A 3-month, Prospective, Multicentre, Investigator-masked, Parallel-group, Active-controlled, Randomised, Non-inferiority Study in Adult Patients With Moderate to Severe Dry Eye Disease Related to Keratitis or Keratoconjunctivitis
Phase: NA
Conditions: Dry Eye Syndromes
Sponsor: Santen SAS

 
 
 
PROTOCOL RE-015B 
A 3-MONTH, PROSPECTIVE, MULTICENTRE, INVESTIGATOR-MASKED, PARALLEL-GROUP, 
ACTIVE-CONTROLLED, RANDOMISED, NON-INFERIORITY STUDY IN ADULT PATIENTS 
WITH MODERATE-TO-SEVERE DRY EYE DISEASE RELATED TO KERATITIS OR 
KERATOCONJUNCTIVITIS 
THE “ALHENA” STUDY 
 
 
Sponsor: 
SANTEN SAS 
Genavenir IV, 1 rue Pierre Fontaine 
F-91058 Evry-Courcouronnes, France 
Study Number: 
Alhena RE-015B 
IND Number: 
N/A 
ID RCB Number: 
2020-A01190-39 
Compound: 
ALOCROSS® (cross-linked sodium hyaluronate 0.20% and Aloe 
vera 0.10%) 
Date: 
Version 2 - 06 July 2020  
 
 
 
 
 
CONFIDENTIAL PROPERTY OF SANTEN 
This document is a confidential communication of Santen. Acceptance of this document constitutes the agreement by 
the recipient that no information contained herein will be published or disclosed without written authorization from 
Santen except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her staff, 
and applicable institutional review committee and regulatory agencies to enable conduct of the study. 

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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the information notice, and any other 
device information provided by the Sponsor. I agree to conduct this study in accordance with the 
requirements of this protocol and also protect the rights, safety, privacy, and well-being of study 
patients in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki (Appendix D). 
• 
International Conference on Harmonisation E6 (R2) Good Clinical Practice: Consolidated 
Guideline. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.  
• 
Regulatory requirements for reporting serious adverse events defined in the Section 11.2 of 
this protocol. 
• 
Terms outlined in the Clinical Study Site Agreement. 
 
I further authorise that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol. 
Investigator Name (print or type) 
Investigator’s Title 
Location of Facility (City, State) 
Location of Facility (Country) 
Signature of Investigator 
Date 

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PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
 
Role in Study 
Name 
Address and Telephone Number 
Medical Monitor 
(Sponsor – Santen) 
Filis Ayan 
Medical Affairs Manager 
Santen UK Ltd. 
Salisbury Hall, St Albans, AL2 
1BU, United Kingdom 
Email: filis.ayan@santen.com  
Tel. +447483081791 
Safety Vigilance Unit 
(Sponsor – Santen) 
Piritta Maunu 
Manager, Medical Devices 
Safety Vigilance 
 
Santen Oy 
Kelloportinkatu 1 
P.O. Box 33,  
FIN-33101 Tampere, Finland 
Email: safetyEU@santen.com 
Pharmacovigilance Unit 
– ITEC Services 
Stéphanie TAN 
ITEC Services 
7 avenue Pierre Mendès France, 
Bat. C, 33270 Floirac - France 
Email: alhena@itecservices.com 
Tel. +33 5 57 77 85 00  
 
 
 

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1. 
SYNOPSIS 
Name of Sponsor/Company: SANTEN SAS, France 
Title of Study:  
A 3-month, prospective, multicentre, investigator-masked, parallel-group, active-controlled, 
randomised, non-inferiority study in adult patients with moderate-to-severe dry eye disease 
related to keratitis or keratoconjunctivitis 
Coordinating Investigators: 
Pr. Marc Labetoulle, MD, Ophthalmology Department, Bicêtre Hospital, APHP, Le Kremlin-
Bicêtre, France 
Studied period (years):  
Estimated date first patient enrolled:  September 2020 
Estimated date last patient completed: July 2021 
Phase of development:  
IV 
Objectives:  
Primary: 
• To compare the ocular efficacy of ALOCROSS® with that of VISMED® in patients with 
moderate to severe DED related to keratitis or keratoconjunctivitis after a 4-week treatment 
period (Day 28). 
Secondary: 
• To compare the ocular efficacy of ALOCROSS® with that of VISMED® in patients with 
moderate to severe DED related to keratitis or keratoconjunctivitis over a 12-week treatment 
period  
• To evaluate the ocular tolerability and safety of ALOCROSS® versus VISMED® in 
patients with moderate to severe DED related to keratitis or keratoconjunctivitis throughout 
the duration of treatment  
Number of patients (planned): 80 
Study centres: Approximately 10 centres in France 
Methodology:  
Prospective, multicentre, investigator-masked, parallel-group, active-controlled, randomised, 
non-inferiority study  
 
 

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Study design  
 
Diagnosis and main criteria for inclusion:  
Patient eligibility is determined according to the following inclusion criteria: 
1. Male or female patient aged 18 years or above 
2. Patient using artificial tears for at least 3 months prior to the Screening visit 
3. Patient experiencing at least 2 symptoms of ocular discomfort rated ≥23 mm on the 
0 to 100 mm visual analogue scale (VAS) (among itching, eye dryness, sticky 
feeling, photophobia, pain, burning or stinging, sandy feeling or grittiness, or 
foreign body sensation) at Screening and Baseline visits 
4. OSS score (sum of nasal and temporal interpalpebral conjunctival and corneal vital 
staining) ≥4 and ≤9 on a modified Oxford scale at Screening and Baseline visits in 
at least one eye 
5. TBUT of ≤10 seconds at Screening and Baseline visits and/or Schirmer’s tear test 
of ≥3 and ≤9 mm/5 min at Screening visit in the same eye that fulfil inclusion criteria 
#4 
6. The patient has signed and dated a written informed consent form prior to the 
initiation of any study procedures 
Any patient who meets any of the following criteria (in any eye) will not qualify for 
entry into the study: 
Ocular: 
1. CFS score ≥4 on a modified Oxford scale at Screening and Baseline visits 
2. Ocular hypertension or glaucoma requiring IOP-lowering medication(s) 

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3. History of ocular trauma, infection or ocular inflammatory condition within the 
last 3 months before the screening visit 
4. Severe blepharitis and/or severe meibomian gland disease 
5. Filamentary keratitis 
6. Any ocular surface anomaly not related to DED 
7. Active ocular infection or history of ocular allergy or ocular herpes 
8. Patient with only one sighted eye or with a best corrected distance visual acuity 
≤1/10 
9. Use of any topical ocular treatment other than study device during the study (all 
non-study topical ocular treatment(s) must be stopped at the screening visit) 
10. Onset of lid hygiene (whatever the method) less than 2 months before the 
Screening Visit 
11. Use of topical corticosteroids within one month prior the Screening Visit 
12. Use of isotretinoin, ciclosporin, tacrolimus, sirolimus, pimecrolimus or ocular 
cauterisation procedures within 2 months prior the screening visit and throughout 
the study 
13. Use of VISMED® within 6 weeks prior to the screening visit  
14. Refractive surgery (e.g. LASIK, LASEK, PRK) within 6 months and/or any other 
ocular laser/surgery within 3 months prior to the screening visit and during the 
study  
15. Insertion of temporary punctal plug(s) within 2 months prior to the Screening visit 
or permanent occlusion of lacrimal puncta on one or both sides 
16. Known hypersensitivity to any of the components of the study device or 
investigational products  
Non-ocular: 
17. History of severe systemic allergy  
18. Systemic disease not stabilised within 1 month prior to the screening visit (e.g. 
diabetes with glycaemia out of range, thyroid dysfunction) or judged by the 
investigator to be incompatible with the conduct of the study procedures or the 
interpretation of the study results   
19. Any change of systemic concomitant medication within the month before the 
screening visit or planned change during the study period, except paracetamol  
20. Pregnancy or lactation at the screening and/or Baseline visit. 
21. Women of childbearing potential not using a medically acceptable, highly 
effective method of birth control (such as hormonal implants, injectable or oral 
contraceptives together with condoms, some intrauterine devices, sexual 
abstinence or vasectomised partner) from the Baseline visit throughout the 
conduct of the study treatment periods and up to 2 weeks after the study end. 

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Post-menopausal women (two years without menstruation) do not need to use any 
method of birth control. 
22. Participation in a clinical trial with an investigational substance within the past 30 
days prior to Baseline visit. 
23. Participation in another clinical study at the same time as the present study 
Investigational device, dosage and mode of administration:  
Investigational device: ALOCROSS®, cross-linked sodium hyaluronate (0,20%) and Aloe 
vera (0,10%) 
Regimen: Instillation of one drop into both eyes, 4 times daily (morning, noon, afternoon and 
evening).  
Reference therapy, dosage and mode of administration:  
Reference Product: VISMED®, sodium hyaluronate (0,18%) 
Regimen: Instillation of one drop into both eyes, 4 times daily (morning, noon, afternoon and 
evening). 
Duration of treatment: 84 days 
Criteria for evaluation: 
Criteria will be evaluated by comparison between the two treatment groups at predefined 
endpoints and/or in comparing the evolution in each treatment group.  
Efficacy: 
• Ocular surface staining (OSS) score  
• Corneal fluorescein staining (CFS) and clearing 
• Tear Break-up time (TBUT) 
• Schirmer’s test 
• Symptoms of ocular discomfort (Visual Analogue scale) 
• Quality of life questionnaire: NEI-VFQ-25 
• Evaluation of global efficacy by the investigator and by the patient 
Safety: 
• Adverse event (AE) and Serious AE (SAE) 
• Best Corrected Distance Visual Acuity (BCDVA) 
• Intraocular Pressure (IOP) 
• Local ocular tolerance (slit lamp) 
Endpoints: 
Primary Efficacy Endpoint: 
The primary endpoint of the study is the difference between patients treated with 
ALOCROSS® and patients treated with VISMED® in the change of ocular surface staining 
(OSS) score between baseline and D28. 
 

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Secondary Endpoints: 
Efficacy: 
The secondary endpoints are the difference between patients treated with ALOCROSS® and 
patients treated with VISMED® in: 
• 
The change of OSS score between baseline and D14 and between baseline and D84 
• 
The change of ocular stainings (corneal fluorescein staining (CFS) and clearing and 
conjunctival staining) between baseline and D28 and between baseline and D84 
• 
The change of symptoms and tear breakup time (TBUT) between baseline and D28 
and between baseline and D84  
• 
The change of Schirmer’s tear test between baseline and D28 and between baseline 
and D84  
• 
The overall efficacy evaluation of the investigator after 12 weeks of treatment (84 
days) 
• 
The change of subjective assessments evaluation by the patient between baseline and 
D84 
Safety and Tolerability: 
The tolerability and safety endpoints will evaluate: 
• 
The number of patients with at least one ocular adverse event (AE) and the number of 
patients with at least one serious adverse event (SAE) 
• 
The number of ocular AEs and SAEs 
• 
The Best Corrected Distance Visual Acuity (BCDVA) from baseline to D84  
• 
The change in intraocular pressure (IOP) 
• 
The local ocular tolerance 
Statistical methods: 
Study size 
With an alpha risk of 0.025, a power of 90% and a non-inferiority margin of 2 points, a sample-
size of 66 patients was found necessary.  
Study Eye 
The study eye is defined as the eligible eye that fulfils all the criteria listed under the inclusion 
criteria #4 and #5. 
Analysis Populations 
• The Full Analysis Set (FAS) population consists of all randomised patients who 
received at least one dose of the study device and had at least one post-baseline sign or 
symptom assessment of the study eye. This will be the population used for efficacy 
analyses.   
• The Per-Protocol Set (PPS) will be a subset of FAS, restricted to the patients who 
fulfil the protocol in the terms of the eligibility, interventions, and outcome assessment.  

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It will be the analysis population for some sensitivity analyses. The determination of 
the PPS will be done before unmasking. 
• The Safety population consists of all patients enrolled who received at least one dose 
of the study device. It will be the analysis population for safety analyses. 
Analysis of Demographics and Baseline Characteristics 
Descriptive summaries will be performed for demographic (including age, gender, female 
patients’ menopausal status) and baseline characteristics variables (including time since 
diagnosis, past surgery or laser treatment in the study eye, and smoking status) by each FAS 
and safety population. 
Analysis of Primary Efficacy Endpoint 
An MMRM model will be performed to provide the estimate of the least square (LS) means 
difference between groups in the change from baseline of the ocular surface staining score after 
4 weeks of treatment. 
The 95% confidence interval of this difference will then be computed and the upper bound will 
be compared to the non-inferiority margin (2 points). 
Analysis of Secondary Efficacy Endpoint 
For FAS population, mean scores of OSS score, CFS, conjunctival fluorescein staining, 
symptoms of ocular discomfort (VAS), TBUT, Schirmer’s test and quality of life (NEI-VFQ) 
score, and their change from baseline will be summarized by analysis visit. The analysis for 
FAS population will be conducted by treatment groups. 
Analysis of Safety and Tolerability Endpoints 
Frequencies and percentages of adverse events (AEs) will be presented as follows: 1) Overall 
summary; 2) by system organ class and preferred term, 3) by system organ class, preferred 
term and maximal severity, 4) by system organ class, preferred term and relationship to study 
devices and study procedure, respectively, and 5) by system organ class, preferred term, 
maximal severity, and relationship to study devices and study procedure, respectively. 
These analyses will be performed for AEs and SAEs, ocular and systemic AEs and SAEs, 
respectively. Ocular AEs will be summarized for the study eye and the fellow eye separately. 
Other parameters of safety assessments (e.g. slit lamp examination, BCDVA, and IOP) will be 
summarised at each time point of measurement, for the study eye and the fellow eye separately. 
Safety and tolerability analysis will be performed on Safety population. 
Study duration: 11 months 
 
 
 

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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............10 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................14 
4. 
INTRODUCTION ......................................................................................................16 
5. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................17 
 
Primary Objective .......................................................................................................17 
 
Secondary Objectives .................................................................................................17 
 
Endpoints ....................................................................................................................17 
6. 
INVESTIGATIONAL PLAN .....................................................................................18 
 
Study Design ...............................................................................................................18 
 
Number of Patients .....................................................................................................18 
 
Criteria for Study Termination ...................................................................................19 
 
Demographic, Baseline Characteristics, and Medical History ...................................19 
 
Schedule of Assessment .............................................................................................19 
7. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................21 
 
Patient Inclusion Criteria ............................................................................................21 
 
Patient Exclusion Criteria ...........................................................................................21 
 
Screen Failure .............................................................................................................22 
 
Patient Discontinuation or Withdrawal Criteria .........................................................22 
 
Procedures for Discontinuation or Withdrawal of a Patient .......................................24 
 
Completed Enrollment ................................................................................................24 
 
Concomitant Medications/Therapies ..........................................................................24 
 
Randomisation and Masking ......................................................................................24 
8. 
STUDY DEVICE MATERIALS AND MANAGEMENT ........................................25 
 
Study Devices .............................................................................................................25 
 
Study Device Packaging and Labelling ......................................................................25 
 
Study Device Storage .................................................................................................26 
 
Administration ............................................................................................................27 
 
Study Device Accountability and Destruction ...........................................................27 

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Treatment Compliance ................................................................................................28 
9. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES .....................................28 
 
Screening visit (V1): 14 to 7 days before the Baseline visit .......................................28 
 
Baseline visit (V2): Day 1 ..........................................................................................29 
 
Follow-up visit: Visit 3: Day 14 .................................................................................29 
 
Follow-up visit: Visit 4: Day 28 .................................................................................30 
 
End of treatment visit/End of study visit: Visit 5: Day 84 .........................................30 
10. 
ASSESSMENT OF EFFICACY ................................................................................31 
 
Corneal and Conjunctival Fluorescein Staining .........................................................31 
 
Tear Break-Up Time ...................................................................................................31 
 
Schirmer’s Test (without anesthesia) (mm wetting/5min) .........................................32 
 
Symptoms of ocular discomfort – Visual analogue scale ...........................................32 
 
Quality of Life Questionnaire: NEI-VFQ-25 .............................................................32 
 
Investigator and Patient Global Evaluation of Efficacy .............................................32 
11. 
ASSESSMENT OF SAFETY .....................................................................................33 
 
Safety Parameters .......................................................................................................33 
 
Adverse Events and Other Safety Information ...........................................................34 
 
Documentation of Safety Information ........................................................................42 
12. 
STATISTICS ..............................................................................................................42 
 
General Considerations ...............................................................................................42 
 
Analysis Populations ..................................................................................................43 
 
Analysis of Demographics and Baseline Characteristics ...........................................43 
 
Analysis of Primary Endpoint ....................................................................................44 
 
Other Efficacy Variables Analyses .............................................................................44 
 
Analysis of Secondary Endpoints ...............................................................................45 
 
Analysis of Safety and Tolerability Endpoints ...........................................................45 
 
Interim Analysis ..........................................................................................................45 
 
Handling of Missing Values .......................................................................................45 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................46 
 
Study Monitoring ........................................................................................................46 
 
Audits and Inspections ................................................................................................46 
 
Ethics Committee (EC) ...............................................................................................47 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................47 

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15. 
ETHICS ......................................................................................................................47 
 
Ethics Review .............................................................................................................47 
 
Ethical Conduct of the Study ......................................................................................47 
 
Written Informed Consent ..........................................................................................47 
16. 
DATA HANDLING AND RECORD KEEPING ......................................................48 
 
Inspection of Records .................................................................................................48 
 
Retention of Records ..................................................................................................48 
 
Source Documents ......................................................................................................48 
 
Data Collection ...........................................................................................................49 
17. 
PUBLICATION POLICY ..........................................................................................49 
18. 
LIST OF REFERENCES ............................................................................................51 
19. 
APPENDICES ............................................................................................................52 
 
Appendix A-I  Modified Oxford Scale .......................................................................52 
 
Appendix A-II  Slit lamp examination .......................................................................54 
 
Appendix A-III Visual Analog Scale (VAS)_Symptoms of Ocular 
Discomfort ..................................................................................................................56 
 
Appendix A-IV National Eye Institute Visual Function Questionnaire (NEI 
VFQ-25) ......................................................................................................................57 
 
Appendix B  Elements of the Patient Informed Consent ............................................68 
 
Appendix C  Investigator Consent to Use of Personal Information ...........................70 
 
Appendix D Declaration of Helsinki ..........................................................................71 
COMPANY/SPONSOR APPROVERS ........................................................................................76 
 
 
 

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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................14 
Table 3: 
Study Design and Schedule of Assessments ................................................................20 
 
 
LIST OF FIGURES 
Figure 1: Study design and schedule of assessments.....................................................................18 
Figure 2: Study device packaging..................................................................................................26 
 
  
 
 

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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
 
Table 2: 
Abbreviations and Specialist Terms  
 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
ASADE 
Anticipated Serious Adverse Device Effect 
AT 
Artificial Tears 
BCDVA 
Best Corrected Distance Visual Acuity 
CA 
Competent Authority 
CFB 
Change From Baseline 
CFS 
Corneal Fluorescein Staining 
CI 
Confidence Interval 
CIP 
Clinical Investigation Plan 
CRO 
Contract Research Organization 
DED 
Dry Eye Disease 
DEWS 
Dry Eye Workshop 
eCRF 
Electronic Case Report Form 
EC 
Ethics Committee 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IFU 
Instructions For Use 
IOP 
Intraocular Pressure 
IWRS/IVRS 
Interactive Web Response System/ Interactive Voice 
Response System 
LS 
Least square 
NEI-VFQ 
National Eye Institute Visual Function Questionnaire 

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Abbreviation or Specialist Term 
Explanation 
NI 
Non-inferiority 
OD 
Ocular Dexter 
OS 
Ocular Sinister 
OSS 
Ocular Surface Staining 
PPS 
Per Protocol Set 
QOL 
Quality of Life 
RSI 
Reference Safety Information 
SADE 
Serious Adverse Device Effect 
SAE 
Serious Adverse Effect 
SAP 
Statistical Analysis Plan 
SDU 
Single Dose Unit 
TBUT 
Tear Breakup Time 
USADE 
Unanticipated Serious Adverse Device Effect 
VAS 
Visual Analogue Scale 
 
 
  
 
 

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4. 
INTRODUCTION 
Since the 2017 International Dry Eye Workshop (DEWS), the term dry eye disease (DED), also 
known as keratoconjunctivitis sicca, describes “a multifactorial disease of the ocular surface 
characterised by a loss of homeostasis of the tear film. This loss is accompanied by ocular 
symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and 
damage, and neurosensory abnormalities play etiological roles (DEWS 2017a (1))”. The 
prevalence of DED ranges from 5% to 50% (DEWS 2017b (2)), and it has become one of the 
principal causes for ophthalmic consultation. 
First-line treatments of dry eye focus on the relief of symptoms of ocular discomfort. One of the 
most extended treatment is instilling artificial tears onto the eye (Dry Eye Syndrome Guidance, 
2016 (3)). A variety of solutions with different compositions are available on the market. 
Hyaluronic acid is an agent used in some eyedrops because of its water retention and lubricant 
properties, which allow increasing corneal wettability in dry eye patients (Nakamura, 1993 (4)). 
Several studies have proved the efficacy of hyaluronic acid in achieving improvement in both 
ocular discomfort symptoms and ocular signs, with good tolerance (Baeyens, 2012 (5); Vogel, 
2010 (6); Brignole, 2005 (7); Sand, 1989 (8)). However, the benefit of using eyedrops containing 
hyaluronic acid over other artificial tears, including saline has not been largely evidenced 
(Doughty, 2014 (9)). A recent phase III, randomised, crossover, double-blind study by Pinto-
Fraga et al showed that Visaid 0.2% was effective in improving some clinical symptoms and 
signs in comparison with the use of 0.9% saline solution in mild dry eye patients during a 1-
month management period (Pinto-Fraga, 2017 (10)). The most important difference was the 
significant decrease in corneal and conjunctival staining induced by Visaid 0.2%. Additionally, 
the safety of the solution was proved. 
ALOCROSS® is a lubricating ophthalmic solution, based on cross-linked sodium hyaluronate, 
formulated for the treatment of ocular discomfort and corneal protection. ALOCROSS® obtained 
the CE mark on May 2017. In addition to the hyaluronic acid component, ALOCROSS® contains 
Aloe vera, which has known moisturizing, decongestant and lubricating properties. Aloe vera has 
also proven to improve visual comfort, to prolong the feeling of freshness and to be useful in 
case of redness or particularly sensitive eyes, fostering an important and long lasting protective 
action. A 2012 study by Wozniak et al that tested filtered Aloe vera extract on human corneal 
cells found evidence that Aloe vera may help reduce eye inflammation and dryness (Wozniak, 
2012 (11)). The study also noted that Aloe vera, at low concentrations, did not appear to have a 
negative effect on eye cells, supporting previous findings involving research on animals. 
To our knowledge, no other studies have assessed the efficacy and safety of an ophthalmic 
solution containing both hyaluronic acid salts and Aloe vera. The aim of this study is to 
demonstrate that ALOCROSS® is non-inferior in terms of efficacy to VISMED® (sodium 
hyaluronate) for the treatment of signs and symptoms in patients with dry eye. 
 

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5. 
TRIAL OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
The primary objective of the study is to compare the ocular efficacy of ALOCROSS® with that of 
VISMED® in patients with moderate to severe DED related to keratitis or keratoconjunctivitis after 
a 4-week treatment period (Day 28). 
 
Secondary Objectives 
The secondary objectives are: 
• to compare the ocular efficacy of ALOCROSS® with that of VISMED® in patients with 
moderate to severe DED related to keratitis or keratoconjunctivitis over a 12-week treatment 
period (Day 84)  
• to evaluate the ocular tolerability and safety of ALOCROSS® versus VISMED® in patients 
with moderate to severe DED related to keratitis or keratoconjunctivitis throughout the 
duration of treatment 
 
Endpoints 
5.3.1. 
Primary Efficacy Endpoint 
The primary endpoint of the study is the difference between patients treated with ALOCROSS® 
and patients treated with VISMED® in the change of ocular surface staining (OSS) score between 
baseline and D28. 
5.3.2. 
Secondary Endpoints 
5.3.2.1. 
Secondary Efficacy Endpoints 
The secondary endpoints are the difference between patients treated with ALOCROSS® and 
patients treated with VISMED® in: 
• The change of OSS score between baseline and D14 and between baseline and D84 
• The change of ocular stainings (corneal fluorescein staining (CFS) and clearing and 
conjunctival staining) between baseline and D28 and between baseline and D84 
• The change of symptoms and tear breakup time (TBUT) between baseline and D28 and 
between baseline and D84  
• The change of Schirmer’s tear test between baseline and D28 and between baseline and D84  
• The overall efficacy evaluation of the investigator after 12 weeks of treatment (84 days) 
• The change of subjective assessments evaluation by the patient between baseline and D84 
5.3.2.2. 
Safety and Tolerability Endpoints 
The tolerability and safety endpoints will evaluate: 

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• The number of patients with at least one ocular adverse event (AE) and the number of patients 
with at least one serious adverse event (SAE) 
• The number of ocular AEs and SAEs 
• The Best Corrected Distance Visual Acuity (BCDVA) from baseline to D84  
• The change in intraocular pressure (IOP) 
• The local ocular tolerance 
6. 
INVESTIGATIONAL PLAN 
 
Study Design 
This study is a prospective, multicentre, parallel-group, active-controlled, non-inferiority study 
conducted in adult patients with moderate-to-severe dry eye disease (DED) related to keratitis or 
keratoconjunctivitis. This study is conducted at a national level, in France. 
The patients will be randomised to receive ALOCROSS® or the reference treatment, VISMED® 
(ratio 1:1) in an investigator-masked fashion (Figure 1). 
Figure 1: Study design and schedule of assessments 
 
 
HA: Hyaluronic Acid 
 
Number of Patients 
A total of 80 patients are planned to be enrolled in approximately 10 trial sites (see section 12.1.1). 

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Criteria for Study Termination 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study device that 
indicates a change in the known risk/benefit profile for the compound, such that the risk/benefit 
is no longer acceptable for patients participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises patient safety. 
The Sponsor reserves the right to discontinue the study conduct for any safety, ethical or 
administrative (force majeure) reason at any time.  
If the trial is prematurely terminated or suspended, the Sponsor should promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. The ECs should also be informed promptly and 
provided the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s). 
 
Demographic, Baseline Characteristics, and Medical 
History 
Demographic information will include demographic characteristics, baseline disease 
characteristics, age at informed consent, sex and smoking status of the patient at baseline.  
Medical history to be obtained will include whether the patient has any significant condition or 
disease relevant to the condition/disease under study that stopped at or prior to signing the 
informed consent. Ongoing conditions are considered concurrent medical conditions.  
Medication history information to be obtained includes any ophthalmic medication taken within 1 
year of signing the informed consent and any other medication stopped at or within 3 months prior 
to signing the informed consent. 
 
Schedule of Assessment

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Table 3: 
Study Design and Schedule of Assessments 
 
Screening Visit 
Baseline Visit 
Follow-up Visit 
Follow-up Visit 
End of treatment/end 
of study visit a 
 
V1 
V2 
V3 
V4 
V5 
 
-14 to -7 days 
Day 1 
Day 14 ± 3 days 
Day 28 ± 7 days 
Day 84 ± 14 days 
Informed consent 
X 
 
 
 
 
Demographic information 
X 
 
 
 
 
Ocular and systemic medical history 
X 
 
 
 
 
Previous and concomitant ocular and systemic medications  
X 
X 
X 
X 
X 
Review of Inclusion/Exclusion Criteria  
X 
X 
 
 
 
Symptoms of ocular discomfort: Visual analogue scale 
X 
X 
 
X 
X 
Quality of life questionnaire: NEI-VFQ 25 
 
X 
 
X 
X 
Best corrected distance visual acuity (BCDVA) 
X 
X 
 
X 
X 
Slit lamp examination 
X 
X 
 
X 
X 
Tear break up time (TBUT) 
X 
X 
 
X 
X 
Ocular surface staining score b 
X 
X 
X 
X (primary endpoint) 
X 
Schirmer’s test (without anesthesia) 
X 
 
 
X 
X 
Intraocular Pressure (IOP)  
X 
X 
 
X 
X 
Urine pregnancy test c 
 
X 
 
X 
X 
Dispensation of unpreserved artificial tears 
(LARMABAK®) 
X 
 
 
 
 
Randomisation 
 
X 
 
 
 
Investigator and patient global assessment of efficacy 
 
 
X 
X 
X 
Ocular and systemic adverse events (AEs) 
 
X 
X 
X 
X 
Dispensation of masked study device  
 
X 
 
X 
 
Collection of unused study device containers 
 
X 
 
X 
X 
Compliance with study device regimen 
 
 
X 
X 
X 
a In case of premature discontinuation, the investigator will perform the final visit of the CRF. It includes all the examinations, if possible. 
b On modified Oxford scale  
c For women of childbearing potential only

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7. 
SELECTION AND WITHDRAWAL OF PATIENTS 
 
Patient Inclusion Criteria 
Patient eligibility is determined according to the following criteria: 
1. Male or female patient aged 18 years or above. 
2. Patient using artificial tears for at least 3 months prior to the Screening visit. 
3. Patient experiencing at least 2 symptoms of ocular discomfort rated ≥23 mm on the 0 
to 100 mm visual analogue scale (VAS) (among itching, eye dryness, sticky feeling, 
photophobia, pain, burning or stinging, sandy feeling or grittiness, or foreign body 
sensation) at Screening and Baseline visits. 
4. OSS score (sum of nasal and temporal interpalpebral conjunctival and corneal vital 
staining) ≥4 and ≤9 on a modified Oxford scale at Screening and Baseline visits in at 
least one eye. 
5. TBUT of ≤10 seconds at Screening and Baseline visits and/or Schirmer’s tear test of ≥3 
and ≤9 mm/5 min at Screening visit in the same eye that fulfil inclusion criteria #4. 
6. The patient has signed and dated a written informed consent form prior to the initiation 
of any study procedures.  
 
Patient Exclusion Criteria 
Any patient who meets any of the following criteria (in any eye) will not qualify for entry into 
the study: 
Ocular 
1. CFS score ≥4 on a modified Oxford scale 
2. Ocular hypertension or glaucoma requiring IOP-lowering medication(s) 
3. History of ocular trauma, infection or ocular inflammatory condition within the last 3 
months before the screening visit. 
4. Severe blepharitis and/or severe meibomian gland disease 
5. Filamentary keratitis 
6. Any ocular surface anomaly not related to DED 
7. Active ocular infection or history of ocular allergy or ocular herpes  
8. Patient with only one sighted eye or with a best corrected distance visual acuity ≤1/10  
9. Use of any topical ocular treatment other than study device during the study (all non-
study topical ocular treatment(s) must be stopped at the screening visit)  
10. Onset of lid hygiene (whatever the method) less than 2 months before the Screening 
visit 
11. Use of topical corticosteroids one month before the Screening Visit 

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12. Use of isotretinoin, ciclosporin, tacrolimus, sirolimus, pimecrolimus or ocular 
cauterisation procedures 2 months before the screening visit and throughout the study  
13. Use of VISMED® within 6 weeks prior to the screening visit  
14. Refractive surgery (e.g. LASIK, LASEK, PRK) within 6 months and/or any other 
ocular laser/surgery within 3 months prior to the screening visit and during the study  
15. Insertion of temporary punctal plug(s) within 2 months prior to the Screening visit or 
permanent occlusion of lacrimal puncta on one or both sides 
16. Known hypersensitivity to any of the components of the study device or investigational 
products  
Non-ocular 
17. History of severe systemic allergy  
18. Systemic disease not stabilised within 1 month prior to the screening visit (e.g. diabetes 
with glycaemia out of range, thyroid dysfunction) or judged by the investigator to be 
incompatible with the conduct of the study procedures or the interpretation of the study 
results   
19. Any change of systemic concomitant medication within the month before the screening 
visit or planned change during the study period, except paracetamol  
20. Pregnancy or lactation at the screening and/or Baseline visit. 
21. Women of childbearing potential not using a medically acceptable, highly effective 
method of birth control (such as hormonal implants, injectable or oral contraceptives 
together with condoms, some intrauterine devices, sexual abstinence or vasectomised 
partner) from the Baseline visit throughout the conduct of the study treatment periods 
and up to 2 weeks after the study end. Post-menopausal women (two years without 
menstruation) do not need to use any method of birth control. 
22. Participation in a clinical trial with an investigational substance within the past 30 days 
prior to Baseline visit. 
23. Participation in another clinical study at the same time as the present study. 
 
Screen Failure 
Investigators must account for all patients who sign the informed consent form. If the patient is 
found to be not eligible at the Baseline Visit after signing the informed consent, the investigator 
should complete the eCRF to record the primary reason of failure. 
Patient numbers assigned to patients who fail eligibility assessments should not be reused.  
Re-assessment is possible. Patients may undergo a new Baseline visit after the signature of a new 
informed consent form, and a new patient number will be assigned. 
 
Patient Discontinuation or Withdrawal Criteria 
The primary reason for discontinuation or withdrawal of a patient from the study should be 
recorded in the electronic case report form (eCRF) using the following categories:  

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1. Adverse event (AE).  
The patient experiences an AE that requires early termination because continued 
participation imposes an unacceptable risk to the patient’s health or the patient is 
unwilling to continue because of an AE. Patients discontinued for device-related AE(s) 
will be followed-up after patient’s discontinuation until the effect is resolved, stabilized 
or a final assessment can otherwise be done by the investigator. 
2. Protocol deviation.  
The discovery after the administration of the first dose of the study device that the 
patient failed to meet protocol entry criteria or that the patient did not adhere to protocol 
requirements, and continued participation poses an unacceptable risk to the patient’s 
health. 
3. Lost to follow-up.  
The patient does not return to the clinic and attempts to contact the patient are 
unsuccessful. In case of a patient lost-to-follow-up, the investigator must do his/her 
best to contact the patient initially by phone, then by letter, and finally by certified mail. 
If no response is obtained from the patient, the investigator is encouraged to contact 
one of the patient’s relatives or his/her general physician. These attempts must be 
documented and associated documentation filed in the patient medical chart. 
4. Voluntary withdrawal.  
The patient (or patient’s legally acceptable representative) wishes to withdraw from the 
study. The reason for withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded (i.e., 
withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category). 
5. Study termination.  
The Sponsor, EC, or regulatory agency terminates the study. 
6. Lack of efficacy.  
The patient or the physician does not feel that the study device has adequately relieved 
his/her patient’s symptoms. 
7. Pregnancy.  
The patient is found to be pregnant.  
Note: If the patient is found to be pregnant, the patient must be withdrawn immediately. 
The procedure is described in Section 7.5. 
8. Investigator decision due to non-compliance (to study devices, study visits or study 
related procedure). 
9. Other reason, specify. 

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Note: All attempts should be made to determine the reason if Other is chosen (e.g. a 
patient moves to another part of the country, or to a different country, and can no longer 
be traced) and the specific primary reason should be recorded in the “specify” field of 
the eCRF. 
 
Procedures for Discontinuation or Withdrawal of a 
Patient 
The investigator may terminate a patient’s study participation at any time during the study when 
the patient meets one or more of the study withdrawal criteria described in Section 7.4. Efforts 
should be made to perform all procedures scheduled for the End of Study Visit (D84/End of 
treatment). Discontinued patients will not be replaced. 
 
Completed Enrollment 
The study enrolment will be considered as completed when the desired number of at least 80 
included patients is reached. 
 
Concomitant Medications/Therapies 
Concomitant therapies consist of any treatment or medication given concurrently with the study 
devices. The following concomitant medication(s)/treatment(s) are prohibited during study 
participation:  
- 
Use of any artificial tears other than those provided by the Sponsor during the 
screening period. 
- 
Use of any artificial tears after the Baseline visit 
- 
Use of any topical ocular treatments other than the study devices and preservative-
free IOP lowering agents.   
- 
Insertion of temporary punctal plugs during the study. 
- 
Use of any topical corticosteroids after the Baseline visit 
- 
Use of any isotretinoin, ciclosporin, tacrolimus, sirolimus, pimecrolimus or ocular 
cauterisation procedures after the Baseline visit 
The initiation or use during the course of the study of any treatments or procedures described above 
will be considered as a protocol deviation. 
 
Randomisation and Masking  
The patients who fulfil the inclusion criteria will be randomly assigned (by IWRS/IVRS) in a 1:1 
ratio to receive either ALOCROSS or VISMED for 12 weeks (84 days) in an investigator-
masked fashion.  
Each randomised patient will receive numbered study device kits as assigned by the system. 
Treatment assignments will be masked to Santen and ITEC employees (except for the Drug Supply 
personnel), and Investigators. The investigator should try to avoid breaking the masking codes. 
However, IN CASE OF EMERGENCY ONLY, (i.e. SERIOUS ADVERSE EVENT [SAE] 

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AND ONLY WHEN THIS INFORMATION INFLUENCES THE MANAGEMENT OF 
THE PATIENT CARE), the investigator is entitled to unmask the patient by using IWRS, in 
order to obtain the study device information (i.e. ALOCROSS® or VISMED) to immediately start 
the appropriate treatment [to be recorded in the source data and eCRF (electronic Case Report 
Form)]. The date, time and reason for breaking the code will be recorded. The investigator should 
inform the Sponsor immediately after unmasking. The details of this unmasking procedure will be 
described in a separate document. Patients unmasked for the management of a SAE will be 
discontinued from the study. 
8. 
STUDY DEVICE MATERIALS AND MANAGEMENT 
 
Study Devices 
8.1.1. 
Description of tested device, ALOCROSS® 
ALOCROSS® is class IIb medical device and is a lubricant ophthalmic solution based on cross-
linked hyaluronic acid 0,20% and Aloe vera gel 0,10% in a buffered solution at pH 7.2. 
The batch number and the expiration dates of the study device will be provided in the certificate 
of analysis. 
The legal manufacturer will be OFF Health located in Florence, Italy. 
8.1.2. 
Description of reference treatment, VISMED® 
VISMED® is a sterile medical device that contains a preservative-free, drug-free solution of 
sodium hyaluronate at 0.18%. VISMED® is commonly used as a preservative-free artificial tear 
treatment in France for patients with keratitis or keratoconjunctivitis. VISMED® will be purchased 
from a commercial source. 
8.1.3. 
Description of artificial tears, LARMABAK® 
LARMABAK® is a sterile unpreserved solution for topical ophthalmic use, containing NaCl at 
0.9% (0.9 g/100 mL). LARMABAK® will be purchased from a commercial source. 
 
Study Device Packaging and Labelling 
8.2.1. 
LARMABAK® 
At the screening visit and after review of the selection criteria, selected patients will be provided 
with 1 bottle of LARMABAK® to perform the wash-out treatment period. 
Dosage and mode of administration of LARMABAK®: Instillation of one drop into both eyes, 
4 times and up to 8 times daily. 
LARMABAK® bottles will bear an investigational label to indicate that the content is intended for 
investigational use only and to allocate a treatment number to the unit.  

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8.2.2. 
Study device 
At the Baseline visit (V2), after confirmation of fulfilment of the inclusion criteria and 
randomisation, the patient will be provided with the study devices (i.e. ALOCROSS® or 
VISMED®) (see Figure 2) 
The study devices will be supplied in double-masked polyethylene single-dose unit (SDU) 
containers presented 
▪ in sealed laminate aluminium pouch package (1 pouch contains 5 single-dose unit containers, 
sufficient for a one-day treatment of both eyes – daily pouch). 
▪ 7 aluminium pouches (i.e. 35 single-dose unit containers, sufficient for a one-week 
treatment) will be placed together in a small cardboard box – weekly box.  
▪ 4 cardboard boxes of 7 aluminium pouches (i.e. 140 SDU of study device, sufficient for a 4-
week treatment) will be placed together in a large sealed cardboard box – monthly box. 
One ‘monthly’ box of 140 SDU will be dispensed at the Baseline visit. 
Two ‘monthly’ boxes of 140 SDU will be dispensed at the D28 visit. 
Figure 2: Study device packaging 
 
8.2.3. 
Labelling 
The single dose containers will not be labelled.  
- 
VISMED® single dose unit containers will receive a blank green sticker to mask the 
commercial device name. 
- 
ALOCROSS® single dose unit containers will receive a blank white sticker to mask the 
commercial device name. 
Each aluminium pouch and sealed cardboard will bear an investigational label, indicating that the 
content is intended for investigational use only, the treatment number and the weekday (Monday, 
Tuesday, …).  
In addition, each large cardboard box will bear a white detachable label bearing the protocol and 
treatment numbers. This label will be torn off by the person dispensing the study device to the 
patient on Day 1, and stuck onto the space provided in the accountability log. 
 
Study Device Storage 
All clinical trial material must be kept in an appropriate, limited-access, secure location until it is 
used or returned to the Sponsor or designee for destruction. All study devices must be stored under 

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the conditions specified on the label, and remain in the original container until it is dispensed. A 
daily temperature log of the study device storage area must be maintained every working day. Any 
temperature excursion of study devices should be notified to the Sponsor and the supplies placed 
in quarantine until further instruction is received from the Sponsor. The study device and 
unpreserved artificial tears will be delivered to the study centres by the clinical supplies distributor. 
The study devices and unpreserved artificial tears must be stored below 25°C and must not be 
frozen. Light exposure must be avoided. 
Initially each centre will receive adequate supplies (study devices and unpreserved artificial tears) 
to cover the study treatment period for a pre-defined number of patients. Additional supplies will 
be dispatched after taking into account the recruitment rate of each study centre. The investigator 
or his/her designee will be responsible for correct handling and storage of the study devices and 
unpreserved artificial tears during the course of the study.  
 
Administration 
The study device will be instilled 4 times daily into both eyes (morning, noon, afternoon and 
evening).  
The study device and the unpreserved artificial tears provided by the Sponsor are to be dispensed 
only by the investigator or his/her designee, and will be used in accordance with this protocol.  
Under no circumstances will the investigator allow the study products to be used other than 
directed by the protocol. All dispensations and returns of study device have to be documented in 
the masked pharmacy file provided by the Sponsor (see section 8.5). 
In order to ensure patient anonymity, patients will be identified by codes or other means of record 
identification. 
 
Study Device Accountability and Destruction 
The Principal Investigator has overall responsibility for ensuring that an inventory is conducted 
upon receipt of the clinical supplies. Due to the study being Investigator Masked, all study device 
accountability and destruction must be undertaken by the Investigator’s unmasked designee. The 
receipt of clinical supplies should be completed, signed and returned as directed by Santen (or 
designee). A copy must be maintained at the site for the Investigator’s records. The Principal 
Investigator’s unmasked designee will keep a current record of the inventory and dispensing of all 
study devices. This record will be made available to Santen’s Un-masked Monitor (or designee) 
for the purpose of accounting for all clinical supplies. Any discrepancy and/or deficiency must be 
recorded with an explanation. All supplies sent to investigator must be accounted for and in no 
case will study device be used in any unauthorised situation.  
It is a responsibility of the Principal Investigator to return any unused supplies to the Santen Un-
masked monitor (or designee) at the conclusion of the study.  
Patients will be instructed to keep all unused, expired or malfunctioning containers (bottle, SDU 
and box) and will be required to bring unused, expired or malfunctioning study device containers 
to each clinic visit. The destruction of the unused, expired or malfunctioning containers of study 
device will be performed according to the instructions of the clinical monitor and has to be 
documented. 

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Upon completion or earlier termination of the study the investigator’s unmasked designee will, 
unless otherwise agreed, return to the clinical supplies distributor any surplus quantities, unused 
containers/bottles/SDU, of study device or unpreserved artificial tears. The investigator’s 
unmasked designee will record each quantity of study device or unpreserved artificial tears that 
has been damaged or is missing. 
Study device supplies will be counted and reconciled at the site before being returned to Santen or 
designee or being destroyed by the site. 
 
Treatment Compliance 
Patient compliance will be assessed at each visit by the investigator’s unmasked designee by 
questioning the patient and comparing to study device accountability. All reported lack of 
compliance will be recorded on the eCRF with the reasons. If a patient is persistently non 
compliant with the study device, the patient should be withdrawn from the study. All patients 
should be reinstructed about the dosing requirement at each study visit. The authorized unmasked 
study personnel conducting the re-education must document the process in the patient source 
records. 
9. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES 
The schedule for all study-related procedures and evaluations is shown in Table 3. Assessments 
should be completed at the designated visit/time point(s), and should be performed in both eyes. 
All assessments should be done in the mentioned order to ensure that additional procedure doesn’t 
interfere with the results of other examinations. 
 
Screening visit (V1): 14 to 7 days before the Baseline visit 
• Written informed consent 
• Demographic information 
• Ocular and systemic medical history 
• Previous and concomitant ocular and systemic medications [including artificial tears (AT) 
usage] 
• Verify inclusion and exclusion criteria based on the evaluations just performed: 
o Patients fulfilling the inclusion criteria will discontinue all previous treatments related to 
dry eye including artificial tears and any prohibited ocular treatments and receive study 
specific artificial tears for 7 to 14 days 
o Patients not fulfilling the inclusion criteria will be considered as having failed the 
screening and will not be included in the study  
• Filling by the patient of the VAS for the symptoms evaluation of ocular discomfort 
• BCDVA 
• Slit lamp examination 

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• TBUT 
• Ocular surface staining score (corneal fluorescein staining and nasal and temporal 
interpalpebral conjunctival staining (modified Oxford scale)) 
• Schirmer’s test (without anaesthesia) 
• IOP 
• Dispensation of unpreserved artificial tears (LARMABAK®) 
• Patients will be scheduled to return to the site in 7 to 14 days for the Baseline visit. 
 
Baseline visit (V2): Day 1 
• Collection of the artificial tears bottle 
• Inclusion/exclusion criteria review 
• Record of previous and concomitant ocular and systemic medications [other than artificial tear 
(AT) usage] 
• Record adverse events (AEs) 
• Filling by the patient of the VAS for the symptoms evaluation of ocular discomfort 
• Completion by the patient of the Quality of life questionnaire NEI-VFQ 
• BCDVA 
• Slit lamp examination 
• TBUT 
• Ocular surface staining score (corneal fluorescein staining and nasal and temporal 
interpalpebral conjunctival staining (modified Oxford scale)) 
• IOP 
• Urine pregnancy test (women of childbearing potential only) 
• Randomisation in IWRS 
• Dispensation of masked study device for a 4-week period according to the randomisation 
number 
• Patients will be scheduled to return to the site in 2 weeks (Day 14 +/-3 days) for the first follow-
up visit (V3) 
 
Follow-up visit: Visit 3: Day 14 
• Record of concomitant ocular and systemic medications 
• Record adverse events (AEs) 
• Ocular surface staining score (corneal fluorescein staining and nasal and temporal 
interpalpebral conjunctival l staining (modified Oxford scale)) 
• Assessment of compliance to study device 

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• Global assessment of efficacy by the investigator and the patient 
• Patients will be scheduled to return to the site in 2 weeks (Day 28 +/-7 days) for the next study 
visit (V4) 
 
Follow-up visit: Visit 4: Day 28 
• Record of concomitant ocular and systemic medications 
• Record adverse events (AEs) 
• Filling by the patient of the VAS for the symptoms evaluation of ocular discomfort 
• Completion by the patient of the Quality of life questionnaire NEI-VFQ-25 
• BCDVA  
• Slit lamp examination  
• TBUT 
• Ocular surface staining score (corneal fluorescein staining and nasal and temporal 
interpalpebral conjunctival staining (modified Oxford scale)) 
• Schirmer’s test (without anaesthesia) 
• IOP 
• Urine pregnancy test (women of childbearing potential only) 
• Collection of unused, expired or malfunctioning study device containers  
• Assessment of compliance to study device 
• Global assessment of efficacy by the investigator and the patient 
• Dispensation of study device for an 8-week period  
• Patients will be scheduled to return to the clinic in 8 weeks (Day 84 +/- 14 days) for the last 
study visit (V5) 
 
End of treatment visit/End of study visit: Visit 5: Day 84 
• Record of concomitant ocular and systemic medications 
• Record adverse events (AEs) 
• Filling by the patient of the VAS for the symptoms evaluation of ocular discomfort 
• Completion by the patient of the Quality of life questionnaire NEI-VFQ-25 
• BCDVA  
• Slit lamp examination  
• TBUT 
• Ocular surface staining score (corneal fluorescein staining and nasal and temporal 
interpalpebral conjunctival staining (modified Oxford scale)) 

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• Schirmer’s test (without anaesthesia) 
• IOP 
• Urine pregnancy test (women of childbearing potential only) 
• Collection of unused, expired or malfunctioning study device containers  
• Assessment of compliance to study device 
• Global assessment of efficacy by the investigator and the patient 
In case of patient’s premature study discontinuation:  
- the investigator will be asked to perform all the examinations and assessments scheduled for the 
End of Study Visit  
-  the investigator will ensure that unused, expired or malfunctioning study devices for the study 
period has been collected from the patient by the appointed person at the study site 
10. 
ASSESSMENT OF EFFICACY 
 
Corneal and Conjunctival Fluorescein Staining  
Corneal and conjunctival fluorescein staining will be assessed immediately following the TBUT. 
Reading will be performed between 1 and 4 minutes after fluorescein instillation for the TBUT, to 
ensure that the dye does not diffuse into stroma blurring the discrete margin of any staining defects. 
Both eyes will then be examined at the slit lamp (16X magnification) using a yellow barrier filter 
and cobalt blue illumination to enhance visibility of staining.  
Staining using fluorescein will be graded using the modified Oxford scale (7-point ordinal scale, 
score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal conjunctiva]) for cornea and 
conjunctiva separately, see Appendix A-I  
Modified Oxford Scale. On this modified scale, the 
score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per area.  
A CFS grade of 0 represents complete corneal clearing. 
 
Tear Break-Up Time 
Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The TBUT 
will be performed after instillation of 5 µL of 2% preservative-free sodium fluorescein solution 
into the inferior conjunctival cul-de-sac of each eye. To thoroughly mix the fluorescein with the 
tear film, the patient will be instructed to blink several times. In order to achieve maximum 
fluorescence, the examiner should wait approximately 30 seconds after instillation before 
evaluating TBUT. With the aid of a slit lamp at 10X magnification using cobalt blue illumination, 
the examiner will monitor the integrity of the tear film, noting the time it takes to form lacunae 
(clear spaces in the tear film) from the time that the eye is opened after the last blink. The TBUT 
will be measured twice during the first minute after the instillation of the fluorescein. If the 2 
readings differ by more than 2 seconds, then a third reading will be taken. The TBUT value will 
be the average of the 2 or 3 measurements. 

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Schirmer’s Test (without anesthesia) (mm wetting/5min) 
Schirmer’s test will be performed without anesthesia, 15 minutes after corneal fluorescein test. 
This test will be conducted in a dimly lit room. While the patient looks upwards, the lower lid will 
be drawn gently downwards and temporally. The rounded bent end of a sterile strip will be inserted 
into the lower conjunctival sac over the temporal one-third of the lower eyelid margin. The test 
should be done without touching the Schirmer test strip directly with the fingers to avoid 
contamination by skin oils. After 5 minutes have elapsed, the Schirmer test strip will be removed 
and the length of the tear absorption on the strip will be measured.  
 
Symptoms of ocular discomfort – Visual analogue scale  
The visual analogue scale is a self-administered questionnaire and must be completed by the 
patient him/herself. 
Itching, foreign body sensation or sandy feeling or grittiness, photophobia, burning/stinging, eye 
dryness, pain or ocular discomfort and sticky feeling will be assessed by the study patients using 
a visual analog scale from no discomfort to maximal discomfort (0 to 100%). Symptoms will be 
evaluated for both eyes together. (see Appendix A-III Visual Analog Scale (VAS)_Symptoms of 
Ocular Discomfort).   
 
Quality of Life Questionnaire: NEI-VFQ-25 
The NEI-VFQ-25 is a questionnaire designed to assess health-related quality of life of patients 
with visual impairments. It is a short-form version of the 51-item NEI-VFQ Field Test Version, 
composed of 25 items relating to vision–targeted QoL grouped into the following scales: general 
vision (1 item), ocular pain (2 items), difficulty with near-vision activities (3 items), difficulty with 
distant-vision activities (3 items), limitations in social functioning due to vision (2 items), mental 
health symptoms due to vision (4 items), role limitations due to vision (2 items), dependency on 
others due to vision (3 items), driving difficulties (2 items), limitations with colour vision (1 item), 
limitations with peripheral vision (1 item), and one widely accepted general health item. Its 
reliability and validity are comparable to those of the 51-item NEI-VFQ Field Test Version 
(Mangione, et al 2001).  
Each item is scored 0–100, with higher scores indicating better vision-targeted QOL. Items in the 
same scale are averaged together to create 12 scale scores. Missing items are not scored. A scale 
score can be generated if at least one item is answered.  
The NEI-VFQ-25 represents the patient perspective on the impact of vision problems on 
functioning. Although not considered to be sensitive to fully capture treatment response in DED, 
many consider the NEI-VFQ-25 to be the standard to assess vision-targeted functioning.  
In this trial the NEI-VFQ-25 will be administered in the local language. The responses to NEI-
VFQ-25 are to be obtained from the patient through a self-administered format (see Appendix A-
IV National Eye Institute Visual Function Questionnaire (NEI VFQ-25)).  
 
Investigator and Patient Global Evaluation of Efficacy 
The study investigator at each centre will conduct an overall assessment of the effect of the study 
device on improvement in the patients DED using the following rating scale:  
• 0 = Unsatisfactory 

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• 1 = Not very satisfactory 
• 2 = Satisfactory 
• 3 = Very satisfactory 
 
The patient will rate his global evaluation of efficacy using the same rating scale. 
11. 
ASSESSMENT OF SAFETY 
 
Safety Parameters 
11.1.1. 
Best Corrected Distance Visual Acuity (BCDVA) 
Best corrected distance visual acuity will be measured with the patient’s best correction and 
recorded in decimal.  
11.1.2. 
Tonometry for measurement of Intraocular Pressure (IOP) (mmHg) 
Investigator should use the same tonometer throughout the course of the study. Both eyes will be 
tested, with the right eye preceding the left eye. IOP will be assessed after completion of all other 
slit lamp examinations and dry eye assessments to avoid oxybuprocaine interference with the other 
examinations (Schirmer’s test especially) in case a tonometry measurement needs to be performed 
with an anesthetic. 
All tonometers must be calibrated according to manufacturer’s instructions. Data need to be 
measured in absolute figures. 
11.1.3. 
Slit lamp examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp. The 
patient will be seated while being examined; grading of the Meibomian glands, lids, lashes, 
conjunctiva, tear film debris, anterior chamber and lens will be done according the scales in 
Appendix A-II  
Slit lamp examination. 
11.1.4. 
Adverse Events (AEs) 
Adverse events, including ocular AEs, ocular complications, and systemic AEs will be recorded 
in the eCRFs. Any clinically significant change in concomitant disease or new concomitant 
conditions will be reported as AEs. 
11.1.5. 
Pregnancy Screen 
Women of childbearing potential not using a medically acceptable, highly effective method of 
birth control (such as hormonal implants, injectable or oral contraceptives together with condoms, 
some intrauterine devices, sexual abstinence or vasectomized partner) from the Baseline visit 
throughout the conduct of the study treatment periods and up to 2 weeks after the study end cannot 
be included in the study. Post-menopausal women (two years without menstruation) do not need 
to use any method of birth control. For women of childbearing potential only, urine hCG pregnancy 
tests will be performed during the course of the study, and they will receive continued guidance 
with respect to the avoidance of pregnancy, as part of the Schedule of Study Procedures. 

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Patients must have a negative urine pregnancy test at baseline.  
 
Adverse Events and Other Safety Information 
11.2.1. 
Definitions 
11.2.1.1. Adverse Event (AE) 
An adverse event is any untoward medical occurrence, unintended disease or injury or any 
untoward clinical signs (including an abnormal laboratory finding) in patients, users or other 
persons whether or not related to the investigational medical device.    
NOTE 1: This definition includes events related to the investigational medical 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. 
Any significant change in a patient’s condition from screening, regardless of causality, is to be 
considered an AE (unless the change is determined to be a continuation of a pre-existing condition 
documented in the patient’s medical history). A clinically significant worsening in severity, 
intensity, or frequency of a pre-existing condition may indicate an AE.  
Worsening of findings e.g. in biomicroscopy from no findings to finding graded as 
moderate/severe, or change in grading from mild to severe, may be an indication of an AE. By 
investigator’s judgment, also milder changes can be recorded as AEs. 
An elective surgical procedure scheduled or planned prior to study entry is not considered an AE, 
and the underlying diagnosis for the procedure should be captured in the medical history as a 
pre-existing condition. 
The lack of efficacy of the study treatment for the condition being investigated is not considered 
an AE unless a clinically significant change is assessed by the investigator. 
Patients’ answers given to study questionnaires (or changes in these) are not reviewed as basis for 
occurrence of AEs. However, the investigators will collect information on AEs at each patient 
contact by asking an open question on the patient’s general health. 
For this study, the study devices are LARMABAK®, ALOCROSS® and VISMED®. Regardless of 
causality to the study device, an AE can be an unintended sign temporally associated with the use 
of study device.  
11.2.1.2. Device deficiency 
Any 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. 
11.2.1.3. Adverse Device Effect (ADE) 
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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. 
11.2.1.4. Serious Adverse Event (SAE) 
Adverse event that: 
a) led to a death, injury or permanent impairment to a body structure or a body function. 
b) 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, or 
• in-patient hospitalization or prolongation of existing hospitalization, or 
• in medical or surgical intervention to prevent life threatening illness 
c) led to foetal distress, foetal death or a congenital abnormality or birth defect. 
NOTE 1: Planned hospitalization for pre-existing condition, or a procedure required by the 
Clinical Investigation Plan (CIP), without a serious deterioration in health, is not considered a 
serious adverse event. 
11.2.1.5. Serious Adverse Device Effect (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a serious 
adverse event. A SADE is device or procedure related. 
11.2.1.6. Unanticipated Serious Adverse Device Effect (USADE) 
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. An USADE is device or procedure 
related. 
NOTE 1: Anticipated SADE (ASADE): an effect which by its nature, incidence, severity or 
outcome has been previously identified in the risk analysis report. The ASADE shall be 
documented in the CIP, the Instruction For Use (IFU) and the informed consent form. 
NOTE 2: This enables compliance with any reporting requirements for anticipated and 
unanticipated SADEs. 
 
11.2.1.7. Serious Ocular Adverse Events 
Serious ocular adverse events include, but are not limited to the following adverse events which 
are considered to be sight-threatening and are to be reported as SAEs (medically important 
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- 
Adverse Events that cause a decrease in visual acuity > 6 lines (compared with the last 
assessment of visual acuity at the last visit) 
- 
Adverse Events that cause a decrease in visual acuity to the level of Light Perception or 
worse 
- 
Adverse Events that required surgical intervention or laser to prevent permanent loss of 
Sight 
- 
Adverse Events associated with severe intraocular inflammation (i.e. 3+ anterior chamber 
cell/flare or 3+ vitritis) 
- 
Corneal perforation 
- 
Adverse Events that, in the opinion of the investigator, may require medical intervention 
to prevent permanent loss of sight 
11.2.2. 
Assessment of Adverse Events 
All AEs (non-serious and serious) spontaneously reported by the patient and/or in response to an 
open question from the study personnel or revealed by observation will be recorded and assessed 
during the study at the investigational site. Regardless of relationship to the clinical study, all AEs 
that occur at any time from the point of signing of ICF to participate in the study until patient 
withdrawal or the scheduled exit visit must be recorded. 
Information about all AEs will be collected from the signing of consent form until the end of the 
study. Even after completion of the study, the investigator shall notify ITEC services of any new 
SAEs that may be associated with the study device. 
Non-serious AEs will be evaluated until recovery or until the last study visit. The investigator must 
follow-up with the patients with a SAE until it has resolved, stabilized or a final assessment can 
otherwise be done. The same principle applies to all study device-related AEs which caused early 
termination. 
The investigator will take appropriate and necessary therapeutic measures required for resolution 
of the AE. Any medication necessary for the treatment of an AE must be recorded. During the 
investigator masked treatment period, the investigator should only unmask the treatment allocation 
if this is relevant to the safety of the patient. 
During the study, patients will also be allowed to use unpreserved artificial tears provided by the 
Sponsor. The events with causal relationship to the artificial tears are considered as AEs. 
11.2.2.1. Seriousness assessment 
The seriousness of each AE must be assessed by the investigator according to the criteria set for 
SAEs in section 11.2.1.4. If the event does not meet the criteria of a SAE, it is assessed as non-
serious. 
11.2.2.2. Causality assessment 
An investigator who is qualified in medicine must make the determination of causality to the study 
devices and artificial tears provided by the Sponsor for each AE occurred during the study as 
defined in section 11.2.1.1.  

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The relationship between the use of the medical device (including the medical procedure) and the 
occurrence of each adverse event shall be assessed and categorized. During causality assessment 
activity, clinical judgement shall be used and the relevant documents, such as the IFU, the Clinical 
Protocol or the Risk Analysis Report shall be consulted, as all the foreseeable serious adverse 
events and the potential risks are listed and assessed there. The presence of confounding factors, 
such as concomitant medication/treatment, the natural history of the underlying disease, other 
concurrent illness or risk factors shall also be considered. 
The sponsor and the investigators will use the following definitions to assess the relationship of 
the serious adverse event to the investigational medical device or procedures. 
• Not related: relationship to the device or procedures can be excluded when: 
o the event is not a known side effect of the product category the device belongs to 
or of similar devices and procedures; 
o the event has no temporal relationship with the use of the investigational device or 
the procedures; 
o the serious event does not follow a known response pattern to the medical device 
(if the response pattern is previously known) and is biologically implausible; 
o 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 serious event; 
o the event involves a body-site or an organ not expected to be affected by the device 
or procedure; 
o the serious 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);  
o the event does not depend on a false result given by the investigational device used 
for diagnosis, when applicable;  
o harms to the subject are not clearly due to use error;  
o 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 serious 
event.  
• 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.  
• 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 were 
relatedness cannot be assessed or no information has been obtained should also be 
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• Probable: the relationship with the use of the investigational device seems relevant and/or 
the event cannot reasonably explain by another cause, but additional information may be 
obtained. 
• Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
o the event is a known side effect of the product category the device belongs to or of 
similar devices and procedures; 
o the event has a temporal relationship with investigational device use/application or 
procedures; 
o 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; 
o the serious event follows a known response pattern to the medical device (if the 
response pattern is previously known); 
o 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 serious event (when clinically feasible); 
o 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; 
o harm to the subject is due to error in use; 
o the event depends on a false result given by the investigational device used for 
diagnosis, when applicable; 
o 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 serious event. 
The sponsor and the investigators will distinguish between the serious adverse events related to 
the investigational device and those related to the procedures (any procedure specific to the clinical 
investigation). An adverse event can be related both to procedures and the investigational device. 
Complications of procedures are considered not related if the said procedures would have been 
applied to the patients also in the absence of investigational device use/application. 
In some particular cases the event may be not adequately assessed because information is 
insufficient or contradictory and/or the data cannot be verified or supplemented. The sponsor and 
the Investigators will make the maximum effort to define and categorize the event and avoid these 
situations. Where the sponsor remains uncertain about classifying the serious event, it should not 
exclude the relatedness and classify the event as “possible”. 
Particular attention shall be given to the causality evaluation of unanticipated serious adverse 
(device) events. The occurrence of USADE could suggest that the clinical investigation places 
subjects at increased risk of harm than was to be expected beforehand. 

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11.2.2.3. Severity of the Adverse Event 
Severity (intensity) of the AE will be assessed according to the following scale: 
• Mild: awareness of sign or symptom, but easily tolerated 
• Moderate: discomfort sufficient to cause interference with normal activities 
• Severe: incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 11.2.1.4. An AE of severe intensity 
may not be considered serious. 
11.2.2.4. Expectedness 
AEs will be evaluated as to whether they are anticipated or unanticipated. The assessment is 
performed by the sponsor and in this study it is based on the list of adverse device effects in the 
IFU of ALOCROSS® which acts as a Reference Safety Information (RSI). Only allergic or 
hypersensitivity reactions to its components may be observed according to the IFU. 
• Expected: An AE is anticipated when the nature or severity of which is consistent with the 
applicable product information. 
• Unexpected: An AE is unanticipated when the nature or severity of which is not consistent 
with the applicable product information. 
11.2.3. 
Reporting of Safety Information 
11.2.3.1. Recording and Reporting of Adverse Events 
1. The sponsor or its designee shall fully record all of the following: 
a) any adverse event of a type identified in the clinical investigation plan as being critical to 
the evaluation of the results of that clinical investigation; 
b) any serious adverse event; 
c) any device deficiency that might have led to a serious adverse event if appropriate action 
had not been taken, intervention had not occurred, or circumstances had been less fortunate; 
d) any new findings in relation to any event referred to in points (a) to (c). 
 
2. The sponsor or its designee shall report, without delay to all Member States in which the 
clinical investigation is being conducted, all of the following: 
a) Until 25th of May 2021: any serious adverse event with the investigational device, the 
comparator or the investigation procedure regardless of relatedness; 
b) From 26th of May 2021: any serious adverse event that has a causal relationship with the 
investigational device, the comparator or the investigation procedure or where such causal 
relationship is reasonably possible;  
c) As from 26th of May 2021 follow-up reports for events that have earlier been deemed “not 
related” are no longer submitted.  

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d) any device deficiency that might have led to a serious adverse event if appropriate action 
had not been taken, intervention had not occurred, or circumstances had been less fortunate; 
e) any new findings in relation to any event referred to in points (a) to (d). 
The period for reporting shall take account of the severity of the event. Where necessary to ensure 
timely reporting, the sponsor or its designee may submit an initial report that is incomplete 
followed up by a complete report. 
Upon request by any Member State in which the clinical investigation is being conducted, the 
sponsor or its designee shall provide all information referred to in paragraph 1. 
 
3. The sponsor or its designee shall report any event as referred to in paragraph 2. Upon receipt, 
this report shall be sent electronically to all Member States in which the clinical investigation 
is being conducted. 
The CRO ITEC Services will record all SAEs and Pregnancy reports and will inform Sponsor 
about received reports as soon as possible, not later than 1 work day from the first awareness of 
the event. At the same time, Santen will record any SAEs to Santen safety database. Santen will 
then perform medical review. ITEC Services will take care of the reporting to EC and CA. 
The sponsor is responsible for ongoing safety evaluation of the study device. If there is at least a 
reasonable possibility that the event is related to the study device and it is both serious and 
unanticipated (USADE), ITEC services shall initiate expedited reporting, as soon as the medical 
review is finalized by Santen, according to applicable reporting requirements to all relevant parties, 
including regulatory authorities and ethics committees. Reporting responsibilities are described in 
the study specific safety management plan. 
Investigators will also be notified of all suspected, unanticipated serious study device –related 
adverse device effects (USADEs) that occur during the clinical trial. 
All serious and non-serious AEs, must be reported on the adverse event electronic case report form 
(AE e-CRF). In addition, any SAEs, any Device Deficiency that might have led to an SAE if 
suitable action had not been taken/intervention had not been made/if circumstances had been less 
fortunate, any new findings/updates in relation to already reported events - must be reported 
expeditedly to the sponsor (Section 11.2.3.3). 
For each AE, the investigator will evaluate and report  
• The date site became aware of the event  
• The AE/safety information term (verbatim) 
• The onset date  
• Outcome of event  
• The end date, if applicable 
• Severity  
• Location (e.g. right/left eye, both eyes, or not applicable if non ocular event) 

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• Causality to study devices (Not related/Unlikely/Possible/Probable/Causal Relationship) 
• Causality to artificial tears (Not related/Unlikely/Possible/Probable/Causal Relationship) 
• Relationship to study procedures (Not related/Unlikely/Possible/Probable/Causal 
Relationship) 
• Action taken with the study device (for AEs only)  
• Seriousness  
• Treatment medications, if applicable 
• Historical/concurrent medical conditions relevant for the AE 
• Whether or not AE caused the patient to discontinue the study. 
 
The AE term should be reported in standard medical terminology when possible. 
If known, the diagnosis (i.e., disease or syndrome) must be recorded rather than component signs 
and symptoms (e.g., record as "worsening of cataract" rather than "drop in vision"). However, 
other events that are considered unrelated to an encountered syndrome or disease should be 
recorded as individual AEs (e.g., if worsening of macular edema and worsening of panuveitis are 
observed at the same time and are clinically unrelated, each event should be recorded as an 
individual AE). 
11.2.3.2. Reporting of Pregnancy 
Spontaneously reported pregnancy in a patient must be recorded in the source documents at the 
investigation site and reported expeditedly to ITEC services (Section 11.2.3.3). 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
device may have interfered with the effectiveness of a contraceptive medication. The pregnancy 
which occurs during the study or within 14 days of completing the study must be reported. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient was discontinued 
from the study presuming that the informed consent is obtained for this from the patient. The 
outcome (health of infant) must also be reported to ITEC services. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 
11.2.3.3. Expedited reporting 
The investigator must complete, sign and date the SAE (or Pregnancy) pages, verify the accuracy 
of the information recorded on the SAE (or Pregnancy) pages, and send a copy by e-mail or fax 
to ITEC services: 
 
ITEC SERVICES 
Email to alhena@itecservices.com or 

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Fax to +33 5 5 77 85 01 
(Phone +33 5 5 77 85 00) 
 
The CRO ITEC Services will record all SAEs and Pregnancy reports and will inform Sponsor 
about received reports as soon as possible, not later than 1 work day from the first awareness of 
the event. At the same time, Santen will record any SAEs to Santen safety database. Santen will 
then perform medical review. ITEC Services will take care of the reporting to EC and CA. 
Additional follow-up information, if required or available, should all be sent by e-mail or faxed to 
ITEC Services immediately but no later than within 24 hours of receipt and this should be 
completed on a follow-up SAE (or Pregnancy) form and placed with the original information and 
kept with the appropriate section of the eCRF and/or study file. 
The sponsor is responsible for ongoing safety evaluation of the study device. If there is at least a 
reasonable possibility that the event is related to the study device and it is both serious and 
unanticipated (USADE), ITEC services shall initiate expedited reporting, as soon as the medical 
review is finalized by Santen, according to applicable reporting requirements to all relevant parties, 
including regulatory authorities and ethics committees. Reporting responsibilities are described in 
the study specific safety management plan. 
Investigators will also be notified of all suspected, unanticipated serious study device –related 
adverse device effects (USADEs) that occur during the clinical trial. 
 
Documentation of Safety Information 
All AEs will be recorded during the study in the patient’s medical records and on the appropriate 
AE eCRF at the investigational site. Pregnancies will be recorded in the source documents. The 
sponsor records all SAEs and Pregnancy reports in the safety database of Santen. 
ITEC records all AEs (including SAEs, ADEs etc.) during the study. Santen records all SAEs 
during the study. 
At the end of the study ITEC will send all AEs (including SAEs, ADEs etc.) to Santen. 
12. 
STATISTICS 
 
General Considerations 
Unless specified otherwise, efficacy measures will be summarized by planned treatment, and 
safety measures will be summarized by actual treatment received. Continuous variables will be 
summarized using descriptive statistics such as number of observations (n), mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be tabulated using 
frequency (n) and percent (%). For the variables recorded for both eyes, the descriptions will be 
given separately for the study eye and for the fellow eye, when considered relevant. 
All data manipulations and descriptive summaries will be performed using SAS Version 9.4 or 
later.  

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A Statistical Analysis Plan (SAP) will be written and finalized before the start of the analysis of 
the study data, which will present the details of how all the analyses will be performed.  
12.1.1. 
Sample Size 
The sample size calculation was performed in order to test the non-inferiority of ALOCROSS® 
versus VISMED®, a commonly used preservative free artificial tear treatment in France for 
patients with keratitis or keratoconjunctivitis, on the main criterion (ocular surface staining score, 
the sum of the temporal and nasal interpalpebral conjunctival and corneal fluorescein staining 
graded using the modified Oxford scale). A standard deviation of 2.5 is expected for this 
parameter.  
With an alpha risk of 0.025 (unilateral test of comparison versus the non-inferiority margin), a 
power of 90% and a non-inferiority (NI) margin of 2 points, a sample-size of 66 patients was 
found necessary.  
To reach this sample-size in the per protocol population (population of interest in a NI study), a 
sample-size of 80 patients will be randomised in this study, to allow 15% of patients to be excluded 
from this population (withdrawals, major deviations…). 
12.1.2. 
Study Eye 
The study eye is defined as the eligible eye that fulfils all the criteria listed under the inclusion 
criteria #4 and #5. If both eyes are eligible, the eye with the highest baseline CFS score will be 
chosen. If both eyes have the same baseline CFS score, the eye with the lowest Schirmer’s test 
value will be chosen. If both eyes have the same Schirmer’s test value, the right eye will be chosen 
as the study eye. 
All the efficacy analyses will be performed on the study eye only. 
 
Analysis Populations 
Analysis populations are defined below: 
• The Full Analysis Set (FAS) population consists of all randomised patients who received 
at least one dose of the study device and had at least one post-baseline sign or symptom 
assessment of the study eye. This will be the population used for efficacy analyses.   
• The Per-Protocol Set (PPS) will be a subset of FAS, restricted to the patients who fulfil 
the protocol in the terms of the eligibility, interventions, and outcome assessment. It will 
be the analysis population for some sensitivity analyses. The determination of the PPS will 
be done before unmasking. 
• The Safety population consists of all patients enrolled who received at least one dose of 
the study device. It will be the analysis population for safety analyses. 
 
Analysis of Demographics and Baseline Characteristics 
Descriptive summaries will be performed for demographic (including age, gender, female patients’ 
menopausal status) and baseline characteristics variables (including time since diagnosis, past 
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In addition, medical history (ocular and systemic) and prior and concomitant medication uses will 
be summarised. Prior medication is defined as any medication or medical device that was used by 
the patients that is discontinued before the Baseline visit (Day 1).  
 
Analysis of Primary Endpoint 
The main hypothesis to be tested is the non-inferiority of ALOCROSS® versus VISMED® on the 
change from baseline (CFB) for the ocular surface staining score, after 4 weeks of treatment:  
H0 : (ALOCROSS® CFB – VISMED® CFB) > 2  
Ha : (ALOCROSS® CFB – VISMED® CFB) <= 2  
An MMRM model will be performed to provide the estimate of the least square (LS) means 
difference between groups in the change from baseline of the ocular surface staining score after 4 
weeks of treatment. This model will include the treatment, visit, and treatment-by-visit interaction 
as fixed factors, the ocular surface staining score at the baseline and the interaction between the 
treatment and the ocular surface staining score at baseline as covariates.  
The 95% confidence interval (CI) of this difference will then be computed and the upper bound 
will be compared to the NI margin (2 points). In case where the upper bound will be found less 
than or equal to the NI margin, the NI of ALOCROSS® versus VISMED® will be demonstrated.  
Positive results on the FAS population will be confirmed in the PP population, as for a NI study 
the two sets of analysis have the same importance (ref. ICHE9).  
 
Other Efficacy Variables Analyses 
12.5.1. 
Parameters related to the primary criterion 
The main model (MMRM) will also be used to analyse the endpoints related to the main criterion 
(individual components of the ocular surface staining score – nasal and temporal interpalpebral 
and corneal fluorescein staining scores) after 4 weeks of treatment (28 days).  
12.5.2. 
Other parameters of efficacy 
Corneal fluorescein clearing: the number and percentage of patients reaching a score of 0 at their 
CFS will be presented by group at each time point (week 2, week 4 and week 12), with the 
corresponding 95% CI ().  
Symptoms of ocular discomfort (individual VAS and their mean) will be analysed with an MMRM 
model using the corresponding baseline value as covariate, at week 2, week 4 and week 12 for the 
Schirmer test and TBUT at week 4 and week 12. 
Evaluation of the efficacy of the treatment by the investigator will be compared between groups 
at week 2, week 4 and week 12 by a Wilcoxon test.  
An exploratory analysis of the NEI-VFQ (QOL Questionnaire) subscale scores and composite 
score will also be performed. The change from baseline in either total score or appropriate subscale 
scores will be summarized using descriptive statistics. At week 4, the mean change from baseline 
will be compared between the groups using an MMRM model with treatment, visit, and treatment-
by-visit interaction as fixed effects, baseline value of the corresponding score and the interaction 

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between the treatment and the ocular surface staining score at baseline as covariates. In order to 
give more interpretable results, the corresponding LS means will also be expressed in term of 
effect-size.  
 
Analysis of Secondary Endpoints 
For FAS population, means for OSS score, CFS, conjunctival fluorescein staining, symptoms of 
ocular discomfort (VAS), TBUT, Schirmer’s test and quality of life (NEI-VFQ) score, and their 
change from baseline will be summarized by analysis visit. The analysis for FAS population will 
be conducted by treatment groups. 
Summary statistics on the scores of Quality of Life variables will be provided as well as their 
change from baseline at each visit. 
Missing data will not be imputed. 
 
Analysis of Safety and Tolerability Endpoints 
All safety and tolerability endpoints analyses will be performed with the Safety population. 
12.7.1. 
Adverse Events 
An adverse event is treatment emergent if it occurs or worsens after the first dose of study 
treatment.  
Adverse events will be coded using standard medical terminology. Frequencies and percentages 
will be given as follows: 1) Overall summary; 2) by system organ class and preferred term, 3) by 
system organ class, preferred term and maximal severity, 4) by system organ class, preferred term 
and relationship to study devices and study procedure, respectively, and 5) by system organ class, 
preferred term, maximal severity, and relationship to study devices and study procedure, 
respectively.  
Separate analyses will be performed for AEs and SAEs, and for ocular and systemic AEs and 
SAEs, respectively. Ocular AEs will be summarized for the study eye and the fellow eye 
separately. 
12.7.2. 
Other Safety Assessments 
Other parameters of safety assessments (e.g. slit lamp examination, BCDVA, and IOP) will be 
summarised at each time point of measurement for each safety population. They will be 
summarised/ analysed for the study eye and the fellow eye separately. The analysis for safety 
population will be conducted by treatment group. 
 
Interim Analysis 
Not applicable 
 
Handling of Missing Values 
No imputation for missing data will be performed on primary and secondary endpoint analyses. 
Unless specified otherwise, descriptive summaries will be based on observed cases. 

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For medical events including AEs, completely or partially missing onset and resolution dates will 
be imputed in a conservative fashion to be detailed in the Statistical Analysis Plan (SAP).  Same 
rules will be followed to impute the completely or partially missing start and end dates of non-
study devices. 
13. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of the Sponsor will 
either visit the investigational study site or review the feasibility questionnaire to: 
• Determine the adequacy of the facilities. 
• Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Santen SAS or its representatives.  This will 
be documented in a Clinical Study Agreement between Santen or its designee and the 
investigator. 
During the study, a monitor from Santen or representative will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the investigator(s). 
• Confirm that facilities remain acceptable. 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational device accountability 
checks are being performed. 
• Perform source data verification.  This includes a comparison of the data in the case report 
forms with the patient’s medical records at the hospital or practice, and other records 
relevant to the study.  This will require direct access to all original records for each patient 
(e.g. clinic charts). 
• Record and report any protocol deviations not previously sent to Santen. 
• Confirm non-serious AEs and SAEs have been properly documented on eCRFs and 
confirm any safety information requiring expedited reporting to ITEC Services (including 
SAEs and Pregnancies) have been forwarded to ITEC and those SAEs that met criteria for 
reporting have been forwarded to Santen, to the EC and to the national Competent 
Authorities. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
 
Audits and Inspections 
Authorised representatives of Santen, a regulatory authority (national or foreign), an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
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systematically and independently examine all study-related activities and documents to determine 
whether these activities were conducted, and data were recorded, analysed, and accurately reported 
according to the protocol, Good Clinical Practice guidelines of the International Conference on 
Harmonization, and any applicable regulatory requirements.  The investigator should contact 
Santen immediately if contacted by a regulatory agency about an inspection. 
 
Ethics Committee (EC) 
A written favourable opinion of EC (as appropriate) must be obtained before starting the study. 
Initial EC approval, and all materials approved by the EC for this study including the patient 
consent form and recruitment materials must be maintained by the Investigator and made available 
for inspection. 
14. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Santen may conduct a quality assurance audit.  Please see Section 13.2 for more details regarding 
the audit process. 
15. 
ETHICS 
 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favourable opinion in writing by an EC.  A copy of the letter indicating EC 
approval or a favourable opinion must be available at the investigational site before the site can 
enroll any patient into the study. 
Any amendment to the protocol must be reviewed by EC in accordance with local requirements.  
In addition, the EC must approve all advertising used to recruit patients for the study.   
Progress reports and notifications of SAEs will be provided to the EC according to local 
regulations and guidelines. 
 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, ISO 14155:2011 
“Clinical investigation of medical devices and applicable regulatory requirements. Please see 
Appendix D Declaration of Helsinki.  
 
Written Informed Consent 
The Principal Investigator(s) at each centre will ensure that the patient is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
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patient should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The patient’s signed and dated informed consent must be obtained before any protocol-directed 
procedures are performed. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the patient. 
In accordance with Act No 78-17 of January 6, 1978 on Information Technology, Data Files and 
Civil Liberties, the patient will also be informed in writing of his/her right to access, oppose and 
rectify data recorded in this study. 
16. 
DATA HANDLING AND RECORD KEEPING 
 
Inspection of Records 
Santen or Santen’s designee will be allowed to conduct site visits to the investigation facilities for 
the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor 
to inspect the device storage area, study drug stocks, drug accountability records, patient charts 
and study source documents, and other records relative to study conduct. 
 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. In addition, ICH E6 Section 4.9.5 states that the 
study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Ste Agreement between the investigator 
and sponsor. If it becomes necessary for Santen or the Regulatory Authority to review any 
documentation relating to the study, the Investigator must permit access to such records. 
 
Source Documents 
The patient source documentation should include hospital reports, doctor’s/nurse’s notes, 
laboratory results, reports of special examinations, the signed consent forms, consultants letters. 
The Investigator is asked to report the following information in the patient’s medical file (source 
documents) according to Sources Data Agreement signed by the Principal Investigator of each 
Investigational site: 
- 
Mention of patient’s participation in the study, patient code and treatment number, date 
and process of signature of informed consent form 
- 
Demographic data (partial date of birth, sex, name) 
- 
Past medical and surgery history 
- 
Past and recent treatments 
- 
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- 
Change in concomitant treatments throughout the study 
- 
Date of each study visit 
- 
Date of the final visit 
- 
Date and reason of premature withdrawal 
- 
All data related to study procedures 
- 
Any non-serious ADEs and SADEs occurred during the time course of the study and 
study drug-related SAEs which occurred after the completion of the study 
- 
Any pregnancy occurring during the study or within 14 days of completing the study 
- 
Any data that could be judged by the Investigator as relevant 
This list is not exhaustive. 
 
 Data Collection 
The Principal Investigator must maintain detailed records on all patients who provided informed 
consent. Data for screened and enrolled patients will be entered into eCRFs, designed according 
to the protocol. Review of the eCRFs will be completed remotely by Santen (or designee). At 
designated intervals, a study monitor will perform source data verification on site. During those 
visits, Santen (or designee) will monitor the patient data recorded in the eCRF against source 
documents at the study site. Santen (or designee) will review and evaluate eCRF data and use 
standard system edits, and may use centralised monitoring evaluations, to detect errors in data 
collection. At the end of the stud, a copy of the completed eCRFs will be sent to the site to be 
maintained as study records.  
17. 
PUBLICATION POLICY 
The investigator is obliged to provide the Sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the Sponsor may make study information 
available to other study investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the Sponsor. 
The Sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Any published data will be 
written in accordance with prevailing guidelines including International Committee of Medical 
Journal Editors and Good Publication Practice for Communicating Company-Sponsored Medical 
Research. Manuscript authorship for any peer-reviewed publication will appropriately reflect 
contributions to the production and review of the document. All publications and presentations 
must be prepared in accordance with this section and the Master Services Agreement or equivalent 
agreement. In the event of any discrepancy between the protocol and the Master Services 
Agreement or equivalent agreement the Master Services Agreement or equivalent agreement will 
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18. 
LIST OF REFERENCES 
1. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II 
Definition and Classification Report. The ocular surface. 2017 Jul;15(3):276-83. PubMed PMID: 
28736335. 
2. Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II 
Epidemiology Report. The ocular surface. 2017 Jul;15(3):334-65. PubMed PMID: 28736337. 
3. All Wales Medicines Strategy Group. Dry Eye Syndrome Guidance. December 2016. 
4. Nakamura M, Hikida M, Nakano T, Ito S, Hamano T, Kinoshita S. Characterization of water 
retentive properties of hyaluronan. Cornea. 1993 Sep;12(5):433-6. PubMed PMID: 8306665. 
5. Baeyens V, Bron A, Baudouin C, Vismed/Hylovis Study G. Efficacy of 0.18% hypotonic 
sodium hyaluronate ophthalmic solution in the treatment of signs and symptoms of dry eye 
disease. J Fr Ophtalmol. 2012 Jun;35(6):412-9. PubMed PMID: 22483761. 
6. Vogel R, Crockett RS, Oden N, Laliberte TW, Molina L, Sodium Hyaluronate Ophthalmic 
Solution Study G. Demonstration of efficacy in the treatment of dry eye disease with 0.18% 
sodium hyaluronate ophthalmic solution (vismed, rejena). Am J Ophthalmol. 2010 
Apr;149(4):594-601. PubMed PMID: 20346777. 
7. Brignole F, Pisella PJ, Dupas B, Baeyens V, Baudouin C. Efficacy and safety of 0.18% 
sodium hyaluronate in patients with moderate dry eye syndrome and superficial keratitis. Graefes 
Arch Clin Exp Ophthalmol. 2005 Dec 17. PubMed PMID: 15605267. 
8. Sand BB, Marner K, Norn MS. Sodium hyaluronate in the treatment of keratoconjunctivitis 
sicca. A double masked clinical trial. Acta Ophthalmol (Copenh). 1989 Apr;67(2):181-3. 
PubMed PMID: 2658462. 
9. Doughty MJ. Fluorescein-tear breakup time as an assessment of efficacy of tear replacement 
therapy in dry eye patients: a systematic review and meta-analysis. The ocular surface. 2014 
Apr;12(2):100-11. PubMed PMID: 24725322. 
10. Pinto-Fraga J, Lopez-de la Rosa A, Blazquez Arauzo F, Urbano Rodriguez R, Gonzalez-
Garcia MJ. Efficacy and Safety of 0.2% Hyaluronic Acid in the Management of Dry Eye 
Disease. Eye Contact Lens. 2017 Jan;43(1):57-63. PubMed PMID: 26783978. 
11. Wozniak A, Paduch R. Aloe vera extract activity on human corneal cells. Pharm Biol. 2012 
Feb;50(2):147-54. PubMed PMID: 22338121. 
 
 

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19. 
APPENDICES 
 
Appendix A-I  Modified Oxford Scale 
Grading of corneal fluorescein staining, corneal fluorescein clearing and staining of the nasal and 
temporal interpalpebral conjunctiva  
 
 

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Grading of corneal fluorescein staining, corneal fluorescein clearing and staining of the nasal and 
temporal interpalpebral conjunctiva according to the modified Oxford scale. 
 
OD 
OS 
Temporal 
interpalpebral 
conjunctiva 
Corneal area 
Nasal 
interpalpebral 
conjunctiva 
Nasal 
interpalpebral 
conjunctiva 
Corneal area 
Temporal 
interpalpebral 
conjunctiva 
A 
B 
C 
C 
B 
A 
 
 
 
 
 
 
 
 
 
 
A 
B* 
C 
C 
B* 
A 
0   0.5    1     2  
           
 3     4     5  
       
0   0.5    1     2  
           
 3     4     5  
       
0   0.5    1     2  
           
 3     4     5  
       
0   0.5    1     2  
           
 3     4     5  
       
0   0.5    1     2  
           
 3     4     5  
       
0   0.5    1     2  
           
 3     4     5  
       
Ocular Surface Staining Score** = A+B+C =  
 
*If score B ≥ 4, the patient cannot be enrolled  
** Patients must have an ocular surface staining 
score of ≥4 and ≤9 to be enrolled  
 
Ocular Surface Staining Score** = C+B+A =  
 
*If score B ≥ 4, the patient cannot be enrolled  
** Patients must have an ocular surface staining 
score of ≥4 and ≤9 to be enrolled  
 
 
Staining scores range from 0-5 for the cornea, temporal and nasal conjunctiva and 0-15 for the 
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Appendix A-II  Slit lamp examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp. 
The patient will be seated while being examined; grading of the Meibomian glands, lids, lashes, 
conjunctiva, tear film debris, anterior chamber and lens will be done according to the following 
scales: 
Meibomian glands (evaluation of the central ten Meibomian gland openings in the mid-portion 
of the upper eyelid): 
0 = 
None (none are plugged). 
1 = 
Mild (1 to 2 glands are plugged). 
2 = 
Moderate (3 to 4 glands are plugged). 
3 = 
Severe (All glands are plugged). 
Lid - Erythema 
0 = 
None (normal). 
1 = 
Mild (redness localised to a small region of the lid(s) margin OR skin). 
2 = 
Moderate (redness of most or all lid margin OR skin). 
3 = 
Severe (redness of most or all lid margin AND skin). 
4 = 
Very severe (marked diffuse redness of both lid margin AND skin). 
Lid - Oedema 
0 = 
None (normal). 
1 = 
Mild (localised to a small region of the lid). 
2 = 
Moderate (diffuse, most or all lid but not prominent/protruding). 
3 = 
Severe (diffuse, most or all lid AND prominent/protruding). 
4 = 
Very severe (diffuse AND prominent/protruding AND reversion of the lid). 
Lashes 
0 = 
Normal 
1 = 
Abnormal (specify) 
Conjunctiva – Erythema 
0 = 
None (normal). 
1 = Mild (a flush reddish colour predominantly confined to the palpebral or bulbar 
conjunctiva). 
2 = 
Moderate (more prominent red colour of the palpebral or bulbar conjunctiva). 
3 = 
Severe (definite redness of palpebral or bulbar conjunctiva). 
 

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Conjunctiva - Oedema 
0 = 
None (normal). 
1 = 
Mild (slight localised swelling). 
2 = 
Moderate (moderate/medium localised swelling or mild diffuse swelling). 
3 = 
Severe (severe diffuse swelling). 
4 = 
Very severe (very prominent/protruding diffuse swelling). 
Tear Film Debris 
0 = 
None (absence of debris). 
1 = 
Mild (presence of debris in inferior tear meniscus). 
2 = Moderate (presence of debris in inferior tear meniscus and in tear film overlying 
cornea). 
3 = Severe (presence of debris in inferior tear meniscus and in tear film overlying cornea. 
Presence of mucus strands in inferior fornix of on bulbar conjunctiva). 
4 = Very severe (presence of debris in inferior tear meniscus and in tear film overlying 
cornea. Presence of numerous AND/OR adherent mucus strands in inferior fornix and 
on bulbar conjunctiva or filamentary keratitis). 
Anterior Chamber Inflammation  
0 = 
None (no Tyndall effect). 
1 = 
Mild (Tyndall effect barely discernible).  
2 = 
Moderate (Tyndall beam in the anterior chamber is moderately intense). 
3 = 
Severe (Tyndall beam in the anterior chamber is severely intense). 
Lens 
0 = 
No opacification (normal lens). 
1 = 
Mild lens opacification. 
2 = 
Moderate lens opacification. 
3 = 
Severe lens opacification. 
 
 

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Appendix A-III Visual Analog Scale (VAS)_Symptoms of 
Ocular Discomfort 
The patient will be asked to assess each symptom regarding ocular discomfort unrelated to 
instillation among a list of 7 symptoms, i.e. itching, foreign body sensation or sandy feeling or 
grittiness, photophobia, burning/stinging, eye dryness, pain or ocular discomfort and sticky 
feeling. The patient will be asked to rate each ocular symptoms by placing a vertical mark on the 
horizontal line to indicate the level of each ocular symptoms. 
0% corresponds to ‘no discomfort” and 100% corresponds to “maximal discomfort”. 
The response will be measured in % between 0 – 100%, on a 100 mm line. 
 
Itching 
 
 
Foreign body sensation or  
sandy feeling or grittiness 
 
 
Photophobia 
 
 
Burning/stinging 
 
 
Eye dryness 
 
 
Pain or ocular discomfort 
 
 
Sticky feeling 
 
 
 
 

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Appendix A-IV National Eye Institute Visual Function 
Questionnaire (NEI VFQ-25) 
The NEI-VFQ-25 is self-administered and should be completed by the patient. 
 

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1Development of the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) (2001) 
Mangione, C. M., Lee, P. P., Gutierrez, P. R., Spritzer, K., Berry, S., & Hays, R. D. 
Archives of Ophthalmology, 119, 1050-1058 
 

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Appendix B  Elements of the Patient Informed Consent 
In seeking informed consent, the following information shall be provided to each patient: 
• A statement that the study involves research. 
• An explanation of the purposes of the research. 
• The expected duration of the patient’s participation. 
• A description of the procedures to be followed, including invasive procedures. 
• The identification of any procedures that are experimental. 
• The estimated number of patients involved in the study. 
• A description of the patient’s responsibilities. 
• A description of the conduct of the study. 
• A statement describing the treatment(s) and the probability for random assignment to 
each treatment. 
• A description of the possible side effects of the treatment that the patient may receive. 
• A description of any reasonably foreseeable risks or discomforts to the patient and, 
when applicable, to an embryo, foetus, or nursing infant. 
• A description of any benefits to the patient or to others that reasonably may be expected 
from the research. When there is no intended clinical benefit to the patient, the patient 
should be made aware of this. 
• Disclosures of appropriate alternative procedures or courses of treatment, if any, that 
might be advantageous to the patient and their important potential risks and benefits. 
• A statement describing the extent to which confidentiality of records identifying the 
patient will be maintained, and a note of the possibility that regulatory agencies, 
auditor(s), IRB/IEC, and the monitor may inspect the records. By signing a written 
informed consent form, the patient or the patient’s legally acceptable representative is 
authorizing such access. 
• For research involving more than minimal risk, an explanation as to whether any 
compensation and an explanation as to whether any medical treatments are available if 
injury occurs and, if so, what they consist of or where further information may be 
obtained. 
• The anticipated prorated payment(s), if any, to the patient for participating in the study. 
• The anticipated expenses, if any, to the patient for participating in the study. 
• An explanation of whom to contact for answers to pertinent questions about the 
research (investigator), patient’s rights, and IRB/IEC and whom to contact in the event 
of a research-related injury to the patient. 
• A statement that participation is voluntary, that refusal to participate will involve no 
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may discontinue participation at any time without penalty or loss of benefits to which 
the patient is otherwise entitled. 
• The consequences of a patient’s decision to withdraw from the research and procedures 
for orderly termination of participation by the patient. 
• A statement that the patient or the patient’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be relevant to 
the patient’s willingness to continue participation in the study. 
• The foreseeable circumstances or reasons under which the patient’s participation in the 
study may be terminated. 
• A statement that significant new findings developed during the course of the research, 
which may relate to the patient’s willingness to continue participation, will be provided 
to the patient. 
• A written patient authorization (either contained within the informed consent form or 
provided as a separate document) describing to the patient the contemplated and 
permissible uses and disclosures of the patient’s personal information (including 
personal health information) for purposes of conducting the study. The patient 
authorization must contain the following statements regarding the uses and disclosures 
of the patient’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting 
purposes, including, without limitation, to the following: (1) Santen, its affiliates, and 
licensing partners; (2) business partners assisting Santen, its affiliates, and licensing 
partners; (3) regulatory agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be 
processed and transferred to countries that do not have data protection laws that offer 
patients the same level of protection as the data protection laws within this country; 
however, Santen will make every effort to keep your personal information confidential, 
and your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to Santen’s 
research databases for purposes of developing a better understanding of the safety and 
effectiveness of the study device(s), studying other therapies for patients, developing a 
better understanding of disease, and improving the efficiency of future clinical studies; 
d) that patients agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) that the patient’s identity will remain confidential in the event that study results are 
published.    
 
 

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Appendix C  Investigator Consent to Use of Personal 
Information  
Santen will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (e.g., the 
United Kingdom, United States, Japan), including the following: 
• Santen, its affiliates, and licensing partners. 
• Business partners assisting Santen, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs and IECs. 
Investigator’s personal information may be retained, processed, and transferred by Santen and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the study and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the study. 
• Analysis, review, and verification of the study results. 
• Safety reporting and pharmacovigilance relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study device. 
• Inspections and investigations by regulatory authorities relating to the study. 
Self-inspection and internal audit within Santen, its affiliates, and licensing partners. 
• Archiving and audit of study records. 
• Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country. 
Investigator acknowledges and consents to the use of his or her personal information by Santen 
and other parties for the purposes described above. 
 
 

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Appendix D Declaration of Helsinki 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble  
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement 
of ethical principles for medical research involving human subjects, including research on identifiable 
human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent paragraphs should be 
applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The 
WMA encourages others who are involved in medical research involving human subjects to adopt these 
principles.  
General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The health of my 
patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A 
physician shall act in the patient's best interest when providing medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician's knowledge and conscience are 
dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies involving human 
subjects. 
6.         The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions 
(methods, procedures and treatments). Even the best proven interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect for all human 
subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this goal can never 
take precedence over the rights and interests of individual research subjects. 

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9.         It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research 
subjects. The responsibility for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for research 
involving human subjects in their own countries as well as applicable international norms and standards. 
No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm to the environment. 
12.       Medical research involving human subjects must be conducted only by individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on patients or healthy 
volunteers requires the supervision of a competent and appropriately qualified physician or other health 
care professional. 
13.       Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14.       Physicians who combine medical research with medical care should involve their patients in 
research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value 
and if the physician has good reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and burdens. 
           Medical research involving human subjects may only be conducted if the importance of the objective 
outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful assessment of 
predictable risks and burdens to the individuals and groups involved in the research in comparison with 
foreseeable benefits to them and to other individuals or groups affected by the condition under investigation. 
           Measures to minimise the risks must be implemented. The risks must be continuously monitored, 
assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects unless they are 
confident that the risks have been adequately assessed and can be satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is conclusive proof of 
definitive outcomes, physicians must assess whether to continue, modify or immediately stop the 
study.            
Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an increased likelihood of 
being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered protection. 

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20.       Medical research with a vulnerable group is only justified if the research is responsive to the health 
needs or priorities of this group and the research cannot be carried out in a non-vulnerable group. In 
addition, this group should stand to benefit from the knowledge, practices or interventions that result from 
the research. 
Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted scientific 
principles, be based on a thorough knowledge of the scientific literature, other relevant sources of 
information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals 
used for research must be respected. 
22.       The design and performance of each research study involving human subjects must be clearly 
described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and should indicate 
how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects 
and information regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
functioning, must be independent of the researcher, the sponsor and any other undue influence and must be 
duly qualified. It must take into consideration the laws and regulations of the country or countries in which 
the research is to be performed as well as applicable international norms and standards but these must not 
be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration.  
           The committee must have the right to monitor ongoing studies. The researcher must provide 
monitoring information to the committee, especially information about any serious adverse events. No 
amendment to the protocol may be made without consideration and approval by the committee. After the 
end of the study, the researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions.  
Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the confidentiality of 
their personal information. 
Informed Consent  
25.       Participation by individuals capable of giving informed consent as subjects in medical research must 
be voluntary. Although it may be appropriate to consult family members or community leaders, no 
individual capable of giving informed consent may be enrolled in a research study unless he or she freely 
agrees. 
26.       In medical research involving human subjects capable of giving informed consent, each potential 
subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of 
interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study 
and the discomfort it may entail, post-study provisions and any other relevant aspects of the study. The 

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potential subject must be informed of the right to refuse to participate in the study or to withdraw consent 
to participate at any time without reprisal. Special attention should be given to the specific information 
needs of individual potential subjects as well as to the methods used to deliver the information. 
           After ensuring that the potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject’s freely-given informed consent, 
preferably in writing. If the consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed.       
           All medical research subjects should be given the option of being informed about the general outcome 
and results of the study. 
27.       When seeking informed consent for participation in a research study the physician must be 
particularly cautious if the potential subject is in a dependent relationship with the physician or may consent 
under duress. In such situations the informed consent must be sought by an appropriately qualified 
individual who is completely independent of this relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the physician must 
seek informed consent from the legally authorised representative. These individuals must not be included 
in a research study that has no likelihood of benefit for them unless it is intended to promote the health of 
the group represented by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed consent is able to 
give assent to decisions about participation in research, the physician must seek that assent in addition to 
the consent of the legally authorised representative. The potential subject’s dissent should be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving consent, for 
example, unconscious patients, may be done only if the physical or mental condition that prevents giving 
informed consent is a necessary characteristic of the research group. In such circumstances the physician 
must seek informed consent from the legally authorised representative. If no such representative is available 
and if the research cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give informed consent 
have been stated in the research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research must be obtained as soon as possible from the subject or a legally 
authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related to the research. 
The refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must 
never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, 
storage and/or reuse. There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may be done only after 
consideration and approval of a research ethics committee. 
Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of 
the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 

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           Where for compelling and scientifically sound methodological reasons the use of any intervention 
less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the 
efficacy or safety of an intervention  
           and the patients who receive any intervention less effective than the best proven one, placebo, or no 
intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving 
the best proven intervention.  
           Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments should make 
provisions for post-trial access for all participants who still need an intervention identified as beneficial in 
the trial. This information must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35.       Every research study involving human subjects must be registered in a publicly accessible database 
before recruitment of the first subject. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly available 
the results of their research on human subjects and are accountable for the completeness and accuracy of 
their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative and 
inconclusive as well as positive results must be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the publication. Reports of 
research not in accordance with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent from 
the patient or a legally authorised representative, may use an unproven intervention if in the physician's 
judgement it offers hope of saving life, re-establishing health or alleviating suffering. This intervention 
should subsequently be made the object of research, designed to evaluate its safety and efficacy. In all cases, 
new information must be recorded and, where appropriate, made publicly available. 
 
 

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COMPANY/SPONSOR APPROVERS 
 
Company/Sponsor Address 
SANTEN SAS 
Genavenir IV, 1 rue Pierre Fontaine 
F-91058 Evry, France 
 
 
Company/Sponsor signatory 
Bogdan Lytvyn, MD, PhD 
Associate Director, Medical Affairs Front of 
the Eye, EMEA 
Office: +41 79 88 59 051 
 
Company/Sponsor signatory 
Dahlia Ismail, Msc 
Associate Director Clinical Science 
Intelligence  
Ocular surface & Anterior Segment 
Therapeutic Area Strategy  
Office: +33 64 09 65 185