb to 
be suitably qualified by training and experience to conduct this study in compliance with 
all applicable GCPs and all applicable regulatory requirements. Sub-Investigators will be 
identified on t he FDA Form 1572 a nd in the regulatory documents required by the 
country in which the study is being conducted. 
Each Investigator will enroll approximately 5 subjects. In the event that selected sites do 
not meet full enrollment, the Sponsor may decide to increase enrollment as needed at 
other currently active sites and additional site(s) may be added to satisfy the enrollment 
requirements of the study.  
3.4 
Study Duration 
Study duration will be approximately 11-19 weeks depending on the time between 
screening, the day of surgery, and the last study visit (Visit 8, Postoperative Day 90). The 
enrollment period is expected to be completed in 24 months. 
Eligible subjects who are enrolled in the study will be seen for eight scheduled study 
visits. Visit 1 will be the Screening Visit and will occur up to a maximum of 29 days 
prior to surgery. Visit 2 will be on the day of surgery. At the end of surgery on Visit 2, 
eligibility for randomization into the study will be assessed and, if appropriate, subjects 
will be randomized at this time. Randomized subjects will complete postoperative study 
Visits 3 through 8 (Postoperative Days 1, 7, 14, 28, 42, and 90, respectively). 


Study #670 - Protocol 
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3.5 
Treatments 
A total of 140 subjects will be randomly assigned in a 1:1 ratio to receive either LE 
Ophthalmic Gel, 0.5% or Prednisolone Acetate Ophthalmic Suspension, 1%. 
4.0 
STUDY MATERIALS 
4.1 
Description of Test Article  
Loteprednol Etabonate Ophthalmic Gel, 0.5%, contains the active ingredient loteprednol 
etabonate 0.5% and the preservative benzalkonium chloride (BAK), 0.003%. It also 
contains the inactive ingredients glycerin, propylene glycol, sodium chloride, 
polycarbophil, sodium hydroxide, tyloxapol, edetate disodium dihydrate, boric acid, and 
water for injection. 
4.2 
Description of Comparator  
Prednisolone Acetate Ophthalmic Suspension, 1% contains the active ingredient 
prednisolone acetate 1% and the preservative BAK 0.004%. The inactive ingredients are 
comprised of: 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. 
4.3 
Instructions for Use and Administration  
Following the initial drop administration by the unmasked study personnel at the end of 
the surgery, either the unmasked designee or the subject’s parent/legal guardian will 
administer 1 to 2 drops of study drug into the study eye once in the evening on the day of 
surgery and then QID, at approximately four hour intervals, beginning on the morning 
after surgery. QID dosing will continue until postoperative day 14. Treatment will be 
tapered from QID to BID during the interval between postoperative days 15 a nd 21. 
Treatment will be further tapered from postoperative day 22 until day 28 to QD with the 
last dose being administered on the day prior to Visit 6 (Postoperative Day 28).  
Parents/legal guardians will be trained with regard to the instillation of eye drops prior to 
administration of the initial dose. 
Site personnel will instruct the subject’s parent/legal guardian on the proper instillation of 
their study medication without using the study drug. 
Subject’s parent/legal guardian will be instructed to return the study drug at  
Visits 4, 5 a nd 6 for weighing, and for collection in the original packaging at Visit 6 or 
early study discontinuation. Both the Investigator and the subjects will be masked to the 
study drug assignment. 
4.3.1 
Storage Requirements 
All clinical trial material will be stored in an area free of environmental extremes, 
avoiding excessive heat. Clinical trial material should be stored upright at 15-25°C  
(59-77°F). A daily temperature log will be maintained at the site. The storage location at 
the clinical sites will have limited access.  
Subject’s parent/legal guardian must be instructed regarding proper storage. 


Study #670 - Protocol 
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Page 24 
4.4 
Other Materials  
Additional materials (eg, scales) will be provided by the Sponsor, depending on the 
requirements by the site.  
4.5 
Packaging and Labeling  
The test and control articles will be packaged and labeled in a manner consistent with the 
study design. All investigational products will be labeled and supplied by the Sponsor. 
The test article will be manufactured and filled (5-mL) into 10-mL, white, low density 
polyethylene (LDPE) bottles with pink polypropylene caps by Bausch & Lomb 
Incorporated (Tampa, FL). The control article, Prednisolone Acetate Ophthalmic 
Suspension, 1%, will be sourced from readily available commercial supply. The control 
article will be provided in 10-mL industry standard ophthalmic bottles.  
The investigational products will be packaged and labeled in a manner consistent with the 
study design. Investigational products will be provided in kit boxes (one study kit per 
subject) each with two dropper bottles containing sufficient doses for duration of 
treatment. Supply labeling will minimally include the protocol number, kit identification 
number, product description, directions for use, storage conditions, caution statement, 
and Sponsor information. Labeling for European sites will follow the requirements of the 
EU Directive 2001/20/EC (Annex 13). 
Subject kit boxes and subject-specific reserve kit boxes will be labeled with a 2 -part,  
tear-off masked label. The left part of the label will remain affixed to the subject kit. 
Upon dispensing, the right portion of the label, which contains hidden drug information, 
will be detached and placed in the subject’s source document. 
Subject supplies will be labeled according to a co mputer-generated randomization 
scheme. The medication will be identified as a new drug, limited by federal law,   
EU Directive, and AP local regulation to investigational use, and appropriately labeled 
for investigational use for this age group. 
4.6 
Accountability 
The Investigator or designee will be responsible for keeping current and accurate records 
of the amount of study drug received and dispensed, and its disposition. The study drug 
must be stored under the appropriate conditions in a secure area and are to be dispensed 
only to subjects enrolled in the study, in accordance with the conditions specified in this 
protocol. In order to assess compliance of administration, subject’s parent/legal guardian 
will be instructed to record the date and time of each study drug administration on a diary 
provided by the Sponsor. Site personnel will dispense diaries and the unmasked designee 
will weigh study drug (each bottle) before dispensing at Visit 2. Subjects should bring 
their study diaries and study drug (both bottles) to Visits 3 through 6. Site personnel will 
review the diaries and the unmasked designee will weigh the study drug (each bottle) at 
Visits 3 through 6 to assess compliance. 
During the course of the study, the Investigator’s unmasked designee must maintain an 
inventory of all study drug, dispensed to or returned by the subject, including subject 
identifiers. 
At time points throughout the study and/or upon c ompletion of the study, the 
Sponsor/Sponsor's representative will review and verify the Investigator's accountability 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 25 
records. Following verification, and as directed by the Sponsor, all used, unused and 
returned product must be returned to the Sponsor at the address provided on t he 
Personnel and Facilities page, or with the Sponsor's permission, disposed of at the site in 
an appropriate manner. 
4.7 
Masking/Unmasking  
The Investigator, subject/subject’s parent/legal guardian, and Sponsor personnel involved 
in the monitoring or conduct of the study will be masked to the study drug. The 
randomization list will be produced prior to study enrollment by an unmasked statistician 
not otherwise involved in the study. Although the test and active comparator bottles will 
be visibly different, attempts will be made to mask the subjects by removing commercial 
labeling, replacing with identical investigational labels, and packaging in identical kit 
boxes. An unmasked designee will be able to view both test and comparator bottles as 
part of their study activities and are therefore considered as unmasked although the 
designee will not have access to the randomization code. The unmasked designee will be 
responsible for instilling the first drop after surgery, and dispensing, weighing and 
collecting the test articles. The unmasked designee will not be responsible for any study 
assessments for this study. Site Monitors will be able to monitor subject diaries and 
accountability records but will not be able to reconcile the bottles in the boxes with the 
accountability records. 
The Investigator must contact the Medical Monitor prior to unmasking of study treatment. 
In an emergency situation, however, where knowledge of the study treatment is critical to 
subject safety, the code may be broken. If unmasking is necessary, the masked section of 
the two-part label, which is placed in the subject’s source documentation, can be 
scratched off to reveal the treatment assignment for that subject. 
The Investigator must notify the Medical Monitor and/or Study Manager as soon as 
possible after unmasking. In addition, the Investigator must record the date, time, and 
reason for unmasking the study treatment in the source documentation. 
4.8 
Methods of Assigning Subjects to Treatment Groups 
4.8.1 
Treatment Allocation 
Study drug will be allocated to eligible subjects at Visit 2, which will be the day the 
subject has undergone routine, uncomplicated surgery for childhood cataract. Each 
enrolled subject will receive sufficient study drug for the duration of treatment  
(ie, two bottles). The unmasked designee will dispense the next sequential kit number and 
administer the first dose after surgery.  
4.8.2 
Treatment Replacement 
Reserve supplies of each subject’s study drug (ie, one bottle) will be provided to the 
Investigators, to be dispensed only if the original subject kit is lost, damaged, or 
consumed prior to the end of treatment. 
4.9 
Risk Assessment 
Refer to the Investigator’s Brochure provided by the Sponsor which includes a summary 
of data and guidance for the Investigator in regards to the clinical pharmacology and 
safety profile of LE. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
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The subject’s parent/legal guardian will be informed of any risks in the ICF. 
4.10 
Selection of Dose 
The dose regimen in this study is the same regimen across both treatment groups  
(ie, 1 to 2 drops of study drug instilled in the study eye, QID, at approximately 4 hour 
intervals). This regimen was selected for the study based on the dose regimen of the 
currently marketed Lotemax (LE Ophthalmic Gel, 0.5%) and is also the treatment 
recommended in the Package Insert (PI) and Summary of Product Characteristics (SmPC) 
of the comparator drug.  
Based on the standard of care for the treatment of postoperative inflammation in the US, 
both treatment groups will be dosed QID for the first 14 days and then tapered to BID 
from postoperative days 15 through 21 and the further tapered to QD from postoperative 
day 22 until the day prior to Visit 6 (Postoperative Day 28).  
5.0 
STUDY METHODS 
5.1 
Study Visits  
Refer to Appendix A for a schedule of visits and parameters and Appendix B for methods 
of clinical evaluation.  
Following identification of a potential subject, the Investigator (or designee) will explain 
the purpose of the study, procedures, risks/benefits, and subject responsibilities to the 
potential subject’s parent/legal guardian. The subject’s/subject’s parent/legal guardian 
willingness and ability to meet the follow-up requirements of the study will be 
determined. If the subject’s parent/legal guardian chooses to participate in the 
investigation, then the subject’s assent (when applicable and according to local 
regulations) and written informed consent will be obtained. The subject’s parent/legal 
guardian and the person obtaining written consent will sign and date the IRB/EC-
approved ICF. The original signed document will be retained in the subject records, and a 
copy will be provided to the subject’s parent/legal guardian. In addition, the applicable 
privacy regulation requirements must be met. 
5.1.1 
Visit 1 (Screening, Day -15 ±14 days) 
Visit 1 will proceed as follows: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
obtain assent (when applicable), written informed consent (US, EU, and AP) and 
HIPAA authorization (US only) 
• 
determine if the subject meets preliminary eligibility criteria: 
− 
documentation of demographic information 
− 
current and relevant medical and ophthalmic history 
− 
concomitant medications 
• 
if the subject meets the preliminary eligibility criteria, the following assessments will 
be performed: 
− 
ocular symptoms  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 27 
− 
pediatric visual acuity (VA) testing 
− 
biomicroscopy  
− 
IOP measurement  
NOTE:  Measurement of IOP must occur after the assessment of ocular symptoms, VA and 
biomicroscopy 
NOTE:  Surgery will be scheduled to occur within 29 days of the Screening Visit. Screening and surgery 
cannot take place on the same day. 
5.1.2 
Visit 2 (Surgery/Randomization, Day 0 [within 29 days of screening]) 
Visit 2 will proceed as follows: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
record adverse events (AEs) and changes in concomitant medications 
• 
pediatric VA assessment  
• 
biomicroscopy  
• 
IOP measurement  
• 
fundoscopy, if performed during surgery, if not, then perform at Visit 3 
• 
immediately following surgery, determine eligibility  
NOTE: Subjects who, in the Investigator's opinion, have surgical complications such that it is not in 
their best interest to continue in the study are considered screen failures and will not be 
randomized into the trial. 
 
If during the surgery it is determined that additional manipulations, such as pupil stretching or 
the use of iris hooks are required, it is left to the Investigator’s discretion whether or not it is 
safe to randomize the subject into the trial.  
 
At the conclusion of the surgery, no subconjunctival or intracameral steroid injections are 
permitted. If a steroid injection is deemed necessary by the Investigator, the subject cannot be 
randomized and is considered a screen failure. 
• 
randomize eligible subjects by assigning the next sequential subject kit box 
• 
the unmasked designee must weigh both bottles of study drug prior to dispensing  
• 
at the conclusion of surgery, the randomized subject will receive the first dose of 
study drug from the unmasked designee followed by an antibiotic of the 
Investigator’s choice and an eye patch  
• 
study drug will be dispensed to the subject’s parent/legal guardian by the unmasked 
designee 
• 
a study drug administration diary will be provided to the subject’s parent/legal 
guardian who will be instructed to record the time of each instillation and to bring the 
diary and study drug (both bottles) to each visit. The subject’s parent/legal guardian 
will be reminded that no other information should be recorded in the diary 
• 
the subject’s parent/legal guardian will be trained by site personnel with regard to the 
correct instillation of eye drops prior to administration of the initial dose at any time 
at Visit 1 or 2 without using the study drug, but prior to their first instillation of study 
drug outside of the office. The time and method is left to the Investigator’s discretion  
• 
either the unmasked designee or the subject’s parent/legal guardian will administer 
approximately one to two drops of study drug into the lower cul-de-sac of the study 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 28 
eye in the evening, after removing the patch and before applying the shield, which 
will cover the study eye overnight 
• 
the subject’s parent/legal guardian will proceed with administration of the study drug 
on the morning of the first postoperative day with QID dosing at approximately four 
hour intervals, independently of when Visit 3 is scheduled to occur 
5.1.3 
Visit 3 (Postoperative Day 1; First Calendar Day after Surgery) 
At Visit 3, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug  
• 
ocular symptoms  
• 
pediatric VA 
• 
biomicroscopy  
• 
IOP measurement  
NOTE:  Measurement of IOP must occur after the assessment of ocular symptoms, VA and 
biomicroscopy. 
NOTE:  If, at any time point after surgery, IOP is elevated, treatment or intervention is left to the 
Investigator's discretion and the subject is to continue the study. 
• 
fundoscopy, if not performed during surgery  
NOTE: Topical antibiotic drops should be administered at least 15 m inutes AFTER study drug 
application. 
• 
review and collect study drug administration diary for compliance. Instruct subject’s 
parent/legal guardian to record time of each instillation on the diary and to bring the 
diary and study drug (both bottles) to their next visit. Remind subjects that no other 
information should be recorded in the diary 
• 
dispense new diary  
• 
the unmasked designee must redispense study drug 
• 
instruct subject’s parent/legal guardian to continue dosing the study drug QID, at 
approximately four hour intervals for the next 2 weeks 
5.1.4 
Visit 4 (Postoperative Day 7, ±2 days) 
At Visit 4, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug  
• 
ocular symptoms  
• 
pediatric VA 
• 
biomicroscopy 
• 
IOP measurement  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
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NOTE: Measurement of IOP must occur after the assessment of ocular symptoms, VA and 
biomicroscopy 
• 
review study drug administration diary for compliance. Instruct subject’s parent/legal 
guardian to record time of each instillation in the diary and to bring the diary and 
study drug (both bottles) to their next visit. Remind subject’s parent/legal guardian 
that no other information should be recorded in the diary 
• 
dispense new diary  
• 
the unmasked designee must redispense study drug 
• 
remind subject’s parent/legal guardian that the dosing is QID for another week and 
then BID for one week 
5.1.5 
Visit 5 (Postoperative Day 14, ±3 days) 
At Visit 5, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug  
• 
ocular symptoms  
• 
pediatric VA 
• 
biomicroscopy 
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular symptoms, VA and 
biomicroscopy 
• 
fundoscopy (it is at the Investigator’s discretion whether to perform fundoscopy with 
or without mydriasis) 
• 
review study drug administration diary for compliance. Instruct subject’s parent/legal 
guardian to record time of each instillation in the diary and to bring the diary and 
study drug (both bottles) to their next visit. Remind subject’s parent/legal guardian 
that no other information should be recorded in the diary 
• 
dispense diary  
• 
the unmasked designee must re-dispense study drug 
• 
remind subject’s parent/legal guardian that the dosing is BID for the rest of the week 
and QD for the last week 
5.1.6 
Visit 6 (Postoperative Day 28, ±7 days; End of Treatment) 
At Visit 6, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
the unmasked designee must weigh both bottles of study drug and collect all used and 
unused study drug (both bottles) 
• 
collect diaries  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 30 
• 
ocular symptoms  
• 
pediatric VA  
• 
biomicroscopy 
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular symptoms, VA and 
biomicroscopy 
5.1.7 
Visit 7 (Postoperative Day 42, ±7 days) 
At Visit 7, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
ocular symptoms  
• 
pediatric VA 
• 
biomicroscopy 
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular symptoms, VA and 
biomicroscopy 
5.1.8 
Visit 8 (Postoperative Day 90, ±14 days; Study Exit) 
At Visit 8, the following assessments will be performed: 
NOTE: All ocular assessments and VA will be performed bilaterally. 
• 
AEs and changes in concomitant medications 
• 
ocular symptoms  
• 
pediatric VA  
• 
biomicroscopy  
• 
IOP measurement  
NOTE: Measurement of IOP must occur after the assessment of ocular symptoms, VA and 
biomicroscopy 
• 
fundoscopy (it is at the Investigator’s discretion whether to perform fundoscopy with 
or without mydriasis) 
• 
subject exits from study 
5.1.9 
Unscheduled Visits 
Additional visits may be scheduled, as necessary, to ensure the safety and well-being of 
subjects. All additional exams should be fully documented in the source documents and 
on Unscheduled Visit eCRFs, as appropriate. Visits intended to fulfill scheduled visit 
requirements that fall outside the designated scheduled visit range, are not Unscheduled 
Visits. In these cases, the visit data will be collected and transcribed to the appropriate 
scheduled visit eCRF. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
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If a subject is seen for multiple visits during a given visit timeframe, the data from the 
visit that is intended to meet the protocol requirements for the scheduled visit should be 
captured on the visit eCRF. Where such a determination cannot be made, the first visit 
within the scheduled visit interval will be used for completion of the protocol required 
scheduled visit eCRF. Data from any additional visits within a scheduled visit interval 
will be captured on an Unscheduled Visit eCRF. 
5.1.10 
Missed Visits  
If a subject misses any scheduled follow-up visit and cannot be seen prior to the start of 
the visit range for the next scheduled follow-up visit, the visit is considered missed. 
5.2 
Post-study Follow-up  
If a subject requires further follow-up of AEs upon discontinuation or completion of the 
study, the Investigator must schedule post-study follow-up visits, as necessary.  
Refer to Sections 6.3 and 6.4 for follow-up of AEs following study exit. 
5.3 
Study Completion  
Depending on local regulations, Bausch + Lomb Global Clinical Operations will notify 
the Investigator when to contact the IRB/EC to inform them that the study is complete or 
Bausch + Lomb will do this on the behalf of the Investigator. In the EU, Bausch + Lomb 
will inform the regulatory agencies in the concerned member states in addition. 
5.3.1 
Early Study Termination 
If during the study it becomes evident to the Sponsor that the study should be stopped 
prematurely or placed on hol d, appropriate notification will be given to the 
Investigator(s), IRB/EC, FDA, and appropriate EU regulatory agencies, as applicable. 
Bausch + Lomb Global Clinical Operations will instruct the Investigators to stop/restart 
dispensing study materials and will arrange for study closeout, if applicable, at each site. 
5.4 
Concomitant Medications/Therapy  
Administration of all medications used by the subject, the breastfeeding mother, or wet 
nurse up to 30 days prior to study entry (date ICF signed) through study exit must be 
recorded in the source documentation and in the Concomitant Medications eCRF. 
Indications for these medications should be recorded in the subject's Medical History 
eCRF, as applicable. 
5.4.1 
Permitted Therapy  
Permitted therapy applies to the subject, breastfeeding mother, or wet nurse. Use of 
topical antibiotics is allowed if they are not used in combination with any steroid in the 
study eye (eg, Zylet® or TobraDex should not be used). Topical antibiotics used 
preoperatively and postoperatively are allowed bilaterally and must be recorded in the 
Concomitant Medications eCRF provided by the Sponsor. Intraoperative use of topical 
antibiotics or other standard of care surgical medications should be recorded in the source 
documentation only. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
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In the event that the subject requires surgery on the contralateral eye at any time during 
the study, the fellow eye will be treated at the Investigator’s discretion with standard of 
care medication.  The standard of care medication must be recorded under concomitant 
medications in the eCRF provided by the sponsor.  
With the exception of the disallowed medications in Section 5.4.2, any medications that, 
in the Investigator’s judgment, will not interfere with the study parameters are allowed to 
be used concurrently by the subject, breastfeeding mother, or wet nurse; for example, the 
following medications are permitted: 
• 
systemic analgesics (eg, 
acetaminophen/paracetamol) 
• 
systemic antimicrobials 
• 
oral birth control pills 
• 
antidepressants 
• 
≤100 mg/day acetylsalicylic acid (for 
breastfeeding mother/wet nurse only) 
• 
thyroid preparations 
• 
hypoglycemic agents 
• 
antihypertensive agents 
• 
anticholesterol medications 
• 
cardiovascular agents 
• 
insulin 
 
− 
Standard anesthetic and mydriatic agents may be used intraoperatively or for 
postoperative diagnostic purposes (ie, IOP and funduscopy). Ocular NSAIDs may 
not be used for mydriasis or at any other time point during the study in the study 
eye. Ocular therapy with NSAIDs and/or corticosteroids in the fellow eye is 
permitted. 
− 
The long term use of systemic NSAIDs is not allowed during the study. If 
unavoidable, use of systemic NSAIDs can be permitted only after Visit 5, but 
should be kept to a minimum and treatment duration with NSAIDs should be kept 
short (for example, one day per treatment period). 
− 
Topical ocular hypotensive agents, if used at the end of surgery by the study site, 
will be used with ALL subjects treated at that site.  
− 
Intracameral injection of antibiotic is allowed at the end of surgery. 
5.4.2 
Disallowed Therapy 
A disallowed medication could be administered in an emergency if the subject’s safety 
was in jeopardy. The Investigator must notify the Medical Monitor as soon as possible 
after administering a disallowed medication to verify if the subject can continue in the 
study. If a subject has taken any disallowed medication, this should be recorded as a 
protocol deviation. Disallowed therapy that is used for persistent or worsening 
inflammation, however, is called “Rescue Therapy” and is discussed in detail in  
Section 3.2.3.  
Disallowed medications include the following: 
• 
Ocular (study eye): 
− 
corticosteroids 
− 
NSAIDs  
− 
topical antibiotic-steroid combination products (eg, Zylet, TobraDex, etc) 
• 
Ocular (study and fellow eye): 
− 
mast cell stabilizers 
− 
antihistamines 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 33 
− 
decongestants  
− 
immunosuppressants (eg, Restasis) 
• 
Systemic (subject, breastfeeding mother, or wet nurse): 
− 
corticosteroids (except corticosteroid inhalers and dermatological corticosteroids, 
as long as they are not used on the eyelids or surrounding area) 
− 
NSAIDs (short term use of systemic NSAIDs is permitted only after Visit 5.  
Please refer to section 5.4.1 for details) 
− 
immunosuppressants  
• 
Any medication that the Investigator feels may interfere with study parameters 
5.5 
Treatment Compliance  
Any subject/subject’s parent/legal guardian who does not follow instructions to a degree 
that, in the Sponsor or Investigator’s opinion, jeopardizes the subject’s well-being or the 
validity of the study, may be discontinued. 
5.6 
Protocol Deviations 
The date of and reason for deviations will be documented in all cases. Protocol deviations 
impacting the safety of the subject or the integrity of the study must be reported by the 
Investigator to the IRB/EC immediately. Reporting of all other protocol deviations must 
adhere to the requirements of the governing IRB/EC.  
Protocol assessments will continue until the end of the study, unless the protocol 
deviations put the subject at risk or the subject’s condition requires that he/she be 
discontinued from the study. 
6.0 
ADVERSE EVENTS 
6.1 
Definition of Adverse Events 
• 
Any untoward medical occurrence in a subject participating in a clinical study which 
does not necessarily have a causal relationship with the study procedure or with the 
study treatment.  
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease with onset following the signing of informed consent through 
study exit, whether or not considered related to the study. An AE can also include a 
progression/worsening of underlying disease, hypersensitivity, and extravasation. 
• 
Events occurring from drug overdose, whether accidental or intentional, events 
occurring from drug abuse, drug misuse, drug interactions, drug dependency, events 
occurring from drug withdrawal, and medication errors. 
6.2 
Definition of Serious Adverse Events  
Information about every serious adverse event (SAE) will be collected and recorded. An 
SAE is any untoward medical occurrence (at any dose) that results in any of the 
following outcomes: 
• 
death  
• 
a life-threatening adverse drug experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 34 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect 
• 
is sight threatening (may result in persistent or significant loss of vision) 
• 
encompasses any medically significant event that may jeopardize a subject and may 
require medical or surgical intervention to prevent any of the outcomes listed above  
• 
is medically significant, as determined by the Principal Investigator or medically 
qualified Sub-Investigator 
As above, important medical events that may not have resulted in death, be life-
threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the 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. 
Additionally, any suspected transmission of an infectious agent by a Bausch + Lomb 
product, pathogenic or non-pathogenic, is considered an SAE. The event may be 
suspected from clinical symptoms or laboratory findings indicating an infection in a 
subject exposed to a Bausch + Lomb product. The terms “suspected transmission” and 
“transmission” are considered synonymous.  
Hospitalization is a criterion for assessment of seriousness. Hospitalization in the absence 
of a medical AE is not in itself an AE. For example, the following reports of 
hospitalization without a medical AE should not be considered either serious, or an AE: 
• 
admission for treatment of a pre-existing condition not associated with the 
development of a new AE or with worsening of the pre-existing condition (eg, for 
work-up of persistent pre-treatment lab abnormality) 
• 
social admission (eg, subject has no place to sleep) 
• 
administrative admission (eg, for yearly physical exam) 
• 
optional admission not associated with a precipitating medical AE (eg, for elective 
cosmetic surgery) 
6.3 
Reporting Adverse Events and Follow-up 
Throughout the course of the study, efforts will be made by the Investigator to remain 
alert to possible AEs that are either systemic or ocular in nature. The period of 
observation for collection of AEs extends from the time the subject’s parent/legal 
guardian gives informed consent until the last study visit, Visit 8 (Postoperative Day 90). 
The first concern will be the safety of the subject, and appropriate medical intervention 
will be made. 
The Investigator or designee will elicit reports of AEs from the subject/subject’s 
parent/legal guardian at each study visit and record all AEs. An assessment of all AEs 
will be made by the Investigator as to the severity, action taken with study treatment, and 
causal relationship to study drug.  
The terms used to assess the causal relationship of the event to the study drug are:  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 35 
• Related: There is at least a reasonable possibility that the AE/SAE is related to 
the study drug.  Reasonable possibility means that there is evidence to suggest a 
causal relationship between the drug and the AE. 
• Not Related: There is little or no reasonable possibility that the AE/SAE is 
related to the study drug. This assessment implies that the AE/SAE has little or no 
temporal relationship to the study drug and/or a more likely or certain alternative 
etiology exists. 
When the investigator assesses the AE as “not related” to the study drug, an alternative 
etiology (ie, concomitant drug, medical history, prior AE, or other source as indicated) 
must be provided.    
The subject’s parent/legal guardian will be instructed to contact the Investigator 
immediately if any unusual systemic or ocular AEs are noticed between visits. 
Additional assessments/visits may be scheduled, as necessary, to ensure the safety of the 
subject, during the study period. A subject who discontinues due to an AE should be seen 
for post-study follow-up visits as necessary. 
Non-serious AEs that are ongoing upon early discontinuation or at the study exit visit will 
be followed by the Investigator up to 30 days after the subject exits the study. 
6.4 
Reporting Serious Adverse Events and Follow-up 
Any SAE must be reported to Bausch + Lomb Global Safety & Vigilance; independent of 
the circumstance or suspected cause, within 24 hour s from the time the event was 
reported to the Investigator. All SAEs experienced from consent through the Exit Visit 
(Visit 8, Postoperative Day 90) must be reported to Bausch + Lomb regardless of the 
relationship to the study drug. After the Exit Visit (Visit 8, Postoperative Day 90), or 
following early discontinuation from the study, only SAEs considered related to the study 
drug should be reported promptly. For US sites, these should be reported to Bausch + 
Lomb Global Safety & Vigilance; for EU sites, these should be reported to the EU Study 
Manager who will be responsible for forwarding to Bausch + Lomb Global Safety & 
Vigilance; for AP sites, these should be reported to Bausch + Lomb AP Global Safety & 
Vigilance (Seoul, Korea), who will be responsible for forwarding to Bausch + Lomb 
Global Safety & Vigilance (Madison, NJ, US). Within 24 hour s of notification the 
Investigator will fax a completed Serious Adverse Event Report to the Bausch + Lomb 
contact noted below. For SAEs with fatal outcomes, a summary of available autopsy 
findings should be submitted as soon as possible.  
Bausch + Lomb Contact Information: 
Name of Contact 
Contact Information 
US Sites: 
Saberi Rana Ali, MBBS, MS (Ophth), MPH 
Associate Director, Global Safety and 
Vigilance 
Bausch & Lomb Incorporated 
7 Giralda Farms, Suite 1001 
Madison, NJ 07940 
US 
 
Tel: +1 973 360 6478 
Fax: +1 813 975 7750 
Mobile: +1 862 579 8366 
SAE Inbox: SAE@bausch.com 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 36 
EU Sites: 
Natasa Orlic-Pleyer, MD  
Clinical Study Manager 
Dr. Gerhard Mann chem.-pharm. Fabrik 
GmbH/Bausch & Lomb 
Brunsbütteler Damm 165-173 
13581 Berlin  
Germany 
 
Tel. +49 (0) 30 33093 -318   
Fax: + 49 (0) 30 33093 6699 
Email: natasa.orlic-pleyer@bausch.com  
AP Sites: 
Bausch + Lomb Asia Pacific Global Safety 
and Vigilance 
Bausch & Lomb Korea 
13F, KT&G Kosmo Daechi-Tower, 
#945-10 Daechi-dong, Gangnam-gu, 
Seoul 135-280, Korea 
 
 
Tel: + 82 70 7167 9784 
Mobile: + 82 10 9112 9784 
Fax: + 82 2 6442 1460 
Email: safety.asia@bausch.com  
The Investigator or Bausch + Lomb, as appropriate for local regulations, will notify their 
IRB/EC in writing of any SAE in accordance with the IRB/EC requirements. 
Bausch + Lomb or its designee will be responsible for submitting SAE reports to 
regulatory authorities based on applicable regulations. The Sponsor will also send a 
notification to all participating Investigators of any SAE that is unexpected and 
associated with the study (refer to Section 6.5). This notification will be made within 15 
calendar days from the time Bausch + Lomb becomes aware of the event.  
If the Investigator becomes aware of any new information regarding a Serious Adverse 
Event (ie, resolution, change in condition, or new treatment), a new Serious Adverse 
Event Form must be completed and faxed to Bausch + Lomb (refer to contact information 
above) as soon as new information becomes available. The original SAE form is not to be 
altered. The report should describe whether the event has resolved or continues and how 
the event was treated.  
Serious adverse events that have previously been reported, and that continue after the 
subject’s discontinuation or completion of the study will be followed until their medical 
endpoints are determined or until no further change in the conditions is expected. For US 
sites, the events and endpoints will be reported in writing by the Investigator to Bausch + 
Lomb Global Safety & Vigilance; for the EU sites, the SAE form should be sent to the 
EU Study Manager who will be responsible for forwarding to Bausch + Lomb Global 
Safety & Vigilance; for AP sites,  these should be reported to Bausch + Lomb AP Global 
Safety & Vigilance (Seoul, Korea), who will be responsible for forwarding to Bausch + 
Lomb Global Safety & Vigilance (Madison, NJ, US). 
Following the subject's discontinuation or completion of the study, for any timeframe 
afterward deemed medically significant, any SAEs, which are assessed as causally related 
to study drug, should also be reported to Bausch + Lomb Global Safety & Vigilance.  
6.5 
Submitting an Expedited Safety Report to the IRB (Central or Local) 
Any Suspected Unexpected Serious Adverse Reaction (SUSAR) or unexpected SAE 
related to a subject’s participation in the study, regardless if the study drug was 
administered, warrants expedited reporting.  
Each expedited safety report will routinely include a brief cover memorandum, the 
completed MedWatch Form FDA 3500A or Council for International Organizations of 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 37 
Medical Sciences I Form (CIOMS I Form), or relevant reporting form for the global 
region. Where relevant, a clinical analysis of the event with any similar events that have 
occurred with the product, and any additional pertinent information recommended by the 
study Medical Monitor. Once the report is compiled by Bausch + Lomb Global Safety & 
Vigilance, the site Investigator must submit the expedited safety report to the local 
IRB/EC and for EU sites the Sponsor will submit them to the EC and health authorities 
within the required reporting timeframe. Follow-up reports should be submitted when 
requested or when pertinent information becomes available. The site principal 
Investigators must retain a complete copy of each expedited safety report as it was 
submitted to the IRB/EC. It is important that the principal Investigators review these 
expedited reports, as they contain safety information that may be relevant to each of the 
participating subjects. 
6.6 
Medical Monitor 
The Medical Monitor information is as follows: 
Name of Contact 
Contact Information 
James Gow, MD 
Clinical Affairs 
Bausch & Lomb Incorporated 
50 Technology Drive 
Irvine, CA  92618-2301 
US 
 
Tel: + 1 949 788 5359  
Mobile: + 1 949 701 6398 
Email: james.gow@bausch.com  
 
7.0 
STATISTICAL METHODS 
7.1 
Study Endpoints 
7.1.1 
Primary Efficacy Endpoints 
The primary efficacy endpoint is the mean grade of anterior chamber inflammation at 
Visit 5 (Postoperative Day 14). For each subject, the mean grade of anterior chamber 
inflammation will be derived using the following table:  
Anterior Chamber Inflammation 
Grade 
Slit lamp 
Penlight with handheld 
magnifying 20 diopter 
lens 
Grade 0 = None 
Grades 0 cells and flare 
Grade 0 
Grade 1 = Mild 
Maximum of cells and flare Grade is 1 
Grade 1 
Grade 2 = Moderate 
Maximum of cells and flare Grade is 2 
Grade 2 
Grade 3 = Severe 
Maximum of cells and flare Grade is 3 
Grade 3 
Grade 4 = Very Severe 
Maximum of cells and flare Grade is 4 
Grade 4 
 
7.1.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• 
mean grade of anterior chamber inflammation at Visits 4 and 6 (Postoperative Days 7 
and 28) 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 38 
• 
proportion of subjects with Grade 0, Grade 1, Grade 2, Grade 3, and Grade 4 
converted anterior chamber inflammation at each visit (Postoperative Days 7, 14, and 
28) 
• 
presence/absence and total area, if present, of synechiae at each visit (Postoperative 
Days 7, 14, and 28) 
• 
presence/absence and total number, if present, of precipitates on t he implant and 
cornea at each visit (Postoperative Days 7, 14, and 28) 
7.1.3 
Safety Endpoints 
The safety endpoints are as follows: 
• 
incidence of overall and specific AEs 
• 
type and incidence of AEs at each visit  
• 
change in IOP from baseline (Visit 2, Surgery/Randomization) to each visit 
• 
greatest IOP change from baseline - including the measurement at Visit 3 
(Postoperative Day 1) 
• 
greatest IOP change from baseline - excluding the measurement at Visit 3 
(Postoperative Day 1) 
• 
ocular signs (biomicroscopic examination of the lids, conjunctiva, cornea, anterior 
chamber without pupil dilation) at each visit 
7.1.4 
Tolerability Endpoints 
The tolerability endpoint is as follows: 
• 
ocular symptoms (photophobia) at each visit 
7.2 
Hypotheses 
Test for the non-inferiority of LE Ophthalmic Gel, 0.5% to Prednisolone Acetate 
Ophthalmic Suspension, 1% will be primarily based on t he following one-sided null 
hypothesis (Ho) and alternative hypothesis (Ha): 
Ho: µLE - µPR ≥ 0.35     versus              Ha: µLE - µPR < 0.35 
where µLE and µPR are the mean grade of anterior chamber inflammation at Visit 4 
(Postoperative Day 7) for LE Ophthalmic Gel, 0.5% and Prednisolone Acetate 
Ophthalmic Suspension, 1% treatment group, respectively. 
7.3 
Sample Size 
A sample size of 120 subjects (60 subjects per treatment group) yields 98% power to 
detect non-inferiority of LE Ophthalmic Gel, 0.5% to Prednisolone Acetate Ophthalmic 
Suspension, 1%. This sample size assumes a common standard deviation of 0.47, a two-
sided alpha=0.05, a non-inferiority margin of 0.35 and an expected difference of 0 for the 
difference in means between treatment groups using anterior chamber inflammation at 
Visit 5 (Postoperative Day 14).  Assuming a subject dropout rate (including the initiation 
of rescue medication) of 12%, approximately 140 subjects will be randomized, of which 
at least 60 subjects will be in the age group 0-3 years as per the FDA’s Written Request. 
The power and sample size calculations were done using nQuery Advisor version 7.0.  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 39 
7.4 
Randomization 
A total of 140 subjects from ages 0-11 will be randomized to receive LE Ophthalmic Gel, 
0.5% or Prednisolone Acetate Ophthalmic Suspension, 1% in a 1:1 ratio. The subgroup 
age 0-3 years will consist of at least 60 subjects.  
7.5 
Analysis Populations 
The analysis populations that will be used in this study are: 
• 
Intent-to-Treat (ITT) Population: includes all subjects who were randomized and have 
at least one post-treatment assessment. Analysis on the ITT population will be used 
for primary efficacy analyses and will be performed for all efficacy endpoints, 
analyzing subjects under the treatment to which they were randomized.  
• 
Per Protocol (PP) Population: includes all of the subjects in the ITT population that 
remained in the study through Visit 5 (Postoperative Day 14) and who did not deviate 
from the protocol in any way likely to seriously affect the primary outcome of the 
study. Analysis using the PP population will be used to supplement the ITT analysis, 
analyzing subjects according to the treatment received.  
• 
Safety Set: includes all participants who received at least one dose of study drug. 
7.6 
Statistical Analysis  
7.6.1 
Methods of Analysis 
Summaries for continuous variables will include the sample size, mean, standard 
deviation (SD), median, minimum, and maximum. Summaries for discrete variables will 
include the tabulation of frequencies and percentages. Means and medians will be 
presented to one more decimal place than the recorded data. Standard deviations will be 
presented to two more decimal places than the recorded data. Minimum and maximum 
values will be presented using the same number of decimal places as the recorded data. 
Confidence intervals (CIs) will be presented using the same number of decimal places as 
the parameters (eg, mean). Percentages will be presented to one decimal place.  
The primary efficacy analysis will be based on the ITT population with missing data 
imputed using the last observation carried forward (LOCF) method  and the primary 
endpoint mean grade of anterior chamber inflammation at Visit 5 (Postoperative Day 14). 
The mean grade of anterior chamber inflammation at Visit 5 (Postoperative Day 14) will 
be analyzed using an analysis of variance (ANOVA) model with treatment as a 
classification variable. 
The least squares mean for each treatment group, the difference in the least squares mean 
between the two treatment groups (LE Ophthalmic Gel, 0.5% – Prednisolone Acetate 
Ophthalmic Suspension, 1%), and the two-sided 95% confidence interval for the 
difference will be presented. The null hypothesis will be rejected and non-inferiority 
established if the upper limit of the confidence interval does not exceed0.35.  
To supplement the primary analyses, the analyses above will be repeated for the PP 
population; no imputation will be conducted for missing data. Any discrepancy between 
the ITT and PP analyses will be explained. 
The secondary efficacy analyses will be conducted based on the ITT population as well 
as the PP population. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 40 
As a secondary analysis, the analysis of the mean grade of anterior chamber inflammation 
will be repeated as above for Visits 4 and 6 (Postoperative Days 7 and 28, respectively). 
Additional secondary analyses include:  
• 
the proportion of subjects with anterior chamber inflammation of Grade 0, Grade 1, 
Grade 2, Grade 3, and Grade 4 for each visit (Postoperative Days 7, 14, and 28) 
• 
the proportion of subjects with presence/absence and total area, if present, of 
synechiae for each visit (Postoperative Days 7, 14, and 28) 
• 
the proportion of subjects with presence/absence and total number, if present, of 
precipitates on the implant and cornea at each visit (Postoperative Days 7, 14, and 28) 
For each of the above endpoints, treatment groups will be compared using the Pearson 
Chi-squared test or fisher’s exact test as appropriate. Differences between the proportions 
of treatment groups and 95% confidence interval about the differences will be presented. 
Subgroup analyses will be performed for anterior chamber inflammation, anterior 
chamber cells, and anterior chamber flare as appropriate by method of assessment (slit 
lamp versus penlight with handheld magnifying 20 diopter lens), country (region), age 
group, IOL implantation, and iris color. 
All subjects in the safety set will be included in the safety analyses. Intraocular pressure 
will be summarized by visit using continuous summaries (including change from baseline 
and change from screening) for the following items: 
• 
change in IOP from baseline (Visit 2, Surgery/Randomization) to each visit 
• 
greatest IOP change from baseline - including the measurement at Visit 3 
(Postoperative Day 1) 
• 
greatest IOP change from baseline - excluding the measurement at Visit 3 
(Postoperative Day 1) 
• 
ocular signs (biomicroscopic examination of the lids, conjunctiva, cornea, anterior 
chamber without pupil dilation) 
Treatment emergent systemic AEs will be summarized using discrete summaries at the 
subject and event level by system organ class and preferred term for each treatment group. 
Treatment emergent ocular AEs will be summarized for treated eyes and fellow eyes 
separately. Similarly, treatment emergent AEs will be summarized by severity and 
relationship separately. All AEs will be coded using a MedDRA dictionary (the most 
current version available at the start of the study will be used). 
Ocular symptoms will be summarized using discrete summary statistics by visit and 
treatment group. These data will be summarized under the safety analyses.  
7.6.2 
Subject Demographics and Baseline Characteristics 
Subject demographics: race, gender, and age will be summarized using discrete summary 
statistics. Age will also be presented using continuous summary statistics. 
7.6.3 
Subject Disposition 
A disposition of subjects includes the number and percentage of subjects in each of the 
following categories: 
• 
subjects randomized (ITT population) 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 41 
• 
subjects treated (Safety population) 
• 
subjects in the PP population 
Within each of the previous categories, the number and percentage of subjects who 
completed and discontinued from the study will be summarized. The primary reason for 
study discontinuation described in Section 3.2.4 will also be summarized.  
7.6.4 
Protocol Deviations 
The number of subjects within each type of protocol deviations will be presented using 
listings and discrete summary statistics as appropriate.  
7.6.5 
Treatment Compliance 
Treatment compliance will be assessed as the percentage of prescribed instillations 
received and will be presented using discrete summary statistics in the following 
categories: (≤ 50%, 51-60%, 61-70%, 71-80%, 81-120%, and > 120%). Percentages will 
be calculated out of the number of subjects who returned diaries from that dosing period. 
The number and percentage of subjects in each compliance rate category will be 
presented. 
7.6.6 
Treatment Exposure 
Extent of exposure is defined as the total number of days from the first dose date to the 
last dose date, as recorded at the randomization study visit and the study exit eCRF page. 
Subjects who fail to return all bottles dispensed will be excluded from this summary. The 
extent of exposure will be summarized using continuous summary statistics. 
7.6.7 
Missing Data 
For the primary efficacy endpoint analyzed using the ITT population, missing data and 
data from subjects placed on r escue medication will be imputed using the LOCF 
methodology. For the PP analysis, missing data and data from subjects placed on rescue 
medication will not be imputed. 
8.0 
DATA QUALITY ASSURANCE  
8.1 
Study Monitoring 
Bausch + Lomb Global Clinical Operations representatives must be allowed to visit all 
study site locations to assess the data, quality, and study integrity in a manner consistent 
with applicable health authority regulations and the procedures adopted by the 
Bausch + Lomb Global Clinical Operations Department.  
Prior to the start of the study, member(s) of the Bausch + Lomb Global Clinical 
Operations Department (or designees) will review the protocol, eCRF, regulatory 
obligations, and other material or equipment relevant to the conduct of the study with the 
Investigator/Sub-Investigator and relevant study site personnel.  
Monitoring visits and telephone consultations will occur as necessary, during the course 
of the investigation to verify the following: 
• 
the rights and well-being of subjects are protected 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 42 
• 
the conduct of the investigation is in compliance with the currently approved 
protocol/amendment, ICH GCPs and IRB/EC requirements 
• 
the integrity of the data, including adequate study documentation 
• 
the facilities remain acceptable 
• 
the Investigator and site personnel remains qualified and able to conduct the study 
• 
test article accountability 
During the course of the study, if the Sponsor determines that an Investigator is  
non-compliant with the study plan and/or applicable regulatory requirements, the Sponsor 
will take action to secure compliance. In addition, the Sponsor may terminate the 
Investigator’s participation in the study if appropriate, or if the Investigator remains  
non-compliant despite the Sponsor’s actions. 
8.2 
Source Documentation 
All medical information obtained at each study visit must be recorded in the subject’s 
record (source documentation) in real time as it is collected. Source documentation 
consists of original subject documents, as well as data and records with information 
relevant to the subject and his/her participation in the study.  
Subject completed forms are also considered source data. Designated site personnel will 
pre-record appropriate dates of study drug administration and subject identifiers (initials 
and/or study number) on the diary. With this exception, only subject’s parents/legal 
guardians are to record information in subject diaries and questionnaires. In no instance, 
should an Investigator or study site personnel record any data or make changes to subject 
completed forms. The Investigator or designee should review subject completed forms 
during study visits. If an entry is found to be illegible or a mistake is found (eg, incorrect 
year was recorded), the subject’s parent/legal guardian should be instructed to edit the 
entry by drawing a single line through the original entry, entering the new information, 
and dating and initialing (US and AP only)/writing year of birth to acknowledge (EU 
only) the change. 
8.3 
Case Report Forms and Data Verification 
Subject data required by this protocol are to be recorded on eCRFs. The Investigator and 
study site personnel will be responsible for completing the eCRFs. The Investigator is 
required to verify that all of the requested information is accurately recorded on t he 
eCRFs. All information requested on the eCRFs needs to be supplied, including subject 
identification, date(s), assessment values, etc, and any omission or discrepancy will 
require explanation. All information on eCRFs must be traceable to source documents.  
The study monitor will be responsible for reviewing and verifying the data recorded on 
the eCRFs, utilizing the original source documentation and will query discrepant findings. 
The Investigator and study site personnel will be responsible for answering all queries. 
The eCRFs will be submitted electronically via an electronic data capture system to 
Bausch + Lomb Global Clinical Operations for quality assurance review, data entry, and 
statistical analysis.  
A copy of the eCRFs (on CD or DVD) will be retained by the Investigator at the 
conclusion of the study, who must ensure that it is stored in a secure place. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 43 
8.4 
Recording of Data and Retention of Documents 
Subject data recorded on eCRFs during the study will be documented in a coded fashion. 
The subject will only be identified by the subject number, and by their year of birth. 
Confidentiality of subject records must be maintained to ensure adherence to applicable 
local privacy regulations. 
The Investigator must retain essential documents indefinitely after the completion of the 
study, unless otherwise notified by the Sponsor. The Investigator agrees to adhere to the 
document retention procedures when signing the protocol Investigator Statement of 
Approval.  
Essential documents include but are not limited to the following: 
• 
IRB/EC approvals for the study protocol, all amendments, ICF(s), and advertisements 
• 
IRB/EC annual study review 
• 
IRB/EC correspondence and reports (eg, SAE reports, protocol deviations, and safety 
updates) 
• 
regulatory documents (eg, financial disclosure and delegation of authority forms) 
• 
all source documents  
• 
copy of eCRFs 
• 
subject’s signed ICF 
• 
FDA Form 1572 
• 
accountability records for the test article(s) 
• 
correspondence from and to the Sponsor 
• 
any other documents relevant to the conduct of the study 
In the event that the Investigator withdraws from the study (eg, retirement, relocation), 
study records will be transferred to a mutually agreed upon d esignee (eg, another 
Investigator, site IRB/EC). The Investigator will provide notice of such transfer in writing 
to Bausch + Lomb Global Clinical Operations. 
8.5 
Auditing Procedures 
Audits of clinical research activities in accordance with the Sponsor’s internal Standard 
Operating Procedures (SOPs) to evaluate compliance with the principles of GCP may 
take place. A regulatory authority may also wish to conduct an inspection (during the 
study or after its completion). If an inspection is requested by a regulatory authority 
and/or IRB/EC, the Investigator must inform the Sponsor immediately that this request 
has been made. 
8.6 
Institutional Review Board/Ethics Committee Approval 
In the US and AP, the Investigator, or in the EU, the Sponsor or designee should ensure 
that participation in the study, in addition to the protocol, subject recruitment materials 
(written information or materials including web pages, radio advertisements, television 
spots or written text developed to encourage subject enrollment) and the ICF to be used 
in this study are approved by their institution IRB/EC, or if not using their institution's 
IRB/EC, approved by the reviewing central IRB/EC prior to entering any subjects in the 
study. Documentation of IRB/EC approval of the study protocol and informed consent 
must be provided to the Sponsor prior to initiation of the study. In addition, in the US and 
AP, the Investigator, or in the EU, the Sponsor or designee must ensure that the 
reviewing IRB/EC has provided approval for any protocol amendments prior to 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 44 
implementation. If the amendment necessitates a revision to the ICF, the Investigator 
should ensure the revised form is also submitted to and approved by the Sponsor and the 
IRB/EC prior to implementation.  
8.7 
Publication of Results 
All study data generated as a result of this study will be regarded as confidential, until 
appropriate analysis and review by the Sponsor or its designee and the Investigator(s) are 
completed. The results of the study may be published or presented by the Investigator(s) 
after the review by, and in consultation and agreement with the Sponsor, and such that 
confidential or proprietary information is not disclosed. 
Prior to publication or presentation, a copy of the final text should be forwarded by the 
Investigator(s) to the Sponsor or its designee, for comment. Such comments shall aim to 
ensure the scientific integrity of the proposed publications and/or presentations and 
ensure that the data and material referring to Bausch & Lomb Incorporated products and 
activities receive fair, accurate, and reasonable presentation.  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page 45 
9.0 
REFERENCES  
1 Jaanus, S.D., Lesher, G.A., Anti-inflammatory drugs. In Clinical Ocular 
Pharmacology, Bartlett, J.D. and Jaanus, S.D., Eds. 3rd ed. Butterworth-Heinemann, 
Boston, 1995, p. 303-335. 
2 Becker, B., Intraocular pressure response to topical corticosteroids. Invest Ophthalmol 
4: 198-205, 1965. 
3 Armaly, M.F. Effects of corticosteroids on intraocular pressure and fluid dynamics. I. 
The effect of dexamethasone in the normal eye. Arch Ophthalmol 70: 482, 1963. 
4 Burde, R.M., Becker, B. Corticosteroid-induced glaucoma and cataracts in contact 
lens wearers. JAMA 1970; 213: 2075-2078. 
5 Sheppard, J., Bartlett, J. Loteprednol Etabonate in Ocular Inflammation. US 
Ophthalmic Review [Extract]. Spring 2011; 4(1):1-7. 
6 Bartlett, J.D., Horwitz, B., Laibovitz, R., Howes, J.F. Intraocular Pressure Response to 
Loteprednol Etabonate in Known Steroid Responders. Journal of Ocular 
Pharmacology 9(2):157-165, 1993. 
7 Novack, G.D., Howes, J., Crockett, R.S., Sherwood, M.B. Change in intraocular 
pressure during long-term use of loteprednol etabonate. Glaucoma 7:266-269, 1998. 
8  Bausch + Lomb Incorporated. Clinical Study Report #576: A Randomized, 
Multicenter, Double-Masked, Parallel-Group Clinical Safety and Efficacy Evaluation 
of Loteprednol Etabonate Ophthalmic Gel, 0.5% versus Vehicle for the Treatment of 
Inflammation and Pain Following Cataract Surgery, v1.0. 28 Feb 2011. 
9  Bausch + Lomb Incorporated. Clinical Study Report #577: A Randomized, 
Multicenter, Double-Masked, Parallel-Group Clinical Safety and Efficacy Evaluation 
of Loteprednol Etabonate Ophthalmic Gel, 0.5% versus Vehicle for the Treatment of 
Inflammation and Pain Following Cataract Surgery,  v1.0.  28 Feb 2011. 
 
 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page A-1 
APPENDIX A: SCHEDULE OF VISITS AND PARAMETERS  
All study tasks should be performed by qualified study site personnel as indicated on the delegation of authority log under the supervision of the 
Principal Investigator. Furthermore, all ocular signs must be evaluated by an ophthalmologist. 
PROCEDURE/ASSESSMENTS1 
Visit 1 
Screening 
Visit 2 
Surgery/Randomization
/Begin Treatment 
Visit 3 
Follow-up 
Visit 4 
Follow-up 
Visit 5 
Follow-up 
Visit 6 
Follow-up/End 
Treatment 
Visit 7 
Follow-up 
Visit 8 
Study Exit 
Day -15 
(±14 days) 
Day 02 
Day 13 
Day 7 
(±2 days) 
Day 14 
(±3 days) 
Day 28 
(±7 days) 
Day 42 
(±7 days) 
Day 90 
(±14 days) 
Informed 
consent, 
assent 
(when 
applicable), 
and 
authorization 
as 
appropriate for local privacy regulations 
X 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Current and relevant medical and ocular 
history 
X 
 
 
 
 
 
 
 
Ocular symptoms  
X 
 
X 
X 
X 
X 
X 
X 
VA assessment  
X 
X 
X 
X 
X 
X 
X 
X 
Slit lamp (biomicroscopy or magnifying 
lens with penlight)4 
X 
X 
X 
X 
X 
X 
X 
X 
IOP (Goldman or equivalent)4 
X 
X 
X 
X 
X 
X 
X 
X 
Fundoscopy5  
 
X 
X 
 
X 
 
 
X 
Eligibility determination  
X 
X 
 
 
 
 
 
 
Randomization  
 
X 
 
 
 
 
 
 
AEs6/Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Weigh study drug and inspect diaries 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug and diaries 
 
X7 
X 
X 
X 
 
 
 
Collect study drug and diaries 
 
 
 
 
 
X 
 
 
Exit subject 
 
 
 
 
 
 
 
X 
1 All ophthalmic assessments will be performed bilaterally. 
2 Visit 2 must occur within 29 days of Visit 1. Screening and surgery cannot take place on the same day.  
3 Visit 3 (postoperative day 1) should occur on the next calendar day post-surgery.  
4 Every effort should be made to obtain slit lamp assessments and the assessment with the 20 dpt magnifying lens and penlight should only be performed if a slit lamp or handheld 
slit lamp examination cannot be performed. Once one of the methods has been chosen it should be employed throughout the study for each subject. IOP should also be measured 
with the same method throughout the study for each subject.  
5 Fundoscopy will be performed bilaterally either at Visit 2 (surgery/randomization) or Visit 3 (postoperative day 1), at Visit 5 (postoperative day 14 ±3 days), and at Visit 8 
(postoperative day 90 ±14 days). 
6 Collection of AEs extends from the time the subject’s parent/guardian signs informed consent until the last study visit. 
7 The subject’s parent/legal guardian will be trained with regard to the correct instillation of eye drops without using study drug prior to their administration of the initial dose. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page B-1 
APPENDIX B: 
METHODS OF CLINICAL EVALUATION  
Any changes to the procedures described in this appendix will be provided under separate 
cover. 
All ophthalmic assessments will be performed bilaterally at all visits. 
1. PEDIATRIC VISUAL ACUITY 
Whenever possible best corrected (if applicable) Snellen distance VA will be measured in 
both eyes. Otherwise, the Investigator will attempt the following techniques in sequential 
order: 
1. Single Letter VA (eg, HOTV, Sheridan Gardiner, Tumbling E) 
2. Picture VA (eg, Allen, Lea) 
3. Visual Behavior (eg, fix and follow, cover test) 
Whenever possible, the same VA testing method should be employed for all study visits 
for each subject. 
2. BIOMICROSCOPY 
• 
To be performed by an ophthalmologist 
• 
Use of fixed or handheld slit lamp or ophthalmic operating microscope is preferred 
• 
Use of a penlight with a 20 dpt magnifying lens is permitted if slit lamp examination 
is not possible 
• 
Method needs to be indicated in eCRF, the same method should be used throughout 
the study for each subject  
• 
If the anterior chamber is assessed with a slit lamp, a high power field slit beam of 
1 mm x 1 mm is to be used 
Ocular Tearing:  Assess degree of ocular tearing. 
0 = Absent  
Normal tear production. 
1 = Mild  
Fullness of the conjunctival sac without tears spilling over the lid 
margin. 
2 = Moderate  
Infrequent or intermittent spilling of tears over the lid margin. 
3 = Severe  
Constant or nearly constant spilling of tears over the lid margin; may 
be associated with runny nose. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page B-2 
Ocular Discharge:  Assess degree of ocular discharge. 
0 = Absent 
No abnormal discharge 
1 = Mild 
Small amount of mucopurulent or purulent discharge noted in the 
lower cul-de-sac. No true matting of the eyelids in the morning upon 
awakening 
2 = Moderate 
Moderate amount of mucopurulent or purulent discharge is noted in 
the lower cul-de-sac. Frank matting together of the eyelids in the 
morning upon awakening 
3 = Severe 
Profuse amount of mucopurulent or purulent discharge is noted in the 
lower cul-de-sac and in the marginal tear strip. Eyelids tightly matted 
together in the morning upon awakening, requiring warm soaks to pry 
the lids apart 
Conjunctival Chemosis:  Assess swelling of the conjunctiva. 
0 = Absent  
No edema 
1 = Mild  
Edema present in one segment of the bulbar conjunctiva 
2 = Moderate  
Diffuse and uniform edema present all over the bulbar conjunctiva, 
edema does not protrude over the gray line 
3 = Severe  
Conjunctival swelling extends anterior to the gray line, outside of 
palpebral fissure 
Bulbar Conjunctival Injection: Assess redness and swelling from dilated blood vessels 
in the bulbar conjunctiva. 
0 = Absent 
A normal, quiet eye; some subjects will exhibit rare vessels which are 
naturally prominent either by location or a large normal vessel 
diameter 
1 = Mild 
Slightly dilated blood vessels; color of vessels is typically pink; can be 
quadrantic 
2 = Moderate 
More apparent dilation of blood vessels; vessels color is more intense 
(redder); involves the vast majority of the vessel bed 
3 = Severe 
Numerous and obvious dilated blood vessels; in the absence of 
chemosis the color is deep red – in the presence of chemosis, the 
leaking interstitial fluid may make the color appear less red or even 
pinkish; is not quadrantic 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page B-3 
Standardized Photographs for Grading Bulbar Conjunctival Injection: 
 
Ciliary Flush: Assess external congestion of blood vessels surrounding the corneal 
limbus.  
0 = Absent  
1 = Present 
Hyphema: Assess presence or absence of hyphema.  
0 = Absent  
1 = Present 
Corneal Edema:  Assess degree of corneal edema. 
0 = Absent 
Clear cornea 
1 = Mild 
Less than 25% of the cornea is clouded and thickened without 
Descemet's folds and with clear iris details 
2 = Moderate 
25%-50% of the cornea is clouded and thickened with few Descemet's 
folds and hazy iris details 
3 = Severe 
More than 50% of the cornea is clouded and thickened with 
Descemet's folds and indistinguishable iris details 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page B-4 
Anterior Chamber Cells (for those subjects that can be examined with a s lit lamp): 
Assess accumulation of white blood cells in aqueous. Pigment cells and red blood cells 
are to be ignored. Assess anterior chamber using a high power field slit beam of 1 mm x 
1 mm. 
0 = No cells seen  
1 = 1 - 5 cells 
2 = 6 - 15 cells 
3 = 16 - 30 cells 
4 = >30 cells 
Anterior Chamber Flare (for those subjects that can be examined with a s lit lamp): 
Assess scattering of a slit lamp light beam when directed into the anterior chamber 
(Tyndall effect). 
0 = None 
No Tyndall effect 
1 = Mild 
Tyndall effect barely discernible 
2 = Moderate 
Tyndall effect in anterior chamber is moderately intense. Iris pattern is 
seen clearly 
3 = Severe 
Tyndall effect in anterior chamber is severely intense. Iris pattern 
cannot be seen clearly 
4 = Very severe 
Tyndall effect is very severely intense. The aqueous has a white and 
milky appearance 
Anterior Chamber Inflammation (for subjects that can only be examined with a pen 
light and a 20 dpt magnifying lens):  
0 = None 
Clear anterior chamber with no vi sible clouding (Tyndall effect and 
cells combined). Red reflex normal 
1 = Mild 
Mild anterior chamber clouding. Clear iris pattern on vi sualization. 
Red reflex normal 
2 = Moderate 
Moderate anterior chamber clouding 
3 = Severe 
Severe anterior chamber clouding. Iris pattern not clearly visualized. 
Red reflex diminished 
4 = Very severe 
Severe anterior chamber clouding with a white and/or milky 
appearance of the anterior chamber. Red reflex absent or severely 
diminished 
Posterior Synechiae: Assess for presence of adhesions between the iris and the lens.  
0 = Absent  
1 = Present*  
*If present, indicate the total area of synechiae in full clock hours. 


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page B-5 
Precipitates: Assess for presence of precipitates on implant and cornea. 
0 = Absent 
1 = Present* 
*If present, indicate the total number of the precipitates. 
Hypopyon: Assess presence or absence of hypopyon. 
0= Absent 
1= Present 
3. INTRAOCULAR PRESSURE 
• 
Evaluated by an ophthalmologist 
• 
Preferred methods: Goldmann or Perkins 
• 
If Goldmann or Perkins are not possible: Tono-Pen or rebound (Icare) 
• 
For each subject, the same method should be used throughout the study 
• 
Well calibrated (monthly, at minimum) measuring instruments will be used to 
measure IOP  
4. FUNDOSCOPY 
• 
Bilateral fundus exam at Visit 2 (Surgery/Randomization) or Visit 3 (Postoperative 
Day 1), at Visit 5 (Postoperative Day 14), and at Visit 8 (Study Exit)  
• 
Fundoscopy can be performed either via direct ophthalmoscopy (ophthalmoscope) or 
indirect ophthalmoscopy (either slit lamp or with a penlight and handheld 20 dpt lens) 
• 
It is at the Investigator’s discretion whether fundoscopy is done with dilated or 
undilated pupils  
• 
Mydriatic drugs should only be administered after all vision testing is complete 
• 
NSAIDs cannot be used as a mydriatic agent 
Posterior pole: Assess for abnormalities in the posterior pole.  
0 = Normal  
1 = Abnormal  
Optic Nerve: Assess for abnormalities in the optic nerve.  
0 = Normal  
1 = Abnormal  
Cup/Disc Ratio: Assess the cup/disc ratio. The largest cup to disc ratio measured should 
be entered on the eCRF.  


Study #670 - Protocol 
Amendment 6, 22 May 2013 
 
Page B-6 
5. OCULAR SYMPTOMS 
Photophobia:  
0 = Absent 
Absence of positive sensation. (For babies, a normal reaction to any 
light source.) 
1 = Mild 
Very minimal light intolerance which may require some degree of 
sunglass protection to eliminate the symptom, noticed primarily in 
sunlight. (For babies, a normal reaction to room light but more 
squinting or discomfort is shown to brighter room light or sunlight 
than normal reaction.) 
2 = Moderate 
Infrequent or intermittent discomfort in the globe associated with 
exposure to room light or sunlight which is only partially relieved by 
dark glasses or subdued light. The symptoms still persist to some 
degree even with sunglasses. (For babies, discomfort at normal room 
light is shown and more comfort is shown in dimly lit environments.) 
3 = Severe 
Constant or nearly constant exquisite pain in the eye that is not 
relieved by sunglasses and is only relieved by total occlusion of the 
eye. This total occlusion can be achieved with an eye patch or by 
closing the eyes. This sensation is severe enough to commonly require 
bed rest and, in some instances, systemic sedation. (For babies, 
squinting of the eyes or crying at any light source is shown and only 
total occlusion seems comforting.) 

SAP_001.pdf: 
 
                                                                                              
 
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 STATISTICAL ANALYSIS PLAN 
 
 
 
 
Protocol Title: 
A Randomized, Multicenter, Double Masked, Parallel-Group 
Study Assessing the Safety and Efficacy of Loteprednol 
Etabonate Ophthalmic Gel, 0.5% versus Prednisolone Acetate 
Ophthalmic Suspension, 1% for the Treatment of Intraocular 
Inflammation Following Surgery for Childhood Cataract 
Protocol number: 
670 
Phase:  
IV 
Protocol Version: Amendment 6 
Protocol Date: 
22 May 2013 
Author: 
Xiao Wang, MS 
Version: 
2.0 
Date: 
12 April 2017 
 


 
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SIGNATURES: 
 
 
Analysis Plan Approval 
 
 
Prepared by: 
 
 
 
 
 
           
_____ 
 
 
 
 
Xiao Wang, MS  
 
 
            Date 
 
 
 
 
Associate Biostatistician 
 
 
 
 
Statistics & Data Corporation 
 
 
 
Reviewed by: 
 
_____________________           ___________ 
 
 
 
 
Kirk Bateman, MS 
 
 
 
Date 
 
 
 
 
Director of Biostatistics 
 
 
 
 
Statistics & Data Corporation 
 
 
Approved by: 
 
_____________________           ___________ 
 
 
 
 
Gary Mosehauer, MS 
 
 
             Date 
                                                    Principal Statistician 
 
 
                          Bausch & Lomb, Inc.   
 
 
 
 
 
 
                            
 
 
 
 
 
 
 
 
                                                                                                                                                                        


 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS .................................................................................... 5 
1 
ADMINISTRATIVE STRUCTURE ................................................................. 6 
2 
DATA QUALITY ASSURANCE ...................................................................... 6 
3 
INTRODUCTION............................................................................................... 6 
4 
STUDY OBJECTIVE ......................................................................................... 6 
5 
STUDY METHODS............................................................................................ 6 
5.1 
Study Design .................................................................................................. 6 
5.2 
Study Endpoints ............................................................................................. 9 
5.2.1 
Primary Efficacy Endpoint ..................................................................... 9 
5.2.2 
Secondary Efficacy Endpoints ................................................................ 9 
5.2.3 
Safety Endpoints ..................................................................................... 9 
5.2.4 
Tolerability Endpoints ............................................................................ 9 
5.3 
Statistical Hypotheses .................................................................................. 10 
5.4 
Sample Size .................................................................................................. 10 
5.5 
Randomization and Masking ........................................................................ 10 
5.6 
Study Sample................................................................................................ 11 
5.6.1 
Inclusion Criteria .................................................................................. 11 
5.6.2 
Exclusion Criteria ................................................................................. 11 
5.7 
Procedures for Discontinuing Treatment and Removal of Subjects from 
Study 11 
5.8 
Test Article/Comparator Product ................................................................. 11 
5.8.1 
Selection and Timing of Dose............................................................... 12 
5.9 
Dose Adjustment/Modifications .................................................................. 12 
5.10 
Treatment Compliance Follow-up ............................................................ 12 
6 
GENERAL STATISTICAL CONSIDERATIONS ....................................... 12 
6.1 
Analysis Populations .................................................................................... 13 
6.1.1 
Intent to Treat (ITT) .............................................................................. 13 
6.1.2 
Per Protocol (PP)................................................................................... 13 
6.1.3 
Safety (SAF) ......................................................................................... 13 
6.2 
Handling of Missing Data ............................................................................ 13 
6.3 
Changes in the Planned Analysis ................................................................. 14 
7 
SUBJECT DISPOSITION ............................................................................... 14 
7.1 
Protocol Deviations ...................................................................................... 15 


 
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8 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................... 15 
8.1 
Demographics............................................................................................... 15 
8.2 
Non-Ocular and Ocular Medical History ..................................................... 15 
8.4 
Inclusion and Exclusion Criteria .................................................................. 15 
9 
TREATMENTS AND MEDICATIONS ......................................................... 15 
9.1 
Prior and Concomitant Medications ............................................................. 15 
9.2 
Study Treatments.......................................................................................... 16 
9.2.1 
Extent of Exposure ................................................................................ 16 
9.2.2 
Treatment Compliance .......................................................................... 16 
10 STATISTICAL ANALYSES ........................................................................... 16 
10.1 
Primary Efficacy Analysis ........................................................................ 17 
10.2 
Secondary Efficacy Analysis .................................................................... 17 
10.3 
Other Analysis .......................................................................................... 18 
10.4 
Safety Analysis ......................................................................................... 18 
10.4.1 Treatment Emergent Adverse Events ................................................... 18 
10.4.1.1 
Incidence of Treatment-Emergent Adverse Events ....................... 18 
10.4.1.2 
Relationship of Treatment-Emergent Adverse Events to Study 
Drug 
19 
10.4.1.3 
Severity of Treatment-Emergent Adverse Events ......................... 19 
10.4.1.4 
Seriousness of Adverse Events ...................................................... 19 
10.4.1.5 
Treatment-Emergent Adverse Events Leading to Discontinuation 19 
10.4.1.6 
Treatment-Emergent Adverse Events Related to Study Drug ....... 19 
10.4.1.7 
Death .............................................................................................. 19 
10.4.2 Surgical Intervention ............................................................................. 19 
10.4.3 Other Safety Data .................................................................................. 20 
10.4.3.1 
Biomicroscopy / Fundoscopy ........................................................ 20 
10.4.3.2 
Visual Acuity ................................................................................. 20 
10.4.3.3 
Intraocular Pressure ....................................................................... 21 
10.4.3.4 
Ocular Symptoms .......................................................................... 21 
11 INTERIM ANALYSIS ..................................................................................... 21 
12 REVISION HISTORY ..................................................................................... 21 
12.1     Revision 01 ................................................................................................. 21 


 
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List of Abbreviations 
Abbreviation/ 
Acronym 
 
Term 
ACI Anterior Chamber Inflammation 
AE Adverse Event 
ANOVA Analysis of Variance 
ANCOVA Analysis of Covariance 
AP Asia Pacific 
BAK Benzalkonium Chloride 
BID Twice per day 
CI Confidence Interval 
eCRF Electronic Case Report Form 
EU European Union 
IOL Intraocular Lens 
IOP Intraocular Pressure 
ITT Intent to Treat Population 
LE Loteprednol Etabonate 
LOCF Last Observation Carried Forward 
LSmean Least Square Mean 
MedDRA Medical Dictionary for Regulatory Affairs 
OTC Over the Counter 
PP Per Protocol Population 
QD Once per day 
QID Four times per day 
SAF Safety Population 
SAP Statistical Analysis Plan 
SAE Serious Adverse Event 
TEAE Treatment Emergent Adverse Event 
SD Standard Deviation 
US United States 
VA Visual Acuity 
WHO  World Health Organization 
 


 
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1 
Administrative Structure 
This study is being conducted under the sponsorship of Bausch + Lomb, Inc. 
 
2 
Data Quality Assurance 
The study monitors will be responsible for reviewing, verifying, and querying 
discrepant findings in the data recorded on the electronic case report forms (eCRFs) 
and the Investigators will be responsible for accuracy of the recorded data and 
answering all discrepant queries.   The eCRFs will be submitted electronically via an 
electronic data capture system for quality assurance review, data entry, and statistical 
analysis. 
 
3 
Introduction 
This document describes the statistical analyses and data presentations to be 
performed on this Phase IV, randomized, parallel group, double-masked, multi-center 
study of the safety and efficacy of Loteprednol Etabonate Ophthalmic Gel, 0.5% 
(QID) versus Prednisolone Acetate Ophthalmic Suspension, 1% (QID) for the 
treatment of intraocular inflammation following surgery for childhood cataract.  
 
The purpose of this statistical analysis plan (SAP) is to ensure the credibility of the 
study findings by specifying the statistical approaches to the analysis of the data prior 
to database lock.  This SAP covers the planned analyses of all data collected on the 
eCRFs, and will identify handling of data issues. The statistical analysis plan 
presented in this document will supersede the statistical analysis methods described in 
the clinical protocol. Any deviations/changes from the planned analyses described in 
this SAP will be identified, with justification, in the appropriate section of the clinical 
study report. This SAP is based on the final Protocol Study #670, amendment 6, dated 
22 May, 2013 and on Administrative Change Memo 1, dated 19 Aug 2013. 
 
4 
Study Objective  
The primary study objective is to compare the efficacy and safety of Loteprednol 
Etabonate (LE) Ophthalmic Gel, 0.5% to Prednisolone Acetate Ophthalmic 
Suspension, 1% for the treatment of postoperative inflammation following ocular 
surgery for childhood cataract.  
 
5 
Study Methods 
5.1 
Study Design  
This study is a randomized, double-masked, parallel-group, active-controlled, 
multicenter study involving approximately 10 investigative sites in the United States 
(US),  European Union (EU), and Asia Pacific (AP). 


 
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A total of 140 subjects aged 0-11 years will be randomized in a 1:1 ratio to LE 
Ophthalmic Gel, 0.5% or Prednisolone Acetate Ophthalmic Suspension, 1%. Of the 
140 randomized subjects, at least 60 subjects (approximately 30 subjects per 
treatment group) will be in the age range from 0-3 years. Prednisolone Acetate 
Ophthalmic Suspension, 1% was chosen as the active-control because it has a long 
history as the standard of care for pediatric cataract surgeries in the US. 
 
Study duration will be approximately 11-19 weeks from screening to the last visit 
(Visit 8, Postoperative Day 90). Subjects will visit the clinic eight times. Visit 1 will 
be the Screening Visit and will occur up to a maximum of 29 days prior to surgery. 
Visit 2 will be on the day of surgery. At the end of surgery on Visit 2, eligibility for 
randomization into the study will be assessed and, if appropriate, subjects will be 
randomized at this time. Randomized subjects will complete postoperative study 
Visits 3 through 8 (Postoperative Days 1, 7, 14, 28, 42, and 90, respectively).  
 
Subject’s eyes meeting eligibility criteria at both Visit 1 (Screening) and Visit 2 
(Surgery/Randomization) were randomized to receive study medication. If both eyes 
of 
a 
subject 
underwent 
routine, 
uncomplicated 
surgery 
at 
Visit 
2 
(Surgery/Randomization) and met eligibility criteria, the subject’s right eye was 
considered the study eye. In the event that the subject required surgery on the 
contralateral eye at any time during the study, the fellow eye was treated with 
standard of care medication. 
 
The subject will receive the first dose of study drug by the unmasked designee at the 
end of the surgery. Either the unmasked designee or the subject’s parent/legal 
guardian will then administer 1 to 2 drops of study drug to the lower cul-de-sac of the 
study eye once in the evening on the day of surgery and then 4 times a day (QID), at 
approximately 4 hour intervals, beginning on the morning after surgery. QID dosing 
will continue until postoperative day 14, including dosing at appropriate time 
intervals on the day of a visit. Treatment will be tapered by altering the frequency of 
study drug dosing to twice a day (BID) during the intervalbetween postoperative days 
15 and 21. Treatment will be further tapered to once a day (QD) from postoperative 
day 22 until day 28, with the last dose being administered on the day prior to Visit 6 
(Postoperative Day ). No study drug doses were delivered after Visit 6, and subjects 
returned for post-dosing assessments at Visit 7 (Day 42) and Visit 8 (Day 90).  
Subjects then exited from the study.28). 


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Schedule of Visits and Parameters 
 


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5.2 
Study Endpoints 
5.2.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the mean grade of anterior chamber inflammation (ACI) 
in the study eye at Visit 5 (Postoperative Day 14). The ACI grade will be determined 
using either slit lamp biomicroscopy or a penlight with handheld magnification. The 
grading from each method will be combined into one ACI grade to be used as the primary 
endpoint, derived using the following table: 
 
 
 
ACI Grade  
Slit lamp 
Penlight with handheld 
magnifying 20 diopter 
lens  
0 = None  
Grades 0 cells and flare  
Grade 0 
1 = Mild  
Maximum of cells and flare Grade is 1  
Grade 1 
2 = Moderate  
Maximum of cells and flare Grade is 2  
Grade 2 
3 = Severe  
Maximum of cells and flare Grade is 3 
Grade 3 
4 = Very Severe  Maximum of cells and flare Grade is 4  
Grade 4 
 
5.2.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following: 
 Mean grade of ACI  at Visits 4 and 6 (Postoperative Days 7 and 28) 
 Proportion of subjects with Grade 0, Grade 1, Grade 2, Grade 3, and Grade 4 
converted ACI  at each visit (Postoperative Days 7, 14, and 28)  
 Presence/absence and total area, if present, of synechiae at each visit 
(Postoperative Days 7, 14, and 28)  
 Presence/absence and total number, if present, of precipitates on the implant and 
cornea at each visit (Postoperative Days 7, 14, and 28)  
 
5.2.3 Safety Endpoints 
The safety endpoints include the following: 
 Incidence of overall and specific adverse events (AEs)  
 Type and incidence of AEs at each visit  
 Change in IOP from baseline (Visit 2, Surgery/Randomization) to each visit  
 Greatest IOP change from baseline - including the measurement at Visit 3 
(Postoperative Day 1)  
 Greatest IOP change from baseline - excluding the measurement at Visit 3 
(Postoperative Day 1)  
 Ocular signs (biomicroscopic examination of the lids, conjunctiva, cornea, 
anterior chamber without pupil dilation) at each visit  
 
 
5.2.4 Tolerability Endpoints 
The tolerability endpoint is as follows: 
 Ocular symptoms (photophobia) at each visit  


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5.3 
Statistical Hypotheses 
The test for the non-inferiority of LE Ophthalmic Gel, 0.5% to Prednisolone Acetate 
Ophthalmic Suspension, 1% will be based on the following one-sided null hypothesis 
(H0) and alternative hypothesis (Ha):  
H0: μLE - μPR ≥ 0.35 versus Ha: μLE - μPR < 0.35, 
where μLE and μPR are the mean grade of ACI at Visit 5 (Postoperative Day 14) for LE 
Ophthalmic Gel, 0.5% and Prednisolone Acetate Ophthalmic Suspension, 1% treatment 
groups, respectively.  
 
5.4 
Sample Size 
The planned sample size of 120 completed subjects (60 subjects per treatment group) 
yields 98% power to detect non-inferiority of LE Ophthalmic Gel, 0.5% to Prednisolone 
Acetate Ophthalmic Suspension, 1%. This sample size assumes a common standard 
deviation of 0.47, a two-sided alpha=0.05, a non-inferiority margin of 0.35 and an 
expected difference of 0 for the difference in means between treatment groups using ACI 
at Visit 5 (Postoperative Day 14). Assuming a subject dropout rate (including the 
initiation of rescue medication) of 12%, approximately 140 subjects will be randomized, 
of which at least 60 subjects will be in the age group 0-3 years as per the FDA’s Written 
Request.  
 
The power and sample size calculations were done using nQuery Advisor version 7.0. 
 
5.5 
Randomization and Masking 
A total of approximately 140 subjects from ages 0-11 will be randomized at Visit 2 (Day 
0 to receive LE Ophthalmic Gel, 0.5% or Prednisolone Acetate Ophthalmic Suspension, 
1% in a 1:1 ratio. The subgroup age 0-3 years will consist of at least 60 subjects.  
 
The final randomization list will be created prior to study enrollment by an unmasked 
statistician not otherwise involved in the trial. Each randomization number will 
correspond to a treatment group assignment. The Investigator and Sponsor personnel 
involved in the conduct of the study will be fully masked to the study medication.  
Designees at each study site will be able to view both test and comparator bottles and are 
therefore considered unmasked, although they will not have access to the randomization 
codes.   
 
The randomization code can be broken in an emergency situation before the database 
lock where knowledge of the study treatment is critical to subject safety.   
 


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5.6 
Study Sample 
Approximately 140 subjects will be enrolled in this double-masked, parallel-group, 
active-controlled study at approximately 30 investigative sites in the United States (US), 
European Union (EU), and Asia Pacific (AP). 
 
5.6.1 Inclusion Criteria 
Subjects must meet all the inclusion criteria listed in Section 3.2.1.1 of the clinical trial 
protocol. 
 
5.6.2 Exclusion Criteria 
Subjects have to meet (ie, respond “NO” to) all the exclusion criteria listed in Section 
3.2.1.2 of the clinical trial protocol. 
 
5.7 
Procedures for Discontinuing Treatment and Removal of Subjects from 
Study 
A subject CAN be discontinued (at the discretion of the Investigator, the Sponsor, and/or 
the Institutional Review Board/Ethics Committee) prior to the final study visit for any of 
several reasons, including, but not limited to: 
  
 A serious adverse event (SAE) occurring during the course of the study, which 
precludes continued treatment or follow-up  
 The subject’s parent/legally authorized representative not following required 
study procedures  
 
A subject HAS TO be discontinued prior to the final study visit for any of the following 
reasons:  
 Voluntary withdrawal 
 Onset of menarche during the study 
 Death 
 Investigator decision that it is not in the best medical interest of the subject to 
continue participation in the investigation 
 Requires rescue medication 
Adverse events and reasons for withdrawal and discontinuation will be documented 
appropriately according to the protocol. The assessments scheduled for Visit 8 
(Postoperative Day 90) should be performed at this early termination visit. Any 
randomized subject discontinued from the study will not be replaced. 
 
5.8 
Test Article/Comparator Product 
Loteprednol Etabonate Ophthalmic Gel, 0.5%, contains the active ingredient loteprednol 
etabonate 0.5% and the preservative benzalkonium chloride (BAK), 0.003%. It also 
contains the inactive ingredients glycerin, propylene glycol, sodium chloride, 


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polycarbophil, sodium hydroxide, tyloxapol, edetate disodium dihydrate, boric acid, and 
water for injection. 
 
Prednisolone Acetate Ophthalmic Suspension, 1% contains the active ingredient 
prednisolone acetate 1% and the preservative BAK, 0.004%. It also contains the inactive 
ingredients 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. 
 
5.8.1 Selection and Timing of Dose 
The subject will receive the first dose of study drug by the unmasked designee at the end 
of the surgery. Either the unmasked designee or the subject’s parent/legal guardian will 
then administer 1 to 2 drops of study drug to the lower cul-de-sac of the study eye once in 
the evening on the day of surgery and then QID, at approximately 4 hour intervals, 
beginning on the morning after surgery. QID dosing will continue until postoperative day 
14, including dosing at appropriate time intervals on the day of a visit.  Dosing of both 
test articles was subsequently adjusted as described in Section 5.9. 
 
5.9 
Dose Adjustment/Modifications 
Treatment will be tapered from QID to BID during the interval between postoperative 
days 15 and 21. Treatment will be further tapered to QD from postoperative day 22 until 
day 28, with the last dose being administered on the day prior to Visit 6 (Postoperative 
Day 28). 
 
5.10 
Treatment Compliance Follow-up 
In order to assess compliance of treatment administration, subject/subject’s parent/legal 
guardian will be instructed to record the date and time of each study drug administration 
on a diary provided by the Sponsor. 
 
6 
General Statistical Considerations 
All statistical analyses will be conducted using SAS Version 9.4 or higher. 
 
Continuous data will be summarized using descriptive statistics: n, mean, standard 
deviation, median, minimum, and maximum.  Means and medians will be presented to 1 
more decimal place than the recorded data.  Standard deviations will be presented to 2 
more decimal places than the recorded data.  Minimum and maximum values will be 
presented using the same number of decimal places as the recorded data.  Categorical 
data will be summarized using counts for each category and corresponding percentages.  
Percentages will be presented to 1 decimal place.  Confidence intervals will be presented 
using the same number of decimal places as the parameter (i.e. mean).  


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All statistical analyses will generally include summaries by treatment group or by 
treatment group and scheduled time point, as appropriate. 
 
In general, the baseline value for a variable is defined as the last observation prior to the 
first dose of double masked study medication (Day 0), including the screening value, if 
necessary. 
 
Study Day 0 is defined as the date on which a subject was randomized and took the first 
dose of double masked study medication. Other study days are defined relative to the 
Study Day 0 as Dose Date – Day 0 date + 1. The visit window for Day 7 is ±2, for Day 
14 is ±3, for Day 28, 42, is ±7, and for Day 90 is ±14.  
 
6.1 
Analysis Populations 
6.1.1 Intent to Treat (ITT) 
Intent-to-Treat (ITT) population: includes all subjects who were randomized and have at 
least one post-treatment assessment. Analysis of the ITT population will be used for 
primary efficacy analyses and will be performed for all efficacy endpoints, analyzing 
subjects under the treatment to which they were randomized.  
 
6.1.2 Per Protocol (PP) 
Per Protocol (PP) population: includes all of the subjects in the ITT population that 
remained in the study through Visit 5 (Postoperative Day 14) and who did not deviate 
from the protocol in any way likely to seriously affect the primary outcome of the study. 
Analyses using the PP population will be used to supplement the ITT analysis, analyzing 
subjects according to the treatment received. 
 
6.1.3 Safety (SAF) 
Safety analysis population: includes all participants who received at least one dose of 
study drug.  
All subjects in the Safety analysis population will be analyzed according to the treatment 
received.  All safety and tolerability analyses will be based on the Safety analysis 
population. 
 
6.2 
Handling of Missing Data  
For the primary efficacy endpoint analyzed using the ITT population, missing data and 
data from subjects placed on rescue medication prior to Day 14 will be analyzed using 


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the last observation carried forward (LOCF). For the PP analysis, missing data and data 
from subjects placed on rescue medication will not be imputed.  
 
Data from unscheduled/repeated visits will be presented in listings and will be included 
in safety summaries for considering the worst-case scenario.  
 
6.3 
Changes in the Planned Analysis 
Change from protocol: Investigation site is added as a covariate in the primary analysis 
model, and the model was changed from a one-way ANOVA to an ANCOVA model. 
Any deviations from this statistical analysis plan will be documented in the final clinical 
study report. 
 
7 
Subject Disposition 
A disposition table of subjects will include the number and percentage of subjects in each 
of the following categories: 
 
Subjects randomized (ITT analysis population) 
 
Subjects treated (Safety analysis population) 
 
Subjects in the PP analysis population 
Within each of the previous categories, the number and percentage of subjects who 
completed and discontinued from the study will be summarized. 
The reasons for study discontinuation will also be summarized. The reason for 
discontinuation may include any of the following: 
 
Withdrew consent 
 
Lost to follow-up 
 
Administrative issue 
 
Adverse event 
 
Rescue Therapy 
 
Failure to follow required study procedures 
 
Investigator decision that it is not in the best medical interest of the subject 
 
Onset of menarche 
 
Other 
Only 1 reason (primary) for study discontinuation will be recorded for each subject. 
A listing will present data concerning subject disposition and other reasons for 
discontinuation  
 


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7.1 
Protocol Deviations 
The date of and reason for protocol deviations will be documented in all cases. Major 
protocol deviations will be finalized before the database lock.   Major protocol deviations 
will be summarized. A listing of all protocol deviations will be presented.  
 
8 
Demographics and Baseline Characteristics 
8.1 
Demographics 
Demographic characteristics including race, ethnicity, gender, iris color, and age will be 
summarized by treatment group for the ITT, PP and SAF.  Age (≤ 3 years, > 3 years), 
race, ethnicity, iris color, source of breast milk, and gender will be summarized as 
categorical variables, while age will also be summarized as a continuous variable.  All 
percentages will be based on the number of randomized subjects. Comparability of 
baseline variables will be tested using two-sided t-test or Chi-square test, as appropriate. 
 
8.2 
Non-Ocular and Ocular Medical History 
Non-ocular medical history will be listed by subject and summarized as categorical 
variables at the subject and event level by system organ class and preferred term for each 
treatment group.  Ocular history will be listed and summarized similarly for study and 
fellow eyes separately.     
   
8.4 
Inclusion and Exclusion Criteria 
A listing of inclusion and exclusion criteria along with date of informed consent will be 
listed by subject.   
 
9 
Treatments and Medications 
9.1 
Prior and Concomitant Medications 
All medications will be coded using the World Health Organization (WHO) drug 
dictionary version 1Q2010.  All non-study drugs (including prescribed and over the 
counter [OTC] medications) used within 30 days prior to study entry and all non-study 
drugs used during the course of the study will be collected on the eCRF. 
 
Concomitant medication use will be summarized by the number and percentage of 
subjects taking each medication. Medications taken prior to study drug will be presented 
in a listing. Rescue medication will be listed and summarized, if appropriate. 
 


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9.2 
Study Treatments 
9.2.1 Extent of Exposure 
Extent of exposure is defined as the total number of days from the first dose date to the 
last dose date, as recorded at the randomization study visit and the study exit eCRF page. 
Study drug exposure will be calculated based on subject diary data.  
 
The extent of exposure and study drug exposure will be summarized in a table by 
summary statistics including the mean, standard deviation, median, minimum, and 
maximum exposure. 
 
9.2.2 Treatment Compliance  
Study drug compliance will be calculated for each subject by taking into account whether 
a subject takes all doses of study drug as instructed. Compliance will be based solely on 
the subject diaries. The study drug compliance rate will be presented overall, at Visit 4, 
Visit 5 and Visit 6. The study drug compliance rate for Visit 5 will be calculated by 
dividing the total number of dosingl recorded in the diary for the subject for that period 
by the total number of days times 4 and then multiplying by 100. The first day of dosing 
will be ignored entirely, since subjects may be compliant with any number of doses.  
 
The overall study drug compliance rate will be calculated by dividing the total number of 
dosing recorded in the diary for a subject across the entire treatment period by the total 
number of days times 4 for days  14, times 2 for days between days 15 and 21 and times 
1 for days between 22 and 28 and then multiplying by 100. The first day of dosing will be 
ignored entirely, since subjects may be compliant with any number of doses. The number 
and percentage of subjects in each of the following compliance rate categories will also 
be reported: (≤50%, 51-60%, 61-70%, 71-80%, 81-120%, and >120%). Percentages will 
be calculated out of the number of subjects who returned diaries from that dosing period. 
The number and percentage of subjects in each compliance rate category will be 
presented overall, at Visit 4, Visit 5 and Visit 6.  
 
10 
Statistical Analyses 
All efficacy analyses will use a 2-sided alpha = 0.05 test unless otherwise stated.  No 
adjustments will be made for multiplicity testing. 
 
Analyses will be performed on the ITT and PP analysis set for both the primary efficacy 
endpoint and secondary efficacy endpoints.  The safety analyses will be performed on the 
SAF. 
 


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All continuous efficacy endpoints will be summarized graphically by treatment group 
displaying the mean and corresponding standard errors at each time point for the primary 
efficacy endpoint or line graphs of the continuous secondary efficacy endpoints over 
scheduled time.  
10.1 
Primary Efficacy Analysis   
The primary efficacy analysis will be based on the ITT population with missing data 
imputed using the last observation carried forward (LOCF) method and the primary 
endpoint will be mean grade of ACI at Visit 5 (Postoperative Day 14). The mean grade of 
ACI at Visit 5 (Postoperative Day 14) will be analyzed using an ANCOVA model with 
treatment as a classification variable and investigational site as a covariate.  
 
The least squares mean for each treatment group, the difference in the least squares mean 
between the 2 treatment groups (LE Gel minus Pred Forte), and the 2-sided 95% 
confidence interval for the difference will be presented. The null hypothesis will be 
rejected and non-inferiority established if the upper limit of the confidence interval is less 
than 0.35. 
 
To support the interpretation of the primary analysis, the analyses above will be repeated 
for the PP population; no imputation will be conducted for missing data or for subjects 
placed on rescue medication for the PP analysis. Any discrepancy between the ITT and 
PP analyses will be explained. 
 
10.2 
Secondary Efficacy Analysis 
All secondary analyses will be based on the ITT and PP. 
 
As a secondary analysis, the analysis of the observed mean grade of ACI will be repeated 
as above for Visits 4 and 6 (Postoperative Days 7 and 28, respectively).  
 
Additional secondary analyses include:  
 
The proportion of subjects with ACI of Grade 0, Grade 1, Grade 2, Grade 3, and 
Grade 4 for each visit (Postoperative Days 7, 14, and 28) 
 
The proportion of subjects with presence/absence and total area, if present, of 
synechiae in the study eye for each visit (Postoperative Days 7, 14, and 28) 
 
The proportion of subjects with presence/absence and total number, if present, of 
precipitates on the implant and cornea in the study eye at each visit (Postoperative 
Days 7, 14, and 28) 
For each of the above endpoints, treatment groups will be compared using the Pearson 
Chi-squared test or Fisher’s exact test as appropriate. Differences between the 


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proportions of treatment groups and 95% confidence interval about the differences will 
be presented.  
 
10.3 
Other Analysis 
Subgroup analyses will be performed for ACI and anterior chamber cells, anterior 
chamber flare as appropriate by method of assessment (slit lamp versus penlight with 
handheld magnifying 20 diopter lens), country (region), age group, intraocular lens (IOL) 
implantation, and iris color. 
 
10.4 
Safety Analysis 
Safety analyses will be based on the SAF.  The SAF will include all subjects who are 
confirmed to have received the study drug.  All subjects in the SAF will be analyzed 
according to the treatment received.   
 
10.4.1 Treatment Emergent Adverse Events  
Adverse events (AEs) are defined in Section 6.1 of the protocol and initiating collection 
of AEs is defined in Section 5.1.2 of the protocol. Adverse events will be coded using 
MedDRA dictionary version 13.0.   
 
All AEs collected with start dates following the first administration of study drug or that 
worsen following the first administration of study drug are considered treatment-
emergent adverse events (TEAE).   
 
Adverse events with unknown severity will be counted as severe.  Adverse events with 
unknown relationship to study drug will be counted as related to study drug.  Adverse 
events with partial dates will have their start dates imputed.  If the partial date is 
consistent with the first day of treatment, it will be imputed with this value; otherwise it 
will be imputed as the earliest possible date consistent with the partial data (first day of 
month/ year).  If a start or end date are completely missing, then the date will be imputed 
with the dates of the first or last date of treatment, respectively. 
 
10.4.1.1 
Incidence of Treatment-Emergent Adverse Events 
Treatment emergent non-ocular AEs will be summarized using discrete summaries at the 
subject and event level by system organ class and preferred term for each treatment 
group.  Treatment emergent ocular AEs will be summarized for treated study eyes and 
fellow eyes separately. 


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10.4.1.2 
Relationship of Treatment-Emergent Adverse Events to Study Drug  
Treatment emergent AEs will be summarized by relationship to study drug.  Relationship 
of adverse events to study drug may be ‘Not Related’ or ‘Related’. Adverse events that 
are missing relationship will be presented in the summary table as “Related” but will be 
presented in the data listing with a missing relationship.  Percentages will be calculated 
out of the number of subjects in the Safety sample. 
   
10.4.1.3 
Severity of Treatment-Emergent Adverse Events   
A summary of TEAEs by severity will be presented in a table.  The severity that will be 
presented represents the most extreme severity captured.  Adverse events will be assessed 
by the Investigator as “Mild,” “Moderate,” or “Severe.”  In the AE severity table, if a 
subject reported multiple occurrences of the same AE, only the most severe will be 
presented.  Adverse events that are missing severity will be presented on tables as 
“Severe” but will be presented in the data listing with a missing severity.  Percentages 
will be calculated out of the number of subjects in the Safety sample.   
   
10.4.1.4 
Seriousness of Adverse Events   
Serious adverse events (SAEs) are defined in Section 6.2 of the protocol. A listing and 
table of SAEs will be presented.  
 
10.4.1.5 
Treatment-Emergent Adverse Events Leading to Discontinuation 
All TEAEs resulting in study discontinuation will be presented in a listing. 
 
10.4.1.6 
Treatment-Emergent Adverse Events Related to Study Drug 
All TEAEs assessed as related to the study drug will be presented with time to onset and 
outcome in a listing by treatment group. 
 
10.4.1.7 
Death 
All subject deaths during this study will be collected and presented in a listing.  The 
information presented will include date of death, days on study, cause of death, and 
relationship of death to study drug. 
 
10.4.2 Surgical Intervention 
Surgical procedure data will be presented in a listing. 


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10.4.3 Other Safety Data 
10.4.3.1 
Biomicroscopy / Fundoscopy 
The slit lamp/penlight with magnifying lens biomicroscopy will be performed at all 
visits.  The biomicroscopy parameters will include:   
 Anterior chamber cells or ACI 
 Anterior chamber flare or ACI 
 Ciliary flush 
 Chemosis 
 Ocular discharge 
 Ocular tearing 
 Bulbar conjunctival injection 
 Corneal edema 
 Hyphema 
 Hypopyon 
 Posterior synechiae 
 Precipitates 
Biomicroscopy findings will be summarized at each visit and for the worst case on 
treatment by subject and parameter. Incidence of treatment-emergent biomicroscopy 
findingswill be tested using the Pearson Chi-squared Test or Fisher’s Exact Test as 
applicable. 
 
The fundoscopy parameters will include: 
 Posterior Pole 
 Optic Nerve 
 Cup/Disc Ratio 
Fundoscopy measures will be summarized by visit. Incidence of treatment-emergent 
fundoscopy findings will be tested using a Pearson Chi-squared Test or Fisher’s Exact 
Test, if applicable. 
 
10.4.3.2 
Visual Acuity 
Visual Acuity (VA) method will be summarized.  VA assessments will be summarized at 
each visit as a categorical variable (ie: 20/20, 20/40, or fix and follow etc) and as a line 
change from baseline as applicable.  Worst line change from baseline will also be 
presented.  Subjects presenting a line change of >2 lines will be tested using a Pearson 
Chi-squared Test or Fisher’s Exact Test as applicable.   


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10.4.3.3 
Intraocular Pressure 
Intraocular pressure (IOP) will be summarized at each visit and worst case on treatment 
for each subject using both continuous summaries (including change from baseline) and 
discrete summaries.  Discrete summaries will include: 
 Change in IOP from baseline (Visit 2) to each visit 
 The proportion of subjects with change in IOP from baseline ≥5 and ≥10 mm Hg 
 The proportion of subjects with treatment-emergent IOP ≥25 mm Hg 
 IOP at each visit categorized into:   4, 5 to 7, 8 to 12, 13 to 16, 17 to 20, 20 to 
25, and 25 
 Greatest IOP change from baseline - including the measurement at Visit 3 
(Postoperative Day 1)  
 Greatest IOP change from baseline - excluding the measurement at Visit 3 
(Postoperative Day 1)  
 Change from baseline in IOP at each visit categorized into:  ≤-5, -4 to 0, 1 to 4, 5 
to 9, 10 to 14, and 15 
 
10.4.3.4 
Ocular Symptoms  
Ocular symptom/tolerability (photophobia) data will be summarized by visit and 
treatment group. The listing will use the SAF population with actual treatment received. 
 
11 
Interim Analysis 
In order to provide the primary CSR for FDA review, an interim analysis will be 
performed for all subjects who exited (not completed, but exited, including discontinued 
subjects) on or before 28Feb2017. This interim analysis will contain all tables, listings 
and figures as the final analysis. There will be no statistical adjustments to the study-wide 
alpha level for the interim analysis.  
 
12 
Revision History 
12.1     Revision 01 
This revision was issued following protocol amendment 6, issued on 22MAY2013. 
Summary of changes from the prior SAP version: 1.0, dated 04June2012. 
 
Section # 
Description of Change 
Rationale 
All 
Administrative changes 
To 
provide 
clarity 
and 
consistency to the SAP text 


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Section # 
Description of Change 
Rationale 
3 
Changed phase number from 3b to 4 
Change based on protocol 
amendment 6 
5.1 
Changed subject number from 158 to 140; 79 to 
60 and 40 to 30. 
Change based on protocol 
amendment 6 
5.1 
Changed description of study duration as 
follows: 
“Study duration will be approximately 12-18 11-
19 weeks…” 
Change based on protocol 
amendment 6 
5.1 
Deleted the “Design Schematic” 
Change based on protocol 
amendment 6 
5.1 
Updated the schedule of visits and parameters 
Change based on protocol 
amendment 6 
5.2.1 
Changed Visit 4 to Visit 5, and Day 7 to Day 14 
Change based on protocol 
amendment 6 
5.2.1 
Added “The ACI grade will be determined using 
either slit lamp biomicroscopy or a penlight with 
handheld magnification.  The grading from each 
method will be combined into one ACI grade to 
be used as the primary endpoint” 
The original SAP is not clear 
about 
the 
ACI 
grade 
calculation.  
5.2.2 
Changed Visit 5 to Visit 4, and Day 14 to Day 7 
Change based on protocol 
amendment 6 
5.2.2 
Changed Day 29 to Day 28 
Change based on protocol 
amendment 6 
5.3 
Changed the non-inferiority margin from 0.5 to 
0.35 
Change based on protocol 
amendment 6 
5.3 
Changed Visit 4-Day 7 to Visit 5-Day 14 
Change based on protocol 
amendment 6 
5.4 
Changed the sample size calculation to be the 
same as the protocol 
Change based on protocol 
amendment 6 
5.5 
Changed subject number from 158 to 140 
Changed: the subgroup age 0-3 years will consist 
of at least 60 subjects. The subgroup age 0-3 
years will be randomized in approximately equal 
proportion. 
Change based on protocol 
amendment 6 
5.6 
Changed subject number from 158 to 140 
Added Asia Pacific (AP) 
Change based on protocol 
amendment 6 
5.7 
Added onset of menarche during the study 
Change based on protocol 
amendment 6 
5.7 
Changed: The assessments scheduled for Visit 8 
(Postoperative Day 90) should be performed at 
Change based on protocol 
amendment 6 


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Section # 
Description of Change 
Rationale 
this 
early 
termination 
visit. 
Assessments 
scheduled for the planned Visit will be performed 
at the early discontinuation visit 
5.9 
Changed Day 29 to Day 28 
Change based on protocol 
amendment 6 
6 
Changed version 9.1 to version 9.4 
SDC will use the latest SAS 
version 
6 
Changed: The visit window for Day 7 is ±2, and 
for Day 14 is ±31, and the visit window for Days 
298, 42, is and 90 is ±73, and for Day 90 is ±14. 
Change based on protocol 
amendment 6 
6.1.1 
Changed the “secondary” to “primary” 
Change based on protocol 
amendment 6 
6.1.2 
Changed Visit 4-Day 7 to Visit 5-Day 14 
Change based on protocol 
amendment 6 
6.1.2 
Changed: Analyses on the using the PP set will 
be used for the primary efficacy analysis and will 
be performed to supplement the ITT analysis, 
analyzing subjects according to the treatment 
received.or the primary and secondary efficacy 
endpoint, analyzing subjects according to the 
treatment received. 
Change based on protocol 
amendment 6 
6.2 
Deleted: Subjects with missing data or with 
rescue medication prior to Day 7 will be 
excluded from the primary PP analysis. 
Change based on protocol 
amendment 6 
6.2 
Changed Day 7 to Day 14 
Change based on protocol 
amendment 6 
6.2 
Changed: For the secondary efficacy endpoints 
analyzed using the ITT set PP analysis, missing 
data and data from subjects placed on rescue 
medication prior to the visit being summarized 
will not be imputed as LOCF and will also be 
summarized as missing. 
Change based on protocol 
amendment 6 
8.1 
Changed analysis of variance (ANOVA) to two-
sided t-test 
Change based on protocol 
amendment 6 
9.2.2 
Changed: Visit 4-Day 7 to Visit 5-Day 14 
Change based on protocol 
amendment 6 
10.1 
Changed Visit 4-Day 7 to Visit 5-Day 14 
Change based on protocol 
amendment 6 
10.1 
Changed the non-inferiority margin from 0.5 to 
0.35 
Change based on protocol 
amendment 6 
10.1 
Change the primary endpoint into ITT with 
LOCF 
Change based on protocol 


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Section # 
Description of Change 
Rationale 
amendment 6 
10.1 
Delete the pattern mixture model part 
Change based on protocol 
amendment 6 
10.1 
Add “and investigational site as a covariate.” 
Site might have significant 
impact 
on 
the 
primary 
endpoint.  
10.2 
Changed Visit 5 to Visit 4, and Day 14 to Day 7 
Change based on protocol 
amendment 6 
10.2 
Changed Day 29 to Day 28 
Change based on protocol 
amendment 6 
10.2 
Removed the whole ANCOVA model section 
The baseline measurements 
on Visit 2 (Day 0) were 
taken prior to the surgery, 
which means the results 
should all be negative (no 
ACI). So it’s not meaningful 
to use baseline as a covariate 
in this case 
10.2 
Added “in the study eye” in the second and third 
bulletins  
To clarify that these two 
tables are only summarized 
for study eye 
10.4.1.1 
Added “Treatment-Emergent” 
Sponsor requested to clarify 
10.4.1.2 
Added “Treatment-Emergent” 
Sponsor requested to clarify 
10.4.1.3 
Added “Treatment-Emergent” 
Sponsor requested to clarify 
10.4.1.5 
Added “Treatment-Emergent” 
Sponsor requested to clarify 
10.4.1.6 
Added “Treatment-Emergent” 
Sponsor requested to clarify