A Single-Arm, Single-Center, Randomized, Single-Masked Study to Evaluate Restylane Defyne for Canalicular Occlusion in Participants With Mild to Moderate Dry Eye Disease
Phase: NA
Conditions: Mild to Moderate Dry Eye Disease
Sponsor: John C Meyer, MD

 
 
 
 
 
 
Single-Arm, Single-Center, Randomized, Single-Masked Study to Evaluate Restylane-
Defyne for Canalicular Occlusion in Participants with Mild to Moderate Dry Eye Disease 
 
Protocol Number: 
0918 
Protocol Date:  
July 9, 2018 
Version 
1.0 
Revision History 
None 
Principal Investigator 
and Sponsor 
John Meyer, MD  
The Eye Care Institute 
1536 Story Avenue 
Louisville, KY  40206 
 
Monitor 
Mark Packer MD FACS CPI 
Mark Packer MD Consulting, Inc. 
1400 Bluebell Ave. 
Boulder, CO 80302 
 
 
 

 
PROTOCOL 0918 STUDY SYNOPSIS 
Protocol 
Title 
Single-Arm, Single-Center, Randomized, Single-Masked Study to 
Evaluate Restylane-Defyne for Punctal Occlusion in Participants with 
Mild to Moderate Dry Eye Disease 
Study 
Period 
Up to 3 months 
Study 
Population 
13 adult participants with mild to moderate dry eye disease  
Primary 
Study 
Objectives 
Safety and effectiveness assessments of Restylane-Defyne for punctal 
occlusion 
Treatments 
Participants will receive Restylane-Defyne in the inferior punctum of one eye 
and a sham injection in the inferior punctum of the fellow eye. 
Study 
Design 
Prospective, randomized, single-masked study with unilateral placement of 
Restylane-Defyne.  
Sample Size 
Up to 13 participants, with a goal of 10 participants finishing study. 
Examination 
Schedule 
Participants will have a Baseline Visit within 30 days prior to the initial device 
application.  Device application will be initiated at Day 0 with follow-up visits 
at 3 days, 14 days and 42 days. Participants will exit the study after the 6-week 
visit exam. 
 
 
 
Clinical Assessments 
 
Assessments performed will include: 
 Ocular Surface Disease Index questionnaire  
 Slit-lamp biomicroscopy with grading of corneal staining 
 Schirmer test with topical anesthetic 
 Tear break-up time 
 Tear meniscus height 
 Corrected Distance Visual Acuity 
 
Study Endpoints 
 
 Primary effectiveness endpoint 
Change in Schirmer score from baseline  
 
 Additional effectiveness endpoints  
Changes in OSDI score, corneal staining score, tear break-up time and tear meniscus height 

 
 
 Primary safety endpoint  
Proportion of participants that experience one or more device-related adverse events (e.g., 
irritation, conjunctival injection, epiphora, subconjunctival hemorrhage, canaliculitis, punctal 
stenosis, eyelid telangiectasia, eyelid edema, eyelid induration, eyelid erythema).  
  
 Additional safety assessments  
Corrected distance visual acuity, slit lamp biomicroscopy findings  
Inclusion Criteria 
 
To be eligible for the study, potential participants must meet all of the following inclusion 
criteria at the Screening Visit: 
 Twenty-one (21) to 80 years of age 
 Baseline Ocular Surface Disease Index score of at least 13 with no more than 3 
responses of “not applicable” for each eye individually 
 In the study eye, a baseline Schirmer test with anesthetic of ≤ 10 mm/5 minutes  
 Literate, able to speak English and able to complete the questionnaire 
independently 
 Willing to sign the informed consent and deemed capable of complying with the 
requirements of the study protocol. 
 
Exclusion Criteria 
 
 To be eligible for the study, potential participants must not meet any of the following 
exclusion criteria: 
 Use of ophthalmic cyclosporine or lifitegrast within 30 days prior to Day 0 
 History of surgical punctal occlusion (e.g., cautery), canalicular infection or 
canalicular surgery 
 Corneal transplant in either eye 
 Ocular surgery (such as cataract surgery or LASIK) in either eye within six 
months of the Baseline Visit 
 A systemic condition or disease not stabilized or judged by the investigator to be 
incompatible with participation in the study (e.g. current systemic infection, 
uncontrolled autoimmune disease, uncontrolled immunodeficiency disease)  
 The history or presence of any ocular disorder or condition in either eye that, in 
the opinion of the investigator, would interfere with the interpretation of the study 
results (e.g., significant corneal or conjunctival scarring, pterygium or nodular 
pinguecula; current ocular infection (except mild blepharitis), conjunctivitis or 
inflammation not associated with dry eye; anterior (epithelial) basement 
membrane corneal dystrophy or other clinically significant corneal dystrophy or 
degeneration; history of ocular herpetic infection; evidence of keratoconus; lid or 
lacrimal cancer. 

 
 Active severe systemic allergy, seasonal allergies, rhinitis or sinusitis requiring 
treatment (i.e. antihistamines, decongestants, oral or aerosol steroids) 
 Use of steroids, including administration by systemic, inhaled or topical ocular 
routes (dermatologic steroids not applied to the eyelids are allowed)  
 Participation in a clinical trial during the past 30 days 
 Women who are pregnant, planning a pregnancy, or nursing at study entry. 

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TABLE OF ABBREVIATIONS 
AE 
Adverse event 
ATD 
Aqueous tear deficiency 
CDVA 
Corrected distance visual acuity 
CE 
Conformité Européenne (European Conformity) 
CRF 
Case report form 
DED 
Dry eye disease 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HA 
Hyaluronic Acid 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ISO 
International Standards Organization 
logMAR 
Logarithm of the minimum angle of resolution 
NEI 
National Eye Institute 
OSDI 
Ocular Surface Disease Index 
PP 
Per protocol 
SAE 
Serious adverse event 
UADE 
Unanticipated adverse device effect 
 
 
 

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1. INTRODUCTION 
1.1. Background 
The 1995 National Eye Institute (NEI)/Industry Dry Eye Workshop defined dry eye 
disease (DED) as a multifactorial disease of the tears and ocular surface that results in 
symptoms of discomfort, visual disturbance, and tear instability with potential damage 
to the ocular surface.  Dry eye disease has a complex pathophysiology and a 
multifactorial etiology related to an inadequacy of one or more layers of the tear film.  
It is accompanied by increased osmolarity of the tears and inflammation of the ocular 
surface.1  An estimated 25 million Americans are reported to have DED,2 one of the 
most common reasons patients seek care with their eye care professional.3 
DED has multiple causes and consequences, ranging in severity from mild discomfort 
and pain to a decrement in visual acuity resulting from irregularities in the corneal 
surface.  Signs of DED include reduced tear volume, delayed tear clearance, abnormal 
tear osmolarity, decreased tear breakup time, punctate keratitis and distorted mires on 
keratometry or corneal topography.  Symptoms include dryness, grittiness, burning, 
stinging, discomfort, photophobia, redness, tearing, reduced ability for prolonged 
reading or computer work, and fluctuating vision.  These symptoms are typically worse 
later in the day and can be triggered or exacerbated by environmental conditions such 
as low humidity. 
The severity and prevalence of DED in the general population increases with age and is 
particularly common in post-menopausal women and in those age 65 and older. While 
patients with mild to moderate dry eye experience a range of complaints, as described 
above, patients with severe dry eye are at risk for more serious ocular findings, such as 
punctate keratopathy evidenced by significant fluorescein staining of the cornea. More 
severely affected patients can experience a quality of life deficiency comparable to that 
of moderate to severe angina.4  Studies suggest that dry eye is associated with 
significant impact on visual function, including reading and driving5 as well as daily 
activities, social and physical functioning, workplace productivity and quality of life.6  
Treatment for DED is generally palliative in nature and intended to supplement the 
patient’s natural tears or to improve the residence time of the limited volume of tears 
present.  Depending on the severity of disease and the underlying etiology of DED, 
options include artificial tear substitutes (solutions, ointments, and gels), punctal plugs, 
warm compresses, environmental modification, omega-3 fatty acid supplements, and 
moisture chamber goggles.7, 8  For patients with an inflammatory component to their 
DED, topical cyclosporine (Restasis; Allergan) and lifitegrast (Xiidra; Shire) are 
options, and an eyelid thermal pulsation system (Lipiflow Thermal Pulsation System; 
TearScience Inc.) can be used by patients with concomitant evaporative dry eye (i.e. 
lipid deficiency dry eye).  Patients with aqueous tear deficiency can use a nasal 
neurostimulator to temporarily increase tear production (TrueTear; Allergan).  Patients 
with more severe disease may be treated with punctal cautery, systemic cholinergic 
agonists, systemic anti-inflammatory agents, mucolytic agents, autologous serum tears, 
PROSE scleral contact lenses9 and tarsorrhaphy.      

3 
 
The most commonly used palliative option for DED, artificial tear substitutes, have 
significant limitations as therapeutic modalities for this condition.  Many artificial tear 
formulations contain preservatives such as benzalkonium chloride, which have been 
shown to be toxic to the corneal epithelium. Although commercially available, 
preservative-free artificial tear products include a risk of microbial contamination if 
improperly stored, a limited time after opening before disposal, and a significantly greater 
expense than the preserved option. 
Punctal plugs are associated with poor retention and complications.  A study focused on 
the time course of retention showed that 29% of plugs were lost within the first month of 
use10 and another showed that only 56% of silicone plugs were retained after two years.11  
Complications include plug migration, biofilm formation and infection.12  Punctal plugs 
that are displaced into the lacrimal system may pass through the system, but blockage 
and secondary infection have been reported.  
Given the limitations of the most commonly available therapies for DED (artificial tears 
and punctal plugs), it is not surprising that DED continues to be considered one of the 
most poorly treated diseases in ophthalmology.  
1.2. Cross-Linked Hyaluronic Acid as a Device for Punctal Occlusion  
Hyaluronic acid (HA) is a colorless and odorless mucopolysaccharide gel that occurs 
naturally in the human body, including in the eye, and serves as a scaffolding for 
collagen.   
Hyaluronic acid is a substance well known in medicine with several FDA approved 
applications. HA has been used for years by cataract surgeons, who inject it directly 
into the anterior chamber of the eye to maintain space during surgery. More recently 
HA has been utilized to fill wrinkles in the face.  Approved for this indication (PMA 
P140029), Restylane Defyne is a sterile transparent gel composed of cross-linked 
sodium hyaluronate of bacterial origin.  The product has a HA concentration of 20 
mg/ml in phosphate buffered saline at pH 7 and contains 3 mg/ml lidocaine 
hydrochloride added to the gel to achieve a pain-relieving effect.  
Adding HA to artificial tears has been reported to be beneficial in treatment of dry 
eyes.13 Because HA is soft enough to conform to the delicate inner walls of the 
canaliculus and block tear outflow, a canalicular plug made of HA could be useful in 
blocking the outflow of tears and also potentially adding its own lubricating effects.  
The HA would be injected into the canaliculus below the lid margin and would not rub 
on the lid or irritate the eye.   
A unique advantage of the HA plug is full reversibility. HA is degraded by the enzyme 
hyaluronidase, and this is routinely used in eye surgery and with facial fillers. The 
effect of removing the HA is almost instantaneous. If a patient no longer needed plugs, 
then the procedure to remove an HA plug is to irrigate the tear duct with hyaluronidase. 
Both hyaluronic acid and hyaluronidase are FDA approved compounds in eye and skin 
procedures, with a long safety record. The placement of these products does not require 

4 
 
injection with a needle, but rather a gentle, simple placement with a tapered cannula in 
an existing body cavity of the tear duct outflow system, the canaliculus. 
 
1.3. Summary of Findings from Previous Studies 
In a pilot clinical study, Restylane was used to bilaterally occlude the lower lacrimal 
canaliculi in 74 participants. A total of 148 plugs were inserted as all participants had 
both lower puncta treated. 58 patients completed the study; 46 patients were female and 
12 were male. Of the patients that did not complete the study, most missed a critical 
follow up visit and were excluded from evaluation per the study protocol. No patient 
dropped out due to dissatisfaction or a complication. The average age in the study was 

5 
 
66.5 years. All but 3 participants were Caucasian (2 African Americans and 1 Asian). 
The investigator noted that the HA plug was easy to insert. 
A statistically significant increase in Schirmer score was observed in each eye at the 1- 
and 3-month visits by two-tail t-test (Figure 1).  
 
 
 
 
Figure 1.  Schirmer scores. **p = 0.0006 and 0.0015 at 1 and 3 months, respectively; 
*p = 0.028 and 0.032 at 1 and 3 months, respectively.  
 
In addition, significant improvements in tear break-up time (TBUT) and tear meniscus 
height were observed (Figures 2 and 3).   
 
 
Figure 2.  TBUT.  ***p < 0.000 at 1 and 3 months.   
 

6 
 
 
Figure 3.  Tear meniscus height.  ***p < 0.000 at 1 and 3 months.  
 
When questioned at 6-moths, 83% of participants responded that they would have the 
treatment again.  On a numerical scale, with “1” for agree to “5” for disagree, the 
average score was 2.4 when patients were asked if their eyes felt better after receiving 
the HA plug. Of note, these numerical values were reported at a 6- month phone 
interview, indicating that some patients were benefitting from the HA filler even after 6 
months from injection.  
There was one case of conjunctivitis that resolved and was believed to be an incidental 
viral infection. There were no other adverse events reported, including no canaliculitis, 
swelling, bruising or intraocular inflammation. 
A complete study report is provided in Appendix D, Pilot Study Report.   
 
1.4. Risks and Benefits. 
The risks associated with the use of this non-significant risk device are low.  Restylane-
Defyne is an approved product, and HA has been used as both a topical and 
intracameral ocular agent.  Punctal plugs in general are not considered significant risk 
devices, and the use of cross-linked HA for punctal occlusion has previously been 
recognized as a non-significant risk device by the Sarasota Memorial Hospital 
Institutional Review Board in Sarasota, FL.  For further information see documentation 
provided in Appendix C, Correspondence with Sarasota Memorial Hospital 
Institutional Review Board.   
Potential adverse events which may occur during the course of this study include 
irritation, conjunctival injection, epiphora, subconjunctival hemorrhage, canaliculitis, 
punctal stenosis, eyelid telangiectasia, eyelid edema, eyelid induration and eyelid 
erythema.  Potential benefits include decreased signs and symptoms of dry eye disease.  
 

7 
 
2. STUDY OBJECTIVES 
The objective of this pilot study is to investigate the safety and effectiveness of HA 
lacrimal occlusion in patients with mild to moderate dry eye disease. 
 
3. STUDY DESIGN 
3.1. Description of Study Design 
The study is a single-arm, single-center, randomized, single-masked prospective study 
to evaluate Restylane-Defyne for canalicular occlusion in participants with mild to 
moderate dry eye disease.   
Each participant will have a Screening Visit to determine eligibility. Prior to 
performing any testing specifically for the Screening Visit, participants will be 
provided with an IRB approved informed consent form and be given the chance to 
review and ask questions before written informed consent is obtained.  The Screening 
Visit should occur within 30 days prior to application of the HA gel on Study Day 0 
and may occur on Day 0. Participants that meet all eligibility criteria will be invited to 
participate in the study. 
Participants that return or are present for Study Day 0 will be enrolled in the study and 
will receive the device. Participants will be followed for 42 days and will be seen for 
follow-up exams at 3, 14 and 42 days. 
Participants may continue to use their artificial tears.  The use of artificial tears will be 
recorded. 
 
3.2. Study Endpoints 
3.2.1. Effectiveness Endpoints 
The primary effectiveness endpoint will be change in Schirmer score from 
baseline.  Secondary effectiveness endpoints include changes in Ocular Surface 
Disease Index (OSDI) score, corneal staining score, tear break-up time and tear 
meniscus height 
3.2.2. Safety Endpoints 
The primary safety endpoint will be the proportion of participants that experience 
one or more device-related adverse events (e.g., irritation, conjunctival injection, 
epiphora, subconjunctival hemorrhage, canaliculitis, punctal stenosis, eyelid 
telangiectasia, eyelid edema, eyelid induration, eyelid erythema).  
 
3.3. Study Population 
The study will enroll up to 13 participants at one site that provide informed 
consent and meet the eligibility criteria below. 

8 
 
3.3.1. Inclusion Criteria 
To be eligible for the study, potential participants must meet all of the following 
inclusion criteria at the Screening Visit: 
 
 Twenty-one (21) to 80 years of age  
 Baseline OSDI score of at least 13 with no more than 3 responses of “not 
applicable” 
 In both eyes, a baseline Schirmer test with anesthetic of ≤ 10 mm/5 minutes  
 Literate, able to speak English and able to complete the questionnaire 
independently 
 Willing to sign the informed consent and deemed capable of complying with the 
requirements of the study protocol. 
 
3.3.2. Exclusion Criteria 
To be eligible for the study, potential participants must not meet any of the 
following exclusion criteria: 
 
 Use of ophthalmic cyclosporine or lifitegrast within 30 days prior to Day 0 
 History of surgical punctal occlusion (e.g., cautery), canalicular infection or 
canalicular surgery 
 Corneal transplant in either eye 
 Ocular surgery (such as cataract surgery or LASIK) in either eye within six 
months of the Baseline Visit 
 A systemic condition or disease not stabilized or judged by the investigator to be 
incompatible with participation in the study (e.g. current systemic infection, 
uncontrolled autoimmune disease, uncontrolled immunodeficiency disease)  
 The history or presence of any ocular disorder or condition in either eye that, in 
the opinion of the investigator, would interfere with the interpretation of the study 
results (e.g., significant corneal or conjunctival scarring, pterygium or nodular 
pinguecula; current ocular infection (except mild blepharitis), conjunctivitis or 
inflammation not associated with dry eye; anterior (epithelial) basement 
membrane corneal dystrophy or other clinically significant corneal dystrophy or 
degeneration; history of ocular herpetic infection; evidence of keratoconus; lid or 
lacrimal cancer. 
 Active severe systemic allergy, seasonal allergies, rhinitis or sinusitis requiring 
treatment (i.e. antihistamines, decongestants, oral or aerosol steroids) 
 Use of steroids, including administration by systemic, inhaled or topical ocular 
routes (dermatologic steroids not applied to the eyelids are allowed)  
 Participation in a clinical trial during the past 30 days 
 Women who are pregnant, planning a pregnancy, or nursing at study entry. 
 
3.3.3. Inclusion/Exclusion Exceptions 
The investigator has the right to exclude a potential participant’s enrollment in the 
study if s/he deems it in the best interest of the participant.  Reasons for exclusion 
on this basis will be recorded.   

9 
 
 
3.3.4. Discontinuation 
A participant may voluntarily discontinue participation in the study at any time 
without prejudice.  The investigator may elect to discontinue a participant for 
reasons unrelated to the study device (e.g. failure to comply with the study 
protocol, missed visits, etc.) or for reasons related to the study device (e.g. 
adverse event).  In any event, the reason(s) for discontinuation should be recorded 
on the CRF.  Possible reasons for study discontinuation can include the following: 
• AEs necessitating discontinuation from the study 
• The participant fails to comply with the study protocol or misses visits 
• Participant decision unrelated to AEs 
• Investigator decision (specify on CRF) 
• Other reason (specify on CRF) 
If a participant chooses to discontinue his/her participation or is discontinued by 
the investigator, the exit CRF should be completed.  In case of premature 
discontinuation from the study, the examiner should perform any testing required 
to ensure that the participant’s ocular health is within normal limits, if the 
participant agrees.     
Participants to be discontinued for AE(s) will be followed until the event is 
resolved or considered medically stable by the investigator if the participant 
agrees.  If a participant is lost-to-follow-up, the investigator should do his/her best 
to contact the participant initially by phone, then by letter, and finally by certified 
mail.  Evidence of these contacts should be recorded in the participant’s medical 
chart.   
Participants discontinued prior to the initial device application (Day 0) may be 
replaced and new participants will be assigned new study ID numbers.   
3.3.5. Pregnancy 
Women of childbearing potential (WOCBP) includes any females who have 
experienced menarche and who have not undergone successful surgical 
sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or 
are not postmenopausal with at least 12 months since last menses.  WOCBP will 
be required to use designated methods of birth control during the course of the 
study.  All women who are pregnant, nursing an infant, or planning a pregnancy 
will be excluded from participation.  
During the study, all WOCBP should be instructed to contact the investigator 
immediately if they suspect they might be pregnant (e.g., missed or late menstrual 
period).  A pregnancy test should be performed and, if the results are positive, the 
participant should discontinue use of the device and exit from the study.  The Exit 
CRF should be completed and the reason for discontinuing the study should be 
recorded as pregnancy. 

10 
 
If a participant or investigator suspects that the participant may be pregnant prior 
to study device application, the study device must be withheld until the results of 
pregnancy testing are available.  If pregnancy is confirmed, the participant must 
not administer the study device and must not be enrolled in the study or will be 
withdrawn from the study.  
3.4. Expected Duration of Follow-up and of Study 
Participants will have the investigational device for up to 42 days.  Total elapsed time 
for study participation will be up to 72 days.  The expected duration for the entire study 
will be up to approximately 3 months. 
3.5. Enrollment 
Prior to the Screening Visit, potential participants will be provided with an IRB 
approved informed consent document and have the opportunity to review and ask 
questions before giving written informed consent.  If required, the participant will sign 
and date the informed consent document in the presence of a witness.  The investigator 
or appropriate staff member will also sign and date the consent form as required.  The 
original will be retained with the participant records and a copy will be provided to the 
participant. 
Once informed consent has been provided, the participant can undergo screening 
procedures.  During the screening examination, participants should be identified only 
by their initials in the screening and enrollment log.  For participants who have no 
middle name, a dash (-) should be used in place of the middle initial.  After the 
participant has completed the required testing and met eligibility, the participant is 
considered eligible to participate and will be scheduled to return for Day 0.  Once the 
participant returns for Day 0 and uses the device, they will be considered enrolled in the 
study and receive a unique identification number. 
3.6. Randomization 
This is a single-arm, randomized, single-masked study in which one eye will receive 
the device in the lower canaliculus and the fellow eye will receive a sham injection of 
saline in the lower canaliculus.  The eye which receives the device will be determined 
by a randomization sequence.  The participant will remain masked as to which eye 
received the device and which eye received the sham. 
3.7. Clinical Assessments 
The following clinical assessments will be performed for this study: 
• Ocular Surface Disease Index (OSDI) questionnaire for each eye individually 
• Corrected Distance Visual Acuity 
• Tear break-up time 
• Tear meniscus height 
• Slit-lamp biomicroscopy 
• Corneal staining scored using the NEI grid and grading system 
• Schirmer test with topical anesthetic 

11 
 
A detailed description of the procedure for each assessment can be found in Appendix 
B. 
3.8. Visit Schedule  
This study consists of five visits: Screening, Day 0, Day 3, Day 14 and Day 30. A 
Schedule of Assessment with a summary of the testing required at each visit can be 
found in Appendix A. 
3.8.1. Screening (Day -30 to 0) 
Any tests or procedures that are performed to confirm eligibility and are not 
standard of care must be performed AFTER the potential participant has signed 
the Informed Consent Form. 
The following procedures are performed at the Screening visit: 
• Obtain medical history and confirm potential participant’s age 
• Obtain written informed consent 
• Perform urine pregnancy test for women of childbearing age 
• Have potential participant complete the Ocular Surface Disease Index 
OSDI) for each eye individually 
• Perform Corrected Distance Visual Acuity 
• Perform baseline TBUT test 
• Perform baseline tear meniscus height test 
• Administer fluorescein stain 
• Perform slit-lamp biomicroscopy and assess corneal staining using the 
NEI grid and scoring system 
• Perform baseline Schirmer test with topical anesthetic 
If at any point in this process, the potential participant fails to meet eligibility, the 
process should be discontinued, and the potential participant should be recorded 
as a screen failure along with the reason.   
3.8.2. Day 0 
The following procedures are performed at the Day 0 visit: 
• Have participant complete the OSDI for each eye individually 
• Perform Corrected Distance Visual Acuity 
• Instill HA device in inferior canaliculus of eye randomized to the device 
• Instill saline in inferior canaliculus of fellow eye  
3.8.3. Day 3 and 14 
The following procedures are performed at the intermediate follow-up visits, 
Days 3 and 14: 

12 
 
• Have participant complete the OSDI for each eye individually 
• Perform corrected distance visual acuity 
• Perform slit-lamp biomicroscopy  
3.8.4. Day 42 
The following procedures are performed at the Day 30 visit: 
• Have participant complete the Ocular Surface Disease Index OSDI) for 
each eye individually 
• Perform Corrected Distance Visual Acuity 
• Perform TBUT test 
• Perform tear meniscus height test 
• Administer fluorescein stain 
• Perform slit-lamp biomicroscopy and assess corneal staining using the 
NEI grid and scoring system 
• Perform Schirmer test with topical anesthetic 
• Remove device from inferior canaliculus by irrigation (if necessary for 
complete removal, hyaluronidase may be used) 
3.9. Concomitant Medications and Therapies  
All concomitant medications used within the 30 days prior to the screening visit, 
including medications used for relief of dry eye symptoms, will be documented on the 
case report form.  Any initiation of new medications or changes to current medications 
during the course of the study should be recorded on the appropriate case report form. 
No other experimental drug or device should be used within 30 days prior to the 
Screening Visit or during the course of the clinical trial.   
At the end of the Screening Visit, participants should be instructed not to use perfume 
or make-up on study days.  Participants should also be instructed to refrain from 
administration of any chronic ophthalmic medication for two hours before their visit.   
3.10. Participant Completion Procedures 
A participant’s participation in the study will be considered to have been completed 
when all assessments have been performed in accordance with the study protocol.  At 
the end of the study, participants will be exited.  If a participant chooses to discontinue 
the study before completion, the participant will be exited from the study.    
3.11. Study Termination 
The investigator reserves the right to discontinue the study for any safety or ethical 
reason at any time. 

13 
 
4. STATISTICS 
4.1. Sample Size 
This is a pilot, feasibility study.  No sample size calculation has been performed.  
  
4.2. Clinical Hypothesis 
As a pilot, feasibility study, there is no clinical hypothesis.   
 
4.3. Randomization 
This is a single-arm, randomized, single-masked study in which one eye will receive 
the device in the lower canaliculus and the fellow eye will receive a sham injection of 
saline in the lower canaliculus.  The eye which receives the device will be determined 
by a randomization sequence. 
 
4.4. General Statistical Considerations 
4.4.1. Participant Accountability and Missing Data 
Participants who withdraw from the study will be tabulated with the reasons for 
the withdrawal.   
 
4.5. Participant Demographic and Baseline Characteristics 
The demographic and baseline characteristics of the study population observed will be 
presented descriptively.  For continuous variables such as participant age, the mean, 
standard deviation (SD), median and range will be presented.  For categorical variables 
such as gender, the number with or experiencing the condition, the total number 
evaluated, the percentage, and the exact 95% confidence interval on the percentage will 
be presented. 
 
4.6. Effectiveness Analyses 
The assessment of effectiveness will be based on the changes in the primary and 
secondary effectiveness endpoints from baseline to 6 weeks in the eye which receives 
the device as compared with the eye which receives the sham injection. 
 
4.7. Safety Analyses 
The primary safety endpoint will be the proportion of participants that experience one 
or more device-related adverse events.  For corrected distance visual acuity, the 
proportion of participants s with an improvement of more than two lines (11 or more 
letters), a worsening of more than two lines and a change of two lines or less will be 
summarized along with the exact 95% confidence interval at each visit.  Biomicroscopy 

14 
 
results will also be presented as the proportion of participants with a clinically 
significant change from Baseline at each visit.  Particular attention will be paid to any 
changes to the corneal surface.  Summaries will be provided of the proportion of 
participants that experienced an unexpected device-related serious adverse event, the 
proportion of participants that experienced any adverse event and the proportion of 
participants that experienced each unique adverse event.   
 
4.8. Final Clinical Report 
A final clinical study report will be prepared after completion of the study. 
 
5. DATA MANAGEMENT 
Standardized CRFs will be used for reporting the results of the study.  All data from the study 
will be entered from the CRFs into a central database.  Study participants will be identified 
on the CRFs and in the database using the participant ID to maintain confidentiality.  
Incoming data will be reviewed to identify inconsistent or missing data and any adverse 
events.  Any data issues are to be promptly addressed by the investigator.   
 
6. ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
6.1. Definitions 
Adverse Event (AE):  An adverse event is defined as any untoward medical occurrence, 
unintended disease or injury, or any untoward clinical signs (including an abnormal 
laboratory finding) in participants, users or other persons whether or not related to the 
investigational medical device.  This includes events related to the investigational 
device or any procedures involved (any procedure in the study protocol).  For users or 
other persons this is restricted to events related to the investigational medical device. 
Serious Adverse Event (SAE):  An AE should be classified as an SAE and reported as 
such if it meets one or more of the following criteria: 
• It results in death (i.e., the AE actually causes or leads to death); 
• It is life threatening (i.e., the AE places the participant at immediate risk of 
death); 
• It requires or prolongs inpatient hospitalization. If a participant is hospitalized 
to undergo a medical or surgical procedure as a result of an AE, the event 
responsible for the procedure, not the procedure itself, should be recorded as 
the event.  For example, if a participant is hospitalized to undergo coronary 
bypass surgery, the heart condition that necessitated the bypass should be 
recorded. Hospitalizations for diagnostic or elective surgical procedures or 
hospitalizations required to allow outcome measurement for the study should 
not be recorded as SAEs: 

15 
 
• It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the participant’s ability to conduct normal life 
functions); 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the investigational device; 
• It is considered a significant medical event by the investigator based on 
medical judgment (e.g. may jeopardize the participant or may require 
medical/surgical intervention to prevent one of the outcomes listed above); 
• It is considered sight-threatening by the investigator. 
Unanticipated Adverse Device Effect (UADE):  An unanticipated adverse device effect 
(UADE) is any serious adverse effect on health or safety or 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 informed 
consent form.  UADEs also include any unanticipated sight-threatening events and any 
other unanticipated serious problem associated with a device that relates to the rights, 
safety or welfare of participants. 
6.2. Adverse Event Assessment and Documentation 
All participants who have been exposed to application of the study device should be 
evaluated for adverse events.  All adverse events, regardless of severity and whether or 
not they are ascribed to the study device, should be recorded in the source documents 
and CRFs using standard medical terminology.  
All adverse events should be evaluated beginning with onset and evaluation should 
continue until resolution is noted or until the investigator determines that the 
participant’s condition is stable.  The investigator should take appropriate and 
necessary therapeutic measures required for resolution of the adverse event.  Any 
medication necessary for the treatment of an adverse event must be recorded on the 
concomitant medication CRF.  
Pre-existing conditions or diseases that are chronic but stable should not be recorded on 
AE pages of the CRF but should be recorded in the medical history.  Changes in a 
chronic condition or disease that are consistent with natural disease progression do not 
need to be recorded as adverse events and should not be recorded on the AE pages of 
the CRF.  Clinical study staff should start assessing participants for AEs from the time 
of the first device application.  
Whenever possible, recognized medical terms should be used when recording AEs.  
Colloquialisms and/or abbreviations should not be used.  Only one medical concept, 
preferably a diagnosis instead of individual symptoms, should be recorded as the event.  
If more than one distinct adverse event occurs, each event should be recorded 
separately.  However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual 
event should be recorded as a separate AE.  A diagnosis that is subsequently 
established should be reported as follow-up information.  However, signs and 
symptoms that are considered unrelated to an encountered syndrome or disease should 

16 
 
be recorded as individual AEs (e.g. if congestive heart failure and severe headache are 
observed at the same time, each event should be recorded as an individual AE). 
Adverse events occurring secondary to other events (e.g. sequelae) should be identified 
by the primary cause.  A "primary" event, if clearly identifiable, should represent the 
most accurate clinical term to record as the AE event term.  For example:  Orthostatic 
hypotension  ⇒ fainting and fall to floor ⇒ head trauma ⇒ neck pain.  The primary 
event is orthostatic hypotension and the sequelae are head trauma and neck pain. 
6.3. Classification 
6.3.1. Intensity / Severity 
All adverse events should be graded on a 4 point scale (mild, moderate, marked, 
severe) for intensity / severity.  These definitions are as follows: 
• Mild:  Transient discomfort; no medical intervention / therapy required 
and does not interfere with daily activities. 
• Moderate:  Low level of discomfort or concern with mild to moderate 
limitation in daily activities; some assistance may be needed; minimal or 
no medical intervention/therapy required. 
• Marked:  Considerable discomfort with limitation in daily activities; some 
assistance usually required; medical intervention/therapy usually required. 
• Severe:  Extreme discomfort and limitation in daily activities; significant 
assistance required; significant medical intervention/therapy required. 
Note:  There is a distinction between the severity and the seriousness of an 
adverse event.  Severity is a measurement of intensity; thus, a severe reaction is 
not necessarily a serious adverse event (SAE).  For example, a headache may be 
severe in intensity, but would not be serious unless it met one of the criteria for 
serious adverse events. 
6.3.2. Expectedness  
All AEs should be evaluated as to whether they are expected or unexpected.  
• Expected (anticipated):  An adverse event is expected when the nature, 
severity or degree of incidence was previously described.   
• Unexpected (unanticipated):  An adverse event is unexpected when the 
nature, severity or degree of incidence was not previously described.  
6.3.3. Relatedness  
The study investigator should evaluate if the AE is related to the use of the study 
device.  Relationship is defined in the following manner: 
Not related:  Evidence indicates no plausible direct relationship to the study 
device such that: 
• A clinically plausible temporal sequence is inconsistent with the onset of 
the AE and device application, and/or 
• A causal relationship is considered biologically implausible, and/or 
• The AE can be attributed to concurrent/underlying illness, other drugs or 
procedures. 

17 
 
Possibly related:  Evidence indicates a possible relationship to the study device 
such that: 
• The event occurs within a reasonable period of time relative to the 
application that makes a causal relationship possible, but plausible 
explanations may also be provided by other causes such as other drugs, 
products, chemicals, underlying disease, environment, etc., and/or 
• The event is possibly related to the study application. 
Related:  Evidence indicates a reasonable temporal sequence of the event with the 
study device application exists or that the association of the event with study 
device application is unknown and the event is not reasonably supported by other 
conditions such that: 
• There is a clinically plausible time sequence between onset of the AE and 
study device application a, and/or 
• There is a biologically plausible mechanism for study application causing 
or contributing to the AE, and/or 
• The AE cannot be reasonably attributed to concurrent/underlying illness, 
other drugs or procedures. 
6.3.4. Outcome 
The clinical outcome of an AE should be characterized as follows: 
• Resolved without sequelae 
• Resolved with sequelae (specify) 
• Ongoing (i.e. continuing at time of study discontinuation) 
• Death 
6.3.5. Treatment or Action Taken 
The clinical treatment or action taken from an AE should be characterized as 
follows: 
• None 
• Medical intervention 
• Surgical intervention 
• Other 
6.4. Anticipated Adverse Events 
The following is a list of anticipated adverse events:  
• Ocular discomfort or irritation 
• Conjunctival injection 
• Canaliculitis 
• Subconjunctival hemorrhage 
• Punctal stenosis 
• Eyelid telangiectasia 
• Eyelid edema 

18 
 
• Eyelid induration 
• Eyelid erythema 
• Epiphora 
• Clinically significant decrease (>10 letters) in Corrected Distance Visual 
Acuity  
• Clinically significant increase in corneal epithelial staining, e.g., an increase in 
corneal staining score of 2 or more in at least one corneal region or an 
increase in the sum for all corneal regions of 4 or more (using NEI grid and 
scale) 
 
 
7. INVESTIGATOR QUALIFICATIONS AND RESPONSIBILITIES 
7.1. Qualifications 
The investigator is a licensed physician who has completed a residency in 
ophthalmology. 
7.2. Responsibilities 
The investigator has the following responsibilities: 
• Ensure that the clinical study is conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki, ISO 
14155:2011, GCP, ICH guidelines, and any regional or national regulations as 
appropriate.   
• Ensure that participants undergo no investigational procedures other than 
those described in this protocol and approved by the IRB, except those 
procedures deemed necessary to protect the health and well-being of the 
participants.  Any such procedures will be documented in the participant’s 
records and reported to the sponsor and the IRB.   
• Report any use of the investigational device without first obtaining informed 
consent to the IRB and sponsor 
• Assure that all participants entering the study conform to the participant 
selection criteria 
• Assure that IRB approval of the study protocol and informed consent has been 
obtained and provided to the site prior to initiation of the study 
• Perform the participant evaluations as described in the study protocol and not 
deviate from the study protocol unless protection of the health, safety or 
welfare of study participants requires prompt action 
• Notify the IRB of unanticipated adverse device effects 
• Ensure participant confidentiality 

19 
 
• Submit regular progress reports to the IRB as required 
• Report any emergency deviations from the protocol that are necessary to 
protect study participants to the IRB within five working days of occurrence 
• Submit a final report for the study to the IRB in a timely manner   
• If any additional requirements are imposed by the IRB or regulatory authority, 
these requirements shall be followed. 
 
7.3. Informed Consent Process 
The site will submit the proposed informed consent to the IRB.  Potential participants 
cannot be asked to sign the informed consent form until the study has been fully 
approved by the IRB.  The following information should be provided in the informed 
consent: 
• The study is research 
• Purpose of the study, including the approximate duration of participation by 
the participant and a description of the procedures 
• Possible side effects, risks or discomforts of the investigational device 
• Reasonably expected benefits 
• The existence of alternative therapy options and/or alternatives to 
participating in the study 
• Confidentiality of records  
• Costs and compensation or treatment for injury 
• Person to contact regarding participant rights or for questions on research or 
research-associated injury 
• That participation is voluntary 
• The right to discontinue participation from the study at any time without 
disadvantage to the participant 
• That the participant will be informed of new information learned during the 
study, which may affect the participant’s decision to continue participation in 
the study 
The investigator will obtain written informed consent from each participant prior to the 
initiation of any study-specific activities.  Copies of the informed consent form used in 
the study should include the IRB-approved stamp (if applicable) and version date.  The 
participant or participant’s legally authorized representative (if applicable) will be 
allowed sufficient time to thoroughly read, or have read and explained to them, the 
informed consent form.  The investigator will answer any questions that the participant 
or representative might have.  If the participant agrees to participate in the study, all 
required parties should sign and date the informed consent form.  The original signed 

20 
 
informed consent form will be retained by the site and a copy will be given to the 
participant for his/her records.  The obtaining of informed consent and the date of that 
informed consent should be noted in the participant’s medical record.  It should also be 
noted in the participant’s medical record that informed consent was obtained prior to 
conducting any study-specific activities. 
 
7.4. Records 
7.4.1. Source Documents 
Source documentation for this study will be maintained to document the 
application and study course of each participant and to substantiate the integrity of 
the trial data.  Source documentation will include, but may not be limited to, 
worksheets, hospital and/or clinic or office records documenting participant visits 
including study and other treatments or procedures, medical/ophthalmologic 
history and physical examination information, laboratory and special assessment 
results, pharmacy records, device accountability records, and medical 
consultations.  In this study, case report forms can be used as source documents 
where appropriate. 
The investigator is responsible for maintaining adequate case histories in the 
source documents of each participant.  The following data will be reported by the 
investigator in the source medical records of each participant enrolled in the 
study:   
• The date the participant entered the study and the participant number 
• The study protocol number  
• The date that informed consent was obtained 
• Evidence that the participant met the study eligibility requirements (e.g., 
medical history, study procedures and/or evaluations) 
• The dates of all study-related participant visits 
• Evidence that required procedures and/or evaluations were completed 
• Use of any concurrent medications 
• Occurrence and status of any adverse events 
• The date the participant exited the study and a notation as to whether the 
participant completed the study or was discontinued, including the reason 
for discontinuation. 
7.4.2. Case Report Forms 
Case report forms will be filled out completely for each participant in accordance 
with instructions.  The investigator should ensure that all data on the CRF is 
accurate and consistent with the source documents.  Only the principal 
investigator may sign and date the designated CRF page(s). 

21 
 
7.4.3. Screening/Enrollment Log 
The investigator will maintain a screening log that will record the date of 
screening, the enrollment status (enrolled/excluded), the date of informed consent 
and the reason for exclusion for all screen failures. 
7.4.4. Device Accountability 
The investigator will be responsible for maintaining a device accountability log 
that will track device usage for all study participants.  Information tracked will 
include date of device application, lot number and the participant ID. 
7.4.5. Record Retention 
The investigator is responsible for maintaining adequate records to enable the 
conduct of the study to be fully documented.  This includes: 
• Signed protocol and amendments 
• Signed and dated informed consents per institutional policy 
• Signed, dated, and completed CRFs and documentation of CRF 
corrections 
• Notification of SAEs and related reports 
• All study device dispensing and accountability logs 
• Shipping records of investigational device and trial-related materials 
• Dated and documented IRB protocol approvals and all correspondence 
between the investigator and IRB 
• Curriculum vitae and current medical license for principal investigator  
The investigator must maintain a copy of all study documents for the period of 
time that is required by the regulatory authorities.   
 
7.4.6. Deviations from the Investigational Plan 
The investigator shall notify the IRB of any deviation from the Investigational 
Plan to protect the life or physical well-being of a participant in an emergency.  
Such notice shall be given as soon as possible, but in no event later than five (5) 
working days after the emergency occurred.  
8. ETHICS 
8.1. Study Conduct 
The study will be performed in accordance with the relevant parts of the Code of 
Federal Regulations, ICH Guidelines for Good Clinical Practices, the Declaration of 
Helsinki and any other applicable regional and/or national regulations. 

22 
 
8.2. Ethics Review 
Before any participant can be enrolled in this study, the IRB will review and approve 
the protocol and the Informed Consent Form to be used.   
8.3. Confidentiality 
Confidentiality of participants will be maintained throughout the study.  A unique 
identification code will be assigned to each participant enrolled in this study.  Any data 
that may be published in abstracts, scientific journals, or presented at medical meetings 
will reference a unique code and will not reveal the participant’s identity.   
8.4. Amendments to the Protocol 
Any amendment containing major modifications (particularly if it may involve an 
increased risk to the participants) must be approved by the IRB before it may be 
implemented.  No change in the conduct of the study will be instituted without written 
approval from the Sponsor. 
 
 

23 
 
 
 
9. APPENDICES 
9.1. Appendix A – Schedule of Assessments 
Procedure/Assessments 
Baseline 
 
Day -30 to 0 
Application 
 
Day 0 
Form 1 
 
Day 3 ± 1 
Form 2 
 
Day 14 ± 2 
Form 3 
 
Day 42 ± 5 
Informed Consent/HIPAA 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Eligibility 
X 
 
 
 
 
OSDI Questionnaire  
(OD, OS separately) 
X 
X 
X 
X 
X 
CDVA  
X 
X 
X 
X 
X 
Slit Lamp Examination 
X 
X 
X 
X 
X 
Grading of Corneal 
Staining 
X 
 
 
 
X 
Schirmer Test 
X 
 
 
 
X 
Tear break-up time 
X 
 
 
 
X 
Tear meniscus height 
X 
 
 
 
X 
Application of device and 
control 
 
X 
 
 
 
Removal of device  
 
 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
 
 
 

24 
 
 
9.2. Appendix B – Examinations and Procedures 
9.2.1. Questionnaire 
To minimize bias, participants will be asked to complete the questionnaire 
independently and in private after instructions have been provided by site 
personnel.  The questionnaire should be completed twice and answered by the 
participant with reference to each eye individually. 
Ocular Surface Disease Index (OSDI) 
The OSDI is a 12-item questionnaire generated by the Outcomes Research Group 
at Allergan (Irvine, CA),14 which asks participants to describe the severity and the 
nature of their irritation symptoms.  The participant will answer the 12 questions 
by circling the number that best represents each answer:  4 (all of the time), 3 
(most of the time), 2 (half of the time), 1 (some of the time), or 0 (none of the 
time).  The final score for the questionnaire is calculated as follows: 
Add subtotals from Sections I, II, and III =  A 
Determine total number of questions answered from Sections I, II, and III (do not 
include N/A) = B 
Final OSDI score = A x 25 divided by B   
An example of the questionnaire is as follows: 

25 
 
 

26 
 
 
 
 
9.2.2. Corrected Distance Visual Acuity    
Corrected distance visual acuity (CDVA) should be recorded with the 
participant’s current spectacle correction or with the most current spectacle 
correction in a trial frame using the Early Treatment Diabetic Retinopathy Study 
(ETDRS) chart.  The number of letters read correctly will be recorded.  The 
CDVA should be collected at the screening examination and on the application 
day, both before and after the three randomized applications are administered, 
using the same spectacle correction used during the screening examination.  If the 
CDVA is not believed to be maximal during the screening visit, pinhole visual 

27 
 
acuity should be recorded for this reading throughout the study or a manifest 
refraction should be performed. 
Note:  Repeated use of topical anesthetic and Schirmer testing may result in a 
transient decrease in CDVA. 
Early Treatment Diabetic Retinopathy Study (ETDRS) Corrected Distance Visual 
Acuity 
The equipment used will include a set of two Lighthouse Distance Visual Acuity 
Test charts (ETDRS Charts 1 and 2; Lighthouse Low Vision Products Precision 
Vision, Long Island, New York) and a retroilluminated box providing 
standardized chart illumination.  Most of the room lights should be turned off 
during the visual acuity test as the box itself provides sufficient illumination for 
the examiner to record the test results.  Additional light can have an adverse 
effect.  With the box light off, not more than 15 foot-candles of light should fall 
on the center of the chart.  A distance of exactly 4 meters is required between the 
participant’s eyes and the visual acuity chart for the 4-meter test and a distance of 
exactly 1 meter is required for the 1-meter test.   
The participant can be standing or sitting and will be asked to focus on an ETDRS 
visual acuity chart.  Testing of all eyes should begin at the 4 meter test distance.  
The examiner should ensure that the head does not move forward or backward 
during testing.  After careful instruction, testing should begin with the right eye 
using Chart 1. 
The participant should be told (and reminded if appropriate) that the chart has 
letters only and no numbers.  The participant should be asked to read at a steady 
pace, at a rate no faster than about one letter per second, and not to proceed until 
providing a definitive response.  Examiners should not point to specific letters on 
the chart or read any of the letters during testing.  If the participant says s/he 
cannot read a letter, s/he should be encouraged to guess.  If the participant 
identifies a letter as one of two or more letters, s/he should be asked to choose one 
letter.  When it becomes evident that no further meaningful readings can be made 
despite encouragements to read or guess, the examiner should stop the test for that 
eye.   
Each letter is scored as right or wrong.  Once a participant has identified a letter 
with a definite single-letter response and has read the next letter, a correction of 
the previous letter should not be accepted.  If the participant changes a response 
aloud (e.g. “That was a ‘C,’ not an ‘O’) before s/he has read the next letter aloud, 
then the change should be accepted.  If the participant changes a response after 
beginning to read the next letter, the change is not accepted.  The test is repeated 
for the left eye using Chart 2.  Chart 1 should not be exposed to the left eye and 
Chart 2 should not be exposed to the right eye, even when switching charts and 
occlusion. 
1-Meter Test 
Eyes reading 19 or fewer letters correctly at 4 meters should be tested at 1 meter.  
If the spectacles or trial frame is to be removed when changing the test distance 

28 
 
from 4 meters to 1 meter, the testing chart should first be removed from view to 
prevent the participant from reading the chart with the fellow eye.  Before testing 
at 1 meter, a +0.75 D sphere should be added to the 4-meter correction already in 
the trial frame to compensate for the closer testing distance.  The avoidance of 
any head movement forward to backward is particularly important during the 1-
meter test.  The participant should be asked to read only the first six lines at 1 
meter, making 30 the maximum score attainable at that distance. 
Light Perception   
If visual acuity is so poor that the participant cannot read any of the largest letters 
at 1 meter (i.e., the number of letters read correctly at 1 meter is zero), light 
perception should be tested with an indirect ophthalmoscope in a darkened room.  
The indirect ophthalmoscope light should be in focus at 3 feet with the rheostat 
set at maximum voltage.  From a distance of 3 feet, the beam should be directed 
in and out of the eye at least four times and the participant should be asked to 
respond when s/he sees the light.  If the examiner is convinced that the participant 
perceives the light, vision should be recorded as “light perception,” and, if not, 
vision should be recorded as “no light perception.” 
Corrected Distance Visual Acuity Scoring Instructions 
The ETDRS visual acuity worksheets are for clinic use only.  The examiner 
records each letter identified correctly by circling the corresponding letter on the 
appropriate worksheet.  The examiner records letters read incorrectly with an ‘X’ 
and leaves letters for which the participant makes no guesses unmarked.  Each 
letter read correctly is scored as one point.  After testing is completed, the score 
for each line (which is zero if no letters are read correctly) and the total score for 
each eye are recorded on the visual acuity worksheet.  If testing at 1 meter is not 
required, 30 points are automatically scored for the 1-meter test.  The total 
combined score (i.e., the sum of the 4- and 1-meter scores) are entered on the 
worksheet as the final visual acuity letter score.  
Note:  A clinically significant visual acuity decrease (defined as an increase of 
0.22 or greater in logMAR score from Day 0) at a Follow-up visit will be 
considered an adverse event. 
9.2.3. Slit Lamp Biomicroscopy 
A slit lamp examination will be performed at the screening and twice during the 
application visit, once prior to the first application and once following the 
completion of all three applications.  Biomicroscopy will be used to assess the 
following structures for pathology: 
• Eyelids (i.e., Meibomian glands, lid margin, puncta, lashes) 
• Cornea (the presence or absence of corneal edema will be noted) 
• Conjunctiva 
• Anterior chamber 
• Lens 

29 
 
9.2.4. Ocular Surface Staining – Corneal Staining Using Fluorescein 
Ocular surface staining using fluorescein will be assessed and recorded in the 
schematic representation of 5 corneal regions per eye on the case report form 
using the NEI grading system.15   
First, corneal staining should be assessed using 1.0 mg sodium fluorescein strips.  
After moistening the tip of the strip with sterile buffered saline, the excess is 
shaken into a waste bin with a sharp flick.  The lower lid is then pulled down and 
the flat end of the tip should be gently applied to the inferior tarsal conjunctiva 
with the intent of not inducing reflex tearing and instilling a very small volume of 
dye.  The patient will be instructed to blink naturally several times without forced 
closure of the eyelid to distribute the fluorescein.  After allowing fluorescein to 
remain on the eye for at least one minute, 5 corneal regions will be graded using a 
cobalt (blue) filter to maximize the view of the fluorescence.  The upper eyelid is 
lifted slightly to grade the entire corneal surface.  
9.2.5. Schirmer Test 
The Schirmer test with topical anesthetic16 will be used to assess tear production 
using the following steps:   
1. Topical anesthetic drops such as 0.5% proparacaine hydrochloride or 
equivalent should be instilled in both eyes of the participant. 
2. As soon as the anesthetic drop has been instilled, the participant will be 
instructed to keep the eyes gently closed for one minute.  The closed eyes can 
be gently blotted.   
3. After opening the eyes and allowing the eyes to recover for approximately one 
additional minute, excess moisture in the inferior fornix is gently removed 
with a spear. 
4. Schirmer strips (35 mm x 5 mm size filter paper strip) will be placed in each 
eye at the junction of the middle and lateral thirds of the lower eye lid.  
5. Under ambient light, the participant will be instructed to look forward and to 
blink normally during the course of the test.  The test should be performed in a 
room with no direct air on the participant’s face. 
6. After five minutes, strips will be removed from both eyes and the amount of 
wetting will be recorded.  The strips should be taped to the CRF.   
Note:  Should the Schirmer score reach maximum prior to the five minute 
endpoint, the time it took to reach maximum should be recorded for each 
individual strip.   
 

30 
 
9.2.6. Tear Break-up Time Test 
 
A non-invasive tear break-up time test will be performed with the Keratograph 5M 
according to the manufacturer’s directions, as reproduced below.   
 
 
 
 
 
 
 
 
 
 

31 
 
 
 

32 
 
 
 

33 
 
 

34 
 
9.2.1. Tear Meniscus Height 
A tear meniscus height test will be performed with the Keratograph 5M according to the 
manufacturer’s directions, as reproduced below.   

35 
 
 
 

36 
 
 
 
 

37 
 
 
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2007;5(2):93-107. 
2 Market Scope. 2011 Comprehensive Report on the Global Dry Eye Products Market. St. Louis, 
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3 Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to 
treatment recommendations. Cornea 2006;25:900-907. 
4 Schiffman RM, Walt JG Jacobson G, Doyle JJ, Lebovics G, Sumner W. Utility assessment 
among patients with dry eye disease. Ophthalmol 2003;110(7):1412-1419. 
5 Miljanović B, Dana R, Sullivan DA, Schaumberg DA. Impact of Dry Eye Syndrome on Vision-
Related Quality of Life. Am. J. Ophthalmol. 2007;143.\. 
6 Mertzanis P, Abetz L, Rajagopalan K, et al. The relative burden of dry eye in patients’ lives: 
Comparisons to a U.S. normative sample. Investig. Ophthalmol. Vis. Sci. 2005;46:46-50. 
doi:10.1167/iovs.03-0915. 
7 Subcommittee T. DEWS Management and Therapy Management and Therapy of Dry Eye 
Disease : Ocul. Surf. 2007;5:163-178. 
8 American Academy of Ophthalmology. Preferred Practice Patterns: Dry Eye Syndrome. 2008. 
9 Jacobs DS, Rosenthal P. Boston scleral lens prosthetic device for treatment of severe dry eye in 
chronic graft-versus-host disease. Cornea 2007;26(10):1195-1199. 
10 Sakamoto A, Kitagawa K, Tatami A. Efficacy and retention rate of two types of silicone 
punctal plugs in patients with and without Sjögren syndrome. Cornea 2004;23:249-254.. 
11 Howarth-Winter, J, Thaci, A, Gruber, A, Boldin I. Long-term retention rates and complications 
of silicone punctal plugs in dry eye. Am. J. Ophthalmol. 2007;144(3):441-444. 
12 Sugita J, Yokoi N, Fullwood NJ, et al. The detection of bacteria and bacterial biofilms in 
punctal plug holes. Cornea 2001;20:362-365.. 
13 Montani G.   Intraparticipant tear osmolarity changes with two different types of eyedrops. 
    Optom Vis Sci. 2013 Apr;90(4):372-7.  
14 Walt JG, Rowe MM, Stern KL. Evaluating the functional impact of dry eye: the Ocular 
Surface Disease Index [abstract]. Drug In J 1997;31:1436. 
15 Lemp MA. National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes, CLAO J 
1995;21:221-232. 
16 Nelson DJ. In-office diagnostic tests for dry eye disease. In: Dry Eye Disease, The Clinician’s 
Guide to Diagnosis and Treatment, Editors: Asbell PA, Lemp MA. 2006 New York: Thieme, 
page 39.