Clinical trial NCT04144413
Conditions: Dry Eye Disease With Severe Keratitis
Sponsor: Santen SAS
Start date: 2019-05-31; Completion date: 2023-07-14
Enrollment: 350 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The proposed 36-month Post Approval Efficacy Study (PAES) is a prospective, interventional, multicentre study to explore the long-term evolution of signs and symptoms, and occurrence of complications in Dry Eye Disease (DED) patients with severe keratitis receiving Ikervis® (1mg/mL ciclosporin) eye drops administered once daily

Detailed description:

Arms: arm 1: Period 1 for all patients: IKERVIS® (1mg/ml CsA). Instillation of one drop in each affected eye, once daily at bedtime. From Baseline for the first 12 months of treatment. arm 2: Period 2 for markedly improved patients at Month 12 only, and double-masked fashion.

IKERVIS® (1mg/ml CsA). Instillation of one drop in each affected eye, once daily at bedtime. From Month 12 to Month 36. arm 3: Other: Vehicle Comparator. Period 2 for markedly improved patients at Month 12 only, and double-masked fashion.

Vehicle. Instillation of one drop in each affected eye, once daily at bedtime. From Month 12 to Month 36.
Interventions: intervention 1: Open-label Ikervis intervention 2: Masked Ikervis intervention 3: Vehicle Comparator: Masked Vehicle
Intervention descriptions: intervention 1: NOVA22007, IKERVIS® is a sterile, ophthalmic cationic oil-in-water emulsion containing 1mg/ml CsA. intervention 2: NOVA22007, IKERVIS® is a sterile, ophthalmic cationic oil-in-water emulsion containing 1mg/ml CsA. intervention 3: Vehicle of IKERVIS® - sterile, ophthalmic cationic oil-in-water emulsion containing no active substance.

Protocol documents:
Prot_000.pdf: 
 
 
Study Protocol Cover Page 
 
Official Study Title:   
A Phase IIIb, Prospective, Interventional, Multicentre, 3-year Study 
to Explore the Long-term Evolution of Sign and Symptoms, and 
Occurence of Complications in Dry Eye Patients With Severe 
Keratitis Receiving Ikervis® (1mg/mL Ciclosporin) 
 
 
NCT Number:  
 NCT04144413 
 
Date of the document: 
 17 October 2018
 
 
 


 
 
 
 
 
PROTOCOL NVG14L127 
A PHASE IIIb, PROSPECTIVE, INTERVENTIONAL, MULTICENTRE, THREE-YEAR STUDY TO 
EXPLORE THE LONG-TERM EVOLUTION OF SIGN AND SYMPTOMS, AND OCCURRENCE OF 
COMPLICATIONS IN DRY EYE DISEASE PATIENTS WITH SEVERE KERATITIS RECEIVING 
IKERVIS® (1MG/ML CICLOSPORIN) EYE DROPS 
 
Sponsor: 
SANTEN SAS 
Genavenir IV, 1 rue Pierre Fontaine 
F-91058 Evry, France 
Study Number: 
NVG14L127 
IND Number: 
N/A 
EudraCT Number: 
2017-002660-41 
Compound: 
IKERVIS® (1mg/mL Ciclosporin) 
Date: 
Version 3.0  17 October 2018  
Amendment 1  
 
 
 
 
 
 
CONFIDENTIAL PROPERTY OF SANTEN 
This document is a confidential communication of Santen. Acceptance of this document constitutes the agreement 
by the recipient that no information contained herein will be published or disclosed without written authorization 
from Santen except to the extent necessary to obtain informed consent from those persons to whom the drug may be 
administered. Furthermore, the information is only meant for review and compliance by the recipient, his or her 
staff, and applicable institutional review committee and regulatory agencies to enable conduct of the study. 
 
 


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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, the 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 12.2.4.3 of 
this protocol. 
 
Terms outlined in the Clinical Study Site Agreement. 
I confirm my responsibilities noted on Appendix B of this Protocol. 
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D 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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1.
SYNOPSIS 
Name of Sponsor/Company: SANTEN SAS, France 
 
Name of Active Ingredient: Ciclosporin  
Title of Study: A Phase IIIb, prospective, interventional, multicentre, three-year study to 
explore the long-term evolution of sign and symptoms, and occurrence of complications in 
Dry Eye Disease patients with severe keratitis receiving IKERVIS® (1mg/ml ciclosporin) eye 
drops 
Coordinating Investigators: 
Studied period (years):  
Estimated date first patient enrolled:  February 2019 
Estimated date last patient completed: February  2023 
Phase of development:  
IIIb 
Objectives:  
Primary: 
 To evaluate the long-term efficacy of a continuous treatment of IKERVIS® (1mg/mL 
ciclosporin) eye drops in adult dry eye disease (DED) patients with severe keratitis on corneal 
sign and DED symptoms, and to estimate the lag time (if any) to improvement in symptoms (if 
any). 
 To assess the ocular surface complications (defined as corneal ulceration, corneal 
perforation, loss of visual acuity, and ocular infection) over the three-year study period. 
Secondary: 
 To evaluate the efficacy parameters (signs and symptoms), the ocular surface 
complications, and the quality of life over treatment Periods 1 and 2. 
 For 12-month markedly improved patients, to evaluate and compare signs and symptoms 
evolution in IKERVIS® group versus Vehicle group during the randomised period of the study 
(Period 2).  
 To evaluate the safety and tolerability of IKERVIS® (1mg/mL ciclosporin) eye drops 
treatment over the three-year study period. 
Methodology:  
Phase IIIb, prospective, interventional, multicentre study. 
Duration of the study: 
All enrolled patients will enter a period of 12 months of treatment (Period 1) and attend 5 


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visits:  
 Period 1 (12-month open-label IKERVIS® treatment period): Baseline visit (Day 1), 
Month 3, Month 6, Month 9 and Month 12  
 At Month 12 visit, markedly improved patients will continue the study during 24 
additional months until Month 36 (Period 2) and will be randomised to receive 
IKERVIS®  or vehicle (using a ratio of 3:2) in a double-masked fashion; the patients 
will attend 8 visits:  Period 2 (Double-masked randomised period IKERVIS® or vehicle 
treatment for markedly improved partients at Month 12): Month 15, Month 18, Month 
21, Month 24, Month 27, Month 30, and Month 33 visits and Final visit Month 36 
 Markedly improved patients are defined as patients having a corneal fluorescein staining 
(CFS) score improvement from baseline of 2 grades or more on the modified Oxford scale 
[unless if the patient had a CFS score of 5 at baseline, the improvement in CFS has to be 3 
grades or more] in the analysis eye.  
Patients who will not be markedly improved at Month 12 (cf. definition above) will be early 
terminated from the study.   
Number of patients (planned): 350 DED adult patients with severe keratitis having CFS 
grade 3 or above on the modified Oxford scale and with at least half of them having a CFS 
grade 4 or 5. 
It is expected that almost 70% of the included patients (approximately 245 patients) would 
enter the Period 2 (Double-masked randomised period) after Month 12. 
This study will be conducted in about 52 trial sites.  
Diagnosis and main criteria for inclusion:  
Patient eligibility is determined according to the following inclusion criteria: 
1. In the opinion of the investigator, the patient is capable of understanding and 
complying with protocol requirements.  
2. The patient has signed and dated 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. At least 4 weeks of use of tear substitutes prior to the Baseline Visit. 
5. DED patients with severe keratitis defined as the following: 
 CFS score of 3, 4 or 5 on the modified Oxford scale in at least one eye 
at Baseline Visit 
AND 
 Schirmer test without anaesthesia scored < 10 mm/5min in the same eye 
at Baseline Visit,  
AND 


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 At least two moderate to very severe symptoms of dry eye disease with 
a score ≥2 (severity graded on a 0 to 4 grade scale), among the 
following symptoms: burning/stinging, foreign body sensation, eye 
dryness, eye pain and blurred/poor vision at Baseline Visit.  
6. Patient must be willing and able to undergo and return for scheduled study-related 
examinations.  
Any patient who meets any of the following criteria will not qualify for entry into the 
study: 
1. Active herpes keratitis or history of ocular herpes. 
2. History of ocular trauma or ocular infection (viral, bacterial, fungal, protozoal) 
within 90 days before the Baseline Visit. 
3. Any ocular diseases other than DED requiring topical ocular treatment during the 
course of the study. Patients taking preservative-free IOP lowering medications are 
eligible for study enrolment. 
4. Concurrent ocular allergy (including seasonal conjunctivitis) or chronic 
conjunctivitis other than dry eye. 
5. Anticipated use of temporary punctal plugs during the study. Patients with punctal 
plugs placed prior to the Baseline Visit are eligible for enrolment; however, punctal 
plugs must remain in place during the study. 
6. Best corrected distance visual acuity (BCDVA) score ≤ 20/200 Snellen in each eye. 
7. 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 or judged by the investigator to be incompatible with 
the study (e.g., diabetes with glycemia out of range, thyroid malfunction, 
uncontrolled autoimmune disease, current systemic infections, ocular infection…). 
8. Known hypersensitivity to one of the components of the study or procedural 
medications (e.g., fluorescein,  etc...). 
9. History of ophthalmic malignancy. 
10. History of malignancy (other than ophthalmic) in the last 5 years 
11. 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 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. 
12. Use of topical ciclosporin in the past 3 months prior to Baseline visit. 


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13. Any change in systemic immunosuppressant drugs within 30 days before the 
Baseline Visit or anticipated change during the course of the study.  
14. Pregnancy or lactation at the Baseline Visit. 
15. Women of childbearing potential not using a medically acceptable, highly effective 
method of birth control (such as hormonal implants, injectable or oral 
contraceptives together with condoms, some intrauterine devices, sexual abstinence 
or vasectomised partner) from the Baseline Visit throughout the conduct of the 
study treatment periods and up to 2 weeks after the study end. Post-menopausal 
women (two years without menstruation) do not need to use any method of birth 
control. 
16. Participation in a clinical trial with an investigational substance within the past 30 
days prior to Baseline Visit. 
17. Participation in another clinical study at the same time as the present study.   
 
Investigational product, dosage and mode of administration:  
Investigational product: IKERVIS® (1 mg/ml ciclosporin) eye drops single-dose containers. 
Investigational product dose: 1mg/ml ciclosporin (CsA)  
Regimen: Instillation of one drop in each affected eye, once daily at bedtime.  
Duration of treatment:  
The duration of treatment is up to 36 months except for non markedly improved patients at 
Month 12 for whom the duration of treatment is up to 12 months. 
Reference therapy, dosage and mode of administration:  
Reference Product (for markedly improved patients at Month 12 to use in Period 2): Vehicle 
of IKERVIS® - sterile, ophthalmic cationic oil-in-water emulsion containing no active 
substance. 
Regimen: Instillation of one drop in each affected eye, once daily at bedtime. 
Criteria for evaluation: 
Efficacy: 
Efficacy will be assessed by evaluating CFS score, symptoms score (“Symptom Assessment 
iN Dry Eye” [SANDE] questionnaire and 5-point scale), correlation between sign and 
symptoms, conjunctival fluorescein staining score, TBUT, Schimer test, use of artificial tears, 
and quality of life. 
Safety: 
Safety assessments will be composed of ocular surface complications, adverse events, 
Intraocular Pressure (IOP), and Best Corrected Distance Visaul Acuity (BCDVA) 
Endpoints: 
Primary Efficacy and Safety Endpoints: 


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• 
The correlation between mean change from baseline in CFS score and SANDE 
symptoms score at each visit, and cross correlation of sign at visit X versus symptoms 
at visit X+i (i starting from 0), if any. 
• 
Incident rate and time to onset of ocular surface complications (defined as corneal 
ulceration, corneal perforation, loss of visual acuity and ocular infection) 
Secondary Endpoints: 
Efficacy: 
A) In Period 1: 
• 
CFS score and change from baseline at each visit  
• 
Conjunctival fluorescein staining score and change from baseline at each visit 
• 
SANDE symptoms score and change from baseline at each visit  
• 
Symptoms score (5-point scale) and change from baseline at each visit, for each of the 
five symptoms assessed  
• 
Occurrence and time to become markedly improved (defined as CFS score 
improvement of 2 or more on the modified Oxford scale at Month 12)  
• 
TBUT and change from baseline at each visit  
• 
Schirmer test and change from baseline at Month 12 visit 
• 
Use of Artificial Tears over the last week and change from baseline at each visit 
B) In Period 2: 
• 
CFS score and change from Month 12 visit at each visit  
• 
Conjunctival fluorescein staining score and change from Month 12 at each visit  
• 
SANDE symptoms score and change from Month 12 visit at each visit  
• 
Symptoms score (5-point scale) and change from Month 12 visit at each visit, for each 
of the five symptoms assessed  
• 
TBUT and change  from Month 12 visit at each visit  
• 
Schirmer test and change from Month 12 visit at Month 24 and Month 36 visits 
• 
Use of Artificial Tears (over the last week and change from Month 12 visit at each visit 
• 
Occurrence and time to relapse (increase of CFS score of 2 or more on the modified 
Oxford scale) 
C) In entire study: 
• 
CFS score and change from baseline at each visit  
• 
Conjunctival fluorescein staining score and change from baseline at each visit 
• 
SANDE symptoms score and change from baseline at each visit  
• 
Symptoms score (5-point scale) and change from baseline at each visit, for each of the 
five symptoms assessed  
• 
TBUT and change from baseline at each visit  
• 
Schirmer test and change from baseline at each visit 


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• 
Use of Artificial Tears over the last week and change from baseline at each visit 
 
Quality of life: 
In the randomised markedly improved population,  
• 
Dry Eye related Quality of life Score (DEQS) overall score, and change from baseline 
at Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 Visits.  Change 
from Month 12 will also be summarized for scores collected in Period 2. 
Safety and Tolerability: 
In the Safety population, safety and tolerability endpoints are: 
• 
Intraocular pressure (IOP) and change from baseline at Month 12, Month 24 and 
Month 36 visits 
• 
Best Corrected Distance Visual Acuity (BCDVA) and change from baseline at Month 
6, Month 12, Month 24 and Month 36 visits visits.  
• 
Incidence and severity of ocular and systemic adverse events (AEs) over the three-year 
study period. 
Statistical methods: 
Analysis Eye 
All the efficacy analysis will be performed on the analysis eye only that fulfils all the criteria 
listed under the inclusion criteria #5. If both eyes are eligible, the eye with the highest baseline 
CFS score will be chosen. If not discriminant, the eye with the lowest Schirmer test value will 
be chosen.  If not discriminant, the right eye will be chosen as the analysis eye. 
Analysis Populations 
Analysis populations are defined based on study period. 
For Period 1:  
 The Full Analysis Set (FAS) population consists of all enrolled subjects who received 
at least one dose of the study medication and had at least one post-baseline sign or 
symptom assessment of the study eye during Period 1. This will be the population used 
for efficacy analyses.   
 The Per-Protocol Set (PPS) will be a subset of FAS, restricted to the subjects who 
fulfill the protocol in the terms of the eligibility, interventions, and outcome 
assessment.  It will be the analysis population for some sensitivity analyses. 
 The Safety population consists of all patients enrolled in Period 1 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 to be performed with 
subjects as treated. 
 The following analysis subpopulation will be defined according to the treatment 
response to efficacy variables: 


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o Markedly Improved Patients are defined as FAS subjects who achieve CFS 
score improvement from baseline of 2 grades or more (unless if the patient had 
a CFS score of 5 at baseline, the improvement in CFS has to be 3 grades or 
more) at Month 12 visit.  
For Period 2: 
 The FAS population consists of all randomised patients who received at least one dose 
of the study medication and had at least one post-Month 12 sign or symptom 
assessment of the study eye during Period 2. This will be the population used for 
efficacy analyses.   
 The Per-Protocol Set (PPS) will be a subset of FAS, restricted to the subjects who 
fulfill the protocol in the terms of the eligibility, interventions, and outcome 
assessment.  It will be the analysis population for some sensitivity analyses. 
 The Safety population consists of all patients enrolled in Period 2 for whom any 
follow-up information is available. It will be the analysis population for safety analyses 
to be performed with subjects as treated. 
For entire study: 
 The FAS population consists of the Markedly Improved Patients who were randomised 
to IKERVIS in Period 2 and received at least one dose of IKERVIS in Period 2 and 
had at least one post-Month 12 sign or symptom assessment of the study eye during 
Period 2. 
 The Per-Protocol Set (PPS) will be a subset of FAS, restricted to the subjects who 
fulfill the protocol in the terms of the eligibility, interventions, and outcome 
assessment.  It will be the analysis population for some sensitivity analyses. 
 The Safety population consists of the Markedly Improved Patients who were 
randomised to IKERVIS in Period 2 and had at least one post-Month 12 sign or 
symptom assessment of the study eye during Period 2. It will be the analysis 
population for safety analyses to be performed with subjects as treated. 
The Sjögren patients population will be specifically described separately for some analyses.  
 
Analysis of Demographics and Baseline Characteristics 
Descriptive summaries will be performed for demographic (including age, gender, race, 
ethnicity, female patients’ menopausal status) and baseline characteristics variables (including 
Sjögren Disease status, time since diagnosis, past surgery or laser treatment in the analysis 
eye, and smoking status).   
In addition, medical history (ocular and systemic) and prior and concomitant medication use 
will be summarised by treatment response status and for the overall population.  
 
Analysis of Primary Efficacy and Safety Endpoints 


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Spearman correlation coefficient will be obtained between mean change from baseline in CFS 
score at visit X and SANDE symptoms score at each visit X+i for each FAS population  in 
Period 1, Period 2, and entire study. For Period 1, visit X includes Day1, Month 3, Month 6, 
Month 9 and Month 12, and i is from 0 (Day 1) up to 4 (Month 12). For Period 2, X includes 
Month 12, Month 15, Month 18, Month 21, Month 24, Month 27, Month 30, Month 33, and 
Month 36, and i is from 0 (Month 12) up to 8 (Month 36). Correlation coefficient will be 
analized by treatment group. For entire study, visit X includes all the scheduled visits from 
Day 1 to Month 36, and i is from 0 (Day1) up to 12 (Month 36). Missing data will not be 
imputed. 
The incident rate of ocular surface complications (defined as corneal ulceration, corneal 
perforation, loss of visual acuity, and ocular infection) will be estimated with its 95% CI for 
each safety population in Period 1, Period 2, and the entire study . The analysis for safety 
population in Period 2 will be conducted by treatment group.These rates will be compared to 
existing epidemiologic rates in a comparable population. Time to onset and time to resolution 
of the ocular complications will also be summarized.  
Missing data will not be imputed. 
 
Analysis of Secondary Efficacy Endpoints 
For FAS population in Period 1, Period 2 and entire study, mean scores of CFS, conjunctival 
fluorescein staining, symptoms (SANDE and 5-point scale), TBUT, Schirmer test, artificial 
tear use and quality of life overall  DEQS scores, and their change from baseline (Period 1 and 
Period 2) or from Month 12 (Period 2) will be summarized by analysis visit. The analysis for 
FAS population in Period 2 wil be performed by planned treatment groups.  
Occurrence and time to relapse defined as an increase of CFS modified Oxford score of 2 or 
more will be summarized for FAS population in Period 2 by treatment group.  
Survival analysis method will be employed to analyze the time to become Markedly Improved 
Patients for Period 1. 
Summary statistics on the scores of Quality of Life variables and exploratory investigation 
variables will be provided as well as their change from baseline at each visit. 
Missing data will not be imputed.  
 
Analysis of Safety and Tolerability Endpoints 
All safety and tolerability endpoints analyses will be performed with the Safety population. 
Adverse Events 
An adverse event (AE) is treatment emergent if it occurs or worsens after the first dose of 
study treatment.  
AEs will be coded using the MedDRA dictionary. Frequencies and percentages will be given 
as follows:  1) Overall summary; 2) by system organ class and preferred term; 3) by system 
organ class, preferred term and maximal severity, 4) by system organ class, preferred term and 
relationship to study medication and study procedure, respectively, and 5) by system organ 


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class, preferred term, maximal severity, and relationship to study medication and study 
procedure, respectively.  
Separate analyses will be performed AEs and serious adverse events (SAEs), and for ocular 
and systemic AEs and SAEs, respectively. Ocular AEs will be summarized for the analysis eye 
and the fellow eye separately. 
 
Other Safety Assessments 
Other parameters of safety assessments (e.g. slit lamp examination, BCDVA, and IOP) will be 
summarized at each time point of measurement. They will be summarized/ analysed for both 
the analysis eye and the fellow eye separately. 
 
Interim Analysis 
Once all patients will have performed their Month 12 visit or Early Termination  visit, CFS, 
symptoms, quality of life and AEs will be analysed on clean data. 
Mean and mean change from baseline (signs, symptoms and QOLs) will be provided. 
Correlation coefficient between mean change from baseline in CFS score at visit X and 
symptoms score at each visit X+i will be summarised.  
Since the first 12 months of the study will be open-label study, no adjustment of alpha level 
and no Data Monitoring Committee will be needed for this study. 
 


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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................20 
4. 
INTRODUCTION ......................................................................................................22 
4.1. 
Background on IKERVIS® .........................................................................................22 
4.1.1. 
Clinical Experience .....................................................................................................23 
4.2. 
Rationale for the Proposed Study ...............................................................................25 
4.3. 
Benefit Risk Assessment ............................................................................................26 
5. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................27 
5.1. 
Primary Objective .......................................................................................................27 
5.2. 
Secondary Objectives .................................................................................................27 
5.3. 
Endpoints ....................................................................................................................27 
5.3.1. 
Primary Efficacy and Safety Endpoints ......................................................................27 
5.3.2. 
Secondary Endpoints ..................................................................................................27 
5.3.2.1 
Secondary Efficacy Endpoints ....................................................................................27 
5.3.2.2 
Quality of Life Endpoints ...........................................................................................28 
5.3.2.3 
Safety and Tolerability Endpoints ..............................................................................29 
6. 
INVESTIGATIONAL PLAN .....................................................................................30 
6.1. 
Overall Study Design ..................................................................................................30 
6.2. 
Number of Subjects ....................................................................................................30 
6.3. 
Dose Adjustment Criteria ...........................................................................................31 
6.3.1. 
Safety Criteria for Adjustment or Stopping Doses .....................................................31 
6.3.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses ....................................31 
6.4. 
Criteria for Study Termination ...................................................................................31 
6.5. 
Demographic, Baseline Characteristics, and Medical History ...................................31 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................35 
7.1. 
Subject Inclusion Criteria ...........................................................................................35 


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7.2. 
Subject Exclusion Criteria ..........................................................................................35 
7.3. 
Screen Failure .............................................................................................................37 
7.4. 
Subject Discontinuation or Withdrawal Criteria ........................................................37 
7.5. 
Procedures for Discontinuation or Withdrawal of a Patient .......................................38 
7.6. 
Completed Enrollment ................................................................................................38 
8. 
TREATMENT OF SUBJECTS ..................................................................................39 
8.1. 
Description of Study Drug and Vehicle ......................................................................39 
8.2. 
Concomitant Medications/Therapies ..........................................................................39 
8.3. 
Treatment Compliance ................................................................................................40 
8.4. 
Randomisation and Masking ......................................................................................40 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................41 
9.1. 
Study Drug ..................................................................................................................41 
9.2. 
Study Drug Packaging and Labeling ..........................................................................41 
9.3. 
Study Drug Storage .....................................................................................................41 
9.4. 
Study Drug Preparation ..............................................................................................42 
9.5. 
Administration ............................................................................................................42 
9.6. 
Study Drug Accountability and Destruction ...............................................................42 
10. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES .....................................44 
10.1. 
Treatment Phase ..........................................................................................................44 
10.1.1. 
Baseline: Day 1 ...........................................................................................................44 
10.1.2. 
Month 3 (D90) (±7 days), Month 6 (D180) (±7 days), and Month 9 (D270) 
(±7 days) .....................................................................................................................45 
10.1.3. 
Month 12 (D360) (±7 days) ........................................................................................45 
10.1.4. 
Month 15 (D450) (±7 days), Month 21 (D630) (±7days), Month 27 (D810) 
(±7 days), and Month 33 (D990) (±7 days) ................................................................46 
10.1.5. 
Month 18 (D540) (±7 days), Month 24 (D720) (±7 days), and Month 30 
(D900) (±7 days) .........................................................................................................47 
10.1.6. 
Month 36 (D1080) (±7 days)/End of Study/Early Termination .................................47 
10.1.7. 
Unscheduled Visit .......................................................................................................48 
11. 
ASSESSMENT OF EFFICACY ................................................................................50 
11.1. 
Corneal and Conjunctival Fluorescein Staining .........................................................50 
11.2. 
Tear Break-Up Time ...................................................................................................50 


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11.3. 
Schirmer Test (without anesthesia) (mm wetting/5min) ............................................50 
11.4. 
Slit lamp examination .................................................................................................51 
11.5. 
Use of Concomitant Artificial Tears...........................................................................51 
11.6. 
Symptoms Evaluation (SANDE) ................................................................................51 
11.7. 
Symptoms Evaluation Using 0-4 Point Scale .............................................................51 
11.8. 
Quality of Life Questionnaires ...................................................................................52 
11.8.1. 
Dry Eye symptoms-related Quality of Life Score (DEQS) ........................................52 
12. 
ASSESSMENT OF SAFETY .....................................................................................53 
12.1. 
Safety Parameters .......................................................................................................53 
12.1.1. 
Best Corrected Distance Visual Acuity (BCDVA) ....................................................53 
12.1.2. 
Tonometry for measurement of Intraocular Pressure (IOP) (mmHg) ........................53 
12.1.3. 
Adverse Events (AEs) .................................................................................................53 
12.1.4. 
Pregnancy Screen ........................................................................................................53 
12.2. 
Adverse Events and Other Safety Information ...........................................................53 
12.2.1. 
Definitions ..................................................................................................................53 
12.2.1.1. 
Adverse Event (AE) ....................................................................................................53 
12.2.1.2. 
Serious Adverse Event (SAE) ....................................................................................54 
12.2.1.3. 
Case of Special Interest (CSI) .....................................................................................55 
12.2.1.4. 
Pregnancy Reports ......................................................................................................55 
12.2.2. 
Assessment of Adverse Events ...................................................................................56 
12.2.2.1. 
Seriousness .................................................................................................................56 
12.2.2.2. 
Causality to Study Drug or Artificial Tears ................................................................56 
12.2.3. 
Relationship to Study Procedures ...............................................................................57 
12.2.3.1. 
Severity of the Adverse Event ....................................................................................57 
12.2.3.2. 
Expectedness ...............................................................................................................57 
12.2.4. 
Reporting of Safety Information .................................................................................57 
12.2.4.1. 
Reporting of Adverse Events ......................................................................................57 
12.2.4.2. 
Reporting of Case of Special Interest and Pregnancy ................................................58 
12.2.4.3. 
Expedited reporting ....................................................................................................59 
12.2.5. 
Documentation of Safety Information ........................................................................59 
13. 
STATISTICS ..............................................................................................................60 


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13.1. 
General Considerations ...............................................................................................60 
13.1.1. 
Sample Size ................................................................................................................60 
13.1.2. 
Statistical Hypotheses and Level of Significance .......................................................60 
13.1.3. 
Analysis Eye ...............................................................................................................60 
13.2. 
Analysis Populations ..................................................................................................61 
13.3. 
The Sjögren patients population will be specifically described separately for 
some analyses. Analysis of Demographics and Baseline Characteristics ..................62 
13.4. 
Analysis of Primary Endpoints ...................................................................................62 
13.5. 
Analysis of Secondary Endpoints ...............................................................................62 
13.6. 
Analysis of Safety and Tolerability Endpoints ...........................................................63 
13.6.1. 
Adverse Events ...........................................................................................................63 
13.6.2. 
Ocular Surface Complications ....................................................................................63 
13.6.3. 
Other Safety Assessments ...........................................................................................63 
13.7. 
Interim Analysis ..........................................................................................................63 
13.8. 
Handling of Missing Values .......................................................................................64 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................65 
14.1. 
Study Monitoring ........................................................................................................65 
14.2. 
Audits and Inspections ................................................................................................65 
14.3. 
Institutional Review Board (IRB)/ Independent Ethics Committee (IEC) .................66 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................67 
16. 
ETHICS ......................................................................................................................68 
16.1. 
Ethics Review .............................................................................................................68 
16.2. 
Ethical Conduct of the Study ......................................................................................68 
16.3. 
Written Informed Consent ..........................................................................................68 
17. 
DATA HANDLING AND RECORD KEEPING ......................................................69 
17.1. 
Inspection of Records .................................................................................................69 
17.2. 
Retention of Records ..................................................................................................69 
17.3. 
Source Documents ......................................................................................................69 
17.4. 
Data Collection ...........................................................................................................70 
18. 
PUBLICATION POLICY ..........................................................................................71 
19. 
LIST OF REFERENCES ............................................................................................72 


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20. 
APPENDICES ............................................................................................................74 
Appendix A-I  Symptom Assessment iN Dry Eye (SANDE) questionnaire ..............................74 
Appendix A-II Evaluation of 5 symptoms of DED using the 5-point Likert scale .......................75 
Appendix A-III  Slit lamp examination.......................................................................................76 
Appendix A-IV  Modified Oxford Scale.....................................................................................79 
Appendix A-V  Dry Eye related Quality of life Score (DEQS) ..................................................80 
Appendix B  Responsibilities of the Investigator........................................................................82 
Appendix C  Elements of the Patient Informed Consent ............................................................84 
Appendix D  Investigator Consent to Use of Personal Information ...........................................86 
Appendix E Declaration of Helsinki ..............................................................................................87 
 


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LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................20 
Table 3: 
Study Design and Schedule of Assessments ..............................................................32 
 


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LIST OF FIGURES 
Figure 1: 
Study Design and Schedule of Assessments ..............................................................30 
 
  


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
The following abbreviations and specialist terms are used in this study protocol. 
 
Table 2: 
Abbreviations and Specialist Terms  
 
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse Event 
AR 
Adverse Reaction 
AT 
Artificial Tears 
BCDVA 
Best Corrected Distance Visual Acuity 
CA 
Competent Authority 
CHMP 
Committee for Medicinal Products for Human Use 
CKC 
Cetalkonium Chloride 
CFS 
Corneal Fluorescein Staining 
CRO 
Contract Research Organization 
CsA 
Ciclosporin 
CSI 
Case of Special Interest 
DED 
Dry Eye Disease 
DEQS 
Dry Eye-related  Quality-of-Life Score 
DEWS 
Dry Eye Workshop 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EoS 
End of Study 
ET 
Early Termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HLA-DR 
Human Leucocyte Antigen-DR 
ICH 
International Conference on Harmonization 


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Abbreviation or Specialist Term 
Explanation 
IEC 
Independent Ethics Committee 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MCT 
Medium Chain Triglycerides 
MGD 
Meinbomian Gland Disease 
OSDI 
Ocular Surface Disease Index 
PEO  
Polyethylene Oxide 
PI 
Principal Investigator 
The investigator who leads the study conduct at an 
individual study center.  Every study center has a principal 
investigator. 
PVU 
Pharmacovigilance Unit 
QD 
Quaque Die 
QOL 
Quality of Life 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SANDE 
Symptom Assessment iN Dry Eye 
SAP 
Statistical Analysis Plan 
SAR 
Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SmPC 
Summary of Product Characteristics 
TBUT 
Tear Breakup Time 
TEAE 
Treatment Emergent Adverse Event 
VA 
Visual Acuity 
VAS 
Visual Analogue Scale 
 
 
  


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4. 
INTRODUCTION 
Since the 2017 International Dry Eye Workshop (DEWS), the term dry eye disease (DED), also 
known as keratoconjunctivitis sicca, describes “a multifactorial disease of the ocular surface 
characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in 
which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and 
neurosensory abnormalities play etiological roles (DEWS 2017a)”. The prevalence of DED 
ranges from 5% to 50% (DEWS 2017b).  
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 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 possible vision loss (AAO 2013). Even though epidemiological data on DED long 
term evolution is rare, Petroutsos et al., 1992 showed, after a 6-year follow-up, a lower-bound of 
the estimate of the complication rate of 4% in severe patients (Petroutsos 1992).Thus for these 
severe diseases which need long-term treatment, clinical guidelines recommend using anti-
inflammatory agents such as ciclosporin A (CsA) when lubricants are inadequate (DEWS 
2017d).  
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 Commission1 for the once daily treatment of 
                                                 
1 http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002066/human_med_001851.jsp&mid=WC0b01ac058001d124  


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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 with indication covers the 
need for a treatment of severe keratitis in dry eye patients.  
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). 
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. 
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). 
In 
the 
12 
month, 
double-masked, 
vehicle 
controlled, 
pivotal 
clinical 
trial 
(NVG10E117/SANSIKA study - Leonardi 2016), 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 randomised to one drop of IKERVIS® or vehicle daily at bedtime for 6 
months. Patients randomised 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 (adjusted mean change from baseline was -1.764 with 
IKERVIS® vs. -1.418 with vehicle, p=0.037). The proportion of IKERVIS®-treated patients with 
at least a 3-grade improvement in CFS score at Month 6 (from 4 to 1, 0.5 or 0) was 35.6%, 
compared to 14.4% of vehicle-treated patients (p=0.001, post-hoc analysis). The beneficial effect 
on keratitis was maintained in the open phase of the study, from Month 6 and up to Month 12. 
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 


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evaluation of efficacy, tear break-up time, lissamine green staining, quality of life score, and tear 
osmolarity. 
However tear film osmolarity was also analysed post hoc in a subgroup of patients with baseline 
levels >308 mOsms/L, a threshold known to be indicative of DED. A total of 55 patients met this 
criterion, 34 (22.1%) in IKERVIS® group and 21 (23.1%) in the vehicle group. IKERVIS® 
subgroup showed a significantly greater change from baseline at Month 6 than the vehicle 
subgroup (p=0.048), with the mean and median values of worst tear film osmolarity in 
IKERVIS® subgroup lower than 308 mOsms/L, whereas they remained slightly higher than this 
threshold in the vehicle subgroup 
A reduction in the ocular surface inflammation assessed with Human Leukocyte Antigen-DR 
(HLA-DR) expression, was observed at Month 6 in favour of IKERVIS® (p=0.021). 
The most frequently reported treatment-related ocular adverse event was Instillation site pain, 
reported in a higher proportion of patients treated with IKERVIS® (29.2%) than with vehicle 
(8.9%) and was mostly mild (mild: 16.9%, moderate: 8.4%, and severe: 3.9% in the IKERVIS® 
group versus 4.4%, 2.2%, and 2.2%, respectively, in the vehicle group). 
Upon completion of the SANSIKA study (Month 12 visit), patients were invited to enter a 24-
month extension study (NVG12D122/Post-SANSIKA study), assessing the sustained efficacy of 
IKERVIS® after treatment discontinuation. Time to relapse (CFS score ≥4) was assessed 
following treatment discontinuation in patients from the SANSIKA study who had CFS 
improvement from grade 4 to ≤2 after 6 or 12 months of treatment with IKERVIS®. The Full 
Population included 66 patients. Of 62 patients who achieved a CFS ≤2 at the end of the 
SANSIKA study, 38 did not relapse and 24 (39%) relapsed during the 24-month period 
following IKERVIS® discontinuation; the latter (relapse) group comprised 35% of patients 
initially treated with IKERVIS® for 12 months in SANSIKA versus 47% of those treated for 6 
months only. Patients spent the most time during the extension study at CFS scores of 1 or 2 
(median duration 8.5 weeks and 14.7 weeks per year, respectively), indicating marked 
improvement, and less time at CFS scores of 3/4/5 (median time 2.03 weeks/0.0 weeks/0.0 
weeks per year, respectively).  
Of 23 patients eligible for safety analysis (patients who received the study treatment at least 
once), 5 ocular adverse events, reported in 5 patients (21.7%), were considered related to study 
treatment: 3 events of mild instillation site pain in 3 patients (13.0%) and eye discharge and 
foreign body sensation, each reported in 1 patient (4.3%). 
In 
the 
6 
month, 
double-masked, 
vehicle 
controlled, 
supportive 
clinical 
trial 
(NVG06C103/SICCANOVE study - Baudouin 2017), 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 statistically significant difference in CFS improvement was observed 


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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). 
The most common treatment-related adverse event was eye irritation, reported for 39 patients 
treated with IKERVIS® (16.1%) versus 6 patients  (2.4%) with vehicle. 
 
4.2. 
Rationale for the Proposed Study 
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 following over 6 months and 12 months 
(SICCANOVE and SANSIKA, respectively) in adult patients with dry eye disease 
(keratoconjunctivitis sicca). However, these studies did not demonstrate a beneficial effect of 
IKERVIS® compared to Vehicle on symptoms. The CHMP acknowledged the difficulty to reach 
both endpoints (ie. significant effect on both signs and symptoms) as 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 DED patients with severe keratitis, a positive effect of a medication on symptoms may be 
impaired by the high degree of ocular surface damage which may reduce the corneal sensation. 
Additionally, there might be a delay in improvement of symptoms after improvement in signs are 
observed. Post-hoc analyses of SANSIKA support a lag time effect on symptoms: Spearman 
correlation coefficient between the change in CFS and OSDI overtime increased slightly from 
Month 1 to 6, even though it was not conclusive. Furthermore the pharmacologic and clinical 
profile of IKERVIS® suggests that it has the potential to provide consistent and efficacious anti-
inflammatory effects, which may translate into a clinical benefit for the ocular surface. 
In this context, the CHMP has recommended Santen to conduct a PAES (Post-Approval Efficacy 
Study) to further explore long term effects of IKERVIS® on signs, symptoms and ocular surface 
complications. 
In order to establish IKERVIS® long-term efficacy and safety, the NVG14L127 trial proposes a 
2-Period design: a one-year open label period (Period 1) to establish patient’s response status 
according to the improvement on sign (ie. CFS); and Period 2 to assess, over 24 months, 
IKERVIS® long-term response in patients markedly improved after period 1, who will be 
randomised to receive either IKERVIS® or Vehicle, once daily. 
4.3. 
Benefit Risk Assessment  
The patients participating in the study will benefit from IKERVIS®, a product marketed in 
Europe and some Asian countries, for the treatment of severe keratitis in adult patients with dry 


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eye disease, which has not improved despite treatment with tear substitutes. Based on inclusion 
criteria patients will have 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 3 months) 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 profile is considered favourable. 
 


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5. 
TRIAL OBJECTIVES AND ENDPOINTS 
5.1. 
Primary Objective 
The primary objectives of the study are: 
 To evaluate the long-term efficacy of a continuous treatment of IKERVIS® (1mg/mL 
ciclosporin) eye drops in adult dry eye disease (DED) patients with severe keratitis on 
corneal sign and DED symptoms, and to estimate the lag time (if any) to improvement in 
symptoms (if any) . 
 To assess the ocular surface complications (defined as corneal ulceration, corneal 
perforation, loss of visual acuity, and ocular infection) over the three-year study period. 
5.2. 
Secondary Objectives 
The secondary objectives are: 
 To evaluate the efficacy parameters (signs and symptoms), the ocular surface complications, 
and the quality of life over treatment Periods 1 and 2. 
 For 12-month markedly improved patients, to evaluate and compare signs and symptoms 
evolution in IKERVIS® group versus Vehicle group during the randomised period of the 
study (Period 2).  
 To evaluate the safety and tolerability of IKERVIS® (1mg/mL ciclosporin) eye drops 
treatment over the three-year study period. 
5.3. 
Endpoints 
5.3.1. 
Primary Efficacy and Safety Endpoints 
• 
The correlation between mean change from baseline in CFS score and SANDE symptoms 
score at each visit, and cross correlation of sign at visit X versus symptoms at visit X+i (i 
starting from 0), if any. 
• 
Incident rate and time to onset of ocular surface complications (defined as corneal 
ulceration, corneal perforation, loss of visual acuity and ocular infection) 
5.3.2. 
 Secondary Endpoints 
5.3.2.1 
Secondary Efficacy Endpoints 
A) In Period 1: 
• 
CFS score and change from baseline at each visit  
• 
Conjunctival fluorescein staining score and change from baseline at each visit  
• 
SANDE symptoms score and change from baseline at each visit  


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• 
Symptoms score (5-point scale) and change from baseline at each visit, for each of the 
five symptoms assessed  
• 
Occurrence and time to become markedly improved (defined as CFS score improvement 
of 2 grades or more on the modified Oxford scale at Month 12)  
• 
TBUT and change from baseline at each visit  
• 
Schirmer test and change from baseline at Month 12 visit 
• 
Use of Artificial Tears over the last week and change from baseline at each visit 
B) In Period 2: 
• 
CFS score and change from Month 12 visit at each visit  
• 
Conjunctival fluorescein staining score and change from Month 12 at each visit  
• 
SANDE symptoms score and change from Month 12 visit at each visit  
• 
Symptoms score (5-point scale) and change from Month 12 visit at each visit, for each of 
the five symptoms assessed  
• 
TBUT and change from Month 12 visit at each visit  
• 
Schirmer test and change from Month 12 visit at Month 24 and Month 36 visits 
• 
Use of Artificial Tears over the last week and change from Month 12 visit at each visit 
• 
Occurrence and time to relapse (increase of CFS score of 2 or more on the modified 
Oxford scale) 
C) In entire study: 
• 
CFS score and change from baseline at each visit  
• 
Conjunctival fluorescein staining score and change from baseline at each visit 
• 
SANDE symptoms score and change from baseline at each visit  
• 
Symptoms score (5-point scale) and change from baseline at each visit, for each of the 
five symptoms assessed  
• 
TBUT and change from baseline at each visit  
• 
Schirmer test and change from baseline at each visit 
• 
Use of Artificial Tears over the last week and change from baseline at each visit 
 
5.3.2.2 
Quality of Life Endpoints 
In the randomised markedly improved population, Quality of Life endpoints are: 
• 
Dry Eye related Quality of life Score (DEQS) overall score, and change from baseline at 
Month 6, Month 12, Month 18, Month 24, Month 30 and Month 36 Visits. Change from 
Month 12 will also be summarized for scores collected in Period 2. 


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5.3.2.3 
Safety and Tolerability Endpoints 
In the Safety population, safety and tolerability endpoints are: 
• 
Intraocular pressure (IOP) and change from baseline at Month 12, Month 24 and Month 
36 visits 
• 
Best Corrected Distance Visual Acuity (BCDVA) and change from baseline at Month 6, 
Month 12, Month 24 and Month 36 visits  
• 
Incidence and severity of ocular and systemic adverse events (AEs) over the three-year 
study period. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
The proposed 36-month PAES is a prospective, interventional, multicentre study to explore the 
long-term evolution of signs and symptoms, and occurrence of complications in Dry Eye Disease 
(DED) patients with severe keratitis receiving IKERVIS® (1mg/mL ciclosporin) eye drops 
administered once daily (Table 3). In order to assess the response to IKERVIS® for DED patients 
with severe keratitis, after 12-month IKERVIS® (once daily) treatment, patients who have shown 
a marked improvement at Month 12 (as defined below) will be randomised to receive IKERVIS®  
or Vehicle (ration 3:2)  in double-masked fashion (Figure 1): 
 
Figure 1: 
Study Design and Schedule of Assessments  
 
Marked improvement is defined as CFS score improvement from baseline of 2 grades or more on 
the modified Oxford scale [unless if the patient had a CFS score of 5 at baseline, the 
improvement in CFS has to be 3 grades or more] in the analysis eye. 
Non markedly improved patients at Month 12 will be early terminated from the study. 
6.2. 
Number of Subjects 
A total of 350 patients are planned to be enrolled in approximately 52 trial sites. 
It is expected that almost 70% of the included patients (approximately 245 patients) would enter 
the Period 2 (Double-masked randomised period) after Month 12. 


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6.3. 
Dose Adjustment Criteria 
Not applicable. 
6.3.1. 
Safety Criteria for Adjustment or Stopping Doses 
Not applicable. 
6.3.2. 
Pharmacokinetic Criteria for Adjustment or Stopping Doses 
Not applicable. 
6.4. 
Criteria for Study Termination 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• 
New information or other evaluation regarding the safety or efficacy of the study 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. 
The sponsor reserves the right to discontinue the study conduct for any safety, ethical or 
administrative (force majeure) reason at any time.  
If the trial is prematurely terminated or suspended, the sponsor should promptly inform the 
investigators/institutions, and the regulatory authority(ies) of the termination or suspension and 
the reason(s) for the termination or suspension. The IECs should also be informed promptly and 
provided the reason(s) for the termination or suspension by the sponsor or by the 
investigator/institution, as specified by the applicable regulatory requirement(s). 
 
6.5. 
Demographic, Baseline Characteristics, and Medical History 
Demographic information to be obtained will include baseline disease characteristics, date of 
birth or age, sex, alcohol and smoking status of the patient at Baseline.  
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 ophthalmic medication within 1 year 
to signing of informed consent and any other medication stopped at or within 3 months prior to 
signing of informed consent. 


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Table 3: 
Study Design and Schedule of Assessments 
 
Baseline 
Period 1 
Period 2 
End of Study Visit 
 
 
Day 1 
Month a       
3 (D90),       
6 (D180) and 
9 (D270) 
(± 7 days) 
Month ah         
12 (D360) 
(± 7 days) 
Month a        
15 (D450),    
21 (D630),    
27 (810) and 
33 (D990) 
(± 7 days) 
Month a     
18 (D540), 
24 (D720) 
and          
30 (D900) 
(± 7 days) 
Month a 36 (D1080) 
 (± 7 days)/ 
Early Termination 
Unscheduled visit 
Informed consent 
X 
 
 
 
 
 
 
Demographic 
information 
X 
 
 
 
 
 
 
Review of 
Inclusion/Exclusion 
Criteria  
X 
 
 
 
 
 
 
Ocular and systemic 
medical history 
X 
 
 
 
 
 
 
Previous and 
concomitant ocular and 
systemic medications  
X 
X 
X 
X 
X 
X 
X 
Artificial tears use  b 
X 
X 
X 
X 
X 
X 
X 
Symptoms evaluation 
(SANDE) c 
X 
X 
X 
X 
X 
X 
X 
Symptoms evaluation 
(0-4 point scale) c  
X 
X 
X 
X 
X 
X 
X 
Quality of life 
questionnaire  
(DEQS) 
X 
Xd 
X 
 
X 
X 
 
Best corrected distance 
visual acuity (BCDVA) 
X 
Xd 
X 
 
X 
X 
 


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Baseline 
Period 1 
Period 2 
End of Study Visit 
 
 
Day 1 
Month a       
3 (D90),       
6 (D180) and 
9 (D270) 
(± 7 days) 
Month ah         
12 (D360) 
(± 7 days) 
Month a        
15 (D450),    
21 (D630),    
27 (810) and 
33 (D990) 
(± 7 days) 
Month a     
18 (D540), 
24 (D720) 
and          
30 (D900) 
(± 7 days) 
Month a 36 (D1080) 
 (± 7 days)/ 
Early Termination 
Unscheduled visit 
Slit lamp examination 
X 
Xd 
X 
 
X 
X 
 
Tear break up time 
(TBUT) 
X 
X 
X 
X 
X 
X 
X 
Corneal and 
Conjunctival 
Fluorescein staining  
(Modified Oxford 
Scale) 
X 
X 
X 
X 
X 
X 
X 
Schirmer test  
(without anesthesia) 
X 
 
X 
 
Xe 
X 
 
Intraocular Pressure  
(IOP)  
X 
 
X 
 
Xe 
X 
X 
Urine pregnancy test 
(women of childbearing 
potential only) 
X 
X 
X 
X 
X 
X 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X 
Xf 
Registration of patients 
status in IWRS/IVRS 
(e.g. enrolment, 
randomisation, EoS/ET) 
X 
 
X 
 
 
X 
X 
Compliance with study 
medication regimen 
 
X 
X 
X 
X 
X 
X 


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Baseline 
Period 1 
Period 2 
End of Study Visit 
 
 
Day 1 
Month a       
3 (D90),       
6 (D180) and 
9 (D270) 
(± 7 days) 
Month ah         
12 (D360) 
(± 7 days) 
Month a        
15 (D450),    
21 (D630),    
27 (810) and 
33 (D990) 
(± 7 days) 
Month a     
18 (D540), 
24 (D720) 
and          
30 (D900) 
(± 7 days) 
Month a 36 (D1080) 
 (± 7 days)/ 
Early Termination 
Unscheduled visit 
Dispensation of 
unpreserved artificial 
tears 
X 
X 
X 
X 
X 
 
X g 
Dispensation of open-
label study medication 
X 
X 
 
 
 
 
X g 
Dispensation of masked 
study medication  
 
 
Xhi 
Xi 
Xi 
 
X g 
Collection of used study 
medication 
X 
X 
X 
X 
X 
X 
X 
a Months of 30 days. 
b Artificial tears (AT) use assessed by questioning the patient at each study visit. 
c Symptom of dry eye  will be evaluated at each study visit by completing SANDE questionnaire and 5 symptoms using a 0-4 point scale.. 
d QoL and BCDVA will NOT be assessed and slit lamp examination will not be performed at Month 3 and 9.TBUT and corneal and conjunctival fluorescein 
staining which will be performed at each visit.  
e Schirmer test and IOP will NOT be performed at Month 18 and 30 visits. 
f Record AEs if the unscheduled visit is after the first study drug administration. 
g Dispensation of study medication and/or unpreserved artificial tears if necessary.  
hRandomisation of markedly improved patients at Month 12 visit.  
iDispensation of masked study medication (IKERVIS® or Vehicle).  
 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject 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 has signed and dated 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. At least 4 weeks of use of tear substitutes prior to the Baseline Visit 
5. DED patients with severe keratitis defined as the following: 
 CFS score of 3, 4 or 5 on the modified Oxford scale in at least one eye at 
Baseline Visits, 
AND 
 Schirmer test without anaesthesia scored <10 mm/5min in the same eye at 
Baseline Visit,  
AND 
 At least two moderate to very severe symptoms of dry eye disease with a 
score ≥2 (severity graded on a 0 to 4 grade scale), among the following 
symptoms: burning/stinging, foreign body sensation, eye dryness, eye pain 
and blurred/poor vision at Baseline Visit.  
6. Patient must be willing and able to undergo and return for scheduled study-related 
examinations.  
 
7.2. 
Subject Exclusion Criteria 
 
Any patient who meets any of the following criteria will not qualify for entry into the study: 
1. Active herpes keratitis or history of ocular herpes. 
2. History of ocular trauma or ocular infection (viral, bacterial, fungal, protozoal) within 
90 days before the Baseline Visit. 
3. Any ocular diseases other than DED requiring topical ocular treatment during the 
course of the study. Patients taking preservative-free IOP lowering medications are 
eligible for study enrolment. 
4. Concurrent ocular allergy (including seasonal conjunctivitis) or chronic conjunctivitis 
other than dry eye. 


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5. Anticipated use of temporary punctal plugs during the study. Patients with punctal 
plugs placed prior to the Baseline Visit are eligible for enrolment; however, punctal 
plugs must remain in place during the study. 
6. Best corrected distance visual acuity (BCDVA) score  ≤ 20/200 Snellen in each eye. 
7. 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 or judged by the investigator to be incompatible with 
the study (e.g., diabetes with glycemia out of range, thyroid malfunction, uncontrolled 
autoimmune disease, current systemic infections, ocular infection…). 
8. Known hypersensitivity to one of the components of the study or procedural 
medications (e.g., fluorescein, etc.). 
9. History of ophthalmic malignancy 
10. History of malignancy (other than ophthalmic) in the last 5 years. 
11. 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 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. 
12. Use of topical ciclosporin in the past 3 months prior to Baseline visit. 
13. Any change in systemic immunosuppressant drugs within 30 days before the Baseline 
Visit or anticipated change during the course of the study.  
14. Pregnancy or lactation at the Baseline Visit. 
15. Women of childbearing potential not using a medically acceptable, highly effective 
method of birth control (such as hormonal implants, injectable or oral contraceptives 
together with condoms, some intrauterine devices, sexual abstinence or vasectomised 
partner) from the Baseline Visit throughout the conduct of the study treatment periods 
and up to 2 weeks after the study end. Post-menopausal women (two years without 
menstruation) do not need to use any method of birth control. 
16. Participation in a clinical trial with an investigational substance within the past 30 
days prior to Baseline Visit. 
17. Participation in another clinical study at the same time as the present study. 
 
7.3. 
Screen Failure 
Investigators must account for all patients who sign informed consent. If the patient is found to 
be not eligible at Baseline Visit after informed consent signature, the investigator should 
complete the eCRF to record the primary reason of failure. 
Patient numbers assigned to patients who fail eligibility assessments should not be reused.  


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Re-assessment is possible. Patients may undergo a new Baseline visit after the signature of a new 
informed consent form, and new patient number will be assigned. 
 
7.4. 
Subject Discontinuation or Withdrawal Criteria 
The primary reason for discontinuation or withdrawal of the patient from the study should be 
recorded in the electronic case report form (eCRF) using the following categories.  
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. Patients 
discontinued for drug–related AE(s) will be followed-up after patient’s 
discontinuation until the event is resolved, stabilized or a final assessment can 
otherwise be done by the investigator. 
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. In case of a patient lost-to-follow-up, the investigator must 
do his/her best to contact the patient initially by phone, then by letter, and finally by 
certified mail. If no response is obtained from the patient, the investigator is 
encouraged to contact one of the patient’s relatives or his/her general physician. 
These attempts must be documented and associated documentation filed in the patient 
medical chart. 
4. Voluntary withdrawal. The patient (or patient’s legally acceptable representative) 
wishes to withdraw from the study. The reason for withdrawal, if provided, should be 
recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the 
withdrawal and, where possible, the primary underlying reason should be recorded 
(i.e., withdrawal due to an AE should not be recorded in the “voluntary withdrawal” 
category). 
5. Study termination. The Sponsor, 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 12.2.1.5. 
8. Investigator decision due to non-compliance (to IMP, study visits or study related 
procedure). 
9. Other reason, specify. 


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Note: All attempts should be made to determine the reason if Other is chosen (e.g. 
moving…) and specific primary reason should be recorded in the “specify” field of 
the eCRF. 
 
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 withdrawal criteria described in Section 7.4. Efforts should be made 
to perform all procedures scheduled for the End of Study Visit (Month 36/Early Termination). 
Discontinued patients will not be replaced. 
 
7.6. 
Completed Enrollment 
The study enrolment will be considered as completed when the desired number of at least 350 
included patients is reached.  


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug and Vehicle 
 
IKERVIS® is a sterile, ophthalmic cationic oil-in-water emulsion containing 1 mg/ml CsA. 
Vehicle is a sterile, ophthalmic cationic oil-in-water emulsion containing no active substance 
CsA. 
IKERVIS® and vehicle 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 stabilised 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 for injections: as diluents and the main emulsion component. 
Batch number and expiration dates of the investigational drug and vehicle will be provided in the 
certificate of analysis. 
The manufacturer will be Excelvision located in Annonay, France. 
8.2. 
Concomitant Medications/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 other than those provided by the Sponsor.  
- 
Use of any topical ocular treatments other than the study medication and 
preservative-free IOP lowering agents.   
- 
Insertion of temporary punctal plugs during the study. 


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- 
Initiation or change in the dose of any of the following 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 deviation. 
8.3. 
Treatment Compliance 
Patient compliance will be assessed at each visit by investigator by questioning the patient and 
comparison to drug accountablity. All reported incidents of the lack of compliance will be 
recorded on the eCRF with the reasons. If a patient is persistently noncompliant with the study 
medication, the patient should 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. 
8.4. 
Randomisation and Masking  
Period 1 of the study is open-label, single arm treatment with IKERVIS.  No randomization is 
needed in Period 1 (from Baseline for the first 12 months of treatment). 
At the beginning of Period 2, (ie. the Month 12 visit), subjects who achieve a marked 
improvement (ie. CFS score improvement from baseline of 2 grades or more [unless if the 
patient had a CFS score of 5 at baseline, the improvement in CFS has to be 3 grades or more]) 
will be randomly assigned (by the IWRS/IVRS) in a 3:2 ratio to receive either IKERVIS or 
Vehicle for two years in a double-masked fashion. The randomization will be stratified by 
pooled country or region (Europe vs. non-Europe) pending the distribution of eligible subjects 
for Period 2,  and the permuted block randomization will be used within each strata. 
The randomization schedule will be generated and implemented using central randomization via 
Interactive Response Technology (Rave RTSM). Each randomized subject will receive 
numbered study medication kits as assigned by Rave RTSM. 
Treatment assignments during the Double-Masked Treatment Period will be masked to Santen 
employees (except Drug Supply personnel), study subjects, and Investigators. The investigator 
should try to avoid breaking the masking codes. However, IN CASE OF EMERGENCY 
ONLY, (i.e. SERIOUS ADVERSE EVENT (SAE) AND ONLY WHEN THIS 
INFORMATION INFLUENCES THE PATIENT'S MANAGEMENT), the investigator is 
entitled to unmask the patient by using IWRS, in order to obtain the study medication 
information (i.e. IKERVIS® or vehicle) to immediately start the appropriate treatment [to be 
recorded in the source data and eCRF (electronic Case Report Form)]. A record will be made of 
the date, time and reason for breaking the code. The investigator should inform the sponsor 
immediately after unsmasking. The details of this unmasking procedure will be described in a 
separate document. Patients unmasked for the management of a SAE will be discontinued from 
the study. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Study Drug 
Refer to section 8.1. 
9.2. 
Study Drug Packaging and Labeling 
Open-label study treatment of Period 1  
For all the patients during the first 12-month period, IKERVIS® will be provided at each 
quarterly visit.  
IKERVIS® will be supplied in polyethylene single-dose containers presented in sealed laminate 
aluminum pouch package (1 pouch contains 5 single-dose containers). 
 22 aluminum pouches (i.e. 110 single-dose containers) of IKERVIS® will be placed together 
in a sealed cardboard box. 
Each single dose container, aluminum pouch and sealed cardboard will carry an investigational 
label, indicating that the content is intended for investigational use only. Each single-dose 
container is sufficient to treat both eyes. 
In addition, each cardboard box will carry a label bearing the protocol and treatment numbers.  
 
Double-masked study treatment sequence of Period 2 
For the markedly improved patients at Month 12 visit, after randomisation, the investigational 
medical products (IKERVIS® or its Vehicle) will be supplied in double masked polyethylene 
single-dose containers presented in sealed laminate aluminum pouch package (1 pouch contains 
5 single-dose containers). 
 22 aluminum pouches (i.e. 110 single-dose containers) of IKERVIS® or its Vehicle will be 
placed together in a sealed cardboard box. One identical box will be dispensed at each 
quarterly visit.  
Each single dose container, aluminum pouch and sealed cardboard will carry an investigational 
label, indicating that the content is intended for investigational use only. Each single-dose 
container is sufficient to treat both eyes. 
In addition, each cardboard box will carry a label bearing the protocol and treatment numbers. 
9.3. 
Study Drug 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. 


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Any temperature excursion of study drug should be notified to the sponsor and the supplies 
placed in quarantine before further instruction is received from the sponsor. 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 below 30°C  and it must not be 
freezed. 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.  
9.4. 
Study Drug Preparation 
Not applicable. 
9.5. 
Administration 
The investigational product will be instilled once daily into the affected eye(s), at bedtime.  
The study medication and sponsor provided unpreserved artificial tears are to be dispensed only 
by the investigator or his/her designee, and will be used in accordance with this protocol.  
Under no circumstances will the investigator allow the study products to be used other than 
directed by the protocol. All dispensations and returns of study medication have to be 
documented in the investigator’s file provided by the Sponsor. 
In order to ensure patient anonymity, patients will be identified by codes or other means of 
record identification. 
 
9.6. 
Study Drug Accountability and Destruction 
The Principal investigator is responsible for ensuring that an inventory is conducted upon receipt 
of the clinical supplies. The receipt of clinical supplies should be completed, signed and returned 
as directed by Santen (or designee). A copy must be maintained at the site for the Investigator’s 
records. The Principal Investigator will keep a current record of the inventory and dispensing of 
all study drugs. This record will be made available to Santen Monitor (or designee) for the 
purpose of accounting for all clinical supplies. Any discrepancy and/or deficiency must be 
recorded with an explanation. All supplies sent to investigator must be accounted for and in no 
case will study drugs be used in any unauthorised situation.  
It is a responsibility of the Principal Investigator to return any used and unused supplies to the 
Santen monitor (or designee) at the conclusion of the study.  
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 


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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. 
Drug supplies will be counted and reconciled at the site before being returned to Santen or 
designee or being destroyed by the site. 


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10. 
SCHEDULE OF OBSERVATIONS AND PROCEDURES 
The schedule for all study-related procedures and evaluations is shown in Table 3. Assessments 
should be completed at the designated visit/time point(s), and should be performed in both eyes. 
The study period will include the initial Baseline Visit (Day 1), the 12-month open-label study 
treatment phase, and then the two-arm randomised double-blind design up to Month 36 (D1080) 
study visit. 
10.1. 
Treatment Phase 
All assessments should be done in the mentioned order to ensure that additional procedure 
doesn’t interfere with the results of other examinations. 
10.1.1. 
Baseline: Day 1 
 Informed consent 
 Inclusion/exclusion criteria review  
 Demographics 
 Ocular and systemic medical history 
 Previous and concomitant ocular and systemic medications [including artificial tears (AT) 
usage] 
 Symptoms evaluation by completing SANDE questionnaire 
 Symptoms evaluation by completing the 0-4 point scale  
 Quality of life questionnaires (DEQS) 
 BCDVA 
 Slit lamp examination 
 TBUT 
 Corneal and conjunctival fluorescein staining (modified Oxford scale) 
 Schirmer test (without anaesthesia) 
 IOP 
 Urine pregnancy test (women of childbearing potential only) 
 Record adverse events (AEs)  
 Verify inclusion and exclusion criteria based on evaluations just performed: 
o Patients fulfilling the inclusion / exclusion criteria will discontinue all previous 
treatments related to dry eye including artificial tears and any prohibited ocular 
treatments  and receive the study treatment for the next 3 months. The enrolment will be 
registered in IWRS/IVRS Rave RTSM.  
o Patients not fulfilling the inclusion / exclusion criteria will become screen failure  


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 Dispensation of study medication and unpreserved artificial tears for a 3-month period 
 Patients will be scheduled to return to the clinic in 3 months (90 days + 7 days) for the next 
study visit 
10.1.2. 
Month 3 (D90) (±7 days), Month 6 (D180) (±7 days), and Month 9 (D270) (±7 
days) 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) 
usage] 
 Urine pregnancy test (women of childbearing potential only) 
 Record adverse events (AEs) 
 Assessment  of Artificial tears use by questioning the patient 
 Symptoms evaluation by completing SANDE questionnaire 
 Symptoms evaluation by completing the 0-4 point scale  
 Quality of life questionnaires (DEQS) ONLY at Month 6 (D180)  
 BCDVA ONLY at Month 6 (D180) 
 Slit lamp examination ONLY at Month 6 (D180) 
 TBUT 
 Corneal and conjunctival fluorescein staining (modified Oxford scale) 
 Collection of used/not used study medication containers and unpreserved artificial tear 
bottles  
 Assessment of compliance to study medication 
 Dispensation of study medication and unpreserved artificial tears for a 3-month period  
 Patients will be scheduled to return to the clinic in 3 months (90 days + 7 days) for the next 
study visit 
10.1.3. 
 Month 12 (D360) (±7 days) 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) 
usage] 
 Urine pregnancy test (women of childbearing potential only) 
 Record adverse events (AEs) 
 Assessment  of Artificial tears use by questioning the patient 
 Symptoms evaluation by completing SANDE questionnaire 
 Symptoms evaluation by completing the 0-4 point scale  
 Quality of life questionnaires (DEQS) 
 BCDVA  


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 Slit lamp examination  
 TBUT 
 Corneal and conjunctival fluorescein staining (modified Oxford scale) 
 Schirmer test (without anaesthesia) 
 IOP 
 Collection of used/not used study medication containers and unpreserved artificial tear 
bottles 
 Assessment of compliance to study medication 
 Assessment of patient’s improvement status.   Access to IWRS/IVRS system-  Rave RTSM-  
- 
To either randomise the markedly improved patient to receive IKERVIS® or vehicle in a 
double-masked fashion.  
- 
Or to report a withdrawal of not markedly improved patient.  
 Dispensation of study medication and unpreserved artificial tears for a 3-month period  
 Patients will be scheduled to return to the clinic in 3 months (90 days + 7 days) for the next 
study visit 
10.1.4. 
Month 15 (D450) (±7 days), Month 21 (D630) (±7days), Month 27 (D810) (±7 
days), and Month 33 (D990) (±7 days) 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) 
usage] 
 Urine pregnancy test (women of childbearing potential only) 
 Record adverse events (AEs) 
 Assessment of Artificial tears use by questioning the patient 
 Symptoms evaluation by completing SANDE questionnaire 
 Symptoms evaluation by completing the 0-4 point scale  
 TBUT 
 Corneal and conjunctival fluorescein staining (modified Oxford scale) 
 Collection of used/not used study medication containers and unpreserved artificial tear 
bottles 
 Assessment of compliance to study medication 
 Dispensation of study medication and unpreserved artificial tears for a 3-month period  
 Patients will be scheduled to return to the clinic in 3 months (90 days + 7 days) for the next 
study visit 


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10.1.5. 
Month 18 (D540) (±7 days), Month 24 (D720) (±7 days), and Month 30 (D900) 
(±7 days) 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) 
usage] 
 Urine pregnancy test (women of childbearing potential only) 
 Record adverse events (AEs) 
 Assessment of Artificial tears use by questioning the patient 
 Symptoms evaluation by completing SANDE questionnaire 
 Symptoms evaluation by completing the 0-4 point scale  
 Quality of life questionnaires (DEQS) 
 BCDVA  
 Slit lamp examination  
 TBUT 
 Corneal and conjunctival fluorescein staining (modified Oxford scale) 
 Schirmer test (without anaesthesia) ONLY at Month 24 (D720) 
 IOP ONLY at Month 24 (D720) 
 Collection of used/not used study medication containers and unpreserved artificial tear 
bottles 
 Assessment of compliance to study medication  
 Dispensation of study medication and unpreserved artificial tears for a 3-month period  
 Patients will be scheduled to return to the clinic in 3 months (90 days + 7 days) for the next 
study visit 
10.1.6. 
Month 36 (D1080) (±7 days)/End of Study/Early Termination 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) 
usage] 
 Urine pregnancy test (women of childbearing potential only) 
 Record adverse events (AEs) 
 Assessment of Artificial tears use by questioning the patient 
 Symptoms evaluation by completing SANDE questionnaire 
 Symptoms evaluation by completing the 0-4 point scale  
 Quality of life questionnaires (DEQS) 
 BCDVA 


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 Slit lamp examination  
 TBUT 
 Corneal and conjunctival fluorescein staining (modified Oxford scale) 
 Schirmer test (without anaesthesia) 
 IOP 
 Collection of used/not used study medication containers and unpreserved artificial tear 
bottles 
 Assessment of compliance to study medication 
 Registration of End of Study or Early Termination in IWRS/IVRS Rave RTSM 
 
10.1.7. 
Unscheduled Visit 
An Unscheduled visit will be performed if required between two scheduled visits (e.g: patient’s 
request, check of medical event needed, but not for routine care that is not related to the 
protocol) and the reason for such a visit will be recorded in the CRF. In this case, the investigator 
will be asked to perform all the following procedures and examinations at his discretion (which 
must be performed in the chronological order defined below): 
 Record of concomitant ocular and systemic medications [other than artificial tear (AT) 
usage] 
 Record adverse events (AEs) 
 Assessment of Artificial tears use by questioning the patient  
 Symptoms evaluation by completing SANDE questionnaire 
 Symptoms evaluation by completing the 0-4 point scale  
 TBUT 
 Corneal and conjunctival fluorescein staining (modified Oxford scale) 
 IOP 
 Collection of used/not used study medication containers and unpreserved artificial tear 
bottles, if any, or ask for patient’s compliance with study medication regimen 
 If needed, dispensation of study medication and unpreserved artificial tears for a 3-month 
period   
 Patients will will be scheduled to return to the clinic at next planned scheduled visit 
If necessary (e.g. to follow up an AE) the investigator may schedule further visits at his 
discretion. 
In case of patient’s premature study discontinuation:  


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- the investigator will be asked to perform all the examinations and assessments scheduled for 
the End of Study Visit (Month 36/Early Termination)   
-  the investigator will ensure that used and unused study medication for the study period has 
been collected from the patient by the appointed person at the study site 
 
 
 


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11. 
ASSESSMENT OF EFFICACY 
11.1. 
Corneal and Conjunctival Fluorescein Staining  
Corneal and conjunctival fluorescein staining will be assessed immediately following the TBUT.  
Reading will be performed between 1 and 4 minutes after fluorescein instillation for the TBUT, 
to ensure that the dye does not diffuse into stroma blurring the discrete margin of any staining 
defects. 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 (provided by the Sponsor) will be graded using the modified Oxford 
scale (7-point ordinal scale, score 0, 0.5, and 1 to 5 per area [cornea + nasal and temporal 
conjunctiva]) for cornea and conjunctiva separately, see Appendix A-IV. On this modified scale, 
the score 0 corresponds to no staining dots and the score 0.5 corresponds to one staining dot per 
area.  
A CFS grade of 0 represents complete corneal clearing. 
A negative change score from baseline (Period 1) or from Month 12 (Period 2) will indicate 
improvement. 
11.2. 
Tear Break-Up Time 
Tear break-up time (TBUT) will be measured by determining the time to tear break-up. The 
TBUT will be performed after instillation of 2 µl of 2% preservative-free sodium fluorescein 
solution (provided by the sponsor) into the inferior conjunctival cul-de-sac of each eye. To 
thoroughly mix the fluorescein with the tear film, the patient will be instructed to blink several 
times. In order to achieve maximum fluorescence, the examiner should wait approximately 30 
seconds after instillation before evaluating TBUT. With the aid of a slit lamp at 10X 
magnification using cobalt blue illumination, the examiner will monitor the integrity of the tear 
film, noting the time it takes to form lacunae (clear spaces in the tear film) from the time that the 
eye is opened after the last blink. The TBUT will be measured twice during the first minute after 
the instillation of the fluorescein. If the 2 readings differ by more than 2 seconds, then a third 
reading will be taken.  
The TBUT value will be the average of the 2 or 3 measurements.  
A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate 
improvement. 
11.3. 
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 will be removed 
and the length of the tear absorption on the strip will be measured.  


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A positive change from baseline (Period 1) or from Month 12 (Period 2) will indicate 
improvement. 
11.4. 
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-III. 
11.5. 
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 over the last 
week, 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 Baseline Visit 
patients will be allowed to instill 1 unpreserved artificial tear drop, up to six 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. 
11.6. 
Symptoms Evaluation (SANDE) 
The self-administered Symptom Assessment iN Dry Eye (SANDE) questionnaire must be 
completed by the patient him/herself.  
SANDE questionnaire will be used to score both severity and frequency of dry eye symptoms 
(see Appendix A-I). This 2-item frequency- and severity-based visual analogue scales (0-100mm 
VAS ranging respectively from” rarely” to “all the time”, and from “very mild” to “very severe”) 
is short and quick, and provides reliable measure for DED symptoms assessment. Symptoms will 
be evaluated for both eyes together. 
A negative change from baseline (Period 1) or from Month 12 (Period 2) will indicate an 
improvement in dry eye disease symptoms.  
 
11.7. 
Symptoms Evaluation Using 0-4 Point Scale 
 
The 5-point Likert scales are a self-administered questionnaire and must be completed by the 
patient him/herself. 
Burning/stinging, foreign body sensation, eye dryness, photophobia, pain and blurred/poor 
vision, will be assessed by the study patients using a 5-point Likert scale from none to very 
severe (0 to 4). Symptoms will be evaluated for both eyes together. (see Appendix A-II).   


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A decrease in symptom score from baseline (Period 1) or from Month 12 (Period 2) will indicate 
improvement of the symptom. 
 
11.8. 
Quality of Life Questionnaires 
11.8.1. 
Dry Eye symptoms-related Quality of Life Score (DEQS) 
The DEQS consists of 15 items related to dry eye symptoms and influence on daily life, and the 
overall degree of Quality of Life impairment is calculated as a summary score (0 to 100). 
The responses to DEQS are to be obtained from the patient through a self-administered format 
(completed by the patient him/herself). (see Appendix A-V). 
 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
12.1.1. 
Best Corrected Distance Visual Acuity (BCDVA) 
Best corrected distance VA will be measured with the patient’s best correction and recorded 
using a Snellen chart.  
12.1.2. 
Tonometry for measurement of Intraocular Pressure (IOP) (mmHg) 
Investigator should use the same tonometer throughout the course of the study. Both eyes will be 
tested, with the right eye preceding the left eye. IOP will be assessed after completion of all other 
slit lamp examinations and dry eye assessments to avoid oxybuprocaine interference with the 
other examinations (Schirmer test especially) in case a tonometry measurement needs to be 
performed with an anesthetic. 
All tonometers must be calibrated according to manufacturer’s instructions . 
12.1.3. 
Adverse Events (AEs) 
Adverse events, including ocular AEs, including the ocular complications, and systemic AEs will 
be recorded in the eCRFs. Any clinically significant change in concomitant disease or new 
concomitant conditions will be reported as AEs. 
12.1.4. 
Pregnancy Screen 
Women of childbearing potential not using a medically acceptable, highly effective method of 
birth control (such as hormonal implants, injectable or oral contraceptives together with 
condoms, some intrauterine devices, sexual abstinence or vasectomized partner) from the 
Baseline Visit throughout the conduct of the study treatment periods and up to 2 weeks after the 
study end cannot be included in the study. Post-menopausal women (two years without 
menstruation) do not need to use any method of birth control. For women of childbearing 
potential only, urine hCG pregnancy tests will be performed during the course of the study, and 
they will receive continued guidance with respect to the avoidance of pregnancy, as part of the 
Schedule of Study Procedures  
Patients must have a negative urine pregnancy test at Baseline and throughout the study.  
 
12.2. 
Adverse Events and Other Safety Information 
12.2.1. 
Definitions 
12.2.1.1. Adverse Event (AE) 
An adverse event is any untoward medical occurrence in a clinical investigation subject 
administered a study drug. An AE does not necessarily have a causal relationship with the study 
drug.  For this study, the study drugs are IKERVIS® and vehicle. Regardless of causality to the 


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study treatment, an AE can be an unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of study treatment.  
Any significant change in a subject’s condition from baseline, regardless of causality, is to be 
considered an AE (unless the change is determined to be a continuation of a pre-existing 
condition documented in the subject’s medical history). A clinically significant worsening in 
severity, intensity, or frequency of a pre-existing condition may indicate an AE.  
Worsening of findings e.g. in biomicroscopy from no findings to finding graded as 
moderate/severe, or change in grading from mild to severe, may be an indication of an AE. By 
investigator’s judgment, also milder changes can be recorded as AEs. 
An elective surgical procedure scheduled or planned prior to study entry is not considered an AE, 
and the underlying diagnosis for the procedure should be captured in the medical history as a 
pre-existing condition. 
The lack of efficacy of the study treatment for the condition being investigated is not considered 
an AE unless a clinically significant change is assessed by the investigator. 
Patients’ answers given to study questionnaires (or changes in these) are not reviewed as basis 
for occurrence of AEs. However, the investigators will collect information on AEs at each 
subject contact by asking an open question on the subject’s general health. 
12.2.1.2. Serious Adverse Event (SAE) 
A serious AE (SAE) may occur during any study phase (ie, baseline, treatment, or follow-up). 
SAE must fulfil one or more of the following criteria: 
 Results in death 
 It is immediately life-threatening* 
 It requires in-patient hospitalization or prolongation of existing hospitalization 
 It results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 It is an important medical event that may jeopardize the patient or may require medical 
intervention to prevent one of the outcomes listed above (including sight-threatening** 
events and cancer or neoplasm of any type). 
*Herein ‘Life-threatening’ refers to an event in which the patient was at immediate risk of death at the time of event; 
it does not refer to an event which hypothetically might have caused death.  
**Similarly ‘Sight-threatening’ refers to an event in which the patient was at immediate risk of losing sight; it does 
not refer to an event which hypothetically might have caused losing of sight. 
Serious ocular adverse events include, but are not limited to the following adverse events which 
are considered to be sight-threatening and are to be reported as SAEs (medically important 
criteria): 
- 
Adverse Events that caused a decrease in visual acuity > 6 lines (compared with the last 
assessment of visual acuity at the last visit) 


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- 
Adverse Events that caused a decrease in visual acuity to the level of Light Perception or 
worse 
- 
Adverse Events that  required surgical intervention or laser to prevent permanent loss of 
sight 
- 
Adverse Events associated with severe intraocular inflammation (i.e., 3+ anterior 
chamber cell/flare or 3+ vitritis) 
- 
Corneal perforation 
- 
Adverse Events that, in the opinion of the investigator,  may require medical intervention 
to prevent permanent loss of sight 
12.2.1.3. Case of Special Interest (CSI) 
The following cases are considered to be of special interest by the sponsor: 
- 
Non-serious AEs requiring (24 h) reporting to the sponsor: 
 Corneal ulceration 
 Decrease in visual acuity of 3 to 6 lines (compared with the last assessment of 
visual acuity at the last visit) 
- 
Overdose of study drug 
 Administration of a quantity of a medicinal product exceeding the dose defined in 
the study protocol. 
- 
Misuse of study drug 
 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 or patient. 
- 
Abuse of study drug 
 Persistent or sporadic, intentional excessive use of medicinal product which is 
accompanied by harmful physical or psychological effects. 
12.2.1.4. Pregnancy Reports 
It is required that women of childbearing potential are using a medically acceptable, highly 
effective method of birth control during the study and up to 2 weeks after the study end. Any 
pregnancy occurring during the study or within 14 days of completing the study should be 
reported to Santen EMEA Pharmacovigilance Unit (PVU) and the subject will be removed from 
the study. 
Pregnancies of partners to study subjects with paternal drug exposure must also be reported to 
Santen EMEA PVU. 


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12.2.2. 
Assessment of Adverse Events 
All AEs (non-serious and serious) spontaneously reported by the subject and/or in response to an 
open question from the study personnel or revealed by observation will be recorded and assessed 
during the study at the investigational site. Regardless of relationship to the clinical study, all 
AEs that occur at any time from the point of signing of ICF to participate in the study until 
patient withdrawal or the scheduled exit visit must be recorded. 
Information about all AEs will be collected from the signing of consent form until the end of the 
study. Even after completion of the study, the investigator shall notify Santen EMEA PVU of 
any new SAEs that may be associated with the study drug. 
Non-serious AEs will be evaluated until recovery or until the last study visit.  The investigator 
must follow up subjects with a SAE until it has resolved, stabilized or a final assessment can 
otherwise be done. The same principle applies to all study drug -related AEs which caused early 
termination and AEs which are under special interest. 
The investigator will take appropriate and necessary therapeutic measures required for resolution 
of the AE. Any medication necessary for the treatment of a AE must be recorded. During the 
double-masked treatment period, the investigator should only unmask the treatment allocation if 
this is relevant to the safety of the subject. 
During the study, patients will also be allowed to use unpreserved artificial tears provided by the 
Sponsor. The events with causal relationship to the artificial tears are considered as AEs. 
12.2.2.1. Seriousness 
The seriousness of each AE must be assessed by the investigator according to the criteria set for 
SAEs in section 12.2.1.2. If the event does not meet the criteria of a SAE, it is assessed as non-
serious. 
12.2.2.2. Causality to Study Drug or Artificial Tears 
An investigator who is qualified in medicine must make the determination of causality to the 
study drug and artificial tears provided by the Sponsor for each AE occurred during the study as 
defined in section 12.2.2. The following categories shall be used:  
Related: There is a reasonable possibility that the AE may have been caused by the study 
drug or artificial tears.  
Not related: There is no reasonable possibility that the AE may have been caused by the 
study drug or artificial tears. 
The investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the study drug or artificial tears. If no valid 
reason exists for suggesting a relationship, then the AE should be classified as “unrelated”. If 
there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the study drug (or artificial tears) and the occurrence of the AE, then the 
AE should be considered “related”. 


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12.2.3. 
Relationship to Study Procedures 
The relationship to study procedures (e.g., Schirmer test) should be determined for AE using the 
following categories: 
Related: There is a reasonable possibility that an event may have been caused by a study 
procedure. 
Not Related: There is no reasonable possibility that an event may have been caused by a 
study procedure. 
12.2.3.1. Severity of the Adverse Event 
Severity (intensity) of the AE will be assessed according to the following scale: 
 Mild: awareness of sign or symptom, but easily tolerated 
 Moderate: discomfort sufficient to cause interference with normal activities 
 Severe: incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
whereas seriousness is defined by the criteria under Section 12.2.1.2. An AE of severe intensity 
may not be considered serious. 
12.2.3.2. Expectedness 
AEs will be evaluated as to whether they are expected or unexpected. The assessment is 
performed by the sponsor and in this study it is based on the list of adverse reactions in the section 
4.8 ‘Undesirable Effects’ in the approved IKERVIS® EU Summary of Product Characteristics 
(SmPC) which acts as a Reference Safety Information (RSI). 
 Expected: An AE is expected when the nature or severity of which is consistent with the 
applicable product information. 
 Unexpected: An AE is unexpected when the nature or severity of which is not consistent 
with the applicable product information. 
 
12.2.4. 
Reporting of Safety Information 
12.2.4.1. Reporting of Adverse Events 
All serious and non-serious AEs including non-serious AEs considered to be of special interest 
(CSI) by sponsor (in Section 12.2.1.3), must be reported on the adverse event electronic case 
report form (AE e-CRF). In addition, SAEs and non-serious AEs, which have been considered to 
be CSI, must be reported expeditedly to the sponsor (Section 12.2.4.3). 
For each AE, the investigator will evaluate and report  
 The date site became aware of the event  
 The AE/safety information term (verbatim) 
 the onset date  


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 outcome of event  
 The end date, if applicable 
 severity  
 location (e.g. right/left eye, both eyes, or not applicable if non ocular event) 
 causality to study drug (Related / Not related) 
 causality to artificial tears 
 relationship to study procedures  
 action taken with the study drug (for AEs only)  
 seriousness  
 Treatment medications, if applicable 
 Historical/concurrent medical conditions relevant for the AE 
 whether or not AE caused the patient to discontinue the study. 
 
The AE term should be reported in standard medical terminology when possible. 
If known, the diagnosis (i.e., disease or syndrome) must be recorded rather than component signs 
and symptoms (e.g., record as "worsening of cataract" rather than "drop in vision"). However, 
other events that are considered unrelated to an encountered syndrome or disease should be 
recorded as individual AEs (e.g., if worsening of macular edema and worsening of panuveitis are 
observed at the same time and are clinically unrelated, each event should be recorded as an 
individual AE). 
12.2.4.2. Reporting of Case of Special Interest and Pregnancy 
Other CSIs (non-serious AEs covered in the Section 12.2.1.3) or spontaneously reported 
pregnancy in a patient or in a partner to the patient must be recorded in the source documents at 
the investigation site and reported expeditedly to Santen EMEA PVU (Section 12.2.4.3). 
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication. The pregnancy 
which occurs during the study or within 14 days of completing the study must be reported. 
The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study presuming that the informed consent is obtained for this from the 
patient. The outcome (health of infant) must also be reported to the Santen EMEA PVU. 
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. 


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12.2.4.3. Expedited reporting 
All SAE, CSI and Pregnancy reports must be reported to Santen EMEA PVU immediatey but no 
later than within 24 hours of the first awareness of the event. The investigator must complete, 
sign and date the SAE (or CSI/Pregnancy) pages, verify the accuracy of the information recorded 
on the SAE (or CSI/Pregnancy) pages, and send a copy by e-mail or fax to Santen EMEA PVU: 
 
Santen EMEA, Pharmacovigilance Unit (PVU) 
Email to safetyEU@santen.com or 
Fax to +358 3 318 1060 
(Phone +358 3 284 8625) 
 
The sponsor records all SAE, CSI and Pregnancy reports in the safety database of Santen. 
Additional follow-up information, if required or available, should all be sent by e-mail or faxed 
to Santen EMEA PVU immediately but no later than within 24 hours of receipt and this should 
be completed on a follow-up SAE (or CSI/Pregnancy) form and placed with the original 
information and kept with the appropriate section of the eCRF and/or study file. 
The sponsor is responsible for ongoing safety evaluation of the study drug. If there is at least a 
reasonable possibility that the event is related to the study drug and it is both serious and 
unexpected (SUSAR), the sponsor shall initiate expedited reporting according to applicable 
reporting requirements to all relevant parties, including regulatory authorities and ethics 
committees. Reporting responsibilities are described in the study specific safety management 
plan. 
Investigators will also be notified of all suspected, unexpected serious study drug –related 
adverse reactions (SUSARs) that occur during the clinical trial. 
12.2.5. 
Documentation of Safety Information 
All AEs will be recorded during the study in the subject’s medicinal records and on the 
appropriate AE eCRF at the investigational site. CSIs and Pregnancies will be recorded in the 
source documents. The sponsor records all SAEs, CSIs and Pregnancy reports in the safety 
database of Santen. 
 


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13. 
STATISTICS 
13.1. 
 General Considerations 
Unless specified otherwise, efficacy measures will be summarized by planned treatment, and 
safety measures will be summarized by actual treatment received.  Continuous variables will be 
summarized using descriptive statistics such as number of observations (n), mean, standard 
deviation, medium, minimum, and maximum.  Categorical variables will be tabulated using 
frequency (n) and percent (%).  For the variables recorded for both eyes, the descriptions will be 
given separately for the analysis eye and for the fellow eye, when considered relevant. 
All data manipulations and descriptive summaries will be performed using SAS Version 9.4 or 
later.  The FDA guidance on case report tabulations (annotated eCRFs, SAS datasets, metadata, 
and SAS programs) in electronic submission will be followed.  Data definition tables will be 
created for SDTM and ADaM datasets, separately. 
A Statistical Analysis Plan (SAP) will be written and finalized before the start of the analysis of 
the study data, which will present the details of how all the analyses will be performed.  
13.1.1. 
Sample Size 
This sample size of this study is not planned from a formal sample size calculation since formal 
statistical hypothesis testing will not be performed for the primary endpoints.In this study, we 
plan to enroll 350 subjects. Of the 350 subjects, it is estimated that approximately 70% (245 
subjects) would become markedly improved in CFS after Month 12 and enter the Period 2 
(Double-masked randomised period), based on Santen previous IKERVIS studies. With a 3:2 
randomization allocation ratio, a sample size of 147 for IKERVIS® and 98 for Vehicle will allow 
to detect a difference of 0.4 or more in CFS score with 80% power assuming the standard 
deviation of the difference is 1.10. 
Petroutsos et al. (1992) showed that after 6 years of follow-up on DED patients, a lower-bound 
of the estimated complication rate was 4% in severe DED patients.  In the current study, 350 
subjects treated with IKERVIS® for at least one year would have 95% power to detect at least 
one ocular complication that occurs at 1% rate with type I error rate of 0.05. 
13.1.2. 
Statistical Hypotheses and Level of Significance 
There will be no statistical hypotheses for the primary and secondary endpoints. 
13.1.3. 
Analysis Eye 
The analysis eye is defined as the eligible eye that fulfils all the criteria listed under the inclusion 
criteria #5.  If both eyes are eligible, the eye with the highest baseline CFS score will be chosen.  
If both eyes have the same baseline CFS score, the eye with the lowest Schirmer test value will 
be chosen.  If both eyes have the same Schirmer test value, the right eye will be chosen as the 
analysis eye. 
All the efficacy analysis will be performed on the analysis eye only. 


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13.2. 
Analysis Populations 
Analysis populations are defined based on study period. 
For Period 1:  
 The Full Analysis Set (FAS) population consists of all enrolled subjects who received at 
least one dose of the study medication and had at least one post-baseline sign or symptom 
assessment of the study eye during Period 1. This will be the population used for efficacy 
analyses.   
 The Per-Protocol Set (PPS) will be a subset of FAS, restricted to the subjects who fulfill 
the protocol in the terms of the eligibility, interventions, and outcome assessment.  It will 
be the analysis population for some sensitivity analyses. 
 The Safety population consists of all patients enrolled in Period 1 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 to be performed with subjects as 
treated. 
 The following analysis subpopulation will be defined according to the treatment response 
to efficacy variables: 
o Markedly Improved Patients are defined as FAS subjects who achieve CFS 
score improvement from baseline of 2 grades or more (unless if the patient had a 
CFS score of 5 at baseline, the improvement in CFS has to be 3 grades or more) at 
Month 12 visit. 
For Period 2: 
 The FAS population consists of all randomised patients who received at least one dose of 
the study medication and had at least one post-Month 12 sign or symptom assessment of 
the study eye during Period 2. This will be the population used for efficacy analyses.   
 The PPS will be a subset of FAS, restricted to the subjects who fulfill the protocol in the 
terms of the eligibility, interventions, and outcome assessment.  It will be the analysis 
population for some sensitivity analyses.The Safety population consists of all patients 
enrolled in Period 2 for whom any follow-up information is available. It will be the 
analysis population for safety analyses to be performed with subjects as treated. 
For entire study: 
 The FAS population consists of the Markedly Improved Patients who were randomised to 
IKERVIS in Period 2 and received at least one dose of IKERVIS in Period 2 and had at 
least one post-Month 12 sign or symptom assessment of the study eye during Period 2. 
This will be the population used for efficacy analyses.   
 The PPS will be a subset of FAS, restricted to the subjects who fulfill the protocol in the 
terms of the eligibility, interventions, and outcome assessment.  It will be the analysis 
population for some sensitivity analyses. 
 The Safety population consists of the Markedly Improved Patients who were 
randomised to IKERVIS in Period 2 and had at least one post-Month 12 sign or symptom 


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assessment of the study eye during Period 2. It will be the analysis population for safety 
analyses to be performed with subjects as treated. 
13.3. 
The Sjögren patients population will be specifically described 
separately for some analyses. Analysis of Demographics and Baseline 
Characteristics 
Descriptive summaries will be performed for demographic (including age, gender, race, 
ethnicity, female patients’ menopausal status) and baseline characteristics variables (including 
Sjögren Disease status, time since diagnosis, past surgery or laser treatment in the analysis eye, 
and smoking status) by each FAS and safety population in Period 1, Period 2 and entire study. 
In addition, medical history (ocular and systemic) and prior and concomitant medication uses will 
be summarised . Prior medication is defined as any medication that was used by the patients that 
is discontinued before the Baseline visit (Day 1).  
13.4. 
Analysis of Primary Endpoints 
Spearman correlation coefficient and p-values will be obtatined for the correlation analysis 
between mean change from baseline in CFS score at visit X and symptoms score at each visit 
X+i for each FAS population in Period 1, Period 2 and entire study. For Period 1, visit X 
includes Day1, Month 3, Month 6, Month 9 and Month 12, and i is from 0 (Day 1) up to 4 
(Month 12). For Period 2, X includes Month 12, Month 15, Month 18, Month 21, Month 24, 
Month 27, Month 30, Month 33, and Month 36, and i is from 0 (Month 12) up to 8 (Month 36). 
Correlation coefficient will be analized by treatment group. For entire study, visit X includes all 
the scheduled visits from Day 1 to Month 36, and i is from 0 (Day1) up to 12 (Month 36). 
Missing data will not be imputed. 
The incident rate of ocular surface complications (defined as corneal ulceration, corneal 
perforation, loss of visual acuity, and ocular infection) will be estimated with its 95% CI for each 
safety population in Period 1, Period 2, and the entire study. The analysis for safety population in 
Period 2 will be conducted by treatment group. The incident rates will be compared to existing 
epidemiologic rates in a comparable population. Time to onset and time to resolution of the 
ocular complications will also be summarized. Missing data will not be imputed. 
Subgroup analysis by randomization stratification factor will be conducted to test the 
homogeneity of treatment effects in Period 2.  
 
13.5. 
Analysis of Secondary Endpoints 
For FAS population in Period 1, Period 2 and entire study, mean scores of CFS, conjunctival 
fluorescein staining, symptoms (SANDE and 5-point scale), TBUT, Schirmer test, artificial tear 
use and quality of life (DEQS) score, and their change from baseline (Period 1 and Period 2) and 
change from Month 12 (Period 2) will be summarized by analysis visit.  The analysis for FAS 
population in Period 2 will be conducted by treatment groups. 
Occurrence and time to relapse defined as an increase of CFS modified Oxford score of 2 or 
more will be summarized for FAS population in Period 2 by treatment group. 


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Survival analysis method will be employed to analyze the time to become Markedly Improved 
Patients in Period 1. 
Summary statistics on the scores of Quality of Life variables will be provided as well as their 
change from baseline at each visit. 
Missing data will not be imputed. 
13.6. 
Analysis of Safety and Tolerability Endpoints 
All safety and tolerability endpoints analyses will be performed with the Safety population. 
13.6.1. 
Adverse Events 
An adverse event is treatment emergent if it occurs or worsens after the first dose of study 
treatment.  
Adverse events will be coded using the MedDRA dictionary. Frequencies and percentages will 
be given as follows:  1) Overall summary; 2) by system organ class and preferred term, 3) by 
system organ class, preferred term and maximal severity, 4) by system organ class, preferred 
term and relationship to study medication and study procedure, respectively, and 5) by system 
organ class, preferred term, maximal severity, and relationship to study medication and study 
procedure, respectively.  
Separate analyses will be performed for AEs and SAEs, and for ocular and systemic AEs and 
SAEs, respectively. Ocular AEs will be summarized for the analysis eye and the fellow eye 
separately. 
13.6.2. 
Ocular Surface Complications 
Ocular surface complications will be analised as one of the primary endpoints. See details in 
section 13.4. 
13.6.3. 
Other Safety Assessments 
Other parameters of safety assessments (e.g. slit lamp examination, BCDVA, and IOP) will be 
summarised at each time point of measurement for each safety population in Peirod 1, Period 2 
and entire study. They will be summarised/ analysed for the analysis eye and the fellow eye 
separately. The analysis for safety population in Period 2 will be conducted by treatment group. 
13.7. 
Interim Analysis 
Interim analysis will be conducted once all patients will have performed their Month 12 visit or 
withdrawal visit, CFS, symptoms (SANDE and 5-point scale), quality of life and AEs will be 
analyzed on clean data.  The purpose of the interim analysis is to present signs, symptoms and 
QoL data as well as calculation of correlation and lag time in FAS population in Period 1 and in 
patients with a Sjögren disease.  
Mean and mean change from baseline (signs, symptoms and QOLs) will be provided. 
Correlation coefficient between mean change from baseline in CFS score at visit X and symptom 
score at each visit X+i will be analized, where X includes scheduled visits from Day 1 to Month 
12, and i is from 0 up to 4. 


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Since the first 12 months of the study will be open-label study, no adjustment of alpha level 
and no Data Monitoring Committee will be needed for this study. 
13.8. 
Handling of Missing Values 
No imputation for missing data will be performed on primary and secondary endpoint analyses. 
Unless specified otherwise, descriptive summaries will be based on observed cases. 
For medical events including AEs, completely or partially missing onset and resolution dates will 
be imputed in a conservative fashion to be detailed in the Statistical Analysis Plan (SAP).  Same 
rules will be followed to impute the completely or partially missing start and end dates of non-
study medications. 
 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a patient into the study, a representative of theSponsor 
will visit the investigational study site to: 
 Determine the adequacy of the facilities. 
 Discuss with the investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Santen SAS or its representatives.  This 
will be documented in a Clinical Study Agreement between Santen or its designee and 
the investigator. 
During the study, a monitor from Santen or representative will have regular contacts with the 
investigational site, for the following: 
 Provide information and support to the investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed. 
 Perform source data verification.  This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the study.  This will require direct access to all original records for 
each patient (e.g. clinic charts). 
 Record and report any protocol deviations not previously sent to Santen. 
 Confirm non-serious AEs and SAEs have been properly documented on eCRFs and 
confirm any safety information requiring expedited reporting to Santen EMEA PVU 
(including SAEs, CSIs and Pregnancies) have been forwarded to Santen and those SAEs 
that met criteria for reporting have been forwarded to the IRB. 
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorised representatives of Santen, a regulatory authority (national or foreign), an Independent 
Ethics Committee or an Institutional Review Board may visit the site to perform audits or 
inspections, including source data verification.  The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements.  The 
investigator should contact Santen immediately if contacted by a regulatory agency about an 
inspection. 


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14.3. 
Institutional Review Board (IRB)/ Independent Ethics Committee 
(IEC) 
A written favourable opinion of IRB or IEC (as appropriate) must be obtain prior starting the 
study. Initial IRB/IEC approval, and all materials approved by the IRB/IEC for this study 
including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
Santen may conduct a quality assurance audit.  Please see Section 14.2 for more details regarding 
the audit process. 
 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the Informed Consent Form, must be 
approved or given a favorable opinion in writing by an IRB or IEC as appropriate.  A copy of the 
letter indicating IRB/IEC approval or a favorable opinion must be available at the investigational 
site before the site can enroll any patient/subject into the study. 
Any amendment to the protocol must be reviewed by IRB/IEC in accordance with local 
requirements.  In addition, the IRB or IEC must approve all advertising used to recruit patients 
for the study.   
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice and applicable 
regulatory requirements. Please see Appendix B- “Responsibilities of the Investigator” and 
Appendix E- Declaration of Helsinki.  
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the patient is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Patients must also be notified that they are free to discontinue from the study at any time.  The 
patient should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The patient’s signed and dated informed consent must be obtained before any protocol-directed 
procedures are performed. 
The Principal Investigator(s) must maintain the original, signed Informed Consent Form.  A copy 
of the signed Informed Consent Form must be given to the patient. 
 


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17. 
DATA HANDLING AND RECORD KEEPING 
17.1. 
Inspection of Records 
Santen or Santen’s designee  will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, subject 
charts and study source documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 2 
years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation. In addition, ICH E6 Section 4.9.5 states that 
the study records should be retained until an amount of time specified by applicable regulatory 
requirements or for a time specified in the Clinical Study Ste Agreement between the 
investigator and sponsor. If it becomes necessary for Santen or the Regulatory Authority to 
review any documentation relating to the study, the Investigator must permit access to such 
records. 
17.3. 
Source Documents 
The patient source documentation should include hospital reports, doctor’s/nurse’s notes, 
laboratory results, reports of special examinations, the signed consent forms, consultants letters. 
The Investigator is asked to report the following information in the patient’s medical file (source 
documents) according to Sources Data Agreement signed by the Principal Investigator of each 
Investigational site: 
- 
Mention of patient’s participation in the study, patient code and treatment number, date 
and process of signature of informed consent form 
- 
Demographic data (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 non-serious AEs, SAEs and CSIs occurred during the time course of the study and 
study drug-related SAEs which occurred after the completion of the study 
- 
Any pregnancy occurring during the study or within 14 days of completing the study 


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- 
Any data that could be judged by the Investigator as relevant 
This list is not exhaustive. 
17.4. 
 Data Collection 
The Principal Investigator must maintain detailed records on all subjects who provided informed 
consent. Data for screened and enrolled subjects will be entered into eCRFs, designed according 
to the protocol. Review of the eCRFs will be completed remotely by Santen (or designee). At 
designated intervals, a study monitor will perform source data verification on site. During those 
visits, Santen (or designee) will monitor the subject data recorded in the eCRF against source 
documents at the study site. Santen (or designee) will review and evaluate eCRF data and use 
standard system edits, and may use centralised monitoring evaluations, to detect errors in data 
collection. At the end of the stud, a copy of the completed eCRFs will be sent to the site to be 
maintained as study records.  
 


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18. 
PUBLICATION POLICY 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. 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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19. 
LIST OF REFERENCES 
AAO. Cornea/External Disease Panel. Preferred Practice Pattern® Guidelines. Dry Eye 
Syndrome.  American Academy of Ophthalmology; San Francisco2013. 
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. 
Baudouin C. A new approach for better comprehension of diseases of the ocular surface. J Fr 
Ophtalmol. 2007 Mar;30(3):239-46. 
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. 
Baudouin C, et al. Diagnosing the severity of dry eye: a clear and practical algorithm. Br J 
Ophthalmol. 2014 Sep;98(9):1168-76. 
Baudouin, et al. A randomized study of the efficacy and safety of 0.1% cyclosporine A cationic 
emulsion in treatment of moderate to severe dry eye. Eur J Ophthalmol. 2017; 27(5): 520 - 530. 
doi: 10.5301/ejo.5000952 
DEWS. Craig JP, Nichols K, Akpeik EK, et al. TFOS DEWS II Definition and classification 
report. Ocul Surf 2017;15:276–83.  
DEWS. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf 
2017;15:334–65. 
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. 
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. 
Kymionis GD, et al. Treatment of chronic dry eye: focus on cyclosporine. Clin Ophthalmol. 
2008 Dec;2(4):829-36. 
Labetoulle M, et al. From pathogenic considerations to a simplified decision-making schema in 
dry eye disease. J Fr Ophtalmol. 2013 May 21. 
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/. 
Lallemand F, et al. Cyclosporine A delivery to the eye: A pharmaceutical challenge. Eur J Pharm 
Biopharm. 2003 Nov;56(3):307-18. 
Leonardi A, et al. Efficacy and safety of 0.1% cyclosporine A cationic emulsion in the treatment 
of severe dry eye disease: a multicenter randomized trial. Eur J Ophthalmol. 2016 Jun 
10;26(4):287-96. doi: 10.5301/ejo.5000779. 
Petroutsos G, et al. [Sterile corneal ulcers in dry eye. Incidence and factors of occurrence]. J Fr 
Ophtalmol. 1992;15(2):103-5. French. 


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Stevenson W, et al. Dry eye disease: an immune-mediated ocular surface disorder. Arch 
Ophthalmol. 2012 Jan;130(1):90-100. 
 


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20. 
APPENDICES 
Appendix A-I  Symptom Assessment iN Dry Eye (SANDE) questionnaire 
Symptom Assessment iN Dry Eye (SANDE) questionnaire is based on visual analog scales 
(VAS) to quantify both severity and frequency of dry eye symptoms1,2.  
The patient will thus be asked to rate severity and frequency of dry eye symptoms by placing a 
vertical mark on the horizontal line to indicate each level on the 100 mm line. The measurement 
of symptom frequency ranges from “rarely” to “all of the time”, and the symptom severity ranges 
from “very mild” to “very severe”.  Symptoms will be evaluated for both eyes together. 
 
 
Please complete the following questions regarding the frequency and severity of your dry eye 
symptoms 
1. Frequency of symptoms 
Please place a vertical mark over the line to indicate how often, on average, your eyes feel dry 
and/or irritated: 
Rarely  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All the time 
 
2. Severity of symptoms 
Please place a vertical mark over the line to indicate how severe, on average, you feel your 
symptoms of dryness and/or irritation: 
Very mild  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very severe 
 
The response will be measured in mm between 0 – 100 mm.  
 
1 Gulati A, Sullivan R, Buring JE, et al. Validation and repeatability of a short questionnaire for dry eye syndrome. 
Am J Ophthalmol 2006; 142:125 31 
2 Schaumberg DA, Gulati A, Mathers WD, et al. Development and validation of a short global dry eye symptom 
index. Ocul Surf 2007; 5:50 7 
 
 


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Appendix A-II Evaluation of 5 symptoms of DED using the 5-point Likert 
scale   
The 5-point Likert scales are a self-administered questionnaire and should be completed by the 
patient. The patient will be asked to rate the severity of the 5 symptoms by ticking the box for 
each symptom that best represents his/her answer. Symptoms will be evaluated for both eyes 
together. 
 
SYMPTOMS  
None 
Mild 
Moderate 
Severe 
Very severe 
Burning/stinging 
 0 
 1 
 2 
 3 
 4 
Foreign body sensation 
 0 
 1 
 2 
 3 
 4 
Eye dryness 
 0 
 1 
 2 
 3 
 4 
Eye pain 
 0 
 1 
 2 
 3 
 4 
Blurred/poor vision 
 0 
 1 
 2 
 3 
 4 
 
 
 
 


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Appendix A-III  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 localised to a small region of the lid(s) margin OR skin). 
2 = Moderate (redness of most or all lid margin OR skin). 
3 = Severe (redness of most or all lid margin AND skin). 
4 = Very severe (marked diffuse redness of both lid margin AND skin). 
 
Lid - Oedema 
0 = None (normal). 
1 = Mild (localised to a small region of the lid). 
2 = Moderate (diffuse, most or all lid but not prominent/protruding). 
3 = Severe (diffuse, most or all lid AND prominent/protruding). 
4 = Very severe (diffuse AND prominent/protruding AND reversion of the lid). 
 
Lashes 
0 = Normal 
1 = Abnormal (specify) 
 
Conjunctiva – Erythema 


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


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0 = No opacification (normal lens). 
1 = Mild lens opacification. 
2 = Moderate lens opacification. 
3 = Severe lens opacification. 
 


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Appendix A-IV  Modified Oxford Scale 
 
(Grading of corneal and conjunctival fluorescein staining) 
 
 
 


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Appendix A-V  
Dry Eye related Quality of life Score (DEQS) 
 
  
The DEQS is self-administered and should be completed by the patient. 
 
 
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are patient to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarised in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study. 
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures; including study specific (non-routine/non-
standard panel) eligibility assessments are NOT performed on potential patients, prior 
to the receipt of written approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are 
informed of these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that 
conform to 21 CFR Part 56, ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and 
approval of the protocol. Promptly report to the IRB/IEC all changes in research 
activity and all anticipated risks to patients. Make at least yearly reports on the 
progress of the study to the IRB/IEC, and issue a final report within 3 months of 
study completion. 
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH 
and local regulations, are met. 
8. Obtain valid informed consent from each patient who participates in the study, and 
document the date of consent in the patient’s medical chart. Valid informed consent is 
the most current version approved by the IRB/IEC. Each informed consent form 
should contain a patient authorization section that describes the uses and disclosures 
of a patient’s personal information (including personal health information) that will 
take place in connection with the study. If an informed consent form does not include 
such a patient authorization, then the investigator must obtain a separate patient 
authorization form from each patient or the patient’s legally acceptable 
representative. 
9. Prepare and maintain adequate case histories of all persons entered into the study, 
including eCRFs, hospital records, laboratory results, etc, and maintain these data for 
a minimum of 2 years following notification by the sponsor that all investigations 
have been discontinued or that the regulatory authority has approved the marketing 
application. The investigator should contact and receive written approval from the 
sponsor before disposing of any such documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified 
essential documents. 


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11. Maintain current records of the receipt, administration, and disposition of sponsor-
supplied drugs and return all unused sponsor-supplied drugs to the sponsor. 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the 
sponsor within 24 hours. 


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Appendix C 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. 
 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. 


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 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. 
 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, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies; 
d) that patients agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) that the patient’s identity will remain confidential in the event that study results are 
published.    
 


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


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


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


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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 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 


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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. 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to 
the publication and dissemination of the results of research. Researchers have a duty to make publicly 
available the results of their research on human subjects and are accountable for the completeness and 
accuracy of their reports. All parties should adhere to accepted guidelines for ethical reporting. Negative 
and inconclusive as well as positive results must be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be accepted for 
publication. 
Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent 
from the patient or a legally authorised representative, may use an unproven intervention if in the 
physician's judgement it offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, made publicly available. 


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SAP_001.pdf: 
 
 
Statistical Analysis Plan Cover Page 
 
Official Study Title:  
A Phase IIIb, Prospective, Interventional, Multicentre, 3-year Study 
to Explore the Long-term Evolution of Sign and Symptoms, and 
Occurence of Complications in Dry Eye Patients With Severe 
Keratitis Receiving Ikervis® (1mg/mL Ciclosporin) 
 
 
NCT Number:  
NCT04144413
 
Date of the document:
 01 September 2023 
 
 
 


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STATISTICAL ANALYSIS PLAN 
Protocol NVG14L127 
 
Protocol 
Title: 
A phase IIIb, prospective, interventional, multicentre, three-year study to explore the 
long-term evolution of sign and symptoms, and occurrence of complications in dry 
eye disease subjects with severe keratitis receiving IKERVIS® (1mg/ml ciclosporin) 
eye drops 
 
 
Product: 
IKERVIS® (1mg/mL Ciclosporin) 
 
 
Protocol 
Number:  
NVG14L127 
 
 
Sponsor: 
Santen SAS 
Genavenir IV, 1 rue Pierre Fontaine 
F-91058 Evry, France 
 
 
 
Date:  
September 1st, 2023 
 
 
Status:  
Version 2.0  
 
 
 
CONFIDENTIAL 
 
The information in this document is considered privileged and confidential by Santen Inc/Santen Ltd., 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 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
ABBREVIATIONS .........................................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
2.1. 
Objectives ...................................................................................................................10 
2.2. 
Endpoints ....................................................................................................................10 
2.2.1. 
Primary Efficacy and Safety Endpoints ......................................................................10 
2.2.2. 
Secondary Endpoints ..................................................................................................10 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
General Study Design .................................................................................................12 
3.2. 
Randomization and Masking ......................................................................................12 
3.3. 
Sample Size Determination ........................................................................................13 
3.4. 
Visits and Assessments ...............................................................................................13 
4. 
DEFINITIONS ...........................................................................................................16 
4.1. 
Time-Related Terms ...................................................................................................16 
4.1.1. 
Baseline Visit ..............................................................................................................16 
4.1.2. 
Treatment Start Date and End Date ............................................................................16 
4.1.3. 
Study Day ...................................................................................................................17 
4.1.4. 
Analysis Visit and Analysis Window .........................................................................17 
4.1.5. 
Extent of Exposure .....................................................................................................18 
4.2. 
Endpoint-Related Definitions .....................................................................................18 
4.2.1. 
Study Eye and Fellow Eye ..........................................................................................18 
4.2.2. 
Baseline Score ............................................................................................................18 
4.2.3. 
Change from a Reference Point ..................................................................................19 
4.3. 
Efficacy-Related Definitions ......................................................................................19 
4.3.1. 
SANDE Global Score .................................................................................................19 
4.3.2. 
Dry Eye symptoms-related Quality of Life Score (DEQS) ........................................19 
4.3.3. 
Conjunctival Fluorescein Staining Total Score ..........................................................20 
4.3.4. 
Markedly Improved Status .........................................................................................20 
4.3.5. 
Relapse Status .............................................................................................................20 


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4.4. 
Safety-Related Definitions ..........................................................................................20 
4.4.1. 
Adverse Event .............................................................................................................20 
4.4.2. 
Other Safety Measures ................................................................................................23 
4.5. 
Other Definitions ........................................................................................................23 
4.5.1. 
Prior and Concomitant Medications ...........................................................................23 
4.5.2. 
Concurrent Medical Conditions ..................................................................................23 
5. 
GENERAL CONSIDERATIONS ..............................................................................24 
5.1. 
Adjustments for Covariates ........................................................................................24 
5.2. 
Handling of Missing Data ...........................................................................................24 
5.3. 
Multi-Center Studies ...................................................................................................25 
5.4. 
Multiple Comparisons / Multiplicity ..........................................................................26 
5.5. 
Interim Analysis ..........................................................................................................26 
6. 
ANALYSIS POPULATION ......................................................................................27 
7. 
SUMMARY OF STUDY POPULATION DATA .....................................................28 
7.1. 
Subject Disposition .....................................................................................................28 
7.2. 
Demographics and Other Baseline Characteristics .....................................................28 
7.3. 
Medical History ..........................................................................................................29 
7.4. 
Protocol Deviations ....................................................................................................29 
7.5. 
Prior and Concomitant Medications ...........................................................................30 
7.6. 
Treatment Compliance ................................................................................................30 
7.7. 
Exposure to Study Medication ....................................................................................31 
8. 
EFFICACY ANALYSES ...........................................................................................32 
8.1. 
Analysis of Primary Efficacy Endpoint ......................................................................32 
8.1.1. 
Primary Analysis ........................................................................................................32 
8.1.2. 
Sensitivity Analysis ....................................................................................................34 
8.2. 
Analysis of Secondary Efficacy Endpoints ................................................................34 
8.2.1. 
Analysis of Continuous Endpoints .............................................................................34 
8.2.2. 
Analysis of DEQS-15 Questionnaire ..........................................................................35 
8.2.3. 
Analysis of Time-to-Event Endpoints ........................................................................36 
8.2.4. 
Analysis of Others ......................................................................................................37 
8.3. 
Subgroup Analyses .....................................................................................................37 
9. 
SAFETY ANALYSES ...............................................................................................37 
9.1. 
Analysis of Primary Safety Endpoint .........................................................................37 


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9.2. 
Adverse Event .............................................................................................................38 
9.3. 
Intraocular pressure (IOP) ..........................................................................................38 
9.4. 
Best-Corrected Distance Visual Acuity (BCDVA) ....................................................38 
9.5. 
Slit-Lamp Biomicroscopy ...........................................................................................39 
9.6. 
Urine Pregnancy Test .................................................................................................39 
10. 
CHANGES TO THE PROTOCOL-SPECIFIED ANALYSES .................................40 
10.1. 
The Term “Study Eye” ...............................................................................................40 
10.2. 
Primary Efficacy Endpoint .........................................................................................40 
10.3. 
Descriptions of the Interim Analysis ..........................................................................40 
10.4. 
Safety Population Definitions .....................................................................................41 
11. 
REFERENCES ...........................................................................................................42 
12. 
APPENDICES ............................................................................................................43 
 
 
LIST OF TABLES 
Table 1. 
Study Design and Schedule of Assessments ..............................................................14 
Table 2. 
Safety Assessments .....................................................................................................23 
Table 3  
Data Cut Plan for Interim Analysis ............................................................................26 
Table 4 
Analysis of Correlation between Change from Reference Point in CFS Score 
at Visit X and Change from Reference Point in SANDE Symptom Score at 
Visit X + i ...................................................................................................................33 
 
 
LIST OF FIGURES 
  
Figure 1. 
Study Design Diagram ................................................................................................12 


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Figure 2. 
A Sample Plot of Correlation between Change from Baseline in CFS Score 
at Visit X vs. Change from Baseline in SANDE Score at Visit X + i ........................32 
Figure 3 
Kaplan-Meier Curve of Time-to-become Markedly Improved ..................................36 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Explanation 
ADaM 
Analysis Data Model 
ADR 
adverse drug reaction 
AE 
adverse event 
AT 
Artificial Tears 
ATC 
Anatomical-Therapeutic-Chemical  
BCDVA 
best-corrected distance visual acuity 
CI 
confidence interval 
CFS 
Corneal Fluorescein Staining 
CM 
concomitant medications  
CSI 
case of special interest 
CSR 
clinical study report 
eCRF 
electronic case report form 
DED 
dry eye disease 
DEQS 
Dry Eye-related Quality-of-Life Score 
FAS 
full analysis set 
QD 
quaque die 
QoL 
quality of life 
IOP 
intraocular pressure 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LogMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
medical history 
OD 
oculus dexter (right eye) 
OS 
oculus sinister (left eye) 
OU 
oculus uterque (both eyes) 
PPS 
per-protocol set 
 
PT 
preferred term 
SAE 
serious adverse event 
SANDE 
Symptom Assessment iN Dry Eye questionnaire 
SAP 
statistical analysis plan 


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Abbreviation 
Explanation 
SAS 
Statistical Analysis System 
SDTM 
Study Data Tabulation Model 
SOC 
system organ classification 
TBUT 
Tear Breakup Time 
TEAE 
treatment-emergent adverse event 
VA 
Visual Acuity 
 
    
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) specifies the statistical methods and analyses to be 
implemented for the data collected from the IKERVIS PAES study within the scope of Santen’s 
Protocol NVG14L127, “A phase IIIb, prospective, interventional, multicentre, three-year study 
to explore the long-term evolution of sign and symptoms, and occurrence of complications in dry 
eye disease subjects with severe keratitis receiving IKERVIS® (1mg/ml ciclosporin) eye drops”.  
It applies to the study protocol Amendment 1 (version 3.0), dated 17-OCT-2018, 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.  Deviations from the final 
approved version of the SAP must be substantiated by sound statistical reasoning and 
documented in the CSR. 
 
REVISION HISTORY FROM THE PREVIOUS VERSION (1.0):  
 Reflected the latest version of MedDRA (Sec. 4.4) 
 Updated the definitions of ocular surface complication (Sec. 4.4.1.1) 
 Updated analysis set (Sec. 6) 
 Added Sjogren patient population summary (Sec. 7 and 8) 
 Added medical history summary for period 2 (Sec. 7.5) 
 Added CFS shift table (Sec. 8.2) 
 Added CFS complete resolution summary (CFS=0 at post BL) (Sec. 8.2)  
 Added MMRM to estimate treatment difference for secondary endpoints (Sec. 8.2) and 
updated related section (Sec. 5.1 and 5.4) 
 Clarified the duration of detail for ocular surface complication (Sec. 9.1) 
 Added SAS sample code (Sec. 12) 
 
 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objectives of this study are: 
 To evaluate the long-term efficacy of a continuous treatment of IKERVIS® (1mg/mL 
ciclosporin) eye drops in adult dry eye disease (DED) subjects with severe keratitis on 
corneal sign and DED symptoms, and to estimate the lag time (if any) to improvement in 
symptoms (if any). 
 To assess the ocular surface complications (defined as corneal ulceration, corneal 
perforation, loss of visual acuity, and ocular infection) over the three-year study period. 
The secondary objectives of this study are: 
 To evaluate the efficacy parameters (signs and symptoms), the ocular surface 
complications, and the quality of life over treatment Periods 1 and 2. 
 For 12-month markedly improved subjects, to evaluate and compare signs and symptoms 
evolution in IKERVIS® group versus Vehicle group during the randomised period of the 
study (Period 2). 
 To evaluate the safety and tolerability of IKERVIS® (1mg/mL ciclosporin) eye drops 
treatment over the three-year study period. 
2.2. 
Endpoints 
2.2.1. 
Primary Efficacy and Safety Endpoints 
 The correlation between change from baseline in CFS score and SANDE symptoms score 
at each visit, and cross correlation of sign at visit X versus symptoms at visit X+i (i 
starting from 0), if any. 
 Incident rate of ocular surface complications (defined as corneal ulceration, corneal 
perforation, loss of visual acuity and ocular infection   
 Time to onset of ocular surface complications 
2.2.2. 
Secondary Endpoints 
Efficacy: 
   A)  In Period 1: 
 CFS score and change from baseline at each visit  
 Conjunctival fluorescein staining score and change from baseline at each visit 
 SANDE symptoms score and change from baseline at each visit  
 Symptoms score (5-point scale) and change from baseline at each visit, for each of the 
five symptoms assessed  
 Occurrence and time to become markedly improved (defined as CFS score 
improvement of 2 or more on the modified Oxford scale during Period 1)  


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 TBUT and change from baseline at each visit  
 Schirmer test and change from baseline at Month 12 visit 
 Use of Artificial Tears over the last week and change from baseline at each visit 
   B)  In Period 2: 
 CFS score and change from Month 12 visit at each visit  
 Conjunctival fluorescein staining score and change from Month 12 at each visit  
 SANDE symptoms score and change from Month 12 visit at each visit  
 Symptoms score (5-point scale) and change from Month 12 visit at each visit, for each 
of the five symptoms assessed  
 TBUT and change from Month 12 visit at each visit  
 Schirmer test and change from Month 12 visit at Month 24 and Month 36 visits 
 Use of Artificial Tears (over the last week and change from Month 12 visit at each visit 
 Occurrence and time to relapse (increase of CFS score of 2 or more on the modified 
Oxford scale) 
   C)  In entire study: 
 CFS score and change from baseline at each visit  
 Conjunctival fluorescein staining score and change from baseline at each visit 
 SANDE symptoms score and change from baseline at each visit  
 Symptoms score (5-point scale) and change from baseline at each visit, for each of the 
five symptoms assessed  
 TBUT and change from baseline at each visit  
 Schirmer test and change from baseline at each visit 
 Use of Artificial Tears over the last week and change from baseline at each visit 
Quality of Life: 
In the randomised markedly improved subpopulation,  
 Dry Eye related Quality of life Score (DEQS) summary scores, and change from 
baseline at Month 6, Month 9, and Month 12 will be presented for Period 1.  Change 
from Month 12 will also be summarized for scores collected in Period 2 
Safety and Tolerability: 
In the Safety population, safety and tolerability endpoints are: 
 Intraocular pressure (IOP) and change from baseline at Month 12, Month 24 and Month 
36 visits 
 
Best Corrected Distance Visual Acuity (BCDVA) and change from baseline at Month 6, 
Month 12, Month 24 and Month 36 visits 
 
Incidence and severity of ocular and systemic adverse events (AEs) over the three-year 
study period. 


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3. 
STUDY DESIGN 
3.1. 
General Study Design  
This is a phase IIIb, prospective, interventional, multicentre, three-year study to explore the long-
term evolution of sign and symptoms, and occurrence of complications in dry eye disease 
subjects with severe keratitis receiving IKERVIS® (1mg/ml ciclosporin) eye drops.  All enrolled 
subjects will enter a period of 12 months of treatment (Period 1) with open-label IKERVIS® 
treatment [once daily (QD) into the affected eye(s) at bedtime].  At Month 12 visit, markedly 
improved subjects will continue the study for an additional 24 months randomized, double-
masked treatment period (Period 2) to receive either IKERVIS® QD or vehicle QD (at a ratio of 
3:2), Figure 1.   
Figure 1. 
Study Design Diagram 
 
Markedly improved subjects are defined as subjects having a corneal fluorescein staining (CFS) 
score improvement from baseline of 2 grades or more on the modified Oxford scale [unless if the 
subject had a CFS score of 5 at baseline, the improvement in CFS has to be 3 grades or more] in 
the study eye.  Subjects who are not markedly improved at Month 12 based on the above 
definition will be terminated from the study. 
This study will be conducted in about 36 sites located in European and non-European countries. 
 
3.2. 
Randomization and Masking 
Period 1 of the study is open-label, single arm treatment with IKERVIS.  No randomization is 
needed in Period 1 (from Baseline for the first 12 months of treatment). 
At the beginning of Period 2, (ie. the Month 12 visit), subjects who achieve a marked improvement 
(ie. CFS score improvement from baseline of 2 grades or more [unless if the subject had a CFS 


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score of 5 at baseline, the improvement in CFS has to be 3 grades or more]) will be randomly 
assigned (by the IWRS/IVRS) in a 3:2 ratio to receive either IKERVIS or Vehicle for two years 
in a double-masked fashion. The randomization will be stratified by region (Europe vs. non-
Europe), and the permuted block randomization will be used within each stratum. 
The randomization schedule will be generated and implemented using central randomization via 
Interactive Response Technology (Rave RTSM). Each randomized subject will receive numbered 
study medication kits as assigned by Rave RTSM. 
Treatment assignments during the Double-Masked Treatment Period will be masked to Santen 
employees (except Drug Supply personnel), study subjects, and Investigators. The investigator 
should try to avoid breaking the masking codes. However, in case of emergency only, (i.e. 
serious adverse event [SAE] and only when this information influences the subject's 
management), the investigator is entitled to unmask the subject by using IWRS, in order to 
obtain the study medication information (i.e. IKERVIS® or vehicle) to immediately start the 
appropriate treatment [to be recorded in the source data and eCRF (electronic Case Report 
Form)]. A record will be made of the date, time and reason for breaking the code. The 
investigator should inform the Sponsor immediately after unmasking. The details of this 
unmasking procedure will be described in a separate document. Subjects unmasked for the 
management of a SAE will be discontinued from the study. 
3.3. 
Sample Size Determination 
The sample size of this study is not planned from a formal sample size calculation since formal 
statistical hypothesis testing will not be performed for the primary endpoints.  In this study, we 
plan to enroll 350 subjects. Of the 350 subjects, it is estimated that approximately 70% (245 
subjects) would become markedly improved in CFS after Month 12 and enter the Period 2 (double-
masked randomized period), based on Santen previous IKERVIS studies. With a 3:2 
randomization allocation ratio, a sample size of 147 for IKERVIS® and 98 for Vehicle will allow 
us to detect a difference of 0.4 or more in CFS score with 80% power assuming the standard 
deviation of the difference is 1.10. 
Petroutsos et al. (1992) showed that after 6 years of follow-up on DED subjects, a lower-bound 
of the estimated complication rate was 4% in severe DED subjects.  In the current study, 350 
subjects treated with IKERVIS® for at least one year would have 95% power to detect at least 
one ocular complication that occurs at 1% rate with type I error rate of 0.05. 
3.4. 
Visits and Assessments    
There are 5 scheduled visits for each subject in Period 1 (open-label treatment period, Day 1 
Visit to Month 12 Visit) and 8 additional visits for markedly improved subjects who enter Period 
2 (double-masked treatment period, Month 12 Visit to Month 36 Visit).  Assessments at each 
visit and the visit window for each post-baseline assessment are specified in the Assessment 
Schedule shown on Table 1.    


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Table 1. 
Study Design and Schedule of Assessments 
 
Baseline 
Period 1 
Period 2 
End of Study 
Visit 
 
 
Day 1 
 
Montha 3 (D90),  
6 (D180) and 
9 (D270) 
(± 7 days) 
Month ah        
12 (D360) 
(± 7 days) 
Month a 15 
(D450),    21 
(D630), 27 (810) 
and 33 (D990) 
(± 7 days) 
Month a 18 
(D540), 
24 (D720) and     
30 (D900) 
(± 7 days) 
Month a 36 
(D1080) 
(± 7 days)/ 
Early 
Termination 
Unscheduled 
visit 
Informed consent 
X 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria  
X 
 
 
 
 
 
 
Ocular and systemic medical history 
X 
 
 
 
 
 
 
Previous and concomitant ocular and 
systemic medications  
X 
X 
X 
X 
X 
X 
X 
Artificial tears use b 
X 
X 
X 
X 
X 
X 
X 
Symptoms evaluation (SANDE)c 
X 
X 
X 
X 
X 
X 
X 
Symptoms evaluation (0-4 point scale) c  
X 
X 
X 
X 
X 
X 
X 
Quality of life questionnaire  
(DEQS) 
X 
Xd 
X 
 
X 
X 
 
Best corrected distance visual acuity 
(BCDVA) 
X 
Xd 
X 
 
X 
X 
 
Slit lamp examination 
X 
Xd 
X 
 
X 
X 
 
Tear break up time (TBUT) 
X 
X 
X 
X 
X 
X 
X 
Corneal and Conjunctival Fluorescein 
staining (Modified Oxford Scale) 
X 
X 
X 
X 
X 
X 
X 
Schirmer test  
(without anesthesia) 
X 
 
X 
 
Xe 
X 
 
Intraocular Pressure  (IOP)  
X 
 
X 
 
Xe 
X 
X 
Urine pregnancy test (women of 
childbearing potential only) 
X 
X 
X 
X 
X 
X 
 
Adverse events (AEs) 
 
X 
X 
X 
X 
X 
Xf 


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Baseline 
Period 1 
Period 2 
End of Study 
Visit 
 
 
Day 1 
 
Montha 3 (D90),  
6 (D180) and 
9 (D270) 
(± 7 days) 
Month ah        
12 (D360) 
(± 7 days) 
Month a 15 
(D450),    21 
(D630), 27 (810) 
and 33 (D990) 
(± 7 days) 
Month a 18 
(D540), 
24 (D720) and     
30 (D900) 
(± 7 days) 
Month a 36 
(D1080) 
(± 7 days)/ 
Early 
Termination 
Unscheduled 
visit 
Registration of subjects status in 
IWRS/IVRS (e.g. enrolment, 
randomisation, EoS/ET) 
X 
 
X 
 
 
X 
X 
Compliance with study medication 
regimen 
 
X 
X 
X 
X 
X 
X 
Dispensation of unpreserved artificial 
tears 
X 
X 
X 
X 
X 
 
X g 
Dispensation of open-label study 
medication 
X 
X 
 
 
 
 
X g 
Dispensation of masked study 
medication  
 
 
Xhi 
Xi 
Xi 
 
X g 
Collection of used study medication 
X 
X 
X 
X 
X 
X 
X 
a   Months of 30 days. 
b  Artificial tears (AT) use assessed by questioning the subject at each study visit. 
c  Symptom of dry eye will be evaluated at each study visit by completing SANDE questionnaire and 5 symptoms using a 0-4 point scale. 
d   QoL and BCDVA will NOT be assessed and slit lamp examination will not be performed at Month 3 and 9. TBUT and corneal and conjunctival fluorescein staining 
which will be performed at each visit.  
e  Schirmer test and IOP will NOT be performed at Month 18 and 30 visits. 
f  Record AEs if the unscheduled visit is after the first study drug administration. 
g  Dispensation of study medication and/or unpreserved artificial tears if necessary.  
h  Randomisation of markedly improved subjects at Month 12 visit.  
I  Dispensation of masked study medication (IKERVIS® or Vehicle). 
 


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4. 
DEFINITIONS 
4.1. 
Time-Related Terms  
4.1.1. 
Baseline Visit 
For this study, the baseline visit is the Day 1 Visit when a subject was enrolled into this study (as 
a non-screen failure subject who signed informed consent) and received open-label IKERVIS 
treatment in Period 1.  
4.1.2. 
Treatment Start Date and End Date 
The treatment start and end dates for each treatment period and the study are defined as follows: 
Treatment Period 
Treatment Start Date 
Treatment End Date 
Open-Label 
Treatment Period 
(Period 1) 
The date of the first dose of 
the open-label IKERVIS 
treatment (or Day 1 date) 
The date of the last dose of the open-label 
IKERVIS treatment 
 The date of the day before the Month 12 
Visit will be considered the Period 1 
treatment end date for subjects who 
completed Period 1 treatment. 
 The date of the day before the Exit Visit will 
be used for subjects who prematurely 
discontinued from the study.  If the Exit Visit 
date of a non-completer is not available, then 
the day before the last available visit date 
will be considered the treatment end date. 
Double-Masked 
Treatment Period 
(Period 2) 
The date of the first dose of 
the double-masked study 
treatment (or Month 12 Visit 
date) 
The date of the last dose of the double-masked 
study treatment 
 The date of the day before the Month 36 
Visit will be considered the Period 2 
treatment end date for subjects who 
completed the study. 
 The date of the day before the Exit Visit will 
be used for subjects who prematurely 
discontinued from the study.  If the Exit Visit 
date of a non-completer is not available, then 
the day before the last available visit date 
will be considered the treatment end date. 
For each treatment period, the treatment end date will be set to missing if the treatment start date 
is missing. 


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4.1.3. 
Study Day 
The study day describes the relative day of an observation starting with the reference date 
designated as Study Day 1.  In this study, the treatment start date is the reference date. 
For Period 1 and entire study period, the study day will be calculated as: 
Study Day = Date – Period 1 Treatment Start Date + 1 
For subjects who entered Period 2 (i.e., got randomized), their Period 2 study day will be 
calculated as: 
Period 2 Study Day = Date – Period 2 Treatment Start Date + 1 
4.1.4. 
Analysis Visit and Analysis Window 
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 a measurement should be mapped to. 
The following analysis windows will be applied to minimize the amount of missing data for 
analysis purposes: 
Analysis Visit (Target Study Day) 
Protocol Visit Window 
Analysis Window 
Period 1 
(Refers to Study Day for the 
entire study period) 
(Refers to Period 1 Study Day) 
Baseline (Day 1) 
[1, 1] 
[-, 1] 
Month 3 (Day 90) 
[83, 97] 
[2, 135] 
Month 6 (Day 180) 
[173, 187] 
[136, 225] 
Month 9 (Day 270) 
[263, 277] 
[226, 315] 
Month 12 (Day 360) 
[353, 367] 
[316, ET in Period 1 or 
Randomization First Dose Date in 
Period 2] 
Period 2 
(Refers to Study Day for the 
entire study period) 
(Refers to Period 2 Study Day) 
Month 12 (Day 360) 
[353, 367] 
[-, 1(First Dose Date in Period 2)] 
Month 15 (Day 450) 
[443, 457] 
[2, 135] 
Month 18 (Day 540) 
[533, 547] 
[136, 225] 
Month 21 (Day 630) 
[623, 637] 
[226, 315] 
Month 24 (Day 720) 
[713, 727] 
[316, 405] 
Month 27 (Day 810) 
[803, 817] 
[406, 495] 
Month 30 (Day 900) 
[893, 907] 
[496, 585] 
Month 33 (Day 990) 
[983, 997] 
[586, 675] 
Month 36 (Day 1080) 
[1073, 1087] 
[676, 765] 
ET= Early Termination.  


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The analysis visit of a measurement will be determined based on the study day of the 
measurement and specified analysis window, and is not necessarily the same with the protocol 
study visit where the measurement was collected.  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 latter one will be selected for that visit.   
4.1.5. 
Extent of Exposure 
The extent of exposure (days) to study medication will be assessed by duration of treatment 
exposure. 
 For subjects who only received study treatment in Period 1 and exited the study, their 
duration of treatment exposure will be derived as: 
            Duration of IKERVIS exposure =  
                            
(Period 1 Treatment end date – Period 1 Treatment start date) + 1 
 For subjects who entered Period 2 and received IKERVIS treatment, their duration of 
treatment exposure will be derived as: 
            Duration of IKERVIS exposure =  
(Period 2 Treatment end date – Period 1 Treatment start date) + 1 
 For subjects who entered Period 2 and actually received the Vehicle treatment, their 
duration of treatment exposure will be derived as: 
   Duration of IKERVIS exposure =  
(Period 1 Treatment end date – Period 1 Treatment start date) + 1 
         Duration of Vehicle exposure =  
(Period 2 Treatment end date – Period 2 Treatment start date) + 1 
4.2. 
Endpoint-Related Definitions 
4.2.1. 
Study Eye and Fellow Eye 
The study eye will be the eye that fulfils all the criteria listed under the inclusion criteria #5. If 
both eyes are eligible, the eye with the highest baseline CFS score will be chosen. If not 
discriminant, the eye with the lowest Schirmer test value will be chosen. If not discriminant, the 
right eye will be chosen as the study eye.  The other eye will be the non-study eye, or fellow eye. 
4.2.2. 
Baseline Score 
The baseline score is the observed measurement at Baseline (Day 1). 
In addition, for subjects who got randomized in Period 2, the observed measurements made at 
Month 12 Visit will be used as baseline scores for Period 2.  If a Month 12 measurement is 


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missing, the last observed measurement or derived score prior to the first dose of the Period 2 
double-masked study treatment will be used to impute the baseline score for Period 2. 
4.2.3. 
Change from a Reference Point 
For Period 1 and Entire Study analyses, the change from baseline at a post-baseline visit will be 
derived as: 
Change = (Score at the Post-Baseline Visit) – (Baseline Score) 
For Period 2 analyses, change from Month 12 will be the change used in the analyses.  
4.3. 
Efficacy-Related Definitions 
4.3.1. 
SANDE Global Score 
The SANDE global score will be calculated using the following formula: 
SANDE Global Score = ඥ(Frequency of symptom score) x (Severity of symptom score) 
If frequency or severity will be missing for a subject at the same visit, the SANDE global score 
will be missing. 
4.3.2. 
Dry Eye symptoms-related Quality of Life Score (DEQS) 
Dry Eye related Quality of life Score (DEQS) consists of 15 items related to dry eye symptoms 
and influence on daily life. The overall degree of Quality of Life impairment is calculated as a 
summary score (0 to 100). 
The DEQS includes two subscales, which first assess the frequency of the symptoms and 
disability (0 to 4) and then assess symptom degree (1 to 4). 
The DEQS overall frequency of impairment score will be calculated with the following 
formula (Inomata et al., 2020; Sakane et al., 2013):  
 score  =  
(ୱ୳୫ ୭୤ ୲୦ୣ ୊୰ୣ୯୳ୣ୬ୡ୷ ୱୡ୭୰ୣୱ ୭୤ ୟ୪୪ ୯୳ୣୱ୲୧୭୬ୱ ୟ୬ୱ୵ୣ୰ୣୢ)× ଶହ
୲୭୲ୟ୪ ୬୳୫ୠୣ୰ ୭୤ ୯୳ୣୱ୲୧୭୬ୱ ୟ୬ୱ୵ୣ୰ୣୢ
 
The DEQS overall degree of impairment score will be calculated by the following steps: 
1. For all questions with the frequency score (Column A) 0, set the degree score 
(Column B) to 0. 
2. Calculate overall degree score with the formula:  
 score  =  
(ୱ୳୫ ୭୤ ୲୦ୣ ୈୣ୥୰ୣୣ ୱୡ୭୰ୣୱ ୤୭୰ ୟ୪୪ ୯୳ୣୱ୲୧୭୬ୱ ୟ୬ୱ୵ୣ୰ୣୢ)× ଶହ
୲୭୲ୟ୪ ୬୳୫ୠୣ୰ ୭୤ ୯୳ୣୱ୲୧୭୬ୱ ୟ୬ୱ୵ୣ୰ୣୢ
 . 
The summary scores range from 0 to100, with a higher score representing greater disability.   


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4.3.3. 
Conjunctival Fluorescein Staining Total Score 
Conjunctival fluorescein staining total score will be the sum of conjunctival fluorescein staining 
score from nasal and temporal sides. 
 
4.3.4. 
Markedly Improved Status 
Markedly improved patients are defined for the Period 1 portion of study. The markedly 
improved status is defined as: 
 If a subject’s study eye had CFS score of 3 or 4 at Baseline, the improvement in CFS 
score at a post-baseline visit has to be 2 or more on the modified Oxford scale. 
 If a subject’s study eye had a CFS score of 5 at Baseline, the improvement in CFS score 
at a post-baseline visit has to be 3 grades or more on the modified Oxford scale. 
4.3.5. 
Relapse Status 
For this study, the relapse status is defined as an increase of CFS score of 2 or more on the 
modified Oxford scale (compared to CFS score at Month 12) during Period 2. 
4.4. 
Safety-Related Definitions  
4.4.1. 
Adverse Event 
Under the Protocol NVG14L127, an adverse event is any untoward medical occurrence in a 
clinical investigation subject administered a study drug. An AE does not necessarily have a 
causal relationship with the study drug.  For this study, the study drugs are IKERVIS® and 
Vehicle. Regardless of causality to the study treatment, an AE can be an unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of study treatment. 
An on-study AE can occur any time after the date of informed consent through the last study 
visit.  An AE will be considered as treatment-emergent if the onset date of the AE occurred on or 
after the treatment start date of the analysis period.  Treatment-emergent AEs (TEAEs) are a 
subset of on-study AEs.  Both on-study and TEAEs will be collected, but only TEAEs will be 
tabulated. 
The severity of each AE will be graded by the Clinical Investigator as Mild, Moderate, or 
Severe. AEs will be rated by the Investigator as to their causality/relationship to the study drug. 
Each AE will be classified into a system organ class (SOC) and coded to a preferred term (PT) 
using Medical Dictionary for Regulatory Activities (MedDRA), version 23.1 published in 2020. 
4.4.1.1. 
Ocular Surface Complications 
Under the Protocol NVG14L127, ocular surface complication is defined as the occurrence of 
any AE defined as corneal ulceration, corneal perforation, loss of visual acuity, or ocular 
infection. 


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4.4.1.1.1. Ocular Infection 
Ocular infection is defined as any ocular events (location reported as “ocular”) under SOC 
“Infections and infestations.”  
4.4.1.1.2. Corneal Perforation 
Corneal perforation is defined as PT of “Corneal perforation.” 
 
4.4.1.1.3. Corneal Ulceration 
Corneal ulceration is defined as PT of “Ulcerative keratitis.” 
 
4.4.1.1.4. Loss of Visual Acuity 
Loss of visual acuity is defined as all PTs under HLT “Visual impairment and blindness” except 
for PT of “colour blindness”. 
 
The list of AEs will be reviewed based on the above four definitions via a data review meeting. 
 
4.4.1.2. 
Serious Adverse Event 
An AE will be counted as a serious adverse event (SAE) if the Clinical Investigator selected “Yes” 
to the question ‘Is the adverse event serious?’ on the AE eCRF.  A serious AE may occur during 
any study phase (ie, baseline, treatment, or follow-up). SAE must fulfil one or more of the 
following criteria: 
 Results in death 
 It is immediately life-threatening* 
 It requires in-subject hospitalization or prolongation of existing hospitalization 
 It results in persistent or significant disability or incapacity 
 Results in a congenital abnormality or birth defect 
 It is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above (including sight-threatening** 
events and cancer or neoplasm of any type). 
*   Herein ‘Life-threatening’ refers to an event in which the subject was at immediate risk of death at the time of 
event; it does not refer to an event which hypothetically might have caused death.  
** Similarly ‘Sight-threatening’ refers to an event in which the subject was at immediate risk of losing sight; it 
does not refer to an event which hypothetically might have caused losing of sight. 


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Serious ocular adverse events include, but are not limited to the following adverse events which 
are considered to be sight-threatening and are to be reported as SAEs (medically important 
criteria): 
- 
Adverse Events that caused a decrease in visual acuity > 6 lines (compared with the last 
assessment of visual acuity at the last visit) 
- 
Adverse Events that caused a decrease in visual acuity to the level of Light Perception or 
worse 
- 
Adverse Events that  required surgical intervention or laser to prevent permanent loss of 
sight 
- 
Adverse Events associated with severe intraocular inflammation (i.e., 3+ anterior chamber 
cell/flare or 3+ vitritis) 
- 
Corneal perforation 
- 
Adverse Events that, in the opinion of the investigator,  may require medical intervention 
to prevent permanent loss of sight 
4.4.1.3. 
Case of Special Interest (CSI) 
The following cases are the AEs considered to be of special interest by the sponsor: 
 CSI related to AEs requiring (24 h) reporting to the sponsor: 
 Corneal ulceration 
 Decrease in visual acuity of 3 to 6 lines (compared with the last assessment of visual 
acuity at the last visit) 
 CSI related to medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional or 
subject 
 Overdose of study drug: Administration of a quantity of a medicinal product 
exceeding the dose defined in the study protocol. 
 Misuse of study drug: Situations where the medicinal product is intentionally and 
inappropriately used not in accordance with the study protocol. 
 Abuse of study drug: Persistent or sporadic, intentional excessive use of medicinal 
product which is accompanied by harmful physical or psychological effects. 
 Other 
4.4.1.4. 
Ocular Adverse Event 
An AE will be counted as an ocular AE if the Clinical Investigator selected “OD”, “OS”, or 
“OU” under ‘Eye(s) affected’ on the AE eCRF. 
4.4.1.5. 
Adverse Drug Reactions (ADR) 
An AE will be counted as an adverse drug reaction (ADR) if the Clinical Investigator answered 
‘Related’ to the AE eCRF question “Relationship to Study Drug”. 


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4.4.2. 
Other Safety Measures 
Table 2 lists the safety measures to be evaluated for this study. 
Table 2. 
Safety Assessments 
Safety Measures 
Note 
Intraocular pressure (IOP) 
IOP will be measured on both eyes at Baseline, Month 12, 
Month 24, and Month 36. 
Best-corrected distance visual 
acuity (BCDVA) 
BCDVA will be measured for each eye at Baseline, 
Month 6 and Month 12 in Period 1 and at Month 18, 
Month 24, Month 30, and Month 36 in Period 2 using a 
Snellen chart. 
BCDVA in Snellen scale will be converted to logMAR 
scale using the following equation and be used in all the 
BCDVA analyses: 
LogMAR VA = −logଵ଴൬Snellen numerator
Snellen denominator൰ 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy examinations will be performed 
at Baseline, Month 6 and Month 12 in Period 1 and at 
Month 18, Month 24, Month 30, and Month 36 in Period 
2. Grading of the Meibomian glands, lids, lashes, 
conjunctiva, tear film debris, anterior chamber and lens 
will be done on an ordinal scale.  Cataract severity will be 
assessed for phakic eyes only.  
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 study medication start date.  Concomitant medication is defined as any non-study medication 
taken concurrently while receiving study medication, i.e., the treatment period (period of time 
from first dose to last dose) of a concomitant medication taken by a subject must overlap with 
the treatment period (period of time from first dose to last dose) of the study medication. 
All prior and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Global, Version September 2019, format B3.  Each prior or concomitant 
medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) classification 
system and mapped to a WHO Drug preferred drug name. 
4.5.2. 
Concurrent Medical Conditions 
Concurrent medical conditions are those ongoing conditions or diseases that are present at the 
signing of informed consent. 
 


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5. 
GENERAL CONSIDERATIONS 
All measures will be summarized for Overall subjects in Period 1 and by treatment group in 
Period 2 as well as for the entire study descriptively.  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 (%).   
Unless otherwise specified, the following conventions on decimal places will be followed in 
reporting numerical results.   
Statistic 
Reporting Decimal Places 
Range (Low Value, High Value) 
Recorded decimal places 
Mean, Median  
Recorded value + 1 decimal places 
Confidence interval, standard deviation, standard error 
Recorded value + 2 decimal places 
P-value 
4 Decimal places (ex. 0.0021) 
No statistical testing will be conducted for both the efficacy and safety measures for Period 1 in 
this study. 
All data summary/analysis will be performed using SAS Version 9.4 or later.  Individual data, 
including relevant derived variables, will be listed. Additional analyses not specified in this SAP 
may be conducted if deemed necessary and will be documented in the CSR. 
5.1. 
Adjustments for Covariates 
For better understanding the long-term efficacy of IKERVIS, model based analysis (MMRM) 
will be conducted with corresponding baseline of each endpoint and geographic region (Europe 
vs. non-Europe) as covariates.  The detail of each model will be described in Section 8.   
5.2. 
Handling of Missing Data 
No imputation for missing data will be performed on any efficacy and safety endpoints. Unless 
specified otherwise, descriptive summaries will be based on observed cases. 
Completely or partially missing onset and resolution dates for AEs, Concomitant Medications 
(CM), and Medical History (MH) will be imputed in a conservative fashion as follows:   
Incomplete Adverse Event Onset Date 
1. Year imputation  
o If year is missing (or AE onset date is completely missing), then the onset date will 
not be imputed. 
2. Month imputation 
o If year is not missing but month is missing, then:  


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 
If year = year of first study dose date, then set the month and day to the day and 
month of first study dose 
 
Else if year ≠ year of first study dose: set month to January 
3. Day imputation 
o If day is missing (month and year not missing), then: 
 If year = year and month = month of first study dose, then set day to day of first 
study dose 
 Else if year ≠ year and month ≠ month of first study dose, then set day to first 
day of the month in the year 
Incomplete Adverse Event Resolution Date 
Do not impute if any resolution date is missing.  
If the duration of AE is needed, the following approach may be considered: 
o 
If year is missing (or AE resolution date is completely missing): do not impute 
o 
If year is not missing but month and day are missing: impute December 31st for missing 
month and day 
o 
If year and day are not missing but month is missing: impute December for missing 
month 
o 
If year and month are not missing but day is missing: impute last day of the month for 
missing day. 
Incomplete CM or MH Onset Date  
1. If year is missing (or CM/MH onset date is completely missing), do not impute 
2. If year is not missing but month and day are missing, impute January 1st for missing 
month and day 
3. If year and day are not missing but month is missing, impute January for missing month 
4. If year and month are not missing but day is missing, impute 01 for missing day 
Incomplete CM or MH Resolution Date 
1. If a resolution date is completely missing, do not impute.  
2. If year is not missing but month and day are missing, use the last day of the year to 
impute the missing month and date parts of the resolution date. 
3. If year and month are not missing but day is missing, use the last day of the month to 
impute the missing date part of the resolution date 
5.3. 
Multi-Center Studies 
This study will be conducted in about 36 sites located in European and non-European countries.  
Sites will not be pooled for any inferential analysis.     


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5.4. 
Multiple Comparisons / Multiplicity 
The objective of this study is to better understanding of long-term efficacy for exploratory 
purpose.  No multiple comparison will be planned. 
5.5. 
Interim Analysis 
There is one interim analysis planned for this study.  The purpose of the interim analysis is to 
present appropriate summary of data collected for the period 1. Interim analysis will be conducted 
once all subjects will have completed their Month 12 Visit or withdrawal visit.  
Data cut criteria for this interim analysis is shown in Table 3. 
 
Table 3  
Data Cut Plan for Interim Analysis 
Analysis Data 
Data Example 
Data Cut Criteria 
Visit Data  
IOP, TBUT, DEQS, etc. that are 
collected on visit date 
Data collected at Month 12 or earlier 
will be included. 
Non-visit Data 
AE, medication, procedures, 
CSI, etc. 
Incidents that happened up to the day 
of the first dose in Period 2 study drug 
will be included in the analysis. 
 
Since the first 12 months of the study will be open-label study, no adjustment of alpha level 
and no Data Monitoring Committee will be needed for this study. 
 
 


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6. 
ANALYSIS POPULATION  
Analysis populations defined for each analysis period are as follows.  
For Period 1:  
 The FAS (Full Analysis Set) Period 1 population consists of all enrolled subjects who 
received at least one dose of the study medication and had at least one post-baseline sign 
or symptom assessment of the study eye during Period 1. This will be the population used 
for efficacy analyses of Period 1.   
 The PPS (Per-Protocol Set) Period 1 will be a subset of FAS, restricted to the subjects 
who fulfill the protocol in the terms of the eligibility, interventions, and outcome 
assessment.  It will be the analysis population for some sensitivity analyses. 
 The Safety Population Period 1 consists of all subjects enrolled in Period 1 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 to be performed with 
subjects as treated. 
 The Sjögren Patients Population consists of subjects who were known to have diagnostic 
status of the Sjögren disease based on the medical history obtained at baseline.  
 The Subjects Markedly Improved during Period 1 are defined as FAS subjects who 
achieve CFS score improvement from baseline of 2 grades or more (unless if the subject 
had a CFS score of 5 at baseline, the improvement in CFS has to be 3 grades or more) at 
anytime during Period 1. 
For Period 2 and Entire Study: 
 The FAS Period 2 (or FAS Entire Study) population consists of all randomized subjects 
who received at least one dose of the double-masked study medication and had at least one 
post-Month 12 sign or symptom assessment of the study eye during Period 2. This will be 
the population used for efficacy analyses.   
 The PPS Period 2 (or PPS Entire Study) will be a subset of FAS Period 2, restricted to 
the subjects who fulfill the protocol in the terms of the eligibility, interventions, and 
outcome assessment.  It will be the analysis population for some sensitivity analyses.   
 The Safety Population Period 2 (or Safety Population Entire Study) consists of all 
subjects randomized in Period 2 who received at least one dose of the double-masked study 
medication and for whom any follow-up information is available in Period 2. It will be the 
analysis population for safety analyses to be performed with subjects as treated. 
 The Sjögren Patients Population (Period 2 or Entire Study) consists of subjects who 
were known to have diagnostic status of the Sjögren disease based on the medical history 
obtained at baseline and satisfies FAS Period 2 or Safety Population Period2 criteria 
depending on analysis. 
 
 


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7. 
SUMMARY OF STUDY POPULATION DATA 
7.1. 
Subject Disposition 
The disposition of all subjects who are enrolled in Period 1 will be presented in a table. The 
disposition summary will include the number and percentage of subjects in FAS Period 1, PPS 
Period 1, Safety Population Period 1, completers and non-completers at Month 12 Visit. In 
addition, Sjögren Patients in Period 1, Subjects Markedly Improved in Period 1 will also be 
presented.   
In addition, the subject enrollment will be summarized by geographic region, country, and site.       
Subject disposition of Period 2 will be presented in a separate table in terms of all subjects who 
are randomized in Period 2 by treatment and overall.  The summary will include the number of 
subjects in the FAS Period 2, PPS Period 2, Sjögren Patients in Period 2,  and Safety Population 
Period 2 as well as completers and non-completers at Month 36 Visit along with the primary 
discontinuation reason.   
The subject distribution of randomized subjects in Period 2 will also be summarized by 
geographic region, country, and site.       
7.2. 
Demographics and Other Baseline Characteristics 
For Period 1 summary, subject demographics and baseline characteristics will be summarized for 
the FAS Period 1 population, the Sjögren Patients Population, and the Markedly Improved 
Subjects in Period 1.  The descriptive summary will be repeated for the FAS Period 2 population 
for each treatment group and overall for Period 2 summary and Sjögren Patients to satisfy FAS 
Period 2. The Entire Study summary will not be provided because the FAS Entire Study 
population is same as the FAS Period 2 population. 
For subject demographics, the following variables will be summarized:  
 Age at enrollment (continuous and categorical: < 65 years or ≥ 65 years) 
 Sex (categorical: male or female) 
 Ethnicity (categorical: Hispanic/Latino or Not) 
 Race (categorical: American Indian or Alaska Native, Asian, Black or African American, 
Native Hawaiian or Other Pacific Islander, White, or Other) 
For baseline characteristics, the following variables will be summarized for study eye 
(summarize for fellow eye if needed):   
 CFS Score on the Modified Oxford Scale (<3 and each category) 
 Schirmer test without anaesthesia (<10 mm/5 min or ≥10 mm/5 min) 
 Symptom Score (Number of subjects with a score ≥ 2) 
 Primary diagnosis (dry eye disease: both eyes or single eye)  
 Duration of dry eye disease (years) 


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 Sjögren Disease status (yes or no) where appropriate 
 Alcohol use [yes or no; if yes, ≤ 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 or no) 
 Tobacco use  
o Yes  
 Ex-smoker (number of packets per year and duration of smoking) 
 Current smoker (number of packets per year and duration of smoking) 
o No  
 Passive tobacco use (yes, no) 
7.3. 
Medical History 
For this study, medical and surgical history and adverse events will be coded using  
MedDRA 23.1.  Each medical event will be classified into a SOC and mapped to a Preferred 
Term (PT). 
The medical and surgical history will be summarized for the FAS Period 1 population, the 
Sjögren patients population, and the subjects markedly improved in Period 1.  Subjects reporting 
any medical and surgical history at baseline will be tabulated by SOC and PT for each planned 
treatment and overall.  These will be also summarized for the FAS Period 2 population and 
Sjögren Patients to satisfy FAS Period 2. 
7.4. 
Protocol Deviations 
In this study, protocol deviations are categorized as follows: 
 Informed consent 
 Inclusion/exclusion criteria 
 Concomitant treatment  
 Investigational product  
 Procedures/tests/assessments 
 Protocol Implementation 
 Randomization 
 Safety reporting  
 Time Window 
 Other 
A protocol deviation is considered important 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 important protocol deviations prior to 
database lock.   


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The protocol deviations will be summarized for Period 1 and Period 2 separately using the FAS 
Period 1 subjects and the FAS Period 2 respectively. Subjects with any important protocol 
deviations will be tabulated by deviation category by study period and for each planned 
treatment and overall for Period 2.  In addition, important protocol deviations will also be listed. 
7.5. 
Prior and Concomitant Medications 
Non-study medications will be categorized into prior medications and concomitant medications.  
Specifically, the prior medication is defined as any non-study medication taken and ended prior 
to the treatment start date.  The concomitant medication is defined as any non-study medication 
taken concurrently while on the study medication, i.e., the treatment period of a concomitant 
medication taken by a subject needs to overlap with his/her treatment period of the study 
medication. 
For this study, non-study medications, including prior and concomitant medications, will be 
coded using WHO Drug, Version Enhanced (September 2019) format B3.  Each non-study 
medication will be classified using the Anatomical-Therapeutic-Chemical (ATC) classification 
system and mapped to a WHO Drug preferred drug name.   
Non-study medications will be summarized for the Safety population.  Prior medications will be 
summarized for both the Safety Population Period 1 and Period 2. Concomitant medications will 
be summarized by study period. For Period 2, concomitant medications will be summarized by 
each actual treatment received and overall. A subject will be counted at most once for each 
medication per period, even if the subject took the same medication on multiple occasions. In 
addition, prior medications and concomitant medications will also be listed, separately.  
For the Sjögren patients population, prior and concomitant medication uses will be summarised 
separately. 
7.6. 
Treatment Compliance 
Compliance to the study medication use is tracked on the Compliance eCRF as the number of 
single dose medication containers not used and returned.  
Due to the irregularities in returning containers caused by COVID-19 situation, the treatment 
compliance will be assessed by study period rather than by intervals based on scheduled visits as 
specified in the protocol. Since some visits, for example, happened remotely, dispensing or 
returning of study drug could not happen on a scheduled time.  Compliance rate will be 
calculated for Period 1, and Period 2, respectively. 
For a given analysis period, compliance rate will be calculated using the following formula, 
which assumes that the unreturned containers are not used: 
Treatment Compliance Rate (%) in Period x 
  =  
୒୭.  ୭୤ ୢ୧ୱ୮ୣ୬ୱୣୢ ୡ୭୬୲ୟ୧୬ୣ୰ୱ–(୒୭.  ୭୤ ୰ୣ୲୳୰୬ୣୢ ୳୬୳ୱୣୢ ୡ୭୬୲ୟ୧୬ୣ୰ୱ ା  ୒୭.  ୭୤ ୳୬୰ୣ୲୳୰୬ୣୢ ୡ୭୬୲ୟ୧୬ୣ୰ୱ) 
ୈ୳୰ୟ୲୧୭୬ ୭୤ ୔ୣ୰୧୭ୢ ୶
 × 100 
where the Duration of Period x is the number of days subjects should have administered study 
medication in the analysis period, calculated as  
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Compliance rate of ≥ 80% will be treated as compliant. Compliance will be summarized 
continuously and categorically (compliant and non-compliant) for FAS subjects for Period 1 and 
Period 2 separately. Period 2 summaries will be performed by planned treatment and overall.     
7.7. 
Exposure to Study Medication 
The extent of exposure to study medication will be assessed by duration of treatment exposure, 
derived as: 
Duration of treatment exposure = Treatment end date – Treatment start date + 1 
Specially, 
Period 
Treatment Start Date 
Treatment End Date 
Period 1 
Period 1 treatment start date 
Period 1 treatment end date 
Period 2 
Period 2 treatment start date 
Period 2 treatment end date 
Entire Study Period  
(for subjects who entered 
Period 2 and received 
IKERVIS treatment only) 
Period 1 treatment start date 
Period 2 treatment end date 
For subjects in the Safety Population, the duration of exposure will be summarized using 
descriptive statistics continuously and categorically for Period 1, Period 2 (by actual treatment 
received and overall), and for the entire study (for subjects who entered Period 2 and received 
treatment (IKERVIS/IKERVIS or IKERVIS/Vehicle) or for subjects who received IKERVIS 
treatment during Period 1 or 2) separately.  
The duration of exposure categories are: 
 Period 1: 1-90, 91-180, 181-270, or ≥ 271 days 
 Period 2: 1-90, 91-180, 181-270, 271-360, 361-450, 451-540, 541-630, ≥ 631days 
 Entire study period: 1-90, 91-180, 181-270, 271-360, 361-450, 451-540, 541-630, 631-
720, 721-810, 811-900, 901-990, or ≥ 991 days 
   
 
 
 


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8. 
EFFICACY ANALYSES 
Unless otherwise specified, all efficacy analyses will be performed on the study eyes of the FAS 
Period 1 population, the Sjögren Patients in Period 1, the Subjects Markedly Improved in Period 
1, the FAS Period 2 population, the FAS Entire Study population, and Sjögren Patients to satisfy 
FAS Period 2 (or FAS Entire Study Population) .      
8.1. 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the correlation between change from baseline in CFS score and 
SANDE symptoms score at each visit, and cross correlation of sign at visit X versus symptoms at 
visit X+i, if any.  Missing data will not be imputed. 
8.1.1. 
Primary Analysis  
For Period 1 analysis, Spearman correlation coefficient and its 95% confidence interval will be 
calculated for the correlation analysis between change from baseline in CFS score at visit X and 
SANDE symptoms score at each visit X+i in period 1 using the FAS Period 1 population.  
The primary efficacy endpoint analysis result will be presented graphically by plotting Spearman 
correlation coefficients calculated at each visit. Spearman correlation coefficients will be plotted 
for the timepoints where more than 2 lagtime correlations are calculated. The plots will have x-
axis to show lags, i, and y-axis to show Spearman correlation coefficients as shown in Figure 2, 
which is for X = Month 3.   
 
Figure 2. A Sample Plot of Correlation between Change from Baseline in CFS Score at 
Visit X vs. Change from Baseline in SANDE Score at Visit X + i 
Spearman Correlation Coefficients Calculated at Month 3 
 


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Interpretation of the results from graphical analysis:  
o If any individual graph shows a “bump” or a plateau at any lag > 0 point, as shown in 
Figure 2, it would be considered as an indication of existence of a lagged symptom 
response for CFS score at that particular visit X. 
o If there are at least half (50%) of the graphs show lagged symptom responses, we would 
conclude that dry eye symptoms (measured by SANDE questionnaire) show lagged 
response improvement in comparison to dry eye sign improvement. 
For Period 2 analysis, Spearman correlation coefficient between change from baseline in CFS 
score at visit X and SANDE symptoms score at each visit X+i, its 95% confidence interval will 
be calculated by treatment group. The analysis will be based on the FAS Period 2 population. 
For long term efficacy, the Entire Study analysis will be performed by repeating the Period 1 
analysis for the entire 3 year duration using the FAS Entire Study population. 
The analysis details are shown in Table 4 by study period. 
Table 4 
Analysis of Correlation between Change from Reference Point in CFS Score 
at Visit X and Change from Reference Point in SANDE Symptom Score at 
Visit X + i 
Study Period /  
      Analysis Population 
Reference Point 
Visit X 
Visit X + i 
Period 1 
      FAS Period 1 subjects 
Baseline 
Month 3* 
Month 3, Month 6,  Month 9, 
Month 12 
Month 6* 
Month 6, Month 9, Month 12 
Month 9 
Month 9, Month 12 
Month 12 
Month 12  
Period 2 
      FAS Period 2 subjects 
(by treatment arm) 
Month 12 
Month 15* 
Month 15,  Month 18,  Month 21,  
Month 24,  Month 27,  Month 30, 
Month 33,  Month 36 
Month 18* 
Month 18,  Month 21,  Month 24, 
Month 27,  Month 30,  Month 33,  
Month 36 
Month 21* 
Month 21,  Month 24,  Month 27,  
Month 30,  Month 33,  Month 36 
Month 24* 
Month 24,  Month 27,  Month 30, 
Month 33,  Month 36 
Month 27* 
Month 27,  Month 30, Month 33,  
Month 36 
Month 30* 
Month 30, Month 33,  Month 36 
Month 33 
Month 33,  Month 36 
Month 36 
Month 36 


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Study Period /  
      Analysis Population 
Reference Point 
Visit X 
Visit X + i 
Entire Study   
(Period 1 + Period 2)        
FAS Entire Study  
subjects  
 
Baseline 
Month 3* 
 
Month 3,  Month 6,  Month 9, 
Month 12, Month 15, Month 18, 
Month 21, Month 24, Month 27, 
Month 30, Month 33, Month 36 
Month 6* 
Month 6,  Month 9, Month 12,  
Month 15, Month 18, Month 21, 
Month 24, Month 27, Month 30, 
Month 33, Month 36 
. . . 
 
Month 27* 
Month 27, Month 30, Month 33, 
Month 36 
Month 30* 
Month 30, Month 33, Month 36 
Month 33 
Month 33, Month 36 
Month 36 
Month 36 
* Spearman correlation coefficients will be plotted 
 
8.1.2. 
Sensitivity Analysis  
Sensitivity analyses will be performed by using the subjects in the PPS Period 1 population, 
the PPS Period 2 population, and the PPS Entire Study population respectively for the data from 
corresponding analysis period.  
 
8.2. 
Analysis of Secondary Efficacy Endpoints 
8.2.1. 
Analysis of Continuous Endpoints 
The following secondary efficacy endpoints will be summarized using descriptive statistics such 
as number of observations (n), mean, standard deviation, median, minimum, and maximum by 
study period and visit. Also, Period 2 summaries will be done by the randomized treatment. 
 CFS score and change from baseline at each visit for Period 1 and Entire Study, and 
change from Month 12 for each visit in Period 2.  Shift tables that show the change 
from baseline (or Month 12) in CFS score as categorical variable will also be 
provided. 
 Conjunctival fluorescein staining score (nasal, temporal, and total scores separately) 
and change from baseline at each visit for Period 1 and Entire Study, and change from 
Month 12 for each visit in Period 2. Shift tables for nasal and temporal conjunctival 
staining scores will be presented as well. 


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 SANDE symptoms score and change from baseline at each visit for Period 1 and 
Entire Study, and change from Month 12 for each visit in Period 2 
 Symptoms score (5-point scale) and change from baseline at each visit, for each of 
the five symptoms assessed for Period 1 and Entire Study, and change from Month 12 
for each visit in Period 2 
 TBUT and change from baseline at each visit for Period 1 and Entire Study, and 
change from Month 12 for each visit in Period 2 
 Schirmer test and change from baseline at Month 12 visit (Period 1), change from 
Month 12 visit at Month 24 and Month 36 visits (Period 2), and at each visit (Entire 
Study) 
 Use of Artificial Tears over the last week (the average number of times per day and 
the number of days the artificial tears were used will be summarized separately) and 
change from baseline at each visit for Period 1 and Entire Study, and change from 
Month 12 for each visit in Period 2 
 
In addition to descriptive statistics and shift table, mixed model for repeated measures (MMRM) 
will be applied to estimate the response of change from Month 12 for the following endpoints;  
- 
CFS, Conjunctival fluorescein staining score, SANDE symptoms score, Symptoms score 
(5-point scale), TBUT, Schirmer test and Use of Artificial Tears over the last week.   
In each endpoint, separate MMRM will be applied, and the analysis will be performed using 
observed case of each endpoint with the FAS population Period 2.  Each model will include 
(randomized) treatment, visit, treatment by visit interaction as fixed effects, and the 
corresponding Month 12 value and geographic region (Europe vs. non-Europe) as covariates.  
Within-subject errors will be modeled using an unstructured (UN) covariance matrix.   If there 
are convergence issues, covariance matrix structures other than unstructured will be tried in the 
following order: (1) heterogeneous Toeplitz (TOEPH), (2) heterogeneous autoregressive of order 
1 (ARH(1)), (3) heterogeneous compound symmetry (CSH), and (4) compound  
symmetry (CS).  The first covariance structure that converges will be used.   
Least squares mean values for each treatment arm and the differences between least squares 
treatment arm means and associated 95% confidence intervals with t-distribution will be reported 
for each visit in addition nominal p-value. 
 
8.2.2. 
Analysis of DEQS-15 Questionnaire 
Dry Eye related Quality of life Score (DEQS) overall frequency score, overall degree score, and 
1 item overall assessment of symptom will be summarized by visit. For these summary scores, 
the change from baseline will also be provided for the FAS Period 1, for the subjects who 
experienced marked improvement during Period 1, and for the FAS Period 2 Entire Study.  
For subjects who are randomized in Period 2, the DEQS summary scores and change from 
Month 12 will be summarized at each visit by treatment group for data collected in Period 2 
using the FAS Period 2 population.   


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To describe a long term effect of study treatment on the quality of life, the DEQS scores and 
change from baseline will be summarized for the entire 3 year period using the FAS Entire Study 
population.   
   
8.2.3. 
Analysis of Time-to-Event Endpoints 
There are two time-to-event secondary efficacy endpoints in this study: 
 Occurrence and time-to-become markedly improved (defined as CFS score 
improvement of 2 or more on the modified Oxford scale at post-baseline)  
 Occurrence and time-to-relapse (increase of CFS score of 2 or more on the modified 
Oxford scale) 
For each endpoint, the occurrence rate will be tabulated using frequency (n) and percent (%). 
The time-to-event data will be summarized by median time to event and its 95% confidence 
interval or minimum, median and maximum in case total number of events will not be enough.  
Survival functions will be presented graphically with the Kaplan-Meier curve (Kaplan et al., 
1958) of event plot (failure plot). 
 
Figure 3 
Kaplan-Meier Curve of Time-to-become Markedly Improved 
 
Follow-up time in Period 1 (month) 
 
Time-to-become markedly improved will be analyzed using the FAS Period 1 population data.  
Time-to-relapse will be analyzed by using the FAS Period 2 data.  Median time-to-relapse, 
hazard ratio and 95% CI will be calculated from a Cox proportional hazards model with 
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geographic region (Europe vs. non-Europe) and treatment as factors, and CFS score at Month 12 
in the study eye as a covariate. 
 
8.2.4. 
Analysis of Others 
To evaluate the magnitude of corneal cleanliness (complete resolution), proportion of subjects 
with 0 score of CFS will be summarized by treatment group at each visit for period 2 with FAS 
period 2.  The number of subjects with 0 score of CFS, proportion (%) of subjects, difference of 
the proportion, the corresponding 95% confidence interval and p-value (Chi-square test) will be 
provided.   
 
 
8.3. 
Subgroup Analyses 
For period 1, the clinical subgroup of interest are 
 Sjögren patients  
 Subjects who experienced marked improvement during Period 1 where marked  
improvement is defined as CFS score improvement from baseline of 2 grades or more on 
the modified Oxford scale [unless if the patient had a CFS score of 5 at baseline, the 
improvement in CFS has to be 3 grades or more] in the analysis eye.  
Efficacy analysis of Period 1 will be repeated using this subpopulation. 
For Period 2, subgroup analysis by Sjögren patients will be conducted to investigate the 
treatment effects of the target population across region in Period 2.  Other subgroup analyses 
may be performed as deemed necessary. 
 
9. 
SAFETY ANALYSES 
The safety-related measures collected in this study include AEs, intraocular pressure (IOP), best-
corrected distance visual acuity (BCDVA), and slit-lamp biomicroscopy.  All the safety-related 
measures will be summarized descriptively on the Safety population by study period and by 
actual treatment received (Period 2). 
9.1. 
Analysis of Primary Safety Endpoint 
The primary safety endpoint for this study is the incidence rate and time-to-onset of ocular 
surface complications, which include corneal ulceration, corneal perforation, loss of visual 
acuity, or ocular infection. Missing data will not be imputed. 
The ocular surface complications incidence rate will be tabulated using frequency (n) and 
percentage (%) at Month 1-12, Month 13-24, Month 25-36 and for overall period 2 (Month 13-
36). Month 1-12 incidence rate will be summarized for Period 1 Safety population.  Month 13-


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24, Month 25-36, and Month 13-36 (overall period 2) summaries will be conducted for Period 2 
Safety population.  The relative risk of the ocular surface complications incidence rate between 
the two treatment groups will be assessed at Month 13-24, Month 25-36 and Month 13-36 by 
producing odds ratio and its 2-sided 95% exact confidence interval.  
For entire study analysis, the ocular surface complications incidence rate of IKERVIS group (a 
treatment group with IKERVIS during period) at Month 36 (1-36) will be compared to the 
existing epidemiologic rate in a comparable population, which was 4% based on results 
published by Petroutsos et al. (1992).  The ocular surface complications incidence rate at Month 
36 will be compared. This will be done using the Safety population Entire Study. Binomial 
proportions will be compared using SAS procedure PROC FREQ with binomial options.    
The relative risk of the two treatment groups in terms of the time-to-first-onset of ocular surface 
complications (first event of each subject) will be assessed by producing the hazard ratio and its 
2-sided 95% confidence interval if enough events are observed to make the analysis possible for 
period 2 (double masked period).  The estimated hazard ratio and 95% CI will be obtained from 
a Cox proportional hazards model with treatment group as a covariate and region as stratification 
factor.  Survival functions will be estimated using the Kaplan-Meier method, and Log-Rank test 
will be conducted to calculate nominal p-value. 
9.2. 
Adverse Event 
Subjects with any AE(s) will be tabulated by type of AE(s) by study period and for each actual 
treatment received and overall (Period 2 and Entire Study) for all AEs, ocular AEs, and non-
ocular AEs separately.  Unless otherwise specified, any AE experienced by either eye or both 
eyes will be counted once for that AE.  In addition to the overall AE summary, subjects with any 
AE(s) will be tabulated by SOC and preferred term.  A subject who experienced multiple AEs 
within a SOC or preferred term will be counted only once for that SOC or preferred term.  SAEs, 
ADRs, serious ADRs will be tabulated similarly. Non-serious AEs (including number of events) 
and CSIs will also be summarized by SOC and preferred term. 
AEs, SAEs, ADRs, serious ADRs, ocular AEs, AEs leading to death, AEs leading to study drug 
discontinuation, non-TEAEs, and CSIs, if any, will be listed separately.    
9.3. 
Intraocular pressure (IOP) 
Intraocular pressure (IOP) and its change from baseline (or change from Month 12) at each post-
baseline visit will be summarized by study period and treatment (Period 2 and Entire Study) for 
study eyes and fellow eyes separately. 
IOP scores and its change from baseline will be listed and records with IOP increase ≥ 10 mmHg 
at a particular visit will be flagged. 
9.4. 
Best-Corrected Distance Visual Acuity (BCDVA) 
Best-corrected distance visual acuity (converted in logMAR scale, see details in Table 2. Safety 
Assessments) and its change from baseline at each post-baseline visit will be summarized by 
study period and treatment (Period 2 and Entire Study) for study eyes and fellow eyes separately. 


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BCVA scores and its change from baseline will be listed and records with BCVA worsening of 3 
lines or more (i.e., increase in logMAR score ≥ 0.3) at a particular visit will be flagged.  Increase 
in logMAR scores means worsening in visual acuity. 
9.5. 
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, or 4=Very severe), rating 
scores and changes from baseline will be summarized by study period and analysis visit for study 
eyes and fellow eyes, separately. 
For lashes (Normal or Abnormal) and lens (Aphakic, Pseudophakic, or Phakic), shift from 
baseline in status will be summarized by analysis visit for study eyes and fellow eyes, separately. 
For phakic eyes, cataracts severity will be summarized by study period and analysis visit.  Any 
worsening in status from Normal at baseline to Abnormal after baseline in eye lashes will be 
listed.   
Slit-lamp parameters at each visit will be listed. Subjects with any worsening of ≥ 2 units (except 
for lashes and lens) from baseline, or lashes changed from normal at baseline to abnormal post-
baseline, or lens status change from phakic to pseudophakic or aphakic will be flagged.    
9.6. 
Urine Pregnancy Test  
Positive urine pregnancy test results will be listed.   


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10.  CHANGES TO THE PROTOCOL-SPECIFIED ANALYSES 
10.1.  The Term “Study Eye” 
The terms “analysis eye” and “study eye” were used interchangeably throughout the protocol.   
In this SAP the term “study eye” will be used throughout. 
10.2. 
Primary Efficacy Endpoint 
Primary Efficacy Endpoint  
"The correlation between mean change from baseline in CFS score and SANDE symptoms score 
at each visit, and cross correlation of sign at visit X versus symptoms at visit X+i (i starting from 
0), if any." was changed to "The correlation between change from baseline in CFS score and 
SANDE symptoms score at each visit, and cross correlation of sign at visit X versus symptoms at 
visit X+i (i starting from 0), if any." 
Secondary Efficacy Endpoint 
"Occurrence and time to become markedly improved (defined as CFS score improvement of 2 or 
more on the modified Oxford scale at Month 12)" was changed to " Occurrence and time to 
become markedly improved (defined as CFS score improvement of 2 or more on the modified 
Oxford scale)." 
10.3.  Descriptions of the Interim Analysis 
Once all patients will have performed their Month 12 visit or Early Termination visit, CFS, 
symptoms, quality of life and AEs will be analysed on clean data. 
Mean and mean change from baseline (signs, symptoms and QOLs) will be provided. 
Correlation coefficient between change from baseline in CFS score at visit X and symptoms 
score at each visit X+i will be summarised.  
The protocol section 13.7 says “Mean and mean change from baseline (signs, symptoms and 
QOLs) will be provided. Correlation coefficient between change from baseline in CFS score at 
visit X and symptom score at each visit X+i will be analized, where X includes scheduled visits 
from Day 1 to Month 12, and i is from 0 up to 4”.   
Revised in this SAP: “Mean and mean change from baseline (signs, symptoms and QoL 
parameters) will be summarized. Correlation coefficient between change from baseline in CFS 
score at visit X and symptom score at each visit X+i will be calculated, where X includes 
scheduled visits from Month 3 to Month 12, and i is from 0 up to 3 (for Month 3, Month 6, 
Month 9, and Month 12, respectively)”.   
 Day 1 is changed to Month 3 for the starting visit of X because Day 1 would have no 
changes in any score.  
 The ending number for i is changed from 4 to 3 due to one less visit. 
 Added “(for Month 3, Month 6, Month 9, and Month 12, respectively)” to the end for 
clarification purpose. 


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10.4. 
 Safety Population Definitions 
Definitions for the Safety population for Period 2 and the entire study are updated in Section 6. 
For Period 2 and Entire Study: 
 The FAS Period 2 (or FAS Entire Study) population consists of all randomized subjects 
who received at least one dose of the double-masked study medication and had at least one 
post-Month 12 sign or symptom assessment of the study eye during Period 2. This will be 
the population used for efficacy analyses.   
 The PPS Period 2 (or PPS Entire Study) will be a subset of FAS Period 2, restricted to 
the subjects who fulfill the protocol in the terms of the eligibility, interventions, and 
outcome assessment.  It will be the analysis population for some sensitivity analyses.   
 The Safety Population Period 2 (or Safety Population Entire Study) consists of all 
subjects randomized in Period 2 who received at least one dose of the double-masked study 
medication and for whom any follow-up information is available in Period 2. It will be the 
analysis population for safety analyses to be performed with subjects as treated. 
 The Sjögren Patients Population (Period 2 or Entire Study) consists of subjects who 
were known to have diagnostic status of the Sjögren disease based on the medical history 
obtained at baseline and satisfies FAS Period 2 or Safety Population Period2 criteria 
depending on analysis. 
 


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11. 
REFERENCES 
1. 
Inomata, T., Nakamura, M., Iwagami, M., Midorikawa-Inomata, A., Okumura, Y., 
Fujimoto, K., ... & Murakami, A. (2020). Comparing the Japanese version of the ocular 
surface disease index and dry eye-related quality-of-life score for dry eye symptom 
assessment. Diagnostics, 10(4), 203.   
2. 
Kaplan, E., Meier, P. (1958).  Nonparametric Estimation from Incomplete Observations.  
Journal of the American Statistical Association 53(282):457-81. 
3. 
Petroutsos G, et al. (1992). Sterile corneal ulcers in dry eye. Incidence and factors of 
occurrence. J Fr Ophtalmol. 1992;15(2):103-5. French. 
4. 
Sakane, Y., Yamaguchi, M., Yokoi, N., Uchino, M., Dogru, M., Oishi, T., ... & Ohashi, Y. 
(2013). Development and validation of the dry eye–related quality-of-life score 
questionnaire. JAMA ophthalmology, 131(10), 1331-1338.  
 
 
 


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12. 
APPENDICES 


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