The Utility of in Vivo Confocal Microscopy (IVCM) to Assess Cellular Response and Efficacy of Long-term Topical Steroid Treatment in Patients With Dry Eye Disease (DED)
Phase: PHASE4
Conditions: Dry Eye Disease
Sponsor: Tufts Medical Center

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 1 of 51 
 
COVER PAGE 
Clinical Protocol Title:  
The utility of in vivo confocal microscopy to assess cellular response and efficacy 
of long-term topical steroid treatment in patients with dry eye disease 
 
Version number and date: Version 2 – 01/13/2017 
Phase of clinical investigation: Phase IV 
Name of all sites (if applicable): MEEI and Tufts Medical Center 
IND/IDE number: N/A 
Investigational drug(s) or device(s):  
Loteprednol etabonate 0.5% ophthalmic suspension (Lotemax, Bausch & Lomb, Inc); 
Soothe Tired Eyes Lubricant Eye Drop (Glycerin 1%, Bausch & Lomb Inc.) 
Regulatory Sponsor:   
Pedram Hamrah, MD   
Funding Sponsor: GlaxoSmithKline plc 
Study Monitor 
Medical Director:  N/A 
Investigator(s): 
Pedram Hamrah, MD 
Tufts Medical Center 
800 Washington Street 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 2 of 51 
Boston, MA 02111 
Phone: 617-636-5720 
Email: PHamrah@tuftsmedicalcenter.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 3 of 51 
Acronym List: 
 
AE 
 
 
Adverse Event 
ANOVA 
 
Analysis of Variance 
BCVA 
 
Best Corrected Visual Acuity 
BID  
 
Twice Daily 
CRF   
 
Case Report Form 
DED  
 
Dry Eye Disease 
FDA  
 
Food and Drug Administration 
IOP  
 
Intraocular Pressure 
IRB  
 
Institutional Review Board 
IVCM 
 
In-Vivo Confocal Microscopy 
LMR  
 
Longitudinal Medical Record 
MEEI  
 
Massachusetts Eye and Ear Infirmary  
HSC  
 
Human Studies Committee 
NEI  
 
National Eye Institute 
OSDI  
 
Ocular Surface Disease Index 
PI 
 
 
Principal Investigator 
SAE  
 
Serious Adverse Event  
SANDE 
 
Symptom Assessment In Dry Eye 
TBUT  
 
Tear break-up time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 4 of 51 
 
Table of Contents 
Study Design Schematic …………………………………………………………….8 
1.0 Clinical Protocol ………………………………………………………………….9 
1.1 Background …………………………………………………………………9 
1.2 Rationale ……………………………………………………………………9 
2.0 Study Objectives ………………………………………………………………11 
2.1 Primary Objective …………………………………………………………11 
2.2 Secondary Objective …………………………………………………...…11 
3.0 Study Design …………………………………………………………………….12 
3.1 Study Design Description ………………………………………………12 
3.2 Allocation to Treatment ………………………………………………..12 
3.2.1 Randomization Procedures …………………………………..12 
3.2.2 Masking Procedures …………………………………………...12 
3.2.3 Breaking the Mask ……………………………………………..13 
4.0 Subject Selection …………...…………………………………………………..13 
4.1 Subject Inclusion Criteria ……………………………………………...13 
4.2 Subject Exclusion Criteria ……………………………………………..14 
5.0 Study Drug(s)/Devices ………………………………………………………...16 
5.1 Study Drug/Device Information ……………………………………...16 
5.2 Study Drug/Device Compliance/Adherence ………………………17 
5.3 Study Drug Supplies ……………………………………………………17 
5.4 Study Drug/Device Storage and Accountability ………………….18 
5.5 Other Medications ………………………………………………………18 
6.0 Biospecimen Collection ………………………………………………............21 
6.1 Specimen preparation, handling, and shipping …………………..21 
6.2 Instruction for specimen preparation, handling and storage ....21 
6.3 Specimen shipment ……………………………………………………..21 
6.4 Future use of stored specimens ……………………………………...21 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 5 of 51 
7.0 Study Procedures ………………………………………………………………22 
7.1 Screening Procedures …………………………………………………..22 
7.2 Enrollment/Baseline Procedures ……………………………………..24 
7.3 Study Drug or Device Procedures ……………………………………26 
7.4 Standard of Care Procedures …………………………………………27 
7.5 Follow-Up Procedures …………………………………………………..27 
7.6 Unscheduled Visits ……………………………………………………...28 
7.7 Early Termination ……………………………………………………….28 
7.8 Schedule of Activities (Study Table) ………………………………...28 
8.0 Safety and Effectiveness Assessments ………………………………........30 
8.1 Safety Assessments ……………………………………………………..30 
8.2 Effective Assessments ………………………………………………….31 
9.0 Adverse Event Recording and Reporting ……………………………........33 
9.1 Recording Requirements ………………………………………………33 
9.2 Reporting Requirements ……………………………………………….34 
9.3 Withdrawal of Subjects due to Adverse Events …………………..34 
10.0 Statistical Methods/Data Analysis ………………………………………..36 
10.1 Primary Endpoint(s) or Outcome Measure(s) …………………….36 
10.2 Secondary Endpoint(s) or Outcome Measure(s) …………………36 
10.3 Sample Size Determination ………………………………………….37 
10.4 Analysis Population …………………………………………………...37 
10.5 Effectiveness Analysis ………………………………………………..37 
10.6 Safety Analysis …………………………………………………………38 
10.7 Interim Analysis ……………………………………………………….39 
11.0 Data and Safety Monitoring ………………………………………………...40 
11.1 Data and Safety Monitoring Plan …………………………………...40 
12.0 Data Handling, Record-Keeping and Monitoring ………………………42 
12.1 Data Recording, Record Keeping and Monitoring ………………42 
13.0 Study Discontinuation Criteria …………………………………………….43 
13.1 Discontinuation ………………………………………………………..43 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 6 of 51 
13.2 Sponsor-Investigator Discontinuation of the Clinical Research     
Study ……………………………………………………………………………43 
14.0 Appendices …………………………………………………………………….44 
14.1 Schedule of Events …………………………………………………...44 
14.2 Case Report Form(s) ………………………………………………….44 
Appendix I: Ocular Tolerability and Compliance Questionnaire …45 
Appendix II: Ocular Surface Disease Index (OSDI ……………………47 
Appendix III: Symptom Assessment in Dry Eye (SANDE) 
Questionnaire I and II……………………………………………………….48 
Appendix IV: Corneal Fluorescein Staining and Conjunctival 
Lissamine Green Staining ………………………………………………….50 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 7 of 51 
 
STUDY DESIGN SCHEMATIC 
 
 
Subjects with          
dry eye disease 
(n=50) 
Lotemax 
(n=25) 
Artificial 
Tears (n=25) 
2 weeks 
2 weeks 
6 weeks 
6 weeks 
Screening and Baseline Visit 
Randomization 
Intermediate Visit 
Final Visit 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 8 of 51 
 
1. CLINICAL PROTOCOL 
 
1.1 Background  
Recent studies have shown that inflammation plays an important role in the 
pathogenesis of Dry Eye Disease (DED).  Ocular surface inflammation often 
exacerbates the subject’s signs and symptoms, and results in an increase in the 
immune cells and other inflammatory mediators located in the ocular surface. Dry 
eye disease is one of the most commonly encountered ophthalmic disorders. It is a 
multifactorial disease of the ocular surface and tear film, characterized by symptoms 
of eye irritation, tear instability and vision impairment. Despite being very common, 
standardized therapy is not available.  
Due to the underlying inflammation associated with DED, anti-inflammatory steroid 
medications are used for the treatment of DED. “Soft steroids” are often preferred 
because their chance of increasing intraocular pressure (IOP) is lower than other 
steroids. One of the “soft steroids” that is commonly used for the treatment of 
inflammation associated with ocular surface disease is loteprednol etabonate 0.5% 
ophthalmic suspension (Lotemax, Bausch & Lomb, Inc). 
Current steroid therapy in DED is comprised of pulse therapy (to avoid adverse 
events associated with long-term steroid use) of usually 2 weeks duration, 
administered BID.  This timeframe is often too short to meaningfully resolve the 
inflammation associated with DED. More recently steroid treatment of at least 6 
weeks with tapered dosing has been advocated. 
1.2 Rationale 
Lotemax, an FDA-approved medication for ocular inflammatory disease, is commonly 
used to treat inflammation associated with DED with a regimen of twice daily for 2 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 9 of 51 
weeks. However, because DED is a chronic disease, this short duration of steroid 
therapy may not be enough to meaningfully resolve the inflammation associated with 
DED. Thus, corneal specialists, including here at MEEI, have begun using Lotemax for 
at least 6 weeks with tapered dosing. This study has been designed to evaluate the 
effects of this tapering regimen on inflammation associated with DED. 
Clinical signs and symptoms are used to evaluate the efficacy of a treatment for DED, 
including Schirmer’s test, tear break-up test, corneal fluorescein staining, and 
conjunctival lissamine green staining. However, none of these tests evaluate the 
underlying inflammatory and immune response changes in DED. Therefore, to 
determine the efficacy of any treatment for DED, it is ideal to evaluate these 
underlying changes in addition to the clinical parameters.  
In vivo confocal microscopy (IVCM) is a novel imaging technology that allows the 
visualization and quantification of corneal structures at the cellular level. IVCM has 
recently been used to evaluate the corneal changes in DED, such as hyperfluorescent 
superficial epithelial cells, immune dendritic cells, and sub-basal nerves.  
Therefore, in this randomized clinical trial, IVCM images will be used to determine the 
changes in corneal immune cells and nerves during a 6-week taper regimen of 
Lotemax versus Soothe Tired Eyes Lubricant Eye Drop (Glycerin 1.0%, Bausch & Lomb 
Inc.) (an artificial tear) for treatment of inflammation associated with DED.    

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 10 of 51 
 
2. STUDY OBJECTIVES 
 
2.1 Primary Objective 
To evaluate the efficacy of Lotemax as compared to Artificial Tear over a period of 6 
weeks, using clinical and in vivo confocal microscopic findings.  
2.2 Secondary Objective(s) 
N/A 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 11 of 51 
 
3. STUDY DESIGN 
 
3.1 Study Design Description 
This is a single site, prospective, randomized, controlled, double-masked clinical trial 
including 50 subjects with DED. The participants will be randomized to take either 
Lotemax or Soothe Tired Eyes Lubricant Eye Drops for 6 weeks. Both Lotemax and the 
artificial tear will be used 4 times a day for 2 weeks, 2 times a day for 2 weeks, and 
once a day for 2 weeks. After screening/baseline examination and enrolling into the 
study, the participants will have follow-up visits at 2 weeks as well as 6 weeks.  
 
3.2 Allocation to Treatment  
The subjects will be randomized in two groups, one group will receive Lotemax and 
the other group will receive Soothe Tired Eye Lubricant Eye Drops. 
 
3.2.1 Randomization Procedures 
Once the investigator determines that the subject has met all of the inclusion and 
exclusion criteria, the subject will be randomized to take either Lotemax or Soothe 
Tired Eyes Lubricant Eye Drops (artificial tears). The randomization will be in a 1:1 
ratio using a permuted-block design (which will be obtained using a computer-based 
random code generator) into the two groups.  
 
3.2.2 Masking Procedures 
The study drugs will be labeled by the Massachusetts Eye & Ear pharmacy with 
instructions for storage, the name of the study, an expiration date, and a notice that 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 12 of 51 
the bottle may contain Lotemax. The pharmacy will maintain a master list of the 
participants’ name, unique identifier, and the coded treatment assignment. The 
randomization scheme and treatment assignment will be held in the pharmacy to 
ensure that the investigator and study team remain masked. Participants, 
investigators, image analysts, and the sponsor (GSK) will be masked to the treatment 
group. 
 
3.2.3 Breaking the Mask 
A subject’s medication may be unmasked at any point for a medical emergency or to 
supplement a serious adverse event (SAE) report. The subjects will be unmasked at 
the end of the study in order to provide optimal ongoing care. 
4. SUBJECT SELECTION 
 
4.1 Subject Inclusion Criteria 
 Age 18-89 years.  
 Willing and able to provide written informed consent.  
 Willing and able to comply with study assessments for the full duration of the 
study.  
 Diagnosis of dry eye disease based on the followings: 
o Symptoms of dry eye disease such as foreign body sensation, burning, 
stinging, light sensitivity for at least 6 months.  
o Two or more of the following objective signs: 
 Schirmer test with anesthesia <10 mm at 5 minutes [mean Schirmer 
between eyes. 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 13 of 51 
 Tear break-up time (TBUT) of <10 seconds. 
 Corneal fluorescein staining of 4 (NEI grading scheme, 0-15) in at 
least one eye 
 Lissamine green staining of the nasal and temporal conjunctiva 
(NEI grading scheme, 0-18) in at least one eye  
 Corneal dendritiform cell count by confocal microscopy of >=75/mm2 (13 
immune cells per image) 
 In good stable overall health.  
 
4.2 Subject Exclusion Criteria 
 Central corneal subbasal dendritic cell count by in vivo confocal microscopy of 
<75/mm2  in both eyes 
 Active ocular allergies  
 Active allergies to steroids, aminoglycosides, or benzalkonium chloride (BAK)  
 History of contact lens wear within 3 months before enrollment. 
 Intraocular surgery or ocular laser surgery within 3 months before enrollment. 
 History of ocular infection within 3 months before enrollment. 
 History of topical or systemic steroid treatment within 1 month before 
enrollment. In case of topical steroid use, a wash-out period of 1 month is 
required. 
 History of increased intraocular pressure after using topical steroids (steroid 
responsive) 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 14 of 51 
 History of systemic immunosuppressive treatment within 1 month before 
enrollment. 
 History of any change in the frequency of topical cyclosporine or oral 
tetracycline compounds (tetracycline, doxycycline, and minocycline) within 1 
month before enrollment. 
 Any condition (including language barrier) that precludes subject’s ability to 
comply with study requirements including completion of study. 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 15 of 51 
 
5. STUDY DRUG(S)/DEVICE(S)  
 
5.1 Study Drug/Device Information 
The participants will receive either Lotemax or Soothe Tired Eye Drop. 
 
Lotemax 
Lotemax (loteprednol etabonate) 0.5% is a prescription-only, preserved ophthalmic 
suspension supplied by Bausch & Lomb, Inc. Lotemax (loteprednol etabonate) 0.5% 
has been approved by the FDA for treatment of ocular inflammation with a maximum 
dosing frequency of 24 drops per eye per day. It is a C-20 ester-based corticosteroid, 
with a potent anti-inflammatory efficacy, but decreased impact on intraocular 
pressure (IOP) compared to other corticosteroids, which may increase IOP.  The 
medication will be applied topically to both eyes for 6 weeks with the following 
regimen: four times a day for 2 weeks, twice daily for 2 weeks, and once daily for 2 
weeks. 
 
Soothe Tired Eyes Lubricant Eye Drop 
Soothe Tired Eyes Lubricant Eye Drop (Bausch & Lomb Inc.) is a preserved artificial 
tear whichis used to relieve the dryness of the eye and to prevent further irritation. 
Its active ingredient is glycerin 1%. The artificial tear will be applied topically to both 
eyes for 6 weeks with the following regimen: four times a day for 2 weeks, twice daily 
for 2 weeks, and once daily for 2 weeks. 
  
In the case of increased intraocular pressure due to Lotemax, the medication will be 
tapered rapidly and stopped within 1 week. In addition, for cases where subjects 
withdraw from the study, the medication will be tapered and stopped within 1 week. 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 16 of 51 
5.2 Study Drug/Device Compliance/Adherence  
Directed questioning using the (Ocular Tolerability and Compliance Questionnaire – 
Appendix I) will be administerd by the investigator or research staff. Results on the 
participants’ compliance and adherence to the study protocol and study drug will be 
recorded on the paper case report form (CRF) at the second and third visits (2 and 6 
weeks after enrollment). 
 
Subjects will not be withdrawn for lack of compliance with the study drug regimen.  
 
During the study, all concomitant medication treatment regimens, ocular hygiene 
treatments (i.e., lid scrubs and warm compresses), or insertion of punctal plugs will 
be kept constant as permitted by accepted medical practice. If one of the 
aforementioned treatment regimens needs to be modified, the participant may be 
withdrawn based on the investigator’s discretion. 
 
Additionally, if there is an administration of a prohibited medication (including any 
other steroid) or procedure (any ocular surgery), the participant may be withdrawn 
based on the investigator’s discretion. 
 
Participants must be compliant with IVCM imaging on at least 2 of their 3 visits or 
they will be withdrawn. Subjects who are withdrawn may be replaced by new enrolled 
subjects to maintain the sample size in each group. 
 
5.3 Study Drug Supplies 
Both Lotemax and Soothe Tired Eyes Lubricant Eye Drop are commercially available 
from Bausch & Lomb Inc as eye drops. 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 17 of 51 
 Preparing and Dispensing 
To mask the identity of the medication, the Massachusetts Eye and Ear 
Pharmacy will prepare, label and distribute both Lotemax and Soothe Tired Eyes 
Lubricant Eye Drop to the study participants. 
 
 Administration 
Regardless of study drug assignment, each participant will self-administer one 
drop of the study medication to both eyes with the following regimen: 4 times a 
day for 2 weeks, 2 times a day for 2 weeks, and once daily for 2 weeks. The 
participants are being advised not to allow the dropper tip to touch any 
surface, as this may contaminate the medication.  
 
Participants will be instructed on how to instill an eye drop at the baseline visit 
and will be asked to demonstrate application of an eye drop in front of 
research personnel to confirm that the appropriate technique is being used.  
 
5.4 Study Drug/Device Storage and Accountability 
The subjects will be instructed to store the medication at room temperature (15-25ºC 
/ 59-77ºF) and to shake it vigorously before using it. If a subject contracts infectious 
conjunctivitis, they will be instructed to discard the remainder of the study drug. The 
subject will be scheduled for a clinic visit where an investigator will assess the 
severity of the infectious conjunctivitis as well as the subject’s eligibility. If the 
investigator determines that the subject is still eligible, a new study drug will be sent 
from the host site pharmacy, Massachusetts Eye and Ear Infirmary, and given to the 
subject during their visit. 
 
The participants will not be asked to return the unused drug following the completion 
of the study. Additionally, subjects who are withdrawn from the study will be asked 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 18 of 51 
to discard the rest of their unused study drug. Therefore, the study drug will not be 
accounted for following dispensing and will not be destroyed by the MEEI pharmacy.  
 
5.5 Other Medications 
 Administration 
The use of any concurrent, prescription, or over-the-counter medication, is to 
be recorded along with the reason the medication was taken. During the study, 
all concomitant medication treatment regimens, ocular hygiene treatments (i.e., 
lid scrubs and warm compresses), or insertion of punctal plugs will be kept as 
constant as permitted by accepted medical practice. 
 
Using artificial tears (preserved and non-preserved) are permissible at the 
screening visits and during the study. However, concomitant use of artificial 
tears will be monitored. At each study visit, subjects will be queried about the 
average number of times they used artificial tears each day during the past 
week and the number of days during the past week when they did not use any 
artificial tears. 
 
Systemic and topical ophthalmic medications, that the subjects are already 
taking as part of their current treatment for dry eye disease will be maintained, 
without a change in frequency.  
 
When necessary, treatment and administration of any other therapy, besides 
their current and study’s regimen, will be done as the safety of the study 
participant is the primary consideration. The administration of a prohibited 
medication or procedure will be considered a protocol violation and the subject 
may be discontinued from the study. Prohibited medications include other 
ophthalmic steroids. Prohibited procedures include any ocular surgery. 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 19 of 51 
 Rescue Medication or Therapy 
When necessary, administration of any other therapy besides the study 
medication and their current medications will occur for the safety of the 
subject, which is the primary concern. If treatment with artificial tears is 
inadequate, or if the subject develops a severe form of ocular surface disease 
and dry eye, the subject may be unmasked by the investigator. To ensure the 
subject’s safety and proper treatment, unmasking of the study treatment 
assignment will allow the investigator to institute appropriate follow-up care. 
The subject will be kept in the study so that we can do an “intention to treat” 
analysis. 
 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 20 of 51 
 
6. BIOSPECIMEN COLLECTION (IF APPLICABLE) 
 
 
6.1 Specimen preparation, handling, and shipping: N/A 
 
6.2 Instruction for specimen preparation, handling and storage: N/A 
 
6.3 Specimen shipment: N/A 
 
6.4 Future use of stored specimens: N/A 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 21 of 51 
 
7. STUDY PROCEDURES 
 
7.1 Screening Procedures 
Prospective participants, as defined by the inclusion/exclusion criteria, will be 
considered for entry into this study. Concurrent enrollment of subjects who are 
participants in other studies will be allowed based on the investigator’s discretion. 
 
During the consent process, study design and treatment regimen will be discussed 
with each subject. Written informed consent will be obtained before any study 
specific procedures are performed. However, standard of care clinical information 
(such as: medical history, TBUT, staining, and Schirmer’s test) obtained during a 
subject’s clinical visit within the previous 48 hours can be used during the screening 
visit to determine eligibility and as their baseline assessments. Additionally, standard 
of care IVCM images taken within a week of, or during, the subject’s screening visit 
may be used to determine eligibility and as a baseline assessment.  
The following evaluations and procedures will be performed for all subjects during 
the screening and baseline period: 
• 
Written informed consent  
• 
Record of current ocular and systemic medications  
• 
Record of significant medical/surgical history in the past 5 years  
• 
Record of demographic data, including date of birth, sex, and race/ethnicity 
• 
Tear Break-up Time (TBUT) 
• 
Eye examination (best corrected visual acuity, slit lamp biomicroscopy, 
applanation tonometry, funduscopy) 
• 
Corneal fluorescein staining  
• 
Conjunctival lissamine green staining 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 22 of 51 
• 
Schirmer’s test with anesthesia 
• 
Central corneal in vivo confocal microscopy (IVCM) 
 
Researchers will document type and frequency of artificial tear, ocular ointment, and 
other dry eye therapies use by the subject. 
 
Subjects will start the study medication the first day after their screening visit, while 
continuing the use of their current medications. 
 
Tear Break-Up Time (TBUT): The standard TBUT measurement will be performed by 
dropping of a fluorescein drop to the inferior tarsal conjunctiva. After several blinks, 
the tear film will be examined using a broad beam of the slit lamp with a blue filter. 
The time lapse between the last blink and the appearance of the first randomly 
distributed dark discontinuity in the fluorescein stained tear film will be measured 
three times and the mean value of the measurements will be calculated. The tear 
break-up time will be evaluated prior to the instillation of any eye drops and before 
the eyelids are manipulated in any way. Break-up times less than 10 seconds are 
considered abnormal. A positive change from baseline indicates improvement. 
 
Corneal Fluorescein Staining (Appendix IV): Corneal fluorescein staining will be 
performed after 3 minutes of application of a fluorescein drop. The entire cornea will 
be then examined using slit-lamp evaluation with cobalt blue illumination. Staining 
will be graded using the NEI grading scheme, with a total range of 0-15.  
 
 
 
      
 
Schirmer’s Test with Anesthesia: The Schirmer’s test will be performed 3 minutes 
after a drop of topical anesthesia with 0.5% proparacaine (Alcon Inc., Ft Worth TX) is 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 23 of 51 
applied to the eye. The Schirmer test is performed by placing a narrow filter-paper 
strip (5 x 35 mm strip of Whatman #41 filter paper) in the inferior cul-de-sac. This 
test is to be conducted in a dimly lit room. The subject should gently close their eyes 
until five minutes have elapsed and the strips are removed. Since the tear front will 
continue advancing a few millimeters after it has been removed from the eyes, it is 
important to mark the tear front with a ball-point pen at precisely five minutes. 
Aqueous tear production will be measured by the length in millimeters that the strip 
wets during 5 minutes. 
 
Conjunctival Lissamine Green Staining (Appendix IV): Grading of conjunctival 
lissamine green staining will be performed after 2 minutes of application of a 
lissamine green drop. The nasal and temporal conjunctiva will be examined using slit-
lamp evaluation with white light. Staining will be graded using the NEI grading 
scheme, with a total range of 0-18.  
 
In Vivo Confocal Microscopy (IVCM):  
In vivo confocal microscopy (IVCM) is a new imaging method which allows 
visualization of the corneal structures at the cellular level. With a magnification of 
800 times, it makes it possible to detect and quantify changes in the epithelial layers 
and sub-basal nerve plexus. With this technology, size and reflectivity of superficial 
epithelial cells, as well as the number of immune dendritic cells (DC) can be readily 
evaluated.    
This is a contact imaging procedure and therefore a drop of topical anesthesia will be 
used for both eyes. A topical gel is applied to the imaging cap as well as the subject’s 
eye to provide a coupling medium between these two surfaces. Three to four 
locations in the central part of the cornea will be imaged at the depth of the 
superficial epithelium and sub-basal layer which is 50 to 80 microns deep. A sequence 
of 100 images will be obtained. 
  
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 24 of 51 
7.2 Enrollment/Baseline Procedures 
The baseline visit may occur immediately after the screening assessments.  Following 
the baseline assessments, subjects will be randomized into a treatment group. If an 
individual is deemed eligible to participate, the following baseline procedures will be 
performed: 
 
 Symptom Assessment iN Dry Eye (SANDE) questionnaire: 
SANDE Questionnaire (Appendix III): The Symptom Assessment in Dry Eye 
(SANDE) questionnaire utilizes a 100-mm horizontal visual analog scale (a 100-
mm line) to quantify subject symptoms of ocular dryness and/or irritation. In 
the SANDE symptom questionnaire-I, subjects will be asked to put a mark on 
two given lines to depict the extent of their dry eye symptoms separately in 
terms of frequency and severity. At the screening visit and all follow-up visits, 
the SANDE symptom questionnaire-I will be administered. At each follow-up 
visit, the SANDE symptom questionnaire-II will be also administered. To 
indicate whether there are any differences in symptoms from the previous visit, 
subjects will compare the frequency and severity of their current level of 
symptoms with the level at their previous visit by placing a mark to the left of 
central anchor (if less than previous visit) or to the right of central anchor (if 
more than the previous visit), according to how much of a change they perceive. 
The location of the mark made by the subject for each question of the SANDE-I 
will be measured in mm from the left-hand side of the 100 mm line, and the 
number will be recorded in mm. For the second version of the questionnaire 
SANDE-II, the distance between the mark made by the subject and the central 
anchor will be measured and it will be recorded as a negative value if to the left 
of the central anchor and as a positive value if placed to the right of the central 
anchor. Then a global score will be calculated by multiplying the frequency 
score by the severity score and taking the square root of the result to transform 
back to the original centesimal scale. 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 25 of 51 
 
 Ocular Surface Disease Index (OSDI) questionnaire: 
OSDI Questionnaire (Appendix II): 12-item questionnaire designed to provide a 
rapid assessment of the symptoms of ocular irritation consistent with dry eye 
disease and their impact on vision-related functioning. The 12 items of the 
OSDI questionnaire are graded on a scale of 0 to 4, where 0 indicates none of 
the time; 1, some of the time; 2, half of the time; 3, most of the time; and 4, all 
of the time. The total OSDI score is then calculated on the basis of the following 
formula: OSDI=[(sum of scores for all questions answered) x 100]/[(total 
number of questions answered) x 4]. 
 
7.3 Study Drug or Device Procedures 
At visits 1 and 3, the following procedures will be done for study specific purposes in 
addition to standard of care procedures: 
 Schirmer’s Test with anesthesia (may be standard of care) 
 Ocular Surface Disease Index questionnaire 
 Symptom Assessment iN Dry Eye questionnaire 
 Central Cornea In Vivo Confocal Microscopy (may be standard of care) 
 Corneal fluorescein staining 
 
At visit 2, the following procedures will be done for study specific purposes: 
 Eye examination (best corrected visual acuity, bio-microscopy, applanation 
tonometry, funduscopy) 
 Tear Break-up Time 
 Corneal fluorescein staining 
 Conjunctival lissamine green staining 
 Schirmer’s Test with anesthesia 
 Ocular Surface Disease Index questionnaire 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 26 of 51 
 Symptom Assessment in Dry Eye (SANDE) questionnaire 
 Central Cornea In Vivo Confocal Microscopy  
 
 
7.4 Standard of Care Procedures 
The following procedures are the standard of care: 
 Eye examination (best corrected visual acuity, bio-microscopy, applanation 
tonometry, funduscopy) 
 Tear Break-up Time 
 Corneal fluorescein staining 
 Conjunctival lissamine green staining 
 Schirmer’s Test with anesthesia (may be study specific) 
 Central Cornea In Vivo Confocal Microscopy (may be study specific) 
 
7.5 Follow-up Procedures  
After enrollment, the subjects will be scheduled for a second visit (Week 2 ± 3 days) 
and a third visit (Week 6 ± 1 week). 
 
The following procedures will be performed at all follow-up visits: 
 Eye examination (best corrected visual acuity, bio-microscopy, applanation 
tonometry, funduscopy) 
 Tear Break-up Time 
 Corneal fluorescein staining 
 Conjunctival lissamine green staining 
 Schirmer’s Test with anesthesia 
 Ocular Surface Disease Index questionnaire 
 Symptom Assessment in Dry Eye (SANDE) questionnaire 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 27 of 51 
 Central Cornea In Vivo Confocal Microscopy  
 
7.6 Unscheduled Visits 
If the subject reports to the Cornea Department for a visit that is not related to the 
study, only a review of adverse assessments will be required per the study.  
 
7.7 Early Termination 
If a subject withdraws or is withdrawn from the study prior to completion of all study 
visits, there will be no additional procedures performed  
7.8 Schedule of Activities (Study Table) 
Table1- Schedule of events and procedures 
Visit # 
1 
 
2 
3 
Visit Description  
Screening  
Baseline 
Day 1 
Week 2  
(± 3 days) 
Week 6  (± 
1 week) 
Obtain Informed 
Consent  
 
X 
 
START OF STUDY MEDICATION 
 
 
Inclusion/ exclusion 
criteria  
 
X 
 
 
 
Medical and 
Ophthalmic History  
X 
 
X 
X 
Medication History 
X 
 
 
 
BCVA  
 
X 
 
X 
X 
OSDI 
 
X 
X 
X 
SANDE 
 
X 
X 
X 
TBUT 
X 
 
X 
X 
Biomicroscopy 
 
X 
 
X 
X 
Corneal staining 
X 
 
X 
X 
Schirmer with 
anesthesia 
X 
 
X 
X 
Conjunctival staining 
X 
 
X 
X 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 28 of 51 
 Intraocular Pressure  
X 
 
X 
X 
Funduscopy  
X 
 
X 
X 
In vivo confocal 
microscopy 
X 
 
X 
X 
Concommitant 
medications 
 
 
X 
X 
Compliance and 
adverse events check 
X 
X 
X 
X 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 29 of 51 
 
8. SAFETY AND EFFECTIVENESS ASSESSMENTS 
 
8.1 Safety Assessments 
The primary safety variable monitored will be the occurrence of adverse events. The 
severity of each adverse event observed will be evaluated as serious or not serious 
and the occurrence will be evaluated as expected or unexpected. The relationship of 
the event to the study medication will be assessed by the investigator as possibly, 
probably, or definitely related. Safety variables will be evaluated at all study visits. If 
adverse events occur, the first concern will be the safety of the study participants. 
Any serious adverse event occurring during the study period will be immediately 
reported to MEEI IRB. At each visit throughout the study, the investigator will begin 
querying for adverse events by asking each subject a general, non-directed question 
such as “How have you been feeling since the last visit?” or “How have your eyes been 
since the last visit?” 
The investigator will ask questions to subjects at each visit to determine if they have 
had any changes to the use of concomitant medications since the previous visit.  A 
comprehensive eye examination including best-corrected visual acuity, measuring 
intraocular pressure, evaluation of the condition of conjunctiva, cornea, anterior 
chamber, iris/pupil, lens, vitreous, macula and optic nerve will be performed. Any 
changes in the study eyes from the screening visit will be recorded. If a subject 
contracts infectious conjunctivitis, they will be instructed to discard the remainder of 
the study drug and new drug will be sent from the host site pharmacy, Massachusetts 
Eye and Ear Infirmary. 
If treatment with artificial tears is inadequate, or the subject develops severe form of 
ocular surface disease and dry eye, for the safety and proper treatment of the subject, 
the investigator can unmask the subject's treatment assignment to determine which 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 30 of 51 
treatment has been assigned and institute appropriate follow-up care. However, the 
subject will be kept in the study so we can do the “intent-to-treat” analysis.  
Withdrawal from the study will happen if any of the following occurs: 
 Investigator determination that it is not in the best interest of the subject to  
continue participation.          
 Subject’s wish to withdraw for any reason. 
After being withdrawn, subjects will be followed according to each case until the 
adverse event is resolved. 
 
8.2 Effectiveness Assessments 
Comparison of the efficacy of the taper Lotemax versus artificial tear will be 
evaluated using both clinical and IVCM parameters which include the followings: 
Ocular Signs 
 Corneal epitheliopathy (corneal fluorescein staining using the NEI grading 
scheme). (Appendix IV)  
 Conjunctival epitheliopathy (conjunctival lissamine green staining using 
NEI grading scheme). (Appendix IV) 
 Tear Film Break Up Time (TBUT) 
 Schirmer’s Test with Anesthesia 
 
Ocular Symptoms 
 Ocular Surface Disease Index (OSDI) questionnaire. (Appendix II) 
 Symptom Assessment iN Dry Eye (SANDE) questionnaire. (Appendix III) 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 31 of 51 
In Vivo Confocal Microscopy 
 Superficial corneal epithelial cells: Density, size, and hypereflectivity  
 Corneal subbasal immune dendritiform cells: Density, size, and cell field 
 Corneal subbasal nerves: Number and length of the total, main nerves 
and the branches    
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 32 of 51 
 
9. ADVERSE EVENT RECORDING AND REPORTING 
 
9.1 Recording Requirements 
Research subjects will be routinely questioned about adverse events at study visits. 
All observed or volunteered adverse events (serious or non-serious) and abnormal test 
findings, regardless of study group or suspected causal relationship to the study 
drug(s) or device(s) will be recorded in the subjects’ case histories (source data, case 
report form).  For all adverse events, sufficient information will be pursued and/or 
obtained so as to permit 1) an adequate determination of the outcome of the event 
(i.e., whether the event should be classified as a serious adverse event) and; 2)  an 
assessment of the causal relationship between the adverse event and the study 
drug(s) or device(s).    
Adverse events or abnormal test findings thought to be associated with the study 
drug(s) or device(s) will be followed until the event (or its sequel) or the abnormal test 
finding resolves or stabilizes at a level acceptable to the Investigator. 
An abnormal test finding will be classified as an adverse event if one or more of the 
following criteria are met: 
o The test finding is accompanied by clinical symptoms 
o The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional 
concomitant drug treatment or other therapy  
o The test finding leads to a change in study drug dosing or 
discontinuation of subject participation in the clinical research study 
o The test finding is considered an adverse event by the Investigator. 
Note: simply repeating a test finding, in the absence of any of the 
other listed criteria, does not constitute an adverse event.   

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 33 of 51 
 
The Investigator will promptly review documented adverse events and abnormal test 
findings to determine 1) if the abnormal test finding should be classified as an 
adverse event; 2) if there is a reasonable possibility that the adverse event was caused 
by the study drug(s); and 3) if the adverse event meets the criteria for a serious 
adverse event. 
If the Investigator’s final determination of causality is “unknown and of questionable 
relationship to the study drug(s)”, the adverse event will be classified as associated 
with the use of the study drug(s) for reporting purposes.  If the Investigator’s final 
determination of causality is “unknown but not related to the study drug(s)”, this 
determination and the rationale for the determination will be documented in the 
respective subject’s case history (source data or case report form).  
9.2 REPORTING PROCEDURES 
 REPORTING OF ADVERSE EVENTS TO FDA 
 If an investigator determines that a serious adverse event (SAE) is related to 
one of the study medications the SAE will be reported to the FDA. 
  Reporting Adverse Events to Other External Entities 
The sponsor (GSK) does not require reports on adverse events. Therefore no 
reports on adverse events will be submitted to external entities. 
Reporting Adverse Events to the Human Studies Committee 
MEEI HSC policy for “REPORTING ADVERSE EVENTS AND UNANTICIPATED PROBLEMS” 
will be followed. 
 
9.3 Withdrawal of Subjects due to Adverse Events 
Withdrawal from the study will happen if any of the following occurs: 
 Investigator determines that is not in the best interest of the subject to 
continue participation. 
 Subject’s wish to withdraw for any reason. 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 34 of 51 
After being withdrawn, subjects will be followed according to each case until the 
adverse event is resolved. 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 35 of 51 
 
10. STATISTICAL METHODS/DATA ANALYSIS 
10.1 Primary endpoint(s) or outcome measure(s) 
In Vivo Confocal Microscopy 
 Superficial corneal epithelial cells: Density, size, and hypereflectivity  
 Corneal subbasal immune dendritiform cells: Density, size, and cell field 
 Corneal subbasal nerves: Number and length of the main nerves and the 
branches    
 
10.2 Secondary endpoints or outcome measure(s) 
Ocular Signs 
 Corneal epitheliopathy (corneal fluorescein staining using the NEI grading 
scheme). (Appendix IV)  
 Conjunctival epitheliopathy (conjunctival lissamine green staining using 
NEI grading scheme). (Appendix IV) 
 Tear Break Up Time (TBUT) 
 Schirmer’s Test with Anesthesia 
 Intraocular pressure (IOP) by measure of applanation tonometry 
 
Ocular Symptoms 
 Ocular Surface Disease Index (OSDI) questionnaire. (Appendix II) 
 Symptom Assessment iN Dry Eye (SANDE) questionnaire. (Appendix III) 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 36 of 51 
10.3 Sample Size Determination 
To calculate sample size, density of sub-basal dendritic cells in the central cornea was 
used as an outcome measure. Based on a previous published paper (Villani et al, 
Innate Immunity. 2013;19(4) 420–427), a difference of 52 cell/mm2 with a standard 
deviation of 44 were used to calculate the sample size with the following formula:1-3 
 
 
With α = 0.05 (Zα = 1.96), d = 52, and p = 44, a sample size of 22 was calculated for 
each group (44 for both groups). To compensate for potential loss to follow-up, a 
total of 50 subjects will be enrolled in this study. 
 
1) Daniel WW. Biostatistics: a foundation for analysis in the health sciences 7th ed. New York, NY: Wiley, 
1999; 180-185, 268– 270. 
2) Snedecor GW, Cochran WG. Statistical methods 8th ed. Ames, Iowa: Iowa State University Press, 1989; 
52, 439. 
3) Eng G. Sample size estimation: how many individuals should be studied? Radiology. 2003; 227:309-13. 
 
10.4 Analysis Population  
N/A 
 
10.5 Effectiveness Analysis  
For efficacy variables and any other variables except for safety, all subjects will be 
analyzed with the treatment to which they were randomized (the intent-to-treat 
population). Subjects that are not compliant with the study medication or study 
procedures may or may not be withdrawn according to the investigators discretion. 
Subjects that are noncompliant, but remain active in the study, will be followed so 
that an intent-to-treat analysis can be conducted. For safety variables, subjects will be 
analyzed with the treatment actually received (the safety population). 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 37 of 51 
The primary analysis for the proposed study will be based on a standard intention-to-
treat analysis with each study participant analyzed with respect to the randomized 
treatment assignment, regardless of eventual compliance. A secondary analysis may 
include imputation of missing data for select variables. A per-protocol analysis, 
disqualifying subjects or subject visits, might also be done, but is not planned 
because observational analyses of actual treatment use could introduce bias if the 
pattern of use is in some way related to the outcome.  
Despite the randomized nature of the treatment assignments, in this relatively small 
sample of study subjects there may be imbalances with regard to potential 
confounding variables. Thus, as an initial step in the analysis, we will compare those 
assigned to Lotemax versus those randomized to the artificial tear with regard to 
demographic characteristics and potential confounding variables, using the non-
parametric Wilcoxon rank sum test for continuous or ordinal variables, and chi-
square or Fisher’s exact tests for categorical variables.  
The changes in primary end-points within each group during the course of treatment 
will be analyzed using Analysis of Variance (ANOVA) with post hoc analysis of 
Bonferroni correction. The values between the Lotemax and artificial tear groups will 
be compared with non-parametric Wilcoxon rank sum test. P values of 0.05 or less 
will be considered as statistically significant.    
 
10.6 Safety Analysis 
The primary safety variable monitored will be the occurrence of adverse events. The 
severity of each adverse event observed will be evaluated as serious or not serious as 
defined by the MEEI HSC and the occurrence will be evaluated as expected or 
unexpected. The relationship of the event to the study medication will be assessed by 
the investigator as possibly, probably, or definitely related. Safety variables will be 
evaluated at screening and at all study visits. If adverse events occur, the first concern 
will be the safety of the study participants. Any serious adverse event occurring 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 38 of 51 
during the study period will be immediately reported to MEEI IRB.  Directed 
questioning (Ocular Tolerability and Compliance Questionnaire – Appendix I) and 
examination will then be done to assess tolerability.  These questions are used to 
assess common and expected symptoms related to instillation or use of the study eye 
drops. Subjects will be asked to rate their symptoms from trace to severe.  
Additional steps taken to assess safety will be followed as outlined in section 8.1 of 
this SUPP M form.  
 
 
10.7 Interim Analysis  
N/A 
 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 39 of 51 
 
11. DATA AND SAFETY MONITORING  
 
11.1 Data and Safety Monitoring Plan  
The PI, research fellows, research coordinators, and technicians involved with this 
protocol will be required to read the protocol, participate in a group meeting to 
discuss roles before the protocol is approved, and participate in weekly clinical 
research meetings. The pharmacy and the clinical fellows on the protocol will be 
required to read the protocol and separate meetings will be created to discuss roles 
as they relate to the protocol. 
A copy of the approved protocol and study related materials will be placed on a 
shared network drive accessible to authorized research staff involved in this study 
and on IRBnet.org. 
The primary safety variable monitored will be the occurrence of adverse events. The 
severity of each adverse event observed will be evaluated as outlined in section 10.6 
by the treating investigator. The PI will be made aware of all AEs within one week. The 
number of AEs related to increased pressure will be monitored and collated 
throughout the course of the study. Should the investigator need to be un-masked to 
treatment assignment to determine if there is a relationship with one of the study 
medications, treatment information will be provided by the MEEI Pharmacy.  
The ocular surface exam and IVCM imaging will only be performed by a research 
technician, fellow, or investigator to ensure adherence to the required tests and 
accurate assessments.  
The study coordinator will be responsible for monitoring each visit to ensure that the 
procedures are performed as outlined in the protocol and documented appropriately. 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 40 of 51 
The images acquired will be checked for accuracy by the research fellows after 
acquisition and also during image analysis to ensure that the nasal conjunctiva has 
been imaged appropriately as laid out in the IRB-approved protocol. 
Raw data collected for this study will be entered into a master database by the study 
coordinator, research technician, or fellow and uploaded for access to the principal 
investigator and all authorized research staff members on the U-Drive of password-
protected computers located in the Cornea Research Department.  
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 41 of 51 
 
12. DATA HANDLING, RECORD-KEEPING AND MONITORING 
 
12.1 Data Recording, Record-Keeping and Monitoring  
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical 
study.  The Investigator will review, approve and sign/date each completed CRF; the 
Investigator’s signature serving as attestation of the responsibility for ensuring that 
all clinical data entered on the CRF are complete, accurate and authentic.   
The LMR will be considered Source Data and will contain the clinical findings and 
observations, and other information collected during the visit. Subject consents will 
be maintained within the Department of Ophthalmology Clinical Research Office. 
Drug dispensing and randomization logs will be maintained within the Clinical 
Pharmacy, Massachusetts Eye and Ear Pharmacy. 
All data will be stored on in the U-drive located on encrypted, password protected 
computers in the Cornea Research Department. Only the PI and researchers specific 
to this study who have been granted access to the data by the PI will be able to view 
the data in the MEEI network protected folder. When data is sent out to be analyzed 
the data will be de-identified. The data will contain subject identification numbers, 
which are linked to identifiers on a separately secured spreadsheet. The data will be 
coded by assigning each participant a subject identification number and removing 
any identifiable information. The code will be secured by the PI and Study 
Coordinator in in the U-drive located on encrypted, password protected computers in 
the Cornea Research Department. The code that links information that can identify 
the participant to the data collected for this research will be kept separate from their 
health information, which will be destroyed once this study is complete and the 
manuscript has been published. 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 42 of 51 
 
13. STUDY DISCONTINUATION CRITERIA 
 
13.1 Discontinuation of Individual Research Subjects 
Please see sections 9.3. 
 
13.2 Sponsor-Investigator Discontinuation of the Clinical Research Study 
Potential reasons for discontinuation of this study include if 50% of subjects 
experience an increase in IOP resulting in a total IOP of greater than 30. Additionally, 
if one of the study drugs is discontinued by the manufacturer and is no longer 
commercially available, the study will be discontinued. 
 
Should the clinical research study be discontinued, the MEEI HSC will be notified 
immediately.  Given the frequency of the visits, all enrolled subjects will be notified 
by phone of discontinuation of the study and ensured that discontinuation will have 
no effect on standard of care treatment. 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 43 of 51 
 
14. APPENDICES 
 
Appendix I: Ocular Tolerability and Compliance Questionnaire 
Appendix II: Ocular Surface Disease Index (OSDI) 
Appendix III: Symptom Assessment in Dry Eye (SANDE) Questionnaire I and II 
Appendix IV: Corneal Fluorescein Staining and Conjunctival Lissamine Green 
Staining 
 
14.1 Schedule of Events  
See Section 7.8 
 
14.2 Case Report Form(s) 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 44 of 51 
Appendix I: Ocular Tolerability and Compliance Questionnaire 
After you instill the study medication, how intensely have you experienced the following 
symptoms in each eye? 
Itching 
   Right Eye:     
None 
Trace 
Mild 
Moderate 
Severe 
 
     Left Eye: 
None      Trace      Mild       Moderate      Severe 
 
Burning Sensation 
   Right Eye:       
None 
Trace 
Mild 
Moderate 
Severe 
 
     Left Eye: 
None      Trace      Mild       Moderate      Severe 
 
Foreign Body Sensation 
   Right Eye:       
None 
Trace 
Mild 
Moderate 
Severe 
 
     Left Eye: 
None      Trace      Mild       Moderate      Severe 
 
Discharge 
   Right Eye:       
None 
Trace 
Mild 
Moderate 
Severe 
 
     Left Eye: 
None      Trace      Mild       Moderate      Severe 
 
Redness 
   Right Eye:       
None 
Trace 
Mild 
Moderate 
Severe 
 
     Left Eye: 
None      Trace      Mild       Moderate      Severe 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 45 of 51 
Appendix I: Ocular Tolerability and Compliance Questionnaire (Continued) 
Have you experienced any other symptoms after instillation of the study drug? 
YES  
NO 
 
If yes, which one(s)__________________________________________________ 
__________________________________________________________________ 
 
In the past week, approximately how many times per day have you used the following? 
  
Artificial Tears 
______ 
 
Warm Compresses 
______ 
 
 
Study Medications    
______ 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 46 of 51 
Appendix II: Ocular Surface Disease Index (OSDI) 
Have you experienced any of the following during the last week: 
 
 
 
 
 
 
Have problems with your eyes limited you in performing any of the following during the last week: 
 
 
 
 
 
 
Have your eyes felt uncomfortable in any of the following situations during the last week: 
 
 
 
 
 
             Total score for answers 1 to 12:    ____         
 
Total number of questions answered:    ____ 
 
(Do not include questions answered N/A)  
 
                                                                               

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 47 of 51 
 OSDI = (sum of scores) x 25/(# of questions answered):     ____ 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 48 of 51 
Appendix III: Symptom Assessment in Dry Eye (SANDE) Questionnaire-I 
 
Please complete the following questions regarding the frequency and severity of your dry eye 
symptoms. 
 
 
1. Frequency of symptoms:  
 
Please place an ‘X’ on the line to indicate how often, on average, your eyes feels dry and/or 
irritated:  
 
_______________________________________________ 
Rarely                                                            All of the Time 
 
 
 
2. Severity of symptoms:  
 
Please place an ‘X’ on the line to indicate how severe, on average, your eyes feel dry and/or 
irritated:  
 
_______________________________________________ 
 
Very Mild                                                       Very Severe 
 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 49 of 51 
Appendix III: Symptom Assessment in Dry Eye (SANDE) Questionnaire-II 
 
 
 
Please complete the following questions regarding the frequency and severity of your dry eye 
symptoms.  
 
 
 
1. Frequency of symptoms:  
 
Please place an ‘X’ on the line to indicate how often, on average, your eyes feels dry and/or irritated 
now compared to your last visit:  
 
 
_______________________________________________ 
Much Less Frequent                          Much More Frequent 
 
Last Visit 
 
 
 
2. Severity of symptoms:  
 
Please place an ‘X’ on the line to indicate how severe, on average, your eyes feels dry and/or irritated 
now compared to your last visit:  
 
 
_______________________________________________ 
Much Less Severe                              Much More Severe 
 
Last Visit 
 
                                                                        

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 50 of 51 
Appendix IV: Corneal Fluorescein Staining and Conjunctival Lissamine 
Green Staining 
Fluorescein instillation: 
Fluorescein strip wetted with buffered saline. Drop instilled on inferior 
palpebral conjunctiva. The participant is asked to blink several times. 
Staining:  
5 corneal regions and 6 conjunctival regions (shown below) will be graded with 
a staining scale of 0-3. The “total scores” of the cornea as well as of the 
conjunctiva will be measured. 
 
 
 
 
 

MEEI and Tufts Medical Center    
 
 
 
VERSION 2.0: 01/13/2017 
 
Page 51 of 51 
Appendix V: Study Medical Calendar