Conditions: Dry Eye
Keywords: Dry Eye Tear Film Lipid Layer Dynamics Tear Film Stability
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: yes

Brief summary:
Dry eye disease (DED) is pervasive with some reports estimating over 16 million adults diagnosed in the United States. Currently, artificial tears remain an integral part of managing dry eyes and are mainly used for symptomatic relief. Recent studies have shown there may be therapeutic benefits with regular use of lipid-based artificial tears to improve the structure of the tear film, which may improve tear film stability and provide relief of symptoms. In this study the investigators propose to compare effects on the tear lipid film and its dynamics between 3 lipid based artificial tears and a widely available non-lipid based artificial tear.

Detailed description:
This is a prospective, double-masked, randomized, controlled, parallel-group trial designed to compare the impact of Systane Complete PF lipid-based artificial tears (the Treatment solution under study) on tear lipid layer thickness compared with a non-lipid Control solution, Refresh Relieva PF. Secondarily, the study will compare changes in tear lipid layer thickness, lipid layer uniformity, tear film thinning dynamics, and symptoms between the Treatment solution, the non-lipid Control solution, and 2 other available lipid-based solutions (Active Comparators: Refresh Optive Mega-3 PF and CVS Health Lubricant Eye Drop (PG 0.6%)). The study will include 4 clinic visits, and require 1 week of single-masked run-in with Systane Ultra PF (an over-the-counter non-lipid-based solution) followed by 3 months of study treatment dosing. All subjects will complete a screening interview, then an in-clinic baseline ocular health examination and study eligibility determination followed by dispensing of the Control solution to all subjects for 1 week of run-in. After that week, subjects will be randomized to 1 of the 4 artificial tear solutions and have an in-clinic ocular examination and dispense of the assigned solution to use for 3 months. An in-clinic follow-up examination is completed after 1 month of study solution use, followed by a phone interview at 2 months, and a final in-clinic examination at 3 months post-dispensing.

Arms:
arm 1: Masked subjects assigned to Arm 1 will use Systane Complete PF artificial tear drops 4 times per day (QID) to treat dry eye symptoms over a 3 month period. arm 2: Masked subjects assigned to Arm 2 will use Refresh Relieva PF artificial tear drops 4 times per day (QID) to treat dry eye symptoms over a 3 month period. arm 3: Masked subjects assigned to Arm 3 will use Refresh Optive Mega-3 PF artificial tear drops 4 times per day (QID) to treat dry eye symptoms over a 3 month period. arm 4: Masked subjects assigned to Arm 4 will use CVS Health Lubricant Eye Drop (PG 0.6%) artificial tear drops 4 times per day (QID) to treat dry eye symptoms over a 3 month period.

Interventions: intervention 1: Systane Complete PF intervention 2: Refresh Relieva PF intervention 3: Refresh Optive Mega-3 PF intervention 4: CVS Health Lubricant Eye Drop (PG 0.6%)
Intervention descriptions: intervention 1: 3 month use, 4 times daily, of Systane Complete PF, a lipid-based, preservative-free artificial tear product intervention 2: 3 month use, 4 times daily, of Refresh Relieva PF, a non-lipid-based, preservative-free artificial tear product intervention 3: 3 month use, 4 times daily, of Refresh Optive Mega-3 PF, a lipid-based, preservative-free artificial tear product intervention 4: 3 month use, 4 times daily, of CVS Health Lubricant Eye Drop (PG 0.6%), a lipid-based, preserved artificial tear product

Protocol document:
Prot_SAP_001.pdf: 
COVER PAGE 
 Artificial Tears, Tear Lipids and Tear Film Dynamics 
NCT05705518 
Document Date: 
02/02/2023
STUDY PROTOCOL 


 
 
Effects Of Artificial Tears on Tear Lipid Films and Tear Film 
Dynamics In Vivo 
 
 
Principal Investigator: 
Meng C. Lin, OD, PhD, FAAO1 
 
Co-Investigators: 
Thao N. Yeh, OD, PhD, MPH, FAAO1 
Mohinder M. Merchea, OD, PhD, MBA, FAAO2 
 
 
University of California, Berkeley1 
School of Optometry 
380 Minor Hall 
Berkeley, CA 94720-2020 
 
Alcon Vision, LLC2 
Fort Worth, TX 
 
 
 
 
 


 
 
I. INTRODUCTION & RATIONALE 
 
     Dry eye disease (DED) is pervasive with some reports estimating over 16 million adults diagnosed with 
DED in the United States.1 Currently, artificial tears remain an integral part of managing dry eyes and are 
mainly used for symptomatic relief. Recent studies have shown there may be therapeutic benefits with regular 
use of lipid based artificial tears to improve the structure of the tear film.2,3,4 Lipid based artificial tears have 
been shown to increase lipid layer thickness and improve tear film breakup time in addition to providing 
subjective improvements of dry eye symptoms.2,3,4 The ability to increase lipid layer thickness and improve tear 
film stability could possibly reduce evaporative dry eye disease. In this study we propose to recruit a large 
group of subjects spanning a range of ages and ethnicities and administer three lipid based artificial tears 
against a non-lipid based artificial tear to compare their effects on the subject’s tear lipid film and tear film 
dynamics.  
 
II. SPECIFIC AIMS 
 
We plan to accomplish our goals by pursuing the following specific aims and testing the associated 
hypotheses: 
 
Aim 1 (Primary): Determine if the change in lipid layer thickness at 3 months compared to post-run-
in baseline is different between Systane Complete PF and Refresh Relieva PF 
Hypothesis: The change in tear lipid layer thickness will be significantly greater with Systane Complete 
PF compared to Refresh Relieva PF. 
 
Aim 2 (Exploratory): Compare the 3-month changes in tear lipid layer uniformity and tear film 
thinning dynamics between the Systane Complete PF and Refresh Relieva PF 
Hypothesis: The 3-month change in lipid layer uniformity will be significantly better with Systane 
Complete PF compared to Refresh Relieva. 
 
Hypothesis: The 3-month change in tear film dynamics will be significantly better with Systane 
Complete PF compared to Refresh Relieva. 
 
Aim 3 (Exploratory): Compare the 3-month changes in tear lipid layer thickness between the 
Systane Complete PF and the other two lipid products (Refresh Optive Mega-3 PF, CVS Health 
Lubricant Eye Drop (PG 0.6%)) 
Hypothesis: The 3-month change in tear lipid layer thickness will be significantly greater with Systane 
Complete PF compared to the other lipid-containing products. 
 
Aim 4 (Exploratory): Compare the 3-month changes in tear lipid layer uniformity and tear film 
thinning dynamics between the Systane Complete PF and the other two lipid products (Refresh 
Optive Mega-3 PF, CVS Health Lubricant Eye Drop (PG 0.6%)) 
Hypothesis: The 3-month change in lipid layer uniformity will be significantly greater with Systane 
Complete PF compared to the other lipid-containing products. 
 
Hypothesis: The 3-month change in lipid layer uniformity and tear film dynamics will be significantly 
greater with Systane Complete PF compared to the other lipid-containing products. 
 
Aim 5 (Exploratory): Compare the 3-month changes in symptoms between the Systane Complete 
PF and the other two products (Refresh Relieva PF, Refresh Optive Mega-3 PF, CVS Health 
Lubricant Eye Drop (PG 0.6%)) 
Hypothesis: The 3-month change in symptoms will be significantly greater with Systane Complete PF 
compared to the other products. 
 
 
 


 
 
 
III. STUDY DESIGN  
 
Subjects 
 
A total of 84 subjects will complete the study with 21 subjects in each study arm. This four-visit study will be 
conducted at the University of California Berkeley, School of Optometry, Clinical Research Center (Berkeley, 
CA, USA). Subjects will be recruited via email and fliers. Subjects will be screened prior to the study visit with 
an IRB approved phone screening survey.  
 
Inclusion Criteria 
● Adult (>18 years) subjects who have a best corrected visual acuity of 20/30 or better 
● Have symptoms of dry eye (OSDI > 13) 
 
Exclusion Criteria 
● Currently using any topical eye medication (not including OTC drops) 
● Have known systemic health conditions that might alter tear film physiology, have a history of viral eye 
disease, have a history of diabetes, have a history of ocular surgery, have a history of severe ocular 
trauma, have an active ocular infection or inflammation, are currently using isotretinoin-derivatives, or if 
pregnant or breast feeding  
● Contact lens wearers  
● Subjects with a condition or in a situation, which in the examiner’s opinion, may put the subject at 
significant risk, may confound the study results, or may significantly interfere with their participation in 
the study will be excluded.  
 
Trial Design  
 
This will be a prospective, double-masked, randomized, controlled, parallel-group study designed to compare 
the impact of Systane Complete PF artificial tears on tear lipid layer thickness compared with a control, 
Refresh Relieva PF.  Secondarily, the study will compare the differences in changes in tear lipid layer 
thickness, lipid layer uniformity, tear film thinning dynamics, and symptoms between Systane Complete PF and 
other study products (Refresh Optive Mega-3 PF and CVS Health Lubricant Eye Drop (PG 0.6%)).  The study 
will include 4 clinic visits, including one week of single-masked run-in with Systane Ultra PF followed by 3 
months of study treatment dosing.  Participants will be asked to instill drops QID, regardless of assigned drops, 
throughout the study period. 
 
Visit Schedule will be as follows: 
 
Outcomes 
 
Primary: Mean change from post-run-in baseline at 3 months in tear lipid layer thickness (Systane Complete 
PF vs Refresh Relieva PF) 
 
Secondary: 
● Mean change from post-run-in baseline at 3 months in tear lipid layer uniformity (Systane Complete PF 
vs Refresh Relieva PF) 
● Mean change from post-run-in baseline at 3 months in tear film thinning rate (Systane Complete PF vs 
Refresh Relieva PF) 
 
 


 
 
Exploratory: 
● Mean change from post-run-in baseline at 1 and 3 months in tear lipid layer thickness (Systane 
Complete PF vs all lipid drops) 
● Mean change from post-run-in baseline at 1 and 3 months in tear lipid layer uniformity (Systane 
Complete PF vs all lipid drops) 
● Mean change from post-run-in baseline at 1 and 3 months in tear film thinning rate (Systane Complete 
PF vs all lipid drops) 
● Mean change from post-run-in baseline at 1 and 3 months in symptoms (Systane Complete PF vs all 
lipid drops) 
 
 
 
Sample Size  
 
The primary outcome of this study will be the difference in mean 3-month change in tear lipid layer thickness 
between Systane Complete PF and Refresh Relieva PF. Fogt and colleagues were able to establish statistical 
significance in the differences in short-term (15 min) change from baseline in tear lipid layer thickness when 
comparing a lipid-emulsion to non-emulsion in two separate studies with 20 subjects (10 subjects/arm).3, 4 In 
this study we are implementing a complete 3-month treatment regimen, and additionally will increase the target 
sample size to N=84 (4 study arms, 21 subjects/arm), and therefore can be reasonably assured of having 
sufficient statistical power to detect any treatment-control differences that may present. 
 
Surveys and Clinical Tests 
 
Clinical measurements will be obtained from both eyes of each subject and testing will be performed in the below 
order. Testing order was designed to sequentially administer the least invasive to most invasive test. This 
methodology will ensure that a previous procedure will have a minimal effect on subsequent assessments  
 
Study Visit 
 
A. Baseline/Screening Visit  
 
(Visit 1A) 
1. Subject History, Eligibility, Informed Consent: Subjects will be asked to repeat the IRB approved 
screening survey at the study visit to verify that they are still eligible for the study. Non-eligible subjects will be 
dismissed or rescheduled depending upon the reason for ineligibility. Eligible subjects will be enrolled, 
consented, and requested to sign a privacy document. 
 
2. Baseline Questionnaires: Subjects  demographics, lifestyle, ocular and medical history will be collected. 
They will be asked to complete the PSQ, Likert, DEFC, SPEED II, OSDI, VAS, SANDE, and DEQ-5 
questionnaires to determine baseline comfort. 
 
(Visit 1B) 
 
1. Baseline Visual Acuity: The subject’s habitual visual acuity will be measured.  
 
2. Tear Lipid Layer Thickness and Blinks: The Lipiview interferometer will be used to determine the 
subject’s tear lipid layer thickness and blinks. 
 
3. Tear Meniscus Height, Ocular Redness, and Keratometry: The Oculus Keratograph 5M will be used to 
determine the tear meniscus height, redness, and curvature of the eyes.  
 


 
 
4. Non-Invasive Tear Breakup Time (NITBUT): The Oculus Keratograph 5M and Medmont Topographer will 
be used to determine NITBUT with the machine’s standard software by taking one to three successive 
measurements. 
 
5. Slit-Lamp Biomicroscopy: The investigator will use a slit-lamp biomicroscope to document normal and/or 
remarkable findings of the anterior eye structures: eyelashes (blepharitis), eyelids, conjunctiva, and cornea.  
 
6. Fluorescein Tear Breakup Time (FTBUT): The investigator will instill 1 μl of 1% w/v of sodium fluorescein 
by pipette and take 3 successive measurements for each eye. 
 
7. Slit Lamp Recordings with EasyTear View: Capture videos with diffuse white light and cobalt blue light to 
analyze tear film lipids (thickness and uniformity) and tear film thinning dynamics. 
 
8. Schirmer’s Test: Investigator will use a modified technique3 for aqueous tear production rate measurement. 
 
9. Meibomian Gland Expression: The investigator will use the Korb Meibomian gland expressor to apply 
pressure along both the upper and lower eyelids and score gland secretion quality on central/nasal/temporal 
regions of each lid (i.e., ~5 glands in each region) with scores ranging from 0-3 (0=no secretion, 1=inspissated, 
2=cloudy, 3=clear), such that each lid will have a maximum score of 45. 
 
10. Lissamine Green Evaluation: The investigator will evaluate the quality of the front surface of the eyes by 
instilling a small amount of lissamine green ophthalmic dye.    
 
11. Meibography: The Oculus Keratograph 5M will be used to image the tear glands (e.g., Meibomian glands) 
of the upper and lower eyelids.   
 
12. Dispense Run-In Drops and Instructions: Investigators will dispense one week’s worth of Systane Ultra 
PF (label removed) to all qualified, enrolled subjects and instruct them to instill drops 4 times daily for one 
week.  Patients are then scheduled for their next visit at least 90 minutes after their planned last dose. 
 
B. Visit 2: Post-Run-In Period, Randomization, Treatment 
 
1. Subject History: Subjects will be asked to confirm any changes to medical or ocular history.  
 
2. Questionnaires: Subjects will be asked to complete an abbreviated questionnaire package to determine 
comfort. 
 
3. Visual Acuity: The subject’s habitual visual acuity will be measured.  
 
4. Tear Lipid Layer Thickness and Blinks: The Lipiview interferometer will be used to re-assess the subject’s 
tear lipid layer thickness and blinks. 
 
5. Tear Meniscus Height, Ocular Redness, and Keratometry: The Oculus Keratograph 5M will be used to 
determine the tear meniscus height, redness, and curvature of the eyes. 
 
6. Non-Invasive Tear Breakup Time (NITBUT): The Oculus Keratograph 5M will be used to determine 
NITBUT with the machine’s standard software by taking three successive measurements. 
 
7. Slit-Lamp Biomicroscopy: The investigator will use a slit-lamp biomicroscope to document normal and/or 
remarkable findings of the anterior eye structures: eyelashes (blepharitis), eyelids, conjunctiva, and cornea. 
 
8. Fluorescein Tear Breakup Time (FTBUT): The investigator will instill 1 μl of 1% w/v of sodium fluorescein 
by pipette and take 3 successive measurements for each eye. 
 


 
 
9. Slit Lamp Recordings with EasyTear View: Capture videos with diffuse white light and cobalt blue light to 
analyze tear film lipids (thickness and uniformity) and tear film thinning dynamics. 
 
 
10. Confocal Microscope: The confocal microscope will be used to examine anatomy and physiology of the 
front surface of the eyes.    
 
11. Randomize, Dispense Study Drops, and Instructions: Subjects will be randomized to one of four study 
drops (Refresh Relieva PF, Systane Complete PF, Refresh Optive Mega-3 PF, or CVS Health Lubricant Eye 
Drop (PG 0.6%)). Investigators will dispense a 1-month supply of the assigned study drops and provide 
instructions to instill drops 4 times daily for 3 months.  Patients are then scheduled for their 1-month follow-up 
visit, ensuring visit is scheduled at least 90 minutes after their planned last dose. 
 
C. Visit 3: One Month Follow-Up 
 
1. Repeat measurements (Part B) 1-9 and 11 from baseline visit. 
 
2. Dispense study drops. The investigator will dispense drops for the next two months and schedule the 
follow-up phone call at 2 months and the final visit at 3 months. 
 
D. Phone Call: Two Month Follow-Up 
 
1. Subject History: Subjects will be asked to confirm any changes to medical or ocular history.  
 
2. Follow-up to ensure no changes in habitual regimen, protocol is being followed, supply of drops is adequate 
to reach the end of the study. 
 
3. Questionnaires: Subjects will be asked to complete an abbreviated questionnaire package to determine 
comfort. 
 
E. Visit 4: Three Month Follow-Up 
 
1. Repeat measurements (Part B) 1-10 from baseline visit. 
 
2. Exit Visual Acuity: The subject’s habitual visual acuity will be measured.  
 
3. Study Completion: Subjects will be compensated for their time and exited from the study.  
 
F. Schedule of Study Procedures and Assessments 
 
Procedure/Assessment 
Visit 1 
Visit 2 
Visit 3 
Phone Call 
Visit 4 
Inclusion/Exclusion 
✔ 
 
 
 
 
Informed Consent 
✔ 
 
 
 
 
Demographics 
✔ 
 
 
 
 
Medical and Ocular History 
✔ 
✔ 
✔ 
✔ 
✔ 
PSQ, Likert, DEFC, 
SPEED II, 
OSDI, VAS, SANDE, & 
DEQ-5 
✔ 
✔ 
✔ 
✔ 
✔ 
Randomization 
 
✔ 
 
 
 
Visual Acuity 
✔ 
✔ 
✔ 
 
✔ 
Tear Lipid Layer Thickness 
and Blinks 
✔ 
✔ 
✔ 
 
✔ 


 
 
Tear Meniscus Height, 
Ocular Redness and 
Keratometry 
✔ 
✔ 
✔ 
 
✔ 
Non-Invasive Tear 
Breakup Time 
✔ 
✔ 
✔ 
 
✔ 
Slit-Lamp Exam 
✔ 
✔ 
✔ 
 
✔ 
Fluorescein Tear Breakup 
Time 
✔ 
✔ 
✔ 
 
✔ 
Easy TearView Recordings 
✔ 
✔ 
✔ 
 
✔ 
Schirmer’s Test 
✔ 
 
✔ 
 
✔ 
Meibomian Gland 
Expression 
✔ 
 
 
 
✔ 
Lissamine Green 
Evaluation 
✔ 
 
 
 
 
Meibography 
✔ 
 
 
 
 
Confocal Microscope 
 
✔ 
 
 
✔ 
Adverse Events 
 
✔ 
✔ 
✔ 
✔ 
Exit 
 
 
 
 
✔ 
 
 
Data Analysis 
 
Primary Model (Aim 1):   
● The primary outcome of tear lipid layer thickness (LipiView) change from post-run-in baseline to 3 
months will be analyzed using a repeated measures mixed effects model. This modeling approach will 
produce an unbiased estimate of the treatment effects (Systane Complete PF vs. Refresh Relieva PF), 
while accounting for the internal correlations engendered by the repeated measures study design 
(repeat visits, two eyes per subject). 
 
Additional Analyses (Aims 2-5, Exploratory):   
● The same modeling approach will be employed to analyze the changes from post-run-in baseline to 3 
months in tear lipid layer uniformity and in tear thinning time between the Treatment (Systane Complete 
PF) and Control (Refresh Relieva PF) solutions.  
● The same modeling approach will be employed to analyze changes from post-run-in baseline to 3 
months in lipid layer thickness and uniformity, tear thinning time, and symptom scores among 3 
solutions (Systane Complete PF, Refresh Optive Mega-3 PF, CVS Health Lubricant Eye Drop (PG 
0.6%)). 
● Additional exploratory modeling for all outcomes will be performed to determine the impact of baseline 
subject characteristics including demographics, visual acuity, tear film stability (NITBUT and FTBUT), 
tear production (Schirmers), and any ocular surface findings. 
● Exploratory models will be assessed by F-test p-values, residual and other diagnostic plots, fit statistics 
such as the log-likelihood and the AIC, and clinical relevance of effect sizes. Both additive and 
interaction models will be examined. 
● All study variables will also be subjected to a thorough descriptive analysis, in order to better 
understand the modeling results and the relationships among the model variables. This analysis will 
include descriptive statistics (minimum, maximum, median, mean, SD), histograms of the distributions 
of continuous variables (including lipid layer thickness and coefficient of variation, tear thinning rate, 
non-invasive and fluorescein tear breakup times, modified Schirmer strip wetted lengths and tear 
production rate, and symptom questionnaire scores), and tabulations of ordinal and categorical 
variables (including clinical grades of the anterior eye structures cornea, conjunctiva, eyelids and 
lashes).  
● Additional exploratory analyses will examine the basic univariate relationships between the model 
outcome variables and potential explanatory variables via box-and-whisker plots, scatterplots, and 
simple linear regressions / t-tests / univariate ANOVA models (as appropriate for the data types).  


 
 
 
  
 
IV. Study Timeline 
 
  
2022 
2022 
2022 
2023 
2023 
2023 
2023 
2023 
2023 
2023 
2023 
  
Oct 
Nov 
Dec 
Jan 
Feb 
Mar 
April 
May 
June 
July 
Aug 
Activity  
 
 
 
 
 
 
 
 
 
 
 
Contracting 
 
 
 
 
 
 
 
 
 
 
 
IRB Preparation  
 
 
 
 
 
 
 
 
 
 
 
Data Collection  
 
 
 
 
 
 
 
 
 
 
 
Data Analysis 
 
 
 
 
 
 
 
 
 
 
 
Final Study Report 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VI. Publication Plans 
 
An abstract describing the comparison of tear film lipid layer between Systane Complete and Refresh Relieva 
will be submitted for presentation at American Academy of Optometry 2023. A manuscript describing the initial 
drop experience and drop comfort data will be submitted to Optometry and Vision Science or Contact Lens and 
Anterior Eye or Eye and Contact Lens, or Scientific Reports. 
  
 
References 
 
1.  
Farrand KF, Fridman M, Stillman IO, Schaumberg DA. Prevalence of diagnosed dry eye disease in the 
United States among adults aged 18 years and older. Am J Ophthalmol. 2017;182:90-8. 
2.  
Craig JP, Muntz A, Wang MTM, Luensmann D, Tan J, Trave Huarte S, Xue AL, Jones L, Willcox MDP, 
Wolffsohn JS. Developing evidence-based guidance for the treatment of dry eye disease with artificial tear 
supplements: A six-month multicentre, double-masked randomised controlled trial. Ocul Surf. 2021;20:62–69.  
3. 
Fogt JS, Fogt N, King-Smith PE, et al. Changes in Tear Lipid Layer Thickness and Symptoms 
Following the Use of Artificial Tears with and Without Omega-3 Fatty Acids: A Randomized, Double-Masked, 
Crossover Study. Clin Ophthalmol 2019;13:2553-61. 
4. 
Weisenberger K, Fogt N, Swingle Fogt J. Comparison of nanoemulsion and non-emollient artificial tears 
on tear lipid layer thickness and symptoms. J Optom 2021;14(1):20-7. 
5. 
Kim YH, Graham AD, Li W, Radke CJ, Lin MC. Human lacrimal production rate and wetted length of 
modified Schirmer’s Tear Test strips. Translat Vis Sci Tech. 2019;8(3):40.