Clinical trial NCT02013791
Conditions: Dry Eye Syndromes
Sponsor: Allergan
Start date: 2014-04-29; Completion date: 2017-04-12
Enrollment: 55 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate a new ophthalmic formulation of cyclosporine (Restasis® X) in patients with moderate to severe dry eye disease in two stages. Up to 3 doses will be studied in Stage 2 based on results from Stage 1. No patients participating in Stage 1 will participate in Stage 2 of this study. This study was terminated and Stage 2 of the study was cancelled.

Detailed description:

Arms: arm 1: Vehicle administered to study eye and Sham administered to non-study eye on Day 1. arm 2: Cyclosporine New Ophthalmic Formulation Dose A administered to study eye and Vehicle administered to non-study eye on Day 1. arm 3: Cyclosporine New Ophthalmic Formulation Dose B administered to study eye and Vehicle administered to non-study eye on Day 1. arm 4: Cyclosporine New Ophthalmic Formulation Dose C administered to study eye and Vehicle administered to non-study eye on Day 1. arm 5: Cyclosporine New Ophthalmic Formulation Dose D administered to the study eye and vehicle administered to the non-study eye on Day 1. arm 6: Cyclosporine New Ophthalmic Formulation Dose E administered to study eye and Vehicle administered to non-study eye on Day 1. arm 7: Cyclosporine New Ophthalmic Formulation Dose F administered to study eye and Vehicle administered to non-study eye on Day 1. arm 8: Cyclosporine New Ophthalmic Formulation Dose C administered to study eye and Vehicle administered to non-study eye on Day 1 and retreatment at Week 12 if applicable. arm 9: Cyclosporine New Ophthalmic Formulation Dose F administered to study eye and Vehicle administered to non-study eye on Day 1 and retreatment at Week 12 if applicable.
Interventions: intervention 1: Vehicle intervention 2: Sham intervention 3: Cyclosporine New Ophthalmic Formulation
Intervention descriptions: intervention 1: Vehicle of cyclosporine administered as per protocol intervention 2: Sham administered to non-study eye as per protocol on Day 1 intervention 3: Cyclosporine New Ophthalmic Formulation administered as per protocol

Protocol documents:
Prot_000.pdf: 
NCT02013791 
 
 
Study 192371-024 
 
 
Title: A Phase 2, Multi-center, Vehicle- and Sham-controlled, Randomized Study of 
RESTASIS® X in Patients With Moderate to Severe Dry Eye Disease 
 
 
 
Protocol Amendment 6 Date: Jan 19, 2017 
 
 
Statistical Analysis Plan (SAP) Date: June, 20, 2017 






 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
  
  
Investigator Printed Name  
  Signature 
  Date 
 
 


 
 
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Table of Contents 
Table of Contents 
...................................................................................................................... 4
 
List of Tables 
............................................................................................................................. 8
 
List of Figures 
........................................................................................................................... 8
 
Protocol Summary .................................................................................................................... 9
 
1  Background and Clinical Rationale 
................................................................................. 25 
1.1  Study Rationale 
...................................................................................................... 25 
1.2  Nonclinical Safety and Pharmacokinetics 
.............................................................. 27 
2  Study Objectives and Clinical Hypotheses 
...................................................................... 28 
2.1  Study Objectives 
.................................................................................................... 28 
2.2  Clinical Hypotheses ............................................................................................... 28 
3  Study Design 
.................................................................................................................... 29
 
3.1  Additional Study Design Details 
............................................................................ 31 
3.2  Data Review Committee 
........................................................................................ 31 
4  Study Population and Entry Criteria 
................................................................................ 32 
4.1  Number of Patients 
................................................................................................. 32 
4.2  Study Population Characteristics 
........................................................................... 32 
4.3  Inclusion Criteria 
.................................................................................................... 32 
4.4  Exclusion Criteria................................................................................................... 33 
4.5  Permissible and Prohibited Medications/Treatments 
............................................. 37 
4.5.1  Permissible Medications/Treatments 
........................................................ 37 
4.5.2  Prohibited Medications/Treatments 
.......................................................... 38 
4.5.3  Rescue Medications 
.................................................................................. 39 
5  Study Treatments 
............................................................................................................. 40 
5.1  Study Treatments and Formulations ...................................................................... 40 
5.2  Control Treatments 
................................................................................................. 40 
5.3  Methods for Masking 
............................................................................................. 40 
5.4  Treatment Allocation Ratio and Stratification ....................................................... 41 
5.5  Method for Assignment to Treatment Groups/Randomization 
.............................. 41 
5.6  Treatment Regimen and Dosing 
............................................................................. 42 
5.7  Storage of Study Medications/Treatments 
............................................................. 43 
5.8  Preparation of Study Medications/Treatments 
....................................................... 43 


 
 
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5.9  Treatment Administration ...................................................................................... 43 
5.10 Retreatment 
............................................................................................................ 43 
6  Response Measures and Summary of Data Collection Methods 
..................................... 44
 
6.1  Safety Measures 
..................................................................................................... 44 
6.2  Pharmacokinetic Measures..................................................................................... 45 
6.3  Exploratory Efficacy Measures 
.............................................................................. 46 
6.3.1  Health Outcomes Measures ...................................................................... 46 
6.4  Study Supplies 
........................................................................................................ 46 
6.5  Summary of Methods of Data Collection 
.............................................................. 47 
7  Statistical Procedures 
....................................................................................................... 48 
7.1  Analysis Populations 
.............................................................................................. 48 
7.2  Collection and Derivation of Exploratory Efficacy  Assessments 
......................... 49 
7.3  Hypothesis and Methods of Analysis 
..................................................................... 49 
7.3.1  Safety Analyses 
......................................................................................... 49 
7.3.2  Exploratory Efficacy Analyses ................................................................. 49 
7.3.3  Pharmacokinetic Analyses 
........................................................................ 49 
7.4  Subgroup Analyses 
................................................................................................. 50 
7.5  Sample Size Calculation ........................................................................................ 50 
7.6  Interim Analyses..................................................................................................... 50 
8  Study Visit Schedule and Procedures 
.............................................................................. 50 
8.1  Patient Entry Procedures 
........................................................................................ 51 
8.1.1  Overview of Entry Procedures 
.................................................................. 51 
8.1.2  Informed Consent and Patient Privacy ..................................................... 51 
8.2  Washout Intervals/Run-in 
....................................................................................... 51 
8.3  Procedures for Final Study Entry 
........................................................................... 52 
8.4  Visits and Associated Procedures 
........................................................................... 52 
8.4.1  Stage 1 
....................................................................................................... 52 
8.4.2  Stage 2 
....................................................................................................... 62 
8.5  Instructions for the Patients 
.................................................................................... 74 
8.6  Unscheduled Visits 
................................................................................................. 74 
8.7  Compliance With Protocol 
..................................................................................... 74 
8.8  Early Discontinuation of Patients .......................................................................... 75 
8.9  Withdrawal Criteria 
................................................................................................ 75 


 
 
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8.10 Study Termination 
.................................................................................................. 75 
8.11 Adverse Events ...................................................................................................... 75 
8.12 Definitions 
.............................................................................................................. 76 
8.12.1 Adverse Event 
........................................................................................... 76 
8.12.2 Serious Adverse Event 
.............................................................................. 76 
8.12.3 Severity 
..................................................................................................... 77 
8.12.4 Relationship to Study Drug or Study Procedure 
....................................... 77 
8.13 Procedures for Reporting Adverse Events 
............................................................. 77 
8.14 Procedures for Reporting a Serious Adverse Event 
............................................... 78 
8.15 Procedures for Unmasking of Study Medication 
................................................... 78 
9  Administrative Items ....................................................................................................... 79 
9.1  Protection of Human Patients ................................................................................ 79 
9.1.1  Compliance With Informed Consent Regulations (US 21  CFR Part 50) 
and Relevant Country Regulations ........................................................... 79 
9.1.2  Compliance With IRB or IEC Regulations 
............................................... 79 
9.1.3  Compliance With Good Clinical Practice 
................................................. 79 
9.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) 
................................................................................. 80 
9.2  Changes to the Protocol ......................................................................................... 80 
9.3  Patient Confidentiality ........................................................................................... 80 
9.3.1  Patient Privacy 
.......................................................................................... 80 
9.4  Documentation 
....................................................................................................... 81 
9.4.1  Source Documents 
.................................................................................... 81 
9.4.2  Case Report Form Completion ................................................................. 82 
9.4.3  Study Summary 
......................................................................................... 82 
9.4.4  Retention of Documentation 
..................................................................... 82 
9.5  Labeling, Packaging, and Return or Disposal of Study  Medications/Treatments  84 
9.5.1  Labeling/Packaging 
................................................................................... 84 
9.5.2  Clinical Supply Inventory 
......................................................................... 84 
9.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies 
.... 84 
9.6  Monitoring by the Sponsor .................................................................................... 84 
9.7  Handling of Biological Specimens......................................................................... 85 
9.7.1  Blood and Urine Samples for Safety Analysis 
.......................................... 85 
9.7.2  Blood Samples for Pharmacokinetic Analysis 
.......................................... 85 
9.7.3  Tear Samples 
............................................................................................. 85 
9.7.4  Impression Cytology Samples 
.................................................................. 85 


 
 
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9.8  Publications 
............................................................................................................ 86 
10 References 
........................................................................................................................ 87
 
11 Attachments 
..................................................................................................................... 89
 
11.1 Examination Procedures, Tests, Equipment, and Techniques 
................................ 89 
11.1.1 Vital Signs 
................................................................................................. 89 
11.1.2 Pregnancy Test 
.......................................................................................... 89 
11.1.3 Ocular Surface Disease Index 
................................................................... 89 
11.1.4 Patient Symptoms (Visual Analog Scale) 
................................................. 91 
11.1.5 Supplemental Dry Eye Patient Reported Outcomes  Questionnaire 
......... 91 
11.1.6 Dry Eye Treatment Satisfaction Questionnaire 
......................................... 92 
11.1.7 Treatment Assessment 
............................................................................... 92 
11.1.8 Best-corrected Visual Acuity .................................................................... 92 
11.1.9 Macroscopic Bulbar Hyperemia 
............................................................... 94 
11.1.10 Photographic Conjunctival Hyperemia Assessment 
................................. 94 
11.1.11 HRT3-Rostock — Ocular Surface Imaging 
.............................................. 94 
11.1.12 Slit-lamp Biomicroscopy Examinations 
................................................... 94 
11.1.13 Dilated Ophthalmic Examinations (conducted by treating  investigator) 
. 97 
11.1.14 Intraocular Pressure .................................................................................. 98 
11.1.15 Schirmer’s Tear Test with Anesthesia 
....................................................... 99 
11.1.16 Impression Cytology for Biomarker Analysis (conducted by treating 
investigator) 
.............................................................................................. 99
 
11.1.17 Tear Film Break-up Time Using a Dry Eye Test Fluorescein  Strip 
....... 100 
11.1.18 Corneal Sodium Fluorescein Staining .................................................... 100 
11.1.19 Lissamine Green Conjunctival Staining ................................................. 102 
11.1.20 Pharmacokinetic Tear Samples 
............................................................... 103 
11.1.21 Pharmacokinetic Blood Samples 
............................................................ 104 
11.1.22 Blood and Urine Sample Collection 
....................................................... 104 
11.1.23 Blood and Urine Sample Analysis 
.......................................................... 104 
11.2 RESTASIS X Administration 
............................................................................... 105 
11.3 Handling of Biological Specimens....................................................................... 105 
11.4 Glossary of Abbreviations 
.................................................................................... 106 
11.5 Protocol Amendment 1 Summary 
........................................................................ 108 
11.6 Protocol Amendment 2 Summary 
......................................................................... 111 
11.7 Protocol Amendment 3 Summary 
........................................................................ 113 
11.8 Protocol Amendment 4 Summary 
........................................................................ 115 
11.9 Protocol Amendment 5 Summary 
........................................................................ 118 


 
 
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11.10 Protocol Amendment 6 Summary 
........................................................................ 126 
 
List of Tables 
Table 1 
Dosage/Dose Regimen – Stage 1 Dose Escalation in Patients With Moderate 
to Severe Dry Eye Disease 
.............................................................................. 12
 
Table 2 
Dosage/Dose Regimen – Stage 2:  Baseline Dose and Retreatment in Patients 
With Moderate to Severe Dry Eye Disease .................................................... 13 
Table 3 
SCHEDULE OF VISITS AND PROCEDURES:  Stage 1 
............................. 20 
Table 4 
SCHEDULE OF VISITS AND PROCEDURES:  Stage 2 
............................. 22 
Table 5 
Investigator Procedure Assignments 
............................................................... 24 
Table 6 
Stage 2:  Randomization/Stratification Groups 
.............................................. 41 
Table 7 
Baseline Treatment and Retreatment Regions 
................................................ 44
 
 
List of Figures 
Figure 1 
Stage 1 Study Flow – Dose Escalation in Patients With Moderate to Severe 
Dry Eye Disease 
.............................................................................................. 14 
Figure 2 
Stage 2 Study Flow – Baseline Dose and Retreatment in Patients With 
Moderate to Severe Dry Eye Disease ............................................................. 15 




 
 
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Structure:    
 
Stage 1:  multicenter, randomized, investigator-masked, dose escalation, vehicle-controlled  
• single-dose, paired-eye comparison 
• paired-eye comparison, retreatment at week 12 (cohorts 6C and 6D) 
Stage 2:  multicenter, randomized, investigator-masked, parallel treatment groups, vehicle-controlled 
• single dose, bilateral treatment at baseline  
• bilateral retreatment at week 12 
 
Duration:   
Stage 1:  The duration per patient will be approximately 26 weeks (from screening to week 24 visit). 
Stage 2:  The duration per patient will be approximately 26 weeks (from screening to week 24 visit). 
 
Study Treatment Groups:    
Stage 1:  Vehicle, F1
 and F2 
 
  
Baseline and retreatment cohort 6C and 6D:  F1  
 and F2 
 
Stage 2:  Baseline and retreatment groups:  up to 3 dose groups:  vehicle, CFI  
, and CFI  
 
 
Controls:  
Stage 1:  sham 
treatment, vehicle 
Stage 2:  vehicle 
 
Dosage/Dose Regimen:   
Stage 1 will sequentially examine the safety of doses  
 of F1 and F2 administered 
 
 
 
 
 
 
 
 
 
 
 
   
 
y, 


 
 
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Stage 2: 
• participation in stage 1 of this study 
 
Response Measures 
Stage 1: 
Safety:   
• adverse events 
• best-corrected visual acuity (BCVA; manifest refraction at screening and exit visits) 
• macroscopic hyperemia assessment and slit-lamp biomicroscopy 
• dilated ophthalmic exam 
• photographic conjunctival hyperemia assessment  
• intraocular pressure (IOP) 
• vital signs 
• laboratory tests (chemistry, hematology, urinalysis) 
• urine pregnancy test (for females of childbearing potential) 
 
Pharmacokinetics:   
• ocular pharmacokinetics (assessed from tear samples)  
• systemic pharmacokinetics  
 
   
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
Health Outcomes: 
• Supplemental Dry Eye Patient Reported Outcomes Questionnaire 
 
 
   
 
  
 
 




 
 
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For both stages 1 and 2, a model-independent approach will be used to calculate pharmacokinetic parameters of 
CsA, if appropriate, for tears and blood.  Pharmacokinetic parameters for blood and tears will only be calculated 
for samples collected from patients who receive study treatment.   
The Medical Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code adverse 
events.  The number and percentage of patients with treatment-emergent adverse events will be tabulated based 
on the primary system organ class and the preferred term using the safety population.  The adverse events will 
be classified as ocular versus nonocular adverse events and analyzed separately.    
Sample Size Calculation:  The sample sizes for stages 1 and 2 were determined empirically. 
 
 


 
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1 
Background and Clinical Rationale 
This study represents the first evaluation in patients of the safety
, exploratory efficacy
, and 
pharmacokinetics of RESTASIS® X, 
 cyclosporine (CsA).  The 
study will be conducted in patients with moderate to severe dry eye disease.    
 
 
 
 
 
 
 (CFI) is a new formulation of CsA
 
 
  To fully evaluate F1, F2, 
and CFI, this phase 2 study will be conducted in 2 stages. 
1.1 
Study Rationale 
Cyclosporine, a cyclic peptide containing 11 amino acids with a total molecular weight of 
1202 Daltons, has long been known as a potent immunosuppressant and anti-inflammatory 
agent that specifically inhibits T lymphocyte proliferation via inhibition of Interleukin-2 
(IL-2) expression and cytokine production (Nussenblatt and Palestine, 1986; 
Petcher et al, 1976).  At the molecular level, CsA
 functions by binding to and forming a 
complex with cytosolic Cyclophilin A.  The CsA:Cyclophilin A
 complex in turn inhibits the 
calcium/calmodulin-dependent phosphatase activity of calcineurin that is responsible for 
dephosphorylation and translocation of nuclear factor of activated T cells (NFATc), a 
transcription factor required for IL-2 gene expression and T-cell activation (Ho et al, 1996).  
In addition to NFATc inhibition, CsA
 negatively regulates inflammation through its ability to 
bind and inhibit the phosphorylation of Inhibitor of κB (IκB), thereby preventing nuclear 
translocation of NF-κB, a key transcription factor for multiple proinflammatory 
cytokine/chemokine genes.  Additional molecular mechanisms reported to be inhibited by 
CsA
 include c-fos/jun and AP-1 transcription factors, and key inflammation-related 
intracellular signaling pathways including p38 mitogen-activated protein kinase, c-Jun 
N-terminal kinase, and extracellular signal-related kinase.   
In ophthalmology
, prior to its use as a topical treatment for dry eye disease, systemic 
(intravenous and oral) CsA
 was used for the treatment of severe posterior segment 
inflammation (Masuda et al, 1989).  Ulcerative keratitis associated with Wegener’s 






 
 
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2 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
The study will be conducted in 2 stages: 
Stage 1:  
To evaluate the safety
, exploratory efficacy
, and pharmacokinetics of F1 and F2 administered 
 in patients with moderate to severe dry eye disease. 
Stage 2:  
To evaluate the safety
, exploratory efficacy
, and pharmacokinetics of CFI administered   
 in patients with moderate to severe dry eye disease.   
2.2 
Clinical Hypotheses 
 
 
 
 
 




 
 
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significant safety findings 
, the remaining 2 patients in cohort 2 
will be given a
vehicle in one eye and 
 F1  
) in the other eye.  
After 2 weeks of monitoring, and in the absence 
of significant safety findings 
, four patients in cohort 3 will 
receive 
 vehicle in one eye and  
 
 F1 
) in the other eye.  After 2 weeks of monitoring the 
fourth patient in cohort 3, 
 
 
 
 
 
.  Four 
patients in cohort 4 will receive 
 of vehicle in one eye 
and 
 F1 
 in the other eye.  Two weeks 
after dosing the fourth patient in cohort 4, 
 
 
.  In 
the absence of significant safety findings from the first 4 patients in cohort 4, cohorts 5A
 and 
6A
 will begin.  For cohort 5A, patients will be administered 
 
 F1 
) in one eye and 
 
 vehicle in the other eye.  After 2 weeks of monitoring the first 4 patients in 
cohort 5A, 
 
 
  If there are no significant safety findings for the first 4 patients in cohort 5A, the 
dosing of the remaining 4 patients in cohort 5A
 will proceed, and then the first 4 patients of 
cohort 5B will be administered 
 of F1 
 
 in one eye and 
 vehicle in the other eye.  
For cohorts 6A
 and 6B, patients will receive 
 either F2 or 
vehicle (see Figure 1 and Table 1).  For cohorts 6C and 6D, patients will receive 
 of either F1 or F2 and vehicle (see Figure 1 and Table 1).  The 
doses 
 associated with cohorts 6A, 6B, 6C, and 6D will be determined 
  The progression from cohort 6A
 to 6B 
will be conducted in the same manner as for cohorts 3 through 5, with decisions to continue 
with dosing of a given cohort and/or to escalate to the next higher dose cohort based upon 
  
 
 






 
 
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1. male or female, at least 18 years of age at screening visit (week -2) 
2. at baseline (day 1) visit, dry eye disease (keratoconjunctivitis sicca) in both eyes, 
characterized by the following clinical signs: 
 
 
  
3. 
 
 
4. best-corrected visual acuity (BCVA) of 20/100 or better (Snellen equivalent), using 
the logarithm of the minimum angle of resolution (LogMAR) in each eye at the 
screening (week –2) and baseline (day 1) visits 
 
 
 
 
 
 
 
 
 
4.4 
Exclusion Criteria 
The following are criteria for exclusion from participating in the study: 
For Stages 1 and 2: 
1. use of topical RESTASIS or any other topical ophthalmic preparation of CsA
 within 
3 months prior to the baseline visit (day 1) and unwilling/unable to discontinue use 
for 3 months prior to baseline, or anticipated use during the study 
2. any use of systemic or dermatologic CsA
 or other calcineurin inhibitors within 3 
months prior to the screening visit (week -2), or anticipated use during study 


 
 
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3. topical ophthalmic use of anti-inflammatory medications (nonsteroidal anti-
inflammatory drugs [NSAIDs] and/or glucocorticoids) within 1 month prior to the 
screening visit (week -2) or anticipated use during study 
4. 
 
 
5. 
 
6. any use of topical ocular medication other than artificial tears within 1 month prior to 
the screening visit (week -2), or anticipated use during the study  
7. use of contact lenses in either eye within one month prior to the screening visit 
(week -2), or anticipated use during the study   
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 




 
 
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Stage 2: 
35. participation in stage 1 of this study 
4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
Allergan will provide patients with REFRESH PLUS, the only topical artificial tear 
permitted during the study
.  Patients will be required to replace any existing artificial tear 
product with REFRESH PLUS.   
During the 2-week period between the screening and baseline visits, REFRESH PLUS  
should be instilled in both eyes 4 times per day
.   
Following the baseline visit, REFRESH PLUS can be used up to 4 times per day
.  Use of 
REFRESH PLUS should not occur within 6 hours prior to any study visit.  
Use of inhaled corticosteroids (as needed) is permitted during the study
. 
Use of the following systemic medications and supplements is permitted during the study
, 
providing a stable dosing regimen is established (dosing is not stable if a patient starts, stops, 
or changes dose/drug during the study): 
• cholinergic agonists or antihistamines, antimuscarinics, diuretics, tricyclic 
antidepressants, phenothiazines, cholesterol lowering agents  
• systemic vitamins and/or systemic supplements containing omega 3 fatty acids; 
vitamins A, B, and E; fish oil; or Evening Primrose oil 
• hormone replacement therapy program, oral or transdermal contraception use, use of 
other estrogen or progesterone treatment  
• systemic androgen replacement therapy 
• systemic inhibitors of steroidogenesis, spironolactone, cyproterone acetate, or other 
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• oral macrolides, tetracyclines, tetracycline derivative drugs (including doxycycline 
and minocycline) 
• non-ophthalmic retinoids (eg, isotretinoin), non-ophthalmic corticosteroids, or other 
non-ophthalmic anti-inflammatory medications or immune modulators used for 
prolonged treatment of systemic immune-mediated diseases 
4.5.1.1 
Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods 
Women who are not of childbearing potential are either postmenopausal (and with at least 
12 consecutive months without menstruation) or permanently sterilized (eg, tubal occlusion, 
hysterectomy
, bilateral salpingectomy).   
Natural menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any other 
obvious pathological or physiological cause. For women of childbearing potential who may 
participate in the study
, the following methods of contraception, if properly used, are 
generally considered reliable: oral contraceptives, patch contraceptives, injection 
contraceptives, male condom with intravaginal spermicide, diaphragm or cervical cap with 
spermicide, vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral 
tubal ligation), vasectomized partner, or sexual abstinence.  
The investigator and each patient will determine the appropriate method of contraception for 
the patient during their participation in the study
. 
If a female becomes pregnant during the study
, the investigator will notify Allergan 
immediately after the pregnancy is confirmed and the patient will be exited from the study 
after appropriate safety follow-up.  The investigator will (1) notify the patient’s physician 
that the patient was being treated with an investigational drug (RESTASIS X/CsA), and (2) 
follow the progress of the pregnancy
.  The investigator must document the outcome of the 
pregnancy and provide a copy of the documentation to Allergan. 
4.5.2 
Prohibited Medications/Treatments 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, Allergan should be notified 
before the prohibited medication/treatment is administered. 
The following medications or classes of medications are prohibited during the study: 


 
 
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• any systemic/dermatological/ophthalmic use of RESTASIS/CsA
 or other 
calcineurin inhibitors  
• any artificial tear product other than REFRESH PLUS 
• use of REFRESH PLUS greater than 4 times per day or within 6 hours prior to a 
study visit 
• use of any topical ocular medication other than REFRESH PLUS 
• use of Lacrisert™ (hydroxypropyl cellulose ophthalmic insert) or methylcellulose 
ocular inserts  
The following procedures/treatments are prohibited during the study:  
• insertion of punctal plugs  
• punctal cautery in either eye  
• use of contact lenses in either eye  
• use of scleral lenses, or sealed compartment ocular frames  
• LipiFlow or other lid-heating therapy, meibomian gland probing or therapeutic 
gland expression in either eye  
• anterior segment surgery or trauma that could affect corneal sensitivity (eg, 
cataract surgery or any surgery involving a limbal or corneal incision) in either 
eye  
• insertion or removal of glaucoma filtration shunts or devices  
4.5.3 
Rescue Medications 
In the event that rescue medication is required for worsening signs or symptoms of dry eye 
disease during the course of the study
, patients will be provided an appropriate rescue 
regimen by the investigator/treating clinician, and be monitored through the end of the study
. 






 
 
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An automated interactive voice response system (IVRS)/interactive web-based response 
system (IWRS) will be used to manage the randomization, stratification, and treatment 
assignment.  
Stage 1:  
For each cohort, Allergan Biostatistics will prepare a scheme that will randomly 
assign patients with respect to the eye, right or left, to receive F1 or F2 (vehicle for 
cohort 1) (see Table 1).  At baseline, if the patient is eligible to be randomized, the 
IVRS/IWRS will assign the next available randomization number for that cohort to 
the patient at the time the investigator requests randomization.   
Stage 2:  
Allergan Biostatistics will prepare a scheme that will randomly assign patients to 1 of 
3 treatment groups (Table 2).  The randomization will be stratified by Sjögren’s 
syndrome (presence or absence of Sjögren’s syndrome at screening). 
At baseline, if the patient is eligible to be randomized, he/she will be assigned to a 
treatment group through the IVRS/IWRS.  Randomization numbers will be assigned 
in blocks for each Sjögren’s stratum (absent/present).  Based on the randomization 
scheme, a randomization number will be assigned to each patient sequentially 
according to the order of enrollment in the stratum.  That is, IVRS/IWRS will assign 
the next available randomization number to the patient at the time the investigator 
requests randomization.  The treatment-group assignment will be based on an equal 
allocation ratio across the study (not by site). 
For both stages, study medication labeled with medication kit numbers will be shipped to 
each study site.  The IVRS/IWRS will report a medication kit number to use for each patient 
corresponding to the randomization number
.  Sites will receive the IVRS/IWRS confirmation 
notifications for each transaction.  All notifications are to be maintained with the study 
source documents. 
5.6 
Treatment Regimen and Dosing 
Following a 2-week run-in period whereby signs and symptoms of dry eye disease will be 
verified and washout of artificial tears other than REFRESH PLUS will be facilitated by 
run-in with REFRESH PLUS, 
 RESTASIS X or vehicle will be initiated.    
Each eye will receive either 
vehicle or 
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patient will not be retreated in either eye but continue to be observed for safety (see Table 3) 
for the duration of the study
.  
 
 
For stage 2, patients in treatment groups 2 and 3 will be retreated (at week 12) with CFI in 
both eyes at the same dose used for the baseline (day 1)  
 Treatment group 1 patients 
will be retreated at week 12 with vehicle.  If retreatment is not administered, the patient will 
continue to be observed for safety (see Table 4) and exited at the Week 24/Week 12R/Exit 
visit. 
In stage 2, the investigator can elect to 
 if a ≥ +2 hyperemia grade 
 is present.  
 
  
 
 
 
 
6 
Response Measures and Summary of Data Collection Methods 
6.1 
Safety Measures 
For stages 1 and 2, the following safety measures will be examined: 
• adverse events (ocular and nonocular) 
• BCVA 
• macroscopic hyperemia assessment and slit-lamp biomicroscopy  
• IOP 
• dilated ophthalmic exam 
• photographic conjunctival hyperemia assessment  


 
 
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• vital signs 
• laboratory tests (chemistry, hematology
, urinalysis) 
• urine pregnancy test 
Laboratory test results will be forwarded from the central laboratory to the study site and to 
Allergan or its designee.  The laboratory results from screening will be reviewed prior to 
randomization.  Laboratory tests at screening may be repeated once at the discretion of the 
investigator and pending discussion with Allergan, to confirm exclusionary status.  Study 
treatment will be performed only if the investigator deems the laboratory results to be 
acceptable.  The most current specimen results will be reviewed prior to randomization.  The 
investigator will review all laboratory results for the clinical significance of any 
abnormalities.  Evaluation and management of abnormal laboratory results should be 
conducted according to local site practice.  Clinically significant abnormalities are to be 
recorded on an adverse event electronic case report form (eCRF) page. 
6.2 
Pharmacokinetic Measures 
Stage 1:   
Ocular and systemic pharmacokinetic samples will be collected (Table 3).  For 
determinations of drug concentration in the tear film, tear samples will be collected from 
both eyes at baseline (prior to treatment), weeks 1, 4, 8, 12, and 24/12R or Exit for cohorts 2 
through 6D.  For determination of drug concentration in the circulation, blood samples will 
be collected at baseline (prior to treatment), weeks 1, 4, 8, 12, and 24/12R or Exit for cohorts 
2 through 6D.  For cohorts 6C and 6D only
, tear and blood samples will be collected 
post retreatment at weeks 1R, 4R, and 8R, and 24/12R or Exit (see Table 3). 
Stage 2:   
Ocular drug concentrations will be determined from tears sampled at baseline (prior to 
treatment), weeks 1, 4, 8, 12, and post-retreatment at weeks 1R, 4R, 8R, and 24/12 R or Exit 
(see Table 4).  For determination of systemic drug concentration, blood samples will be 
collected at baseline (prior to treatment), weeks 1, 4, 8, 12, and post retreatment at weeks 1R, 
4R, 8R, and 24/12R or Exit (see Table 4).   


 
 
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6.3.1 
Health Outcomes Measures 
In stage 1, a Supplemental Dry Eye Patient Reported Outcomes (PRO) Questionnaire, 
developed to assess symptoms individually in each eye, will be administered at the study 
visits indicated in Table 3.  In stage 2, the Supplemental Dry Eye PRO Questionnaire and the 
Dry Eye Treatment Satisfaction PRO will be administered at the study visits indicated in 
Table 4.  
 
 
 
 
  
 
 
 
 
 
 
 
 
  


 
 
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6.5 
Summary of Methods of Data Collection 
This protocol will use eCRFs with remote data capture through a qualified third-party vendor
. 
Data entered into the eCRF will correspond to, and be supported by
, source documentation 
maintained at the sites.  The investigator is responsible for ensuring that data are properly 
recorded on each patient’s eCRFs and related documents.  The data will be entered on the 
eCRFs in a timely manner and on an ongoing basis. 


 
 
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An IVRS/IWRS will be used to assign patient identification numbers, patient initials, 
randomize/stratify patients, and manage study medication inventory
.  Data will be transferred 
to Allergan on a periodic basis throughout the study
. 
Qualified laboratories will be used for the analysis of blood and urine samples.  Laboratory 
data will be transferred to Allergan on a periodic basis throughout the study
. 
A
 qualified image reading center will be used to collect and analyze photographs taken by the 
study sites.  Photographs will be transferred from the reading center to Allergan on a periodic 
basis.  All digital images will be transferred from the reading center to Allergan at the end of 
the study
. 
In the event external data need to be captured within the eCRFs by the vendor, the vendor 
will handle the data as a site would and the vendor will be responsible for ensuring that these 
data are properly recorded on each patient’s eCRFs and related documents.  A
 vendor 
representative will also be required to sign for the eCRFs that they have completed. 
7 
Statistical Procedures 
 
  An interim database lock of stage 1 will not be conducted until after all patients 
in cohorts 1 through 6B complete the study and all patients in cohorts 6C and 6D completed 
at least week 1 following retreatment.   An interim database lock of stage 2 will not be 
conducted until after all patients in stage 2 complete at least week 1 following retreatment.  A
 
final database lock will occur after all enrolled patients have completed stage 2 of the study
.  
The statistical analysis plan (SAP) will be developed and finalized before database lock. 
7.1 
Analysis Populations 
The safety population will include all treated patients.  This population will be used for the 
safety analyses.  The modified intent-to-treat (mITT) population will be all patients who are 
treated and have baseline and at least 1 postbaseline assessment for 1 or more of the 
exploratory efficacy measurements (see Section 6.3).  The mITT population will be used for 
the exploratory efficacy analyses. The population consisting of subjects who received the 
active study treatment will be used for pharmacokinetic analysis. 


 
 
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7.2 
Collection and Derivation of Exploratory Efficacy 
 Assessments
 
Exploratory efficacy (stage 1 and stage 2) measures (Section 6.3) will be evaluated.  Baseline 
and change from baseline measure will be assessed. Also, number (percent) of responders 
may be assessed. 
7.3 
Hypothesis and Methods of Analysis 
In general, continuous variables will be summarized by descriptive statistics including 
sample size (N), mean, standard deviation, median, minimum and maximum. Categorical 
variables will be summarized by frequency count and percentage.  
7.3.1 
Safety
 Analyses
 
Safety measures will be analyzed using the safety population.  The Medical Dictionary for 
Regulatory Activities (MedDRA) nomenclature will be used to code adverse events. The  
number and percentage of patients with  treatment-emergent adverse events will be 
summarized.  The adverse events will be classified into ocular and nonocular types and will 
be summarized separately
.  Detailed methods for the analyses of adverse events and other 
safety variables will be described in the SAP
. 
 
 
 
 
 
 
 
 
 
 
  
 
 
. 


 
 
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7.4 
Subgroup
 Analyses
 
Subgroup analyses will be conducted for all safety and efficacy measures by presence and 
absence of Sjögren’s syndrome for stage 2.  No other subgroup analyses are planned, but they 
may be performed for exploratory purposes. 
7.5 
Sample Size Calculation 
The sample sizes for both stages 1 and 2 are determined empirically
.   
7.6 
Interim
 Analyses
 
An interim database lock of stage 1 will not be conducted until after all patients in cohorts 1 
through 6B complete the study and all patients in cohorts 6C and 6D complete at least 
week 1 following retreatment.  An interim database lock of stage 2 will not be conducted 
until after all patients in stage 2 completed at least week 1 following retreatment.  Statistical 
analyses will be performed following each database lock to support the design of future 
clinical studies. 
8 
Study Visit Schedule and Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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8.1 
Patient Entry Procedures 
8.1.1 
Overview of Entry Procedures 
Prospective patients will be considered for entry into this study by applying the criteria in 
Sections 4.3 and 4.4 (inclusion/exclusion criteria) at the screening and baseline visits. 
8.1.2 
Informed Consent and Patient Privacy 
The study procedures will be discussed with the patient.  Any patient wishing to participate 
must give informed consent prior to any study-related procedures or change in treatment.  
The patient must also give authorization and other written documentation in accordance with 
the relevant local privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment.   
Patients who provide informed consent will be assigned a patient number that will be used on 
patient documentation throughout the study
.   
8.2 
Washout Intervals/Run-in 
For patients not on RESTASIS at the screening visit, there will be a 2-week run-in period 
with REFRESH PLUS, for use 4 times per day
.  If patients are using topical RESTASIS at 
screening, their screening period will be extended to a 13-week period to allow for washout 
of topical RESTASIS in conjunction with the 2-week run-in with REFRESH PLUS.  Any 
screening diagnostic procedures that were performed at the start of the extended screening 
period will be repeated within days -14 to -2.   


 
 
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8.3 
Procedures for Final Study Entry 
During the 2-week run-in period, signs and symptoms of dry eye disease will be verified in 
both eyes at screening (week -2) and baseline (day 1) visits.  Specific scores for qualification 
tests can be found in the inclusion criteria (Section 4.3).  
Female patients of childbearing potential MUST have a negative urine pregnancy test result 
at screening (week -2) and baseline (day 1) visits.  Only eligible patients will be enrolled into 
the study.  A
 patient is considered to have enrolled in the study at the time of randomization 
to treatment at baseline (day 1).  
See Section 5.5 for the method of assignment to treatment groups/randomization. 
8.4 
Visits and Associated Procedures 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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8.5 
Instructions for the Patients 
Patients are to be instructed not to instill REFRESH PLUS within 6 hours prior to a study 
visit.  
Patients will be instructed to strictly follow the study visit schedule and to report all changes 
in condition to the investigative site. 
Instruction should be given to the patient to maintain a stable dose whenever possible of any 
chronically used concomitant medication.  Patients should be instructed to communicate any 
changes to their medication or any new medications at their next study visit.  Patients should 
also be reminded to contact the study site if they are experiencing any ocular or nonocular 
medical changes between study visits, or if they have had any medical procedures (including 
diagnostic procedures) performed between study visits.   
8.6 
Unscheduled Visits 
Unscheduled visits can be performed if safety concerns arise, at the discretion of the 
investigator.  Additional examinations may be performed as necessary to ensure the safety 
and wellbeing of patients during the study. 
If a patient is seen for an unscheduled visit, an assessment and record of adverse events 
should be completed.  Additional evaluations should be performed as necessary, and the 
appropriate eCRFs should be completed. 
8.7 
Compliance With Protocol 
Patients will be scheduled for follow-up visits and these should occur as closely as possible 
to the day specified in the visit schedule. 


 
 
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At each postbaseline visit, the investigator or designee will ask patients if they have been 
compliant with use of only REFRESH PLUS (up to 4 times per day
, both eyes), used any 
concomitant medications, or have had any medical procedure performed since the previous 
visit. 
8.8 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time; these patients will be 
encouraged to return for the week 24/12R or Exit visit and have exit procedures completed 
when possible.   
Notification of early patient discontinuation from the study and the reason for discontinuation 
will be made to Allergan and will be clearly documented on the appropriate eCRF
. 
8.9 
Withdrawal Criteria 
The investigator and Allergan have the right to withdraw a patient from the study at any time 
for any reason.  When possible, the decision to withdraw a patient from study treatment or 
the study should be discussed with Allergan. 
Patients should be discontinued from the study if any of the following criteria are met: 
• patient develops (or has an exacerbation of) any medical condition that, in the opinion 
of the investigator, would put the patient at an unacceptable medical risk or 
compromises the patient’s ability to participate in the study 
• patient is unwilling or unable to continue to comply with study procedures 
Patients who are withdrawn early from the study during a study visit should have the exit 
procedures completed when possible. 
8.10 
Study Termination 
The study may be stopped at a study site at any time by the site investigator
.  Allergan may 
stop the study (and/or the study site) for any reason, with appropriate notification.  
8.11 
Adverse Events 
Adverse events occurring during the study will be recorded on the adverse event eCRF
.  If 
adverse events occur, the first concern will be the safety of the study participants.  


 
 
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8.12 
Definitions 
8.12.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product.   
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and/or lack of efficacy
, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
Adverse events will be assessed, documented, and recorded in the eCRF throughout the study 
(ie, after informed consent has been obtained).  At each visit, the investigator will begin by 
querying for adverse events by asking each patient a general, non-directed question such as 
“How have you been feeling since the last visit?”  Directed questioning and examination will 
then be done as appropriate.  All reported adverse events will be documented on the 
appropriate eCRF
.   
8.12.2 
Serious
 Adverse
 Event
 
A
 serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity
, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  See Section 8.14 for procedures for reporting a serious adverse event. 


 
 
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Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any preplanned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study
.  If it has not been documented at the time of the patient’s entry into the study
, then it 
should be documented as a serious adverse event and reported to Allergan. 
8.12.3 
Severity 
A
 clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated 
Moderate  
Discomfort enough to cause interference with usual activity 
Severe  
Incapacitating with inability to work or do usual activity 
Not applicable  In some cases, an adverse event may be an ‘all or nothing’
 finding 
which cannot be graded. 
 
8.12.4 
Relationship to Study Drug or Study Procedure 
A
 determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A
 causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure.   
8.13 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF
. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator
's Brochure) must be reported to the governing Institutional Review 
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regulations, and the governing health authorities.  Any adverse event that is marked ‘ongoing’
 
at the exit visit must be followed-up as appropriate. 
8.14 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 12 weeks after the last dose of study drug must be immediately 
reported, but no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events must be reported to Allergan (or Agent of Allergan) as listed on the Allergan Study 
Contacts Sheet and recorded on the serious adverse event form.  All patients with a serious 
adverse event must be followed up and the outcomes reported.  The investigator must supply 
Allergan and the IRB/IEC with any additional requested information (eg, autopsy reports and 
discharge summaries).  
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of the 
protocol. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically
, including any 
treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational drug. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
8.15 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
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and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unmasking study medication.  The investigator 
should inform the sponsor (Allergan Medical Safety Physician) of the unmasking if there is 
no notification prior to the unmasking.   
The treatment assignment for the patient can be determined by designated site personnel 
calling into the IVRS or IWRS system via password protected access.  The reason for 
breaking the code must be recorded in the patient’s source documents. 
9 
Administrative Items 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines, eg, the ICH Guideline on GCP
. 
9.1 
Protection of Human Patients 
9.1.1 
Compliance With Informed Consent Regulations (US 21 
  
CFR Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study
, and/or from the patient
's legally authorized 
representative.  If the patient is under the legal age of consent, the consent form must be 
signed by the legally authorized representative in accordance with the relevant country and 
local regulatory requirements. 
9.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually
.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 
9.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines.  


 
 
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9.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21 CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
9.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
9.3 
Patient Confidentiality 
A
 report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient
's name may be 
disclosed to the sponsor of the study
, Allergan, or the governing health authorities or the FDA
 
if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
9.3.1 
Patient Privacy 
Written authorization and other documentation in accordance with the relevant local privacy 
requirements (where applicable) is to be obtained from each patient prior to enrollment into 
the study
, and/or from the patient
's legally authorized representative in accordance with the 
applicable privacy requirements (eg, the Health Insurance Portability and Accountability Act 
[HIPAA] Standards for Privacy of Individually Identifiable Health Information). 
In accordance with HIPAA
 requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study
.  


 
 
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9.4 
Documentation 
9.4.1 
Source Documents 
Source documents may include a patient
's medical records, hospital charts, clinic charts, the 
investigator
's patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator
's copy of the eCRFs serves as part 
of the investigator
's record of a patient
's study-related data.   
The following information should be entered into the patient
's medical record: 
• patient’s name 
• patient’s contact information 
• date that the patient entered the study and patient number  
• study title and/or protocol number of the study and the name of Allergan 
• A
 statement that informed consent was obtained (including the date).  A
 statement that 
written authorization or other local patient privacy required documentation for this 
study has been obtained (including the date). 
• dates of all patient visits 
• medical history including childbearing potential (if female) 
• ophthalmic history 
• All concurrent medications:  list all prescription and nonprescription medications 
being taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded. 
• study variables (eg, vital signs, manifest refraction and visual acuity worksheets, IOP 
measurements, Schirmer’s test, biomicroscopy and ophthalmoscopy results, 
macroscopic hyperemia assessment, HRT-Rostock printouts, staining results, tear film 
break-up time)   
• patient questionnaires 
• occurrence and status of any adverse events 


 
 
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• Procedural notes of study treatment preparation and procedure should include the 
following:  date and start/stop time of study treatment preparation, date and time of 
the procedure, 
, 
and complications, if any
. 
• date the patient exited the study
, and a notation as to whether the patient completed 
the study or reason for discontinuation 
• results of laboratory tests performed by the site (eg, results of urine pregnancy tests, 
see Section 11.1.23) 
9.4.2 
Case Report Form Completion 
The investigator is responsible for ensuring that data are properly recorded on each patient
's 
eCRFs and related documents.  An investigator who has signed the protocol signature page 
should personally sign for the eCRFs (as indicated in the eCRFs) to ensure that the 
observations and findings are recorded on the eCRFs correctly and completely
.  The eCRFs 
are to be submitted to Allergan in a timely manner at the completion of the study
, or as 
otherwise specified by Allergan and will be maintained in a central data repository
. 
9.4.3 
Study Summary 
An investigator
's summary will be provided to Allergan within a short time after the 
completion of the study
, or as designated by Allergan.  A
 summary is also to be provided to 
the responsible IRB/IEC. 
9.4.4 
Retention of Documentation 
All study related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of eCRFs should be maintained on file. 
For countries falling within the scope of the ICH guidelines, Allergan-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by Allergan. 


 
 
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In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
9.4.4.1 
Study Site 
The study site should retain the essential documents to be kept at the study site, such as 
source documents, contracts, informed consent form, protocol, records on control of the 
investigational product, or other study-related documents until either item 1 or 2 listed below
, 
whichever is later
.  However, when Allergan requires that these documents are to be retained 
for longer period, the study site should discuss with Allergan regarding the period and 
method of preservation.  The record retainer designated for each record should be responsible 
for the preservation. 
1. The date of approval for manufacturing and marketing applications of the relevant 
investigational products (in case of discontinuing its development, until at least 
3 years after the date of development discontinuation) 
2. The day at least 3 years after the date of the termination or completion of the clinical 
study 
The study site and the record retainer should take measures in such a way that these records 
are not lost or abandoned during the designated period of preservation and that they are 
presented upon request. 
9.4.4.2 
Institutional Review Board  
The IRB should retain all relevant records such as standard operating procedures (SOPs), 
membership lists (including qualifications of the members), submitted documents, minutes of 
meetings, and correspondence until either item 1 or 2 listed below
, whichever is later
.   
1. The date of approval for manufacturing and marketing applications of the relevant 
investigational products (in case of discontinuing its development, until at least 
3 years after the date of development discontinuation) 
2. The day at least 3 years after the date of the termination or completion of the clinical 
study 


 
 
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When the study site or Allergan requests the SOPs and membership lists, the IRB should 
comply with the request. 
9.5 
Labeling, Packaging, and Return or Disposal of Study 
 Medications/Treatments
 
9.5.1 
Labeling/Packaging 
All study medication will be packaged, labeled, and supplied by Allergan. The investigational 
materials will be packaged in identically appearing containers consistent with all applicable 
regulations. The medication will be identified as an investigational compound. The kit 
number will be identified on the unit label. 
9.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed to the patients, the number of units returned to the 
investigator by the patient, and the number of units returned to Allergan during and at the 
completion of the study
.  A
 detailed inventory must be completed for the study medication.  
The study medication must be dispensed only by an appropriately qualified person to patients 
in the study
.  The medication is to be used in accordance with the protocol by patients who 
are under the direct supervision of an investigator
.  A
 unit is defined as a kit.   
 
 
 
 
 
 
9.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction. 
9.6 
Monitoring by the Sponsor 
A
 representative of Allergan will monitor the study on a periodic basis.  The determination of 
the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity
, blinding, size, and endpoints of the study
.   




 
 
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meet GLP requirements.  Details of sample collection, handling, storage, and shipping 
procedures are found in Attachment 11.1.16 and in the procedure manual. 
9.8 
Publications 
Allergan as the sponsor, has proprietary interest in this study
.  Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel.  Authorship will be established prior to the writing of the manuscript.  As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan.   
 
 


 
 
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10 
References 
Bron AJ, Evans VE, Smith JA.  Grading of corneal and conjunctival staining in the context of 
other dry eye tests.  Cornea.  2003;22:640-650.  
Dry Eye Workshop.  Methodologies to diagnose and monitor dry eye disease:  report of the 
Diagnostic Methodology subcommittee of the International Dry Eye Workshop (2007).  
Ocular Surf.  2007;5(2):108-152. 
Georganas C, Ioakimidis D, Iatrou C, Vidalaki B, Iliadou K, Athanassiou P
, et al.  Relapsing 
Wegener
's granulomatosis: successful treatment with cyclosporin-A.  Clin Rheumatol.  
1996;15:189-192.  
Ho S, Clipstone N, Timmermann L, Northrop J, Graef I, Fiorentino D, et al.  The mechanism 
of action of cyclosporin A
 and FK506.  Clin Immunol Immunopathol.  1996;80(3 Pt 2):S40-
S45. 
Kim H, Csaky KG, Gilger BC, Dunn JP
, Lee SS, Tremblay M, et al.  Preclinical evaluation of 
a novel episcleral cyclosporine implant for Ocular Graft-Versus-Host Disease.  Invest 
Ophthalmol.  Vis Sci.  2005;46:655–662. 
Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK.  Analysis of topical cyclosporine 
treatment of patients with dry eye syndrome:  effect on conjunctival lymphocytes.  Arch 
Ophthalmol.  2000;118:1489-1496. 
Masuda K, Nakajima A, Urayama A, Nakae K, Kogure M, Inaba G.  Double-masked trial of 
cyclosporin versus colchicine and long-term open study of cyclosporin in Behçet
's disease.  
Lancet.  1989;20:1093-1096.  
Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y
, Nickeleit V
, Ryffel B.  The side-effects of 
ciclosporine-A
 and tacrolimus.  Clin Nephrol.  1998;49:356-363. 
Neoral® (package insert).  East Hanover, NJ: Novartis Pharmaceutical Corporation; 2015. 
Nussenblatt RB, Palestine AG, Chan CC, Stevens G Jr, Mellow SD, Green SB.  Randomized, 
double-masked study of cyclosporine compared to prednisolone in the treatment of 
endogenous uveitis.  Am J Ophthalmol.  1991;112:138–146.  
Nussenblatt RB, Palestine AG.  Cyclosporine:  Immunology
, pharmacology and therapeutic 
Uses.  Surv Ophthalmol.  1986;31:159-169.  


 
 
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Petcher TJ, Weber HP
, Ruegger A.  Crystal and molecular structure of an iodo-derivative of 
the cyclic undecapeptide cyclosporine A.  Helv Chem Acta.  1976;59:1480-1488. 
Prummel MF
, Mourits MP
, Berghout A, Krenning EP, van der Gaag R, Koornneef L, et al.  
Prednisone and cyclosporine in the treatment of severe Graves
' ophthalmopathy
.  N Engl J 
Med.  1989;20:1353-1359.  
Reinhard T
, Sundmacher R, Godehardt E, Heering P
.  Preventive systemic cyclosporin A
 after 
keratoplasty at increased risk for immune reactions as the only elevated risk factor
.  
Ophthalmologe.  1997;94:496–500.  (German) 
Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL.  Reliability and validity 
of the ocular surface disease index.  Arch Ophthalmol.  2000;118:615-621.  
Standardization of Uveitis Nomenclature (SUN) working group.  Standardization of uveitis 
nomenclature for reporting clinical data.  Results of the first international workshop.  Am J 
Ophthalmol.  2005;140(3):509-516.   
 


 
 
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11 
Attachments 
11.1 
Examination Procedures, Tests, Equipment, and Techniques 
These tests may not be described in the order in which they are to be conducted.  Refer to the 
Schedule of Visits and Procedures (Table 3 and Table 4) and Section 8.4 for the order in 
which procedures should be conducted for each visit.  Certain study tests and procedures are 
assigned to the treating investigator to maintain masking of the follow-up investigator to the 
study treatments.  See Table 5 for assignments of procedures and tests by investigator
.  When 
not specified, procedures and tests may be done by either the follow-up investigator or 
appropriately trained and qualified site personnel. 
11.1.1 
Vital Signs 
Systolic and diastolic blood pressure will be measured using an appropriate 
sphygmomanometer after patients have been at rest (seated) for at least 5 minutes.  Blood 
pressure will be recorded in mm Hg. 
Pulse rate will be measured in bpm after the patient has been in a resting state (seated) for at 
least 5 minutes.  Pulse will be counted for 30 seconds, multiplied by 2, and recorded in bpm. 
11.1.2 
Pregnancy Test 
Female patients of childbearing potential will have urine pregnancy tests performed.  
Pregnancy test kits will be provided by an Allergan-designated supplier and will be 
administered according to the instructions provided with the tests. 
11.1.3 
Ocular Surface Disease Index  
The OSDI© questionnaire consists of 12 questions regarding ocular symptoms, 
environmental triggers, and vision-related functioning in patients with dry eye disease 
(Schiffman et al, 2000).  The patient will be asked to rate each symptom using a 5-point scale 
(0 to 4), where 0 indicates none of the time; 1, some of the time; 2, half of the time; 3, most 
of the time; and 4, all of the time.  Seven questions related to visual functioning allow a 
response of “N/A” (not applicable); no more than 3 of these 7 questions may be answered as 
N/A
 for the questionnaire to be evaluable.  The total OSDI score is calculated as:  ([sum of 
scores for all questions answered] X 100)/([total number of questions answered] X 4). 
An example of the questionnaire follows. 




 
 
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and used for BCVA
 until exit.  If there is a decrease in BCVA, the manifest refraction should 
be repeated as confirmation.  Visual acuity (in Snellen equivalents) will be measured for each 
eye using a logarithmic visual acuity chart for testing at 10 feet (3 meters).  Since most 
examination rooms do not allow for a 10 feet (3 meters) testing distance, the results from the 
manifest refraction may be placed in a trial frame and visual acuities measured.  The chart 
should be set at approximately eye level to the average height of a seated patient.  Mark a 
spot on the floor (eg, with tape) that is 10 feet away from the chart.  The test distance and 
illumination for the chart must be kept constant throughout the study
. 
Begin by testing the right eye.  The patient is asked to read each letter, line by line, left to 
right, beginning with line 1 at the top.  The patient should be told that the chart has letters 
only
, no numbers.  If the patient reads a number, he or she should be reminded that the chart 
contains no numbers, and the examiner should then request a letter in lieu of the number
.  
The patient is not to proceed to the next letter until she/he has given a finite answer
. 
If the patient changes a response (eg, that was a “C” not an “O”) before he/she has read aloud 
the next letter, then the change must be accepted.  If the patient changes a response after 
having read the next letter, then the change is not accepted.  The examiner must not point to 
specific letters on the chart during the test. 
When the letters become difficult to read, or if the patient identifies a letter as 1 or 2 letters, 
he/she should be asked to choose one letter and, if necessary
, to guess.  Record the visual 
acuity as the lowest line read with one or no mistakes.  Record the acuity in Snellen 
equivalent units (eg, 20/63).  Repeat for the left eye. 
The pinhole method for measuring visual acuity is not acceptable. 


 
 
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11.1.9 
Macroscopic Bulbar Hyperemia 
The macroscopic (gross) bulbar hyperemia grading should be completed prior to any other 
eye examinations.  Macroscopic bulbar hyperemia grading will consist of both global and 
regional hyperemia assessments.  The global assessment will be done by the follow-up 
investigator and the regional (quadrant) assessment will be done by the treating investigator
.  
Macroscopic hyperemia assessments will be done under consistent illumination by 
comparing the appearance of the bulbar conjunctiva to standard photographs (Allergan bulbar 
conjunctival hyperemia grading guide).  
  0  (None)  
=  Normal.  Vessels of bulbar conjunctiva easily observed 
+0.5  (Trace)  
=  Trace flush, reddish-pink color 
+1  (Mild)  
=  
Mild flush, reddish color 
+2  (Moderate)  =  Bright red color 
+3  (Severe)  
=  Deep, bright diffuse redness 
 
The gross macroscopic hyperemia evaluation should be performed by the same evaluator in 
the same facility with consistent lighting throughout the entire study
, whenever possible.  
11.1.10 
Photographic Conjunctival Hyperemia Assessment 
A
 Canfield camera will be used at all study sites for ocular surface photography
.  Images will 
be uploaded to a reading center to evaluate global and regional hyperemia scores.  The global 
hyperemia scores will be determined from interpalpebral images, and regional hyperemia 
scores will be determined from 4 quadrant images.  The site personnel conducting 
photographic conjunctival hyperemia assessment will not perform other tasks for the study 
other than those outlined in Section 5.3.  See the procedure manual for further details. 
11.1.11 
HRT3-Rostock — Ocular Surface Imaging 
The Heidelberg Retinal Tomograph 3 (HRT3) is a confocal laser scanning system.  The 
addition of the Rostock Cornea Module (Rostock) converts the HRT3 to a confocal 
microscope for in vivo histological views of the ocular surface.  The HRT3-Rostock will be 
used at select study sites and in select patients.  Additional details can be found in the 
procedure manual.   
11.1.12 
Slit-lamp Biomicroscopy Examinations 
Findings other than those listed below should be recorded under “other” for the appropriate 
location of the finding.   






 
 
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Cells 
  0  
=  0 cells  
+0.5  =  1 to 5 cells (trace)  
+1  
=  6 to 15 cells 
+2  
=  16 to 25 cells 
+3  
=  26 to 50 cells 
+4  
=  > 50 cells  
Flare 
  0  
=  None:  no flare seen 
+1  
=  Faint:  faint flare seen 
+2  
=  
Moderate:  iris and lens details clear 
+3  
=  
Marked:  iris and lens details hazy 
+4  
=  Intense:  fibrin or plastic aqueous 
 
11.1.12.5 Iris/Pupil (conducted by follow-up investigator) 
The iris/pupil will be evaluated for pathology
.  If pathology is present, it will be described. 
11.1.13 
Dilated Ophthalmic Examinations (conducted by treating 
 investigator)
 
Use biomicroscopic examination, indirect lenses, direct/indirect ophthalmoscopy
, etc as 
appropriate to visualize.  Dilating drops should not be administered until slit lamp 
biomicroscopy and IOP measurements are completed.   
11.1.13.1 Lens 
Lens Status 
Lens status will be assessed as phakic, pseudophakic, or aphakic.  The lens (including the 
posterior capsule for patients who have undergone lens extraction) will also be evaluated for 
pathology
.  If pathology is present, it will be described. 


 
 
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Cataract Assessment (phakic eyes only) 
Under dilated examination, the presence and severity of nuclear, cortical and posterior 
subcapsular cataract lens opacities will be evaluated.  At the first dilated examination, each 
type of cataract, if present, will be graded using the scale below
.  At the last follow-up dilated 
examination, each type of cataract will be assessed for change from first dilated exam and if 
changed, the current severity will be graded using the scale below: 
 0 
= 
None 
+1 
= 
Mild 
+2 
= 
Moderate 
+3  
=  
Severe 
 
11.1.13.2 Vitreous 
The vitreous will be evaluated for pathology
.  If pathology is present, it will be described.  
Note if the condition is not evaluable. 
11.1.13.3 Fundus 
The fundus (posterior pole; periphery
, when dilated) will be evaluated for pathology
.  If 
pathology is present, it will be described.  Note if the condition is not evaluable. 
11.1.13.4 Optic Nerve 
The optic nerve will be evaluated for pathology
.  If pathology is present, it will be described. 
Note if the condition is not evaluable. 
Cup/disc ratio will be reported using a 0.0 to 1.0 scale.  The Armaly chart provided by 
Allergan provides a pictorial scale of cup/disc ratio of 0.0 to 0.8.  Note if the condition is not 
evaluable. 
11.1.14 
Intraocular Pressure 
IOP should be measured only after the biomicroscopic exam is completed and must be 
measured prior to pupil dilation.  Measurements will be taken using a Goldmann applanation 
tonometer affixed to a slit lamp with the patient seated.  The patient and slit lamp should be 
adjusted so that the patient’s head is firmly positioned on the chin rest and against the 
forehead rest without  leaning forward or straining.  Tight fitting neckwear should be 
loosened.  Both eyes will be tested, with the right eye preceding the left eye. 


 
 
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The measurer looks through the binocular viewer of the slit lamp at low power
.  The tension 
knob is preset at a low pressure value (4 to 6 mm Hg).  The measurer follows the image of 
the fluorescein-stained semicircles while s/he slowly rotates the tension knob until the inner 
borders of the fluorescein rings touch each other at the midpoint of their pulsation in 
response to the cardiac cycle.  When this image is reached, the measurer takes his/her fingers 
off the tension knob and records the IOP reading along with the date and time of day in the 
source document. 
11.1.15 
Schirmer’s Tear Test with Anesthesia 
Procedure   
This test is to be conducted in a dimly lit room.  Instill 1 drop of anesthetic into each eye and 
wait approximately 4 minutes.  Gentle blotting of the corners of the eyelids with a facial 
tissue is allowed to catch the over spill.  Any direct, active blotting of the cul-de-sac will not 
be allowed.  Ask the patient to look up and draw the lower lid gently downward and 
temporally.  Hook the rounded bent end of the sterile strip into the lower cul-de-sac at the 
temporal one-third of the lower eyelid margin.  Start the timer.  To minimize artifacts from 
this test, patients should gently close their eyelids until 5 minutes have elapsed, patients then 
open their eyes and the strips are removed.  Because the tear front will continue advancing a 
few millimeters after it has been removed from the eyes, it is important to mark the tear front 
with a ball point pen at precisely 5 minutes.   
Strip Measuring   
Write the letter “R” on the strip used in the right (OD) eye and the letter “L” on the strip used 
in the left (OS) eye.  Each strip has graduated sections on it that will aid in capturing the 
appropriate measurement.  Record only whole numbers, rounding up to the nearest whole 
number if the tear front is at or greater than the half-millimeter mark.  Once marked, each 
strip will be affixed to the source document (marked side up), in the space provided, and 
covered completely with transparent tape.  The measurement is then to be captured on the 
source document and transcribed onto the eCRF. 
11.1.16 
Impression Cytology for Biomarker Analysis (conducted by
 treating
 
investigator)
 
Prior to initiation of impression cytology
, each site must ensure the availability of a 4º C 
refrigerator for immediate storage of samples.   


 
 
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Conjunctival epithelial cells will be collected via impression cytology from each eye from 
2 locations around the superior–temporal bulbar conjunctiva.  Sample collection, handling, 
storage, and shipping details can be found in the procedure manual. 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
   
11.1.18 
Corneal Sodium Fluorescein Staining 
The examination will be performed by the follow-up investigator with the slit lamp at 10X 
magnification.  A
 fluorescein strip will be moistened with balanced salt solution and the strip 
will be gently touched against the superior bulbar conjunctiva of the right eye.  A
 stopwatch 
will be started immediately after application.  The corneal staining will be graded 
approximately 2 minutes after instillation of the fluorescein.  Evaluate the entire cornea for 
staining using the supplied yellow barrier filter placed directly in front of the objective lens 


 
 
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of the slit lamp.  The slit lamp’s cobalt blue filter must be used to illuminate the cornea.  
Corneal fluorescein staining should be evaluated as close to the 2-minute timepoint as 
possible.  Refer to the Oxford Scheme (Bron et al, 2003; DEWS, 2007) outlined in the 
laminated chart provided to grade the staining.  Although the scheme depicts the grading of 
conjunctival staining, only corneal fluorescein staining is to be graded.  Once grading of the 
right eye is complete, the entire procedure will be repeated for the left eye.   
For grades 0 to 2, the dot count will be collected and recorded. 
 




 
 
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interpalpebral region of the nasal and temporal zones.  Refer to the Oxford scheme of 
staining to grade.  Grade staining independently in each of the 2 areas of the conjunctiva 
(2 areas each:  temporal [a] and nasal [b]) as shown in the diagram below based upon a 6-
point scale (0, 1, 2, 3, 4, 5).  Grading should be done within approximately 3 minutes of 
instillation of the lissamine green stain.  The staining values obtained from the Oxford 
scheme (Section 11.1.18) are then to be captured on the source document (as shown in the 
diagram below) and transcribed onto the eCRF
. 
The procedure is then repeated for the left eye. 
11.1.20 
Pharmacokinetic Tear Samples 
Prior to tear sample collection, each site must ensure the availability of dry ice for immediate 
storage of tear samples prior to transfer to a freezer
.   
Tear samples will be obtained using a single use, sterilized microcapillary tube for each 
collection per patient.  Tear collection will continue until a maximum of 5 µL is collected 
from each eye or until 5 minutes have elapsed (per eye).  Complete handling, labeling, and 
packaging instructions are provided in the procedure manual.    


 
 
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11.1.21 
Pharmacokinetic Blood Samples 
All blood samples for pharmacokinetic analysis will be collected as described in the 
procedure manual.  
11.1.22 
Blood and Urine Sample Collection  
Prior to blood and urine sample collection, each site must ensure the availability of dry ice 
for immediate storage of samples prior to transfer to a  freezer
.  The nonfasting blood and 
urine samples should be sent on dry ice to 
 for analysis on the same day that they are 
collected.  Patient number should be left blank on the lab requisition form for the baseline 
visit. 
Blood and urine samples will be collected under normal conditions.  Normal phlebotomy 
procedures will be followed for collection of blood samples.  Tubes for blood sample 
collection for pharmacokinetic measures will be filled first.  All blood and urine sample 
collection tubes should be appropriately labeled.  Refer to the procedure manual for 
additional details. 
Specimen Collection kits 
A
 specimen collection kit has been designed for each visit requiring laboratory data within 
the protocol.  Each kit is labeled with the pharmaceutical company name, protocol number, 
investigator number and visit.  For the content of each kit, specimen collections, and shipping 
instructions, please refer to the 
.  All necessary venipuncture and 
shipping materials are provided in the kits.  Supplies not included in the kits are:  tourniquets, 
cotton swabs and Band-Aids
®. 
Safety labs will be collected nonfasting.  All blood and urine specimens will be shipped by 
the site to the central laboratory
.  Refer to the central laboratory manual for instruction on 
sample collection, processing, storage, and shipment procedures.  The central laboratory will 
analyze all blood and urine specimens. 
11.1.23 
Blood and Urine Sample Analysis  
Hematology parameters will include hematocrit, hemoglobin, HbA1c, mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean 
corpuscular volume (MCV), platelets, red blood cell (RBC) count, RBC morphology
, total 
white blood cell (WBC) count, and differential (neutrophils, bands, lymphocytes, monocytes, 
basophils, and eosinophils). 


 
 
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Serum chemistry parameters will include albumin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartase aminotransferase (AST), gamma-glutamyl transferase 
(GGT), bicarbonate, calcium, chloride, creatinine, creatine kinase, direct bilirubin, glucose, 
indirect bilirubin, magnesium, phosphorous, potassium, sodium, total bilirubin, total 
cholesterol, total protein, urea nitrogen, and uric acid.  The urine will be analyzed for specific 
gravity
, pH, color, protein, glucose, blood, bilirubin, and microscopic examination (WBC, 
RBC, epithelial cells, bacteria, mucus, casts, crystals).  
11.2 
RESTASIS X Administration 
RESTASIS X administration should be conducted by the treating investigator
.   
 
 
   
11.3 
Handling of Biological Specimens 
Additional details for handling, processing, and shipping biological specimens are in the 
procedure manual. 


 
 
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11.4 
Glossary of Abbreviations 
Term/Abbreviation
 Definition
 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-12h 
area under the concentration-time curve from 0 to 12 hours  
BCVA 
best-corrected visual acuity 
CFI 
cyclosporine  
 
CFR 
Code of Federal Regulations 
Cmax 
maximal concentration  
CsA 
cyclosporine 
DET 
dry eye test 
 
 
eCRF 
electronic case report form 
F1 
   
F2 
   
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HbA1c 
hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HLA-DR 
human leukocyte antigen type DR 
HRT3-Rostock  
Heidelberg retinal tomograph with Rostock cornea module 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IκB 
Inhibitor of κB 
IL-2 
Interleukin-2 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web-based response system 
LogMAR 
logarithm of the minimum angle of resolution 


 
 
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MedDRA 
Medical Dictionary for Regulatory Activities  
MCH 
mean corpuscular hemoglobin  
MCHC 
mean corpuscular hemoglobin concentration  
MCV 
mean corpuscular volume 
mITT 
modified intent-to-treat  
N 
sample size 
NFATc 
nuclear factor of activated T cells 
NF-κB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
NSAID 
nonsteroidal anti-inflammatory drug 
OD 
right eye 
OS 
left eye 
OSDI 
Ocular Surface Disease Index 
OU 
both eyes 
PRO 
patient-reported outcome 
RBC 
red blood cell 
SOP 
standard operating procedure 
TBUT 
tear film break-up time 
VAS 
visual analog scale 
WBC 
white blood cell 
 










 
 
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Section
 Revision
 
Rationale
 
Table 5, 
12.1.16 
Clarified that grading of TBUT should 
be done by the follow-up investigator. 
However, instillation of fluorescein for 
the TBUT exam should be done by the 
treating investigator or qualified 
personnel that assist the treating 
investigator.  
For the TBUT exam, fluorescein is 
applied to the superior conjunctiva, 
thus potentially exposing the site   
  Having 
either the treating investigator or 
qualified personnel that assist the 
treating investigator apply the 
fluorescein will preserve masking for 
the follow-up investigator to the study 
treatment. 
5.3 
The site personnel conducting 
photographic conjunctival hyperemia 
assessments will not perform other tasks 
for the study may assist with study tasks 
consistent with the role of the treating 
investigator.  
Clarified role of site personnel 
conducting photographic conjunctival 
hyperemia assessment.  
Summary, 7.3.3  Pharmacokinetic parameters for blood 
and tears will only be calculated for 
samples collected from patients who 
receive study treatment.  
Pharmacokinetic parameters for tears 
will only be calculated for samples 
collected from drug treated eyes of 
patients who receive study treatment. 
Modified to analyze tear samples from 
both drug treated and untreated 
(contralateral) eyes of patients. 










 
 
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Section
 Revision
 
Rationale
 
Section 5.6  
Additional dose groups of
 
were added. 
For consistency with other 
earlier sections. 
Section 7  
Added:  A database lock may also be performed 
for all patients in stage 2 at 4 weeks following 
retreatment (ie, Week 4R). 
An additional data analysis was 
added at Week 4R for 
administrative purposes. 
Section 8  
Changes to the number of cohorts, dose groups, 
highest dose group, 
 are 
made throughout. 
For consistency with other 
earlier sections.  






















































 
 
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Section
 Revision
 
Rationale
 
Section 8 
For stage 1, changed “RESTASIS X” to “F1 or 
F2.” 
Stage 2 will enroll patients with moderate to 
severe dry eye disease.  and 1 or more 
concomitant immune mediated diseases (at least 
50% of patients will have Sjögren’s syndrome).  
Four.  Three dose groups will be enrolled in 
parallel, with patients randomized across dose 
groups; all patients will receive 
RESTASIS® XCFI or vehicle treatment in both 
eyes.  Screening and run-in with REFRESH 
PLUS will be similar to stage 1.  At week 12, 
patients will be retreated with the same dose of 
RESTASIS® XCFI or vehicle in both eyes 
unless safety results preclude retreatment. 
 
Deleted the following text: 
The scheduled examinations for a given 
timepoint should be performed in the order 
shown (from top to bottom) in the schedule of 
visits and procedures (Table 3 and Table 4) and 
in Section 8 below 
For clarification. Deleted the 
requirement for patients in 
stage 2 to have 1 or more 
concomitant systemic immune-
mediated diseases based on 
feedback from a global advisory 
board. Removed the 
requirement for 50% of subjects 
to have Sjögren’s syndrome. 
For clarification of the number 
of dose groups and formulation 
to be used in stage 2. 
 
 
 
 
For clarification. 
Section 8.4.1 
Per protocol, procedures Procedures at each 
visit should generally be, but are not required to 
be, performed in the order listed in Table 3 
(Schedule of Visits and Procedures).  Every 
effort should be made to follow this order to 
ensure that the performance of particular 
procedures do not affect the results of 
subsequent assessments.  ,   However, should 
Should the site need to reorder some of the 
procedures to fit into their standard practices, 
the following procedures MUST be completed 
in the order shown below due to potential 
impact on the subsequent assessments: 
For clarification. 
Section 8.4.1 
Removed blood sampling for pharmacokinetic 
analysis.  
To eliminate redundancy. 




 
 
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ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) Signed by: 
Justification 
  
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 192371-024 Amendment 6
19-Jan-2017 07:56 GMT-080
Clinical Development Approval

SAP_001.pdf: 
NCT02013791 
 
 
Study 192371-024 
 
 
Title: A Phase 2, Multi-center, Vehicle- and Sham-controlled, Randomized Study of 
RESTASIS® X in Patients With Moderate to Severe Dry Eye Disease 
 
 
 
Protocol Amendment 6 Date: Jan 19, 2017 
 
 
Statistical Analysis Plan (SAP) Date: June, 20, 2017 


Allergan Confidential 
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1. 
Title Page 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Multicenter, Vehicle- and Sham-controlled, Randomized Study of 
RESTASIS® X in Patients With Moderate to Severe Dry Eye Disease 
 
Stage 1 
 
  
 
Protocol Number: 
192371-024 
Development Phase: 
2 
Product Name: 
RESTASIS® X 
Study Statistician: 
 
Sponsor: 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612  
+1-714-246-4500 
+1-800-347-4500 
 
This document is the property of Allergan, Inc. and may not, in full or part, be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan, Inc.


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2. 
Table of Contents 
1. 
Title Page ................................................................................................................................. 1 
2. 
Table of Contents ..................................................................................................................... 2 
2.1 
List of Tables .................................................................................................................. 3 
2.2 
List of Figures ................................................................................................................ 5 
3. 
List of Abbreviations and Definition of Terms ........................................................................ 6 
4. 
Introduction .............................................................................................................................. 7 
4.1 
Study Design Summary ................................................................................................. 7 
4.2 
Study Objectives and Assessments .............................................................................. 12 
4.3 
Schedule of Activities .................................................................................................. 13 
5. 
Statistical Methodology and Study Endpoints ....................................................................... 18 
5.1 
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 18 
5.1.1  Statistical and Analytical Plans ........................................................................ 18 
5.1.1.1  Common Conventions ....................................................................... 18 
5.1.1.2  Demographics .................................................................................... 20 
5.1.1.3  Exploratory Efficacy Analyses .......................................................... 22 
5.1.1.4  Safety Analyses ................................................................................. 26 
5.1.1.5  Health Outcomes Data Analyses ....................................................... 32 
5.1.1.6  Subgroup Analyses ............................................................................ 33 
5.1.1.7  Interim Analyses ................................................................................ 33 
5.1.2  Determination of Sample Size ......................................................................... 33 
5.2 
Changes in the Conduct of the Study or Planned Analyses ......................................... 33 
5.2.1  Changes in the Conduct of the Study ............................................................... 33 
5.2.2  Changes to Analyses Prior to Database Lock .................................................. 33 
6. 
Data Handling and Analysis Conventions ............................................................................. 34 
6.1 
Study Treatment Conventions ...................................................................................... 34 
6.1.1  Analysis Days .................................................................................................. 34 
6.2 
Analysis Visit Windows ............................................................................................... 34 
6.2.1  Treatment Cycle 1 ............................................................................................ 34 
6.2.2  Treatment Cycle 2 ............................................................................................ 36 
6.3 
Missing/Incomplete Date Conventions ........................................................................ 38 
6.3.1  Missing/Incomplete AE Start Date .................................................................. 39 
6.3.2  Missing/Incomplete Medication Start Date ..................................................... 39 
6.3.3  Missing/Incomplete AE/Medication End Date ................................................ 39 


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6.4 
Exploratory Efficacy Endpoint Conventions ............................................................... 39 
6.4.1  Patient Symptoms (Visual Analog Scale) ........................................................ 39 
6.4.2  Ocular Surface Disease Index .......................................................................... 40 
6.5 
Safety Endpoint Conventions ....................................................................................... 40 
6.5.1  Adverse Events ................................................................................................ 40 
6.5.1.1  Missing Intensity or Relationship ...................................................... 40 
6.5.2  Clinical Laboratory Assessments ..................................................................... 41 
6.5.3  Vital Signs ........................................................................................................ 41 
6.5.4  Slit-lamp Biomicroscopy ................................................................................. 41 
6.5.5  Dilated Ophthalmic Examinations ................................................................... 44 
6.6 
Health Outcomes Endpoint Conventions ..................................................................... 44 
6.7 
Imputed Value Listing Conventions ............................................................................. 45 
 
2.1 
List of Tables 
Table 3-1 
Abbreviations and Definitions of Terms ................................................................. 6 
Table 4-1 
Dosage/Dose Regimen – Stage 1 Dose Escalation in Patients With Moderate to 
Severe Dry Eye Disease .......................................................................................... 9 
Table 4-2 
Study Objectives and Corresponding Endpoints - Stage 1 ................................... 12 
Table 4-3 
Schedule of Activities - Stage 1 ............................................................................ 14 
Table 4-4 
Schedule of Activities - Stage 2 ............................................................................ 16 
Table 5-1 
Analysis Populations – Stage 1 ............................................................................. 18 
Table 5-2 
Statistical Methodology – Stage 1 ........................................................................ 19 
Table 5-3 
Analysis Population Summaries ........................................................................... 20 
Table 5-4 
Patient Disposition Summaries ............................................................................. 20 
Table 5-5 
Protocol Deviation Summary ................................................................................ 21 
Table 5-6 
Demographic Summaries ...................................................................................... 21 
Table 5-7 
Medical History Summary .................................................................................... 21 
Table 5-8 
Medication Summaries ......................................................................................... 22 
Table 5-9 
Schirmer’s Tear Test Summaries ........................................................................... 22 


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Table 5-10 
Tear Film Break-Up Time Summaries .................................................................. 23 
Table 5-11 
Sodium Fluorescein Corneal Staining Summaries ............................................... 23 
Table 5-12 
Lissamine Green Conjunctival Staining Summaries ............................................ 23 
Table 5-13 
Patient Symptoms (Visual Analog Scale) Summaries .......................................... 24 
Table 5-14 
Ocular Surface Disease Index (OSDI) Summaries ............................................... 25 
Table 5-15 
Treatment Assessment by Investigator Summaries .............................................. 25 
Table 5-16 
Study Treatment Summaries ................................................................................. 26 
Table 5-17 
AE Terms .............................................................................................................. 26 
Table 5-18 
AE Summaries ...................................................................................................... 26 
Table 5-19 
Clinical Laboratory Summaries ............................................................................ 28 
Table 5-20 
Vital Signs Summaries .......................................................................................... 28 
Table 5-21 
BCVA Summaries ................................................................................................. 29 
Table 5-22 
Macroscopic Bulbar Hyperemia Summaries ........................................................ 30 
Table 5-23 
Slit-lamp Biomicroscopy Summaries ................................................................... 30 
Table 5-24 
Dilated Ophthalmic Examinations Summaries ..................................................... 31 
Table 5-25 
Photographic Conjunctival Hyperemia Summaries .............................................. 31 
Table 5-26 
Intraocular Pressure Summaries ........................................................................... 32 
Table 5-27 
REFRESH PLUS Use and Compliance Summaries ............................................. 32 
Table 5-28 
Health Outcomes Data Summaries ....................................................................... 32 
Table 6-1 
Analysis Day Definitions ...................................................................................... 34 
Table 6-2 
Analysis Visit Definitions 1 .................................................................................. 34 
Table 6-3 
Analysis Visit Definitions 2 .................................................................................. 34 
Table 6-4 
Analysis Visit Definitions 3 .................................................................................. 35 
Table 6-5 
Analysis Visit Definitions 4 .................................................................................. 35 
Table 6-6 
Analysis Visit Definitions 5 .................................................................................. 35 


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Table 6-7 
Analysis Visit Definitions 6 .................................................................................. 36 
Table 6-8 
Analysis Visit Definitions 7 .................................................................................. 36 
Table 6-9 
Analysis Visit Definitions 8 .................................................................................. 36 
Table 6-10 
Analysis Visit Definitions 1 (Retreatment) ........................................................... 36 
Table 6-11 
Analysis Visit Definitions 2 (Retreatment) ........................................................... 37 
Table 6-12 
Analysis Visit Definitions 3 (Retreatment) ........................................................... 37 
Table 6-13 
Analysis Visit Definitions 4 (Retreatment) ........................................................... 37 
Table 6-14 
Analysis Visit Definitions 5 (Retreatment) ........................................................... 37 
Table 6-15 
Analysis Visit Definitions 6 (Retreatment) ........................................................... 38 
Table 6-16 
Imputation Scenarios ............................................................................................ 38 
Table 6-17 
Initial Imputed Date Algorithm ............................................................................. 39 
Table 6-18 
Patient Symptoms (Visual Analog Scale) ............................................................. 39 
Table 6-19 
OSDI Questionnaire .............................................................................................. 40 
Table 6-20 
OSDI Score Derivation ......................................................................................... 40 
Table 6-21 
Missing AE Intensity and Relationship Imputation Algorithms ........................... 40 
Table 6-22 
Clinical laboratory Descriptive and Shift Table Parameters ................................. 41 
Table 6-23 
Vital Sign Descriptive Parameters ........................................................................ 41 
Table 6-24 
Slit-lamp Biomicroscopy Scales ........................................................................... 41 
Table 6-25 
Dilated Ophthalmic Examinations Grade ............................................................. 44 
Table 6-26 
Supplemental Dry Eye Questionnaire ................................................................... 44 
  
2.2 
List of Figures 
Figure 4-1 
Stage 1 Study Flow – Dose Escalation In Patients With Moderate To Severe Dry 
Eye Disease ........................................................................................................... 10 
 


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3. 
List of Abbreviations and Definition of Terms 
Table 3-1 
Abbreviations and Definitions of Terms 
Abbreviation/Term 
Definition 
AE 
adverse event 
BCVA 
best-corrected visual acuity 
CFB 
change from baseline 
DDE 
Drug Dictionary Enhanced 
 
 
eCRF 
electronic case report form 
F1 
  
F2 
  
IOP 
intraocular pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
OSDI 
Ocular Surface Disease Index 
PK 
pharmacokinetic 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
TBUT 
treatment-emergent adverse event 
tear film break-up time 
VAS 
visual analog scale 
WHO 
World Health Organization 










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Randomization/Stratification:   
Stage 1:  Within each cohort, patients will be randomly assigned with respect to the eye, right or 
left, to receive F1 or F2 (or vehicle for Cohort 1). The contralateral eye will receive 
vehicle (sham for Cohort 1). 
   
 
 
 
 
 
Number of Patients: 
Stage 1: Stage 1 will have up to 63 patients and approximately 10 cohorts (Cohorts 1 to 6D). The 
anticipated numbers of patients per cohort are 3 for Cohort 1; 4 for Cohorts 2, 6C, and 
6D; and 8 each for Cohorts 3 through 6B. 
 
 


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4.2 
Study Objectives and Assessments 
The study objective for stage 1 is presented with corresponding assessments in Table 4-2. 
Table 4-2 
Study Objective and Corresponding Assessments - Stage 1 
Objective 
Assessments 
To evaluate the safety, exploratory 
efficacy, and pharmacokinetics of 
F1 and F2 administered as a 
 
in patients with moderate to severe 
dry eye disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
• AEs 
• BCVA (manifest refraction at screening and exit visits) 
• Macroscopic hyperemia assessment and slit-lamp biomicroscopy 
• Dilated ophthalmic exam 
• Photographic conjunctival hyperemia assessment 
• IOP 
• Vital signs 
• Laboratory tests (chemistry, hematology, urinalysis) 
• Urine pregnancy test (for females of childbearing potential) 
 
Pharmacokinetic Assessments 
• PK assessments will be detailed in a separate PK analysis plan. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE = adverse event; BCVA = best-corrected visual acuity; F1 
 F2 =
 IOP = intraocular pressure; OSDI = Ocular 
Surface Disease Index; PK = pharmacokinetic; TBUT = tear film break-up time; VAS = visual analog scale 
 
 
 
 


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4.3 
Schedule of Activities 
The schedule of activities is presented in Table 4-3 (stage 1) and Table 4-4 (stage 2). If 
retreatment is given at Week 12, the stage 1 retreatment schedule will be following the stage 2 
retreatment schedule (see post-retreatment follow-up visits in Table 4-4). 
 
 
 


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5. 
Statistical Methodology and Study Endpoints 
5.1 
Statistical Methods Planned in the Protocol and Determination of 
Sample Size 
This SAP for stage 1 will be approved prior to final database lock. The SAP expands the 
statistical section of the protocol and contains a detailed description of methods to analyze data 
collected in the study. The text portion of the SAP will be included in the clinical study report 
report as Appendix 16.1.9. Information on the PK analyses can be found in the PK data analysis 
plan, which is a separate document. 
5.1.1 
Statistical and Analytical Plans 
 
5.1.1.1 
Common Conventions 
5.1.1.1.1 
Analysis Populations 
The analysis populations will consist of patientss as defined in Table 5-1. 
Table 5-1 
Analysis Populations – Stage 1 
Population 
Definition 
Study Treatment 
Safety 
All patients who are treated 
Actual receiveda 
Modified intent-to-
treat (mITT) 
All randomized patients who have baseline and at least 1 
postbaseline assessment for 1 or more of the exploratory efficacy 
measurements  
 
Randomized assignment 
a 
Patients will be summarized according to the first study treatment received or study treatment received for 
majority of treatment period. 
 
5.1.1.1.2 
Study Treatments 
The following treatment groups and cohorts are defined for stage 1 in this study: 
Cohort 
Treatment Group 
Cohort 5A RESTASIS X F1 
 
Cohort 4 
RESTASIS X F1 
  
Cohort 6C RESTASIS X F1 
 with retreatment at week 12 
Cohort 3 
RESTASIS X F1 
 
Cohort 2 
RESTASIS X F1 
 
Cohort 6B RESTASIS X F2 
  
Cohort 6D RESTASIS X F2 
 with retreatment at week 12 
Cohort 6A RESTASIS X F2 
 
Cohort 1 
Vehicle 
Data will be analyzed by treatment group/cohort, unless otherwise specified.   




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5.1.1.1.4 
Missing Data 
General missing data handling conventions are summarized as follows: 
• Missing data will not be imputed and all analyses will be based on observed data. 
• Partial dates handling conventions are specified in Section 6.3, but will be listed in the 
data listings as they appear on the electronic case report forms (eCRFs).  
5.1.1.2 
Demographics 
The safety population will be used to summarize demographics. 
5.1.1.2.1 
 Analysis Populations 
The distribution of patients within the analysis populations will be summarized as described in 
Table 5-3. 
Table 5-3 
Analysis Population Summaries 
Population  
Description 
Timing 
Methodology 
mITT and safety 
populations 
Distribution in total and by treatment 
group 
— 
Categorical counts 
 
5.1.1.2.2 
Patient Disposition 
Patient disposition encompasses the distribution of patients who enter, complete, and discontinue 
each specified analysis period, along with eCRF-reported discontinuation reasons from each 
respective analysis period. Patient disposition will be summarized as shown in Table 5-4. 
Table 5-4 
Patient Disposition Summaries 
Parameter 
Description 
Timing 
Methodology 
Study disposition 
Distribution in total and by treatment 
group 
During study 
Categorical 
descriptives 
Patient dispositiona by 
phase 
Distribution in the safety population in 
total and by treatment group 
Treatment Period 
Categorical 
descriptives 
a Patients who prematurely discontinued will be listed. 
 
5.1.1.2.3 
Protocol Deviations 
Protocol deviations will be defined in a separate document, including importance classification. 
Protocol deviations will be summarized as shown in Table 5-5. 


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Table 5-5 
Protocol Deviation Summary 
Parameter 
Description 
Timing 
Methodology 
Significant protocol 
deviationsa 
Distribution in the safety population in 
total and by treatment group 
— 
Categorical 
descriptives 
a Patients with significant protocol deviations will be listed. 
 
5.1.1.2.4 
Demographics 
Demographics will be summarized in total and by treatment group for the safety population as 
shown in Table 5-6. 
Table 5-6 
Demographic Summaries 
Parameter 
Description 
Timing 
Methodology 
Agea 
Age (years) relative to informed consent 
date 
Informed consent 
Continuous 
descriptives 
Age group 
• 
< 45 years 
• 
45-65 years 
• 
> 65 years 
Informed consent 
Categorical 
descriptives 
Sex, and race1 
• 
eCRF categories 
• 
Race group 1 
o 
Caucasian  
o 
Black 
o 
Asian 
o 
Hispanic 
o 
Other 
• 
Race group 2 
o 
Caucasian  
o 
Non-caucasian 
Screening period 
Categorical 
descriptives 
a Patient demographics will be listed. 
 
5.1.1.2.5 
Medical History 
Medical and ophthalmic history, encompassing abnormalities and surgeries reported as occurring 
before the Screening Visit, will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), version 19.0 or newer. Unique patients who report medical history events will be 
summarized by MedDRA system organ class (SOC) and preferred term (PT) in total and by 
treatment group for the safety population as shown in Table 5-7. 
Table 5-7 
Medical History Summary 
Parameter 
Description 
Timing 
Methodology 
Medical history 
Abnormalities and surgeries  
Past 
Categorical 
descriptives 
Medical condition at 
trial initiation 
Abnormalities and surgeries  
Currently at the time 
informed consent 
was obtained 
Categorical 
descriptives 
Ophthalmic history 
Ophthalmic abnormalities and surgeries  
Past 
Categorical 
descriptives 
Ophthalmic condition at 
Ophthalmic abnormalities and surgeries  
Currently at the time 
Categorical 


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Parameter 
Description 
Timing 
Methodology 
trial nitiation 
informed consent 
was obtained 
descriptives 
 
5.1.1.2.6 
Prior and Concomitant Medications 
Medications will be coded using the WHO Drug Dictionary Enhanced (DDE), version 
MAR2016 or newer. Unique patients who reported medications will be summarized by MedDRA 
SOC, and PT, and WHO DDE drug base preferred name in total and by treatment group for the 
safety population as shown in Table 5-8. 
Table 5-8 
Medication Summaries 
Parameter 
Description 
Timing 
Methodology 
Prior medications 
Medications taken ≥ 1 time before the 
study treatment start date, regardless of 
medication end date 
Screening period 
Categorical 
descriptives 
Concomitant 
medications 
Medications taken ≥ 1 time on or after the 
study treatment start date, regardless of 
medication start date 
Treatment period 
Categorical 
descriptives 
 
5.1.1.3 
Exploratory Efficacy Analyses 
 
5.1.1.3.1 
Schirmer’s Tear Test (With Anesthesia) 
Schirmer’s tear test (with anesthesia) will be summarized by treatment group as shown in Table 
5-9. 
Table 5-9 
Schirmer’s Tear Test Summaries 
Endpoint 
Description 
Timing 
Methodology 
Schirmer’s tear test 
scorea   
Summary by analysis visit 
 
Cycle 1: Study 
baseline (Day 1) and 
Weeks 4, 8, 12, and 
24 
 
Cycle 2: Cycle 
baseline and 
Weeks 4R, 8R, and 
12R 
CFB descriptives  
Number (percent) of 
responders 
Summary by analysis visit  
• 
Responder defined as ≥ 10 mm/5 min 
increase from study baseline in 
Schirmer’s tear test score 
Cycle 1: Weeks 4, 8, 
12, and 24 
Categorical 
descriptives 
a All schirmer’s tear test data will be listed. 
 


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5.1.1.3.2 
Tear Film Break-Up Time 
Tear film break-up time (TBUT) will be summarized by treatment group as shown in Table 5-10. 
Table 5-10 
Tear Film Break-Up Time Summaries 
Endpoint 
Description 
Timing 
Methodology 
TBUT   
Summary by analysis visit 
• 
The average value of 3 measurements 
in each eye at each visit will be used 
Cycle 1: Study 
baseline (Day 1) and 
Weeks 4, 8, 12, and 
24 
 
Cycle 2: Cycle 
baseline and 
Weeks 4R, 8R, and 
12R 
CFB descriptives  
 
5.1.1.3.3 
Sodium Fluorescein Corneal Staining 
Sodium fluorescein corneal staining will be summarized by treatment group as shown in Table 
5-11. 
Table 5-11 
Sodium Fluorescein Corneal Staining Summaries 
Endpoint 
Description 
Timing 
Methodology 
CFB in ordinal scale  
Summary by analysis visit 
Cycle 1: Study 
baseline (Day 1) and 
Weeks 4, 8, 12, and 
24 
 
Cycle 2: Cycle 
baseline and 
Weeks 4R, 8R, and 
12R 
CFB descriptives  
 
5.1.1.3.4 
Lissamine Green Conjunctival Staining 
Lissamine green conjunctival staining will be summarized by treatment group as shown in Table 
5-12. 
Table 5-12 
Lissamine Green Conjunctival Staining Summaries 
Endpoint 
Description 
Timing 
Methodology 
CFB in ordinal scale of  
conjunctival staining 
 
Summary by analysis visit and by area 
(nasal, temporal) and in total 
• 
Total is calculated as the sum of areas –
nasal and temporal 
Cycle 1: Study 
baseline (Day 1) and 
Weeks 4, 8, 12, and 
24 
 
Cycle 2: Cycle 
baseline and 
Weeks 4R, 8R, and 
12R 
CFB descriptives  


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Endpoint 
Description 
Timing 
Methodology 
CFB in ordinal scale of  
total corneal and 
conjunctival staining 
Summary by analysis visit  
• 
Total corneal and conjunctival staining 
is the sum of corneal staining plus 
conjunctival staining (nasal plus 
temporal) 
Cycle 1: Study 
baseline (Day 1) and 
Weeks 4, 8, 12, and 
24 
 
Cycle 2: Cycle 
baseline and 
Weeks 4R, 8R, and 
12R 
CFB descriptives  
 
5.1.1.3.5 
Patient Symptoms (Visual Analog Scale) 
A short questionnaire utilizing a VAS to quantify the severity of symptoms of dry eye will be 
administered. The questions refer to TODAY only including overall ocular discomfort from dry 
eye disease, level of discomfort experienced from symptoms as specified in Table 6-18. The 
score will be 0 to 100 with 0 = none and 100 = extreme. 
Patient symptoms (VAS) will be summarized by treatment group as shown in Table 5-13. 
Table 5-13 
Patient Symptoms (Visual Analog Scale) Summaries 
Endpoint 
Description 
Timing 
Methodology 
Overall VAS scorea 
Summary by analysis visit  
Cycle 1: Study 
baseline (Day 1) and 
Weeks 12 and 24 
 
Cycle 2: Cycle 
baseline and 
Weeks 8R and 12R 
CFB descriptives  
Worse VAS scorea 
Summary by analysis visit  
• 
For each patient, the symptom among 
all 9 symptoms (specified in Table 
6-18) with the worst VAS at baseline 
(Day 1) will be used. If no single 
symptom can be identified at baseline 
(Day 1), the symptom with the worst 
VAS score at screening will be used. 
Cycle 1: Study 
baseline (Day 1) and 
Weeks 12 and 24 
 
Cycle 2: Cycle 
baseline and 
Weeks 8R and 12R 
CFB descriptives  
a All patient symptoms (VAS) data will be listed. 
 
5.1.1.3.6 
Ocular Surface Disease Index 
The Ocular Surface Disease Index (OSDI) Questionnaire consists of 12 questions based on 
which the total score (questions 1-12) and 3 subscales including ocular symptoms (questions 1-3), 
vision-related functioning (questions 4-9), and environmental triggers (questions 10-12) will be 
computed. The patients will be asked to rate each symptom using a 5-point scale (0 to 4), where 
0 = none of the time, 1 = some of the time, 2 = half of the time, 3 = most of the time, and 4 = all 
of the time. Seven questions allow a response of not applicable (N/A). A higher score represents 
greater disability. 


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The OSDI Questionnaire scores will be summarized by treatment group as shown in Table 5-14. 
Table 5-14 
Ocular Surface Disease Index Summaries 
Endpoint 
Description 
Timing 
Methodology 
OSDI scorea 
Summary by analysis visit and by  
• 
The total OSDI score 
• 
The 3 subscale scores (specified in 
Table 6-20) 
Cycle 1: Study 
baseline (Day 1) and 
Weeks 4, 12, and 24 
 
Cycle 2: Cycle 
baseline and 
Weeks 4R and 
Week 12R 
CFB descriptives  
Number (percent) of 
responders 
Summary by analysis visit  
• 
Responder is defined as ≥ 20 point 
decrease from study baseline in total 
OSDI score  
Cycle 1: Weeks 4, 
12, and 24 
 
 
Categorical 
descriptives 
a All ocular surface disease index data will be listed. 
5.1.1.3.7 
Treatment Assessment by Investigator 
The follow-up investigator will complete a global evaluation of the overall effect of 
investigational medication administered in reference to the Baseline visit (Day 1) prior to the 
of the investigational medication for each eye at the scheduled visits. The global 
evaluation score will be assessed based on the following scale: 
0 
= 
Completely cleared, no sign or symptom of disease 
1 
= 
Almost cleared: very significant clearance in disease with only traces of active disease 
remaining (approximately 90% improvement) 
2 
= 
Marked response: significant improvement with some disease remaining (approximately 
75% improvement) 
3 
= 
Moderate response: intermediate improvement, between slight and marked 
(approximately 50% improvement) 
4 
= 
Slight response: some improvement in disease state but significant disease remains 
(approximately 25% improvement) 
5 
= 
Condition unchanged 
6 
= 
Condition worsened 
 
Treatment assessment by investigator will be summarized by treatment group as shown in Table 
5-15. 
Table 5-15 
Treatment Assessment by Investigator Summaries 
Endpoint 
Description 
Timing 
Methodology 
Global evaluation 
score 
Summary by analysis visit for the raw score 
Cycle 1: Weeks 8, 
12, and 24 
 
Cycle 2: Week 8R, 
and Week 12R 
Continuous 
descriptives 
 


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5.1.1.4 
Safety Analyses 
Safety analyses will be based on the safety population. 
5.1.1.4.1 
Study Treatment Exposure 
Study treatment exposure and compliance will be summarized by treatment group for the safety 
population as shown in Table 5-16.  
Table 5-16 
Study Treatment Summaries 
Parameter 
Description 
Timing 
Methodology 
Study treatment 
exposure (days) 
Date of study exit – date of 1st injection + 1 
Treatment period 
Continuous 
descriptives 
 
5.1.1.4.2 
Adverse Events 
Adverse events (AEs) are defined as shown in Table 5-17. 
Table 5-17 
AE Terms 
Term 
Description 
TEAE 
An adverse event recorded on the eCRF would be considered treatment-emergent if either of 
the following conditions are met: 
    AE onset date ≥ first study treatment date; or 
    AE onset date < first study treatment date and either:  
• 
the severity of the event worsened on or after the first study treatment date, or 
• 
the event became serious on or after the first study treatment date 
SeriousTEAE 
An event identified as TEAE that further meets SAE criteria at any time would be a serious 
TEAE. 
SAE = serious adverse event; TEAE = treatment-emergent adverse event 
 
 
AEs, encompassing abnormalities and surgeries reported as occurring after the Screening Visit, 
will be coded using MedDRA version 19.0 or newer. Unique patients reporting AEs in the 
following AE categories will be summarized by treatment group for the safety population as 
shown in Table 5-18.  
Table 5-18 
AE Summaries 
Parameter 
Description 
Timing 
Methodology 
Overall summary 
Overall summary for the following 
categories: 
• 
TEAEs (ocular vs. non-ocular) 
• 
Study drug-related TEAEs (ocular 
vs. non-ocular) 
• 
Study procedure-related TEAEs 
(ocular vs. non-ocular) 
• 
Serious TEAEs (ocular vs. non-
ocular) 
• 
TEAEs leading to study 
From treatment start 
date until 
Week 24/Week 12R or 
early termination date, 
whichever comes first 
Categorical 
descriptives 


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Parameter 
Description 
Timing 
Methodology 
discontinuation (ocular vs. non-
ocular) 
• 
Deaths 
TEAEsa  
Overall summary and by SOC in 
alphabetical order, PT and  worst severity  
 
The worst severity is defined as the greater 
of the onset severity and maximum 
severity following onset recorded on the 
eCRF. If the same TEAE term has been 
reported more than once for a subject with 
different severity grades, the worst severity 
grade will be used in the tabulation. 
From treatment start 
date until 
Week 24/Week 12R  
or early termination 
date, whichever comes 
first 
Categorical 
descriptives 
Ocular TEAEs  
Overall summary and by SOC in 
alphabetical order, PT and  worst severity  
 
The worst severity is defined as the greater 
of the onset severity and maximum 
severity following onset recorded on the 
eCRF. If the same TEAE term has been 
reported more than once for a subject with 
different severity grades, the worst severity 
grade will be used in the tabulation. 
From treatment start 
date until 
Week 24/Week 12R  
or early termination 
date, whichever comes 
first 
Categorical 
descriptives 
Study drug-related 
ocular TEAEs 
Overall summary and by SOC in 
alphabetical order and PT  
From treatment start 
date until 
Week 24/Week 12R  
or early termination 
date, whichever comes 
first 
Categorical 
descriptives 
Study procedure-related 
ocular TEAEs 
Overall summary and by SOC in 
alphabetical order and PT  
From treatment start 
date until 
Week 24/Week 12R  
or early termination 
date, whichever comes 
first 
Categorical 
descriptives 
Serious TEAEs 
Overall summary and by SOC in 
alphabetical order and PT  
From treatment start 
date until 
Week 24/Week 12R  
or early termination 
date, whichever comes 
first 
Categorical 
descriptives 
TEAEs leading to study 
discontinuation 
Overall summary and by SOC in 
alphabetical order and PT  
From treatment start 
date until 
Week 24/Week 12R  
or early termination 
date, whichever comes 
first 
Categorical 
descriptives 
eCRF = electronic case report form; PT = preferred term; SAE = serious adverse event; SOC = system organ class; 
TEAE = treatment-emergent adverse event 
a All AEs including pretreatment AEs and TEAEs, and SAEs will be listed. 
 


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5.1.1.4.3 
Clinical Laboratory Assessments 
Clinical laboratory assessments will be summarized by treatment group for the safety population 
as shown in Table 5-19. 
Table 5-19 
Clinical Laboratory Summaries 
Endpoint 
Description 
Timing 
Methodology 
Descriptives 
Summary by laboratory category, 
parameter and analysis visit 
• 
Parameters specified in Table 
6-22 
Cycle 1: Study 
baseline (screening), 
Week 12 (for 
Cohorts 6C and 6D 
only), and Week 24 
 
Cycle 2: Cycle 
baseline and 
Week 12R 
CFB descriptives  
 
5.1.1.4.4 
Vital Signs 
Vital signs will be summarized by treatment group for the safety population as shown in Table 
5-20. 
Table 5-20 
Vital Signs Summaries 
Endpoint 
Description 
Timing 
Methodology 
Descriptives   
Summary by parameter and analysis visit 
• 
Parameters specified in Table 
6-23 
Cycle 1: Study 
baseline andWeeks 
1, 8, 12 (for Cohorts 
6C and 6D only), 
and 24 
 
Cycle 2: Cycle 
baseline, Day 1R, 
and Week 12R 
CFB descriptives  
 
5.1.1.4.5 
Other Safety Analyses 
5.1.1.4.5.1 
Best-Corrected Visual Acuity  
Manifest refraction will be performed at screening and used for BCVA at all subsequent visits 
until study exit. If there is a decrease in BCVA, the manifest refraction should be repeated as 
confirmation. Visual acuity (in Snellen equivalents) will be measured for each eye using a 
logarithmic visual acuity chart for testing at 10 feet (3 meters) at the scheduled visits.  
The visual acuity will be recorded on the eCRF in Snellen equivalent units (eg, 20/63) as the 
lowest line read with 1 or 0 mistakes.   
The line CFB at each evaluation is calculated using the following algorithm: 


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line change = (10)*[log10 (XB/20) - log10 (XF/20)], where 
• 
XB = denominator of the Snellen equivalent unit at baseline 
• 
XF = denominator of the Snellen equivalent unit at post treatment visit 
Each logarithmic value is to be rounded to the nearest tenth before subtraction. A positive value 
indicates an improvement and a negative value indicates a worsening. For example, the line 
change for a Snellen equivalent unit of 20/25 at baseline followed by a Snellen equivalent unit of 
20/80 at day 2 would be 
 
Line change = 10 x [log10(25/20) – log10 (80/20)]  = 10 x (0.1 – 0.6) = -5 
which represents a worsening of 5 lines in visual acuity. 
BCVA will be summarized by treatment group for the safety population as shown in Table 5-21. 
Table 5-21 
BCVA Summaries 
Endpoint 
Description 
Timing 
Methodology 
Line CFBa  
Summary by analysis visit and line change 
categories defined below or line change of 
≤ -2, -1, 0, +1, or ≥ +2: 
• 
Better (line changes of ≥ +2) 
• 
No change (line changes of -1, 0, 
+1) 
o 
Line change of +1 
o 
Line change of 0 
o 
Line change of -1 
• 
Worse (line changes of ≤ -2)  
Cycle 1: Day 2 and 
Weeks 1, 2, 4, 8, 12, 
and 24 
 
Cycle 2: Day 1R 
and Weeks 1R, 4R, 
8R, and 12R 
Categorical 
descriptives 
CFB = change from baseline 
a All BCVA will be listed. 
 
 
5.1.1.4.5.2 
Macroscopic Bulbar Hyperemia 
The macroscopic (gross) bulbar hyperemia grading consists of global assessments and regional 
assessments, which will be done under consistent illumination by comparing the appearance of 
the bulbar conjunctiva to standard photographs (Allergan bulbar conjunctival hyperemia grading 
guide) at the scheduled visits. Regional assessment includes superior temporal, superior nasal, 
inferior temporal, and inferior nasal assessment. It will be graded using a 5-point scale described 
as follows:  
 0 
(None) 
= 
Normal;  vessels of bulbar conjunctiva easily observed 
+0.5 
(Trace) 
= 
Trace flush, reddish-pink color 
+1 
(Mild) 
= 
Mild flush, reddish color 
+2 
(Moderate) = 
Bright red color 
+3 
(Severe) 
= 
Deep, bright diffuse redness 
 


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Macroscopic  bulbar hyperemia will be summarized by treatment group for the safety population 
as shown in Table 5-22. 
Table 5-22 
Macroscopic Bulbar Hyperemia Summaries 
Endpoint 
Description 
Timing 
Methodology 
Global assessment: 
severity grade 
Summary by analysis visit  
Cycle 1: Study 
baseline (Day 1), 
Day 2, and Weeks 1, 
2, 4, 8, 12, and 24 
 
Cycle 2: Cycle 
baseline, Day 1R, 
and Weeks 1R, 4R, 
8R, and 12R 
Categorical 
descriptives 
 
5.1.1.4.5.3 
Slit-lamp Biomicroscopy 
Slit-lamp biomicroscopy will be summarized by treatment group for the safety population. 
Biomicroscopy findings will be coded using MedDRA terminology and summarized for each eye 
by treatment group as shown in Table 5-23. 
Table 5-23 
Slit-lamp Biomicroscopy Summaries 
Endpoint 
Description 
Timing 
Methodology 
One or more severity 
grade increase from 
baseline 
Overall summary and by PT  
From treatment start 
date until 
Week 24/Week 12R  
or early termination 
date, whichever 
comes first 
Categorical 
descriptives 
PT = preferred term 
 
5.1.1.4.5.4 
Dilated Ophthalmic Examinations 
Ophthalmoscopy findings will be coded using MedDRA terminology.   
Cup/disc ratio will be reported using a 0.0 to 1.0 scale. The Armaly chart provided by Allergan 
provides a pictorial scale of cup/disc ratio of 0.0 to 0.8. Only listing will be provided for cup/disc 
ratio. 
Dilated ophthalmic examinations will be summarized by treatment group for the safety 
population as shown in Table 5-24. 


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Table 5-24 
Dilated Ophthalmic Examinations Summaries 
Endpoint 
Description 
Timing 
Methodology 
One or more severity 
grade increase from 
baseline 
Overall summary and by PT 
Week 12 (for 
Cohorts 6C and 6D 
only), 
Week 24/Week 12R  
or early termination 
date, whichever 
comes first 
Categorical 
descriptives 
PT = preferred term 
 
5.1.1.4.5.5 
Photographic Conjunctival Hyperemia 
The photographic conjunctival hyperemia grading consists of global assessments and regional 
assessments, which will be done using a Canfield camera in each eye at the scheduled visits. 
Global assessment includes global, global nasal and global temporal assessment, and regional 
assessment includes superior temporal, superior nasal, inferior temporal, and inferior nasal 
assessment. It will be graded as 0 = none, +0.5 = trace, +1 = mild, +2 = moderate, +3 = severe, 
CG = cannot grade, and NE = not evaluated.  
Photographic conjunctival hyperemia will be summarized by treatment group for the safety 
population as shown in Table 5-25. 
Table 5-25 
Photographic Conjunctival Hyperemia Summaries 
Endpoint 
Description 
Timing 
Methodology 
Global assessment: 
severity grade 
Summary by analysis visit  
Cycle 1: Study 
baseline (Day 1), 
Day 2, and Weeks 1, 
2, 4, 8, 12, and 24 
 
Cycle 2: Cycle 
baseline, Day 1R, 
and Weeks 1R, 4R, 
8R, and 12R 
Categorical 
descriptives 
 


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5.1.1.4.5.6 
Intraocular Pressure 
Measurement of intraocular pressure (IOP) will be taken for each eye using the Goldmann 
applanation tonometer affixed to a slit lamp at the scheduled visits. 
IOP will be summarized by treatment group for the safety population as shown in Table 5-26. 
Table 5-26 
Intraocular Pressure Summaries 
Endpoint 
Description 
Timing 
Methodology 
IOPa 
Summary by analysis visit  
Cycle 1: Study 
baseline (Day 1), 
Week 12 (for 
Cohorts 6C and 6D 
only), and Week 24 
 
Cycle 2: Cycle 
baseline, Week 12R 
CFB descriptives  
IOP = intraocular pressure 
a All IOP data will be listed. 
 
5.1.1.4.5.7 
REFRESH PLUS Use  
REFRESH PLUS use will be summarized by treatment group for the safety population as shown 
in Table 5-27. 
Table 5-27 
REFRESH PLUS Use and Compliance Summaries 
Endpoint 
Description 
Timing 
Methodology 
REFRESH PLUS 
descriptives   
Summary by analysis visit  
Cycle 1: Study 
baseline (Day 1), 
Day 2, and Weeks 1, 
2, 4, 8, 12, and 24 
 
Cycle 2: Cycle 
baseline, Day 1R, 
and Weeks 1R, 4R, 
8R, and 12R 
CFB descriptives  
 
5.1.1.5 
Health Outcomes Data Analyses 
The Supplemental Dry Eye Patient Reported Outcomes Questionnaire is a series of questions 
designed to gather information about the types and severity of dry eye symptoms that are 
experienced by patients in each eye. Health outcomes data will be summarized by treatment 
group for the mITT Population as shown in Table 5-28. 
Table 5-28 
Health Outcomes Data Summaries 
Endpoint 
Description 
Timing 
Methodology 
Treatment satisfaction 
Summary of raw score by analysis visit 
Cycle 1: Weeks 4, 8, 
12, and 24 
Continuous 
descriptives 


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Endpoint 
Description 
Timing 
Methodology 
 
Cycle 2: Weeks 4R, 
8R, and 12R 
 
 
5.1.1.6 
Subgroup Analyses 
Subgroup analyses are not planned for stage 1. 
5.1.1.7 
Interim Analyses 
An interim database lock of stage 1 will not be conducted until after all patients in Cohorts 1 
through 6B complete the study and all patients in Cohorts 6C and 6D complete at least Week 1 
following retreatment. Statistical analyses will be performed following the database lock to 
support the design of future clinical studies. 
5.1.2 
Determination of Sample Size 
The sample size for stage 1 is determined empirically.   
Stage 1: Stage 1 will have up to 63 patients and approximately 10 cohorts (Cohorts 1 to 6D). The 
anticipated numbers of patients per cohort are 3 for Cohort 1; 4 each for Cohorts 2, 6C, and 6D; 
and 8 each for Cohorts 3 through 6B. 
5.2 
Changes in the Conduct of the Study or Planned Analyses 
5.2.1 
Changes in the Conduct of the Study 
Not applicable.  
5.2.2 
Changes to Analyses Prior to Database Lock 
The definition of modified intent-to-treat (mITT) population is changed to all randomized 
patients who have baseline and at least 1 postbaseline assessment for 1 or more of the 
exploratory efficacy measurements from all patients who receive study treatment and have 
baseline and at least 1 postbaseline assessment for 1 or more of the exploratory efficacy 
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6. 
Data Handling and Analysis Conventions 
6.1 
Study Treatment Conventions 
6.1.1 
Analysis Days 
Treatment days are defined as shown in Table 6-1. 
Table 6-1 
Analysis Day Definitions 
Term 
Description 
Treatment Day 
 
Relative to treatment start date 
If analysis date ≥ treatment start date: 
• 
Day = analysis date – treatment start date + 1 
o 
Day 1 = treatment start date 
If analysis date < treatment start date: 
• 
Day = analysis date – treatment start date 
o 
Day -1 = day before treatment start date 
o 
There is no Day 0 
 
6.2 
Analysis Visit Windows 
All stage 1 analyses will be performed based on the analysis visit windows defined below.  
The analysis visit windows for exploratory efficacy and safety endpoints follow the schedule of 
visits in the protocol and are defined as follows: 
6.2.1 
Treatment Cycle 1 
Table 6-2 
Analysis Visit Definitions 1 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Pretreatment 
Study Baseline 
Day 1 
Treatment Day 1 
Treatment 
Day 2 
Day 2 
Treatment Day [2, 4] 
Week 1 
Day 7 
Treatment Day [5, 10] 
Week 2 
Day 14 
Treatment Day [11, 20] 
Week 4 
Day 28 
Treatment Day [21, 41] 
Week 8 
Day 56 
Treatment Day [42, 69] 
Week 12 
Day 84 
Treatment Day [70, 125] 
Week 24 
Day 168 
Treatment Day ≥126 
For endpoints with scheduled visits of  Study Baseline (Day 1), Day 2, Week 1, Week 2, Week 4, Week 8, Week 12, and 
Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 
Table 6-3 
Analysis Visit Definitions 2 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Pretreatment 
Study Baseline 
Day 1 
Treatment Day 1 
Treatment 
Week 4 
Day 28 
Treatment Day [2, 41] 


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Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Week 8 
Day 56 
Treatment Day [42, 69] 
Week 12 
Day 84 
Treatment Day [70, 125] 
Week 24 
Day 168 
Treatment Day >=126 
For endpoints with scheduled visits of  Study Baseline (Day 1), Week 4, Week 8, Week 12, and Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 
Table 6-4 
Analysis Visit Definitions 3 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Pretreatment 
Study Baseline 
Day 1 
Treatment Day 1 
Treatment 
Week 1 
Day 7 
Treatment Day [2, 31] 
Week 8 
Day 56 
Treatment Day [32, 69] 
Week 12 
Day 84 
Treatment Day [70, 125] 
Week 24 
Day 168 
Treatment Day >=126 
For endpoints with scheduled visits of  Study Baseline (Day 1), Week 1, Week 8, Week 12, and Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 
Table 6-5 
Analysis Visit Definitions 4 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Pretreatment 
Study Baseline 
Day 1 
Treatment Day 1 
Treatment 
Week 1 
Day 7 
Treatment Day [2, 31] 
Week 8 
Day 56 
Treatment Day [32, 111] 
Week 24 
Day 168 
Treatment Day >=112 
For endpoints with scheduled visits of  Study Baseline (Day 1), Week 1, Week 8, and Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 
Table 6-6 
Analysis Visit Definitions 5 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Pretreatment 
Study Baseline 
Day 1 
Treatment Day 1 
Treatment 
Week 4 
Day 28 
Treatment Day [2, 55] 
Week 12 
Day 84 
Treatment Day [56, 125] 
Week 24 
Day 168 
Treatment Day >=126 
For endpoints with scheduled visits of  Study Baseline (Day 1), Week 4, Week 12, and Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 


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Table 6-7 
Analysis Visit Definitions 6 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Treatment 
Week 8 
Day 56 
Treatment Day [2, 69] 
Week 12 
Day 84 
Treatment Day [70, 125] 
Week 24 
Day 168 
Treatment Day >=126 
For endpoints with scheduled visits of  Week 8, Week 12, and Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 
Table 6-8 
Analysis Visit Definitions 7 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Pretreatment 
Study Baseline 
Day 1 
Treatment Day 1 
Treatment 
Week 12 
Day 84 
Treatment Day [2, 125] 
Week 24 
Day 168 
Treatment Day >=126 
For endpoints with scheduled visits of  Study Baseline (Day 1), Week 12, and Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 
Table 6-9 
Analysis Visit Definitions 8 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Treatment 
Windowa 
Pretreatment 
Study Baseline 
Day 1 
Treatment Day 1 
Treatment 
Week 24 
Day 168 
Treatment Day >=2 
For endpoints with scheduled visits of  Study Baseline (Day 1), and Week 24. 
a Study days are calculated based on the visit date – Treatment (Day 1) visit date + 1. 
 
6.2.2 
Treatment Cycle 2 
Table 6-10 
Analysis Visit Definitions 1 (Retreatment) 
Analysis Phase 
Analysis Visit 
(Derived) 
 
Target Number of Days 
from Retreatment 
Windowa 
Pre-retreatment 
Cycle Baseline 
Day 1 
Retreatment Day 1 (Week 12 from 
treatment start) 
Retreatment 
 
Day 1R 
Day 2 
Treatment Day [2, 4] 
Week 1R 
Day 7 
Treatment Day [5,  17] 
Week 4R 
Day 28 
Treatment Day [18,  41] 
Week 8R 
Day 56 
Treatment Day [42,  69] 
Week 12R 
Day 84 
Treatment Day ≥70 
For endpoints with scheduled visits of  Cycle Baseline (Day 1), Day 1R, Week 1R, Week 4R, Week 8R, and 
Week 12R. 
a Study days from retreatment are calculated based on the visit date – retreatment visit date + 1. 
 


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Table 6-11 
Analysis Visit Definitions 2 (Retreatment) 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Retreatment 
Windowa 
Pre retreatment 
Cycle Baseline 
Day 1 
Retreatment Day 1 (Week 12 from 
treatment start) 
Retreatment 
Week 4R 
Day 28 
Treatment Day [2,  41] 
Week 8R 
Day 56 
Treatment Day [42,  69] 
Week 12R 
Day 84 
Treatment Day ≥ 70 
For endpoints with scheduled visits of  Cycle Baseline (Day 1), Week 4R, Week 8R, and Week 12R. 
a Study days from retreatment are calculated based on the visit date – retreatment visit date + 1. 
 
Table 6-12 
Analysis Visit Definitions 3 (Retreatment) 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Retreatment 
Windowa 
Pre retreatment 
Cycle Baseline 
Day 1 
Retreatment Day 1 (Week 12 from 
treatment start) 
Retreatment 
Day 1R 
Day 2 
Treatment Day [2,  42] 
Week 12R 
Day 84 
Treatment Day ≥ 43 
For endpoints with scheduled visits of  Cycle Baseline (Day 1), Day 1R, and Week 12R. 
a Study days from retreatment are calculated based on the visit date – retreatment visit date + 1. 
 
Table 6-13 
Analysis Visit Definitions 4 (Retreatment) 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Retreatment 
Windowa 
Pre retreatment 
Cycle Baseline 
Day 1 
Retreatment Day 1 (Week 12 from 
treatment start) 
Retreatment 
Week 8R 
Day 56 
Treatment Day [2,  69] 
Week 12R 
Day 84 
Treatment Day ≥ 70 
For endpoints with scheduled visits of  Cycle Baseline (Day 1), Week 8R, and Week 12R. 
a Study days from retreatment are calculated based on the visit date – retreatment visit date + 1. 
 
Table 6-14 
Analysis Visit Definitions 5 (Retreatment) 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Retreatment 
Windowa 
Pre retreatment 
Cycle Baseline 
Day 1 
Retreatment Day 1 (Week 12 from 
treatment start) 
Retreatment 
Week 4R 
Day 28 
Treatment Day [2,  55] 
Week 12R 
Day 84 
Treatment Day  ≥ 56 
For endpoints with scheduled visits of  Cycle Baseline (Day 1), Week 4R, and Week 12R. 
a Study days from retreatment are calculated based on the visit date – retreatment visit date + 1. 
 


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Table 6-15 
Analysis Visit Definitions 6 (Retreatment) 
Analysis Phase 
Analysis Visit 
(Derived) 
Target Number of Days 
from Retreatment 
Windowa 
Pre retreatment 
Cycle Baseline 
Day 1 
Retreatment Day 1 (Week 12 from 
treatment start) 
Retreatment 
Week 12R 
Day 84 
Treatment Day ≥ 2 
For endpoints with scheduled visits of  Cycle Baseline (Day 1), and Week 12R. 
a Study days from retreatment are calculated based on the visit date – retreatment visit date + 1. 
 
The following general conventions will apply unless otherwise specified: 
• If both scheduled and unscheduled visits occur within a single window, the scheduled 
visit will be used; unscheduled visits will be used only if there is no scheduled visits 
available in that window. If multiple visits are eligible for windowing within a single visit 
window, the visit closest to the target day will be used in the analysis. If multiple visits 
are equidistant to the target day, the latest visit will be used. 
• For clinical laboratory variables, the latest nonmissing assessment within any analysis 
window will be flagged as the analysis value. This rule will be applied separately for each 
variable for nonmissing data only. (The exception is because re–runs of laboratory 
variables may only involve one or a few variables and would thus include missing data 
for many variables) 
• All assessments will be included in respective listings. 
6.3 
Missing/Incomplete Date Conventions 
Dates may be imputed with year, month, and day values under certain scenarios: 
Table 6-16 
Imputation Scenarios 
 
 
Complete
 
Scenario 
Year 
Month 
Day 
Imputable 
1 
Yes 
Yes 
Yes 
Complete 
2 
Yes 
Yes 
— 
Yes 
3 
Yes 
— 
Yes 
Noa 
4 
Yes 
— 
— 
Yes 
5 
— 
Yes 
Yes 
Noa 
6 
— 
Yes 
— 
Noa 
7 
— 
— 
Yes 
Noa 
8 
— 
— 
— 
Yes 
a Not allowed per database design. 
 
Dates will be imputed initially toward a specified target date for imputable scenarios 2, 4, and 8, 
and adjusted against the latest reasonable dates. The initial imputed date is determined by the 
algorithm show in Table 6-17. 






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6.5.2 
Clinical Laboratory Assessments 
The laboratory parameters will be included as shown in Table 6-22. 
Table 6-22 
Clinical laboratory Parameters 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, HbA1c mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), platelets, red blood cell 
(RBC) count, RBC morphology, total white blood cell (WBC) count, and differential (neutrophils, 
bands, lymphocytes, monocytes, basophils, and eosinophils) 
Chemistry 
Albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartase aminotransferase (AST), 
gamma-glutamyl transferase (GGT), bicarbonate, calcium, chloride, creatinine, creatine kinase, 
direct bilirubin, glucose, indirect bilirubin, magnesium, phosphorous, potassium, sodium, total 
bilirubin, total cholesterol, total protein, urea nitrogen, and uric acid 
Urinalysis 
Specific gravity, pH, color, protein, glucose, blood, bilirubin, and microscopic examination (WBC, 
RBC, epithelial cells, bacteria, mucus, casts, crystals) 
 
6.5.3 
Vital Signs 
The vital sign parameters as shown in Table 6-23 will be summarized. 
Table 6-23 
Vital Sign Descriptive Parameters 
Parameters
Systolic blood pressure (mmHg) 
Diastolic blood pressure (mmHg) 
Pulse rate (bpm) 
 
 
 
6.5.4 
Slit-lamp Biomicroscopy 
The slit-lamp biomicroscopy examination consists of evaluation of the eye area/condition using a 
5-point or 6-point scales, as well as present no or yes, as shown in Table 6-24. 
Table 6-24 
Slit-lamp Biomicroscopy Scales 
Eye Area/Condition 
Scale 
Eyelids/Eyelid Margins/Lashes  
• 
Edema (eyelids) 
• 
Erythema 
Conjunctiva (Bulbar or Palpebral) 
• 
Hyperemia 
• 
Edema 
• 
Subconjunctival Hemorrhage 
Cornea 
• 
Edema 
• 
Superficial Punctate Keratopathy 
0 
(None)  
+0.5 
(Trace) 
+1 
(Mild) 
+2 
(Moderate) 
+3 
(Severe) 
Anterior Chamber 
• 
Cells 
 
0 = 
0 cells  
+0.5 = 1 to 5 cells (trace)  
+1 = 
6 to 15 cells 


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Eye Area/Condition 
Scale 
+2 = 
16 to 25 cells 
+3 = 
26 to 50 cells 
+4 = 
> 50 cells 
Anterior Chamber 
• 
Flare 
0 = 
None:  no flare seen 
+1 = 
Faint:  faint flare seen 
+2 = 
Moderate:  iris and lens details clear 
+3 = 
Marked:  iris and lens details hazy 
+4 = 
Intense:  fibrin or plastic aqueous 
Presence of  Iris/Pupil Pathology and Other Pathology 
Yes 
No 
Other Pathology if present 
+0.5 (trace) 
+1 (mild) 
+2 (moderate) 
+3 (severe) 
 
Explanation: 
 
Eyelids/Eyelid Margins/Lashes  
Edema (eyelids) 
0 
(None) 
No edema 
+0.5 
(Trace) 
Localized, minimal (trace) swelling 
+1 
(Mild) 
Localized, mild swelling 
+2 
(Moderate) 
Diffuse, moderate swelling 
+3 
(Severe) 
Diffuse, severe swelling 
 
Erythema 
0 
(None) 
No erythema 
+0.5 
(Trace) 
Localized, minimal (trace) flush reddish color 
+1 
(Mild) 
Localized, mild, flush reddish color 
+2 
(Moderate) 
Diffuse reddish color encompassing the entire lid margin 
+3 
(Severe) 
Deep diffuse reddish color of lid margins and superior and/or inferior eyelid 
 
Conjunctiva (Bulbar or Palpebral) 
Hyperemia 
0 
(None) 
No hyperemia 
+0.5 
(Trace) 
Minimal (trace) flush, reddish color  
+1 
(Mild) 
Mild flush, reddish color  
+2 
(Moderate) 
Bright red color 
+3 
(Severe) 
Deep, bright diffuse redness 
 
Edema 
0 
(None) 
No edema 
+0.5 
(Trace) 
Localized, minimal (trace) swelling 


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+1 
(Mild) 
Localized, mild swelling 
+2 
(Moderate) 
Diffuse, moderate swelling   
+3 
(Severe) 
Diffuse, severe swelling 
 
Subconjunctival Hemorrhage  
0 
(None) 
No hemorrhage 
+0.5 
(Trace) 
Flat hemorrhage ≤ 1 quadrant 
+1 
(Mild) 
Elevated hemorrhage ≤ 1 quadrant, or flat and > 1 quadrant 
+2 
(Moderate) 
Elevated hemorrhage > 1 but ≤ 2 quadrants 
+3 
(Severe) 
Elevated hemorrhage > 2 quadrants 
 
Cornea 
Edema 
0 
(None) 
No edema  
+0.5 
(Trace) 
Localized, minimal (trace) epithelial haze 
+1 
(Mild) 
Dull glass appearance of epithelium that may include fine localized microcystic changes 
+2 
(Moderate) 
Dull glass appearance of epithelium with large number of cystic changes with or without 
stromal edema 
+3 
(Severe) 
Epithelial bullae and/or stromal edema, localized or diffuse, with or without stromal 
striae 
 
Superficial Punctate Keratopathy 
0 
= 
No superficial punctate keratopathy 
+0.5 
= 
Trace 
+1 
= 
Mild 
+2 
= 
Moderate 
+3 
= 
Severe 
 
Anterior Chamber 
Cells 
0 
= 
0 cells  
+0.5 
= 
1 to 5 cells (trace)  
+1 
= 
6 to 15 cells 
+2 
= 
16 to 25 cells 
+3 
= 
26 to 50 cells 
+4 
= 
> 50 cells  
 
Flare 
0 
= 
None:  no flare seen 
+1 
= 
Faint:  faint flare seen 
+2 
= 
Moderate:  iris and lens details clear 
+3 
= 
Marked:  iris and lens details hazy 
+4 
= 
Intense:  fibrin or plastic aqueous 
 
Iris/Pupil and Other Pathology 


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The presence of iris/pupil pathology and any other pathology will be evaluated. Other pathology will be graded as 
+0.5 = trace, +1 = mild, +2 = moderate, and +3 = severe. 
6.5.5 
Dilated Ophthalmic Examinations 
The evaluation of dilated ophthalmic examinations is shown in Table 6-25. 
Table 6-25 
Dilated Ophthalmic Examinations Grade 
Description 
Grade 
Lens Status: 
• 
Phakic 
o 
Cortical lens opacity  
o 
Nuclear lens opacity 
o 
Posterior Subcapsular lens opacity 
• 
Pseudophakic  
• 
Aphakic 
Severity: 
0 
(None) 
1 
(Mild) 
2 
(Moderate) 
3 
(Severe) 
Presence of Other Pathology 
Yes 
No 
Other pathology if present: 
• 
Lens 
• 
Vitreous 
• 
Fundus 
• 
Optic nerve 
+0.5 
(Trace) 
+1 
(Mild) 
+2 
(Moderate) 
+3 
(Severe) 
NE 
(Not Evaluable) 
6.6 
Health Outcomes Endpoint Conventions 
The supplemental dry eye questionnaire will be collected as shown in Table 6-26. 
Table 6-26 
Supplemental Dry Eye Questionnaire 
Dry Eye Symptoms Questionnaire 
Score 
In the last 7 days, have you experienced the following symptoms in your right (or 
left) eye? 
1. Dryness 
2. Sensitivity to light 
3. Pain 
4. Decreased or blurred vision 
5. Tearing  
6. Experienced feeling like something doesn't belong in your eye 
7. Secretion or discharge 
8. Burning or stinging 
9. Redness 
10. Swelling in the upper eyelid 
11. Swelling in the lower eyelid 
12. Irritation 
13. Grittiness or feeling as if small specks of sand are in your eye 
14. Discomfort 
Frequency: 
• 
0=All of the time 
• 
1=Most of the time 
• 
2=Half of the time 
• 
3=Some of the time 
• 
4=None of the time 
 
Severity: 
• 
0=Very mild 
• 
1=Mild 
• 
2=Moderate 
• 
3=Severe 
• 
4=Very severe 
 
Treatment Satisfaction Questionnaire 
 


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Dry Eye Symptoms Questionnaire 
Score 
Taking your entire treatment experience into consideration, if given the choice 
again, how likely would you be to repeat the procedure you received in your right 
(or left) eye? 
• 
0=Very unlikely 
• 
1=Unlikely 
• 
2=Neither likely or 
unlikely 
• 
3=Likely 
• 
4=Very likely Mild 
 
 
6.7 
Imputed Value Listing Conventions 
In general, listings will present the actual partial or missing values rather than the imputed values. 
 


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