An International, Multicenter, Randomized, Blinded-assessor, Parallel-group Clinical Study Comparing Eye Drops of Combined LEvofloxAcin + DExamethasone foR 7 Days Followed by Dexamethasone Alone for an Additional 7 Days vs. Tobramycin + Dexamethasone for 14 Days for the Prevention and Treatment of Inflammation and Prevention of Infection Associated With Cataract Surgery in Adults - LEADER 7
Phase: PHASE3
Conditions: Cataract
Sponsor: NTC srl

 
CLINICAL TRIAL PROTOCOL 
An international, multicenter, randomized, blinded-
assessor, parallel-group clinical study comparing eye drops 
of combined LEvofloxAcin + DExamethasone foR 7 days 
followed by dexamethasone alone for an additional 7 days 
vs. tobramycin + dexamethasone for 14 days for the 
prevention and treatment of inflammation and  
prevention of infection associated with cataract  
surgery in adults – LEADER 7 
 
PROTOCOL NUMBER: LEVODESA_04-2017 
EUDRACT NUMBER: 2018-000286-36 
VERSION: 2.0 (AMENDED PROTOCOL) 
DOCUMENT DATE: 12 JULY 2018 
 
 
 
Confidential: further dissemination may only be made with the 
expressed written permission of NTC S.r.l. 
 

Sponsor: NTC S.r.l. 
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Amended Protocol No.: LEVODESA_04-2017 
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Table of Contents 
AMENDMENT 1 .................................................................................................................................................. 5 
STATEMENT OF COMPLIANCE ..................................................................................................................... 6 
1 
PROTOCOL SUMMARY ............................................................................................................................ 7 
1.1 
SYNOPSIS ........................................................................................................................................................ 7 
1.2 
STUDY DESIGN ............................................................................................................................................. 12 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .................................................................................................................. 13 
2 
INTRODUCTION ...................................................................................................................................... 14 
2.1 
STUDY RATIONALE ....................................................................................................................................... 14 
2.2 
BACKGROUND .............................................................................................................................................. 14 
2.3 
RISK/BENEFIT ASSESSMENT ......................................................................................................................... 19 
2.3.1 
Known Potential Risks ......................................................................................................................... 19 
2.3.2 
Known Potential Benefits ..................................................................................................................... 19 
2.3.3 
Assessment of Potential Risks and Benefits ......................................................................................... 19 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................ 20 
4 
STUDY DESIGN ........................................................................................................................................ 21 
4.1 
OVERALL DESIGN ......................................................................................................................................... 21 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ................................................................................................ 21 
4.3 
JUSTIFICATION FOR DOSE ............................................................................................................................. 22 
4.4 
END OF STUDY DEFINITION .......................................................................................................................... 22 
5 
STUDY POPULATION .............................................................................................................................. 22 
5.1 
INCLUSION CRITERIA .................................................................................................................................... 22 
5.1.1 
Inclusion criteria prior to surgery ....................................................................................................... 22 
5.1.2 
Inclusion criteria following surgery .................................................................................................... 23 
5.2 
EXCLUSION CRITERIA ................................................................................................................................... 23 
5.3 
SCREEN FAILURES ........................................................................................................................................ 24 
5.4 
STRATEGIES FOR RECRUITMENT AND RETENTION ........................................................................................ 24 
6 
STUDY INTERVENTION ......................................................................................................................... 24 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION ................................................................................................ 24 
6.1.1 
Study Intervention Description ............................................................................................................ 24 
6.1.2 
Dosing and Administration .................................................................................................................. 24 
6.1.2.1 
Missed doses ................................................................................................................................................. 25 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY .............................................................................. 25 
6.2.1 
Acquisition and accountability ............................................................................................................ 25 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .......................................................................... 25 
6.2.3 
Product Storage and Stability .............................................................................................................. 26 
6.2.4 
Preparation .......................................................................................................................................... 26 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ................................................................ 26 
6.4 
STUDY INTERVENTION COMPLIANCE ............................................................................................................ 27 
6.5 
CONCOMITANT THERAPY ............................................................................................................................. 27 

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6.5.1 
Prohibited concomitant therapy .......................................................................................................... 27 
6.5.2 
Rescue therapy ..................................................................................................................................... 27 
6.6 
WARNINGS AND PRECAUTIONS RELATED TO STUDY TREATMENTS ............................................................... 27 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................................... 29 
7.1 
DISCONTINUATION OF STUDY INTERVENTION .............................................................................................. 29 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY ............................................................. 30 
7.3 
LOST TO FOLLOW-UP ................................................................................................................................... 31 
8 
STUDY ASSESSMENTS AND PROCEDURES........................................................................................ 31 
8.1 
SCHEDULE OF ASSESSMENTS ........................................................................................................................ 31 
8.2 
EFFICACY ASSESSMENTS .............................................................................................................................. 33 
8.3 
SAFETY, TOLLERABILITY AND OTHER ASSESSMENTS ................................................................................... 34 
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ..................................................................................... 35 
8.4.1 
Definition of Adverse Events (AE) ....................................................................................................... 35 
8.4.2 
Definition of Serious Adverse Events (SAE) ........................................................................................ 35 
8.4.3 
Classification of an Adverse Event ...................................................................................................... 35 
8.4.3.1 
Severity of Event ........................................................................................................................................... 35 
8.4.3.2 
Relationship to study intervention ............................................................................................................... 35 
8.4.3.3 
Expectedness ................................................................................................................................................ 35 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up .................................................... 36 
8.4.5 
Adverse Event Reporting ..................................................................................................................... 36 
8.4.6 
Serious Adverse Event Reporting ......................................................................................................... 36 
8.4.7 
Reporting Events to Participants ......................................................................................................... 37 
8.4.8 
Events of Special Interest ..................................................................................................................... 37 
8.4.9 
Reporting of Pregnancy ....................................................................................................................... 37 
9 
STATISTICAL CONSIDERATIONS ........................................................................................................ 38 
9.1 
STATISTICAL HYPOTHESES ........................................................................................................................... 38 
9.2 
SAMPLE SIZE DETERMINATION ..................................................................................................................... 38 
9.3 
POPULATIONS FOR ANALYSES ...................................................................................................................... 39 
9.4 
STATISTICAL ANALYSES ............................................................................................................................... 39 
9.4.1 
General Approach ............................................................................................................................... 39 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ...................................................................................... 39 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................................................ 40 
9.4.4 
Safety Analyses .................................................................................................................................... 40 
9.4.5 
Tolerability Analyses ........................................................................................................................... 41 
9.4.6 
Analysis of compliance ........................................................................................................................ 41 
9.4.7 
Baseline Descriptive Statistics ............................................................................................................. 41 
9.4.8 
Planned Interim Analyses .................................................................................................................... 41 
9.4.9 
Sub-Group Analyses ............................................................................................................................ 41 
9.4.10 
Tabulation of Individual participant Data ........................................................................................... 41 
9.4.11 
Exploratory Analyses ........................................................................................................................... 42 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......................... 42 
10.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ........................................................... 42 

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10.1.1 
Informed Consent Process ................................................................................................................... 42 
10.1.1.1 
Consent and Other Informational Documents Provided to participants ............................................ 42 
10.1.2 
Consent Procedures and Documentation ............................................................................................ 42 
10.1.3 
Study Discontinuation and Closure ..................................................................................................... 42 
10.1.4 
Confidentiality and Privacy ................................................................................................................. 43 
10.1.5 
Future Use of Stored Specimens and Data .......................................................................................... 44 
10.1.6 
Clinical Monitoring ............................................................................................................................. 44 
10.1.7 
Quality Assurance and Quality Control............................................................................................... 44 
10.1.8 
Data Handling and Record Keeping .................................................................................................... 45 
10.1.8.1 
Data Collection and Management Responsibilities .............................................................................. 45 
10.1.9 
Study Records Retention ...................................................................................................................... 46 
10.1.10 
Protocol Deviations ......................................................................................................................... 46 
10.1.11 
Insurance ......................................................................................................................................... 46 
10.1.12 
Publication and Data Sharing Policy .............................................................................................. 47 
10.1.13 
Conflict of Interest Policy ................................................................................................................ 48 
10.2 
ABBREVIATIONS ........................................................................................................................................... 49 
11 
REFERENCES ....................................................................................................................................... 50 
12 
APPENDICES ......................................................................................................................................... 54 
APPENDIX 1: TOTAL OCULAR SYMPTOMS SCORE (TOSS) ....................................................................................... 54 
 

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AMENDMENT 1 
The main purpose of this amendment is to address concerns raised during review of the study 
protocol by regulatory authorities (BfArM) regarding inclusion/exclusion criteria and the 
conditions requiring temporary interruption or permanent discontinuation of study treatments. The 
following changes to the protocol have been made in light of these requests: 
· Inclusion criterion 3 was modified to clarify that the study will enroll patients scheduled 
for cataract surgery (not yet performed) (Section 5.1). The criterion has been split into two, 
one indicating the inclusion of patients scheduled for surgery (not yet performed), and the 
other stating that only patients who completed surgery without complications will be 
randomized. 
· Exclusion criterion 9, which previously referred to contraindications to ocular treatment 
with levofloxacin, tobramycin or dexamethasone in general terms, now indicates all the 
specific contraindications to study treatments as stated in their respective Summary of 
Product Characteristics (SPC) or Investigator’s Brochure (IB) (Section 5.2). Since the 
warnings and precautions related to study treatments apply to situations that may arise 
following screening, a sub-section has been added to the treatment section of the protocol 
listing all the warnings and precautions as per SPC or IB (Section 6.6). Specific situations 
requiring study treatment discontinuation according to SPC or IB have been added to 
Section 7.1. 
· Exclusion Criterion 11 now states that participation in previous clinical studies is possible 
if at least 5 half-lives of the IMP used in the previous studies have passed between the end 
of treatment in the previous study and the start of treatment in this clinical study. 
· The amendment now states that temporary interruption of study treatment and dose 
modifications are not foreseen in the protocol (Section 7.1). Additional information has 
also been added indicating the conditions for permanent discontinuation. 
The amended protocol also clarifies that testing of visual acuity is to be performed according to 
local practice. Minimum visual acuity of the contralateral eye required for study entry (Exclusion 
criteria 8) has consequently been converted and is now stated using various standards (Section 
5.2). 
Changes to specific sections of the protocol are shown in the track changes version of the protocol 
using strike through red font for deletions and red underline for insertions. 
 
 

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STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and all applicable laws and regulations. The Principal Investigator 
will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the Sponsor and documented approval from the Institutional Review Board (IRB) 
or Independent Ethics Committee (IEC) and/or Competent Authority, except where necessary to 
eliminate an immediate hazard to the trial participants. All personnel involved in the conduct of 
this study have completed ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB/IEC for review and approval. Approval of both the protocol and the 
consent form must be obtained before any participant is enrolled. Any amendment to the protocol 
will require review and approval by the IEC before the changes are implemented. All changes to 
the consent form will be IEC approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent, using a previously approved 
consent form. 
 
 

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1 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Protocol Number 
LevoDesa_04-2017 
EudraCT Number 
2018-000286-36 
Title 
An international, multicenter, randomized, blinded-assessor, parallel-group 
clinical study comparing eye drops of combined LEvofloxAcin + 
DExamethasone foR 7 days followed by dexamethasone alone for an 
additional 7 days vs. tobramycin + dexamethasone for 14 days for the 
prevention and treatment of inflammation and prevention of infection 
associated with cataract surgery in adults – LEADER 7. 
Phase 
III 
Sponsor 
NTC S.r.l. 
International 
Chairman 
Prof. Francesco Bandello, Full Professor of Ophthalmology, Director of 
Clinica Oculistica of the Università Vita-Salute, Istituto Scientifico San 
Raffaele, Milan. 
Investigational sites 
The study will be conducted at approximately 80 centers located in Italy, 
Germany, Spain and Russia. 
Rationale 
In clinical practice, topical treatment following cataract surgery is frequently 
administered using a combination between an antibiotic and a 
corticosteroid to promote patient adherence to therapy and to obtain both 
prevention of infection and treatment of post-surgical inflammation. The 
combination of tobramycin and dexamethasone is among the most widely 
used combinations, but treatment usually lasts for two or more weeks, 
sometimes tapering posology over several weeks afterwards. This 
therapeutic strategy may however be inappropriate in terms of preventing 
the development of bacterial resistance, which is favored by prolonged 
treatment and the use of sub-therapeutic doses. For this reason, antibiotic 
treatment should not be prolonged beyond the time necessary for the 
healing of surgically induced epithelial lesions, and therefore should not last 
more than a week.  
Based on these considerations, a product associating a broad-spectrum 
antibiotic with a highly effective corticosteroid that can be used for a short 
period of time (one week) would be of considerable interest.  
The combination of levofloxacin 0.5% and dexamethasone 0.1% tested in 
this study is the first combination of a steroid and a quinolone under 
development and represents a major step forward in this direction.  
The purpose of this study is to evaluate the efficacy of a combination of 
levofloxacin and dexamethasone by demonstrating that its use for a limited 
time of one week, followed by treatment with dexamethasone alone, is not 
inferior to longer treatment with tobramycin + dexamethasone in 

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preventing and treating ocular inflammation and in preventing post-
operative infection while limiting the emergence of antibiotic resistance. 
Objectives 
Efficacy: to demonstrate the non-inferiority of combined levofloxacin + 
dexamethasone eye drops for 7 days followed by dexamethasone eye drops 
alone for an additional 7 days vs. standard treatment tobramycin + 
dexamethasone eye drops for 14 days in the prevention and treatment of 
postoperative ocular inflammation and prevention of infection. 
Safety and tolerability: 
· To evaluate the safety of combined levofloxacin + dexamethasone 
eye drops. 
· To 
evaluate 
the 
tolerability 
of 
combined 
levofloxacin 
+ 
dexamethasone eye drops. 
Compliance: to evaluate compliance with prescribed treatment. 
Endpoints 
Primary efficacy 
The proportion of patients without signs of anterior ocular chamber 
inflammation (sum of cells and flare score = 0) after 14 days of treatment. 
Secondary efficacy 
· Incidence of endophthalmitis 
· Proportion of patients without signs of anterior ocular chamber 
inflammation after 3 and 7 days of treatment 
· Conjunctival hyperemia after 3, 7 and 14 days of treatment 
· Total Ocular Symptoms Score (TOSS) after 3, 7 and 14 days of 
treatment 
· Ocular pain/discomfort after 3, 7 and 14 days of treatment 
· Use of rescue therapy during treatment 
Safety 
· Intraocular pressure (IOP) 
· Visual acuity 
· Adverse events 
Tolerability 
· Global evaluation 
· Burning, stinging, blurred vision 
Compliance  
· Assessment of patient diary 
Type of study 
This is an international, multicenter, randomized, blinded-assessor, parallel-
group clinical study. The Investigators in charge of evaluating study 
parameters will be blinded to treatment assignment. A separate 
investigational staff will be unblinded and responsible for assigning and 
dispensing/return study products.  
Study Population 
The study will enroll 800 adult male and female patients undergoing 
cataract surgery. 
Inclusion criteria 
Inclusion criteria prior to surgery 

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1. 
Signed written informed consent must be obtained before any 
assessment is performed 
2. 
Male or female, age ≥40 years 
3. 
Scheduled senile or presenile cataract surgery (not yet performed). 
4. 
Willing to interrupt the use of contact lenses for the entire duration of 
the study 
5. 
Able and willing to follow study procedures 
6. 
For females of childbearing potential, the use of highly effective 
contraception and agreement to use such a method during study 
participation 
Inclusion criteria following surgery 
7. 
Surgery completed without complications 
Exclusion criteria 
1. Ocular conditions that at the discretion of the Investigator may 
interfere with the efficacy and/or safety evaluations (e.g. ocular 
herpes, 
blepharitis, 
conjunctivitis, 
uveitis, 
keratitis, 
diabetic 
retinopathy, retinal vein occlusions, retinal vasculitis, retinal 
angiomatous 
proliferation, 
pseudoexfoliation 
syndrome, 
intraoperative floppy iris syndrome, etc.) 
2. Patients undergoing bilateral cataract surgery 
3. 
Patients under treatment with prostaglandin analogues or intravitreal 
injections of anti-VEGF (vascular endothelial growth factor) drugs 
4. 
Systemic diseases that may interfere with the results of the study (e.g. 
rheumatoid arthritis, Sjögren's syndrome, Behçet's disease, systemic 
lupus erythematosus, scleroderma with major ocular involvement, 
etc.)  
5. 
Any condition that could interfere with correct instillation of eye drops 
6. 
Ocular surgery in the study eye (including laser surgery) in the 3 months 
before screening 
7. 
Monocular patients 
8. 
Visual Acuity (VA) < 20/80 of the contralateral eye measured as ETDRS 
or Snellen 20 feet, equal to 0.25 in decimal 
9. 
Contraindication to ocular treatment with Tobradex®, Maxidex® or 
levofloxacin/dexamethasone as follows: 
· Herpes simplex keratitis, vaccinia, varicella and other viral 
diseases of the cornea and conjunctiva 
· Fungal and mycobacterial diseases of ocular structures or 
untreated parasitic eye infections 
· Uncontrolled intraocular hypertension 
· Uncontrolled glaucoma 
Tobradex® is contraindicated also in case of untreated purulent 
infections of the eye, whereas Maxidex® is contraindicated in acute, 
untreated bacterial infections. 
10. Hypersensitivity to the products or their excipients 
11. Participation in other clinical studies if at least 5 half-lives of the IMP 
used in the previous studies have not passed between the end of 
treatment in the previous study and the start of treatment in this 
clinical study. 

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12. Pregnancy or breastfeeding 
Study drugs 
Test arm: levofloxacin + dexamethasone ophthalmic solution containing 
levofloxacin hemihydrate 5.12 mg/ml, corresponding to 5 mg/ml 
levofloxacin + dexamethasone 21-phosphate 1.32 mg/ml, corresponding to 
dexamethasone 1 mg/ml for 7 days, 1 drop - 4 times a day, followed by 
dexamethasone ophthalmic suspension 1.0 mg/ml (Maxidex®) for an 
additional 7 days, 1 drop - 4 times a day. 
Control arm: tobramycin + dexamethasone ophthalmic suspension 
containing tobramycin 3 mg/ml + dexamethasone 1 mg/ml (Tobradex®) for 
14 days, 1 drop - 4 times a day. 
Study procedures 
Patients scheduled for cataract surgery who have provided written 
informed consent will undergo screening procedures to verify eligibility. 
Immediately following phacoemulsification performed by an experienced 
surgeon, patients who complete surgery without complications will be 
assigned to one of the following two treatment groups in a 1:1 ratio 
according to a randomization list stratified by center:  
v Study arm: levofloxacin + dexamethasone eye drops for 7 days 
followed by dexamethasone eye drops (Maxidex®) for another 7 days. 
v Control arm: tobramycin + dexamethasone eye drops (Tobradex®) for 
14 days. 
Treatment will begin either immediately after randomization according to 
local routine clinical practice (in those patients who are not bandaged after 
surgery), or immediately after removal of dressing of operated eye. Doses 
administered on the same day as surgery will be considered additional to 
the full protocol dosage regimen (4 instillations per day for 14 days). 
Patients will be given a diary on which to record times of instillation. Diaries 
will be collected to evaluate compliance with treatment.  
After surgery, patients will undergo visits on Day 4, Day 8 and Day 15 (end 
of study) to evaluate efficacy, safety and tolerability.  
Sample size 
The study plans to enroll 800 patients: 400 patients will be assigned to the 
test treatment and 400 to standard treatment. 
A sample size of 362 patients in each group is required to assess the non-
inferiority of the test treatment vs. the standard therapy (i.e. lower limit of 
the 95% Confidence Interval of the difference in proportions, πT - πS > -0.10) 
with 80% power and by applying a two-group large-sample normal 
approximation test of proportions with a one-sided 0.025 significance level, 
assuming that the expected difference in proportions is 0 and the 
proportion in the standard group is 0.64.  
The total sample size (362 + 362 = 724) is adjusted to 800 patients 
considering an expected dropout rate of about 10% using Freedman’s 
formula: n’= 100*n/100-x, where x is the expected dropout rate. 
Statistics 
Primary endpoint: The proportion of patients without signs of anterior 
chamber inflammation (sum of cells and flare score = 0) after 14 days of 
treatment will be calculated to evaluate the non-inferiority of the test 
treatment vs. the standard therapy. Non-inferiority will be assessed by 
computing the two-tailed 95% confidence interval (CI) of the difference 

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between the two proportions pT - pS. Non-inferiority is met if the 95% CI 
does not cross the predefined non-inferiority margin Δ = -0.10 and lies 
entirely to the right of the margin (i.e. non-inferiority will be demonstrated 
if the lower bound of the two-sided 95% CI of the difference is > -0.10).  
If the 95% CI of the difference lies completely to the right of 0, the test 
treatment can be considered more effective than the standard treatment at 
a 5% significance level. 
Secondary endpoints: Descriptive statistics and two-sided 95% CIs of the 
difference between treatments will be computed for the secondary 
endpoints. 
Duration of the study 
Estimated date of the first visit of the first patient (FPFV): Q3, 2018 
Estimated date of the first visit of the last patient (LPFV): Q1, 2019 
Estimated date of the last visit of the last patient (LPLV): Q1, 2019 
Participant Duration 
The study, for each patient, will last 14 days following cataract surgery. 
Version and Date 
V 2.0 – 12 July 2018 

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12 July 2018 
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1.2 
STUDY DESIGN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Levo/Dex=levofloxacin/dexamethasone 
Dex=dexamethasone 
Tobra/Dex=tobramycin/dexamethasone 
* Treatment begins either immediately after randomization in patients not bandaged after surgery, or immediately after removal of eye dressing  
 
Tobra/Dex 
Levo/Dex 
Dex 
Start 
Treatment* 
Day 8 
Day 15 
Surgery and 
Randomization 
Screening 
≤28 days 
Day 4 
Day 0 

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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
 
Visit 1 
Screeninga 
-28 days max 
Visit 2 
Surgery 
Visit 3 
Day 4 
Visit 4 
Day 8 
Visit 5 
Day 15 (EOS) 
Signed written 
informed consent 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
Urine pregnancy testb 
 
X 
 
 
 
Surgery 
 
X 
 
 
 
Randomizationc 
 
X 
 
 
 
Dispensation of 
treatment and diary 
 
X 
 
Xf 
 
Slit lamp examinationd  
X 
 
X 
X 
X 
TOSS 
 
 
X 
X 
X 
Diagnosis of 
endophthalmitis 
 
 
X 
X 
X 
Ocular pain and 
discomfort 
 
 
X 
X 
X 
Use of rescue therapy 
 
 
X 
X 
X 
Intraocular pressure 
X 
 
X 
X 
X 
Visual acuity 
(as per local practice) 
X 
 
 
 
X 
Local tolerabilitye 
 
 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Return of treatment 
 
 
 
X 
X 
Return of 
diary/compliance 
 
 
X 
X 
X 
TOSS = Total Ocular Symptoms Score; EOS = End of Study 
Additional visits may be scheduled in case of patient need. 
a Screening to be performed not more than 28 days prior to surgery 
b A urine pregnancy test (dipstick) is required for women of childbearing potential. 
c Patients who complete surgery without complications will be randomized immediately after surgery. 
d Slit lamp examination of anterior chamber: cells score and aqueous flare (Tyndall effect) score; assessment of 
conjunctival hyperemia. 
e Global evaluation on a 4-point scale. Burning, stinging, blurred vision on a 4-point scale. 
f Second period of treatment will start after drug dispensation at Day 8 
 
 

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2 
INTRODUCTION 
 
2.1 STUDY RATIONALE  
In clinical practice, topical treatment following cataract surgery is frequently administered using a 
combination between an antibiotic and a corticosteroid to promote patient adherence to therapy 
and to obtain both the prevention of infection and the treatment of post-surgical inflammation. The 
combination of tobramycin and dexamethasone is among the most widely used combinations, but 
treatment usually lasts for two or more weeks, sometimes tapering posology over several weeks. 
This therapeutic strategy may however be inappropriate in terms of preventing the development 
of bacterial resistance, which is favored by prolonged treatment and the use of sub-therapeutic 
doses. For this reason, antibiotic treatment should not be prolonged beyond the time necessary for 
the healing of surgically induced epithelial lesions, and therefore should not last more than a week. 
Based on these considerations, a product associating a broad-spectrum antibiotic with a highly 
effective corticosteroid that can be used for a short period of time (one week) would be of 
considerable interest.  
The combination of levofloxacin and dexamethasone tested in this study is the first combination 
of a quinolone and a steroid under development and represents a major step forward in this 
direction. Levofloxacin 0.5% + dexamethasone 0.1% ophthalmic solution is an antibiotic/anti- 
inflammatory combination indicated for the treatment of inflammatory ocular conditions, where 
bacterial ocular infection or a risk of bacterial ocular infection exists. The active components of 
this combination are currently available in marketed ophthalmic products.  
The purpose of this study is to evaluate the efficacy of a combination between levofloxacin and 
dexamethasone by demonstrating that the short-term use of this combination for a limited time of 
one week, followed by treatment with dexamethasone alone, is not inferior to longer treatment 
with 
tobramycin 
+ 
dexamethasone 
in 
reducing 
the 
incidence 
of 
post-operative 
inflammation/infections while limiting emergence of antibiotic resistance. 
2.2 BACKGROUND 
Cataract is an ocular condition that causes vision impairment due to changes in opacity of the 
ocular lens. Cataract is an age-related condition, but smoking, ocular trauma, exposure to 
ultraviolet light, diabetes and drug-induced metabolic changes in the lens are risk factors for lens 
opacification causing cataract.1  
The only cure for cataract is a surgical procedure: the opaque lens is removed and replaced with 
an artificial intraocular lens.2, 3 Nowadays, the surgical procedure of choice is phacoemulsification 
with intraocular lens implantation.4 The technique, initially developed in 1967, is based on high-
energy ultrasound to emulsify the cataractous lens nucleus, with the fragments being subsequently 
aspirated with an ultrasound probe. The corneal incision required for this technique is much 

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smaller (3 mm or less) than the limbal incision (usually an 11-mm incision between cornea and 
sclera) used in the past to remove the entire lens.2 
As the surgical procedure has become less invasive, patients usually no longer require in-patient 
hospital care after surgery, with recovery usually uneventful and pain-free. Cataract surgery may 
however cause corneal trauma, ocular inflammation and ocular dryness, which can result in ocular 
irritation during the recovery period.5-7 These conditions may cause different types of ocular 
discomfort such as pain, burning, stinging, foreign body sensation, itchiness and glare in the 
operated eye. The incidence of ocular irritation symptoms experienced during the first 
postoperative hours may be as high as 98%.8 
Conjunctival hyperemia, anterior chamber cells and flare, and cystoid macular edema are some 
possible signs of inflammation after cataract surgery.9 The severity of the inflammation varies 
from patient to patient. In many cases, inflammation is self-limiting, but drug therapy is used to 
shorten resolution time and alleviate ocular discomfort.10 
Steroidal agents and non-steroidal anti-inflammatory drugs (NSAIDs) are used to prevent and treat 
postoperative inflammation occurring after surgery. Corticosteroids inhibit the lipoxygenase 
pathway leading to the leukotriene production and thus reduce tissue swelling and prevent 
edema.9,11 They have been used for decades to prevent ocular inflammation and many ophthalmic 
surgeons prefer a 1 to 6-week period of topical corticosteroids after cataract surgery.  
According to the practice pattern studies published by the ASCRS (American Society of Cataract 
Refractive Surgery 2012, practice pattern study), Canadian Ophthalmological Society study 201212 
and European Society of Cataract and Refractive Surgeons (ESCRS), there are variations in 
postoperative drug therapy provided to individual patients and among different countries. In 
Europe, dexamethasone was the most commonly used steroidal anti-inflammatory drug and was 
chosen as the preferred drug by 71% of ophthalmological surgeons.13 
Endophthalmitis is a rare yet severe condition that occurs in 0.03–0.3% of patients undergoing 
cataract surgery.14,15 Endophthalmitis is a vision-threatening complication of cataract surgery. 
Swollen eyelids, ocular pain, conjunctival hyperemia, decreased visual acuity, anterior chamber 
cells and an opaque vitreous are signs of endophthalmitis. This condition usually appears during 
the first days after surgery, and in 80% of cases endophthalmitis will have developed during the 
first 6 weeks after surgery.15,16 
Topically applied antibiotics are routinely used for the prophylaxis of postoperative bacterial 
ocular infections such as endophthalmitis. Intraocular, usually intracameral, or subconjunctival, 
antibiotics are used during surgery, and both pre- and postoperative topical applications are also 
provided.14  
To increase the efficacy of this approach, a broad antibacterial spectrum antibiotic should be 
chosen. A prospective observational study was conducted to determine the antibiotic susceptibility 
patterns of conjunctival bacterial flora isolated preoperatively from patients undergoing anterior 

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segment surgery. Conjunctival cultures were obtained from 120 eyes on the day of surgery before 
povidone-iodine or antibiotic application. Bacterial isolates were identified and tested for 
antibiotic susceptibility. Of these 120 eyes, 21 (18%) showed no bacterial growth. Of the 143 
bacterial strains isolated from the remaining 99 eyes, 112 (78%) were coagulase-negative 
staphylococci (CNS). Among the CNS, greater than 90% were susceptible to cefotaxime, 
levofloxacin, imipenem, meropenem, vancomycin, and each of the aminoglycosides except 
neomycin. Between 70% and 90% of the CNS were susceptible to cefazolin, neomycin, 
ciprofloxacin, ofloxacin, norfloxacin, and chloramphenicol. Less than 70% of the isolated CNS 
were sensitive to the penicillin analogues, ceftazidime, erythromycin, and tetracycline.17  
Based on the previously mentioned results, quinolones clearly represent a rational approach to the 
prevention of ocular infections after cataract surgery. Indeed, among available antibiotics for 
ophthalmic use, quinolones are characterized by a broad spectrum that includes both the Gram-
positive and Gram-negative bacteria that are most frequently responsible for ocular bacterial 
infections. 
Levofloxacin belongs to the class of quinolones. The mechanism of action of levofloxacin and 
other fluoroquinolone consists in the inhibition of bacterial topoisomerase IV and DNA gyrase, 
enzymes required for DNA replication, transcription, repair and recombination.18,19 
The spectrum of activity against ocular pathogens includes aerobic Gram-positive microorganisms 
(S. aureus MSSA, S. pyogenes, S. pneumoniae, viridans group streptococci), aerobic Gram-
negative bacteria (E. coli, H. influenzae, P. aeruginosa commonly isolates) and other organisms 
(e.g. Chlamydia trachomatis). Caution should be taken for Methicillin-resistant Staphylococcus 
Aureus (MRSA), S. epidermidis and P. aeruginosa hospital isolates, due to possible acquired 
resistance19. Literature data confirm that resistance is not common for levofloxacin, which is active 
against several fluoroquinolone or other antibiotic-resistant strains, but cross-resistance with other 
fluoroquinolones cannot be ruled out.19  
A prospective, randomized, controlled trial compared the efficacy of topical levofloxacin in 
combination with povidone iodine irrigation vs. povidone iodine alone in reducing conjunctival 
bacteria. The authors concluded that the study showed an enhancing effect of using topical 
levofloxacin in combination with povidone irrigation in reducing conjunctival bacteria in patients 
undergoing intraocular surgery.20 
Results from a retrospective, 10-year review of all cases with culture-proven endophthalmitis at a 
single institute revealed that susceptibility of the most common organisms to levofloxacin was 
58.5% for gram-positive organisms and 100% for gram-negatives. No single antibiotic provided 
coverage for all the microbes isolated.21 
A prospective observational study of consecutive cases of patients registered from April 2006 to 
March 2007 to have a routine conjunctival culture was carried out before cataract operation. This 
study documents the resistance of conjunctival bacteria of patients undergoing cataract surgery to 
the most common antibiotics. The authors concluded that none of the antibiotics tested, including 

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cefuroxime and levofloxacin, was active against all isolated conjunctival bacteria. Based on the 
resistance patterns and other prophylactic effects, two phases of local prophylaxis were suggested: 
first, eliminating Staphylococci and respiratory bacteria with rifampicin or chloramphenicol 
preoperatively; second, giving levofloxacin from 1 h before surgery until 6 days afterwards to 
eradicate the small quantity of Enterococci and Gram-negative rods since the visual outcome of 
the post-surgical endophthalmitis cases caused by these bacteria was the most serious.22,23 
When comparing the efficacy of quinolones in bacterial conjunctivitis, levofloxacin (third 
generation) eye drops showed significantly greater microbial eradication rates than ofloxacin24 
(second generation), and very similar efficacy when compared to gatifloxacin25 and moxifloxacin 
(fourth generation)26. 
In most cases, postoperative care after cataract surgery consists of topical anti-inflammatory and 
antibacterial drug therapy. The combined administration of corticosteroids and antibiotics 
guarantees a powerful anti-inflammatory effect, and contemporarily a preventive/therapeutic 
action against infections related either to the intensity of the inflammatory process or to the 
immunosuppressive effect of the steroid. Combined administration also favors the proper 
administration of the two agents, reduces the possibility of inaccurate dosage and improves patient 
compliance with medication.  
However, use of such a combination should also be in line with the modern approach to 
antimicrobial therapy aimed at avoiding the increase of bacterial resistance caused by 
inappropriate use of the antibiotic.27 ESCRS guidelines emphasize the importance of rational use 
especially when a broad-spectrum antibiotic is used.28 
Among the most widely used combination is the one between tobramycin and dexamethasone, 
whose administration usually lasts for two or more weeks, sometimes tapering posology over 
several weeks. Tapering is however inappropriate in terms of preventing the development of 
bacterial resistance, which is favored by prolonged treatment and the use of sub-therapeutic doses.  
For this reason, antibiotic treatment should not be prolonged beyond the time necessary for the 
healing of surgically induced epithelial lesions, and therefore should not last more than a week.29 
The confirmation that non-rational therapeutic practice remains widespread comes from a recent 
study on the adherence of some Italian ophthalmology centers to the recommendations of the 
ESCRS Guidelines. This study has shown that topical postoperative treatment is used in 100% of 
the centers and that in more than half of them treatment is continued for two or more weeks. In 
most cases, the antibiotic is administered using corticosteroid combinations, and in one third of 
the cases dosage is tapered over a few weeks. The study divided the participating centers according 
to the incidence of endophthalmitis in two groups (one with incidence < 0.13 per thousand, the 
other with incidence > 0.13 per thousand) and observed that in the group with lower incidence of 
infections, centers that prescribe topical post-operative antibiotic for one week and do not taper 
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Based on these considerations, there is a clear interest in having a combination between a broad-
spectrum antibiotic and a highly effective corticosteroid to be used for a short period, followed by 
treatment with corticosteroid alone. The combination of levofloxacin and dexamethasone tested in 
this study is the first combination of a quinolone and a steroid under development and represents 
a major step forward in the management of these patients. The therapeutic strategy tested in this 
trial, with the combination of levofloxacin and dexamethasone to be used for just one week 
followed by another week of treatment with dexamethasone alone, is ideal in providing the same 
anti-inflammatory activity as compared to standard therapy while doing away with the tapering 
routinely adopted at present. This approach is in line with more recent guidelines issued by 
scientific societies and health organizations in terms of preventing antibiotic resistance.31, 32  
The combination of levofloxacin 5 mg/ml and dexamethasone 1 mg/ml is a new fixed dose 
combination of an antibiotic, levofloxacin 5 mg/ml, and a corticosteroid, dexamethasone sodium 
phosphate, corresponding to dexamethasone 1 mg/ml.  
The concentration of dexamethasone (1 mg/ml) is well established in ophthalmic solutions both as 
sole active ingredient and in combination with an antibiotic (e.g. tobramycin) to prevent ocular 
inflammation following cataract surgery. The penetration of this agent from 0.1% solutions in the 
aqueous humor is adequate to exert its potent anti-inflammatory activity at the site of action.33 The 
dexamethasone 21-phosphate salt is freely soluble in water, allowing its use in water solution. The 
solution does not require shaking before application and guarantees homogeneity of content of the 
active ingredient at each application.  
Dexamethasone is considered the gold standard in the management of postoperative ocular 
inflammation and constitutes the reference treatment of controlled studies on new drugs or 
treatments in development. 
The pharmacokinetics of both levofloxacin and dexamethasone confirm that after application to 
the eye in the form of eye drop solution, both active drugs reach high concentrations in the aqueous 
humor, with a peak of aqueous levels between 90 and 150 minutes, and detectable concentrations 
after 12 hours from dosing.33-38 Conversely, the concentrations in plasma are negligible, 
guaranteeing a lack of systemic effects at least during the short course treatment in this study. The 
best dosage schedule indicated in literature on the pharmacokinetics of both ingredients is every 6 
hours.24, 39 
The purpose of this study is to demonstrate that the use of a combination of levofloxacin and 
dexamethasone for a limited time of one week, followed by treatment with corticosteroid alone, is 
not inferior in preventing or reducing post-operative inflammation and preventing post-operative 
infections as compared to a two-week treatment with a combination of tobramycin and 
dexamethasone, while being in line with the most recent guidelines issued by scientific societies 
and health organizations in terms of preventing antibiotic resistance. 
 

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2.3 RISK/BENEFIT ASSESSMENT   
 
2.3.1 
KNOWN POTENTIAL RISKS  
In toxicity studies, the only toxicity data reported for dexamethasone were those related to an 
exaggerated pharmacological activity including a negative feedback on the pituitary-adrenal axis. 
Systemic effects are however not expected or are negligible when the drug is topically 
administered as eye drops and for a limited period. Nevertheless, its potential effect on fetal 
development and on newborns suggests it be used very carefully in pregnant women and to discard 
the milk during lactation.40,41 
Possible adverse effects of topical ocular corticosteroid therapy include an increase of intraocular 
pressure (IOP), inhibition of corneal wound healing and increased likelihood of infection and 
serious complications, but systemic adverse effects are rare.9,10 
Levofloxacin is not toxic on reproduction and does not have mutagenic or carcinogenic potential. 
It is not irritating after eye instillation, but it is phototoxic at very high doses and photosensitization 
cannot be excluded.19,42 Patients should therefore not be exposed to direct sunlight during treatment 
with eye drops containing levofloxacin.  
In clinical studies involving over 1600 patients, no serious ophthalmic or systemic adverse 
reactions were reported for the combination of tobramycin + dexamethasone (Tobradex®), 
comparator drug for this study. The most frequently reported adverse reactions were eye pain, 
increased intraocular pressure, eye irritation (burning upon instillation) and eye pruritus occurring 
in less than 1% of patients.43 
2.3.2 
KNOWN POTENTIAL BENEFITS  
The efficacy of dexamethasone as an anti-inflammatory agent and of levofloxacin as antibiotic in 
ophthalmology is well established. Combining the two agents would favor their proper 
administration, reduce the possibility of inaccurate dosage and improve patient compliance.  
The combination would also allow the implementation of a shorter antibiotic treatment period as 
compared to other marketed products and thus prevent the emergence of antibiotic resistance.  
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
In light of the considerations stated above, the potential benefits of this study surely appear to 
outweigh the potential risks. 
 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS  
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Efficacy 
To demonstrate the non-inferiority 
of combined levofloxacin + 
dexamethasone eye drops for 7 days 
followed by dexamethasone eye 
drops alone for an additional 7 days 
vs. standard treatment tobramycin + 
dexamethasone eye drops for 14 
days in the prevention and 
treatment of postoperative ocular 
inflammation and prevention of 
infection. 
 
Primary endpoint 
The proportion of patients without 
signs of anterior chamber inflammation 
(sum of cells and flare score = 0) after 
14 days of treatment 
Secondary endpoints 
· 
Incidence of endophthalmitis  
· 
Proportion of patients without 
signs of anterior ocular chamber 
inflammation after 3 and 7 days of 
treatment 
· 
Conjunctival hyperemia after 3, 7 
and 14 days of treatment 
· 
Total Ocular Symptoms Score 
(TOSS) after 3, 7 and 14 days of 
treatment 
· 
Ocular pain/discomfort after 3, 7 
and 14 days of treatment 
· 
Use of rescue therapy during 
treatment 
The endpoints are 
considered suitable for 
evaluating ocular 
inflammation and 
infection following 
cataract surgery.  
Safety and tolerability 
To evaluate the safety of combined 
levofloxacin – dexamethasone eye 
drops. 
· 
Intraocular pressure (IOP) 
· 
Visual acuity 
· 
Adverse events 
The safety endpoints 
are considered 
standard for the 
indication and for the 
drugs under study. 
To evaluate the tolerability of 
combined levofloxacin – 
dexamethasone eye drops. 
· 
Global evaluation 
· 
Burning, stinging, blurred vision 
 
The endpoints are 
considered suitable for 
evaluating the 
tolerability of an 
ophthalmic product.  
Compliance 
To evaluate compliance with 
prescribed treatment. 
· 
Assessment of patient diary 
 
 
 
 
 
 
 

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4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
This is an international, multicenter, phase III, randomized, blinded-assessor, parallel-group 
clinical study to evaluate the non-inferiority of the test treatment vs. standard treatment. The 
Investigator in charge of evaluating study parameters will be blinded to treatment assignment. A 
separate investigational staff will be unblinded and responsible for assigning and dispensing/return 
study products.  
Patients scheduled for cataract surgery who have provided written informed consent will undergo 
screening procedures. Immediately following phacoemulsification performed by an experienced 
surgeon, patients who complete surgery without complications will be assigned to one of the 
following two treatment groups in a 1:1 ratio according to a randomization done by IWRS stratified 
by center:  
v Test arm 
· Levofloxacin + dexamethasone eye drops for 7 days, followed by dexamethasone eye drops 
(Maxidex®) for an additional 7 days. 
v Control arm 
· Tobramycin + dexamethasone eye drops (Tobradex®) for 14 days. 
Treatment will begin immediately or after removal of dressing of the operated eye. Doses 
administered on the same day as surgery will be considered additional to the full protocol dosage 
regimen (4 instillations per day for 14 days). 
Patients will be given a diary on which to record times of instillation. Diaries will be collected to 
evaluate compliance with treatment.  
After surgery, patients will undergo visits on Day 4, Day 8 and Day 15 (end of study) to evaluate 
efficacy, safety and tolerability.  
The study will be conducted at approximately 80 centers located in Italy, Germany, Spain and 
Russia and will enroll 800 patients. 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The combination of tobramycin and dexamethasone has been chosen as control treatment since it 
is the most commonly used fixed combination in ophthalmology in both Europe and the U.S. As 
the primary efficacy endpoint of the study is related to the prevention and resolution of ocular 
inflammation, and given that the anti-inflammatory component of the test and control 

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combinations is the same (dexamethasone 1 mg/ml), a non-inferiority design was deemed 
appropriate for this study. In fact, the study aims to demonstrate that levofloxacin 5 mg/ml + 
dexamethasone 1 mg/ml eye drops is at least as effective as the control treatment in terms of anti-
inflammatory effect, while offering significant advantages such as the possibility of administering 
a proven, effective, broad-spectrum antibiotic for a shorter treatment period, thereby reducing the 
risk of developing antibiotic resistance. 
A blinded-assessor design was chosen because particularly suitable for studies involving the 
topical administration of the drug to be tested when a double-blinded design is not feasible. 
Furthermore, compared to the double-dummy methodology, the blinded-assessor design has the 
advantage of not having to administer both active drug and placebo, which can cause dilution of 
the active test drug or control and an increase of clearance from the site of action. 
4.3 JUSTIFICATION FOR DOSE 
The concentration of dexamethasone (1 mg/ml) and dose (1 drop, 4 times a day) in both the test 
and standard combinations is well established in ophthalmic solutions, both as sole active 
ingredient or in combination with an antibiotic. Levofloxacin is also well established as sole active 
ingredient of ophthalmic solutions at a concentration of 5 mg/ml and at a dose of 1 drop, 4 times 
a day. 
Tobradex® will be administered as per label. 
4.4 END OF STUDY DEFINITION 
A participant is considered as having completed the study if he or she has completed all phases of 
the study including the last visit as indicated in the Schedule of Activities (SoA), Section 1.3. 
The end of the study is defined as completion of the last visit as shown in the SoA in the trial 
globally. 
5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
To be eligible to participate in this study, a subject must meet all the following criteria: 
5.1.1 
INCLUSION CRITERIA PRIOR TO SURGERY 
1. Signed written informed consent must be obtained before any assessment is performed 
2. Male or female, age ≥40 years 
3. Scheduled senile or presenile cataract surgery (not yet performed). 
4. Willing to interrupt the use of contact lenses for the entire duration of the study 

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5. Able and willing to follow study procedures 
6. Female patients must be postmenopausal (24 months of amenorrhea), surgically sterile or 
must agree to use an effective method of contraception, which include an established 
hormonal therapy or intrauterine device for females, and the use of a barrier contraceptive 
(i.e. diaphragm or condoms) with spermicide. 
5.1.2 
INCLUSION CRITERIA FOLLOWING SURGERY 
7. Surgery completed without complications 
5.2 EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Ocular conditions that at the discretion of the Investigator may interfere with the efficacy 
and/or safety evaluations (e.g. ocular herpes, blepharitis, conjunctivitis, uveitis, keratitis, 
diabetic retinopathy, retinal vein occlusions, retinal vasculitis, retinal angiomatous 
proliferation, pseudoexfoliation syndrome, intraoperative floppy iris syndrome, etc.) 
2. Patients undergoing bilateral cataract surgery 
3. Patients under treatment with prostaglandin analogues or intravitreal injections of anti-
VEGF (vascular endothelial growth factor) drugs 
4. Systemic diseases that may interfere with the results of the study (e.g. rheumatoid arthritis, 
Sjögren's syndrome, Behçet's disease, systemic lupus erythematosus, scleroderma with 
major ocular involvement, etc.) 
5. Any condition that could interfere with correct instillation of eye drops   
6. Ocular surgery in the study eye (including laser surgery) in the 3 months before screening 
7. Monocular patients 
8.  Visual Acuity (VA) < 20/80 of the contralateral eye measured as ETDRS or Snellen 20 
feet, equal to 0.25 in decimal 
9. Contraindications 
to 
ocular 
treatment 
with 
Tobradex®, 
Maxidex® 
or 
levofloxacin/dexamethasone as follows: 
· Herpes simplex keratitis, vaccinia, varicella and other viral diseases of the cornea 
and conjunctiva 
· Fungal and mycobacterial diseases of ocular structures or untreated parasitic eye 
infections 
· Uncontrolled intraocular hypertension 
· Uncontrolled glaucoma 
Tobradex® is contraindicated also in case of untreated purulent infection of the eye, 
whereas Maxidex® is contraindicated in acute, untreated bacterial infections. 
10. Hypersensitivity to the study product or its excipients 

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11. Participation in other clinical studies if at least 5 half-lives of the IMP used in the previous 
studies have not passed between the end of treatment in the previous study and the start of 
treatment in this clinical study. 
12. Pregnancy or breastfeeding 
5.3 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention. A minimal set of data about screen 
failure patients is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
5.4 STRATEGIES FOR RECRUITMENT AND RETENTION 
This study will enroll subjects already scheduled for cataract surgery and no other recruitment 
strategies are required. 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
The study drugs for the two treatment arms are as follow: 
· Test arm: levofloxacin + dexamethasone ophthalmic solution followed by dexamethasone 
ophthalmic suspension (Maxidex®) 
· Control arm: tobramycin + dexamethasone ophthalmic suspension (Tobradex®) 
6.1.2 
DOSING AND ADMINISTRATION 
v Test arm 
· Levofloxacin + dexamethasone eye drops for 7 days, 1 drop - 4 times a day (hours 8.00, 
13.00, 18.00 and 23.00 ± 30 minutes), followed by dexamethasone eye drops alone 
(Maxidex®) for an additional 7 days, 1 drop - 4 times a day (hours 8.00, 13.00, 18.00 and 
23.00 ± 30 minutes). 
v Control arm 
· Tobramycin + dexamethasone eye drops (Tobradex®) for 14 days, 1 drop - 4 times a day 
(hours 8.00, 13.00, 18.00 and 23.00 ± 30 minutes). 

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In both arms, patients will start treatment according to local routine clinical practice, i.e. either 
immediately after randomization in those patients who are not bandaged after surgery, or soon 
after removal of dressing of operated eye. Doses administered on the same day as surgery will be 
considered additional to the full protocol dosage regimen (4 instillations per day for 14 days). 
6.1.2.1 
MISSED DOSES 
If one dose of study treatments is missed, the patient should get in touch with the unblinded site 
staff and get advice on how to continue treatment. If this is not possible, the following approach 
should be implemented: if time to next dose is more than 2.5 hours, medication should be taken as 
soon as possible. If time to next dose is less than 2.5 hours, the patient should wait until it is time 
to apply the next dose.  
Missing more than one dose per day or more than three doses per week will be considered a major 
deviation from the protocol. 
The patient must be instructed to indicate the doses not applied and the reason in the diary 
accurately. 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
Study drugs will be provided by the Sponsor. Upon arrival of investigational products at the site, 
the pharmacist and/or unblinded staff should check them for any damage and verify their proper 
identity, quantity, integrity of seals and report any deviations. Upon receipt, all study treatments 
must be stored according to the label instructions in a secured location. Unblinded site staff 
designated by the Principal Investigator, will maintain accurate records of the product’s delivery 
to the study site, the inventory at the site, the use by each subject (compliance will be verified 
through patient diaries) and the return to the Sponsor or alternative disposition of unused products. 
Monitoring of drug inventory will be performed by the field monitor during the study conduct and 
a copy of the reconciliation log will be provided by the investigators at the completion of the study. 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
Test arm 
· Levofloxacin 5 mg/ml – dexamethasone 1 mg/ml eye drops 
Composition in active ingredients: levofloxacin hemihydrate 5.12 mg/ml, corresponding to 5 
mg/ml, and dexamethasone 21-phosphate 1.32 mg/ml, corresponding to dexamethasone 1 mg/ml. 

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The Investigational Medicinal Product (IMP) is a sterile ophthalmic, clear, greenish-yellow 
isotonic solution with a pH of 7.2. The finished product is packaged in a 5 ml light-resistant LDPE 
bottle with ophthalmic dropper and PP screw cap. 
· Dexamethasone 1 mg/ml eye drops suspension (Maxidex®) 
Control arm 
· Tobramycin 3 mg/ml + dexamethasone 1 mg/ml eye drops suspension (Tobradex®). 
Each treatment kit contains two boxes. Each box contains one bottle of eye drops. Kit boxes 
assigned to patients in the levofloxacin + dexamethasone arm will contain one packaged bottle of 
levofloxacin + dexamethasone eye drops and one packaged bottle of dexamethasone eye drops 
(Maxidex®), whereas kits assigned to patients in the tobramycin + dexamethasone arm will contain 
two packaged bottles of tobramycin + dexamethasone eye drops (Tobradex®). Patients will be 
given one packaged bottle of eye drops upon randomization following surgery and the other one 
at the visit on day 8 of the study. 
Medication labels will comply with legal requirements and will be printed in the local language.  
6.2.3 
PRODUCT STORAGE AND STABILITY 
All study drugs (Tobradex®, Maxidex® and Levofloxacin 5 mg/ml – dexamethasone 1 mg/ml eye 
drops) are to be stored at room temperature not higher than 25o C, not frozen and not refrigerated. 
6.2.4 
PREPARATION 
Study treatments are ready for use and do not require preparation. 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This is a randomized, blinded-assessor study. Patients will be assigned to one of the two following 
treatment groups in 1:1 ratio according to a randomization list stratified by center:  
· Test arm: levofloxacin + dexamethasone ophthalmic solution for 7 days followed by 
dexamethasone ophthalmic suspension (Maxidex®) alone for an additional 7 days 
· Control arm: tobramycin 3 mg/ml + dexamethasone 1 mg/ml (Tobradex®) ophthalmic 
suspension for 14 days 
The randomization numbers will be generated using procedures that ensure that treatment 
assignment is unbiased. A patient randomization list will be produced using a validated system 
that automates the assignment of randomization numbers. 
Patients who fulfill all inclusion criteria and none of the exclusion criteria will be randomized 
following surgery via an Interactive Web Response System (IWRS) that will assign the patient a 

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randomization number linked to a treatment arm. Unblinded staff is to use the IWRS to obtain the 
study treatment to be given to the patient. 
The physician in charge of assessing study parameters will be blinded to treatment assignment 
(blinded assessor). The blinded assessor will not have access to the randomization page of the 
eCRF. A separate investigational staff will be unblinded and responsible for assigning and 
dispensing/return study products. Study treatment will be dispensed upon randomization and on 
Day 8. 
6.4 STUDY INTERVENTION COMPLIANCE 
Compliance will be evaluated through the patient diary, in which the subject is to record all 
treatment administrations. 
6.5 CONCOMITANT THERAPY 
Medications to be reported in the electronic Case Report Form (eCRF) are concomitant 
prescription medications, over-the-counter medications and supplements. The use of concomitant 
medications is to be recorded at each visit. 
6.5.1 
PROHIBITED CONCOMITANT THERAPY 
The following treatments are not permitted: 
· Topical antibiotics 
· Systemic antibiotics for prophylactic purposes  
· Topical or systemic steroids 
6.5.2 
RESCUE THERAPY 
Rescue therapy is defined as the introduction or dose modification of any local or systemic non-
randomized medication required to manage the emergence or worsening of ocular inflammation 
and or infection. 
The name and dosage regimen of the rescue medication as well as the date and time of 
administration must be recorded in the eCRF. 
6.6 WARNINGS AND PRECAUTIONS RELATED TO STUDY TREATMENTS 
The 
warnings 
and 
precautions 
related 
to 
the 
use 
Tobradex®, 
Maxidex® 
and 
levofloxacin/dexamethasone as stated in their respective SPCs/IB are listed in the tables below: 
 
 

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Tobradex® 
Both topical corticosteroids and NSAIDs may slow corneal healing. Caution is therefore advised 
when using topical dexamethasone and topical NSAIDs concomitantly. 
Prolonged use of topical ophthalmic corticosteroids (i.e. longer than the maximum duration used 
in clinical trials [24 days]) may result in ocular hypertension/glaucoma with resultant damage 
to the optic nerve and reduced visual acuity and visual fields defects. It is advisable that 
intraocular pressure be checked frequently. The risk of corticosteroid-induced raised intraocular 
pressure is increased in predisposed patients (e.g. diabetes). 
Corticosteroids can reduce resistance to bacterial, viral, fungal, or parasitic infections and 
promote their development and mask clinical signs of an infection. 
Sensitivity to topically administered aminoglycosides may occur in some patients. Severity of 
hypersensitivity reactions may vary from local effects to generalized reactions such as erythema, 
itching, urticarial, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If 
hypersensitivity develops during use of this medicine, treatment should be discontinued. Cross-
hypersensitivity to other aminoglycosides can occur, and the possibility that patients who 
become sensitized to topical tobramycin may also be sensitive to other topical and/or systemic 
aminoglycosides should be considered. 
Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred 
in patients receiving systemic aminoglycoside therapy. Caution is advised when used 
concomitantly. 
Cushing’s syndrome and/or adrenal suppression associated with systemic absorption of ocular 
dexamethasone may occur after intensive or long-term continuous therapy in predisposed 
patients. In these cases, treatment should be progressively discontinued 
Fungal infection should be suspected in patients with persistent corneal ulceration. If fungal 
infection occurs, corticosteroids therapy should be discontinued. 
Prolonged use of antibiotics may result in overgrowth of non-susceptible organisms, including 
fungi. If superinfection occurs, appropriate therapy should be initiated. 
In those diseases causing thinning of the cornea or sclera, perforations have been known to occur 
with the use of topical corticosteroids. 
Benzalkonium chloride used as a preservative may cause irritation of the eye. 
 
Maxidex® 
Both topical corticosteroids and NSAIDs may slow corneal healing. Caution is therefore advised 
when using topical dexamethasone and topical NSAIDs concomitantly. 
Prolonged use of topical ophthalmic corticosteroids may result in ocular hypertension/glaucoma 
with resultant damage to the optic nerve and reduced visual acuity and visual fields defects. It 
is advisable that intraocular pressure be checked frequently. The risk of corticosteroid-induced 
raised intraocular pressure is increased in predisposed patients (e.g. diabetes). 
Corticosteroids may reduce resistance to and aid in the establishment of bacterial, viral and 
fungal infections and mask the clinical signs of infections. In such cases antibiotic therapy is 

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Maxidex® 
mandatory. Fungal infection should be suspected in patients with persistent corneal ulceration 
and corticosteroids therapy should be discontinued if fungal infection occurs. 
In those diseases causing thinning of the cornea or sclera, perforations have been known to occur 
with the use of topical corticosteroids. 
Benzalkonium chloride used as a preservative may cause irritation of the eye. 
 
Levofloxacin/dexamethasone 
Both topical corticosteroids and NSAIDs may slow corneal healing. Caution is therefore advised 
when using topical dexamethasone and topical NSAIDs concomitantly. 
Systemic fluoroquinolones have been associated with hypersensitivity reactions, even following 
a single dose. If an allergic reaction does occur, discontinue the medication.  
As levofloxacin is phototoxic at very high doses and photosensitization may not be excluded, 
patients should not be exposed to direct sunlight during treatment. 
Prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If 
worsening of infection occurs, or if a clinical improvement is not noted within a reasonable 
period, discontinue use and institute alternative therapy. 
Prolonged use of topical ophthalmic corticosteroids may result in ocular hypertension and/or 
glaucoma, with damage to the optic nerve, reduced visual acuity, visual field defects and 
posterior sub-capsular cataract formation. In patients receiving prolonged ophthalmic 
corticosteroid therapy, intraocular pressure and lens should be checked routinely and frequently. 
The risk of corticosteroid-induced raised intraocular pressure is increased in predisposed 
patients (e.g. diabetes). 
Fungal infection should be suspected in patients with persistent corneal ulceration and 
corticosteroids therapy should be discontinued if fungal infection occurs. 
In those diseases causing thinning of the cornea or sclera, perforations have been known to occur 
with the use of topical corticosteroids. 
Topical corticosteroids should not be used for longer than one week except under ophthalmic 
supervision, with regular checks of intraocular pressure. 
Benzalkonium chloride used as preservative may cause irritation of the eye. 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Treatment may be discontinued permanently, regardless of treatment arm, if any adverse event, 
medical condition or situation warrants discontinuation of treatment. The following situations call 
for permanent discontinuation of study treatments as per SPC/IB: 

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Hypersensitivity to Tobradex®. 
Cushing’s syndrome and/or adrenal suppression. 
Fungal infections. 
 
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Fungal infections. 
 
Levofloxacin/dexamethasone 
Allergic reactions. 
Worsening of infection or lack of clinical improvement. 
Fungal infections. 
 
Discontinuation from treatment does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated in the study protocol. If a clinically significant 
finding is identified after enrollment, the investigator will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event 
(AE). 
Patients discontinuing treatment will be asked to undergo the assessments planned for the End of 
Study (EOS) Visit (see the SoA in Section 1.3). 
Temporary treatment interruptions and dose modifications are not foreseen in the protocol. See 
Section 6.1.2.1 for information concerning the management of missed doses. 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. An 
investigator may discontinue or withdraw a participant from the study for the following reasons: 
· Pregnancy 
· Significant study intervention non-compliance 
· If any clinical adverse event (AE) or other medical condition or situation occurs such that 
continued participation in the study would not be in the best interest of the participant 
· If the participant meets an exclusion criterion (either newly developed or not previously 
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The reason for participant discontinuation or withdrawal from the study will be recorded on the 
eCRF. Subjects who sign the informed consent form and are randomized but do not complete the 
study will not be replaced.  
7.3 LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for scheduled visits 
and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
· The site will attempt to contact the participant and reschedule the missed visit and counsel 
the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 
· Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, three telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file.  
· Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 SCHEDULE OF ASSESSMENTS 
The following visits will be performed as listed in the SoA. Additional visits will be made available 
to patients in case of need. 
Visit 1: Screening (to be performed not more than 28 days prior to surgery) 
Upon signing the informed consent form each patient is uniquely identified by a patient ID number 
which is composed of the site number and a sequential number assigned automatically by the 
eCRF. Once assigned to a patient, the patient ID number will not be reused. 
At screening, after obtaining signed written informed consent, inclusion/exclusion criteria will be 
checked and the following assessments will be performed/data collected:  
· Demographics 
· Medical history  
· Use of concomitant medications  

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· Slit lamp examination 
· Intraocular pressure 
· Visual acuity 
· Adverse events 
Visit 2 - Day of surgery 
Prior to surgery, inclusion/exclusion criteria will be rechecked, and the following assessments will 
be performed/data collected: 
· Use of concomitant medications, including prophylactic pre-operative medications to be 
stopped before surgery 
· Adverse events occurred after previous visit.  
Women of childbearing potential will be required to undergo a urine pregnancy test (dipstick).  
Patients who completed surgery without complications will be randomized to one of the two 
treatment arms and will be provided with study drug needed until visit at day 8 (first period of 
treatment) and a diary on which to record times of instillations. 
Visit 3 - Visit on day 4 after 3 full days of treatment 
On Day 4, patients should return their diaries to evaluate compliance. The following assessments 
will be performed/data collected on Day 4: 
· Concomitant medications 
· Slit lamp examination 
· Evaluation of any ocular infections  
· Total Ocular Symptom Score (TOSS) 
· Ocular pain/discomfort 
· Use of rescue therapy 
· Intraocular pressure 
· Local tolerability (global evaluation/burning, stinging, blurred vision) 
· Adverse events occurred after previous visit 
Visit 4 - Visit on day 8 after 7 full days of treatment 
On Day 8, patients should return unused medication and completed diary to evaluate compliance 
and will receive a new supply of medication needed until end of study and a new diary. The second 
period of treatment will start after the new supply. 
The following assessments will be performed/data collected on Day 8: 
· Concomitant medications 

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· Slit lamp examination 
· Evaluation of any ocular infections  
· TOSS 
· Ocular pain/discomfort 
· Use of rescue therapy 
· Intraocular pressure 
· Local tolerability (global evaluation/burning, stinging, blurred vision) 
· Adverse events occurred after previous visit 
Visit 5 - Visit on day 15 after 14 full days of treatment (end of study) 
On Day 15, patients should return unused medication and completed diary to evaluate compliance. 
The following assessments will be performed/data collected on Day 15: 
· Concomitant medications 
· Slit lamp examination 
· Evaluation of any ocular infections  
· TOSS 
· Ocular pain/discomfort 
· Use of rescue therapy 
· Intraocular pressure 
· Visual acuity 
· Local tolerability (global evaluation/burning, stinging, blurred vision) 
· Adverse events occurred after previous visit 
END OF STUDY 
After the end of study visit performed at day 15, patients will be managed according to standard 
routine practice applied by each center. 
8.2 EFFICACY ASSESSMENTS  
· Slit lamp examination 
A slit lamp examination will be performed at Visit 1 (screening) and on Day 4 (Visit 3), Day 8 
(Visit 4), and Day 15 (Visit 5) to evaluate cells in the anterior chamber and aqueous flare as 
follows: 
Cells in anterior chamber: results are to be provided as a score: 0 = no cells; 1 = 1–5 cells; 2 = 6–
15 cells; 3 = 16-30 cells; 4 = >30 cells.48  

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Aqueous flare (Tyndall effect): results are to be provided as a score: 0 = absent; 1 = trace barely 
detectable; 2 = mild intensity (iris and lens details clear); 3 = moderate intensity (iris and lens 
details not clear); 4 = strong intensity (iris and lens details not visible and fibrin in the anterior 
chamber).44 
Conjunctival hyperemia will be evaluated and results provided as a score as follows: 0 = absence 
of inflammation, 1 = mild inflammation (some vessels injected), 2 = moderate inflammation 
(diffuse injection of vessels, but individual vessels are still discernable) 3 = severe inflammation 
(intense injection of vessels, individual vessels not easily discernable).45 
· Endophthalmitis 
All cases of endophthalmitis occurring following cataract surgery are to be reported at all visits. 
· Total Ocular Symptom Score (TOSS) 
The TOSS is a patient-reported evaluation of 3 ocular symptoms: itching/burning, hyperemia of 
conjunctiva and tearing. Each symptom is given a score: 0 = none, 1 = mild, 2 = moderate, 3 = 
severe. The TOSS will be evaluated on Days 4, 8, and 15.46 See Appendix 1. 
· Ocular pain/discomfort 
Overall ocular pain and discomfort will be evaluated by the subject at Days 4, 8 and 15 on a 4-
point scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe). 
· Use of rescue therapy 
All rescue therapy used following cataract surgery is to be reported at all visits (see Section 6.5.2). 
8.3 SAFETY, TOLLERABILITY AND OTHER ASSESSMENTS 
Safety will be monitored by evaluating all adverse events, especially increases in intraocular 
pressure (IOP) (measured at each visit following surgery) and drop in visual acuity assessed as per 
local clinical practice (measured on Day 15). 
Local tolerability will be evaluated at all visits following surgery as follows: 
· Global evaluation on a 4-point scale: 0 = no intolerability, 1 = mild intolerability, 2 = 
moderate intolerability, 3 = maximum intolerability. 
· Burning, stinging, blurred vision on a 4-point scale: 0 = none, 1 = mild, 2 = moderate, 3 = 
severe. 
Compliance will be evaluated on Day 4, Day 8 and Day 15 by means of a patient diary in which 
the instillations are to be recorded. 

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8.4 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.4.1 
DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event can be defined as any untoward medical occurrence associated with the use of 
an intervention in humans after providing written informed consent for participation in the study 
until the end of study visit, whether considered intervention-related or not.  
8.4.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or Sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
8.4.3 
CLASSIFICATION OF AN ADVERSE EVENT 
8.4.3.1 
SEVERITY OF EVENT 
The following guidelines will be used to describe severity:  
· Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
· Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
· Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
8.4.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. Investigators are to judge the causal relationship of the event with the study 
intervention as “suspected”, “unsuspected” or “unknown”. 
8.4.3.3 
EXPECTEDNESS  

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The Sponsor will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event 
is not consistent with the risk information previously described for the study intervention. 
8.4.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention 
of study personnel during study visits and interviews of a study participant presenting for medical 
care, or upon review by a study monitor. 
All AEs including local and systemic reactions will be captured on the eCRF. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, relationship 
to study product (assessed only by those with the training and authority to make a diagnosis), and 
time of resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity. AEs characterized as intermittent require documentation of onset 
and duration of each episode. 
The investigator will record all reportable events with onset dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day 
of study participation. At each study visit, the investigator will inquire about the occurrence of 
AE/SAEs since the previous visit. Events will be followed for outcome information until resolution 
or stabilization. 
8.4.5 
ADVERSE EVENT REPORTING  
All identified non-serious AEs (related and unrelated) must be recorded and described on the 
eCRF. 
8.4.6 
SERIOUS ADVERSE EVENT REPORTING  
Every Serious Adverse Event (SAE), regardless of suspected causality, occurring after the subject 
has provided informed consent and until at least 30 days after the subject has stopped study 
treatment must be reported to the Sponsor within 24 hours of site awareness. 
Any SAE experienced after this 30-day period should only be reported to the Sponsor if the 
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complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. 
Information about all SAEs will be recorded on the eCRF. In case of technical difficulties, SAE 
notification can be carried out by contacting the Contract Research Organization (CRO) OPIS in 
charge of Pharmacovigilance via email at all_phv@opis.it or by fax using the following number: 
Fax: +39 0362 633622. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event 
to be chronic or the adherence to be stable. Other supporting documentation of the event may be 
requested by the study Sponsor and should be provided as soon as possible. The study Sponsor 
will be responsible for notifying Health Authorities of any unexpected fatal or life-threatening 
suspected adverse reaction as soon as possible, but in no case later than seven calendar days after 
the Sponsor's initial receipt of the information. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to the 
competent authorities and relevant ethics committees in accordance with Directive 2001/20/EC 
and as per national regulatory requirements in participating countries. 
8.4.7 
REPORTING EVENTS TO PARTICIPANTS  
Should an event occur that changes the overall benefit/risk ratio of the study, the Sponsor shall 
evaluate if a risk minimization measure is needed. Should this measure require a substantial 
amendment to the protocol, the informed consent and patient information will be revised and 
submitted to the patient for written consent. 
8.4.8 
EVENTS OF SPECIAL INTEREST  
Not applicable. 
8.4.9 
REPORTING OF PREGNANCY  
The investigator shall report all pregnancy exposure occurring in a female patient or in a male 
patient’s partner within 24 hours to the Sponsor using the Pregnancy Reporting Form of the eCRF. 
In case of technical difficulties, pregnancy notification can be carried out by contacting the 
Contract Research Organization (CRO) OPIS in charge of Pharmacovigilance via email at 
all_phv@opis.it or by fax using the following number: Fax: +39 0362 633622. The investigator 
should counsel the subject; discuss the risks of continuing with the pregnancy and the possible 
effects on the fetus. Monitoring of the subject should continue until conclusion of the pregnancy. 
 
 

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9 
STATISTICAL CONSIDERATIONS  
 
9.1 STATISTICAL HYPOTHESES 
The primary objective of the trial is to demonstrate the non-inferiority of combined levofloxacin 
+ dexamethasone for 7 days followed by dexamethasone alone for an additional 7 days vs. standard 
treatment tobramycin + dexamethasone for 14 days in the prevention and treatment of 
postoperative ocular inflammation and prevention of infection. 
The primary endpoint is the proportion of patients without signs of anterior chamber inflammation 
(sum of cells and flare score = 0) after 14 days of treatment. The following non-inferiority 
hypotheses will be tested: 
H0 : πT – πS ≤ - Δ 
H1 : πT – πS > - Δ 
Where πT and πS are the proportions of patients without signs of anterior chamber inflammation in 
the test and standard treatments, respectively, and the non-inferiority margin is Δ = 10%. 
Secondary endpoints: 
· Incidence of endophthalmitis  
· Proportion of patients without signs of anterior ocular chamber inflammation after 3 and 7 
days of treatment 
· Conjunctival hyperemia after 3, 7 and 14 days of treatment 
· Total Ocular Symptoms Score (TOSS) after 3, 7 and 14 days of treatment 
· Ocular pain/discomfort after 3, 7 and 14 days of treatment 
· Use of rescue therapy during treatment 
No formal statistical hypotheses will be tested for the secondary endpoints.  
9.2 SAMPLE SIZE DETERMINATION 
The study plans to enroll 800 patients: 400 patients will be assigned to the test treatment and 400 
to standard treatment. 
A sample size of 362 patients in each group is required to assess the non-inferiority of the test 
treatment vs. the standard therapy (i.e. lower limit of the 95% Confident Interval of the difference 
in proportions, pT - pS > -0.10) with 80% power and by applying a two-group large-sample normal 
approximation test of proportions with a one-sided 0.025 significance level, assuming that the 
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The total sample size (362 + 362 = 724) is adjusted to 800 patients considering an expected dropout 
rate of about 10% using Freedman’s formula48: n’= 100*n/100-x, where x is the expected dropout 
rate. 
9.3 POPULATIONS FOR ANALYSES 
The following populations have been defined for analysis: 
· Safety set: all randomized patients who take at least one dose of study treatments. 
· Full Analysis Set (FAS): all randomized patients who take at least one dose of study 
treatment. According to the Intention to Treat (ITT) principle, patients who discontinue the 
study treatment are considered as failures. Appropriate methods for the replacement of 
missing values will be detailed in the statistical analysis plan. 
· Per protocol (PP) set: All randomized patients who do not have significant protocol 
violations that regard inclusion/exclusion criteria or that can condition efficacy 
evaluations, including the use of rescue medication. 
The efficacy analyses will be performed on the FAS, having those on the PP population as 
supportive. The safety and tolerability analyses will be performed on the Safety population. 
9.4 STATISTICAL ANALYSES 
 
9.4.1 
GENERAL APPROACH 
Continuous data will be summarized with standard descriptive statistics (i.e. the mean, standard 
deviation, minimum, median and maximum, 95% confidence limits). Categorical data will be 
summarized by frequencies and percentages. 
No statistical test will be performed for between-group differences in demographic and baseline 
features (medical history and efficacy data). 
Medical history and adverse events will be described according to System Organ Classes (SOC) 
and Preferred Terms (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) and 
will be presented by treatment group.  
Previous/concomitant medications will be presented by treatment group using the World Health 
Organization Drug Dictionary (WHO-DD). 
All analysis will be performed using SAS version 9.4 or later. 
9.4.2 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The proportion of patients without signs of anterior chamber inflammation (sum of cells and flare 
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treatment vs. the standard therapy. Non-inferiority will be assessed by computing the two-tailed 
95% confidence interval (CI) of the difference between the two proportions pT - pS. Non-inferiority 
is met if the 95% CI does not cross the predefined non-inferiority margin Δ = -0.10 and lies entirely 
to the right of the margin (i.e. non-inferiority will be demonstrated if the lower bound of the two-
sided 95% CI of the difference is > -0,10).   
If the 95% CI of the difference lies completely to the right of 0, the test treatment can be considered 
more effective than the standard treatment at a 5% significance level. 
9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Descriptive statistics and two-sided 95% CIs of the difference between treatments will be 
computed for the following secondary endpoints: 
· Incidence of endophthalmitis 
· Proportion of patients without signs of anterior chamber inflammation (sum of cells and 
flare score = 0) after 3 and 7 days of treatment 
· Proportion of patients with conjunctival hyperemia score equal to 0 after 3, 7 and 14 days 
of treatment  
· Proportion of patients with TOSS score equal to 0 after 3, 7 e 14 days of treatment 
· Proportion of patients with ocular pain/discomfort score equal to 0 after 3, 7 and 14 days 
of treatment 
· Proportion of patients using rescue therapy during treatment 
9.4.4 
SAFETY ANALYSES 
Adverse Events 
All safety analyses will be performed on the Safety set. No missing data handling approach will 
be applied. 
The incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) recorded throughout 
the study will be presented overall and by treatment group. According to the onset date of the 
event, AEs will be defined as follows: 
· Treatment-emergent AE: event with an onset date after treatment initiation 
· Non-treatment-emergent AE: event with an onset date between informed consent and 
treatment initiation 
Non-treatment-emergent AEs will be listed only. 
Treatment-emergent AEs will be summarized by MedDRA dictionary system organ class and 
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severity will be also provided. All related treatment-emergent AEs, treatment-emergent SAEs, 
treatment-emergent AEs with an outcome of death, treatment-emergent AEs leading to treatment 
discontinuation will be summarized by MedDRA dictionary system organ class and preferred term and 
will also be listed.  
All deaths will be listed together with all their details. 
Intraocular pressure  
The number of patients with a significant increase (> 6 mmHg) in intraocular pressure will be 
recorded and summarized descriptively. The comparison between test treatment and standard 
treatment in the incidence of significant increase of IOP will be made by means of 95% CI of the 
difference between treatments. 
Visual acuity 
The number of patients with a decrease in visual acuity measured as per local clinical practice will 
be recorded and summarized descriptively. The comparison between test treatment and standard 
treatment in the drop of visual acuity will be made by means of 95% CI of the difference between 
treatments. 
9.4.5 
TOLERABILITY ANALYSES 
Local tolerability will be analyzed descriptively. Two-sided 95% CI will also be provided. 
9.4.6 
ANALYSIS OF COMPLIANCE 
For each treatment, compliance will be evaluated through an evaluation of the number of 
instillations recorded in the patient diary. 
9.4.7 
BASELINE DESCRIPTIVE STATISTICS 
Medical history and demographic features will be summarized descriptively. No statistical test will 
be performed for between-group differences in demographic and baseline features. 
9.4.8 
PLANNED INTERIM ANALYSES  
No interim analysis is planned. 
9.4.9 
SUB-GROUP ANALYSES 
No sub-group analyses are planned. 
9.4.10 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Patient listings will be provided. 

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9.4.11 EXPLORATORY ANALYSES 
No exploratory analyses are planned. 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1  CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to 
the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention. 
10.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
approved by the IRB/IEC and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may 
arise. A verbal explanation will be provided in terms suited to the participant’s comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent form and ask 
questions prior to signing. The participants should have the opportunity to discuss the study with 
their family or surrogates or think about it prior to agreeing to participate. The participant will sign 
the informed consent document prior to any procedures being done specifically for the study. 
Participants must be informed that participation is voluntary and that they may withdraw from the 
study at any time, without prejudice. A copy of the informed consent document will be given to 
the participants for their records. The informed consent process will be conducted and documented 
in the source document (including the date), and the form signed, before the participant undergoes 
any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
10.1.3 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 

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investigator, Sponsor and regulatory authorities. If the study is prematurely terminated or 
suspended, the Principal Investigator will promptly inform study participants, the IRB/IEC, 
Regulatory Authorities and Sponsor, and will provide the reason(s) for the termination or 
suspension. Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to 
· Determination of unexpected, significant, or unacceptable risk to participants 
· Insufficient compliance to protocol requirements 
· Data that are not sufficiently complete and/or evaluable 
· Determination of futility 
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor, IEC and regulatory authorities. 
10.1.4 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the Sponsor and their interventions. This confidentiality is extended to cover testing 
of biological samples (urine for pregnancy test) in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB/IEC 
and regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
records for the participants in this study. The clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB/IEC, Institutional policies, or Sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the Contract Research Organization (CRO) (OPIS s.r.l.) 
working on behalf of the Sponsor. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique 
study identification number. Only the study center will be able to link the study ID number to the 

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patient’s identity. The study data entry and study management systems used by clinical sites and 
by OPIS research staff will be secured and password protected.  
10.1.5 FUTURE USE OF STORED SPECIMENS AND DATA  
Not applicable, no biological samples will be stored for future use during this study. 
10.1.6 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct 
of the trial is compliant with the currently approved protocol/amendment(s), with International 
Conference on Harmonization Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
The field monitor will visit the site to check the completeness of patient records, the accuracy of 
entries on the eCRFs, the adherence to the protocol and to GCP, the progress of enrolment, and to 
ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these visits.  
The investigator must maintain source documents for each patient in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information. All information on CRFs must be traceable to these source documents in the patient's 
file. The investigator must also keep the original informed consent form signed by the patient (a 
signed copy is given to the patient). 
Monitoring standards require full verification for the presence of informed consent, adherence to 
the inclusion/exclusion criteria, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the eCRFs are 
performed according to the study-specific Monitoring Plan (MP). No information in source 
documents about the identity of the patients/subjects will be disclosed. 
10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
Following written Standard Operating Procedures, monitors will verify that the clinical trial is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonization Good Clinical Practice (ICH GCP), and 
applicable regulatory requirements.  
The investigational site will provide direct access to all trial related facilities, source 
data/documents, and reports for the purpose of monitoring and auditing by the Sponsor, and 
inspection by regulatory authorities. 

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Independent audits may be conducted by the Sponsor to ensure compliance with the protocol and 
GCP, and that monitoring practices are performed consistently across all participating sites and 
that monitors are following the MP. 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRF using fully 
validated software that conforms to 21 CFR Part 11 requirements. Designated investigator site 
staff will not be given access to the Electronic Data Capture system until they are trained.  
Web-based software will be used and no installation procedure is needed. Each site will be 
authorized by the administrator to access the eCRF. Each site-qualified personnel will be allowed 
to access the eCRF by means of a ‘login mask’ requiring user ID and password and may read, 
modify, and update only the information entered at his or her site and according to their profile. 
Each page reports site code and subject code. 
On-line validation programs will check for data discrepancies and, by generating appropriate error 
messages, allow the data to be confirmed or corrected before transfer to the CRO working on 
behalf of the Sponsor. The investigator will certify that the data entered in the eCRF are complete 
and accurate.  
After database lock, the investigator will receive a CD-ROM of subject data for archiving at the 
investigational site. 
Database management and quality control 
The CRO working on behalf of the Sponsor will review the data entered in the eCRF by 
investigational staff for completeness and accuracy and instruct site personnel to make any 
necessary corrections or additions. The Data Manager will perform the cleaning session by 
reviewing the warning messages raised by on-line checks and by running post-entry checks by 
means of validation programs and data listings specific for the study. The occurrence of any 
protocol deviations will also be checked. 
If clarifications are needed, the Data Manager will raise queries through the web application. 
Designated investigator site staff will be required to respond to queries and the Data Manager will 
make the correction to the database according to the responses. 
Data collection and query flows, as well as the on-line and off-line checks, are detailed in the Data 
Management Plan and Data Validation documents. 

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Concomitant medications and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the ATC classification system. Medical history/current 
medical conditions and AEs will be coded using MedDRA. 
The database will be locked after all the above actions have been completed and the database has 
been declared complete and accurate. 
10.1.9  STUDY RECORDS RETENTION  
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.  
Essential documents (written and electronic) should be retained for a period of not less than 
twenty-five (25) years from the completion of the study unless the Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period because of 
applicable laws, regulations and/or guidelines. The subjects’ medical files will be archived in 
accordance with the national laws. 
10.1.10 PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonization Good Clinical Practice (ICH GCP). The noncompliance may be on 
the part of either the participant, the investigator, or the study site staff. As a result of deviations, 
corrective actions are to be developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
protocol deviations. All deviations must be addressed in study source documents. 
10.1.11 INSURANCE 
The Sponsor certifies that it has taken out a liability insurance policy covering this clinical trial. 
This insurance policy is in accordance with local laws and requirements. The insurance of the 
Sponsor does not relieve the Investigator and the collaborators from any obligation to maintain 
their own liability insurance policy. An insurance certificate will be provided to the IRB/IEC 
and/or regulatory authorities. 

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10.1.12 PUBLICATION AND DATA SHARING POLICY 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the Sponsor, who may utilize them in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. 
This study will ensure that the public has access to the published results of the research.  
Enrolment of patients in the study will be competitive. Therefore, pending confirmation from the 
journal accepting the manuscript, the main publication reporting the results of the study will 
include as main authors the names of the Chairman of the study, National Coordinators and 
Principal Investigators of the five centers enrolling the most patients. Names of Principal 
Investigators of all other sites will be mentioned in the full list of participating centers added to 
the text of the publication.  
As this is a multicenter study, the first publication must be related to data collected from all patients 
enrolled and analyzed under the Sponsor’s responsibility. The investigator shall not publish or 
communicate data collected in only one center or part of the centers before publication of the 
complete results of the study, unless prior written authorization from the Sponsor has been 
provided. 
Any publication and/or communication project regarding the study and/or its results, whether 
obtained during the study or after the study end, shall be submitted to the Sponsor at least 30 days 
for a publication and 15 days for an abstract before the planned date of communication and/or 
submission for a publication. The Sponsor shall make comments on the project within 15 days of 
receipt of the project for a publication and within 7 days for an abstract. The investigator who 
submitted the project shall take the Sponsor's comments into due consideration. Nevertheless, 
should the investigator who submitted the project decide not to modify the project according to 
the Sponsor's comments, he/she shall provide the Sponsor with the grounds for his/her decision in 
writing. 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication. The ICMJE defines a clinical trial 
as any research project that prospectively assigns human subjects to intervention or concurrent 
comparison or control groups to study the cause-and-effect relationship between a medical 
intervention and a health outcome. Medical interventions include drugs, surgical procedures, 
devices, behavioral treatments, process-of-care changes, and the like. Health outcomes include any 
biomedical or health-related measures obtained in patients or subjects, including pharmacokinetic 
measures and adverse events. The ICMJE policy requires that all clinical trials be registered in a 
public trials registry such as ClinicalTrials.gov, which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. 

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10.1.13 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management 
of all reported dualities of interest. 
 
 

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10.2 ABBREVIATIONS 
 
AE 
Adverse Event 
ASCRS 
American Society of Cataract Refractive Surgery 
CI 
Confidence Interval 
CNS 
Coagulase-Negative Staphylococci 
CONSORT Consolidated Standards of Reporting Trials 
CRO 
Contract Research Organization 
eCRF 
electronic Case Report Forms 
VEGF 
Vascular Endothelial Growth Factor 
EOS 
End of Study 
ESCRS 
European Society of Cataract and Refractive Surgeons 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonization  
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IWRS 
Interactive Web Response System 
LOCF 
Last Observation Carried Forward 
MP 
Monitoring Plan 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRSA 
Methicillin-Resistant Staphylococcus Aureus 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TOSS 
Total Ocular Symptoms Score 
VA 
Visual Acuity 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 

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12 APPENDICES 
 
APPENDIX 1: TOTAL OCULAR SYMPTOMS SCORE (TOSS) 
TOSS Questionnaire 
Please answer the following questions by marking the box that best represents your answer: 
Have you experienced any of the 
following, and if so with what 
intensity? 
None 
Mild 
Moderate 
Severe 
1. Itching/burning? 
 
 
 
 
2. Redness? 
 
 
 
 
3. Tearing (eyes watering)? 
 
 
 
 
 
TOSS Questionnaire Scoring 
Total Ocular Symptom Score 
1. Add up scores for the three symptoms. 
None = 0 
Mild = 1 
Moderate = 2 
Severe = 3