Conditions: Dry Eye
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 121
Healthy volunteers: yes

Brief summary:
This is a 30-Day, multi-site, single-masked, bilateral, active- controlled, 2-Arm parallel group study to evaluate the safety and efficacy of an Investigational product.

Detailed description:

Arms:
arm 1: Eligible subjects will be randomly assigned the investigational product to be used in both eyes for the duration of the study. arm 2: Eligible subjects will be randomly assigned the control product to be used in both eyes for the duration of the study

Interventions: intervention 1: Investigational Lubricating Eye Drop in a Novelia® bottle intervention 2: Blink® Tears eye Drops
Intervention descriptions: intervention 1: Investigational Product intervention 2: Control Product

Protocol document:
Prot_SAP_000.pdf: 
Clinical Evaluation of a Multidose Preservative-free Lubricating Eye Drops Contained in Novelia® 
Eye Dropper in Non-Contact Lens Wearing Patients 
 
Protocol CR-6502  
 
Version: 3.0  
 
Date: 25 April 2023  
 
 
Investigational Products: Investigational Lubricating Eye Drop (
) in a Novelia® Multidose 
Eyedropper 
 
Approved Product: Blink® Tears lubricating eyedrops 
 
Keywords: artificial tears, dispensing, Visual Analogue Scale (VAS) comfort, dry eye, 
subject-reported ocular symptoms (SROS) 
 
 
Statement of Compliance to protocol, GCP and applicable regulatory guidelines: 
 
This clinical trial will be conducted in compliance with ISO 14155:2020 Clinical investigation of 
medical devices for human subjects – Good clinical practice1, International Council for Harmonization 
Good Clinical Practice E6(R2) (ICH GCP)2 and the Declaration of Helsinki3 as applicable. 
 
Confidentiality Statement: 
This document contains confidential information, which should not be copied, referred to, released or 
published without written approval from Johnson & Johnson Vision Care, Inc. The information may 
not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board/Independent Ethics Committee approval and informed consent, or as required by International, 
Federal and State Laws, as applicable. Persons to whom this information is disclosed must be informed 
that this information is privileged and confidential and that it should not be further disclosed without 
the written permission of Johnson & Johnson Vision Care, Inc. Any supplemental information that may 
be added to this document is also confidential and proprietary to Johnson & Johnson Vision Care, Inc. 
and must be kept in confidence in the same manner as the contents of this document. 
 
 
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TABLE OF CONTENTS  
PROTOCOL TITLE, NUMBER, VERSION AND DATE ................................................................... 6 
SPONSOR NAME AND ADDRESS .................................................................................................... 6 
MEDICAL MONITOR .......................................................................................................................... 6 
AUTHORIZED SIGNATURES ............................................................................................................ 7 
CHANGE HISTORY ............................................................................................................................. 8 
SYNOPSIS ........................................................................................................................................... 10 
COMMONLY USED ABBREVIATIONS, ACRONYMS AND DEFINITIONS OF TERMS ......... 14 
1. 
INTRODUCTION AND BACKGROUND ............................................................................. 16 
1.1. 
Name and Descriptions of Investigational Products ................................................ 16 
1.2. 
Intended Use of Investigational Products................................................................. 17 
1.3. 
Summary of Findings from Nonclinical Studies ...................................................... 17 
1.4. 
Summary of Known Risks and Benefits to Human Subjects ................................... 17 
1.5. 
Relevant Literature References and Prior Clinical Data Relevant to Proposed Clinical 
Study ……………………………………………………………………………………...18 
2. 
STUDY OBJECTIVES, ENDPOINTS AND HYPOTHESES ................................................ 18 
2.1. 
Objectives ................................................................................................................. 18 
2.2. 
Endpoints .................................................................................................................. 18 
2.3. 
Hypotheses ............................................................................................................... 18 
3. 
TARGETED STUDY POPULATION ..................................................................................... 19 
3.1. 
General Characteristics ............................................................................................ 19 
3.2. 
Inclusion Criteria ...................................................................................................... 19 
3.3. 
Exclusion Criteria ..................................................................................................... 19 
3.4. 
Enrollment Strategy.................................................................................................. 20 
4. 
STUDY DESIGN AND RATIONALE .................................................................................... 20 
4.1. 
Description of Study Design .................................................................................... 20 
4.2. 
Study Design Rationale ............................................................................................ 21 
4.3. 
Enrollment Target and Study Duration .................................................................... 21 
5. 
TEST ARTICLE ALLOCATION AND MASKING ............................................................... 21 
5.1. 
Test Article Allocation ............................................................................................. 21 
5.2. 
Masking .................................................................................................................... 22 
5.3. 
Procedures for Maintaining and Breaking the Masking........................................... 22 
6. 
STUDY INTERVENTION ...................................................................................................... 22 
6.1. 
Identity of Test Articles............................................................................................ 22 
6.2. 
Ancillary Supplies/Products ..................................................................................... 23 
6.3. 
Administration of Test Article ................................................................................. 23 
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6.4. 
Packaging and Labeling ........................................................................................... 24 
6.5. 
Storage Conditions ................................................................................................... 24 
6.6. 
Collection and Storage of Samples .......................................................................... 24 
6.7. 
Accountability of Test Articles ................................................................................ 24 
7. 
STUDY EVALUATIONS ........................................................................................................ 25 
7.1. 
Time and Event Schedule ......................................................................................... 25 
7.2. 
Detailed Study Procedures ....................................................................................... 26 
VISIT 1 ........................................................................................................................... 26 
VISIT 2 ........................................................................................................................... 28 
VISIT 3 ........................................................................................................................... 29 
FINAL EVALUATION .................................................................................................. 30 
7.3. 
Unscheduled Visits ................................................................................................... 30 
7.4. 
Laboratory Procedures ............................................................................................. 31 
8. 
SUBJECTS COMPLETION/WITHDRAWAL ....................................................................... 32 
8.1. 
Completion Criteria .................................................................................................. 32 
8.2. 
Withdrawal/Discontinuation from the Study ........................................................... 32 
9. 
PRE-STUDY AND CONCOMITANT INTERVENTION/MEDICATION ........................... 32 
9.1. 
Systemic Medications .............................................................................................. 33 
10. 
DEVIATIONS FROM THE PROTOCOL ............................................................................... 34 
11. 
STUDY TERMINATION ........................................................................................................ 35 
12. 
PROCEDURE FOR HANDLING PRODUCT QUALITY COMPLAINTS ........................... 35 
13. 
ADVERSE EVENTS ............................................................................................................... 36 
13.1. Definitions and Classifications................................................................................. 36 
13.2. Assessing Adverse Events ........................................................................................ 38 
13.2.1. 
Causality Assessment .................................................................................... 38 
13.2.2. 
Severity Assessment ...................................................................................... 39 
13.3. Documentation and Follow-Up of Adverse Events ................................................. 39 
13.4. Reporting Adverse Events ........................................................................................ 40 
13.4.1. 
Reporting Adverse Events to Sponsor .......................................................... 40 
13.4.2. 
Reporting Adverse Events to the Responsible IEC/IRB and Health Authorities
 
………………………………………………………………………………41 
13.5. Event of Special Interest .......................................................................................... 41 
13.6. Reporting of Pregnancy ............................................................................................ 41 
14. 
STATISTICAL METHODS .................................................................................................... 41 
14.1. General Considerations ............................................................................................ 41 
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14.2. Sample Size Justification ......................................................................................... 42 
14.3. Analysis Populations ................................................................................................ 43 
14.4. Level of Statistical Significance ............................................................................... 43 
14.5. Primary Analysis ...................................................................................................... 43 
14.6. Secondary Analysis .................................................................................................. 45 
14.7. Other Exploratory Analysis ...................................................................................... 45 
14.8. Interim Analysis ....................................................................................................... 46 
14.9. Procedure for Handling Missing Data and Drop-Outs ............................................. 46 
14.10. Procedure for Reporting Deviations from Statistical Plan ....................................... 46 
15. 
DATA HANDLING AND RECORD KEEPING/ARCHIVING............................................. 46 
15.1. Electronic Case Report Form/Data Collection ......................................................... 46 
15.2. Subject Record ......................................................................................................... 46 
15.3. Trial Registration on ClinicalTrials.gov................................................................... 47 
16. 
DATA MANAGEMENT ......................................................................................................... 47 
16.1. Access to Source Data/Document ............................................................................ 47 
16.2. Confidentiality of Information ................................................................................. 47 
16.3. Data Quality Assurance ............................................................................................ 47 
16.4. Data Monitoring Committee (DMC)........................................................................ 48 
17. 
CLINICAL MONITORING ..................................................................................................... 48 
18. 
ETHICAL AND REGULATORY ASPECTS ......................................................................... 48 
18.1. Study-Specific Design Considerations ..................................................................... 48 
18.2. Investigator Responsibility ....................................................................................... 48 
18.3. Independent Ethics Committee or Institutional Review Board (IEC/IRB) .............. 49 
18.4. Informed Consent ..................................................................................................... 50 
18.5. Privacy of Personal Data .......................................................................................... 50 
19. 
STUDY RECORD RETENTION ............................................................................................ 51 
20. 
FINANCIAL CONSIDERATIONS ......................................................................................... 51 
21. 
PUBLICATION ....................................................................................................................... 52 
22. 
REFERENCES ......................................................................................................................... 52 
APPENDIX A: PATIENT REPORTED OUTCOMES (STUDY QUESTIONNAIRES) ................... 54 
APPENDIX B: PATIENT INSTRUCTION GUIDE ........................................................................... 66 
APPENDIX C: PACKAGE INSERT (APPROVED PRODUCT) ...................................................... 67 
APPENDIX D: NON-INVASIVE TEAR BREAK-UP TIME (NIBUT) MEASUREMENT USING 
THE MEDMONT E300 CORNEAL TOPOGRAPHER WORK AID ................................................ 69 
APPENDIX E: 
 ..................................................... 74 
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 EXPANDED SODIUM FLUORESCEIN CORNEAL STAINING ................................. 75 
 SUBJECT REPORTED OCULAR SYMPTOMS/PROBLEMS ...................................... 82 
 DETERMINATION OF DISTANCE SPHEROCYLINDRICAL REFRACTIVE ERROR 
………………………………………………………………………………………………………...84 
 BIOMICROSCOPY SCALE ............................................................................................. 90 
 DISTANCE AND NEAR SNELLEN VISUAL ACUITY EVALUATION ..................... 96 
 PATIENT REPORTED OUTCOMES ............................................................................ 101 
APPENDIX F: 
 GUIDELINES FOR COVID-19 RISK MITIGATION .......................... 103 
PROTOCOL COMPLIANCE INVESTIGATOR(S) SIGNATURE PAGE ...................................... 115 
 
LIST OF TABLES 
Table 1: Target number of subjects by arm and site ............................................................... 21 
Table 2: Test Articles .............................................................................................................. 23 
Table 3: Ancillary Supplies .................................................................................................... 23 
Table 4: Time and Events ....................................................................................................... 25 
Table 5: Systemic medications list ......................................................................................... 33 
Table 6: Disallowed systemic antihistamines ......................................................................... 33 
Table 7: Examples of major and minor protocol deviations ................................................... 34 
Table 8: Summaries for Historical Overall Comfort Score Change from Baseline at 30-Day 
Follow-up using Visual Analog Scale (VAS) Questionnaire - Intent-To-Treat Population ... 42 
Table 9: Sample size calculations using two-sample t-test for non-inferiority ...................... 42 
Table 10: Sample size calculations using Wilcoxon Rank Sum test for non-inferiority ........ 43 
 
LIST OF FIGURES 
Figure 1: Study Flowchart ...................................................................................................... 14 
Figure 2: The mechanism for dispensing drops in the Novelia® system ................................ 16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SYNOPSIS  
Protocol Title 
Clinical Evaluation of a Multidose Preservative-free Lubricating 
Eye Drops Contained in Novelia® Eye Dropper in Non-Contact 
Lens Wearing Patients 
Sponsor 
JJVC, 7500 Centurion Parkway, Jacksonville, FL  32256 
Clinical Phase 
Clinical trial phase: Confirmatory 
Design control phase: Development phase 2  
 
Trial Registration 
This study will be registered on ClinicalTrials.gov based on 
the following: this confirmatory study meets the criteria for 
registration in 
 
Test Article(s) 
Investigational Products:  
Investigational Eye Drops 
 in a Novelia® eyedropper 
(Test) 
 
 Approved Products: Blink® Tears eye Drops (Control)   
Treatment Doses 
Dosage: Instill 1-2 drops OU at least 3-4 times a day or as needed 
(Not exceeding up to 6 times a day) 
Objectives  
The objective of this study is to evaluate the safety and the 
efficacy of an Investigational lubricating eye drops (Test) 
contained in a Novelia® eyedropper by comparison with Blink® 
Tears eye drops (Control). This study is being conducted to 
support product registration in the European Union. 
Stuy Endpoints 
Primary endpoint(s): 
• 
Change in overall ocular comfort from baseline at 30-
Day follow-up using VAS 
 
Secondary endpoint(s): 
• 
Change in overall quality of vision from baseline at 30-
Day follow-up collected using VAS 
 
Other Observations 
• 
Corneal staining Grade 2 or higher using FDA scale 
• 
Subject’s reported ocular symptoms (yes/no) 
• 
Tear film break up time 
• 
Slit Lamp Findings using FDA scale 
• 
End of day ocular comfort 
• 
Snellen best corrected distance visual acuity 
• 
Subjective Evaluation of Symptom of Dryness 
• 
Adverse Events 
• 
Number and reasons for discontinuation will be 
monitored. 
 
Separate endpoint(s) 
• 
Change in overall ocular comfort from baseline at 14-
Day follow-up using VAS 
• 
Change in overall quality of vision from baseline at 14-
Day follow-up using VAS 
• 
PRO Questionnaires 
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Study Design 
This is a 30-Day, multi-site, single-masked, bilateral, active-
controlled, 2-Arm parallel group study. Subjects are scheduled 
for 3 study visits (screening/baseline, 14-Day and 30-Day 
follow-up visits) over a period of one month. 
Sample Size 
Approximately 116 subjects (~58 per arm) will be enrolled and 
approximately 104 subjects (52 per arm) are targeted to 
complete the study. 
Study Duration 
The study will last approximately 4 months and including the 
enrollment period. 
Anticipated Study Population 
Non-contact lens wearers 18-69 years of age with self-reported 
symptoms of ocular dryness or irritation and/or the history of the 
use of artificial tears in the last 3 months. 
Eligibility Criteria - Inclusion 
Potential subjects must satisfy all of the following criteria to be 
enrolled in the study: 
 
Inclusion Criteria following Screening 
The subject must: 
1. Read, understand, and sign the STATEMENT OF 
INFORMED CONSENT and receive a fully executed 
copy of the form. 
2. Appear able and willing to adhere to the instructions set 
forth in this clinical protocol. 
3. Be between 18 and 69 (inclusive) years of age at the 
time of screening. 
4. Possess a wearable pair of spectacles that provide 
correction for distance vision and bring them to every 
visit (only if applicable- to the investigator’s discretion). 
5. Self-reported symptoms of ocular dryness and/or the use 
of artificial tears in the last 3 months. 
6. Subjects must be non-contact lens wearers. 
 
Inclusion Criteria at Baseline Evaluation 
 
7. Subjects must achieve visual acuity of 20/30 or better in 
each eye, either unaided or best corrected. 
 
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Eligibility Criteria - Exclusion 
Potential subjects who meet any of the following criteria will be 
excluded from participating in the study:  
 
Exclusion Criteria following Screening 
The subject must not: 
1. Be currently pregnant or lactating. 
2. Be diabetic.  
3. Be currently using any ocular medications or have any 
ocular infection of any type which may interfere with 
the clinical trial (at the investigator’s discretion). 
4. By self-report, have any ocular or systemic disease, 
allergies, infection, or use of medication that might 
contraindicate or interfere with the clinical trial, or 
otherwise compromise study endpoints, including 
infectious 
disease 
(e.g., 
hepatitis, 
tuberculosis), 
contagious immunosuppressive disease (e.g., Human 
Immunodeficiency Virus [HIV]), autoimmune disease 
(e.g., rheumatoid arthritis, Sjögren’s syndrome), or 
history of serious mental illness or seizures. See section 
9.1 for additional details regarding excluded systemic 
medications. 
5. Have habitually worn rigid gas permeable (RGP) lenses, 
orthokeratology lenses, or hybrid lenses (e.g., 
SynergEyes, SoftPerm) within the past 3 months and 
soft contact lenses in the past 1 month. 
6. Have participated in any pharmaceutical or medical 
device related clinical trial within 30 days prior to study 
enrollment.  
7. Be an employee (e.g., Investigator, Coordinator, 
Technician) or immediate family member of an 
employee (including partner, child, parent, grandparent, 
grandchild or sibling of the employee or their spouse) of 
the clinical site. 
8. Be a current habitual user of prescription medication to 
treat dry eye and ocular discomfort, ocular steroids, or 
any medication (Rx or OTC) that would interfere with 
the clinical study, except for artificial tears (at the 
discretion of the investigator).  
9. Have any known allergy or sensitivity to ingredients 
that the investigational product may contain (e.g., 
Sodium 
Chlorite, 
Boric 
Acid, 
Sodium 
Borate 
Decahydrate, Sodium Chloride, Potassium Chloride, 
Calcium Chloride Dihydrate, Magnesium Chloride 
Hexahydrate, Polyethylene Glycol 400, Sodium 
Hyaluronate and Purified Water). 
 
Exclusion Criteria at Baseline Evaluation 
The subject must not: 
10. Have clinically significant (grade 3 or higher on the 
FDA grading scale) slit lamp findings (e.g., corneal 
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edema, 
neovascularization 
or 
staining, 
tarsal 
abnormalities, or bulbar injection) or other corneal or 
ocular disease or abnormalities that contraindicate 
participation or may otherwise compromise study 
endpoints (including entropion, ectropion, chalazia, 
recurrent styes, glaucoma, history of recurrent corneal 
erosions, aphakia, moderate or above corneal distortion, 
herpetic keratitis). 
11. Have a history of strabismus or amblyopia. 
12. Have had or have planned (within the study period) any 
ocular or intraocular surgery (e.g., radial keratotomy, 
PRK, LASIK, iridotomy, cataract removal, retinal laser 
photocoagulation, etc.). 
13. Have any significant corneal distortion due to previous 
contact lens wear, surgery, or pathology (At the 
discretion of the investigator). 
 
Disallowed 
Medications/Interventions 
Current habitual use of Prescription Medicines to treat dry eye 
or ocular discomfort, ocular steroids, or any medication (RX or 
OTC) that would interfere with the clinical study (at the 
discretion of the investigator). 
Measurements and Procedures 
Subjective assessment of ocular comfort using visual analog 
scale (VAS), subjective evaluation of symptom of dryness, 
Snellen visual acuity, slit lamp finding using FDA scale, tear 
film break time, subjective reported ocular symptoms.   
Microbiology or Other 
Laboratory Testing 
None 
Study Termination 
The occurrence of a Serious Adverse Event (SAE) for which a 
causal relationship to a test article cannot be ruled out, will result 
in stopping further dispensing investigational product. In the 
event of a SAE, the Sponsor Medical Monitor may unmask the 
treatment regimen of subject(s) and may discuss this with the 
Principal Investigator before any further subjects are enrolled. 
Ancillary Supplies/ Study-
Specific Materials 
ScleralFil (Bausch + Lomb), Fluorescein (Akorn, Inc.) or 
another country-specific alternative approved by the sponsor. 
Principal Investigator(s) and 
Study Institution(s)/Site(s) 
A full list of Principal Investigators, clinical sites, and 
institutions is kept separately from the Study Protocol and is 
included in the study Trial Master File. 
 
 
 
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Figure 1: Study Flowchart 
 
COMMONLY USED ABBREVIATIONS, ACRONYMS AND DEFINITIONS OF TERMS 
Add 
 
 
Near addition; the additional power required for near vision correction  
ADR 
 
 
Adverse Drug Reaction 
AE 
 
 
Adverse Event/Adverse Experience 
BCVA  
 
Best Corrected Visual Acuity 
BSCVA 
 
Best Spectacle Corrected Visual Acuity 
CFR 
 
 
Code of Federal Regulations 
COAS  
 
Complete Ophthalmic Analysis System 
COM  
 
Clinical Operations Manager 
COVID-19 
 
Coronavirus Disease 2019 
CRA 
 
 
Clinical Research Associate 
CRF 
 
 
Case Report Form 
CRO 
 
 
Contract Research Organization 
CT 
 
 
Center Thickness 
 
 
 
 
D 
 
 
Diopter 
DMC  
 
Data Monitoring Committee 
eCRF  
 
Electronic Case Report Form 
EDC 
 
 
Electronic Data Capture 
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ETDRS  
 
Early Treatment Diabetic Retinopathy Study 
FDA 
 
 
Food and Drug Administration 
GCP 
 
 
Good Clinical Practice 
HIPAA  
 
Health Insurance Portability and Accountability Act 
IB 
 
 
Investigator’s Brochure 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
The International Council for Harmonization 
IDE 
 
 
Investigational Device Exemption 
IEC 
 
 
Independent Ethics Committee 
IRB 
 
 
Institutional Review Board 
ISO 
 
 
International Organization for Standardization 
ITT 
 
 
Intent-to-Treat 
JJVC 
 
 
Johnson & Johnson Vision Care, Inc. 
LC 
 
 
Limbus Center 
LogMAR 
 
Logarithm of Minimal Angle of Resolution 
MedDRA© 
 
Medical Dictionary for Regulatory Activities 
MOP 
 
 
Manual of Procedures 
NAVQ  
 
Near Activity Visual Questionnaire 
NIH 
 
 
National Institutes of Health 
NIBUT                        Non-Invasive Tear Break-Up Time 
OD 
 
 
Right Eye 
OHRP  
 
Office for Human Research Protections 
OHSR  
 
Office for Human Subjects Research 
OS 
 
 
Left Eye 
OU 
 
 
Both Eyes 
PD 
 
 
Protocol Deviation 
PHI 
 
 
Protected Health Information 
PI 
 
 
Principal Investigator 
PIG 
 
 
Patient Instruction Guide 
PQC 
 
 
Product Quality Complaint 
PRO 
 
 
Patient Reported Outcome 
QA 
 
 
Quality Assurance 
SAE 
 
 
Serious Adverse Event/Serious Adverse Experience 
SAP 
 
 
Statistical Analysis Plan 
SAS 
 
 
Statistical Analysis System 
SD 
 
 
Standard Deviation 
SROS                             Subject Reported Ocular Symptoms 
VA 
 
 
Visual Acuity 
 
 
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1. 
INTRODUCTION AND BACKGROUND 
It is estimated that Dry Eye Diseases (DED) affect approximately 16 million patients over 18 years of 
age in the United States5. Topical artificial tears or tear supplements are often used to treat the symptoms 
of dryness and discomfort associated with the condition. Toxic effects of preservatives used in topical 
ocular formulations have been documented to induce conjunctival inflammation and tear-film 
instability in human and animal studies, highlighting the need for preservative-free options in topical 
preparations6. Given the potential of additional benefit of preservative-free topical tear supplements, 
JJV CEH has already introduced Blink® Tears Preservative Free lubricating eye drops in single dose 
vials. However, JJV CEH currently does not offer preservative-free topical tear supplements in a 
multidose dropper.   
 
This study will investigate a new formulation of Investigational Lubricating eye drops 
 in 
a Novelia® eyedropper, along with the marketed Blink® Tears (Johnson & Johnson Surgical Vision, 
Santa Ana, CA) as a control in up to 8 clinical sites in the US. 
 
Figure 2: The mechanism for dispensing drops in the Novelia® system 
 
Figure 2 above shows the mechanism of drug delivery system utilized by in a Novelia® (Nemera Inc, 
France) eyedropper where the squeezing action of the bottle/eyedropper opens a valve which 
facilitates the dispensing of a single drop. The intricate system of valves closes immediately which 
stops the potential backflow of the drop which comes into contact with air/external environment, 
hence maintaining sterility of the formulations contained in the bottle.      
1.1. 
Name and Descriptions of Investigational Products  
The products which will be used in this clinical study is listed below: 
 
x 
Investigational Eye Drops 
 in a Novelia® eyedropper (Test) 
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x 
Approved Products: Blink® Tears eye Drops (Control) 
 
Blink® Tears is a marketed product with preservatives while the investigational lubricating eye drops 
do not contain any preservatives and are maintained sterile in a multi-dose Novelia® eyedropper.  
1.2. 
Intended Use of Investigational Products 
The investigational eye drops are developed as preservative-free lubricating eye drops, and the other 
product, proposed control drop is an FDA and CE approved and marketed eye drop, available over the 
counter (without a prescription). They will be used as indicated on-label to reduce symptoms of ocular 
dryness. Subjects will be required to use 1-2 drops in both eyes at least 3-4 times a day or as needed 
(Up to 6 times a day) for 30 days. 
 
The intended use of the study artificial tears is treatment of subjects with symptoms of ocular dryness. 
The indications for the investigational eyedrops are consistent with 21 CFR Part 349.60 pertaining 
to the demulcent eyedrops as per the FDA OTC monograph. The following are the indications: 
x 
For the temporary relief of burning and irritation due to dryness of the eye. 
x 
For the temporary relief of discomfort due to minor irritation of the eye or to exposure to 
wind or sun. 
x 
For use as a protectant against further irritation or to relieve dryness of eye. 
x 
For use as a lubricant to prevent further irritation or relieve dryness of the eye. 
 
1.3. Summary of Findings from Nonclinical Studies 
All previous pre-clinical findings were deemed satisfactory prior to proceeding with clinical trials on 
humans. For the most comprehensive nonclinical information regarding the investigational eye drops 
in a Novelia® eyedropper, refer to the latest version of the Investigator’s Brochure. 
 
1.4. 
Summary of Known Risks and Benefits to Human Subjects 
The following risks/adverse events can be associated with using artificial tears, in general: 
x 
There may be less comfort than when the drop was first placed on the eye. 
x 
The eyes may burn, sting and/or itch. 
x 
There may be a feeling of something in the eye (foreign body, scratched area). 
x 
There may be the potential for some temporary impairment due to peripheral infiltrates, 
peripheral corneal ulcers, and corneal erosion. 
x 
There may be the potential for other physiological observations, such as local or generalized 
edema, corneal neovascularization, corneal staining, injection, tarsal abnormalities, iritis, and 
conjunctivitis, some of which are clinically acceptable in low amounts. 
x 
There may be excessive watering, unusual eye secretions, or redness of the eye. 
x 
Poor visual acuity, blurred vision, rainbows or halos around objects, photosensitivity, or dry 
eyes may also occur if the drops are used continuously or for too long a time. 
 
There is no direct benefit to the subject for participating in the study, although they will be able to try 
out new artificial tears. The information from this study will aid in the further development and design 
of new artificial tears. 
 
For the most comprehensive clinical information regarding the control eyedrops refer to the package 
insert (Appendix C). 
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1.5. 
Relevant Literature References and Prior Clinical Data Relevant to Proposed Clinical 
Study 
Refer to the Investigator’s Brochure and package insert (Appendix C) for additional information.  
2. 
STUDY OBJECTIVES, ENDPOINTS AND HYPOTHESES 
2.1. 
Objectives  
The objective of this study is to evaluate the safety and the efficacy of an Investigational lubricating 
eye drops (Test) by comparison with Blink® Tears eye drops (Control).  
 
This study is being conducted to support product registration in the European Union. 
2.2. 
Endpoints  
Primary Endpoint: 
The primary endpoint in this study is change in overall ocular comfort score from baseline at 30-Day 
follow-up. Subjective overall ocular comfort will be assessed at baseline, 14-Day and 30-Day follow-
up using a Visual Analogue Scale (VAS) with continuous scale from 0 (extremely uncomfortable) to 
100 (extremely comfortable)7.  
 
Secondary endpoint: 
The secondary endpoint in this study is change in overall quality of vision score from baseline at 30-
Day follow-up. Change in quality of vision from baseline will be assessed using Visual Analogue Scale 
(VAS) with continuous scale from 0 (extremely uncomfortable) to 100 (extremely comfortable) at 30-
Day follow-up7.  
 
Other Exploratory Endpoints:  
• 
Corneal Staining 
• 
Subject’s reported ocular symptoms  
• 
Tear film break up time 
• 
Slit lamp findings using FDA scale 
• 
End of day ocular comfort 
• 
Snellen best corrected distance visual acuity 
• 
Subjective evaluation of symptom of dryness 
• 
Adverse Events 
• 
Number and reasons for discontinuation will be monitored. 
• 
Change in overall quality of vision from baseline at 14-Day follow-up using VAS 
• 
Change in overall ocular comfort from baseline at 14-Day follow-up using VAS 
• 
PRO and MRD analysis 
2.3. 
Hypotheses 
Primary Hypothesis: 
x 
The Test eye drops will be non-inferior to the Control eye drops with respect to change in 
ocular comfort from baseline at 30-Day follow-up. A non-inferiority margin of -20 point ocular 
comfort VAS scale will be used. 
 
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Secondary Hypothesis: 
x 
The Test eye drops will be non-inferior to the Control eye drop with respect to change in overall 
quality of vision on a VAS scale from baseline at 30-Day follow-up. A non-inferiority margin 
of -20 point change in quality of vision VAS scale will be used.  
3. 
TARGETED STUDY POPULATION 
3.1. 
General Characteristics  
The study populations will be healthy non-contact lens wearers between 18-69 years of age from up to 
8 sites in the US. 
3.2. 
Inclusion Criteria 
Potential subjects must satisfy all of the following criteria to be enrolled in the study: 
 
Inclusion Criteria following Screening 
The subject must: 
1. Read, understand, and sign the STATEMENT OF INFORMED CONSENT and receive a fully 
executed copy of the form. 
2. Appear able and willing to adhere to the instructions set forth in this clinical protocol. 
3. Be between 18 and 69 (inclusive) years of age at the time of screening. 
4. Possess a wearable pair of spectacles that provide correction for distance vision and bring them 
to every visit (only if applicable- to the investigator’s discretion). 
5. Self-reported symptoms of ocular dryness and/or the use of artificial tears in the last 3 months. 
6. Subjects must be non-contact lens wearers. 
 
Inclusion Criteria at Baseline Evaluation 
7. The monocular, distance visual acuity must be 20/30 or better in each eye, either unaided or 
best corrected. 
3.3. 
Exclusion Criteria 
Potential subjects who meet any of the following criteria will be excluded from participating in the 
study:  
 
Exclusion Criteria following Screening 
The subject must not: 
1. Be currently pregnant or lactating. 
2. Be diabetic.  
3. Be currently using any ocular medications or have any ocular infection of any type which 
may interfere with the clinical trial (at the investigator’s discretion). 
4. By self-report, have any ocular or systemic disease, allergies, infection, or use of medication 
that might contraindicate or interfere with the clinical trial, or otherwise compromise study 
endpoints, 
including 
infectious 
disease 
(e.g., 
hepatitis, 
tuberculosis), 
contagious 
immunosuppressive disease (e.g., Human Immunodeficiency Virus [HIV]), autoimmune 
disease (e.g., rheumatoid arthritis, Sjögren’s syndrome), or history of serious mental illness or 
seizures. See section 9.1 for additional details regarding excluded systemic medications. 
5. Have habitually worn rigid gas permeable (RGP) lenses, orthokeratology lenses, or hybrid 
lenses (e.g., SynergEyes, SoftPerm) within the past 3 months or soft contact lenses in the past 
1 month. 
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6. Have participated in any pharmaceutical or medical device related clinical trial within 30 days 
prior to study enrollment.  
7. Be an employee (e.g., Investigator, Coordinator, Technician) or immediate family member of 
an employee (including partner, child, parent, grandparent, grandchild or sibling of the 
employee or their spouse) of the clinical site. 
8. Be a current habitual user of prescription medication to treat dry eye and ocular discomfort, 
ocular steroids, or any medication (RX or OTC), except for artificial tears that would interfere 
with the clinical study (at the discretion of the investigator).  
9. Have any known allergy or sensitivity to ingredients that the investigational product may 
contain (e.g., Sodium Chlorite, Boric Acid, Sodium Borate Decahydrate, Sodium Chloride, 
Potassium Chloride, Calcium Chloride Dihydrate, Magnesium Chloride Hexahydrate, 
Polyethylene Glycol 400, Sodium Hyaluronate and Purified Water). 
 
Exclusion Criteria at Baseline Evaluation 
The subject must not: 
10. Have clinically significant (grade 3 or higher on the FDA grading scale) slit lamp findings (e.g., 
corneal edema, neovascularization or staining, tarsal abnormalities, or bulbar injection) or other 
corneal or ocular disease or abnormalities that contraindicate participation or may otherwise 
compromise study endpoints (including entropion, ectropion, chalazia, recurrent styes, 
glaucoma, history of recurrent corneal erosions, aphakia, moderate or above corneal distortion, 
herpetic keratitis). 
11. Have a history of strabismus or amblyopia. 
12. Have had or have planned (within the study period) any ocular or intraocular surgery (e.g., 
radial keratotomy, PRK, LASIK, iridotomy, cataract removal, retinal laser photocoagulation, 
etc.). 
13. Have any significant corneal distortion due to previous contact lens wear, surgery, or pathology 
(At the discretion of the investigator). 
3.4. 
Enrollment Strategy 
Study subjects will be recruited from the Institution/clinical site’s subject database and/or utilizing 
Independent Ethics Committee (IEC) or Institutional Review Board (IRB) approved materials.  
4. 
STUDY DESIGN AND RATIONALE 
4.1. 
Description of Study Design 
This is a 30-Day multi-site, randomized, single-masked, bilateral, controlled, 2-Arm parallel group, 
dispensing study. Approximately 116 subjects will be screened and randomly assigned to either Test 
or Control groups (58 subjects/arm). The goal is for a sample size of 104 (52 subjects/arm) after subjects 
who withdraw or are lost-to-follow-up. Subjects are scheduled for 3 study visits (screening/baseline, 
14-Day, and 30-Day follow-up visits) over a period of one month.  
 
At Visit 1, subjects will be consented and screened for inclusion/exclusion criteria. If a subject is found 
to meet all eligibility criteria, they will be dispensed with artificial tears eye drops based on the 
randomization scheme; otherwise, the subject will be discontinued from the study. Subjects will be 
dispensed with their randomly assigned eye drops and instructed to use them in both eyes, 3-4 times a 
day, or as needed (not exceeding 6 times a day) over a 14±2 day period. The follow-up evaluation (Visit 
2) will occur 14±2 days after Visit 1.  
 
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At Visit 2, VAS, PRO and MRD questionnaires, SROS and slit lamp findings will be evaluated, and 
the subject will be dispensed with a new bottle of drops. Subjects will be instructed to use them in both 
eyes 3-4 times a day until the next scheduled study visit. Visit 3 will take place 30+/-2 days after Visit 
1.  
 
At Visit 3, VAS, PRO and MRD questionnaires, SROS, NITBUT and slit lamp findings will be 
evaluated, and the subject will have a final evaluation before exiting from the study. All used and 
unused test articles will be collected from the subjects during the exit visit. 
4.2. 
Study Design Rationale 
Randomized, masked, controlled designs are the gold standard to perform scientifically sound 
evaluations of the intervention by reducing bias associated with the conduct and interpretation of a 
clinical trial and avoiding confounding from other factors. Due to the difference in the shape of the 
eyedroppers, double masking will not be possible. However, the subjects will be masked from the 
identity of the lubricating eye drops. A parallel-group design allows for the comparison of the 
investigational eyedrops to existing marketed product which has received a CE mark in the EU. A 30- 
Day period is recommended for follow up in pivotal studies and is an appropriate review period based 
on studies which recognize the impact of cyclical changes to tear quality in female subjects8. 
4.3. 
Enrollment Target and Study Duration 
A total of up to 116 subjects will be enrolled (informed consent signed) and randomized (58 per arm) 
from up to 8 clinical sites in the US. The goal is for 104 subjects (52 per arm) to complete. The 
Investigator is responsible for ensuring that all subjects entering the study conform to subject 
selection criteria. The number of subjects targeted for randomization and completion are as follows: 
 
Table 1: Target number of subjects by arm and site 
 
Test (Investigational 
Lubricating Eye Drop 
in a Novelia® bottle) 
Control 
(Marketed 
Blink® Tears) 
Total 
Randomization 
58 
58 
116 
Completion 
54 
54 
104 
Number of sites 
8 
8 
8 
Number of subjects per site 
6-8 
6-8 
12-16 
 
The study will last approximately 4 months and includes an approximately 1-month enrollment period. 
Once the informed consent has been signed the subject will be considered enrolled. An additional 
subject may be enrolled if a subject discontinues from the study prematurely. Subjects who are 
discontinued prior to the final evaluation may be replaced at the discretion of the study sponsor. The 
investigation will end at the time that the study data is hard locked. 
5. 
TEST ARTICLE ALLOCATION AND MASKING 
5.1. 
Test Article Allocation  
Subjects will be randomly assigned to a Test group, or a Control group based on a computer-generated 
randomization schedule prepared before the start of the study in a 1:1 order. Equal number of subjects 
will be randomized to the 2 treatment arms. The randomization will be stratified by investigational site 
and randomly permuted blocks will be used within each study site. The randomization scheme will be 
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generated using the PROC PLAN procedure from the Statistical Analysis System (SAS) Software 
version 9.4 or higher10. The study site will follow the randomization scheme provided and will complete 
enrollment according to the randomization list and will not pre-select or assign subjects. The 
assignment of the subjects must be performed at the first baseline visit (Visit 1). If there are any Grade 
3 or higher other slit-lamp findings, the subject is ineligible to continue at this time, but may return up 
to one additional time to determine eligibility. The following must have occurred prior to 
randomization: 
x 
Informed consent has been obtained 
x 
Subject meets all the inclusion / exclusion criteria 
x 
Subject history and baseline information has been collected 
 
When dispensing test articles, the following steps should be followed to maintain randomization codes: 
1. Investigator or designee (documented on the Delegation Log) will consult the randomization 
schedule to obtain the test article assignment for that subject prior to dispensing. 
2. Investigator or designee will record the subject’s number on the appropriate line of the 
schedule. 
3. Investigator or designee will pull the appropriate test articles from the study supply. All test 
articles that are opened, whether dispensed (placed on eye or dispensed outside the clinical site) 
or not, must be recorded on the Test Article Accountability Log in the “Dispensed” section. 
5.2. 
Masking 
Masking will be used to reduce potential bias. Due to the difference in shape of the marketed eye drops 
compared to the test eye drops, double masking is not possible. However, the subjects will be masked 
from the identity of the eye drops. The identity of the investigational products will be masked by over 
labeling the eye drop bottles with a label containing the study number, expiration date and the 
randomization codes. Investigators and clinical site personnel involved in the data collection will not 
be masked as to the identity of the investigational product. 
5.3. 
Procedures for Maintaining and Breaking the Masking 
 
Under normal circumstances, the mask should not be broken until all subjects have completed the study 
and the database is finalized. Otherwise, the mask should be broken only if specific emergency 
treatment/course of action would be dictated by knowing the treatment status of the subject. In such 
cases, the investigator may, in an emergency, contact the medical monitor. In the event the mask is 
broken, the sponsor must be informed as soon as possible. The date, time, and reason for the unmasking 
must be documented in the subject record. The investigator is also advised not to reveal the study 
treatment assignment to the clinical site or sponsor personnel. 
 
Subjects who have had their treatment assignment unmasked are expected to return for all remaining 
scheduled evaluations. Subjects who are discontinued will be replaced. 
6. 
STUDY INTERVENTION 
6.1. 
Identity of Test Articles  
The following test articles will be used in this study: 
 
 
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6.4. 
Packaging and Labeling 
The test articles will be packaged in bottles as the primary packaging. The test article will be over-
labeled to mask the subject to the identity of the eyedrops. The test articles will be in plastic bags as the 
secondary packaging form. The sample study label is shown below: 
 
 
 
6.5. 
Storage Conditions 
Test articles will be maintained at ambient temperatures at the clinical site. Test articles must be kept 
under secure conditions. 
6.6. 
Collection and Storage of Samples 
When possible, any test article associated with an Adverse Event and/or a Product Quality Complaint 
must be retained pending directions from the sponsor for potential return to JJVC. 
6.7. 
Accountability of Test Articles 
JJVC will provide the Investigator with sufficient quantities of study articles and supplies to complete 
the investigation. The Investigator is asked to retain all test article shipment documentation for the test 
article accountability records. 
 
Test articles must be kept in a locked storage cabinet, accessible only to those assigned by the 
Investigator for dispensing. The Investigator may delegate this activity to authorized study site 
personnel listed on the Site Delegation Log. All test articles must be accounted. This includes: 
1. What was dispensed for the subject, to use out of the office, or issued for the subject to replace 
appropriately between visits.  
2. What was returned to the Investigator unused, including expired or malfunctioning product. 
3. The number and reason for unplanned replacements. 
 
The Investigator will collect all unused test articles from the subjects at the end of the subject’s 
participation. Subject returned unused test articles must be separated from the clinical study inventory 
of un-dispensed test articles and must be labeled with the subject number and date of return. Following 
final reconciliation of test articles by the monitor, the Investigator or monitor will return all unused test 
articles to JJVC. 
 
If there is a discrepancy between the shipment documents and the contents, contact the study monitor 
immediately. 
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8. 
SUBJECTS COMPLETION/WITHDRAWAL  
8.1. 
Completion Criteria 
Subjects are considered to have completed the study if they:  
x 
provided informed consent. 
x 
they are eligible. 
x 
Completed all study visits 
x 
Not have withdrawn/ discontinued from the study for any reason described in section 4.2. 
8.2. 
Withdrawal/Discontinuation from the Study 
A subject will be withdrawn from the study for any of the following reasons: 
x 
Subject withdrawal of consent. 
x 
Subject not compliant to protocol including drop usage schedule 
x 
Subject lost to follow-up. 
x 
Subject no longer meets eligibility criteria (e.g. the subject becomes pregnant). 
x 
Subject develops significant or serious adverse events necessitating discontinuation of study 
eyedrops  
x 
Subjects who have experienced a Corneal Infiltrative Event (CIE). 
x 
Investigator’s clinical judgment regarding the subject safety reasons (that it is in the best 
interest of the subject to stop treatment). 
x 
Subject deemed incapable of dispensing the drops safely and effectively (Based on 
investigator’s judgment. 
 
For discontinued subjects, the Investigator will: 
x 
Complete the current visit (scheduled or unscheduled). 
x 
Complete the Final Evaluation, indicating the reason that the subject was discontinued from 
the study. 
x 
Record the spherocylindrical refraction with best corrected distance visual acuity. 
x 
Collect used test article(s) (used or brought to the visit) from the subject and discard them, 
unless otherwise stated in section 7.2. 
x 
Collect all unused test article(s) from the subject. 
x 
Make arrangements for subject care, if needed, due to their study participation 
 
Additional subjects will be enrolled if a subject discontinues from the study prematurely (within the 
enrollment window specified by the sponsor).  
 
In cases where a subject is lost to follow-up, every possible effort must be made to contact the subject 
and determine the reason for discontinuation/withdrawal. The measures taken to follow up must be 
documented including two written attempts and a certified letter (or equivalent) as the final attempt.  
9. 
PRE-STUDY AND CONCOMITANT INTERVENTION/MEDICATION 
Concomitant medications will be documented during screening and updated during the study. 
Disallowed medications for this study include: Current habitual use of Prescription-only medicines for 
Dry Eye Diseases or ocular discomfort, ocular steroids, or any medications (either prescription-only or 
OTC) that would interfere with the clinical study (at the discretion of the investigator). 
 
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11. STUDY TERMINATION 
If more than 2 subjects in the investigational lubricating eyedrop group develop serious expected (e.g., 
definite, or probable MK) or unexpected eyedrop related adverse events, the study will be suspended. 
Upon review and consultation with IRB, DMC, and JJVC Safety Management Team, the study may be 
terminated.  
 
The occurrence of one or more unexpected Serious Adverse Drug Reactions (ADR), or any SAE where 
the relationship to study agent cannot be ruled out, may result in stopping further dispensing of test 
article. In the event of an unexpected ADR or SAE, the Sponsor may unmask the treatment regimen 
for the subject(s) and will discuss this with the Investigator before any further subjects are enrolled. 
 
The Sponsor will determine when a study will be stopped. The Principal Investigator always has the 
discretion to initiate stopping the study based on patient safety or if information indicates the study’s 
results are compromised. 
 
JJVC reserves the right to terminate the study at any time for any reason. Additionally, the IEC/IRB 
reserves the right to terminate the study if an unreasonable risk is determined. The study can be 
terminated by the Principal Investigator at the individual clinical site due to specific clinical 
observations, if in their opinion, after a discussion with JJVC, it is determined that it would be unwise 
to continue at the clinical site. 
 
JJVC (and the IEC/IRB and DMC, if applicable) will evaluate all adverse events. If it is determined 
that an adverse event presents an unreasonable risk, the investigation, or that part of the investigation 
presenting the risk, will be terminated as soon as possible. 
 
Should the study be terminated (either prematurely or as scheduled), the Investigator will notify the 
IEC/IRB and Regulatory Authority as required by local regulatory requirements. 
12. PROCEDURE FOR HANDLING PRODUCT QUALITY COMPLAINTS 
A Product Quality Complaint (PQC) refers to any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of test articles after they have been released for clinical trial use.   
 
Potential complaints may come from a variety of sources including but not limited to subjects, clinical 
research associates (CRA), clinical operations managers (COM), medical monitors, and site personnel, 
etc. The following are not considered product quality complaints: 
x 
Subject satisfaction inquiries reported via “Subjective Questionnaires” and “Patient Reported 
Outcomes (PRO).” 
x 
Clinical test articles that are stored improperly or damaged after receipt at the investigational 
site. 
x 
Artificial tear replacements that occur due to loss/run out. 
x 
Damage deemed by clinicians or clinical staff to be caused by handling by the user, and not 
indicative of a quality deficiency (i.e. tears, rips, etc.), only in situations where there is no 
deficiency alleged by the subject. 
 
Within 24 hours of site personnel becoming aware that a PQC has occurred, the PQC must be recorded 
in the EDC system, which will trigger an automatic email notification to the appropriate COM/CRA 
and Clinical QA representative. In cases where the EDC system in use is not configured to send 
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automatic notifications or when an EDC system is not used, the COM/CRA is responsible for notifying 
Clinical QA upon discovery that a PQC has occurred.   
 
Upon receipt of the EDC notification, the COM/CRA will contact the study site to collect additional 
information which will include:  
x 
Date the complaint was received/recorded in the EDC System (Date of Sponsor Awareness). 
x 
Who received the complaint. 
x 
Study number. 
x 
Clinical site information (contact name, site ID, telephone number). 
x 
Lot number(s). 
x 
Unique Subject Identifier(s). 
x 
Indication of who first observed complaint (site personnel or subject). 
x 
OD/OS indication, along with whether the eyedrop was used. 
x 
Any related AE number if applicable. 
x 
Detailed complaint description (scheduled/unscheduled visit, time of eyedrop usage, 
symptoms, resolution of symptoms, etc.). 
x 
Eye Care Provider objective (slit lamp) findings if applicable. 
x 
Confirmation of product availability for return (and tracking information, if available), or 
rationale if product is not available for return 
 
 
 
Once a complaint is received, it will be assessed by the COM, CRA, or trained site personnel to 
determine if it is an Adverse Event/Serious Adverse Event (AE/SAE). If the complaint results in an 
AE/SAE, the COM/CRA, or trained site personnel will follow section 13 of this protocol. If the 
AE/SAE was potentially the result of a product quality related deficiency, these procedures also apply 
and will be executed in parallel.   
 
In some cases, a PQC form may be generated in EDC by the site in error. In this event, the PQC forms 
will be marked “Intentionally Left Blank” or “ILB”.  Justification for ILB must be documented. 
13. ADVERSE EVENTS 
13.1. Definitions and Classifications 
Adverse Event (AE) – An AE is “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 adverse event (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”  
 
NOTE: This definition includes events related to the investigational medical device or the 
comparator, and to the procedures involved. For users or other persons, this definition is 
restricted to events related to investigational medical devices/drugs. 1 
 
An AE includes any condition (including a pre-existing condition) that: 
1. Was not present prior to the study, but appeared or reappeared following initiation of the study. 
2. Was present prior to the study but worsened during the study. This would include any condition 
resulting from concomitant illnesses, reactions to concomitant medications, or progression of 
disease states. 
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NOTE: Pregnancy must be documented as an adverse event and must be reported to the clinical 
monitor and to the Sponsor immediately upon learning of the event. 
 
Serious Adverse Event (SAE) – An SAE is any adverse event that led to any of the following: 
x 
Death 
x 
Serious deterioration in the health of the subject that resulted in any of the following: 
x 
Life-threatening illness or injury 
x 
Permanent or persistent impairment of a body structure or a body function 
x 
Hospitalization or prolongation of patient hospitalization 
x 
Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function. 
x 
Chronic disease 
x 
Foetal distress, foetal death or a congenital physical or mental impairment of birth defect. 
 
Diagnoses and conditions that are considered Ocular Serious Adverse Events include, but not limited 
to: 
x 
Microbial Keratitis (MK) 
x 
Iritis (including cells in the anterior chamber) 
x 
Permanent decrease in best spectacle corrected visual acuity equivalent to 2 acuity lines or 
greater 
x 
Central Corneal Opacity 
x 
Central Corneal Neovascularization 
x 
Uveitis 
x 
Endophthalmitis 
x 
Hypopyon 
x 
Hyphemia 
x 
Penetration of Bowman’s Membrane 
x 
Persistent Epithelial Defect 
x 
Limbal cell Damage leading to Conjunctivalization 
 
Significant Adverse Events – are defined as events that are symptomatic and warrant discontinuation 
(temporary or permanent) of the test articles (excluding Serious Adverse Events). 
 
Diagnoses and conditions that are considered Ocular Significant Adverse Events include, but not 
limited to the following: 
x 
Significant Infiltrative Events (SIE) 
x 
Any Temporary Loss of > 2 Lines of BSCVA 
x 
Other grade 3 or higher corneal findings, such as abrasions or edema 
x 
Corneal events - e.g. Epidemic Keratoconjunctivitis (EKC) 
x 
Asymptomatic Corneal Scar 
x 
Any corneal event which necessitates temporary eyedrop discontinuation > 2 weeks 
 
Non-Significant Adverse Events – are defined as those events that are usually asymptomatic and 
usually do not warrant discontinuation of tear supplement use but may cause further symptoms.  
However, the Investigator may choose to prescribe treatment as a precautionary measure.   
 
Diagnoses and conditions that are considered Ocular Non-Significant Adverse Events include, but not 
limited to the following: 
x 
Non-significant Infiltrative Event (NSIE) 
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x 
Papillary Conjunctivitis 
x 
Superficial Punctate Keratitis (SPK) 
x 
Conjunctivitis: Bacterial, Viral, Allergic 
x 
Blepharitis 
x 
Meibomianitis 
x 
Contact Dermatitis 
x 
Localized Allergic Reactions or infections 
x 
Any corneal event not explicitly defined as serious or significant adverse event, which 
necessitates temporary eyedrop discontinuation < 2 weeks 
 
Adverse Drug Reaction (ADR) – An ADR is referred to all “noxious and unintended 
responses to a drug product related to any dose where a causal relationship between a medical 
product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be 
ruled out.”2  
13.2. Assessing Adverse Events 
In conjunction with the medical monitor, the Investigator will evaluate adverse events to ensure the 
events are categorized correctly. Elements of categorization will include: 
x 
Seriousness/Classifications (see definition in section 13.1). 
x 
Causality or Relatedness – i.e. the relationship between the test article, study treatment or study 
procedures and the adverse event (not related, unlikely related, possibly related, or related - see 
definition in section 13.2.1). 
x 
Adverse Event Severity – Adverse event severity is used to assess the degree of intensity of the 
adverse event (mild, moderate, or severe - see definition in section 13.2.2). 
x 
Outcome – not recovered or not resolved, recovering, or resolving, recovered, or resolved with 
sequelae, recovered or resolved, death related to adverse event, or unknown. 
x 
Actions Taken – none, temporarily discontinued, permanently discontinued, or other. 
13.2.1. Causality Assessment 
Causality Assessment – A determination of the relationship between an adverse event and the test 
article. The test article relationship for each adverse event should be determined by the investigator 
using these explanations: 
x 
Not Related- An adverse event that is not related to the use of the test article, study treatment 
or study procedures. 
x 
Unlikely Related – An adverse event for which an alternative explanation is more likely, e.g. 
concomitant treatment, concomitant disease(s), or the relationship of time suggests that a causal 
relationship is not likely. 
x 
Possibly Related – An adverse event that might be due to the use of the test article, or to the 
study treatment or study procedures. An alternative explanation, e.g. concomitant treatment, 
concomitant disease(s), is inconclusive. The relationship in time is reasonable. Therefore, the 
causal relationship cannot be excluded. 
x 
Related – An adverse event that is listed as a possible adverse effect (device) or adverse reaction 
(drug) and cannot be reasonably explained by an alternative explanation, e.g. concomitant 
treatment of concomitant disease(s). The relationship in time is very suggestive, e.g. it is 
confirmed by de-challenge and re-challenge. 
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13.2.2. Severity Assessment 
Severity Assessment – A qualitative assessment of the degree of intensity of an adverse event as 
determined by the Investigator or reported to him/her by the subject. The assessment of severity is made 
irrespective of test article, study treatment or study procedure relationship or seriousness of the event 
and should be evaluated according to the following scale: 
x 
Mild – Event is noticeable to the subject but is easily tolerated and does not interfere with the 
subject’s daily activities. 
x 
Moderate – Event is bothersome, possible requiring additional therapy, and may interfere with 
the subject’s daily activities. 
x 
Severe – Event is intolerable, necessitates additional therapy or alteration of therapy and 
interferes with the subject’s daily activities. 
13.3. Documentation and Follow-Up of Adverse Events 
The recording and documenting of adverse events (ocular and non-ocular) begin when the subjects are 
exposed to the test article, study treatment or study procedure.  Adverse events reported before the use 
of test article, start of study treatment, or study procedures will be recorded as medical history. 
However, if the condition deteriorates at any time during the study, it will be recorded and reported as 
an AE. Untoward medical events reported after the subject’s exit from the study will be recorded as 
adverse events at the discretion of the Investigator. 
 
Upon finding an adverse event, the Principal Investigator will document the condition in the subject 
record and in the eCRFs and complete the Adverse Event eCRF.   
Complete descriptions of all adverse events must be available in the subject record. All Adverse Events 
including local and systemic reactions not meeting the criteria for “serious adverse events” shall be 
captured on the appropriate case report form or electronic data system. All adverse events occurring 
while the subject is enrolled in the study must be documented appropriately regardless of relationship.   
 
It is the Investigator’s responsibility to maintain documentation of each reported adverse event. All 
adverse events will be followed in accordance with applicable licensing requirements. Such 
documentation will include the following: 
x 
Adverse event (diagnosis not symptom). 
x 
Drawings or photographs (where appropriate) that detail the finding (e.g., size, location, and 
depth, etc.). 
x 
Date the clinical site was notified. 
x 
Date and time of onset. 
x 
Date and time of resolution. 
x 
Adverse event classification, severity, and relationship to test articles, as applicable. 
x 
Treatment regimen instituted (where appropriate), including concomitant medications 
prescribed, in accordance with applicable licensing requirements. 
x 
Any referral to another health care provider if needed. 
x 
Outcome, ocular damage (if any). 
x 
Likely etiology. 
x 
Best corrected visual acuity at the discovery of the event and upon conclusion of the event, if 
the AE is related to the visual system. 
 
Upon discovery of an AE that is deemed ‘possibly related’ or ‘related’ to the test article or study 
procedures (whether related to the visual system or not), an AE review form 
 must be 
completed. Additional dated and initialed entries should be made at follow-up evaluations. Separate 
forms must be completed for each eye if the AE is bilateral.  
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In addition, if an infiltrate(s) is present, he/she will complete the Corneal Infiltrate Assessment eCRF. 
Where necessary, a culture of the corneal lesion will be collected to determine if the infection is 
microbial in nature. If cultures are collected, the date of culture collection and laboratory utilized will 
be recorded.  
 
Changes in the severity of an AE shall be documented to allow an assessment of the duration of the 
event at each level of intensity to be performed. Adverse events characterized as intermittent require 
documentation of the onset and duration of each episode. Changes in the assessment of relationship to 
the Test Article shall also be clearly documented. 
 
Subjects who present with an adverse event shall be followed by the Investigator, within licensure, until 
all signs and symptoms have returned to pre-treatment status, stabilized, or been satisfactorily resolved. 
If further treatment beyond licensure is required, the patient will be referred to the appropriate health 
care provider. The Investigator will use his/her clinical judgment as to whether a subject reporting with 
an adverse event will continue in the study. If a subject is discontinued from the study, it will be the 
responsibility of the Investigator to record the reason for discontinuation. The Investigator will also 
document the adverse event appropriately and complete the Adverse Event eCRF. Any subjects with 
ongoing adverse events related to the test article, study treatment or study procedures, as of the final 
study visit date, should be followed to resolution of the adverse event or until referral to an appropriate 
health care provider, as recommended by the Investigator. Non-ocular adverse events that are not 
related to the test article, study treatment, or study procedures may be recorded as “ongoing” without 
further follow-up. 
13.4. Reporting Adverse Events  
The Investigator will notify the Sponsor of an adverse event by e-mail, facsimile, or telephone as soon 
as possible and no later than 24 hours from discovery for any serious /significant adverse events, and 2 
days from discovery for any non-significant adverse event. In addition, a written report will be 
submitted by the Principal Investigator to the IEC/IRB according to their requirements (section 13.4.2). 
The report will comment whether the adverse event was considered to be related to the test article, 
study treatment or study procedures. 
13.4.1. Reporting Adverse Events to Sponsor 
Serious/Significant Adverse Events 
The Investigator will inform the sponsor of all serious/significant adverse events occurring during the 
study period as soon as possible by e-mail or telephone, but no later than 24 hours following discovery 
of the event. The Investigator is obligated to pursue and obtain information requested by the Sponsor 
in addition to that information reported on the eCRF. All subjects experiencing a serious/significant 
adverse event must be followed up and all outcomes must be reported. 
 
When medically necessary, the Investigator may break the randomization code to determine the identity 
of the treatment that the subject received. The Sponsor and study monitor should be notified prior to 
unmasking the test articles. 
 
In the event of a serious/significant adverse event, the Investigator must: 
x 
Notify the Sponsor immediately. 
x 
Obtain and maintain in the subject’s records all pertinent medical information and medical 
judgment for colleagues who assisted in the treatment and follow-up of the subject. 
x 
Provide the Sponsor with a complete case history which includes a statement as to whether the 
event was or was not related to the use of the test article. 
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x 
Notify the IEC/IRB as required by the IEC/IRB reporting procedure according to national 
regulations. 
 
Non-Serious Adverse Events 
All non-serious adverse events, including non-serious adverse drug reactions, will be reported to the 
sponsor by the Investigator no later than 2 days from discovery. 
13.4.2. Reporting Adverse Events to the Responsible IEC/IRB and Health Authorities 
Adverse events that meet the IEC/IRB requirements for reporting must be reported within the 
IEC/IRB’s written guidelines. Each clinical site will refer to and follow any guidelines set forth by their 
Approving IEC/IRB. Each clinical site will refer to and follow any guidelines set forth by their local 
governing Health Authorities. 
 
The Sponsor will report applicable Adverse Events to the local health authorities according to the 
written guidelines, including reporting timelines.  
13.5. Event of Special Interest 
None 
13.6. Reporting of Pregnancy 
Subjects reporting pregnancy (by self-report) during the study will be discontinued after the event is 
recorded as an Adverse Event. Once discontinued, pregnant participants and their fetuses will not be 
monitored for study related purposes. Pregnant participants are not discontinued from artificial tear 
solution related studies for safety concerns, but due to general concerns relating to pregnancy and 
solution use. Specifically, pregnant women are discontinued due to fluctuations in refractive error 
and/or visual acuity that occur secondary to systemic hormonal changes, and not due to unforeseen 
health risks to the mother or fetus. 
14. STATISTICAL METHODS 
14.1. General Considerations 
Statistical Analysis will be undertaken by the sponsor or under the authority of the sponsor. A general 
description of the statistical methods to be implemented in this clinical trial is outlined below.  
 
All data summaries and statistical analyses will be performed using the SAS software Version 9.4 or 
higher10. Throughout the analysis of data, the results for each subject/eye will be used when available 
for summarization and statistical analysis. Unscheduled visits will be summarized separately and will 
be excluded from any efficacy analyses. However, unscheduled visits will be included in any analysis 
that may be conducted on safety endpoints. 
 
Summary tables (descriptive statistics and/or frequency tables) will be provided for all baseline 
variables, efficacy variables and safety variables as appropriate. Continuous variables will be 
summarized with descriptive statistics (n, mean, standard deviation (SD), median, minimum, and 
maximum). Frequency count and percentage of subjects or eyes within each category will be provided 
for categorical data. 
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14.2. Sample Size Justification 
This study was designed and powered to test for non-inferiority of the Test relative to the Control eye 
drops with respect to the overall ocular comfort score using Visual Analog Scale for Ocular Comfort 
(VAS), with a minimum power of 90% and two-sided Type I error rate of 0.05. A non-inferiority margin 
of -20 will be used to test the hypothesis. If the Test eye drops perform on average worse by more than 
20 points on the VAS may be considered clinically unacceptable. 
 
Historical data from a previous study, 
, was utilized in assessing scenarios for power analysis 
of the VAS. Summary statistics from the historical study 
 are presented in Table 8. The 
historical VAS, for the difference of 30 days follow-up from baseline scores, shows a slight left skew, 
indicating there is a possibility of a non-normally distributed result in this study. Hence, the sample 
size calculations were conducted using (i) two-sided, parametric two-sample t-test for normally 
distributed data, and (ii) non-parametric Wilcoxon Rank Sum test for non-normal data in PASS 
software Version 21.0.6 (2021) (NCSS LLC, Kaysville UT)11. 
Table 8: Summaries for Historical Overall Comfort Score Change from Baseline at 30-Day Follow-up 
using Visual Analog Scale (VAS) Questionnaire - Intent-To-Treat Population 
Group 
Number 
Analyzed 
Mean 
Difference 
Standard 
Deviation 
Minimum Median Maximum 
Blink® Tears 
80 
12.5 
25.74 
-69 
13.0 
62.0 
Investigational Lipid 
Drop     
75 
20.3 
23.24 
-21 
18.0 
78.0 
 
The common standard deviation considered was based on results from study 
, in which the 
estimated standard deviation of change in overall ocular comfort score from baseline at 30-day in the 
control group was estimated to be 25.74. In addition to the historical standard deviation value (25), the 
standard deviation was assumed to be 30 and 35, respectively, given the possibility of more variation 
being observed in the Test group. The estimated effect size (difference in change from baseline at 30-
day follow-up between Test and Control) was assumed to be 0 as a more conservative estimate 
compared to the effect size observed in 
   
 
Sample Size Calculation using Parametric Method 
 
Table 9 displays the sample size estimates for the primary endpoint using a two-sample t-test for non-
inferiority, for different scenarios of standard deviations and dropout rates. 
Table 9: Sample size calculations using two-sample t-test for non-inferiority 
Standard 
deviation 
Sample 
size 
per 
arm 
Total  
sample 
size 
Sample size per 
arm including a 
5% dropout rate 
Total sample 
size including 
5% 
dropout 
rate 
Sample size per 
arm including a 
10% 
dropout 
rate 
Total 
sample 
size including 
10% 
dropout 
rate 
25 
34 
68 
36 
72 
38 
76 
30 
49 
98 
52 
104 
55 
110 
35 
66 
132 
70 
140 
74 
148 
Note: Sample size relating to 90% power, Type I Error rate of 0.05, assumed effect size of 0, non-
inferiority margin of -20. 
 
Sample Size Calculation using Non-Parametric Method 
 
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Primary Hypotheses for Plan A or Plan B: 
The null and alternative hypotheses for non-inferiority of Test relative to Control are as follows: 
 
ܪ଴: ο ൑െ20  
ܪ஺: ο > െ20 
 
where ο is the difference in mean change from baseline at 30-Day follow-up between treatment group 
and control group (Test minus Control).   
 
The Ocular Comfort Scores will be analyzed for normality using the Shapiro-Wilk test. If the data is 
normally distributed, then Primary Analysis Plan A will be implemented. Otherwise, Primary Analysis 
Plan B will be implemented.  
 
Primary Analysis Plan A (Assuming Normality) 
 
The overall change of ocular comfort score from baseline at 30-Day follow-up will be analyzed using 
a linear mixed model. The subjects are the level one units, and the investigational sites are the level two 
units. The model will include treatment group (Test, Control) as a fixed effect, and investigational site 
as a random effect. Age and gender will be included in the model as covariates. The log-likelihood ratio 
test may be used to assess the homogeneity of the variances with respect to treatment and sites. The 
Kenward and Roger12 method will be used to calculate the denominator degree of freedom. 
 
The model for each hypothesis is: 
Let ݕ௜௝ denote the change in VAS ocular comfort score from baseline at 30-Day follow-up for the ݆௧௛ 
subject from the ݅௧௛ site (݆= 1, … , ݊; ݅= 1, 2, … , 8). The linear mixed model will be constructed as 
follows: 
ݕ௜௝= ߚ଴+ ߚଵή ܤܣܵܧ௜௝+ ߚଶή ܴܶܶ௜௝+ ߚଷή ܣ݃݁௜௝+ ߚସή ܩ݁݊݀݁ݎ௜௝ + Ɂ௜+ ߳௜௝, 
where 
x 
ߚ଴ = Intercept 
x 
ܤܣܵܧ௜௝= VAS ocular comfort score at baseline for the ݆௧௛ subject in the ݅௧௛ investigational 
site 
x 
ܴܶܶ௜௝=  treatment assigned to the ݆௧௛ subject in the ݅௧௛ investigational site (Test vs Control 
eye drop group) 
x 
ߚଶ= the treatment effect of interest 
x 
ߜ௜= a random effect (subject-specific intercept) term for the ݅௧௛ site 
x 
߳௜௝= a random error associated with the ݆௧௛ subject in the ݅௧௛ investigational site. 
 
Assume that ߜ௜ and ߳௜௝ are independent and identically distributed such that ߜ௜ ~ ܰ(0, ߪ௦௜௧௘
ଶ
); 
 ߳௜௝~ ܰ(0, ߪଶ), and are independent of each other. 
 
The non-inferiority test will be based on the least square mean change difference and corresponding 
95% confidence interval from the final model. Non-inferiority will be concluded if the lower limit of 
the 95% confidence interval is above non-inferiority margin of -20. 
 
Primary Analysis Plan B (Assuming-non-normal distribution) 
 
The difference of VAS Ocular comfort scores between treatment group and control group in mean 
change from baseline at 30-Day follow-up (Test minus Control) and two-sided 95% confidence interval 
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will be computed using a bootstrap methodology13. A total of 4000 bootstrap iterations will be used 
following the suggestions of Samuelson and Petrick14. Bias-adjusted 95% confidence interval will also 
be calculated. The assessment of the impact of the autocorrelation for between subjects repeated 
measurements, is defined by the difference between the observed statistic compared to the bootstrapped 
population mean (bias = observed minus bootstrapped population mean). This approach was 
recommended for all estimations of statistical inference since it accommodates correlated data. The 
bootstrap analysis will be performed using SAS MACRO procedures as discussed by Davison, AC and 
Hinkley, DV12. 
 
The non-inferiority test will be based on mean change difference and corresponding 95% confidence 
interval using the 2.5th percentile and 97.5th percentile from the bootstrapping model. The lower bound 
of the 95% confidence interval will be compared to the non-inferiority margin of -20. If the lower bound 
is greater than or equal to -20, the null hypothesis will be rejected, and the Test will be considered non-
inferior to Control. 
14.6. Secondary Analysis  
Change in Overall Quality of Vision from Baseline at 30-Day Follow-Up Using VAS Scores 
The overall change of quality of vision from baseline at 30-Day follow-up will be analyzed with the 
same hypotheses and models as primary analyses. If the Shapiro-Wilks test result is significant, then 
Primary Analysis Plan B will be adapted for overall change of quality of vision at 30-Day follow-up. 
Otherwise, Primary Analysis Plan A will be adapted for this secondary analysis.   
 
Hypothesis Testing:   
The two separate null and alternative hypotheses for non-inferiority of Test relative to Control are as 
follows:  
ܪ଴: ο ൑െ20  
ܪ஺: ο > െ20 
 
where ο is the difference between treatment group in mean change from baseline at 30-Day follow-up 
(Test minus Control).  
 
14.7. Other Exploratory Analysis  
Exploratory analyses will only be conducted if all primary and secondary hypotheses are met. If 
conducted, exploratory analysis will be analyzed for the Safety population. The exploratory analyses 
will be analyzed as follows: 
 
Change in Overall Ocular Comfort from Baseline at 14-Day Follow-Up Using VAS Scores 
The overall change in ocular comfort from baseline at 14-Day follow-up will be analyzed as described 
in primary analyses (section 14.5). 
 
Change in Overall Quality of Vision from Baseline at 14-Day Follow-Up Using VAS Scores 
The overall change in ocular comfort from baseline at 14-Day follow-up will be analyzed as described 
in secondary analyses (section 14.5).  
 
Corneal Staining (Grade 2 or higher) Using FDA Scale  
Corneal staining response using FDA grading scale (i.e. Grade 0 = None, Grade 1 = Trace, Grade 2 = 
Mild, Grade 3 = Moderate and Grade 4 = Severe) will be monitored by surveillance tabulation by 
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treatment group. If the rates between groups are significantly different from each other, then further 
analyses will be performed.   
 
Subject’s reported ocular symptoms 
Subjects are asked to report if they experienced any ocular symptoms at Baseline and during each 
follow-up. If the number of reported ocular symptoms exceeds 5% total population, further analyses 
will be done to investigate the correlation of ocular symptoms to the Test drops.   
14.8. Interim Analysis 
No interim analysis is planned in this study.  
14.9. Procedure for Handling Missing Data and Drop-Outs 
All analyses will be performed on observed case data. Missing values will not be imputed. The count 
of missing values will be included in the summary tables and listings. In the event that more than 10% 
(10 subjects) have missing data, a sensitivity analysis will be conducted for the primary and secondary 
endpoints using multiple imputation method. Full details regarding methods for the imputations will be 
outlined in SAP.  
14.10. Procedure for Reporting Deviations from Statistical Plan 
The analysis will be conducted according to that specified in above sections. There are no known 
reasons for which it is planned to deviate from these analysis methods. If for any reason a change is 
made, the change will be documented in the study report along with a justification for the change. 
15. DATA HANDLING AND RECORD KEEPING/ARCHIVING 
15.1. Electronic Case Report Form/Data Collection 
The data for this study will be captured on electronic case report forms (eCRFs) using the Clario EDC 
system. An authorized data originator will enter study data into the eCRFs using the EDC system. Data 
collected on equipment that is not captured in EDC will be formatted to the specification of the JJVC 
database manager and sent to JJVC for analysis. External data sources for this study are not applicable 
 
The clinical data will be recorded on dedicated eCRFs specifically designed to match the study 
procedures for each visit. Only specifically delegated staff can enter data on a CRF.  Once completed, 
the eCRFs will be reviewed for accuracy and completeness and signed by the Investigator. The sponsor 
or sponsor’s representatives will be authorized to gain access to the subject recordation for the purposes 
of monitoring and auditing the study.  
 
Edit checks, electronic queries, and audit trails are built into the system to ensure accurate and complete 
data collection. Data will be transmitted from the clinical site to a secure central database as forms are 
completed or updated, ensuring information accuracy, security, and confidentiality. After the final 
database lock, the Investigator will be provided with Individual Patient Profiles (IPP) including the full 
audit trail on electronic media in PDF format for all of the study data. The IPP must be retained in the 
study files as a certified copy of the source data for the study.  
 
The content and structure of the eCRFs are compliant with ISO14155:2020. 1 
15.2. Subject Record 
At a minimum, subject record should be available for the following:  
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x 
subject identification 
x 
eligibility 
x 
study identification 
x 
study discussion 
x 
provision of and date of informed consent 
x 
visit dates 
x 
results of safety and efficacy parameters as required by the protocol 
x 
a record of all adverse events 
x 
follow-up of adverse events 
x 
medical history and concomitant medication 
x 
test article receipt/dispensing/return records 
x 
date of study completion 
x 
reason for early discontinuation of test article or withdrawal from the study, if applicable 
 
The subject record is the eCRF or an external record. The author of an entry in the subject record must 
be identifiable. The first point of entry is considered to be the source record. 
 
Adverse event notes must be reviewed and initialed by the Investigator. 
15.3. Trial Registration on ClinicalTrials.gov  
This study will be registered on ClinicalTrials.gov by the Sponsor.  
16. DATA MANAGEMENT 
16.1. Access to Source Data/Document 
The Investigator/Institution will permit trial-related monitoring, audits, IEC/IRB review and regulatory 
inspection(s) by providing direct access to source data/documents. Should the clinical site be contacted 
for an audit by an IEC/IRB or regulatory authority, JJVC must be contacted and notified in writing 
within 24 hours. 
16.2. Confidentiality of Information 
Information concerning the investigational product and patent application processes, scientific data or 
other pertinent information is confidential and remains the property of JJVC. The Investigator may use 
this information for the purposes of the study only. It is understood by the Investigator that JJVC will 
use information developed in this clinical study in connection with the development of the 
investigational product and therefore may disclose it as required to other clinical investigators and to 
regulatory agencies. In order to allow the use of the information derived from this clinical study, the 
Investigator understands that he/she has an obligation to provide complete test results and all data 
developed during this study to the Sponsor. 
16.3. Data Quality Assurance 
Steps will be taken to ensure the accuracy and reliability of data, include the selection of qualified 
investigators and appropriate clinical sites and review of protocol procedures with the Principal 
Investigator. The Principal Investigator, in turn, must ensure that all Sub-Investigators and clinical site 
personnel are familiar with the protocol and all study-specific procedures and have appropriate 
knowledge of the study article. 
 
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Training on case report form completion will be provided to clinical site personnel before the start of 
the study. The Sponsor will review case report forms for accuracy and completeness remotely during 
the conduct of the study, during monitoring visits, and after transmission to data management. Any data 
discrepancies will be resolved with the Investigator or designee, as appropriate. 
 
Quality Assurance representatives from JJVC may visit clinical sites to review data produced during 
the study and to access compliance with applicable regulations pertaining to the conduct of clinical 
trials. The clinical sites will provide direct access to study-related source data/documents and reports 
for the purpose of monitoring and auditing by JJVC and for inspection by local and regulatory 
authorities. 
16.4. Data Monitoring Committee (DMC) 
Not applicable 
17. CLINICAL MONITORING 
The study monitors will maintain close contact with the Principal Investigator and the Investigator’s 
designated clinical site personnel. The monitor’s responsibilities will include: 
x 
Ensuring that the investigation is being conducted according to the protocol, any subsequent 
versions, and regulatory requirements are maintained. 
x 
Ensuring the rights and wellbeing of subjects are protected. 
x 
Ensuring adequate resources, including facilities, laboratories, equipment, and qualified 
clinical site personnel. 
x 
Ensuring that protocol deviations are documented with corrective action plans, as applicable. 
x 
Ensuring that the clinical site has sufficient test article and supplies. 
x 
Clarifying questions regarding the study. 
x 
Resolving study issues or problems that may arise. 
x 
Reviewing of study records and source documentation verification in accordance with the 
monitoring plan. 
18. ETHICAL AND REGULATORY ASPECTS 
18.1. Study-Specific Design Considerations 
Potential subjects will be fully informed of the risks and requirements of the study, and, during the 
study, subjects will be given any new information that may affect their decision to continue 
participation. Subjects will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which they would 
otherwise be entitled. Subjects will only be enrolled if the subject is fully able to understand the risks, 
benefits, and potential adverse events of the study and provide their consent voluntarily 
18.2. Investigator Responsibility 
The Principal Investigator is responsible for ensuring that the clinical study is performed in accordance 
with the signed agreement, the investigational plan, according to ISO 14155:2020,1  ICH-GCP E6 (R2)2 
and applicable regulatory requirements. GCP is an international ethical and scientific quality standard 
for designing, conducting, recording, and reporting studies that involve the participation of human 
subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being 
of study subjects are protected, consistent with the principles of the Declaration of Helsinki 64th WMA 
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General Assembly 20132 and that the clinical study data are credible. The Investigator must maintain 
clinical study files in accordance with applicable regulatory requirements. 
18.3. Independent Ethics Committee or Institutional Review Board (IEC/IRB) 
Before the start of the study, the Investigator (or Sponsor when applicable) will provide the IEC/IRB 
with current and complete copies of the following documents (where applicable): 
x 
Final protocol. 
x 
Sponsor-approved informed consent form (and any other written materials to be provided to 
the subjects) 
x 
Investigator’s Brochure (or equivalent information). 
x 
Sponsor-approved subject recruitment materials. 
x 
Information on compensation for study-related injuries or payment to subjects for participation 
in the study. 
x 
Investigator’s curriculum vitae, clinical licenses, or equivalent information (unless not 
required, as documented by IEC/IRB). 
x 
Information regarding funding, name of the Sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects. 
x 
Any other documents that the IEC/IRB requests to fulfill its obligation. 
 
This study will be undertaken only after IEC/IRB has given full approval of the final protocol, the 
informed consent form, applicable recruiting materials, and subject compensation programs, and the 
Sponsor has received a copy of this approval. This approval letter must be dated and must clearly 
identify the documents being approved. 
 
During the study, the Investigator (or Sponsor when applicable) will send the following documents to 
the IEC/IRB for their review and approval, where appropriate: 
x 
Protocol revisions 
x 
Revision(s) to informed consent form and any other written materials to be provided to subjects 
x 
If applicable, new, or revised subject recruitment materials approved by the Sponsor 
x 
Revisions to compensation for study-related injuries or payment to subjects for participation in 
the study 
x 
Investigator’s Brochure revisions  
x 
Summaries of the status of the study (at least annually or at intervals stipulated in guidelines of 
the IEC/IRB) 
x 
Reports of adverse events that are serious, unanticipated, and associated with the test articles, 
according to the IRB’s requirements 
x 
New information that may adversely affect the safety of the subjects or the conduct of the study 
x 
Major protocol deviations as required by the IEC/IRB 
x 
Report of deaths of subjects under the Investigator's care 
x 
Notification if a new Investigator is responsible for the study at the clinical site 
x 
Any other requirements of the IEC/IRB 
 
For protocol revisions that increase subject risk, the revisions and applicable informed consent form 
revisions must be submitted promptly to the IEC/IRB for review and approval before implementation 
of the change(s). 
 
At least once a year, the IEC/IRB will review and reapprove this clinical study. This request should be 
documented in writing. 
 
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At the end of the study, the Investigator (or Sponsor where required) will notify the IEC/IRB about the 
study completion. Documentation of this notification must be retained at the clinical site and a copy 
provided to the CRO or Sponsor as applicable. 
18.4. Informed Consent 
Each subject or their representative, must give written consent according to local requirements after the 
nature of the study has been fully explained. The consent form must be signed before performance of 
any study-related activity. The consent form that is used must be approved by both the Sponsor and by 
the reviewing IEC/IRB. The informed consent is in accordance with principles that originated in the 
Declaration of Helsinki,2 and ISO 14155:2020 guidelines1, applicable regulatory requirements, and 
Sponsor Policy. 
 
Before entry into the study, the Investigator or an authorized member of the clinical site personnel must 
explain to potential subject the aims, methods, reasonably anticipated benefits, and potential hazards of 
the study, and any discomfort it may entail. Subjects will be informed that their participation is 
voluntary and that they may withdraw consent to participate at any time.  
 
The subject will be given sufficient time to read the informed consent form and the opportunity to ask 
questions. After this explanation and before entry into the study, consent should be appropriately 
recorded by means of the subject's dated signature. After having obtained the consent, a copy of the 
informed consent form must be given to the subject. 
 
18.5. Privacy of Personal Data 
The collection, processing and disclosure of personal data and medical information related to the Study 
Subject, and personal data related to Principal Investigator and any clinical site personnel (e.g., name, 
clinic address and phone number, curriculum vitae) is subject to compliance with the Health 
Information Portability and Accountability Act (HIPAA) in the United States15  and other applicable 
personal data protection and security laws and regulations. Appropriate measures will be employed to 
safeguard these data, to maintain the confidentiality of the person’s related health and medical 
information, to properly inform the concerned persons about the collection and processing of their 
personal data, to grant them reasonable access to their personal data and to prevent access by 
unauthorized persons. 
 
All information obtained during the course of the investigation will be regarded as confidential. All 
personal data gathered in this trial will be treated in strictest confidence by Investigators, monitors, 
Sponsor’s personnel and IEC/IRB. No data will be disclosed to any third party without the express 
permission of the subject concerned, with the exception of Sponsor personnel (monitor, auditor), 
IEC/IRB and regulatory organizations in the context of their investigation related activities that, as part 
of the investigation will have access to the CRFs and subject records. 
 
The collection and processing of personal data from subjects enrolled in this study will be limited to 
those data that are necessary to investigate the efficacy, safety, quality, and utility of the investigational 
product(s) used in this study. 
 
These data must be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations. 
The Sponsor ensures that the personal data will be: 
x 
processed fairly and lawfully. 
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x 
collected for specified, explicit, and legitimate purposes and not further processed in a way 
incompatible with these purposes. 
x 
adequate, relevant, and not excessive in relation to said purposes. 
x 
accurate and, where necessary, kept current. 
 
Explicit consent for the processing of personal data will be obtained from the participating subject 
before collection of data. Such consent should also address the transfer of the data to other entities and 
to other countries. 
 
The subject has the right to request through the Investigator access to his personal data and the right to 
request rectification of any data that are not correct or complete. Reasonable steps should be taken to 
respond to such a request, taking into consideration the nature of the request, the conditions of the study, 
and the applicable laws and regulations. 
 
Appropriate technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be put in 
place. Sponsor personnel whose responsibilities require access to personal data agree to keep the 
identity of study subjects confidential. 
19. STUDY RECORD RETENTION 
In compliance with the ISO 14155:20201, guidelines, the Investigator/Institution will maintain all CRFs 
and all subject records that support the data collected from each subject, as well as all study documents 
as specified in ISO 14155:2020,1 and all study documents as specified by the applicable regulatory 
requirement(s). The Investigator/Institution will take measures to prevent accidental or premature 
destruction of these documents. 
 
Essential documents must be retained until at least two (2) years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in 
an ICH region or until at least two (2) years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period if 
required by the applicable regulatory requirements or instructed by the Sponsor. It is the responsibility 
of the Sponsor to inform the Investigator/Institution as to when these documents no longer need to be 
retained. 
 
If the responsible Investigator retires, relocates, or for other reasons withdraws from the responsibility 
of keeping the study records, custody must be transferred to a person who will accept the responsibility. 
The Sponsor must be notified in writing of the name and address of the new custodian. Under no 
circumstance shall the Investigator relocate or dispose of any study documents before having obtained 
written approval from the Sponsor. 
 
If it becomes necessary for the Sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator must permit access to such reports.  
If the Investigator has a question regarding retention of study records, he/she should contact JJVC. 
20. FINANCIAL CONSIDERATIONS 
Remuneration for study services and expenses will be set forth in detail in the Clinical Research 
Agreement. The Research Agreement will be signed by the Principal Investigator and a JJVC 
management representative prior to study initiation. 
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JJVC reserves the right to withhold remuneration for costs associated with protocol violations such as: 
x 
Continuing an ineligible subject in the study. 
x 
Scheduling a study visit outside the subject’s acceptable visit range. 
 
JJVC reserves the right to withhold final remuneration until all study related activities have been 
completed, such as: 
x 
Query resolution. 
x 
Case Report Form signature. 
x 
Completion of any follow-up action items. 
21. PUBLICATION 
 
There is currently no plan to publish this outcome of this investigation. 
22. REFERENCES 
 
1. 
ISO 14155:2020: Clinical investigation of medical devices for human subjects — Good 
clinical practice. Available at: https://www.iso.org/standard/71690.html   
2. 
International Council for Harmonisation Good Clinical Practice E6(R2) (ICH-GCP). 
Available at: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf 
3. 
Declaration of Helsinki – Ethical principles for Medical Research Involving Human 
Subjects. 
Available 
at: 
https://www.wma.net/policies-post/wma-declaration-of-
helsinki-ethical-principles-for-medical-research-involving-human-subjects/   
4. 
United States (US) Code of Federal Regulations (CFR). Available at: 
https://www.gpo.gov/fdsys/browse/collectionCfr.action?collectionCode=CFR 
5. 
Clayton JA. 2018. New England Journal of Medicine. 378(23):2212-2223.  
6. 
Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. Prevalence of diagnosed dry 
eye disease in the United States among adults aged 18 years and older. American 
journal of ophthalmology. 2017;182:90-98.  
7. 
Figus M, Agnifili L, Lanzini M, et al. Topical preservative-free ophthalmic treatments: 
An unmet clinical need. Expert Opinion on Drug Delivery. 2021;18(6):655-672.  
8. 
Begley CG, Nichols KK, Chalmers R. Responses of contact lens wearers to a dry eye 
survey. Optometry and Vision Science. 2000;77(1):40-46.  
9. 
Versura P FM, Campos E. Ocular surface changes over the menstrual cycle in women 
with and without dry eye. Gynecological endocrinology. 2007;23(7):385-390.  
10. 
SAS/STAT® 15.1 User’s Guide. Cary, NC: SAS Institute Inc.; 2018. 
11. 
PASS: Power Analysis and Sample Size Software. Kaysville, Utah, USA.: NCSS LLC; 
2021. 
12. 
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics. 1997:983-997.  
13. 
Davison AC, Hinkley DV. Bootstrap methods and their application. Cambridge 
university press; 1997. 
14. 
Samuelson FW, Petrick N. Comparing image detection algorithms using resampling. 
IEEE; 2006:1312-1315. 
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15. 
Health Information Portability and Accountability Act (HIPAA). Available at: 
https://www.hhs.gov/hipaa/for-professionals/privacy/index.html  
 
 
 
 
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APPENDIX A: PATIENT REPORTED OUTCOMES (STUDY QUESTIONNAIRES) 
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APPENDIX B: PATIENT INSTRUCTION GUIDE   
A patient instruction guide (PIG) will be provided separately. 
 
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APPENDIX C: PACKAGE INSERT (APPROVED PRODUCT) 
 
 
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Drug Facts
Active Ingredient  
Purpose
Polyethylene Glycol 400 0.25% . . . . . . . Eye lubricant
Uses  ■  For the temporary relief of burning, 
irritation, and discomfort due to dryness of the eye or 
exposure to wind or sun.
■  May be used as a protectant against further irritation. 
Warnings
■  For external use only.
■  To avoid contamination, do not touch tip of 
container to any surface. Replace cap after using. 
■  Do not use if solution changes color or becomes cloudy.
Stop use and ask a doctor if:
You experience eye pain, changes in vision, continued 
redness or irritation of the eye, or if the condition 
worsens or persists for more than 72 hours.
Keep out of the reach of children.
If swallowed, get medical help or contact a Poison 
Control Center right away. 
Directions
Instill 1 or 2 drops in the affected eye(s) as needed or 
as directed by your eye care professional.
Inactive Ingredients 
Boric Acid; Calcium Chloride; Magnesium Chloride; 
Potassium Chloride; Puriﬁed Water; Sodium Borate; 
Sodium Chloride; Sodium Chlorite (OcuPure® brand) 
as a preservative; Sodium Hyaluronate. 
Other Information
Use only if tape seals on top and bottom ﬂaps are intact.
RETAIN THIS CARTON FOR FUTURE REFERENCE.
Lubricating Eye Drops
blink
ting Eye Drops
Tears
Tears
Discard solution 90 days after opening
Product of China made in accordance with US FDA guidelines
Blink is a trademark of Johnson & Johnson Surgical Vision, Inc.
No. 93286BT
© Johnson & Johnson 
Surgical Vision, Inc. 2017
Santa Ana, CA 92705
AM60870US12C
9587X
Revision Date: 07/2018
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APPENDIX D: NON-INVASIVE TEAR BREAK-UP TIME (NIBUT) MEASUREMENT USING 
THE MEDMONT E300 CORNEAL TOPOGRAPHER WORK AID 
 
 
 
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Title: 
Non-Invasive Tear Break-Up Time (NIBUT) Measurement using the 
Medmont E300 Corneal Topographer Work Aid 
Document Type: 
 
 
Page 3 of 4 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Title: 
Non-Invasive Tear Break-Up Time (NIBUT) Measurement using the 
Medmont E300 Corneal Topographer Work Aid 
Document Type: 
 
 
Page 4 of 4 
 
 
 
 
 
    
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APPENDIX E: 
 
 
x 
 EXPANDED SODIUM FLUORESCEIN CORNEAL STAINING 
x 
 SUBJECT REPORTED OCULAR SYMPTOMS/PROBLEMS 
x 
 DETERMINATION OF DISTANCE SPHEROCYLINDRICAL 
REFRACTIVE ERROR 
x 
 BIOMICROSCOPY SCALE 
x 
 DISTANCE AND NEAR SNELLEN VISUAL ACUITY EVALUATION 
x 
 PATIENT REPORTED OUTCOMES 
 
 
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Title:                        Expanded Sodium Fluorescein Corneal Staining
Document Type:       
Document Number:
Revision Number:  6 
.
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Title:                        Expanded Sodium Fluorescein Corneal Staining
Document Type:       
Document Number:
Revision Number:  6 
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DETERMINATION 
OF 
DISTANCE 
SPHEROCYLINDRICAL 
REFRACTIVE ERROR 
 
 
 
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Title:                           Determination of Distance Spherocylindrical Refractive Error
Document Type:  
Document Number:
Revision Number:  5 
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 BIOMICROSCOPY SCALE 
 
 
 
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Title:                          Distance and Near Snellen Visual Acuity Evaluation
Document Type:  
Document Number:
Revision Number:  5 
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Title:                          Distance and Near Snellen Visual Acuity Evaluation
Document Type:  
Document Number:
Revision Number:  5 
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 PATIENT REPORTED OUTCOMES 
 
 
 
 
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APPENDIX F: 
 GUIDELINES FOR COVID-19 RISK MITIGATION 
 
 
 
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PROTOCOL COMPLIANCE INVESTIGATOR(S) SIGNATURE PAGE 
Protocol Number and Title: CR-6502 Clinical Evaluation of a Multidose Preservative-free Lubricating 
Eye Drops Contained in Novelia® Eye Dropper in Non-Contact Lens Wearing Patients 
 
Version and Date: 3.0 25 April 2023 
 
I have read and understand the protocol specified above and agree on its content.   
 
I agree to conduct this study according to ISO 14155:2020,1 the Declaration of Helsinki,2 United States 
(US) Code of Federal Regulations (CFR)3, and the pertinent individual country laws/regulations and to 
comply with its obligations, subject to ethical and safety considerations. I, as the Principal Investigator, 
am responsible for ensuring that all clinical site personnel, including Sub-Investigators, adhere to all 
regulations and GCP guidelines regarding clinical trials during and after study completion. 
 
I will assure that no deviation from or changes to the protocol will take place without prior agreement 
from the Sponsor and documented approval from the Institutional Review Board (IRB), except where 
necessary to eliminate an immediate hazard(s) to the trial participants. 
 
All clinical site personnel involved in the conduct of this study have completed Human Subjects 
Protection Training.  
 
I agree to ensure that all clinical site personnel involved in the conduct of this study are informed about 
their obligations in meeting the above commitments. 
 
I shall not disclose the information contained in this protocol or any results obtained from this study 
without written authorization. 
 
I have read the suggested guidance provided by JJVCI pertaining to the COVID-19 risk mitigation, 
(COVID-19 Work Instruction in the Appendix F of this protocol). I agree to conduct this study in 
compliance with local, state, governmental guidance for COVID-19 risks. 
 
 
Principal 
Investigator: 
 
 
 
 
Signature 
 
 
 
Date 
 
Name and Professional Position (Printed) 
 
 
 
Institution/Site:  
 
 
 
Institution/Site Name 
 
 
 
 
 
 
Institution/Site Address 
 
 
 
 
 
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