Conditions: Keratoconus Dry Eye Allergy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 36
Healthy volunteers: yes

Brief summary:
Drug delivery platforms are an innovative exciting advancement in ophthalmology. They allow patients to eliminate topical medications which are generally associated with lack of compliance, difficulty of use and requiring help from family members. These delivery systems can be applied easily in office, and patients do not have to worry about drop insertion in their post-operative regimen.

The results of this research project should help to answer the following question: Does the use of a physician administered intracanalicular dexamethasone insert improve the signs and symptoms of ocular allergy and dry eye disease in KC patients compared to the use of topical loteprednol etabonate ophthalmic gel 0.38%?

Detailed description:
This prospective, open-label, single-center, randomized, fellow-eye, investigator-sponsored clinical study seeks to investigate the safety and efficacy of the dexamethasone insert in the treatment of allergic conjunctivitis and DED signs and symptoms in patients with Keratoconus using RGP contact lenses when compared to topical standard of care loteprednol etabonate ophthalmic gel 0.38%.

Patients with keratoconus who present for their routine visit who have signs and symptoms of dry eye and allergies, will be asked if they want to participate in the study. After screening a given patient for inclusion and exclusion criteria, and gaining informed consent, one eye will be randomized to receive the dexamethasone insert as determined by a coin flip at the screening visit. The remaining eye will be prescribed a loteprednol etabonate ophthalmic gel 0.38% following a 4,3,2,1 weekly taper. Per enrolled eye, the study period will last for approximately 90 days, consisting of five visits. At Screening/ Baseline, Day 0, Day 7, Day 30 and Day 90, primary and secondary endpoints will be assessed alongside standard-of-care procedures. Adjusting for enrollment period, the study will last a total of approximately 3 months

Inclusion Criteria

A patient's study eye must meet the following criteria to be eligible for inclusion in the study:

* 18 years of age or older
* Bilateral Keratoconus
* Bilateral RGP contact lenses
* Bilateral allergic conjunctivitis as determined by the Papillae Efron Scale score of at least 1 and symptoms of itching
* Bilateral underlying dry eye disease as determined by the NEI Fluorescein Staining Scale score of at least 1 and a TBUT of less than 10 and must correlate with dryness on OSDI

Exclusion Criteria

A patient who meets any of the following criteria will be excluded from the study:

* Patients under the age of 18.
* Pregnancy (must be ruled out in women of child-bearing age with pregnancy test)
* Active infectious systemic disease
* Active infectious ocular or extraocular disease
* Obstructed nasolacrimal duct in the study eye(s)
* Hypersensitivity to dexamethasone
* Patients being treated with immunomodulating agents in the study eye(s)
* Patients being treated with immunosuppressants and/or oral steroids Patients with severe disease that warrants critical attention, deemed unsafe for the study by the investigator

Study Procedures Screening/Baseline (Visit 1)

After the patient has provided informed consent, the following information will be collected:

* Inclusion/Exclusion
* Demographics
* Medical History and Concurrent Illnesses
* Concomitant Medications
* Uncorrected and best-corrected visual acuity with manifest refraction as measured by ETDRS chart at 4 meters
* Ophthalmic Examination (with or without dilation)
* QOL assessment as measured by OSDI questionnaire
* Osmolarity (Needs to be done prior to any drop instillation)
* MMP9 (Needs to be done prior to any drop instillation)
* Grading of itching (scale 0-4)
* Papillae conjunctivitis assessment (Efron Scale)
* Conjunctival Injection
* Corneal Staining
* TBUT
* Intraocular Pressure

Insertion Visit/Day 0 (Visit 2)

* Concomitant Medications
* Uncorrected and best-corrected visual acuity with manifest refraction as measured by ETDRS chart at 4 meters
* Ophthalmic Examination (with or without dilation)
* QOL assessment as measured by OSDI questionnaire
* Osmolarity (Needs to be done prior to any drop instillation)
* MMP9 (Needs to be done prior to any drop instillation)
* Grading of itching (scale 0-4)
* Papillae conjunctivitis assessment (Efron Scale)
* Conjunctival Injection
* Corneal Staining
* TBUT
* Intraocular Pressure
* Insertion of Dextenza (intracanalicular dexamethasone insert)
* Insert Visualization
* Subject reported AEs after insertion
* Physician ease of insertion grading

Day 7 (Visit 3)

* Concomitant Medications
* Uncorrected and best-corrected visual acuity with manifest refraction as measured by ETDRS chart at 4 meters
* Ophthalmic Examination (with or without dilation)
* QOL assessment as measured by OSDI questionnaire
* Osmolarity (Needs to be done prior to any drop instillation)
* MMP9 (Needs to be done prior to any drop instillation)
* Grading of itching (scale 0-4)
* Papillae conjunctivitis assessment (Efron Scale)
* Conjunctival Injection
* Corneal Staining
* TBUT
* Intraocular Pressure
* Insert Visualization
* Subject reported AEs after insertion

Day 30 (Visit 4)

* Concomitant Medications
* Uncorrected and best-corrected visual acuity with manifest refraction as measured by ETDRS chart at 4 meters
* Ophthalmic Examination (with or without dilation)
* QOL assessment as measured by OSDI questionnaire
* Osmolarity (Needs to be done prior to any drop instillation)
* MMP9 (Needs to be done prior to any drop instillation)
* Grading of itching (scale 0-4)
* Papillae conjunctivitis assessment (Efron Scale)
* Conjunctival Injection
* Corneal Staining
* TBUT
* Intraocular Pressure
* Insert Visualization
* Subject reported AEs after insertion

Day 90 (Visit 5) or Early Termination

* Concomitant Medications
* Uncorrected and best-corrected visual acuity with manifest refraction as measured by ETDRS chart at 4 meters
* Ophthalmic Examination (with or without dilation)
* QOL assessment as measured by OSDI questionnaire
* Osmolarity (Needs to be done prior to any drop instillation)
* MMP9 (Needs to be done prior to any drop instillation)
* Grading of itching (scale 0-4)
* Papillae conjunctivitis assessment (Efron Scale)
* Conjunctival Injection
* Corneal Staining
* TBUT
* Intraocular Pressure
* Insert Visualization
* Subject reported AEs after insertion
* COMTOL

Arms:
arm 1: Per participant, one eye will be randomized to receive the intracanalicular dexamethasone insert at the baseline visit (study eye). DEXTENZA is an ophthalmic insert that is inserted in the lower lacrimal punctum into the canaliculus at the day 1 visit by pulling the lower lid taught and using a forceps to insert the medication into the lower canaliculus through the lower punctum. arm 2: Per participant, one eye will be randomized to receive the standard of care topical lotemax etabonate ophthalmic gel 0.38% (control eye). Patients will be prescribed a loteprednol etabonate ophthalmic gel 0.38% and will instill one drop into the eye following a 4x/day,3x/day,2x/day,1/xday weekly taper

Interventions: intervention 1: dexamethasone ophthalmic insert 0.4 mg, for intracanalicular use intervention 2: Loteprednol Etabonate 0.38% Ophthalmic Gel/Jelly
Intervention descriptions: intervention 1: Experimental intervention 2: Active Comparator

Protocol document:
Prot_SAP_000.pdf: 
The HARTHAN Study (V1) 
February 5th, 2020 
 
Page 1 
 
CONFIDENTIAL 
 
 
 
Investigator-Initiated Trial Study Protocol 
 
 
Safety and Efficacy of an Intracanalicular Dexamethasone Insert compared 
to Topical Loteprednol Etabonate Ophthalmic gel 0.38% in Patients with 
Keratoconus (KC) wearing Rigid Gas Permeable (RGP) Contact Lenses who 
have been diagnosed with Allergic Conjunctivitis and underlying Dry Eye 
Disease (DED) 
 
The HARTHAN Study 
 
 
 
Compound: 
DEXTENZA (dexamethasone ophthalmic 
insert) 0.4 mg, for intracanalicular use  
 
 
Study Name: 
The HARTHAN STUDY  
 
 
Clinical Phase: 
Open-label, Prospective, 
Interventional 
 
 
Date of Issue: 
February 20, 2020 
 
 
Primary Investigator: 
Jennifer Harthan, OD  
JHarthan@ico.edu 
 
 
Research Coordinator: 
Elyse Nylin 
Senior Research Coordinator  
 
Site Name & Location: 
Cornea Center for Clinical 
Excellence  
Illinois College of Optometry  
Illinois Eye Institute  
312-949-7137 
 
 


The HARTHAN Study (V1) 
 
 
Page 2 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
TITLE 
Safety and Efficacy of an Intracanalicular 
Dexamethasone Insert compared to Topical 
Loteprednol Etabonate Ophthalmic gel 0.38% in 
Patients with Keratoconus (KC) wearing Rigid Gas 
Permeable (RGP) Contact Lenses who have been 
diagnosed with Allergic Conjunctivitis and 
underlying Dry Eye Disease (DED)- The 
HARTHAN Study 
SITE LOCATION(S) 
 
Cornea Center for Clinical Excellence  
Illinois College of Optometry  
Illinois Eye Institute  
312-949-7137 
PRINCIPAL 
INVESTIGATOR 
Jennifer Harthan,OD 
JHarthan@ico.edu 
OBJECTIVE(S) 
To determine if physician administered 
intracanalicular dexamethasone insert improve the 
signs and symptoms of ocular allergy and dry eye 
disease in KC patients compared to topical 
loteprednol etabonate ophthalmic gel 0.38%.  
STUDY DESIGN 
Prospective Open-label Interventional Study 
STUDY DURATION 
4 months after IRB approval   
ESTIMATED STUDY 
COMPLETION DATE 
3 months after DEXTENZA insertion 
POPULATION 
 
Sample Size: 
20 patients (40 eyes) 
Target Population: 
Patients with bilateral keratoconus, wearing RGP 
contact lenses in both eyes, who have been 
diagnosed with bilateral allergic conjunctivitis and 
underlying dry eye disease 
TREATMENT(S) 
 
Study Drug 
 
 
 
Dose/Route/Schedule: 
DEXTENZA (dexamethasone ophthalmic insert) 0.4 
mg, for intracanalicular use  
 
Patients 
with 
Keratoconus, 
with 
Allergic 
Conjunctivitis and underlying Dry Eye Disease, 
wearing RGP contact lenses will have one eye 
randomized to receive the Sustained Release 
Dexamethasone, 0.4mg intracanalicular insert 
(study eye). The fellow-eye will receive topical 
loteprednol (control eye) on a 4,3,2,1 weekly taper 
schedule.  
 
ENDPOINT(S) 
 


The HARTHAN Study (V1) 
 
 
Page 3 
 
CONFIDENTIAL 
Primary: 
 
 
 
 
 
 
 
 
 
 
 
 
 
To determine the effect of dexamethasone 
intracanalicular insert through Day 90 as 
measured by: 
• Mean change in itching score from Baseline 
measured at all visits (Visits 1-5) 
o Graded on a scale of 0-4 and 
determined by asking the patient  
• Mean change in palpebral conjunctivitis 
papillae score from Baseline measured at all 
visits (Visits 1-5) 
o Graded using the Papillae Efron Scale 
as graded by the physician  
• Mean change in conjunctival injection score 
from Baseline measured at all visits (Visits 
1-5) 
o Graded on a scale of 0-4 as graded by 
the physician 
• Mean change in corneal staining score from 
Baseline measured at all visits (Visits 1-5) 
o Graded using the NEI Fluorescein 
Staining Scale as graded by the 
physician 
 
 
Secondary: 
To determine the effect of dexamethasone, insert 
through Day 90 as measured by: 
• Physician ease of insertion as measured by a 
0-10-point scale   
• Vision-related Quality of Life (QOL) 
assessment as measured with OSDI 
Questionnaire measured at all visits (Visits 
1-5) 
• Uncorrected and corrected VA mean change 
from Baseline measured at all visits (Visits 
1-5) 
• Patient`s therapy of preference as measured 
by the Comparison of Ophthalmic 
Medications for Tolerability Questionnaire 
(COMTOL) at final visit (Visit 5) 
• Mean change in MMP9/osmolarity from 
Baseline measured at all visits (Visits 1-5) 
• Incidence of IOP spikes (IOP increased >or = 
10mmHg from baseline) 
 


The HARTHAN Study (V1) 
 
 
Page 4 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
Clinical Study Protocol Synopsis ...................................................................................... 2 
List of Tables ......................................................................................................................... 5 
1. 
Introduction and Rationale ........................................................................................ 6 
1.1 
Introduction ............................................................................................................... 6 
1.2 
Rationale ..................................................................................................................... 6 
1.2.1 
Rationale for Study Design ........................................................................ 7 
2. 
Study Objectives ........................................................................................................... 7 
2.1 
Primary Objective ..................................................................................................... 7 
2.2 
Secondary Objectives ............................................................................................... 7 
3. 
Study Design .................................................................................................................. 8 
3.1 
Study Description and Duration ........................................................................... 8 
4. 
Selection, Withdrawal, and Replacement of Patients .......................................... 8 
4.1 
Study Population ...................................................................................................... 8 
4.1.1 
Inclusion Criteria .......................................................................................... 8 
4.1.2 
Exclusion Criteria ......................................................................................... 8 
4.2 
Treatment Logistics and Accountability ............................................................. 9 
4.2.1 
Packaging, Labeling, and Storage ............................................................ 9 
4.2.2 
Supply and Disposition of Treatments .................................................... 9 
4.2.3 
Treatment Accountability ........................................................................... 9 
4.3 
Concomitant Medications and Procedures ....................................................... 10 
5. 
Study Schedule of Events and Visit Descriptions ............................................... 10 
5.1 
Schedule of Events ................................................................................................. 10 
5.2 
Study Visit Descriptions ....................................................................................... 12 
5.2.1 
Study Procedures ........................................................................................ 12 
5.2.2 
Unscheduled Visits ..................................................................................... 14 
5.2.3 
Adverse Event Information Collection................................................... 14 
5.3 
Rescue Criteria ........................................................................................................ 14 
6. 
Safety Definitions, Reporting, and Monitoring .................................................... 14 
6.1 
Definitions ................................................................................................................ 14 
6.1.1 
Adverse Event ............................................................................................. 14 
6.1.2 
Serious Adverse Event .............................................................................. 14 


The HARTHAN Study (V1) 
 
 
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CONFIDENTIAL 
6.2 
Recording and Reporting Adverse Events ........................................................ 15 
7. 
Ethical and Regulatory Considerations................................................................. 15 
7.1 
Good Clinical Practice Statement ....................................................................... 15 
7.2 
Informed Consent ................................................................................................... 16 
7.3 
Patient Confidentiality and Data Protection ................................................... 16 
7.4 
Institutional Review Board .................................................................................. 16 
 
LIST OF TABLES 
Table 1 
Schedule of Events ......................................................................................... 11 
  
 


The HARTHAN Study (V1) 
 
 
Page 6 
 
CONFIDENTIAL 
1. 
INTRODUCTION AND RATIONALE 
1.1 
Introduction 
Keratoconus is a bilateral, asymmetric, non-inflammatory corneal ectasia 
characterized by progressive thinning of the corneal stroma resulting in corneal 
bulging and distortion.iii Such pathological changes to the cornea not only cause 
decreased visual acuity, but also have been associated with reduced tear film 
qualityiii and overall ocular discomfort.iv  A recent study demonstrated that 
keratoconic patients have a greater incidence of dry eye pathology – specifically, 
greater tear instability and corneal staining as well as decreased tear volumes.v  
There is emerging evidence demonstrating  that the predominance of dry eye is 
evaporative in naturevi—the major cause being meibomian gland dysfunction 
(MGD).vii Eye rubbing, family history of keratoconus, allergy, asthma, and 
eczema have been demonstrated to be important risk factors according to the 
most recent systematic review and meta-analysis.v 
Ocular allergy can alter the dry eye disease cycle including tear film 
instability, ocular surface inflammation and neurosensory abnormalities. The 
TFOS DEWS II Report has included allergic conjunctivitis among one of the 
likely risk factors for dry eye disease. Both allergic conjunctivitis and dry eye are 
associated with inflammation. Inflammation may be present before the clinical 
signs of dry eye, contributing to increased corneal desquamation and corneal 
surface irregularity.  
Steroids play an important role in in the treatment of both allergic 
conjunctivitis and dry eye disease. The anti-inflammatory properties of 
dexamethasone and other synthetic glucocorticoids can benefit the status of dry 
eye and allergic conjunctivitis via modification of a wide variety of immune 
functions.viii The immune-modifying properties of dexamethasone can improve 
dry eye and allergy status not only by inhibiting the inflammation that has 
already occurred as a result of the initiated immunological priming, but also by 
potentially preventing initiating immune responses from recurring. 
 
 
1.2 
Rationale 
Drug delivery platforms are an innovative exciting advancement in 
ophthalmology. They allow patients to eliminate topical medications which are 
generally associated with lack of compliance, difficulty of use and requiring help 
from family members. These delivery systems can be applied easily in office, and 
patients do not have to worry about drop insertion in their post-operative regimen. 
The results of this research project should help to answer the following 
question: Does the use of a physician administered intracanalicular 
dexamethasone insert improve the signs and symptoms of ocular allergy and dry 
eye disease in KC patients compared to the use of topical loteprednol etabonate 
ophthalmic gel 0.38%? 


The HARTHAN Study (V1) 
 
 
Page 7 
 
CONFIDENTIAL 
1.2.1 
Rationale for Study Design 
This prospective study will use a fellow-eye design for 20 participants (40 
eyes) with bilateral keratoconus, wearing RGP contact lenses in both eyes, who 
have been diagnosed with bilateral allergic conjunctivitis and underlying dry eye 
disease. Per participant, one eye will be randomized to receive the intracanalicular 
dexamethasone insert at the baseline visit (study eye), while the other eye will be 
assigned to receive the standard of care topical lotemax etabonate ophthalmic gel 
0.38% (control eye). Thus, for every eye in the study group, there will be a paired 
eye with similar baseline characteristics in the control group sourced from the 
same participant. The fellow-eye design allows for greater control of potential 
confounders tied to participants’ systemic and ocular health.  
 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To determine the effect of dexamethasone intracanalicular insert through Day 
90 as measured by: 
• Mean change in itching score from Baseline measured at all visits (Visits 
1-5) 
o Graded on a scale of 0-4 and determined by asking the patient  
• Mean change in palpebral conjunctivitis papillae score from Baseline 
measured at all visits (Visits 1-5) 
o Graded using the Papillae Efron Scale as graded by the physician 
• Mean change in conjunctival injection score from Baseline measured at all 
visits (Visits 1-5) 
o Graded on a scale of 0-4 as graded by the physician 
• Mean change in corneal staining score from Baseline measured at all 
visits (Visits 1-5) 
o Graded using the NEI Fluorescein Staining Scale as graded by the 
physician 
 
 
2.2 
Secondary Objectives 
To determine the effect of dexamethasone, insert through Day 90 as measured 
by: 
• Physician ease of insertion as measured by a 0-10-point scale   
• Vision-related Quality of Life (QOL) assessment as measured with OSDI 
Questionnaire measured at all visits (Visits 1-5) 
• Uncorrected and corrected VA mean change from Baseline measured at all 
visits (Visits 1-5) 
• Patient`s therapy of preference as measured by the Comparison of 
Ophthalmic Medications for Tolerability Questionnaire (COMTOL) at 
final visit (Visit 5) 
• Mean change in MMP9/osmolarity from Baseline measured at all visits 
(Visits 1-5) 


The HARTHAN Study (V1) 
 
 
Page 8 
 
CONFIDENTIAL 
• Incidence of IOP spikes (IOP increased >or = 10mmHg from baseline) 
3. 
STUDY DESIGN 
3.1 
Study Description and Duration 
This prospective, open-label, single-center, randomized, fellow-eye, investigator-
sponsored clinical study seeks to investigate the safety and efficacy of the 
dexamethasone insert in the treatment of allergic conjunctivitis and DED signs 
and symptoms in patients with Keratoconus using RGP contact lenses when 
compared to topical standard of care loteprednol etabonate ophthalmic gel 0.38%.   
After screening a given patient for inclusion and exclusion criteria, and gaining 
informed consent, one eye will be randomized to receive the dexamethasone insert 
as determined by a coin flip at the screening visit. The remaining eye will be 
prescribed a loteprednol etabonate ophthalmic gel 0.38% following a 4,3,2,1 
weekly taper. Per enrolled eye, the study period will last for approximately 90 
days, consisting of five visits. At Screening/ Baseline, Day 0, Day 7, Day 30 and 
Day 90, primary and secondary endpoints will be assessed alongside standard-of-
care procedures. Adjusting for enrollment period, the study will last a total of 
approximately 3 months. An abstract with preliminary results will be submitted 
by May 2020 for the AAOpt conference. 
 
4. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS 
4.1 
Study Population 
The study aims to enroll 20 patients with keratoconus, wo have been diagnosed 
with allergic conjunctivitis and underlying dry eye disease.  
 
4.1.1 
Inclusion Criteria 
A patient’s study eye must meet the following criteria to be eligible for inclusion 
in the study: 
• 18 years of age or older  
• Bilateral Keratoconus 
• Bilateral RGP contact lenses 
• Bilateral allergic conjunctivitis as determined by the Papillae Efron 
Scale score of at least 1 and symptoms of itching 
• Bilateral underlying dry eye disease as determined by the NEI 
Fluorescein Staining Scale score of at least 1 and a TBUT of less than 
10 and must correlate with dryness on OSDI 
 
4.1.2 
Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from the study: 
• Patients under the age of 18. 
• Pregnancy (must be ruled out in women of child-bearing age with 
pregnancy test) 
• Active infectious systemic disease 
• Active infectious ocular or extraocular disease 
• Obstructed nasolacrimal duct in the study eye(s) 


The HARTHAN Study (V1) 
 
 
Page 9 
 
CONFIDENTIAL 
• Hypersensitivity to dexamethasone 
• Patients being treated with immunomodulating agents in the study 
eye(s)  
• Patients being treated with immunosuppressants and/or oral steroids 
Patients with severe disease that warrants critical attention, deemed 
unsafe for the study by the investigator 
 
 
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 2o C and 80 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 ocular surface for up to 30 
days for the reduction of post-surgical inflammation and pain associated with 
ocular surgery. 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 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 as 
needed during the study.  
 
4.2.3 Treatment Accountability 
All study insert accountability records will be kept current. 


The HARTHAN Study (V1) 
 
 
Page 10 
 
CONFIDENTIAL 
 
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. 
 
5. 
STUDY SCHEDULE OF EVENTS AND VISIT DESCRIPTIONS 
5.1 
Schedule of Events 
Study assessments and procedures are presented by visit in Table 1.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


The HARTHAN Study (V1) 
 
 
Page 11 
 
CONFIDENTIAL 
 
Table 1 
Schedule of Events 
 
Study Procedure 
Screening/ 
Baseline 
Insertion 
Visit 
Day 0 
Day 7 
Day 30 
Day 90 
Early 
Termin
ation 
Visit 
VISIT 1 
VISIT 2 
VISIT 3 
VISIT 4 
VISIT 5 
 
Windows for Visits 
(Day -30 to -
1) 
 
(+/- 2 
days) 
(+/- 3 
days) 
(+/- 3 
days) 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History and 
Concurrent Illnesses 
X 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Uncorrected Distance VA 
testing (ETDRS at 4m) 
X 
X 
X 
X 
X 
X 
MR/BCVA (ETDRS at 4m) 
X 
X 
X 
X 
X 
X 
Ophthalmic Examination (with 
or without dilation) 
X 
X 
X 
X 
X 
X 
QOL Assessment 
(OSDI questionnaire) 
X 
X 
X 
X 
X 
X 
Osmolarity 
(Needs to be done prior to any 
drop instillation) 
 
X 
X 
X 
X 
X 
X 
MMP9   
(Needs to be done prior to any 
drop instillation) 
 
X 
X 
X 
X 
X 
X 
Grading of itching (Scale 0-4) 
X 
X 
X 
X 
X 
X 
Papillae conjunctivitis 
assessment (Efron Scale) 
X 
X 
X 
X 
X 
X 
Conjunctival Injection (Scale 0-
4) 
X 
X 
X 
X 
X 
X 
Corneal staining (NEI 
Fluorescein Scale) 
X 
X 
X 
X 
X 
X 
TBUT  
X 
X 
X 
X 
X 
X 
Intraocular Pressure (IOP) 
X 
X 
X 
X 
X 
X 
Intracanalicular 
dexamethasone insert* 
 
 
X 
 
 
 
 
Insert Visualization 
 
X 
X 
X 
X 
X 
Subject reported AEs after 
insertion 
 
 
X 
X 
X 
X 
X 
Physician ease of insertion as 
measured on a 0-10 point scale 
 
X 
 
 
 
 


The HARTHAN Study (V1) 
 
 
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CONFIDENTIAL 
5.2 
Study Visit Descriptions 
5.2.1 Study Procedures 
Screening/Baseline (Visit 1) 
After the patient has provided informed consent, the following information will be 
collected: 
• Inclusion/Exclusion 
• Demographics 
• Medical History and Concurrent Illnesses 
• Concomitant Medications 
• Uncorrected and best-corrected visual acuity with manifest refraction as 
measured by ETDRS chart at 4 meters 
• Ophthalmic Examination (with or without dilation) 
• QOL assessment as measured by OSDI questionnaire 
• Osmolarity (Needs to be done prior to any drop instillation) 
• MMP9 (Needs to be done prior to any drop instillation) 
• Grading of itching (scale 0-4) 
• Papillae conjunctivitis assessment (Efron Scale) 
• Conjunctival Injection 
• Corneal Staining 
• TBUT 
• Intraocular Pressure 
 
Insertion Visit/Day 0 (Visit 2) 
• Concomitant Medications 
• Uncorrected and best-corrected visual acuity with manifest refraction as 
measured by ETDRS chart at 4 meters 
• Ophthalmic Examination (with or without dilation) 
• QOL assessment as measured by OSDI questionnaire 
• Osmolarity (Needs to be done prior to any drop instillation) 
• MMP9 (Needs to be done prior to any drop instillation) 
• Grading of itching (scale 0-4) 
• Papillae conjunctivitis assessment (Efron Scale) 
• Conjunctival Injection 
• Corneal Staining 
• TBUT 
• Intraocular Pressure 
• Insertion of Dextenza (intracanalicular dexamethasone insert) 
• Insert Visualization 
• Subject reported AEs after insertion 
• Physician ease of insertion grading 
 
Day 7 (Visit 3) 
• Concomitant Medications 
COMTOL  
 
 
 
 
X 
X 


The HARTHAN Study (V1) 
 
 
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CONFIDENTIAL 
• Uncorrected and best-corrected visual acuity with manifest refraction as 
measured by ETDRS chart at 4 meters 
• Ophthalmic Examination (with or without dilation) 
• QOL assessment as measured by OSDI questionnaire 
• Osmolarity (Needs to be done prior to any drop instillation) 
• MMP9 (Needs to be done prior to any drop instillation) 
• Grading of itching (scale 0-4) 
• Papillae conjunctivitis assessment (Efron Scale) 
• Conjunctival Injection 
• Corneal Staining 
• TBUT 
• Intraocular Pressure 
• Insert Visualization 
• Subject reported AEs after insertion 
 
Day 30 (Visit 4) 
• Concomitant Medications 
• Uncorrected and best-corrected visual acuity with manifest refraction as 
measured by ETDRS chart at 4 meters 
• Ophthalmic Examination (with or without dilation) 
• QOL assessment as measured by OSDI questionnaire 
• Osmolarity (Needs to be done prior to any drop instillation) 
• MMP9 (Needs to be done prior to any drop instillation) 
• Grading of itching (scale 0-4) 
• Papillae conjunctivitis assessment (Efron Scale) 
• Conjunctival Injection 
• Corneal Staining 
• TBUT 
• Intraocular Pressure 
• Insert Visualization 
• Subject reported AEs after insertion 
 
Day 90 (Visit 5) or Early Termination 
• Concomitant Medications 
• Uncorrected and best-corrected visual acuity with manifest refraction as 
measured by ETDRS chart at 4 meters 
• Ophthalmic Examination (with or without dilation) 
• QOL assessment as measured by OSDI questionnaire 
• Osmolarity (Needs to be done prior to any drop instillation) 
• MMP9 (Needs to be done prior to any drop instillation) 
• Grading of itching (scale 0-4) 
• Papillae conjunctivitis assessment (Efron Scale) 
• Conjunctival Injection 
• Corneal Staining 


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CONFIDENTIAL 
• TBUT 
• Intraocular Pressure 
• Insert Visualization 
• Subject reported AEs after insertion 
• COMTOL 
 
5.2.2 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, 
for follow-up of AEs, or for any other reason, as warranted. 
 
5.2.3 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 6.  
5.3 
Rescue Criteria 
Patients can be rescued at any time at the discretion of the investigator with 
loteprednol etabonate ophthalmic gel 0.38%. Rescue criteria includes:  
• A score greater than or equal to 2+ in one or more of the following 
categories: 
o Itching 
o Papillae 
o Injection  
o Staining  
6. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
6.1 
Definitions 
6.1.1 Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study 
drug 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. 
 
6.1.2 Serious Adverse Event 
A SAE is any untoward medical occurrence that at any dose: 


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CONFIDENTIAL 
• 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). 
• 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. 
 
6.2 
Recording and Reporting Adverse Events 
All AEs and SAEs will be recorded only if they are medically relevant. 
 
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. 
 
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. 


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CONFIDENTIAL 
 
7.2 
Informed Consent 
The principles of informed consent are described in ICH Guidelines for GCP. 
 
Ocular Therapeutix will have the right to review and comment on the informed 
consent form. 
 
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 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. 
 
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  


The HARTHAN Study (V1) 
 
 
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CONFIDENTIAL 
• 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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CONFIDENTIAL 
 
 
 
 
APPENDICES  
 
I. Itching Score 
The physician will ask the patient to grade their current level of itching on a 0 to 
4-point scale. The Investigator will record patient graded level of itching on the 
appropriate Case Report Form. 
 
0 = None 
1 = Mild 
2 = Moderate 
3 = Severe 
4 = Extremely Severe  
 
II. Palpebral Conjunctivitis Papillae Score 
The investigator will grade the level of papillae with the Papillae Efron scale. 
 
 
 
III. Conjunctival Injection Score  
The investigator will grade the level of ocular injection on a 0 to 4-point scale. 
 
0 = None  
1 = Mild – Slightly dilated blood vessels; color of vessels is typically pink; can be 
quadrantal  


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2 = Moderate – More apparent dilation of blood vessels; vessel color is more intense 
(redder); involves the majority of the vessel bed  
3 = Severe – Numerous and obvious dilated blood vessels; in the absence of chemosis the 
color is deep red, may be less red or pink in presence of chemosis, is not quadrantic  
4 = Extremely Severe – Large, numerous, dilated blood vessels characterized by 
unusually severe deep red color, regardless of grade of chemosis, which involves the 
entire vessel bed  
 
IV. NEI Fluorescein Corneal Staining Scale 
 
 
 
 
V. Ocular Surface Disease Index (OSDI) 
PDF attached 
 
VI. Comparison of Ophthalmic Medications for Tolerability Questionnaire 
(COMTOL Adapted) 
PDF attached 
 
VII. Physician Ease of Insertion Grading 
The investigator will grade the level of ease of insertion of the intracanalicular 
insert on a 0 to 10-point scale. The Investigator will record ease of insertion 
procedure on the appropriate Case Report Form. 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Very Easy  
 
 
 
 
 
 
 
 
              Very Hard 
 
 
 
 
 


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REFERENCES 
 
1. Dextenza (dexamethasone insert) Prescribing Information, Ocular 
Therapeutix,Inc.2019http://www.dextenza.com/wp-
content/uploads/2019/06/NDA-208742-S001-Dextenza-labeling-
19Jun19.pdf 
2. Tyson, SL, Bafna, S., Gira, J.P. et al. Multicenter randomized phase 3 study 
of a sustained-release intracanalicular dexamethasone insert for treatment 
of ocular inflammation and pain after cataract surgery. J Cataract Refract 
Surg. 2018; 45(2): 204-12 
3. Walters TR, et al. Efficacy and Safety of Sustained Release Dexamethasone 
for the Treatment of Ocular Pain and Inflammation after Cataract Surgery: 
Results from Two Phase 3 Studies. J Clin Exp Ophthalmol. 2016; 7(4): 572. 
 
 
 
 
i Br J Ophthalmol. 2015 Aug 20 pii: bjophthalmol-2015-307059. 
ii Br J Ophthalmol 2011;95:1044-1050 
iii Ophthalmology 2003;110:1110–1118 
iv Am J Ophthalmol 2008;145:611–617. 
v Curr Eye Res. 2015 Nov;40(11):1088-94. 
vi Cornea. 2012 May;31(5):472-8.2 
vii Invest Ophthalmol Vis Sci. 2011 Mar;52(4):1922-9 
viii J Leukocyte Biology. 2014 Jun 19;96(5);675-684 
 

ICF_001.pdf: 
IRB# 19027 
Approved: 4-10-2020 
Expires: 4-9-2021 
 
CONSENT TO PARTICIPATE IN A RESEARCH STUDY 
 
Comparison of Intracanalicular Dexamethasone Insert to Topical Loteprednol Etabonate 
Ophthalmic gel 0.38% in Patients with Keratoconus (KC) with Allergic Conjunctivitis and 
underlying Dry Eye Disease (DED) 
 
 
DESCRIPTION 
 
 
 
Keratoconus may cause your vision to be blurry with glasses alone. Often contact 
lenses are needed to improve vision. Patients with keratoconus may have dry eye and 
allergies. Dry eye can cause your eyes to feel as if they are gritty and may cause you to 
rub them more often than normal. Dry eye and allergies may be treated by putting 
topical steroid drops in your eyes several times a day. Treatment is important to prevent 
further damage to the eye which can cause your vision to be cloudy. Treatment may 
also make your contact lenses more comfortable. Some patients have difficulty putting 
in drops while wearing their contact lenses and some drops cause irritation to the eye. 
We want to know if one method of treatment (intracanalicular insert of dexamethasone) 
improves the signs and symptoms of ocular allergy and dry eye compared to the use of 
topical loteprednol etabonate ophthalmic gel 0.38%.  
 
METHOD 
You will be among 20 people selected for this study from the Illinois Eye Institute patient 
population. You must have a complete eye examination at the Illinois Eye Institute 
within the last year. You must have a problem with keratoconus and wear contact 
lenses. You must have dry eye and ocular allergies and we have to be able to tell that 
you have this by looking at your cornea. If you have had a history of elevated eye 
pressure with topical steroid use, you will not be eligible to participate in the study. 
You will have a total of five visits if you participate in this study.  
 
If you have these problems, then we will need to take a few measurements to tell how 
dry your eyes are and put fluorescein dye in your eyes so that we can look at the front 
of your eye and record how it looks today.  The dye will be placed on the white part of 
your eye. You should not feel the dye in your eye and it should not affect your vision. 
Also, you will be asked questions describing how dry your eyes feel today by the 
researcher and she will document your answers.  
 
We will insert dexamethasone into one puncta (the drainage opening of your tears in 
your lower lid) of one eye.  We will use an instrument to help widen the drainage 
opening of your tears in your lower lid.  You may feel a little pressure while this is being 
done, but it will not hurt.  We will use forceps to insert the medication into the drainage 
opening of your tears in your lower lid.  If you begin to feel this, we will instill a numbing 
drop to make you more comfortable. The medication will stay in place for one month 
and the insert will dissolve within 60-90 days. You do not need to do anything additional 


IRB# 19027 
Approved: 4-10-2020 
Expires: 4-9-2021 
for this eye when you get home. If you feel slight discomfort, you may use preservative 
free artificial tears 4 times per day which will be provided to you.  
 
You will be given loteprednol gel drops for the other eye. You will receive a free month's 
supply of loteprednol etabonate ophthalmic gel at the beginning of the study to use 
during the study. We will tell you which eye to use the drops.  We ask that you put one 
drop in each eye four times per day for the first week. These drops will then be reduced 
as instructed by the investigator. You will be given 2 bottles of the loteprednol.  At the 
end of the study, you will be asked to turn in your bottles. Steroid drops may cause an 
increase in eye pressure. To monitor this, your eye pressure will be measured at each 
visit by using a probe to gently touch the eye. A numbing drop will be used so that you 
do not feel this. Looking at the front of your eye, taking the measurements and 
explaining how to use the medication should take about 30 minutes. 
 
We will then schedule an appointment for you to come back in one day, one week, one 
month and at 3 months so that we can discuss how your eyes are feeling, look at your 
cornea, and collect your calendar. This part should take about 30 minutes also. 
 
BENEFITS 
The study will help us understand which method of medication is preferred for patients 
with keratoconus with ocular allergy and dry eye.  
 
RISKS 
Sometimes, people are sensitive to the fluorescein dye and medications. When this 
happens, then the front of their eye can be damaged when fluorescein is put in their 
eye. Therefore, if you have ever had problems when the eye doctor has used 
fluorescein in your eye or have a sensitivity to any medication, then please tell us. 
 
Also, when you put drops in your eyes, the bottle that the drops come in can become 
dirty, especially if you use older bottles of drops. Dirty bottles may cause an eye 
infection. If your bottle becomes dirty, stop using it and open a new bottle. You will be 
provided 2 bottles at the start of the study. Sometimes patients notice discomfort when 
having medications and/or instruments inserted into their puncta. If this happens, your 
eye may become red and itchy.  A new medication and sterilized instrument will be used 
on each patient to prevent this.  
 
Steroid drops may cause an increase in eye pressure. To monitor this, your eye 
pressure will be measured at each visit by using a probe to gently touch the eye. A 
numbing drop will be used so that you do not feel this. Steroid use may also increase 
the risk of infection. When you have an eye infection, your eye may become red, 
painful, itchy and watery. 
 
Rubbing your eyes, washing your face, taking a shower, and going swimming will not 
make the insert be dislodged. You can use your normal eye drops while participating in 
this study such as artificial tears and prescribed medications. If you wear make-up, you 
can continue to do so during this study.  


IRB# 19027 
Approved: 4-10-2020 
Expires: 4-9-2021 
 
 
If any of these happen, please call Dr. Jennifer Harthan at the Illinois Eye Institute 
immediately for help or treatment. The phone number for the Illinois Eye Institute is 312-
225-6200. 
 
CONFIDENTIALITY 
Every effort will be made to keep your information private. Your name or other 
identifying information will not be given out without your written permission. Data from 
this study may be used in professional presentations, but that data will not contain your 
name and will include the data from all of the research participants, not just yours. 
Information collected for the research will be stripped of identifiers and may be used in 
other research in the future. 
 
COST OF THE STUDY 
There is no cost for you to participate in this study. You will be paid $25 cash per visit. If 
you complete the study, you will receive $125 cash. You will receive a free month's 
supply of loteprednol etabonate ophthalmic gel drops at the beginning of the study to 
use for the duration of the study. You will be told which eye to use this medication in. 
Only information for the study will be assessed during your return exam, no other exams 
will be administered. The cost of your annual health examination, contact lens fitting, 
and contact lens materials will not be covered by this study.  
 
CONTACT PERSONS 
If you have questions concerning this study, you should contact Dr. Jennifer Harthan at 
(312)-949-7137. If you have questions concerning your rights as a research subject you 
are asked to contact Dr. Robert Donati (312)-949-7136, the person who oversees all 
research at the Illinois College of Optometry. 
 
 
PARTICIPATION IN THIS STUDY 
Your participation in this study is voluntary. You do not have to agree to do this study. 
You can stop being part of this study at any time. If you decide to not participate in this 
study, it will not affect your eye care at the Illinois Eye Institute. If you are a student, and 
you choose to not participate or withdraw from this study, it will not affect your eye care 
at the Illinois Eye Institute or your academic status at the Illinois College of Optometry. 
 
I have read and understood the above information. I have had the opportunity to ask 
questions concerning this study and I agree to participate in this study. 
 
 
 
 
 
 
 


IRB# 19027 
Approved: 4-10-2020 
Expires: 4-9-2021 
Study Participant or Parent/Legal Guardian name (printed and signature with date) 
 
 
_____________________________________________ 
Print 
 
_____________________________________________ 
Date_________________ 
Signature 
 
Witness Signature 
 
_____________________________________________ 
Date_________________