A Study to Evaluate the Performance and Safety of CBL-102 Versus Vismed® Multi Eye Drops in the Management of Dry Eye
Phase: NA
Conditions: Dry Eye
Sponsor: Laboratoire Chauvin

Study #CBL-2017-01- Protocol 
Version 3, 25 Jul 2017 
TITLE PAGE 
A Study to Evaluate the Performance and Safety of CBL-102 versus Vismed® Multi
Eye Drops in the Management of Dry Eye  
PROTOCOL 
STUDY # CBL-2017-01 
Sponsor: 
Laboratoire Chauvin  
Affiliate of Bausch & Lomb Incorporated, a Valeant Pharmaceuticals International, Inc. company 
This clinical investigation is being conducted in accordance with ISO 14155 (2011) Clinical Investigation 
of Medical Devices for Human Subjects, ICH GCPs, and applicable local regulations. 
ID RCB : 2017-A01099-44 
Revision Chronology: 
Original  
Version 2  
Version 3   
20 Apr 2017 
06 Jun 2017 
25 Jul 2017 
The confidential information in the following document is provided to you, as an Investigator or consultant, 
for review by you, your study personnel, and the applicable EC. By accepting this document, you agree that 
the information contained herein will not be disclosed to others without written authorization from Valeant 
Incorporated or its affiliates, except to the extent necessary to obtain consent from those persons who 
participate in this study.  
All brand/product names are trademarks of their respective owners. 
ClinicalTrials.gov ID: NCT03368404

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INVESTIGATOR STATEMENT OF APPROVAL 
A Study to Evaluate the Performance and Safety of CBL-102 versus Vismed® Multi 
Eye Drops in the Management of Dry Eye 
PROTOCOL 
STUDY # CBL-2017-01 
I have read the attached document, concur that it contains all information necessary to 
conduct the study, and agree to abide by all provisions set forth therein.  
I agree to conduct this study in accordance with ICH GCPs, ISO 14155 and applicable 
local regulations. I will not initiate the study until I have obtained written approval by the 
appropriate IRB/EC and have complied with all financial and administrative requirements 
of the governing body of the clinical institution and the Sponsor. I will obtain written 
informed consent (and, if applicable, assent for children) from each study subject prior to 
performing any study specific procedures.  
I understand that my signature on a case report form indicates that the data therein has 
been reviewed and accepted by me. 
I understand that this document and related information is subject to confidentiality terms 
found in my signed Confidentiality or Clinical Services Agreement. I agree to protect the 
confidentiality of my patients when allowing the Sponsor of this clinical investigation, 
and/or relevant regulatory authorities and IRB/ECs, direct access to my medical records 
for study subjects. 
Principal Investigator, Printed Name 
Principal Investigator, Signature 
Date 
Upon signing, provide the original signed page to the Sponsor and retain a copy for your files. 

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PERSONNEL AND FACILITIES 
NOTE: The information on this page is subject to change. All changes will be provided under separate 
cover. 
Sponsor  
Laboratoire Chauvin* 
 416, rue Samuel Morse 
34961 Montpellier Cedex 2  France 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Laboratoire Chauvin is an affiliate of Bausch & 
Lomb Inc. aValeant Pharmaceuticals International, 
Inc. company 
 
 
 
 
  
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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TABLE OF CONTENTS  
 
TITLE PAGE ................................................................................................................................................ 1 
SPONSOR APPROVAL PAGE .................................................................................................................. 2 
INVESTIGATOR STATEMENT OF APPROVAL ................................................................................. 3 
PERSONNEL AND FACILITIES .............................................................................................................. 4 
TABLE OF CONTENTS ............................................................................................................................. 5 
LIST OF ABBREVIATIONS ...................................................................................................................... 8 
SYNOPSIS .................................................................................................................................................... 9 
INTRODUCTION .......................................................................................................................................16 
1.0 OBJECTIVES .....................................................................................................................................17 
2.0 STUDY DESIGN .................................................................................................................................17 
2.1 DESCRIPTION OF STUDY DESIGN INCLUDING CHOICE OF CONTROL GROUPS ....................................17 
2.2 SELECTION OF STUDY POPULATION ..................................................................................................18 
2.2.1 
Eligibility ...............................................................................................................................18 
2.2.2 
Subject Completion ...............................................................................................................20 
2.2.3 
Subject Discontinuation .........................................................................................................20 
2.2.4 
Screening Failures .................................................................................................................21 
2.2.5 
Lost to Follow-up ..................................................................................................................21 
2.3 INVESTIGATORS ................................................................................................................................21 
2.4 STUDY DURATION ............................................................................................................................21 
2.5 TREATMENTS ....................................................................................................................................22 
3.0 STUDY MATERIALS ........................................................................................................................22 
3.1 DESCRIPTION OF TEST ARTICLE ........................................................................................................22 
3.2 DESCRIPTION OF COMPARATOR ARTICLE .........................................................................................22 
3.3 DESCRIPTION OF RUN-IN ARTICLE ....................................................................................................22 
3.4 INSTRUCTIONS FOR USE AND ADMINISTRATION ...............................................................................23 
Storage Requirements: .........................................................................................................................24 
3.5 OTHER MATERIALS ...........................................................................................................................24 
3.6 PACKAGING AND LABELING .............................................................................................................24 
3.7 ACCOUNTABILITY .............................................................................................................................25 
3.8 MASKING/UNMASKING .....................................................................................................................25 
3.9 METHODS OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ..........................................................26 
3.9.1 
Treatment Allocation .............................................................................................................26 
3.9.2 
Randomization Method .........................................................................................................26 
3.9.3 
Treatment Replacement .........................................................................................................26 
4.0 PERFORMANCE AND SAFETY VARIABLES .............................................................................26 
4.1 PRIMARY PERFORMANCE VARIABLES ...............................................................................................26 
4.2 SECONDARY PERFORMANCE VARIABLES ..........................................................................................26 
4.3 SAFETY VARIABLES ..........................................................................................................................27 
4.4 TOLERABILITY AND EASE-OF-USE VARIABLES .................................................................................27 
4.5 APPROPRIATENESS OF VARIABLES ....................................................................................................27 
4.6 RISK ASSESSMENT ............................................................................................................................27 
5.0 STUDY METHODS............................................................................................................................28 
5.1 STUDY VISITS ...................................................................................................................................28 
5.1.1 
Visit 1 (Screening, Day -14 (up to -16 days)) ........................................................................28 

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5.1.2 
Visit 2 (Baseline/Randomization, Day 0) ..............................................................................29 
5.1.3 
Visit 3 (Day 7 ± 1 day, Safety/compliance Telephone Assessment) .....................................29 
5.1.4 
Visit 4 (Day 28 ± 3 days) .......................................................................................................30 
5.1.5 
Visit 5 (Study Exit, Day 90 ± 10 days) ..................................................................................31 
5.1.6 
Unscheduled Visits ................................................................................................................31 
5.1.7 
Missed Visits .........................................................................................................................31 
5.2 POST-STUDY FOLLOW-UP .................................................................................................................32 
5.3 STUDY COMPLETION .........................................................................................................................32 
5.3.1 
Early Study Termination........................................................................................................32 
5.4 CONCOMITANT MEDICATIONS/THERAPY ..........................................................................................32 
5.4.1 
Permitted Therapy .................................................................................................................32 
5.4.2 
Disallowed Therapy ...............................................................................................................32 
5.5 TREATMENT COMPLIANCE ................................................................................................................33 
5.6 PROTOCOL DEVIATIONS ....................................................................................................................33 
6.0 ADVERSE EVENTS34 ........................................................................................................................33 
6.1 DEFINITION OF ADVERSE EVENTS.....................................................................................................33 
6.2 DEFINITION OF ADVERSE DEVICE EFFECT ........................................................................................33 
6.3 DEFINITION OF SERIOUS ADVERSE EVENTS ......................................................................................34 
6.4 DEFINITION OF SERIOUS ADVERSE DEVICE EFFECT ..........................................................................34 
6.5 DEFINITION OF UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT AND ANTICIPATED SERIOUS 
ADVERSE DEVICE EFFECT ................................................................................................................34 
6.6 DEFINITION OF DEVICE DEFICIENCY (DD) ........................................................................................34 
6.7 CAUSALITY ASSESSMENT ..................................................................................................................35 
6.8 REPORTING ADVERSE EVENTS AND FOLLOW-UP ..............................................................................36 
6.9 REPORTING SERIOUS ADVERSE EVENTS AND FOLLOW-UP ................................................................36 
6.10 REPORTING PREGNANCIES AND FOLLOW-UP ....................................................................................37 
6.11 REPORTING COMPLAINTS FOR ANCILLARY MARKETED BAUSCH & LOMB PRODUCTS .....................38 
6.12 SUBMITTING AN EXPEDITED SAFETY REPORT TO COMPETENT AUTHORITIES ...................................38 
7.0 STATISTICAL METHODS ..............................................................................................................38 
7.1 STUDY ENDPOINTS ...........................................................................................................................38 
7.1.1 
Primary Performance Endpoints ............................................................................................38 
7.1.2 
Secondary Performance Endpoints ........................................................................................38 
7.1.3 
Safety Endpoints ....................................................................................................................39 
7.1.4 
Tolerability and Ease-of-Use Endpoints ................................................................................39 
7.2 HYPOTHESES.....................................................................................................................................39 
7.3 SAMPLE SIZE ....................................................................................................................................39 
7.4 RANDOMIZATION ..............................................................................................................................39 
7.5 ANALYSIS SETS ................................................................................................................................40 
7.6 STATISTICAL ANALYSIS ....................................................................................................................40 
7.6.1 
Methods of Analysis ..............................................................................................................40 
7.6.2 
Subject Demographics and Baseline Characteristics .............................................................41 
7.6.3 
Medical History .....................................................................................................................41 
7.6.4 
Prior and Concomitant Medications ......................................................................................41 
7.6.5 
Subject Discontinuation .........................................................................................................42 
7.6.6 
Protocol Deviations ...............................................................................................................42 
7.6.7 
Treatment Compliance...........................................................................................................42 
7.6.8 
Treatment Exposure ...............................................................................................................42 
7.6.9 
Missing Data ..........................................................................................................................43 
8.0 DATA QUALITY ASSURANCE ......................................................................................................43 
8.1 STUDY MONITORING ........................................................................................................................43 
8.2 SOURCE DOCUMENTATION ...............................................................................................................43 
8.3 CASE REPORT FORMS AND DATA VERIFICATION ..............................................................................44 
8.4 RECORDING OF DATA AND RETENTION OF DOCUMENTS...................................................................44 
8.5 AUDITING PROCEDURES ...................................................................................................................45 
8.6 INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE APPROVAL ....................................................45 

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8.7 PUBLICATION OF RESULTS ................................................................................................................45 
9.0 REFERENCES ....................................................................................................................................46 
 
 
 
 
APPENDICES 
APPENDIX A: 
SCHEDULE OF VISITS AND PARAMETERS .................................................. A-1 
APPENDIX B: 
METHODS OF CLINICAL EVALUATION ........................................................B-1 
APPENDIX C: 
GRADING OF CORNEAL AND CONJUNCTIVAL STAINING ..................... C-1 
 
 

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LIST OF ABBREVIATIONS 
Abbreviation/Acronym  
Term  
AE  Adverse Event 
ADE Adverse Device Effect 
ANCOVA Analysis of Covariance 
ART Artificial Tears 
ASADE Anticipated Serious Device Adverse Events 
ATC Anatomical Therapeutic Classification 
CFB Change from Baseline 
CI Confidence Interval 
CIOMS Council for International Organizations of Medical Sciences 
CRO Contract Research Organization 
DD Device Deficiency 
DED Dry Eye Disease 
DEWS Dry Eye Workshop 
EC Ethics Committee 
e-CRF Electronic Case Report Form 
GCP Good Clinical Practice 
IB Investigator’s Brochure 
ICF Informed Consent Form  
ICH International Conference on Harmonisation 
ID Identification 
ITT Intent-to-Treat 
HRQoL Health Related Quality of Life 
LDPE Low Density Polyethylene 
MGD Meibomian Gland Dysfunction 
OSD-QoL Ocular Surface Disease-Quality of Life 
OTC Over The Counter 
PP Per Protocol 
SADE Serious Adverse Device Effect 
SAE Serious Adverse Event 
SAP Statistical Analysis Plan 
SD Standard Deviation 
SOP Standard Operating Procedure 
SUSAR Suspected Unexpected Serious Adverse Reaction 
TEAE Treatment-Emergent Adverse Event 
TFBUT Tear Film Break-Up Time 
TID Three Times Per Day 
USADE Unanticipated Serious Adverse Device Event 
VA Visual Acuity 
NOTE: The first occurrence of some abbreviations is not spelled out in the document (eg, units of 
measure). 

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SYNOPSIS 
CBL-102 Eye Drops Study # CBL-2017-01 
Title: 
A Study to Evaluate the Performance and Safety of CBL-102 versus 
Vismed® Multi Eye drops in the Management of Dry Eye  
Phase of study:  
NA (Medical Device) 
Number of study 
centers and subjects: 
A total of approximately 84 subjects at approximately 14 clinical sites in 
France will be enrolled in this investigation. 
Objective(s): 
The primary objectives of this investigation are to show that the 
performance of CBL-102 Eye Drops is non-inferior to that of Vismed® 
Multi eye drops in subjects with moderate to severe keratoconjunctivitis 
sicca after 28 days, and to assess the safety of CBL-102 Eye Drops during a 
90-day period with treatment administered 3 to 6 times per day. 
Study design: 
This is a multicenter, randomized, parallel group, investigator-masked, non-
inferiority study.   
Approximately 84 subjects will be randomized in a 1:1 ratio to yield 33 
subjects in each treatment group completing the study without major 
protocol deviations. Subjects will be randomized to one of the following 
treatment groups: 
 
CBL-102 Eye Drops  
 
Vismed® Multi Eye Drops 
Study duration will be approximately 15 weeks from screening to the last 
visit.  Subjects will visit the clinic approximately 4 times. Visit 1 will be the 
Screening Visit and will occur 14 to 16 days prior to randomization. 
Subjects will be randomized to treatment on Visit 2 (Day 0). Visit 3 (Day 7 
± 1 day) will be a telephone visit, i.e. evaluation will be done on the phone 
for safety/compliance. After this interview, the investigator will determine 
whether the subject should come to the site or not. Then subjects will return 
to the clinic for assessment on Visit 4 (Day 28 ± 3 days), and Visit 5 (Day 
90 ± 10 days).  
Subjects will begin artificial tear (ART) run-in on Day -14 (up to -16 days) 
and continue until Day 0. Subjects will begin investigational eye drop 
dosing on Day 0 and continue dosing for 90 days (± 10 days) of treatment. 
Subjects will be asked not to instill their tear substitute (if possible) within 
the hour before each visit. 
Study endpoints: 
Primary Performance Endpoint 
The primary performance endpoint for this study is mean change from 
baseline (CFB) in the study eye at Visit 4 (Day 28 ± 3 days) in ocular 
surface fluorescein staining score according to a scale from 0 to 15, 
combining corneal, nasal and temporal bulbar conjunctival fluorescein 
staining, each graded 0 to 5, according to the Oxford Scheme. The 
investigator will record the total score per eye (the maximum total score is 
15 [maximum of 5 for each of the 3 areas]). 
The study eye will be the eligible eye with the highest total ocular surface 
fluorescein staining score at baseline or, if both eyes are eligible and have 
the same score, the study eye will be the right eye. 
Secondary Performance Endpoints 
The secondary endpoints will include the following: 
 
Mean CFB in the study eye at Visit 5 in total ocular surface fluorescein 
staining score 

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CBL-102 Eye Drops Study # CBL-2017-01 
 
Mean CFB in the study eye in fluorescein staining score for each area 
(cornea, nasal conjunctiva and temporal conjunctiva) at  Visits 4 and 5 
 
Mean CFB in the study eye in tear film break-up time (TFBUT) at 
Visits 4 and 5  
 
Evolution from baseline of Ocular Surface Disease-Quality of Life 
(OSD-QoL®) questionnaire scores at Visit 5 for all 7 dimensions: Daily 
Activities, Handicap and Work Difficulties, Giving up Make-up, 
Acknowledgement, Acceptance, Fear for the Future and Emotional 
Well-Being,.  
 
Mean CFB in the global sum score of dry eye symptoms at Visits 4 
and 5: sensation of dryness, foreign body, burning, stinging, itching, 
blurred vision, sensitivity to light, each graded from 0 to 4 
 
Mean CFB in the study eye in volume of tear fluid secretion as 
assessed by the unanaesthetized Schirmer test at Visit 4 
 
Frequency of investigational eye drop instillations, as reported in 
subject diary 
Safety Endpoints 
The safety endpoints for this study will include the following:   
 
Occurrence rates of ocular and non-ocular treatment emergent adverse 
events (TEAEs)  
 
Visual acuity (VA) measured with habitual correction, using Monoyer 
scale. 
Tolerability and Ease-of use Endpoints 
 
Assessment of investigational eye drop tolerability upon instillation as 
reported in subject diary  
 
Assessment of ease-of-use of the bottle as reported in subject diary 
Criteria for inclusion: 
1. Subjects must be of legal age (at least 18) on the date the Informed 
Consent Form (ICF) is signed and must be able to read, understand, and 
provide written voluntary informed consent on the Ethics Committee 
(EC) approved ICF 
2. Subjects who are able and willing to comply with all treatment and 
follow-up/study procedures 
3. Subjects who have been using tear substitutes for at least 2.5 months 
prior to inclusion, and who will use multidose preservative-free ART 
(Aqualarm® U.P. povidone 2% eye drops in 10 mL bottles) up to 6 
times a day for at least 2 weeks immediately prior to randomization 
4. Subjects with a score ≥ 1 for at least 2 out of the 7 following symptoms  
(rated 0 to 4): sensation of dryness, foreign body, burning, stinging, 
itching, blurred vision, sensitivity to light  
5. Subjects with at least 1 eye with the following signs of 
keratoconjunctivitis sicca : 
 
Tear break-up time of  10sec (mean of 3 measurements) at both 
screening visit and inclusion visit 
 
Total ocular surface staining score ≥ 4 and ≤ 9 at both screening 
visit and inclusion visit. This assessment combines corneal, nasal 
and temporal bulbar conjunctival fluorescein staining, each graded 
0-5 according to the Oxford Scheme 
6. Subjects who have a decimal visual acuity (VA) with habitual 
correction equal to or better than 0.1 (Monoyer chart) in both eyes 
7. Subjects with no systemic treatment or who are receiving stable 

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CBL-102 Eye Drops Study # CBL-2017-01 
systemic treatment (unchanged for 1 month or longer)  
8. For Female subjects, they must fall into 1 of the following categories:  
 
Post-menopausal 
 
Surgically sterile 
 
Using one of the following birth control methods throughout the 
duration of the study: 
o 
Intrauterine device (> 14 days) 
o 
Barrier method (condom or diaphragm) with spermicide  
(> 14 days) 
o 
Hormonal contraception (same dose and same formulation for 
at least 6 months) 
9. For Female subjects who are of childbearing potential (i.e. who are not 
post-menopausal or not surgically sterile), they must have a negative 
urine pregnancy test result at screening 
Criteria for exclusion: 
Ocular Exclusion Criteria 
1. Subjects with severe blepharitis defined by severe (a score of >2 from a 
range of 0 to 3) eyelid margin hyperemia or severe eyelid swelling or 
both and severe eyelid debris or severe plugging of meibomian glands 
or both. 
2. Subjects who have severe ocular dryness accompanied by 1 of the 
following: 
 
Lid abnormality (except mild or moderate blepharitis) 
 
Corneal disease 
 
Ocular surface metaplasia 
 
Filamentary keratitis 
 
Corneal neovascularization 
3. Subjects who currently wear contact lenses or have worn contact lenses 
within 90 days prior to study start 
4. Subjects who have received ocular surgery, including laser surgery, in 
either eye within 180 days prior to study start 
5. Subjects with a history of ocular trauma, non-dry eye ocular 
inflammation, or ocular infection within 90 days prior to study start 
6. Subjects with a history of ocular allergic disease or ocular herpes 
within 1 year prior to study start 
7. Subjects with a history of any inflammatory ulcerative keratitis, 
recurrent corneal erosion, or uveitis 
Treatment Exclusion Criteria 
8. Subjects with known hypersensitivity or contraindications to any of the 
ingredients in the test or comparator products or ART (especially 
povidone, hyaluronic acid, boric acid, glycerol, Myritol and carbomer) 
9. Subjects with  initiation of, or changes to, concomitant medication that 
could affect dry eye within 30 days prior to Visit 1 (Screening) or with 
planned initiation or changes of such medications during the study 
10. Subjects who have received ocular therapy (either eye) with any 
ophthalmic medication, except tear substitutes, within 2 weeks prior to 
study start  
11. Subjects expected to receive ocular therapy during the study 
12. Subjects treated with topical ocular steroidal or non-steroidal anti-

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CBL-102 Eye Drops Study # CBL-2017-01 
inflammatory medication within 30 days prior to study start 
13. Subjects expected to receive ocular therapy with immunosuppressants 
(eg, cyclosporine) during the study or who have used ocular 
immunosuppressants within 90 days prior to study start 
14. Subjects who have received occlusion therapy with non resorbable 
lacrimal or punctum plugs within 90 days prior to study start or 
subjects with resorbable plugs 
15. Subjects who have received or who are planned to receive therapy such 
as LipiFlow® or BlephEx® 
General Exclusion Criteria 
16. Females who are breastfeeding 
17. Subjects participating in any drug or device clinical investigation 
within 30 days prior to entry into this study and/or during the period of 
study participation 
Investigational product: 
Test Article: The test article, CBL-102 Eye Drops, is a CE-marked medical 
device manufactured by Dr. Mann Pharma/Bausch & Lomb and containing 
0.24% Hyaluronic acid salt, 
Carbomer, 
Medium chain 
triglycerides (Myritol), 
 Glycerol, 
 Sodium hydroxide and 
sterile water.  The formula is unpreserved and presented in 10 mL bottles. 
Comparator product 
and run-in therapy: 
Control Article: The comparator product, Vismed® Multi ophthalmic 
solution (CE marked), contains 0.18% sodium hyaluronate, sodium 
chloride, potassium chloride, magnesium chloride, calcium chloride, 
disodium hydrogen phosphate, sodium citrate, and water for injection.  The 
formula is unpreserved and presented in 10 mL bottles.   
Run-In Therapy: Artificial tears will be dispensed as packaged for 
marketing. The run-in ART will be multidose preservative-free CE marked 
ART (Aqualarm® U.P. containing povidone 2%, sodium chloride, sodium 
hydroxide, boric acid and water for injections and presented in 10 mL 
bottles), manufactured by Dr. Gerhard Mann. The ART should be used no 
more than 6 times per day during the run-in period. 
Study procedures: 
Visit 1 (Screening, Day -14 (up to -16 days))   
Visit 1 will proceed as follows: 
 
Obtain written informed consent 
 
Determine if the subject meets preliminary eligibility criteria  
 
Collect demographic information 
 
Collect current and relevant medical and ophthalmic history 
 
Identify concomitant medications used 
 
Perform a urine pregnancy test, as applicable 
 
If the subject meets the preliminary eligibility criteria, perform the 
following: 
 
Symptoms assessment  
 
VA measurement 
 
Biomicroscopy assessments 
Biomicroscopy will be assessed for each of the following:  
o 
Lids  
o 
Ocular discharge 
o 
Conjunctiva (chemosis and hyperemia) 
o 
Cornea (erosion, edema, and infiltrates) 

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CBL-102 Eye Drops Study # CBL-2017-01 
 
TFBUT measurement 
 
Fluorescein staining 
 
If the subject meets the dry eye eligibility criteria on Visit 1, complete 
the following: 
 
Dispense a subject diary (Diary A) to record run-in ART 
instillation frequency per day 
 
Dispense run-in ART 
 
Remind the subject that both eyes should be treated as needed (not 
by habit) up to 6 times per day with run-in ART to relieve dry eye 
symptoms 
 
Instruct subject to bring run-in ART and subject diary (Diary A) to 
Visit 2 and that dry eye eligibility testing will be completed at 
Visit 2 
 
Visit 2 (Baseline, Day 0) 
 
Collect adverse events (AEs) and changes in concomitant medications 
 
Collect subject diary (Diary A) and review for compliance 
 
Collect run-in ART 
 
Determine if the subject meets Visit 2 dry eye eligibility criteria by 
performing the following: 
 
Symptoms assessment  
 
VA measurement 
 
Biomicroscopy 
 
TFBUT measurement 
 
Fluorescein staining 
 
If the subject meets the dry eye eligibility criteria on Visit 2, proceed as 
follows: 
 
Perform the Schirmer test 
 
Have the OSD-QoL® questionnaire completed by the subject 
 
Dispense the investigational eye drops from the next sequential kit 
number to the subject  
 
Instruct the subject to instill 1 drop of the investigational eye drops 
in each eye 3 to 6 times per day 
 
Provide new subject diary (Diary B) to the subject to record 
investigational eye drop instillation frequency, investigational eye 
drop tolerability upon instillation and ease-of-use of the vial 
 
Instruct the subject to bring their subject diary with them to Visit 4 
 
Instruct the subject to put their used and remaining unused bottles 
in the container (kit box provided at Visit 2) for retrieval at the end 
of the study 
 
Visit 3 (Day 7, ± 1 day, Safety/compliance Telephone Assessment) 
 
Assess treatment compliance 
 
Collect any adverse event since the previous visit and changes in 
concomitant medication 

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CBL-102 Eye Drops Study # CBL-2017-01 
 
Determine in the subject should come to the site for a visit or not 
If the subject comes to the site, proceed as follows: 
 
Confirm AEs and changes in concomitant medications 
 
Perform the following assessments: 
 
VA measurement 
 
Biomicroscopy 
 
Study personnel will review the subject diary (Diary B) for compliance 
and then return it to the patient 
For both the telephone assessment and the visit at site: 
 
Remind the subject to instill 1 drop of investigational eye drops in each 
eye 3 to 6 times per day 
 
Remind the subject to record investigational eye drop instillation 
frequency, investigational eye drop tolerability upon instillation and 
ease-of-use of the vial in the diary 
 
Instruct the subject to bring their subject diary with them to Visit 4 
 
Remind the subject to continue to put their used and remaining unused 
bottles in the container (kit box provided at Visit 2) for retrieval at the 
end of the study 
 
Visit 4 (Day 28, ± 3 days) 
 
Collect AEs and changes in concomitant medications 
 
Perform the following assessments: 
 
Symptoms 
 
VA 
 
Biomicroscopy 
 
TFBUT measurement 
 
Fluorescein staining 
 
Schirmer test 
 
Collect subject diary (Diary B) and review for compliance 
 
Dispense new investigational eye drops kit  
 
Remind the subject to instill 1 drop of investigational eye drop in each 
eye 3 to 6 times per day 
 
Provide new subject diary (Diary C) to the subject  
 
Remind the subject to record in diary investigational eye drop 
instillation frequency, investigational eye drop tolerability upon 
instillation and ease-of-use of the vial 
 
Instruct the subject to bring their subject diary with them to Visit 5 
 
Instruct the subject to put their used and remaining unused bottles in 
the container (kit box provided to them at Visit 4) and to bring the two 
kit boxes in a sealed container at Visit 5  
 
Visit 5 (Day 90, ± 10 days) 
 
Collect AEs and changes in concomitant medications 
 
Perform the following assessments: 
 
Symptoms 

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CBL-102 Eye Drops Study # CBL-2017-01 
 
OSD-QoL® questionnaire 
 
VA 
 
Biomicroscopy 
 
TFBUT measurement 
 
Fluorescein staining 
 
Collect subject diary (Diary C) and review for compliance 
 
Collect the sealed container of investigational eye drops for 
accountability 
 
Exit the subject from the study 
NOTE: All investigational eye drops and subject diaries should be 
returned at this visit.  
Statistical methods: 
A validated macro SAS v. 9.4 was used for sample size calculation. 
Assuming a unilateral α risk of 2.5%, a β risk of 10% (90% power), a non-
inferiority margin of 2 and a standard deviation of 2.5 on the primary 
endpoint, a sample size of 33 evaluable subjects per treatment group is 
necessary to demonstrate non-inferiority of CBL-102 Eye Drops to 
Vismed® Multi. 
With a projected dropout rate of 10% and a protocol violation rate of 10%, a 
total of approximately 84 subjects with moderate to severe dry eye will be 
randomized in this clinical investigation. 
Summaries for continuous variables will include the sample size, mean, 
standard deviation (SD), median, minimum, and maximum. Calculations 
will be based on the number of subjects (or eyes) with non-missing values 
for the study population being summarized. Summaries for discrete 
variables will include the tabulation of frequencies and percentages. 
Percentages will be based on the number of subjects (eyes) with non-
missing values. The denominator for percentage will be the number of 
subjects (eyes) from the study population being analyzed.  
The primary performance endpoint is the mean CFB to Day 28 in total 
ocular surface fluorescein staining score (corneal, nasal and temporal bulbar 
conjunctival fluorescein staining) with each area graded (0 to 5) according 
to the Oxford Scheme. The investigator will record the total score per eye 
(the maximum score is 15).  
The study eye will be the eligible eye with the highest total ocular surface 
staining score at baseline or, if both eyes are eligible and have the same 
score, the study eye will be the right eye. An analysis of covariance 
(ANCOVA) model with main effects of treatment and baseline ocular 
surface staining score as covariates will be used to analyze the primary 
endpoint. Sensitivity analyses including investigator site as covariate will be 
performed. A 95% 2-sided confidence interval (CI) based on the ANCOVA 
model will be computed for the effect difference (CBL-102 Eye Drops 
minus Vismed® Multi). Non-inferiority will be demonstrated if the upper 
bound of the 95% CI is less than 2 grades in the per protocol (PP) analysis. 
Supportive analysis of the primary endpoint will be performed on the intent-
to-treat (ITT) population. The same ANCOVA model will be used to 
analyze secondary continuous endpoints. Supportive analyses on secondary 
performance endpoints will be performed in the ITT and PP populations. 
Safety endpoints analysis will be performed on the safety population. 

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INTRODUCTION  
Dry eye disease involves multiple physiological components and is a disease that is not 
completely understood. It is a common clinical problem, with surveys over the last 20 
years estimating a prevalence of between 5% to more than 30% at various ages.1 The 
2007 Report of the International Dry Eye Workshop (DEWS) defines dry eye disease as 
“A multifactorial disease of the tears and ocular surface that results in symptoms of 
discomfort, visual disturbance, and tear film instability, with potential damage to the 
ocular surface. It is accompanied by increased osmolarity of the tear film and 
inflammation of the ocular surface”.2 Intrinsic factors such as aging, hormonal balance, 
autoimmune disease, or systemic medications, and extrinsic factors such as topical 
medications, environmental stresses, contact lens wear, or refractive surgery contribute to 
dry eye disease (DED).2, 3  
Dry Eye Disease incidence increases significantly with age, (from 10.7% in subjects aged 
48 to 59 years to 17.9% in those 80 years or older).4  
The pathophysiology of DED involves multiple interacting mechanisms. Dysfunction of 
any lacrimal functional unit component can lead to DED by causing alterations in the 
volume, composition, distribution, and/or clearance of the tear film. Two mutually 
reinforcing global mechanisms, tear hyperosmolarity and tear film instability, have been 
identified2. 
Aqueous-deficient DED can be caused by either lacrimal alterations (including 
autoimmune disorders either primary or secondary to systemic autoimmune diseases such 
as rheumatoid arthritis) or blockade of reflex secretion or medications causes.1 
Evaporative DED also has various causes, including meibomian gland disease, eyelid 
aperture disorders or lid/globe incongruity, blink disorders, and ocular surface disorders. 
The most common cause is meibomian gland dysfunction (MGD; also called posterior 
blepharitis), a condition of meibomian gland obstruction.5 
Although these major categories seem clear-cut, in reality there is considerable overlap 
between them. Any form of dry eye may be associated with any other form.6 Second, 
because of the interaction between the 2 global DED mechanisms, tear hyperosmolarity 
and tear film instability, the differentiation between aqueous deficient and evaporative 
DED is often unclear. Certain DED etiologies involve multiple mechanisms. 
Patients with dry eye disease can suffer from ocular irritation and discomfort, 
photophobia, blurred vision and a host of other bothersome symptoms. 
Tear substitutes represent the basis of dry eye treatment.7 CBL-102 Eye Drops are a new 
CE marked multi-component tear substitute (i.e. medical device) designed to provide 
long-lasting moisturization of the eye by supporting the 3 layers of the tear film (lipid, 
aqueous and mucin) for the relief of dry eye. As a matter of fact, CBL-102 Eye Drops 
combine well known components used in the field of dry eye, i.e. 0.24% Hyaluronic acid 
salt, 
 Carbomer, 
Medium chain triglycerides (Myritol); they also include 
Glycerol, 
 Sodium hydroxide and 
sterile water. 
Hyaluronic acid, carbomer and glycerol are characterized by highly moisturizing 
properties and medium-chain triglycerides support the lipid layer of the tear film. 

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Hyaluronic acid is known for its properties of retention of water, slow release of 
moisture, tear film stabilization, lubrication and mucomimetic behaviour. It is a naturally 
occurring glycosaminoglycan that is present in the human eye structure and tear fluid, 
and it has been reported that hyaluronic acid concentrations were reduced in patients with 
dry eye.8-9 Sodium hyaluronate eye drops have been shown to increase precorneal tear 
film stability and corneal wettability and reduce the healing time of corneal epithelium.10-
13 Clinically, sodium hyaluronate has been widely used in the management of dry eye14-22 
and it is a component of several tear substitutes approved for market in Europe.  
Carbomer (carbopol 980) is a water soluble high molecular weight acrylic acid polymer 
that expand in aqueous media to form three-dimensional gel network, increasing tear 
stability and prolonging residence time.23 Carbomer acts together with hyaluronic acid as 
viscosity modifier and protectant, providing relief to ocular symptoms and improvement 
of signs of dry eye.24-26 
Medium chain triglycerides help restore the lipid layer and prevent evaporation of the 
aqueous phase27-28.  
The formula is free of buffer and unpreserved. 
The main intended purpose of CBL-102 Eye Drops is to improve the lubrication and 
wetting of the ocular surface, and the tear film stability in both evaporative and aqueous-
deficient dry eye. 
CBL-102 Eye Drops are currently marketed in some European countries to provide relief 
and protection for dry eye caused by persistent tear dysfunction. They are not yet 
marketed in France. 
 
1.0 
OBJECTIVES 
The primary objectives of this investigation are to show that the performance of CBL-102 
Eye Drops is non-inferior to that of Vismed® Multi Eye Drops in subjects with moderate 
to severe keratoconjunctivitis sicca after 28 days, and to assess the safety of CBL-102 
Eye Drops during a 90-day period with treatment administered 3 to 6 times per day. 
2.0 
STUDY DESIGN 
2.1 
Description of Study Design Including Choice of Control Groups 
This is a multicenter, randomized, parallel group, investigator-masked, non-inferiority 
study to evaluate the performance and safety of CBL-102 Eye Drops in subjects with 
moderate to severe dry eye.  
Subjects will visit the clinic approximately 4 times. Visit 1 will be the Screening Visit 
and will occur 14 to 16 days prior to randomization (Screening, Day -14 (up to -16 days). 
Subjects will be randomized to treatment on Visit 2 (Baseline, Day 0). Visit 3 (Follow-up 
Telephone call, Day 7 ± 1) will be done as a telephone call assessment for 
safety/compliance, and subjects will return to the clinic for assessment on Visit 4 
(Follow-up, Day 28 ± 3), and Visit 5 (Study Exit, Day 90 ± 10). Subjects will be 
randomized on Visit 2 in a 1:1 ratio to 1 of the following investigational treatment 
groups:  

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 CBL-102 Eye Drops 
 Vismed® Multi Eye Drops  
Approximately 84 subjects of either gender, aged 18 or older, having a clinical diagnosis 
of moderate to severe dry eye disease in at least 1 eye at Visit 1 (Screening) and Visit 2 
(Baseline) will be enrolled in the study. 
The study will be conducted in a 90-day (± 10 days) treatment phase (assigned 
investigational eye drop, i.e. investigational medical device), preceded by a 2-week 
screening phase when subjects are limited to the use of run-in artificial tears (ART) only. 
The ART will be used up to 6 times a day as needed during the run-in period.  In the 
treatment phase, subjects will instill 1 drop of investigational eye drops 3 to 6 times per 
day for 90 days (± 10 days).  
2.2 
Selection of Study Population  
A total of up to approximately 84 subjects at approximately 14 clinical sites in France 
with a clinical diagnosis of moderate to severe keratoconjunctivitis sicca will be enrolled 
in this investigation.  
2.2.1 
Eligibility 
2.2.1.1 
Inclusion Criteria  
1. Subjects must be of legal age (at least 18) on the date the Informed Consent Form 
(ICF) is signed and must be able to read, understand, and provide written voluntary 
informed consent on the Ethics Committee (EC) approved ICF 
2. Subjects who are able and willing to comply with all treatment and follow-up/study 
procedures 
3. Subjects who have been using tear substitutes for at least 2.5 months prior to 
inclusion, and who will use multidose preservative-free ART (Aqualarm® U.P. 
povidone 2% eye drops in 10 mL bottles) up to 6 times a day for at least 2 weeks 
immediately prior to randomization 
4. Subjects with a score ≥ 1 for at least 2 out of the 7 following symptoms (rated 0 to 4): 
sensation of dryness, foreign body, burning, stinging, itching, blurred vision, 
sensitivity to light  
5. Subjects with at least 1 eye with the following signs of keratoconjunctivitis sicca: 
 Tear break-up time of  10sec (mean of 3 measurements) at both screening visit 
and inclusion visit 
 Total ocular surface staining score ≥ 4 and ≤ 9 at both screening visit and 
inclusion visit. This assessment combines corneal, nasal and temporal bulbar 
conjunctival fluorescein staining, each graded 0-5 according to the Oxford 
Scheme 
6. Subjects who have a decimal visual acuity (VA) with habitual correction equal to or 
better than 0.1 (Monoyer chart) in both eyes 
7. Subjects with no systemic treatment or who are receiving stable systemic treatment 
(unchanged for 1 month or longer) 

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8. For female subjects, they must fall into 1 of the following categories:  
 Post-menopausal 
 Surgically sterile 
 Using one of the following birth control methods throughout the duration of the 
study: 
○ Intrauterine device (> 14 days) 
○ Barrier 
method 
(condom 
or 
diaphragm) 
with 
spermicide  
(> 14 days) 
○ Hormonal contraception (same dose and same formulation for at least 6 
months) 
9. For female subjects who are of childbearing potential (i.e. who are not post-
menopausal or not surgically sterile), they must have a negative urine pregnancy test 
result at screening 
 
 
2.2.1.2 
Exclusion Criteria 
Ocular Exclusion Criteria 
1. Subjects with severe blepharitis defined by severe (a score of >2 from a range of 0 to 
3) eyelid margin hyperemia or severe eyelid swelling or both and severe eyelid debris 
or severe plugging of meibomian glands or both. 
2. Subjects who have severe ocular dryness accompanied by 1 of the following: 
 Lid abnormality (except mild or moderate blepharitis) 
 Corneal disease 
 Ocular surface metaplasia 
 Filamentary keratitis 
 Corneal neovascularization 
3. Subjects who currently wear contact lenses or have worn contact lenses within 90 
days prior to study start 
4. Subjects who have received ocular surgery, including laser surgery, in either eye 
within 180 days prior to study start 
5. Subjects with a history of ocular trauma, non-dry eye ocular inflammation, or ocular 
infection within 90 days prior to study start 
6. Subjects with a history of ocular allergic disease or ocular herpes within 1 year prior 
to study start 
7. Subjects with a history of any inflammatory ulcerative keratitis, recurrent corneal 
erosion, or uveitis 
 
 

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Treatment Exclusion Criteria 
8. Subjects with known hypersensitivity or contraindications to any of the ingredients in 
the test or comparator products or ART (especially povidone, hyaluronic acid, boric 
acid, glycerol, Myritol and carbomer) 
9. Subjects with  initiation of, or changes to, concomitant medication that could affect 
dry eye within 30 days prior to Visit 1 (Screening) or with planned initiation or 
changes of such medications during the study 
10. Subjects who have received ocular therapy (either eye) with any ophthalmic 
medication, except tear substitutes, within 2 weeks prior to study start 
11. Subjects expected to receive ocular therapy during the study 
12. Subjects treated with topical ocular steroidal or non-steroidal anti-inflammatory 
medication within 30 days prior to study start 
13. Subjects expected to receive ocular therapy with immunosuppressants (eg, 
cyclosporine) during the study or who have used ocular immunosuppressants within 
90 days prior to study start 
14. Subjects who have received occlusion therapy with non resorbable lacrimal or 
punctum plugs within 90 days prior to study start or subjects with resorbable plugs 
15. Subjects who have received or who are planned to receive therapy such as LipiFlow® 
or BlephEx® 
 
General Exclusion Criteria  
16. Females who are breastfeeding 
17. Subjects participating in any drug or device clinical investigation within 30 days prior 
to entry into this study and/or during the period of study participation 
2.2.2 
Subject Completion 
A subject has completed the study after completion of Visit 5 (Study Exit, Day 90 ± 10). 
Subjects who require further follow-up for an AE will be followed according to  
Section 6.8. 
2.2.3 
Subject Discontinuation 
A subject MAY be discontinued (at the discretion of the Investigator, the Sponsor, and/or 
the EC) prior to the final visit for several reasons, including, but not limited to:  
 A serious adverse event (SAE) occurring during the course of the study, which 
precludes continued treatment or follow-up  
 The subject not following required study procedures 
 If a subject exhibits intolerable AEs (related or not related to the investigational 
medical device), or if a subject fails to show improvement or the clinical status 
worsens, the treating Investigator may opt to withdraw the subject from the study and 
implement necessary intervention. 

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A subject MUST be discontinued prior to the final visit for any of the following reasons: 
 Voluntary withdrawal  
 Death  
 Investigator decision that it is not in the best medical interest of the subject to 
continue participation in the investigation. In case a subject administers more than 8 
instillations per day for both eyes on a regularly continued basis (approximately 70 
%) as assessed on Visit 4, the subject will be discontinued from the study and the 
investigator will prescribe an appropriate treatment. 
Prior to discontinuing a subject, every effort should be made to contact the subject, 
schedule a final visit, obtain as much follow-up data as possible, and to retrieve all 
investigational materials. Adverse events will be followed as described in Section 6.5 . 
Subject withdrawals will be documented clearly on the source document and applicable 
electronic case report form (eCRF). The assessments scheduled for Visit 5 should be 
performed at this early termination visit. 
Notification of subject discontinuation will be made to the Sponsor Representative and 
will be clearly documented on the applicable eCRF. Any subject discontinued from the 
study will not be replaced.  
2.2.4 
Screening Failures 
Subjects failing to meet eligibility criteria at Visit 1 (Screening) and Visit 2 
(Baseline/Randomization) are considered screening failures. 
2.2.5 
Lost to Follow-up 
Subjects who do not return for scheduled follow-up visits, as defined by the visit window 
and cannot be contacted, may be considered lost to follow-up. All follow-up attempts will 
be documented and kept with the subject’s source documentation, and the applicable 
eCRFs will be completed. 
2.3 
Investigators 
 The study will be conducted at approximately 14 investigative sites located in France. 
 The study will be conducted by Investigators who are determined by the Sponsor or 
Sponsor Representative to be suitably qualified by training and experience to conduct 
this study in compliance with all applicable GCPs and local regulations.  
 Each Investigator will enroll approximately 6 subjects. In the event that selected sites 
do not meet full enrollment, the Sponsor may decide to increase enrollment as needed 
at other currently active sites and additional sites may be added to satisfy the 
enrollment requirements of the study.  
2.4 
Study Duration 
The duration of the study, including the time to enroll all subjects, will be approximately 
10 months.  
Study duration per subject will be approximately 15 weeks from screening to the last 
visit. Subjects will begin ART run-in on Day -14 (up to -16 days) and continue until Day 
0. Subjects will begin investigational medical device dosing on Day 0 and continue 

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dosing for 90 days (± 10 days) of treatment. Last dose of investigational medical device 
will be administered on the day of the last visit.  
2.5 
Treatments 
Approximately 84 subjects will be randomized in a 1:1 ratio to receive either CBL-102 
Eye Drops or Vismed® Multi. 
At least 1 eye in each subject must meet eligibility criteria at Visit 1 (Screening) and Visit 
2 (Randomization), as indicated in the inclusion criteria. Both eyes will be treated with 
investigational eye drops starting at Visit 2.  
Beginning with Visit 1, both eyes may be treated as needed (not by habit) up to 6 times 
per day with run-in ART to relieve symptoms of dry eye syndrome. The subject must 
record the frequency of run-in ART instillations daily on the diary provided. 
Starting with Visit 2, subjects will begin dosing with investigational eye drops (i.e. 
investigational medical device) for total treatment duration of 90 days (± 10 days). The 
frequency of investigational eye drop instillations will be recorded on the diary provided 
to the subjects as well as the tolerability upon instillation and the assessment of the ease-
of-use of the bottle.  
3.0 
STUDY MATERIALS 
All study materials are CE marked devices and are being tested within the scope of their 
intended use. 
To maintain a level of treatment masking, the outer carton of control article will be 
packaged identically to the test article, labeled with identical study-specific information.  
 
3.1 
Description of Test Article 
The test article, CBL-102 Eye Drops, is a CE marked medical device containing 0.24% 
Hyaluronic acid salt, 
Carbomer, 
 Medium chain triglycerides (Myritol), 
Glycerol, 
Sodium hydroxide and 
sterile water. The formula is 
unpreserved and presented in bottles with a fill volume of 10 mL.  
3.2 
Description of Comparator Article 
The comparator article, Vismed® Multi ophthalmic solution (CE marked), contains 
0.18% sodium hyaluronate, sodium chloride, potassium chloride, magnesium chloride, 
calcium chloride, disodium hydrogen phosphate, sodium citrate, and water for injection. 
The formula is presented in preservative-free bottles of 10 mL.   
3.3 
Description of run-in Article 
The run-in therapy will be dispensed as packaged for marketing. The run-in ART will be 
multidose preservative-free CE marked ART (Aqualarm® U.P. eye drops in 10 mL 
bottles) containing povidone 2%, boric acid, sodium chloride, sodium hydroxide and 
water for injection. 

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3.4 
Instructions for Use and Administration   
The subject will be instructed by the site staff on the proper instillation of the topical eye 
drops as follows: 
Preservative-free multidose bottles for the run-in period: 
Before first use or after not having used it for a certain time, the pump should be primed: 
remove the cap and overturn the bottle down, press the device several times (around 20) 
until a drop appears. The device is ready for use. 
1. Carefully wash your hands before using the device. 
2. Remove the protective cap from the tip of the bottle before each use. Make sure 
that your fingers or any other surface do not touch the tip of the bottle so as to 
avoid any contamination of the solution. 
3. Lean your head back slightly. Gently pull your lower eyelid down with a finger of 
your free hand, hold the bottle vertically above your eye and press the pump 
mechanism to apply one drop into your eye. Avoid touching the eye surface with 
the tip of the bottle to prevent any possible injury. Close your eye then roll it 
slowly in all directions to optimally spread the drop on the surface of your eye. 
4. Immediately after use, shake the bottle to remove potential remaining drops and 
replace the protective cap on the dry tip of the bottle. 
The ART will be used up to 6 times a day as needed during the run-in period. 
After the run-in period, eligible subjects will be dispensed a kit at Visit 2 and resupplied 
with a kit at Visit 4.  The kit dispensed at Visit 2 will contain investigational eye drops to 
dose for the first approximate 30 days of treatment. The kit dispensed at Visit 4 will 
contain investigational eye drops to dose for the remaining approximate 70 days of 
treatment. 
 
For the treatment period, multidose bottles instructions for use are as follows: 
1. Carefully wash your hands 
2. If there is a tamper-evident seal, remove it before first use. 
3. Turn up and remove the protective cap from the tip of the bottle before each use. 
Make sure that the tip of the bottle does not touch your fingers. Before first use, if 
there is a pump mechanism, lean the bottle downwards and squeeze the bottle 
several times until a drop appear. 
4. Lean your head back slightly and gently pull your lower eyelid down with a finger 
of your free hand and hold the bottle vertically above your eye with the nozzle 
pointing downwards. 
5. Make sure that the tip of the bottle does not touch your eye to prevent any 
possible injury or damage. Then, gently squeeze the bottle or the pump 
mechanism to apply 1 drop into the eye. 
6. Close your eye afterwards and slowly roll it in order to optimally spread the drop 
on the surface of your eye. 

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7. Just after use, shake to remove potential remaining drops and replace the cap on 
the bottle. 
Subjects will be instructed to instill 1 drop of their assigned investigational eye drops 3 to 
6 times per day according to the kit instructions for 90 days (± 10 days) starting at  
Visit 2. The frequency of instillations must be recorded in the subject diary provided by 
the Sponsor. Subject instillation instructions will be provided.  
Subjects will also be instructed to maintain whatever lid hygiene practices are employed 
at the time of randomization throughout the study. If lid hygiene practices (eg, warm 
compresses or lid scrubs or masks) have been prescribed for the subject, they should 
continue to do so prior to instillation of investigational eye drop; if not, subjects should 
not initiate these practices during the study. 
Storage Requirements: 
All investigational material must be stored in an upright position, in an area free from 
environmental extremes, at controlled temperatures between 2-25ºC in accordance with 
the conditions specified on the study label. The product should be kept away from 
sunlight. The storage location at the clinical site must have limited access, available to 
study personnel only and temperature must be controlled appropriately. 
Should a temperature extreme occur, then the Study Manager should be contacted prior to 
further use of the material.  The contact information is located on the Personnel and 
Facilities page of this protocol. 
3.5 
Other Materials  
The Sponsor will supply the following additional study materials:  
 Diaries  
 OSD-QoL® questionnaires 
 fluorescein strips  
 Sterile saline single dose units 
 Schirmer test strips (for unanesthetized testing) 
 Yellow barrier filter for slit lamp 
 Stopwatch 
 Urine pregnancy test kits 
 Temperature recorder  
3.6 
Packaging and Labeling  
The test articles will be packaged and labeled in a manner consistent with the study 
design. 
Investigational eye drop kits will be provided at Visits 2 and 4. The kit dispensed at Visit 
2 will contain 7 bottles of investigational eye drops to dose for the first approximate 30 
days of treatment. The kit dispensed at Visit 4 will contain 16 bottles of investigational 
eye drops to dose for the remaining approximate 70 days of treatment. Within each kit 
will be 10mL bottles of investigational eye drops.  

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Supply labeling will minimally include the protocol number, kit identification (ID) 
number, product description, directions for use, storage conditions, caution statement and 
Sponsor information.  The labeling may also contain additional information as required 
by local regulations. 
Each kit will be labeled with a 2-part tear-off label.  Upon dispensing, the site designee 
will remove the tear-off portion and affix it to a printed form (label page) provided by the 
Sponsor. The printed form must be placed in a binder maintained by the Investigator or 
designee. 
3.7 
Accountability 
During the course of the study, the Investigator will be responsible for keeping current 
and accurate records of the amount of study boxes received and dispensed, and its 
disposition. All study kits must be stored under the appropriate conditions in a secure 
area and are to be dispensed only to subjects enrolled in the study, in accordance with the 
conditions specified in this protocol. The Investigator must maintain an inventory of kits 
dispensed to the subject, including subject identifiers. At time points throughout the study 
and/or upon completion of the study, the Sponsor's representative will review and verify 
the Investigative Site inventory. 
 
To maintain Investigator masking, an unmasked designee will be responsible for 
investigational eye drops accountability. 
Upon completion of the study, the unmasked Sponsor's representative will review and 
verify the test articles accountability. Following verification, and as directed by the 
Sponsor, study articles must be returned to the designated Contract Development and 
Manufacturing Organization at the address on the Personnel and Facilities page.  
3.8 
Masking/Unmasking 
The Investigator and Sponsor personnel involved in the monitoring or conduct of the 
study will be masked to the investigational eye drop codes. Investigational eye drops kits 
will be packaged in a sealed outer carton to maintain treatment masking upon 
dispensation. Subjects will be instructed to put their used and remaining unused bottles in 
the containers (kit boxes provided to them at Visits 2 and 4) and to bring the sealed 
containers at Visit 5. An unmasked designee, who is responsible for collecting returned 
investigational eye drops for accountability at study end, may not be masked to the 
investigational eye drop codes.  
 
The randomization list will be produced prior to study enrollment.  
Investigational eye drop codes will not be available to the above personnel until after the 
study is completed and the database is finalized. If unmasking is necessary, sealed 
unmasking envelopes will be unsealed by the Investigator to reveal the treatment 
assigned to the subject. 
The Investigator must notify the Sponsor as soon as possible after unmasking. In 
addition, the Investigator must record the date, time, and reason for unmasking the 
investigational medical device in the source documentation. 

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3.9 
Methods of Assigning Subjects to Treatment Groups 
3.9.1 
Treatment Allocation 
During Visit 1 (Screening) subjects who fulfill all inclusion criteria and none of the 
exclusion criteria will receive Aqualarm® U.P. for run-in ART.  
During Visit 2 (Baseline/Randomization), subjects who fulfill all inclusion criteria and 
none of the exclusion criteria will be randomized in a 1:1 ratio to receive either CBL-102 
Eye Drops or Vismed® Multi. 
3.9.2 
Randomization Method 
The randomization list will be produced prior to study enrollment by an unmasked 
statistician who is not otherwise involved in the study. Each randomization number will 
correspond to a treatment group assignment. Investigational eye drop kits will be 
dispensed in consecutive order from the lowest sequential kit number available at the site. 
3.9.3 
Treatment Replacement 
In the event that a subject’s original kit is lost, damaged, or consumed prior to the end of 
treatment, the Investigator will contact the Sponsor’s Representative as soon as he/she is 
made aware of the need of a replacement kit. The Sponsor’s Representative will ask the 
Contract Development and Manufacturing Organization to provide a replacement kit 
corresponding to the subject treatment straight away. 
4.0 
PERFORMANCE AND SAFETY VARIABLES 
4.1 
Primary Performance Variables 
Clinical assessments of ocular surface fluorescein staining will be performed according to 
the schedule in Appendix A and graded according to the 0 to 5 scale in Appendix C. The 
primary performance variable is the mean change from baseline (CFB) in ocular surface 
fluorescein staining score according to a scale from 0 to 15 in the study eye at Visit 4. 
The ocular surface staining score is the combination of corneal, nasal and temporal bulbar 
conjunctival fluorescein staining (each graded from 0 to 5). These evaluations will be 
performed by the same ophthalmologist for the same patient at all visits. 
4.2 
Secondary Performance Variables 
Each performance variable will be performed according to the schedule in Appendix A. 
Individual clinical assessments of fluorescein staining (cornea, nasal and temporal bulbar 
conjunctiva) each graded according to the 0 to 5 scale in Appendix C will be determined. 
Mean CFB for each individual staining score and for the total ocular surface staining 
score will be determined. 
Clinical assessment of tear film break-up time (TFBUT) will be performed as defined in 
Appendix B. Mean CFB in TFBUT will be determined.  
Clinical assessment of tear fluid secretion will be measured by the unanaesthetized 
Schirmer test according to Appendix B. Mean CFB in volume of tear fluid secretion will 
be determined. 

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Discomfort linked to dry eye disease will be evaluated through 7 items: sensation of 
dryness, foreign body, burning, stinging, pruritus, blurred vision and sensitivity to light, 
each graded from 0 to 4 as defined in Appendix B.  
Impact of dry eye disease symptoms on patients’ health-related quality of life (HRQoL) 
will be evaluated using the ocular surface disease quality of life (OSD-QoL®) 
questionnaire. Subjects will be instructed to complete the questionnaire according to 
Appendix B. OSD-QoL® scores will be calculated. 
The frequency of investigational eye drop instillation will be captured every day in 
subject diaries. 
4.3 
Safety Variables  
The incidence and type of ocular and non-ocular treatment-emergent adverse events 
(TEAEs) will be assessed. All adverse events reported by the subject or observed by the 
investigator at each visit, will be collected from the time the subject signs the ICF until 
study exit. 
Visual acuity (VA) testing will be performed at each visit. Visual acuity will be measured 
with habitual correction at each visit using a Monoyer chart. The same VA testing 
method is to be employed for all visits for each subject. 
Biomicroscopy assessments will be performed at each visit. Biomicroscopy variables will 
be evaluated using the grading scales defined in Appendix B. 
4.4 
Tolerability and Ease-of-Use Variables 
Investigational eye drop tolerability (eye drop sensation upon instillation), as reported by 
each subject, will be captured in subject diaries as defined in Appendix B. 
Ease-of-use of the bottle will be also assessed by each subject and captured in the diary 
according to Appendix B. 
4.5 
Appropriateness of Variables 
In this study, all assessments and variables to assess the performance and safety of CBL-
102 Eye Drops are considered standard practice in the field of ophthalmology for 
diagnosis and management of subjects with dry eye29-33. 
Ocular surface staining has been chosen as the primary endpoint as it assesses the 
protective properties of the tear substitutes on the cornea and conjunctiva in dry eye13. 
The Oxford Scheme provides a logarithmic scale for grading of the ocular surface 
staining and is considered valuable for distinguishing changes29-30.  
4.6 
Risk Assessment 
In rare cases Aqualarm® U.P., CBL-102 Eye Drops, and Vismed® Multi can cause 
hypersensitive reactions such as local allergic reactions. Refer to the patient information 
leaflet for approved product information for Aqualarm® U.P., CBL-102 Eye Drops, and 
Vismed® Multi which will be provided with the ICF. 
The subjects will be informed of any known risks in the ICF. If additional risks are 
identified, the Sponsor will notify the Investigators. 

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5.0 
STUDY METHODS 
5.1 
Study Visits  
Refer to Appendix A for a schedule of visits and parameters and Appendix B for methods 
of clinical evaluation. 
Subjects will be asked not to instill their tear substitute (if possible) within the hour 
before each visit.  
Following identification of a potential subject, the Investigator (or designee) will explain 
the purpose of the study, procedures, risks/benefits, and subject responsibilities to the 
potential subject. The subject’s willingness and ability to meet the follow-up 
requirements of the study will be determined. If the subject chooses to participate in the 
investigation, written informed consent will be obtained. The subject and the person 
obtaining written consent will sign and date the EC-approved ICF, at which point the 
subject is considered part of the study population. The original signed document will be 
retained in the subject records, and a copy will be provided to the subject. In addition, the 
applicable privacy regulation requirements must be met.  An ICF must be signed prior to 
the start of any study-related procedures/assessments.  
5.1.1 
Visit 1 (Screening, Day -14 (up to -16 days)) 
 After obtaining written informed consent, prospective subjects will be screened to 
determine whether they meet the preliminary eligibility criteria for the study as 
follows: 
 Collect demographic information 
 Collect current and relevant medical and ophthalmic history 
 Identify concomitant medications used 
 Perform a urine pregnancy test, as applicable 
 If the subject meets the preliminary eligibility criteria, perform the following: 
 Symptoms assessment 
 VA measurement 
 Biomicroscopy assessments 
Biomicroscopy will be assessed for each of the following:  
 Lids  
 Ocular discharge 
 Conjunctiva (chemosis and hyperemia) 
 Cornea (erosion, edema, and infiltrates) 
 TFBUT measurement 
 Fluorescein staining 
 If the subject meets the dry eye eligibility criteria on Visit 1, complete the following: 

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 Dispense a subject diary (Diary A) to record run-in ART instillation frequency 
per day 
 Dispense run-in ART 
 Remind the subject that both eyes should be treated as needed (not by habit) 
up to 6 times per day with run-in ART to relieve dry eye symptoms 
 Instruct subject to bring run-in ART and subject diary (Diary A) to Visit 2 and 
that dry eye eligibility testing will be completed at Visit 2 
5.1.2 
Visit 2 (Baseline/Randomization, Day 0) 
 Collect AEs and changes in concomitant medications 
 Collect subject diary (Diary A) and review for compliance 
 Collect run-in ART 
 Determine if the subject meets Visit 2 dry eye eligibility criteria by performing the 
following: 
 Symptoms assessment 
 VA measurement 
 Biomicroscopy 
 TFBUT measurement 
 Fluorescein staining  
 If the subject meets the dry eye eligibility criteria on Visit 2, proceed as follows: 
 Perform the Schirmer test 
 Have the OSD-QoL® questionnaire completed by the subject 
 Dispense the investigational eye drops from the next sequential kit number to 
the subject 
 Instruct the subject to instill 1 drop of investigational eye drops in each eye 3 
to 6 times per day 
 Provide new subject diary (Diary B) to the subject to record investigational 
eye drop instillation frequency, investigational eye drop tolerability upon 
instillation and ease-of-use of the bottle 
 Instruct the subject to bring their diary (Diary B) with them to Visit 4 
 Instruct the subject to put their used and remaining unused bottles in the 
container (kit box provided at Visit 2) for retrieval at the end of the study 
5.1.3 
Visit 3 (Day 7 ± 1 day, Safety/compliance Telephone Assessment) 
 Assess treatment compliance 
 Collect any adverse event since the previous visit and changes in concomitant 
medication 

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 Determine in the subject should come to the site for a visit or not 
 
If the subject comes to the site, proceed as follows: 
 Confirm AEs and changes in concomitant medications 
 Perform the following assessments: 
 VA measurement 
 Biomicroscopy 
 Study personnel will review the subject diary (Diary B) for compliance and then 
return it to the patient 
 
For both the telephone assessment and the visit at site: 
 Remind the subject to instill 1 drop of investigational eye drops in each eye 3 to 6 
times per day 
 Remind the subject to record investigational eye drop instillation frequency, 
investigational eye drop tolerability upon instillation and ease-of-use of the bottle  in 
diary 
 Instruct the subject to bring their subject diary with them to Visit 4 
 Remind the subject to continue to put their used and remaining unused bottles in the 
container (kit box provided at Visit 2) for retrieval at the end of the study 
 
5.1.4 
Visit 4 (Day 28 ± 3 days) 
 Collect AEs and changes in concomitant medications 
 Perform the following assessments: 
 Symptoms 
 VA 
 Biomicroscopy 
 TFBUT measurement 
 Fluorescein staining 
 Schirmer test 
 Collect subject diary (Diary B) and review for compliance 
 Dispense new investigational eye drops kit 
 Remind the subject to instill 1 drop of investigational eye drop in each eye 3 to 6 
times per day 
 Provide new subject diary (Diary C) to the subject 

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 Remind the subject to record in diary investigational eye drop instillation frequency, 
investigational eye drop tolerability upon instillation and ease-of-use of the bottle   
 Instruct the subject to bring their subject diary with them to Visit 5 
 Instruct the subject to put their used and remaining unused bottles in the box (kit box 
provided at Visit 4) and to bring the two kit boxes in a sealed container at Visit 5 
5.1.5 
Visit 5 (Study Exit, Day 90 ± 10 days) 
 Collect AEs and changes in concomitant medications 
 Perform the following assessments: 
 Symptoms 
 OSD-QoL® questionnaire 
 VA 
 Biomicroscopy 
 TFBUT measurement 
 Fluorescein staining 
 Collect subject diary (Diary C) and review for compliance 
 Collect the sealed container of investigational eye drops for accountability 
 Exit the subject from the study 
NOTE: 
All investigational eye drops and subject diaries should be returned at this 
 
visit. 
5.1.6 
Unscheduled Visits 
Additional visits may be scheduled, as necessary, to ensure the safety and well-being of 
subjects. All additional exams should be fully documented in the source documents and 
on Unscheduled Visit eCRFs, as appropriate. Visits intended to fulfill scheduled visit 
requirements that fall outside the designated scheduled visit range, are not Unscheduled 
Visits. In these cases, the visit data will be collected and transcribed to the appropriate 
scheduled visit eCRF. 
If a subject is seen for multiple visits during a given visit time frame, the data from the 
visit that is intended to meet the protocol requirements for the scheduled visit should be 
captured on the visit eCRF. Where such a determination cannot be made, the first visit 
within the scheduled visit interval will be used for completion of the protocol required 
scheduled visit eCRF. Data from any additional visits within a scheduled visit interval 
will be captured on an Unscheduled Visit eCRF.  
5.1.7 
Missed Visits  
If a subject misses any scheduled follow-up visit and cannot be seen prior to the start of 
the visit range for the next scheduled follow-up visit, the visit is considered missed.  

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5.2 
Post-study Follow-up  
If a subject requires further follow-up on AEs upon discontinuation or completion of the 
study, the Investigator should schedule post-study follow-up visits, as necessary. Refer to 
Sections 6.0  for follow-up of AEs following study exit. 
5.3 
Study Completion  
The Sponsor Representative will contact the EC to inform them that the study is 
completed. 
5.3.1 
Early Study Termination 
If during the study it becomes evident to the Sponsor that the study should be stopped 
prematurely, then the study will be terminated and appropriate notification will be given 
to the Investigator(s), EC, and Local Health Authority, as applicable. The Sponsor will 
instruct the Investigators to stop dispensing study materials/treatment and to arrange for 
study closeout at each site. 
5.4 
Concomitant Medications/Therapy  
Administration of all medications used up to 30 days prior (immunosuppressants up to 90 
days prior) to study entry (date ICF signed) through study exit must be reported in the 
source and appropriate section of the Concomitant Medications eCRF. 
5.4.1 
Permitted Therapy 
 With the exception of the disallowed medications in Section 5.4.2, any medications 
that, in the Investigator’s judgment, will not interfere with the study parameters are 
allowed to be used concurrently.  
 Concomitant systemic medication that could affect dry eye (Section 5.4.2) but whose 
condition is stable for at least 1 month prior to Visit 1 will be continued, provided that 
it is not intended to alter the type, dose, and regimen of the medication during the 
trial. 
5.4.2 
Disallowed Therapy 
No other ocular medications (with the exception of run-in ART) may be used during the 
study. A disallowed medication may be administered in an emergency if the subject’s 
safety is in jeopardy. Disallowed medications include the following: 
 Ocular therapy (either eye) with any ophthalmic solutions, including tear substitutes 
except the run-in ART provided. 
 Systemic medication prescribed during the study and that could affect dry eye: 
antiparkinsonians, antidepressants, anxiolytics, neuroleptics, beta-blockers, clonidine, 
amiodarone, thiazide diuretics, anticholinergics, antihistamines, tetracyclines, anti-
androgens, hormone replacement therapy, oral retinoids, anti-inflammatories, 
antineoplastic agents and immunomodulators 1,31. 
 Any medication that the Investigator feels may interfere with study parameters. 

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5.5 
Treatment Compliance 
To document treatment compliance, subjects will be provided with diaries and instructed 
to record the frequency of instillations of investigational eye drops and the frequency of 
run-in ART instillations. Subjects will also be instructed to bring the diary to each visit.  
Any subject who does not follow instructions to a degree that, in the Sponsor or 
Investigator’s opinion, jeopardizes the subject’s well-being or the validity of the study, 
must be discontinued. 
5.6 
Protocol Deviations 
The date of and reason for protocol deviations will be documented in all cases.  
Protocol assessments will continue until the end of the study, unless the protocol 
deviations put the subject at risk or the subject’s condition requires that he/she be 
discontinued from the study. 
6.0 
ADVERSE EVENTS34 
6.1 
Definition of Adverse Events 
Information about every adverse event (AE) will be collected and recorded. 
 Any untoward medical occurrence, unintended disease or injury or any untoward 
clinical signs (including an abnormal laboratory finding) in subjects, users or 
other persons whether or not related to the investigational medical device. 
NOTE 1: This definition includes events related to the investigational device or 
the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related 
to investigational medical devices. 
 
A treatment-emergent AE (TEAE) is defined as an AE that meets either of the following 
conditions: 
 Begins on or after the first instillation of investigational medical device on Visit 2 
(Day 0). 
 Begins before Visit 2 (Day 0), and worsens in severity on or after the first 
instillation of investigational medical device on Visit 2 (Day 0). 
6.2 
Definition of Adverse Device Effect 
Information about every adverse device effect (ADE) will be collected and recorded. 
Adverse event related to the use of an investigational medical device. 
NOTE 1- This includes any adverse event resulting from insufficiencies or inadequacies 
in the instructions for use, the deployment, the implantation, the installation, the 
operation, or any malfunction of the investigational medical device. 
NOTE 2- This includes any event that is a result of a use error or intentional abnormal 
use of the investigational medical device. 

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The Investigator is obliged to determine the severity of the event and evaluate the causal 
relationship of the event to the investigational medical device. 
6.3 
Definition of Serious Adverse Events 
Information about every serious adverse event (SAE) will be collected and recorded.  
Adverse event that: 
 led to a death, injury or permanent impairment to a body structure or a body function 
 led to a serious deterioration in health of the subject, that either resulted in: 
- a life-threatening illness or injury, or  
- a permanent impairment of a body structure or a body function (e.g., blindness), or 
- in-patient hospitalization or prolongation of existing hospitalization, or 
- medical or surgical intervention to prevent life threatening illness 
 Led to foetal distress, foetal death or congenital abnormality or birth defect. 
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by 
the Clinical Investigation Plan, without a serious deterioration in health, is not considered 
a serious adverse event. 
A medically significant event that does not result in any of the above, may be considered 
an SAE when, based upon appropriate medical judgment, the event may jeopardize a 
subject condition and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
6.4 
Definition of Serious Adverse Device Effect 
Information about every serious adverse device effect (SADE) will be collected and 
recorded.  
Adverse device effect that has resulted in any of the consequences characteristic of a 
serious adverse event. 
6.5 
Definition of Unanticipated Serious Adverse Device Effect and Anticipated 
Serious Adverse Device Effect 
Information about every Unanticipated Serious Adverse Device Effect and Anticipated 
Serious Adverse Device Effect (ASADE) will be collected and recorded. 
Serious adverse device effect which by its nature, incidence, severity or outcome has not 
been identified in the current version of the risk analysis report is considered as an 
unanticipated serious adverse device effect (USADE).  
An anticipated serious adverse device effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk analysis report. 
6.6 
Definition of Device Deficiency (DD) 
Information about Device Deficiency (DD) will be collected and recorded. 

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Inadequacy of an investigational medical device related to its identity, quality, durability, 
reliability, safety or performance. This may include malfunctions, use error, or 
inadequacy in the information supplied by the manufacturer. 
Device Deficiency that might have led to a SAE if: 
a) suitable action had not been taken or 
b) intervention had not been made or 
c) circumstances had been less fortunate 
6.7 
Causality assessment 
The relationship between the use of the investigational medical device (including the 
procedure) and the occurrence of each adverse event shall be assessed and categorized as 
follows: 
1) Not related: relationship to the device or procedures can be excluded when:  
- the event is not a known side effect of the product category the device belongs to or of 
similar devices and procedures;  
- the event has no temporal relationship with the use of the investigational device or the 
procedures;  
- the event does not follow a known response pattern to the medical device (if the response 
pattern is previously known) and is biologically implausible;  
- the discontinuation of medical device application or the reduction of the level of 
activation/exposure - when clinically feasible - and reintroduction of its use (or increase of 
the level of activation/exposure), do not impact on the event;  
- the event involves a body-site or an organ not expected to be affected by the device or 
procedure;  
- the event can be attributed to another cause (e.g. an underlying or concurrent illness/ 
clinical condition, an effect of another device, drug, treatment or other risk factors);  
- harms to the subject are not clearly due to use error. 
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the event.  
2) Unlikely: the relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be obtained.  
 
3) Possible: the relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (e.g. an underlying or concurrent 
illness/ clinical condition or/and an effect of another device, drug or treatment). Cases where 
relatedness cannot be assessed or no information has been obtained should also be classified 
as possible.  
4) Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably be explained by another cause, but additional information may 
be obtained.  
5) Causal relationship (Certain): the event is associated with the investigational device or 
with procedures beyond reasonable doubt when:  

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- the event is a known side effect of the product category the device belongs to or of similar 
devices and procedures;  
- the event has a temporal relationship with investigational device use/application or 
procedures;  
- the event involves a body-site or organ that  
   . the investigational device or procedures are applied to;  
   . the investigational device or procedures have an effect on;  
- the event follows a known response pattern to the medical device (if the response pattern is 
previously known);  
- the discontinuation of medical device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure), impact on the event (when clinically feasible);  
- other possible causes (e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment) have been adequately ruled out;  
- harm to the subject is due to error in use. 
In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the event.  
 
Related adverse events (including serious adverse events) are AEs with at least a possible 
relationship to the investigational medical device or procedure. 
6.8 
Reporting Adverse Events and Follow-up 
Throughout the course of the study, efforts will be made by the Investigator to remain 
alert to possible AEs that are either systemic or ocular in nature. The period of 
observation for collection of AEs extends from the time the subject gives informed 
consent until the last study visit, Visit 5 (Day 90 ± 10 days). The first concern will be the 
safety of the subject, and appropriate medical intervention will be made. 
The Investigator or designee will elicit reports of AEs from the subject at each study visit 
and record all AEs. An assessment of each event will be made by the Investigator as to 
severity and causal relationship to investigational medical device, as well as, start and 
end dates. 
The subject will be instructed to contact the Investigator immediately if any unusual 
systemic or ocular AEs occur between visits. 
Additional assessments/visits may be scheduled, as necessary, to ensure the safety of the 
subject, during the study period. A subject who discontinues due to an AE should be seen 
for post-study follow-up visits as necessary. 
Non-serious AEs that are ongoing at the study exit visit will be followed by the 
Investigator up to 30 days after the subject exits the study.  
6.9 
Reporting Serious Adverse Events and Follow-up 
Any SAE must be reported to the Sponsor, independent of the circumstance or suspected 
cause, within 24 hours from the time the event was reported to the Investigator.  

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All SAEs (whether or not considered related) experienced from consent through 30 days 
from the last dose of the investigational medical device must be reported to the Sponsor 
regardless of the causal relationship to the investigational medical device. Following 
Visit 5 (Study Exit, Day 90 ± 10 days) + 30 days or early discontinuation from the 
study+30 days, only SAEs considered related to the study should be reported within 24 
hours to the Sponsor (cf Personnel and Facilities page).  
Within 24 hours of notification the Investigator will fax or send by e-mail using contact 
details provided in Personnel and Facilities page completed Serious Adverse Event 
Report to the Sponsor contact. For SAEs with fatal outcomes, a summary of available 
autopsy findings should be submitted within 24 hours from the time the document was 
reported to the Investigator. 
The Sponsor / Sponsor Representative will notify the EC in writing of any SAE in 
accordance with the EC requirements. 
The Sponsor will be responsible for submitting SAE reports to regulatory authorities 
based on applicable regulations. The Sponsor / Sponsor Representative will also send 
notifications to all participating Investigators of any SAE that is unanticipated and 
associated with the study. It is important that the Principal Investigator reviews these 
expedited reports, as they contain safety information that may be relevant to each of the 
participating subjects. For related SAEs that resulted in death, life-threatening events, 
imminent risk of death, or serious injury/illness that requires prompt remedial action, 
SAEs will be submitted to the applicable regulatory authorities within 2 calendar days 
from the time the Sponsor becomes aware of the event. All other related SAEs and 
investigational medical device deficiency that might have led to an SAE will be 
submitted within 7 calendar days.  
If the Investigator becomes aware of any new information regarding an SAE (ie, 
resolution, change in condition, or new treatment), a new Serious Adverse Event Form 
must be completed and faxed or e-mailed to the Sponsor using contact details provided in 
Personnel and Facilities page within 24 hours. The original SAE form is not to be altered. 
The report should describe whether the event has resolved or continues and how the event 
was treated.  
Serious adverse events that have previously been reported and continue after the subject’s 
discontinuation or completion of the study will be followed until their medical endpoints 
are determined or until no further change in the conditions is expected. The events and 
endpoints will be reported in writing by the Investigator to the Sponsor (cf Personnel and 
Facilities page).  
Following the subject's discontinuation or completion of the study, for any timeframe 
afterward deemed medically significant, any SAEs, which are assessed as causally related 
to the investigational medical device, should also be reported to the Sponsor (cf 
Personnel and Facilities page). 
6.10 
Reporting Pregnancies and Follow-up 
In the event that a study subject becomes pregnant, a notification will be sent to the 
Sponsor (cf Personnel and Facilities page), regardless of whether an AE/SAE was 
reported. All pregnancies will be followed to term. Every effort will be made to obtain 

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the health status of the mother and infant or the fetus (in cases of miscarriage or 
therapeutic abortion). 
6.11 
Reporting Complaints for Ancillary Marketed Bausch & Lomb Products 
For Bausch & Lomb marketed products used as ancillary products in the study, the 
Investigator should report any complaints, malfunctions, or similar events related to these 
products as they would in their normal clinical practice. 
6.12 
Submitting an Expedited Safety Report to Competent Authorities 
All SAE must be fully recorded and notified to all competent authorities of member 
States in which the clinical investigation is being performed within the required 
timeframe (whether or not the event is unanticipated or anticipated) In addition, any 
unanticipated SAE related to a subject’s participation in the study (or conduct of study), 
regardless if the investigational product was administered, will be evaluated by 
Materiovigilance to determine if expedited reporting is required. For example, an 
unanticipated, serious and severe reaction which could be associated to the study 
procedures, and which could modify the study conduct requires expedited reporting. 
The Sponsor will compile the report and submit the expedited safety report to the EC and 
competent authority within the required reporting timeframe.  
 
7.0 
STATISTICAL METHODS 
7.1 
Study Endpoints 
7.1.1 
Primary Performance Endpoints 
The primary performance endpoint for this study is mean change from baseline (CFB) in 
the study eye at Visit 4 (Day 28 ± 3 days) in ocular surface fluorescein staining score, 
combining corneal, nasal and temporal bulbar conjunctival fluorescein staining, each 
graded 0 to 5, according to the Oxford Scheme. The investigator will record the total 
score per eye (the maximum score is 15 [maximum of 5 for each of the 3 areas]). 
The study eye will be the eligible eye with the highest total ocular surface fluorescein 
staining score at baseline or, if both eyes are eligible and have the same score, the study 
eye will be the right eye. 
7.1.2 
Secondary Performance Endpoints 
The secondary performance endpoints include the following: 
 Mean CFB in the study eye at Visit 5 in total ocular surface fluorescein staining 
score 
 Mean CFB in the study eye in fluorescein staining score for each area (cornea, 
nasal conjunctiva and temporal conjunctiva) at Visits 4 and 5 
 Mean CFB in the study eye in TFBUT at Visits 4 and 5  
 Evolution from baseline of Ocular Surface Disease-Quality of Life (OSD-QoL®) 
questionnaire scores at Visit 5 for all 7 dimensions: Daily Activities, Handicap 

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and Work Difficulties, Giving up Make-up, Acknowledgement, Acceptance, Fear 
for the Future, and Emotional Well-Being.  
 Mean CFB in the global sum score of dry eye symptoms at Visits 4 and 5: 
sensation of dryness, foreign body, burning, stinging, itching, blurred vision, 
sensitivity to light, each graded from 0 to 4 
 Mean CFB in the study eye in volume of tear fluid secretion as assessed by the 
unanaesthetized Schirmer test at Visit 4 
 Frequency of investigational eye drop instillations, as reported in subject diary  
7.1.3 
Safety Endpoints 
The safety endpoints include the following: 
 Occurrence rates of ocular and non-ocular TEAEs.  
 Visual Acuity measured with habitual correction, using Monoyer chart. 
7.1.4 
Tolerability and Ease-of-Use Endpoints 
The tolerability endpoints are as follows: 
 Assessment of investigational eye drop tolerability upon instillation as reported in 
subject diary  
 Assessment of ease-of-use of the bottle as reported in subject diary 
7.2 
Hypotheses 
H0: (μCBL-102 Eye Drops  - μVismed ≥ 2) 
versus 
H1: (μCBL-102 Eye Drops  - μVismed < 2) 
Where µ= mean CFB in the study eye at Visit 4 (Day 28 ± 3 days) in total ocular surface 
staining score. 
7.3 
Sample Size 
A validated macro SAS v. 9.4 was used for sample size calculation. Assuming a 
unilateral α risk of 2.5%, a β risk of 10% (90% power), a non-inferiority margin of 2 and 
a standard deviation of 2.5 on the primary endpoint22, a sample size of 33 evaluable 
subjects per treatment group is necessary to demonstrate non-inferiority of CBL-102 Eye 
Drops to Vismed® Multi. 
With a projected dropout rate of 10% and a protocol violation rate of 10%, a total of 
approximately 84 subjects with moderate to severe dry eye will be randomized in this 
clinical investigation. 
 
7.4 
Randomization 
A total of 84 subjects will be randomized to receive CBL-102 Eye Drops or Vismed® 
Multi in a 1:1 ratio. 

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7.5 
Analysis Sets 
The analysis sets that will be used in this study are: 
 Intent-to-Treat (ITT) Population: includes all subjects who were randomized, 
who received at least 1 eye drop instillation and have a baseline and at least 1 
post-baseline assessment. The ITT population will be used to analyze all 
performance endpoints. Subjects will be analyzed according to the treatment to 
which they were randomized. It is expected that subjects will be dispensed a 
correct investigational medical device. However, if a subject does receive 
incorrect investigational medical device, the impact to the study results will be 
investigated using ad hoc analyses. 
 Per Protocol (PP) Population: includes all of the subjects in the ITT population 
who remained in the study through Visit 4 (Day 28) and who did not have any 
major protocol deviations. The PP population will be used for the primary 
performance analysis and for secondary performance endpoints.  
 Safety Population: includes all subjects who received at least 1 dose of 
investigational eye drops. 
7.6 
Statistical Analysis 
7.6.1 
Methods of Analysis 
Summaries for continuous variables will include the sample size (n), mean, standard 
deviation (SD), median, minimum, and maximum. Calculations will be based on the 
number of subjects (or eyes) with non-missing values for the study population being 
summarized.  
Summaries for discrete variables will include frequencies and percentages. Percentages 
will be based on the number of subjects (eyes) with non-missing values. The denominator 
for percents will be the number of subjects (eyes) from the study population being 
analyzed. For each subject, baseline will be defined as the last non-missing measure prior 
to initiation of investigational treatment and endpoint will be defined as the measure of 
any follow-up scheduled visit. Change from baseline will be defined as (follow-up 
measure – baseline measure) and will be calculated if both baseline and follow-up 
endpoint are not missing.  
The study eye will be the eligible eye with the highest total ocular surface fluorescein 
staining score at baseline or, if both eyes are eligible and have the same score, the study 
eye will be the right eye.  
For each subject, the number of investigational eye drops used per day and for how many 
days during the course of study will be evaluated. It is expected that most subjects will 
not perform more than 6 applications per day on a continued regularly basis during the 
study.  
The primary performance endpoint (mean change from baseline in total ocular surface 
fluorescein staining score) will be analyzed using analysis of covariance (ANCOVA) 
model. The model will include terms of treatment and baseline ocular surface staining 
score as covariates. Sensitivity analyses including investigator site as covariate will be 
performed. A 2-sided 95% confidence interval (CI) based on the ANCOVA model will 
be computed for the effect difference (CBL-102 Eye Drops minus Vismed® Multi). Non-

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41 
inferiority will be demonstrated if the upper bound of the 95% CI is less than 2 grades in 
the PP analysis. Supportive analysis of the primary endpoint will be performed on ITT 
population. The same ANCOVA model used to analyze the primary endpoint will be 
employed to analyze secondary continuous performance endpoints. Supportive analyses 
on secondary performance endpoints will be performed in the ITT and PP populations.  
Ocular biomicroscopic assessment will be summarized at each visit using discrete 
summary statistics and presented by treatment.  
Treatment-emergent systemic AEs will be summarized using discrete summary statistics 
at the subject and event level by system organ class and preferred term for each treatment 
group. Treatment-emergent ocular AEs will be summarized for treated eyes and fellow 
eyes separately. Similarly, TEAEs will be summarized by severity and relationship 
separately. 
Categorical endpoints will be analyzed using Fisher’s exact test or chi-square test where 
it is appropriate. 
All the statistical tests will be performed at significance level α=0.05. 
The details of the analysis will be documented in the Statistical Analysis Plan (SAP) 
which will be reviewed at the masked data review and finalized before breaking the 
treatment codes. 
7.6.2 
Subject Demographics and Baseline Characteristics 
Subject demographics of gender and age will be summarized using discrete summary 
statistics and presented by treatment group. Age will also be summarized using 
continuous summary statistics. Total ocular surface staining score at baseline will be 
summarized using continuous summary statistics. 
7.6.3 
Medical History 
Non-ocular and ocular medical history will be summarized using discrete summary 
statistics and presented by treatment group at the subject and event level by system organ 
class and preferred term. Ocular medical history will be similarly summarized separately 
at the subject level for study and fellow eyes separately. If a subject reports the same 
preferred term multiple times within the same system organ class, then that preferred 
term will only be reported once within that system organ class. As with the preferred 
term, if a subject reports multiple conditions within the same system organ class, then 
that system organ class will only be reported once.  
7.6.4 
Prior and Concomitant Medications 
Ocular and non-ocular prior and concomitant medications will be summarized in separate 
tables, by Anatomical Therapeutic Classification (ATC) text and preferred term using 
discrete summary statistics and presented by treatment group. Subjects may have more 
than one medication per ATC text. At each level of subject summarization, a subject will 
be counted once if he/she reports one or more medications. Percentages will be based on 
the number of subjects in each treatment group. 

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7.6.5 
Subject Discontinuation 
A disposition of subjects includes the number and percentage of subjects in each of the 
following categories: 
 Subjects in the ITT population 
 Subjects in the Safety population 
 Subjects in the PP population 
For each population, the number and percentage of subjects who completed and 
discontinued from the study will be summarized using discrete summary statistics and 
presented by treatment group. The primary reason for study discontinuation described in 
Section 2.2.3 will also be summarized for each treatment group. 
7.6.6 
Protocol Deviations 
The number of subjects within each type of protocol deviations will be presented using 
listings and discrete summary statistics as appropriate. Protocol deviations will include, 
but are not limited to: 
 Non-compliance with any scheduled study visit 
 Non-compliance with investigational medical device treatment 
 Disallowed concomitant medications 
 Non-compliance with study inclusion or exclusion criteria 
 Non-compliance with study assessment procedures 
 
Deviations with a significant impact on the primary endpoint will be assessed as major 
deviations. 
7.6.7 
Treatment Compliance 
Subject treatment compliance rate will be calculated by dividing the total frequency of 
drop instillations recorded in the diary for a subject across the entire treatment period by 
the total number of days times the expected frequency of drop instillations per day and 
then multiplying by 100. e.g., ([total frequency of drop instillations recorded in the diary 
across the entire treatment period] / [(the total number of days of exposure) x (the 
expected frequency of drop instillations per day)]) x 100. 
Overall investigational medical device treatment compliance will be summarized using 
continuous summary statistics and presented by treatment group. Treatment compliance 
will also be presented using discrete summary statistics in the following categories: (< 
80%, 80-120%, and > 120%). Percentages will be calculated out of the number of 
subjects who returned diaries from that dosing period. The number and percentage of 
subjects in each compliance rate category will be presented by treatment group. 
7.6.8 
Treatment Exposure 
Extent of exposure is defined as the total number of days from the first dose date to the 
last dose date, as recorded at the randomization study visit and the study exit eCRF page. 
For subjects who are lost to follow-up, extent of exposure will be calculated based on the 

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last study visit attended. The extent of exposure will be summarized using continuous 
summary statistics and presented by treatment group. 
7.6.9 
Missing Data 
For subjects who discontinue the study early, analyses of change from baseline to 
endpoint for continuous variables will be based on the last non-missing post-baseline data 
(last observation carried forward data imputation methodology). 
8.0 
DATA QUALITY ASSURANCE  
8.1 
Study Monitoring 
The Sponsor Representatives must be allowed to visit all study site locations to assess the 
data, quality, and study integrity in a manner consistent with applicable health authority 
regulations and the procedures adopted by the Sponsor Representatives. 
Prior to the start of the study the Sponsor Representatives will review the protocol, eCRF, 
regulatory obligations, and other material or equipment relevant to the conduct of the 
study with the Investigator/Sub-Investigator and relevant study site personnel.  
Monitoring visits and telephone consultations will occur per the monitoring plan during 
the course of the investigation to verify the following: 
 The rights and well-being of subjects are protected 
 The conduct of the investigation is in compliance with the currently approved 
protocol/amendment, ICH GCPs, ISO 14155, and EC requirements 
 The integrity of the data, including adequate study documentation 
 The facilities remain acceptable 
 The Investigator and site personnel remains qualified and able to conduct the 
study 
 Test article accountability 
During the course of the study, if the Sponsor determines that an Investigator is  
non-compliant with the study plan and/or applicable regulatory requirements, the 
Sponsor, in cooperation with the Sponsor Representatives, will take action to secure 
compliance. In addition, the Sponsor may terminate the Investigator’s participation in the 
study if appropriate, or if the Investigator remains non-compliant despite the Sponsor’s 
actions.  
8.2 
Source Documentation 
All medical information obtained at each study visit must be recorded in the subject’s 
record (source documentation) in real time as it is collected. Source documentation 
consists of original subject documents, as well as data and records with information 
relevant to the subject and his/her participation in the study.  
Subject completed forms and diaries are considered source data. Designated site 
personnel will pre-record appropriate start dates of run-in ART or investigational eye 
drop administration and subject identifiers (year of birth and/or subject study number) on 
the diary. With this exception, only subjects are to record information in subject diaries. 
In no instance, should an Investigator or study site personnel record any data or make 

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changes to subject completed forms. The Investigator or designee should review diary 
entries during study visits. If an entry is found to be illegible or a mistake is found (eg, 
incorrect year was recorded), the subject should be instructed to edit the entry by drawing 
a single line through the original entry, entering the new information, and adding the date 
and year of birth next to the change.   
8.3 
Case Report Forms and Data Verification 
Subject data required by this protocol are to be recorded on eCRFs. With the exception of 
subject diaries, the Investigator and his/her study site personnel will be responsible for 
completing the eCRFs. The Investigator is required to verify that all of the requested 
information is accurately recorded on the eCRFs. All information requested on the eCRFs 
needs to be supplied, including subject identification and date(s), assessment values, etc., 
and any omission or discrepancy will require explanation. All information on eCRFs 
must be traceable to source documents. Subject diaries will be handled as described in 
Section 5.5, Treatment Compliance. Diaries will be sent to Sponsor Representative’s 
Data Management for data capture in the database. A copy of the diary will be left at site 
as  source document. 
The study monitor will be responsible for reviewing and verifying the data recorded on 
the eCRFs, utilizing the original source documentation and will query discrepant 
findings. The Investigator and study site personnel will be responsible for answering all 
queries. The eCRFs will be submitted to the Sponsor Representative for quality assurance 
review, and statistical analysis.  
A copy of the eCRFs (on CD or DVD) will be retained by the Investigator, who must 
ensure that it is stored in a secure place. 
8.4 
Recording of Data and Retention of Documents 
Subject data recorded on eCRFs during the study will be documented in a coded fashion. 
The subject will only be identified by the subject number and by year of birth, if also 
required. Confidentiality of subject records must be maintained to ensure adherence to 
applicable local privacy regulations. 
The Investigator must retain essential documents indefinitely after the completion of the 
study, unless otherwise notified by the Sponsor. The Investigator agrees to adhere to the 
document retention procedures when signing the protocol Investigator Statement of 
Approval.  
Essential documents include but are not limited to the following: 
 EC and /or Competent Authority approvals for the study protocol, all 
amendments, ICF(s), and advertisements 
 EC correspondence and reports (eg, SAE reports, protocol deviations, and safety 
updates) 
 Regulatory documents (eg, financial disclosure and delegation of authority forms) 
 All source documents  
 eCRFs (on CD or DVD) 
 Subject’s signed ICF 
 Accountability records for the test article(s) 

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 Correspondence from and to the Sponsor 
 Any other documents relevant to the conduct of the study 
In the event that the Investigator withdraws from the study (eg, retirement, relocation), 
study records will be transferred to a mutually agreed upon designee (eg, another 
Investigator, site IRB/EC). The Investigator will provide notice of such transfer in writing 
to the Sponsor. 
8.5 
Auditing Procedures 
Audits of clinical research activities may take place. A regulatory authority may also 
wish to conduct an inspection (during the study or after its completion). If an inspection 
is requested by a regulatory authority and/or IRB/EC, the Investigator must inform the 
Sponsor immediately that this request has been made. 
8.6 
Institutional Review Board/Ethics Committee Approval 
The Investigator should ensure that his/her participation in the study, in addition to the 
protocol, subject recruitment materials (written information or materials including web 
pages, radio advertisements, television spots or written text developed to encourage 
subject enrollment) and the ICF to be used in this study are approved by their institution 
IRB/EC, or if not using their institution's IRB/EC, approved by the reviewing central 
IRB/EC prior to entering any subjects in the study. Documentation of IRB/EC approval 
of the study protocol and informed consent must be provided to the Sponsor prior to 
initiation of the study. In addition, the Investigator must ensure that the reviewing 
IRB/EC has provided approval for any protocol amendments prior to implementation. If 
the amendment necessitates a revision to the ICF, the Investigator should ensure the 
revised form is also submitted to and approved by the Sponsor and the IRB/EC prior to 
implementation.  
8.7 
Publication of Results 
All study data generated as a result of this study will be regarded as confidential, until 
appropriate analysis and review by the Sponsor or its designee and the Investigator(s) are 
completed. The results of the study may be published or presented by the Investigator(s) 
after the review by, and in consultation and agreement with the Sponsor, and such that 
confidential or proprietary information is not disclosed. 
Prior to publication or presentation, a copy of the final text should be forwarded by the 
Investigator(s) to the Sponsor or its designee, for comment. Such comments shall aim to 
ensure the scientific integrity of the proposed publications and/or presentations and 
ensure that the data and material referring to Bausch & Lomb Incorporated products and 
activities receive fair, accurate, and reasonable presentation. 

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9.0 
REFERENCES  
1. Smith JA, et al. The Epidemiology of Dry Eye Disease: Report of the Epidemiology 
Subcommittee of the International Dry Eye WorkShop (2007). The Ocular Surface. 2007;5:93-
107. 
2. Lemp MA, Baudouin C, Baum J, et al. The Definition and Classification of Dry Eye Disease: 
Report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop 
(2007). The Ocular Surface. 2007;5:75-92. 
3. Lemp MA. Advances in Understanding and Managing Dry Eye Disease. American Journal of 
Ophthalmology. 2008;146:350-356. 
4. Schaumberg DA et al. Dry Eye a Serious Public Health Problem. Ophthalmology Times. 
10/15/08; p64. 
5. Foulks GN. The correlation between the tear film lipid layer and dry eye disease. Surv 
Ophthalmol. 2007;52:369-374. 
6. Lemp MA. Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry 
Eyes. CLAO J. 1995;21:221-232. 
7. Pflugfelder SC, Geerling G, Kinoshita S et al. Management and Therapy of Dry Eye Disease: 
Report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop 
(2007). The Ocular Surface. 2007;5:163-178 
8. Berry M, Pastis WK, Ellingham RB, Frost L, Corfield AP, Easty DL. Hyaluronan in dry eye 
and contact lens wearers. Adv Exp Med Biol. 1998;438:785-790. 
9. Fukuda M, Miyamoto Y, Miyara Y, Mishima H, Otori T. Hyaluronic acid concentration in 
human tear fluids. Invest Ophthalmol Vis Sci. 1996;37: S848. 
10. Nakamura M, Hikida M, Nakano T, Ito S, Hamano T, Kinoshita S. Characterization of water 
retentive properties of hyaluronan. Cornea; 1993,12(5):433-6. 
11.Snibson GR, Greaves JL, Soper ND, Tiffany JM, Wilson CG, Bron AJ. Ocular surface 
residence times of artificial tear solutions.Cornea. 1992 Jul;11(4):288-93. 
12. Snibson GR, Greaves JL, Soper ND, Prydal JI, Wilson CG, Bron AJ.Precorneal residence 
times of sodium hyaluronate solutions studied by quantitative gamma scintigraphy. Eye. 1990;4 ( 
Pt 4):594-602. 
13. Camillieri G, Bucolo C, Rossi S, Drago F. Hyaluronan-induced stimulation of corneal wound 
healing is a pure pharmacological effect. J Ocul Pharmacol Ther.: 2004 Dec;20(6): 548-53. 
14. Sweetman SC. The complete drug reference, 33rd ed. London: Pharmaceutical Press, 
2002;1620. 
15. Polack F, McNiece M. The Treatment of Dry Eyes With Na Hyaluronate (Healon). Cornea. 
1982;1:1333. 
16. DeLuise V, Peterson W. The Use of Topical Healon Tears in the Management of Refractory 
Dry-Eye Syndrome. Ann Ophthalmol. 1984;16:823-824. 
17. Stuart JC, Linn JG. Dilute Sodium Hyaluronate (Healon) in the Treatment of Ocular Surface 
Disorders. Ann Ophthalmol. 1985;17:190-192. 
18. Sand B, Marner K, Norn M. Sodium Hyaluronate in the Treatment of Keratoconjuctivitis 
Sicca. Acta Ophthalmol. 1989;67:181-183. 

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47 
19. Iester M, Orsoni GJ, Gamba G, Taffara M, Mangiafico P, Giuffrida S, Rolando M: 
Improvements of the ocular surface using hypotonic 0.4% hyaluronic acid drops in 
keratoconjunctivitis sicca. Eye 14: 892-898, 2000. 
20. Johnson ME, Murphy PJ, Boulton M. Effectiveness of sodium hyaluronate eyedrops in the 
treatment of dry eye. Graefes Arch Clin Exp Ophthalmol. 2006 Jan;244(1): 109-12. 
21. Baeyens V, Bron A, Baudouin C. Efficacy of 0.18% sodium hyaluronate ophthalmic solution 
in the treatment of signs and symptoms of dry eye disease. JFOphtalmol. 2012. 
22. Baudouin C, Cochener B, Pisella PJ et al. Randomized phase III study comparing 
osmoprotective carboxymethylcellulose with sodium hyaluronate in dry eye disease. European J 
Ophthalmol 2012; 22:751-61 
23. Johnson ME, Murphy PJ, Boulton M. Carbomer and sodium hyaluronate eyedrops for 
moderate dry eye treatment. Optom Vis Sci. 2008 Aug;85(8):750-7. 
24. Chiambaretta F, Pouliquen P, Menerath JM, Pilotaz F, Rebika H, Rigal D. [Efficacy and 
safety of a fluid carbomer gel versus a conventional carbomer gel in dry eye treatment]. J Fr 
Ophtalmol. 2004 Feb;27(2):130-5. (French). 
25. Sullivan LJ, McCurrach F, Lee S, Taylor HR, Rolando M, Marechal-Courtois C, Creuzot-
Garcher C, Easty DL, Karabatsas C, Bingh Hoh M, Faschinger C, Laroche L. Efficacy and safety 
of 0.3% carbomer gel compared to placebo in patients with moderateto- severe dry eye syndrome. 
Ophthalmology. 1997 Sep;104(9):1402-8. 
26. Bron AJ, Daubas P, Siou-Mermet R, Trinquand C. Comparison of the efficacy and safety of 
two eye gels in the treatment of dry eyes: Lacrinorm and Viscotears. Eye (Lond). 1998;12 ( Pt 
5):839 47. 
27. Rantamäki AH, Seppänen-Laakso T, Oresic M, Jauhiainen M, Holopainen JM. Human tear 
fluid lipidome: from composition to function. PLoS One. 2011 May 5;6(5):e19553. 
28. Telenius J, Koivuniemi A, Kulovesi P, Holopainen JM, Vattulainen I. Role of neutral lipids in 
tear fluid lipid layer: coarse-grained simulation study. Langmuir. 2012 Dec 11;28(49):17092-100. 
29. Foulks GN. Challenges and Pitfalls in Clinical Trials of Treatments for Dry Eyes. The Ocular 
Surface. 2003;1:20-30.  
30.  Bron A. Grading of corneal and conjunctival staining in the context of other dry eye tests. 
Cornea.2003; 22: 640-650 
31. Liotet S, Van Bijterveld OP, Bletry O et al. L’oeil sec. Rapport de la Société Française 
d’Ophtalmologie. Paris Masson 1987. 
32. Guillemin I, Begley C, Chalmers R et al. Appraisal of Patient-Reported Outcome instruments 
available for randomized clinical trials in dry eye: revisiting the standards. The Ocular Surface. 
2012; 10:84-99 
33. Baudouin C, Aragona P, Van Setten G et al. Diagnosing the severity of dry eye : a clear and 
practical algorithm. B J Ophthalmol 2014; 98: 1168-1176 
34. MEDDEV 2.7/3 revision 3. May 2015. Guidelines on medical devices 
35. Arita R, Minura I, Morishige N et al. Development of definitive and reliable grading scales 
for meibomian gland dysfunction. Am J Ophthalmol. 2016;169: 125–137. 
 
. 

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A-1 
APPENDIX A: 
SCHEDULE OF VISITS AND PARAMETERS  
All study tasks should be performed by qualified study site personnel as indicated on the delegation of authority log under the supervision of the 
Principal Investigator. Furthermore, all ocular signs must be evaluated by an ophthalmologist. 
 
PROCEDURE/ASSESSMENTS 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Screening 
Inclusion 
Follow-up 
Telephone calld 
Follow-up 
Study Exit 
ART run in 
Baseline 
Day -14 (up to -16 days) 
Day 0 
Day 7 (± 1 day) 
Day 28 (± 3 days) 
Day 90 (± 10 days) 
Informed Consent 
X 
 
 
 
 
Demographic data 
X 
 
 
 
 
Current and relevant medical and ocular history 
X 
 
 
 
 
Pregnancy test, if applicable 
X 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
Dry eye symptoms 
X 
X 
 
X 
X 
OSD-QoL® questionnaire 
 
X 
 
 
X 
Visual acuity 
X 
X 
Xe 
X 
X 
Biomicroscopy 
X 
X 
Xe 
X 
X 
TFBUT 
X 
X 
 
X 
X 
Fluorescein staining 
X 
X 
 
X 
X 
Schirmer test 
 
X 
 
X 
 
Eligibility determination 
X 
X 
 
 
 
Randomization 
 
X 
 
 
 
Dispense run-in ART 
X 
 
 
 
 

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A-2 
PROCEDURE/ASSESSMENTS 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Screening 
Inclusion 
Follow-up 
Telephone calld 
Follow-up 
Study Exit 
ART run in 
Baseline 
Day -14 (up to -16 days) 
Day 0 
Day 7 (± 1 day) 
Day 28 (± 3 days) 
Day 90 (± 10 days) 
Collect run-in ART 
 
X 
 
 
 
Dispense diary a 
X 
X 
 
X 
 
Collect diary b 
 
X 
 
X 
X 
Dispense investigational eye drops  
 
X 
 
X 
 
Collect investigational eye drops in a sealed 
container 
 
 
 
 
X 
Review subject diary for compliance 
 
X 
Xe 
X 
X 
Adverse events c 
X 
X 
X 
X 
X 
Exit subject 
 
 
 
 
X 
Abbreviations:  ART = artificial tears; OSD-QoL = Ocular Surface Disease-Quality of Life; TFBUT = tear film break-up time  
a Diary A will be dispensed at Visit 1, Diary B will be dispensed at Visit 2, and Diary C will be dispensed at Visit 4   
b Diary A will be collected at Visit 2, Diary B will be collected at Visit 4, and Diary C will be collected at Visit 5   
c Adverse events will be collected from the time the subject signs the ICF to study exit  
d  Telephone call assessment for compliance and collection of adverse events  by the Investigator or designee  The Investigator should determine whether subject should come for a 
visit or not  
e If visit performed 

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APPENDIX B: 
METHODS OF CLINICAL EVALUATION  
Any changes to the procedures described in this appendix will be provided under separate 
cover. 
1. OCULAR 
SURFACE 
DISEASE-QUALITY 
of 
LIFE 
(OSD-QoL®) 
QUESTIONNAIRE 
Subjects will be instructed to complete the OSD-QoL® questionnaire at Visits 2 and 5 or, 
in case of premature study discontinuation, at the time of withdrawal.  
OSD-QoL® is a specific questionnaire for evaluating OSD symptoms impact on patients’ 
health-related quality of life (HRQoL)26. The Sponsor will provide OSD-QoL® to 
designated personnel at the site as part of the source documents, who will provide it to 
the subject for completion. The questionnaire includes 28 items divided into seven 
dimensions: “Daily activities,” “Difficulties with work and handicap,” “Giving up make-
up,” “Acknowledgement of the disease,” “Acceptance of the disease,” “Fear for the 
future” and “Emotional well-being.”  
OSD-QoL® is a validated and reliable instrument for measuring dry eye disease severity 
and impairment in HRQoL.  
2. SYMPTOMS OF DRY EYE 
Discomfort linked to dry eye will be evaluated through 7 items: sensation of dryness, 
foreign body, burning, stinging, pruritus, blurred vision and sensitivity to light, each 
graded from 0 to 42: 
0 = Absent 
1 = Mild and/or episodic; occurs under environmental stress 
2 = Moderate, episodic or chronic, stress or no stress 
3 = Severe, frequent or constant without stress 
4 = Severe and/or disabling and constant 
3. VISUAL ACUITY 
Visual acuity through historical correction will be measured for both eyes at each visit 
using a Monoyer chart. The same VA testing method is to be employed for all study 
visits for each subject. Visual acuity will be entered in the eCRF in decimal format. 
4. BIOMICROSCOPY 
Slit lamp examination of lids, conjunctiva and cornea will be performed without pupil 
dilation at all study visits for each eye.  
Using a high power field slit beam of 1 mm x 1 mm, perform the following assessments: 
At Visits 1 and 2 only: 
Eyelid Margin Hyperemia: Assess degree of eyelid margin hyperemia35. 
0 = Absent: no or slight redness in lid margin conjunctiva and no telangiectasia crossing 
meibomian gland orifices 
 

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B-2 
1 = Mild: redness in lid margin conjunctiva and no telangiectasia crossing meibomian 
gland orifices    
 
2 = Moderate: redness in lid margin conjunctiva and telangiectasia crossing meibomian 
gland orifices with a distribution of less than half of the full length of the lid 
3 = Severe: redness in lid margin conjunctiva and telangiectasia crossing meibomian 
gland orifices with a distribution of half or more of the full length of the lid  
Eyelid Debris: Assess degree of eyelid debris. 
0 = Absent 
 
1 = Mild  
 
2 = Moderate   
3 = Severe 
Plugging of Meibomian Glands:  Assess degree of plugging of meibomian glands35. 
0 = Absent: no plugging of gland orifices 
 
1 = Mild: fewer than 3 pluggings of gland orifices    
2 = Moderate: three or more pluggings of gland orifices with a distribution of less than 
half of the full length of the lid   
 
3 = Severe: three or more pluggings of gland orifices with a distribution of half or more 
of the full length of the lid 
 
At all Visits (Visits 1 – 5): 
Eyelid Erythema: Assess upper and lower eyelids and surrounding tissues for abnormal 
skin redness. 
0 = Absent 
 
1 = Mild  
 
2 = Moderate   
3 = Severe 
 
Eyelid Swelling:  Assess degree of eyelid swelling. 
0 = Absent 
 
1 = Mild  
 
2 = Moderate   
3 = Severe  
 
Ocular Discharge:  Assess degree of ocular discharge 
0 = Absent 
1 = Mild 
Small amount of mucopurulent or purulent discharge noted in the lower 
cul-de-sac. No true matting of the eyelids in the morning upon awakening. 
2 = Moderate Moderate amount of mucopurulent or purulent discharge noted in the 
lower cul-de-sac. Frank matting together of the eyelids in the morning 
upon awakening. 

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B-3 
3 = Severe 
Profuse amount of mucopurulent or purulent discharge noted in the lower 
cul-de-sac and in the marginal tear strip. Eyelids tightly matted together in 
the morning upon awakening, requiring warm soaks to pry the lids apart. 
Conjunctival Chemosis:  Assess swelling of the conjunctiva. 
0 = Absent 
 
1 = Mild  
 
2 = Moderate   
3 = Severe  
 
Conjunctival Hyperemia:  Assess degree of redness and inflammation of bulbar and 
eyelid conjunctival tissue. 
0 = Normal 
1 = Mild 
2 = Moderate 
3 = Severe 
Corneal Erosion, Edema, Infiltrates:  Assess degree of corneal erosion, edema and 
infiltrates. 
0 = Absent 
1 = Mild 
2 = Moderate 
3 = Severe 
5. TEAR FILM BREAK-UP TIME (TFBUT) AND OCULAR SURFACE 
FLUORESCEIN STAINING 
Tear film break-up time will be measured first and then ocular surface fluorescein 
staining will be assessed. For eligibility determination on Visit 1 and Visit 2, both 
tests will be conducted on the right eye first, and then both tests will be performed 
on the left eye. For subsequent visits, only the study eye will be assessed. The study 
eye will be the eligible eye with the highest total ocular surface fluorescein staining 
score at baseline or, if both eyes are eligible and have the same score, the study eye 
will be the right eye. 
The TFBUT measurement will be performed in conjunction with ocular surface 
fluorescein staining using fluorescein strips previously wetted with 1 drop of sterile saline 
(supplied by the Sponsor). As soon as the tip is fully wetted, the excess will be shaken off 
briskly and the drop delivered quickly to the lower tarsal plate. The Investigator will ask 
the subject to blink freely several times to distribute the fluorescein and then to keep the 
eyelids open. The subject is asked to look straight ahead and the Investigator uses the x10 
setting on the slit lamp with cobalt blue light viewed through the supplied yellow filter.  
The endpoint is the time it takes from the final blink until the first appearance of a dry 
spot or a disruption of the tear film (micelles). The TFBUT will be measured with a 
stopwatch. The TFBUT will be conducted at least 3 times and the endpoints of 3 
consecutive tests will be reported. 

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The yellow barrier filter supplied by the Sponsor must be used to assess ocular surface 
staining, which will be performed at approximately 2 minutes after instillation of the 
fluorescein. 
To observe and grade staining over the entire corneal surface, it is important for the 
examiner to raise the subject’s upper eyelid slightly. The temporal conjunctiva is to be 
observed with the subject looking nasally along the horizontal plane and the nasal 
conjunctiva is observed with the subject looking temporally. 
The staining in each area will be graded using the Oxford Scheme which consists of a 
series of panels labeled A-E in order of increasing severity, A corresponding to grade 0 
and more than in picture E corresponding to grade 5. In each chart, staining is represented 
by punctate dots as shown in Appendix C.  
 
6. SCHIRMER TEST 
A Schirmer test without anesthesia will be performed at Visit 2 and at Visit 4 on the 
study eye for each subject 5 minutes after the fluorescein staining test. 
The strips supplied by the Sponsor will be carefully inserted over the lower eyelid margin 
of the eye approximately 2/3 temporal to the nasal canthus (to avoid irritating the cornea). 
The subject will be asked to close both eyes. The strips are removed after 5 minutes and 
the amount of tear fluid secretion is read to the nearest mm from the graduated strip 
markings.  
7. SUBJECT DIARY 
The subject will be asked to fill in a diary. 
a. Diary Card A for Run-In ART (Visit 1): This diary will be provided to each 
subject on the day of Visit 1 (Screening, Day -14) and will be used for 2 weeks 
until Visit 2 (Day 0, baseline). 
This diary will capture the frequency per day of run-in ART instillations. 
b. Diary Card B and C for Investigational Eye Drops (Visits 2-5): Diary Card B 
will be provided to each subject at Visit 2 (Baseline) and will be used through 
Visit 4 (Day 28 ± 3 days). Diary Card C will be provided to each subject at Visit 4 
(Day 28 ± 3 days) and will be used through Visit 5 (Day 90 ± 10 days).  
This diary will capture the following information: 
  Daily: frequency per day of investigational eye drop instillations  
 At the end of the first week and then at the end of each month: 
investigational eye drop tolerability just after the first instillation of the 
day. The subject will be asked to provide information on: 
- Investigational eye drop sensation : “upon instillation these eye 
drops 
are 
comfortable 
in 
my 
eyes” 
(strongly  
agree/agree/disagree/strongly disagree) 
 At the end of Diary Cards B and C: ease-of-use. The subject will be asked 
to grade the following sentences: 

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- “The bottle is easy to use” (strongly  agree/agree/disagree/strongly 
disagree) 
- “With this bottle I can dispense exactly one drop” (strongly  
agree/agree/disagree/strongly disagree) 
 
 
 

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APPENDIX C: 
GRADING OF CORNEAL AND CONJUNCTIVAL STAINING 
 
Oxford Scheme 24