Safety and Efficacy of Dexamethasone Ophthalmic Insert (Dextenza®) in the Management of Clinically Significant Dry Eye
Phase: PHASE4
Conditions: Dry Eye
Sponsor: Johns Hopkins University

Safety and Efficacy of Dexamethasone Ophthalmic Insert (Dextenza®) in the Management of 
Clinically Significant Dry Eye 
NCT04498468 
Date: September 21, 2020 

Safety and Efficacy of Dextenza in Dry Eye (V3) 
 
 
Clinical Study Protocol 
 
 
Safety and Efficacy of Dexamethasone Ophthalmic Insert (Dextenza®) in the 
Management of Clinically Significant Dry Eye 
 
 
 
Compound: 
Sustained Release Dexamethasone, 0.4 
mg. 
 
 
Study Name: 
Safety and Efficacy of Dexamethasone 
Ophthalmic Insert (Dextenza®) in the 
Management of Clinically Significant Dry 
Eye. 
 
 
 
Clinical Phase: 
Phase IV, prospective, masked trial. 
 
 
Date of Issue: 
September 21, 2020 
 
 
Principal Investigator: 
Esen K. Akpek, MD. 
 
 
 
 
Sub Investigators: 
Sezen Karakus, MD. 
Lee Guo, OD. 
 
Site Name & Location: 
Ocular Surface Diseases and Dry Eye 
Clinic, The Wilmer Eye Institute, The 
Johns Hopkins University School Of 
Medicine, Baltimore, Maryland. 
 
 
 

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CLINICAL STUDY PROTOCOL SYNOPSIS 
TITLE 
Safety and Efficacy of Dexamethasone Ophthalmic Insert 
(Dextenza®) in the Management of Clinically Significant 
Dry Eye. 
 
SITE LOCATION(S) 
 
Ocular Surface Diseases and Dry Eye Clinic, The Wilmer 
Eye Institute, The Johns Hopkins University School Of 
Medicine, Baltimore, Maryland. 
 
PRINCIPAL 
INVESTIGATOR 
Esen K. Akpek, MD.  
OBJECTIVE(S) 
To determine efficacy and safety profile of 
dexamethasone 0.4mg lacrimal insert in dry eye related 
ocular surface inflammation. 
STUDY DESIGN 
Prospective, double-masked, interventional clinical trial. 
STUDY DURATION 
42 Days per patient, There will be 5 visits (run in, Day 1, 
14, 28, and 42) with 12 months of active enrollment.  
 
Start-up period (finalizing the protocol and case report 
forms, obtaining approvals from institutional review board, 
etc): 3 months. 
Enrollment period: 12 months. 
Close-out (data completion and lock, statistical analyses, 
and multiple manuscript preparations etc): 3 months.  
Interim data analysis at 6 months. 
 
Total of 18 months 
 
ESTIMATED STUDY 
COMPLETION DATE 
December 31, 2021 
POPULATION 
Adult patients with significant dry eye or 
keratoconjunctivitis sicca, requiring topical steroid 
treatment. 
Sample Size: 
85 patients [1 treatment eye/1 control eye = 170 eyes] will 
be enrolled at a single site. 
Treatment(s) 
 

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Study Drug 
 
 
DOSE/ROUTE/SCHEDULE: 
Sustained release dexamethasone, 0.4 mg  
 
Each patient’s right eye will be randomized to receive either 
the treatment or the control. The left eye will automatically 
receive the alternative. For example if the right eye of the 
patient gets randomized to receive the study medication, 
left eye will automatically be the control eye. If the right 
eye gets randomized to receive the control treatment, the 
left eye will receive the study medication.   
 
Control eye will receive a sham treatment: commercially 
available tear duct plug without the dexamethasone 
(Vera90TM EXTENDED WEAR SYNTHETIC 
ABSORBABLE PUNCTAL PLUG made of E-
Caprolactone-L-Lactide copolymer (PCL). Absorbs in 60 
to 180 days. Size 0.5mm which is comparable to the study 
treatment)  
 
RESCUE MEDICINE:  
In patients with worsening of signs or symptoms, topical 
loteprednol 0.5% (Lotemax) drops up to 4 times a day, 
mimicking the usual practice, can be used at the discretion 
of the principle investigator.  
 
In patients with increased intraocular pressure (more than 
5 points greater than baseline or more than 5 points higher 
than the fellow eye) treatment with topical beta 
blocker/betaxolol 0.5% (Betoptic) drops can be used 2 
times a day to bring down the pressure at the discretion of 
the principle investigator.  
 
Endpoint(s) 
 

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PRIMARY EFFICACY: 
Efficacy will be measured at 28 days.)  
 
We have two co-primary end points: 
1- Dry eye Sign: Corneal staining score measured 
using OSS scale on Day 28. The difference 
between the average corneal staining in the treated 
arm versus the average corneal staining in the 
sham arm will be compared statistically. 
 
2- Patient reported symptom: Most bothersome 
symptom (any one of the (1)eye dryness, (2)eye 
discomfort, or (3)eye fatigue will be established as 
the most bothersome symptom at baseline for each 
eye) measured using visual analogue scale (0 to 
100). The difference between the average most 
bothersome symptom in the treated arm versus the 
average most bothersome symptom in the sham 
arm will be compared statistically.  
 
 
Secondary Efficacy: 
  
 
We have two secondary end points: 
1- Corneal staining responder analysis. Responder is 
defined as one full severity grade improvement in 
corneal staining. The percentage of subjects 
achieving 1 severity grade improvement in corneal 
staining (responders) in the treated arm versus 
sham arm will be compared statistically. 
2- Symptom responder analysis. Responder is defined 
as 30% improvement in the most bothersome 
symptom. The percentage of subjects achieving a 
30% improvement in their most bothersome 
symptom (responders) in the treated arm versus the 
sham arm will be compared statistically.  
 
Safety:  
Safety Endpoint(s): Safety measures will be performed at 
42 days. IOP measurement using applanation tonometry, 
cataract formation or worsening of cataract, other local 
adverse events (AEs) such as redness, pain, stinging, etc 
will be recorded.   
 
 
 
 

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TABLE OF CONTENTS 
Clinical Study Protocol Synopsis ..................................................................................... 2 
List of Tables ..................................................................................................................... 6 
1. 
Introduction and Rationale ...................................................................................... 7 
1.1 
Introduction ............................................................................................................. 7 
1.2 
Rationale ................................................................................................................. 7 
1.2.1 
Rationale for Study Design ............................................................................. 8 
2. 
Study Objectives ........................................................................................................ 9 
2.1 
Primary Objective ................................................................................................... 9 
2.2 
Secondary Objectives .............................................................................................. 9 
3. 
Study Design .............................................................................................................. 9 
3.1 
Study Description and Duration .............................................................................. 9 
4. 
Selection, Withdrawal, and Replacement of Patients .......................................... 10 
4.1 
Study Population ................................................................................................... 10 
4.1.1 
Inclusion Criteria .......................................................................................... 10 
4.1.2 
Exclusion Criteria ......................................................................................... 10 
4.2 
Treatment Logistics and Accountability ............................................................... 11 
4.2.1 
Packaging, Labeling, and Storage ................................................................. 11 
4.2.2 
Supply and Disposition of Treatments .......................................................... 11 
4.2.3 
Treatment Accountability ............................................................................. 11 
4.3 
Concomitant Medications and Procedures ............................................................ 12 
4.4 
Potential Risks ...................................................................................................... 12 
5. 
Study Schedule of Events and Visit Descriptions ................................................. 12 
5.1 
Schedule of Events ................................................................................................ 12 
5.1.1 
Study Procedures .......................................................................................... 16 
5.1.2 
Unscheduled Visits ....................................................................................... 18 
5.1.3 
Adverse Event Information Collection ......................................................... 18 
5.2 
Safety and Rescue Criteria. ................................................................................... 18 
5.2.1 
Adverse Event ............................................................................................... 18 
5.2.2 
Serious Adverse Event .................................................................................. 19 
5.3 
Recording and Reporting Adverse Events ............................................................ 19 
6. 
Study Variables ....................................................................................................... 19 
6.1 
Demographic and Baseline Characteristics .......................................................... 19 

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6.2 
Primary and Secondary Endpoints ........................................................................ 20 
6.3 
Primary Objective ................................................................................................. 20 
6.4 
Secondary Objectives ............................................................................................ 20 
7. 
Ethical and Regulatory Considerations ................................................................ 20 
7.1 
Good Clinical Practice Statement ......................................................................... 20 
7.2 
Informed Consent .................................................................................................. 20 
7.3 
Patient Confidentiality and Data Protection ......................................................... 21 
7.4 
Institutional Review Board ................................................................................... 21 
 
LIST OF TABLES 
Table 1 
Schedule of Events ........................................................................................ 13 
  
 

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1. 
INTRODUCTION AND RATIONALE 
1.1 
Introduction 
Dry eye is a common public health problem with an estimated 25 million Americans 
affected by this condition (1). It is a chronic, possibly progressive inflammatory condition 
that leads to symptoms of ocular discomfort as well as blurred vision (2). Regardless of 
the underlying etiology, dry eye has been shown to be associated with abnormalities in 
the pre-corneal tear film and subsequent inflammatory changes in the entire ocular 
surface including the adnexa, conjunctiva and cornea (3). Since the recognition of the 
role of inflammation in dry eye, a number of anti-inflammatory treatments have been 
investigated designed to inhibit various inflammatory pathways. Previously loteprednol 
etabonate 0.5% and dexamethasone 0.1% drops have been shown to improve ocular 
surface inflammation and benefit patients with dry eye (4-7).  
 
1.2 
Rationale 
Previous studies showed that dexamethasone and loteprednol topical drops have led to 
favorable results (4-7). However, the requirement of frequent instillation of drops by the 
patients is problematic causing discomfort and blurring of vision and requires 
remembering and dexterity for instillation, poor compliance is not uncommon (7). In 
addition we believe that instillation of drops disturbs the homeostasis of the natural tear 
film due to physical and chemical trauma due to large drop volume (50 microliters) 
hammering on the eye surface (which can only hold 7 to 10 microliters). Particularly 
washing away of the mucin layer that holds all the “good ingredients” in the tears is 
harmful to the ocular surface. Therefore, “dropless” treatment of dry eye is desirable.  
 
Dextenza® (dexamethasone ophthalmic insert, Ocular Therapeutix Inc., Bedford, MA) is 
a corticosteroid intracanalicular insert approved by US-FDA in November 2018 for the 
treatment of post-surgical ocular inflammation and pain. It is inserted into the lower 
lacrimal punctum and into the canaliculus. A single insert releases a 0.4 mg dose of 
dexamethasone for up to 30 days following insertion. Dextenza® is resorbable and does 
not require removal. We hypothesize that Dextenza® could mimic short-term topical 
steroid use in a tapering manner in patients with clinically significant dry eye and show 
efficacy in improving its symptoms and signs, as was previously shown with other steroid 
preparations. If proven, the use of Dextenza® may shift paradigms in the management of 
the clinically significant ocular surface disease. To test this hypothesis, we propose to 
study the effects of Dextenza® in the treatment of clinically significant dry eye. This 
proposal has several strengths over a non-masked protocol: 
 
1- We have identified a tear duct plug with a comparable size (size 0.5mm) that lasts 
60-180 days (Vera90TM). This would serve as an excellent comparison to 
Dextenza and allow the study to be a double-masked design. Both devices are not 
visible at the slit-lamp once inserted.  
2- The investigator enrolling the patient (inserting the study treatment versus the 
control treatment) will be different than the examining investigator for each 
patient to allow the study to be truly double masked.  
3- Because each patient will have one Dextenza eye and one control eye, the efficacy 
and safety of the treatment will be fairly, effectively, and accurately assessed. The 

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“patient” related factors in this small scale study (such as difference in use of 
computers or sleep/wake hours, environmental factors such as humidity during 
this short-term study, or severity of ocular surface inflammation particularly 
whether underlying Sjögren’s syndrome is present or not, as well as the severity 
of evaporative component of the dry eye) will be comparable between the 
treatment and the control. 
4- Also, this design allows both eyes of the same patients enrolled as study eyes 
thereby decreasing the sample size, hence the cost.  
 
1.2.1 
Rationale for Study Design 
We determined the sample size using STATA Statistical Software (STATA Release 12.1; 
STATA Corp., College Station, TX).  Standard deviations from previously published data 
sets were used for calculations (8).   
 
Efficacy  There will be two primary efficacy measures performed at day 28. The 
improvement in corneal staining score (using the OSS scale) and improvement in the 
most bothersome symptom (using the VAS scale between 0 to 100). 
Efficacy Endpoint 1: Improvement in the corneal staining score measured using OSS scoring system (0-
6). With a power of 80% and significance level of 0.05, 23 persons in each group (having both eyes 
eligible) need to be enrolled to detect a clinically significant 3 point difference in the mean corneal staining 
between the treated arm versus the sham arm at day 28.  
 
Efficacy Endpoint 2: Improvement in most bothersome dry eye symptom as measured 
using VAS (0 to 100). With  power of 80% and significance level of 0.05, 85 persons in 
each group (having both eyes eligible) need to be enrolled to detect a clinically 
meaningful 30 point difference in the most bothersome dry eye symptom Assuming that 
there will be a clinically significant 30% difference in the mean most bothersome 
symptom between the treated arm versus the sham arm at day 28. 
 
One problematic issue in the field of dry eye is the lack of widely agreed upon core 
outcomes (9). It is currently not well known for example whether improving corneal 
staining is clinically meaningful and how much improvement would be necessary to 
make a difference in what the patient is experiencing. Our previous investigator initiated 
studies demonstrated that corneal fluorescein staining directly relates to impairment of 
visual function, and reduction in reading speed (10). The relationship is linear and for 
each 1 severity grade increase in corneal staining (0-6), we found an average of two 
words per minute reduction in reading speed, using iRest out loud testing and 10 words 
per minute reduction in reading speed using the sustained silent reading test. Therefore, 
perhaps corneal staining can be used as a clinically meaningful core outcome.  
 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
To determine the safety and efficacy of dexamethasone insert at Day 28 and Day 42 
respectively, as measured by – 

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• Improvement in the corneal fluorescein staining in the treatment arm versus the 
sham arm 
• Improvement in most bothersome dry eye symptoms ((1) eye dryness, or (2) eye 
fatigue, or (3) eye discomfort) as measured using VAS (0 to 100) in the treatment 
arm versus sham arm 
• We also will determine efficacy of the treatment by determining the responder 
rate in the treatment versus sham arm.  
•  
• 1- 
One full severity grade improvement in corneal staining. The percentage 
of subjects achieving 1 severity grade improvement in corneal staining 
(responders) in the treated arm versus sham arm will be compared statistically  
2- 
 30% improvement in the most bothersome symptom (responders). The 
percentage of subjects achieving a 30% improvement in their most bothersome symptom 
in the treated arm versus the sham arm will be compared statistically. 
 
2.2 
Secondary Objectives 
To determine the safety of dexamethasone insert through Day 42, as measured by – 
• Intraocular pressure monitoring  
• Cataract formation or worsening of existing cataract as determined by slit-lamp 
examination and best spectacle corrected visual acuity.  
• Other adverse events (unsolicited, but volunteered by the subjects) 
 
3. 
STUDY DESIGN 
3.1 
Study Description and Duration 
This prospective, double-masked, randomized, sham-controlled, single-center, phase IV 
investigator-sponsored clinical study seeks to investigate the safety and efficacy of 
dexamethasone 0.4 mg lacrimal insert over a 42 day period.  
 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS 
4.1 
Study Population 
The study aims to enroll 85 Patients (170 eyes) with dry eye syndrome (DES) or 
keratoconjunctivitis sicca (KCS), requiring topical steroid treatment.  
 
4.1.1 
Inclusion Criteria 
A patient’s study eye must meet the following criteria to be eligible for inclusion in the 
study: 
 
1) Male or Female Age 18-100 
2) Capacity to give informed consent 
3) Ability to follow study direction and complete all study visits 
4) A previous or current diagnosis of dry eye by an eye care specialist, whereas treatment 
is requiring the use of a topical steroid 
5) Able to have a lacrimal plug placement into both lower puncta. If lower puncta are 
already plugged or cauterized/sealed, upper puncta will be used  

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6) Females of childbearing potential unwilling to use reliable form(s) of birth control 
throughout study period 
7) Clinical diagnosis of dry eye syndrome (DES) or keratoconjunctivitis sicca (KCS), in 
which the following has been bilaterally documented in the ophthalmic and medical 
histories:  
 
i. history/diagnosis of dry eye 
 
ii. has taken or is on prescription drops (including but not limited to topical 
steroids, cyclosporine or lifitegrast) 
8) Presence of all of the following in both eyes at Baseline (Day 1):  
 
i. Total OSS of 3 or more with at least 2+ corneal staining (0-6) 
 
ii. Unaesthetized Schirmer level of <10 mm at 5 minutes 
 
iii. Presence of significant symptoms defined as 30mm or higher score of (1) eye 
dryness, or (2) eye fatigue, or (3) eye discomfort as measured using VAS, in both eyes. 
At the baseline visit, the most bothersome symptom (of the three) will be determined and 
used as the main symptom outcome measure throughout the study.  
 
 
4.1.2 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
1) Use of Contact lenses within 1 week of screening visit or during the study  
2) Any ocular surgery (including tear duct cauterization) within the 3 months 
3) Inability to place a lacrimal device into upper or lower puncta of both eyes (if upper 
in R eye should be upper in the left eye and vice versa) 
4) Inability to participate in the wash out period 
5) Use of topical glaucoma medications (With exception of rescue medication) 
6) Pregnancy, nursing or intention of pregnancy or nursing in the study period.  
7) Monocular patients 
8) Uncontrolled systemic disease (defined as frequent or recent change in the medication 
regimen) 
9) Patients who are currently on with stable doses of oral steroids, topical cyclosporine 
or lifitigrast, topical tacrolimus or pimecrolimus are eligible as long as there has been 
no change in the dose in the last 3 months 
10) Patients who are on topical steroids (with the exception of rescue medication)  
Patients who have used steroids recently but have been off for at least 2 weeks will be 
eligible. 
11) Current enrollment in any other investigational drug or device study or participation 
of study within 30 days of baseline visit.  
12) Known allergy or sensitivity to any of the clinical or experimental drugs used in this 
study including history of steroid response.  
 
4.2 
Treatment Logistics and Accountability 
4.2.1 Packaging, Labeling, and Storage 
Intracanalicular dexamethasone insert must be stored in a secure area accessible only to 
the Investigator and their designee(s) and refrigerated and stored between 2! "C and 8#"C. 
Intracanalicular dexamethasone insert contains 0.4 mg dexamethasone and is designed to 
provide a sustained and tapered release of therapeutic levels of dexamethasone to the 

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ocular surface for up to 30 days. Dexamethasone is an anti-inflammatory 9-fluoro-
glucocorticoid (also termed a glucocorticoid agonist) and is the active ingredient found in 
MAXIDEX® 0.1% (dexamethasone ophthalmic suspension), which contains 
approximately 50 μg of dexamethasone per drop.  
Study inserts will be supplied in an unmasked fashion by Ocular Therapeutix in a sealed 
foil pouch containing one intracanalicular dexamethasone insert in a foam carrier. 
Study inserts will be shipped to the site via overnight shipping using cold packs to 
maintain a temperature of 2° to 8° C. The Investigator, or an approved representative 
(e.g. pharmacist), will ensure that all study drug inserts are stored in a secured area, under 
recommended storage conditions and in accordance with applicable regulatory 
requirements. The shipping box is to be opened and stored immediately at the site in a 
refrigerator intended for investigational products at a temperature of 2° to 8°C.  
 
When the insert is removed from the refrigerator, it should be visually inspected. 
Exposure of the insert to temperatures outside these limits it not recommended. Records 
of actual storage conditions (i.e. temperature log) at the study site must be maintained; 
and must include a record of the dates, when the refrigerator was checked, the initials of 
person checking, and the temperature. 
 
4.2.2 Supply and Disposition of Treatments 
Study insert will be shipped at a temperature of 2° to 8°C to the investigator by sponsor 
as needed during the study.  
 
4.2.3 Treatment Accountability 
All study insert accountability records will be kept current. 
 
The investigator will account for all opened and unopened packaging of study inserts.  
These records will contain the dates, quantity, and study medication 
• Inserted in each patient, 
• disposed of at the site or returned to Ocular Therapeutix 
All accountability records will be made available for inspection by regulatory agency 
inspectors. 
 
4.3 
Concomitant Medications and Procedures 
At the discretion of their physician, patients may continue to receive all medications and 
standard treatments administered for other conditions. 
 
4.4 
Potential Risks of Study  
Steroids are known to increase eye pressure, which might be a finding of glaucoma, which 
is a vision threatening disease if not treated appropriately and promptly. In order to detect 
this, eye pressure will be checked at every visit as explained in sections: Schedule of Events 
(5.1), Study procedures (5.1.1), and rescue medications (5.2).  
 

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Additionally, steroids may mask signs of and enhance or and exacerbate the severity of 
ocular bacterial, viral, and fungal infections. The use of ocular steroids may slow the rate 
of ocular healing.  
 
 
5. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
5.1 
Schedule of Events 
Study assessments and procedures are presented by visit in Table 1  
 
 

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Table 1 
Schedule of Events 
Procedure 
Run In*  
(Day -14 to 
-7) 
Visit 
1*  
(Day 1) 
Visit 2  
(Day 
14) 
Visit 3  
(Day 
28) 
Visit 4  
(Day 
42) 
Early 
Termination 
Informed Consent 
X 
X** 
 
 
 
 
Inclusion/Exclusion/Demographics 
X 
X** 
 
 
 
 
Medical history and concurrent illnesses 
X 
X** 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Pregnancy Test 
 
X 
 
 
X 
X 
Log/Dispense Rescue Meds 
X 
X 
X 
X 
X 
 
Insert Study Drug/Control 
 
X 
 
 
 
 
BSCVA 
 
X 
 
 
X 
X 
VAS 
X 
X 
 
X 
X 
X 
Schirmer (W/O anesthesia) 
X 
X 
 
 
X 
X 
OSS (corneal and conjunctival) 
X 
X 
X 
X 
X 
X 
IOP 
X 
X 
X 
X 
X 
X 
SLE 
X 
X 
X 
X 
X 
X 
Dilated Fundus Exam 
X 
X** 
 
 
X 
X 
Rescue med recording 
X 
 
X 
X 
X 
X 
AE recording 
 
X 
X 
X 
X 
X 
*If no run-in required, patient will start at baseline visit/ Day 1 
**Required in absence of run-in visit 
 
After having obtained an informed consent patients will be assigned a unique patient 
number and undergo the below procedures in the order they are listed.  
 
1. Medical History and Review of Systems 
i. 
Contact lens and glasses wearing (contact lens wear has to be 
discontinued 1 week prior and for the duration of the study) 
ii. 
Current eye drops used: 
a. Patients who are on dry eye drops, such as artificial 
tears, cyclosporine, or lifitigrast treatment will be 
eligible as long as the doses have been stable for at least 
3 months 
b.Patients who are on steroid drops will be placed in a 14 
day wash-out period, in both eyes, before they can be 
eligible. If in the discretion of the principle investigator, 
discontinuation of the topical treatment could pose any 
harm to the patient’s ocular health, the patient will be 
excluded. 
c. Patients who are on anti-histamines, oral (doxycycline 
or azithromycin) or topical antibiotics (bacitracin or 
erythromycin ointment) are eligible for as long as the 
doses have been stable in the past 2 weeks 

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d.Patients who are on oral steroids or other anti-
inflammatory or immunomodulatory medications are 
eligible for as long as the doses have been stable in the 
past 3 months 
e. Patients using glaucoma drops in either eye will be 
excluded (with the exception of rescue medication)  
 
iii.Current systemic medications (see above) 
iv.History of eye diseases and previous eye or eyelid surgery 
a. Patients who had eye surgery in the past 3 months prior 
to study are ineligible 
b.Patients who had penetrating corneal transplantation are 
not eligible 
c. Patients who had endothelial corneal transplantation are 
eligible as long as the surgery was 3 months or longer 
ago 
 
v.History of other inflammatory or autoimmune medical disease 
(GVHD, RA, SLE, etc), in particular presence of SS (primary 
or secondary), and related symptoms.  
a. These patients are eligible as long as they do not have 
cicatrizing conjunctivitis (such as SJS, MMP, etc) 
 
2. Informed consent  
Informed consent will be given to the patient to review at the time of 
approach in the clinical setting, or sent to the patients home if identified 
via chart review. The patient will be given ample time review the consent 
form, and will return on the day of the study visit with any questions. All 
questions will be answered and a discussion will be had with the person 
obtaining consent prior to the consent form being signed.  
 
3. Pregnancy test 
A standard urine pregnancy test provided by Ocular Therapeutix will be 
performed on women of childbearing potential at Baseline and Exit visit. 
A positive test will exclude patient from enrollment into the study as well 
as will be considered a serious adverse event if occurred during the study 
period.  
 
4. Dry eye symptoms as measured using Visual Analog Scale (VAS). 
 
Patients will complete VAS questionnaires for each eye in regard to 
eye dryness, eye discomfort, and eye fatigue. The most bothersome 
symptoms will be determined (of the three symptoms) at baseline and 
used throughout the study as the main symptom.  
 

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Patients will be given the questionnaire and expected to complete on 
their own. Help may be given to patients who have difficulty reading 
or understanding of the definition of the questions which will 
accompany the three questions. 
 
The patient marks on the line the point that they feel represents their 
perception of their current state at each visit. 
 
The VAS score is determined by measuring in millimeters using a 
ruler from the left hand end of the line (0) to the point that the patient 
marks, to a maximum 100. 
 
 
5. Visual acuity (VA) 
Distance visual acuity will be measured under monocular conditions using 
the subjects’ habitual correction for distance (if wearing). The Snellen 
Chart will be used. If less than 20/20, pt will have Best Spectacle 
Corrected Visual Acuity (BSCVA) measured via Manifest Refraction.  
 
6. Schirmer’s test without anesthesia.  
This test involves placing a small piece of filter paper against the 
conjunctiva for 5 minutes to observe how much tear volume is being 
produced in the temporal part of the lower cul-de-sac. The filter paper is 
removed after 5 minutes, and the length of the paper wetted is measured to 
approximate tear production. The testing will be performed as minimally 
disturbing to the ocular surface as possible. Time will be recorded if 
Schirmer’s are completely saturated prior to the 5 minutes. 
 
7. Ocular surface staining (OSS). 
i. 
Corneal fluorescein staining: About 2.5 minutes after 
instillation of the fluorescein eye drops (one drop of saline 
placed on the commercially available fluorescein strips) the 
staining will be scored according to the criteria published by 
SICCA (11). 
ii. 
Conjunctival lissamine green staining: Within 1 minute after 
instillation of lissamine green eye drops (one drop of saline 
placed on the commercially available strips) the staining will 
be scored. Conjunctival staining will be measured based on 
SICCA criteria (11). 
 
8. Dilated Fundus Examination (DFE) 
1 drop of Tropicamide 1% and Phenylepherine 2.5% will be used in each 
eye for purpose of dilation. Macula, blood vessels and cup to disk ratio 
will be recorded.  
 
9. Insertion of study drug.  

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Treatment eye will be randomized by a Randomization list made by the 
Biostat Center at Johns Hopkins School of Medicine (using REDcap 
database) contralateral eye of each patient will serve as the control  
 
The Treatment Physician will place the study device and contralateral plug/sham 
treatment at Day 1. The Treatment or the Examining physician can do the baseline 
exam.   
 
The Examining Physician will perform the study exams (Day 1 through 42) to 
preserve masking.  
 
10. Unmasking procedures (Day 42 or for serious AE)  
 
All tests require both eyes testing and will be performed in the right eyes first, then the 
left eyes.  
 
 
5.1.1 Study Procedures 
Patients will be instructed not to instill any eye drops one hour prior to any study visit.  
 
 
 
SCREENING VISIT/RUN IN (Day -14 to -7) – Either Examining or Treating 
physician will perform. 
 
The following information will be collected: 
• Informed Consent 
• Inclusion/exclusion 
• Demographics 
• Medical history and concurrent illnesses 
• Concomitant medications 
• Log/Dispense Rescue medications  
• Ocular Surface Disease Index Questionnaire (OSDI) 
• Schirmer test without anesthesia 
• OSS (Corneal and conjunctival)  
• Intraocular Pressure (IOP) 
• Slit Lamp Examination (SLE) 
• Dilated Fundus Exam (DFE) 
• Rescue Med Recording  
 
BASELINE VISIT (Day 1)- Treating Physician (Unmasked) 
 
If run-in Visit was NOT performed: 
• Informed Consent  
• Inclusion/Exclusion 
• Demographics  

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• Medical History and concurrent illnesses 
• Dilated Fundus Exam (DFE)  
 
Needed for all Baseline Day 1: 
 
• Concomitant medications 
• Urine Pregnancy Test 
• Log/Dispense Rescue Meds 
• Insert Study Drug/Control 
• Best Corrected Spectacle Visual Acuity (BSCVA) 
• VAS 
• Schirmer without anesthesia  
• OSS 
• IOP 
• SLE 
• AE recording  
 
VISIT 2 (14+/-3 days) – Examining Physician (Masked) 
 
• Concomitant medications 
• Log/Dispense Rescue Meds 
• OSS 
• IOP 
• SLE 
• Rescue med recording 
• AE recording  
 
VISIT 3 (28+/-3 days) – Examining physician (Masked) 
 
• Concomitant medications 
• Log/Dispense Rescue Meds 
• VAS 
• OSS 
• IOP 
• SLE 
• Rescue med recording 
• AE recording  
  
VISIT 4 (42+/-3 days) – Examining Physician  
• Concomitant Medications 
• Log/Dispense Rescue Meds 
• Pregnancy Test 
• BSCVA 
• VAS 

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• Schirmer W/O anesthesia 
• OSS 
• IOP 
• SLE 
• Dilated Fundus Exam  
• Rescue med recording 
• AE recording  
 
5.1.2 Unscheduled Visits 
All attempts should be made to keep patients on the study schedule.  Unscheduled visits 
may be necessary to repeat testing following abnormal laboratory results or clinical 
findings (high IOP), for follow-up of AEs, or for any other reason, as warranted. 
 
5.1.3 Adverse Event Information Collection 
The investigator (or designee) will record all AEs that occur during the study.  
The definition of an AE and SAE, and information on the determination of severity and 
relationship to treatment are provided in Section 7. 
 
5.2 
Safety and Rescue Criteria.  
In the opinion of investigator, if the patient is at harm due to the treatment such as high eye 
IOP or due to control such as worsening of dry eye parameters, rescue medications can be 
used. To start IOP lowering medication, the IOP should be about 5 points higher than 
baseline. For additional dry eye medications/treatments the corneal staining should worsen 
a full severity grade. 
 
5.2.1 Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study 
drug/treatment which may or may not have a causal relationship with the study drug.  
Therefore, an AE is any unfavorable and unintended sign (including abnormal laboratory 
finding), symptom, or disease which is temporally associated with the use of a study 
drug, whether or not considered related to the study drug.   
 
An AE also includes any worsening (i.e. any clinically significant change in frequency 
and/or intensity) of a pre-existing condition that is temporally associated with the use of 
the study drug. 
All AEs in this study are Physician documented signs or results or exam findings. Local 
instillation discomfort, burning, stinging, blurred vision, redness etc will not be 
necessarily queried but documented in response to “how are you feeling” or how are your 
eyes feeling” questions.  
 
5.2.2 Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (e.g. a car accident in which a patient is a passenger). 

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• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event.  This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  In-
patient hospitalization is defined as admission to a hospital or an emergency room for 
longer than 24 hours.  Prolongation of existing hospitalization is defined as a hospital 
stay that is longer than was originally anticipated for the event, or is prolonged due to 
the development of a new AE as determined by the investigator or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event – Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent 1 of the other serious outcomes listed above (e.g., 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development 
of drug dependency or drug abuse).  Any malignancy (other than basal cell skin 
cancers) would be considered a medically important event. 
Serious AEs will be queried by asking “has anything changed in your medical or ocular 
history since the last visit”.  
 
5.3 
Recording and Reporting Adverse Events 
All AEs and SAEs will be recorded. 
 
All SAEs, regardless of assessment of causal relationship to study insert will be reported 
to Ocular Therapeutix. 
To report an SAE, Ocular Therapeutix will be contacted at the following: 
ocutx.pharmacovigilance@propharmagroup.com 
SAE hotline: 844-668-3948 
 
The investigator will promptly report to the IRB all unanticipated problems involving 
risks to patients.  This includes death from any cause and all SAEs related to the use of 
the study insert.  All SAEs will be reported to the IRB, regardless of assessed causality. 
 
6. 
STUDY VARIABLES 
6.1 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (e.g. age, race, etc.), disease 
characteristics including medical history, and medication history for each patient. 
 
6.2 
Primary and Secondary Endpoints 
6.3 
Primary Objective(s) 
To determine the efficacy of dexamethasone insert through Day 28, as measured by – 
• Improvement in corneal staining score in the treatment versus sham arm 
• Improvement in worst/most bothersome symptom in the treatment versus control 
group   
 

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In addition 
• % of patients with improvement of corneal staining score by one severity grade 
(clinically meaningful) in treatment versus control group 
• % of patients with improvement of worst/most bothersome symptom by 30 points 
(clinically meaningful) in the treatment versus control group 
 
6.4 
Secondary Objectives 
To determine the safety of dexamethasone insert through Day 42, as measured by – 
• Improvement in Schirmer test without anesthesia 
• Improvement of conjunctival lissamine green staining score  
• Intraocular pressure monitoring  
• Cataract Formation  
• Adverse Events 
 
7. 
ETHICAL AND REGULATORY CONSIDERATIONS 
7.1 
Good Clinical Practice Statement 
It is the responsibility of the investigator(s) to ensure that this clinical study will be 
conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki, and that are consistent with the ICH guidelines for Good Clinical 
Practice (GCP) and applicable regulatory requirements. 
 
7.2 
Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. Standard 
Johns Hopkins Hospital template must be used.  
 
It is the responsibility of the investigator or designee (if acceptable by local regulations) 
to obtain written informed consent from each patient prior to his/her participation in the 
study and after the aims, methods, objectives, and potential hazards of the study have 
been explained to the patient in language that he/she can understand.  The informed 
consent form (ICF) will be signed and dated by the patient and by the investigator or 
authorized designee who reviewed the ICF with the patient.   
 
Patients who can write but cannot read will have the ICF read to them before signing and 
dating the ICF. 
Patients who can understand but who can neither write nor read will have the ICF read to 
them in presence of an impartial witness, who will sign and date the ICF to confirm that 
informed consent was given. 
 
The original ICF will be retained by the investigator as part of the patient’s study record, 
and a copy of the signed ICF will be given to the patient. 
 
If new safety information results in significant changes in the risk/benefit assessment, the 
ICF will be reviewed and updated appropriately.  All study patients will be informed of 
the new information and provide their written consent if they wish to continue in the 
study.  The original signed revised ICF will be maintained in the patient’s study record 
and a copy will be given to the patient. 

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7.3 
Patient Confidentiality and Data Protection 
The investigator will take all appropriate measures to ensure that the anonymity of each 
study patient will be maintained.   
 
The patient’s and investigator’s personal data will be treated in compliance with all 
applicable laws and regulations.   
 
7.4 
Institutional Review Board  
An appropriately constituted IRB, as described in ICH Guidelines for GCP, will review 
and approve:  
• The protocol, ICF, and any other materials to be provided to the patients 
(e.g. advertising) before any patient may be enrolled in the study  
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patients, in 
which case the IRB will be informed as soon as possible  
 
Ongoing studies will be reviewed by the IRB/EC on an annual basis or at intervals 
appropriate to the degree of risk.  
 
In addition, the IRB will be informed of any event likely to affect the safety of patients or 
the continued conduct of the clinical study. 
 
A copy of the IRB approval letter will be sent to Ocular Therapeutix prior to shipment of 
drug insert supplies to the investigator.  The approval letter will include the study title, 
the documents reviewed, and the date of the review. 
 
Records of the IRB review and approval of all study documents (including approval of 
ongoing studies) will be kept on file by the investigator. 
 
 
 
 

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REFERENCES 
 
1. 
Uchino, Miki, and Debra A. Schaumberg. “Dry Eye Disease: Impact on 
Quality of Life and Vision.” Current Ophthalmology Reports, vol. 1, no. 2, 
2013, pp. 51–57. 
2. 
Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson 
JD, Nichols JJ, Tsubota K, Stapleton F. TFOS DEWS II Definition and 
Classification Report. Ocul Surf 2017;15:276-283. 
3. 
Hessen M, Akpek EK. Dry eye: an inflammatory ocular disease. J Ophthalmic 
Vis Res 2014;9:240-50. 
4. 
Pflugfelder SC, Maskin SL, Anderson B, Chodosh J, Holland EJ, De Paiva 
CS, Bartels SP, Micuda T, Proskin HM, Vogel R. A randomized, double-
masked, placebo-controlled, multicenter comparison of loteprednol etabonate 
ophthalmic suspension, 0.5%, and placebo for treatment of 
keratoconjunctivitis sicca in patients with delayed tear clearance. Am J 
Ophthalmol 2004;138:444-57. 
5. 
Moore QL, De Paiva CS, Pflugfelder SC. Effects of Dry Eye Therapies on 
Environmentally Induced Ocular Surface Disease. Am J Ophthalmol 
2015;160:135-42. 
6. 
Sheppard, John D. M.D.; Donnenfeld, Eric D. M.D.; Holland, Edward J. 
M.D.; Slonim, Charles B. M.D.; Solomon, Renee M.D.; Solomon, Kerry D. 
M.D.; McDonald, Marguerite B. M.D.; Perry, Henry D. M.D.; Lane, Stephen 
S. M.D.; Pflugfelder, Stephen C. M.D.; Samudre, Sandeep S. Ph.D., M.P.H. 
Effect of Loteprednol Etabonate 0.5% on Initiation of Dry Eye Treatment 
With Topical Cyclosporine 0.05% Eye & Contact Lens: Science & Clinical 
Practice. Issue: Volume 40(5), September 2014, p 289-296 
7. 
 Terry G. Coursey 1, Johanna Tukler Henriksson 1, Daniela C. Marcano, 
Crystal S. Shin, Lucas C. Isenhart, Faheem Ahmed, Cintia S. De Paiva, 
Stephen C. Pflugfelder, Ghanashyam Acharya. Dexamethasone nanowafer as 
an effective therapy for dry eye disease. Journal of Controlled Release 213 
(2015) 168–174 
8. 
 Mathews PM, Karakus S, Agrawal D, Hindman HB, Ramulu PY, Akpek EK. 
Tear Osmolarity and Correlation With Ocular Surface Parameters in Patients 
With Dry Eye. Cornea. 2017 Nov;36(11):1352-1357 
9. 
Saldanha IJ, Le JT, Solomon SD, Repka MX, Akpek EK, Li T. 
Ophthalmology Outcomes Working Groups. Choosing Core Outcomes for 
Use in Clinical Trials in Ophthalmology: Perspectives from Three 
Ophthalmology Outcomes Working Groups. Ophthalmology. 2019;126:6-9 
10. 
Karakus S, Matthews PM, Agrawal D, Henrich C, Ramulu PY, Akpek EK; 
Optom Vis Sci. 2018 Dec;95(12):1105-1113. 
11. 
Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplified quantitative 
method for assessing keratoconjunctivitis sicca from the Sjögren's Syndrome 
International Registry. Sjögren's International Collaborative Clinical Alliance 
Research Groups. Am J Ophthalmol 2010;149:405-15. 
 

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APPENDICES 
 
Appendix 1 
 
Ocular Surface Staining: 
 
 
 
 
 

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Appendix 2: VAS Scales  
 
! "#$%#&$’ #( ) *+( $, --&--( &. *$
$
 Eye Dryness  
This questionnaire is in regards to your current eye dryness. Please remember to 
evaluate each eye separately. 
Please rate your level of “eye dryness” by placing a vertical mark on the horizontal line 
on the below scale to indicate the level of dryness.  
Please think of the feelings of dryness or “stickiness or the need for use of artificial 
tears BUT NOT sandiness/grittiness, sensitivity to light, redness, or itching.  
Zero corresponds to “no dryness” and 100 correspond to “maximal dryness.”  
 
 
 
 
RIGHT EYE: 
 
 
 
LEFT EYE:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eye Dryness 
Eye Dryness 

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Eye Discomfort  
This questionnaire is in regards to your current eye discomfort. Please remember to 
evaluate each eye separately. 
Please rate your level of “eye discomfort” by placing a vertical mark on the horizontal 
line on the below scale to indicate the level of discomfort.  
Please think of pain, stinging, burning, sandiness/grittiness, sensitivity to light, itching, 
irritation or feeling that something is in the eye.  
Zero corresponds to “no discomfort” and 100 correspond to “maximal discomfort.”  
 
 

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Eye Fatigue  
This questionnaire is in regards to your current eye fatigue. Please remember to 
evaluate each eye separately. 
Please rate your level of “eye fatigue” by placing a vertical mark on the horizontal line 
on the below scale to indicate the level of fatigue.  
Please think of feeling of heaviness in the lids, difficulty keeping eye open, difficulty 
reading, or just wanting to rest your eyes.  
Zero corresponds to “no fatigue” and 100 correspond to “maximal fatigue.”  
 
 
 
RIGHT EYE: 
 
 
 
LEFT EYE:  
 
 

Clinical Study Protocol 
 
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Ocular Therapeutix 
 
 
 
 
 
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