Clinical trial NCT04393441
Conditions: Dry Eye Disease (DED)
Keywords: Dry Eye Disease DED
Sponsor: Allergan
Start date: 2020-06-29; Completion date: 2021-06-15
Enrollment: 400 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy and safety of a new artificial tear formulation (011516X) with Systane® Ultra Multidose for 90 days in participants with Dry Eye Disease (DED).

Detailed description:

Arms: arm 1: All participants administered 1 to 2 drops of REFRESH PLUS® 3 times daily in each eye for approximately 7 days during a run-in period prior to randomization on Day 1. Participants then administered 1 to 2 drops of Systane® Ultra Multidose in each eye 3 times daily for up to 90 days. arm 2: All participants administered 1 to 2 drops of REFRESH PLUS® 3 times daily in each eye for approximately 7 days during a run-in period prior to randomization on Day 1. Participants then administered 1 to 2 drops of 011516X in each eye 3 times daily for up to 90 days.
Interventions: intervention 1: 011516X (New Artificial Tear Formulation) intervention 2: Systane Ultra Multidose intervention 3: REFRESH PLUS®
Intervention descriptions: intervention 1: Topical eye drops intervention 2: Topical eye drops intervention 3: Topical eye drops

Protocol documents:
Prot_000.pdf: 
NCT04393441


CONFIDENTIAL
Protocol 2007-301-005 Amendment 2
011516X
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GRD-CLN-T-01-01 v3.0
Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Amendment 2
Amendment 1
June 2020
February 2020
Original Protocol
July 2019
Amendment 2 (June 2020)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
The rationale for changes implemented in Protocol Amendment 2 is to clarify inclusion and 
exclusion criteria such that there are no corneal staining scores that could potentially conflict, 
and to remove an error related to OSDI scores.
Section Number and Name
Description of Change
Brief Rationale
Section 5.1 Inclusion Criteria, 
Inclusion Criterion 2.01
Added need not be the same eye at 
Screening and Baseline
Clarification
Section 5.1 Inclusion Criteria, 
Inclusion Criterion 2.02
Added need not be the same eye at 
Screening and Baseline or the same eye 
that meets Inclusion Criterion 2.01
Clarification
Section 5.2 Exclusion Criteria, 
Exclusion Criterion 1.02
Removed the lower bound of < 5 for 
the total cornea staining score, and 
changed application of the criterion 
from one or both eyes to either eye
Clarification to prevent potential 
corneal staining scores from 
conflicting with inclusion criterion 
2.01
Section 8.1.3.5 Ocular Surface 
Disease Index Questionnaire
Removed sentence that reiterated entry 
criteria related to the OSDI score and 
contained an error (> 65)
Clarification to avoid unnecessarily 
repeating entry criteria language
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CONFIDENTIAL
Protocol 2007-301-005 Amendment 2
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Table of Contents
Title Page .........................................................................................................................................1
Protocol Amendment Summary of Changes Table .........................................................................2
Table of Contents.............................................................................................................................3
List of Tables ...................................................................................................................................6
List of Figures..................................................................................................................................6
1.
Protocol Summary ..................................................................................................................7
1.1.
Synopsis......................................................................................................................7
1.2.
Schema........................................................................................................................8
1.3.
Schedule of Activities (SoA) ....................................................................................10
2.
Introduction...........................................................................................................................12
2.1.
Study Rationale.........................................................................................................12
2.2.
Background...............................................................................................................12
2.3.
Benefit/Risk Assessment ..........................................................................................13
3.
Objectives and Endpoints .....................................................................................................15
4.
Study Design.........................................................................................................................16
4.1.
Overall Design ..........................................................................................................16
4.2.
Scientific Rationale for Study Design.......................................................................16
4.3.
Justification for Dose................................................................................................16
4.4.
End of Study Definition............................................................................................17
5.
Study Population...................................................................................................................18
5.1.
Inclusion Criteria ......................................................................................................18
5.2.
Exclusion Criteria .....................................................................................................20
5.3.
Lifestyle Considerations ...........................................................................................23
5.4.
Screen Failures..........................................................................................................23
6.
Study Intervention.................................................................................................................24
6.1.
Study Interventions Administered ............................................................................24
6.1.1.
Run-in Medications and Administration....................................................24
6.1.2.
Study Supplies ...........................................................................................25
6.1.3.
Instructions for Use and Administration....................................................25
6.2.
Preparation/Handling/Storage/Accountability..........................................................26
6.3.
Measures to Minimize Bias: Randomization and Masking......................................26
6.4.
Study Intervention Compliance ................................................................................27
6.5.
Concomitant Therapy................................................................................................27
6.5.1.
Prohibited Treatments and Washout Before the 
Study ..........................................................................................................28
6.5.2.
Permitted Treatments.................................................................................28
6.5.3.
Prohibited Treatments During the Study ...................................................29
6.5.4.
Rescue Medicine........................................................................................30
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6.6.
Dose Modification ....................................................................................................30
6.7.
Intervention after the End of the Study.....................................................................30
7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal.................................................................................................31
7.1.
Discontinuation of Study Intervention......................................................................31
7.2.
Participant Discontinuation/Withdrawal from the Study..........................................31
7.3.
Lost to Follow-Up.....................................................................................................32
8.
Study Assessments and Procedures ......................................................................................32
8.1.
Efficacy Assessments................................................................................................33
8.1.1.
Primary Efficacy Assessment ....................................................................34
8.1.1.1.
Total Staining..............................................................................34
8.1.2.
Secondary Efficacy Assessment ................................................................34
8.1.2.1.
Current Symptom Survey ...........................................................34
8.1.3.
Other Efficacy Assessments ......................................................................35
8.1.3.1.
Tear Break-up Time (with Fluorescein) .....................................35
8.1.3.2.
Corneal Staining (Modified NEI Grading 
Scheme, with Fluorescein)..........................................................35
8.1.3.3.
Conjunctival Staining (Modified NEI 
Grading Scheme, with Lissamine Green)...................................36
8.1.3.4.
Schirmer Test (with Anesthesia).................................................37
8.1.3.5.
Ocular Surface Disease Index 
Questionnaire..............................................................................38
8.1.3.6.
Study Eye Drop Experience and 
Tolerability Questionnaire ..........................................................40
8.1.3.7.
Functional Vision Questionnaire ................................................40
8.1.3.8.
5-Minute Blurry Vision and Ocular 
Discomfort Questionnaire...........................................................42
8.2.
Safety Assessments...................................................................................................43
8.2.1.
Currently Corrected Distance Visual Acuity.............................................43
8.2.2.
Best-Corrected Distance Visual Acuity.....................................................44
8.2.3.
Slit-Lamp Biomicroscopy..........................................................................44
8.2.4.
Urine Pregnancy Test.................................................................................46
8.2.5.
Intraocular Pressure (with Anesthesia and 
Fluorescein)................................................................................................46
8.3.
Adverse Events and Serious Adverse Events ...........................................................47
8.3.1.
Time Period and Frequency for Collecting AE and 
SAE Information........................................................................................47
8.3.2.
Method of Detecting AEs and SAEs .........................................................47
8.3.3.
Follow-up of AEs and SAEs......................................................................48
8.3.4.
Regulatory Reporting Requirements for SAEs..........................................48
8.3.5.
Pregnancy...................................................................................................48
8.3.6.
Medication Errors ......................................................................................49
8.4.
Treatment of Overdose .............................................................................................49
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8.5.
Pharmacokinetics......................................................................................................49
8.6.
Pharmacodynamics ...................................................................................................49
8.7.
Genetics.....................................................................................................................49
8.8.
Biomarkers and Other Assessments..........................................................................49
8.8.1.
Study Eye Drop Usage Questionnaire .......................................................49
8.9.
Health Economics.....................................................................................................50
9.
Statistical Considerations......................................................................................................51
9.1.
Statistical Hypotheses ...............................................................................................51
9.2.
Sample Size Determination.......................................................................................51
9.3.
Populations for Analyses ..........................................................................................51
9.4.
Statistical Analyses ...................................................................................................52
9.4.1.
Efficacy Analyses ......................................................................................52
9.4.1.1.
Analysis Endpoints .....................................................................52
9.4.1.2.
Primary Analyses........................................................................53
9.4.1.3.
Secondary Analyses....................................................................53
9.4.1.4.
Other Efficacy Analyses .............................................................53
9.4.2.
Safety Analyses..........................................................................................53
9.4.2.1.
Adverse Events ...........................................................................54
9.4.3.
Other Safety Analyses................................................................................54
9.4.3.1.
Subgroup Analyses .....................................................................54
9.5.
Interim Analyses .......................................................................................................54
9.5.1.
Data Monitoring Committee......................................................................55
10.
Supporting Documentation and Operational Considerations ...............................................56
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations...........................................................................................................56
10.1.1.
Regulatory and Ethical Considerations......................................................56
10.1.2.
Financial Disclosure...................................................................................56
10.1.3.
Informed Consent Process .........................................................................57
10.1.4.
Data Protection...........................................................................................57
10.1.5.
Posting Clinical Study Data.......................................................................57
10.1.6.
Data Quality Assurance .............................................................................58
10.1.7.
Source Documents .....................................................................................58
10.1.8.
Study and Site Closure...............................................................................58
10.1.9.
Publication Policy......................................................................................59
10.1.10. Compliance with Protocol..........................................................................59
10.2.
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting...................................................60
Definition of AE .......................................................................................................60
Definition of SAE .....................................................................................................61
Recording and Follow-up of AEs and/or SAEs........................................................62
Reporting of SAEs....................................................................................................64
10.3.
Appendix 3: Abbreviations.......................................................................................65
10.4.
Appendix 4: Standard Discontinuation Criteria........................................................67
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10.5.
Appendix 5: Study Tabular Summary ......................................................................69
10.6.
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information..............................................................................................71
Definitions: ...............................................................................................................71
Contraception Guidance: ..........................................................................................71
Pregnancy Testing:....................................................................................................73
Collection of Pregnancy Information: ......................................................................73
10.7.
Appendix 9: Study Schedule Supplement.................................................................74
10.7.1.
Screening (Day -7 [-3 days])......................................................................74
10.7.2.
Baseline (Day 1) ........................................................................................74
10.7.3.
Day 7 (±3 days)..........................................................................................75
10.7.4.
Days 30 and 60 (±7 days) ..........................................................................75
10.7.5.
Day 90/Early Exit (±7 days) ......................................................................76
10.8.
Appendix 10: Protocol Amendment History ............................................................77
11.
References.............................................................................................................................80
List of Tables
Table 8-1
Efficacy Assessments............................................................................................ 33
Table 10-1
Highly Effective and Acceptable Contraceptive Methods.................................... 72
List of Figures
Figure 1-1
Study Schema.......................................................................................................... 9
Figure 8-1
Modified NEI Grading Scheme Part 1: Corneal Staining Grading Scheme......... 36
Figure 8-2
Modified NEI Grading Scheme Part 2: Conjunctival Staining Grading Scheme. 37
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CONFIDENTIAL
Protocol 2007-301-005 Amendment 2
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GRD-CLN-T-01-01 v3.0
1.
Protocol Summary
1.1.
Synopsis
Protocol Title: A Multicenter, Single-masked, Randomized Study to Compare the Efficacy and 
Safety of a New Artificial Tear Formulation (011516X) with Systane® Ultra Multidose for 90 
Days in Participants with Dry Eye Disease
Protocol Number: 2007-301-005
Brief Title: Efficacy and safety of a new artificial tear formulation compared with Systane Ultra 
multidose in participants with dry eye disease
Study Phase: 3
Study Rationale: The purpose of this study is to evaluate the efficacy and safety of a new
artificial tear formulation (NATF; 011516X) compared with Systane® Ultra multidose (MD) in 
participants with dry eye disease (DED). This study will provide final guidance towards selection 
of the formulation for commercialization and will support Allergan quality standards and product 
requirements.
Objectives and Endpoints:
Objectives
Measures
Primary
!
To evaluate the efficacy and safety of 
011516X in participants with signs and 
symptoms of DED compared with 
Systane Ultra MD
Primary Efficacy Measure
!
Total staining (sum of corneal and conjunctival staining) 
Secondary Efficacy Measure
!
Current Symptom Survey 
Other Efficacy Measures
!
Corneal staining (modified National Eye Institute [NEI] 
grading scheme, with fluorescein)
!
Conjunctival staining (modified NEI grading scheme, with 
lissamine green)
!
Tear break-up time (TBUT, with fluorescein)
!
Schirmer test (with anesthesia)
!
Ocular Surface Disease Index© (OSDI)
!
Study Eye Drop Experience and Tolerability Questionnaire
!
Functional Vision Questionnaire
!
5-Minute Blurry Vision and Ocular Discomfort Questionnaire
Safety Measures
!
Adverse events (AEs)
!
Slit-lamp biomicroscopy
!
Currently corrected distance visual acuity
!
Best-corrected distance visual acuity (BCDVA)
!
Intraocular pressure (IOP) (participants with glaucoma or 
ocular hypertension [OHT] only)
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Overall Study Design:
This study is designed as a multicenter, single-masked, randomized, 2-arm, parallel-group study 
comparing the efficacy and safety of a NATF (011516X) with Systane Ultra MD (see 
Figure 1-1). All qualified study participants will receive REFRESH PLUS® for approximately 7 
days during a run-in period prior to the Day 1 (Baseline) visit. If still qualified at the Day 1 
(Baseline) visit, participants will then be randomized in a 1:1 ratio to use 011516X or Systane 
Ultra MD, with central stratification by Day 1 (Baseline) total ocular staining score of the study
eye (mild/moderate = score of 6 to 25 versus [vs] severe = score of 26 to 43). The primary
efficacy measure is total ocular staining and the primary analysis timepoint is at Day 90.
Number of Participants:
Approximately 400 participants (200 participants in each arm) will be randomized in order to 
have 340 participants (170 participants in each arm) complete the study through Day 90, 
assuming an approximate 15% dropout rate. Participants who prematurely discontinue from the 
study will not be replaced.
Number of Sites:
The study will be conducted at approximately 28 sites in the United States (US).
Intervention Groups and Study Duration:
All qualified study participants will receive REFRESH PLUS for approximately 7 days during a 
run-in period prior to the Day 1 (Baseline) visit. Participants will be instructed to instill 1 to 
2 drops of the run-in medication in each eye, 3 times per day for 7 days. If still qualified at the 
Day 1 (Baseline) visit, participants will then be randomized in a 1:1 ratio to use 011516X or 
Systane Ultra MD, with central stratification by Day 1 (Baseline) total ocular staining score of 
the study eye (mild/moderate = score of 6 to 25 vs severe = score of 26 to 43). Participants will 
be instructed to instill 1 to 2 drops of their assigned study intervention (investigational eye drops)
in each eye, 3 times per day for approximately 90 days.
Data Monitoring Committee: There will be no Data Monitoring Committee for this study.
1.2.
Schema
The study design is presented in Figure 1-1.
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1.3.
Schedule of Activities (SoA)
Study procedures are recommended to be done in sequence as listed in the schedule below.
Study Day 
Screening 
(Day -7)
Day 1
(Baseline)
Day 7
Day 30
Day 60
Day 90/ 
Early Exit
Notes
Visit Window 
(-3 days)
(±3 days)
(±7 days)
(±7 days)
(±7 days)
Each follow-up visit should be 
consistently scheduled within 
±90 minutes of the time of the Day 1 
(Baseline) visit.
Written informed consent and written 
documentation in accordance with the 
relevant country and local privacy 
requirements (HIPAA for US sites)
X
Inclusion/exclusion criteria assessment
X
X
Demography
X
Self-assessed surveys/questionnaires:
Not performed if a participant reports 
use of a prohibited intervention. Does 
not apply to Screening visit.
Study Eye Drop Usage Questionnaire
X
X
X
X
X
Current Symptom Survey 
X
X
X
X
X
X
OSDI Questionnaire
X
X
X
X
X
X
Study Eye Drop Experience and 
Tolerability Questionnaire
X
X
X
X
Functional Vision Questionnaire
X
X
X
X
X
Medical and ophthalmic histories
X
X
Prestudy or concomitant medication 
assessment
X
X
X
X
X
X
Urine pregnancy test (for females of 
childbearing potential only)
X
X
Currently corrected distance visual
acuity
X
X
X
X
X
X
Best-corrected distance visual acuity
X
X
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Study Day 
Screening 
(Day -7)
Day 1
(Baseline)
Day 7
Day 30
Day 60
Day 90/ 
Early Exit
Notes
Visit Window 
(-3 days)
(±3 days)
(±7 days)
(±7 days)
(±7 days)
Each follow-up visit should be 
consistently scheduled within 
±90 minutes of the time of the Day 1 
(Baseline) visit.
Biomicroscopy 
X
X
X
X
X
X
Tear break-up time (with fluorescein)
X
X
X
X
X
X
Not performed if a participant reports 
use of a prohibited intervention. 
Corneal staining (modified NEI grading 
scheme, with fluorescein)
X
X
X
X
X
X
Not performed if a participant reports 
use of a prohibited intervention. 
Conjunctival staining (modified NEI 
grading scheme, with lissamine green)
X
X
X
X
X
X
Not performed if a participant reports 
use of a prohibited intervention. 
Schirmer test (with anesthesia)
X
X
X
X
X
X
Not performed if a participant reports 
use of a prohibited intervention. 
Intraocular Pressure (Goldmann 
applanation tonometer)
X
X
X
X
X
X
After the Screening visit, this needs to 
be completed only for participants who 
are treated for glaucoma or ocular 
hypertension.
Adverse event assessment
X
X
X
X
X
X
Access IxRS
X
X
X
X
X
Randomization
X
Run-in medication dispensed
X
Run-in medication returned
X
Study intervention dispensed
X
X
X
Predose and postdose 5-Minute Blurry 
Vision and Ocular Discomfort 
Questionnaire
X
X
Must be performed at least 20 minutes 
after anesthesia application. Not 
performed if a participant reports use of 
a prohibited intervention. 
Used and unused study intervention
returned
X
X
X
HIPAA = Health Insurance Portability and Accountability Act; IxRS = interactive response system; NEI = National Eye Institute; OSDI = ocular surface disease index; US = 
United States
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2.
Introduction
2.1.
Study Rationale
The purpose of this study is to evaluate the efficacy and safety of a new artificial tear 
formulation (NATF; 011516X) compared with Systane® Ultra multidose (MD) in participants 
with dry eye disease (DED). This study will provide final guidance towards selection of the 
formulation for commercialization and will support Allergan quality standards and product 
requirements.
2.2.
Background
Dry eye disease is a multifactorial disease of the ocular surface characterized by a loss of 
homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability
and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities 
play etiological roles (Craig 2017). An estimated 25 million Americans are reported to have 
DED, making DED one of the most common reasons patients seek care with their eye care 
professional (Behrens 2006, Stapleton 2017).
Mechanistically, DED is recognized as a disturbance of the lacrimal functional unit, an 
integrated system comprised of the ocular surface (cornea, conjunctiva, accessory lacrimal 
glands, and Meibomian glands), the main lacrimal glands, and the sensory and interconnecting 
innervation (Stern 1998). The diagnosis and classification (ie, mild/moderate/severe) of DED is 
achieved by assessing both clinical signs (ocular surface epithelial damage [corneal and 
conjunctival staining]), tear volume (Schirmer score), tear film stability (tear break-up time 
[TBUT]), and patient-reported symptoms (questionnaires such as the Ocular Surface Disease 
Index© [OSDI] and Eye Dryness Score - Visual Analog Scale [EDS-VAS]) (Wolffsohn 2017).
The normal tear film is a relatively stable, thin film composed of a superficial lipid layer and an 
aqueous layer intermixed with a mucus gel layer, which is partially adherent to the corneal and 
conjunctival surface epithelium. The tear film is important for lubrication, protection, and 
nourishment of the ocular surface and serves as the primary refractive surface of the eyes visual 
system. DED is a complex disease characterized by a dysfunction of 1 or more components of 
the tear film, leading to the loss of tear film stability, a hyperosmolar shift in the tear film 
osmotic balance, and/or an inadequate amount of fluid on the ocular surface. This is 
characterized by rapid break-up of the tear film and numerous symptoms, including 
burning/stinging, foreign body sensation, blurred vision and photophobia. 
DED is often brought about or exacerbated by a variety of adverse environmental conditions, 
including prolonged computer use (visual display terminal syndrome), excessive wind or air 
conditioning, and overheated or dry air. The majority of patients with DED are initially managed 
with artificial tears. Environmental modifications, lid compresses and scrubs, and the addition of 
essential fatty acids to the diet are often recommended as well. With advancing severity of DED, 
treatment options, if needed, can include topical cyclosporine or other anti-inflammatory
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medications, as well as surgical options ranging from insertion of punctal plugs to tarsorraphy of 
the eyelids (Jones 2017).
The NATF (011516X) under investigation in this study is a sterile, buffered, preservative-free 
artificial tear solution that is designed to provide protection to the ocular surface and improve
symptoms of DED. The NATF 011516X is specifically formulated to relieve DED symptoms
such as burning, irritation, and eye dryness and to protect against further irritation. The NATF 
contains carboxymethylcellulose and glycerin as active ingredients that lubricate and moisturize 
the ocular surface. The solution also contains other inactive compatible solutes such as carnitine, 
erythritol, and trehalose. The NATF 011516X conforms to the US Food and Drug 
Administration (FDA) monograph on ophthalmic demulcents.
The comparator product is Systane Ultra MD from Alcon, which is currently one of the leading 
marketed artificial tear products in the US. Key ingredients in Systane Ultra MD include 
polyethylene glycol 400 (0.4%), propylene glycol (0.3%), and hydroxypropyl guar. 
The purpose of this study is to evaluate the efficacy and safety of the NATF 011516X compared 
with Systane Ultra MD.
2.3.
Benefit/Risk Assessment
To date, management and treatment of DED remains a large unmet medical need. Current 
mainstays include use of artificial tears and in more severe cases, tear retention (temporarily or 
permanently plugging the tear ducts) and anti-inflammatory therapies. Each approach has its own 
risk-benefit ratio. Artificial tears have been used in DED for decades and have proven to be safe 
and effective for lubricating and protecting the ocular surface from further irritation and relieving 
DED symptoms. Very few adverse events (AEs) are generally reported with artificial tears, such 
as blurred vision, eye redness, discomfort or other irritation not present before use of artificial 
tears, increased light sensitivity, matting or stickiness of eyelashes, swelling of eyelids, and 
watering of eyes. Because the risk-benefit ratio with artificial tears is low, they have been 
recognized as the first-line DED management option in both historical and contemporary
practice ahead of the alternatives mentioned above.
Patients with DED generally present with ocular surface epithelial damage attributed to either or 
both inadequate tear production and tear film instability. These pathophysiological changes are 
generally accompanied by patient-reported symptoms of ocular surface discomfort, often 
described as dryness, burning, pain, blurred vision and grittiness.
For many people with DED symptoms, the regular use of artificial tears represents a suitable and 
affordable option. Artificial tears are used to lubricate the eyes and relieve burning, irritation, 
and eye dryness attributed to DED as well as protect against further irritation. The benefit of the 
new generation of artificial tears developed by Allergan is their ability to improve DED 
symptoms and provide lubrication and protection against further irritation, thus providing a 
valuable option for patients with DED.
The use of artificial tears is safe and well-tolerated and there are no unexpected safety concerns, 
although common side effects may include the following: mild eye burning or irritation, itching 
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or redness of eyes, watery eyes, blurred vision, unpleasant taste in mouth, and/or allergy to the 
product or its ingredients.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of 011516X may be found in the investigator’s brochure (IB).
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3.
Objectives and Endpoints
Objectives
Measures
Primary
!
To evaluate the efficacy and safety of 011516X in 
participants with signs and symptoms of DED 
compared with Systane Ultra MD
Primary Efficacy Measure
!
Total staining (sum of corneal and conjunctival 
staining) 
Secondary Efficacy Measure
!
Current Symptom Survey
Other Efficacy Measures
!
Corneal staining (modified National Eye Institute 
[NEI] grading scheme, with fluorescein)
!
Conjunctival staining (modified NEI grading 
scheme, with lissamine green)
!
Tear break-up time (TBUT, with fluorescein)
!
Schirmer test (with anesthesia)
!
OSDI
!
Study Eye Drop Experience and Tolerability 
Questionnaire
!
Functional Vision Questionnaire
!
5-Minute Blurry Vision and Ocular Discomfort 
Questionnaire
Safety Measures
!
AEs
!
Slit-lamp biomicroscopy
!
Currently corrected distance visual acuity
!
Best-corrected distance visual acuity (BCDVA)
!
Intraocular pressure (IOP) (participants with 
glaucoma or ocular hypertension [OHT] only)
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4.
Study Design
4.1.
Overall Design
This study is designed as a multicenter, single-masked, randomized, 2-arm, parallel-group study 
comparing the efficacy and safety of a NATF (011516X) with Systane Ultra MD (see 
Figure 1-1). All qualified study participants will receive REFRESH PLUS® for approximately 7 
days during a run-in period prior to the Day 1 (Baseline) visit. Participants will be instructed to 
instill 1 to 2 drops of the run-in medication in each eye, 3 times per day for 7 days. If still 
qualified at the Day 1 (Baseline) visit, participants will then be randomized in a 1:1 ratio to use 
011516X or Systane Ultra MD, with central stratification by Day 1 (Baseline) total ocular 
staining score of the study eye (mild/moderate = score of 6 to 25 vs severe = score of 26 to 43). 
Participants will be instructed to instill 1 to 2 drops of their assigned study intervention
(investigational eye drops) in each eye, 3 times per day for approximately 90 days. The primary
efficacy measure is total ocular staining and the primary analysis timepoint is at Day 90.
Approximately 400 participants (200 participants in each arm) will be enrolled at approximately
28 sites in the US in order to have 340 participants (170 participants in each arm) complete the 
study through Day 90, assuming an approximate 15% dropout rate. Participants who prematurely
discontinue from the study will not be replaced.
4.2.
Scientific Rationale for Study Design
This Phase 3 clinical study is designed to evaluate the efficacy and safety of the NATF 011516X
versus a leading marketed artificial tear product, Systane Ultra MD, over a 90-day study
intervention period in participants with DED.
The test formulation contains the same active ingredients (carboxymethylcellulose and glycerin) 
as the currently marketed REFRESH OPTIVE products. The solution also contains other inactive 
compatible solutes such as carnitine, erythritol, and trehalose. 
The formulation of Systane Ultra MD incorporates hydroxypropyl-guar, and is currently the 
market leader.
The present study is designed to compare the relative relief of symptoms of DED between the 
formulations as well as to characterize the effect on ocular surface staining. In order to be able to 
show a reduction in DED symptoms and in ocular surface staining at Day 90, the inclusion 
criteria were selected to include a participant population with clinically significant ocular surface 
staining and symptoms of DED at the Screening (Day -7) and Day 1 (Baseline) visits. These 
participants are anticipated to have a clinically treatable condition with sufficient room for 
improvement.
4.3.
Justification for Dose
The dosing regimen during the study will be to instill 1 to 2 drops in each eye, 3 times per day. 
Although use as needed is the typical dosing instruction in artificial tear product label, for this 
specific study, a controlled dose is necessary to ensure accurate comparison between the test and 
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control arms. Dosing 3 times per day is based on the average dosing frequency from prior 
Allergan artificial tear product clinical studies.
4.4.
End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study.
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit (Day 90).
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5.
Study Population
The study population will consist of adult male and female participants with objective and 
subjective evidence of DED. Approximately 400 participants will be randomized at 
approximately 28 US sites in order to have 340 participants (170 participants in each arm) 
complete the study, assuming an approximate 15% dropout rate.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Participant must be ≥ 18 years of age
2.
Type of Participant and Disease Characteristics
2.01
At the Screening (Day -7) and Baseline (Day 1) visits, at least 1 eye must qualify
with both of the following ocular staining scores:
!
Corneal staining score of ≥ 0 to ≤ 4 in each of the 5 zones with a total of ≥5 to 
≤19 based on the modified NEI grading scheme (score range = 0 to 5; graded in 
5 zones of the cornea for a total score range of 0 to 25)
!
Conjunctival staining score of ≥ 0 to ≤ 4 in each of the 6 zones with a total of ≥1 
based on the modified NEI grading scheme (score range = 0 to 5 per zone)
(Need not be the same eye at Screening and Baseline)
2.02
At the Screening (Day -7) and Baseline (Day 1) visits, have 3 consecutive TBUT 
tests of ≤ 10 seconds in at least 1 eye 
(Need not be the same eye at Screening and Baseline or the same eye that meets 
Inclusion Criterion 2.01)
2.03
At the Screening (Day -7) and Baseline (Day 1) visits, have a Current Symptom 
Survey total mean score of ≥ 25 
2.04
At the Screening (Day -7) visit, have an OSDI total score of ≥ 23; and at Baseline 
(Day 1) visit, have an OSDI total score of ≥ 18, with no more than 3 responses 
answered as not applicable (N/A)
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2.05
Have used an artificial tear product for DED within 6 months of the 
Screening (Day -7) visit
2.06
Have ability/agreement to continue to wear existing current spectacle correction 
during the study period (if applicable)
2.07
Have corrected distance visual acuity of at least 20/32 Snellen equivalent in each eye 
using the 3-meter LogMar chart, with current correction (if necessary) at Screening 
(Day -7) visit 
2.08
If using any form of topical ophthalmic cyclosporine (ie, RESTASIS®) or lifitegrast 
5% ophthalmic solution (Xiidra®), participants must be using the drops for ≥90 days 
prior to the Screening (Day -7) visit and plan to continue without change for the 
duration of the study
3.
Sex
3.01
Male or female
4.
Contraceptives
4.01
A female participant is eligible to participate if she is not pregnant (ie, has a negative 
in-office urine pregnancy test at Screening [Day -7] and does not verbally report 
pregnancy at the Day 1 [Baseline] visit; see Appendix 6), is not breastfeeding, and at 
least 1 of the following conditions applies:
a.
A woman not of childbearing potential (WOCBP) as defined in Appendix 6
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 6
for the duration of the study
5.
Informed Consent
5.01
Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol
5.02
Written informed consent from the participant has been obtained prior to any
study-related procedures
5.03
Written documentation has been obtained in accordance with the relevant country
and local privacy requirements, where applicable
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6.
Other
6.01
Able, as assessed by the investigator, to understand and willing to complete all 
study-related questionnaires/surveys, follow study instructions and likely to 
complete all required study visits
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1.
Medical Conditions
1.01
Have uncontrolled severe systemic disease that, in the assessment of the investigator, 
would put safety of the participant at risk through participation, or which would prevent 
or confound protocol-specified assessments (eg, hypertension and diabetes, Sjögren's 
syndrome, rheumatoid arthritis, systemic lupus erythematosus, immunodeficiency
disease, etc.)
1.02
At the Screening (Day -7) or Baseline (Day 1) visits, either eye has
!
Corneal staining score of 5 in any of the 5 zones or a total score of > 19 based on 
the modified NEI grading scheme (score range = 0 to 5; graded in 5 zones of the 
cornea for a total score range of 0 to 25)
or
!
Conjunctival staining score of 5 in any of the 6 zones based on the modified NEI 
grading scheme (score range = 0 to 5 per zone)
1.03
Participant has worn contact lenses in the last 90 days prior to the Screening (Day -7) 
visit and/or participant anticipates contact lens wear during the study
1.04
Have any scheduled or planned systemic surgery or procedure during the study, which in 
the investigator’s opinion, may impact the participant’s study participation
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1.05
Presence of 1 or more of the following ocular conditions:
!
Active ocular infection or non-keratoconjunctivitis sicca (KCS) ocular inflammation
!
Active ocular allergy
!
History of recurrent herpes keratitis or active disease within 6 months prior to the 
Screening (Day -7) visit 
!
Corneal disorder or abnormality that affects corneal sensitivity or normal spreading 
of the tear film (except superficial punctate keratitis)
!
Severe blepharitis or obvious inflammation of the lid margin, which in the judgment 
of the investigator, may interfere with the interpretation of the study results
!
Keratoconjunctivitis sicca secondary to the destruction of conjunctival goblet cells, 
such as occurs with vitamin A deficiency or scarring such as that with cicatricial 
pemphigoid, alkali burns, Stevens-Johnson syndrome, trachoma, or irradiation
!
Substantial non-KCS keratitis with overlying corneal stain or other significant 
corneal findings not directly related to DED; in addition, participants with DED 
signs/symptoms (eg, filamentary keratitis) of a severity where topical monotherapy
with an artificial tear would be inappropriate
2.
Prior/Concomitant Therapy
2.01
The start date of any systemic medication (including over-the-counter [OTC], herbal, 
prescription, or nutritional supplements) which may affect DED or vision is < 90 days 
prior to the Screening (Day -7) visit or a change in dosage is anticipated during the study. 
Systemic medications, which may affect DED or vision, include but are not limited to the 
following: flax seed oil, fish oil, omega-3 supplements, cyclosporine, antihistamines, 
cholinergic agents, anticholinergics, antimuscarinics, beta blocking agents, tricyclic 
antidepressants, phenothiazines, estrogen, progesterone, and other estrogen derivatives
2.02
Have occlusion of the lacrimal puncta for either eye, with punctal plugs or cauterization 
< 6 months prior to the Screening (Day -7) visit or anticipated use of such procedures 
during the study 
2.03
Use of lid-heating therapy (ie, LipiFlow®, iLUX®, etc.), Meibomian gland probing, or 
therapeutic Meibomian gland expression in either eye < 6 months prior to the Screening 
visit (Day -7) or anticipated use during the study
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2.04
Have history of ocular/ophthalmic surgery or trauma, which could affect corneal 
sensitivity and/or tear distribution (eg, cataract surgery, laser-assisted in situ 
keratomileusis [LASIK], photorefractive keratectomy, or any surgery involving a limbal 
or corneal incision) within 12 months prior to the Screening (Day -7) visit 
2.05
Are currently using topical ocular medication (OTC, herbal or prescription) or TrueTear®
(intranasal neurostimulator), or have used topical ocular medication (OTC, herbal or 
prescription) or TrueTear within 1 month of the Screening (Day -7) visit or plan use of
such treatments during the study. Exception: participants who are using the following can 
be considered: 
!
Marketed artificial tear product for the management of DED, which must be 
discontinued at the Screening (Day -7) visit
!
Monotherapy for glaucoma or OHT using a prostaglandin analog, beta blocker, 
alpha-2 agonist, or carbonic anhydrase inhibitor; any topical IOP-lowering 
medications must have a start date of ≥ 90 days prior to the Screening (Day -7) visit 
and dosage is not expected to change during the study
!
Cyclosporine topical ophthalmic preparation (eg, RESTASIS or other ophthalmic 
form) or lifitegrast 5% ophthalmic solution (Xiidra), with a start date of ≥ 90 days 
prior to the Screening (Day -7) visit and dosage is not expected to change during the 
study
NOTE: Participants currently being treated with BOTH an IOP-lowering 
medication and topical ocular cyclosporine or lifitegrast cannot be enrolled.
2.06
IOP > 21 mm Hg at the Screening (Day -7) visit in both eyes. Participants with primary
open-angle glaucoma or OHT may be included provided they are on stable monotherapy
bilaterally as mentioned in exclusion criterion 2.05, with both eyes IOP controlled (≤ 21 
mm Hg). The type of medication will be recorded at the Screening (Day -7) visit along 
with other concomitant medications
3.
Prior/Concurrent Clinical Study Experience
3.01
Are currently enrollment in an investigational drug or device study or participation in 
such a study within 30 days of entry into this study at the Screening (Day -7) visit
4.
Diagnostic Assessments
4.01
Have a Schirmer test (with anesthesia) ≤ 2 mm in either eye at the Screening (Day -7) 
visit
4.02
Report an average daily artificial tear use of > 6 times per day within 6 months of the 
Screening (Day -7) visit 
5.
Other
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5.01
Females who are pregnant, nursing, or planning a pregnancy during the study or females 
who are of childbearing potential and not using a reliable method of contraception (see 
Appendix 6)
5.02
Have history of allergies or sensitivity to the study interventions or its components 
(including all REFRESH and Systane product lines) or diagnostics (eg, topical ocular 
anesthetic, sodium fluorescein, or lissamine green)
5.03
Have a condition or is in a situation which, in the investigator’s opinion, may put the 
participant at significant risk, may confound the study results, or may interfere 
significantly with the participant’s participation in the study
5.04
Are directly or indirectly involved in the conduct and administration of this study as an 
investigator, subinvestigator, study coordinator or other study staff member; employee of 
Allergan or a first-degree family member, significant other or relative residing with one 
of the above persons involved directly or indirectly in the study; are enrolled in this study
at another clinical site; or, are a student with a direct relationship with the investigator or 
investigational site staff
5.3.
Lifestyle Considerations
No restrictions are required.
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory
authorities. Minimal information includes indicating screen failure as reason for ending the 
study, demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened with sponsor pre-approval. 
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6.
Study Intervention
Study intervention is defined as any investigational interventions intended to be administered to 
a study participant according to the study protocol.
6.1.
Study Interventions Administered
The study interventions to be administered are as follows:
Study Intervention 
Name
NATF (011516X)
Systane Ultra MD 
REFRESH PLUS (8197X)
Dosage Formulation
Topical eye drop
Topical eye drop
Topical eye drop
Manufacturer
Allergan, Waco, TX
Alcon
Allergan, Waco, TX
Identity of 
Formulation and 
Strengths
Carboxymethyl-cellulose 
sodium 0.5%
Glycerin 0.9% with 
trehalose
Polyethylene glycol 400 
0.4%
Propylene glycol 0.3%
Carboxymethyl-cellulose 
sodium 0.5%
Route of 
Administration 
Topical eye drop
Topical eye drop
Topical eye drop
Dosing Instructions
Instill 1 to 2 drops in each 
eye, 3 times per day
Instill 1 to 2 drops in each 
eye, 3 times per day
Instill 1 to 2 drops in each 
eye, 3 times per day
Packaging and 
Labeling
Study intervention will be 
provided in unit-dose vials. 
Study intervention will be 
labeled as required.
Study intervention will be 
provided in MD bottles. 
Study intervention will be 
labeled as required.
Study intervention will be 
provided in unit-dose vials. 
Study intervention will be 
labeled as required.
Number and Timing 
of Interventions
Participants will administer 
1 to 2 drops in each eye 3 
times daily
Participants will 
administer 1 to 2 drops in 
each eye 3 times daily
Participants will administer 
1 to 2 drops in each eye 
3 times daily
Volume Per 
Intervention Vial or 
Bottle
0.4 mL vial
10 mL bottle
0.4 mL vial
As this is a single-masked study, 011516X and Systane Ultra MD will each be supplied in 
identical outer cartons (kit). Each kit label will include the study number, kit number, and a place 
for the site to write-in the participant’s study ID once assigned by the interactive response system 
(IxRS) to a particular participant.
6.1.1.
Run-in Medications and Administration
The REFRESH PLUS solution (8197X) contains the following: CMC sodium, sodium 
hydroxide, sodium chloride, sodium lactate, potassium chloride, calcium chloride, magnesium 
chloride, and water for injection/purified water. The solution is supplied in 0.4 mL unit-dose
vials. The solution is sterile and isotonic.
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6.1.2.
Study Supplies
The following supplies will be provided by Allergan:
!
Urine pregnancy tests
!
Distance logarithmic visual acuity chart for testing at 3 meters
!
Stopwatch (for TBUT)
!
2% preservative-free liquid sodium fluorescein (for TBUT and corneal staining)
!
Micropipettes and sterile disposable tips (for fluorescein administration)
!
Yellow barrier filter (for TBUT and corneal staining with fluorescein)
!
Lissamine green strips (for conjunctival staining)
!
Saline (used to wet the lissamine green strips)
!
Timer (for Schirmer test with anesthesia)
!
Topical anesthetic (for IOP measure and Schirmer test)
!
Schirmer strips (for Schirmer test with anesthesia)
!
Visual analog scale ruler (for converting the participant’s VAS responses to numerical 
values)
The following will be provided by the investigator:
!
Slit-lamp biomicroscope
!
Goldmann applanation tonometer 
!
Internet connection (high-speed connection for electronic case report form [eCRF]
completion)
!
Temperature monitoring device for study intervention storage
6.1.3.
Instructions for Use and Administration
At Screening (Day -7), run-in medication (REFRESH PLUS) will be dispensed to each eligible
participant. Each participant will be instructed to instill 1 to 2 drops in each eye, 3 times per day. 
The same vial can be used for both eyes, and should be used 1 time only. The used and unused 
vials should be collected and returned to the sites for accountability as instructed.
Assigned study intervention will be dispensed to each randomized participant at the Days 1, 30, 
and 60 by the impartial dispenser. Participants randomized to the NATF unit-dose formulation 
(011516X) will be instructed to instill 1 to 2 drops in each eye, 3 times per day. The same vial 
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can be used for both eyes, and should be used 1 time only. The used and unused vials should be 
collected and returned to the site for accountability as instructed. Participants randomized to 
Systane Ultra MD (10 mL bottles) are to use 1 bottle until the bottle is empty, and then use a new
bottle. Both the used and unused bottles are to be returned to the site for accountability as 
instructed. If the participant is concurrently using an ocular cyclosporine product, lifitegrast 5% 
ophthalmic solution (Xiidra) or glaucoma therapy drops as allowed per inclusion/exclusion 
criteria during the study, the participant should be instructed to wait a minimum of 15 minutes 
between drop instillations (with study intervention being administered first). In addition, 
participants should be instructed to not use study intervention within 4 hours of each 
follow-up visit (ie, Days 7, 30, 60, and 90/Early Exit).
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention, and only
authorized site staff may supply or administer study intervention. All study intervention 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized site staff.
3. Participants will be instructed on the proper storage of study intervention and to keep it 
out of the reach of children at all times.
4. Acceptance of the returned used and unused vials and used and unused bottles should be 
handled by the impartial dispenser. However, the investigator, institution, or the head of 
the medical institution (where applicable) is ultimately responsible for study intervention 
accountability, reconciliation, and record maintenance (ie, receipt, reconciliation, and final 
disposition records).
5. At the end of the study, all used and unused study intervention will be reconciled and used 
and unused vials and bottles must be returned to Allergan.
6.3.
Measures to Minimize Bias: Randomization and Masking
This study will use a 1:1 treatment allocation to 011516X:Systane Ultra MD, with a central 
stratification by Day 1 (Baseline) total ocular staining score in the study eye (mild/moderate = 
score of 6 to 25 vs severe = score of 26 to 43). The study eye is defined as the worst eye based on 
total ocular staining score at Day 1 (Baseline). If both eyes have the same total ocular staining 
score, the right eye will be designated as the study eye.
Prior to initiation of study intervention, each participant who provides informed consent will be 
assigned to a participant number through an automated IxRS that will serve as the participant’s
identification number on all study documents. Participant numbers will be assigned in ascending 
order across all sites and should not be omitted or reused.
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At the end of the Screening (Day -7) visit, all eligible participants will receive a run-in
medication kit (REFRESH PLUS) for use during the 7-day run-in period. Sites will dispense the 
run-in medication kit according to the IxRS instructions. 
At the end of the Day 1 (Baseline) visit, all eligible participants will be stratified by their Day 1 
(Baseline) study eye total ocular staining score and be randomly assigned to 1 of 2 treatment 
arms in a 1:1 ratio based on a randomization scheme prepared by Allergan Biostatistics. This will 
require the delegated site personnel to enter the participant’s Screening Visit (Day -7) and 
Baseline (Day 1) total corneal and conjunctival staining scores of each eye directly into IxRS. 
IxRs will then determine which eye is the study eye and assign the participant to a stratification 
group and a treatment arm, thus providing the site with the specific study intervention kit 
assignment. Sites will dispense study intervention according to the IxRS instructions.
Sites will also need to access the IxRS at the Days 30 and 60 visits to obtain a study intervention
kit (30-day supply) number to dispense to the participant. Sites will receive the IxRS 
confirmation notifications for each transaction. All notifications are to be maintained with the 
study source documents.
In addition, sites will need to access IxRS to “complete” the participant at Day 90 or to 
“discontinue” the participant if they exit the study early.
6.4.
Study Intervention Compliance
When the participants are dispensed their intervention kits (Days 1 [Baseline], 30, and 60), they
will be instructed to use 1 to 2 drops in each eye, 3 times per day.
Study intervention compliance will be monitored by: 1) having the participants complete the 
Study Eye Drop Usage Questionnaire at Day 1 (Baseline) and at each follow-up visit, and 2) 
having the participants return both their used and unused vials for those participants stratified to 
the NATF formulation and both their used and unused bottles for those participants stratified to 
Systane Ultra MD.
The used and unused vials and bottles will be returned at each participant’s Day 30, Day 60, and 
Day 90/Early Exit Visits and the study site’s impartial dispenser will keep an accurate record of 
what is dispensed and returned for each participant throughout the study.
6.5.
Concomitant Therapy
The use of any new concomitant medication, prescription or OTC, is to be recorded on the 
participant’s source document at each visit along with the reason the medication is being taken.
At Screening (Day -7), Baseline (Day 1), and at each follow-up visit, study staff will question 
each participant specifically on the use of concomitant medications. Whenever possible, study
staff should notify Allergan immediately if a participant uses any concomitant medications not 
permitted by the protocol. Participants who used prohibited concomitant medications (see 
Section 6.5.3), will be discontinued from the study and early termination procedures pertaining 
to safety assessments are recommended to be followed (see Section 1.3).
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6.5.1.
Prohibited Treatments and Washout Before the Study
Any systemic medication (including OTC, herbal, prescription, or nutritional supplements) that 
may affect DED or vision should be stably used for at least 90 days prior to the Screening 
(Day -7) visit. Systemic medications, which may affect DED or vision, include but are not 
limited to the following: flax seed oil, fish oil, omega-3 supplements, cyclosporine, 
antihistamines, cholinergic agents, anticholinergics, antimuscarinics, beta-blocking agents, 
tricyclic antidepressants, phenothiazines, estrogen, progesterone, and other estrogen derivatives.
Contact lens use is prohibited 90 days prior to the screening (Day -7) visit. Participants are not 
allowed to have any scheduled or planned ocular or systemic surgery or procedure during the 
study that, in the investigator’s opinion, may inhibit the participant’s study participation. 
Participants are not allowed to receive temporary or permanent occlusion or cauterization of the 
lacrimal puncta < 6 months prior to the Screening (Day -7) visit.
Participants should not have ocular/ophthalmic surgery or trauma, which could affect corneal 
sensitivity and/or tear distribution (eg, cataract surgery, LASIK, photorefractive keratectomy, or 
any surgery involving a limbal or corneal incision) within 12 months prior to the Screening 
(Day -7) visit.
Participants should not use lid-heating therapy (ie, LipiFlow, iLUX, etc.), Meibomian gland 
probing, or therapeutic Meibomian gland expression in either eye within 6 months prior to the 
Screening (Day -7) visit.
Participants should not use TrueTear or other topical ocular medications (OTC or prescription), 
except the monotherapy for glaucoma or OHT, or cyclosporine topical ophthalmic preparation 
(eg, RESTASIS or other ophthalmic form) or lifitegrast 5% ophthalmic solution (Xiidra) within 
1 month of the Screening (Day -7) visit.
Lastly, nonstudy artificial tear products can only be used before the Screening (Day -7) visit and 
cannot be used for the remainder of the study.
6.5.2.
Permitted Treatments
Therapy considered necessary for the participant's welfare may be given at the discretion of the 
investigator. Systemic medications that do not cause or affect DED, dry mouth, changes in 
vision (as per exclusion criterion 2.01) or other ocular changes are considered permissible 
medications. Use of artificial tear products will be limited to only REFRESH PLUS during the 
run-in period. Thereafter, use of any artificial tear product, except the assigned study
intervention, is prohibited for the duration of the study. Topical ocular medications are not 
allowed during the study, except for participants meeting all inclusion and exclusion criteria for 
their use of monotherapy for glaucoma or OHT, or use of a cyclosporine topical ophthalmic 
preparation (eg, RESTASIS or other ophthalmic form) or lifitegrast 5% ophthalmic solution 
(Xiidra). Participants using any of these products, should continue to use their drops at the same 
dose and frequency for the duration of the study. If the permissibility of a specific 
medication/treatment is in question, please contact Allergan.
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Any medication or vaccine (including OTC or prescription medicines, vitamins, and/or herbal 
supplements) that the participant is receiving at the time of enrollment or receives during the 
study must be recorded along with the following:
!
Indication
!
Dates of administration including start and end dates
!
Dosage information including route, dose and frequency
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact Allergan.
Allergan should be contacted if there are any questions regarding prior or concomitant therapy.
Any medication taken during the study between the date of the first dose (Day 1 [Baseline]) of 
study intervention and the date of the study exit will be recorded on the source document as a 
concomitant medication; any medication started after the study exit will not be considered a 
concomitant medication and should not be captured in the eCRF.
6.5.3.
Prohibited Treatments During the Study
!
Participants are not allowed to have any scheduled or planned ocular or systemic surgery or 
procedure during the study that, in the investigator’s opinion, may inhibit the participant’s 
study participation.
!
Participants are not allowed to receive temporary or permanent occlusion or cauterization of 
the lacrimal puncta during the study.
!
After Screening (Day -7), participants should not begin or stop the use of or change dose on 
any systemic medications (OTC, herbal, prescription, or nutritional supplements) that may
affect a dry eye condition or affect vision (eg, may cause blurred vision, cataracts, or 
glaucoma). Sites should look up the potential adverse reactions of each medication to 
ensure they do not fall within these exclusionary drug families. The following exceptions 
are applicable after the Screening Visit (Day -7) for participants that initiate the following to 
facilitate short-term treatment of systemic conditions such as allergies, cold/flu, and 
pain/headache:
o
Use of systemic antihistamines for up to 7 consecutive days 
o
Use of cold/flu medications used for up to 7 consecutive days
o
Use of over-the-counter pain medications (aspirin, acetaminophen, etc.) for up 
to 7 consecutive days
!
Participants should not use any lid-heating therapy (ie, LipiFlow, iLUX, etc.), Meibomian 
gland probing, or therapeutic Meibomian gland expression in either eye during the study.
!
Participants should not begin or stop any topical ophthalmic medication.
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!
Participants should not change dose on allowable topical ophthalmic medications per 
inclusion/exclusion criteria (monotherapy for glaucoma or OHT, cyclosporine topical 
ophthalmic preparation (eg, RESTASIS or other ophthalmic form) or lifitegrast 5% 
ophthalmic solution (Xiidra) while enrolled in the study.
!
Participants may not use any artificial tear product, except the run-in medication (during the 
screening period) and the assigned study intervention (after randomization).
!
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.
6.5.4.
Rescue Medicine
Rescue medicine is not applicable.
6.6.
Dose Modification
Dose modification is not applicable.
6.7.
Intervention after the End of the Study
No interventions after the end of the study are planned.
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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
A premature discontinuation will occur if a participant, who signs the ICF and is dosed, ceases 
participation in the study and the completion of the protocol-defined study procedures and visits, 
regardless of the circumstances.
Reasons for discontinuation from the study treatment and/or the study may include the following 
commonly used or other acceptable terms:
Commonly Used Terms
Other Acceptable Terms
AE
Death
Lack of efficacy
Lost to follow-up
Noncompliance with study intervention
Other
Physician decision
Pregnancy
Protocol deviation
Screen failure
Site terminated by Allergan
Study terminated by Allergan
Withdrawal by participant
7.1.
Discontinuation of Study Intervention
See the SoA (Section 1.3) for data to be collected at the time of early exit.
7.2.
Participant Discontinuation/Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons.
!
Participants will be discontinued if they use any prohibited treatments described in 
Section 6.5.3 of this protocol.
!
For participants who discontinue the study early, every effort should be made to have 
these participants return to the clinical center for completion of the early exit visit. 
Adverse events leading to a participant’s early discontinuation must be followed up as 
appropriate.
!
If the participant withdraws consent for disclosure of future information, Allergan may 
retain and continue to use any data collected before such a withdrawal of consent.
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!
See the SoA (Section 1.3) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
7.3.
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the study site for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether the participant wishes to and/or should continue in the 
study.
!
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, and if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts will be documented in the participant’s 
source document.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.
!
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1.
8.
Study Assessments and Procedures
!
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed.
!
Any safety concerns should be discussed with Allergan immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study
intervention.
!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screen failure, as applicable.
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8.1.
Efficacy Assessments
Efficacy assessments include the following: corneal staining, conjunctival staining, Schirmer test 
(with anesthesia), OSDI score, TBUT, and self-assessed questionnaires/surveys.
Timing and measurement details are provided in Table 8-1.
Table 8-1
Efficacy Assessments
Assessment
Timing
Measurement
Primary Efficacy Measure
Total staining 
! Screening and Days 1, 7, 30, 
60, and 90/Early Exit
!
Total staining score will be the sum of corneal and 
conjunctival staining score.
Secondary Efficacy Measure
Current Symptom 
Survey
! Screening and Days 1, 7, 30, 
60, and 90/Early Exit
!
A self-assessed 6-item visual analog scale (VAS) 
survey that assesses various symptoms of DED 
disease.
Other Efficacy Measures
Corneal Staining 
(modified NEI 
grading scheme, 
with fluorescein)
! Screening and Days 1, 7, 30, 
60, and 90/Early Exit
!
Corneal staining will be assessed in each eye after 
the evaluation of TBUT, using the modified NEI 
grading scheme).
Conjunctival 
staining (Modified 
NEI grading 
scheme, with 
lissamine green)
! Screening and Days 1, 7, 30, 
60, and 90/Early Exit
!
Conjunctival staining will be assessed in each eye
using the modified NEI grading scheme
Schirmer test (with 
anaesthesia)
! Screening and Days 1, 7, 30, 
60, and 90/Early Exit
!
Schirmer test with anesthesia will be performed in 
each eye after all other ophthalmic testing.
TBUT (with 
fluorescein)
! Screening and Days 1, 7, 30, 
60, and 90/Early Exit
!
TBUT is the time in seconds required for dry spots to 
appear on the corneal surface after blinking.
OSDI Questionnaire 
Score
! Screening and Days 1, 7, 30, 
60, and 90/Early Exit
!
Participants will be asked to evaluate the frequency 
of various symptoms, related visual functions, and 
environmental triggers of DED using a 5-point scale. 
This is a self-assessed overall evaluation, not per 
eye.
Study Eye Drop 
Experience and 
Tolerability 
Questionnaire
! Days 7, 30, 60, and 90/Early 
Exit
!
A self-assessed survey that evaluates the immediate, 
short- and long-term participant experience in 
comfort and vision with the study intervention, as 
well as tolerability of the assigned study intervention
over the past week in selected performance 
measures, using a VAS.
Functional Vision 
Questionnaire
! Days 1, 7, 30, 60, and 
90/Early Exit
!
A self-assessed questionnaire to assess visual 
function within the past 3 days.
5-Minute Blurry 
Vision and Ocular 
Discomfort 
Questionnaire
! Days 1 and 90/Early Exit
!
A 2-question VAS survey evaluates the participant’s 
blurry vision and ocular discomfort before dosing 
and at 30 seconds, 1 minute, 90 seconds, and 2, 3, 4, 
and 5 minutes after dosing.
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8.1.1.
Primary Efficacy Assessment
8.1.1.1.
Total Staining
Total staining score will be determined as the sum of corneal and conjunctival staining scores.
8.1.2.
Secondary Efficacy Assessment
8.1.2.1.
Current Symptom Survey
At all visits, the Current Symptom Survey will be completed by each participant to measure their 
ocular symptoms over the past 24 hours. Participants should be instructed to mark a vertical line 
on the anchored VAS that best captures how their eyes have been feeling over the past 24 hours, 
except the few minutes immediately after using eye drops. A trained member of the study
personnel will then use the provided VAS ruler to convert the participant’s response to a 
numerical value (0 to 100). This is an overall evaluation, not per eye. The questionnaire will read 
as follows (Note: The VAS scales will be an actual scale and not just text as indicated below for 
the purposes of this protocol): 
Think about how your eyes have felt over the past 24 hours. Using the scales provided below, 
please mark a vertical line at the place that best describes the level of severity you experienced 
with each of the following symptoms over the past 24 hours:
1. Burning (VAS anchors: 0 = no burning, 100 = maximum burning)
2. Dryness (VAS anchors: 0 = no dryness, 100 = maximum dryness)
3. Irritation (VAS anchors: 0 = no irritation, 100 = maximum irritation)
4. Grittiness/foreign body sensation (VAS anchors: 0 = no grittiness/foreign body sensation, 
100 = maximum grittiness/foreign body sensation)
5. Blurry/fluctuating vision (VAS anchors: 0 = no blurry/fluctuating vision, 100 = maximum 
blurry/fluctuating vision)
6. Overall ocular pain/discomfort (VAS anchors: 0 = no pain/discomfort, 100 = maximum 
pain/discomfort)
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8.1.3.
Other Efficacy Assessments
8.1.3.1.
Tear Break-up Time (with Fluorescein)
TBUT will be performed on both eyes at all visits. 
Slit-lamp settings should be adjusted to a magnification of 10X to 16X using a cobalt blue filter 
and yellow barrier filter placed directly in front of the objective lens of the slit-lamp. The 
slit-lamp’s light source must be set to high intensity (increased voltage) when the cobalt blue and 
enhancement filters are in place.
Participants will be asked to tilt their heads slightly back and, starting with the right eye, 5 μL of 
2% preservative-free liquid sodium fluorescein will be applied to the lower cul-de-sac using a 
micropipette and sterile disposable tip. To thoroughly mix the fluorescein with the tear film, the 
participant will be instructed to blink several times over approximately 15 seconds. The 
participant will be instructed to blink 3 times naturally, then stare and not blink. Using a 
stopwatch, TBUT will be measured by the investigator as the time from the last blink until 1 or 
more black (dry) spots appear in the precorneal tear film (not just local thinning or tear film 
irregularity). After the first measurement, the participant will be instructed to blink naturally
3 additional times and a second measurement will be taken. The procedure will be repeated for a 
third measurement. After a 60-second rest period, the entire procedure, starting with instillation 
of liquid sodium fluorescein will be repeated for the left eye. The time in seconds for each of the 
3 measurements will be recorded rounding up to the nearest tenth of a second. 
8.1.3.2.
Corneal Staining (Modified NEI Grading Scheme, with Fluorescein)
Corneal staining will be evaluated in each eye at all visits.
Approximately 3 minutes after instillation of sodium fluorescein and subsequent assessment of 
TBUT in both eyes (see Section 8.1.3.1), the cornea will be evaluated for staining, starting with 
the right eye. No additional liquid sodium fluorescein should be instilled.
Fluorescein staining will be evaluated using a slit-lamp with full slit width and approximately
10X to 16X magnification with cobalt blue illumination and a yellow barrier filter to enhance 
contrast. The yellow barrier filter must be placed directly in front of the objective lens of the slit-
lamp. The slit-lamp’s light source should also be set to high intensity (increased voltage) when 
the cobalt blue and enhancement filters are in place. 
Grading of the resulting corneal staining will be based on the Modified NEI (National Eye 
Institute/Industry Workshop) grading scheme (Lemp 1995, Pflugfelder 2008). The schematic 
representations of the 5 corneal regions per eye are shown in Figure 8-1. Each of the 5 areas on 
the cornea of each eye is to be graded independently (0-5 per region). The upper eyelid is lifted 
slightly to grade the entire corneal surface. This procedure should then be repeated in the left 
eye. The total corneal staining score is calculated as the sum of grading score of 5 regions. The 
maximum possible score for total corneal staining is 25.
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Figure 8-1
Modified NEI Grading Scheme Part 1: Corneal Staining Grading Scheme
Grade each zone using the dot count scale:
Dot Count
Grade
No staining 
0
1 to 5 dots 
1
6 to 15 dots 
2
16 to 30 dots 
3
> 30 dots 
4
> 30 dots + confluence 
5
8.1.3.3.
Conjunctival Staining (Modified NEI Grading Scheme, with Lissamine Green)
Interpalpebral conjunctival staining will be graded following the corneal staining evaluation at 
all visits starting with the right eye. 
With the sterile lissamine green strip still in the package, the impregnated side of the strip should 
be grasped, and the outer package torn in half vertically, exposing the white portion of the strip. 
Grasping the white portion of the strip, the impregnated side of the strip should be moistened 
with 2 drops of sterile saline solution, allowing the solution to pool into a droplet at the end of 
the strip. The participant should then be instructed to look up such that 1 drop of lissamine green 
can be applied to the right eye by gently pulling down on the lower lid and touching the droplet 
to the bulbar conjunctiva, releasing the droplet. Ensure not to touch the paper strip to bulbar 
conjunctiva. A second (new) lissamine green strip will then be immediately wetted with 2 drops 
of sterile saline solution such that a drop of lissamine green can be added to the left eye. To 
thoroughly mix the lissamine green with the tear film, the participant will be instructed to blink 
several times over approximately 15 seconds. Approximately 1 minute after instillation and 
starting with the right eye, grading of the resulting corneal staining will be based on the Modified 
NEI (National Eye Institute/Industry Workshop) grading scale. 
Using the white light of low to moderate intensity, the 6 conjunctival regions (3 nasal and 
3 temporal) will be graded using the modified NEI grading scheme (score between 0 and 5 per 
region) yielding a maximum possible score per eye of 30. The schematic representation of the 
6 conjunctival regions per eye is shown in Figure 8-2. To grade the temporal zone, the 
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participant should be instructed to look nasally; to grade the nasal zone, the participant should be 
instructed to look temporally. 
Figure 8-2
Modified NEI Grading Scheme Part 2: Conjunctival Staining Grading Scheme
Grade each zone using the dot count scale:
Dot Count
Grade
No staining 
0
1 to 5 dots
1
6 to 15 dots 
2
16 to 30 dots 
3
> 30 dots 
4
> 30 dots + confluence 
5
8.1.3.4.
Schirmer Test (with Anesthesia)
The Schirmer test (with anesthesia) should be performed in each eye after completion of both 
corneal and conjunctival staining at each study visit. 
One drop of anesthetic will be instilled into each eye. The participant will be instructed to keep 
the eyes gently closed for 1 minute. Gentle blotting of the corners of the eye lids with a facial 
tissue is allowed to catch the over spill, but this should be performed by site staff. Any direct, 
active blotting of the cul-de-sac is not allowed. After opening the eyes, the participant will be 
asked to rest with eyes open for approximately 1 additional minute. 
The participant will be asked to look up and the Schirmer strips will be placed in each eyelid in 
the lower cul-de-sac of the junction of the temporal and central one-third of the lower eyelid 
margin. Once in place, a stopwatch (timer) should be started. To minimize artifacts from this 
test, participants should gently close their eyelids until 5 minutes have elapsed. Once 5 minutes 
have elapsed, participants will be asked to 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 ballpoint pen at precisely 5 minutes. This test is to be 
conducted in a dimly lit room.
Strip Measuring: Write the letter “R” on the strip used in the OD (right) eye and the letter “L” on 
the strip used in the OS (left) eye. Each strip has graduated sections on it that will aid in 
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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.
8.1.3.5.
Ocular Surface Disease Index Questionnaire
At all visits, participants will complete an OSDI Questionnaire (see next page). The purpose of 
this assessment is to capture a range of ocular surface symptoms, including symptoms related to 
dry eye, their severity, and their impact on the participant’s ability to function, scaled into a 0 (no 
disease) to 100 (maximum severity of disease) score. The OSDI score is calculated as follows:
OSDI = (sum of scores) × 25/(number of questions answered)
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OCULAR SURFACE DISEASE INDEX© (OSDI) – To be completed by the participant
Please answer the following questions by marking the box that best represents your answer.
Have you experienced any of the following during the last 
week?
All of 
the 
Time
Most 
of the 
Time
Half 
of the 
Time
Some 
of the 
Time
None 
of the 
Time
1.
Eyes that are sensitive to light?
2.
Eyes that feel gritty?
3.
Painful or sore eyes?
4.
Blurred vision?
5.
Poor vision?
Have problems with your eyes limited you in performing 
any of the following during the last week?
All of 
the 
Time
Most 
of the 
Time
Half 
of the 
Time
Some 
of the 
Time
None 
of the 
Time
N/A
6.
Reading?
7.
Driving at night?
8.
Working with a computer or bank machine 
(ATM)?
9.
Watching TV?
Have your eyes felt uncomfortable in any of the following 
situations during the last week?
All
of the 
Time
Most 
of the 
Time
Half 
of the 
Time
Some 
of the 
Time
None 
of the 
Time
N/A
10. Windy conditions?
11. Places or areas with low humidity (very dry)?
12. Areas that are air-conditioned?
Participant Signature: _____________________
     
      
   
                                                                              Day              Month               Year  
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8.1.3.6.
Study Eye Drop Experience and Tolerability Questionnaire
This questionnaire evaluates the short- and long-term subjective experience in comfort and 
vision with the study eye drops, as well as the tolerability of the assigned study eye drops over 
the past week, using a VAS. At Day 1 (Baseline) and all follow-up visits, the Study Eye Drop 
Experience and Tolerability Survey will be completed by each participant. Participants should be 
instructed to mark a vertical line on the anchored VAS that best describes their agreement with 
the statements within the questionnaire. A trained member of the study site personnel will then 
use the provided VAS ruler to convert the participant’s response to a numerical value (0 to 100). 
This is an overall evaluation, not per eye. The questionnaire will read as follows (Note: The 
VAS scales will be actual scales and not just text as indicated below for the purposes of this 
protocol.):
Think about your experience with the study eye drops within the first 5 minutes of applying 
them. Using the scales provided below, please mark a vertical line at the place that best 
describes your agreement with the following statements:
1. The study eye drops do not cause stinging or burning in my eyes. (VAS anchors: 
0 = strongly disagree, 100 = strongly agree)
2. The study eye drops provided immediate relief of my eye dryness. (VAS anchors: 
0 = strongly disagree, 100 = strongly agree)
Now think about your experience with the study eye drops 30 minutes after you applied them. 
Using the scales provided below, please mark a vertical line at the place that best describes 
your agreement with the following statements:
3. The study eye drops are very soothing for my eyes. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
4. The study eye drops did not feel sticky. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
5. The study eye drops continued to provide relief of my eye dryness. (VAS anchors: 
0 = strongly disagree, 100 = strongly agree)
Lastly, think about how you have felt over the last week while using the study eye drops. Using 
the scales provided below, please mark a vertical line at the place that best describes your 
agreement with the following statements:
6. The study eye drops provided long-lasting relief of my eye dryness. (VAS anchors: 
0 = strongly disagree, 100 = strongly agree) 
8.1.3.7.
Functional Vision Questionnaire
This questionnaire evaluates the functional vision as a consequence of using the study eye drops 
over the past 3 days in selected performance measures using a VAS. At Day 1 (Baseline) and all 
follow-up visits, the Functional Vision Questionnaire should be completed by each participant to 
obtain functional vision ratings from participants for selected performance measures. All 
measurements will be done on an anchored VAS. Participants should be instructed to mark a 
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vertical line on the anchored VAS that best describes their agreement with the statements within 
the questionnaire. A trained member of the study personnel will then use the provided ruler to 
convert the participant’s response to a numerical value (0 to 100). This is an overall evaluation, 
not per eye. Participants will be asked 19 questions. The questionnaire will read as follows 
(Note: The VAS scales will be actual scales and not just text as indicated below for the purposes 
of this protocol):
Think about your vision over the past 3 days. You will be asked several questions about your 
general vision, then questions on specific activities such as watching television (TV), using a 
computer, using a cell phone and reading a book or magazine. If a particular question does 
not apply to you, you may check N/A (not applicable) where specified. Using the scales 
provided below, please mark a vertical line at the place that best describes your agreement with 
the following statements:
GENERAL VISION – Over the past 3 days:
1. My vision was blurry. (VAS anchors: 0 = strongly disagree, 100 = strongly agree)
2. I needed to blink frequently because of blurry vision. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
3. My eyes got tired because of blurry vision. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
WATCHING TV – Over the past 3 days:
4. I have clear vision when watching TV. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
5. I can watch TV for as long as I would like. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
6. I never stop watching TV due to blurry vision. (VAS anchors: 0 = strongly disagree, 100 = 
strongly agree)
7. I enjoy watching TV more as I have less blurry vision. (VAS anchors: 0 = strongly 
disagree, 100 = strongly agree)
USING A COMPUTER – Over the past 3 days:
8. I have clear vision when looking at my computer screen. (VAS anchors: 0 = strongly 
disagree, 100 = strongly agree)
9. I can read the computer screen as fast as I would like. (VAS anchors: 0 = strongly 
disagree, 100 = strongly agree)
10. I can use my computer for as long as I would like. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
11. I never stop using my computer due to blurry vision. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
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USING A CELL PHONE – Over the past 3 days:
12. I have clear vision when looking at my cell phone. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
13. I never have a problem using my cell phone due to blurry vision. (VAS anchors: 
0 = strongly disagree, 100 = strongly agree)
14. I can use my cell phone more as I have less blurry vision. (VAS anchors: 0 = strongly 
disagree, 100 = strongly agree)
READING A BOOK OR MAGAZINE – Over the past 3 days:
15. I have clear vision when reading. (VAS anchors: 0 = strongly disagree, 100 = strongly 
agree)
16. I can read as fast as I would like. (VAS anchors: 0 = strongly disagree, 100 = strongly 
agree)
17. I can read for as long as I would like. (VAS anchors: 0 = strongly disagree, 100 = strongly 
agree)
18. I never stop reading due to blurry vision. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
19. I enjoy reading more as I have less blurry vision. (VAS anchors: 0 = strongly disagree, 
100 = strongly agree)
8.1.3.8.
5-Minute Blurry Vision and Ocular Discomfort Questionnaire
The 5-Minute Blurry Vision and Ocular Discomfort Questionnaire will be used to assess the 
degree of the participant’s blurry vision and ocular discomfort. The questionnaire will be 
completed by each study participant at Day 1 (Baseline) and Day 90/Early Exit before the study
eye drop instillation and at 30 seconds, 1 minute, 90 seconds, 2 minutes, 3 minutes, 4 minutes, 
and 5 minutes after instillation of one drop of the assigned study eye drop in each eye by the 
impartial dispenser. Participants should be instructed to mark a vertical line on the anchored 
VAS that best describes the amount of blurry vision, respective ocular discomfort they are 
experiencing at each timepoint. A trained member of the study site personnel will then use the 
provided VAS ruler to convert the participant’s response to a numerical value (0 to 100). This is 
an overall evaluation, not per eye. The questionnaire will read as follows (Note: The VAS scales 
will be an actual scale and not just text as indicated below for the purposes of this protocol.): 
Using the 2 sets of scales below, you will be asked to rate the amount of blurry vision and 
ocular discomfort you are experiencing before the instillation and over the 5 minutes 
immediately after instillation of the study eye drop.
The amount of blurry vision you are experiencing can range from “No Blurry Vision” (Score 
of 0) to “Extreme Blurry Vision” (Score of 100) and this may change over the 5 minutes you 
are rating.
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The amount of ocular discomfort you are experiencing can range from “No Ocular 
Discomfort” (Score of 0) to “Extreme Ocular Discomfort” (Score of 100) and this may change 
over the 5 minutes you are rating.
8.2.
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA.
8.2.1.
Currently Corrected Distance Visual Acuity
At all visits, corrected visual acuity will be measured using a logarithmic visual acuity chart with 
Sloan letters for testing at 3 meters (9 feet, 10 inches). One chart is provided with right, left, and 
center acuity targets, and will be used as described below. Make sure the participant is tested 
using his/her current distance correction, if applicable. (Note: Participants should use the same 
distance correction, if required, at each visit, whenever possible). To provide standardized 
assessments of visual acuity during the study, all visual acuity assessments should be consistently 
carried out using the same lighting conditions during the entire study. Note: Test under normal 
office-like lighting conditions such that the chart is evenly lit without glare. Attach the chart to 
the wall at approximately eye level to the average height of a seated participant. Mark a spot on 
the floor (eg, with tape) that is 3 meters from the chart. Using this mark as a reference, position 
the participant so his/her eyes are 3 meters from the chart.
Begin by first testing the right eye. Occlude the left eye. The participant should be asked to start 
on the top line of the bottom right chart (20/50 equivalent). Participants should be told to read the 
letters from left to right on each line and that the chart has letters only, no numbers. If the 
participant reads a number, he/she should be reminded that the chart contains no numbers, and 
the examiner should then request a letter in lieu of the number. The participant should be asked 
to read slowly so as to achieve best identification of each letter and not to proceed to the next 
letter until he/she has given a definite answer.
If the participant 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 participant changes a response after 
having read the next letter, then the change will not be accepted. The examiner must not point to 
specific letters during the test.
When the letters become difficult to read, or if the participant identifies a letter as one of 
2 letters, he/she should be asked to choose one letter and, if necessary, to guess. Participants 
should be encouraged to continue trying even when letters become difficult to read. Stop testing 
when 3 or more errors are made on the same line. Use the supplied source document worksheet 
to mark the letters missed for each line and to enter the number of letters correctly read for each 
line.
If a participant cannot read the 20/50 equivalent line when instructed, verify that the proper 
current correction is in place. If the participant is still unable to read the 20/50 equivalent line, 
have him/her read from the top of the full center chart, letter by letter, and record the number of 
letters missed and the number of letters correctly read for each line in the source document. 
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Test the left eye following the same procedures outlined above, except have the participant start 
on the top line of the bottom left chart (20/50 equivalent). This strategy minimizes letter 
memorization.
8.2.2.
Best-Corrected Distance Visual Acuity 
Best-corrected visual acuity will be measured at Day -7 (Screening) and Day 90/Early Exit visits 
using the same logarithmic visual acuity chart with Sloan letters for testing at 3 meters (9 feet, 
10 inches) that will be used for the currently corrected distance visual acuity. The LogMar chart 
will be viewed using a trial frame holding the best-corrected distance endpoint manifest 
refraction. (Measuring acuity using the phoropter is acceptable so long as the chart distance is 
3 meters.)
Sphere, cylinder, and axis will be determined and a consistent endpoint should be used, which is 
generally the least minus sphere that provides the participant's best measured acuity. Visual 
acuity should be determined using the same procedure used for currently corrected distance 
visual acuity. The phoropter may be either a plus or minus cylinder design. Values generated 
should be recorded directly from the phoropter without conversion.
Whenever possible, the same individual should perform the refraction and the same examination 
lane should be used.
8.2.3.
Slit-Lamp Biomicroscopy 
Slit-lamp biomicroscopy (without pupil dilation) will be performed on both eyes at all visits 
during the study. Observations for the slit-lamp biomicroscopy examination will be graded as 
described below. Findings other than those listed below should be recorded under “other” for the 
appropriate location of the finding.
The following will be examined at each visit:
!
Eyelid/eyelid margins/lashes
!
Conjunctiva 
!
Cornea
!
Anterior Chamber
EYELID / EYELID MARGINS / LASHES
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
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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
CONJUNCTIVA (BULBAR AND 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
+ 1
(Mild)
Localized, mild swelling
+ 2
(Moderate)
Diffuse, moderate swelling 
+ 3
(Severe)
Diffuse, severe swelling
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
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ANTERIOR CHAMBER
For the measurements of cells and flare based on standardized uveitis nomenclature, the 
following settings should be used:
!
1 × 1 mm slit 
!
High magnification
!
Highest slit-lamp voltage 
!
Low ambient lighting
!
Illumination angle of 45 degrees
!
Same grader and slit-lamp whenever possible
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
8.2.4.
Urine Pregnancy Test
Women of childbearing potential will have urine pregnancy tests performed at the Screening 
(Day -7) and Day 90/Early Exit visits. At each visit, the investigator should discuss contraceptive 
use compliance with WOCBP. Additional details are provided in Appendix 6.
8.2.5.
Intraocular Pressure (with Anesthesia and Fluorescein)
After the Schirmer test with anesthetic is administered, IOP will be measured for each eye at 
Screening (Day -7) and Baseline (Day 1) and at all follow-up visits for participants with 
glaucoma or OHT only. Measurements should be taken using a Goldmann applanation tonometer 
affixed to a slit-lamp with the participant seated. Additional sodium fluorescein can be applied if 
needed. The participant and slit-lamp should be adjusted so that the participant’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. 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 he/she 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 
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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.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 2.
AEs will be reported by the participant.
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or study (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All SAEs from the signing of the ICF until 30 days after the last dose of study intervention will 
be collected at the timepoints specified in the SoA (Section 1.3), and as observed or reported 
spontaneously by study participants.
All AEs from the signing of the ICF until 30 days after the last dose of study intervention will be 
collected at the timepoints specified in the SoA (Section 1.3), and as observed or reported 
spontaneously by study participants.
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent, will be recorded on the source document and transcribed onto the AE section 
of the eCRF and will be considered pretreatment AEs.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 2. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly
notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken to not introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
If a participant dies during participation in the study, the investigator will provide the sponsor or 
designee with a copy of any postmortem findings including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to sponsor or designee within 24 hours of 
receipt of the information.
8.3.4.
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
!
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, institutional review boards (IRBs), 
and investigators.
!
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB, if appropriate according to local 
requirements.
8.3.5.
Pregnancy
!
If a pregnancy is confirmed after the participant has received the study intervention, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in 
the study for all safety and efficacy follow-up assessments through their Day 90/Early
Exit visit.
!
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and through the duration 
of the pregnancy.
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!
If a pregnancy is reported, the investigator should inform the sponsor or designee within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 6.
!
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an 
elective abortion or not) are considered SAEs.
8.3.6.
Medication Errors
Medication error refers to any unintended error in the dosing and/or administration of the study
intervention as per instructions in the protocol. Medication errors generally fall into 3 categories 
as follows:
!
Wrong study intervention
!
Wrong dose (including dosing regimen, strength, form, concentration, amount)
!
Wrong participant (ie, not administered to the intended participant)
8.4.
Treatment of Overdose
Treatment of overdose is not applicable to this study.
8.5.
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers and Other Assessments
8.8.1.
Study Eye Drop Usage Questionnaire
The 2-question Study Eye Drop Usage Questionnaire will be completed by each participant at 
Day 1 (Baseline) and all follow-up visits to capture the date and time of their last study eye drop 
instillation and their overall compliance to study drop usage. 
Question 1: “What date and time did you last use your study eye drops?”
Question 2: “In general, did you use your study eye drops 3 times a day?” (yes / no)
Sites should review each participant’s response to ensure that the last instillation of their study
eye drops was ≥ 4 hours from the start of completing this questionnaire and that they are 
generally using their study eye drops 3 times per day. Should either of the participant’s responses 
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be out of compliance, the site should discuss with the participant to ensure they dose correctly 
from that point forward.
8.9.
Health Economics
Health economics are not evaluated in this study.
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9.
Statistical Considerations
One database lock is planned for the study and will occur at the completion of the study. Detailed 
statistical analyses will be described in the analysis plan, which will be finalized prior to 
database lock.
9.1.
Statistical Hypotheses
The null and alternative hypotheses for the primary efficacy endpoint are:
Superiority
!
H0: The NATF (011516X) is not superior to Systane Ultra MD as measured by the mean 
change from baseline in total staining score at Day 90.
!
HA: The NATF (011516X) is superior to Systane Ultra MD as measured by the mean 
change from baseline in total staining score at Day 90.
Noninferiority
!
H0: The NATF (011516X) is inferior compared to Systane Ultra MD as measured by the 
mean change from baseline in total staining score at Day 90.
!
HA: The NATF (011516X) is noninferior compared to Systane Ultra MD as measured by 
the mean change from baseline in total staining score at Day 90.
9.2.
Sample Size Determination
The primary efficacy variable is change from baseline in total staining score at Day 90. Based on 
the assumption of noninferiority test for a between-group difference (ie, the noninferiority 
margin) of 2.3 units in mean change from baseline in total staining at Day 90 with no inherent 
treatment difference with common standard deviation of 5.98, 170 participants will be required 
in each intervention to detect the above intervention difference with a power of 90% or greater at 
the 1-sided 1.25% significance level. Assuming a 15% dropout rate, 200 participants will be 
randomized for each arm with a total of 400 participants.
9.3.
Populations for Analyses
The analysis populations will consist of participants as defined below:
!
The intent-to-treat (ITT) population includes all randomized participants. Participants will 
be summarized according to the randomized study intervention.
!
The per-protocol (PP) population includes all randomized participants who have no 
protocol deviations affecting the primary analysis. Participants will be summarized 
according to the randomized study intervention.
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!
The safety population includes all treated participants who receive/take ≥ 1 administration 
of study intervention. Participants will be summarized according to the study intervention 
they actually received.
9.4.
Statistical Analyses
The statistical analysis plan (SAP) will be developed and finalized before database lock will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. 
All data will be summarized with descriptive statistics and/or frequency tables. In general, 
nominal categorical data will be analyzed using Pearson’s chi-square test or Fisher’s exact test. 
Continuous variables will be analyzed using analysis of variance (ANOVA) models, 
mixed-effects model repeated measures (MMRM), or t-tests.
9.4.1.
Efficacy Analyses
The efficacy analyses will be based on the ITT and PP population.
9.4.1.1.
Analysis Endpoints
The primary and secondary efficacy endpoints are listed below and analyses will be defined in 
the following sections. All analyses for other efficacy/effectiveness endpoints listed below will 
be defined in the SAP.
Primary efficacy endpoint:
!
Change from baseline in total staining score at Day 90
Secondary efficacy endpoint:
!
Change from baseline in Current Symptom Survey (composite of all symptoms) at Day 90
Other efficacy endpoints:
!
Change from baseline in corneal staining score
!
Change from baseline in conjunctival staining score
!
Change from baseline in total staining score other than Day 90
!
Change from baseline in Current Symptom Survey (composite of all symptoms) other 
than Day 90
!
Change from baseline in individual symptom scores from Current Symptom Survey
!
Change from baseline in Schirmer test
!
Change from baseline in TBUT 
!
Change from baseline in Functional Vision Questionnaire, 5-Minute Blurry Vision, and 
Ocular Discomfort Questionnaire
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!
Study Eye Drop Experience and Tolerability Questionnaire
In addition to those endpoints listed above, other analyses of exploratory efficacy such as 
responder analyses will be defined in the SAP.
9.4.1.2.
Primary Analyses
The primary efficacy variable is the change from baseline in total staining score at Day 90.
The primary efficacy analysis will be performed in the ITT population using MMRM. The 
differences and the intervals will be constructed with the least squares means from the MMRM 
model with treatment, visit, visit by treatment interaction, and baseline total staining stratum, and 
baseline total staining stratum by visit interaction as the fixed effects. In order to control the 
overall type I error rate in the primary efficacy analysis, the sequential procedures will be 
performed. Under this procedure, the noninferiority will be performed first and the superiority 
test will be performed next only if the null hypothesis of noninferiority is rejected. To test the 
hypothesis of noninferiority, a 2-sided 95% confidence interval will be constructed for the 
difference in the mean change from baseline in total staining at Day 90. If the upper limit of 
2-sided CI is less than 2.3 units, then the NATF tear formulation will be considered noninferior 
to Systane Ultra MD at the 2.3 unit margin. To test the hypothesis of superiority, a 2-sided test 
for superiority will be performed at the 0.05 significance level.
The primary efficacy variable will also be analyzed similarly on PP population as a sensitivity
analysis.
9.4.1.3.
Secondary Analyses
The secondary efficacy variable is the change from baseline in Current Symptom Survey total 
score (composite of all symptoms) at Day 90. The secondary efficacy variable will be analyzed 
using MMRM.
9.4.1.4.
Other Efficacy Analyses
Other efficacy analyses include comparing the NATF (011516X) with Systane Ultra MD at each 
scheduled visit on corneal staining, conjunctival staining, total staining score other than Day 90, 
Current Symptom Survey (composite of all symptoms) other than Day 90, individual symptom 
scores from Current Symptom Survey, Schirmer test, TBUT, Functional Vision Questionnaire, 
5-Minute Blurry Vision and Ocular Discomfort Questionnaire, and Study Eye Drop Experience 
and Tolerability Questionnaire.
Change from baseline of selected continuous other efficacy variables will be analyzed using 
MMRM. Detailed methods for the analysis of other efficacy variables will be described in the 
SAP.
9.4.2.
Safety Analyses
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP.
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The safety variables include AEs, biomicroscopy, currently corrected distance visual acuity, 
BCDVA, and IOP. All safety analyses will be conducted on the safety population. Medical 
Dictionary for Regulatory Activities (MedDRA) nomenclature will be used to code AEs. For 
each AE reported, the number and percent of participants will be tabulated. Separate tables will 
be generated for pretreatment AEs and treatment-emergent AEs. All AEs will be presented in the 
listings. Detailed analysis methods will be provided in the SAP.
Other safety variables, including biomicroscopy findings, currently corrected distance visual 
acuity, BCDVA, and IOP, will also be analyzed.
9.4.2.1.
Adverse Events
An AE will be considered a treatment-emergent adverse event (TEAE) if:
!
The AE began on or after the date of the first dose of study intervention; or
!
The AE was present before the date of the first dose of study intervention, but increased in 
severity or became serious on or after the date of the first dose of study intervention
An AE will be considered a treatment-emergent SAE if it is a TEAE that additionally meets any
SAE criteria.
The number and percentage of participants reporting TEAEs in each study intervention 
group/during the study will be tabulated by system organ class and preferred term and by system 
organ class, preferred term, and severity.
The number and percentage of participants reporting treatment-related TEAEs in each study
intervention group/during the study will be tabulated by system organ class and preferred term.
If more than 1 AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention.
Summary tables will be provided for participants with SAEs and participants with AEs leading to 
discontinuation if 5 or more participants reported such events. Listings of all AEs, SAEs, and 
AEs leading to discontinuation by participant will be presented.
The definitions of an AE and SAE can be found in Appendix 2.
9.4.3.
Other Safety Analyses
All other safety variables will be analyzed with descriptive statistics. Detailed methods for the 
analysis of other safety variables will be described in the SAP.
9.4.3.1.
Subgroup Analyses 
The primary efficacy variable will also be analyzed by stratification factor.
9.5.
Interim Analyses
Not applicable.
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9.5.1.
Data Monitoring Committee
Not applicable.
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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
o
Consensus ethical principles derived from international guidelines including the 
Council for International Organizations of Medical Sciences (CIOMS) International 
Ethical Guidelines
o
Applicable International Council on Harmonisation (ICH)/International Organization 
for Standardization (ISO)/Good Clinical Practice (GCP) guidelines
o
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB by the investigator and reviewed and 
approved by the IRB before the study is initiated. 
!
Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
!
The investigator will be responsible for the following:
o
Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB
o
Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures
o
Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, 
the IRB, and European regulation 536/2014 for clinical studies (if applicable)
10.1.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.
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10.1.3.
Informed Consent Process
!
The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 
!
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB or study center. 
!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
!
A copy of the ICF(s) must be provided to the participant. 
10.1.4.
Data Protection 
!
Participants will be assigned a unique identifier. Any participant records or datasets that 
are transferred to the sponsor will contain the identifier only; participant names or any
information that would make the participant identifiable will not be transferred. 
!
The participant must be informed that his/her personal study-related data will be used by
the sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
!
The participant must be informed that his/her medical records may be examined by
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities.
10.1.5.
Posting Clinical Study Data
!
Study data and information may be published in nonpromotional, peer-reviewed 
publications either by or on behalf of the sponsor. 
!
Clinical study reports, safety updates, and annual reports will be provided to regulatory
authorities as required.
!
Company-sponsored study information and tabular study results will be posted on the 
United States National Institutes of Health's website www.ClinicalTrials.gov and other 
publicly accessible sites.
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10.1.6.
Data Quality Assurance
!
All participant data relating to the study will be recorded electronic CRFs unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
!
The investigator must permit study-related monitoring, audits, IRB review, and regulatory
agency inspections and provide direct access to source data documents. 
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any
other study agreements, ICH GCP, and all applicable regulatory requirements. 
!
Records and documents, including signed ICFs, pertaining to the conduct of this study
must be retained by the investigator as stated in the clinical trial agreement. No records 
may be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification to 
the sponsor. 
10.1.7.
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
!
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study.
!
Definition of what constitutes source data can be found in Section 4.0 of ICH E6, GCP: 
Consolidated Guidance and records must be attributable, legible, contemporaneous, 
original, and accurate.
10.1.8.
Study and Site Closure
The sponsor or designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
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The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor’s procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development
10.1.9.
Publication Policy
!
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.
!
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data.
!
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.1.10.
Compliance with Protocol
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Significant protocol deviations will be 
reported to the IRB according to the IRB’s reporting requirements.
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10.3.
Appendix 3: Abbreviations
Abbreviation
Definition
AE
adverse event
ANOVA
analysis of variance
BCDVA
best-corrected distance visual acuity
CDISC
Clinical Data Interchange Standards Consortium 
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences 
CONSORT
Consolidated Standards of Reporting Trials
DED
dry eye disease
eCRF
electronic case report form
EDS-VAS
Eye Dryness Score - Visual Analog Scale
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator’s brochure 
ICF
informed consent form
ICH
International Council on Harmonisation
IOP
intraocular pressure
IRB
institutional review board
ISO
International Organization for Standardization
ITT
intent-to-treat
IxRS
interactive response system
KCS
keratoconjunctivitis sicca
LASIK
laser-assisted in situ keratomileusis
MD
multidose
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed-effects model repeated measures
N/A
not applicable
NCI
National Cancer Institute
OD
right eye
OHT
ocular hypertension
OS
left eye
OSDI
Ocular Surface Disease Index® Questionnaire
OTC
over-the-counter
NATF
new artificial tear formulation
NEI
National Eye Institute
PP
per-protocol
SAE
serious adverse event
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Abbreviation
Definition
SAP
statistical analysis plan
SoA
schedule of activities
TBUT
tear break-up time
TEAE
treatment-emergent adverse event
US
United States
VAS
visual analog scale
vs
versus
WOCBP
woman of childbearing potential
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10.4.
Appendix 4: Standard Discontinuation Criteria
This table provides participant discontinuation criteria for this protocol. Clinical Data 
Interchange Standards Consortium (CDISC) terminology is used, and thus subject or patient is 
used instead of participant (as used elsewhere in this protocol). These terms are interchangeable.
CDISC Submission Value
CDISC Definition
AE
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any 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. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary)
Completed
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Disease relapse
The return of a disease after a period of remission
Failure to meet randomization criteria
An indication that the subject has been unable to fulfill/satisfy the 
criteria required for assignment into a randomized group
Lack of efficacy
The lack of expected or desired effect related to a therapy (NCI)
Lost to follow-up
The loss or lack of continuation of a subject to follow-up
Noncompliance with study drug
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI)
Other
Different than the one(s) previously specified or mentioned (NCI)
Physician decision
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI)
Pregnancy
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI)
Progressive disease
A disease process that is increasing in extent or severity (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Recovery
A healing process and/or an outcome implying relative health. The 
term is typically used in the context of direct and indirect effects of 
sickness or injury. (NCI)
Screen failure
The potential subject who does not meet one or more criteria 
required for participation in a trial
Site terminated by sponsor
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI)
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CDISC Submission Value
CDISC Definition
Study terminated by sponsor
An indication that a clinical study was stopped by its sponsor 
(NCI)
Technical problems
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI)
Withdrawal by parent/guardian
An indication that a study participant has been removed from the 
study by the parent or legal guardian
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)
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10.5.
Appendix 5: Study Tabular Summary
This table is intended for use in posting study information to registries (eg, ClinicalTrials.gov).
Parameter Group
Parameter
Value
Study information
Study Title
A Multicenter, Single-masked, 
Randomized Study to Compare the 
Efficacy and Safety of a New
Artificial Tear Formulation (011516X)
with Systane® Ultra Multidose for 90 
Days in Participants with Dry Eye 
Disease
Clinical Study Sponsor
Allergan Sales LLC
Study Phase Classification
Phase 3 study
Study Indication
DED
Study Indication Type
Treatment
Study Type
Efficacy
Safety
Study Length
Approximately 90 days
Planned Country of Investigational Sites
United States
Planned Number of Subjects
400
FDA-regulated Device Study
No
FDA-regulated Drug Study
Yes
Pediatric Study
No
Subject 
information
Diagnosis Group
DED
Healthy Subject Indicator
No
Planned Minimum Age of Subjects
18
Planned Maximum Age of Subjects
Not specified
Sex of Participants
Both
Stable Disease Minimum Duration
Not specified
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Parameter Group
Parameter
Value
Treatments
Investigational Therapy or Treatment
011516X
Intervention Type
Drug
Pharmacological Class of Investigational
Therapy
Artificial tear 
Dose per Administration
1 to 2 drops in each eye
Dose Units
Drop
Dosing Frequency
3 times per day
Route of Administration
Topical eye drop
Current Therapy or Treatment
Artificial tear product
Added on to Existing Treatments
No
Control Type
Active
Comparative Treatment Name
Systane Ultra Multidose
Trial design
Study Type
Interventional
Intervention Model
Parallel
Planned Number of Arms
2
Study Is Randomized
Yes
Randomization Quotient
1:1
Study Blinding Schema
Single-masked
Stratification Factor
Total ocular staining score of the study 
eye (mild/moderate = score of 6 to 25 
vs severe = score of 26 to 43)
Adaptive Design
No
Study Stop Rules
None
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10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP:
1. Premenarchal
2. Premenopausal female with 1 of the following:
!
Documented hysterectomy
!
Documented bilateral salpingectomy
!
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female
!
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
Contraception Guidance:
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective or acceptable method of contraception consistently and correctly as described in 
Table 10-1.
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Table 10-1
Highly Effective and Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of < 1% per year when used consistently and correctly
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation 
!
Oral 
!
Intravaginal 
!
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation
!
Oral 
!
Injectable 
Highly Effective Methods That Are User Independenta
!
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation
!
IUD
!
IUS
!
Etonogestrel implant (ie, Nexplanon®)
!
Bilateral tubal occlusion (eg, Essure®, bilateral tubal ligation)
!
Intrauterine copper contraceptive (ie, ParaGard®)
Vasectomized Partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used.
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.
Acceptable Methods
Acceptable birth control methods that result in a failure of more than 1% per year include:
!
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action
!
Male or female condom with or without spermicide
!
Cap, diaphragm, or sponge with spermicide
!
Nonhormonal intrauterine device
Combinations of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
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Pregnancy Testing:
!
WOCBP should only be included after a negative highly sensitive urine pregnancy test at 
screening.
!
Additional pregnancy testing should be performed at study exit, and as required locally.
!
Pregnancy testing will be performed when pregnancy is otherwise suspected. 
!
Urine pregnancy testing will be used unless the study site requires the use of serum 
testing, in which case serum testing will be used.
Collection of Pregnancy Information:
Female Participants Who Become Pregnant
!
The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to Allergan within 24 hours of learning of a participant’s 
pregnancy. The participant will be followed to determine the outcome of the pregnancy. 
The investigator will collect follow-up information on the participant and the neonate, and 
the information will be forwarded to Allergan. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure.
!
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
will be reported as an AE or SAE. Abnormal pregnancy outcomes (eg, spontaneous 
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) or genetic 
abnormalities (whether leading to an elective abortion or not) are always considered to be 
SAEs and will be reported as such. Any poststudy pregnancy-related SAE considered 
reasonably related to the study intervention by the investigator will be reported to Allergan
as described in Section 8.3.4. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
!
If a pregnancy is confirmed after the participant has received study treatment, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in 
the study for all safety and efficacy follow-up assessments through the end-of-study visit.
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10.7.
Appendix 9: Study Schedule Supplement
10.7.1.
Screening (Day -7 [-3 days])
!
Written informed consent and written documentation in accordance with the relevant 
country and local privacy requirements 
!
Demographic information
!
Medical and ophthalmic histories
!
Inclusion/exclusion criteria assessment
!
Self-assessed surveys/questionnaires: Current Symptom Survey and OSDI 
Questionnaire
!
Adverse event assessment
!
Prestudy medication assessment
!
Urine pregnancy test (for WOCBP only)
!
Currently corrected distance visual acuity, BCVA, biomicroscopy, TBUT (with 
fluorescein), corneal staining (modified NEI grading, with fluorescein), conjunctival 
staining (modified NEI grading scheme, with lissamine green), Schirmer test (with 
anesthesia), and IOP (with anesthesia and fluorescein using a Goldmann applanation 
tonometer)
!
Access IxRS
!
Dispense run-in medication (if the patient meets the required Day -7 [Screening] 
qualifications) 
Patients who fulfill all inclusion and exclusion criteria should be dispensed the run-in 
medication, REFRESH PLUS. They should be given instructions regarding the method of 
instillation and the dose regimen to be followed.
10.7.2.
Baseline (Day 1)
!
Inclusion/exclusion criteria assessment
!
Medical and ophthalmic histories
!
Concomitant medication assessment
!
Adverse event assessment
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!
Self-assessed surveys/questionnaires: Study Eye Drop Usage Questionnaire, Current 
Symptom Survey, OSDI Questionnaire, and Functional Vision Questionnaire
!
Currently corrected distance visual acuity, biomicroscopy, TBUT (with fluorescein), 
corneal staining (modified NEI grading, with fluorescein), conjunctival staining 
(modified NEI grading scheme, with lissamine green), Schirmer test (with anesthesia), 
and IOP (with anesthesia and fluorescein using a Goldmann applanation tonometer, 
only for participants with glaucoma or OHT)
!
Monitor return of unused run-in medication and confirmation of run-in medication
accountability
!
Access IxRS 
!
Randomization
!
Predose and postdose 5-Minute Blurry Vision and Ocular Discomfort Questionnaire
!
Dispense study medication (if the participant qualifies for the study)
10.7.3.
Day 7 (±3 days)
!
Self-assessed surveys/questionnaires: Study Eye Drop Usage Questionnaire, Current 
Symptom Survey, OSDI Questionnaire, Study Eye Drop Experience and Tolerability
Questionnaire, and Functional Vision Questionnaire
!
Adverse event assessment
!
Concomitant medication assessment
!
Currently corrected distance visual acuity, biomicroscopy, TBUT (with fluorescein), 
corneal staining (modified NEI grading, with fluorescein), conjunctival staining 
(modified NEI grading scheme, with lissamine green), Schirmer test (with anesthesia), 
and IOP (with anesthesia and fluorescein using a Goldmann applanation tonometer, 
only for patients with glaucoma or OHT)
10.7.4.
Days 30 and 60 (±7 days)
!
Self-assessed surveys/questionnaires: Study Eye Drop Usage Questionnaire, Current 
Symptom Survey, OSDI Questionnaire, Study Eye Drop Experience and Tolerability
Questionnaire, and Functional Vision Questionnaire
!
Adverse event assessment
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!
Concomitant medication assessment
!
Currently corrected distance visual acuity, biomicroscopy, TBUT (with fluorescein), 
corneal staining (modified NEI grading, with fluorescein), conjunctival staining 
(modified NEI grading scheme, with lissamine green), Schirmer test (with anesthesia), 
and IOP (with anesthesia and fluorescein using a Goldmann applanation tonometer, 
only for patients with glaucoma or OHT)
!
Monitor return of used and unused study intervention and confirmation of study
intervention accountability
!
Access IxRS
!
Dispense study intervention
10.7.5.
Day 90/Early Exit (±7 days)
!
Self-assessed surveys/questionnaires: Study Eye Drop Usage Questionnaire, Current 
Symptom Survey, OSDI Questionnaire, Study Eye Drop Experience and Tolerability
Questionnaire, and Functional Vision Questionnaire
!
Adverse event assessment
!
Concomitant medication assessment
!
Urine pregnancy test (for WOCBP only)
!
Currently corrected distance visual acuity, BCVA, biomicroscopy, TBUT (with 
fluorescein), corneal staining (modified NEI grading, with fluorescein), conjunctival 
staining (modified NEI grading scheme, with lissamine green), Schirmer test (with 
anesthesia), and IOP (with anesthesia and fluorescein using a Goldmann applanation 
tonometer, only for patients with glaucoma or OHT)
!
Access IxRS
!
Predose and postdose 5-Minute Blurry Vision and Ocular Discomfort Questionnaire
!
Monitor return of used and unused study intervention and confirmation of study
intervention accountability
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10.8.
Appendix 10: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC.
Amendment 1 (February 2020)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it neither significantly impacts the safety or physical/mental integrity of participants nor 
the scientific value of the study.
Overall Rationale for the Amendment:
The overall rationale for the changes implemented in Protocol Amendment 1 is to remove the 
evaluation of a second new artificial tear formulation (NATF) formulation (011533X) from the 
study.
Section Number and Name
Description of Change
Brief Rationale
Title Page, Section 1 Synopsis, Figure 1-1, 
Section 2.1 Study Rationale, Section 2.2 
Background, Section 2.3 Benefit/Risk 
Assessment, Section 3 Objectives and 
Endpoints, Section 4.1 Overall Design, 
Section 4.2, Scientific Rationale for Study 
Design, Section 6.1 Study Interventions 
Administered, Section 6.1.3 Instructions for 
Use and Administration, Section 6.3 
Measures to Minimize Bias: Randomization 
and Masking, Section 6.4 Study 
Intervention Compliance, Section 9.1 
Statistical Hypotheses, Section 9.4.1.4 
Other Efficacy Analyses, Section 10.5 
Appendix 5: Study Tabular Summary
Removed the NATF formulation 
011533X arm from the study. 
Administrative decision to 
focus development efforts 
and resources on a single 
formulation. 
Section 1 Synopsis, Section 4.1 Overall 
Design, Section 5 Study Population, Section 
9.2 Sample Size Determination, Appendix 5 
Study Tabular Summary
Changed the total number of 
participants from approximately 
600 to approximately 400 to be 
randomized in order to have 
340 participants (170 participants 
in each arm) complete the study 
through Day 90, assuming an 
approximate 15% dropout rate.
Because the study is 
changing from a 3-arm to a 
2-arm study, a smaller 
number of participants will 
be required. 
Section 1 Synopsis, Section 4.1 Overall 
Design, Section 5 Study Population, 
Appendix 5 Study Tabular Summary
Changed the number of study 
sites from up to 40 sites to 
approximately 28 sites. 
Because the study is 
changing from a 3-arm to a 
2-arm study and a smaller 
number of participants will 
be required, a smaller 
number of sites will be 
required.
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Section Number and Name
Description of Change
Brief Rationale
Section 5.1 Inclusion Criteria
Revised inclusion criterion 2.01 
as follows: At the Screening 
(Day -7) and Baseline (Day 1) 
visits, at least 1 eye must qualify 
with both of the following ocular 
staining scores and the same eye 
must qualify at both visits:
For clarification.
Section 5.2 Exclusion Criteria
Added the following exclusion 
criterion 1.02: At the Screening 
(Day -7) or Baseline (Day 1) 
visits, one or both eyes have
• Corneal staining score of 5 in 
any of the 5 zones or a total score 
of <5 or > 19 based on the 
modified NEI grading scheme 
(score range = 0 to 5; graded in 
5 zones of the cornea for a total 
score range of 0 to 25)
or
• Conjunctival staining score of 5 
in any of the 6 zones based on the 
modified NEI grading scheme 
(score range = 0 to 5 per zone)
For clarification.
Section 8.1.3.2 Corneal Staining (Modified 
NEI Grading Scheme, with Fluorescein)
Revised the following text; 
Fluorescein staining will be 
evaluated using a slit-lamp with 
full slit width and approximately 
10X to 16X magnification with 
cobalt blue illumination and a 
yellow barrier filter to enhance 
contrast.
For clarification. 
Section 8.1.3.3 Conjunctival Staining 
(Modified NEI Grading Scheme, with 
Lissamine Green)
Revised the following text: Using 
the white light of low to moderate 
intensity, tThe 6 conjunctival 
regions (3 nasal and 3 temporal) 
will be graded using the modified 
NEI grading scheme (score 
between 0 and 5 per region) 
yielding a maximum possible 
score per eye of 30.
For clarification.
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Section Number and Name
Description of Change
Brief Rationale
Section 9.1 Statistical Hypotheses
Revised the following text: 
•
H0: The NATF (011516X) is 
not noninferior compared to 
Systane Ultra MD as measured by 
the mean change from baseline in 
total staining score at Day 90.
For clarification.
Section 9.4.1.2 Primary Analyses
Revised the following text: 
In order to control the overall 
type I error rate in the primary 
efficacy analysis, the Hochberg 
Bonferroni reverse fixed 
sequencesequential procedures 
will be used since performed. 
Under this procedure, the null 
hypotheses of noninferiority are 
nested in will be performed first 
and the null hypotheses of
superiority. Under this procedure,
test will be performed next only if 
the null hypothesis of superiority 
is rejected using Hochberg test 
the null hypothesis of 
noninferiority is automatically 
rejected, and if the null 
hypothesis of superiority is not 
rejected using Hochberg 
procedure the null hypothesis of 
noninferiority is tested using 
Bonferroni test. For each NATF 
tear formulation, test for 
superiority will be performed first 
by applying Hochberg’s 
procedure at 0.05 significance 
level rejected. To test the 
hypothesis of noninferiority, a 2-
sided 97.595% confidence 
intervalsinterval will be 
constructed for the difference in 
the mean change from baseline in 
total staining at Day 90. If the 
upper limit of 2-sided CIsCI is 
less than 2.3 units, then the NATF 
tear formulation will be 
considered noninferior to Systane 
Ultra MD at the 2.3 unit margin. 
To test the hypothesis of 
superiority, a 2-sided test for 
superiority will be performed at 
the 0.05 significance level.
Because the study is 
changing from a 3-arm to a 
2-arm study, the primary 
analysis methods were 
updated. 
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11.
References
Behrens A, Doyle JJ, Stern L, Chuck RS, McDonnell PJ, Azar DT, et al. Dysfunctional tear 
syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25(8):900-907.
Craig JP, Nichols KK, Akpek EK, Caffery HS Dua, Joo CK, Liu ZJ, Nelson JD, Nichols JJ, 
Tsubota K, Stapleton F. TFOS DEWS II Definition and Classification Report. Ocul Surf. 
2017;15(3):276-283.
Jones L, Downie LE, Korb D, Benitez-Del-Castillo JM, Dana R, Deng SX. TFOS DEWS II 
Management and Therapy Report. Ocul Surf. 2017;15(3):575-628.
Lemp MA. National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes, CLAO J 
1995;21:221-232.
Pflugfelder S. Baylor Fluorescein Corneal Staining Scheme (Unpublished Personal
Communication, 2008).
Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II 
Epidemiology report. Ocul Surf. 2017;15(3):334-365. 
Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of DED: 
The interaction between the ocular surface and lacrimal glands. Cornea 1998. 
doi:10.1097/00003226-199811000-00002.
Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II 
Diagnostic methodology report. Ocul Surf. 2017;15(3):539-574.
Approval Date: 08-Jun-2020 17:02:44 (GMT)
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SAP_001.pdf: 
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Statistical Analysis Plan
Version Amendment 1 – 2 August 2021
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Statistical Analysis Plan for Study 2007-301-005
A Multicenter, Single-masked, Randomized Study to Compare the 
Efficacy and Safety of a New Artificial Tear Formulation 
(011516X) with Systane® Ultra Multidose for 90 Days in 
Participants with Dry Eye Disease
Date:  2 August 2021
Version Amendment 1
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Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................6
Objectives and Hypotheses........................................................................6
Objectives and Measures ...........................................................................6
Statistical Hypotheses ................................................................................7
Study Design Overview .............................................................................7
Schema.......................................................................................................8
Treatment Assignment and Masking .........................................................9
Sample Size Determination........................................................................9
3.0
Endpoints................................................................................11
Primary Efficacy Endpoint ......................................................................11
Secondary Efficacy Endpoint ..................................................................11
Other Exploratory Efficacy Endpoints.....................................................11
Safety Endpoints ......................................................................................12
4.0
Analysis Populations .............................................................13
5.0
Participant Disposition..........................................................14
6.0
Study Drug Duration.............................................................15
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................16
Demographics and Baseline Characteristics............................................16
Medical and Surgical History ..................................................................16
Ophthalmic Medical and Surgical History...............................................16
Prior and Concomitant Medications ........................................................16
8.0
Efficacy Analyses...................................................................18
General Considerations............................................................................18
Handling of Missing Data........................................................................18
Primary Efficacy Endpoint and Analyses................................................18
Primary Efficacy Endpoint ......................................................................18
Primary Efficacy Analysis .......................................................................18
Sensitivity Analyses.................................................................................19
Secondary Efficacy Analyses...................................................................19
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Exploratory Efficacy Analyses ................................................................19
5-Minute Blurry Vision and Ocular Discomfort Questionnaire ..............20
Efficacy Subgroup Analyses....................................................................20
9.0
Safety Analyses ......................................................................21
General Considerations............................................................................21
Adverse Events ........................................................................................21
Treatment-emergent Adverse Events.......................................................21
Adverse Event Overview .........................................................................22
Treatment-emergent Adverse Events by SOC and/or PT........................22
SAEs, Deaths and Adverse Events Leading to Study Drug 
Discontinuation........................................................................................23
Adverse Events of Special Interest ..........................................................23
Analysis of Laboratory Data....................................................................23
Urine Pregnancy Test...............................................................................23
Clinical Laboratory Parameters ...............................................................23
Analysis of Vital Signs ............................................................................23
Other Safety Analyses..............................................................................23
Biomicroscopy .........................................................................................23
Currently Corrected Distance Visual Acuity ...........................................24
Best Corrected Distance Visual Acuity ...................................................25
Intraocular Pressure .................................................................................25
10.0
Other Analyses.......................................................................25
Pharmacokinetics/Pharmacodynamics.....................................................25
Genetics....................................................................................................25
11.0
Interim Analyses....................................................................26
Data Monitoring Committee....................................................................26
12.0
Overall Type-I Error Control ..............................................27
13.0
SAP Version History .............................................................28
14.0
References...............................................................................29
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List of Appendices
Appendix A.
Protocol Deviations..................................................................................30
Appendix B.
Safety Assessments..................................................................................31
Appendix C.
List of Abbreviations ...............................................................................36
Appendix D.
Changes to Protocol-planned Analyses ...................................................38
List of Tables
Table 2-1
Objectives and Measures ...........................................................................6
Table 4-1
Analysis Populations................................................................................13
List of Figures
Figure 2-1
Study Schematic.........................................................................................8
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1.0
Introduction
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and specified in the final 
Protocol 2007-301-005 Amendment 2 dated 08 Jun 2020. Specifications of tables, figures,
and data listings are contained in a separate document.
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primary efficacy measure is total ocular staining and the primary analysis timepoint is at 
Day 90.
Approximately 400 participants (200 participants in each arm) will be enrolled at 
approximately 28 sites in the US in order to have 340 participants (170 participants in 
each arm) complete the study through Day 90, assuming an approximate 15% dropout 
rate. Participants who prematurely discontinue from the study will not be replaced.
No interim analyses are planned for this study.
Schema
The schematic of the study is shown in Figure 2-1.
Figure 2-1
Study Schematic
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Treatment Assignment and Masking
This study will use a 1:1 treatment allocation to 011516X or Systane Ultra MD, with a 
central stratification by Day 1 (Baseline) total ocular staining score in the study eye 
(mild/moderate = score of 6 to 25 vs severe = score of 26 to 43). The study eye is defined 
as the worst eye based on total ocular staining score at Day 1 (Baseline). If both eyes have 
the same total ocular staining score, the right eye will be designated as the study eye.
Prior to initiation of study intervention, each participant who provides informed consent 
will be assigned to a participant number through an automated IxRS that will serve as the 
participant’s identification number on all study documents. Participant numbers will be 
assigned in ascending order across all sites and should not be omitted or reused.
At the end of the Screening (Day -7) visit, all eligible participants will receive a run-in 
medication kit (REFRESH PLUS) for use during the 7-day run-in period. Sites will 
dispense the run-in medication kit according to the IxRS instructions.
At the end of the Day 1 (Baseline) visit, all eligible participants will be stratified by their 
Day 1 (Baseline) study eye total ocular staining score and be randomly assigned to 1 of 
2 treatment arms in a 1:1 ratio based on a randomization scheme prepared by Allergan 
Biostatistics. This will require the delegated site personnel to enter the participant’s 
Screening Visit (Day -7) and Baseline (Day 1) total corneal and conjunctival staining 
scores of each eye directly into IxRS. IxRS will then determine which eye is the study eye 
and assign the participant to a stratification group and a treatment arm, thus providing the 
site with the specific study intervention kit assignment. Sites will dispense study 
intervention according to the IxRS instructions.
Sample Size Determination
The primary efficacy variable is change from baseline in total staining score at Day 90. 
Based on the assumption of noninferiority test for a between-group difference (ie, the 
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noninferiority margin) of 2.3 units in mean change from baseline in total staining at 
Day 90 with no inherent treatment difference with common standard deviation of 6.01, 
170 participants will be required in each intervention group to detect the above 
intervention difference with a power of 90% or greater at the 1-sided 2.5% significance 
level. Assuming a 15% dropout rate, 200 participants will be randomized for each arm 
with a total of 400 participants to achieve the required sample size at Day 90.
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3.0
Endpoints
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as change from baseline in total staining score 
(sum of corneal and conjunctival staining scores) of study eye at Day 90.
Secondary Efficacy Endpoint
The secondary endpoint is defined as change from baseline in Current Symptom Survey 
total score (composite of all symptoms) at Day 90.
Other Exploratory Efficacy Endpoints
Other efficacy endpoints are listed below.
!
Change from baseline in corneal staining score
!
Change from baseline in conjunctival staining score
!
Change from baseline in total staining score other than Day 90
!
Change from baseline in Current Symptom Survey total score (composite of all 
symptoms) other than Day 90
!
Change from baseline in individual symptom scores from Current Symptom 
Survey
!
Change from baseline in Schirmer test
!
Change from baseline in TBUT
!
Change from baseline in OSDI
!
Change from baseline in Functional Vision Questionnaire, 5-Minute Blurry 
Vision, and Ocular Discomfort Questionnaire
!
Study Eye Drop Experience and Tolerability Questionnaire
Additional endpoints, such as responder proportions, can be added based on the study 
team requests.
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Safety Endpoints
The safety variables include the study drug exposure, AEs, and results from the following 
assessments (Appendix B):
!
Slit-lamp biomicroscopy
!
Currently corrected distance visual acuity
!
BCDVA
!
IOP (participants with glaucoma or OHT only)
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4.0
Analysis Populations
The analysis populations will consist of participants as defined below:
Table 4-1
Analysis Populations
Population
Definition
Treatment Used for 
Analysis
Intent-to-treat (ITT) 
Participants who are randomized
As randomized 
Per-protocol (PP)
Randomized participants who have no 
protocol deviations affecting the primary 
efficacy analysis
As randomized
Safety
Treated participants who receive/take 
≥1 administration of randomized study 
treatment
Actual received
Efficacy analyses will be done using the ITT population. Safety data analyses will be done 
using the safety population. The primary efficacy endpoint will also be done using for PP
population. 
Demographics and baseline characteristics will be done using the ITT population. Study 
drug duration, medical and surgical history, ophthalmic medical and surgical history, prior 
and concomitant medication will be done using the safety population.
The study eye is defined as the worst eye based on total ocular staining score at Day 1 
(Baseline). If both eyes have the same total ocular staining score, the right eye will be 
designated as the study eye. The other eye will be the fellow eye.
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5.0
Participant Disposition
Participant disposition encompasses the distribution of participants who enter the run-in
period, get randomized, complete, and discontinue the 90-day randomized treatment 
period.
The summary of study disposition will be provided for the following:
!
Number of participants in the run-in period
!
Number of participants who fail to be randomized
!
Number of participants randomized (this frequency count will be used as the 
denominator to calculate the percentages described below)
!
Number and percentage of participants treated
!
Number and percentage of participants who completed the study 
!
Number and percentage of participants who discontinued the study
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6.0
Study Drug Duration 
The study will consist of a 90-day treatment period. The treatment duration in days will be 
summarized using descriptive statistics by treatment group for the safety population. 
The treatment duration will be calculated as last treatment date - first treatment date + 1. 
The number and percentage of participants with each treatment duration (days) of ≥1,
≥7, ≥30, ≥60, and ≥90 will be summarized.
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7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics and Baseline Characteristics
Demographic parameters (age, sex, race, ethnicity) will be summarized descriptively by
treatment group for the ITT population.
Medical and Surgical History
Medical and surgical histories will be collected at visits of screening and Day 1. They will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
Version 23.0 or higher.
The number and percentage of participants with medical and surgical history in each 
primary system organ class and preferred term will be summarized by treatment group for 
the safety population.
Ophthalmic Medical and Surgical History
Ophthalmic medical and surgical histories will be collected at visits of screening and 
Day 1. They will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), Version 23.0 or higher.
The number and percentage of participants with ophthalmic medical and surgical history 
in each system organ class and preferred term will be summarized by treatment group for 
the safety population.
Prior and Concomitant Medications
The medication data will be coded using the World Health Organization (WHO) Drug 
Dictionary Enhanced Version. 
Prior medication is defined as any medication taken prior to the start of first randomized 
study treatment regardless of stop date of the medication. Concomitant medication is 
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defined as any medication taken on and after the start of first randomized study treatment
regardless of the start date of the medication. 
Prior and concomitant medications will be coded using the Anatomical Therapeutic 
Chemical code (4th level, or most specific level available if 4th level is unavailable). 
The number and percentage of participants reporting prior or concomitant medications 
will be summarized further by ATC class and code, and preferred drug name. If more than 
one medication is coded to the same preferred drug name for the same participant, the 
participant will be counted only once for that preferred drug name. Prior and concomitant 
medications will be summarized by treatment group for the safety population, separately.
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8.0
Efficacy Analyses
General Considerations
The following are general considerations for efficacy analyses:
!
The efficacy analyses will be based on the ITT populations.
!
Baseline is defined as the last non-missing assessment prior to the first dose of the 
single-masked study treatment.
!
The change from baseline value will be computed as the postbaseline value minus 
the baseline value.
!
Continuous variables will be summarized by number of participants with observed 
values (n), mean, standard deviation (SD), median, 1st and 3rd quartiles (Q1, Q3), 
minimum (min), and maximum (max).
!
Categorical variables will be summarized by number of participants with observed 
values or events and percentages based on the specified population.
!
All statistical analyses will be performed using SAS version 9.4 or higher.
Handling of Missing Data
Efficacy analyses will be based on observed data only.  
Primary Efficacy Endpoint and Analyses
Primary Efficacy Endpoint
The primary efficacy variable is defined as the change from baseline in total staining 
score at Day 90.
Primary Efficacy Analysis
The primary efficacy analysis will be performed upon the ITT population using mixed 
effects repeated measures (MMRM) method. The difference and the 95% confidence 
interval will be constructed with the least squares means from the MMRM model with 
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treatment, visit, visit-by-treatment interaction, baseline total staining stratum, and baseline 
total staining stratum-by-visit interaction as the fixed effects. An unstructured covariance 
matrix will be selected for the repeated measure covariance. 
In order to control the overall type I error rate in the primary efficacy analysis, the 
sequential procedures will be performed. Under this procedure, the noninferiority test will 
be performed first and the superiority test will be performed next only if the null 
hypothesis of noninferiority is rejected. To test the hypothesis of noninferiority, a 2-sided 
95% confidence interval (CI) will be constructed for the difference in the mean change 
from baseline in total staining at Day 90. If the upper limit of 2-sided CI for the treatment 
difference (011516X minus Systane Ultra MD) is less than 2.3 units, then the 011516X 
tear formulation will be considered noninferior to Systane Ultra MD. If the upper limit of 
the aforementioned 2-sided CI is less than 0 units, then the 011516X tear formulation will 
be considered superior to Systane Ultra MD. Details of this procedure will be found in 
Section 12.0.
Sensitivity Analyses 
Sensitivity analyses will be based on the PP population applying the primary efficacy 
analytical approaches.  
Secondary Efficacy Analyses
The secondary efficacy variable will be analyzed with the same model described for the 
primary efficacy analysis in Section 8.3.2. The difference and the 95% CI will be 
constructed.
Exploratory Efficacy Analyses
Total staining score other than Day 90, Current Symptom Survey total score (composite 
of all symptoms) other than Day 90, individual symptom scores from Current Symptom 
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Survey, corneal staining score, and conjunctival staining score will be analyzed with the 
same method described for the secondary efficacy analysis in Section 8.3.2.  
All other efficacy analyses will be performed to provide descriptive statistics. Summaries 
of the 011516X and Systane Ultra MD at each scheduled visit will be performed on 
Schirmer test, TBUT, Functional Vision Questionnaire, and Study Eye Drop Experience 
and Tolerability Questionnaire.
5-Minute Blurry Vision and Ocular Discomfort Questionnaire
The 5-Minute Blurry Vision and Ocular Discomfort Questionnaire will provide an 
assessment of blurry vision and ocular discomfort, each on a 0-100 scale. The assessment 
will be conducted at Day 1 and Day 90/Early Exit. At each visit, measurements will be 
collected before instillation of one drop to each eye (Baseline), and at post dose time 
points of 30 seconds, 1 minute, 90 seconds, 2 minutes, 3 minutes, 4 minutes, and 5 
minutes. Change from baseline is calculated for each time point minus the pre-dose score 
of the same day.  Change from baseline is only calculated for measurements within the 
same day.
Efficacy Subgroup Analyses
The primary efficacy variable will be analyzed by the stratification factor, Day 1 
(Baseline) total ocular staining score in the study eye: 
!
mild/moderate = total ocular staining score of 6 to 25, and
!
severe = total ocular staining score of 26 to 43.
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9.0
Safety Analyses
General Considerations
The following are the general considerations for safety analyses:
!
Safety analyses will be performed based on the safety population by treatment
group.  
!
Baseline for safety endpoints is defined as the last non-missing assessment prior to 
the first dose of the single-blind treatment. 
!
Continuous variables will be summarized by number of participants with observed 
values (n), mean, standard deviation (SD), median, 1st and 3rd quartiles (Q1, Q3), 
minimum (min), and maximum (max).
!
Categorical variables will be summarized by number of participants with observed 
values or events and percentages based on the specified population.
!
AEs will be coded using MedDRA version 23.0 or higher. 
Adverse Events
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered related to 
the study treatment.
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study treatment.
Treatment-emergent Adverse Events
An AE will be considered a TEAE if the AE began or worsened (increased in severity or 
became serious) on or after the date (and time, if known) of the first dose of randomized 
study treatment. However, an AE that occurs more than 30 days after the last dose of 
randomized study treatment for participants will not be counted as a TEAE.
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An AE will be considered a treatment-emergent serious AE (TESAE) if it is a TEAE that 
additionally meets any SAE criterion.
Adverse Event Overview
Overall summary of TEAEs will be provided on a per-participant level for TEAEs, 
treatment-related TEAEs, TESAEs, deaths, and TEAEs leading to study treatment
discontinuation.
Treatment-emergent Adverse Events by SOC and/or PT
The number and percentage of participants with TEAEs will be tabulated by primary 
system organ class (SOC) and preferred term (PT).
The number and percentage of participants with TEAEs will be tabulated by primary 
SOC, preferred term, and severity. If more than one event is coded to the same preferred 
term for the same participant, the participant will be counted only once for that preferred 
term using the greatest severity for the summarization by severity. If the severity of a 
TEAE is missing, the maximum severity will be assigned to the event for the 
summarization by severity. The value will be displayed as missing in the data listing.
The number and percentage of participants with treatment-related TEAEs will be 
tabulated by primary SOC and preferred term; and by primary SOC, preferred term, and 
relationship. If the relationship to the treatment is missing for a TEAE, the event will be 
considered related to the treatment for the summarization. The value will be displayed as 
missing in the data listing.
Ocular treatment-emergent AEs will also be summarized. An ocular TEAE will be 
defined by the location information on the adverse event page in the eCRF. Ocular 
treatment-emergent AEs will be summarized overall by treatment group and preferred 
term.
The incidence of common (≥ 2% [after rounding] of participants in any treatment group) 
TEAEs will be summarized by preferred term and treatment group.
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Summary tables will be provided for TEAEs leading to treatment discontinuation and 
TESAEs if they occurred in 5 or more participants.
SAEs, Deaths and Adverse Events Leading to Study Drug 
Discontinuation
SAEs, deaths and AEs leading to study drug discontinuation will be tabulated by primary
SOC.
Adverse Events of Special Interest
There are no protocol-specified adverse events of special interest for this study.
Analysis of Laboratory Data
Urine Pregnancy Test
Women of childbearing potential will have urine pregnancy tests performed at the 
Screening (Day -7) and Day 90/Early Exit visits. At each visit, the investigator should 
discuss contraceptive use compliance with WOCBP. Positive test results for females of 
childbearing potential will be listed. 
Clinical Laboratory Parameters
Clinical laboratory parameters are not evaluated in this study.
Analysis of Vital Signs
Vital sign parameters are not evaluated in this study.
Other Safety Analyses
Biomicroscopy 
Biomicroscopy will be performed in each eye at each visit, by slit lamp examination,
without pupil dilation, including but not limited to lids/lashes, conjunctiva, cornea and
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anterior chamber. Observations for the examination will be graded on a 5-point scale
(0=none, 0.5=trace, 1=mild, 2=moderate, 3=severe) except for the anterior chamber (in
cells: 0=0 cells, +0.5=1-5 cells, +1=6-15 cells, +2=16-25 cells, +3=26-50 cells, and
+4=>50 cells; in flare: 0=None, +1=faint, +2=moderate, +3= marked and +4=intense).
The number and percent of patients with clinically significant biomicroscopy findings at
one or more visits will be tabulated. A clinically significant finding is defined as more
than one severity grade increase (worsening) from baseline. If a pathology is recorded at a 
follow-up visit but not at baseline, the baseline will be imputed with the same pathology, 
with a grade of zero (none).
Currently Corrected Distance Visual Acuity
Currently corrected distance visual acuity will be measured for each eye using the
provided distance logarithmic visual acuity chart for testing at 3 meters at visits. The total 
number of letters read correctly at each visit will be summarized with descriptive statistics 
by treatment group. 
Frequency tables based on the change from baseline in total number of letters read 
correctly will be provided at each visit for the following categories:
• 3 lines or better than baseline (“Much Better”)
• 2 lines better than baseline (“Better”)
• Between 1 line worse and 1 line better than baseline (“No change”)
• 2 lines worse than baseline e (“Worse”)
• 3 lines or worse than baseline (“Much Worse”)
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Best Corrected Distance Visual Acuity
BCVA is measured via subjective refraction for each eye using the provided distance
logarithmic visual acuity chart for testing at 3 meters at Screening (Day -7) and Day 
90/Early Exit visits. BCVA will be summarized same way described for currently 
corrected distance visual acuity in Section 9.5.2. 
Intraocular Pressure
IOP is measured for each eye using the Goldmann applanation tonometer at each visit.
Baseline IOP and change from baseline IOP will be summarized with descriptive statistics 
by treatment group for participants with glaucoma or ocular hypertension (OHT).
10.0
Other Analyses
Pharmacokinetics/Pharmacodynamics
Pharmacokinetics/pharmacodynamics parameters are not evaluated in this study.
Genetics
Genetics are not evaluated in this study.
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11.0
Interim Analyses
No interim analysis is planned for this study.
Data Monitoring Committee  
Data monitoring committee is not required for this study.
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12.0
Overall Type-I Error Control
To control the family-wise type I error rate at 0.05 for multiplicity across the hypothesis 
tests, a hierarchical gatekeeping procedure will be followed.
Step 1: Test the noninferiority hypothesis. If the upper limit of the 2-sided 95% CI is 
less than 2.3 units, reject H0 and go to Step 2. Otherwise stop.
Step 2: Test the superiority hypothesis. 
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13.0
SAP Version History
This SAP is based on the Protocol 2007-301-005 Amendment 2 dated 08 Jun 2020.
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
07 JAN 2021
Not 
Applicable
Original version
Amendment 1
02 Aug 2021
Amendment 1
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14.0
References
Lemp MA. National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes, 
CLAO J 1995;21:221-232.
Pflugfelder S. Baylor Fluorescein Corneal Staining Scheme (Unpublished Personal 
Communication, 2008).
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Appendix A.
Protocol Deviations
Protocol deviations will be defined in Protocol Deviation Requirement Specification, 
including importance classification. The number and percentage of participants with 
significant protocol deviations that occurred in the randomized treatment period will be 
summarized by treatment group for ITT population. 
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Appendix B.
Safety Assessments
1. Slit-Lamp Biomicroscopy
Slit-lamp biomicroscopy (without pupil dilation) will be performed on both eyes at all 
visits during the study. 
The following will be examined at each visit:
!
Eyelid/eyelid margins/lashes
!
Conjunctiva 
!
Cornea
!
Anterior chamber
Findings other than those listed above will be recorded under “other” for the appropriate 
location of the finding.
EYELID / EYELID MARGINS / LASHES
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
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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
CONJUNCTIVA (BULBAR AND 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
+ 1
(Mild)
Localized, mild swelling
+ 2
(Moderate)
Diffuse, moderate swelling 
+ 3
(Severe)
Diffuse, severe swelling
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
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+ 3
(Severe)
Epithelial bullae and/or stromal edema, localized or diffuse, with or 
without stromal striae
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
2. Currently Corrected Distance Visual Acuity
At all visits, corrected visual acuity will be measured using a logarithmic visual acuity 
chart with Sloan letters for testing at 3 meters (9 feet, 10 inches). 
Begin by first testing the right eye. Occlude the left eye. The participant should be asked 
to start on the top line of the bottom right chart (20/50 equivalent). Participants should be 
told to read the letters from left to right on each line and that the chart has letters only, no 
numbers. If the participant reads a number, he/she should be reminded that the chart 
contains no numbers, and the examiner should then request a letter in lieu of the number. 
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The participant should be asked to read slowly to achieve best identification of each letter 
and not to proceed to the next letter until he/she has given a definite answer.
If the participant 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 participant changes a 
response after having read the next letter, then the change will not be accepted. The 
examiner must not point to specific letters during the test.
When the letters become difficult to read, or if the participant identifies a letter as one of 
2 letters, he/she should be asked to choose one letter and, if necessary, to guess. 
Participants should be encouraged to continue trying even when letters become difficult to 
read. Stop testing when 3 or more errors are made on the same line. Use the supplied 
source document worksheet to mark the letters missed for each line and to enter the 
number of letters correctly read for each line.
If a participant cannot read the 20/50 equivalent line when instructed, verify that the 
proper current correction is in place. If the participant is still unable to read the 20/50 
equivalent line, have him/her read from the top of the full center chart, letter by letter, and 
record the number of letters missed and the number of letters correctly read for each line 
in the source document. 
Test the left eye following the same procedures outlined above, except have the 
participant start on the top line of the bottom left chart (20/50 equivalent). This strategy 
minimizes letter memorization.
3. BCDVA
Best-corrected visual acuity will be measured at Day -7 (Screening) and Day 90/Early 
Exit visits using the same logarithmic visual acuity chart with Sloan letters for testing at 
3 meters (9 feet, 10 inches) that will be used for the currently corrected distance visual 
acuity. The LogMar chart will be viewed using a trial frame holding the best-corrected
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distance endpoint manifest refraction. (Measuring acuity using the phoropter is acceptable 
so long as the chart distance is 3 meters.)
Sphere, cylinder, and axis will be determined, and a consistent endpoint should be used, 
which is generally the least minus sphere that provides the participant’s best measured 
acuity. Visual acuity should be determined using the same procedure used for currently 
corrected distance visual acuity. The phoropter may be either a plus or minus cylinder 
design. Values generated should be recorded directly from the phoropter without 
conversion.
4. IOP (participants with glaucoma or OHT only)
After the Schirmer test with anesthetic is administered, IOP will be measured for each eye 
at Screening (Day -7) and Baseline (Day 1) and at all scheduled visits for participants with 
glaucoma or OHT only. 
Measurements should be taken using a Goldmann applanation tonometer affixed to a 
slit-lamp with the participant seated. Additional sodium fluorescein can be applied if 
needed. Both eyes will be tested, with the right eye preceding the left eye. The measurer 
looks through the binocular viewer of the slit lamp at low power. The tension knob is 
preset at  low pressure value (4 to 6 mm Hg). The measurer follows the image of the 
fluorescein-stained semicircles while he/she 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.
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Appendix C.
List of Abbreviations
Abbreviation
Definition
AE
adverse event
BCDVA
best-corrected distance visual acuity
CI
confidence interval
DED
dry eye disease
eCRF
electronic case report form
EDS-VAS
Eye Dryness Score - Visual Analog Scale
FWER
family-wise error rate
IES
intercurrent event(s) strategy
IOP
intraocular pressure
ITT
intent-to-treat
IxRS
interactive response system
MD
multidose
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed-effects model repeated measures
NATF
novel artificial tear formulation
NCI
National Cancer Institute
NEI
National Eye Institute
OD
right eye
OHT
ocular hypertension
OS
left eye
OSDI
Ocular Surface Disease Index® Questionnaire
OTC
over-the-counter
PP
per-protocol
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SoA
schedule of activities
SOC
system organ class
TBUT
tear break-up time
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
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Abbreviation
Definition
VAS
visual analog scale
vs
versus
WHO
World Health Organization
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Appendix D.
Changes to Protocol-planned Analyses
There are no changes from the protocol-planned analyses.
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Electronic Signatures
User
Date
Justification
02-Aug-2021
20:44:38
(GMT)
Document Originator Approval
04-Aug-2021
19:44:44
(GMT)
NC - Study Director Approval
02-Aug-2021
22:16:07
(GMT)
Subject Matter Expert Approval
03-Aug-2021
21:36:05
(GMT)
Manager Approval
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TITLE PAGE
           
Protocol 2007-301-005
A Multicenter, Single-masked, Randomized Study to Compare the Efficacy and Safety of a 
New Artificial Tear Formulation (011516X) with Systane® Ultra Multidose for 90 Days in 
Participants with Dry Eye Disease
PER-PROTOCOLANALYSES
DATA EXCLUSION ALGORITHM
Draft: 06-Aug-2021
ConfidentialityStatement
Confidentiality Statement
This document is the property of AbbVie, 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 AbbVie, Inc.
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2007-301-005 Per-Protocol Analyses Data Exclusion Algorithm
HISTORY OF CHANGE
Amendment: Not applicable
Date
Description of Change(s)
06-Aug-2021
Initial version (Approved)
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1
Introduction
This document is written to detail the algorithms used to define data exclusions from the per-protocol 
analysis in the 2007-301-005 Amendment 2 and statistical analysis plan (SAP) Amendment 1.0.
The per-protocol (PP) population is defined in SAP section 4.0. The PP analysis will be implemented 
on the primary efficacy endpoint only. The PP population will consist of participants who contribute 
data to the PP analysis after implementing the data exclusion algorithms specified in this document.
PP population will come from ITT population who are treated. Data from the participants with a 
protocol deviation that is deemed to affect primary efficacy assessment from a study visit will be 
excluded from the PP analysis for that study visit.  
2
Algorithms to Define Data Exclusion for PP Analysis
2.1. General Rules
Each participant was randomized to receive either 011516X or Systane Ultra Multidose (MD)
treatment. Algorithms for data exclusion from PP analysis are defined for primary efficacy analysis of 
change from baseline in total ocular staining score data of the study eye at Day 90.  The algorithm will be
applied to all total ocular staining score data of the study eye that are involved in the primary efficacy 
analysis including that the data from baseline (Day 1), Days 7, 30, 60 and 90/Early Exit.
2.2. Ocular Staining Measurement
Ocular staining measurements are conducted at all study visits for cornea and conjunctiva, and the 
change from baseline on total staining score at Day 90 is defined as primary efficacy endpoint.  Same 
analysis windows for ITT analysis specified in Statistical Programming Plan will be used in PP 
analysis.
However, total ocular staining score at Day 90 will use the study visit window of Day 75 to 105 and 
all ocular staining data collected outside the analysis visit window will either be mapped to earlier visits 
or be excluded from PP analysis.
2.3. Prohibited Concomitant Medications
Data from the study visits in which ocular staining is potentially affected by prohibited concomitant 
medications will be considered exclusive for PP analysis. The general rules for total staining data 
exclusion from PP analysis are provided in protocol deviation requirement specification (PDRS) under 
code CM-01. The data to be excluded from PP analysis will be stated in the comment field of 
protocol deviation management tool (PDMT).
2.4. Ocular Concurrent Procedures
Data from the study visits in which ocular staining is potentially affected by ocular concurrent procedures 
will be considered exclusive for PP analysis. PDRS will provide the category of the PP exclusion under 
code CP-100. The data to be excluded from PP analysis will be stated in the comment field of 
PDMT.
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2.5.  Inclusion Criteria of Baseline Total Ocular Staining Score
Protocol inclusion criteria requires patients to have baseline total staining score of between 6 and 43 with 
corneal staining score of 5 to 19 and conjunctival staining score of 1 to 24. If a patient’s baseline staining 
score of cornea and conjunctiva in study eye is outside of inclusion criteria, the study eye baseline and all
follow up visit total staining score data will be excluded from PP analysis.
2.6. Other Protocol Deviations Impacting Total Staining Measurement
Total staining data will be excluded according to Table 2.6-1 for the following protocol deviations.
Table 2.6-1
Protocol Deviation Impacting Total Staining Score
Protocol Deviation 
Code/Category
Description
Excluding Period
SI-02: Dosed with wrong study 
intervention (ICH)
Participant was not dosed with the 
assigned study intervention label ID
All data during period not dosed with the 
assigned study intervention label ID will be 
excluded from the PP analysis.
SI-400: Study Intervention -
Reported incorrect dosing for more 
than 10 days
Participant reported incorrect dosage of 
study intervention for more than 10 
days
All data during incorrect dosing period will be 
excluded from the PP analysis.
SP-200: Primary efficacy study 
procedure – not performed per 
protocol
Corneal and/or Conjunctival Staining 
was not performed per protocol at 
Baseline, Days 7, 30, 60 and/or 90 that 
may impact subject safety or primary 
efficacy analysis
All total staining score at the procedure date will 
be excluded from the PP analysis
EC-01: Prior /concurrent clinical 
study experience
Are currently enrollment in an 
investigational drug or device study or 
participation in such a study within 30 
days of entry into this study at the 
Screening (Day -7) visit
All data will be excluded from the PP analysis.
3
Data Exclusion Reasons and Codes
The reasons and codes for total staining data being excluded from PP analysis is summarized below
(Table 3-1).
Table 3-1
Total Staining Data Exclusion Reasons and Codes
Exclusion Reason
Exclusion Code
Affected Analysis Visit and Description
Ocular staining measurement
A100
All affected visits 
Prohibited Concomitant 
Medications
B100
All affected visits
Ocular concurrent procedures
C100
All affected visits 
Baseline total staining
D100
Baseline
Protocol Deviation on dosed with 
wrong study intervention (SI-02)
E100
All affected visits
Protocol Deviation on study 
intervention – reported incorrect 
dosing more than 10 days (SI-400)
E101
All affected visits
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Protocol Deviation on primary study 
efficacy procedure – not performed per 
protocol (SP-200)
E102
All affected visits
Protocol Deviation on prior /concurrent 
clinical study experience (EC-01)
E-103
All visits
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