Randomized, Controlled Trial to Evaluate the Safety and Effectiveness of the TearCare® System in the Treatment of the Signs and Symptoms of Dry Eye Disease
Phase: NA
Conditions: Dry Eye, Meibomian Gland Dysfunction
Sponsor: Sight Sciences, Inc.

 
RCT of the Safety and Effectiveness of the TearCare® System 
 
Protocol 06196 Rev B 
 
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Official Title : RANDOMIZED, CONTROLLED 
TRIAL TO EVALUATE THE SAFETY AND 
EFFECTIVENESS OF THE TEARCARE® 
SYSTEM IN THE TREATMENT OF THE 
SIGNS AND SYMPTOMS OF DRY EYE 
DISEASE (OLYMPIA) 
Unique Protocol ID: 06196 
NCT number : NCT03857919 
Document Date: 7.31.2019 
Sight Sciences, Inc. 
 

 
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RANDOMIZED, CONTROLLED TRIAL TO EVALUATE THE SAFETY AND 
EFFECTIVENESS OF THE  TEARCARE® SYSTEM IN THE TREATMENT OF THE 
SIGNS AND SYMPTOMS OF DRY EYE DISEASE (OLYMPIA) 
 
PROTOCOL ID #: 
 
06196 
CURRENT REVISION: 
 
B 
REVISION DATE: 
 
July 31, 2019 
SPONSOR: 
Sight Sciences, Inc. 
3000 Sand Hill Road 
Building 3, Suite 105 
Menlo Park, CA  94025 
877-266-1144 
 
 
Agreement of Principal Investigator 
I,  
 
 
 
 
 
  agree to conduct this trial in accordance 
with this clinical protocol and any amendments. 
 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
Center Name  
 
 
 
 
City, State, Country 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation.  It must be held 
confidential and maintained in a secure location. 
Do not copy or distribute without written permission. 
 

 
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Revision History 
 
Revision 
Date Issued 
ECO 
A 
December 12, 2018 
2612 
B 
July 31, 2019 
2864 
 
 
 
 

 
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TABLE OF CONTENTS 
1 
PROTOCOL SYNOPSIS ...................................................................................................................... 8 
2 
STUDY OBJECTIVE ......................................................................................................................... 13 
3 
BACKGROUND AND JUSTIFICATION FOR THE STUDY .................................................................... 13 
4 
DESCRIPTION OF DEVICE ............................................................................................................... 17 
4.1 
CURRENT INDICATION FOR USE .............................................................................................................. 17 
4.2 
PROPOSED INDICATION FOR USE ............................................................................................................ 17 
4.3 
DEVICE DESCRIPTION ........................................................................................................................... 17 
4.4 
DEVICE MODIFICATION ........................................................................................................................ 20 
4.5 
INSTRUCTIONS FOR USE ........................................................................................................................ 21 
4.6 
TRAINING .......................................................................................................................................... 21 
5 
PRIOR INVESTIGATIONS ................................................................................................................ 21 
5.1 
PRECLINICAL TESTING ........................................................................................................................... 21 
5.2 
PREVIOUS CLINICAL EXPERIENCE ............................................................................................................ 22 
 
Clinical Study of the Prototype TearCare System (2013) ...................................................... 22 
 
Clinical Study of the TearCare System (2017) ....................................................................... 23 
 
Summary ............................................................................................................................... 25 
6 
STUDY ENDPOINTS ....................................................................................................................... 25 
6.1 
EFFECTIVENESS ENDPOINTS ................................................................................................................... 25 
6.2 
SAFETY ENDPOINTS.............................................................................................................................. 26 
7 
STUDY DESIGN .............................................................................................................................. 26 
7.1 
STUDY DEVICE AND CONTROL ARM ........................................................................................................ 27 
7.2 
STUDY CENTERS .................................................................................................................................. 27 
8 
STUDY SELECTION CRITERIA .......................................................................................................... 27 
8.1 
INCLUSION CRITERIA ............................................................................................................................ 27 
8.2 
EXCLUSION CRITERIA ............................................................................................................................ 28 
9 
STUDY PROCEDURES ..................................................................................................................... 30 
9.1 
STUDY SCHEDULE ................................................................................................................................ 30 
9.2 
NUMBER OF SUBJECTS, DURATION OF FOLLOW-UP AND STUDY DURATION .................................................... 30 
9.3 
MATERIAL AND EQUIPMENT .................................................................................................................. 31 
9.4 
INFORMED CONSENT AND POINT OF ENROLLMENT .................................................................................... 31 
9.5 
BASELINE AND TREATMENT VISIT(S) ........................................................................................................ 32 
 
Scheduling the Baseline and Treatment Visit(s).................................................................... 32 
 
Baseline Exams, Tests and Questionnaires ........................................................................... 32 
 
Randomization ...................................................................................................................... 33 
 
Treatment for TearCare Group ............................................................................................. 33 
 
Treatment for LipiFlow Group ............................................................................................... 34 
 
Follow-up Instructions for Subjects ....................................................................................... 35 
9.6 
FOLLOW-UP VISITS .............................................................................................................................. 36 
9.7 
PHOTOGRAPHY DURING EXAMS AND TEARCARE PROCEDURE ....................................................................... 37 
9.8 
MASKED ASSESSOR ............................................................................................................................. 37 
9.9 
MANAGEMENT OF DRY EYE SYMPTOMS DURING FOLLOW-UP ..................................................................... 37 
9.10 
WITHDRAWAL AND DISCONTINUATION ............................................................................................... 38 
9.11 
SUBJECTS LOST TO FOLLOW-UP ......................................................................................................... 38 

 
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10 
ADVERSE EVENTS (AES) ................................................................................................................. 38 
10.1 
DEFINITIONS OF AE, SAE, SADE, USADE .......................................................................................... 39 
10.2 
LIST OF ANTICIPATED POTENTIAL ADVERSE EVENTS ............................................................................... 39 
10.3 
REPORTING ADVERSE EVENTS AND UNANTICIPATED ADVERSE DEVICE EFFECTS ........................................... 40 
11 
RISK-BENEFIT ANALYSIS ................................................................................................................ 41 
11.1 
ANTICIPATED CLINICAL BENEFITS ........................................................................................................ 41 
11.2 
ANTICIPATED ADVERSE DEVICE EFFECTS ............................................................................................... 41 
11.3 
RESIDUAL RISKS ASSOCIATED WITH THE TEST DEVICE, AS IDENTIFIED IN THE RISK ANALYSIS REPORT .................. 41 
11.4 
RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL INVESTIGATION ................................................... 41 
11.5 
POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS ....................................................... 41 
11.6 
STEPS THAT WILL BE TAKEN TO CONTROL OR MITIGATE THE RISKS ............................................................. 41 
12 
STATISTICAL CONSIDERATIONS ..................................................................................................... 43 
12.1 
EVALUABILITY ................................................................................................................................ 43 
12.2 
ANALYSIS POPULATIONS .................................................................................................................. 43 
12.3 
SUBJECT ACCOUNTABILITY ................................................................................................................ 43 
12.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ................................................................................ 43 
12.5 
EFFECTIVENESS ENDPOINTS AND ANALYSIS METHODS ........................................................................... 44 
 
Descriptive Analyses......................................................................................................... 44 
 
Primary Effectiveness Endpoints ...................................................................................... 44 
 
Primary Effectiveness Hypotheses ................................................................................... 44 
 
Poolability ........................................................................................................................ 45 
 
Missing Data .................................................................................................................... 46 
 
Secondary Effectiveness Endpoints .................................................................................. 46 
 
Additional Exploratory Analyses ...................................................................................... 47 
12.6 
SAFETY ENDPOINTS AND ANALYSIS ..................................................................................................... 47 
 
Descriptive Analyses......................................................................................................... 47 
 
Primary Safety Endpoint .................................................................................................. 47 
 
Primary Safety Analysis .................................................................................................... 47 
 
Secondary Safety Endpoints ............................................................................................. 47 
12.7 
SAMPLE SIZE CALCULATION .............................................................................................................. 47 
12.8 
DEVIATION FROM THE STATISTICAL PLAN ............................................................................................ 48 
13 
MONITORING PROCEDURES ......................................................................................................... 48 
14 
DATA AND QUALITY MANAGEMENT ............................................................................................. 49 
14.1 
DATABASE MANAGEMENT ............................................................................................................... 49 
14.2 
SUBJECT IDENTIFICATION ................................................................................................................. 49 
14.3 
SUBJECT ACCOUNTABILITY ................................................................................................................ 49 
14.4 
CONFIDENTIALITY ........................................................................................................................... 49 
14.5 
SOURCE DATA AND CASE REPORT FORMS ........................................................................................... 50 
14.6 
RETENTION PERIOD......................................................................................................................... 50 
15 
PROTOCOL MODIFICATIONS AND DEVIATIONS ............................................................................. 50 
16 
DEVICE FAILURES AND MALFUNCTIONS ........................................................................................ 51 
17 
ETHICAL CONSIDERATIONS ........................................................................................................... 51 
17.1 
DECLARATION OF HELSINKI ............................................................................................................... 51 
17.2 
INSTITUTIONAL REVIEW BOARDS (IRB) ............................................................................................... 51 
17.3 
INFORMED CONSENT FORM (ICF) ..................................................................................................... 51 
17.4 
PUBLIC LISTING OF STUDY ................................................................................................................ 52 

 
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18 
STUDY ADMINISTRATION ............................................................................................................. 52 
18.1 
DEVICE ACCOUNTABILITY ................................................................................................................. 52 
18.2 
EARLY TERMINATION OR SUSPENSION OF AN INVESTIGATION .................................................................. 52 
18.3 
INVESTIGATOR RESPONSIBILITIES ....................................................................................................... 53 
 
General Responsibilities of Investigators ......................................................................... 53 
 
Specific Responsibilities of Investigators .......................................................................... 53 
 
Investigator Records ........................................................................................................ 53 
 
Investigator Reports ......................................................................................................... 54 
18.4 
INVESTIGATOR AGREEMENT .............................................................................................................. 55 
19 
PUBLICATION POLICY .................................................................................................................... 55 
20 
BIBLIOGRAPHY .............................................................................................................................. 56 
21 
APPENDIX A – METHODS FOR EXAMS, TESTS AND QUESTIONNAIRES ........................................... 60 
21.1 
MEDICATIONS ................................................................................................................................ 60 
21.2 
MANIFEST REFRACTION AND VISUAL ACUITY ....................................................................................... 60 
21.3 
SLIT LAMP EXAM ............................................................................................................................ 62 
21.4 
TEAR BREAKUP TIME (TBUT) ........................................................................................................... 62 
21.5 
CORNEAL STAINING ........................................................................................................................ 64 
21.6 
CONJUNCTIVAL STAINING ................................................................................................................. 65 
21.7 
SCHIRMER 1 TEST ........................................................................................................................... 66 
21.8 
MEIBOMIAN GLAND SECRETION SCORING ........................................................................................... 66 
21.9 
INTRAOCULAR PRESSURE .................................................................................................................. 67 
21.10 
QUESTIONNAIRES ........................................................................................................................... 68 
 
General Instructions for Questionnaires .......................................................................... 68 
 
OSDI Questionnaire .......................................................................................................... 68 
 
SANDE Questionnaire and Eye Dryness VAS .................................................................... 68 
 
Discomfort/Pain Questionnaire ....................................................................................... 69 
22 
APPENDIX B – STATISTICAL ANALYSIS PLAN .................................................................................. 70 
22.1 
EFFECTIVENESS ENDPOINTS AND ANALYSIS METHODS ........................................................................... 70 
 
Primary Effectiveness Endpoint ........................................................................................ 70 
 
Poolability of Centers ....................................................................................................... 72 
 
Missing Data .................................................................................................................... 73 
 
Secondary Effectiveness Endpoints .................................................................................. 73 
22.2 
SAFETY ENDPOINTS AND ANALYSIS ..................................................................................................... 73 
 
Descriptive Analyses......................................................................................................... 73 
 
Primary Safety Endpoint .................................................................................................. 74 
 
Primary Safety Analysis .................................................................................................... 74 
 
Secondary Safety Endpoints ............................................................................................. 74 
22.3 
SAMPLE SIZE CALCULATIONS ............................................................................................................. 74 
 
Tear Breakup Time ........................................................................................................... 75 
 
Meibomian Gland Secretion Score ................................................................................... 76 
 
Safety ............................................................................................................................... 77 
 
Sample Size Summary ...................................................................................................... 77 
23 
APPENDIX C – PREPARING FLUORESCEIN AND LISSAMINE GREEN SOLUTIONS ............................. 78 
23.1 
PREPARING FLUORESCEIN SOLUTION .................................................................................................. 78 
23.2 
PREPARING LISSAMINE GREEN SOLUTION ............................................................................................ 78 
24 
APPENDIX D - DECLARATION OF HELSINKI .................................................................................... 79 

 
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1 PROTOCOL SYNOPSIS 
Protocol Title 
Randomized, Controlled Trial to Evaluate the Safety and 
Effectiveness of the TearCare® System in the Treatment of 
the Signs and Symptoms of Dry Eye Disease 
Protocol ID Number 
06196 
Study Device 
TearCare® System 
Control Group 
LipiFlow® Thermal Pulsation System 
Primary Objective 
To demonstrate the safety and effectiveness of a single 
TearCare® treatment compared to a single LipiFlow 
treatment to treat the signs and symptoms of dry eye 
disease in adult patients. 
Study Design 
Prospective, randomized, single-masked, multi-center 
non-inferiority, post-market study.   
Primary Effectiveness 
Endpoints 
Mean Change from baseline to 1 month in: 
o Tear Break-Up Time (TBUT) 
o Total Meibomian Gland Secretion Score 
Secondary Effectiveness 
Endpoints 
Mean Change from baseline to 1 month in: 
o Ocular Surface Disease Index (OSDI) score 
o Corneal staining scores 
o Conjunctival staining scores 
o Symptom Assessment in Dry Eye (SANDE) scores  
o Eye Dryness Score 
o Number of Meibomian Glands Yielding any liquid 
o Number of Meibomian Glands Yielding clear liquid 
Primary Safety Endpoint 
o Device-related adverse events 
Secondary Safety 
Endpoints 
o Discomfort/pain during treatment 
o Change in best corrected visual acuity (ETDRS) 
o Change in intraocular pressure (IOP) 

 
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Inclusion Criteria 
1. At least 22 years of age 
2. Reports dry eye symptoms within the past 3 months 
3. Reports having to use artificial tears or lubricants 
regularly over the past month to relieve dry eye 
symptoms. 
4. OSDI Score of 23-79 
5. TBUT of ≤7 seconds in both eyes  
6. Meibomian gland obstruction in both eyes based on a 
total Meibomian Gland Secretion Score ≤12 in each 
eye.  
7. At least 15 glands in each lower eyelid should be 
expressible, with a sterile cotton swab, at the slit lamp. 
8. Best corrected visual acuity of 20/100 or better in both 
eyes. 
9. Willing and able to comply with the study procedures 
and follow-up 
10. Willing and able to provide informed consent 
11. English-speaking 
 
 

 
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Exclusion Criteria 
1. Use of any of the following medications: 
a) Restasis or Xiidra within 60 days prior to 
enrollment;  
b) Antihistamines (oral or topical) within 10 days prior 
to enrollment;   
c) Systemic medication(s) (other than anti-
histamines) that is known to cause ocular dryness 
(e.g. diuretics, anti-hypertensives, anti-
depressants, hormone therapy) and whose dose of 
this medication(s) has not been stable within 30 
days prior to enrollment.  There must be no 
anticipated adjustments to the dose of these 
medications for the duration of the trial; 
d) Accutane (at any time); 
e) Oral tetracyclines or azithromycin within 30 days 
prior to enrollment; or 
f) Topical ophthalmic antibiotics, anti-glaucoma 
medications, steroids, non-steroidal anti-
inflammatory medications within 30 days prior to 
enrollment. 
NOTE: Use of any of the above medications (with the 
exception of 1c) is not permitted during the 1 month 
follow-up period. 
2. Any of the following dry eye treatments: 
a) Office-based dry eye treatment (e.g. IPL, thermal 
pulsation [Lipiflow], etc.) within 12 months prior to 
enrollment;   
b) Meibomian gland expression within 6 months prior 
to enrollment;   
c) Blephex or debridement within 3 months prior to 
enrollment is an exclusion; 
d) Punctal occlusion or punctal plug placement within 
30 days prior to enrollment;   
e) Use of TrueTear device within the past 2 weeks.  
(Subjects must refrain from using the TrueTear 
device for the duration of the study.); or 
f) Any history of meibomian gland probing 
3. History of eyelid, conjunctiva or corneal surgery 
(including refractive surgery) within the past year.  In 
addition, subjects with any history of the following are 
excluded: chalazion surgery, surgery on the tarsal 
conjunctiva, radial keratotomy (RK), complicated 
blepharoplasty, lid reconstruction, or significant 

 
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complications post-refractive surgery. 
4. Contact lens use within the past 2 weeks.  (Subjects 
must refrain from wearing contact lenses during the 1 
month follow-up.) 
5. History of Ocular Herpes Simplex or Ocular Herpes 
Zoster 
6. Any active, clinically significant ocular or peri-ocular 
infection or inflammation 
7. Recurrent clinically significant eye inflammation, other 
than dry eye, within 3 months prior to enrollment 
8. Clinically significant anterior blepharitis.  In addition, 
collarettes or flakes of more than one quarter of the 
eyelid are excluded. 
9. Clinically significant eyelid abnormalities in either eye 
(e.g. entropion/ectropion, blepharospasm, 
aponeurotic ptosis, lagophthalmos, distichiasis, 
trichiasis). 
10. Clinically significant dermatologic or cutaneous disease 
of the eyelid or periocular area. 
11. In the clinical judgement of the investigator, 
meibomian glands have significant capping, atrophy, 
or are unable to be expressed, digitally or with a sterile 
cotton swab.   
12. Clinically significant ocular surface abnormalities that 
may affect tear film distribution or treatment (e.g. 
pterygium, anterior membrane dystrophy, Salzmann’s 
nodules, etc.) 
13. Corneal surface abnormalities such as corneal 
epithelial defects (other than punctate staining), 
ulcers, corneal epithelial dystrophies, keratoconus, 
and ectatic disease of the cornea 
14. Any active, clinically significant allergic, vernal, or giant 
papillary conjunctivitis. 
15. Ocular trauma within 3 months prior to enrollment. 
16. Known history of diminished or abnormal facial, 
periocular, ocular or corneal sensation 
17. Systemic diseases resulting in dry eye (e.g. 
autoimmune diseases such as Sjogren’s syndrome, 
rheumatoid arthritis, lupus, Graves’ disease, 
sarcoidosis, etc.) 
18. Subject is currently using Retin A or Latisse. 
19. Subject has permanent eyeliner/lid tattoos, eyelash 
extensions or wears false eyelashes. 

 
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20. Subject is currently using Lash Boost. 
21. Allergies to silicone tissue adhesives 
22. Participation in another ophthalmic clinical trial within 
one year prior to enrollment.  Subject must also be 
willing to refrain from another ophthalmic study for 
the duration of the study.   
23. Co-existing condition, either ocular or non-ocular that, 
in the judgement of the investigator could affect the 
safety or effectiveness of treatment or the compliance 
of the subject to the protocol.  For example, subjects 
who are pregnant or nursing or have active, wet 
macular degeneration are excluded. 
 
Study Cohorts 
Cohort 1: Initial SmartLid design 
Cohort 2: Modified SmartLid design  
Number of Subjects 
Enrolled and Randomized 
Up to 100 in Cohort 1 + 138 Cohort 2 = Up to 238 subjects 
total 
Randomization 
1:1 
Number of Centers 
Up to 15 
Study Duration for Each 
Subject 
1 month 
Total Study Duration 
Approximately 9-12 months 
Schedule of Visits 
Baseline, Treatment (if not at Baseline Visit), Day 1,  
Week 2, Month 1 
 
 
 

 
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2 STUDY OBJECTIVE 
The objective of this study is to demonstrate the safety and effectiveness of a single 
TearCare® treatment compared to a single LipiFlow treatment to treat the signs and 
symptoms of dry eye disease in adult patients.  This objective will be met by 
demonstrating non-inferiority of the TearCare treatment for each of the primary 
effectiveness endpoints. 
 
This study is being conducted to collect data to support a modification to the TearCare 
indication for use to read as follows, “The TearCare® System is indicated for the 
treatment of the signs and symptoms of dry eye disease (DED).” 
3 BACKGROUND AND JUSTIFICATION FOR THE STUDY 
Dry Eye Disease (DED) is a chronic eye condition that can cause an array of symptoms in 
patients, ranging from periodic ocular discomfort to severe corneal inflammation, 
scarring, and vision loss.1,2  Approximately 1/3 of patients visiting their eye doctor suffer 
from dry eye.  The prevalence of dry eye disease increases with age, especially in 
postmenopausal women.  It is estimated that dry eye disease affects more than 7 
million Americans older 40 years of age1, and approximately 1 million to 4 million 
Americans between 65 to 84 years of age.3   
 
Each year in the U.S., billions of dollars are spent on topical lubricants, medications, tear 
duct occlusions, and other treatments to control the chronic condition of dry eye 
disease.  Yu et al reported that the average annual cost of managing a patient with dry 
eye was $783 (range $757 – 809) from the payers’ perspective.4  When adjusted to the 
prevalence of DED nationwide, the overall burden of DED on the US healthcare system 
was estimated to be $3.84 billion.  Moreover, there is a great cost to society in terms of 
decreased productivity due to the symptoms of dry eye.   Yu, et al estimated the societal 
cost to be $11,302 per patient and $55.4 billion to the US society overall.4  Essentially, 
not only do dry eye patients directly suffer, but there is also a burden to healthcare, 
employers, and society. 
 
 
1 The definition and classification of dry eye disease: report of the Definition and Classification 
Subcommittee of the International Dry Eye Work Shop. Ocul Surf. 2007;5:75–92. 
2 Lemp MA, Crews LA, et al. Distribution of Aqueous-Deficient and Evaporative Dry Eye in a Clinic-Based 
Patient Cohort: A Retrospective Study. Cornea. 2012: 31: 472-478. 
3 Fiscella RG. Understanding dry eye disease: a managed care perspective. Am J Manag Care 2011; 17 
Suppl 16:S432-9. 
4 Yu J, Asche CV, Fairchild CJ.  The economic burden of dry eye disease in the United States:  a decision 
tree analysis.  Cornea 2011;30(4):379-87. 

 
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Historically, dry eye disease has been categorized into one of two forms, aqueous tear 
deficiency and evaporative tear deficiency.  The current understanding is that 
evaporative dry eye is more common than aqueous deficient dry eye.5  However, 
because the symptoms of aqueous-deficient dry eye are difficult to differentiate from 
those of evaporative dry eye, it is often impossible to truly separate patients into 
distinct groups.6  In fact, AAO guidelines state that these conditions coexist in the 
majority of the patients with the disease.7   
 
In terms of the mechanism of action for dry eye disease, the International Dry Eye 
Workshop (DEWS)1 explained that tear hyperosmolarity and the symptoms of dry eye 
result from water evaporation caused by low aqueous tear flow and/or excessive 
evaporation.  This reduced, concentrated tear volume, in turn results in further 
inflammation and tear film instability creating a vicious cycle.  The DEWS report 
concluded the following:  “Since both aqueous tear deficiency and increased 
evaporative tear loss occur in most cases of dry eye disease and are linked by common 
pathogenetic mechanisms, expert clinicians are increasingly basing treatment decisions 
on an assessment of severity rather than discrete deficiencies.”8 
 
Normal tears coat the ocular surface and perform many functions, including lubrication 
of the ocular surface, protection from infection, nourishing the ocular surface cells, and 
providing an optically clear surface to properly refract light. Tears consist of three layers: 
 
1. An underlying mucin layer which acts as a wetting agent to spread tears 
uniformly on the ocular surface to prevent beading or irregularity; 
2. An aqueous layer to maintain an optically clear medium and to keep the ocular 
surface moist and healthy; and 
3. A superficial lipid layer to retard evaporation of the aqueous layer. 
When any of these layers is disturbed, tears may lose their protective and optical 
properties leading to a constellation of symptoms, a cascade of inflammatory processes, 
and the vicious cycle of dry eye. 
 
With the most recent etiologies of dry eye disease in mind, multiple standard-of-care, 
therapeutic approaches are employed: 
 
 
5 Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson JD, Nichols JJ, Tusbota K, 
Stapleton F.  TFOS DEWS II Definition and Classification Report.  The Ocular Surface 2017;15:276-283. 
6 Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: 
report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest 
Ophthal-mol Vis Sci 2011;52:2050-64 
7 American Academy of Ophthalmology’s Dry Eye Syndrome Preferred Practice Pattern 2013.  
8 Lemp M, Foulks, G.  The Definition & Classification of Dry Eye Disease:  Guidelines from the 2007 
International Dry Eye Workshop.  April 2008.  
http://www.tearfilm.org/pdfs/OM%20-%20Definition%20&%20Classification.pdf 

 
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1. Supplementation of the tear film with artificial tears to address evaporation and 
maintain tear volume 
2. Use of warm compress and lid massage to improve lipid production and flow on 
the tear film 
3. Use of immunosuppressives (cyclosporine, corticosteroids, lifitegrast) to reduce 
inflammation  
4. Placement of punctal plugs to address evaporation and maintain tear volume 
 
Recently, a great deal of evidence suggests that obstruction of the meibomian glands, 
which are the glands on the eyelid that produce the lipid layer of tears, is strongly 
associated with dry eye disease.9,10,11,12    The DEWS II report states that meibomian 
gland disease is considered the leading cause of dry eye in clinic and population based 
studies.13  As these glands become either inflamed or obstructed, their ability to supply 
the essential lipids to the ocular surface is diminished. This, in turn, leads to rapid 
evaporation of tears and thus to the signs and symptoms of dry eye disease.14  When 
this occurs, it can result in ocular discomfort and, in many cases, ocular surface 
disorders that can affect vision.   
 
To address this, use of warm compresses and lid massage are recommended for the 
treatment of dry eye by the AOA, AAO, and the International Workshop on Meibomian 
Gland Dysfunction.15,16,17  It is believed that the heat helps melt the oily obstructions in 
the meibomian glands and helps reduce gland inflammation, thereby helping to restore 
the ability of the meibomian glands to effectively secrete oil onto the tear film and 
prevent rapid tear evaporation.    
 
 
9 Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry eye symptoms and 
gland location. Cornea. 2008;27: 1142–1147. 
10 Korb DR, Henriquez AS. Meibomian gland dysfunction and contact lens intolerance. J Am Optom Assoc. 
1980;51:243–251. 
11 Blackie CA, Korb DR, Knop E, et al. Nonobvious obstructive meibomian gland dysfunction. Cornea. 
2010;29:1333–1345. 
12 Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive meibomian gland 
dysfunction. Cornea. 2010;29: 1145–1152. 
13 Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson JD, Nichols JJ, Tusbota K, 
Stapleton F.  TFOS DEWS II Definition and Classification Report.  The Ocular Surface 2017;15:276-283. 
14 Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf. 2004;2:149–165. 
15 American Academy of Ophthalmology’s Dry Eye Syndrome Preferred Practice Pattern 2013. 
16 American Optometric Association’s Clinical Practice Guidelines for Ocular Surface Disorders, updated 
2010. 
17 Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: 
report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest 
Ophthal-mol Vis Sci 2011;52:2050-64 

 
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It has been shown that warm compress therapy can lead to improved lipid production 
and flow on to the tear film.18,19,20  This improved lipid delivery is associated not only 
with an improvement in the profile of the tear film but also an improvement in patient 
symptoms.21,22,23  The tear film is demonstrably thicker and more stable with an 
increased contribution of lipid to its surface.24,25,26    
 
While warm compress and lid massage can be an effective treatment for dry eye 
disease, it has several shortcomings, including the fact that the warm compress may not 
be sufficiently warm or it may cool too quickly.  In addition, use of warm compresses on 
a daily basis is time-consuming and labor-intensive which leads to poor patient 
compliance.  As a result, , various alternative approaches to heating the eyelids have 
been proposed. 27,28,29,30,31     
 
Sight Sciences has developed the TearCare™ System to provide a safe and effective 
treatment for the signs and symptoms of dry eye disease.  The System is designed to 
conform to the eyelids to deliver controlled, precise heat to the tarsal plates and 
underlying meibomian glands of the eyelids for 15 minutes in the monitored setting of 
an ophthalmologist or optometrist office. In addition to blinking during TearCare™ 
 
18 Goto E, Monden Y, Takano Y, et al. Treatment of non-inflamed obstructive meibomian gland 
dysfunction by an infrared warm compression device. Br J Ophthalmol. 2002;86:1403–1407. 
19 Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian gland dysfunction: 
executive summary. Invest Ophthalmol Vis Sci. 2011;52:1922–1929. 
20 Lemp MA. Report of the National Eye Institute/Industry workshop on clinical trials in dry eyes. CLAO J. 
1995;21:221–232. 
21 Korb DR, Blackie CA. Restoration of meibomian gland functionality with novel thermodynamic 
treatment device–a case report. Cornea. 2010;29:930–933. 
22 Friedland BR, Fleming CP, Blackie CA, et al. A novel thermodynamic treatment for meibomian gland 
dysfunction. Curr Eye Res. 2011;36: 79–87. 
23 Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment with warm 
compresses in patients with meibomian gland dysfunction. Eye Contact Lens. 2003;29:96–99. 
24 Mitra M, Menon GJ, Casini A, et al. Tear film lipid layer thickness and ocular comfort after meibomian 
therapy via latent heat with a novel device in normal subjects. Eye (Lond). 2005;19:657–660. 
25 Craig JP, Blades K, Patel S. Tear lipid layer structure and stability following expression of the meibomian 
glands. Ophthalmic Physiol Opt. 1995;15:569–574. 
26 Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment of meibomian gland 
dysfunction. Adv Exp Med Biol. 1994;350:293–298. 
27 Lemp MA, Bardfield L, Blackie CA, et al. Evaluation of a novel method of treatment of dry eye. Invest 
Ophthalmol Vis Sci. 2008; 127/A154. 
28 Majmudar PA. LipiFlow Study Group. A novel thermal pulsation treatment for obstructive meibomian 
gland dysfunction: applying heat to the inner eyelid surfaces. Invest Ophthalmol Vis Sci. 2010; 
6281/D909. 
29 Mori A, Oguchi Y, Goto E, et al. Efficacy and safety of infrared warming of the eyelids. Cornea. 
1999;18:188–193. 
30 Matsumoto Y, Dogru M, Goto E, et al. Efficacy of a new warm moist air device on tear functions of 
patients with simple meibomian gland dysfunction. Cornea. 2006;25:644–650. 
31 Lane SS, DuBiner H, Epstein RJ, et al;  A New System, the LipiFlow, for the Treatment of Meibomian 
Gland Dysfunction. Cornea. 2012: 31 : 396-404. 

 
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treatment to naturally express melted meibum, the physician then uses the Clearance 
Assistant device to further express the meibomian glands manually immediately 
following the eyelid heat treatment.   
 
In this study, the TearCare System will be compared with the LipiFlow Thermal Pulsation 
System27 in patients with dry eye disease.  The objective is to demonstrate that the 
TearCare System is safe and effective in relieving the signs and symptoms of dry eye 
disease and that it is non-inferior to treatment with the LipiFlow System.   
 
The TearCare System is a Class II-exempt device that is currently listed and commercially 
available in the US.  This post-market study is being conducted to collect data to update 
the indication for use for the TearCare System to read as follows, “The TearCare® 
System is indicated for the treatment of the signs and symptoms of dry eye disease 
(DED).” 
4 DESCRIPTION OF DEVICE 
4.1 CURRENT INDICATION FOR USE 
The TearCare System is a Class II exempt device that is listed with the FDA.  It is 
commercially available in the US.  It is currently labeled with the following indication for 
use:   
“The TearCare® System is indicated for the application of localized heat when the 
current medical community recommends the application of a warm compress to 
the eyelids. Such applications would include Meibomian Gland Dysfunction 
(MGD), Dry Eye, or Blepharitis.” 
4.2 PROPOSED INDICATION FOR USE 
This study is being conducted to collect data to support a modification to the TearCare 
indication for use to read as follows: 
 
“The TearCare® System is indicated for the treatment of the signs and symptoms 
of dry eye disease (DED).”   
4.3 DEVICE DESCRIPTION  
The TearCare System is designed to deliver controlled, precise heat to the tarsal plates 
and underlying meibomian glands of the eyelids for 15 minutes, followed immediately 
by manual mechanical meibomian gland expression.  The TearCare procedure takes 
place in the monitored setting of an ophthalmologist or optometrist office. 
 

 
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The Sight Sciences’ TearCare System is comprised of the following components: 
 
• SmartLidTM devices 
• SmartHubTM Kit, including SmartHub, SmartHub Nest, and charging adapter 
• Clearance AssistantTM devices 
 
The SmartLid devices are custom designed to conform to the tarsal plate of each 
respective eyelid so that patients can blink normally throughout the treatment and 
naturally express melted meibum with every blink.  Immediately following the thermal 
treatment, the physician uses the Clearance Assistant device to further express the 
meibomian glands manually to maximize the evacuation of melted meibum. 
 
The SmartLid Devices, shown below in Figure 1, are single-use, flexible, sensor-
controlled devices that adhere to each of the 4 eyelids.  They contain flexible circuits, 
sensors and a microprocessor which provide accurate and precise thermal energy to the 
eyelids to melt oil in the meibomian glands.  Medical grade adhesive on the skin-facing 
surface of the SmartLid devices allow them to be affixed to the external surface of the 
eyelids during the procedure and easily removed at the end of the procedure.  The 
flexibility of the SmartLid devices permit them to remain attached to the eyelids 
throughout the procedure while patient blinks normally.   
The SmartLid devices are connected to the SmartHub via a cable.  The SmartHub, shown 
below in Figure 2, delivers electrical energy to the SmartLids, and this energy is 
subsequently converted into thermal energy.  Embedded software and a closed loop 
sensor system ensures that the temperature delivered at the eyelids is maintained 
within a precise range. A control button on the center of the SmartHub is used to turn 
the system on and off and to initiate or discontinue the TearCare session.  Two buttons, 
“+” and “-“, on the left side of the face of the SmartHub allow the user to adjust the 
temperature to a level that is comfortable for the patient.  The current warmth setting is 
indicated by the warmth level indicators between the two adjustment buttons.  The 
SmartHub also has a display on the right side of its face that indicates how much time is 
left in the session.   The SmartHub is battery operated, with a built-in battery, and is 
recharged by placing it on the charging nest. 
The Clearance Assistant device (shown in Figure 3 below) is single-use, sterile device 
that is designed to facilitate manual expression of the meibomian glands after the 
application of heat by the TearCare SmartLid devices. 
 

 
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Figure 1:  SmartLid Devices applied to the Eyelids 
 
 
Figure 2:  TearCare SmartHub 
 
  
 
Figure 3:  Clearance Assistant Device 
 
 
 
Time remaining 
indicator 
On/Off button 
# Sessions 
remaining on the 
battery 
Temperature 
setting indicator 
and adjustment 
buttons (+ and -) 

 
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To use the System, the flexible SmartLid devices are applied to the external surface of 
the upper and lower eyelids of the patient (Figure 1).   The SmartLids are then 
connected to the TearCare SmartHub.  When the SmartHub is turned on and the 
physician initiates the procedure, the TearCare System begins delivering heat to the 
eyelids.  The system automatically and gradually increases the temperature over 2-3 
minutes until it reaches the maximum set point temperature of 45°C.  A complete 
TearCare session lasts 15 minutes.    
The SmartHub has 5 temperature set points (ranging from 41 to 45°C), which allow the 
user to manually adjust the temperature up or down to a level that is comfortable for 
the subject.  The set points can be adjusted at any time during the treatment session. 
Subjects are able to blink naturally during the session. 
The temperature range for the TearCare System was selected based on research that 
has shown that meibum will melt at temperatures between 32 to 45°C, but obstructed 
glands may require higher temperatures, around 45°C, to effectively melt meibomian 
obstructions.32,33,34  The maximum temperature and 15 minute treatment duration is 
also well below the time-temperature threshold at which heat contacting the skin will 
first show signs of cutaneous damage and edema, and is within the safety limits 
specified for medical electrical equipment.35,36,37 
Immediately following the TearCare session, the clinician uses the Clearance Assistant 
device to manually express the meibomian glands in all four eyelids.     
4.4 DEVICE MODIFICATION 
At the beginning of August 2019, while the study was ongoing, Sight Sciences modified 
the SmartLid device to allow the clinician to gently bend the flexible elements to achieve 
better conformance and adherence of the SmartLids to the eyelids.  Since it is possible 
that this design change could impact the clinical outcomes in the study, additional 
subjects were added to the study to ensure a full sample size of 138 subjects with the 
modified SmartLid design.  We anticipate a final enrollment of approximately 238 
subjects, approximately 100 prior to the modification (Cohort 1 subjects), and 138 after 
the modification was introduced (Cohort 2 subjects).  
 
32 Bron AJ, Tiffany JM.  The contribution of meibomian disease to dry eye.  Ocul Surf. 2004;2:149-165. 
33 Bron AJ, Tiffany JM, Gouveia SM, Yokoi N, Voon LW. Functional aspects of the tear film lipid layer. Exp 
Eye Res 2004;78:347–60. 
34 Jones et al.  TFOS DEWS II Management and Therapy Report.  The Ocular Surface 2017;15:575-628. 
35 Moritz AR, Henriques FC. Studies of thermal injury: the relative importance of time and surface 
temperature in the causation of cutaneous burns. Am J Pathol 1947;23:695–720. 
36 Despa F, Orgill DP, Neuwalder J, Lee RC. The relative thermal stability of tissue macromolecules and 
cellular structure in burn injury. Burns 2005;31:568–77. 
37 Medical electrical equipment  Part 1:  General requirements for basic safety and essential performance 
(IEC 60601-1). 

 
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4.5 INSTRUCTIONS FOR USE 
Instructions for Use are provided with each TearCare System. 
4.6 TRAINING 
Prior to the start of the study, investigators and study staff who have not been 
previously trained in the proper use of the TearCare System will be trained in its use.  
While most investigators should have experience in performing manual expression of 
the meibomian glands, which is a standard procedure for dry eye patients, investigators 
will be trained in the protocol method for performing meibomian gland expression using 
the Clearance Assistant device.  All study staff will receive training on the protocol and 
execution of the study according to applicable regulations and Good Clinical Practices. 
5 PRIOR INVESTIGATIONS 
5.1 PRECLINICAL TESTING 
The TearCare System has been tested extensively on the bench and in clinical validation 
testing to demonstrate that it meets all specified safety and performance requirements.  
The following testing and analyses was performed: 
 
• Thermal Requirements:  Bench testing was performed to demonstrate that the 
TearCare System meets the operational temperature requirements (range 41-
45°C).  Clinical validation testing was also performed to measure the 
temperature at the inner and outer surfaces of the eyelid during operation of the 
System and at the surface of the cornea immediately following the treatment.  
The testing confirmed that the system meets temperature-related performance 
and safety specifications.  No adverse events were observed.    
• Software Functionality:  Testing was performed to demonstrate that the 
software in the TearCare SmartHub and SmartLid Devices meet all software 
design requirements. 
• Electrical Safety:  Testing was performed to demonstrate that the System meets 
the electrical safety requirements specified in IEC 60601-1. 
• Electromagnetic Compatibility:  Testing was performed to demonstrate that the 
System meets the electromagnetic requirements specified in IEC 60601-1-2. 
• Biocompatibility:  All patient-contacting materials were reviewed to confirm that 
that they are biocompatible for short-term (<24 hours), skin contact. 
• Mechanical Strength:  Testing was performed to demonstrate that the system 
meets mechanical strength requirements. 
• Shipping, Storage, and Shelf-Life Testing:  Testing was performed to demonstrate 
that the TearCare System continues to function properly after being exposed to 

 
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environmental and shipping conditions specified in ASTM D4169.  In addition, 
accelerated aging testing was performed to demonstrate the SmartLid devices 
have a minimum shelf life of 6 months. 
5.2 PREVIOUS CLINICAL EXPERIENCE 
The TearCare System has been studied in two pilot studies.  The first study was 
conducted in 2013 as an Investigator-sponsored study with a prototype version of the 
TearCare System.  The second study was initiated in 2017 with a commercial version of 
the TearCare System (Sight Sciences protocol #05429).   These two studies are 
summarized below. 
 
CLINICAL STUDY OF THE PROTOTYPE TEARCARE SYSTEM (2013) 
A prototype version of the TearCare System was tested in a single center, prospective, 
randomized study.  The study enrolled 18 subjects who were randomized to two 
treatment arms:  (a) Prototype TearCare System, or (b) warm compress treatment.  
Subjects randomized to the TearCare arm (n=10 subjects) received one, 10-minute 
session with the prototype device followed by manual expression of the meibomian 
glands.  Subjects randomized to the warm compress arm (n=8 subjects) received 
standard warm compress therapy (Fire & Ice Mask, Rhein Medical, Inc.) for 5 minutes 
per day for 2 weeks.  Subjects were followed for 4 weeks, with follow-up visits at 1 day, 
2 weeks, and 4 weeks.   
 
No adverse events were reported in this study.  Table 1 presents the effectiveness 
outcomes from this study. 
 
This study demonstrated the safety of the TearCare System and provided evidence that 
TearCare System provides statistically significant improvement in meibomian gland 
secretion, tear break-up time, and dry eye symptoms.  Results from this study informed 
the decision to continue development on the TearCare System. 
 

 
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Table 1:  Prototype TearCare System - Study Results (2013) 
 
 
TearCare  
(n=10 subjects, 20 eyes) 
Warm Compress control  
(n=8 subjects, 16 eyes) 
 
Baseline 
4 weeks 
Change BL 
to 4 wks – 
p value 
Baseline 
4 weeks 
Change BL 
to 4 wks – 
p value 
Tear Break-up Time (sec) – Mean (SD) 
4.6 (0.8) 
16.8 (3.1) 
<0.0001 
4.1 (1.1) 
4.6 (1.8) 
0.27 
Dry Eye Symptom Questionnaires 
 
 
 
 
 
 
Total OSDI Score (0 to 100) 
37.0 (17.5) 
19.6 (9.9) 
0.01 
27.8 (23.3) 
34.3 (22.6) 
0.21 
Total SPEED Score (0 to 28) 
13.8 (2.7) 
7.4 (4.0) 
0.001 
13.6 (6.0) 
10.1 (6.7) 
0.19 
Meibomian Gland Assessment 
 
 
 
 
 
 
Total Meibomian Gland Score (0 to 45) 
13.4 (7.4) 
43.2 (1.4) 
<0.0001 
7.6 (4.5) 
15.4 (7.7) 
0.03 
# Glands Secreting Any Liquid (0 to 15) 
3.6 (3.6) 
14.9 (0.3) 
<0.0001 
1.1 (1.1) 
4.4 (3.8) 
0.04 
# Glands Yield Clear Liquid (0 to 15) 
0.3 (0.7) 
12.9 (1.8) 
<0.0001 
0 (0) 
1.25 (1.8) 
0.08 
 
 
CLINICAL STUDY OF THE TEARCARE SYSTEM (2017) 
Following completion of the design and development of the commercial version of the 
TearCare System, a single center pilot study was initiated to collect additional clinical 
data.  The results from this study were published in Clinical Ophthalmology.38 
 
Objectives 
The objective of this study was to evaluate the clinical utility, safety, and effectiveness 
of the TearCare™ System compared to standardized warm compress therapy. 
 
Subjects 
Twenty-four (24) subjects with symptoms of dry eye in the past 3 months were enrolled.  
The average age was 67.6 ± 13.5 years (range 29.7 – 89.8 years).  All subjects were 
female, white and not Hispanic or Latino.  All subjects had a SPEED score ≥6 at the 
Baseline visit.  All subjects had a Tear Break-up Time (TBUT) of <10 seconds in at least 
one eye at baseline and 72% (17/24) had a Schirmer 1 score (non-anesthetized) of ≤10 
mm in at least one eye at the Baseline visit.   
 
Methods 
This was a prospective, single-center, randomized, parallel-group, clinical trial. Subjects 
with DED were randomized to either a single TearCare treatment conducted at the clinic 
or 4 weeks of daily warm compress therapy. The TearCare procedure consisted of 12 
minutes of thermal eyelid treatment immediately followed by manual expression of the 
meibomian glands.  Warm compress therapy consisted of once daily application of the 
compresses to the eyelids for 5 minutes. Subjects were followed to 6 months post-
treatment. The primary effectiveness endpoint was defined as change from baseline to 
 
38 Badawi D.  A novel system, TearCare®, for the treatment of the signs and symptoms of dry eye disease.  
Clinical Ophthalmology 2018;12: 683-694. 

 
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4 weeks for Tear Break-up Time (TBUT).  Secondary effectiveness endpoints included 
meibomian gland assessment, corneal and conjunctival staining scores, and assessment 
of dry eye symptoms using validated questionnaires.  Safety was evaluated by collecting 
device-related adverse events, intraocular pressure, and best spectacle-corrected 
Snellen Visual acuity. 
 
Results 
Twenty-four subjects were enrolled and completed 6 months follow-up.  Data are 
summarized in Table 2 below. 
 
At 1 month follow-up, TearCare subjects demonstrated an improvement from baseline 
in mean (± SD) TBUT of 11.7 ± 2.6 seconds compared with an average worsening of -0.3 
± 1.1 seconds for subjects in the warm compress group (p<0.0001). Significantly greater 
improvements in the change from baseline in meibomian gland scores, as well as 
corneal and conjunctival staining scores were observed in the TearCare group. Subjects 
in the TearCare group also showed significantly greater improvement in dry eye 
symptoms as measured by the three questionnaires.  
   
No adverse events were reported in either group.     
 
Table 2:  TearCare System – Pilot Study Results (2017) 
 
TearCare 
(n=24 eyes, 12 subjects) 
Warm Compress control 
(n=24 eyes, 12 subjects) 
 
Baseline  
4 weeks 
6 months 
Baseline  
4 weeks 
6 months 
Tear Break-up Time (sec) – Mean (SD) 
3.1 (0.8) 
14.8 (2.6) 
7.9 (1.5) 
3.3 (1.0) 
3.1 (0.8) 
3.0 (1.0) 
Dry Eye Symptom Questionnaires 
 
 
 
 
 
 
Total OSDI Score (0 to 100) 
41.0 (18.4) 
15.7 (12.2) 
30.3 (15.1) 
33.0 (19.9) 
24.6 (15.2) 
30.3 (15.1) 
Total SPEED Score (0 to 28) 
15.7 (5.2) 
7.8 (3.5) 
8.2 (6.0) 
14.4 (3.8) 
12.6 (3.3) 
12.2 (4.0) 
Total SANDE Score  
64.9 (25.9) 
40.2 (18.8) 
45.9 (30.5) 
55.9 (31.5) 
57.5 (25.7) 
62.1 (21.8) 
Meibomian Gland Assessment 
 
 
 
 
 
 
Total Meibomian Gland Score (0 to 45) 
6.3 (3.6) 
41.0 (2.1) 
31.5 (5.5) 
9.0 (4.3) 
8.2 (4.0) 
9.4 (3.5) 
# Glands Secreting Any Liquid (0 to 15) 
0.8 (0.9) 
14.6 (0.8) 
11.5 (2.4) 
1.3 (1.7) 
1.3 (1.6) 
1.7 (1.5) 
# Glands Yield Clear Liquid (0 to 15) 
0.0 (0.0) 
11.4 (1.6) 
5.4 (3.0) 
0.3 (0.7) 
0.0 (0.0) 
0.1 (0.4) 
Corneal Staining Score (0 to 15) 
3.5 (1.8) 
0.2 (0.4) 
3.2 (2.6) 
3.4 (2.9) 
3.2 (2.6) 
3.2 (2.8) 
Conjunctival Staining Score (0 to 15) 
3.7 (2.5) 
0.1 (0.3) 
0.3 (0.7) 
3.0 (3.4) 
4.1 (3.5) 
3.2 (3.1) 
 
 
Conclusions 
The TearCare Group consistently showed a significant improvement between the 
baseline and 4 weeks follow-up for all outcome measures, whereas the Warm Compress 
group did not.  For all outcome measures, the TearCare Group’s mean change between 
baseline and 4 weeks follow-up was better than the Warm Compress group.  These 
results were maintained out to 6 months. 
 

 
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This pilot study provided preliminary evidence of the safety and effectiveness of the 
TearCare device in relieving the signs and symptoms of dry eye.   
 
SUMMARY 
The two prior clinical studies provided preliminary clinical data with the TearCare 
System.  Both of these studies were small, single-center pilot studies. 
 
This current trial is being undertaken to evaluate the safety and efficacy of the TearCare 
system versus treatment with the LipiFlow System in a prospective, multi-center, 
hypothesis-driven, randomized, controlled trial.  The study is intended to demonstrate 
that the TearCare System is indicated in the treatment of signs and symptoms of dry eye 
disease. 
6 STUDY ENDPOINTS 
6.1 EFFECTIVENESS ENDPOINTS 
This study will collect data to assess the impact of each treatment on the signs and 
symptoms of dry eye disease.  Tear Break-Up Time and meibomian gland secretion 
scores, which measure the treatment effect of the device on the signs of dry eye 
disease, are the primary endpoints.  The Ocular Surface Disease Index (OSDI) 
questionnaire, which is a validated instrument for measuring the severity of symptoms 
of dry eye disease, is the key secondary endpoint.  The following other secondary 
endpoints have been chosen to collect additional data regarding changes in the signs 
and symptoms of dry eye disease in study subjects:  Corneal and Conjunctival Staining, 
the Symptom Assessment iN Dry Eye (SANDE) questionnaire, the Eye Dryness Score, and 
Meibomian Gland Secretion Score (number of glands yielding clear liquid or any liquid at 
all). 
 
For each outcome measure, results from the TearCare subjects will be compared with 
results from the LipiFlow subjects.   All the primary and secondary endpoints will be at 1 
month. 
 
• Primary effectiveness endpoints    
o Mean Change from baseline in Tear Break-Up Time (TBUT) 
o Mean Change in the total Meibomian Gland Secretion Score39 
 
39 Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and grading of lid changes. 
Eye 1991;5: 395–411. 

 
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• Secondary effectiveness endpoints   
o Mean Change from baseline in OSDI score40 
o Mean Change from baseline in corneal staining scores 
o Mean Change from baseline in conjunctival staining scores 
o Mean Change from baseline in SANDE scores 41,42  
o Eye Dryness Score  
o Mean Change from baseline in the number of meibomian glands yielding 
clear liquid secretions 
o Mean Change from baseline in the number of meibomian glands 
secreting any liquid (clear or cloudy) 
• Additional Exploratory Endpoints 
o Use of dry eye lubricants 
6.2 SAFETY ENDPOINTS 
• Primary Safety Endpoint 
o Device-related adverse events (all adverse events will be recorded) 
• Secondary Safety Endpoints 
o Discomfort/pain during treatment 
o Change in best corrected visual acuity (ETDRS) 
o Change in intraocular pressure (IOP)  
7 STUDY DESIGN 
This is a prospective, randomized, controlled, single-masked, multi-center treatment 
study.  This is a post-market study intended to collect data to update the indication for 
use for the TearCare System.  To reduce potential bias in the study, study staff 
performing the endpoint assessments will be masked as to the subject’s treatment arm.  
Subjects cannot be masked as it will be obvious to them which treatment they are 
receiving. 
 
 
40 Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL.  Reliability and validity of the Ocular 
Surface Disease Index. Arch Ophthalmol 2000;118: 615-621. 
41 Schaumberg DA, Gulati A, Mathers WD, Clinch T, Lemp MA, Nelson JD, Foulks GN, Dana R.  
Development and Validation of a Short Global Dry Eye Symptom Index.  Ocular Surface.  2007;5(1):50-
57. 
42 Amparo F, Schaumberg DA, Dana R.  Comparison of Two Questionnaires for Dry Eye Symptom 
Assessment:  The Ocular Surface Disease Index and the Symptom Assessment iN Dry Eye.  
Ophthalmology.  2015;122(7):1498-1503. 

 
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7.1 STUDY DEVICE AND CONTROL ARM 
In this study, treatment with the TearCare System (study device) will be compared with 
treatment with the LipiFlow System (control arm).   
 
TearCare treatment includes an in-office 15 minute bilateral treatment session with the 
TearCare System immediately followed by manual expression of the meibomian glands 
using the Clearance Assistant device.  Subjects randomized to TearCare will receive one 
in-office TearCare treatment on study Day 0.   
 
The LipiFlow System is indicated for use as follows: 
 
The LipiFlow System is intended for the application of localized heat and 
pressure therapy in adult patients with chronic cystic conditions of the eyelids, 
including Meibomian Gland Dysfunction (MGD), also known as Evaporative Dry 
Eye or Lipid Deficiency Dry Eye. 
 
Subjects randomized to LipiFlow will receive the LipiFlow procedure bilaterally 
conducted per the device instructions for use.  The LipiFlow procedure will be 
performed in-office on study Day 0.   
7.2 STUDY CENTERS 
This study will be conducted at up to 15 centers in the United States.  No center will 
have more than 20% of the target enrollment (i.e. ≤28 subjects per site in Cohort 2). 
8 STUDY SELECTION CRITERIA 
8.1 INCLUSION CRITERIA 
For inclusion in this study, subjects must meet all of the following criteria: 
 
1. At least 22 years of age 
2. Reports dry eye symptoms within the past 3 months 
3. Reports having to use artificial tears or lubricants regularly over the past month 
to relieve dry eye symptoms. 
4. OSDI Score of 23-79 
5. TBUT of ≤7 seconds in both eyes  
6. Meibomian gland obstruction in both eyes based on a total Meibomian Gland 
Secretion Score ≤12 in each eye.  
7. At least 15 glands in each lower eyelid should be expressible, with a sterile 
cotton swab, at the slit lamp. 

 
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8. Best corrected visual acuity of 20/100 or better in both eyes. 
9. Willing and able to comply with the study procedures and follow-up 
10. Willing and able to provide informed consent 
11. English-speaking 
8.2 EXCLUSION CRITERIA 
A subject who meets any of the criteria listed below (in either eye) will be excluded from 
the study: 
 
1. Use of any of the following medications: 
a) Restasis or Xiidra within 60 days prior to enrollment;  
b) Antihistamines (oral or topical) within 10 days prior to enrollment;   
c) Systemic medication(s) (other than anti-histamines) that is known to 
cause ocular dryness (e.g. diuretics, anti-hypertensives, anti-depressants, 
hormone therapy) and whose dose of this medication(s) has not been 
stable within 30 days prior to enrollment.  There must be no anticipated 
adjustments to the dose of these medications for the duration of the 
trial; 
d) Accutane (at any time); 
e) Oral tetracyclines or azithromycin within 30 days prior to enrollment; or 
f) Topical ophthalmic antibiotics, anti-glaucoma medications, steroids, non-
steroidal anti-inflammatory medications within 30 days prior to 
enrollment. 
NOTE: Use of any of the above medications (with the exception of 1c) is not 
permitted during the 1 month follow-up period. 
2. Any of the following dry eye treatments: 
a) Office-based dry eye treatment (e.g. IPL, thermal pulsation [Lipiflow], 
etc.) within 12 months prior to enrollment;   
b) Meibomian gland expression within 6 months prior to enrollment;   
c) Blephex or debridement within 3 months prior to enrollment is an 
exclusion; 
d) Punctal occlusion or punctal plug placement within 30 days prior to 
enrollment;   
e) Use of TrueTear device within the past 2 weeks.  (Subjects must refrain 
from using the TrueTear device for the duration of the study.); or 
f) Any history of meibomian gland probing 
3. History of eyelid, conjunctiva or corneal surgery (including refractive surgery) 
within the past year.  In addition, subjects with any history of the following are 
excluded: chalazion surgery, surgery on the tarsal conjunctiva, radial keratotomy 
(RK), complicated blepharoplasty, lid reconstruction, or significant complications 
post-refractive surgery. 
4. Contact lens use within the past 2 weeks.  (Subjects must refrain from wearing 

 
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contact lenses during the 1 month follow-up.) 
5. History of Ocular Herpes Simplex or Ocular Herpes Zoster 
6. Any active, clinically significant ocular or peri-ocular infection or inflammation 
7. Recurrent clinically significant eye inflammation, other than dry eye, within 3 
months prior to enrollment 
8. Clinically significant anterior blepharitis.  In addition, collarettes or flakes of more 
than one quarter of the eyelid are excluded. 
9. Clinically significant eyelid abnormalities in either eye (e.g. entropion/ectropion, 
blepharospasm, aponeurotic ptosis, lagophthalmos, distichiasis, trichiasis). 
10. Clinically significant dermatologic or cutaneous disease of the eyelid or 
periocular area. 
11. In the clinical judgement of the investigator, meibomian glands have significant 
capping, atrophy, or are unable to be expressed, digitally or with a sterile cotton 
swab.   
12. Clinically significant ocular surface abnormalities that may affect tear film 
distribution or treatment (e.g. pterygium, anterior membrane dystrophy, 
Salzmann’s nodules, etc.) 
13. Corneal surface abnormalities such as corneal epithelial defects (other than 
punctate staining), ulcers, corneal epithelial dystrophies, keratoconus, and 
ectatic disease of the cornea 
14. Any active, clinically significant allergic, vernal, or giant papillary conjunctivitis. 
15. Ocular trauma within 3 months prior to enrollment. 
16. Known history of diminished or abnormal facial, periocular, ocular or corneal 
sensation 
17. Systemic diseases resulting in dry eye (e.g. autoimmune diseases such as 
Sjogren’s syndrome, rheumatoid arthritis, lupus, Graves’ disease, sarcoidosis, 
etc.) 
18. Subject is currently using Retin A or Latisse. 
19. Subject has permanent eyeliner/lid tattoos, eyelash extensions or wears false 
eyelashes. 
20. Subject is currently using Lash Boost. 
21. Allergies to silicone tissue adhesives 
22. Participation in another ophthalmic clinical trial within one year prior to 
enrollment.  Subject must also be willing to refrain from another ophthalmic 
study for the duration of the study.   
23. Co-existing condition, either ocular or non-ocular that, in the judgement of the 
investigator could affect the safety or effectiveness of treatment or the 
compliance of the subject to the protocol.  For example, subjects who are 
pregnant or nursing or have active, wet macular degeneration are excluded.     

 
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9 STUDY PROCEDURES 
9.1 STUDY SCHEDULE 
 
Table 3:  Study Visit Schedule 
Visit 
(Visit Window) 
Baseline 
(Day -7 to 0) 
Treatmentb 
(Day 0) 
Day 1 
(Day 1) 
Week 2 
 (Day 12-16) 
1 Mo 
(Day 21 – 35) 
Informed Consent 
Xa 
 
 
 
 
Demographics, Ocular & Medical History 
X 
 
 
 
 
Medication use 
X 
 
 
X 
X 
Questionnaires:  OSDI, SANDE, Eye 
Dryness Score 
X 
 
 
 
X 
Manifest Refraction and Best-corrected 
visual acuity (ETDRS) 
X 
 
Xc 
Xc 
X 
Slit Lamp Exam 
X 
 
X 
X 
X 
Tear Breakup Time 
X 
 
 
X 
X 
Corneal Staining  
X 
 
 
X 
X 
Conjunctival Staining 
X 
 
 
X 
X 
Schirmer 1 Test (without anesthesia) 
X 
 
 
 
 
Meibomian Gland Secretion Scoring 
X 
 
 
X 
X 
IOP d 
X 
 
X 
X 
X 
Subject Eligibility 
X 
 
 
 
 
Randomization 
X 
 
 
 
 
TearCare or LipiFlow Treatment 
 
X 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
Discomfort/Pain Questionnaire 
 
X 
X 
 
 
Collect Eye Drop/Lubricant Log 
 
 
 
 
X 
a Subjects may sign the informed consent up to 30 days in advance of the baseline visit. 
b  The TearCare or LipiFlow treatment must be performed within 7 calendar days of the Baseline visit.  If 
scheduling permits, it may be performed on the same day as the Baseline visit following Randomization.   
Refer to Section 9.5.1 for details. 
c On Day 1 and Week 2, Best Corrected Spectacle Visual Acuity (BCSVA using EDTRS) is measured without 
manifest refraction (MR).  If the VA has worsened by ≥10 letters (per ETDRS) from baseline, then MR 
should be performed, the ETDRS measurement should be repeated, and the VA post-MR should be 
recorded. 
 d IOP measured via applanation tonometry should be measured at baseline using standard of practice at 
each site with the same method to be used for all consecutive visits in the study. 
9.2 NUMBER OF SUBJECTS, DURATION OF FOLLOW-UP AND STUDY 
DURATION 
A total of up to 238 subjects will be enrolled and randomized in the study.  Assuming a 
15% screen failure rate, approximately 278 subjects will be enrolled and screened to 
obtain up to 100 randomized subjects using the initial SmartLid design (Cohort 1) and 

 
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138 randomized subjects using the modified SmartLid design (Cohort 2).  All subjects will 
be followed for 1 month. 
 
It is anticipated that enrollment in the study will take 8-11 months.  Including the 1-
month follow-up period, the study is expected to last 9-12 months. 
9.3 MATERIAL AND EQUIPMENT 
A listing of general equipment and materials required at the investigational site for the 
study is provided below. 
 
 TearCare System (including a SmartHub, SmartHub Nest, and charging adapter) 
 TearCare SmartLid Devices and Clearance Assistant Devices 
 LipiFlow System and Activators 
 ETDRS Visual Acuity System 
 Slit lamp 
 Wratten filter (yellow) (for corneal staining) 
 Goldmann Tonometer or other applanation tonometer  
 Meibomian Gland Evaluator (TearScience, Inc.) 
 Fluorescein sodium strips (for TBUT and corneal staining) 
 Lissamine green strips (for conjunctival staining) 
 Filter strips (for the Schirmer test) 
 2-20µL & 20-200 µL micropipettes and sterile tips 
 Microcentrifuge tubes 
 Preservative-free sterile saline 
 Proparacaine 0.5% or tetracaine 0.5% ophthalmic drops 
 Akten® (lidocaine hydrochloride ophthalmic gel) 3.5% or equivalent 
 Stopwatch 
 Ruler 
 Makeup remover wipes 
 Sterile scissors 
9.4 INFORMED CONSENT AND POINT OF ENROLLMENT 
The IRB-approved informed consent will be presented and explained to each 
prospective subject by the investigator or a trained clinical professional.  Once the 
subject has had ample time to read the consent form, has been informed of all aspects 
of the study, and has had an opportunity to ask questions, the subject will be given a 
choice to voluntarily confirm his or her participation in the study as documented by 
completion of the Informed Consent.  After signing the Informed Consent and the HIPAA 
(Health Insurance Portability and Accountability Act) authorization, the subject can then 
proceed with the baseline visit.  The baseline visit should be performed within 30 days 

 
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of the subject signing the informed consent.  The subject has the right to withdraw from 
the study at any time without consequences, as indicated in the Informed Consent 
Document. 
 
The subject’s signed and dated informed consent must be obtained before conducting 
any procedure specifically for the study.  Subjects are enrolled upon signing the ICD 
even if they subsequently fail to meet the eligibility criteria.   
 
The principal investigator(s) must retain the original, signed written Informed Consent 
Document.  A copy of the written Informed Consent Document must be given to the 
subject. 
9.5 BASELINE AND TREATMENT VISIT(S) 
 
SCHEDULING THE BASELINE AND TREATMENT VISIT(S) 
To facilitate scheduling, the Baseline and Treatment Visits may be performed in the 
same day or on two separate days.  If these visits are performed over two days, the 
Treatment Visit must be within 7 calendar days of the Baseline Visit.  For follow-up 
scheduling purposes, the date of the Treatment Visit is Day 0.   
 
Refer to Table 3 for which tests and exams are to be performed in each visit.  Endpoint 
assessments performed during the Baseline visit must be performed by a Masked 
Assessor (See Section 9.7). 
 
Since dry eye drops and lubricants can affect the endpoint assessments, instruct 
subjects not to use any of these products within 2 hours of the Baseline visit. 
 
BASELINE EXAMS, TESTS AND QUESTIONNAIRES 
After the subject has signed the informed consent form and agreed to participate in the 
study, the exams, tests and questionnaires listed in the Baseline column of Table 3 
should be performed.  Refer to Appendix A for instructions for performing the exams 
and administering the questionnaires. 
 
At this visit, subjects should undergo the following tests and exams, performed in the 
order indicated below, to screen them for the study qualification and to record baseline 
data.  Items with an asterisk (*) must be performed by a Masked Assessor (Refer to 
Section 9.7 for more information on the Masked Assessor). 
 
1. Questionnaires:  OSDI, SANDE and Eye Dryness VAS 
2. Demographics, medical and ocular history 
3. Medication use: ocular and systemic 

 
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4. Manifest refraction and ETDRS Best-corrected visual acuity* 
5. Slit Lamp Exam* 
6. Tear Breakup Time* 
7. Corneal Staining* 
8. Conjunctival Staining* 
9. Schirmer 1 Test 
10. Meibomian Gland Secretion Scoring* 
11. Intraocular pressure* 
If, at any point during the visit the subjects fails to meet a subject selection criterion, 
then the visit can be terminated.  Subjects who fail to meet all the selection criteria will 
be considered a screen failure and will be withdrawn from the study.   
 
Subjects who fail screening may be re-screened for the study after 60 days.  If they are 
re-enrolled, they should be assigned a new subject ID. 
 
NOTE:  Questionnaires and exam data collected on subjects prior to enrollment as part 
of the routine clinical practice may be used to pre-screen patients for the study.  
However, once the subject signs the consent form and is enrolled in the study, these 
questionnaires and exams must be repeated following the protocol procedures. 
 
After all required measurements have been obtained and it has been confirmed that the 
subject meets all the Subject Selection Criteria, then the subject will be Randomized. 
 
RANDOMIZATION 
Subjects will be randomized to either the TearCare (i.e. “treatment group”) or LipiFlow  
(i.e. “control group”) using a pseudo-random number generator with subjects enrolled 
according to a predetermined list. Randomization will use permuted blocks with random 
block sizes of 2 or 4.  The investigational site will be provided a set of envelopes with 
randomization assignments. Following randomization, the subject should undergo the 
applicable procedures described in the sections below.   
 
TREATMENT FOR TEARCARE GROUP 
Subjects randomized to the TearCare Group will undergo the following procedure 
bilaterally.  Refer to the TearCare Instructions for Use for detailed instructions for 
operating the TearCare System. 
 
1. Obtain a new set of SmartLid devices and a TearCare SmartHub with enough 
battery left for at least one procedure.  
2. Wipe the subject’s eyelids and temple with the makeup removal wipe provided 
by the Sponsor.  Allow the skin to dry or pad dry with a tissue.  Use care not to 
allow any of the wipe to get into the eye. 

 
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3. Place a pair of SmartLid devices on the subject’s eyelids and affix the temple 
housing to the subject’s temple.  Use the clip to secure the cables behind the 
subject’s head. 
4. Connect the SmartLid devices to the SmartHub. 
5. Inform the subject that the SmartLid devices will heat up very quickly once the 
TearCare procedure is started. 
6. Start TearCare procedure.  Subjects should be encouraged keep their eyes open 
and blink naturally during the TearCare procedure.   
7. If the subject indicates the temperature is too hot, decrease the temperature set  
point to a setting that is comfortable for the subject. 
8. Following the thermal portion of the TearCare treatment, remove the SmartLid 
devices from the subject and position the subject at the slit lamp to perform 
expression of the meibomian glands.  Begin performing expression within 3 
minutes of completion of the thermal portion of the procedure. 
9. Apply 1 drop of proparacaine or tetracaine into each eye.  
10. Using the Clearance Assistant Device, express the meibomian glands in all 4 
eyelids using the following technique: 
a. Think of each eyelid as having 3 zones:  nasal, central & temporal. 
b. For each zone, start at the fornix and work your way up to the margin. 
c. Position the forceps horizontal, parallel to the margin. 
d. Apply moderate continuous pressure and adjust based on the gland 
output. 
e. Perform a second pass on the same eyelid to further express the glands. 
f. After treating the lower and upper eyelids, repeat expression on all 4 lids 
to ensure complete expression.  Additional passes of expression may be 
performed to ensure complete expression. 
g. Should the subject experience discomfort, it is reasonable to apply 
additional topical anesthetic (i.e. proparacaine or tetracaine).  
Alternatively, Akten® (lidocaine hydrochloride ophthalmic gel) 3.5% or 
equivalent may be applied into the lower eyelid fornices. 
h. The goal is to express each zone until the meibum coming out is clear.  
Typically, complete expression takes approximately 5 minutes/eye. 
11. Immediately following the treatment, ask the subject to complete the 
Pain/Discomfort Questionnaires.   
 
TREATMENT FOR LIPIFLOW GROUP 
Subjects randomized to the LipiFlow Group will undergo the following procedure 
bilaterally.  Refer to the LipiFlow Instructions for Use for detailed instructions for 
performing the LipiFlow procedure. 
 
1. Seat the subject in a reclining chair. 
2. Place an anesthetic drop in each eye. 

 
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3. Put a lubricating drop on the surface of the sterile, disposable Activator. 
4. With a finger placed on the lid between the lid margin and the orbital bone, roll 
the finger to lift the lid margin of that particular lid off the globe. 
5. Have the subject look down at their feet and slip the Activator below the upper 
lid of the first eye. 
6. Have the subject then look up and place the Activator behind the lower lid. Have 
the subject close their eyes. 
7. Align the handle of the Activator so that it is parallel to the bridge of the 
subject’s nose. Place a piece of tape to secure the handle to the bridge of the 
subject’s nose. 
8. Assure that the outer surface so the bladder comes in full contact with the 
external side of the lids. 
9. Loop the tubing over the subject’s ear. 
10. Repeat for the fellow eye. 
11. Plug the tubing into the LipiFlow console.  
12. Initiate the procedure by pressing start button on the console. 
13. The procedure will last 12 minutes. 
14. Once the procedure is complete, remove the tape from one Activator. Slightly 
depressed the sclera to release any suction between the disposable and the eye. 
15. Have the subject look up and slip the Activator from under the lower lid, and 
then look down and remove from the upper lid. 
16. Repeat for the fellow eye. 
17. Place a lipid based drop in each eye. 
18. Immediately following the treatment, ask the subject to complete the 
Pain/Discomfort Questionnaires.   
 
FOLLOW-UP INSTRUCTIONS FOR SUBJECTS 
Review the following instructions with subjects at the completion of the visit.   
During the 1 month follow-up: 
1. Dry Eye Lubricants/Drops:  Subjects should make every effort to refrain from 
using any dry eye drops, lubricants, or other type of dry eye treatment (e.g. 
warm compresses, prescription medication, etc.).  If they require “rescue 
therapy” to relieve their symptoms, they should use the same type of drops or 
lubricants they were using prior to the study. 
2. Dry Eye Lubricant/Drop Log:  Provide subjects with the Lubricant/Drop log and 
instruct them to record any use of drops or lubricants during the follow-up period. 
3. Other Dry Eye Medications:  Subjects should not use any other medications for dry 
eye disease (e.g. Restasis, Xiidra, etc.) 
4. Other Treatments for Dry Eyes:  Subject should not have any other treatments for 
dry eyes.  For example, they should not use warm compresses or perform lid 

 
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massage.  They should not use the True Tear device or have any other in-office dry 
eye treatments. 
5. Anti-histamines:  Subjects should not use any anti-histamines. 
9.6 FOLLOW-UP VISITS 
Prior to the Visit:  Reminder Call 
 
A few days before the follow-up visit, it is recommended that the coordinator contact 
the subject to remind them not to use dry eye drops or lubricants on the day of the 
follow-up visit since these products can affect the endpoint assessments.   
 
At the Beginning of the Follow-up Visit:  Maintaining Masking of Study Personnel 
 
Endpoint assessments performed during the Follow-up visit must be performed by the 
Masked Assessor (See Section 9.7). 
 
At the beginning of the follow-up visit, the coordinator should remind the subject to not 
reveal their randomization group to the study personnel who will be performing the 
follow-up exams. 
 
Order of Procedures During the Follow-Up Visit 
 
Follow-up procedures will be performed per the Study Schedule provided in Table 3 
(page 30) and the methods included in Appendix A.  Since certain tests/exams can 
impact the ability to perform other tests/exams, the following tests and exams should 
be performed in this order: 
 
1. Questionnaires 
2. Manifest refraction, if required per this protocol, and ETDRS Best-corrected 
visual acuity 
3. Slit Lamp Exam 
4. Tear Breakup Time 
5. Corneal staining 
6. Conjunctival staining  
7. Meibomian Gland Secretion Scoring 
8. IOP 
9. Assessment of adverse events 
The following activities can be performed in any order: 
• Medication Use 
• Collection of Lubricant/Drop Log (for the 1 Month visit only) 

 
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9.7 PHOTOGRAPHY DURING EXAMS AND TEARCARE PROCEDURE 
Photographs or videos may be made during the baseline or follow-up exams or during 
the TearCare procedure.  These images may be used for educational, training or 
marketing purposes.  Subject consent must be obtained prior to taking any photographs 
or videos.  Subjects do not have to agree to consent to being filmed in order to 
participate in the study. 
9.8 MASKED ASSESSOR 
To reduce potential bias in the study, study staff performing endpoint assessments will 
be masked as to the subject’s treatment arm.  In addition, to ensure consistency in 
performing the endpoint assessments the study staff member who performs the 
baseline assessments should also perform the follow-up assessments.  An alternate 
Masked Assessor may be appointed to handle scheduling conflicts, but every effort 
should be made to have the same person performing all endpoint assessments 
throughout the study.  Masked Assessors may not perform the randomization, the 
TearCare procedure, or the Lipiflow procedure 
 
The following assessments must be performed by a Masked Assessor: 
 
• Manifest refraction and BCVA 
• Slit lamp exam 
• Tear Break-up Time 
• Corneal staining 
• Conjunctival staining 
• Meibomian gland secretion scoring 
• IOP 
• AE assessment 
 
9.9 MANAGEMENT OF DRY EYE SYMPTOMS DURING FOLLOW-UP 
During follow-up, subjects should refrain from using any dry eye treatments, including 
drops, lubricants, warm compresses, etc.  If they require “rescue therapy” to relieve 
their symptoms, they should use the same type of drops or lubricants they were using 
prior to the study.  They should document use of drops or lubricants on the 
Lubricant/Drop Log. 
 
Subjects should not use Restasis or Xiidra during the study.  Use of these drugs will 
result in the subject being excluded from the “Per Protocol” analysis from the time of 
initiation of these drugs forward. 

 
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Subject should not be treated with other dry eye treatments (e.g. IPL, TrueTear, punctal 
plugs, etc.) during the course of the study.  Administration of these treatments will 
result in the subject being excluded from the “Per Protocol” analysis from the time of 
initiation of these treatments forward. 
 
NOTE:  If a subject had a punctal plug at the baseline visit and it falls out during the 
study, it should be replaced. 
9.10 WITHDRAWAL AND DISCONTINUATION 
All subjects have the right to withdraw at any point during the treatment without 
prejudice.  The investigator can discontinue any subject at any time if continued 
participation in the study would result in harm to the subject.  All efforts should be 
made by the investigator to retain the subject in the study.  If a subject withdraws 
prematurely from the study, a genuine effort must be made to determine the reason(s) 
the subject discontinued the study.  The reason must be recorded in the subject’s file 
and on the Study Exit Form.   
 
If a subject withdraws from the study post-randomization but prior to receiving the 
TearCare or Warm Compress treatment, then that subject may be replaced in the study 
by a newly enrolled subject. 
9.11 SUBJECTS LOST TO FOLLOW-UP 
Subjects who do not show up for a follow-up must be contacted to attempt to have 
them come for the follow-up.  For those subjects who cannot be reached, at least 3 
phone call attempts should be made and documented.  If still no response, a registered 
letter shall be sent to the address on file for the subject in an attempt to make contact.  
If a subject misses two consecutive follow-up visits without any contact with the study 
staff, the subject will be considered lost-to-follow-up unless there is a further 
communication by the subject. 
10 ADVERSE EVENTS (AES) 
Adverse Events are defined below.  Adverse events that occur in the eye during the trial, 
whether they are considered to be device related or not, must be documented in the 
subject’s records.  Non-ocular adverse events do not need to be recorded as adverse 
events unless they meet the definition of serious adverse event or are believed to be 
related to the study device or a study procedure.  Date of the event, its severity, 
treatment (if any) and the assessed relationship of the event to the study device will be 
recorded on the Adverse Event Form.  Conditions which exist at the time the subject is 

 
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enrolled do not need to be recorded as adverse events unless they increase in severity 
during the study. 
10.1 DEFINITIONS OF AE, SAE, SADE, USADE 
Adverse Event 
Any untoward medical occurrence in a subject who has been 
treated with the device that does not necessarily have causal 
relationship with the treatment. 
Adverse Device 
Effect 
Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease that is possibly related 
to the study device. 
Serious Adverse 
Event (SAE) 
Any untoward medical occurrence that: 
• Results in death 
• Is life-threatening 
• Requires in-patient hospitalization or prolongs existing 
hospitalization 
• Necessitates medical or surgical intervention to preclude 
permanent impairment of a body function or permanent 
damage to a body structure 
• Sight threatening 
Unanticipated 
Adverse Device 
Effect 
Any serious adverse effect on health or safety, any life-
threatening problem or death caused by, or associated with a 
device if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the 
clinical investigational plan; or any other serious problem 
associated with a device that relates to the rights, safety, or 
welfare of subjects (21 CFR 812.3(s)). Any sight-threatening 
event, whether listed in the protocol or not, is considered to be 
reportable as a UADE 
 
10.2 LIST OF ANTICIPATED POTENTIAL ADVERSE EVENTS 
Anticipated potential adverse events include those that might reasonably be expected 
to occur in this study because they are associated with dry eye disease, the risk analysis 
for TearCare System (albeit remote likelihood) or study testing methods.  
• Eyelid/eye pain requiring discontinuation of the procedure 
• Eyelid/eye pain ≥1 day after the procedure 
• Burn, erythema, or swelling of the eyelids 
• Thermal injury to the eye, including conjunctiva, cornea or lens 
• Physical pressure-induced injury to the eyelid 

 
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• Corneal deformation 
• Foreign body sensation 
• Formation of a chalazion or stye 
• Infection of the eyelid or ocular surface 
• Ocular surface irritation or inflammation (e.g. Conjunctival injection, conjunctival 
or corneal abrasion, chemosis) 
• Allergic or inflammatory reaction to the SmartLid or LipiFlow activator 
• Loss in BCVA (ETDRS) of ≥10 letters  
10.3 REPORTING ADVERSE EVENTS AND UNANTICIPATED ADVERSE DEVICE 
EFFECTS 
Identification, collection and reporting of adverse event information is the responsibility 
of the principal investigator.  The investigator records the date of the event, its severity, 
treatment (if any) and the assessed relationship of the event to the study device on the 
Adverse Event Case Report Form (AE CRF).   
Any ocular-related serious adverse event (SAE) should be reported to the study sponsor 
within one working day of learning of the event.  Non-ocular-related SAEs should be 
reported to the study sponsor within two working days of learning of the event.  Email 
the AE CRF to TCsafety@sightsciences.com. 
Any unanticipated adverse device effects (UADE) must be reported to the following 
two entities: 
1. The study sponsor – Within one working day of the investigator first learning of 
the event, e-mail the AE CRF to TCsafety@sightsciences.com; and  
2. The reviewing IRB – As soon as possible, but no later than 10 working days after 
the investigator first learns of the event, report per the IRB’s instructions.  
The sponsor will conduct an evaluation of unanticipated adverse device effects.  If the 
sponsor determines that an unanticipated adverse device effect presents an 
unreasonable risk to subjects, parts of the investigation presenting risks will be 
terminated.  Termination will occur no later than 5 working days after the sponsor 

 
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makes such a determination and no later than 15 working days after the sponsor first 
received notice of the effect. 
11 RISK-BENEFIT ANALYSIS 
11.1 ANTICIPATED CLINICAL BENEFITS 
The TearCare™ procedure will be performed with the aim of reducing the signs and 
symptoms of dry eye.   The goal of the procedure is to provide a safe, reproducible, and 
effective treatment for dry eye disease, a disease for which there is an unmet need for 
effective therapies. 
11.2 ANTICIPATED ADVERSE DEVICE EFFECTS 
Anticipated adverse effects associated with the TearCare System have been described 
above in Section 10.2. 
11.3 RESIDUAL RISKS ASSOCIATED WITH THE TEST DEVICE, AS IDENTIFIED IN 
THE RISK ANALYSIS REPORT 
Sight Sciences believes that there are no Intolerable residual risks from this non-
invasive, controlled heat treatment device that can be easily and quickly removed by the 
subject or by the supervising ophthalmologist, in the event of a complication during a 
TearCare treatment session. 
11.4 RISKS ASSOCIATED WITH PARTICIPATION IN THE CLINICAL 
INVESTIGATION 
All anticipated study risks are listed in Section 10.2. 
11.5 POSSIBLE INTERACTIONS WITH CONCOMITANT MEDICAL TREATMENTS 
It is anticipated that there will be no interactions with concomitant medical treatments.   
11.6 STEPS THAT WILL BE TAKEN TO CONTROL OR MITIGATE THE RISKS 
The major risks to the subjects and the steps taken to control or mitigate them are 
described below: 
 
1. Overheating of the eyelids: All TearCare treatments will be done in the 
investigator’s office under direct supervision of the investigator. The device 

 
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delivers heat to the eyelids at a temperature ranging from 41-45°C.  This 
temperature range was selected because it is both safe for eyelid heating and 
effective for melting obstructions in the meibomian glands.43,44,45,46  The user 
can adjust the temperature up or down to a level that is comfortable, and may 
also shut off the System at any time if it is too uncomfortable or painful.  In 
addition, the TearCare System continuously monitors and regulates the 
temperature at the tissue-contacting surface of the SmartLid devices and has 
been designed to not exceed the maximum allowable temperature.    
 
2. Corneal abrasion: If the SmartLid devices are not positioned properly or come 
loose during the treatment, there is the potential for a corneal abrasion. To 
mitigate this, the supervising physician will apply the strips to the subject and 
will monitor their position during the treatment to ensure they remain in place 
and secure. 
 
In addition, there is the possibility of corneal abrasion or abrasion of the eyelid 
surface during expression of the meibomian glands.  To reduce the chance of 
abrasion, the forceps have been designed with smooth surfaces (i.e. no rough 
edges) and only trained users will perform expression. 
 
In addition to the above, the following mitigation steps have also been taken to reduce 
the risks in this study: 
 
• The device has been tested to demonstrate that it meets performance and 
safety specifications, as described in Section 5.1. 
• Instructions for Use are provided with each device. 
• The clinician using the device will be trained in how to safely and correctly apply 
and remove the SmartLid devices, and operate the TearCare System. 
• The clinician will be trained in how to perform meibomian gland expression using 
the TearCare Clearance Assistant 
• The study staff will be trained to perform procedures required in this protocol 
 
43 Lane SS, DuBiner H, Epstein RJ, et al.  A New System, the LipiFlow, for the Treatment of Meibomian 
Gland Dysfunction. Cornea. 2012: 31 : 396-404 
44 Blackie CA, Solomon JD, Greiner JV, Holmes M, Korb DR.  Inner Eyelid Surface Temperature as a 
Function of Warm Compress Methodology.  Optom Vis Sci 2008;85:675-683. 
45 Moritz AR, Henriques FC. Studies of thermal injury: the relative importance of time and surface 
temperature in the causation of cutaneous burns. Am J Pathol 1947;23:695–720. 
46 Medical electrical equipment  Part 1:  General requirements for basic safety and essential performance 
(IEC 60601-1). 

 
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12 STATISTICAL CONSIDERATIONS 
12.1 EVALUABILITY 
All subjects on whom the TearCare or LipiFlow is attempted will be considered evaluable 
for the safety analysis. All eyes that have at least one follow-up visit and have no major 
protocol deviations will be evaluable for the per protocol analysis.  
12.2 ANALYSIS POPULATIONS 
The per-protocol analysis population includes all subjects who have at least one follow-
up visit and have no major protocol deviations, including specifically no use of dry-eye 
medications (Xiidra, Restasis). The primary and secondary endpoint analysis will be 
performed based on the Cohort 2 per-protocol population.   
The intent-to-treat (ITT) analysis population includes all subjects who are randomized to 
either arm, regardless of treatment received. As a sensitivity analysis, the primary and 
secondary endpoint analyses will also be carried out on the Cohort 2 ITT population as 
well.  
The effectiveness outcomes for Cohort 1 subjects will be summarized descriptively 
based on the available data of the per-protocol population.  The effectiveness data 
listings will be Cohort 1 subjects that are excluded from in the per-protocol population 
will be provided separately. 
12.3 SUBJECT ACCOUNTABILITY 
A complete accounting of subjects by Cohort and visit will be provided, including 
reasons for dropout, if known. 
12.4 DEMOGRAPHICS AND BASELINE CHARACTERISTICS  
Demographic variables gender, race, ethnicity, and age will be summarized for all 
enrolled subjects, along with medical history, by Cohort and combined.  Descriptive 
statistical summaries of pre-treatment parameters (min, max, median, mean, standard 
deviation) will also be provided for each treatment arm. This includes baseline 
measurements for each of the study endpoints: TBUT, Total Meibomian Gland Secretion 
Score, Number of Meibomian glands with any/clear liquid, Corneal Staining, 
Conjunctival Staining, OSDI Score, SANDE Score, and Eye Dryness Score. 
All baseline measurements will be evaluated for adequate balance between the two 
treatment arms. 

 
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12.5 EFFECTIVENESS ENDPOINTS AND ANALYSIS METHODS 
All primary and secondary endpoints will be evaluated at 1 month.  Outcomes measured 
on a per-eye basis will be analyzed using data from both eyes, with linear mixed effect 
models to account for within-person correlation (correlation between right and left 
eyes).  
 DESCRIPTIVE ANALYSES 
All outcome measures, IOP outcomes, and Use of dry eye lubricants, will be tabulated by 
visit and treatment group.  
 PRIMARY EFFECTIVENESS ENDPOINTS 
The primary effectiveness endpoints are  
• the change from baseline in Tear Break-Up Time (TBUT), and 
• the change from baseline in overall Meibomian gland score (MEIB) 
Both endpoints will be evaluated at the 1 month visit. 
Each of the primary endpoints will be analyzed using a linear mixed effects (LME) 
ANCOVA model.  This will allow for the proper incorporation of within-person 
correlation into the statistical model, and will also allow for adjustment for baseline 
measurements.   It should be noted that, as described in Section 12.2, the primary 
analysis on these two primary effectiveness endpoints will be based on the Cohort 2 
per-protocol population. 
Details of the LME models are provided in the Statistical Analysis Plan (SAP) provided in 
Appendix B.  Hypotheses regarding the primary and secondary effectiveness outcomes 
are described below. 
 PRIMARY EFFECTIVENESS HYPOTHESES 
The primary study hypotheses will demonstrate non-inferiority of the TearCare 
treatment as compared to LipiFlow, for both Tear Break-Up Time (TBUT) and overall 
Meibomian gland score (MEIB) in the Cohort 2 subjects (after SmartLid modification).  
The full statistical model for the analyses is described in the SAP (Appendix B). 
To demonstrate non-inferiority of the TearCare treatment to the LipiFlow control for 
TBUT we will test the null hypothesis that 𝛽𝛽1,𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 is less than the non-inferiority margin 
of 3 seconds: 
𝐻𝐻0: 𝛽𝛽1,𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇≤−3.0
𝐻𝐻𝐴𝐴: 𝛽𝛽1,𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇> −3.0 

 
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Where 𝛽𝛽1,𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 represents the difference in change from baseline (1 month – baseline, 
so positive is better) between the TearCare treatment and the LipiFlow control.  The 
hypothesis will be tested by constructing a confidence interval (least squares mean 
interval) for 𝛽𝛽1,𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇 as described in the SAP. 
To demonstrate non-inferiority of the TearCare treatment to the LipiFlow control for 
MEIB we will test the null hypothesis that 𝛽𝛽1,𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 is less than the non-inferiority margin 
of 5 units: 
𝐻𝐻0: 𝛽𝛽1,𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀≤−5.0
𝐻𝐻𝐴𝐴: 𝛽𝛽1,𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀> −5.0 
 
Where 𝛽𝛽1,𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 represents the difference in change from baseline (1 month – baseline, 
so positive is better) between the TearCare treatment and the LipiFlow control for the 
overall Meibomian gland score.  The hypothesis will be tested by constructing a 
confidence interval (least squares mean interval) for 𝛽𝛽1,𝑀𝑀𝑀𝑀𝑀𝑀𝑀𝑀 as described in the SAP. 
 
Both hypotheses will be tested at a one-sided α = 0.05.  As both hypotheses will need to 
be rejected for study success there is no multiplicity adjustment necessary. 
 
If non-inferiority of the TearCare device is established as described above, then we will 
proceed to test for superiority for each of the two primary endpoints, that is, we will 
repeat the two hypothesis tests with non-inferiority margins set to 0.  If either of the 
two superiority tests is rejected then the TearCare device will be declared superior for 
that endpoint. 
The primary effectiveness outcomes of the Cohort 1 per-protocol population will be 
summarized separately by descriptive statistics for continuous variables such as mean, 
median, standard deviation, minimum, and maximum. 
 POOLABILITY 
Using a linear mixed effects modeling approach described in Appendix B, poolability of 
the effectiveness outcomes for Cohort 2 per-protocol population will be evaluated 
across centers by testing a Treatment-by-Center interaction (TxC).  If the TxC interaction 
is significant at α=0.15 a Center effect will be included in the final model and results will 
be reported separately by Center. For this analysis, Centers with less than 5 enrolled 
subjects will be combined into a single virtual center. 
 

 
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 MISSING DATA 
As a sensitivity analysis, multiple imputations for the primary outcome at the 1 month 
time point will be carried out using baseline characteristics and 2-week outcomes as 
predictors.  Details are provided in the SAP.  
 SECONDARY EFFECTIVENESS ENDPOINTS 
The secondary effectiveness endpoints include change from baseline for the following 
outcomes: 
1. Ocular Surface Disease Index (OSDI) score 
2. Corneal staining scores 
3. Conjunctival staining scores 
4. Symptom Assessment iN Dry Eye (SANDE) scores  
5. Eye Dryness Score 
6. Number of Meibomian Glands Yielding any liquid 
7. Number of Meibomian Glands Yielding clear liquid 
 
If both primary effectiveness hypotheses are both met for the Cohort 2 per-protocol 
population, then we will sequentially test each of the secondary effectiveness endpoints 
based on the Cohort 2 per-protocol population to determine whether there is a 
significant change between baseline and 1 month.  In each case we will test the null 
hypothesis that the change is 0 against the appropriate alternative (depending on the 
favorable direction). All testing of the secondary endpoints will be done using a two-
sided alpha of 0.05.  We will test the secondary endpoints in the order listed, stopping 
at the point where a test fails to reject.  This sequential procedure controls the overall 
type I error rate for the secondary endpoints. 
The secondary endpoints can be divided into two groups, those which are measured on 
a per-eye basis (Corneal Staining, Conjunctival Staining, Meibomian gland scores) and 
those measured on a per-subject basis (OSDI Score, SANDE Scores, Eye Dryness Score). 
The per-eye secondary endpoints (Corneal Staining, Conjunctival Staining, Meibomian 
gland counts) will be tested using a similar linear mixed effects modeling approach as for 
the primary endpoint, with treatment as a fixed effect, and including a random intercept 
per subject to account for correlation.   
The per-subject secondary endpoints (OSDI score, SANDE scores, Eye Dryness Score) are 
measured at the subject level so there is only one measurement per subject. For these 
endpoints a paired t-test will be used to evaluate change from baseline to 1 month. 
The secondary effectiveness outcomes of the Cohort 1 per-protocol population will be 
summarized separately by descriptive statistics (mean, median, standard deviation, 

 
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minimum, and maximum for the continuous variables; count and percent for the 
categorical outcomes). 
 ADDITIONAL EXPLORATORY ANALYSES 
The use of dry eye lubricants will be summarized by Treatment group at one month. 
12.6 SAFETY ENDPOINTS AND ANALYSIS 
 DESCRIPTIVE ANALYSES 
All adverse events, measures of pain and discomfort, changes in IOP, and changes in 
BCVA (EDTRS) will be tabulated by visit and treatment group.  
 PRIMARY SAFETY ENDPOINT 
The primary safety endpoint is the incidence of ocular adverse events. 
 PRIMARY SAFETY ANALYSIS 
All adverse events will be reported by treatment group and AE category. Any serious 
adverse events will be completely described in the study report.  The primary safety 
endpoint will be summarized for each treatment group. 
 
We will compute the incidence of ocular events in two ways: first as a simple 
proportion, counting the number of subjects with any event (that is, counting the first 
event per person in either eye), then as an incidence rate, counting all events including 
repeated events per subject. 
 SECONDARY SAFETY ENDPOINTS 
The secondary safety endpoints include: 
• Discomfort/pain during treatment 
• Change in best corrected visual acuity (ETDRS) 
• Change in intraocular pressure (IOP) 
 
These endpoints will be summarized by treatment group and visit. 
12.7 SAMPLE SIZE CALCULATION 
Up to 100 Cohort 1 subjects and 138 Cohort 2 subjects, approximately 119 in the 
TearCare group and 119 in the LipiFlow group, will be enrolled and randomized in the 
study.  Sample size was calculated to provide more than 90% power to meet both the 
TBUT and MEIB effectiveness endpoints in Cohort 2 and sufficient precision around the 

 
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adverse event estimates.  The sample size also takes into account an estimated 10% 
dropout rate.   Details of the sample size calculation can be found in Appendix B. 
 
12.8 DEVIATION FROM THE STATISTICAL PLAN 
Any deviations from the statistical plan will be noted in the final report. 
13 MONITORING PROCEDURES 
Sight Sciences or contract research organization (CRO) personnel will monitor the study 
in a manner consistent with FDA regulations, good clinical practices and the clinical 
research standards adopted by Sight Sciences.  Study monitoring will involve the 
following elements: 
 
• Site Qualification:  Sight Sciences or CRO personnel will meet with investigators 
and clinical study staff prior to the initiation of the study in order to review the 
adequacy of the subject population, facilities, and equipment with respect to 
the needs of the study, and to familiarize the investigator with the study 
protocol.   
• Site Initiation:  Sight Sciences or CRO personnel will meet with the 
investigator(s) and clinical study staff when the site is ready to begin enrolling 
subjects in order to train them in how to properly select subjects, perform the 
study procedure, and record study data.  This visit will include, but not be 
limited to a review of the following: 
o Detailed review of the protocol 
o Informed consent procedures 
o Randomization procedures 
o Instruction in how to use the TearCare System 
o Instruction in how to perform study procedures 
o Guidance in how to administer questionnaires to subjects 
o Procedures for maintaining masking of study personnel 
o Records and reports 
• Interim Monitoring:  Sight Sciences or CRO personnel will visit the clinical site 
routinely during the study to review charts and to perform source document 
verification, to ensure proper adherence to the study protocol, and to review 
regulatory documents.  Interim monitoring visits and telephone consultation 
will occur as necessary during the course of the study to ensure the proper 
progress and documentation of the study findings. 
• Study Closure:  At the conclusion of the trial there will be a study closure visit 
during which several actions, including but not limited to the following, will be 
performed: 

 
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o A final inspection of the study binder 
o Accountability and return of all devices and study materials to the 
sponsor 
o Discussion of record retention requirements with the investigator 
o Close-out notification to the IRB   
14 DATA AND QUALITY MANAGEMENT 
14.1 DATABASE MANAGEMENT 
The study database will be designed using an electric data capture (EDC) system that is 
compliant with 21 CFR Part 11 and relevant guidance documents.  The EDC will be 
developed and maintained by an independent, qualified data management firm. 
 
The database will incorporate time-stamped audit trails, protection of human subjects, 
restricted access, and data security at the component level.  Each database module, 
including each individual eCRF, will be validated by conducting a series of standard tests 
that demonstrate usability and correctness of the database system.  The database will 
be maintained on an ongoing basis and will be routinely backed up.  
14.2 SUBJECT IDENTIFICATION 
The subjects will be identified by a five digit subject number composed of a one-digit 
study identification number, a two digit center identification number followed by a two 
digit sequential subject number.  The subject identification will be assigned when 
informed consent is obtained.  In this way, information contained in the study records 
will be kept as confidential as possible. 
14.3 SUBJECT ACCOUNTABILITY 
All subjects randomized and treated in this clinical investigation shall be monitored for 
the duration of the investigation. The clinical investigation shall be considered 
completed when all subjects that have been enrolled in the investigation have reached 
the final reporting period, excluding subjects who were withdrawn.   
14.4 CONFIDENTIALITY 
All medical records associated with the clinical investigation will be made available for 
review by Sight Sciences personnel, its contract research organization (CRO) and 
governmental/regulatory agencies involved.  The results of the study may be published 
in the future for scientific and marketing purposes, but the identity (name) of each 

 
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subject will not be revealed.  All records will be stored in a secure area at the 
investigator’s facility, the CRO, the data management firm and at Sight Sciences, Inc. 
14.5 SOURCE DATA AND CASE REPORT FORMS 
Source data will be entered into a validated electronic system at each site by trained 
personnel in accordance with 21 CFR Part 11 requirements.  Electronic entries will be 
100% verified against corresponding source data at the sites and queried/corrected if 
needed to the extent possible.  Medical site records serve as source data.  In addition, 
data that are collected exclusively for the purpose of this study and not normally 
recorded in the subjects’ medical records can be collected directly on the study 
worksheets provided by the sponsor and these study worksheets will serve as the 
source data.   
 
Source data and study worksheets are to be maintained at the site in the subject 
records or in the medical records.  All entries must be made in black or blue ink and 
changes must be made by strike-through only with date and initials or signature.  All 
source documents must be completed and signed by the authorized study personnel 
(e.g., study coordinator).    No “white-out” is to be used on the source documents. 
14.6 RETENTION PERIOD 
Clinical sites are to retain any and all clinical trial material (documentation, photographs, 
etc.) for a period of two years from the date the marketing application is approved or 
two years after the investigation has been discontinued, or as directed by their 
institutional document retention requirements, whichever is the longest.  After that 
time, the items must be returned to Sight Sciences for archiving.  Unused medical 
devices are to be returned to the sponsor at the conclusion of the enrollment period. 
15 PROTOCOL MODIFICATIONS AND DEVIATIONS 
Protocol modifications may occur during the study.   Each will be approved by the 
sponsor before implementation. Each will undergo Institutional Review Board (IRB) 
review and approval, as necessary. 
 
Any deviations from this protocol intended to protect the life or physical well-being of a 
subject in an emergency are to be reported to Sight Sciences, Inc. as well as the IRB as 
soon as possible, and no later than 5 working days after the emergency occurred. 
 
All protocol deviations will be documented using the Protocol Deviation form. 

 
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16 DEVICE FAILURES AND MALFUNCTIONS 
All device failures or malfunctions should be recorded on the Device Deficiency Form 
and reported to Sight Sciences Customer Service (877-266-1144). 
 
If the TearCare or LipiFlow procedure cannot be completed due to a product failure or 
malfunction, the procedure may be rescheduled for a different day.  Every effort should 
be made to reschedule the procedure within the next 7 calendar days of the Baseline 
visit. 
17 ETHICAL CONSIDERATIONS 
17.1 DECLARATION OF HELSINKI 
This study shall be conducted in accordance with the Declaration of Helsinki (Appendix 
D).   
17.2 INSTITUTIONAL REVIEW BOARDS (IRB) 
The study shall not begin at a site until approval has been obtained from the reviewing 
IRB.  It is the Investigators’ responsibility to obtain and maintain written approval of the 
study protocol and Informed Consent documents from the appropriate IRB.  It is also the 
Investigators’ responsibility to notify that body about any amendments to these 
documents and to follow the IRBs rules regarding the reporting of Adverse Events and 
Protocol Deviations related to the device and/or this study.  Copies of all written 
approvals (identifying the study, the submitted and approved documents and the date 
reviewed) and the approved versions of the documents must be provided to Sight 
Sciences or its CRO.  
 
The Investigators must file all correspondence with the IRB and forward copies of such 
correspondence to Sight Sciences. 
17.3 INFORMED CONSENT FORM (ICF) 
An Informed Consent template that covers all protocol procedures and follows GCP 
Guidelines will be prepared by Sight Sciences and made available to each Investigator.  
The Investigator may adapt these templates to the requirements of the local IRB and of 
the institution where the study is conducted, but any revisions made to the ICF must be 
submitted to the sponsor for review prior to submission to the IRB.  A copy of each IRB-
approved ICF version is to be made available to Sight Sciences and its CRO.  The 
approved, IRB-stamped ICF is to be kept in its full length in the study Regulatory Binder.  

 
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Original, signed ICFs are to be maintained in the subject’s study records and must be 
made available for monitoring review.  
17.4 PUBLIC LISTING OF STUDY 
The study will be listed on the NIH website www.clinicaltrials.gov.  
18 STUDY ADMINISTRATION 
18.1 DEVICE ACCOUNTABILITY 
With each shipment of study devices, Sight Sciences will include a Packing List that will 
give the amount shipped and the lot numbers. This packing list must be reconciled by 
the investigational site with the contents of the shipment and then recorded on the 
Device Accountability Logs (these logs are contained within the regulatory binder at the 
site).  All study products at the site must be stored in a secured/locked area.  When 
study devices are used, returned or disposed of, their disposition (including the 
disposition and date of disposition) must be recorded on the Device Accountability log. 
 
Device reconciliation activities will also be conducted periodically in conjunction with 
site monitoring visits. The investigator must maintain accurate records of the receipt 
and disposition of all devices shipped by Sight Sciences.   
18.2 EARLY TERMINATION OR SUSPENSION OF AN INVESTIGATION 
Sight Sciences may terminate the study, in which case the investigators and associated 
IRBs will be notified in writing.  Possible reasons for study termination include but are 
not limited to: 
 
• The discovery of an unexpected, significant, or unacceptable risk to the study 
subjects treated with the device 
• Insufficient enrollment in the study 
• Withdrawal of FDA listing of the TearCare product. 
 
Sight Sciences reserves the right to stop the study at a center any time after the 
initiation visit if there have been no subject enrollments or if significant 
protocol/deviations are observed at the site.     
 
Likewise, a principal investigator may terminate the study at his/her institution.  This 
decision must be followed by written notification to Sight Sciences within five working 
days, stating the reasons for termination. 
 

 
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If the study is terminated, every effort should be made to obtain final follow-up from all 
subjects.   
 
In the event that there are significant human use issues with the device, the investigator 
will be consulted to make a determination of whether the study should be terminated 
or not. 
18.3 INVESTIGATOR RESPONSIBILITIES 
 GENERAL RESPONSIBILITIES OF INVESTIGATORS 
An Investigator is responsible for ensuring that an investigation is conducted according 
to the signed agreement, the investigational plan and applicable FDA regulations, for 
protecting the rights, safety, and welfare of subjects under the Investigator’s care, and 
for the control of devices under investigation. An Investigator also is responsible for 
ensuring that informed consent is obtained in accordance with 21 CFR part 50. 
 SPECIFIC RESPONSIBILITIES OF INVESTIGATORS 
1. 
Awaiting approval - An Investigator may determine whether potential subjects 
would be interested in participating in an investigation, but shall not request the 
written informed consent of any subject to participate, and shall not allow any 
subject to participate before obtaining IRB approval. 
2. 
Subject Qualification -The Investigator is responsible for ensuring that all subjects 
entering the study conform to the patient selection criteria. 
3. 
Compliance - An Investigator shall conduct an investigation in accordance with the 
signed agreement with the Sponsor, the investigational plan, all applicable FDA 
regulations, and any conditions of approval imposed by an IRB. 
 INVESTIGATOR RECORDS 
A participating Investigator shall maintain the following accurate, complete, and current 
records relating to the Investigator’s participation in an investigation for the period 
specified in Section 14.6:  
1. 
All correspondence with another Investigator, an IRB, the Sponsor, a monitor, or 
FDA, including required reports. 
2. 
Records of each subject’s case history and exposure to the device. Case histories 
include the study CRF’s/worksheets and supporting data including, for example, 
signed and dated consent forms and medical records.  Such records shall include: 
a) 
Documents evidencing informed consent. 

 
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b) All relevant observations, including records concerning adverse device effects 
(whether anticipated or unanticipated), information and data on the condition 
of each subject upon entering, and during the course of, the investigation, 
including information about relevant previous medical history and the results 
of all diagnostic tests. 
3. 
The protocol, with documents showing the dates and reasons for each deviation 
from the protocol. 
4. 
Any other records that FDA requires to be maintained by regulation or by specific 
requirement for a category of investigations or a particular investigation. 
 INVESTIGATOR REPORTS 
An Investigator shall prepare and submit the following complete, accurate, and timely 
reports: 
1. 
Unanticipated Adverse Device Effects - An Investigator shall submit to the Sponsor 
and to the reviewing IRB a report of any unanticipated adverse device effect 
occurring during an investigation as soon as possible, but in no event later than 10 
working days after the Investigator first learns of the effect. 
2. 
Withdrawal of IRB Approval - An Investigator shall report to the Sponsor, within 5 
working days, a withdrawal of approval by the reviewing IRB of the Investigator’s 
part of an investigation. 
3. 
Progress - An Investigator shall submit progress reports on the investigation to the 
Sponsor, the monitor, and the reviewing IRB at regular intervals, but in no event 
less often than yearly. 
4. 
Deviations from the Investigational Plan - An Investigator shall document and 
report to the Sponsor any deviation from the investigational plan.  
5. 
Informed Consent - If an Investigator enrolls a subject without obtaining informed 
consent, the Investigator shall report such use to the Sponsor and the reviewing 
IRB within 5 working days after the use occurs. 
6. 
Final Report - An Investigator shall, within 3 months after termination or 
completion of the investigation or the Investigator’s part of the investigation, 
submit a final report to the Sponsor and the reviewing IRB. 
7. 
Other - An Investigator shall, upon request by a reviewing IRB or FDA, provide 
accurate, complete, and current information about any aspect of the investigation. 
 

 
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18.4 INVESTIGATOR AGREEMENT 
The principal investigators in each center shall agree to the clinical protocol and any 
amendments and indicate their approval and agreement by signing and dating the cover 
page of the study protocol and the Investigator Responsibility Agreement. 
19 PUBLICATION POLICY 
Sight Sciences recognizes the value of disseminating research results.  It is understood 
that the Study is part of the Multi-Center Clinical Trial and publication of results is 
expected.  This publications policy applies to journal articles, conference abstracts, and 
conference presentations (posters and slides) covering Sight Sciences-sponsored clinical 
studies.  This policy is in addition to any arrangement contained in the Clinical Trial 
Agreement between Sight Sciences and the investigator.  
 
Multi-Site Data 
Clinical site investigators are encouraged to propose publications and abstracts that 
include clinical or research data from multiple clinical sites; such projects will be 
coordinated by Sight Sciences.  Authorship of papers and abstracts resulting from these 
projects will be determined collaboratively according to the following guidelines:  
 
• The first author on such publications will be the person who primarily wrote the 
paper and took the lead on the research.  In the case of clinical trial papers 
where all authors contributed equally, authorship order may be based on site 
enrollment or other criteria at Sight Sciences’ discretion. 
• Other authors include those who significantly contributed to the specific work.   
• At least one person from each clinical site whose study subjects appear in the 
work will be acknowledged in the manuscript/presentation in some way, either 
as an author group member, a non-author contributor, or listed in the 
acknowledgements, depending on the particular policies of the journal or 
conference. 
 
Single Site Data 
After publication of the multi-center study results in a peer-reviewed journal, or if 
Sponsor has not submitted a manuscript for publication in a peer-reviewed journal 
within twelve (12) months after the study has been completed, whichever occurs first, 
Investigators may publish the results of the Study generated by the Investigator, subject 
to the obligations of the Clinical Trial Agreement between Sight Sciences and the 
Investigator, and the prior approval of Sponsor in writing.   
 

 
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Publications Review Policy 
Investigators must submit all presentations, posters, abstracts and manuscripts 
pertaining to this study to Sight Sciences for review in advance of their submission.  
Sight Sciences conducts this review to protect its proprietary rights to information, 
inventions, or products developed under the Study.  Please use the following guideline 
to determine the absolute minimum advance time for submitting an item to Sight 
Sciences for review: 
 
• Presentations/Posters: 5 business days in advance of presentation 
• Abstracts: 5 business days in advance of submission 
• Manuscripts: 30 calendar days in advance of submission for publication 
 
In accordance with the Clinical Trial Agreement, these items must receive written 
approval from Sight Sciences in order for them to be submitted or presented.  If an item 
is not received in the timeframe listed above, approval may not be granted due to 
insufficient time for considered review. In addition, since most of our Clinical Trial 
Agreements require that Sight Sciences has 60 days to review publications, Sight 
Sciences reserves the rights granted in those Agreements if circumstances require a 
longer review. 
20 BIBLIOGRAPHY 
1. American Academy of Ophthalmology’s Dry Eye Syndrome Preferred Practice 
Pattern 2013. 
2. American Optometric Association’s Clinical Practice Guidelines for Ocular Surface 
Disorders, updated 2010. 
3. Amparo F, Schaumberg DA, Dana R.  Comparison of Two Questionnaires for Dry 
Eye Symptom Assessment:  The Ocular Surface Disease Index and the Symptom 
Assessment iN Dry Eye.  Ophthalmology.  2015;122(7):1498-1503. 
4. Badawi D.  A novel system, TearCare®, for the treatment of the signs and 
symptoms of dry eye disease.  Clinical Ophthalmology 2018;12: 683-694. 
5. Blackie CA, Solomon JD, Greiner JV, Holmes M, Korb DR.  Inner Eyelid Surface 
Temperature as a Function of Warm Compress Methodology.  Optom Vis Sci 
2008;85:675-683. 
6. Blackie CA, Korb DR, Knop E, et al. Nonobvious obstructive meibomian gland 
dysfunction. Cornea. 2010;29:1333–1345. 
7. Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and 
grading of lid changes. Eye 1991;5: 395–411. 
8. Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf. 
2004;2:149–165. 
9. Bron AJ, Tiffany JM, Gouveia SM, Yokoi N, Voon LW. Functional aspects of the 
tear film lipid layer. Exp Eye Res 2004;78:347–60. 

 
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10. Craig JP, Blades K, Patel S. Tear lipid layer structure and stability following 
expression of the meibomian glands. Ophthalmic Physiol Opt. 1995;15:569–574. 
11. Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson JD, Nichols 
JJ, Tusbota K, Stapleton F.  TFOS DEWS II Definition and Classification Report.  
The Ocular Surface 2017;15:276-283.The definition and classification of dry eye 
disease: report of the Definition and Classification Subcommittee of the 
International Dry Eye Work Shop. Ocul Surf. 2007;5:75–92. 
12. Despa F, Orgill DP, Neuwalder J, Lee RC. The relative thermal stability of tissue 
macromolecules and cellular structure in burn injury. Burns 2005;31:568–77. 
13. Finis D, Hayajneh J, Konig C et al. (2014a) Evaluation of an automated 
thermodynamic treatment (LipiFlow) system for meibomian gland dysfunction: a 
prospective, randomized, observer-masked trial. The Ocular Surface 12(2):146–
154 
14. Fiscella RG. Understanding dry eye disease: a managed care perspective. Am J 
Manag Care 2011; 17 Suppl 16:S432-9. 
15. Foulks G, Bron AJ.  Meibomian gland dysfunction:  A clinical scheme for 
description, diagnosis, classification, and grading.  Ocular Surface.  2003;1:107-
126. 
16. Friedland BR, Fleming CP, Blackie CA, et al. A novel thermodynamic treatment 
for meibomian gland dysfunction. Curr Eye Res. 2011;36: 79–87. 
17. Geerling G, Tauber J, Baudouin C, et al. The international workshop on 
meibomian gland dysfunction: report of the subcommittee on management and 
treatment of meibomian gland dysfunction. Invest Ophthal-mol Vis Sci 
2011;52:2050-64 
18. Goto E, Monden Y, Takano Y, et al. Treatment of non-inflamed obstructive 
meibomian gland dysfunction by an infrared warm compression device. Br J 
Ophthalmol. 2002;86:1403–1407. 
19. Gyau DA, Begley CF, Nelson JD.  A simple cost effective method for preparing FL 
and LG solutions. Ocular Surface.  2018;16:139-145. 
20. Jones et al.  TFOS DEWS II Management and Therapy Report.  The Ocular Surface 
2017;15:575-628. 
21. Knop N, Knop E, Millar T. The international workshop on meibomian gland 
dysfunction: Report of the subcommittee on anatomy, physiology and 
pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011 Mar; 
52(4): 1938–78. 
22. Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with 
dry eye symptoms and gland location. Cornea. 2008;27: 1142–1147. 
23. Korb DR, Blackie CA. Restoration of meibomian gland functionality with novel 
thermodynamic treatment device–a case report. Cornea. 2010;29:930–933. 
24. Korb DR, Greiner JV. Increase in tear film lipid layer thickness following 
treatment of meibomian gland dysfunction. Adv Exp Med Biol. 1994;350:293–
298. 

 
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25. Korb DR, Henriquez AS. Meibomian gland dysfunction and contact lens 
intolerance. J Am Optom Assoc. 1980;51:243–251. 
26. Lane SS, DuBiner H, Epstein RJ, et al;  A A New System, the LipiFlow, for the 
Treatment of Meibomian Gland Dysfunction. Cornea. 2012: 31 : 396-404 
27. Lemp M, Foulks, G.  The Definition & Classification of Dry Eye Disease:  
Guidelines from the 2007 International Dry Eye Workshop.  April 2008.  
http://www.tearfilm.org/pdfs/OM%20-%20Definition%20&%20Classification.pdf 
28. Lemp MA, Bardfield L, Blackie CA, et al. Evaluation of a novel method of 
treatment of dry eye. Invest Ophthalmol Vis Sci. 2008; 127/A154. 
29. Lemp MA, Crews LA, et al. Distribution of Aqueous-Deficient and Evaporative Dry 
Eye in a Clinic-Based Patient Cohort: A Retrospective Study. Cornea. 2012: 31: 
472-478. 
30. Lemp MA. Report of the National Eye Institute/Industry workshop on clinical 
trials in dry eyes. CLAO J. 1995;21:221–232. 
31. Majmudar PA. LipiFlow Study Group. A novel thermal pulsation treatment for 
obstructive meibomian gland dysfunction: applying heat to the inner eyelid 
surfaces. Invest Ophthalmol Vis Sci. 2010; 6281/D909. 
32. Maskin SL. Intraductal meibomian gland probing relieves symptoms of 
obstructive meibomian gland dysfunction. Cornea. 2010;29: 1145–1152. 
33. Matsumoto Y, Dogru M, Goto E, et al. Efficacy of a new warm moist air device on 
tear functions of patients with simple meibomian gland dysfunction. Cornea. 
2006;25:644–650. 
34. McMonnies CW.  Measurement of Symptoms Pre- and Post-treatment of Dry Eye 
Syndromes.  Optom Vis Sci. 2016;93: 1431-1437. 
35. Miller K, Walt JG, Mink DR, Satram-Hoang S, Wilson SE, Perry HD, Asbell PA, 
Pflugfelder SC.  Minimally Clinically Important Difference for the Ocular Surface 
Disease Index.  Arch Ophthalmol.  2010;128(1):94-101. 
36. Mitra M, Menon GJ, Casini A, et al. Tear film lipid layer thickness and ocular 
comfort after meibomian therapy via latent heat with a novel device in normal 
subjects. Eye (Lond). 2005;19:657–660. 
37. Mori A, Oguchi Y, Goto E, et al. Efficacy and safety of infrared warming of the 
eyelids. Cornea. 1999;18:188–193. 
38. Moritz AR, Henriques FC. Studies of thermal injury: the relative importance of 
time and surface temperature in the causation of cutaneous burns. Am J Pathol 
1947;23:695–720. 
39. Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian 
gland dysfunction: executive summary. Invest Ophthalmol Vis Sci. 2011;52:1922–
1929. 
40. Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness 
following treatment with warm compresses in patients with meibomian gland 
dysfunction. Eye Contact Lens. 2003;29:96–99. 

 
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41. Schaumberg DA, Gulati A, Mathers WD, Clinch T, Lemp MA, Nelson JD, Foulks 
GN, Dana R.  Development and Validation of a Short Global Dry Eye Symptom 
Index.  Ocular Surface.  2007;5(1):50-57. 
42. Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL.  Reliability and 
validity of the Ocular Surface Disease Index. Arch Ophthalmol 2000;118: 615-
621. 
43. Smith GT, Dart J. External eye disease. In: Jackson TL, ed. Moorﬁelds Manual of 
Ophthalmology. Philadelphia: Mosby Elsevier; Chap 4:2008. 
44. Yu J, Asche CV, Fairchild CJ.  The economic burden of dry eye disease in the 
United States:  a decision tree analysis.  Cornea 2011;30(4):379-87. 
 
 

 
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21 APPENDIX A – METHODS FOR EXAMS, TESTS AND 
QUESTIONNAIRES 
21.1 MEDICATIONS 
When recording medications that the subject is taking, be sure to ask the subject to list 
any over-the-counter medications and supplements they are taking that could affect dry 
eye disease including, for example, cold medicines, Benadryl, fish oil supplements and 
Omega 3 products, retinol products, Latisse, etc.  Multivitamins and general health 
supplements do not need to be recorded. 
21.2 MANIFEST REFRACTION AND VISUAL ACUITY 
Masked assessment:  This assessment should be performed by the masked assessor.   
 
Best-corrected visual acuity will be measured using the ETDRS method.  Subjects should 
undergo manifest refraction prior to the ETDRS test, with the exception of the Day 1 and 
week 2 follow-up visit.  On Day 1 and week 2, the subject’s best spectacle corrected 
visual acuity (BSCVA) (i.e., without manifest refraction) will be measured using the 
ETDRS method.  If the subject’s visual acuity has worsened by ≥ 10 letters from baseline, 
then manifest refraction should be performed and the ETDRS measurement should be 
repeated. 
 
Manifest Refraction 
 
Refraction will be performed by the Investigator or staff using standard clinical practice.   
 
ETDRS Testing Methods 
Test Set-up 
Best-corrected visual acuity at Baseline and all scheduled follow-up visits will be 
measured using the ETDRS charts at 1 or 4 meters.   
The ETDRS chart must be placed at a distance of 4.00 meters (13 feet and 1.5 inches, or 
157.5 inches) from cornea to chart surface, when using a 4-meter chart.  For testing at 1 
meter, the distance must be 1.00 (39 and 3/8 inches). A measuring tape or meter stick 
should always be available to verify the chart distance, even if the examining chair is 
supposed to be immovable or if reference marks are placed on the floor or walls.  
 

 
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The 1-meter distance is measured from the eye of the participant, seated comfortably in 
a chair with his/her back firmly placed against the chair, to the center of the 2nd or 4th 
letter of the 3rd line of the chart.  
 
Note:  If it is necessary to refract at the 1-meter distance, remember to add +0.75 
sphere to the trial frame. Subtract the +0.75 sphere from the final refraction obtained at 
the 1-meter distance before recording the refraction on the form.  
 
Methods 
 
Starting at 4 meters, the subject should attempt to read each letter, line-by-line, left to 
right, beginning with line 1 at the top of the chart.  If the subject is unable to read line 1 
(20/200) at 4 meters, then visual acuity testing should be performed at 1 meter. 
 
The subjects should be told that the chart has letters only, no numbers.  If the subject 
reads a number, he or she should be reminded that the chart contains no numbers, and 
the examiner should then request a letter in lieu of the number.  The subject should be 
asked to read slowly, about one letter per second, so as to achieve the best 
identification of each letter.  He/she is not to proceed to the next letter until he/she has 
given a definite response. 
 
A maximum effort should be made to identify each letter on the chart.  When the 
subject says he/she cannot read a letter, the subject should be encouraged to guess.  If 
the subject identified two (2) letters (e.g., A or B), the subject should be asked to choose 
one letter and, if necessary, to guess. When it becomes evident that no further 
meaningful readings can be made despite encouragement to read or guess, the 
examiner should stop the testing for that eye.  However, all letters on the last line 
should be attempted as letter difficulties vary and the last letter may be the only one 
read correctly.  The number of letters missed or read incorrectly should be noted.   
 
In order to provide standardized and well-controlled assessment of visual acuity, all 
visual acuity assessments for a subject should be performed consistently (e.g., the same 
lighting conditions, viewing distance, etc.) at each visit. 
 
Recording and Scoring Best-Corrected Visual Acuity 
 
Using the Visual Acuity Worksheet, circle each letter the subject identifies correctly, 
write total correct for each row in the place provided, and compute the total correct for 
all rows. Do not mark letters read incorrectly or not read at all.  Each letter read 
correctly is recorded as one.  Only move to the next line if 4 or more letters are read 
correctly. If 3 or more letters are read correctly in the final line, then that line is used for 
the Snellen equivalent and the visual acuity score. If 2 or fewer letters are read correctly 

 
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in the final line, letters read from that line are added to the total visual acuity score and 
the previous line is used for the Snellen equivalent. 
 
The number of correct letters will be recorded on the study worksheets and entered 
into the EDC.  For the Day 1 Visual Acuity measurement, if two measurements are made, 
one BSCVA and one with manifest refraction, the latter VA obtained with manifest 
refraction should be entered into the EDC. 
21.3 SLIT LAMP EXAM 
Masked assessment:  This assessment should be performed by the masked assessor.   
 
A standard slit-lamp examination shall be performed including inspection of the cornea 
at a magnification of 10X and/or 16X for the presence or active inflammation or 
structural change, the iris and anterior chamber for inflammation, and the eyelids for 
crusts, collarettes, or scales. 
 
21.4 TEAR BREAKUP TIME (TBUT) 
Masked assessment:  This assessment should be performed by the masked assessor.   
 
Preparation of Fluorescein Solution Per the Gyau Method47 
 
1. Obtain a tube with the pre-cut Fluorescein strips prepared per the instructions 
provided in Appendix C.  Make sure the pieces of the strips are lying at the 
bottom part of the tube. 
2. Pipette 200µL of sterile saline into the tube containing the cut strips.  Gently 
shake the tube to make sure the fluid is covering all the pieces of the cut strips 
and cover with the lid. 
 
 
 
3. Wait 3-15 minutes before using the fluorescein solution.   
 
 
47 Gyau DA, Begley CF, Nelson JD.  A simple cost effective method for preparing FL and LG solutions. 
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Measuring Tear Break-Up Time 
 
1. Using a micropipette, instill 5µL of the fluorescein solution into the lower 
conjunctival fornix. 
2. Measure TBUT quickly after instilling the fluorescein. 
3. Use the cobalt blue illumination of the slit lamp and a Wratten filter. 
4. Ask the subject to blink 3 times and then hold their eye open (e.g., “Blink, blink, 
blink, hold”). 
5. Using a stopwatch, record the time when the tear film breaks-up. 
6. Repeat the test 3 times per eye and take the average of the 3 measurements. 
7. Discard the remaining fluorescein solution and microcentrifuge tube. 
 
Tips for Tear Break-up Time 
 
• TBUT is the number of seconds between a blink and the appearance of a first 
dry spot or negative staining in the tear film.   
• TBUT measurements should be done quickly after installation of the dye 
because, in the presence of epithelial defects, the fluorescein will diffuse into 
the tissue and the borders of staining become indistinct, as does the intensity 
of staining of both tear film and cornea.   
• Clear instructions should be provided to subjects about the blink and hold 
sequence 
• Clear instructions should be provided to the study staff about when to start 
the stop watch 
  

 
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21.5 CORNEAL STAINING 
Masked assessment:  This assessment should be performed by the masked assessor.  
 
Measuring Corneal staining  
 
1. Measure corneal staining within 1-4 minutes of installation of fluorescein dye to 
assure the dye does not diffuse into stroma, blurring the discrete margin of any 
staining defects.   
2. Use moderate illumination on the slit-lamp and use cobalt blue filter on with 
yellow Wratten filter to improve any visualization of corneal staining. Use 3 mm 
width and 10x magnification for assessing corneal staining. . 
3. Grade the corneal staining using the NEI/Industry Grading System provided in 
Figure 4 below. 48 
 
Figure 4:  NEI/Industry Grading System for Corneal Staining 
 
 
Grade 0:  No staining 
Grade 1:  Scattered, micropunctate staining 
Grade 2:  Grouped, micropunctate staining 
Grade 3:  Diffuse micropunctate or macropunctate staining 
 
 
Tips for Corneal Staining 
• Ask subjects to blink several times to assure the uniform distribution of dye in 
cul-de-sac 
• Make sure to use moderate illumination to avoid hyper reflection from the spots 
of fluorescein uptake 
 
48 Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes. 
CLAO J  1995;21: 221–232. 

 
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21.6 CONJUNCTIVAL STAINING 
Masked assessment:  This assessment should be performed by the masked assessor.  
 
Preparation of Lissamine Green Solution Per the Gyau Method49 
 
1. Obtain a tube with the pre-cut lissamine green strips prepared per the 
instructions provided in Appendix C.  Make sure the pieces of the strips are lying 
at the bottom part of the tube. 
2. Pipette 200µL of sterile saline into the tube containing the cut strips.  Gently 
shake the tube to make sure the fluid is covering all the pieces of the cut strips 
and cover with the lid. 
 
 
 
3. Wait 5-15 minutes before using the lissamine green solution.   
 
Grading Conjunctival Staining 
 
1. Instill 5µL of lissamine green solution into the lower conjunctival fornix. 
2. Wait at least 1 minute before grading the conjunctival staining.  Perform grading 
within 4 minutes of instilling the solution. 
3. Start with a low illumination and increase the level until the lissamine green 
staining is most visible.  
4. Grade the conjunctival staining on moderate illumination per the NEI grading 
system shown below in Figure 5.  
5. After use, discard the remaining solution and microcentrifuge tube. 
 
 
49 Gyau DA, Begley CF, Nelson JD.  A simple cost effective method for preparing FL and LG solutions. 
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Figure 5:  NEI/Industry Grading System for Conjunctival Staining 
 
 
Grade 0:  No staining 
Grade 1:  Scattered, micropunctate staining 
Grade 2:  Grouped, micropunctate staining 
Grade 3:  Diffuse micropunctate or macropunctate staining 
 
Tips for Conjunctival Staining 
• Ask subjects to blink several times to assure the uniform distribution of dye in 
cul-de-sac 
• Make sure to identify pooling or a stained mucus strand. Ask subjects to blink a 
couple of times when in doubt. 
21.7 SCHIRMER 1 TEST 
The Schirmer 1 Test measures aqueous tear quantity and is an indication of aqueous-
deficient dry eye.  The Schirmer 1 test, without anesthesia, should be performed by 
placing the filter strip in the inferior fornix for 5 minutes.  Remove the strips and 
measure wetting in millimeters.   
21.8 MEIBOMIAN GLAND SECRETION SCORING 
Masked assessment:  This assessment should be performed by the masked assessor. 
 
The Meibomian Gland Secretion Scoring is an assessment of the quality of the secretions 
produced by the meibomian glands in the lower eyelids.  The Meibomian Gland 
Secretion Scoring should be performed using the Meibomian Gland Evaluator 
(TearScience, Inc.).  Ensure that the instrument has been cleaned using alcohol prior to 
each use.   
 
Grade the quality of secretions in the lateral, central and temporal thirds of the lower 
eyelids.  Grade the 5 central glands in each region, for a total of 15 glands per eye. 
 

 
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Per the method described by Korb et al, 50 place the part of the instrument's contact 
surface onto the skin immediately inferior to the eyelashes of the lower eyelid so that 
the long dimension is parallel to the eyelid margin.  Once full contact is achieved 
between the instrument and the skin immediately below the lash line of the lower lid, 
rotate the shaft of the instrument downward approximately 15 to 45 degrees. Then, 
depress the shaft midway (~3mm) and roll the lower eyelid margin slightly outward.  
Make sure to avoid contact with the ocular surface. 
 
Hold the instrument in place over each third of the lid for a minimum of 10 and a 
maximum of 15 seconds while grading the quality of secretion of the 5 glands in the 
center of the instrument (15 glands total per eye).  Grade the quality of the secretions 
per the following scale described by Lane et al51: 
 
o 0 = nothing 
o 1 = toothpaste 
o 2 = cloudy 
o 3 = clear 
 
From this assessment the following endpoints will be calculated: 
• Total Meibomian Gland Secretion Score:  Sum of the grade (0 – 3) for each of the 
15 glands.  Range for this score is 0-45. 
• Count of the number of Meibomian glands yielding clear liquid secretions.  
Range for this count is 0-15. 
• Count of the number of glands secreting any liquid (clear or cloudy).  Range for 
this count is 0-15. 
21.9 INTRAOCULAR PRESSURE 
Masked assessment:  This assessment should be performed by the masked assessor. 
 
The same method of measuring intraocular pressure should be used at each visit.  
Intraocular pressure should be measured with applanation tonometry (e.g. Goldmann 
tonometer, if available).   
 
50 Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry eye symptoms and 
gland location. Cornea. 2008;27: 1142–1147. 
51 Lane SS, DuBiner H, Epstein RJ, et al;  A New System, the LipiFlow, for the Treatment of Meibomian 
Gland Dysfunction. Cornea. 2012: 31 : 396-404. 

 
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21.10 
QUESTIONNAIRES 
 GENERAL INSTRUCTIONS FOR QUESTIONNAIRES 
The subject should complete all required questionnaires at the beginning of each visit 
before conducting other clinical testing.  The only exception to this guideline is the 
Discomfort/Pain Questionnaire administered on Day 0, which is completed by the 
subject just following the study treatment (refer to instructions provided in Sections 
9.5.4 and 9.5.5).   
 
Provide a paper copy of the questionnaires and a blue or black ink pen to the 
subject.  Review the instructions for each questionnaire with the subject and answer any 
questions they have about how to complete them.  Then allow the subject to complete 
the questionnaires on their own (i.e. self-administered) without any assistance. 
 
Study staff should review the questionnaires before the subject leaves the office to 
check for missing or multiple answers on a given question.  If these are found, please 
point this out to the subject and allow them to revise their response(s) to the specific 
question(s).  Please confirm initials and date of the subject on the last page of the 
questionnaire.  Do not allow the subject to take the questionnaires home. 
 OSDI QUESTIONNAIRE 
The OSDI has 12 questions.  Based on the answers provided by the subject, study staff 
calculate the overall OSDI Total score (from 0-100) and scores for the three subscales 
according to the OSDI instructions.  Based on the recommended cutoffs for OSDI Total 
score, the severity of the subject’s dry eye symptoms will be categorized as follows: 
 
o Normal – 0-12 
o Mild – 13-22 
o Moderate – 23-32 
o Severe – 33 or higher  
 SANDE QUESTIONNAIRE AND EYE DRYNESS VAS 
The SANDE is a simple dry eye instrument containing two items measuring the 
frequency and severity of symptoms, each is assessed on a 100 mm visual analog scale 
(VAS) ranging from ‘Never/Very comfortable’ to ‘All the time/Very severe’ and scored 
from 0 to 100.   The Eye Dryness Visual Analog Scale measures subject’s level of 
discomfort related to eye dryness ranging from “No discomfort/maximal discomfort.”   
 
Three scores will be obtained from the SANDE: 
 

 
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• Frequency score (ranging from 0 to 100):  The distance (in mm) between the left 
end of the scale and the subject’s response. 
• Severity score (ranging from 0 to 100):  The distance (in mm) between the left 
end of the scale and the subject’s response. 
• A SANDE Total score (also ranging from 0 to 100):  This is calculated as the 
square-root of the product of the Frequency and Severity scores.  
 
The Eye Dryness Score is derived from the Eye Dryness Visual Analog Scale.  The Eye 
Dryness Score (ranging from 0 to 100) is the distance (in mm) between the left end of 
the scale and the subject’s response. 
 
Study staff should instruct subjects to record their response to each question by placing 
a vertical line (not an “X”) across the horizontal line of the visual analog scale. 
 
 DISCOMFORT/PAIN QUESTIONNAIRE 
The Discomfort/Pain Questionnaire is designed to assess the degree of discomfort or 
pain that the subject experiences during and immediately after the study treatment on 
Day 0 and post-treatment (Day 1).  Subjects are asked to indicate their level of 
discomfort and pain using a Visual Analog Scale provided in the case report forms. 
 
 
 

 
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22 APPENDIX B – STATISTICAL ANALYSIS PLAN 
22.1 EFFECTIVENESS ENDPOINTS AND ANALYSIS METHODS 
 PRIMARY EFFECTIVENESS ENDPOINT 
The primary effectiveness endpoints are the change from baseline in Tear Break-Up 
Time (TBUT) and the total Meibomian gland secretion score (MEIB) at the 1 month 
follow up.  Change is calculated as: 1 month – baseline, so a positive change is better. 
Both endpoints will be analyzed using a linear mixed effects (LME) model.  This will 
allow for the proper incorporation of within-person correlation into the statistical tests, 
and will also allow for adjustment for baseline measurements. Both of these should 
increase the power over the simple “t-test using one eye” approach. 
 
Since the SmartLid device was modified during the trial, all effectiveness analyses will be 
carried out with the Cohort 2 subjects only (i.e. subjects enrolled after the modified 
device was introduced).  The primary effectiveness outcomes of the Cohort 1 subjects 
will be summarized separately by descriptive statistics (mean, median, standard 
deviation, minimum, and maximum). 
 
The linear mixed effects model for TBUT can be written as follows: 
 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝛽𝛽0 + 𝛽𝛽1𝑇𝑇𝑖𝑖+ 𝛽𝛽2𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖𝑖𝑖,0 + 𝑏𝑏0𝑖𝑖+ 𝜖𝜖𝑖𝑖𝑖𝑖 
  
Where 
• 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖𝑖𝑖,𝑘𝑘 is the TBUT value for subject i, eye j, week k. 
• 𝑦𝑦𝑖𝑖𝑖𝑖 is the 1 month change from baseline TBUT for subject i, eye j. 
𝑦𝑦𝑖𝑖𝑖𝑖= 𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖𝑖𝑖,4 −𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖𝑖𝑖,0 
• 𝑇𝑇𝑖𝑖 is the binary treatment indicator for subject i (0 = LipiFlow, 1 = TearCare) 
• 𝛽𝛽0, 𝛽𝛽1, 𝑎𝑎𝑎𝑎𝑎𝑎 𝛽𝛽2 are the fixed effect parameters: 
o 𝛽𝛽0 is the mean change from baseline for the LipiFlow arm, 
𝛽𝛽1 is the difference between TearCare and LipiFlow in mean change from 
baseline, 
o 𝛽𝛽2 is the effect of each unit change in baseline TBUT. 
• 𝑏𝑏0𝑖𝑖is the random effect (random intercept term) for subject i 
𝑏𝑏0𝑖𝑖~𝑁𝑁(0, 𝜎𝜎𝑎𝑎
2) 
• 𝜖𝜖𝑖𝑖𝑖𝑖 is the normally-distributed error term 
𝜖𝜖𝑖𝑖𝑖𝑖~𝑁𝑁(0, 𝜎𝜎𝑒𝑒
2) 
• {𝑏𝑏0𝑖𝑖} and ൛𝜖𝜖𝑖𝑖𝑖𝑖ൟ are independent 
 

 
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To demonstrate non-inferiority of the TearCare treatment to the LipiFlow control for 
TBUT we will test the null hypothesis that 𝛽𝛽1 is less than the non-inferiority margin of 3 
seconds: 
𝐻𝐻0: 𝛽𝛽1 ≤−3.0
𝐻𝐻𝐴𝐴: 𝛽𝛽1 > −3.0 
 
That is, we seek to reject the non-inferiority null hypothesis that the TearCare change in 
TBUT is more than 3 seconds worse than the LipiFlow change in TBUT. 
For this model there are several equivalent ways to carry out this test: 
• Using our estimates of 𝛽𝛽1 and its standard error, carry out a t-test for the 
hypothesis.   
• Form a confidence interval for 𝛽𝛽1 and show that the lower bound is above -3.0 
seconds, 
• Calculate the least squares mean (LSM) at the mean baseline TBUT for the 
contrast between treatment and control, and its associated confidence interval, 
and show that the lower bound is above -3.0 seconds. 
 
We will use the third (LSM) method since it provides the most flexibility, also allowing 
exploratory analyses examining the effects of other covariates, contrasts between 
groups, etc.  
 
As is standard practice in non-inferiority studies, all tests will be carried out at a one-
sided 𝛼𝛼= 0.05 (or equivalently, using two-sided 90% confidence intervals). 
 
The MEIB endpoint will use the same model and the same testing methods. To 
demonstrate non-inferiority of the TearCare treatment to the LipiFlow control for MEIB 
we will test the null hypothesis that 𝛽𝛽1 is less than the non-inferiority margin of 5 units: 
𝐻𝐻0: 𝛽𝛽1 ≤−5.0
𝐻𝐻𝐴𝐴: 𝛽𝛽1 > −5.0 
 
The study will be a success if the non-inferiority null hypothesis is rejected for both 
TBUT and MEIB.  No alpha adjustments for multiplicity are necessary. 
 
If the two non-inferiority nulls are rejected then each will be re-tested for superiority 
(that is, against 0.0 instead of the non-inferiority margin).  If the TearCare device is 
superior to the LipiFlow control for either endpoint (or both) it will be declared superior 
for that endpoint (or both). 
 
The linear mixed effects models can be fit in SAS or R as follows: 
 

 
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In SAS: 
Proc Mixed data=TearCare method=ml; 
     class SUBJ TRT; 
     model TBUT_DIFF =  TRT TBUT_BL  / solution; 
     random intercept / subject=SUBJ; 
 
In R: 
Library(lme4) 
fit.tbut <- lmer(TBUT.DIFF ~ TRT + TBUT.BL + (1|SUBJ) ,  
REML=FALSE, data=TearCare) 
 
Note that since we are interested in testing the fixed effects, ML (maximum likelihood) 
versus REML (residual maximum likelihood) estimates are being used.   
 
If the estimated between-subject variance 𝜎𝜎ො𝑎𝑎
2 is close to 0 we will repeat the analysis 
without the random intercept term (that is, as a standard ANCOVA without a random 
patient effect). 
 
There are different options for calculating the standard errors/confidence intervals. 
Standard diagnostic tests and plots for outliers, normality of the errors, homogeneity of 
variances, and homogeneity of slopes will be provided.  Based on prior data there is 
every reason to expect that the TBUT and MEIB errors will be approximately normally 
distributed. However, if residuals do not appear sufficiently normally distributed, we will 
calculate the confidence interval for 𝛽𝛽1 using bootstrap methods. 
 
If the ANCOVA model is unsatisfactory (e.g. linearity of change with respect to baseline 
is not supported, or the slopes are different) then we will test the primary hypotheses 
and compute the confidence interval for the difference in change from baseline 
between the two treatments based on a LME model without the baseline covariate (i.e. 
a t-test with adjustment for correlation). 
 
 
 POOLABILITY OF CENTERS 
Using the LME modeling approach outlined above, poolability will be evaluated across 
centers by including fixed effects for Center and  Treatment by Center interaction in the 
model and applying a likelihood ratio test.  If the TxC interaction is significant at α=0.15 
a Center effect will be included in the final model and the results will be reported 
separately by Center. For this analysis, Centers with less than 5 enrolled subjects will be 
combined into a single virtual center. 

 
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 MISSING DATA 
Note that since the primary analysis uses maximum likelihood methods on the complete 
data then any MAR (missing at random) imputation model should provide essentially 
equivalent results.  That is, the missing data are ignorable if they are MAR and we are 
using full maximum likelihood estimation. However, as a sensitivity analysis, missing 
data for the primary TBUT outcome at the 1 month time point will be imputed using 
baseline characteristics and 2-week outcomes.  In this, we follow the advice in sections 
2.8 and 2.10 of “Multiple Imputation and its Application”52  to use an imputation model 
that is more complex than the final analysis model.  In order to carry out the 
imputations we will fit a linear model that predicts TBUT change at 1 month using TBUT 
at baseline and 2 weeks, along with other covariates, as predictors. Based on pilot study 
data, we expect that 1 month outcomes will be strongly predicted by intermediate (2 
week) results.  Using predicted 4-week means and variances from this model we can 
create multiple imputations for the missing 4-week TBUT changes.  Results from the 
multiple imputations will be combined using Rubin’s method.   
 
Further sensitivity analysis can be carried out by extending the mixed effects model for 
the primary analysis described above to also include repeated measurements across 
time for each patient and eye.  Under this model we can carry out maximum likelihood 
estimation that allows for one of the two (Week 2, Week 4) measurements for each 
person to be missing.  
 SECONDARY EFFECTIVENESS ENDPOINTS 
If the primary endpoint is successful (if the null hypothesis for the primary endpoint is 
rejected) then the secondary endpoints will be tested using a hierarchical testing 
procedure as described in 12.5.5 based on the Cohort 2 subjects. 
 
 The secondary effectiveness outcomes of the Cohort 1 subjects will be summarized 
separately by descriptive statistics (mean, median, standard deviation, minimum, and 
maximum for continuous variables; count and percent for categorical variables). 
22.2 SAFETY ENDPOINTS AND ANALYSIS 
 DESCRIPTIVE ANALYSES 
All adverse events, measures of pain and discomfort, changes in ocular surface staining, 
changes in IOP, and chances in BCVA (EDTRS) will be tabulated by visit and treatment 
group.  
 
52 Carpenter, J., and Kenward, M.  Multiple Imputation and its Application (2013), Wiley UK. 

 
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 PRIMARY SAFETY ENDPOINT 
The primary safety endpoint is the incidence of ocular adverse events. 
 PRIMARY SAFETY ANALYSIS 
The primary safety endpoint will be summarized for each treatment group, for each 
Cohort and overall. 
 
We will compute the incidence of ocular adverse events as a simple proportion, 
counting the number of subjects with any event (that is, counting the first event per 
person). 
 
For the simple proportion, we will calculate the 95% CIs using the Agesti and Coull 
“ADD2” method53. 
 SECONDARY SAFETY ENDPOINTS 
The secondary safety endpoints include: 
• Discomfort/pain during treatment 
• Change in best corrected visual acuity (ETDRS) 
• Change in intraocular pressure (IOP) 
 
These endpoints will be summarized by treatment group and visit, for each Cohort and 
overall. 
 
22.3  SAMPLE SIZE CALCULATIONS 
Sample size calculations were originally carried out prior to the modification of the 
SmartLid device.  After device modification the trial was “restarted”, with Cohort 2 
retaining the original sample size of 138 subjects.  The subjects initially enrolled in 
Cohort 1 (up to 100 subjects) will be used in supplemental analyses and to provide 
additional safety information. 
Since the study success criteria is that TearCare will be non-inferior to the control for 
both TBUT and MEIB, we will calculate the required sample size for Tear Break-Up Time 
(TBUT) and total Meibomian gland secretion score (MEIB) separately.  A power of 95% 
for each of these two outcomes will produce an overall experiment-wise power 
between 90.25% (if TBUT and MEIB are uncorrelated), and 95% (if TBUT and MEIB are 
perfectly correlated). 
 
53 Agresti, A., and B.A. Coull (1998) Approximate is better than “exact” for interval estimation of binomial 
proportions.  American Statistician 52:119-126. 

 
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The primary Tear Breakup Time (TBUT) and total Meibomian gland secretion score 
(MEIB) endpoints are measured on a per-eye basis.  In order to account for the 
correlation between eyes the sample size is calculated in two steps.  The first step is to 
carry out a standard sample size calculation for the number of eyes based on a two-
sample t-test with unequal variances.  This test is appropriate for a sample of 
independent eyes from the two groups, that is, a study in which only one eye per 
subject is enrolled. The second step is to allow for two eyes per subject by adjusting the 
independent sample size to account for the correlation between eyes.54  This is done by 
multiplying by a “design effect” (DEFF) that can be calculated from the pilot study data 
(described in Section 5.2.2).  Finally we allow for some loss to follow up and then divide 
by 2 (eyes per subject) to arrive at a final enrolled sample size in terms of number of 
subjects. 
This sample size calculation does not account for the adjustment for baseline in the 
analysis models. That adjustment should only serve to increase the power of the test, so 
the simpler calculation is conservative in that sense. 
 TEAR BREAKUP TIME 
For the TBUT sample size calculation, we assume the same positive treatment effect for 
TearCare and for LipiFlow, reducing the TBUT time per eye by 3 seconds, with a 
standard deviation of 6.0 seconds.   The standard deviation for the change from baseline 
to 1 month was (conservatively) estimated for TearCare from the pilot data, and for 
LipiFlow from published results55.    
The sample size is calculated under the following assumptions: 
• a one-sided α= 0.05 t-test for non-inferiority, 
• with a NI margin of 3.0 seconds, 
• to obtain 95% power. 
The non-inferiority margin was based on published LipiFlow variability55. Under these 
assumptions the required sample size is 176 eyes, 88 eyes per treatment group.  
The design effect for a clustered sample when randomization is at the cluster level is 
calculated as 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷= 1 + 𝛿𝛿(𝑚𝑚−1) where δ is the intraclass correlation and m is the 
 
54 Campbell M, Walters, S. How to Design, Analyse and Report Cluster Randomised Trials in Medicine and 
Health Related Research.  Wiley UK, 2014. 
55 Lane, S.S, H.B. DuBiner, R.J. Epstein, P.H. Earnest, J.V. Greiner, D.R. Hardten, E.J. Holland, M.A. Lemp, 
J.E. McDonald II, D.I. Silbert, C.A. Blackie, C.A. Stevens, and R. Bedi. A New System, the LipiFlow, for the 
Treatment of Meibomian Gland Dysfunction.  Cornea 2012; 31(4): 396-404. 

 
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average size of the clusters in the sample56.  Here m=2 so 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷= 1 + 𝛿𝛿.  To estimate 
the intraclass correlation we fit a linear mixed effects model with a random intercept for 
subjects to obtain estimates of 𝜎𝜎𝑎𝑎
2 and 𝜎𝜎𝑒𝑒
2.  Using these we can estimate the intraclass 
correlation as 𝛿𝛿= 𝜎𝜎𝑎𝑎
2/(𝜎𝜎𝑎𝑎
2 + 𝜎𝜎𝑒𝑒
2).  From the TearCare pilot data the estimates of the 
variance components for TBUT are 𝜎𝜎ො𝑎𝑎
2 = 1.92 and 𝜎𝜎ො𝑒𝑒
2 = 3.39, giving a DEFF of 1.36. We 
will assume that the intraclass correlation for LipiFlow is the same as TearCare. So the 
sample size calculated using the t-test formulas will be inflated by 1.4 to account for 
correlation between eyes.  Thus the DEFF-adjusted sample size is 246 eyes. 
Finally, we will assume that 10% of the enrolled subjects (eyes) will be lost to follow-up.  
The resulting sample size is 274 enrolled eyes, or 137 enrolled subjects (which we round 
up to 69 per group).   
 
 MEIBOMIAN GLAND SECRETION SCORE 
For the MEIB sample size calculation, we assume the same positive treatment effect for 
TearCare and for LipiFlow, reducing the total Meibomian gland secretion score per eye 
by 9 units, with a standard deviation of 9.0. The standard deviation for the change from 
baseline to 1 month was (conservatively) estimated for TearCare from the pilot data, 
and for LipiFlow from published results55.    
The sample size is calculated under the following assumptions: 
• a one-sided α= 0.05 t-test for non-inferiority, 
• with a NI margin of 5.0 units, 
• to obtain 95% power. 
The non-inferiority margin was based on published LipiFlow variability55. Under these 
assumptions the required sample size is 142 eyes, 71 eyes per treatment group.  
From the TearCare pilot data the estimates of the variance components for MEIB are 
𝜎𝜎ො𝑎𝑎
2 = 15.93 and 𝜎𝜎ො𝑒𝑒
2 = 20.11, giving a DEFF of 1.44.   We will assume that the intraclass 
correlation for LipiFlow is the same as TearCare. So the sample size calculated using the 
t-test formulas will be inflated by 1.5 to account for correlation between eyes. Thus the 
DEFF-adjusted sample size is 213 eyes. 
Finally, we will assume that 10% of the enrolled subjects (eyes) will be lost to follow-up.  
The resulting sample size is 237 enrolled eyes, or 119 enrolled subjects (which we round 
up to 60 per group).  
 
56 Campbell M, Walters, S. How to Design, Analyse and Report Cluster Randomised Trials in Medicine and 
Health Related Research.  Wiley UK, 2014. 

 
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 SAFETY 
For a safety sample of size 238 TearCare eyes (from Cohort 1 and Cohort 2) (since the 
expected AE rates are quite low there is unlikely to be any meaningful correlation 
between eyes), if the true incidence rate of ocular adverse events is 2.0% or less then 
the upper 95% one-sided confidence limit for the AE rate will be less than 6% with 
probability approximately 0.95.  In other words, the power to reject a null of 6% if the 
true rate is 2.0% is 95%. 
  SAMPLE SIZE SUMMARY 
Based on the calculations outlined above, an overall enrolled sample of 138 individuals 
in Cohort 2, with 69 in each treatment group (total of 276 enrolled eyes) will provide 
more than 90% power for the combined TBUT and MEIB effectiveness endpoints and 
sufficient precision around the adverse event estimates.  The initial 90-100 subjects 
enrolled in Cohort 1 will be used for supplemental analyses. 
 

 
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23 APPENDIX C – PREPARING FLUORESCEIN AND LISSAMINE GREEN 
SOLUTIONS 
Use the method described by Gyau et al to prepare the fluorescein and lissamine green 
solutions.57 
23.1 PREPARING FLUORESCEIN SOLUTION 
1. Put on a pair of sterile gloves. 
2. Cut three (3) 1.0 mg Fluorescein Sodium Ophthalmic strips at the end of the 
colored portion of the strip using sterile scissors and tear each portion into 3 
pieces.  You should have 9 pieces. 
 
 
 
3. Place the 9 pieces into a disposable microcentrifuge tube.   
23.2 PREPARING LISSAMINE GREEN SOLUTION 
 
1. Put on a pair of sterile gloves. 
2. Cut three (3) Lissamine Green strips at the end of the colored portion of the 
strip using sterile scissors and tear each portion into 3 pieces.  You should have 
9 pieces. 
 
 
 
 
 
57 Gyau DA, Begley CF, Nelson JD.  A simple cost effective method for preparing FL and LG solutions. 
Ocular Surface.  2018;16:139-145. 

 
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3. Place the 9 pieces into a disposable microcentrifuge tube.   
 
24 APPENDIX D - DECLARATION OF HELSINKI 
I. 
PREAMBLE 
 
1. 
The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data. 
 
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant 
paragraphs. 
 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed 
primarily to physicians. The WMA encourages others who are involved in 
medical research involving human subjects to adopt these principles. 
 
II. 
GENERAL PRINCIPLES 
 
1. 
The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.” 
 
2. 
It is the duty of the physician to promote and safeguard the health, well-being 
and rights of patients, including those who are involved in medical research. 
The physician's knowledge and conscience are dedicated to the fulfilment of 
this duty. 
 

 
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3. 
Medical progress is based on research that ultimately must include studies 
involving human subjects. 
 
4. 
The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures 
and treatments). Even the best proven interventions must be evaluated 
continually through research for their safety, effectiveness, efficiency, 
accessibility and quality. 
 
5. 
Medical research is subject to ethical standards that promote and ensure 
respect for all human subjects and protect their health and rights. 
 
6. 
While the primary purpose of medical research is to generate new knowledge, 
this goal can never take precedence over the rights and interests of individual 
research subjects. 
7. 
It is the duty of physicians who are involved in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. The responsibility 
for the protection of research subjects must always rest with the physician or 
other health care professionals and never with the research subjects, even 
though they have given consent. 
 
8. 
Physicians must consider the ethical, legal and regulatory norms and standards 
for research involving human subjects in their own countries as well as 
applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
 
9. 
Medical research should be conducted in a manner that minimizes possible 
harm to the environment. 
 
10. Medical research involving human subjects must be conducted only by 
individuals with the appropriate ethics and scientific education, training and 
qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other 
health care professional. 
 
11. Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
 

 
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12. Physicians who combine medical research with medical care should involve 
their patients in research only to the extent that this is justified by its potential 
preventive, diagnostic or therapeutic value and if the physician has good 
reason to believe that participation in the research study will not adversely 
affect the health of the patients who serve as research subjects. 
 
13. Appropriate compensation and treatment for subjects who are harmed as a 
result of participating in research must be ensured. 
 
III. 
RISKS, BURDENS AND BENEFITS 
 
• 
In medical practice and in medical research, most interventions involve risks 
and burdens. 
 
Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research 
subjects. 
 
• 
All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups 
involved in the research in comparison with foreseeable benefits to them and 
to other individuals or groups affected by the condition under investigation. 
 
Measures to minimize the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher. 
 
• 
Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can 
be satisfactorily managed. 
 
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to 
continue, modify or immediately stop the study. 
 
IV. 
VULNERABLE GROUPS AND INDIVIDUALS 
 
• 
Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm. 
 
All vulnerable groups and individuals should receive specifically considered 
protection. 
 

 
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• 
Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research 
cannot be carried out in a non-vulnerable group. In addition, this group should 
stand to benefit from the knowledge, practices or interventions that result 
from the research. 
 
V. 
SCIENTIFIC REQUIREMENTS AND RESEARCH PROTOCOLS 
 
• 
Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of 
animals used for research must be respected. 
 
• 
The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol. 
 
The protocol should contain a statement of the ethical considerations involved 
and should indicate how the principles in this Declaration have been 
addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, potential conflicts of interest, incentives for 
subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed as a consequence of participation in 
the research study. 
 
In clinical trials, the protocol must also describe appropriate arrangements for 
post-trial provisions. 
 
VI. 
RESEARCH ETHICS COMMITTEES 
 
• 
The research protocol must be submitted for consideration, comment, 
guidance and approval to the concerned research ethics committee before the 
study begins. This committee must be transparent in its functioning, must be 
independent of the researcher, the sponsor and any other undue influence and 
must be duly qualified. It must take into consideration the laws and regulations 
of the country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in 
this Declaration. 
 
The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information 
about any serious adverse events. No amendment to the protocol may be 

 
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made without consideration and approval by the committee. After the end of 
the study, the researchers must submit a final report to the committee 
containing a summary of the study’s findings and conclusions. 
 
VII. PRIVACY AND CONFIDENTIALITY 
 
• 
Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information. 
 
 
VIII. INFORMED CONSENT 
 
• 
Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult 
family members or community leaders, no individual capable of giving 
informed consent may be enrolled in a research study unless he or she freely 
agrees. 
 
• 
In medical research involving human subjects capable of giving informed 
consent, each potential subject must be adequately informed of the aims, 
methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the 
study and the discomfort it may entail, post-study provisions and any other 
relevant aspects of the study. The potential subject must be informed of the 
right to refuse to participate in the study or to withdraw consent to participate 
at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods 
used to deliver the information. 
 
After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the 
potential subject’s freely-given informed consent, preferably in writing. If the 
consent cannot be expressed in writing, the non-written consent must be 
formally documented and witnessed. 
 
All medical research subjects should be given the option of being informed 
about the general outcome and results of the study. 
 
• 
When seeking informed consent for participation in a research study the 
physician must be particularly cautious if the potential subject is in a 
dependent relationship with the physician or may consent under duress. In 
such situations the informed consent must be sought by an appropriately 
qualified individual who is completely independent of this relationship. 

 
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• 
For a potential research subject who is incapable of giving informed consent, 
the physician must seek informed consent from the legally authorized 
representative. These individuals must not be included in a research study that 
has no likelihood of benefit for them unless it is intended to promote the 
health of the group represented by the potential subject, the research cannot 
instead be performed with persons capable of providing informed consent, and 
the research entails only minimal risk and minimal burden. 
 
• 
When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally 
authorized representative. The potential subject’s dissent should be respected. 
 
• 
Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary 
characteristic of the research group. In such circumstances the physician must 
seek informed consent from the legally authorized representative. If no such 
representative is available and if the research cannot be delayed, the study 
may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed 
consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research 
must be obtained as soon as possible from the subject or a legally authorized 
representative. 
 
• 
The physician must fully inform the patient which aspects of their care are 
related to the research. The refusal of a patient to participate in a study or the 
patient’s decision to withdraw from the study must never adversely affect the 
patient-physician relationship. 
 
• 
For medical research using identifiable human material or data, such as 
research on material or data contained in biobanks or similar repositories, 
physicians must seek informed consent for its collection, storage and/or reuse. 
There may be exceptional situations where consent would be impossible or 
impracticable to obtain for such research. In such situations the research may 
be done only after consideration and approval of a research ethics committee. 
 
IX. 
USE OF PLACEBO 
 

 
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• 
The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best proven intervention(s), except in the following 
circumstances: 
 
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
 
Where for compelling and scientifically sound methodological reasons the use 
of any intervention less effective than the best proven one, the use of placebo, 
or no intervention is necessary to determine the efficacy or safety of an 
intervention 
 
and the patients who receive any intervention less effective than the best 
proven one, placebo, or no intervention will not be subject to additional risks 
of serious or irreversible harm as a result of not receiving the best proven 
intervention. 
 
Extreme care must be taken to avoid abuse of this option. 
 
X. 
POST-TRIAL PROVISIONS 
 
• 
In advance of a clinical trial, sponsors, researchers and host country 
governments should make provisions for post-trial access for all participants 
who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent 
process. 
 
XI. 
RESEARCH REGISTRATION AND PUBLICATION AND DISSEMINATION OF RESULTS 
 
• 
Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
 
• 
Researchers, authors, sponsors, editors and publishers all have ethical 
obligations with regard to the publication and dissemination of the results of 
research. Researchers have a duty to make publicly available the results of 
their research on human subjects and are accountable for the completeness 
and accuracy of their reports. All parties should adhere to accepted guidelines 
for ethical reporting. Negative and inconclusive as well as positive results must 
be published or otherwise made publicly available. Sources of funding, 
institutional affiliations and conflicts of interest must be declared in the 
publication. Reports of research not in accordance with the principles of this 
Declaration should not be accepted for publication. 
 
XII. UNPROVEN INTERVENTIONS IN CLINICAL PRACTICE 

 
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In the treatment of an individual patient, where proven interventions do not exist 
or other known interventions have been ineffective, the physician, after seeking 
expert advice, with informed consent from the patient or a legally authorized 
representative, may use an unproven intervention if in the physician's judgment it 
offers hope of saving life, re-establishing health or alleviating suffering. This 
intervention should subsequently be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information must be recorded 
and, where appropriate, made publicly available.