Clinical trial NCT03237936
Conditions: Keratitis
Sponsor: Santen SAS
Start date: 2017-03-28; Completion date: 2018-07-11
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The proposed 3-month study is a prospective, open-label, multicentre, phase IV, proof of concept study. The study is designed to assess the effect on the quality of vision of IKERVIS® (1mg/mL ciclosporin) eye drops administered once daily in dry eye disease (DED) patients with severe keratitis, as well as its safety and efficacy.

Detailed description:
In this phase IV clinical trial the Month 3 visit assessments will be used to assess the efficacy (quality of vision and other parameters) and safety of IKERVIS® in DED patients with severe keratitis.

To assess the effect on the quality of vision of IKERVIS® (1mg/ml ciclosporin) eye drops administered once daily in adult dry eye disease (DED) patients with severe keratitis over 3 months of treatment.

To assess the safety of DED patients with severe keratitis treated with IKERVIS® (1mg/mL ciclosporin) for 3 months.

Arms: arm 1: one drop of study medication (IKERVIS®1mg/mL) once daily in each eye at bedtime during 3 months.
Interventions: intervention 1: 1mg/mL ciclosporin
Intervention descriptions: intervention 1: IKERVIS® (1mg/ml ciclosporin) eye drops administered once daily following 3 months of treatment

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
A PHASE IV, PROSPECTIVE, OPEN-LABEL, MULTICENTRE, 
SINGLE ARM, 3-MONTH PROOF OF CONCEPT STUDY TO 
ASSESS THE EFFECT OF IKERVIS® 1MG/ML (CICLOSPORIN) 
EYE DROPS ADMINISTERED ONCE DAILY ON THE QUALITY 
OF VISION IN DRY EYE DISEASE (DED) PATIENTS WITH 
SEVERE KERATITIS 
 
NCT Number:  
 NCT03237936 
 
Date of the document: 
23 Mar 2018 
 
 
 


1.0 TITLE PAGE
PROTOCOL 
A PHASE IV, PROSPECTIVE, OPEN-LABEL, MULTICENTRE, SINGLE ARM, 3-MONTH 
PROOF OF CONCEPT STUDY TO ASSESS THE EFFECT OF IKERVIS® 1MG/ML 
(CICLOSPORIN) EYE DROPS ADMINISTERED ONCE DAILY ON THE QUALITY OF 
VISION IN DRY EYE DISEASE (DED) PATIENTS WITH SEVERE KERATITIS 
Sponsor: 
SANTEN SAS 
Genavenir IV, 1 rue Pierre Fontaine 
F-91058 Evry, France 
Study Number: 
NVG16E128 
IND Number: 
N/A 
EudraCT Number: 
2016-003497-40 
Compound: 
IKERVIS® 
Date: 
Version 4.0  23 March 2018 
Amendment 2 
 
 
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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1.0
ADMINISTRATIVE INFORMATION 
1.1
Contacts 


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1.2
Approval 
REPRESENTATIVES OF SANTEN 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in accordance with the 
following: 
•
The ethical principles that have their origin in the Declaration of Helsinki. 
•
International Conference on Harmonisation E6 Good Clinical Practice Consolidated 
Guideline. 
•
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws. 
SIGNATURES


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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the Summary of Product 
characteristics, and any other product 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. 
•
International Conference on Harmonisation E6 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 Section 10.2 of this 
protocol. 
•
Terms outlined in the Clinical Study Site Agreement. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix CB 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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TABLE OF CONTENTS 
1.0
ADMINISTRATIVE INFORMATION ..............................................................................2
1.1
Contacts..........................................................................................................................2
1.2
Approval ........................................................................................................................3
2.0
STUDY SUMMARY.........................................................................................................10
3.0
STUDY REFERENCE INFORMATION .........................................................................15
3.1
Study-Related Responsibilities ....................................................................................15
3.2
Principal Investigator ...................................................................................................15
3.3
List of Abbreviations ...................................................................................................16
3.4
Corporate Identification ...............................................................................................17
4.0
INTRODUCTION .............................................................................................................18
4.1
Background on IKERVIS® .........................................................................................18
4.1.1
Pharmacokinetics and Safety of Animals .......................................................19
4.1.2
Clinical Pharmacokinetics and Pharmacodynamics .......................................19
4.1.3
Clinical Experience .........................................................................................20
4.2
Rationale for the Proposed Study ................................................................................21
4.3
Benefit risk balance......................................................................................................22
5.0
STUDY OBJECTIVES AND ENDPOINTS .....................................................................23
5.1
Objectives ....................................................................................................................23
5.1.1
Primary Objective(s) .......................................................................................23
5.1.2
Secondary Objectives .....................................................................................23
5.2
Endpoints .....................................................................................................................23
5.2.1
Primary Efficacy Endpoints ............................................................................23
5.2.2
Secondary Endpoints ......................................................................................24
5.2.2.1
Efficacy Endpoints .....................................................................................24
5.2.2.2
Safety Evaluations .....................................................................................24
6.0
STUDY DESIGN AND DESCRIPTION ..........................................................................25
6.1
Study Design ................................................................................................................25
6.2
Justification for Study Design, Dose and Endpoints ...................................................27
6.2.1
Criteria for Premature Termination or Suspension of the Study ....................27
6.2.2
Criteria for Premature Termination or Suspension of Investigational 
Site(s) ..............................................................................................................27
6.2.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) ...........................................................27
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PATIENTS ...............28


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7.1
Inclusion Criteria .........................................................................................................28
7.2
Exclusion Criteria ........................................................................................................28
7.3
Excluded Medication, Treatments and Procedures ......................................................30
7.3.1
Ocular Treatments ..........................................................................................30
7.3.2
Prohibited Concomitant Therapies .................................................................31
7.3.3
Recording of Medications ...............................................................................31
7.4
Criteria for Discontinuation or Withdrawal of a Patient ..............................................32
7.4.1
Completed Study ............................................................................................32
7.5
Procedures for Discontinuation or Withdrawal of a Patient ........................................33
8.0
CLINICAL TRIAL MATERIAL MANAGEMENT .........................................................34
8.1
Study Medication and Materials ..................................................................................34
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ...............................34
8.1.1.1
Investigational Drug...................................................................................34
8.1.1.2
Washout Medication ..................................................................................34
8.1.1.3
Packaging and Labeling .............................................................................35
8.1.2
Storage ............................................................................................................35
8.1.3
Patient Identification .......................................................................................35
8.1.4
Dose and Regimen ..........................................................................................35
8.1.5
Accountability .................................................................................................36
8.2
Patient’s Compliance ...................................................................................................36
8.3
Accountability and Destruction of All Study Medication ...........................................37
9.0
STUDY PLAN ...................................................................................................................39
9.1
Study Procedures .........................................................................................................39
9.1.1
Informed Consent Procedure ..........................................................................39
9.1.2
Demographics, Medical History, and Medication History Procedure ............39
9.1.3
Safety Assessments .........................................................................................39
9.1.4
Wash-out Period .............................................................................................39
9.1.5
Documentation of Concomitant Medications .................................................39
9.1.6
Documentation of Concurrent Medical Conditions ........................................40
9.1.7
Contraception and Pregnancy Avoidance Procedure .....................................40
9.1.8
Pregnancy .......................................................................................................41
9.1.9
Documentation of Screen Failure ...................................................................41
9.1.10
Documentation of treatment initiation ............................................................41
9.2
Monitoring Patient Treatment Compliance .................................................................42
9.3
Schedule of Observations and Procedures ...................................................................42


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9.3.1
Screening ........................................................................................................42
9.3.1.1
Screening Visit: Day -14 ± 3 days .............................................................42
9.3.2
Treatment Phase ..............................................................................................43
All assessments should be done in the mentioned order to ensure that additional 
product doesn’t interfere for the other result examinations. ...........................43
9.3.2.1
Baseline: Day 1 ..........................................................................................43
9.3.2.2
Month 1:  Day 28 ±3 days ..........................................................................44
9.3.2.3
Month 2:  Day 56 ±3 days ..........................................................................45
9.3.2.4
Month 3:  Day 84 ±7 days ..........................................................................45
9.3.3
Unscheduled Visit/Premature Discontinuation ...............................................46
9.3.4
Efficacy Assessment .......................................................................................46
9.3.4.1
Functional Visual Acuity (FVA) ...............................................................46
9.3.4.2
Objective Scatter Index (OSI) ....................................................................47
9.3.4.3
Corneal Fluorescein Staining including Complete Corneal Clearing ........47
9.3.4.4
Higher Order Aberrations ..........................................................................47
9.3.4.5
Patient Global Evaluation of Efficacy .......................................................47
9.3.4.6
Symptoms Measured on Visual Analogue Scales (VASs) ........................47
9.3.4.7
Tear Break-Up Time ..................................................................................48
9.3.4.8
Schirmer Test (without anesthesia) (mm wetting/5min) ...........................48
9.3.4.9
Use of Concomitant Artificial Tears ..........................................................48
9.3.4.10
Investigator Global Evaluation of Efficacy ...............................................49
9.3.5
Safety Evaluation Parameters .........................................................................49
9.3.5.1
Slit lamp examination ................................................................................49
9.3.5.2
Uncorrected Distance Visual Acuity (UDVA) ..........................................49
9.3.5.3
Best Corrected Distance Visual Acuity (BCDVA) ....................................49
9.3.5.4
Dilated Fundus Examination......................................................................49
9.3.5.5
Tonometry for measurement of Intraocular Pressure (IOP) (mmHg) .......49
9.3.5.6
Ocular Adverse Events (AEs) ....................................................................50
9.3.5.7
Systemic Adverse Events (AEs) ................................................................50
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS ..............................................51
10.1
Definitions....................................................................................................................51
10.1.1
Pre-treatment Events .......................................................................................51
10.1.2
AEs .................................................................................................................51
10.1.3
Sight-threatening Events .................................................................................51
10.1.4
Case of Special Interest ..................................................................................51
10.1.5
Additional Points to Consider for PTEs and AEs ...........................................52


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10.1.6
SAEs ...............................................................................................................54
10.1.7
Severity of PTEs and AEs ..............................................................................55
10.1.8
Causality of AEs .............................................................................................55
10.1.9
Relationship to Study Procedures ...................................................................55
10.2
Procedures ....................................................................................................................55
10.2.1
Collection and Reporting of AEs ....................................................................55
10.2.1.1
PTE and AE Collection Period ..................................................................55
10.2.1.2
PTE and AE Reporting ..............................................................................55
10.2.2
Collection and Reporting of SAEs .................................................................56
10.3
Follow-up of SAEs ......................................................................................................57
10.3.1
Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities ......................................................................................................57
11.0
DATA HANDLING AND RECORD KEEPING .............................................................58
11.1
Electronic eCRFs .........................................................................................................58
11.2
Source Data Documentation ........................................................................................58
11.3
Record Retention .........................................................................................................59
12.0
STATISTICAL METHODS ..............................................................................................60
12.1
Statistical Analysis .......................................................................................................60
12.2
Analysis of Demographics and Other Baseline Characteristics ..................................60
12.3
Primary Efficacy Variable Analysis ............................................................................60
12.4
Analysis of the Secondary Efficacy Variables.............................................................60
12.5
Safety Assessments ......................................................................................................61
12.6
AEs ...............................................................................................................................61
12.7
Interim Analysis ...........................................................................................................61
13.0
QUALITY CONTROL AND QUALITY ASSURANCE .................................................62
13.1
Study-Site Monitoring Visits .......................................................................................62
13.2
Protocol Deviations ......................................................................................................62
13.3
Quality Assurance Audits and Regulatory Agency Inspections ..................................62
14.0
ETHICAL ASPECTS OF THE STUDY ...........................................................................63
14.1
IRB and/or IEC Approval ............................................................................................63
14.2
Patient Information, Informed Consent, and Patient Authorization ............................63
14.3
Patient Confidentiality .................................................................................................65
14.4
Publication, Disclosure, and Clinical Trial Registration Policy ..................................65
14.4.1
Publication and Disclosure .............................................................................65
14.4.2
Clinical Trial Registration ..............................................................................66
14.4.3
Clinical Trial Results Disclosure ....................................................................66


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14.5
Insurance and Compensation for Injury .......................................................................66
15.0
REFERENCES ..................................................................................................................67
Preamble 86
General Principles ............................................................................................................86
Risks, Burdens and Benefits ...........................................................................................88
Vulnerable Groups and Individuals ...............................................................................88
Scientific Requirements and Research Protocols..........................................................88
Research Ethics Committees ...........................................................................................89
Privacy and Confidentiality ............................................................................................89
Informed Consent ............................................................................................................89
Use of Placebo ...................................................................................................................91
Post-Trial Provisions .......................................................................................................91
Research Registration and Publication and Dissemination of Results .......................91
Unproven Interventions in Clinical Practice .................................................................92
LIST OF IN-TEXT FIGURES 
Figure 1 Study flow chart ...............................................................................................................26
Figure 2 Presentation of Landolt optotypes on mini-pointer of the functional visual acuity 
device (Kaido 2013). ..............................................................................................76
Figure 3 flowchart diagram of optotypes during functional visual acuity testing (Kaido 2013). ..76
LIST OF APPENDICES 
Appendix A
Schedule of Study Procedures and Procedures ......................................................70
Appendix B
Elements of the Patient Informed Consent ............................................................82
Appendix C
Investigator Consent to Use of Personal Information ............................................85
Appendix D 
Declaration of Helsinki …………………………………………….……………87 


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2.0
STUDY SUMMARY 
Name of Sponsor(s): 
SANTEN SAS, France 
Compound: 
IKERVIS® 
Title of Protocol: A Phase IV, prospective, open-label, 
multicentre, single arm, 3-month proof of concept study to 
assess the effect of IKERVIS® (1mg/ml ciclosporin) eye 
drops administered once daily on the quality of vision in 
dry eye disease (DED) patients with severe keratitis. 
IND No.: NA 
EudraCT No.: 2016-003497-40 
Study Number: NVG16E128 
Phase: IV 
Study Design: 
The proposed 3-month study is a prospective, open-label, multicentre, phase IV, proof of concept study. The study is 
designed to assess the effect on the quality of vision of IKERVIS® (1mg/mL ciclosporin) eye drops administered 
once daily in dry eye disease (DED) patients with severe keratitis, as well as its safety and efficacy. 
Upon completion of the Screening Visit, all enrolled study participants will undergo a 2-week wash-out phase 
during which prior therapies for DED including artificial tears and prohibited ocular treatments must be 
discontinued. The purpose of the wash-out phase is to eliminate the potential contribution of any prior DED 
treatment on the efficacy of the study medication. During the wash-out phase patients may use unpreserved artificial 
tears provided by the Sponsor as needed in each eye to relieve their dry eye symptoms, up to eight instillations per 
day. No other topical treatments for DED other than the provided unpreserved artificial tears are allowed during the 
wash-out phase. Patients will be instructed in the optimal technique for ophthalmic drop instillation.   
At the Baseline Visit (Day 1) following the 2-week wash-out phase, patients who meet the inclusion criteria for 
DED and severe keratitis will start the treatment phase of the study treatment (IKERVIS® 1mg/mL). Patients not 
fulfilling the inclusion criteria following the wash-out phase will be discontinued from the study without having 
received the study medication, and will start the best treatment for their condition according to their 
ophthalmologist’s opinion.   
During Baseline Visit (Day 1), patients will be instructed to instil one drop of study medication (IKERVIS® 
1mg/mL) once daily in each eye at bedtime and will be scheduled for three additional study visits, Month 1 (Day 
28±3), Month 2 (Day 56±3), and Month 3 (Day 84±7). In addition to the study medication, patients will also be 
allowed to use unpreserved artificial tears provided by the Sponsor, up to eight instillations per day, in each eye, to 
ameliorate their dry eye symptoms. Patients must be instructed not to use artificial tears within 30 minutes before or 
after use of the study medication and within two hours before a scheduled study visit. All concomitant medications 
will be recorded on the case report form (eCRF). A change in the use of the study treatments or any use of topical 
eye drops other than the study medication, sponsor-provided unpreserved artificial tears or topical medications 
allowed during the study will be considered a protocol violation. In this phase IV clinical trial the Month 3 visit 
assessments will be used to assess the efficacy (quality of vision and other parameters) and safety of IKERVIS® in 
DED patients with severe keratitis. 


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Study Flow Chart 
Primary Objective: 
To assess the effect on the quality of vision of IKERVIS® (1mg/ml ciclosporin) eye drops administered once daily 
in adult dry eye disease (DED) patients with severe keratitis following 3 months of treatment, assessed by 
Functional Visual Acuity (FVA) and Objective Scatter Index (OSI), and to estimate the correlation of the change of 
Visual Maintenance Ratio (VMR) measured with FVA system and variance of OSI, separately with the expected 
Corneal fluorescein staining (CFS) improvement. 
Secondary Objectives: 
•
To assess the signs and symptoms of keratitis and DED, and their changes overtime.  
Screening Visit 
Patient meets 
Inclusion /Exclusion
Criteria
Exit Study
Yes
No
Patient enters 3-Month Open-Label Study Treatment 
Period and completes Month 1, Month 2 and Month 3 
study visits 
Patient must discontinue prohibited topical medications and will 
enter the 2-week Wash-out Phase.  
Patients allowed to use Sponsor provided artificial up to 8 
instillations per day in each eye to relieve DED symptoms. 
Baseline Visit 
Patient meets 
Inclusion /Exclusion
Criteria
Exit Study
Yes
No


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•
To estimate the correlation between CFS changes over time and other FVA parameters changes over time. 
•
To estimate the correlation between CFS changes over time and OSI changes over time. 
•
To estimate the correlation between variance of OSI changes overtime and FVA parameters overtime. 
•
To estimate the correlation between OSI changes overtime and FVA parameters changes overtime. 
•
To compare the time course of the CFS improvement vs the time course of FVA and OSI improvement (if any), 
respectively. 
•
To evaluate the ocular tolerability and overall ocular safety of IKERVIS® administered once daily in DED 
patients with severe keratitis at Month 3. 
Patient Population: Adult male or female (aged 18 years or above) DED patients with severe keratitis despite the 
use of tear substitutes. 
Number of Patients: 33 adult patients will be enrolled in 
the study in order to obtain 30 included patients. 
Number of Sites:  
Maximum of 4 sites in France 
Dose Level(s): 
IKERVIS® (1mg/ml ciclosporin) one drop per day at 
bedtime at each affected eye 
Route of Administration: 
Eye drops 
Duration of Treatment: 
14 weeks (2-week wash-out period and 12-week treatment 
period). 
Period of Evaluation: 
•Screening/Wash-out: Days -14 (+/- 3 days) to -1. 
•Treatment Period 1: Day 1 to Day 84  (+/- 7 days) 
Main Criteria for Inclusion: 
Male or female DED adult patients with persistent severe keratitis at the Screening and Baseline visits defined as the 
following: CFS score of 3, 4 or 5 on the modified Oxford scale AND Visual Maintenance Ratio (VMR) <0.95, AND 
OSI  2 AND Variance of OSI  0.5.  
A complete list of inclusion criteria is provided in Section 7.1 
Main Criteria for Exclusion: 
Patients presenting with ocular abnormality that may interfere with aberrometry measurement (e.g. macular disease 
or any loss of transparency of cornea or intraocular structures such as cataract or vitreous hemorrhage) in the eligible 
eye; or active herpes keratitis or history of ocular herpes. Patients with history of ocular trauma in the eligible eye or 
ocular infection (viral, bacterial, fungal, protozoal) within 90 days before the Screening Visit in either eye; and any 
ocular diseases other than dry eye disease requiring topical ocular treatment during the course of the study. Patients 
with ocular rosacea and/or with severe blepharitis and/or Meibomian Gland Disease (MGD) in the eligible eye. 
Patients enrolled with mild to moderate blepharitis and/or MGD should be treated as appropriate during the study. 
Patients with progressive pterygium and/or reaching the optical axis. 
A complete list of exclusion criteria is provided in Section 7.2 


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Primary endpoint(s) with time point(s) of assessment: 
Efficacy endpoints 
• 
Correlation between the change from baseline in VMR measured with FVA system at Month 3 and the 
change from baseline in the CFS at Month 3. 
• 
Correlation between the change from baseline in variance of OSI measured with double pass aberrometer at 
Month 3 and the change from baseline in the CFS at Month 3. 
Main secondary endpoint(s) with time points(s) of assessment:  
Efficacy endpoints 
• 
CFS score assessed with the Modified Oxford Scale and change from baseline at Months 1, 2 and 3.  
• 
FVA parameters (starting visual acuity, FVA, LogMAR FVA, visual maintenance ratio (VMR), and 
maximal and minimal visual acuities) and their changes from baseline at Months 1, 2 and 3. 
• 
OSI and its variance and their changes from baseline at Months 1, 2 and 3.  
•             Correlation between CFS changes over time and OSI changes over time and other FVA parameters changes 
over time, separately. 
• 
Correlation between each OSI parameters changes overtime and FVA parameters changes overtime, 
separately. 
• 
Root mean square (RMS) of higher order aberrations (total, coma-like, spherical like) measured with 
Hartmann-Schack aberrometer and their changes from baseline at Month 3.  
• 
Tear Break Up Time (TBUT) and change from baseline at Months 1, 2 and 3. 
•  
Investigator Global Evaluation of Efficacy at Month 3. 
• 
VAS score (photophobia, blurred vision) and changes from baseline at Months 1, 2 and 3. 
• 
Patient Global Evaluation of Efficacy at Month 3.
• 
Artificial Tear use and change from baseline at Months 1, 2 and 3, and changes from baseline. 
Safety evaluations:  
• 
Slit lamp examination and change from baseline at Months 1, 2 and 3. 
• 
Dilated Fundus Examination and change from baseline at Month 3. 
• 
Uncorrected Distance Visual Acuity (UDVA) and change from baseline at Months 1, 2 and 3. 
•             Best Corrected Distance Visual Acuity (BCDVA) and change from baseline at Months 1, 2 and 3. 
•             IOP and change from baseline at Month 3. 
• 
Incidence and severity of ocular and systemic adverse events over the study period.
Statistical Considerations: 
Sample Size Calculations 
In this pilot proof of concept study, no sample size calculation was performed. In order to obtain 30 included 
patients, 33 patients will be enrolled. 
Main efficacy analysis 
All the efficacy analysis will be performed on the analysis eye, which is defined as the eligible eye, the eye that 
fulfils all the criteria listed under the inclusion criteria #4. If both eyes are eligible, the eye with the highest baseline 
CFS score will be chosen. If both eyes have the same CFS score, the eye with the lowest VMR will be chosen. If 
VMR values are the same for both eyes, the right eye will be chosen. 
Spearman’s coefficient of correlation will be calculated at Month 3 between the change from baseline of CFS and 
respectively the change from baseline of VMR and of variance of OSI.
Secondary and other efficacy endpoints 


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A mixed effects model will be employed to investigate the association between the change of CFS vs. change of 
VMR and change of CFS vs. change of OSI, respectively, during the course of the study (from baseline to M3). 
Changes in VMR and OSI will also be summarized by categorical change in CFS (-5, -4.5, -4, -3.5, -3, -2.5, -2, -1.5, 
-1, 0, +1 unit change) and by analysis visit (M1, M2, M3). 
Spearman’s coefficient of correlation will be calculated at each time-point (M1, M2, M3) between the change from 
baseline of CFS and respectively the change from baseline of FVA parameters and the change from baseline of OSI 
parameters. 
Spearman’s coefficients of correlation will be also calculated at each time-point (M1, M2, M3) between the change 
from baseline of OSI and of variance of OSI separately and the change from baseline of each FVA parameters.   
The graphical curve (with means and error bars at each visit) of each parameter (CFS score, FVA parameters, OSI, 
variance of OSI) will be generated to explore their pattern of evolution over time (from baseline to M3) under the 
IKERVIS® treatment. 
The other efficacy endpoints will be presented with descriptive statistics at each time-point and in term of change 
from baseline. The coefficient of variation will be calculated for each criterion in order to provide reliable 
information on their metric interest for a further study.  
Safety analyses 
Safety variables recorded in both eyes will be summarized / analysed for both the analysis eye and the other eye 
separately.  
Descriptive statistics will be provided at each time-point concerning the local tolerance parameters. 
Usual tables will be produced concerning adverse events (ophthalmic adverse events will be tabulated separately). 


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3.0
STUDY REFERENCE INFORMATION 
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Study-Related Responsibilities (template). The identified vendors in the template for specific 
study-related activities will perform these activities in full or in partnership with the sponsor. 
3.2
Principal Investigator 
Santen SAS will select a Signatory Principal Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study medication, their expertise in the therapeutic area and the conduct of 
clinical research as well as study participation. The Signatory Coordinating Investigator will be 
required to review and sign the clinical study report and by doing so agrees that it accurately 
describes the results of the study. 


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3.3
List of Abbreviations 
AE 
 
Adverse Event 
ATC 
 
Anatomical-Therapeutic-Chemical 
BAK 
 
Benzalkonium Chloride 
BCDVA 
Best Corrected Distance Visual Acuity 
BID 
 
Twice a Day 
CA 
 
Competent Authority 
CFS 
 
Corneal Fluorescein Staining 
CKC 
 
Cetalkonium Chloride 
eCRF 
 
electronic Case Report Form 
CRO 
 
Contract Research Organization 
CsA 
 
Ciclosporin/Cyclosporine 
D 
 
Day 
DED 
 
Dry Eye Disease 
DEWS  
Dry Eye Workshop  
EC 
 
Ethics Committee 
EMA 
 
European Medicines Agency 
ETDRS  
Early Treatment Diabetic Retinopathy Study 
EU 
 
European Union 
FAS 
 
Full Analysis Set 
FDA 
 
Food and Drug Administration 
FVA 
 
Functional Visual Acuity  
g 
 
Gram(s) 
GCP 
 
Good Clinical Practice 
GRAS  
Generally Recognized As Safe  
HLA-DR 
Human Leukocyte Antigen-DR  
IL-2 
 
Interleukin-2 
IOP 
 
Intraocular Pressure 
KCS 
 
Keratoconjunctivitis Sicca 
LogMAR 
Logarithm of the Minimum Angle of Resolution
MCT 
 
Medium chain triglycerides 
mg 
 
Milligrams(s) 
MGD 
 
Meibomian Gland Disease  


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min 
 
Minutes 
mL 
 
Milliliter 
mm 
 
millimeter 
NF-AT  
Nuclear factor of activated T-cells 
OSDI 
 
Ocular Surface Disease Index 
OSI 
 
Objective Scatter Index 
PEO 
 
Polyethylene Oxide 
PPO 
 
Polypropylene Oxide 
PSF 
 
Point Spread Function  
PTE 
 
Pre-Treatment EventQD  
Once a Day 
RMS 
 
Root Mean Square 
SAE 
 
Serious Adverse Event 
SPK 
 
Superficial Punctuate Keratopathy 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
TEAE 
 
Treatment-Emergent Adverse Event 
TBUT  
Tear Break Up Time 
USA 
 
United States of America 
VA  
 
Visual Acuity 
VAS 
 
Visual Analog Scale 
VKC 
 
Vernal Kerato Conjunctivitis  
VMR 
 
Visual Maintenance Ratio 
WHO DRUG 
World Health Organization Drug 
3.4
Corporate Identification 
 
 
Santen SAS 
Genavenir IV 
1 rue Pierre Fontaine 
F-91058 Evry, France 
 
 
 
 
 
 
 
 


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4.0
INTRODUCTION 
Since the 2007 International Dry Eye Workshop (DEWS), the term dry eye disease (DED), also 
known as keratoconjunctivitis sicca, describes “a multifactorial disease of the tears and ocular 
surface that results in symptoms of discomfort, visual disturbance and tear film instability with 
potential damage to the ocular surface (DEWS 2007). It is accompanied by increased osmolarity 
of the tear film and inflammation of the ocular surface”. Based on the 2007 DEWS report, the 
prevalence of DED ranges from 5%-15% in the USA, Australia and Europe, to 30-50% in Asia.  
Any abnormality of the ocular surface can trigger disequilibrium of the ocular surface integrity 
and leads to DED (Labetoulle 2013). This results in a vicious circle (Baudouin 2013) with as 
many ways to enter as there are causes of destabilization of the ocular surface (Baudouin 
2007).The pathogenesis of DED is not fully understood; however inflammation has a prominent 
role in the development and amplification of the signs and symptoms of DED (Stevenson 2012). 
DED prognosis shows considerable variance, depending upon the severity of the condition and 
the severity of the underlying pathology. There are very few approved pharmacological 
treatments for DED in the world, and patients report using artificial tears on a frequent basis 
(Kymionis 2008). Most patients have mild-to-moderate complaints and can be treated 
symptomatically with lubricants for long periods of time.  
Patients with more severe conditions of DED such as those with severe keratitis (or Sjögren’s 
syndrome) represent a group of patients with the worse prognosis (AAO 2013) and in need of 
more effective treatments (Asbell 2010). These DED patients with severe keratitis are trapped in 
a vicious cycle of inflammation and ocular surface injury with the risk of complications such as 
keratinization of the ocular surface, the occurrence of corneal scarring, a thinning or corneal 
neovascularization, sterile or microbial corneal ulcerations with a risk of perforation of the 
cornea and vision loss is possible (AAO 2013). For these severe diseases, clinical guidelines 
recommend using anti-inflammatory agents such as ciclosporin A (CsA) when lubricants are 
inadequate (DEWS 2007). 
4.1
Background on IKERVIS® 
Santen SAS has developed IKERVIS®, a formulation of CsA 1mg/ml designed to optimise the 
topical delivery of the drug. IKERVIS® via the centralised procedure was granted a Marketing 
Authorisation on 2015 March 19, by the European Commission for the once daily treatment of 
severe keratitis in adult patients with dry eye disease, which has not improved despite treatment 
with tear substitutes. This was the first registration for a treatment which indication covers the 
need for a treatment of severe keratitis as it is expressed by the use of RESTASIS® beyond its 
FDA-approved indications when present. 
CsA is a lipophilic substance practically insoluble in water which must be administered topically 
to the eye in lipid based systems such as an oily vehicle (Lallemand 2003). 
                                                 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002066/human_med_001851.jsp&mid=WC0b01ac058001d124


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IKERVIS® combines the anti-inflammatory effect of CsA 0.1% with an innovative cationic 
emulsion formulation (Novasorb® technology) to effectively deliver the drug with once-daily 
dosing for the treatment of severe keratitis in dry eye patients. Novasorb® is a cationic emulsion 
composed of oil nanodroplets stabilized by surfactants and dispersed in an aqueous phase. The 
mean droplet diameter is smaller than 300 nanometers. When cationic emulsions are instilled in 
the eye, the positively-charged nanodroplets are attracted to the negatively-charged mucosal 
cells; as a result the residence time of the drop on the epithelial layer of the eye is prolonged by 
this electrostatic attraction (Lallemand 2012). 
4.1.1
Pharmacokinetics and Safety of Animals 
A single dose pharmacokinetic pivotal study in rabbits was in favour of IKERVIS® (also called 
NOVA22007) 1mg/ml (see SmPC). This result was corroborated by a pharmacokinetic study at 
steady state following multiple administrations which showed that IKERVIS® 1mg/ml 
administered once a day (QD) achieved higher concentrations in the cornea than RESTASIS ® 
(0.05%) administered twice a day (BID) with similar target tissue (cornea and conjunctiva) 
exposure in rabbits.  
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, phototoxicity and photoallergy, genotoxicity, carcinogenic 
potential, toxicity to reproduction and development (see SmPC for detailed information). 
Effects in non-clinical studies were observed only with systemic administration or at exposures 
considered sufficiently in excess of the maximum human exposure indicating little relevance to 
clinical use 
4.1.2
Clinical Pharmacokinetics and Pharmacodynamics 
Formal pharmacokinetic studies have not been conducted in humans with IKERVIS®.  
Blood concentrations of IKERVIS® were measured using a specific high-pressure liquid 
chromatography-mass spectrometry assay.  
In order to evaluate a possible systemic exposure to IKERVIS®, blood samples were collected in 
patients included in the Phase IIa study and in two Phase III clinical studies (SANSIKA and 
SICCANOVE). 
In 374 patients from the two phase III studies, plasma concentrations of ciclosporin were 
measured before administration and after 6 months (SICCANOVE study and SANSIKA study) 
and 12 months of treatment (SANSIKA study). After 6 months of ocular instillation of 
IKERVIS® once per day, 327 patients had values below the lower limit of detection (0.050 
ng/mL) and 35 patients were below the lower limit of quantification (0.100 ng/mL). Measurable 
values not exceeding 0.206 ng/mL were measured in eight patients, values considered to be 
negligible. Three patients had values above the upper limit of quantification (5 ng/mL) however 
they were already taking oral ciclosporin at a stable dose, which was allowed by the studies’ 
protocol. After 12 months of treatment, values were below the low limit of detection for 56 
patients and below the low limit of quantification in 19 patients. Seven patients had measurable 


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values (from 0.105 to 1.27 ng/mL), all considered to be negligible values. Two patients had 
values above the upper limit of quantification, however they were also on oral ciclosporin at a 
stable dose since their inclusion in the study. 
Overall, the use of an ocular CsA emulsion is beneficial as it reduces the systemic toxicity of 
CsA and increases the concentrations of CsA in the conjunctiva and cornea when compared with 
systemic administration. While it is possible that systemic absorption of IKERVIS® could occur 
through the nasal mucosa as a result of the drop being cleared from the ocular surface through 
the lachrymal draining system, both preclinical and clinical studies have shown a negligible 
systemic passage of IKERVIS® after topical administration, both in animals and in humans. 
No specific pharmacology studies were conducted with IKERVIS® since an adequate model of 
DED does not exist. However, the pharmacodynamics of ciclosporin has been extensively 
studied in vitro and in vivo. In patients with dry eye disease, a condition that may be considered 
to have an inflammatory immunological mechanism, following ocular administration, 
ciclosporin is passively absorbed into T-lymphocyte infiltrates in the cornea and conjunctiva and 
inactivates calcineurin phosphatase. Ciclosporin-induced inactivation of calcineurin inhibits the 
dephosphorylation of the transcription nuclear factor of activated T-cells (NF-AT) and prevents 
NF-AT translocation into the nucleus, thus blocking the release of pro-inflammatory cytokines 
such as interleukin-2 (IL-2). 
4.1.3
Clinical Experience 
The approval by the European Commission of IKERVIS® for the treatment of severe keratitis in 
DED patients was mainly based on the efficacy and safety of results of two randomised, double-
masked, vehicle-controlled clinical studies in adult patients with dry eye disease 
(keratoconjunctivitis sicca) who met the International Dry Eye Workshop (DEWS) criteria 
(DEWS 2007). 
In the 12 month, double-masked, vehicle controlled, pivotal clinical trial (SANSIKA study), 246 
Dry Eye Disease (DED) patients with severe keratitis [defined as a corneal fluorescein staining 
(CFS) score of 4 on the modified Oxford scale] were randomized to one drop of IKERVIS® or 
vehicle daily at bedtime for 6 months. Patients randomized to the vehicle group were switched to 
IKERVIS® after 6 months. The primary endpoint was the proportion of patients achieving by 
Month 6 at least a two-grade improvement in keratitis (CFS) and a 30% improvement in 
symptoms, measured with the Ocular Surface Disease Index (OSDI). The proportion of 
responders in the IKERVIS® group was 28.6%, compared to 23.1% in the vehicle group. The 
difference was not statistically significant (p=0.326). 
The severity of keratitis, assessed using CFS, improved significantly from baseline at Month 6 
with IKERVIS® compared to vehicle (mean change from baseline was -1.81 with IKERVIS® 
vs. -1.48 with vehicle, p=0.037). The proportion of IKERVIS®-treated patients with a 3-grade 
improvement in CFS score at Month 6 (from 4 to 1) was 28.8%, compared to 9.6% of vehicle-
treated patients, but this was a post-hoc analysis, which limits the robustness of this outcome. 
The beneficial effect on keratitis was maintained in the open phase of the study, from Month 6 
and up to Month 12. 


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The mean change from baseline in the 100-point OSDI score was -13.6 with IKERVIS® and -
14.1 with vehicle at Month 6 (p=0.858). In addition, no improvement was observed for 
IKERVIS® compared to vehicle at Month 6 for other secondary endpoints, including ocular 
discomfort score, Schirmer test, use of concomitant artificial tears, investigator’s global 
evaluation of efficacy, tear break-up time, lissamine green staining, quality of life score, and tear 
osmolarity. 
A reduction in the ocular surface inflammation assessed with Human Leukocyte Antigen-DR 
(HLA-DR) expression (an exploratory endpoint), was observed at Month 6 in favour of 
IKERVIS® (p=0.021). 
In the 6 month, double-masked, vehicle controlled, supportive clinical trial (SICCANOVE 
study), 492 DED patients with moderate to severe keratitis (defined as a CFS score of 2 to 4) 
were also randomised to IKERVIS® or vehicle daily at bedtime for 6 months. The co-primary 
endpoints were the change in CFS score, and the change in global score of ocular discomfort 
unrelated to study medication instillation, both measured at Month 6. A small but statistically 
significant difference in CFS improvement was observed between the treatment groups at Month 
6 in favour of IKERVIS® (mean change from baseline in CFS -1.05 with IKERVIS® and -0.82 
with vehicle, p=0.009). 
The mean change from baseline in ocular discomfort score (assessed using a Visual Analogic 
Scale, VAS) was -12.82 with IKERVIS® and -11.21 with vehicle (p=0.808). 
In both studies, no significant improvement of symptoms was observed for IKERVIS® 
compared to vehicle after 6 months of treatment, whether using a VAS or the OSDI. 
In both studies one third of the patients in average had Sjögren’s syndrome; as for the overall 
population, a statistically significant improvement in CFS in favour of IKERVIS® was observed 
in this subgroup of patients. 
4.2
Rationale for the Proposed Study 
DED symptoms comprise intermittent blurred vision, discomfort during daily activities, or 
troublesome symptoms of irritation that usually worsened at the end of the day (AAO 2013). 
However, the symptoms of DED patients with severe keratitis usually correlate poorly with the 
objective clinical findings such as epithelial defects visible with fluorescein staining (Baudouin 
2014). In addition many DED patients complain of fluctuated visual acuity despite normal visual 
acuity in conventional evaluations (Kaido 2011).  
Several technics have been used to assess the impact of the severity of keratitis on patient visual 
function impairment. In this context, the Functional Visual Acuity (FVA) measurement has been 
reported to be useful in the assessment of visual quality in DED patients (Goto 2002). FVA is a 
dynamic assessment of the visual acuity which can ascertain DED patients’ performance in 
relation to certain daily activities involving visual tasks by detecting masked impairment of 
visual function due to ocular surface conditions (Kaido 2013).  
Quality of vision can also be assessed using aberrometry technics which measure the ocular 
aberrations. One study showed that there is an increase in ocular aberrations as the ocular surface 


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becomes irregular (Hiraoka 2012). Several studies have shown changes in ocular aberrations 
between blinks (Albarran 1997, Tutt 2000, Koh 2006). Furthermore, using double-pass 
aberrometry which allows the objective measurement of high-order optical aberrations and loss 
of ocular transparency, the variance of the observed Objective Scatter Index (OSI) is an objective 
way to assess the intensity of the subjective visual disturbances reported by DED patients (Habay 
2014). Thus, the impact of the severity of DED on the quality of the vision can be ascertained 
using these new tools. 
During IKERVIS® clinical development, standard visual acuity testing performed in the clinical 
trials didn’t permit to detect any relevant changes on visual acuity. This Proof of Concept study 
will allow assessing the effect of IKERVIS® on the quality of vision in DED patients with 
severe keratitis using FVA measurement system and ocular aberrations measurement and to 
calculate the correlations of these parameters with CFS after 3 months of treatment with 
IKERVIS®, as well as providing meaningful information about the time course of FVA and 
ocular aberrations improvement in relation with the improvement of CFS. A phase IIIb study 
will thereafter be conducted based on the results of this study to expand the indication of 
IKERVIS® for the treatment of symptoms assessed by functional visual acuity. 
4.3
Benefit risk balance  
The patients participating in the study will benefit from IKERVIS®, a product marketed for the 
treatment of severe keratitis in adult patients with dry eye disease, which has not improved 
despite treatment with tear substitutes. Based on inclusion criteria patients will have visual 
function deficiencies in addition to severe keratitis and it is expected to be improved with 
IKERVIS® (main objective of the study).  Patients will benefit from a close follow-up by the 
investigators (every month) which is not the case in the usual clinical practice. The risks related 
to the participation of the study are the adverse events listed on the SmPC, the potential risk of 
allergy to fluorescein, anaesthetic eye drops or artificial tears and the potential irritation related 
to the Schirmer test examination.  
In light of the points listed above the benefit risk balance is considered favourable. 


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5.0
STUDY OBJECTIVES AND ENDPOINTS 
5.1
Objectives 
5.1.1
Primary Objective(s)  
The primary objective of the study is to assess the effect on the quality of vision of IKERVIS® 
(1mg/ml ciclosporin) eye drops administered once daily in adult dry eye disease (DED) patients 
with severe keratitis following 3 months of treatment, assessed by Functional Visual Acuity 
(FVA) and Objective Scatter Index (OSI), and to estimate the correlation of the change of Visual 
Maintenance Ratio (VMR) measured with FVA system and variance of OSI, separately with the 
expected Corneal fluorescein staining (CFS) improvement. 
5.1.2
Secondary Objectives  
The secondary objectives are: 
•
To assess the signs and symptoms of keratitis and DED, and their changes overtime,  
•
To estimate the correlation between CFS changes over time and FVA changes over time,  
•
To estimate the correlation between CFS changes over time and OSI changes over time, 
•
To estimate the correlation between variance of OSI changes overtime and FVA parameters 
overtime. 
•
 To estimate the correlation between OSI changes overtime and FVA parameters changes 
overtime 
•
To compare the time course of the CFS improvement vs the time course of FVA and OSI 
improvement (if any), respectively, 
•
To evaluate the ocular tolerability and overall ocular safety of IKERVIS® administered once 
daily in DED patients with severe keratitis at Month 3. 
5.2
Endpoints 
5.2.1
Primary Efficacy Endpoints 
•
Correlation between the change from baseline in VMR measured with FVA system at Month 
3 and the change from baseline in the CFS at Month 3. 
•
Correlation between the change from baseline in variance of OSI measured with double pass 
aberrometer at Month 3 and the change from baseline in the CFS at Month 3. 


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5.2.2
Secondary Endpoints 
5.2.2.1
Efficacy Endpoints 
•
CFS score assessed with the Modified Oxford Scale and change from baseline at Months 1, 2 
and 3.  
•
FVA parameters (starting visual acuity, FVA, LogMAR FVA, visual maintenance ratio 
(VMR), and maximal and minimal visual acuities) and their change from baseline at Months 
1, 2 and 3. 
•
OSI and its variance and their change from baseline at Months 1, 2 and 3. 
•
Correlation between CFS changes over time and OSI changes over time and other FVA 
parameters changes over time, separately. 
•
Correlation between each OSI parameters changes overtime and FVA parameters changes 
overtime, separately. 
•
Root mean square (RMS) of higher order aberrations (total, coma-like, spherical like) 
measured with Hartmann-Schack aberrometer and their change from baseline at Month 3. 
•
Tear Break Up Time (TBUT) and change from baseline at Months 1, 2 and 3. 
•
Patient Global Evaluation of Efficacy at Month 3. 
•
VAS scores (photophobia, blurred vision) and their change from baseline at Months 1, 2 and 
3. 
•
Investigator Global Evaluation of Efficacy at Month 3. 
•
Artificial Tear use and change from baseline at Months 1, 2 and 3.  
5.2.2.2
Safety Evaluations 
•
Slit lamp examination and change from baseline at Months 1, 2 and 3. 
•
Uncorrected Distance Visual Acuity (UDVA) and change from baseline at Months 1, 2 and 
3. 
•
Best Corrected Distance Visual Acuity (BCDVA) and change from baseline at Months 1, 2 
and 3. 
•
Dilated fundus examination and change from baseline at Month 3. 
•
IOP and change from baseline at Month 3. 
•
Incidence and severity of ocular and systemic adverse events over the study period. 


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6.0
STUDY DESIGN AND DESCRIPTION 
6.1
Study Design 
The proposed 3-month study is a prospective, open-label, multicentre, phase IV, proof of concept 
study. The study is designed to assess the effect on the quality of vision of IKERVIS® (1mg/mL 
ciclosporin) eye drops administered once daily in dry eye disease (DED) patients with severe 
keratitis, as well as its safety and efficacy. 
Upon completion of the Screening Visit, all enrolled study participants will undergo a 2-week 
wash-out phase during which prior therapies for DED including artificial tears and prohibited 
ocular treatments must be discontinued. The purpose of the wash-out phase is to eliminate the 
potential contribution of any prior DED treatment on the efficacy of the study medication. 
During the wash-out phase patients may use unpreserved artificial tears provided by the Sponsor, 
up to eight instillations per day in each eye, to relieve their dry eye symptoms. No other topical 
treatments for DED other than the provided unpreserved artificial tears are allowed during the 
wash-out phase. Patients will be instructed in the optimal technique for ophthalmic drop 
instillation.   
At the Baseline Visit (Day 1) following the 2-week wash-out phase, patients who meet the 
inclusion criteria for DED and severe keratitis will start the treatment phase with the study 
treatment (IKERVIS® 1mg/mL). Patients not fulfilling the inclusion criteria following the wash-
out phase will be discontinued from the study without having received the study medication.  
During Baseline Visit, patients will be instructed to instil one drop of study medication 
(IKERVIS® 1mg/mL) once daily in each eye at bedtime and will be scheduled for three 
additional study visits, Month 1 (Day 28 ±3), Month 2 (Day 56±3), and Month 3 (Day 84±7). In 
addition to the study medication, patients will also be allowed to use unpreserved artificial tears 
provided by the Sponsor, up to eight instillations per day in each eye, to alleviate their dry eye 
symptoms. Patients must be instructed not to use artificial tears within 30 minutes before or after 
use of the study medication and within two hours before a scheduled study visit. All concomitant 
medications will be recorded on the case report form (eCRF). A change in the use of the study 
treatments or any use of topical eye drops other than the study medication, sponsor provided 
unpreserved artificial tears or topical medications allowed during the study will be considered a 
protocol violation. In this phase IV clinical trial, the Month 3 Visit assessments will be used to 
assess the efficacy (quality of vision and other parameters) and safety of IKERVIS® in DED 
patients with severe keratitis. 
The study flowchart is illustrated in Figure 1.  


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Figure 1 Study flow chart
Screening Visit 
Patient meets 
Inclusion /Exclusion
Criteria
Exit Study
Yes
No
Patient enters 3-Month Open-Label Study Treatment 
Period and completes Month 1, Month 2 and Month 3 
study visits 
Patient must discontinue prohibited topical medications and will 
enter the 2-week Wash-out Phase.  
Patients allowed to use Sponsor provided artificial up to 8 
instillations per day in each eye to relieve DED symptoms. 
Baseline Visit 
Patient meets 
Inclusion /Exclusion
Criteria
Exit Study
Yes
No


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6.2
Justification for Study Design, Dose and Endpoints 
Based on development pilot studies, IKERVIS® (CsA 1mg/mL) has been registered in 31 
European countries for the indication: treatment of severe keratitis in adult patients with dry eye 
disease, which has not improved despite treatment with tear substitutes, at the recommended 
dose of one drop of IKERVIS® once daily to be applied to the affected eye(s) at bedtime. During 
IKERVIS® clinical development, standard visual acuity testing performed in the clinical trials 
didn’t permit to detect any relevant changes on visual acuity. However, the symptoms of DED 
patients with severe keratitis usually correlate poorly with the objective clinical findings such as 
epithelial defects visible with fluorescein staining (Baudouin 2014). In addition many DED 
patients complain of decreased visual acuity despite normal visual acuity in conventional testing 
(Kaido 2011). Otherwise, several technics have been used to assess the impact of the severity of 
keratitis on patient visual function impairment. Thus this proof of concept study has been 
designed to assess the effect on the quality of vision of IKERVIS® (1mg/ml ciclosporin) eye 
drops administered once daily in adult dry eye disease (DED) patients with severe keratitis 
following 3 months of treatment, using Functional Visual Acuity (FVA) and Objective Scatter 
Index (OSI), and to estimate their correlation with the expected Corneal fluorescein staining 
(CFS) improvement. 
6.2.1
Criteria for Premature Termination or Suspension of the Study 
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 medication 
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. 
6.2.2
Criteria for Premature Termination or Suspension of Investigational Site(s) 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.2.3
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Investigational Site(s) 
In the event that the sponsor, an institutional review board (IRB)/ independent ethics committee 
(IEC), or regulatory authority elects to terminate or suspend the study or the participation of an 
investigational site, a study-specific procedure for early termination or suspension will be 
provided by the sponsor; the procedure will be followed by applicable investigational sites 
during the course of termination or study suspension. 


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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF PATIENTS 
All entry criteria, including test results, need to be confirmed prior to first dose of study drug on 
Day 1. 
7.1
Inclusion Criteria 
Patient eligibility is determined according to the following criteria: 
1. In the opinion of the investigator, the patient is capable of understanding and 
complying with protocol requirements.  
2. The patient signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures.  
3. Male or female patient is aged 18 years or above. 
4. DED patients with persistent severe keratitis at the Screening and Baseline Visits 
defined as the following: 
•
CFS score of 3, 4 or 5 on the modified Oxford scale  
AND 
•
Visual Maintenance Ratio (VMR) <  0.95 
AND 
•
OSI   2 
AND 
•
Variance of OSI  0.5.  
5. Patient must be willing and able to undergo and return for scheduled study-related 
examinations.  
6. The same eye (eligible eye) should fulfil all the above criteria. 
7.2
Exclusion Criteria 
Any patient who meets any of the following criteria will not qualify for entry into the study: 
1. Any ocular abnormality that may interfere with aberrometry measurement (e.g. 
macular disease or any loss of transparency of intraocular structures such as cataract 
or vitreous haemorrhage ….), in the eligible eye.  
2. Active herpes keratitis or history of ocular herpes. 
3. History of ocular trauma in the eligible eye or history of ocular infection (viral, 
bacterial, fungal, protozoal) within 90 days before the Screening Visit in either eye. 
4. Any ocular diseases other than DED requiring topical ocular treatment during the 
course of the study.  


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5. Patients with ocular rosacea and/or with severe blepharitis and/or Meibomian Gland 
Disease (MGD), in the eligible eye. Patients enrolled with mild to moderate 
blepharitis and/or MGD should be treated as appropriate during the study.  
6. Patients with progressive pterygium. 
7. Concurrent ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis 
other than dry eye. 
8. Anticipated use of temporary punctal plugs in the eligible eye, during the study. 
Patients with punctal plugs placed prior to the Screening Visit are eligible for 
enrolment; however, punctual plugs must remain in place during the study. 
9. Abnormal lid anatomy or blinking function in the eligible eye such as but not limited 
to entropion, ectropion.  
10. Abnormalities of the nasolacrimal drainage system in the eligible eye. 
11. Best corrected distance visual acuity (BCDVA) score  +1.0 LogMAR ( 35 ETDRS 
letters,  20/200 Snellen or  0.1) in each eye. 
12. Use of topical CsA (e.g. IKERVIS®, RESTASIS®), tacrolimus or sirolimus within 
90 days before the Screening Visit in the eligible eye. These treatments are also 
prohibited in both eyes during the course of the study, except IKERVIS® which will 
be administered as study treatment. 
13. Use of topical corticosteroids, antibiotics, pilocarpine, antihistamines, or BAK 
preserved Intraocular Pressure (IOP) lowering medications within the 30 days before 
Screening Visit, in the eligible eye.  
14. Patients with diffractive multifocal intraocular lenses, in the eligible eye. 
15. Any ocular laser/surgery in the eligible eye within 90 days of Screening Visit. 
16. Patient refusing to discontinue the use of contact lenses in the eligible eye, during the 
study.  
17. Disease not stabilized within 30 days before the Screening Visit (e.g., diabetes with 
glycemia out of range, thyroid malfunction, uncontrolled autoimmune disease, current 
systemic infections) or judged by the investigator to be incompatible with the study. 
18. Presence or history of severe systemic allergy. 
19. Known hypersensitivity to one of the components of the study or procedural 
medications (e.g., fluorescein, etc). 
20. History of malignancy in the last 5 years. 
21. Any change within 30 days of the Screening Visit or anticipated change during course 
of the study in the dose of systemic medications that could affect a dry eye condition 
[mainly, estrogen-progesterone or other estrogen derivatives (only allowed for post-
menopausal women), pilocarpine, isotretinoine, tetracycline,  antihistamines, tricyclic 


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antidepressants, anxiolytics, antimuscarinics, beta-blocking agents, phenothiazines, 
omega-3, systemic corticosteroids]. These treatments are allowed during the study 
provided they remain stable throughout the course of the study. 
22. Any change in systemic immunosuppressant drugs within 30 days before the 
Screening Visit or anticipated change during the course of the study.  
23. History of drug addiction or alcohol abuse. 
24. Presence or history of any systemic or ocular disorder, condition or disease that could 
possibly interfere with the conduct of the required study procedures or the 
interpretation of study results 
25. Pregnancy or lactation at the Screening Visit and/or Baseline Visit. 
26. 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 Screening 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. 
27. Vulnerable person referring to the French Health legislation « Code de la Santé 
Publique » articles L.1121-6 and L.1121-8 (patients deprived of liberty due to legal or 
administrative decision, patients with mental disabilities, patients legally protected or 
unable to provide their consent). 
28. Participation in a clinical trial with an investigational substance within the past 30 
days prior to Screening Visit. 
29. Participation in another clinical study at the same time as the present study. 
7.3
Excluded Medication, Treatments and Procedures  
Any patient who uses the following treatment will not qualify for entry into the study. 
7.3.1
Ocular Treatments 
1. Use of topical CsA (e.g. IKERVIS®, RESTASIS®), tacrolimus or sirolimus within 
90 days before the Screening Visit in the eligible eye. These treatments are also 
prohibited in both eyes during the course of the study, except IKERVIS® which will 
be administered as study treatment. 
2. Use of topical corticosteroids, antibiotics, pilocarpine, antihistamines, or BAK 
preserved Intraocular Pressure (IOP) lowering medications within the 30 days before 
Screening Visit in the eligible eye.  
3. Patients with diffractive multifocal intraocular lenses in the eligible eye. 


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4. Any ocular laser/surgery in the eligible eye within 90 days of Screening Visit. 
5. Use of any artificial tears other than those provided by the study sponsor during the 
course of the study i.e. from Screening to Month 3 or Early Termination Visits. 
6. Use of any topical ocular treatment in the eligible eye within 2 hours before any study 
visit. 
7. Patient refusing to discontinue the use of contact lenses in the eligible eye during the 
study 
7.3.2
Prohibited Concomitant Therapies 
Concomitant therapies consist of any treatment or medication given concurrently with the study 
medication. The following concomitant medication(s)/treatment(s) are prohibited during study 
participation:  
- 
Use of any artificial tears in the eligible eye other than those provided by the Sponsor.  
- 
Use of topical CsA (i.e., RESTASIS ®), tacrolimus or sirolimus, in both eyes, and use of  
corticosteroids, antibiotics, pilocarpine, antihistamines, BAK preserved IOP lowering 
medications or any topical ocular treatments other than the study medication and BAK-
free IOP lowering agents in the eligible eye.   
- 
Contact lenses wear in the eligible eye during the study. 
- 
Insertion of temporary punctal plugs in the eligible eye during the study. 
- 
Implantation of diffractive multifocal intraocular lenses in the eligible eye. 
- 
Any planned ocular laser/surgery in the eligible eye during the course of the study. 
- 
Initiation or change in the dose of any of the following topical or systemic medications: 
Estrogen-progesterone or other estrogen derivatives (only for post-menopausal women), 
pilocarpine, 
isotretinoine, 
tetracycline, 
antihistamines, 
tricyclic 
antidepressants, 
anxiolytics, antimuscarinics, beta-blocking agents, phenothiazines, omega-3, systemic 
corticosteroids or other systemic immunosuppressant drugs 
The initiation or use during the course of the study of any treatments or procedures described 
above will be considered as a protocol violation. 
7.3.3
Recording of Medications 
Any local or systemic treatment necessary for the patient's welfare has to be recorded on the 
Medication Form (product name, indication, treated eye, dose, route, frequency, start date and 
end date). Concomitant usage of artificial tears requires special attention, since this is considered 
a secondary endpoint. Patients will be allowed to use unpreserved artificial tears (only those 
provided by the Sponsor) up to eight instillations per day in the each eye, during the study 
period. Patients will be instructed not to use the unpreserved artificial tears within 30 minutes 
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The used/unused bottles of provided unpreserved artificial tears will be collected at each visit 
after the Screening Visit to record the concomitant usage of artificial tears during the study. 
7.4
Criteria for Discontinuation or Withdrawal of a Patient 
The primary reason for discontinuation or withdrawal of the patient from the study should be 
recorded in the case report form (eCRF) using the following categories. For screen failure 
patients, refer to Section 9.1.9. 
1. Adverse event (AE). The patient has experienced 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. 
2. Protocol deviation. The discovery after administration of the first dose of study drug 
that the patient failed to meet protocol entry criteria or 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 did not return to the clinic and attempts to contact the 
patient were unsuccessful. Attempts to contact the patient must be documented. 
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, IRB, IEC, or regulatory agency terminates the study. 
6. Lack of efficacy: the patient or the physician does not feel that the study medication 
has adequately relieved his/her 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 9.1.8. 
8. Investigator decision due to non-compliance (to IMP, study visits or study related 
procedure) 
9. Other reason, specify. 
Note: All attempts should be made to determine the reason if Other (e.g. moving…). 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.4.1
Completed Study 
The study enrolment will be considered as completed when the desired number of at least 33 
included patients is reached. Patients completing the Wash-out Phase at the time the desired 


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number of 33 included patients is achieved are eligible for inclusion if they fulfil the 
inclusion/exclusion criteria at the Baseline Visits.  
The 3-Month open-label study treatment period will be completed when all included patients 
complete the assessments of the Month 3 Visit in accordance with the study protocol. 
7.5
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 the study termination criteria described in Section 7.3.2. In addition, a patient 
may discontinue his or her participation without giving a reason at any time during the study. 
Should a patient’s participation be discontinued, the primary criterion for termination must be 
recorded. In addition, efforts should be made to perform all procedures scheduled for the Month 
3/Early Termination (ET). Discontinued patients will not be replaced. Patients discontinued for 
AE(s) will be followed-up after patient’s discontinuation until the event is resolved or considered 
medically stable by the investigator. In case of a patient lost-to-follow-up, the investigator must 
do his 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. The evidence of these contacts must be recorded 
in the patient medical chart. 


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8.0
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
8.1
Study Medication and Materials 
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
8.1.1.1
Investigational Drug 
IKERVIS® is a sterile, ophthalmic cationic oil-in-water emulsion containing 1 mg/ml CsA.  
IKERVIS®, which was granted an European Marketing Authorization by the European 
Commission in 2015, contains the following excipients:   
- 
Medium Chain Triglycerides (MCT): the emulsion’s oily agent that constitutes the main 
droplet core component and solubilizes the drug. 
- 
Cetalkonium chloride (CKC): a cationic surfactant that provides an efficient 
emulsification and a long-term stability by providing positive charges to the oil droplets 
which are stabilized by electrostatic repulsion. Positively-charged oily droplets are also 
electro-statically attracted to the membranes of the ocular surface epithelial cells that are 
negatively-charged.  
- 
Tyloxapol (octyl phenol polyxyethylene) and poloxamer 188 (polyethylene oxide (PEO), 
polypropylene oxide (PPO) triblock copolymer): two non-ionic surfactants which ensure 
the emulsification by reducing the interfacial tension between the aqueous and the oily 
phases. 
- 
Glycerol: a polyhydric alcohol used as tonicity agent in ophthalmic preparations. 
Glycerol is added in an appropriate quantity to adjust the osmolality of the emulsion. 
- 
NaOH: used as a pH adjuster.  
- 
Water: as diluents and the main emulsion component. 
Batch number and expiration dates will be provided in the certificate of analysis. 
8.1.1.2
Washout Medication 
Unpreserved artificial tears will be provided to the patient during the wash-out phase to use as 
needed to ameliorate their symptoms of DED. Bottles of the unpreserved artificial tears (sodium 
chloride 0.9%, Larmabak®, Laboratoire Théa France) will be dispensed in the French 
commercial packaging.  


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8.1.1.3
Packaging and Labeling 
IKERVIS® will be supplied in polyethylene single-dose containers presented in sealed laminate 
aluminum pouch package (1 pouch contains 5 single-dose containers). 

8 aluminum pouches (i.e. 40 single-dose containers) of IKERVIS® will be placed together in 
a sealed cardboard box. One identical box will be dispensed for each of the three treatment 
phases: D0-M1 (Day 1 - Month 1), M1-M2 (Month 1 - Month 2) and M2-M3 (Month 2 - 
Month 3).  
Each single dose container, aluminum pouch and sealed cardboard will carry an investigational 
label, indicating that the content is intended for investigational use only.  
In addition, each cardboard box will carry a label bearing the protocol and treatment numbers. 
8.1.2
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 medication must be stored 
under the conditions specified on the label, and remain in the original container until dispensed. 
A daily temperature log of the drug storage area must be maintained every working day. The 
study medication and unpreserved artificial tears will be delivered to the study centres by the 
clinical supplies distributor. The study medication must be stored between 15 and 25°C. Initially 
each centre will receive adequate supplies (study medication 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 medication and 
unpreserved artificial tears during the course of the study.  
8.1.3
Patient Identification 
In order to ensure patient anonymity, patients will be identified by codes or other means of 
record identification, e.g.: 2 digits for site number, 2 digits for patient number by chronological 
order of entry in the study. 
8.1.4
Dose and Regimen 
During the 3-month study unpreserved artificial tears and the study medication must be 
dispensed only to study patients in accordance with the study protocol:  
• 
At the Screening Visit each patient will be dispensed unpreserved artificial tears for use 
during the 2-week wash-out phase.  
• 
At the Baseline Visit (on Day 1), after the validation of all inclusion and exclusion 
criteria, each eligible patient will be given unpreserved artificial tears and one sealed cardboard 
box containing enough study medication for the period Day 1 - Month 1.  
• 
At Month 1 Visit, each patient will be given unpreserved artificial tears and one sealed 
cardboard box containing enough treatment for the period Month 1 - Month 2.  


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• 
At Month 2 Visit, each patient will be given unpreserved artificial tears and another 
sealed cardboard box containing enough treatment for the period Month 2 – Month 3. 
At Screening Visit, each patient will be instructed to instil with unpreserved artificial tears up to 
eight times per day in each eye for the relief of their symptoms of DED, during the 3-month 
study treatment period. At the following visits, their compliance will be checked, and they will 
be instructed to pursue the use of unpreserved artificial tears according to their DED symptoms 
within the protocol limits. 
At Baseline Visit (Day 1), each patient will be instructed to instil one drop of study medication 
(IKERVIS®, 1mg/ml ciclosporin) into the lower conjunctival sac of each eye once daily at 
bedtime during the 3-month study treatment period. Each single-unit container of study 
medication yields two drops of study medication (one drop for instillation in each eye) and will 
be used only once. At the following visits, their compliance will be checked, and they will be 
instructed to pursue the treatment with IKERVIS® with the same regimen. 
Changes in the IKERVIS® regimen during the study are not permitted. 
8.1.5
Accountability 
The study medication and sponsor provided unpreserved artificial tears are to be dispensed only 
by the investigator or 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 medication have to be documented in the 
investigator’s file provided by the Sponsor. 
Patients will be instructed to keep all unused and used containers and will be required to bring 
study medication containers to each clinic visit, regardless of whether the study medication 
container is empty. The destruction of the used and unused containers of study medication will 
be performed according to the instructions of the clinical monitor and has to be documented. 
Upon completion or earlier termination of the study the investigator will, unless otherwise 
agreed, return to the clinical supplies distributor any surplus quantities, used and unused 
containers/bottles, of study medication or unpreserved artificial tears. The investigator will 
record each quantity of study medication or unpreserved artificial tears that has been damaged or 
is missing. 
8.2
Patient’s Compliance  
Patient compliance will be assessed at each visit by the number of used and not used single-dose 
containers of study medication in relationship to the duration of the follow-up interval. All 
reported incidents of non-compliance and poor compliance will be recorded on the eCRF with 
the reasons. If a patient is persistently noncompliant with the study medication, the patient might 
be withdrawn from the study. All patients should be reinstructed about the dosing requirement 
during study visits. The authorized study personnel conducting the re-education must document 
the process in the patient source records. 


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8.3
Accountability and Destruction of All Study Medication
Drug supplies will be counted and reconciled at the site before being returned to Santen or 
designee or being destroyed by the site. 
The investigator or designee must ensure that the study medication is used in accordance with 
the approved protocol and is dispensed only to patients enrolled in the study. To document 
appropriate use of study drug, the investigator must maintain records of all study medication 
delivery to the site, site inventory, use by each patient, and return to the sponsor or designee. 
Upon receipt of study medication, the investigator or designee must verify the contents of the 
shipments against the packing list. The verifier should ensure that the quantity is correct, the 
medication is received within the labelled storage conditions, and is in good condition. See 
pharmacy manual for receipt of shipments. If quantity and conditions are acceptable, investigator 
or designee should acknowledge the receipt of the shipment by signing bottom half of the 
packing list and notifying Santen per instructions provided on the form. If there are any 
discrepancies between the packing list versus the actual product received, Santen must be 
contacted to resolve the issue. The packing list should be filed in the investigator’s essential 
document file. 
The investigator must maintain 100% accountability for all study medication received and 
dispensed during his or her entire participation in the study. Proper drug accountability includes, 
but is not limited to: 
•
Continuously monitoring expiration dates if expiry date is provided to the investigator. 
•
Frequently verifying that actual inventory matches documented inventory. 
•
Verifying that the log is completed for the drug lot used to prepare each dose. 
•
Verifying that all containers used are documented accurately on the log. 
•
Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator must record the current inventory of all study medication on a sponsor-approved 
drug accountability log. The following information will be recorded at a minimum: protocol 
number and title, name of investigator, site identifier and number, description of study 
medication, expiry and/or retest date, date and amount dispensed, including the initials of the 
person dispensing and receiving the study medication. The log should include all required 
information as a separate entry for each patient to who study medication is dispensed. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform clinical study material accountability and reconciliation before clinical study 
materials are returned to the sponsor or its designee for destruction or destroyed at the site, as 
applicable. The investigator will retain the original documentation regarding clinical study 


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material accountability, return, and/or destruction, and copies will be sent to the sponsor or 
designee. 
The investigator will be notified of any expiry date or retest date extension of clinical study 
material during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
clinical study material for return to the sponsor or its designee for destruction. 


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9.0
STUDY PLAN 
9.1
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, patients are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A-I.  
9.1.1
Informed Consent Procedure 
The requirements of the informed consent are described in Section 14.1. 
Informed consent must be obtained prior to the patient entering into the study, and before any 
protocol-directed procedures are performed. 
A unique patient identification number will be assigned to each patient at the time that informed 
consent is obtained; this patient number will be used throughout the study. 
9.1.2
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, alcohol and smoking 
status of the patient at Screening.  
Medical history to be obtained will include whether the patient has any significant conditions or 
diseases relevant to the condition/disease under study that stopped at or prior to informed 
consent. Ongoing conditions are considered concurrent medical conditions.  
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 1 year prior to signing of informed consent. 
9.1.3
Safety Assessments 
On Day 1, all the assessments must be reviewed by the investigator prior to study treatment 
initiation to assure eligibility requirements have been met. During the study, all assessments 
should be done prior to administration of study drug unless otherwise indicated. 
9.1.4
Wash-out Period 
During the 2-week wash-out phase all enrolled patients must discontinue all prior DED therapies 
including artificial tears and any prohibited ocular treatments. The sponsor will provide all 
patients with unpreserved artificial tears to use up to eight instillations per day in each eye the 
relief of their symptoms of DED. Patients will be instructed in the optimal technique for 
ophthalmic drop instillation. 
9.1.5
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study medication. These may be 
prescribed by a physician or obtained by the patient over the counter. Concomitant medication is 
not provided by Santen. At each study visit, patients will be asked whether they have taken any 


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medication other than the study medication (used from signing of informed consent through the 
end of the study), and all medication, including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. Documentation will 
include generic medication name, dose, unit, frequency, route of administration, start and end 
dates, and reason for use.  
9.1.6
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, ECG, or 
physical examination abnormalities noted at the Screening examination. The condition (ie.,. 
diagnosis) should be described. 
9.1.7
Contraception and Pregnancy Avoidance Procedure 
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 
Screening 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. 


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During the course of the study, urine hCG pregnancy tests will be performed only for women of 
childbearing potential and patients will receive continued guidance with respect to the avoidance 
of pregnancy as part of the Schedule of Study Procedures (Appendix A 
Schedule of Study 
Procedures and Procedures 
Appendix -I). Patients must have a negative urine pregnancy test on Day 1 and throughout the 
study.  
9.1.8
Pregnancy 
If any patient is found to be pregnant during the study she should be withdrawn and any sponsor-
supplied drug should be immediately discontinued. If the pregnancy occurs during administration 
of active study medication, the pregnancy should be reported within 14 days of completing the 
study  
All reported pregnancies in a patient receiving active study medication will be followed up to 
final outcome, using the pregnancy form. The outcome, including any premature termination, 
must be reported to the sponsor. An evaluation after the birth of the child will also be conducted. 
9.1.9
Documentation of Screen Failure 
Investigators must account for all patients who sign informed consent. If the patient is found to 
be not eligible at Screening or Baseline visit, the investigator should complete the eCRF. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
•
Pre-treatment event/AE. 
•
Did not meet inclusion criteria or did meet exclusion criteria. 
•
Major protocol deviation. 
•
Lost to follow-up. 
•
Voluntary withdrawal, specify reason. 
•
Study termination. 
•
Other, specify reason. 
Patient numbers assigned to patients who fail screening should not be reused. 
9.1.10 Documentation of treatment initiation 
Only patients who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for treatment initiation into the treatment phase. 
If the patient is found to be not eligible for treatment initiation, the investigator should record the 
primary reason for failure on the applicable eCRF. 


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9.2
Monitoring Patient Treatment Compliance 
Study medication will be administered on Day 1, Month 2 and Month 3. The date and time of 
each dose will be recorded in the source documents and on the eCRF. An inventory of the study 
medication supplies dispensed will be performed by the site pharmacist or authorized study 
designee and recorded onto the Drug Accountability Log in the patient’s source document 
records or equivalent. If a patient is persistently noncompliant with the study medication, the 
patient might be withdrawn from the study. All patients should be reinstructed about the dosing 
requirement during study visits. The authorized study personnel conducting the re-education 
must document the process in the patient source records. 
9.3
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A-I. 
Assessments should be completed at the designated visit/time point(s). 
The study period will include the initial Screening Visit, the 2-week wash-out phase, and the 3-
month open-label study treatment phase encompassing the Baseline, Month 1, 2 and 3 study 
visits.  See Appendix A for details of procedures that will be performed and documented. 
9.3.1
Screening  
Patients will be screened for the study within 14 days prior to the first dose of study medication. 
Patients will be screened in accordance with predefined inclusion and exclusion criteria as 
described in Section 7.0. See Section 9.1.9 for procedures for documenting screening failures. 
9.3.1.1
Screening Visit: Day -14 ± 3 days  
Procedures to be completed at Screening Visit include: 
•
Informed consent. 
•
Inclusion/exclusion criteria review. 
•
Demographics. 
•
Ocular and systemic medical history. 
•
Previous and concomitant ocular and systemic medications (including artificial tear usage). 
•
Visual Analogue Scales (0-100%, from 0 = no symptom, 100 = maximal symptom) to assess 
the severity photophobia and blurred vision (Appendix A-II). 
•
Uncorrected distance visual acuity (UDVA). 
•
Best corrected distance visual acuity (BCDVA, Appendix A-III).  
•
Functional visual acuity parameters (FVA, starting visual acuity, LogMAR FVA, VMR, and 
maximal and minimal visual acuities) using FVA measurement system (AS-28; Kowa, Aichi, 
Japan / Nidek, Gamagori, Japan) (Appendix A-IV). 


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•
Ocular Scatter Index (OSI), using double-pass aberrometer (Optical Quality Analyzing 
System, Visiometrics, Spain) (Appendix A-V). 
•
Root mean square (RMS) of higher order aberrations (total, coma-like, spherical like) using 
Hartmann-Shack aberrometer (Appendix A-VI). 
•
Slit lamp examination (Appendix A-VII). 
•
Tear break up time (TBUT). 
•
Corneal fluorescein staining (CFS, modified Oxford scale) (Appendix A-VIII). 
•
Eligible patients will discontinue all previous treatments related to dry eye including artificial 
tears and any prohibited ocular treatments. 
•
Urine pregnancy test (women of childbearing potential only) 
•
Dispense unpreserved artificial tears. 
•
Initiate 1-2 week wash-out phase. 
•
Patients will be scheduled to return to the clinic in 14 days +3 days for the baseline visit. 
9.3.2
Treatment Phase 
All assessments should be done in the mentioned order to ensure that additional product doesn’t 
interfere for the other result examinations. 
9.3.2.1
Baseline: Day 1 
•
Inclusion/exclusion criteria review.  
•
Record Ocular and systemic medical history. 
•
Review of concomitant ocular and systemic concomitant medications (including artificial 
tear usage). 
•
Record adverse events (AEs) 
•
0-100% VAS for photophobia and blurred vision severity 
•
UDVA 
•
BCDVA  
•
FVA parameters using FVA measurement system  
•
OSI using double-pass aberrometry system  
•
Slit lamp examination  
•
Dilated fundus examination 
•
TBUT 


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•
CFS (modified Oxford scale) 
•
IOP 
•
Schirmer test (without anaesthesia) 
•
Urine pregnancy test (women of childbearing potential only) 
•
Collection of unpreserved artificial tear bottles (used/not used) 
•
Verify inclusion and exclusion criteria based on evaluations just performed: 
o
Patients fulfilling the inclusion / exclusion criteria will receive the study treatment for the 
next month 
o
Patients not fulfilling the inclusion / exclusion criteria will be discontinued from the 
study and the patient become screen failure (refer to section 9.1.9) 
•
Dispense study medication and unpreserved artificial tears for a 1-month period. Patients will 
be instructed on dosing of study medication. 
•
Patients will be scheduled to return to the clinic in 28 days + 3 days for Month 1 visit. 
9.3.2.2
Month 1:  Day 28 ±3 days 
•
Record concomitant ocular and systemic concomitant medications (including artificial tear 
usage) 
•
Record adverse events (AEs) 
•
0-100% VAS for photophobia and blurred vision severity 
•
UDVA 
•
BCDVA  
•
FVA parameters using FVA measurement system  
•
OSI using double-pass aberrometry system  
•
Slit lamp examination  
•
TBUT 
•
Corneal fluorescein staining (modified Oxford scale) 
•
Collection of used/not used study medication containers and unpreserved artificial tear 
bottles 
•
Dispense study medication and unpreserved artificial tears for a 1-month period (Month 1 - 
Month 2) 
•
Patients will be scheduled to return to the clinic on Day 56+3 days for Month 2 visit. 


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9.3.2.3
 Month 2:  Day 56 ±3 days 
•
Record concomitant ocular and systemic concomitant medications (including artificial 
tear usage) 
•
Record adverse events (AEs) 
•
0-100% VAS for photophobia and blurred vision severity 
•
UDVA 
•
BCDVA  
•
FVA parameters using FVA measurement system  
•
OSI using double-pass aberrometry system  
•
Slit lamp examination  
•
TBUT 
•
Corneal fluorescein staining (modified Oxford scale) 
•
Collection of used/not used study medication containers and unpreserved artificial tear 
bottles 
•
Dispense study medication and unpreserved artificial tears for a 1-month period (Month 2 
- Month 3) 
•
Patients will be scheduled to return to the clinic on Day 84± 7 days for Month 3 visit. 
9.3.2.4
Month 3:  Day 84 ±7 days   
•
Record concomitant ocular and systemic concomitant medications (including artificial tear 
usage) 
•
Record adverse events (AEs) 
•
Patient global evaluation of efficacy 
•
0-100% VAS for photophobia and blurred vision severity 
•
UDVA 
•
BCDVA  
•
FVA parameters using FVA measurement system  
•
OSI using double-pass aberrometry system  
•
RMS of higher order aberrations using Hartmann-Shack aberrometer  
•
Slit lamp examination 
•
Dilated fundus examination 


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•
TBUT 
•
CFS including assessment of complete corneal clearing (modified Oxford scale) 
•
IOP 
•
Schirmer test (without anaesthesia) 
•
Investigator global evaluation of efficacy 
•
Urine pregnancy test (women of childbearing potential only) 
•
Collection of study medication containers used/not used study medication containers and 
unpreserved artificial tear bottles. 
9.3.3
Unscheduled Visit/Premature Discontinuation 
An unscheduled visit may be performed as needed between two scheduled visits. The reason for 
the visit will be recorded on the eCRF. The examinations required at an unscheduled visit will be 
at the discretion of the investigator.  
If necessary, (e.g. to follow up an AE), the investigator may schedule further “unscheduled” 
visits at his/her discretion. Data from an unscheduled visit will not be collected in the eCRF with 
the exception of information related to an AE or the follow-up of an AE.   
In case of premature study discontinuation between two scheduled visits, the Unscheduled Visit 
Form and the Exit Forms will be completed. If the premature discontinuation occurs during an 
Unscheduled Visit prior to Month 3, the investigator will complete and record all of the exams 
scheduled at the Month 3 Visit on the Unscheduled Visit Form. In case of premature study 
discontinuation, the investigator will ensure that all used and unused study medication for the 
study period has been collected from the patient. 
9.3.4
Efficacy Assessment 
9.3.4.1
Functional Visual Acuity (FVA) 
Functional visual acuity (FVA) will be measured without topical anaesthesia using FVA 
measurement system (AS-28; Kowa, Aichi, Japan) at each study visit (see Appendix A-I). The 
FVA is defined as the mean value of time-wise change of the visual acuity during the overall 
examination (60 seconds). The LogMAR FVA, starting VA, and maximal and minimal VAs will 
also be determined. 
The visual maintenance ratio (VMR) which is the primary efficacy criteria will be calculated: it 
is defined as the ratio of FVA divided by the value of starting VA (Kaido 2006, Kaido 2011)  
An increase in VMR from baseline will indicate improvement. 


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9.3.4.2
Objective Scatter Index (OSI) 
Ocular Scatter Index (OSI) and its variance will be measured using double-pass aberrometer 
(Optical Quality Analyzing System, Visiometrics, Spain) at each study visit (see Appendix A-V).  
A decrease in OSI variance from baseline will indicate improvement. 
9.3.4.3
Corneal Fluorescein Staining including Complete Corneal Clearing 
Corneal 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. The eye 
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 (see Appendix A-VIII). On this modified scale, the score 0 corresponds to 
no staining dots and the score 0.5 to three or less staining dots. A CFS grade of 0 represents 
complete corneal clearing. 
A negative change from baseline will indicate improvement. 
9.3.4.4
Higher Order Aberrations 
Root mean square (RMS) of higher order aberrations (total, coma-like, spherical like) will be 
measured using Hartmann-Shack aberrometer (see Appendix VI). 
A decrease in RMS from baseline will indicate improvement. 
9.3.4.5
 Patient Global Evaluation of Efficacy 
Patient will conduct an overall assessment of the effect of the study medication using the 
following rating scale: 
(3) = Very satisfactory. 
(2) = Satisfactory. 
(1) = Not very satisfactory. 
(0) = Unsatisfactory. 
9.3.4.6
Symptoms Measured on Visual Analogue Scales (VASs) 
Patient’s photophobia and blurred vision will be assessed using a self-administered VASs 
ranging from 0% to 100% (see Appendix A-II).   
A decrease in the VAS % from baseline will indicate improvement. 


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9.3.4.7
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 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.  This measurement will be performed within 10 seconds maximum. 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 a then a third reading is taken.  
The TBUT value will be the average of the 2 or 3 measurements. A measured value of less than 
10 seconds will be recorded or 10 seconds will be indicated.  
A positive change from baseline will indicate improvement. 
9.3.4.8
Schirmer Test (without anesthesia) (mm wetting/5min) 
Schirmer 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 directly the Schirmer test strip with the fingers to avoid 
contamination of skin oils. After 5 minutes have elapsed the Schirmer test strip is removed and 
the length of the tear absorption on the strip will be measured.  
A positive change from baseline will indicate improvement. 
9.3.4.9
Use of Concomitant Artificial Tears 
The use of artificial tears will be monitored over the course of the study for each patient. Patients 
will be asked about the average number of times per day artificial tears was used the week 
preceding the visits, and number of days they were not used during the week preceding the visits 
The Sponsor will provide unpreserved artificial tears for all the patients. After the Screening 
Visit patients will be allowed to instil 1 unpreserved artificial tear drop, up to eight instillations 
per day in each eye, to ameliorate their dry eye symptoms. Patients will be instructed not to use 
the unpreserved artificial tears within 30 minutes before or after the use of the study medication. 
Patients will also be instructed not to use the unpreserved artificial tears two hours before the 
scheduled study visit. 
Patients will be instructed to return the used or not used unpreserved artificial tears at the 
scheduled study visits. 


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9.3.4.10 Investigator Global Evaluation of Efficacy 
The study investigator at each centre will conduct an overall assessment of the effect of the study 
medication on improvement in the patients DED using the following rating scale: 
(3) = Very satisfactory. 
(2) = Satisfactory. 
(1) = Not very satisfactory. 
(0) = Unsatisfactory. 
9.3.5
Safety Evaluation Parameters  
9.3.5.1
Slit lamp examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp. 
The subject 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-VIII. 
9.3.5.2
Uncorrected Distance Visual Acuity (UDVA) 
The uncorrected distance VA will be measured in LogMAR. 
9.3.5.3
Best Corrected Distance Visual Acuity (BCDVA) 
Best corrected distance VA will be measured with the patient’s best correction and recorded in 
LogMAR (see Appendix A-III).   
9.3.5.4
Dilated Fundus Examination 
A dilated fundus examination will be performed after use of mydriatic eye drops to dilate the 
pupil in order to evaluate for posterior segment diseases. Abnormal outcomes will be described.  
9.3.5.5
Tonometry for measurement of Intraocular Pressure (IOP) (mmHg) 
IOP will be measured using Goldman applanation tonometry (one measurement), after 
instillation of one drop of oxybuprocaine 0.4% and fluorescein 0.5% solutions. 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 test especially). The patient 
and slit lamp should be adjusted so that the patient’s head is firmly positioned on the chin rest 
and against the forehead rest without leaning forward or straining.  Both eyes will be tested, with 
the right eye preceding the left eye. The same equipment must be used throughout the course of 
the study. All equipment (i.e., slit lamp) should be calibrated and checked during monitoring 
visit. 


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9.3.5.6
Ocular Adverse Events (AEs) 
Ocular AEs will be recorded in the eCRFs as described in Section 5.6. Any clinically significant 
change in ocular concomitant disease or any new concomitant ocular conditions that occurred 
between the Screening Visit and the Baseline Visit will be reported as AEs. 
9.3.5.7
Systemic Adverse Events (AEs) 
Systemic AEs will be recorded in the eCRF as described in Section 5.6. Any clinically 
significant change in concomitant disease or new concomitant conditions that occurred between 
the Screening Visit and the Baseline Visit will be reported as AEs. 


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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1
Definitions 
10.1.1 Pre-treatment Events 
A pre-treatment event (PTE) is defined as any untoward medical occurrence in a clinical 
investigation patient who has signed informed consent to participate in a study but prior to 
administration of any study medication; it does not necessarily have to have a causal relationship 
with study participation. 
10.1.2 AEs 
An AE is defined as any untoward medical occurrence in patient or clinical investigation patient 
administered an investigational product; it does not necessarily have to have a causal relationship 
with this treatment. 
An AE can therefore be any unfavourable and unintended sign (eg, a clinically significant 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, whether or not it is considered related to the drug. 
10.1.3 Sight-threatening Events 
An event is considered sight-threatening and should be reported as an SAE if it meets one or 
more of the following criteria: 
•
It caused a decrease in visual acuity of >30 letters (compared with the last assessment 
of visual acuity at the last visit) lasting >1 hour
•
It caused a decrease in visual acuity to the level of Light Perception or worse lasting 
>1 hour 
•
It required surgical intervention (e.g., conventional surgery, vitreous tap or biopsy 
with intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) to 
prevent permanent loss of sight 
•
It is associated with severe intraocular inflammation (i.e., 4+ anterior chamber 
cell/flare or 4+ vitritis) 
•
In the opinion of the investigator it may require medical intervention to prevent 
permanent loss of sight 
10.1.4 Case of Special Interest 
The following cases are considered to be of special interest by the sponsor: 
•
Overdose: 
Administration of a quantity of a medicinal product exceeding the dose defined in the 
study protocol/otherwise specify overdose. 


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•
Misuse of study product: 
Situations where the medicinal product is intentionally and inappropriately used not 
in accordance with the study protocol. 
•
Medication error: 
Any unintentional error in the prescribing, dispensing, or administration of a 
medicinal product while in the control of the healthcare professional, patient or 
consumer. 
•
Abuse of study product: 
Persistent or sporadic, intentional excessive use of medicinal products which is 
accompanied by harmful physical or psychological effects. 
10.1.5 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
•
Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre-existing conditions underlying disease should not be considered PTEs or AEs.) 
•
Necessitate therapeutic intervention. 
•
Require an invasive diagnostic procedure. 
•
Require discontinuation or a change in dose of study medication or a concomitant 
medication. 
•
Be considered unfavourable by the investigator for any reason. 
Diagnoses vs signs and symptoms: 
•
Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values) or symptoms should NOT be recorded as additional 
AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded appropriately as a 
PTE(s) or as an AE(s). 
Laboratory values: 
•
Changes in laboratory values are only considered to be PTEs or AEs if they are judged to be 
clinically significant (i.e., if some action or intervention is required or if the investigator 
judges the change to be beyond the range of normal physiologic fluctuation). A laboratory 
retest and/or continued monitoring of an abnormal value are not considered an intervention. 
In addition, repeated or additional non-invasive testing for verification, evaluation or 
monitoring of an abnormality is not considered an intervention. 
•
If abnormal laboratory values are the result of pathology for which there is an overall 
diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be reported 
appropriately as a PTE or as an AE. 


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Pre-existing conditions: 
•
Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (e.g., laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 
related to study procedures. However, if the patient experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) 
or an AE (worsening or complication occurs after start of study medication). Investigators 
should ensure that the event term recorded captures the change in the condition (e.g., 
“worsening of…”). 
•
If a patient has a pre-existing episodic condition (e.g., asthma, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious 
or severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (e.g. “worsening of…”). 
•
If a patient has a degenerative concurrent condition (e.g., cataracts, rheumatoid arthritis), 
worsening of the condition should only be captured as a PTE/AE if occurring to a greater 
extent to that which would be expected. Again, investigators should ensure that the AE term 
recorded captures the change in the condition (e.g., “worsening of…”). 
Worsening of PTEs or AEs: 
•
If the patient experiences a worsening or complication of a PTE after starting administration 
of the study medication, the worsening or complication should be recorded appropriately as 
an AE. Investigators should ensure that the AE term recorded captures the change in the 
condition (e.g., “worsening of…”). 
•
If the patient experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (e.g., 
“worsening of…”). 
Changes in severity of AEs /Serious PTEs: 
•
If the patient experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Pre-planned surgeries or procedures: 
•
Pre-planned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a pre-planned procedure is 
performed early (e.g., as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. 
Complications resulting from any planned surgery should be reported as adverse events. 
Elective surgeries or procedures: 


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•
Elective procedures performed where there is no change in the patient’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the patient’s source 
documents. Complications resulting from an elective surgery should be reported as adverse 
events. 
Overdose, medication error, abuse or misuse: 
•
Cases of overdose, medication error, abuse or misuse with any medication without 
manifested side effects are NOT considered PTEs or AEs, however, theywill be documented 
on the AE page of the eCRF. Any manifested side effects will be considered PTEs or AEs 
and will be recorded separately on the AE page of the eCRF. 
10.1.6 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
•
The term “life threatening” refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
•
May require intervention to prevent items 1 through 5 above. 
•
May expose the patient to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
PTEs that fulfil 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 10.2.1). 


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10.1.7 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the patient. 
Moderate: 
The event causes the patient discomfort and interrupts the patient’s usual activities. 
Severe: 
The event causes considerable interference with the patient’s usual activities. 
10.1.8 Causality of AEs 
The relationship of each AE to study medication(s) will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug can be 
argued, although factors other than the drug, such as underlying diseases, complications, 
concomitant drugs and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant drugs and concurrent treatments. 
10.1.9 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as “Related” if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as “Not related”. 
10.2
Procedures 
10.2.1 Collection and Reporting of AEs 
10.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the patient signs the informed consent to 
participate in the study and continue until the patient is first administered study medication or 
until screen failure. For patients who discontinue prior to study medication administration, PTEs 
are collected until the patient discontinues study participation. 
Collection of AEs will commence from the time that the patient is first administered study 
medication. Routine collection of AEs will continue until the Final Visit. 
10.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any AEs have occurred. A neutral 
question, such as “How have you been feeling since your last visit?” may be asked. Patients may 
report AEs occurring at any other time during the study. Patients experiencing a serious PTE 
must be monitored until the symptoms subside and any clinically relevant changes in laboratory 


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values have returned to Baseline or there is a satisfactory explanation for the change. Non-
serious PTEs, related or not related to the study procedure, need not to be followed-up for the 
purposes of the protocol. 
All patients experiencing AEs, whether considered associated with the use of the study 
medication or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to Baseline or until there is a satisfactory explanation 
for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the 
eCRF, whether or not the investigator concludes that the event is related to the drug treatment. 
The following information will be documented for each event: 
•
Event term. 
•
Start and stop date and time. 
•
Severity. 
•
Investigator’s opinion of the causal relationship between the event and administration of 
study medication(s) (Related or Not related) (not completed for PTEs). 
•
Investigator’s opinion of the causal relationship to study procedure(s), including the details 
of the suspected procedure. 
•
Action concerning study medication (not applicable for PTEs). 
•
Outcome of event. 
•
Seriousness. 
10.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Santen SAE form must be completed, in English, and signed by the investigator immediately 
but not later than within 24 hours of first onset or notification of the event. The information 
should be completed as fully as possible but contain, at a minimum: 
•
A short description of the event and the reason why the event is categorized as serious. 
•
Patient identification number. 
•
Investigator’s name. 
•
Name of the study medication(s). 
•
Causality assessment. 
The SAE form should be transmitted immediately but not later than within 24 hours to the 
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Santen EMEA, Pharmacovigilance Unit (PVU) 
Fax SAE Report Form to:  Fax: +358 3 318 1060 or 
Email to: SafetyEU@santen.com 
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
10.3
Follow-up of SAEs 
If information is not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately but not later than within 24 hours of receipt. Copies of any relevant data from 
the hospital notes (e.g., ECGs, laboratory tests, discharge summary, post-mortem results) should 
be sent to the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities  
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, investigators and IRBs or 
IECs, as applicable, in accordance with national regulations in the countries where the study is 
conducted. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted without any delay for fatal and life-threatening 
events and within 15 days for other serious events, unless otherwise required by national 
regulations. The sponsor will also prepare an expedited report for other safety issues where these 
might materially alter the current benefit-risk assessment of an investigational medicinal product 
or that would be sufficient to consider changes in the investigational medicinal products 
administration or in the overall conduct of the trial. The investigational site also will forward a 
copy of all expedited reports to his or her IRB or IEC in accordance with national regulations. 


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11.0
DATA HANDLING AND RECORD KEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World Health 
Organization (WHO) Drug Dictionary, based upon Anatomical-Therapeutic-Chemical (ATC) 
system. 
11.1
Electronic eCRFs 
Completed eCRFs are required for each patient who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. Data are entered directly onto 
eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Santen 
personnel (or designees) and will be answered by the site.  
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new 
information, identification of the person making the correction, the date the correction was made, 
and the reason for change. Reasons for significant corrections should additionally be included.  
The principal investigator must review the eCRFs s for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
After the database lock of clinical study database, any change of, modification of or addition to 
the data on the eCRFs should be made by the investigator with use of change and modification 
records of eCRFs (Data Clarification Form) provided by the sponsor. The principal investigator 
must review the Data Clarification Form for completeness and accuracy, and must sign, and date 
the form.  
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the patient’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed 
eCRFs are the sole property of the sponsor and should not be made available in any form to third 
parties, except for authorized representatives of appropriate governmental health or regulatory 
authorities, without written permission of the sponsor. 
11.2
Source Data Documentation 
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.  


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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 (date of birth, sex, name) 
- 
Past medical and surgery history 
- 
Past and recent treatments 
- 
Concomitant treatments at inclusion  
- 
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 AE and/or SAEs occurred during the time course of the study an within one month 
after last treatment received 
- 
Any data that could be judged by the Investigator as relevant 
11.3
Record Retention
The investigator agrees to keep the records stipulated in Section 11.2 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating patients, medical records, temporary media such as thermal sensitive paper should 
be copied and certified, source worksheets, all original signed and dated informed consent forms, 
patient authorization forms regarding the use of personal health information (if separate from the 
informed consent forms), electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees. Furthermore, International Conference on Harmonisation (ICH) E6 Section 4.9.5 
requires the investigator to retain essential documents specified in ICH E6 (Section 8) until at 
least 2 years after the last approval of a marketing application for a specified drug indication 
being investigated or, if an application is not approved, until at least 2 years after the 
investigation is discontinued and regulatory authorities are notified. 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 Site Agreement 
between the investigator and sponsor. 


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12.0
STATISTICAL METHODS 
12.1
Statistical Analysis 
Descriptive statistics (mean, standard deviation, 95% confidence interval for mean, minimum, 
median, maximum, and number of observations and missing cases) will be used for quantitative 
variables, and frequencies and percentages will be used for categorical variables. For the 
variables recorded for both eyes, the descriptions will be given separately for the analysis eye 
and for the fellow eye, when considered relevant.  
All the efficacy analysis will be performed on the analysis eye, which is defined as the eligible 
eye that fulfils all the criteria listed under the inclusion criteria #4. If both eyes are eligible, the 
eye with the highest baseline CFS score will be chosen. If both eyes have the same CFS score, 
the eye with the lowest VMR will be chosen. If VMR values are the same for both eyes, the right 
eye will be chosen. 
A Statistical Analysis Plan will be written and signed before starting the analysis of the study 
data. This document will present all the analyses to be performed, and detail some points of the 
protocol. 
12.2
Analysis of Demographics and Other Baseline Characteristics 
Baseline patient characteristics (demographics, ocular history, clinical examination etc.) will be 
summarized using descriptive statistics. 
12.3
Primary Efficacy Variable Analysis 
Spearman’s coefficient of correlation will be calculated at Month 3 between the change from 
baseline of CFS and respectively the change from baseline of VRM and the change from 
baseline of variance of OSI. 
As a sensitivity analysis, a mixed effects model will also be employed to investigate the 
association between the change in CFS vs. change in VMR, and change in CFS vs. change in 
variance of OSI, respectively, during the course of the study (from baseline to Month 3). 
Changes from baseline in VMR and variance of OSI will also be summarized by categorical 
change in CFS (-5, -4.5, -4, -3.5, -3, -2.5, -2, -1.5, -1, 0, +1 unit change) and by analysis visit 
(Month 1, Month 2, and Month 3). 
12.4
Analysis of the Secondary Efficacy Variables 
Spearman’s coefficients of correlation will be calculated at each time-point (M1, M2, M3) 
between the change from baseline of CFS and respectively the change from baseline of other 
FVA parameters  (starting visual acuity, FVA, LogMAR FVA), and maximal and minimal visual 
acuities) and the change from baseline of OSI parameters. 
Spearman’s coefficients of correlation will be also calculated at each time-point (M1, M2, M3) 
between the change from baseline of OSI and of variance of OSI separately and the change from 
baseline of each FVA parameters.   


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The graphical curve (with means and error bars at each visit) of each parameter (CFS score, FVA 
parameters, OSI, variance of OSI) will be generated to explore their pattern of evolution over 
time (from baseline to Month 3) under the IKERVIS® treatment. 
The other efficacy endpoints will be presented with descriptive statistics at each time-point and 
in term of change from baseline. The coefficient of variation will be calculated for each criterion 
in order to provide reliable information on their metric interest for a further study.  
12.5
Safety Assessments 
Other parameters of safety or tolerance (e.g. slit lamp examination, visual acuity, IOP) will be 
described at each time point of measurement, and they will be summarized/ analysed for both the 
analysis eye and the fellow eye separately. 
12.6
AEs 
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages will 
be provided of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and 
TEAEs causing premature discontinuation. An adverse event is treatment emergent if it occurs or 
worsens after the first dose of study treatment. Furthermore, frequencies will be given of patients 
with TEAEs as follows:  1) by system organ class, by system organ class and preferred term, 2) 
by system organ class, preferred term and maximal severity, 3) by system organ class, preferred 
term and strongest relationship, and 4) by system organ class, preferred term, maximal severity, 
and strongest relationship.  
Separate analyses will be performed for ocular and systemic adverse events. Ocular AEs will be 
summarised for the analysis eye and the other eye separately. 
12.7
Interim Analysis  
No interim analysis is planned. 


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13.0
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s 
Binder, study medication, patient medical records, informed consent documentation, 
documentation of patient authorization to use personal health information (if separate from the 
informed consent forms), and review of eCRFs and associated source documents. It is important 
that the investigator and other study personnel are available during the monitoring visits and that 
sufficient time is devoted to the process. 
13.2
Protocol Deviations 
There will be no exemptions (a prospective approved deviation) from the inclusion or exclusion 
criteria. 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study patients. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
medical monitor (and IRB or IEC, as required) to determine the appropriate course of action. 
13.3
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign countries. If the study site is contacted for an inspection by a 
regulatory body, the sponsor should be notified immediately. The investigator and institution 
guarantee access for quality assurance auditors to all study documents as described in Section 
13.1. 


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14.0
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual participants (i.e., 
patients) according to the protocol, the ethical principles that have their origin in the Declaration 
of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will 
conduct the study according to applicable local or regional regulatory requirements. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
14.1
IRB and/or IEC Approval 
IRBs and IECs must be constituted according to the applicable state and federal/local 
requirements of each participating region. The sponsor or designee will require documentation 
noting all names and titles of members who make up the respective IRB or IEC. If any member 
of the IRB or IEC has direct participation in this study, written notification regarding his or her 
abstinence from voting must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the summary of product 
characteristics, the patient information leaflet, a copy of the informed consent form, and, if 
applicable, patient recruitment materials and/or advertisements and other documents required by 
all applicable laws and regulations, must be submitted to a central or local IRB or IEC for 
approval. The IRB’s or IEC’s written approval of the protocol and patient informed consent must 
be obtained and submitted to the sponsor or designee before commencement of the study (i.e., 
before shipment of the sponsor-supplied drug or study specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (e.g., informed consent form) reviewed; and state the approval date. 
The sponsor will [ship drug/notify site] once the sponsor has confirmed the adequacy of site 
regulatory documentation and, when applicable, the sponsor has received written permission 
from competent authority to begin the trial. Until the site receives [drug/notification] no protocol 
activities, including screening may occur. 
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by patients, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee. 
14.2
Patient Information, Informed Consent, and Patient Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations (Appendix B). The informed consent form, patient authorization 
form (if applicable), and patient information sheet (if applicable) describe the planned and 


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permitted uses, transfers, and disclosures of the patient’s personal and personal health 
information for purposes of conducting the study. The informed consent form and the patient 
information sheet (if applicable) further explain the nature of the study, its objectives, and 
potential risks and benefits, as well as the date informed consent is given. The informed consent 
form will detail the requirements of the participant and the fact that he or she is free to withdraw 
at any time without giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the patient authorization form. The informed consent 
form, patient authorization form (if applicable), and patient information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, patient authorization form (if applicable), and patient information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
patient. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form, patient authorization form (if applicable), and patient information sheet (if 
applicable) to the patient. Information should be given in both oral and written form whenever 
possible and in the manner deemed appropriate by the IRB or IEC. In the event the patient is not 
capable of rendering adequate written informed consent, then the patient’s legally acceptable 
representative may provide such consent for the patient in accordance with applicable laws and 
regulations. 
The patient, or the patient’s legally acceptable representative, must be given ample opportunity 
to: (1) inquire about details of the study and (2) decide whether or not to participate in the study. 
If the patient, or the patient’s legally acceptable representative, determines he or she will 
participate in the study, then the informed consent form and patient authorization form (if 
applicable) must be signed and dated by the patient, or the patient’s legally acceptable 
representative, at the time of consent and prior to the patient entering into the study. The patient 
or the patient’s legally acceptable representative should be instructed to sign using their legal 
names, not nicknames, using blue or black ballpoint ink. The investigator must also sign and date 
the informed consent form and patient authorization (if applicable) at the time of consent and 
prior to patient entering into the study; however, the sponsor may allow a designee of the 
investigator to sign to the extent permitted by applicable law. 
Once signed, the original informed consent form, patient authorization form (if applicable), and 
patient information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the patient signs the informed consent in the patient’s 
medical record. Copies of the signed informed consent form, the signed patient authorization 
form (if applicable), and patient information sheet (if applicable) shall be given to the patient. 
All revised informed consent forms must be reviewed and signed by relevant patients or the 
relevant patient’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the patient’s medical 
record, and the patient should receive a copy of the revised informed consent form. 


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14.3
Patient Confidentiality 
The sponsor and designees affirm and uphold the principle of the patient’s right to protection 
against invasion of privacy. Throughout this study, a patient’s source data will only be linked to 
the sponsor’s (or designee) clinical study database or documentation via a unique identification 
number. As permitted by all applicable laws and regulations, limited patient attributes, such as 
sex, age, or date of birth, and patient initials may be used to verify the patient and accuracy of the 
patient’s unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit its monitor or designee’s monitor, External Study 
Coordinator under Confidentiality Agreement, representatives from any regulatory authority 
(e.g., FDA, Medicines and Healthcare products Regulatory Agency, Pharmaceuticals and 
Medical Devices Agency), the sponsor’s designated auditors, and the appropriate IRBs and IECs 
to review the patient’s original medical records (source data or documents), including, but not 
limited to, laboratory test result reports, ECG reports, admission and discharge summaries for 
hospital admissions occurring during a patient’s study participation, and autopsy reports. Access 
to a patient’s original medical records requires the specific authorization of the patient as part of 
the informed consent process (see Section 15.2). 
Copies of any patient source documents that are provided to the sponsor must have certain 
personally identifiable information removed (i.e., patient name, address, and other identifier 
fields not collected on the patient’s eCRF). 
All information from this study (excluding data from the informed consent) are entered into a 
computer under the sponsor’s responsibility in accordance with the French law, "Loi 
Informatique et Libertés" (January 6, 1978 and subsequent amendments) and with the European 
Directive 95/46/EC. 
14.4
Publication, Disclosure, and Clinical Trial Registration Policy 
14.4.1 Publication and Disclosure 
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. 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 prevail. 


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14.4.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable law, regulation and guidance, Santen will, at a minimum, register all 
clinical trials conducted in patients that it sponsors anywhere in the world on ClinicalTrials.gov 
or other publicly accessible websites before trial initiation.  
14.4.3 Clinical Trial Results Disclosure 
Santen will minimally post the results of clinical trials conducted in patients, regardless of 
outcome, on ClinicalTrials.gov or other publicly accessible websites, as required by applicable 
laws and/or regulations. 
14.5
Insurance and Compensation for Injury 
Each patient in the study must be insured in accordance with the regulations applicable to the site 
where the patient is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study patients. 
Refer to the Master Services Agreement or equivalent agreement regarding the sponsor’s policy 
on patient compensation and treatment for injury. If the investigator has questions regarding this 
policy, he or she should contact the sponsor or sponsor’s designee. 


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15.0
REFERENCES 
1. AAO. Cornea/External Disease Panel. Preferred Practice Pattern® Guidelines. Dry 
Eye Syndrome.  American Academy of Ophthalmology; San Francisco2013. 
2. Albarran C, et al. Influence of the tear film on optical quality of the eye. Contact lens 
& anterior eye : the journal of the British Contact Lens Association. 1997;20(4):129-
35. 
3. Asbell PA, et al. Ophthalmologist perceptions regarding treatment of moderate-to-
severe dry eye: results of a physician survey. Eye Contact Lens. 2010 Jan;36(1):33-8. 
4. Baudouin C. A new approach for better comprehension of diseases of the ocular 
surface. J Fr Ophtalmol. 2007 Mar;30(3):239-46. 
5. Baudouin C, et al. Role of hyperosmolarity in the pathogenesis and management of 
dry eye disease: Proceedings of the OCEAN group meeting. Ocular Surface. 
2013;11(4):246-58. 
6. Baudouin C, et al. Diagnosing the severity of dry eye: a clear and practical algorithm. 
Br J Ophthalmol. 2014 Mar 13. 
7. Benito A, et al. Objective optical assessment of tear-film quality dynamics in normal 
and mildly symptomatic dry eyes. J Cataract Refract Surg. 2011 Aug;37(8):1481-7. 
8. Calvo P, et al. Improved ocular bioavailability of indomethacin by novel ocular drug 
carriers. J Pharm Pharmacol. 1996 Nov;48(11):1147-52. 
9. DEWS. Management and therapy of dry eye disease: report of the Management and 
Therapy Subcommittee of the International Dry Eye WorkShop (2007). The ocular 
surface. 2007 Apr;5(2):163-78. 
10. DEWS. The epidemiology of dry eye disease: Report of the Epidemiology 
Subcommittee of the International Dry Eye WorkShop (2007). The ocular surface. 
2007;5:93-107. 
11. DEWS. Design and conduct of clinical trials: report of the Clinical Trials 
Subcommittee of the International Dry Eye WorkShop. The ocular surface. 2007 
Apr;5(2):153-62. 
12. Goto E, et al. Impaired functional visual acuity of dry eye patients. Am J Ophthalmol. 
2002 Feb;133(2):181-6. 
13. Habay T, et al. [Objective assessment of the functional impact of dry eye severity on 
the quality of vision by double-pass aberrometry]. J Fr Ophtalmol. 2014 
Mar;37(3):188-94. 
14. Hiraoka T, et al. Time course of changes in ocular wavefront aberration after 
administration of eye ointment. Eye. 2012 Oct;26(10):1310-7. 


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15. Ismail D, et al. Pan-European survey of the topical ocular use of Ciclosporine A.  
SOE; June 6-9; Vienne 2015. 
16. Kaido M, et al. Functional visual acuity in Stevens-Johnson syndrome. Am J 
Ophthalmol. 2006 Dec;142(6):917-22. 
17. Kaido M, et al. The relation of functional visual acuity measurement methodology to 
tear functions and ocular surface status. Jpn J Ophthalmol. 2011 Sep;55(5):451-9. 
18. Kaido M, et al. Effects of diquafosol tetrasodium administration on visual function in 
short break-up time dry eye. J Ocul Pharmacol Ther. 2013 Jul-Aug;29(6):595-603. 
19. Koh S, et al. Serial measurements of higher-order aberrations after blinking in 
patients with dry eye. Invest Ophthalmol Vis Sci. 2008 Jan;49(1):133-8. 
20. Koh S, et al. Serial measurements of higher-order aberrations after blinking in normal 
subjects. Invest Ophthalmol Vis Sci. 2006 Aug;47(8):3318-24. 
21. Kymionis GD, et al. Treatment of chronic dry eye: focus on cyclosporine. Clin 
Ophthalmol. 2008 Dec;2(4):829-36. 
22. Labetoulle M, et al. From pathogenic considerations to a simplified decision-making 
schema in dry eye disease. J Fr Ophtalmol. 2013 May 21. 
23. Lallemand F, et al. Successfully improving ocular drug delivery using the cationic 
nanoemulsion Novasorb. Journal of Drug Delivery. 2012 January 2012:604204. doi: 
10.1155/2012/. 
24. Lallemand F, et al. Cyclosporine A delivery to the eye: A pharmaceutical challenge. 
Eur J Pharm Biopharm. 2003 Nov;56(3):307-18. 
25. Marsh 
P, 
et 
al. 
Topical 
nonpreserved 
methylprednisolone 
therapy 
for 
keratoconjunctivitis 
sicca 
in 
Sjogren 
syndrome. 
Ophthalmology. 
1999 
Apr;106(4):811-6. 
26. Montes-Mico R, et al. Dynamic changes in the tear film in dry eyes. Invest 
Ophthalmol Vis Sci. 2005 May;46(5):1615-9. 
27. Pflugfelder SC, et al. A randomized, double-masked, placebo-controlled, multicenter 
comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for 
treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J 
Ophthalmol. 2004 Sep;138(3):444-57. 
28. Sall K, et al. Two multicenter, randomized studies of the efficacy and safety of 
cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 
3 Study Group. Ophthalmology. 2000 Apr;107(4):631-9. 
29. Small DS, et al. Blood concentrations of cyclosporin a during long-term treatment 
with cyclosporin a ophthalmic emulsions in patients with moderate to severe dry eye 
disease. J Ocul Pharmacol Ther. 2002 Oct;18(5):411-8. 


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30. Stevenson D, et al. Efficacy and safety of cyclosporin A ophthalmic emulsion in the 
treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. 
The Cyclosporin A Phase 2 Study Group. Ophthalmology. 2000 May;107(5):967-74. 
31. Stevenson W, et al. Dry eye disease: an immune-mediated ocular surface disorder. 
Arch Ophthalmol. 2012 Jan;130(1):90-100. 
32. Tutt R, et al. Optical and visual impact of tear break-up in human eyes. Invest 
Ophthalmol Vis Sci. 2000 Dec;41(13):4117-23. 
33. Vandamme TF. Microemulsions as ocular drug delivery systems: recent 
developments and future challenges. Prog Retin Eye Res. 2002 Jan;21(1):15-34


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Appendix A Schedule of Study Procedures and Procedures 
Appendix A-I  
Schedule of Study Procedures 
Wash out period 
Open-label study treatment Period 
Unscheduled
Visit /
Study procedures 
Screening 
Day –14 ± 3
Baseline 
Day 1
Month 1 
Day 28 ± 3
Month 2 
Day 56 ± 3
Month 3 
Day 84 ± 7
premature 
study 
discontinuation
Informed consent 
X 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
Ocular and systemic medical  
history 
X 
X 
 
 
 
 
Previous and Concomitant  
ocular and systemic 
medications (incl. concomitant 
artificial tear usage) 
X 
X 
X 
X 
X 
X4
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Efficacy Assessments 
Tear break up time (TBUT) 
X 
X 
X 
X 
X 
X4
Corneal fluorescein staining 
(Modified Oxford Scale) 
X 
X 
X 
X 
X 
X4
Schirmer test (without 
anaesthesia) 
 
X 
 
 
X 
X4
Functional visual acuity (FVA 
parameters, FVA system) 
X 
X 
X 
X 
X 
X4
Objective scatter index (OSI) 
(double-pass aberrometer) 
X 
X 
X 
X 
X 
X4
RMS/Higher-order aberrations 
(Hartmann-Schack 
aberrometer) 
X 
 
 
 
X 
X4
Investigator global evaluation  
 
 
 
 
X 
X4


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Wash out period 
Open-label study treatment Period 
Unscheduled
Visit /
Study procedures 
Screening 
Day –14 ± 3
Baseline 
Day 1
Month 1 
Day 28 ± 3
Month 2 
Day 56 ± 3
Month 3 
Day 84 ± 7
premature 
study 
discontinuation
Patient global evaluation 
 
 
 
 
X 
X4
Visual Analog Scale (VAS) 
(photophobia, blurred vision) 
X1 
X1 
X1 
X1 
X1 
X1,4
Safety Evaluations 
Slit lamp examination  
X 
X 
X 
X 
X 
X4
Uncorrected distance visual 
acuity (UDVA in LogMAR) 
X 
X 
X 
X 
X 
X4
Best corrected distance visual 
acuity (BCDVA in LogMAR) 
X 
X 
X 
X 
X 
X4
Dilated fundus examination 
 
X 
 
 
X 
X4
Intraocular Pressure (IOP)  
 
X 
 
 
X 
X4
Urine pregnancy test (women of 
childbearing potential only) 
X 
X3 
 
 
X 
X5
Confirm patient discontinued 
treatment related to dry eye 
X 
 
 
 
 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X4
Treatment Procedures 
Dispense study medication and 
unpreserved artificial tears 
X2 
X2 
X2 
X2 
 
 
Collection of used study 
medication and unpreserved 
artificial tears  
 
X 
X 
X 
X 
X4
Footnotes are on last table page.  
ET/EOT=early termination/end of treatment. 
1 VASs should be performed at the beginning of the visit before medical history and any study assessment see visit schedule section 9.3. 
2 Dispense unpreserved artificial tears. Instruction: to be instilled up to eight times per day in each eye 
3 Only for patients fulfilling criteria for severe keratitis that will be included. 
4 Assessments to be performed during unscheduled visits only in case of premature discontinuation 


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Appendix A-II  
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 2 symptoms, i.e., blurred vision and photophobia. The patient will be 
asked to rate each ocular symptom of each eye by placing a vertical mark on the horizontal line 
to indicate the level of discomfort.  0% corresponds to “no discomfort” and 100% corresponds to 
“maximal discomfort.”  
 
 
Blurred Vision 
 0%                                            50%                                          100% 
|                                                                                                     |       
 
 
Photophobia 
 0%                                            50%                                          100% 
|                                                                                                     |       
The response will be measured in % between 0 – 100%.   


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Appendix A-III  
Best Corrected Distance Visual Acuity Procedure in LogMAR 
The distance visual acuity test should be done with the best correction. The investigator will use 
the same chart for both eyes throughout the study. 
Equipment: 
An ETDRS or modified ETDRS chart may be used.  
If a Lighthouse chart is used (dimensions 62 x 65 cm / 24.5 x 25.5 inches), the patient must be 
seated at 4 meters (13 feet) from the chart. If a smaller reproduction is used (dimensions 45.5 x 
45.5 cm / 18 x 18 inches), the patient must be seated at 3 meters (10 feet) from the chart. 
The same lighting conditions must be used throughout the course of the study. 
Procedure: 
The patient should be seated in front of the chart.  
The right eye must be tested first and the left eye must be covered. The patient should try to read 
each letter, from left to right, beginning at the top of the chart. The patient must be told that the 
chart contain only letters and no numbers. The patient must read slowly (about one letter per 
second). The investigator should not point on the chart during the test, but he must push 
/motivate the patient to read as far as he can during the test. The test is stopped when the patient 
cannot read any correct letter on the chart with the right eye. 
During the test, the investigator must count all the missed letters (=errors): 
- 
If the patient changes his response after reading the next letter, the change is regarded as 
an error.  
- 
If the patient cannot read one letter, this is regarded as an error too. 
Please note that if the patient changes his response before reading the next letter, this change is 
not regarded as an error.  
The same procedure must be repeated with the left eye. 
LogMAR calculation: 


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The investigator must calculate the score as follows: 
LogMAR Visual acuity = baseline value + (N x 0.02) 
With: 
- 
Baseline value: this is the lowest line where the patient can read at least one correct letter  
- 
N: this is the total number of missed letters (letters read incorrectly or letters not read up 
to the last/baseline line) 
- 
0.02 is the value for each letter 
Example: 
If a patient misses 3 letters of 5 at the 0.2 LogMAR line and 4 letters of 5 at the line 0.1 (lowest 
line where the patient can read at least one correct letter), the calculation is: 
- 
Last line read = 0.1 = baseline value 
- 
N = 4+3 = 7 
Then score = 0.1 + (7 x 0.02) = 0.24 LogMAR 
If a patient misses 2 letters of 5 at the 0.0 LogMAR line and 3 letters of 5 at the line -0.1 (lowest 
line where the patient can read at least one correct letter), the calculation is: 
- 
Last line read = -0.1 = baseline value 
- 
N = 2+3 = 5 
Then score = -0.1 + (5 x0.02) = 0.0 LogMAR 


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Appendix A-IV  
Functional Visual Acuity (Kaido 2013).  
The functional visual acuity (FVA) will be measured using FVA measurement system (AS-28; 
Kowa, Aichi, Japan) at each study visit. The changes with time in the continuous visual acuity 
using the Landolt optotypes (Figure 2) with their sizes change depending on the correctness of 
the responses. 
The optotypes are displayed automatically, starting with smaller ones. When the response is 
correct, even smaller optotypes are presented. If the responses are incorrect, larger optotypes are 
presented automatically (Figure 3). Visual acuity is continuously measured from the baseline 
best corrected Landolt visual acuity. The functional visual acuity measurement system can 
measure visual acuity from 150/100 to 20/200. When there is no response within the set display 
time, the answer is assumed to be an error, and the optotype enlarged automatically. 
The outcomes will be recorded as starting visual acuity, LogMAR functional visual acuity, visual 
maintenance ratio, and maximal and minimal visual acuities: 
•
Starting visual acuity is defined as the baseline visual acuity, which is the value of the 
standard best corrected visual acuity measured by the functional visual acuity 
measurement system 
•
Functional visual acuity is defined as the mean value of time-wise change of the visual 
acuity during the overall examination 
•
Visual maintenance ratio (VRM) is calculated as follows (Kaido 2006, Kaido 2011):  
visual maintenance ratio = (lowest LogMAR visual acuity score –functional visual acuity 
at 60 s)/(lowest LogMAR visual acuity score – baseline visual acuity)  
An increase in VMR from baseline will indicate an improvement. 
•
Maximal and minimal visual acuities are defined as the highest and lowest visual acuities 
recorded during the examination. 


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Figure 2 Presentation of Landolt optotypes on mini-pointer of the functional visual acuity device 
(Kaido 2013). 
Figure 3 flowchart diagram of optotypes during functional visual acuity testing (Kaido 2013).


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Appendix A-V  
Objective Scatter Index (Habay et al 2014) 
Objective Scatter Index (OSI) and its variance will be measured using double-pass aberrometer 
at each study visit.  
The system is driven by a software allowing a dynamic measure of the Point Spread Function 
(PSF) over 20 seconds with a resolution of half a second. For each PSF measure, the OSI is 
calculated, corresponding to the ratio of the light recorded in a ring area of 12 to 20 minutes of 
arc, and a circular area of 1 minute of arc. 
Before proceeding to the test, the patient closes his/her eyes for 10 sec, then blinks 5 times to 
obtain the most homogenous spreading of the lachrymal film on the cornea surface.  
Each measure is to be performed once. When measurement is to be performed on both eyes in 
the same patients, results will be considered as independent. 
A decrease in OSI variance from baseline will indicate improvement. 


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Appendix A-VI  
Higher Order Aberrations 
Serial measurements of ocular higher-order aberrations are performed by means of Hartmann-
Shack wavefront aberrometer.  
Higher-order aberrations will be measured during a blink-free period of 20 seconds without 
instillation of topical anesthesia. 
The higher-order aberration data will be analysed quantitatively for the central 4-mm-diameter 
zone up to the fourth order by expanding the set of Zernike polynomials. From the Zernike 
coefficients, the root mean square (RMS) will be calculated to represent the wavefront 
aberrations. The third-order Zernike coefficients (coma-like aberrations, S3), fourth-order 
Zernike coefficients (spherical-like aberrations, S4), and total higher-order aberrations (S3 + S4) 
will be calculated. 


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Appendix A-VII  
Slit lamp examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp. 
The subject 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 localized 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 (localized 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). 


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3 = Severe (definite redness of palpebral or bulbar conjunctiva). 
Conjunctiva - Oedema 
0 = None (normal). 
1 = Mild (slight localized swelling). 
2 = Moderate (moderate/medium localized 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 (Slit beam= 0.3 mm wide, 1.0 mm long) 
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. 
Vitreous 
0 = No haze (normal lens). 
1 = Mild vitreous haze. 
2 = Moderate vitreous haze. 
3 = Severe vitreous haze.


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Appendix A-VIII  
Modified Oxford Scale 


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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, fetus, 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. 


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•
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 
penalty or loss of benefits to which the patient otherwise is entitled, and that the 
patient 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. 
•
A statement that results of pharmacogenomic analysis will not be disclosed to an 
individual, unless prevailing laws require the sponsor to do so. 
•
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 subject’s willingness to continue participation, will be 
provided to the subject. 
•
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 medication(s), studying other therapies for patients, 


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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. 
1. Female patients of childbearing potential (e.g., non-sterilized, premenopausal female 
patients) who are sexually active must use adequate contraception (as defined in the 
informed consent) from Screening through 90 days after the last dose of trial 
treatment. Regular pregnancy tests will be performed throughout the study for all 
female patients of childbearing potential. If a patient is found to be pregnant during 
study, study medication will be discontinued.  
2. Male patients must use adequate contraception (as defined in the informed consent) 
from Screening through 90 days after the last dose of trial treatment. 


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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 medication. 
•
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. 


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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. 
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. 


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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. 
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 


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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. 


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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 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 


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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 
           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. 


IKERVIS®
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Protocol Version 4.0
               23 March 2018
CONFIDENTIAL 
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. 




This is a representation of an electronic record that was signed electronically
and this page is the manifestation of the electronic signature.

SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:   
A PHASE IV, PROSPECTIVE, OPEN-LABEL, MULTICENTRE, 
SINGLE ARM, 3-MONTH PROOF OF CONCEPT STUDY TO 
ASSESS THE EFFECT OF IKERVIS® 1MG/ML (CICLOSPORIN) 
EYE DROPS ADMINISTERED ONCE DAILY ON THE QUALITY 
OF VISION IN DRY EYE DISEASE (DED) PATIENTS WITH 
SEVERE KERATITIS 
 
 
NCT Number:  
 NCT03237936 
 
 
Date of the document: 
19 Feb 2019 
 
 
 


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STATISTICAL ANALYSIS PLAN 
FAST / NVG16E128 
 
 
Protocol 
Title: 
A Phase IV, Prospective, Open-Label, Multicentre, Single Arm, 3-Month 
Proof Of Concept Study To Assess The Effect Of IKERVIS® 1 mg/mL 
(Ciclosporin) Eye Drops Administered Once Daily On The Quality Of Vision 
In Dry Eye Disease (DED) Patients With Severe Keratitis 
Product: 
IKERVIS® Eye Drops (1 mg/mL Ciclosporin)  
Protocol 
Number:  
NVG16E128 
Sponsor: 
Santen SAS 
Genavenir IV, 1 rue Pierre Fontaine 
F-91058 Evry, France 
Date:  
19-February-2019 
Status:  
Version 0.1 
 
 
 
 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen, and may not be 
disclosed to others except to the extent necessary to obtain Institutional Review Board approval and 
informed consent, or as required by Federal and State Laws.  Persons to whom this information is 
disclosed must be informed that this information is privileged and confidential and that it should not be 
further disclosed. 




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TABLE OF CONTENTS 
 
ABBREVIATIONS .........................................................................................................................1 
1 
INTRODUCTION ........................................................................................................3 
2 
OBJECTIVES AND ENDPOINTS ..............................................................................4 
2.1 
Objectives .....................................................................................................................4 
2.1.1 
Primary Objective .........................................................................................................4 
2.1.2 
Secondary Objectives ...................................................................................................4 
2.2 
Endpoints ......................................................................................................................4 
2.2.1 
Primary Efficacy Endpoints ..........................................................................................4 
2.2.2 
Secondary Endpoints ....................................................................................................5 
2.2.2.1  
Efficacy Endpoints ........................................................................................................5 
2.2.2.2  
Safety Evaluations ........................................................................................................5 
3 
STUDY DESIGN .........................................................................................................6 
3.1 
General Study Design ...................................................................................................6 
3.2 
Randomization and Masking ........................................................................................7 
3.3 
Sample Size Planning ...................................................................................................9 
3.4 
Visits and Assessments .................................................................................................9 
4 
DEFINITIONS ...........................................................................................................12 
4.1 
Time-Related Terms ...................................................................................................12 
4.1.1 
Screening Visit (Day -14 ± 3 days) ............................................................................12 
4.1.2 
Baseline Visit (Day 1) ................................................................................................12 
4.1.3 
Analysis Period and Treatment Start and End Dates ..................................................12 
4.1.4 
Study Day ...................................................................................................................12 
4.1.5 
Out-of-Window Measurements, Analysis Visit, and Analysis Window ....................12 
4.1.6 
Extent of Exposure .....................................................................................................13 
4.1.7 
Duration of Quitting Smoke .......................................................................................13 
4.2 
Endpoint-Related Definitions .....................................................................................13 
4.2.1 
Analysis Eye and Fellow Eye .....................................................................................13 
4.2.2 
Baseline Score ............................................................................................................13 
4.2.3 
Change from Baseline .................................................................................................14 
4.3 
Efficacy-Related Definitions ......................................................................................14 


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4.3.1 
Functional Visual Acuity (FVA) Parameters .............................................................14 
4.3.2 
Objective Scatter Index (OSI) ....................................................................................15 
4.3.3 
Corneal Fluorescein Staining (CFS) including Complete Corneal Clearing ..............15 
4.3.4 
Higher-Order Aberrations (HOA) ..............................................................................15 
4.3.5 
Symptoms Measured on Visual Analogue Scales (VAS) ...........................................15 
4.3.6 
Tear Break-Up Time (TBUT) .....................................................................................16 
4.3.7 
Schirmer Test (without Anaesthesia) ..........................................................................16 
4.3.8 
Patient Global Evaluation of Efficacy ........................................................................16 
4.3.9 
Investigator Global Evaluation of Efficacy ................................................................16 
4.3.10 
Use of Concomitant Artificial Tears ...........................................................................16 
4.4 
Safety-Related Definitions ..........................................................................................17 
4.4.1 
Adverse Event (AE) ....................................................................................................17 
4.4.1.1 
Serious Adverse Event (SAE) ....................................................................................17 
4.4.1.2 
Sight-Threatening Adverse Event ...............................................................................18 
4.4.1.3 
Case of Special Interest ..............................................................................................18 
4.4.1.4 
Adverse Event Leading to Discontinuation ................................................................19 
4.4.1.5 
Ocular Adverse Events ...............................................................................................19 
4.4.1.6 
Systemic Adverse Events ...........................................................................................19 
4.4.2 
Other Safety Evaluation Parameters ...........................................................................19 
4.4.2.1 
Slit Lamp Examination ...............................................................................................19 
4.4.2.2 
Uncorrected Distance Visual Acuity (UDVA) ...........................................................19 
4.4.2.3 
Best-Corrected Distance Visual Acuity (BCDVA) ....................................................19 
4.4.2.4 
Dilated Fundus Examination ......................................................................................20 
4.4.2.5 
Intraocular Pressure (IOP) ..........................................................................................20 
4.5 
Other Definitions ........................................................................................................20 
4.5.1 
Prior and Concomitant Medications ...........................................................................20 
4.5.2 
Concurrent Medical Conditions ..................................................................................20 
4.5.3 
Treatment Compliance ................................................................................................20 
5 
STUDY POPULATION .............................................................................................22 
5.1 
Full Analysis Set .........................................................................................................22 
5.2 
Safety Population ........................................................................................................22 
5.3 
Per-Protocol Population ..............................................................................................22 


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6 
GENERAL CONSIDERATIONS ..............................................................................23 
6.1 
Adjustments for Covariates ........................................................................................23 
6.2 
Handling of Missing Data ...........................................................................................23 
6.2.1 
Efficacy Endpoints ......................................................................................................23 
6.2.2 
Safety Endpoints .........................................................................................................23 
6.2.3 
Dates for Medical Events and Medications ................................................................23 
6.3 
Multi-Center Studies ...................................................................................................24 
6.4 
Multiple Comparisons / Multiplicity ..........................................................................24 
6.5 
Interim Analysis ..........................................................................................................24 
7 
SUMMARY OF STUDY POPULATION DATA .....................................................25 
7.1 
Subject Disposition .....................................................................................................25 
7.2 
Demographics and Baseline Characteristics ...............................................................25 
7.3 
Medical and Surgical History .....................................................................................25 
7.4 
Protocol Deviations ....................................................................................................25 
7.5 
Prior and Concomitant Medications ...........................................................................26 
7.6 
Treatment Compliance ................................................................................................26 
7.7 
Treatment Exposure ....................................................................................................26 
7.8 
Pregnancy During the Course of the Study ................................................................27 
8 
EFFICACY ANALYSES ...........................................................................................28 
8.1 
Analyses of Primary Efficacy Endpoints ....................................................................28 
8.1.1 
Primary Analyses of the Primary Endpoints ..............................................................28 
8.1.2 
Sensitivity Analyses of the Primary Endpoints ..........................................................28 
8.2 
Analyses of Secondary Efficacy Endpoints ................................................................29 
8.2.1 
Analyses of Continuous Secondary Efficacy Endpoints ............................................29 
8.2.2 
Analyses of Categorical Secondary Efficacy Endpoints ............................................29 
8.2.3 
Correlation Analyses ..................................................................................................29 
8.2.3.1 
Correlation Analyses for Data Collected from the Same Visits .................................29 
8.2.3.2 
Correlation Analyses for Lagged Data .......................................................................31 
8.2.4 
Graphical Analyses .....................................................................................................32 
9 
SAFETY ANALYSES ...............................................................................................33 
9.1 
Pre-treatment Events (PTEs) and Adverse Events (AEs) ...........................................33 
9.2 
Slit-lamp Biomicroscopy ............................................................................................34 


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9.3 
Uncorrected Distance Visual Acuity (UDVA) ...........................................................34 
9.4 
Best Corrected Distance Visual Acuity (BCDVA) ....................................................34 
9.5 
Dilated Fundus Examination ......................................................................................34 
9.6 
Intraocular Pressure ....................................................................................................34 
10 
CHANGES FROM THE PROTOCOL ......................................................................35 
10.1 
FVA Parameters to be Analyzed ................................................................................35 
10.2 
Scale Conversion of the FVA Parameters ..................................................................35 
10.3 
Sensitivity Analysis of the Primary Efficacy Endpoints ............................................35 
10.4 
Correlation Analysis for Data Collected from the Same Visit ...................................35 
10.5 
Correlation Analysis of the Lagged Data – Change from Baseline in CFS vs. 
Change from Baseline in VAS Symptom Scores .......................................................36 
11 
REFERENCES ...........................................................................................................37 
12 
APPENDICES ............................................................................................................38 
12.1 
Appendix A. Slit Lamp Grading .................................................................................38 
12.2 
Appendix B. Sample SAS Codes for Inferential Analyses .........................................40 
 
 
LIST OF TABLES 
Table 1 
Schedule of Study Procedures…………….………………………………………. 10 
LIST OF FIGURES  
Figure 1 
 Study Flow Chart…………………………………………………………………… 8 
 


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ABBREVIATIONS 
AE 
Adverse Event 
AR(1) 
Autoregressive (covariance structure) 
ARH(1) 
Heterogeneous Autoregressive (covariance structure) 
AT 
Artificial tears 
ATC 
Anatomical-Therapeutic-Chemical  
BCDVA 
Best-Corrected Distance Visual Acuity 
CFR 
Code of Federal Regulations 
CFS 
Corneal Fluorescein Staining 
CRO 
Contract Research Organization 
CS 
Compound Symmetry (covariance structure) 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
DED 
Dry Eye Disease 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FVA 
Functional Visual Acuity 
HOA 
Higher-Order Aberrations 
IOP 
Intraocular Pressure 
LOCF 
Last-Observation-Carried-Forward 
LogMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg/mL 
Milligram per milliliter 
mmHg 
Millimeter of mercury 
OSI 
Objective Scatter Index 
PP 
Per-Protocol 
 
RMS 
Root Mean Square 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 


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SAS 
Statistical Analysis System 
SOC 
System Organ Classification 
TBUT 
Tear Break Up Time 
TEAE 
Treatment-Emergent Adverse Event 
TOEP 
Toeplitz (covariance structure) 
TOEPH 
Heterogeneous Toeplitz (covariance structure) 
UDVA 
Uncorrected Distance Visual Acuity 
UN 
Unstructured (covariance structure) 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
VC 
Variance Components (covariance structure) 
VMR 
Visual Maintenance Ratio 
WHO-DDE 
World Health Organization Drug Dictionary Enhanced 
 


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1 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods to be implemented for the 
analysis of data collected from the FAST study within the scope of Santen’s Protocol 
NVE16E128, “A Phase IV, Prospective, Open-Label, Multicentre, Single Arm, 3-Month Proof 
Of Concept Study To Assess The Effect Of IKERVIS® 1 mg/mL (Ciclosporin) Eye Drops 
Administered Once Daily On The Quality Of Vision In Dry Eye Disease (DED) Patients With 
Severe Keratitis”.  It applies to the Amendment 1 of the study protocol, dated 07 April 2017 
(version 3.0) and provides detailed instructions as to how each analysis will be performed.   
Results obtained from the analyses specified in the final approved version of the SAP will 
become the basis of the clinical study report (CSR) for this protocol.  Any deviations from the 
final approved version of the SAP must be substantiated by sound statistical reasoning and 
documented in the CSR. 


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2 OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
2.1.1 
Primary Objective 
The primary objective of the study is to assess the effect on the quality of vision of IKERVIS® 
(1 mg/mL ciclosporin) eye drops administered once daily in adult dry eye disease (DED) patients 
with severe keratitis following 3 months of treatment, assessed by Functional Visual Acuity 
(FVA) and Objective Scatter Index (OSI), and to estimate the correlation of the change of Visual 
Maintenance Ratio (VMR) measured with FVA system and variance of OSI, separately, with the 
expected Corneal fluorescein staining (CFS) improvement. 
2.1.2 
Secondary Objectives 
The secondary objectives are: 
• To assess the signs and symptoms of keratitis and DED, and their changes over time,  
• To estimate the correlation between CFS changes over time and FVA changes over time,  
• To estimate the correlation between CFS changes over time and OSI changes over time, 
• To estimate the correlation between variance of OSI changes over time and FVA 
parameters over time. 
•  To estimate the correlation between OSI changes over time and FVA parameters 
changes over time 
• To compare the time course of the CFS improvement vs the time course of FVA and OSI 
improvement (if any), respectively. 
• To evaluate the ocular tolerability and overall ocular safety of IKERVIS® administered 
once daily in DED patients with severe keratitis at Month 3. 
2.2 
Endpoints 
Efficacy endpoint-related definitions are provided in Section 4.3. 
2.2.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints are: 
• Correlation between the change from baseline in VMR measured with FVA system at 
Month 3 and the change from baseline in the CFS at Month 3. 
• Correlation between the change from baseline in variance of OSI measured with double 
pass aberrometer at Month 3 and the change from baseline in the CFS at Month 3. 


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2.2.2 
Secondary Endpoints 
2.2.2.1  
Efficacy Endpoints 
• CFS score assessed with the Modified Oxford Scale and change from baseline at Months 
1, 2 and 3.  
• FVA parameters (LogMAR FVA, VMR, starting LogMAR VA, minimal LogMAR VA, 
and maximal LogMAR VA) and their change from baseline at Months 1, 2 and 3. 
• OSI and its variance and their change from baseline at Months 1, 2 and 3. 
• Correlation between CFS changes over time and OSI changes over time and other FVA 
parameters changes over time, separately. 
• Correlation between each OSI parameters changes over time and FVA parameters 
changes over time, separately. 
• Root mean square (RMS) of higher order aberrations (total, coma-like, spherical-like) 
measured with Hartmann-Schack aberrometer and their change from baseline at Month 3. 
• Tear Break Up Time (TBUT) and change from baseline at Months 1, 2 and 3. 
• Patient Global Evaluation of Efficacy at Month 3. 
• VAS scores (photophobia, blurred vision) and their change from baseline at Months 1, 2 
and 3. 
• Investigator Global Evaluation of Efficacy at Month 3. 
• Artificial Tear use and change from baseline at Months 1, 2 and 3.  
2.2.2.2  
Safety Evaluations 
• Slit lamp examination and change from baseline at Months 1, 2 and 3. 
• Uncorrected Distance Visual Acuity (UDVA) and change from baseline at Months 1, 2 and 
3. 
• Best Corrected Distance Visual Acuity (BCDVA) and change from baseline at Months 1, 
2 and 3. 
• Dilated fundus examination and change from baseline at Month 3. 
• IOP and change from baseline at Month 3. 
• Incidence and severity of ocular and systemic adverse events over the study period. 
 


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3 
STUDY DESIGN 
3.1 
General Study Design 
The proposed 3-month study is a prospective, open-label, multi-center, phase IV, proof-of-
concept study.  The study is designed to assess the effect on the quality of vision of IKERVIS® 
(1 mg/mL ciclosporin) eye drops administered once daily in dry eye disease (DED) patients with 
severe keratitis, as well as its safety and efficacy.  Thirty-three adult patients are planned to be 
enrolled in the study in order to obtain 30 completed patients.  However, due to the much slower 
than expected enrollment and budget constraint, this study enrolled 17 patients.  
Upon the completion of the Screening Visit, all enrolled study participants will undergo a 2-week 
wash-out phase during which prior therapies for DED including artificial tears and prohibited 
ocular treatments must be discontinued.  The purpose of the wash-out phase is to eliminate the 
potential contribution of any prior DED treatment on the efficacy of the study medication.  During 
the wash-out phase patients may use unpreserved artificial tears provided by the Sponsor, up to 
eight instillations per day in each eye, to relieve their dry eye symptoms. No other topical 
treatments for DED other than the provided unpreserved artificial tears are allowed during the 
wash-out phase.  
At the Baseline Visit (Day 1) following the 2-week wash-out phase, patients who meet the 
inclusion criteria for DED and severe keratitis will start the treatment phase with the study 
treatment (IKERVIS® 1mg/mL).  Patients not fulfilling the inclusion criteria or meeting any of 
the exclusion criteria following the wash-out phase will exit the study without receiving any study 
medication.  
Major inclusion criteria for the eligible eye are DED patients with persistent severe keratitis at the 
Screening and Baseline Visits defined as the following: 
• CFS score of 3, 4 or 5 on the modified Oxford scale, AND  
• Visual Maintenance Ratio (VMR) <  0.95, AND 
• OSI  ≥ 2, AND 
• Variance of OSI ≥ 0.5. 
During the Baseline Visit, patients will be instructed to instill one drop of study medication 
(IKERVIS® 1mg/mL) once daily in each eye at bedtime and will be scheduled for three additional 
study visits, Month 1 (Day 28 ±3), Month 2 (Day 56±3), and Month 3 (Day 84±7).  In addition to 
the study medication, patients will also be allowed to use unpreserved artificial tears provided by 
the Sponsor, up to eight instillations per day in each eye, to alleviate their dry eye symptoms. 
Patients must be instructed not to use artificial tears within 30 minutes before or after use of the 
study medication and within two hours before a scheduled study visit. All concomitant medications 
will be recorded on the case report form (eCRF).  A change in the use of the study treatments (or 
any topical eye drops other than the study medication or the Sponsor provided unpreserved 
artificial tears or topical medications allowed during the study) will be considered a protocol 
violation.  In this phase IV clinical trial, the Month 3 Visit assessments will be used to assess the 
efficacy (quality of vision and other parameters) and safety of IKERVIS® in DED patients with 
severe keratitis. 


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The study flowchart is illustrated in Figure 1. 
3.2 
Randomization and Masking 
This is a single-arm, open-label study, no randomization and masking will be applied. 


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Figure 1  Study Flow Chart  
 
 
  


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3.3 
Sample Size Planning 
A total of 33 subjects was planned to be enrolled to obtain 30 completed subjects in this study.  
The sample size for this proof-of-concept study was not calculated based on statistical 
considerations.  Clinical judgment and experience were the basis for determining the number of 
subjects needed to achieve study goals. 
3.4 
Visits and Assessments    
The study period will include the initial Screening Visit, the 2-week wash-out phase, and the 3-
month open-label study treatment phase encompassing the Baseline, Month 1, Month 2 and 
Month 3 study visits.  The schedule for all study-related procedures for all evaluations is shown 
in Table 1.  


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Table 1 
Schedule of Study Procedures 
 
Wash out period 
Open-label study treatment Period 
Unscheduled 
Visit / 
 
Study procedures 
Screening 
Day –14 ± 3 
Baseline 
Day 1 
Month 1 
Day 28 ± 3 
Month 2 
Day 56 ± 3 
Month 3 
Day 84 ± 7 
premature 
study 
discontinuation 
Informed consent 
X 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
Ocular and systemic medical  
history 
X 
X 
 
 
 
 
Previous and Concomitant  
ocular and systemic 
medications (incl. concomitant 
artificial tear usage) 
X 
X 
X 
X 
X 
X4 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Efficacy Assessments 
 
Tear break up time (TBUT) 
X 
X 
X 
X 
X 
X4 
Corneal fluorescein staining 
(Modified Oxford Scale) 
X 
X 
X 
X 
X 
X4 
Schirmer test (without 
anaesthesia) 
 
X 
 
 
X 
X4 
Functional visual acuity (FVA 
parameters, FVA system) 
X 
X 
X 
X 
X 
X4 
Objective scatter index (OSI) 
(double-pass aberrometer) 
X 
X 
X 
X 
X 
X4 
RMS/Higher-order aberrations 
(Hartmann-Schack 
aberrometer) 
X 
 
 
 
X 
X4 
Investigator global evaluation  
 
 
 
 
X 
X4 
Patient global evaluation 
 
 
 
 
X 
X4 


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Wash out period 
Open-label study treatment Period 
Unscheduled 
Visit / 
 
Study procedures 
Screening 
Day –14 ± 3 
Baseline 
Day 1 
Month 1 
Day 28 ± 3 
Month 2 
Day 56 ± 3 
Month 3 
Day 84 ± 7 
premature 
study 
discontinuation 
Visual Analog Scale (VAS) 
(photophobia, blurred vision) 
X1 
X1 
X1 
X1 
X1 
X1,4 
Safety Evaluations 
 
Slit lamp examination  
X 
X 
X 
X 
X 
X4 
Uncorrected distance visual 
acuity (UDVA in LogMAR) 
X 
X 
X 
X 
X 
X4 
Best corrected distance visual 
acuity (BCDVA in LogMAR) 
X 
X 
X 
X 
X 
X4 
Dilated fundus examination 
 
X 
 
 
X 
X4 
Intraocular Pressure (IOP)  
 
X 
 
 
X 
X4 
Urine pregnancy test (women 
of childbearing potential only) 
X 
X3 
 
 
X 
X5 
Confirm patient discontinued 
treatment related to dry eye 
X 
 
 
 
 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X4 
Treatment Procedures 
 
Dispense study medication and 
unpreserved artificial tears 
X2 
X2 
X2 
X2 
 
 
Collection of used study 
medication and unpreserved 
artificial tears  
 
X 
X 
X 
X 
X4 
ET/EOT=early termination/end of treatment. 
1 VASs should be performed at the beginning of the visit before medical history and any study assessment. 
2 Dispense unpreserved artificial tears. Instruction: to be instilled up to eight times per day in each eye 
3 Only for patients fulfilling criteria for severe keratitis that will be included. 
4 Assessments to be performed during unscheduled visits only in case of premature discontinuation 
 


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4 
DEFINITIONS 
4.1 
Time-Related Terms  
4.1.1 
Screening Visit (Day -14 ± 3 days) 
The Screening Visit is the visit when the subject will be screened in accordance with the 
protocol-defined inclusion and exclusion criteria.  It will be performed within 14 days prior to 
the first dose of the study medication administration. 
4.1.2 
Baseline Visit (Day 1) 
The Baseline Visit is the Day 1 visit when the subject will receive the first dose of the study 
medication.   
4.1.3 
Analysis Period and Treatment Start and End Dates 
There will be only one analysis period for this study: 
Analysis Period 
Analysis Period Start Date 
Analysis Period End Date 
Open-label treatment period 
The date of the first dose of 
the study medication 
administration  
The Study Exit date 
4.1.4 
Study Day  
The study day describes the relative day of an observation starting with the reference date.  For 
this study, the treatment start date is the reference date and the study day will be calculated as: 
• For days prior to the treatment start date, Study Day = Date – Treatment Start Date  
• For days on/after the treatment start date, Study Day = Date – Treatment Start Date + 1 
Note that there is no Study Day 0.   
4.1.5 
Out-of-Window Measurements, Analysis Visit, and Analysis Window 
For this study, a measurement collected at a visit is an out-of-window measurement if the study 
day of the visit falls outside of a visit window specified in Assessment Schedule (Table 1; 
otherwise, it will be treated as a within-window measurement.   
Analysis visit is a timing variable to be used for analyses involving visits.  For each analysis visit, 
an analysis window is set up to determine the analysis visit to which a measurement should be 
mapped.  The analysis window, which is wider than the visit window, will be employed to 
minimize the amount of missing data for analysis purposes.   


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Post-baseline Visit 
(Target Assessment Date) 
Visit Window 
Analysis Window 
Month 1 (Day 28) 
[25, 31] 
[21, 48] 
Month 2 (Day 56) 
[53, 59] 
[49, 76] 
Month 3 (Day 84) 
[77, 91] 
[77, 104] 
The analysis visit of a measurement will be determined based on the study day of the 
measurement and specified analysis windows, and it is not necessarily the same as the study visit 
at which the measurement was collected.  For example, an out-of-window measurement 
collected at the Month 2 study visit will be mapped to the Month 3 analysis visit, if the study day 
of the measurement falls into the analysis window of Month 3.  
For analyses involving post-baseline visits, if there are two or more measurements that fall into 
the same analysis window of a post-baseline visit, then the measurement closest to the target 
assessment day will be selected for that visit.  In the case that two measurements are closest and 
equidistant to the target assessment day, i.e., one is before and one is after the target assessment 
day, the later one will be selected for that visit.   
4.1.6 
Extent of Exposure 
The extent of exposure to study medication will be assessed by duration of treatment exposure, 
which will be derived using the following formula: 
Duration of treatment exposure = (Treatment end date – Treatment start date) + 1 
4.1.7 
Duration of Quitting Smoke 
For ex-smokers, the duration of quitting smoke will be derived using the following formula: 
Duration of quitting smoke = (Date of Screening Visit – Smoking stop date) + 1  
4.2 
Endpoint-Related Definitions 
4.2.1 
Analysis Eye and Fellow Eye 
The analysis eye of an enrolled subject is defined as the eligible eye, the eye that fulfills all the 
criteria listed under the inclusion criteria #4.  If both eyes are eligible, the eye with the highest 
baseline CFS score will be chosen.  If both eyes have the same CFS score, the eye with the 
lowest baseline VMR will be chosen.  If VMR values are the same for both eyes, the right eye 
will be chosen.  The fellow eye is the non-analysis eye.   
4.2.2 
Baseline Score 
For any measure, the baseline score is the last observed measurement prior to the first dose of 
the study medication.  If any variable is missing a value on Day 1, values from the Screening 


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Visit will be used to impute the baseline score, i.e., the last observation carried forward (LOCF) 
approach will be used. 
4.2.3 
Change from Baseline 
The change from baseline in a measure at a post-baseline visit will be derived as: 
Change = (Score at the Post-Baseline Visit) – (Baseline Score) 
 
4.3 
Efficacy-Related Definitions 
4.3.1 
Functional Visual Acuity (FVA) Parameters 
Functional Visual Acuity (FVA) parameters will be obtained from the FVA measurement system 
at each scheduled visit and at the premature study discontinuation visit. FVA parameters assess 
dynamic visual acuity over a period of 60 seconds. Measurements will be made under natural 
blinking conditions without topical anesthesia.  
FVA parameters include: 
• FVA: FVA is the mean value of time-wise change of visual acuity measured using the 
FVA measurement system during the overall examination period (60 seconds). It is 
measured under the natural blinking state without topical anaesthesia and expressed in 
decimal notation.  
• LogMAR FVA: LogMAR FVA is FVA converted to LogMAR notation. LogMAR FVA 
will be the variable used for all the analyses (instead of FVA). A decrease from baseline in 
LogMAR FVA indicates improvement. 
• Visual Maintenance Ratio (VMR): VMR is an objective index for evaluating changes of 
dynamic vision from baseline visual acuity. It is defined as the ratio of LogMAR FVA over 
the 60 seconds divided by the value of Starting LogMAR VA. An increase from baseline 
in VMR indicates improvement. 
• Starting VA and Starting LogMAR VA: Starting VA is the baseline visual acuity for a 
60-second examination period; it is the value of the best corrected visual acuity measured 
by the FVA measurement system at the beginning of the 60-second examination period. 
Starting LogMAR VA is Starting VA converted to LogMAR notation.  
• Minimal VA and Minimal LogMAR VA: Minimal VA is the lowest visual acuity 
recorded during the 60-second examination period. Minimal LogMAR VA is Minimal VA 
converted to LogMAR notation.  
• Maximal VA and Maximal LogMAR VA: Maximal VA is the highest visual acuity 
recorded during the 60-second examination period. Maximal LogMAR VA is Maximal 
VA converted to LogMAR notation.  


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4.3.2 
Objective Scatter Index (OSI) 
OSI and its variance will be measured using a double-pass aberrometer at each scheduled visit 
and at the premature study discontinuation visit.  OSI is an objective way to assess the intensity 
of the subjective visual disturbances.   
A decrease from baseline in OSI or its variance indicates improvement.  
4.3.3 
Corneal Fluorescein Staining (CFS) including Complete Corneal Clearing 
CFS will be used to assess corneal damage and will be measured at each scheduled visit and at the 
premature study discontinuation visit.  It will be graded using the modified Oxford scale, which is 
a 7-point ordinal scale in which a score of 0 represents no staining dot, and scores of 0.5, 1, 2, 3, 
4, or 5 represent increased numbers of staining dots, corresponding to increased severity of corneal 
damage.  A CFS grade of 0 represents complete corneal clearing.  
A decrease from baseline in CFS indicates improvement. 
4.3.4 
Higher-Order Aberrations (HOA) 
At the Screening Visit and Month 3/premature study discontinuation visit, serial measurements of 
ocular higher-order aberrations (HOA) are performed by means of the Hartmann-Shack wavefront 
aberrometer.  HOA will be measured during a blink-free period of 20 seconds without instillation 
of topical anaesthesia.  Because HOA data will not be collected at the Baseline Visit (Day 1), data 
collected from the Screening Visit will be used as the baseline measures in change from baseline 
analyses. 
The following HOA parameters will be collected: 
• Root mean square (RMS): RMS is calculated from the Zernike coefficients to represent 
the wavefront aberrations.  A decrease from baseline in RMS indicates improvement. 
• Coma-like aberrations (S3): S3 is the RMS of the third-order Zernike coefficients. 
• Spherical-like aberrations (S4): S4 is the RMS of the fourth-order Zernike coefficients. 
• Total higher-order aberrations (S3 + S4): S3 + S4 is the sum of the third-order and 
fourth-order Zernike coefficients. 
4.3.5 
Symptoms Measured on Visual Analogue Scales (VAS) 
Patient’s photophobia and blurred vision will be assessed on each eye, separately, at each 
scheduled visit and at the premature study discontinuation visit using a visual analogue scale 
(VAS). The VAS ranges from 0% to 100%; 0% corresponds to “no discomfort” and 100% 
corresponds to “maximal discomfort”.   
A decrease from baseline in the VAS indicates improvement. 


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4.3.6 
Tear Break-Up Time (TBUT) 
Tear break-up time (TBUT) will be measured by determining the time to tear break-up at each 
scheduled visit and at the premature study discontinuation visit.  At each visit, the TBUT will be 
measured twice.  If the 2 readings differ by more than 2 seconds, a third reading will be taken.  
This measurement will be performed with 10 seconds maximum. The TBUT value will be the 
average of the 2 or 3 measurements. A measured value of less than 10 seconds will be recorded; 
a measured value of 10 seconds or greater will be recorded as 10 seconds.  
An increase from baseline in TBUT indicates improvement. 
4.3.7 
Schirmer Test (without Anaesthesia) 
At the Baseline Visit (Day 1) and Month 3/premature study discontinuation visit, Schirmer test 
will be performed without anaesthesia to record the length of the tear absorption on the strip in 
5 minutes. It will be recorded as mm wetting/5 min.  
An increase from baseline in Schirmer test indicates improvement. 
4.3.8 
Patient Global Evaluation of Efficacy 
At the Month 3/premature study discontinuation visit, patients will provide an overall assessment 
of the effect of the study medication using the following rating scale: 
(3) = Very satisfactory 
(2) = Satisfactory 
(1) = Not very satisfactory 
(0) = Unsatisfactory. 
4.3.9 
Investigator Global Evaluation of Efficacy 
At the Month 3/premature study discontinuation visit, the study investigator will provide an 
overall assessment of the effect of the study medication on the improvement of that patient’s 
DED using the following rating scale: 
(3) = Very satisfactory 
(2) = Satisfactory 
(1) = Not very satisfactory 
(0) = Unsatisfactory. 
4.3.10 
Use of Concomitant Artificial Tears 
The use of artificial tears (AT) will be monitored over the course of the study for each patient. At 
each scheduled visit and at the premature study discontinuation visit, patients will be asked about 
the average number of times per day artificial tears were used the week preceding the visits, and 


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the number of days they were not used during the week preceding the visits. Patients will be 
allowed to instill 1 unpreserved artificial tear drop, up to eight instillations per day in each eye, 
to ameliorate their dry eye symptoms.  Artificial tear usage in the past 7 days will be derived 
using the following equation: 
AT usage = Average number of times per day used AT × (7 – number of days without AT use) 
A decrease from baseline in the AT usage indicates improvement. 
4.4 
Safety-Related Definitions 
4.4.1 
Adverse Event (AE) 
Events reported on the AE electronic case report form (eCRF) will be assessed according to the 
amended FDA regulations 21 CFR Parts 312 and 320.   
Under Protocol NVG16E128, an AE is defined as any untoward medical occurrence in a clinical 
investigation patient administered an investigational product; it does not necessarily have to have 
a causal relationship with the treatment.  An AE will be considered as a pre-treatment event 
(PTE) if the AE occurred after the patient has signed informed consent to participate in the study 
but prior to administration of any study medication; it does not necessarily have to have a causal 
relationship with study participation. An AE will be considered as treatment-emergent if the AE 
occurred on or after the treatment start date up to the last study visit or worsened relative to pre-
treatment state.   
The severity of each AE will be graded by the Clinical Investigator as Mild (aware or unaware of 
event, but easily tolerated), Moderate (discomfort enough to cause interference with usual 
activity), or Severe (incapacitating; unable to work or perform usual activity).  AEs will also be 
rated by the Investigator as to their causality/relationship to the study medication, to the Sponsor 
provided artificial tears, as well as to the study procedures (related vs. not related). 
Each AE will be classified into a system organ classification (SOC) and coded to a preferred 
term (PT) using Medical Dictionary for Regulatory Activities (MedDRA, version v19.1 English, 
March 2016).  
4.4.1.1 
Serious Adverse Event (SAE)    
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
The term “life threatening” refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 


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5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
• May expose the patient to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
7. Sight-threatening events. 
PTEs that fulfill 1 or more of the serious criteria above will also be considered as SAEs and 
should be reported and followed up in the same manner. 
4.4.1.2 
Sight-Threatening Adverse Event    
The sight-threatening AE is defined as any serious ocular AE that places the subject at immediate 
risk of permanent vision loss in either the analysis eye or the fellow eye.  In this study, the 
following serious ocular AEs will be reported as sight-threatening AEs if it meets one or more of 
the following criteria: 
• It caused a decrease in visual acuity of > 30 letters (compared with the last assessment 
of visual acuity at the last visit) lasting > 1 hour 
• It caused a decrease in visual acuity to the level of Light Perception or worse lasting > 
1 hour 
• It required surgical intervention (e.g., conventional surgery, vitreous tap or biopsy with 
intravitreal injection of anti-infectives, or laser or retinal cryopexy with gas) to prevent 
permanent loss of sight 
• It is associated with severe intraocular inflammation (i.e., 4+ anterior chamber cell/flare 
or 4+ vitritis) 
4.4.1.3 
Case of Special Interest 
The following cases are considered to be of special interest by the Sponsor: 
• Overdose: 
Administration of a quantity of a medicinal product exceeding the dose defined in the 
study protocol/otherwise specify overdose. 
• Misuse of study product: 
Situations in which the medicinal product is intentionally and inappropriately used not 
in accordance with the study protocol. 
• Medication error: 
Any unintentional error in the prescribing, dispensing, or administration of a medicinal 
product while in the control of the healthcare professional, patient or consumer. 
• Abuse of study product: 


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Persistent or sporadic, intentional excessive use of medicinal products which is 
accompanied by harmful physical or psychological effects.   
4.4.1.4 
Adverse Event Leading to Discontinuation 
An AE will be counted as an AE leading to Discontinuation if the Investigator selected “AEs” in 
the “Primary reason for discontinuation or withdrawal” checklist on the END OF STUDY eCRF 
and checked “Definitive discontinuation” in the “Action taken regarding study drug” checklist on 
the AE eCRF. 
4.4.1.5 
Ocular Adverse Events 
An AE will be counted as an ocular AE if the Clinical Investigator selected “Right Eye” or “Left 
Eye” or “Both Eyes” under the “Location” on the AE eCRF. 
4.4.1.6 
Systemic Adverse Events 
An AE will be counted as a systemic AE if the Clinical Investigator selected “Other” or with a 
missing value under the “Location” on the AE eCRF.  
4.4.2 
Other Safety Evaluation Parameters  
4.4.2.1 
Slit Lamp Examination 
External ocular examination and undilated biomicroscopy will be performed using a slit lamp at 
each scheduled visit. Grading of the Meibomian glands, conjunctival erythema, anterior chamber 
inflammation, lens, and vitreous will be on a 0 to 3 scale; 0 indicates normal and 3 indicates the 
most severe state. Lid erythema, lid oedema, conjunctival oedema, and tear film debris will be 
graded on a 0 to 4 scale; 0 indicates normal and 4 indicates the most severe state. Lashes will be 
graded as normal or abnormal (Appendix A). 
A decrease in slit lamp grading indicates an improvement in the slit lamp finding.   
4.4.2.2 
Uncorrected Distance Visual Acuity (UDVA) 
UDVA will be measured on LogMAR scale at each scheduled visit and at the premature study 
discontinuation visit. 
A decrease in LogMAR UDVA indicates improvement in the uncorrected distance visual acuity.   
4.4.2.3 
Best-Corrected Distance Visual Acuity (BCDVA) 
BCDVA measures the acuteness or clearness of best-corrected distance vision. It will be 
measured on LogMAR scale at each scheduled visit and at the premature study discontinuation 
visit.  


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A decrease in LogMAR BCDVA indicates improvement in the best-corrected distance visual 
acuity.   
4.4.2.4 
Dilated Fundus Examination 
A dilated fundus examination will be performed after the pupil is dilated at the Baseline and 
Month 3/early termination visits in order to evaluate for posterior segment diseases. It will be 
rated as normal or abnormal.  
4.4.2.5 
Intraocular Pressure (IOP) 
IOP will be measured using Goldman applanation tonometry (one measurement) at the Baseline 
and Month 3/early termination visits. 
A decrease in IOP indicates improvement in the intraocular pressure.   
4.5 
Other Definitions  
4.5.1 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, prior medication is defined as any non-study medication taken and ended prior to 
the treatment start date.  Concomitant medication is defined as any non-study medication taken 
concurrently while on the study medication.  
All prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary Enhanced (WHO-DDE), Format C English, March 2016.  Each prior or concomitant 
medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) classification 
system and mapped to a WHO-DDE preferred drug name. 
4.5.2 
Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent.  
4.5.3 
Treatment Compliance 
Compliance to the study medication use is tracked on the Compliance eCRF as the number of 
single dose medication containers dispensed at the beginning of the study period plus the number 
of single dose containers dispensed at any unscheduled visit during that period, and the number 
of used and unused containers returned or not returned at the following visit (including 
unscheduled visits).  For the purpose of treatment compliance calculation, there will be three 
study periods: 
• Baseline Visit (Day 1) to Month 1 Visit 
• Month 1 Visit to Month 2 Visit 
• Month 2 Visit to Month 3 Visit 


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For a given study period, compliance rate is calculated using the following formula, which 
assumes that the unreturned bottles are not used: 
 
               Compliance =
Number of containers used
Number of days of the follow−up interval  x 100 
             =
Number of USED containers returned 
Date of current visit −Date of preceding visit  x 100 
Compliance rate of ≥ 80% will be treated as compliant. 
For subjects who did not return their used and/or unused bottles at the next visit, that patient will 
be treated as 100% compliant if the site could confirm that the patient was compliant during the 
preceding month. 


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5 
STUDY POPULATION  
5.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all enrolled subjects who received at least one dose of the 
study medication.  This will be the population used for efficacy analyses.        
5.2 
Safety Population 
The Safety population will include all enrolled subjects who received at least one dose of the 
study medication and for whom any follow-up information is available.  It will be the analysis 
population for safety analyses.     
5.3 
Per-Protocol Population 
The Per-Protocol (PP) population will be a subset of the FAS subjects.  It includes all FAS 
subjects without any of the following protocol deviations that could affect the primary efficacy 
endpoint.   
• Failing to fulfill certain inclusion/exclusion criterion(a) 
• Has a significant protocol deviation that could alter his/her efficacy outcome to treatment 
• Without the primary efficacy measures of CFS, VMR, and OSI at the Month 3 visit 
• Other significant protocol deviations identified by Santen’s study team 
Santen’s study team will review all protocol deviations and identify subjects to be excluded from 
the PP population before the database lock.  


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6 
GENERAL CONSIDERATIONS 
Statistical analyses will be performed based on this SAP by the Biometry Unit of Euraxi, a 
contract research organization (CRO) based in Joué Les Tours, France.  
Unless specified otherwise, all efficacy analyses will be performed using data from the analysis 
eye of FAS subjects, and all safety variables will be analyzed separately for both the analysis 
eyes and the fellow eyes on the Safety population.   
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 (%).   
All statistical testing will be conducted at a significance level of 0.05 (two-sided) unless 
specified otherwise.  No statistical testing will be conducted for safety measures. 
All data manipulations, descriptive summaries, and statistical testing will be performed using 
SAS Version 9.4 or later. 
6.1 
Adjustments for Covariates 
Details on covariates to be included in the statistical model for each individual statistical analysis 
are provided in Section 8.1.2. 
6.2 
Handling of Missing Data 
6.2.1 
Efficacy Endpoints 
Missing observations on CFS, VMR, and variance of OSI will be imputed by the last-
observation-carried-forward (LOCF) approach. 
6.2.2 
Safety Endpoints 
Descriptive summaries of safety measures will be based on observed data only.  No imputation 
of missing scores will be implemented. 
6.2.3 
Dates for Medical Events and Medications 
Completely or partially missing onset and/or resolution dates for medical events (including AEs, 
medical history, and concomitant medications) will be imputed in a conservative fashion as 
follows:   
Date 
Type of Missing Date 
Handling of Missing Date 
Event onset date  
(e.g., YYYY-MM-
DD) 
Completely missing 
No imputation will be applied. 
Only YYYY is available 
Use the first day of YYYY to impute the 
missing month and date parts of the onset 
date 


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YYYY and MM are 
available but DD is 
missing 
Use the first day of MM to impute the 
missing date part of the onset date 
Event resolution 
date 
(e.g., YYYY-MM-
DD) 
 
Completely missing 
No imputation will be applied.  The event 
will be considered ongoing (i.e., not 
resolved) at the last visit date.  
Only YYYY is available 
Use the last day of YYYY to impute the 
missing month and date parts of the 
resolution date  
YYYY and MM are 
available but DD is 
missing 
Use the last day of MM to impute the 
missing date part of the resolution date 
6.3 
Multi-Center Studies 
This is a multi-center study enrolling subjects from approximately 4 France centers.  Sites will 
not be pooled into any subgroups for any inferential analysis.  Sites will be included as a 
covariate in the mixed-effects model for repeated measures (MMRM) analysis.   
6.4 
Multiple Comparisons / Multiplicity 
Since the FAST study is a proof-of-concert study and considered as purely exploratory, no 
multiplicity adjustment will be conducted to control the overall Type I error rate. 
6.5 
Interim Analysis 
No formal interim analysis is planned for this study.  
 


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7 
SUMMARY OF STUDY POPULATION DATA 
7.1 
Subject Disposition 
The subject disposition for all enrolled subjects will be tabulated by study population and 
completion status at Month 3.  Subjects who discontinued the study before Month 3 will be 
tabulated by the primary discontinuation reason.  In addition, the subject enrollment will be 
summarized by site.       
7.2 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be descriptively summarized for all FAS 
subjects.  Specifically, for subject demographics, the following variables will be summarized:  
• Age at enrollment (continuous and categorical: < 65 years, ≥ 65 years) 
• Gender (male, female) 
• For female patients, contraception and pregnancy avoidance procedure (confirmed 
menopause, effective contraception, none) 
For baseline characteristics, the following variables will be summarized:   
• Alcohol use [≤ 30 g per day (women) or ≤ 40 g per day (men), > 30 g per day (women) 
or > 40 g per day (men)] 
• Illicit or recreational drug use (yes, no) 
• Tobacco use  
o Yes  
➢ Ex-smoker (number of packets per year, duration of smoking, duration of 
quitting smoke) 
➢ Current smoker (number of packets per year, duration of smoking) 
o No  
➢ Passive tobacco use (yes, no) 
7.3 
Medical and Surgical History 
The medical and surgical history (i.e., medical events) will be coded using MedDRA (version 
v19.1 English, March 2016) and summarized for the FAS population.  Each medical event will 
be classified into a system organ class (SOC) and mapped to a preferred term (PT).  Any subject 
with more than one medical and/or surgical term within the same SOC or mapped to the same PT 
will be counted only once for that SOC or PT. 
7.4 
Protocol Deviations 
In this study, protocol deviations are categorized as follows: 
• Safety issues 
-  Study drug storage condition outside of the protocol-defined condition 


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• Consent issues 
- 
Informed consent not signed 
- 
Informed consent data missing or not available 
• Enrollment issues 
- 
Ineligible subject enrolled 
• Protocol implementation issues 
- 
Visit out of window 
- 
Protocol-required exam(s) not done or missing 
- 
Administered rescue medication/therapy 
- 
Used prohibited medications/therapy 
- 
Non-compliance (compliance rate < 80%) 
• Other 
A protocol deviation is considered major if it may affect the subject’s rights, safety, or well-
being and/or the completeness, accuracy, and reliability of the study data.  Santen’s study team 
will review all protocol deviations and determine the list of major protocol deviations prior to 
database lock.  FAS subjects with any major protocol deviation(s) will be tabulated by deviation 
category.  In addition, protocol deviation(s) will also be listed.   
7.5 
Prior and Concomitant Medications 
All prior and concomitant medications will be coded using WHO-DDE (Format C English, 
March 2016) on the FAS subjects and summarized separately.  Each prior or concomitant 
medication will be classified using the ATC classification system and mapped to a WHO-DDE 
preferred drug name.  A subject will be counted at most once for each prior or concomitant 
medication, respectively, even if the subject took the same prior or concomitant medication on 
multiple occasions. 
7.6 
Treatment Compliance 
Treatment compliance will be calculated as described in Section 4.5.3. Compliance rate for FAS 
subjects will be summarized by study period (Day 1 – Month 1, Month 1 – Month 2, and Month 
2 – Month 3).      
7.7 
Treatment Exposure 
Treatment exposure to the study medication is measured by days on treatment as derived in 
Section 4.1.6.  Subjects in the Safety Population will be tabulated by duration category (0-30, 31-
60, 61-90, and > 90 days).   


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7.8 
Pregnancy During the Course of the Study 
Urine pregnancy test will be performed on all women of childbearing potential at the Screening, 
Baseline (Day 1), Month 3 or early termination visits.  For subjects who become pregnant during 
the course of the study, their positive testing results will be provided in a listing. 
 


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8 
EFFICACY ANALYSES 
Unless specified otherwise, all efficacy analyses will be performed on the analysis eye of the 
FAS population.   
For each efficacy measure listed in Section 4.3, correlation coefficients, scores and change-from-
baseline scores will be summarized descriptively by analysis visit. There will be no formal 
hypothesis testing because this is a single-arm, open-label study. 
8.1 
Analyses of Primary Efficacy Endpoints 
The primary efficacy endpoints are: 
• Correlation between the change from baseline in VMR measured with FVA system at 
Month 3 and the change from baseline in the CFS at Month 3. 
• Correlation between the change from baseline in variance of OSI measured with double 
pass aberrometer at Month 3 and the change from baseline in the CFS at Month 3. 
8.1.1 
Primary Analyses of the Primary Endpoints 
Spearman’s coefficient of correlation and its 95% confidence interval will be calculated at Month 
3 between the change from baseline of CFS and, respectively, the change from baseline of VRM 
and the change from baseline of variance of OSI. 
8.1.2 
Sensitivity Analyses of the Primary Endpoints 
The following sensitivity analyses will be performed on the primary efficacy endpoints: 
• Correlation between the change from baseline in VMR or variance of OSI, respectively, 
and the change from baseline in the CFS will be analyzed using a mixed-effects model for 
repeated measures (MMRM) on observed cases collected up to Month 3 (Laird & Ware, 
1982; Lindstrom & Bates, 1988).  No imputation of missing data will be needed.  Change 
from baseline in CFS will be used as the predictor variable, and VMR or variance in OSI 
will be treated as the dependent variable. Baseline CFS will be included as a covariate and 
subjects as a random effect.   
An unstructured (UN) covariance matrix will be used to model the within-subject errors.  
If the UN model fails to converge, then a heterogeneous Toeplitz (TOEPH) covariance 
matrix will be used to model the within-subject errors.  If the TOEPH model fails to 
converge, then the heterogeneous first-order auto-regressive [ARH(1)] model will be used.  
If ARH(1) model also fails to converge, then the Toeplitz (TOEP) model, the first-order 
auto-regression [AR(1)] model, the compound symmetry (CS) model, and the variance 
components (VC) model will be fitted sequentially until the convergence criteria are met. 
• The primary analyses will be repeated with the PP population. 
• The primary analyses will be repeated with the observed data only. 


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• Changes from baseline in VMR and variance of OSI, respectively, will also be summarized 
by categorical change in CFS (-5, -4.5, -4, -3.5, -3, -2.5, -2, -1, 0, +1 and +2-unit change) 
and by analysis visit (Month 1, Month 2, and Month 3). 
8.2 
Analyses of Secondary Efficacy Endpoints 
8.2.1 
Analyses of Continuous Secondary Efficacy Endpoints 
The following continuous variables will be summarized using descriptive statistics such as 
number of observations (n), mean, standard deviation, coefficient of variation, median, 
minimum, and maximum by analysis visit.   
• CFS scores assessed at each visit with the Modified Oxford Scale and change from baseline 
at Months 1, 2 and 3.  
• FVA parameters (VMR, LogMAR FVA, starting visual acuity, and minimal and maximal 
VAs) assessed at each visit and their change from baseline at Months 1, 2 and 3. 
• OSI and its variance assessed at each visit and their change from baseline at Months 1, 2 
and 3. 
• Root mean square (RMS) of higher order aberrations (total, coma-like, spherical like) 
measured with Hartmann-Schack aberrometer at each visit and their change from 
baseline at Month 3. 
• Tear break up time (TBUT) assessed at each visit and change from baseline at Months 1, 
2 and 3. 
• VAS scores (photophobia, blurred vision) assessed at each visit and their change from 
baseline at Months 1, 2 and 3. 
• Artificial tear usage assessed at each visit and change from baseline at Months 1, 2 and 3. 
8.2.2 
Analyses of Categorical Secondary Efficacy Endpoints 
The following categorical variables will be tabulated using frequency (n) and percent (%). 
• CFS scores assessed at each visit will also be summarized categorically. 
• Shift from baseline in CFS scores at Months 1, 2, and 3. 
• Patient global evaluation of efficacy at Month 3/early termination visit. 
• Investigator global evaluation of efficacy at Month 3/early termination visit. 
8.2.3 
Correlation Analyses 
8.2.3.1 
Correlation Analyses for Data Collected from the Same Visits 
Spearman’s coefficients of correlation and its 95% confidence interval will be calculated at each 
follow-up visit between the change from baseline of the following pairs of variables (Month 1 vs. 
Month 1, Month 2 vs. Month 2, and Month 3 or Month 3, respectively): 


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• Change from baseline in CFS vs. the change from baseline of following variables, 
respectively: 
o FVA parameters  
➢ VMR 
➢ LogMAR FVA 
➢ Starting visual acuity (LogMAR scale) 
➢ Minimal visual acuity (LogMAR scale) 
➢ Maximal visual acuity (LogMAR scale) 
o OSI parameters 
➢ OSI  
➢ Variance of OSI  
o VAS symptom scores 
➢ Blurred vision 
➢ Photophobia 
o TBUT 
o Schirmer’s test 
o HOA RMS 
o Visual acuity 
➢ BCDVA (logMAR) 
➢ UDVA (logMAR) 
• Change from baseline in FVA (logMAR) vs. the change from baseline of following 
variables, respectively: 
o OSI parameters 
➢ OSI  
➢ Variance of OSI  
o VAS symptom scores 
➢ Blurred vision 
➢ Photophobia 
o TBUT 
o Schirmer’s test 
o HOA RMS 
o Visual acuity 


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➢ BCDVA (logMAR) 
➢ UDVA (logMAR) 
• Change from baseline in OSI vs. the change from baseline of following FVA parameters, 
respectively: 
o 
VMR 
o 
Starting visual acuity (LogMAR scale) 
o 
Minimal visual acuity (LogMAR scale) 
o 
Maximal visual acuity (LogMAR scale) 
• Change from baseline in variance of OSI vs. the change from baseline of following FVA 
parameters, respectively: 
o 
VMR 
o 
Starting visual acuity (LogMAR scale) 
o 
Minimal visual acuity (LogMAR scale) 
o 
Maximal visual acuity (LogMAR scale) 
8.2.3.2 
Correlation Analyses for Lagged Data 
Spearman’s coefficients of correlation and its 95% confidence interval will be calculated for the 
following pairs of variables: 
1) 
CFS vs. VMR 
• Change from baseline in CFS at Month 1 vs. change from baseline in VMR at Month 2 
• Change from baseline in CFS at Month 1 vs. change from baseline in VMR at Month 3 
• Change from baseline in CFS at Month 2 vs. change from baseline in VMR at Month 3 
 
2) 
CFS vs. LogMAR FVA 
• Change from baseline in CFS at Month 1 vs. change from baseline in LogMAR FVA at 
Month 2 
• Change from baseline in CFS at Month 1 vs. change from baseline in LogMAR FVA at 
Month 3 
• Change from baseline in CFS at Month 2 vs. change from baseline in LogMAR FVA at 
Month 3 
 
3) 
CFS vs. OSI 
• Change from baseline in CFS at Month 1 vs. change from baseline in OSI at Month 2 
• Change from baseline in CFS at Month 1 vs. change from baseline in OSI at Month 3 
• Change from baseline in CFS at Month 2 vs. change from baseline in OSI at Month 3 
 


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4) 
CFS vs. Variance of OSI 
• Change from baseline in CFS at Month 1 vs. change from baseline in variance of OSI at 
Month 2 
• Change from baseline in CFS at Month 1 vs. change from baseline in variance of OSI at 
Month 3 
• Change from baseline in CFS at Month 2 vs. change from baseline in variance of OSI at 
Month 3 
 
5) 
CFS vs. VAS Symptom Score of Photophobia 
• Change from baseline in CFS at Month 1 vs. change from baseline in VAS symptom 
score of photophobia at Month 2 
• Change from baseline in CFS at Month 1 vs. change from baseline in VAS symptom 
score of photophobia at Month 3 
• Change from baseline in CFS at Month 2 vs. change from baseline in VAS symptom 
score of photophobia at Month 3 
 
6) 
CFS vs. VAS Symptom Score of Blurred Vision 
• Change from baseline in CFS at Month 1 vs. change from baseline in VAS symptom 
score of blurred vision at Month 2 
• Change from baseline in CFS at Month 1 vs. change from baseline in VAS symptom 
score of blurred vision at Month 3 
• Change from baseline in CFS at Month 2 vs. change from baseline in VAS symptom 
score of blurred vision at Month 3 
8.2.4 
Graphical Analyses 
Bar chart (with means and error bars at each visit) of the following variables will be generated, 
separately, to explore their pattern of evolution over time (from baseline to Month 3) under the 
IKERVIS® treatment: 
• CFS score 
• FVA parameters (VMR and LogMAR FVA) 
• OSI 
• Variance of OSI 


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9 
SAFETY ANALYSES 
The safety-related measures collected in this study include systemic and ocular AEs, corrected 
and uncorrected distance visual acuity, slit-lamp biomicroscopy, dilated fundus examinations, 
and IOP.  The Safety population will be used for all safety summaries.   
All the safety-related measures will be summarized descriptively.  Except systemic AEs, which 
will be summarized at the subject level, all the other safety-related measures, including ocular 
AEs, will be summarized for the analysis eyes and fellow eyes separately.  
9.1 
Pre-treatment Events (PTEs) and Adverse Events (AEs) 
PTEs and AEs are defined in Section 4.4.1.  PTEs and treatment-emergent AEs (TEAEs) will be 
summarized separately. 
In the overall AE summaries, subjects with any AE(s) will be tabulated by the following types of 
AEs:  
• AEs 
• SAEs 
• Related AEs 
o AEs related to the study medication 
o AEs related to artificial tears 
o AEs related to study procedures 
• AEs leading to premature discontinuation 
• Sight threatening AEs 
• Case of special interest 
• Death 
The above summaries will be repeated for ocular AEs in the analysis eye, ocular AEs in the 
fellow eye, and non-ocular AEs, respectively.   
Besides the overall AE summaries listed above, AEs will be tabulated by SOC and PT.  A 
subject who experienced multiple AEs within a SOC or PT will be counted only once for that 
SOC or PT, respectively.  SAEs, related AEs, and serious related AEs will be tabulated similarly.  
Ocular and systematic AEs will also be summarized separately. 
In addition, AEs will be tabulated by the following categories: 
• SOC, PT, and maximal severity  
• SOC, PT, and relationship (related to study medication, study procedure, or artificial 
tears)  
• SOC, PT, maximal severity, and relationship (related to study medication, study 
procedure, or artificial tears)  


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Ocular AEs will be summarized for the analysis eye and fellow eye separately.  Any ocular AE 
that occurred simultaneously to both eyes will be counted once for both the analysis eye and the 
fellow eye.  Sight-threatening AEs and cases of special interest will be summarized by type of 
events specified in Section 4.4.1.2 and Section 4.4.1.3. 
AEs, AEs leading to discontinuation, SAEs, sight-threatening AEs, case of special interest, and 
death, if any, will be listed separately.    
9.2 
Slit-lamp Biomicroscopy 
For each biomicroscopy parameter rated on a 0-3 scale (0=None, 1=Mild, 2=Moderate, or 
3=Severe) or 0-4 scale (0=None, 1=Mild, 2=Moderate, 3=Severe, and 4=Very severe), rating 
scores and shift from baseline will be summarized by analysis visit for the analysis eye and the 
fellow eye, separately.  In addition, any worsening (increase) of ≥ 2 units from baseline will be 
listed. 
For lashes, which are collected as Normal or Abnormal, rating scores and shift from baseline in 
status will be summarized by analysis visit for the analysis eye and the fellow eye, separately.  
Any worsening in status from Normal at baseline to Abnormal after baseline will be listed.   
9.3 
Uncorrected Distance Visual Acuity (UDVA)  
UDVA will be collected on LogMAR scale and their values and change from baseline will be 
summarized, separately, using descriptive statistics such as number of observations (n), mean, 
standard deviation, median, minimum, and maximum by analysis visit for the analysis eye and 
the fellow eye, separately. 
9.4 
Best Corrected Distance Visual Acuity (BCDVA) 
BCDVA will be collected on LogMAR scale and their values and change from baseline will be 
summarized, separately, using descriptive statistics such as number of observations (n), mean, 
standard deviation, median, minimum, and maximum by analysis visit for the analysis eye and 
the fellow eye, separately.  Subjects with any BCDVA score of 2.0 or greater after baseline or 
BCDVA change from baseline ≥ 0.30 LogMAR will be listed. 
9.5 
Dilated Fundus Examination 
Dilated fundus exam data will be collected as Normal or Abnormal.  Rating scores and shift from 
baseline in status will be summarized by analysis visit for the analysis eye and the fellow eye, 
separately.  Any worsening in status from Normal at baseline to Abnormal after baseline will be 
listed. 
9.6 
Intraocular Pressure 
IOP and change from baseline in IOP will be summarized by analysis visit for the analysis eye 
and the fellow eye, separately.  Subjects with any increase of ≥ 10 mmHg in IOP at any follow-
up visit will be listed. 
 
 


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10 
CHANGES FROM THE PROTOCOL 
10.1 
FVA Parameters to be Analyzed 
The variable “FVA” was removed from the list of FVA parameters to be analyzed in Section 
2.2.2.1 and Section 8.2.1 due to this variable was not in the FVA system outputs and not 
collected on the eCRF. 
10.2 
Scale Conversion of the FVA Parameters 
FVA parameters (LogMAR FVA, starting VA, minimum VA, and maximum VA) were 
supposed to be collected on LogMAR scale on the eCRFs.  However, due to the first time use of 
the FVA system by Santen and sites, and given the FVA system User Manual as well as the 
system outputs were all written in Japanese, there was some confusions regarding which 
numbers to be read off from the FVA system output.  Instead of the LogMAR scores, the 
decimal VA scores were instructed to be recorded on the eCRFs.  Therefore, at the data analysis 
stage, the following formula will be used to convert decimal VAs to LogMAR VAs before any 
data analyses are performed: 
LogMAR VA = - log10(decimal VA) 
10.3 
Sensitivity Analysis of the Primary Efficacy Endpoints 
The protocol stated “Changes from baseline in VMR and variance of OSI will also be 
summarized by categorical change in CFS (-5, -4.5, -4, -3.5, -3, -2.5, -2, -1.5, -1, 0, +1 unit 
change) and by analysis visit (Month 1, Month 2, and Month 3).” (Section 12.3 of the protocol). 
This is now changed to “Changes from baseline in VMR and variance of OSI will also be 
summarized by categorical change in CFS (-5, -4.5, -4, -3.5, -3, -2.5, -2, -1, 0, +1 and +2-unit 
change) and by analysis visit (Month 1, Month 2, and Month 3).” in Section 8.1.2 of this SAP to 
fix some typographical errors in the categories. 
10.4 
Correlation Analysis for Data Collected from the Same Visit 
Correlation analyses were added to Section 8.2.3.1 for correlation between the change from 
baseline in CFS vs. change from baseline in TBUT, Schirmer’s test, HOA RMS, VAS symptom 
scores (photophobia and blurred vision, separately), and visual acuity (BCDVA and UDVA, 
separately).  Also added were correlation between the change from baseline in logMAR FVA vs. 
change from baseline in OSI parameter (OSI and variance of OSI, separately), TBUT, 
Schirmer’s test, HOA RMS, VAS symptom scores (photophobia and blurred vision, separately), 
and visual acuity (BCDVA and UDVA, separately). 


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10.5 
Correlation Analysis of the Lagged Data – Change from Baseline in 
CFS vs. Change from Baseline in VAS Symptom Scores 
Two lagged analyses were added to Section 8.2.3.2 to check the correlation between the change 
from baseline in CFS vs. the lagged change in VAS symptom scores (photophobia and blurred 
vision, separately). 
 
 


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11 
REFERENCES 
1. Laird, Nan M.; Ware, James H. (1982). Random-Effects Models for Longitudinal Data. 
Biometrics, 38 (4): 963–974. 
2. Lindstrom, ML; Bates, DM (1988). Newton-Raphson and EM algorithms for linear 
mixed-effects models for repeated-measures data. JASA, 83 (404): 1014–1021. 


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12 
APPENDICES 
12.1 Appendix A. Slit Lamp Grading 
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 localized 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 (localized 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 localized swelling). 
2 = Moderate (moderate/medium localized 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 (Slit beam= 0.3 mm wide, 1.0 mm long) 
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. 
Vitreous 
0 = No haze (normal lens). 
1 = Mild vitreous haze. 
2 = Moderate vitreous haze. 
3 = Severe vitreous haze. 


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12.2 
Appendix B. Sample SAS Codes for Inferential Analyses 
(1) Spearman Correlation Analysis. 
For the primary efficacy endpoint: 
ods output SpearmanCorr = outdata; 
proc corr data = indata spearman; 
  where visitnum = 3 and analysis_eye = "Y"; 
  var CFSchg; 
  with VMRchg; 
run; 
 
• In the outdata dataset obtained from the above procedure,  
- n = nCFSchg 
- correlation coefficient = CFSchg 
- p-value = pCFSchg. 
For the secondary efficacy endpoint: 
ods output SpearmanCorr = outdata; 
proc corr data = indata spearman; 
  where visitnum > 0 and analysis_eye = "Y"; 
  var CFSchg; 
  with VMRchg; 
  by visitnum; 
run; 
 
• In the outdata dataset obtained from the above procedure,  
- n = nCFSchg 
- correlation coefficient = CFSchg 
- p-value = pCFSchg. 
(2) Sensitivity Analysis for the primary efficacy endpoint – the MMRM model. 
Please only use the observed (i.e., non-imputed) data for this analysis. 
ods output SolutionF = outdata1; 
proc mixed data = indata method = ml; 
  where visitnum > 0 and analysis_eye = "Y"; 
  class visitnum subjid; 
  model VMRchg = CFSchg visitnum Base_CFS / noint solution ddfm=KR; 
  random int / subject = subjid type = UN; 
run; 
 
ods output Tests3 = outdata2; 
proc mixed data = indata method = ml; 
  where visitnum > 0 and analysis_eye = "Y"; 
  class visitnum subjid; 
  model VMRchg = CFSchg visitnum Base_CFS / solution ddfm=KR; 
  random int / subject = subjid type = UN;  
run; 


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• Slope estimate (“Estimate”) and standard error (“StdErr”) will be obtained from the outdata1 
dataset where EFFECT = “CFSchg”. 
• P-value (“ProbF”) will be obtained from the outdata2 dataset where EFFECT = “CFSchg”. 
• Steps for choosing the covariance structure in the RANDOM statements above:  
1) Start with TYPE = UN. If the model converges, then stop here and get the results from this 
model. 
2) If the model does not converge, then try to replace UN with TOEPH, ARH(1), TOEP, 
AR(1), CS, and VC sequentially, and stop when the model converges, or keep going if 
model does not converge until the convergence criteria are met. 
3) Please record which covariance structure is used for which model and put that in the table 
footnote. 
4) Please note that the model covariance structure can be different for different independent 
variable/dependent variable combinations.  But it should be the same for the two 
procedures used above for the same independent variable/dependent variable combination.  
Choose the covariance structure that converges for both procedures.