A Single-Arm Study to Evaluate and Demonstrate Safety and Performance of a Novel Ocular Lubricant in Adult Subjects With Dry Eye Disease
Phase: NA
Conditions: Dry Eye Disease
Sponsor: Alcon Research

 
 
 
 
 A Single-Arm Study to Evaluate and Demonstrate 
Safety and Performance of a Novel Ocular Lubricant in 
Adult Subjects with Dry Eye Disease 
 
STUDY ID 
DEP918-C001 
 
 
PROTOCOL v.3 
27 August 2024 
 
 
NCT06444516 

Document ID:
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Approved Date: 27 Aug 2024
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Clinical Study Protocol
Study Title:
A Single-Arm Study to Evaluate and Demonstrate Safety and 
Performance of a Novel Ocular Lubricant in Adult Subjects 
with Dry Eye Disease
Study Short Name:
Study of Safety and Performance of a Novel Ocular Lubricant 
in Subjects with Dry Eye Disease
Study Number:
DEP918-C001
Study Phase:
3
Product Name:
FID123300
Indication:
For the temporary relief of burning and irritation in persons 
experiencing dry eye symptoms.
Investigators:
Multicenter, located in the United States
Sponsor:
Alcon Research, LLC, and its affiliates (“Alcon”)
6201 South Freeway
Fort Worth, Texas 76134-2099, US
Property of Alcon
Confidential
May not be used, divulged, published, or otherwise disclosed without the consent of Alcon

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Investigator Agreement:
x
I have read the clinical study described herein, recognize its confidentiality, and 
agree to conduct the described study in compliance with Good Clinical Practice 
(GCP), the ethical medical research principles contained within the Declaration of 
Helsinki, this protocol, all applicable laws, regulatory authority regulations, and 
conditions of approval imposed by the reviewing IRB/IEC or regulatory or 
governmental authority.
x
I will supervise all testing of the Investigational Product(s) involving human 
research subjects and ensure that the requirements relating to obtaining informed 
consent and IRB/IEC review and approval are met in accordance with applicable 
local and governmental laws and regulations.
x
I have read and understand the appropriate use of the Investigational Product(s) as 
described in the protocol, current IB, product information, or other sources provided 
by the sponsor.
x
I understand the potential risks and side effects of the Investigational Product(s).
x
I agree to maintain adequate and accurate records in accordance with applicable 
government laws and regulations and to make those records available for inspection.
x
I agree to comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements of the sponsor and government 
agencies.
x
I agree to ensure that all associates, colleagues, and employees assisting in the conduct 
of the study are informed of their obligations in meeting the above commitments.
Have you ever been disqualified as an investigator by any Regulatory Authority?
 No        Yes
Have you ever been involved in a study or other research that was terminated?
 No        Yes
If yes, please explain here:
Principal investigator:
_____________________________________________
Signature
Date
Name and professional 
position:
Address:

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AMENDMENT DETAILS
History of Amendments
This is the third version of the protocol. Amendment 2. 
Document
Sponsor Approval Date (DD/Mmm/YYYY)
Amendment 1
13/Aug/2024
Original protocol
10/May/2024

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Table of Contents
AMENDMENT DETAILS ........................................................................................................3 
History of Amendments............................................................................................3 
 
 
Table of Contents .......................................................................................................................4 
List of Tables..............................................................................................................................8 
List of Figures............................................................................................................................8 
1 
GLOSSARY OF TERMS ....................................................................................................9 
2 
PROTOCOL SUMMARY.................................................................................................13 
2.1 
Protocol Synopsis...........................................................................................13 
2.1.1 
Primary and Safety Objectives and Endpoints ..................................13 
2.1.2 
Overall Design...................................................................................14 
2.1.3 
Arms and Duration ............................................................................14 
2.1.4 
Masking .............................................................................................15 
2.1.5 
Committees........................................................................................15 
2.2 
Study Schema.................................................................................................15 
2.3 
Schedule of Study Procedures and Assessments............................................16 
3 
INTRODUCTION.............................................................................................................19 
3.1 
Purpose of Study ............................................................................................19 
3.2 
Summary of Benefits and Risks.....................................................................19 
3.2.1 
Benefit Summary...............................................................................19 
3.2.2 
Risk Summary and Mitigation Strategy ............................................19 
3.2.3 
Overall Benefit: Risk Conclusion......................................................20 
4 
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS...........................................20 
4.1 
Primary Objective(s) ......................................................................................20 
4.2 
Primary Estimand...........................................................................................21 
4.3 
Secondary Objective(s) ..................................................................................22 
4.4 
Secondary Estimand.......................................................................................22 
 
 
 
 
5 
STUDY DESIGN ..............................................................................................................22 

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5.1 
Description of Study Design ..........................................................................22 
5.1.1 
Description of Study Duration...........................................................22 
 
 
5.2 
Rationale for Study Design ............................................................................23 
6 
STUDY POPULATION ....................................................................................................23 
6.1 
Selection of Study Population ........................................................................23 
6.2 
Inclusion Criteria............................................................................................24 
6.3 
Exclusion Criteria...........................................................................................25 
6.4 
Lifestyle Considerations.................................................................................27 
6.4.1 
Other Activity ....................................................................................27 
6.5 
Screen Failures and Rescreening of Subjects.................................................27 
6.6 
Study Eye Selection Criteria ..........................................................................27 
7 
INVESTIGATIONAL PRODUCT AND CONCOMITANT THERAPY .........................27 
7.1 
Description of Investigational Product...........................................................27 
7.2 
Rationale for Investigational Product.............................................................28 
7.3 
Dosing and Administration.............................................................................28 
7.4 
Treatment of Overdose...................................................................................29 
7.5 
Preparation, Handling, Storage, and Accountability ......................................29 
7.5.1 
Preparation of Investigational Product ..............................................29 
7.5.2 
Handling and Storage of Investigational Product..............................29 
7.5.3 
Accountability of Investigational Product.........................................30 
7.5.3.1 
Receipt of Investigational Product.....................................31 
7.5.3.2 
Return of Investigational Product......................................31 
7.6 
Subject Assignment, Randomization, and Masking.......................................31 
7.6.1 
Subject Assignment ...........................................................................31 
7.6.2 
Masking and Unmasking...................................................................31 
7.7 
Investigational Product Compliance ..............................................................31 
7.8 
Concomitant Therapy .....................................................................................32 
7.8.1 
Prohibited Concomitant Therapy.......................................................32 
8 
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND SUBJECT 
WITHDRAWAL FROM STUDY......................................................................................32 
8.1 
Discontinuation of Investigational Product....................................................32 
8.1.1 
Criteria for Permanent Discontinuation of Investigational Product..33 

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8.1.2 
Temporary Discontinuation or Interruption of Investigational 
Product...............................................................................................33 
8.1.3 
Rechallenge .......................................................................................33 
8.2 
Subject Withdrawal from the Study ...............................................................34 
8.3 
Lost to Follow-up...........................................................................................34 
8.4 
Follow-up of Subjects After Study Participation has Ended..........................35 
8.5 
Study Stopping Rules.....................................................................................35 
9 
STUDY ASSESSMENTS AND PROCEDURES .............................................................35 
9.1 
Screening/Baseline Assessments and Procedures ..........................................35 
9.1.1 
Connect to Electronic Patient Reported Outcomes ...........................36 
9.1.2 
Demographics....................................................................................36 
9.1.3 
Medical/Ophthalmic History.............................................................36 
9.1.4 
Prior and Concomitant Medication Assessments ..............................36 
9.1.5 
Urine Pregnancy Test.........................................................................37 
9.2 
Efficacy Assessments and Procedures............................................................37 
9.2.1 
IDEEL-SB Questionnaire..................................................................37 
 
 
9.3 
Safety Assessments and Procedures...............................................................37 
9.3.1 
Adverse Event Collection..................................................................37 
9.3.2 
Device Deficiency Collection............................................................37 
9.3.3 
Slit Lamp Biomicroscopy..................................................................38 
9.3.4 
Best Corrected Visual Acuity ............................................................38 
9.3.5 
Unscheduled Visits ............................................................................38 
9.4 
Adverse Events and Serious Adverse Events.................................................39 
9.4.1 
Definitions of AE and SAE ...............................................................39 
9.4.2 
Time Period and Frequency for Collecting AE and SAE 
Information........................................................................................41 
9.4.3 
Identifying AEs and SAEs.................................................................41 
9.4.4 
Recording of AEs and SAEs..............................................................41 
9.4.5 
Follow-up of AEs and SAEs..............................................................42 
9.4.6 
Reporting of SAEs.............................................................................43 
9.4.7 
Regulatory Reporting Requirements for SAEs .................................43 
9.4.8 
Serious and Unexpected Adverse Reaction Reporting......................43 
9.4.9 
Adverse Events of Special Interest....................................................44 
9.4.10 
Disease-related Events or Outcomes Not Qualifying as AEs or 
SAEs..................................................................................................44 
9.5 
Device Deficiencies........................................................................................44 

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9.6 
Pregnancy and Postpartum Information.........................................................45 
9.7 
Device Deficiencies for Drug/Device Combination Products .......................45 
9.8 
Pharmacokinetics............................................................................................45 
9.9 
Genetics..........................................................................................................45 
9.10 Biomarkers .....................................................................................................46 
9.11 Immunogenicity Assessments ........................................................................46 
9.12 Medical Resource Utilization and Health Economics....................................46 
10 STATISTICAL CONSIDERATIONS................................................................................46 
10.1 Analysis Set....................................................................................................46 
10.2 Analyses Supporting Primary Objective(s)....................................................47 
10.2.1 
Statistical Model, Hypothesis, and Method of Analysis....................47 
10.2.2 
Handling of Intercurrent Events of Primary Estimand(s)..................47 
10.2.3 
Handling of Missing Data Not Related to Intercurrent Events .........48 
 
 
 
 
10.3 Analysis Supporting Secondary Objective(s).................................................50 
 
 
10.5 Safety Analyses ..............................................................................................51 
 
 
 
 
 
 
11 PROTOCOL DEVIATIONS..............................................................................................53 
12 GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND STUDY 
OVERSIGHT.....................................................................................................................54 
12.1 Regulatory and Ethical Considerations ..........................................................54 
12.2 Committees.....................................................................................................55 
12.3 Informed Consent Process..............................................................................55 
12.4 Privacy and Data Protection...........................................................................56 
12.5 Early Site Closure or Study Termination........................................................56 
13 GENERAL CONSIDERATIONS: RISK MANAGEMENT AND QUALITY 
ASSURANCE ...................................................................................................................57 
13.1 Quality Tolerance Limits................................................................................57 
13.2 Data Quality Assurance..................................................................................57 

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13.3 Source Data ....................................................................................................57 
14 APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS – 
DEFINITIONS, SEVERITY, AND CAUSALITY ...........................................................59 
14.1 Severity...........................................................................................................59 
14.2 Causality.........................................................................................................59 
14.3 Expectedness ..................................................................................................60 
15 APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL DETAILS............60 
15.1 Contraception and Pregnancy Testings ..........................................................60 
15.2 Country/Region-Specific Differences ............................................................60 
15.3 Prior Protocol Amendments ...........................................................................60 
Summary of Changes in Current Amendment ....................................................61 
16 PUBLICATIONS...............................................................................................................62 
17 REFERENCES ..................................................................................................................62 
17.1.1 
Internal References............................................................................62 
17.1.2 
External References...........................................................................63 
List of Tables
Table 1-1 
List of Terms ......................................................................................................9 
Table 1-2 
List of Acronyms and Abbreviations ...............................................................11 
Table 2-1 
Primary and Safety Objectives and Endpoints.................................................13 
Table 2-2 
Schedule of Study Procedures and Assessments .............................................16 
Table 4-1 
Primary Objectives and Endpoints...................................................................20 
Table 7-1 
Dosing Regimen...............................................................................................28 
Table 7-2 
Prohibited Concomitant Therapies ..................................................................32 
List of Figures
Figure 2-1 
Study Design....................................................................................................15 

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1
GLOSSARY OF TERMS
Table 1-1
List of Terms
Term
Definition
Adverse Drug 
Reaction (ADR)
All noxious and unintended responses to an investigational product 
related to any dose should be considered adverse drug reactions. 
Responses to a medicinal product means that a causal relationship 
between a medicinal product and an adverse event is at least a 
reasonable possibility, i.e., the relationship cannot be ruled out.
Adverse Event (AE)
Any untoward medical occurrence in a subject 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 unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of an investigational 
product, whether or not related to the investigational product.
Device Deficiency
Inadequacy of a medical device with respect to its identity,
quality, durability, reliability, usability, safety, or performance.
Note: This definition includes malfunctions, use errors, and
inadequacy in the information supplied by the manufacturer
including labelling related to the investigational medical device.
Enrollment
A human subject’s, or their legally authorized representative’s, 
agreement to participate in a clinical trial following completion 
of the informed consent process, as required in 21 CFR part 50 
and/or 45 CFR part 46, as applicable. For the purposes of this 
part, potential subjects who are screened for the purpose of 
determining eligibility for a trial, but do not participate in the 
trial, are not considered enrolled, unless otherwise specified by 
the protocol. A subject is enrolled at the time point they begin 
receiving the study investigational product.
Interventional 
Clinical Trial
Clinical trial in which subjects are assigned to groups that receive 
one or more intervention/treatment (or no intervention) so that 
researchers can evaluate the effects of the interventions on 
biomedical or health-related outcomes. The assignments are 
determined by the study's protocol. Subjects may receive 
diagnostic, therapeutic, or other types of interventions.
Investigational 
Product 
A preventative (vaccine), a therapeutic (drug or biologic), device, 
diagnostic, or palliative used as a test or comparator product in a 
clinical study, including a product with a marketing authorization 
when used or assembled (formulated or packaged) in a way 
different from the authorized form, or when used for an 

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Term
Definition
unauthorized indication, or when used to gain further information 
about the authorized form.
Nonserious Adverse 
Event
Adverse event that does not meet the criteria for a serious adverse 
event.
Point of Enrollment
The time at which, following recruitment and before any clinical 
investigation-related procedures are undertaken, a  subject sign and 
dates the informed consent form.
Screen Failure
A subject who did not meet one or more criteria that were required 
for participation in the study.
Screening
A process of active evaluation of potential subjects for enrollment 
in a study. After a patient is recruited, screening occurs during the 
enrollment period, after informed consent has been obtained, to see 
if they meet the inclusion and exclusion criteria. If they meet the 
criteria, the subject is eligible to enroll in the study.
Serious Adverse 
Event (SAE)
Any untoward medical occurrence that at any dose:
results in death,
is life-threatening,
Note: Life-threatening means that the individual was at 
immediate risk of death from the event as it occurred, i.e., it does 
not include an event which hypothetically might have caused 
death had it occurred in a more severe form. 
requires inpatient hospitalization or prolongation of existing 
hospitalization, 
Note: Planned hospitalization for a preexisting condition, 
without serious deterioration in health, is not considered a 
serious adverse event. 
results in persistent or significant disability/incapacity,
is a congenital anomaly/birth defect, or
is a medically important event or reaction.
Note: Medical and scientific judgment should be exercised in 
deciding whether other situations should be considered as 
serious such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization 
but may jeopardize the patient or may require intervention to 
prevent one of the other outcomes listed in the definition above. 
These should also be considered serious.

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Term
Definition
Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse.
Serious Adverse 
Reaction (SAR)
Adverse drug reaction that has resulted in any of the consequences 
characteristic of a serious adverse event.
Study Completion
The completion of the study is considered to coincide with the 
study-level last subject last visit or the decision to terminate the 
study, whichever is later.
Study Start
The start of the study is considered to coincide with the enrollment 
of the first patient.
Subject
A study participant
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR)
Adverse drug reaction that is both unexpected and meets the 
definition of a serious adverse event.
Unexpected Adverse 
Drug Reaction 
(Unexpected ADR)
An adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g., 
investigator's brochure for an unapproved investigational product or 
Company Core Data Sheet and/or package insert/summary of 
product characteristics for an approved product).
Table 1-2
List of Acronyms and Abbreviations
Abbreviation
Definition
ADDE
Aqueous deficient dry eye 
ADR
Adverse drug reaction
AE
Adverse event
AR
Adverse reaction
BCVA
Best corrected visual acuity
°C
Degrees Celsius
CI
Confidence intervals
CL
Confidence limits
CONSORT
Consolidated standards of reporting trials
CRF
Case Report Form
CRO
Contract Research Organization
DED
Dry eye disease

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Abbreviation
Definition
DEP
Data evaluability plan
DES
Dry eye symptom
 
EC
Ethics Committee 
eCRF
Electronic case report form
ePRO
Electronic patient reported outcomes
EDC
Electronic data capture
EDE
Evaporative dry eye
EN
European Standard
EU
European Union
ETDRS
Early Treatment Diabetic Retinopathy Study
FID
Formulation identification 
GCP
Good Clinical Practice
Hr
Hour(s)
ICE
Intercurrent event
ICF
Informed consent form
IB
Investigator’s brochure
ICH
International Conference on Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
IDEEL-SB
Impact of Dry Eye on Everyday Life- Symptom Bother
IEC
Independent Ethics Committee
IFU
Instructions for use
IP
Investigational product
IRB
Institutional Review Board
LogMAR
Log of the minimum angle of resolution
MDE
Mixed dry eye
mL
milliliter
MOP
Manual of procedures
N/A
Not applicable
OD
Right eye
OS
Left eye
OTC
Over the counter

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Abbreviation
Definition
PP
Per Protocol
SAE
Serious adverse events
SAR
Serious adverse reaction
SD
Standard deviation 
SLE
Slit lamp examination 
SOC
Standard of care
SUSAR
Suspected unexpected serious adverse reaction
US
United States
2
PROTOCOL SUMMARY
2.1
Protocol Synopsis
Compound Number(s):
FID123300
Study Phase:
Phase 3
Brief Summary of 
Protocol:
A 30-day prospective, single-arm, multicenter, open label 
study to demonstrate efficacy and safety of a novel lubricant 
eye drop in adult patients with mild to moderate dry eye 
disease (DED). 
2.1.1
Primary and Safety Objectives and Endpoints
Table 2-1 lists the objectives and endpoints. For more information, see Section 4.
Table 2-1
Primary and Safety Objectives and Endpoints
Primary Objective
To demonstrate efficacy of a novel lubricant 
eye drop
Primary Endpoint
Change from baseline in Impact of Dry Eye 
on Everyday Life - Symptom Bother 
(IDEEL-SB) questionnaire score at Day 30
Safety Objective
To evaluate safety of a novel lubricant eye 
drop
x
Adverse events
x
BCVA
x
Biomicroscopy findings 
x
Device deficiencies

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2.1.2
Overall Design
Several key aspects of the study design are summarized below. 
Intervention Model:
Single group
Control:
None/uncontrolled 
Active Comparator:
N/A
Interventional Product 
Assignment Method:
All subjects will receive the same investigational product 
(IP)
Population Type:
Adult subjects 
Population Age:
Minimum: 18 – Maximum: N/A
Number of Subjects:
~185 enrolled
Number of Arms:
1
Site Distribution:
Planned number of clinical sites: ~ 20
Planned locations: United States
2.1.3
Arms and Duration
Total duration of study participation for each subject: approximately 37 days. 

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7 Assessment performed as necessary for unplanned dispense visit
8 Electronic patient reported outcomes unless otherwise specified by sponsor 
9Screening may be rescheduled within 7 days/1 week if connection cannot be established. All remaining criteria will be verified after completing connection. 

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3
INTRODUCTION
3.1
Purpose of Study
The novel formulation (FID123300) is aimed at providing long-lasting comfort to patients 
with dry eyes. The study is designed to evaluate and demonstrate the efficacy and safety of 
this investigational ocular lubricant formulation in patients with mild to moderate DED. 
Endpoints include safety assessments (AEs, BCVA, slit lamp biomicroscopy, and device 
deficiencies), subjective assessment  of symptoms of dry eye (IDEEL-SB 
 
 
 
.
Refer to Sections 2.2 and 2.3 for more information.
3.2
Summary of Benefits and Risks
3.2.1
Benefit Summary
The key benefit expected from the novel ophthalmic lubricant is the temporary relief of dry 
eye symptoms in patients with dry eye similar to other currently marketed dry eye drops such 
as SYSTANE COMPLETE Lubricant Eye Drops 
and SYSTANE 
HYDRATION Lubricant Eye Drops 
SYSTANE COMPLETE Lubricant Eye Drops 
) and SYSTANE HYDRATION 
Lubricant Eye Drops 
 are indicated for the temporary relief of burning and 
irritation due to dryness of the eye. SYSTANE HYDRATION Lubricant Eye Drops may be 
used to lubricate and rewet daily, extended wear and disposable silicone hydrogel and soft 
(hydrophilic) contact lenses.
Benefits of a lubricant eye drop include ocular surface protection, dry eye relief, improved 
visual performance, increased ocular surface retention and lubrication. It also allows re-
epithelialization of cells in the ocular surface.
3.2.2
Risk Summary and Mitigation Strategy
Risk management principles have been applied to both the planning and the intended conduct 
of the clinical investigation, in order to ensure the reliability of the clinical data generated and 
the safety of the subjects. The clinical investigation process risks are managed through 
appropriate training and monitoring according to the protocol-specific monitoring plan. IP 

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risks, including risks associated with use of IP and methods and procedures for application of 
the IP, are defined in the IB and/or product labeling and are managed through review of 
safety assessments outlined in this protocol.
The ingredients in the test formulation are biologically inert (i.e., they have no known on-
target or off-target biological mechanisms of action). Therefore, no dose-dependent side 
effects are anticipated. The risks of administering a viscous topical ocular drop include mild 
transient blurred vision and ocular discomfort. Due to subject variability, there is a risk of 
allergic reaction to one or more of the components of the test formulation. Patients with any 
known allergies to any of the components of the formulation are excluded from participation 
in clinical studies. These anticipated risks are similar to other currently available dry eye 
drops such as SYSTANE COMPLETE Lubricant Eye Drops 
 and SYSTANE 
HYDRATION Lubricant Eye Drops 
.
There may also be unknown risks to use of IP. Any risk to subjects in this clinical study will 
be minimized by compliance with the eligibility criteria and study procedures, clinical 
oversight, and monitoring.
3.2.3
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk for subjects involved in this study, 
the potential risks identified in association with FID123300 are justified by the anticipated 
benefits that may be afforded to subjects for the temporary relief of burning and irritation in 
persons experiencing dry eye symptoms.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) and device deficiencies of FID123300 may be found in the IB.
4
STUDY OBJECTIVES, ENDPOINTS, AND ESTIMANDS
4.1
Primary Objective(s)
Table 4-1
Primary Objectives and Endpoints
Objective(s)
Endpoint(s)
To demonstrate efficacy of a novel lubricant 
eye drop
Primary
x
Change from baseline in Impact of 
Dry Eye on Everyday Life – 
Symptom Bother (IDEEL-SB) 
questionnaire score at Day 30 

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4.2
Primary Estimand
The treatment effect is to be estimated for the population of adult patients with mild to 
moderate DED as defined by the protocol inclusion/exclusion criteria. The efficacy is to be 

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measured using the primary endpoint of the change from baseline in IDEEL-SB 
questionnaire score at Day 30. 
In this single-arm study, an intercurrent event (ICE) may occur with subjects exposing to a 
concomitant medication or discontinuation of IP (permanent or temporary; due to an AE, 
device deficiency, and/or noncompliance). 
The population-level summary is the mean change from baseline in IDEEL-SB questionnaire 
score at Day 30, where baseline is defined as the data collected at Visit 1 prior to IP exposure. 
Change from baseline will be calculated as Day 30 minus baseline.
4.3
Secondary Objective(s)
N/A
4.4
Secondary Estimand
N/A
5
STUDY DESIGN
5.1
Description of Study Design
This is a phase 3, multicenter, uncontrolled, open label, nonrandomized study conducted at 
approximately 20 sites in the US. Approximately 185 subjects will be enrolled. All eligible 
subjects will have mild to moderate DED (inclusion criteria number 4). 
5.1.1
Description of Study Duration
The study is expected to be completed in approximately 7 months. The expected study 
duration for each subject is 37 days with 30 ± 5 days of IP exposure. 
The study will consist of a Screening visit, Baseline visit on Day 1, Remote Compliance 
Check on Day 14, and an Exit visit on Day 30.  
Refer to Section 2.2 for more information and Figure 2-1 for an outline of the study.

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5.2
Rationale for Study Design
This study is designed to evaluate the efficacy and safety of FID123300 in adult patients with 
mild to moderate DED. The primary endpoint of change in IDEEL-SB score was selected to 
fulfill the primary objective of the study. Procedures for measurement of these endpoints 
were selected based on dry eye clinical assessments and tests conducted in clinical practice 
and dry eye research studies. The design of this study is justified based upon preclinical and 
clinical testing, as described within the IB.
The registration of the IP in the US as an over the counter (OTC) product monograph does 
not require the conduct of a clinical study to be performed prior to the product being 
marketed. However, at the time of the first launch of this product, there will be preclinical 
data and data from similar OTC products to understand how patients respond to the new 
formulation. 
 
 
 
 
 
6
STUDY POPULATION
6.1
Selection of Study Population
The study population consists of male and female subjects (age ≥ 18) at the time of informed 
consent. Subjects must have a clinical diagnosis of mild to moderate DED. The study is 
aimed to enroll approximately 185 subjects in approximately 20 sites in the US, with a target 
of 143 completed subjects. Estimated time needed to recruit subjects for the study is 
approximately 20 weeks; however, unanticipated circumstances may shorten or lengthen this 
time and would not require amendment of this protocol. Because a 20-30% screening failure 
rate is expected, approximately 185 subjects are expected to be enrolled. 
Subjects will be recruited by clinical sites that have DED patients. Additional recruitment 
methods may be employed as needed as determined/provided/approved by sponsor or at each 
site’s discretion. 

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Selected population according to the inclusion/exclusion criteria is representative of the target 
population for the product. 
6.2
Inclusion Criteria
Written informed consent must be obtained before any study specific assessment is 
performed. Upon signing the informed consent, the subject is considered enrolled in the 
study. 
Subjects eligible for inclusion in this study must fulfill all of the following criteria:
1. Subject must be at least 18 years of age at the time of informed consent.
2. Subject must be willing and able to understand and sign an IRB/IEC approved 
informed consent form.
3. Subject must be willing and able to attend all required study visits and complete 
subjective questionnaires.
4. Subject must exhibit symptoms of dry eye at the Screening visit (IDEEL- SB ≥ 16 and 
≤ 65).
5. Subject must have BCVA equal to or better than 20/80 (or ≥ 55 letters score or ≥ 0.6 
ETDRS logMAR) in each eye at the Screening visit.
6. Subject must have NITBUT of > 5 and < 10 seconds in each eye at the Screening visit.
7. Subject must meet at least one of the 3 conditions below at the Screening visit (based 
on the criteria below):
a.
ADDE as indicated by a TMH of < 0.2 mm
b. EDE as indicated by a meibum quality score of ≥ 1 (on a 0 to 3 scale) or 
meibum expressibility score of > 1 (on a 0 to 3 scale) in either eye lid (lipid 
deficient (or evaporative) dry eye subgroup) measured by the Meibomian 
Gland Functionality Test.
c.
MDE as indicated by meeting both entry criteria (a) and (b) above (mixed dry 
eye subgroup).
8. Subject must be willing to discontinue use of all artificial tear supplements and use 
only the study product as directed starting at Visit 2/Day 1.
9. Subject must be willing and able to connect to and use electronic patient reported 
outcomes with their mobile device to 
 record 
daily IP usage information. 

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6.3
Exclusion Criteria
Subjects meeting any of the following criteria will be excluded and may not participate in this 
study. Criteria are assessed at Screening/Visit 1.
1. History of hypersensitivity to the study drug or any of its excipients or to drugs of 
similar chemical classes.
2. Women who are pregnant or breastfeeding at the time of study entry or who plan to 
become pregnant during the study.
3. Ocular abnormalities that could adversely affect the safety or efficacy outcome such 
as:
a.
Eyelid anomalies that affect proper lid closure or proper blink function (e.g., 
ectropion or entropion).
b. Corneal disorders or abnormality such as active corneal ulcer, current corneal 
abrasion, keratoconus, or corneal dystrophies which are actively changing or 
affect vision.
c.
Metaplasia of the ocular surface.
d. History of corneal erosion syndrome or recurrent corneal erosion syndrome.
e.
Clinically significant corneal epithelial anterior membrane dystrophy (patients 
with minor/insignificant primary peripheral corneal epithelial dystrophy (not 
central dystrophy) without a history of corneal erosion syndrome can be 
included).
f.
Current filamentous keratitis.
g. Evidence of corneal neovascularization.
h. Any history of herpes simplex or herpes zoster keratitis.
4. Uncontrolled active systemic diseases. These conditions may include but are not 
limited to conditions that in the opinion of the investigator would preclude study 
participation, including unstable diabetes, thyroid diseases, autoimmune diseases, 
and/or poorly controlled hypertension.

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5. Active ocular infection (bacterial, viral, or fungal) or active inflammation not 
associated with dry eye such as uveitis, iritis, active blepharitis, active ocular allergies 
or active allergic conjunctivitis, etc.
6. Current or past participation in any clinical study within 30 days prior to the Screening 
visit.
7. Punctal plug insertion or diathermy procedure initiated within 30 days prior to the 
Screening visit.
8. Lid hygiene therapy initiated ≤ 4 weeks prior to the Screening visit. Note: Patients 
who have been on a consistent lid hygiene therapy (i.e., no change to the type of lid 
hygiene therapy being used or to the frequency of use) for more than 4 weeks prior to 
the Screening visit are not excluded. However, they cannot stop or change this regimen 
for the duration of the study. In addition, patients who do not currently use lid hygiene 
therapy cannot start the regimen while participating in the study.
9. Individuals who were treated with thermal pulsation treatments or other lid treatments 
in either eye in the last 12 months. Patients cannot be treated with thermal pulsation 
treatments or other lid treatments while participating in the study.
10. Any significant illnesses that could, in the opinion of the investigator, interfere with 
the study parameters.
11. Use of any systemic medication known to cause dry eye (e.g., antihistamines, 
antidepressants, antipsychotics, benzodiazepines, etc.) for less than 1 month before the 
Screening visit. If patient is on a stable regimen for at least a month prior to the 
Screening visit, the dosing regimen must not change for the duration of their 
participation in this study. In addition, patients who do not currently use any of these 
medications cannot start a regimen while participating in the study.
12. Contact lens use within one month prior to Screening visit and unwilling to avoid 
contact lens use during the course of the study.
13. History of ocular or intraocular surgery, eyelid surgery, keratorefractive procedure, 
corneal transplant, or serious ocular trauma, within 6 months prior to the Screening 
visit.
14. Initiation of any new topical ocular medication (over the counter or prescribed) 
≤60 days prior to the Screening visit. Note: Patients on Restasis®, Cequa® 
(cyclosporine ophthalmic emulsion), or lifitegrast ophthalmic solution 5% (Xiidra®), 
must be on therapy for at least 6 months prior to the Screening visit.

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6.4
Lifestyle Considerations
6.4.1
Other Activity
Subjects will be advised to maintain and be in a consistent environment and refrain from 
swimming on Day 1.
6.5
Screen Failures and Rescreening of Subjects
A screen failure occurs when a subject who consents to participate in the clinical study does 
not meet inclusion/exclusion criteria. A minimal set of screen failure information is required 
to ensure transparent reporting of screen failure subjects to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse events (SAEs).
Individuals who do not meet the criteria for participation in this study (screen failures) may 
not be rescreened.
Subjects will not be replaced. 
After signing the informed consent form (ICF), subjects will be asked to establish a 
connection to the electronic patient reported outcomes (ePRO) (inclusion criteria number 9) 
prior to any other assessments. In the event this connection cannot be established, subjects 
will be allowed to reschedule the Screening visit within 7 days/1 week. All remaining criteria 
will be verified after completing inclusion criteria number 9. In case the subject is not willing 
to reschedule or the Screening visit can’t be rescheduled within the specified window, the 
subject will be considered a screen failure. 
Enrollment number may be increased based on the tracking of number of completers. 
6.6
Study Eye Selection Criteria
Study subjects will be dosed in both eyes. 
7
INVESTIGATIONAL PRODUCT AND CONCOMITANT THERAPY
7.1
Description of Investigational Product
This study will investigate the IP in a single period. The expected duration of subject 
participation is approximately 37 days; IP exposure is approximately 30 ± 5 days. Visit 
1/Screening will occur 2 to 7 days prior to Visit 2/Day 1 Baseline. At Visit 2/Day 1 Baseline, 

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subjects will administer one drop of IP per eye. 
 
 
 Starting on Day 2, subjects will administer at least one drop of IP per eye 4 times 
daily through to Visit 4/Exit. The Visit 3/Remote Compliance Check will occur on Day 14 ± 
3 days 
 Visit 4/Exit will occur on Day 30 ± 5 days. 
On Visit 4/Exit, subjects will administer at least one drop of IP per eye 4 times with their last 
drop 30 minutes prior to the visit.
More information on the IP can be found in the IB. 
7.2
Rationale for Investigational Product
This study design is justified based upon an evaluation of the results of relevant preclinical 
and clinical testing, as described within the IB.
7.3
Dosing and Administration
This study is evaluating the effect of 1) one ophthalmic drop of IP in each eye on Day 1 and 
2) at least one ophthalmic drop of IP in each eye 4 times daily (additional usage as needed) 
after 30 ± 5 days on subjects with DED. 
There are no time requirements within each day (e.g., morning, afternoon, night) for daily 
dosing from Day 2 to Day 30 ± 5. On Visit 4/Exit, subjects should administer one drop of IP 
in each eye 4 times with the last ophthalmic drop administered approximately 30 minutes 
prior the visit. Subjects should follow drop administration requirements. Instructions for 
delayed or missed drop administration will be outlined within the MOP/instructions. 
Table 7-1
Dosing Regimen 
Intervention:
FID123300
Dosing Regimen:
At Visit 2/Day 1, subjects 
will receive one drop of IP 
per eye in the morning.
 
 
 
 
On Days 2 to 30 ± 5 
(including day of) subjects 
will self-administer at least 

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one drop per eye 4 times 
daily.
On Visit 4/Day 30 ± 5, 
subjects will self-administer 
at least one drop per eye 4 
times with the last drop per 
eye approximately 30 
minutes prior to Visit 4.
7.4
Treatment of Overdose
The components of this product are considered pharmacologically inert, non-toxic, and 
nonirritating. Therefore, no toxic effects are to be expected. For more information refer to IB.
7.5
Preparation, Handling, Storage, and Accountability
7.5.1
Preparation of Investigational Product
No special preparation is needed. Subjects will be dispensed two bottles at Day 1. If subjects 
require resupply, subjects should contact the site. 
For more information refer to the IFU.
7.5.2
Handling and Storage of Investigational Product
Compound Number:
FID123300
Manufacturer
Alcon Laboratories, Inc.
6201 South Freeway
Fort Worth, Texas 76134-2099
US
Indication for use and
intended purpose in the
current study
For the temporary relief of burning and irritation due to 
dryness of the eye
Product description and
parameters available for
this study
Propylene Glycol 0.6% Lubricant Eye Drops

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Formulation
Refer to IB for details.
Number/Amount of
product to be provided to
the subject 
Subject will receive two 11 mL bottles of IP with a 10 mL 
fill.
Subjects will return to office for spare IP.
Labeling description
Label shall include the information below, at minimum:
x
FID number
x
Lot number/batch number
x
Expiration date
x
Content statement
x
Investigational statement
x
Sponsor information
x
Temperature/storage conditions
Training and/or experience
requirements for device
No additional training or experience is required to administer
the IP.
Storage conditions
15 – 25°C (59 – 77°F)
Refer to MOP for details regarding temperature 
monitoring. 
Additional information
N/A
Supply
The IP will be provided by the study sponsor prior to the
start of the study.
Refer to the MOP for a detailed description.
7.5.3
Accountability of Investigational Product
The investigator must keep an accurate accounting of the number of IP units delivered to the 
site, dispensed to subjects, returned to the investigator by the subject, and returned to the 
sponsor or other disposition during and at the completion of the study.

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7.5.3.1
Receipt of Investigational Product
Upon receipt of the IP, the investigator or delegate must conduct an inventory. During the 
study, the investigator or designated study staff must provide the IP to the subjects. 
Throughout the study, the investigator or delegate must maintain records of IP dispensation 
and collection for each subject. This record must be made available to the study monitor for 
the purposes of verifying the accounting of IP supplies. Any discrepancies and/or deficiencies 
between the observed disposition and the written account must be recorded along with an 
explanation. All IP sent to the investigator must be accounted for by study sponsor personnel, 
and in no case be used in an unauthorized situation.
7.5.3.2
Return of Investigational Product
When the site is closed, the study is completed or is terminated by the sponsor, all unused IP 
will be returned to the sponsor (or the sponsor’s designee). The investigator is responsible for 
proper disposition of all used IP at the conclusion of the study after IP reconciliation, 
according to the instructions provided in the MOP. All IP reconciliation procedures must be 
completed before the study is concluded. The responsible person at the investigator’s 
institution must account for all used and unused IP. The IP storage manager or designee will 
complete a study drug returns form or equivalent that will be signed by the investigator or 
designee prior to returning the unused IP to the sponsor’s designee.
7.6
Subject Assignment, Randomization, and Masking
7.6.1
Subject Assignment
Subject assignment is not applicable in this single-arm design, with one IP, as all subjects 
who meet the inclusion/exclusion criteria will receive the same IP. 
7.6.2
Masking and Unmasking
All members associated with the study (at the site and the study sponsor) are unmasked to the 
assigned IP. 
7.7
Investigational Product Compliance
Compliance with IP usage will be assessed at Visit 3/Remote Compliance Check and 
Visit 4/Exit. 
 
 

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7.8
Concomitant Therapy
Pharmacologic and nonpharmacologic therapies and surgeries/procedures will be queried 
during Visit 1/Screening. 
7.8.1
Prohibited Concomitant Therapy 
The table below outlines all prohibited prior and concomitant therapies. Subjects must 
discontinue the use of any of the therapies or interventions listed in Table 7-2 for the 
specified period prior to the specified visit and these therapies or interventions must not be 
used during the course of the study. Use of any of these therapies or interventions during the 
course of the study must be documented as a protocol deviation.
Table 7-2
Prohibited Concomitant Therapies 
Intervention/Therapy
Washout Required 
Precaution(s) and 
Action(s) to be Taken
Rationale
Topical ocular 
medications preserved 
with benzalkonium
chloride. Examples 
include: Travatan, 
Xalatan, Lumigan, etc.
A month before the
Screening visit until
subject is exited from the 
study.
Discontinue subject 
from study if taken
concomitantly during 
IP administration.
May confound 
primary 
efficacy 
variable.
Any artificial tear 
products. Examples of 
prohibited ocular 
lubricants include: Blink, 
Refresh, Biotrue, other 
Systane products, iVizia, 
Visine, Soothe, etc. See 
exclusion criteria number
14 (Section 6.3)
From the beginning of the 
Baseline visit until
subject is exited from the 
study.
Discontinue patient 
from study if any
ocular lubricant is 
taken concomitantly
with IP for more than
2 consecutive days.
May confound 
primary 
efficacy 
variable.
8
DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
SUBJECT WITHDRAWAL FROM STUDY
8.1
Discontinuation of Investigational Product 
Discontinuation of IP for a Subject occurs when IP is stopped earlier than the protocol 
planned duration.

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8.1.1
Criteria for Permanent Discontinuation of Investigational Product
A subject may be discontinued from IP at the discretion of the investigator or the medical 
monitor. Other reasons that a subject may be discontinued from IP may include, but are not 
limited to:
x
*Adverse event(s) (AEs including, in the opinion of the investigator, clinically relevant 
laboratory abnormalities, and intercurrent diseases reported by the subject or observed 
by the investigator) 
x
^Pregnancy 
*AE may result in discontinuation of IP; however, it is up to discretion of the investigator if 
subject should continue safety assessments in the study. 
^Pregnancies occurring in subjects enrolled in the study must be reported and followed to 
outcome. No further study treatments will be administered to pregnant subjects; however, the 
subject will be encouraged to complete all safety assessments in the study.
Subjects that discontinue IP and continue in the study should continue safety assessments. 
8.1.2
Temporary Discontinuation or Interruption of Investigational 
Product
Subjects who have to interrupt treatment for any reason should be discontinued from 
participation in the study at the investigator’s discretion. Subjects who miss a dose(s) of IP 
should resume administration at their earliest convenience 
 
 Subjects should aim to use the minimum required dosage.
Every effort must be made to keep the subject in the study and to continue with the study 
assessments as specified in to Table 2-2 and Section 2.3 until the final visit.
8.1.3
Rechallenge
Subjects that experience an AE and have discontinued IP will not be rechallenged. However, 
this does not apply to suspected or expected AEs (e.g., eye redness, ocular discomfort, or 
temporary blurring of vision) that are reported without subject discontinuation/will not be 
considered rechallenged. 

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8.2
Subject Withdrawal from the Study
A subject may exit the study by their own volition. Any subject may decide to voluntarily 
withdraw from the study at any time without prejudice. The sponsor may retain and continue 
to use any data collected before such a withdrawal of consent.
If possible, an early exit visit should be conducted, in accordance with to Table 2-2 and 
Section 2.3. IP will be discontinued upon subject exit.
The investigator must document the reason for study or IP discontinuation in the subject’s 
case history source documents.
To ensure the safety of all subjects who discontinue early, investigators must assess each 
subject and, if necessary, advise them of any therapies and/or medical procedures that may be 
needed to maintain their health.
A subject may be withdrawn from the study at the discretion of the investigator or the 
medical monitor. Other reasons that a subject may be withdrawn from the study may include, 
but are not limited to:
x
Adverse event(s) (AEs including, in the opinion of the investigator, clinically relevant 
laboratory abnormalities, and intercurrent diseases reported by the subject or observed 
by the investigator) 
x
Death 
x
Lack of efficacy
x
Lost to follow-up 
x
Pregnancy 
x
Protocol violation (specify)
x
Study terminated by sponsor
x
Technical problems
x
Withdrawal by subject (specify)
x
Other (specify) 
8.3
Lost to Follow-up
A subject will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.

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The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:
x
The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible, counsel the subject on the importance of maintaining the assigned visit 
schedule, and ascertain whether the subject wishes to and/or should continue in the 
study.
x
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls, and if 
necessary, a certified letter to the subject's last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject's 
medical record.
x
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8.4
Follow-up of Subjects After Study Participation has Ended
Following this study, the subject will return to their eye care professional for their routine eye 
care.
8.5
Study Stopping Rules
N/A
9
STUDY ASSESSMENTS AND PROCEDURES
Detailed descriptions of assessments and procedures are provided in the MOP. The 
investigator is responsible for ensuring that responsibilities for all procedures and 
assessments are delegated to appropriately qualified site personnel.
9.1
Screening/Baseline Assessments and Procedures
The investigator or delegate must explain the purpose and nature of the study, and have the 
subject read, sign, and date the IRB/IEC-approved ICF. The subject must sign the ICF 
BEFORE any study-specific procedures or assessments can be performed, including study-
specific screening procedures. Additionally, have the individual obtaining consent from the 
subject and a witness, if applicable, sign and date the ICF.

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The investigator or delegate must provide a copy of the signed document to the subject and 
place the original signed document in the subject’s chart, or provide documentation as 
required by local regulations.
9.1.1
Connect to Electronic Patient Reported Outcomes
At Screening, subjects must connect to ePRO with their mobile device after signing the ICF 
and prior performing any other assessments. If subject is unable to connect, the Screening 
visit can be rescheduled within a maximum of 7 days/1week to allow the subject to meet 
inclusion criteria number 9. All remaining eligibility criteria will be verified after completing 
inclusion criteria number 9. 
9.1.2
Demographics
Obtain relevant demographic information including age, race, ethnicity, sex, etc.
9.1.3
Medical/Ophthalmic History
Significant medical and ophthalmic history will be collected at Screening, including:
x
Current medical/ophthalmic conditions
x
Medical/ophthalmic conditions that began within the last 12 months and which may 
have resolved before Screening
x
Resolved medical/ophthalmic conditions that are deemed relevant by the investigator
x
Relevant surgeries/procedures
Throughout the subject’s participation, obtain information on any changes in medical health. 
Medical history will be collected in the eCRF as outlined in the MOP.
9.1.4
Prior and Concomitant Medication Assessments
Any medication (including vaccines, OTC or prescription medicines, vitamins, and/or herbal 
supplements) will be queried and recorded on the appropriate case report form and updated at 
each visit. Prior medications taken up to 30 days prior to the Screening must also be 
recorded.
Concomitant medications will be collected in the eCRF as outlined in the MOP.

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9.1.5
Urine Pregnancy Test
Women who are pregnant or breastfeeding are excluded from participation in the study. A 
urine pregnancy test will be performed at Visit 1/Screening, Visit 4/Exit, Early Exit, and 
Unscheduled Visits (as necessary) in all females of childbearing potential. 
9.2
Efficacy Assessments and Procedures
9.2.1
IDEEL-SB Questionnaire
IDEEL-SB Questionnaire score will be completed by the subject at Visit 1/Screening and 
Visit 4/Exit Day 30 ± 5/Early Exit. 
9.3
Safety Assessments and Procedures
9.3.1
Adverse Event Collection
Assess and record any adverse events that are observed or reported since the previous visit, 
including those associated with changes in concomitant medication dosing.
9.3.2
Device Deficiency Collection
Assess and record any device deficiencies that are observed or reported since the previous 
visit. 

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9.3.3
Slit Lamp Biomicroscopy
SLE of the cornea, conjunctiva, eyelids, and ocular surface must be performed in both eyes.
9.3.4
Best Corrected Visual Acuity
LogMAR visual acuity using the ETDRS and/or SOC chart for both eyes must be performed. 
9.3.5
Unscheduled Visits
If a subject visit occurs between any regularly scheduled visit and the visit is conducted by 
study personnel, this visit must be documented as an Unscheduled Visit. If the subject seeks 
medical attention outside the clinic (for example, at an emergency room) or at the clinic but is 
seen by non-study personnel, the investigator is to capture adverse event-related information 
on the adverse event form upon becoming aware.
If a subject experiences any symptoms of eye infections, including but not limited to eye 
pain, eye redness, eye irritation, they need to schedule an Unscheduled Visit and seek medical 
advice or treatment.
During an Unscheduled Visit (for an adverse event), the investigator must conduct the 
following procedures:
x
Collect adverse event and device deficiencies information
x
Record changes in medical condition or concomitant medication
x
Perform BCVA 
x
Perform slit lamp biomicroscopy exam
The investigator may perform additional procedures for proper diagnosis and treatment of the 
subject. The investigator must document this information in the subjects’ case history source 
documents.
If during an Unscheduled Visit the subject is discontinuing the IP or discontinuing from the 
study, the investigator must conduct Exit procedures according to Table 2-2, as possible.
Spare IP is not dispensed to the subject in this study. If IP is lost, damaged, or needs to be 
replaced due to an AE/device deficiency, the subject will be instructed to return for an 
unplanned dispense visit. Refer to the MOP for more details. 

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9.4
Adverse Events and Serious Adverse Events
9.4.1
Definitions of AE and SAE
The following definitions of terms apply to this section: 
x
Adverse event (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 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) 
product.
x
Adverse drug reaction (ADR): All noxious and unintended responses to a medicinal 
product related to any dose should be considered ADRs. Responses to a medicinal 
product means that a causal relationship between a medicinal product and an adverse 
event is at least a reasonable possibility, i.e., the relationship cannot be ruled out.
x
Adverse Event of Special Interest (AESI): Adverse event (serious or nonserious) of 
scientific and medical concern specific to the sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the investigator to the sponsor can be 
appropriate. Such an event might warrant further investigation in order to characterize 
and understand it. Depending on the nature of the event, rapid communication by the 
trial sponsor to other parties (e.g., regulators) might also be warranted.
x
Life-threatening AE or life-threatening ADR: an AE or ADR is considered “life-
threatening” if, in the view of either the investigator or sponsor, its occurrence places 
the subject at immediate risk of death. It does not include an AE or ADR that, had it 
occurred in a more severe form, might have caused death. 
x
Serious adverse event (SAE) or serious adverse reaction (SAR): an AE or AR is 
considered “serious” if, in the view of either the investigator or sponsor, it results in 
any of the following outcomes: 
o
Death, a life-threatening or sight-threatening AE, 

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o
a subject hospitalization or prolongation of existing hospitalization, Note: 
Planned hospitalization for a preexisting condition, without serious 
deterioration in health, is not considered a serious adverse event. 
Therefore, neither the condition, hospitalization, prolonged hospitalization, 
nor surgery are reported as a serious adverse event when the 
hospitalization or prolonged hospitalization was for an elective surgical 
procedure or for a preexisting condition. In general, hospitalization 
signifies that the individual remained at the hospital or emergency ward 
for observation and/or treatment (usually involving an overnight stay) that 
would not have been appropriate in the physician's office or an outpatient 
setting. Complications that occur during hospitalization are adverse events. 
If a complication prolongs hospitalization or fulfills any other serious 
criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred, the event should be considered serious.
o
a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions (disability), or 
o
a congenital anomaly/birth defect 
o
Important medical event or reaction that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the subject 
and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not 
result in subject hospitalization, or the development of drug dependency or 
drug abuse. 
Note: Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered as serious such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also be considered serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
or development of drug dependency or drug abuse.

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x
Suspected unexpected SAR (SUSAR): Adverse drug reaction that is both unexpected 
and meets the definition of a serious adverse event.
x
Unexpected AE or unexpected ADR: an AE or ADR is considered “unexpected” if it is 
not listed in the IB or is not listed at the specificity or severity that has been observed; 
or, if an IB is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended.
9.4.2
Time Period and Frequency for Collecting AE and SAE 
Information
AEs and SAEs should be documented from the time the subject provides informed consent 
until subject participation in the trial has been completed.
9.4.3
Identifying AEs and SAEs
AE information may be volunteered by the subject or solicited by trial personnel through 
non-leading questions. At each visit, after the subject has had the opportunity to 
spontaneously mention any problems, the investigator should inquire about AEs by asking the 
standard questions shown below and report as applicable:
x
“Have you had any health problems since your last study visit?”
x
“Have there been any changes in the medicines you take since your last study visit?”
AEs should be reported for any clinically relevant change, as determined by the investigator, 
in concomitant medication(s) that is the result of an untoward (unfavorable and unintended) 
change in a subject's medical health.
In addition, changes in any protocol-specific parameters and/or questionnaires evaluated 
during the study are to be reviewed by the investigator. Any untoward (unfavorable and 
unintended) change in a protocol-specific parameter 
 that is 
clinically relevant, in the opinion of the investigator, is to be reported as an AE. These 
clinically relevant changes will be reported regardless of causality.
9.4.4
Recording of AEs and SAEs
All AEs occurring during the trial, regardless of the assumption of causal relationship, must 
be documented on the respective CRF. Qualified trial staff responsible for assessing AEs will 
be listed on the Site Authorization and Delegation Log. This includes assessment of AE 
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Documentation of AEs/ARs will include AE description, start date and stop date, severity, 
relationship, action(s) taken, seriousness, and outcome.
When recording an AE, the following information should be provided on the trial AE CRF:
Action taken with trial intervention:
x
None
x
Trial intervention discontinued
x
Trial intervention interrupted
AE outcome:
x
Fatal
x
Not recovered/not resolved
x
Recovered/resolved
x
Recovered/resolved with sequelae
x
Recovering/resolving
x
Unknown/lost to follow-up
Further details on assessing severity and causality of AEs and SAEs are in Appendix 14.
9.4.5
Follow-up of AEs and SAEs
If an AE/SAE is unresolved at the time of exit, efforts will be made to follow up until the 
AE/SAE is resolved or stabilized, the subject is lost to follow-up, or there is other resolution 
to the event. These follow-up visits will be documented.
The investigator is responsible for adequate and safe medical care of subjects during the 
study and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained after the study.
The investigator should provide the study sponsor with any new safety information (which 
includes new AEs and changes to previously reported AEs) that may affect the safety 
evaluation of the study treatment. For AEs that are unresolved/ongoing at time of subject exit 
from study, any additional information received at follow-up should be documented in the 
eCRFs up to study completion (i.e., database lock). 

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Any additional data received within 30 days after subject has stopped study participation (last 
visit or time of last dose of the study treatment taken (whichever is later) must be 
documented and available upon the study sponsor’s request.
9.4.6
Reporting of SAEs
An investigator must immediately (i.e., within 24 hrs) report any SAE or SAR to the sponsor 
or sponsor representative, whether or not considered trial intervention-related, including 
those listed in the protocol or IB. The investigator must use the SAE report form (eCRF or 
email as a back-up) and include an assessment of whether there is a reasonable possibility 
that the trial intervention caused the event. The investigator must report any SAE or SAR that 
occurs or is observed during the trial. In case of incomplete information, the investigator 
must provide follow-up information as soon as possible, again using the SAE report form. 
The details for SAE/SAR report submission are listed below.
Report SAEs/SARs within 24 hrs via electronic data capture (EDC) system or, in the case of 
the EDC system not being available, the provided SAE source document will be completed 
and sent via the instructions noted on the form to the sponsor representative within the 
expected reporting time frame.
SAE/SAR reports will be evaluated by the medical monitor. Regulatory authorities, IRB/IEC, 
and investigators at each of the trial sites will be informed as required. 
An assessment of seriousness will also be performed for all adverse events by a sponsor 
physician utilizing the same criteria. If an adverse event reported for an investigator’s subject 
is upgraded to a serious adverse event by a sponsor physician, the investigator will receive a 
notification from the sponsor.
9.4.7
Regulatory Reporting Requirements for SAEs
This clinical study is being conducted exclusively in the US where the IP is considered an 
OTC monograph drug. As such, there are no regulatory requirements to report SAEs to the 
health authority. There are no IRB requirements for an OTC monograph drug. 
9.4.8
Serious and Unexpected Adverse Reaction Reporting
An investigator must immediately (i.e., within 24 hrs) report SUSARs. In the event of 
SUSAR, the site must notify the medical monitor for the trial and submit an SAE report form 
in EDC within 24 hrs of notification, observation, or occurrence of the SUSAR, whether or 
not complete information is available to the sponsor or sponsor representative. In the case of 

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incomplete information, the investigator must provide follow-up information as soon as 
possible using the SAE report form. 
9.4.9
Adverse Events of Special Interest
Not applicable to this study.
9.4.10 Disease-related Events or Outcomes Not Qualifying as AEs or SAEs
Any medical condition present prior to informed consent which remains unchanged or 
improved should not be recorded as an AE at subsequent visits. However, an AE should be 
recorded if the frequency, intensity, or the character of a preexisting condition worsens during 
the trial period beyond what would be expected from the natural progression of that 
condition. 
Surgery should not be reported as an adverse event nor as an outcome of an adverse event if 
the purpose of the surgery was diagnostic and the outcome was uneventful.
If there is a question as to whether a medical development should be reported as an adverse 
event, it is recommended the investigator contact the sponsor for guidance.
9.5
Device Deficiencies
A device deficiency is inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. This definition includes malfunctions, use 
errors, and inadequacy in the information supplied by the manufacturer. A device deficiency 
may or may not be associated with patient harm (i.e., AE or SAE); however, not all AEs or 
SAEs are due to a device deficiency. The investigator should determine the applicable 
category listed in the Device Deficiency eCRF for the identified or suspect device deficiency 
and report any patient harm separately. Examples of device deficiencies include the 
following:
x
Defective component
x
Damaged package
x
Mixed/mislabeled
x
Potential contaminant
x
Tampered seal
x
Incorrect capping 

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x
Partial seal
x
Other (specify)
9.6
Pregnancy and Postpartum Information
Pregnancies occurring in subjects enrolled in the study must be reported and followed to 
outcome. No further study treatments will be administered to pregnant subjects; however, the 
subject will be encouraged to complete all visits in the study.
If a woman is of childbearing potential, she must have a pregnancy test performed at the 
Screening and/or Baseline visits prior to confirmation of eligibility (and prior to start of study 
treatment). Additional pregnancy tests may also be required per local regulatory guidelines. 
Subjects with a positive pregnancy test result must be excluded from the study. Subjects with 
a negative pregnancy test result must agree to use a highly effective contraception method 
during the study.
While pregnancy itself is not considered to be an AE, pregnancy reports are tracked by the 
sponsor or sponsor representative. The investigator must complete the Pregnancy Report 
Form and email or fax the form to the sponsor or sponsor representative. Following delivery 
or termination of the pregnancy, the Pregnancy Report Form is to be completed and sent by 
email or fax to the sponsor or sponsor representative.
Premature terminations including miscarriage, spontaneous abortion, or elective termination 
of a pregnancy for medical reasons will be reported as a serious adverse event (SAE). Other 
pregnancy complications should be reported as SAEs if they meet the seriousness criteria. 
Should the pregnancy result in a congenital anomaly or birth defect, a separate SAE must be 
submitted for the child. Furthermore, all neonatal deaths that occur within 30 days of birth, 
without regard to causality, should be reported as SAEs.
9.7
Device Deficiencies for Drug/Device Combination Products
N/A
9.8
Pharmacokinetics
N/A
9.9
Genetics
N/A

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9.10 Biomarkers
N/A
9.11 Immunogenicity Assessments
N/A
9.12 Medical Resource Utilization and Health Economics
N/A
10 STATISTICAL CONSIDERATIONS
Continuous variables will be summarized using the number of observations, mean, standard 
deviation (SD), median, minimum, and maximum, as well as confidence intervals (CIs) or 
confidence limits (CLs) where applicable. Categorical variables will be summarized with 
frequencies and percentages from each category.
Unless otherwise specified, baseline will be defined as the last available measurement prior 
to IP exposure. Change from baseline will be calculated as postbaseline timepoint/visit value 
minus baseline value.
Final subject evaluability must be determined prior to locking the database, based upon the 
data evaluability plan (DEP).
The primary analysis will be conducted on the Safety Analysis Set (Section 10.1) at Day 30, 
for the change from baseline calculation. 
Any deviations to the analysis plan will be updated during the course of the study as part of a 
protocol amendment or will be detailed in the clinical study report.
10.1 Analysis Set
Two analysis data sets will be defined. 
Safety Analysis Set: includes all subjects/eyes exposed to at least one dose of IP. 

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Per Protocol (PP) Analysis Set: is a subset of the Safety Analysis Set and excludes all data 
meeting any of the critical deviation or evaluability criteria specified in the DEP.
10.2 Analyses Supporting Primary Objective(s)
 
 
The Safety Analysis Set will serve as the primary analysis set for the primary efficacy 
endpoint,
 
 
 
 
10.2.1 Statistical Model, Hypothesis, and Method of Analysis
The null and alternative hypotheses for the analysis of the primary efficacy endpoint are:
H0: ȣ(T) ≥ 0
Ha: ȣ(T)  < 0
where ȣ(T)  denotes the mean change from baseline in total IDEEL-SB score at Day 30.
A paired (one-sample) t-test will be used on the change from baseline value at Day 30 to test 
these hypotheses. One-sided p-value will be calculated, and null hypothesis will be rejected if 
p-value < 0.05.
In addition, descriptive statistics for observed and change from baseline values will be 
summarized.
10.2.2 Handling of Intercurrent Events of Primary Estimand(s)
The treatment-policy strategy will be used whereby all subjects exposed to at least one dose 
of IP, regardless of any ICE, will be included in the analysis. In addition, should an ICE result 
in a protocol deviation, data evaluability will be determined prior to final database lock and 
analysis will also be done on a per-protocol basis, as applicable. 

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10.2.3 Handling of Missing Data Not Related to Intercurrent Events
All data obtained in evaluable subjects/eyes will be included in the analysis. No imputation 
for missing values will be carried out for the primary and key exploratory efficacy analysis.

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10.5 Safety Analyses
The safety endpoints are
x
AEs
x
BCVA
x
Biomicroscopy findings
x
Device deficiencies
There are no safety hypotheses planned in this trial. The focus of the safety analysis will be a 
comprehensive descriptive assessment of occurrence of adverse events as well as the other 
listed parameters.
All AEs occurring from the time a subject signs informed consent to study exit will be 
accounted for in the reporting. Safety analyses will be conducted using the safety analysis set 
on a treatment-emergent basis. Descriptive summaries (frequencies and percentages) for 
ocular and nonocular AEs will be presented by Medical Dictionary for Regulatory Activities 
Preferred Terms. AEs leading to study discontinuation and SAEs will be identified. Individual 
subject listings will be provided, as necessary.
Individual subject listings will be provided for AEs that occur after signing informed consent 
but prior to day of first exposure to IP.
Each biomicroscopy parameter will be summarized. For lens and status of lens 
biomicroscopy parameter, counts and percentages of eyes that experience an increase of ≥ 1 
grade from baseline (last assessment prior to study product exposure) to any subsequent visit 
will be presented; all other parameters counts and percentages of eyes that experience an 
increase of ≥ 2 grades from baseline (last assessment prior to study product exposure) to any 
subsequent visit will be presented. A supportive listing will be generated which will include 
all biomicroscopy data from all visits for those eyes experiencing the increase.
Two listings for device deficiencies, prior to exposure of study product and treatment 
emergent, will be provided. Additionally, each device deficiency category will be tabulated.
No inferential testing will be done for safety analyses.

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11 PROTOCOL DEVIATIONS
Per ICH E6 (GCP) R2 Section 4.5.1 the investigator/institution should conduct the study in 
compliance with the protocol agreed with the sponsor and, if required, by the regulatory 
authority and which was given approval/favorable opinion by IRB/IEC. 
Protocol waivers or deviations from the protocol inclusion and exclusion criteria are not 
allowed because they can potentially jeopardize the scientific integrity of the study regulatory 
acceptability or Subject safety. Therefore, adherence to the criteria as specified in the 
protocol is essential. 
The site will contact the sponsor for clarification of inclusion and/or exclusion criteria as 
needed prior to enrollment of the study subject. The sponsor or their representative will 
document clarification requests and responses. If a Subject does not meet any of the 
eligibility criteria, that Subject may not be enrolled into the study.
If the investigator feels that in his/her clinical judgment, it is necessary to promptly 
implement reasonable alternatives to, or deviations from, the protocol in consideration of the 
safety of study subjects, the sponsor is to be notified of these alternatives and deviations, and 
the reasons for such changes are to be documented in the study records. The investigator is to 
also notify his/her IRB/IEC of any such changes.
If a significant protocol deviation is identified by the investigator or through site monitoring 
activities, an immediate submission to the IRB/IEC may be required (as per IRB/IEC 
guidelines). The sponsor will assess any protocol deviation and decide whether any of these 
non compliance should be reported to the relevant competent authority as a serious breach of 
Good Clinical Practice (GCP) and the protocol. If per the relevant competent authorities’ 
requirements, the protocol deviation is not required to be reported immediately but is still 
required to be notified to the IRB/IEC, the specific protocol deviation will be added to the 
annual progress report.

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The sponsor will review, designate, and/or approve all protocol deviations prior to the 
database lock.
12 GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND 
STUDY OVERSIGHT
12.1 Regulatory and Ethical Considerations
The study will be conducted according to this clinical protocol and will be governed by all 
applicable governmental rules and regulations concerning the conduct of clinical trials on 
human subjects. This includes, but is not limited to:
x
The approval of IRB/IEC
x
The Helsinki Declaration (World Medical Association 2013) 
x
US Code of Federal Regulations, Title 21
x
International Conference on Harmonisation (ICH) Consolidated Good Clinical 
Practice Guideline (E6 R2)
x
Standard operating procedures of the sponsor and any other vendors participating in 
the conduct of the trial
x
EU Clinical Trials Regulation 536/2014 and EC local laws and regulations
x
Obtaining prospective informed consent
The investigator must ensure that all personnel involved in the conduct of the study are 
qualified to perform their assigned responsibilities through relevant education, training, and 
experience. The investigator and all clinical study staff must conduct the clinical study in 
compliance with the protocol. The investigator is not allowed to deviate from the protocol 
except to protect the rights, safety, and wellbeing of human subjects under emergency 
circumstances. Emergency deviations may proceed without prior approval of the sponsor and 
the IRB/EC but shall be documented and reported to the sponsor and the IRB/EC as soon as 
possible. Deviations from this protocol, regulatory requirements, and/or GCP must be 
recorded and reported to the sponsor prior to database lock. If needed, corrective and 
preventive action should be identified, implemented, and documented within the study 
records. Failure to implement identified corrective and preventative actions may result in site 
closure by the sponsor. Use of waivers to deviate from the clinical protocol is prohibited.
Before clinical study initiation, this protocol, the ICF, any other written information given to 
subjects, and any advertisements planned for subject recruitment must be approved by an 

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IRB/IEC. The investigator must provide documentation of the IRB/IEC approval to the study 
sponsor. The approval must be dated and must identify the applicable protocol, amendments 
(if any), ICF, assent form (if any), all applicable recruiting materials, written information for 
subject, and subject compensation programs. The IRB/IEC must be provided with a copy of 
the IFU and IB, any periodic safety updates, and all other information as required by local 
regulation and/or the IRB/IEC. Any additional requirements imposed by the EC or regulatory 
authority shall be followed. At the end of the study, the investigator must notify the IRB/IEC 
about the study’s completion. The IRB/IEC also must be notified if the study is terminated 
prematurely. Finally, the investigator must report to the IRB/IEC on the progress of the study 
at intervals stipulated by the IRB/IEC.
Voluntary informed consent must be obtained in writing from every subject. The obtaining of 
consent shall be documented before any procedure specific to the clinical investigation is 
applied to the subject. 
The investigator must have a defined process in case a subject would like to withdraw their 
consent (s). The investigator is the designated contact point for any such withdrawals.
The investigator must have a defined process in case a subject would like to exercise any of 
their rights under applicable data protection laws. The investigator is the designated contact 
point for any such requests. 
The study sponsor assures that the key designs of this protocol will be registered in a public 
database where required by current regulations, and, as applicable, results will be posted. 
12.2 Committees
N/A
12.3 Informed Consent Process
Prior to any study procedures, the study will be discussed with each subject and subjects 
wishing to participate must give written informed consent including appropriate privacy 
authorization, as applicable. The verbal explanation of the study will cover all the elements 
specified in the written information provided for the subject. The investigator will inform the 
subject of the aims, methods, anticipated benefits, and potential hazards of the study, 
including any discomfort it may entail. The subject must be given every opportunity to clarify 
any points he/she does not understand and, if necessary, may ask for more information. At the 
end of the interview, the subject should be given time to reflect. The subjects and/or legally 
authorized representative then will be required to sign and date the ICF. Consent procedures 

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must follow local legal requirements of the study site. A copy of the signed and dated consent 
document will be given to each subject. The original signed and dated informed consent 
document must be maintained in the trial files at the investigator’s site.  
The investigator or staff is responsible for ensuring that no subject undergoes any study 
related examination or activity before the subject has given written informed consent. It 
should be emphasized that the subject is at liberty to withdraw consent to participate at any 
time, without penalty or loss of benefits to which the subject is otherwise entitled. Subjects 
who refuse to give, or withdraw, written informed consent may not be included or continued 
in this study and should be notified that discontinuation from the study will not impact their 
subsequent care.
If the subject is part of a vulnerable population, including without limitation minors, or 
requires any special needs, ensure that a parent or legal guardian signs the informed consent 
and that the subject signs an IRB/IEC-approved assent document as required.
12.4 Privacy and Data Protection
The investigator must ensure that the subject’s identity is kept confidential throughout the 
course of the study. In particular, the investigator must maintain appropriate safeguards to 
prevent unauthorized use or disclosure of, or access to, subject data, and keep an enrollment 
log with confidential identifying information that corresponds to the subject numbers and 
initials of each study subject. The study sponsor may collect a copy of the enrollment log 
without any directly identifying subject information.
The study sponsor may share subject-level data collected in this study with qualified 
researchers to help facilitate product development or enhancements in research that is not 
directly related to the study objectives. The informed consent explains this to the study 
subject.
12.5 Early Site Closure or Study Termination
The study sponsor reserves the right to suspend or close the investigational site or suspend or 
terminate the study in its entirety at any time. The investigator may terminate the site’s 
participation in the study for reasonable cause.
If the clinical study is prematurely terminated or suspended:
x
The study sponsor must:

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o
Immediately notify the investigator(s) and subsequently provide 
instructions for study termination.
o
Inform the investigator and the regulatory authorities of the 
termination/suspension and the reason(s) for the termination/suspension. 
x
The investigator must:
o
Promptly notify the IRB/IEC of the termination or suspension and of the 
reasons. 
o
Provide subjects with recommendations for poststudy treatment options as 
needed.
13 GENERAL CONSIDERATIONS: RISK MANAGEMENT AND 
QUALITY ASSURANCE
13.1 Quality Tolerance Limits
Quality tolerance limits (QTLs) will be predefined through an internal risk management 
process and monitored on an ongoing basis, with documentation of QTLs that are met 
summarized in the CSR.
13.2 Data Quality Assurance
The study sponsor will secure agreement from all involved parties to ensure direct access to 
all study related sites, source data and documents, and reports for the purpose of monitoring 
and auditing by the study sponsor, and inspection by domestic and foreign regulatory 
authorities. Quality control will be applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly. Agreements made by the study sponsor 
with the investigator/institution and any other parties involved in the clinical study will be 
provided in writing as part of the protocol or as a separate agreement.
13.3 Source Data
The nature and location of all source documents will be identified to ensure that original data 
required to complete the CRFs exist and are accessible for verification by the site monitor, 
and all discrepancies shall be appropriately documented via the query resolution process. Site 
monitors are appointed by the study sponsor and are independent of study site staff.
If electronic records are maintained, the method of verification must be determined in 
advance of starting the study.

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At a minimum, source documents include the following information for each subject:
x
Subject identification (name, sex, race/ethnicity)
x
Documentation of subject eligibility
x
Date of informed consent
x
Dates of visits
x
Documentation that protocol-specific procedures were performed
x
Results of study parameters, as required by the protocol
x
IP accountability records
x
Documentation of AEs and other safety parameters (if applicable)
x
Records regarding medical histories and the use of concomitant therapies prior to and 
during the study
x
Date of study completion and reason for early discontinuation, if applicable
It is required that the author of an entry in the source documents be identifiable. Direct access 
to source documentation (medical records) must be allowed for the purpose of verifying that 
the data recorded on the CRF are consistent with the original source data.
Only designated individuals at the site will complete the CRFs. The CRFs must be completed 
at regular intervals following the clinical study visit schedule. It is expected that all data 
reported have corresponding entries in the source documents. The principal investigator is 
responsible for reviewing and certifying that the CRFs are accurate and complete. The only 
subject identifiers recorded on the CRFs will be subject number, and subject demographic 
information.
A review of CRF data to the subject’s source data will be completed by the site monitor to 
ensure completeness and accuracy. After the CRFs have been completed, additional data 
clarifications and/or additions may be needed as a result of the data cleaning process. Data 
clarifications are documented and are part of each subject’s CRF.

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14 APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS – DEFINITIONS, SEVERITY, AND CAUSALITY
14.1 Severity
Severity of an AE is defined as a qualitative assessment of the level of discomfort or the 
degree of intensity of an AE as determined by the investigator or reported to them by the 
subject. The assessment of severity is made irrespective of trial medication relationship or 
seriousness of the event and should be evaluated according to the following scale:
x
1 = Mild: present and noticeable, but not distressing, and no disruption of normal daily 
activities
x
2 = Moderate: bothersome, discomfort sufficient to possibly reduce or affect normal 
daily activity
x
3 = Severe: incapacitating, with inability to work or perform normal daily activity
A change in increased severity for a reported AE will require a stop date for the previous 
severity and a new start and stop date for the new severity. E.g., a change in severity may go 
from mild to moderate, or from moderate to severe. In either case, the start and stop dates 
should be recorded.
Note: A severe AE is not the same as a serious AE. Seriousness of an AE (NOT severity) 
serves as a guide for defining regulatory reporting obligations, if applicable.
14.2 Causality
Relationship between the AE and the trial intervention or trial procedure will be determined 
by the investigator, as applicable, for each AE using these explanations:
x
Not Related: The event is clearly related to other factors such as subject’s clinical 
condition, therapeutic interventions, concomitant disease, or therapy administered to 
the subject and does not follow a known response pattern to the product, device, or 
procedure.

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x
Related: The event follows a reasonable, temporal sequence from the time of trial 
medication administration or trial procedure and/or follows a known response pattern 
to the product, device or procedure and cannot be reasonably explained by other 
factors such as subject’s clinical state, therapeutic interventions or concomitant therapy 
administered to the subject, and either occurs immediately following trial medication 
administration or procedure, or improves on stopping the trial medication, or reappears 
on repeat exposure, or there is a positive reaction at the application site.
14.3 Expectedness
AEs or ARs are considered “unexpected” if they are not listed in the reference safety 
information section of the IB for (trial intervention) or are not listed at the specificity or 
severity that has been observed. “Unexpected,” as used in this definition, also refers to AEs 
or ARs that are mentioned in the IB as occurring with this class of drugs or as anticipated 
from the pharmacological properties of (trial intervention) and are not specifically mentioned 
as occurring with the trial drug. 
E.g., under this definition, glaucoma would be unexpected (by virtue of greater 
severity/specificity) if the IB referred only to elevated intraocular pressure.
An investigator must immediately (i.e., within 24 hrs from time of awareness) report any 
SAE or SAR to the sponsor or its CRO representative, whether or not considered drug-
related, including those listed in the protocol or IB.
15 APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL 
DETAILS
15.1 Contraception and Pregnancy Testings
Urine pregnancy testing will be performed in women of childbearing potential at Visit 
1/Screening and Visit 4/Exit. 
15.2 Country/Region-Specific Differences
N/A

Document ID:
V-CLN-0202003
Status: Approved, Version: 3.0
Approved Date: 27 Aug 2024
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Document ID:
V-CLN-0202003
Status: Approved, Version: 3.0
Approved Date: 27 Aug 2024
Page 62 of 63
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16 PUBLICATIONS
There are no immediate plans to submit the results of this phase 3 study for publication; 
however, the results may be offered for publication if they are of scientific interest, or if the 
results relate to a product that is subsequently approved or cleared for marketing.
17 REFERENCES
17.1.1 Internal References
x
Manual of procedures
x
Investigator brochure
x
Instructions for use

Document ID:
V-CLN-0202003
Status: Approved, Version: 3.0
Approved Date: 27 Aug 2024
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17.1.2 External References
x
21 CFR Part 11 - Electronic Records; Electronic Signatures
x
21 CFR Part 50 - Protection of Human Subjects
x
21 CFR Part 56 - Institutional Review Boards
x
21 CFR Part 54 - Financial Disclosure by Clinical Investigators
x
The Helsinki Declaration (World Medical Association 2013) 
x
US Code of Federal Regulations, Title 21
x
International Conference on Harmonization (ICH) Consolidated Good Clinical 
Practice Guideline (E6 R2)
x
EU Clinical Trials Regulation 536/2014 and EC local laws and regulations
x
EN ISO 14155:2020&LC:2020 Clinical investigation of medical devices for human 
subjects. Good clinical practice.

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