Clinical trial NCT03660475
Conditions: Dry Eye Disease
Keywords: naltrexone dry eye diabetic subjects
Sponsor: Sassani, Joseph S., MD, MHA
Start date: 2018-07-31; Completion date: 2018-11-15
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of this exploratory study is to determine the safety and efficacy of 0.002% Naltrexone Ophthalmic Solution, compared to placebo for the treatment of the signs and symptoms of dry eye in diabetic subjects.

Detailed description:
This is a Phase 2, single-center, double-masked, randomized, placebo-controlled study to compare the safety and efficacy of Naltrexone Ophthalmic Solution, 0.002% to placebo for the treatment of the signs and symptoms of dry eye in diabetic subjects. Subjects eligible to be randomized will receive one of the following treatments to be administered bilaterally BID for 29 days (from Visit 2 to Visit 5): Naltrexone Ophthalmic Solution, 0.002% or Placebo Ophthalmic Solution (Vehicle). During a 10-day study run-in period (for the purpose of subject selection) prior to randomization, all subjects will receive Placebo Ophthalmic Solution (Vehicle) bilaterally BID. Participants who terminate early during the application period will be asked to complete safety assessments (if the participants agree) prior to study exit. Participants who are terminated early from the study will not be replaced.

Arms: arm 1: Naltrexone Ophthalmic Solution 0.002% arm 2: Placebo Ophthalmic Solution
Interventions: intervention 1: Naltrexone intervention 2: Placebos
Intervention descriptions: intervention 1: naltrexone formulated as ophthalmic solution intervention 2: Placebo ophthalmic solution

Protocol documents:
Prot_SAP_001.pdf: 
 
 
Clinical Trial Protocol: DDES001/18-110-0002 
Protocol Title: 
A Single-Center, Randomized, Double Masked, 
Placebo Controlled Clinical Study to Assess the 
Safety and Efficacy of Topical Naltrexone 
Ophthalmic Solution on the Signs and Symptoms 
of Dry Eye in Diabetic Subjects 
Protocol Number: 
DDES001/18-110-0002 
Study Phase: 
2 
Investigational Product 
Name: 
Naltrexone Ophthalmic Solution 
IND/IDE/PMA Number: 
IND 103,624 
Indication: 
Dry Eye Disease 
Investigator / Sponsor: 
Dr. Eugene McLaurin 
Single-center 
Funder: 
Ocunova, Inc. 
225 Market St. Suite 500 
Harrisburg, PA 17101 
Contract Research 
Organization: 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico 
Suite C, #497 
San Clemente, CA 92673 
USA 
 
 
Date 
Original Protocol: 
30 March 2018  
Amendment 1: 
21 June 2018  


Naltrexone Ophthalmic Solution 
Ocunova, Inc.  
Clinical Trial Protocol: DDES001/18-110-0002 
21 June 2018 
 
 
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Page 2 of 66 
 
 
Confidentiality Statement 
 
This protocol contains confidential, proprietary information of Ora, Inc. and/or Ocunova, 
Inc. Further dissemination, distribution or copying of this protocol or its contents is 
strictly prohibited. 
 
FUNDER PERSONNEL 
Funder: 
Ocunova, Inc.  
Tel: 610-733-0446 
Fax: 484-367-7958 
Funder CEO 
Mike Shine  
Tel: 610-733-0446 
Fax: 484-367-7958 
ORA PERSONNEL 
Department Vice President: 
George Ousler 
Tel: (978) 685-8900 x 9481 
Fax: (978) 689-0020 
gousler@oraclinical.com 
Department Director: 
Michael Watson 
Tel: (978) 685-8900 x 9446 
Fax: (978) 849-7371 
mwatson@oraclinical.com 
Project Manager: 
Phoebe Carter  
Tel: (978) 685-8900 x9496  
Fax: (978) 849-7371 
pcarter@oraclinical.com  
 
 
 


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Clinical Trial Protocol: DDES001/18-110-0002 
21 June 2018 
 
 
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SYNOPSIS 
Protocol Title: 
A Single-Center, Randomized, Double Masked, 
Placebo Controlled Clinical Study to Assess the 
Safety and Efficacy of Topical Naltrexone 
Ophthalmic Solution on the Signs and Symptoms 
of Dry Eye in Diabetic Subjects 
Protocol Number: 
DDES001 
Investigational Product: 
1) Naltrexone Ophthalmic Solution, 0.002% 
2) Placebo Ophthalmic Solution 
Study Phase: 
2 
Primary Objective(s): 
The objective of this exploratory study is to 
determine the safety and efficacy of 0.002% 
Naltrexone Ophthalmic Solution, compared to 
placebo for the treatment of the signs and 
symptoms of dry eye in diabetic subjects. 
Secondary Objective(s): 
To assess the tolerability of twice daily 
administered 0.002% Naltrexone Ophthalmic 
Solution, eye drops vs placebo 
Overall Study Design: 
Structure: 
Single-center, double-masked, randomized, 
placebo-controlled study 
Duration: 
An individual subject’s participation is estimated 
to be approximately 38 days 
Controls: 
Placebo (vehicle minus active) Ophthalmic 
Solution 
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
Screening: During a 10-day study run-in period 
(for the purpose of subject selection) prior to 
randomization, all subjects will receive Placebo 
Ophthalmic Solution (Vehicle) bilaterally BID  
Subjects eligible to be randomized will receive one 
of the following treatments to be administered 
bilaterally BID for 29 days (from Visit 2 to Visit 
5). 


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Clinical Trial Protocol: DDES001/18-110-0002 
21 June 2018 
 
 
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1) Naltrexone Ophthalmic Solution, 0.002% 
2) Placebo Ophthalmic Solution (Vehicle) 
Summary of Visit Schedule: 
5 visits over the course of approximately 6 weeks: 
 Visit 1 = Day -10 ± 1, Screening 
 Visit 2 = Day 1, Confirmation / Baseline 
 Visit 3 = Day 8 ± 1, One Week Follow-Up 
 Visit 4 = Day 15 ± 1, Two Week Follow-Up 
 Visit 5 = Day 29 ± 2, Four Week Follow-Up 
and Study Exit 
Measures Taken to Reduce 
Bias: 
This is a randomized treatment assignment, double 
masked study. 
Study Population Characteristics: 
Number of Subjects: 
60 (30 per treatment arm) subjects 
Condition/Disease: 
Diabetic subjects with Dry Eye Syndrome   


Naltrexone Ophthalmic Solution 
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Clinical Trial Protocol: DDES001/18-110-0002 
21 June 2018 
 
 
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Inclusion Criteria: 
Subjects must: 
a. Be at least 18 years of age; 
b. Provide written informed consent; 
c. Have a diagnosis of type 1 or type 2 diabetes 
mellitus prior to Visit 1; 
d. Have a reported history of dry eye for at least 6 
months prior to Visit 1; 
e. Have a history of use or desire to use eye drops 
for dry eye symptoms within 6 months of Visit 
1; 
f. Have a corneal fluorescein staining score of ≥ 
2 in any region (inferior, superior, or central 
regions) in at least one eye at Visits 1 and 2 
(must be the same eye at Visits 1 and 2);  
g. Have at least one of the following at Visits 1 
and 2: 
1. A total lissamine green conjunctival 
score of ≥ 2 in at least one eye, 
based on the sum of the temporal 
and nasal regions at Visits 1 and 2 
(must be the same eye at Visits 1 and 
2); 
2. Report an OSDI score ≥ 20 at Visits 
1 and 2. 
Exclusion Criteria: 
Subjects must not: 
a. Have any clinically significant slit lamp 
findings at Visit 1 that may include active 
blepharitis, meibomian gland dysfunction 
(MGD), lid margin inflammation or active 
ocular allergies that require therapeutic 
treatment, and/or in the opinion of the 
investigator may interfere with study 
parameters; 
b. Be diagnosed with an ongoing ocular infection 
(bacterial, viral, or fungal), or active ocular 
inflammation at Visit 1; 
c. Have concurrent neurotrophic keratopathy 
from a source other than diabetes (h/o HSV 
keratitis, h/o HZO with ocular manifestations, 
or CN VII palsy or other condition resulting in 
lagophthalmos); 
d. Have active diabetic foot ulcers;   


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Clinical Trial Protocol: DDES001/18-110-0002 
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e. Have a corneal sensitivity score ≤ 1.5 cm as 
measured by Cochet-Bonnet at Visit 1; 
f. Report an OSDI score > 75 at Visits 1 and 2;  
g. Have worn contact lenses within 21 days of 
Visit 1 or anticipate using contact lenses during 
the study (no contact lens wear during study); 
h. Have used any eye drops within 2 hours of 
Visit 1; 
i. Have previously had laser-assisted in situ 
keratomileusis (LASIK) surgery within the last 
24 months; 
j. Have used cyclosporine 0.05% or lifitigrast 
5.0% ophthalmic solution within 45 days of 
Visit 1; 
k. Have any planned ocular and/or lid surgeries 
over the study period or any ocular surgery 
within the last 12 months; 
l. Be using or anticipate using temporary punctal 
plugs during the study that have not been 
stable within 30 days of Visit 1; 
m. Be currently taking any topical ophthalmic 
prescription (including medications for 
glaucoma) or over-the-counter (OTC) 
solutions, artificial tears, gels or scrubs, and 
cannot discontinue these medications for the 
duration of the trial (excluding medications 
allowed for the conduct of the study); 
n. Have corrected visual acuity greater than or 
equal to logMAR +0.7 as assessed by Early 
Treatment of Diabetic Retinopathy Study 
(ETDRS) scale in either eye at Visit 1; 
o. Have concurrent autoimmune disease causing 
dry eye (e.g., rheumatoid arthritis, Sjogren’s, 
GVHD, Steven’s Johnson, Grave’s); 
p. Have Fuchs endothelial dystrophy; 
q. Have recurrent corneal erosion syndrome or 
anterior basement membrane dystrophy; 
r. Be a woman who is pregnant, nursing, or 
planning a pregnancy; 
s. Be unwilling to submit a urine pregnancy test 
at Visit 1 and Visit 5 (or early termination 
visit) if of childbearing potential. Non-
childbearing potential is defined as a woman 


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who is permanently sterilized (i.e., has had a 
hysterectomy or bilateral tubal ligation), or is 
post-menopausal (without menses for 12 
consecutive months); 
t. Be a woman of childbearing potential who is 
not using an acceptable means of birth control; 
acceptable methods of contraception include: 
hormonal – oral, implantable, injectable, or 
transdermal contraceptives; mechanical – 
spermicide in conjunction with a barrier such 
as a diaphragm or condom; IUD; or surgical 
sterilization of partner. For non-sexually active 
females, abstinence may be regarded as an 
adequate method of birth control; however, if 
the subject becomes sexually active during the 
study, they must agree to use adequate birth 
control as defined above for the remainder of 
the study; 
u. Have a known allergy and/or sensitivity to the 
test article or its components; 
v. Have a condition or be in a situation which the 
investigator feels may put the subject at 
significant risk, may confound the study 
results, or may interfere significantly with the 
subject’s participation in the study; 
w. Be currently enrolled in an investigational drug 
or device study or have used an investigational 
drug or device within 30 days of Visit 1; 
x. Be currently using any medication known to 
cause ocular drying that is not used on a stable 
dosing regimen for at least 30 days prior to 
Visit 1; 
y. Be unable or unwilling to follow instructions, 
including participation in all study assessments 
and visits. 
z. Be currently using a systemic opioid antagonist 
(e.g., Naltrexone or Naloxone) or have used a 
systemic opioid antagonist in the previous 90 
days 
Study Formulations and 
Formulation Numbers: 
 Naltrexone Ophthalmic Solution, 0.002% 
 Placebo Ophthalmic Solution 


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Efficacy Measures and 
Endpoints: 
Efficacy Measures: 
 Fluorescein staining; regions: inferior, superior, 
central, corneal sum, temporal, nasal, 
conjunctival sum, total eye; 
 Lissamine green staining; regions: inferior, 
superior, central, corneal sum, temporal, nasal, 
conjunctival sum, total eye; 
 Tear film break-up time (TFBUT); 
 Conjunctival redness; 
 Schirmer’s Test (without anesthesia); 
 Cochet-Bonnet Corneal Sensitivity  
 Tear Osmolarity; 
 MMP-9; 
 Total Ocular Surface Disease Index (OSDI); 
 Ocular discomfort (0-4 scale); 
 Ocular discomfort, dryness, grittiness, burning 
and stinging (0-5 scale); 
 VAS.  
Safety Measures: 
 Visual acuity; 
 Slit-lamp biomicroscopy; 
 Adverse event query; 
 IOP; 
 Dilated fundoscopy.  
General Statistical Methods and Types of Analyses 
Analysis Populations 
 Modified Intent-to-Treat Population – The modified intent-to-treat (mITT) 
population includes all randomized subjects with at least one post visit 2 
study assessment. Efficacy analysis will be performed on the mITT 
population. Subjects in the mITT population will be analyzed as 
randomized. 
 
 Safety Population – The safety population includes all subjects who have 
received at least one dose of the investigational product. Subjects in the 
Safety population will be analyzed as treated.  
The statistical analysis of safety data will be performed for the safety population. 
The analysis of baseline and all efficacy data will be performed for the mITT 
population.  
Sample Size: 


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As an exploratory study, the study is not powered to show statistical differences 
for any of the efficacy endpoints.  
With a sample size of 60 subjects in the Safety and Efficacy Assessment, the 
study will have 79% probability of detecting AEs occurring at a rate of 5% or 
more in either treatment arm. 
Multiplicity Consideration: 
There will be no adjustments for multiple endpoints or multiple treatment 
comparisons for this early phase, exploratory study. 
Safety Variables: 
Frequencies and percentages of subjects with treatment-emergent adverse events 
(TEAEs), serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An AE is treatment emergent if it occurs or worsens 
after the first dose of study treatment. Separate summaries will be provided for 
ocular specific and all AEs (including systemic). 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, corneal 
sensitivity, dilated fundoscopy, intraocular pressure will be summarized by 
treatment group and visit using descriptive statistics.  Changes or shifts from 
baseline will also be summarized where appropriate. For assessments performed 
by eye, study eye and fellow eye may be summarized separately.  
Summary of Known and Potential Risks and Benefits to Human Subjects 
The previous human experience with topical naltrexone administered to the eyes of 
healthy volunteers and the nonclinical safety studies conducted have indicated that 
topical naltrexone appears to be well tolerated. Nevertheless, patients will be closely 
monitored for safety-related issues. 


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21 June 2018 
 
 
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TABLE OF CONTENTS 
SYNOPSIS..................................................................................................................3 
TABLE OF CONTENTS..........................................................................................10 
LIST OF ABBREVIATIONS ...................................................................................12 
1 
INTRODUCTION ....................................................................................................14 
2 
STUDY OBJECTIVES .............................................................................................15 
3 
CLINICAL HYPOTHESIS ......................................................................................15 
4 
OVERALL STUDY DESIGN ..................................................................................15 
5 
STUDY POPULATION ...........................................................................................19 
5.1 
Number of Subjects (approximate) ................................................................19 
5.2 
Study Population Characteristics ....................................................................19 
5.3 
Inclusion Criteria ............................................................................................19 
5.4 
Exclusion Criteria ...........................................................................................20 
5.5 
Withdrawal Criteria (if applicable) ................................................................21 
6 
STUDY PARAMETERS ..........................................................................................22 
6.1 
Efficacy Measures and Endpoints ..................................................................22 
6.1.1 
Efficacy Measure(s) ..........................................................................22 
6.2 
Safety Measures .............................................................................................22 
6.3 
Other Measures ...............................................................................................23 
7 
STUDY MATERIALS .............................................................................................23 
7.1 
Study Treatment(s) .........................................................................................23 
7.1.1 
Study Treatment ................................................................................23 
7.1.2 
Description of and Justification for the Route of Administration, 
Dosage, Dosage Regimen, and Treatment Period(s). .......................23 
7.1.3 
Instructions for Use and Administration ...........................................24 
7.2 
Other Study Supplies ......................................................................................24 
8 
STUDY METHODS AND PROCEDURES ............................................................24 
8.1 
Subject Entry Procedures ...............................................................................24 
8.1.1 
Overview ...........................................................................................24 
8.1.2 
Informed Consent..............................................................................25 
8.1.3 
Washout Intervals .............................................................................25 
8.1.4 
Procedures for Final Study Entry ......................................................25 
8.1.5 
Methods for Assignment to Treatment Groups: ...............................25 
8.2 
Concurrent Therapies .....................................................................................25 
8.2.1 
Prohibited Medications/Treatments ..................................................25 
8.2.2 
Escape Medications ..........................................................................25 
8.2.3 
Special Diet or Activities ..................................................................26 
8.3 
Examination Procedures .................................................................................26 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to 
Study Objective(s) ............................................................................26 
8.4 
Schedule of Visits, Measurements and Dosing ..............................................29 
8.4.1 
Scheduled Visits................................................................................29 
8.4.2 
Unscheduled Visits ...........................................................................29 
8.5 
Compliance with Protocol ..............................................................................30 
8.6 
Subject Disposition .........................................................................................30 


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8.6.1 
Completed Subjects ..........................................................................30 
8.6.2 
Discontinued Subjects .......................................................................30 
8.7 
Study Termination ..........................................................................................30 
8.8 
Study Duration ...............................................................................................30 
8.9 
Monitoring and Quality Assurance ................................................................31 
9 
ADVERSE EVENTS ................................................................................................32 
9.1 
Adverse Event ................................................................................................32 
9.1.1 
Severity .............................................................................................32 
9.1.2 
Relationship to Investigational Product ............................................32 
9.1.3 
Expectedness .....................................................................................33 
9.2 
Serious Adverse Events ..................................................................................34 
9.3 
Procedures for Reporting Adverse Events .....................................................34 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................35 
9.3.2 
Reporting a Serious Adverse Event ..................................................35 
9.4 
Procedures for Unmasking (if applicable) ......................................................35 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ........36 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................36 
10.1 Analysis Populations ......................................................................................36 
10.2 Statistical Hypotheses .....................................................................................37 
10.3 Sample Size ....................................................................................................37 
10.4 Statistical Analysis .........................................................................................38 
10.4.1 General Considerations .....................................................................38 
10.4.2 Unit of Analysis ................................................................................38 
10.4.3 Missing Data .....................................................................................38 
10.4.4 Multiplicity Consideration ................................................................38 
10.4.5 Safety Variables ................................................................................38 
10.4.6 Efficacy Analyses .............................................................................39 
10.4.7 Interim Analyses ...............................................................................39 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................39 
11.1 Protection of Human Subjects ........................................................................39 
11.1.1 Subject Informed Consent.................................................................39 
11.1.2 Institutional Review Board (IRB) Approval .....................................40 
11.2 Ethical Conduct of the Study ..........................................................................40 
11.3 Subject Confidentiality ...................................................................................40 
11.4 Documentation ...............................................................................................40 
11.4.1 Retention of Documentation .............................................................41 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ...................................................................................41 
11.5.1 Labeling/Packaging...........................................................................41 
11.5.2 Storage of Investigational Product ....................................................41 
11.5.3 Accountability of Investigational Product ........................................41 
11.5.4 Return or Disposal of Investigational Product ..................................42 
11.6 Recording of Data on Source Documents and Case Reports Forms (CRFs) .42 
11.7 Handling of Biological Specimens .................................................................42 
11.8 Publications ....................................................................................................42 


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12 
REFERENCES .........................................................................................................43 
13 
APPENDICES ..........................................................................................................44 
Appendix 1: Schedule of Visits and Measurements ..........................................................44 
Appendix 2: Examination Procedures, Tests, Equipment, and techniques ........................46 
Appendix 5: Protocol Amendment Summary ....................................................................63 
Appendix 6: Sponsor and Ora Approvals ..........................................................................63 
Appendix 7: Investigator’s Signature ................................ Error! Bookmark not defined. 
 
 
 
LIST OF ABBREVIATIONS 
AE 
adverse event 
BCVA 
best-corrected visual acuity 
BID 
twice daily 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
DED 
dry eye disease 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IND 
investigational new drug application 
IOP 
intraocular pressure 
IP 
investigational product 
IRB 
institutional review board 
ITT 
intent to treat 
KCS 
keratoconjunctivitis sicca 
LASIK 
laser in situ keratomileusis 
logMAR 
logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
Μg 
microgram 
µL 
microliter 
Mm 
millimeter 


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Clinical Trial Protocol: DDES001/18-110-0002 
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NDA 
new drug application 
NEI 
National Eye Institute 
OD 
right eye 
OS 
left eye 
OSDI 
Ocular Surface Disease Index 
OU 
both eyes 
SAE 
serious adverse event 
SD 
standard deviation 
SOP 
standard operating procedure 
TF 
tear film 
TFBUT 
tear film break-up time 
VA 
visual acuity 
 
 


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21 June 2018 
 
 
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1 
INTRODUCTION 
1.1 Dry Eye Disease (DED) 
Dry Eye Disease (DED) is defined by the International Dry Eye Workshop (DEWS) as a 
multifactorial disease of the ocular surface characterized by a loss of homeostasis of the 
tear film, and accompanied by ocular symptoms, in which tear film instability and 
hyperosmolarity, ocular surface inflammation and damage, and neurosensory 
abnormalities play etiological roles (DEWS II Definition and Classification 2017). As 
many as 5 - 35% of patients visiting ophthalmic clinics report dry eye symptoms, making 
it one of the most common conditions seen by ophthalmic specialists (McCarty CA, et al. 
1998; Lin PY, et al. 2003). Estimates range from 20 million people in the United States 
(US) being affected with mild to moderate dry eye, to a high of as many as one out of every 
five Americans. Prevalence is greater in females and the elderly. Schaumberg et al. 
reported prevalence rates ranging from 3.9% in men aged 50–54 years to 7.7% in those 80 
years or older, while an increased rate from 5.7% in women younger than 50 years to 9.8% 
in women >75 years was observed (Schaumberg DA, et al. 2003). Prevalence is affected 
by geographical parameters and appears to be higher in Asian populations. Dry eye can be 
related to external factors, such as the low humidity of air conditioned offices, winter 
heating, a dusty or windy outdoor environment, prolonged computer use, or wearing 
contact lenses, as well as to internal factors, such as hormonal imbalance, autoimmune 
disease, the presence of many widely prescribed systemic medications, anatomical changes 
or trauma, and aging. Symptoms result in mildly decreased quality of life at a minimum, 
and with increasing severity, loss of function and productivity, pain, light sensitivity, and 
the misery that accompanies significantly impaired vision and decreased quality of life. 
With the aging population in the United States and other countries of the developed world, 
and with increasing computer use, DED is expected to continue to become more prevalent 
and finding a treatment is becoming more important (Schaumberg DA, et al. 2009).  
STUDY TREATMENT 
Researchers at Pennsylvania State University/Hershey Medical Center have been 
exploring the role of the Opioid Growth Regulatory System (OGRS), which includes 
Opioid Growth Factor (OGF), and its receptor, OGFr, in the health and healing of the 
corneal epithelium for nearly 20 years. These studies included evaluating the impact of 
the OGRS on healthy corneal epithelium and the healing of wounded corneal epithelium 
utilizing cell and organ culture. Experiments have been performed in living animals. 
Additionally, cell and organ culture experiments were performed utilizing human eye 
bank corneas not suitable for transplantation. These studies have demonstrated the safety 
and efficacy of topically applied naltrexone in expediting the healing of corneal epithelial 
wounds in normal and diabetic rats. This research led to an investigational drug study 
entitled: “Topical Application of Naltrexone to the Ocular Surface of Healthy Volunteers: 
A Tolerability Study” (Liang et al., Volume 32 (2), 2016, pp 127-132; DOI: 
10.1089/jop.2015.0070). It was concluded that topical naltrexone was well tolerated in 
healthy human subjects after 1 or 4 eye drops of naltrexone at dosages up to ~3.76 μg 
administered over a 24-h treatment period and observed for 1 week.  


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2 
STUDY OBJECTIVES 
The objective of this study is to compare the safety and efficacy of Naltrexone 
Ophthalmic Solution, 0.002% to placebo for the treatment of the signs and symptoms of 
dry eye in diabetic subjects. 
3 
CLINICAL HYPOTHESIS 
The clinical hypotheses for this exploratory study is that Naltrexone Ophthalmic Solution 
has a beneficial effect compared to vehicle in improving the signs and symptoms of 
DED.  
4 
OVERALL STUDY DESIGN 
This is a Phase 2, single-center, double-masked, randomized, placebo-controlled study to 
compare the safety and efficacy of Naltrexone Ophthalmic Solution, 0.002% to placebo 
for the treatment of the signs and symptoms of dry eye in diabetic subjects. Subjects 
eligible to be randomized will receive one of the following treatments to be administered 
bilaterally BID for 29 days (from Visit 2 to Visit 5): Naltrexone Ophthalmic Solution, 
0.002% or Placebo Ophthalmic Solution (Vehicle). During a 10-day study run-in period 
(for the purpose of subject selection) prior to randomization, all subjects will receive 
Placebo Ophthalmic Solution (Vehicle) bilaterally BID. Participants who terminate early 
during the application period will be asked to complete safety assessments (if the 
participants agree) prior to study exit. Participants who are terminated early from the 
study will not be replaced. A chart illustrating the study’s structure is below.  
Visit 1 
Day -10 ± 1 day 
Screening 
 Informed consent/Health Information 
Portability and Accountability Act 
(HIPAA) consent 
 Demographic data, medical/medication, 
and ocular history 
 Urine Pregnancy Test (if applicable) 
 Ocular Surface Disease Index (OSDI) 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 
4-Symptom Questionnaire 
 VAS 
 Best Corrected Visual Acuity (BCVA) 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness;   
 Corneal sensitivity (Cochet-Bonnet) 
 TFBUT; 


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 Fluorescein staining (Ora Calibra® scale); 
regions: central, superior, inferior, 
temporal, nasal, corneal sum, 
conjunctival sum, and total eye score 
 Lissamine green staining (Ora Calibra® 
scale); regions: inferior, superior, central, 
temporal, nasal, corneal sum, 
conjunctival sum, and total eye score) 
 Review inclusion and exclusion criteria 
 Run-in (vehicle) dose 
 Dispense vehicle to all qualifying patients 
for BID dosing until Visit 2 
 Dispense dosing diary  
 Adverse Event Query 
 Schedule Visit 2 
↓ 
Approximate 10-Day Run-In Period with Vehicle 
↓ 
Visit 2 
Day 1 
Confirmation/Baseline 
 Run-in and diary collection 
 Medical/medication update 
 Adverse event query 
 Ocular Surface Disease Index (OSDI) 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 
4-Symptom Questionnaire 
 VAS  
 BCVA 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness   
 Corneal Sensitivity (Cochet-Bonnet) 
 Tear Osmolarity 
 InflammaDry® (MMP-9) testing 
 Tear film break-up time (TFBUT) 
 Corneal and conjunctival fluorescein 
staining 


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 Corneal and conjunctival lissamine green 
staining 
 Unanesthetized Schirmer’s Test  
 Intraocular Pressure (IOP) 
 Dilated fundoscopy 
 Review inclusion and exclusion criteria 
 Randomize qualifying subjects 
 Study treatment dose  
 Dispense study drug/placebo for BID 
dosing with active or placebo until Visit 5 
according to randomization 
 Dispense dosing diary 
 Adverse Event Query 
 Schedule Visit 3 
↓ 
Visit 3 
Day 8 ± 1 day 
1-Week Follow-Up 
 Study drug and diary collection 
 Medical/medication update 
 Adverse event query 
 OSDI 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 
4-Symptom Questionnaire 
 VAS 
 BCVA 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness  
 Corneal sensitivity (Cochet-Bonnet) 
 TFBUT 
 Corneal and conjunctival fluorescein 
staining 
 Corneal and conjunctival lissamine green 
staining 
 Unanesthetized Schirmer’s Test 
 Dispense study drug 
 Dispense dosing diary 
 Adverse Event Query 


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 Schedule Visit 4 
↓ 
Visit 4 
Day 15 ± 1 day 
2-Week Follow-Up 
 Study Drug Collection 
 Medical/medication update 
 Adverse event query 
 OSDI 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 
4-Symptom Questionnaire 
 VAS 
 BCVA 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness 
 Corneal Sensitivity (Cochet-Bonnet) 
 TFBUT 
 Corneal and conjunctival fluorescein 
staining 
 Corneal and conjunctival lissamine green 
staining 
 Unanesthetized Schirmer’s Test  
 Dispense study drug 
 Dispense dosing diary 
 Adverse Event Query 
 Schedule Visit 5 
↓ 
Visit 5 
Day 29 ± 2 days 
4-Week Follow-Up and 
Study Exit 
 Study drug and diary collection 
 Medical/medication update 
 Adverse event query 
 Urine Pregnancy Test (if applicable) 
 OSDI 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 
4-Symptom Questionnaire 
 VAS 


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 BCVA 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness 
 Corneal sensitivity Cochet-Bonnet 
 Tear Osmolarity 
 InflammaDry® (MMP-9) testing 
 Tear film break-up time (TFBUT) 
 Corneal and conjunctival fluorescein 
staining 
 Corneal and conjunctival lissamine green 
staining 
 Unanesthetized Schirmer’s Test 
 Intraocular Pressure (IOP) 
 Dilated fundoscopy 
 Blood Draw (optional) for enkephalin 
testing 
 Adverse Event Query 
 Study exit 
 
5 
STUDY POPULATION 
5.1 
Number of Subjects (approximate) 
Approximately 60 (30 per treatment arm) subjects will be enrolled in the study. The total 
number of expected participants, including screen failures, is approximately 120.  
5.2 
Study Population Characteristics 
Approximately 60 subjects of either sex and of any race who are at least 18 years of age 
with a diagnosis of type 1 or type 2 diabetes mellitus and a subject-reported history of dry 
eye in both eyes and meeting all other study eligibility criteria will be randomized at 1 
site in the US to receive treatment with Naltrexone Ophthalmic Solution, 0.002%  or 
vehicle in a 1:1 ratio (approx. 30 subjects per treatment arm). 
5.3 
Inclusion Criteria 
Each subject must: 


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a) 
Be at least 18 years of age; 
b) 
Provide written informed consent; 
c) 
Have a diagnosis of type 1 or type 2 diabetes mellitus prior to Visit 1; 
d) 
Have a reported history of dry eye for at least 6 months prior to Visit 1; 
e) 
Have a history or use or desire to use eye drops for dry eye symptoms within 6  
months of  Visit 1; 
f) 
Have a corneal fluorescein staining score of ≥ 2 in any region (inferior, superior, 
or central regions) in at least one eye at Visits 1 and 2; must be the same eye at 
visits 1 and 2) 
g) 
Have at least one of the following at Visits 1 and 2:  
i. A total lissamine green conjunctival score of ≥ 2 in at least one eye, 
based on the sum of the temporal and nasal regions at Visits 1 and 2; 
(must be the same eye at visits 1 and 2) 
ii. Report an OSDI score ≥ 20 at Visits 1 and 2. 
5.4 
Exclusion Criteria 
Each subject may not: 
a. Have any clinically significant slit lamp findings at Visit 1 that may include active 
blepharitis, meibomian gland dysfunction (MGD), lid margin inflammation or active 
ocular allergies that require therapeutic treatment, and/or in the opinion of the 
investigator may interfere with study parameters; 
b. Be diagnosed with an ongoing ocular infection (bacterial, viral, or fungal), or active 
ocular inflammation at Visit 1; 
c. Have concurrent neurotrophic keratopathy from a source other than diabetes (h/o 
HSV keratitis, h/o HZO with ocular manifestations, or CN VII palsy or other 
condition resulting in lagophthalmos; 
d. Have active diabetic foot ulcers;   
e. Have a corneal sensitivity score ≤ 1.5 cm as measured by Cochet-Bonnet at Visit 1; 
f. Report an OSDI score > 75 at Visits 1 and 2;  
g. Have worn contact lenses within 21 days of Visit 1 or anticipate using contact lenses 
during the study (no contact lens wear during study); 
h. Have used any eye drops within 2 hours of Visit 1; 
i. Have previously had laser-assisted in situ keratomileusis (LASIK) surgery within the 
last 24 months; 
j. Have used cyclosporine 0.05% or lifitigrast 5.0% ophthalmic solution within 45 days 
of Visit 1; 
k. Have any planned ocular and/or lid surgeries over the study period or any ocular 
surgery within the last 12 months; 
l. Be using or anticipate using temporary punctal plugs during the study that have not 
been stable within 30 days of Visit 1; 


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m. Be currently taking any topical ophthalmic prescription (including medications for 
glaucoma) or over-the-counter (OTC) solutions, artificial tears, gels or scrubs, and 
cannot discontinue these medications for the duration of the trial (excluding 
medications allowed for the conduct of the study); 
n. Have corrected visual acuity greater than or equal to logMAR +0.7 as assessed by 
Early Treatment of Diabetic Retinopathy Study (ETDRS) scale in both eyes at Visit 
1; 
o. Have concurrent autoimmune disease causing dry eye (rheumatoid arthritis, 
Sjogren’s, GVHD, Steven’s Johnson, Grave’s); 
p. Have Fuchs endothelial dystrophy; 
q. Have recurrent corneal erosion syndrome or anterior basement membrane dystrophy;    
r. Be a woman who is pregnant, nursing, or planning a pregnancy; 
s. Be unwilling to submit a urine pregnancy test at Visit 1 and Visit 5 (or early 
termination visit) if of childbearing potential.  Non-childbearing potential is defined 
as a woman who is permanently sterilized (e.g. has had a hysterectomy or tubal 
ligation), or is post-menopausal (without menses for 12 consecutive months); 
t. Be a woman of childbearing potential who is not using an acceptable means of birth 
control; acceptable methods of contraception include: hormonal – oral, implantable, 
injectable, or transdermal contraceptives; mechanical – spermicide in conjunction 
with a barrier such as a diaphragm or condom; IUD; or surgical sterilization of 
partner.  For non-sexually active females, abstinence may be regarded as an adequate 
method of birth control; however, if the subject becomes sexually active during the 
study, she must agree to use adequate birth control as defined above for the 
remainder of the study; 
u. Have a known allergy and/or sensitivity to the test article or its components; 
v. Have a condition or be in a situation which the investigator feels may put the subject 
at significant risk, may confound the study results, or may interfere significantly with 
the subject’s participation in the study; 
w. Be currently enrolled in an investigational drug or device study or have used an 
investigational drug or device within 30 days of Visit 1; 
x. Be currently using any medication known to cause ocular drying that is not used on a 
stable dosing regimen for at least 30 days prior to Visit 1; 
y. Be unable or unwilling to follow instructions, including participation in all study 
assessments and visits. 
z. Be currently using a systemic opioid antagonist (e.g. Naltrexone or Naloxone) or 
have used a systemic opioid antagonist in the previous 90 days. 
 
5.5 
Withdrawal Criteria (if applicable) 
If at any time during the study the investigator determines that a subject’s safety has been 
compromised, the subject may be withdrawn from the study in particular: 


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 the occurrence of an exclusion criterion which is clinically relevant and affects the 
subject’s safety, if discontinuation is considered necessary by the investigator. 
 the occurrence of an AE if discontinuation of trial drug is desired or considered 
necessary by the investigator and/or the subject. 
 the occurrence of pregnancy. 
Subjects may withdraw consent from the study at any time without reason. 
The investigator may discontinue any subject for non-compliance or any valid medical 
reason (see Section 8.6). 
The PI and Ora will regularly review the progress of the trial (semi-monthly) including a 
review of all adverse events noted during the period. In the event of a serious adverse 
event, the PI shall notify Ora (within 24 hours). Ora and PI will jointly determine whether 
any amendments to the trial are necessary or if the trial should be discontinued. 
6 
STUDY PARAMETERS 
6.1 
Efficacy Measures and Endpoints 
6.1.1 Efficacy Measure(s) 
 Fluorescein staining; regions: inferior, superior, central, corneal sum, temporal, 
nasal, conjunctival sum, total eye 
 Lissamine green staining; regions: inferior, superior, central, corneal sum, 
temporal, nasal, conjunctival sum, total eye 
 Tear film break-up time (TFBUT) 
 Conjunctival redness 
 Schirmer’s Test (without anesthesia) 
 Cochet-Bonnet 
 Tear Osmolarity 
 MMP-9 
 Total Ocular Surface Disease Index (OSDI) 
 Ocular discomfort (0-4 scale) 
 Ocular discomfort, dryness, grittiness, burning and stinging (0-5 scale) 
 VAS 
6.2 
Safety Measures 
These evaluations will be performed in an effort to ensure subject safety throughout the 
trial: 
 Visual acuity 
 Slit-lamp biomicroscopy 
 Adverse event query 


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 Intraocular Pressure (IOP) 
 Dilated fundoscopy 
6.3 
Other Measures 
 Urine Pregnancy Test at Visit 1 and Visit 5 (if applicable) 
 Enkephelin levels  
7 
STUDY MATERIALS 
7.1 
Study Treatment(s) 
7.1.1 Study Treatment 
Naltrexone Ophthalmic solution will be formulated as a stable, sterile, topical, 
ophthalmic solution containing 21 μg/mL naltrexone hydrochloride in a multi-use 
container for topical administration to the eye. The study treatment will be delivered as a 
drop in each eye BID: 
 Naltrexone Ophthalmic Solution, 0.002% 
 Placebo Ophthalmic Solution 
 
7.1.2 Description of and Justification for the Route of Administration, Dosage, Dosage 
Regimen, and Treatment Period(s). 
Selection of Dose: 
Previous animal studies demonstrated that NTX dissolved in Vigamox® in the range of 
10-5 M or 10-4 M was effective in reversing dry eye after 1 drop.  
In the human study, the highest dosage of NTX was 5 x 10-5 M dissolved in Vigamox® 
and applied four times over a 24-hour period equaling 3.77 µg of NTX.  The compound 
was prepared by Skip’s Pharmacy, FL. 
These molar dosages of NTX were converted by Bionex to yield a final formulation 
containing 20 µg/ml NTX, with each drop (0.028 ml) containing 0.56 µg NTX (assuming 
~35.7 drops per ml).  In the proposed clinical trial, drops will be applied twice daily 
yielding a total NTX dosage of 1.12 µg over a 24-hour period of time. This is one-third 
the clinical dosage shown to be safe for a 24-hour period of time. 
Furthermore, the 20 µg/ml NTX dosage used in the bridge studies was shown to be 
consistently more effective in comparison to the NTX (5x 10-5 M) prepared in 
Vigamox®.  Moreover, the 20 µg/ml NTX dosage was applied 4 times daily for a period 
of 30 days in both rats and rabbits and shown to be safe based on pathological assessment 


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by an outside veterinary ophthalmic pathologist (Yale University).  The total amount of 
NTX applied to the rat or rabbit eye over a 30 day period was 120 µg.   
7.1.3 Instructions for Use and Administration 
Naltrexone will be formulated as a stable, sterile, topical, ophthalmic solution containing 
21 μg/mL naltrexone hydrochloride in a multi-use container for topical administration to 
the eye. 
a) During a 10-day study run-in period (for the purpose of subject selection) prior to 
randomization, all subjects will receive Placebo Ophthalmic Solution (Vehicle) 
bilaterally BID at home. After the run-in period, Subjects eligible to be randomized 
will receive one of the following treatments: Naltrexone Ophthalmic Solution, 
0.002% or Placebo Ophthalmic Solution (Vehicle) to be administered at home 
bilaterally BID for 29 days (from Visit 2 to Visit 5). Subjects will be instructed not 
to administer drug/placebo before the appointment at home on the days they are 
scheduled for clinic visits.  
b) All IP(s) must be stored in a locked container with access limited to the investigator 
and designated personnel. The temperature range for the IP is 2 to 25 degrees 
Celsius. Study drug will be delivered to the clinical site and stored refrigerated at the 
site. Once dispensed, subjects will be instructed to keep study drug at room 
temperature. 
c) Subjects will receive one (1) bottle of run-in for at-home dosing between Visits 1 
and 2. During the randomized dosing portion of the trial (Visits 2-5), subjects will be 
assigned two (2) study drug bottles. Subjects study drug bottles will be labeled with 
the subjects corresponding randomization number and A or B.  The first bottle (A 
bottle) will be dispensed at Visit 2, re-dispensed at Visit 3, and collected at Visit 4. 
The second bottle (B bottle) will be dispensed at Visit 4 and collected at Visit 5.  
 
7.2 
Other Study Supplies 
Urine Pregnancy tests, Sodium fluorescein, Lissamine green, Tear osmolarity cards, 
Tropicamide 1% ophthalmic solution, InflammaDry® cassettes, blood draw supplies.  
8 
STUDY METHODS AND PROCEDURES 
8.1 
Subject Entry Procedures 
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2, 5.3, and 5.4 will be considered for 
entry into this study. 


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8.1.2 Informed Consent 
Prior to a subject’s participation in the trial (i.e., changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent (and/or assent) using 
an informed consent form.  The informed consent form must be the most recent version 
that has received approval/favorable review by a properly constituted Institutional 
Review Board/Independent Ethics Committee (IRB/IEC). 
8.1.3 Washout Intervals 
Prohibited medications and treatments are listed in the Exclusion Criteria (Section 5.4) 
with their respective washout intervals.   
8.1.4 Procedures for Final Study Entry 
Subjects must meet all inclusion criteria and none of the exclusion criteria. 
8.1.5 Methods for Assignment to Treatment Groups: 
Each subject who qualifies will be assigned a screening number. All screening numbers 
will be assigned in strict numerical sequence at a site and no numbers will be skipped or 
omitted. If all inclusion and exclusion criteria are met at Visits 1 & 2, each qualifying 
subject will be assigned a randomization number at the end of Visit 2.  
 
A masked randomization schedule will be provided to the investigational site. There will 
be an approximate equal number of subjects assigned to each of the two treatment arms at 
the site. Subjects will be randomized in sequential order staring with 3001. The site staff 
will dispense to the patient the randomized study drug bottles with the corresponding 
randomization number and “A” or “B”. The randomization number will be recorded on 
the patient’s source document and case report form (CRF). The Funder, Investigators, 
and study staff will be masked during the randomization process and throughout the 
study. 
8.2 
Concurrent Therapies 
The use of any concurrent medication, prescription or over-the-counter, is to be recorded 
on the subject’s source document and corresponding case report form (CRF) along with 
the reason the medication was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
Disallowed medications and treatments are listed in the Exclusion Criteria (Section 5.4).  
8.2.2 Escape Medications 
No escape medications are required for this study. 


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8.2.3 Special Diet or Activities 
No special diets or activities are required for this study. 
8.3 
Examination Procedures 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
The following procedures will be performed (see Appendix 2 for description). 
Visit 1 = Day -10 ± 1, Screening 
 Informed consent/Health Information Portability and Accountability Act 
(HIPAA) consent 
 Demographic data, medical/medication, and ocular history 
 Urine Pregnancy Test (if applicable) 
 Ocular Surface Disease Index (OSDI) 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 Visual Analog Scale (VAS) 
 Best Corrected Visual Acuity (BCVA) 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness 
 Corneal sensitivity Cochet-Bonnet  
 Tear film break-up time (TFBUT) 
 Fluorescein staining (Ora Calibra® scale); regions: central, superior, inferior, 
temporal, nasal, corneal sum, conjunctival sum, and total eye score 
 Lissamine green staining (Ora Calibra® scale); regions: inferior, superior, central, 
temporal, nasal, corneal sum, conjunctival sum, and total eye score) 
 Review inclusion and exclusion criteria 
 Run-in (vehicle) dose 
 Dispense vehicle to all qualifying patients for BID dosing until Visit 2 
 Adverse Event Query 
 Schedule Visit 2 
Visit 2 = Day 1, Confirmation / Baseline 
 Study Drug Collection 
 Medical/medication update 
 Adverse event query 
 Ocular Surface Disease Index (OSDI) 
 Ora Calibra® Ocular Discomfort Scale 


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 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 VAS 
 BCVA 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness 
 Corneal Sensitivity (Cochet-Bonnet) 
 Tear Osmolarity 
 InflammaDry® (MMP-9) testing 
 Tear film break-up time (TFBUT) 
 Corneal and conjunctival fluorescein staining 
 Corneal and conjunctival lissamine green staining 
 Unanesthetized Schirmer’s Test  
 Intraocular Pressure (IOP) 
 Dilated fundoscopy 
 Review inclusion and exclusion criteria 
 Randomize qualifying subjects 
 Study treatment dose 
 Dispense study drug/placebo “A” bottle for BID dosing  
 Dispense dosing diary 
 Adverse Event Query 
 Schedule Visit 3 
Visit 3 = Day 8 ± 1, One Week Follow-Up 
 Study Drug/Diary Collection and Accountability 
 Medical/medication update 
 Adverse event query 
 OSDI 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 VAS  
 BCVA 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness 
 Corneal sensitivity (Cochet-Bonnet) 
 TFBUT 
 Corneal and conjunctival fluorescein staining 
 Corneal and conjunctival lissamine green staining 
 Unanesthetized Schirmer’s Test 


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 Study Drug/Diary Dispensation 
o Re-dispense subject’s “A” bottle 
 Adverse Event Query 
 Schedule Visit 4 
Visit 4 = Day 15 ± 1, Two Week Follow-Up 
 Study Drug/Diary Collection and Accountability 
 Medical/medication update 
 Adverse event query 
 Urine Pregnancy Test (if applicable) 
 OSDI 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 VAS 
 Best Corrected Visual Acuity 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness 
 Corneal Sensitivity (Cochet-Bonnet) 
 TFBUT 
 Corneal and conjunctival fluorescein staining 
 Corneal and conjunctival lissamine green staining 
 Unanesthetized Schirmer’s Test  
 Study Drug/Diary Dispensation 
o Dispense subject’s “B” bottle 
 Schedule Visit 5 
Visit 5 = Day 29 ± 2, Four Week Follow-Up and Study Exit 
 Study Drug/Diary Collection and Accountability 
 Medical/medication update 
 Adverse event query 
 Urine Pregnancy Test (if applicable) 
 OSDI 
 Ora Calibra® Ocular Discomfort Scale 
 Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire 
 VAS 
 BCVA 
 Slit lamp biomicroscopy 
 Ora Calibra® Conjunctival redness  


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 Corneal sensitivity (Cochet-Bonnet) 
 Tear Osmolarity 
 InflammaDry® (MMP-9) testing 
 TFBUT 
 Corneal and conjunctival fluorescein staining 
 Corneal and conjunctival lissamine green staining 
 Unanesthetized Schirmer’s Test 
 Intraocular Pressure (IOP) 
 Dilated fundoscopy 
 Blood Draw (optional) for enkephalin testing 
 Adverse Event Query 
 Study exit 
Adverse Events (AEs) (both elicited and observed) will be monitored throughout the 
study. All AEs (both elicited and observed) will be promptly reviewed by the investigator 
for accuracy and completeness. All AEs will be documented on the appropriate CRF. 
If a female has a positive pregnancy test during the study, then the investigator will notify 
Ora immediately. The investigator shall request from the subject and/or the subject’s 
physician copies of all related medical reports during the pregnancy and shall document 
the outcome of the pregnancy. The investigator will retain these reports together with the 
subject’s source documents and will provide a copy of all documentation to Ora. 
8.4 
Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
These visits may be performed in order to ensure subject safety. All procedures 
performed at an unscheduled visit will be recorded in the source documents and on the 
Unscheduled Visit CRF pages. Any procedure indicated in the CRF that is not performed 
should be indicated as “Not done.”  
Evaluations that may be conducted at an Unscheduled Visit include:  
 Slit-lamp Biomicroscopy;  
 Visual Acuity;  
 Intranasal Examination;  
 Urine Pregnancy Test (if applicable);  
 Assessment of AEs;  
 Assessment of concurrent medications and/or treatments; and  
 Any other assessments needed in the judgment of the investigator.  
 


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8.5 
Compliance with Protocol 
Subjects will be instructed on the proper use and storage of the study drug at Visits 1, 2, 
3, and 4, and provided with written instructions. Subject diaries and study drug will be 
collected at each visit from Visit 1 up to and including Visit 5 to assess subject 
compliance with the protocol. 
Subject dosing compliance will be determined by the subject’s response or lack thereof to 
the prompt “Was the dose taken?” in the subject diary. If more than 20% of the responses 
to the total expected dose-taken prompts are checked “no,” left blank, or missing, then 
the subject will be deemed noncompliant for dosing and a deviation recorded. In addition, 
if more than 20% of all expected diary symptom assessments are missed, then the subject 
will be deemed noncompliant and a diary deviation recorded. 
Subject’s bottles may also be weighed at each visit to determine dosing accountability. 
8.6 
Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
 
subject request/withdrawal 
 
AEs 
 
protocol violations 
 
administrative reasons (e.g., inability to continue, lost to follow up) 
 
sponsor termination of study 
 
other 
Note: In addition, any subject may be discontinued for any sound medical reason. 
Notification of a subject discontinuation and the reason for discontinuation will be made 
to Ora and will be clearly documented on the CRF. 
8.7 
Study Termination 
The study may be stopped at any time by the investigator and/or Ora. 
8.8 
Study Duration 
An individual subject’s participation will involve 5 visits over approximately 38 days. 


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8.9 
Monitoring and Quality Assurance 
For the conduct of this trial, an assigned Ora, Inc. CRA will conduct an initial SIV, 
providing an in-depth review of the protocol with emphasis that the trial will be 
conducted according to the pertinent regulatory requirements.  Interim monitoring visits 
(IMVs) are not planned, however to ensure patient safety and efficacy, weekly contact 
with PI or authorized delegate will occur in order to: 
 Confirm eligible subjects are being properly consented  
 Assess status and document any adverse events associated with the study 
procedures and IP.   Should there be any unexpected adverse events, or an 
abnormally high number of adverse events occurring among enrolled subjects, the 
CRA will alert the Lead CRA and Project Manager in order to determine whether 
an on-site IMV is warranted 
 Confirm administration and storage of IP is being conducted and monitored as per 
protocol design. 
At the conclusion of the trial, after all eligible/enrolled subjects have had their last on-site 
visit, the CRA will conduct a Close-Out Visit (COV).  During the COV the CRA will: 
 Review all ICFs 
 Assess data integrity by selecting a random sampling of 10% of total subjects 
enrolled and conduct a thorough review of source to verify adequacy of data 
collection (GDP), subject eligibility and safety (GCP).   
 CRA will query any discrepant data.  If any findings constitute Major protocol 
deviations, the Lead and PM will be notified to determine if additional data 
review is warranted. 
 Reconcile and return IP 
 Review and reconcile site’s ISF to Ora’s TMF. 
Further details of the study monitoring will be outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies and Ora, Inc. Quality Assurance 
and/or its designees may carry out on-site inspections and/or audits which may include 
source data checks. Therefore, direct access to the original source data will be required 
for inspections and/or audits. All inspections and audits will be carried out giving 
consideration to data protection as well as subject confidentiality to the extent that local, 
state, and federal laws apply. 


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9 
ADVERSE EVENTS 
9.1 
Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise 
from any use of the IP (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. An AE can arise from any delivery, implantation, or use of a medical device, 
including medical device failure, subject characteristics that may impact medical device 
performance (e.g., anatomical limitations), and therapeutic parameters (e.g., energy 
applied, sizing, dose release, and anatomic fit) associated with medical device use. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the source document and on the appropriate 
pages of the CRF. Any clinically relevant deterioration in clinical finding is considered 
an AE and must be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, and relationship to IP, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon indirect questioning.  
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an 
AE as determined by the investigator or reported to him/her by the subject. The 
assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
 
Mild: Event is noticeable to the subject, but is easily tolerated and does not 
interfere with the subject’s daily activities. 
 
Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
 
Severe: Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
9.1.2 Relationship to Investigational Product 
The relationship of each AE to the IP should be determined by the investigator using 
these explanations: 
 Suspected: A reasonable possibility exists that the IP caused the AE. A suspected 
AE can be further defined as: 


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 Definite: Relationship exists when the AE follows a reasonable sequence from 
the time of IP administration, follows a known response pattern of the drug 
class, is confirmed by improvement on stopping the IP and no other 
reasonable cause exists. 
 Probable: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, follows a known response pattern of the 
drug class, is confirmed by improvement on stopping the IP and the suspect IP 
is the most likely of all causes. 
 Possible: Relationship exists when the AE follows a reasonable sequence 
from the time of IP administration, but could also have been produced by the 
subject’s clinical state or by other drugs administered to the subject. 
 Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
 Not Related: Concurrent illness, concurrent medication, or other known cause 
is clearly responsible for the AE, the administration of the IP and the 
occurrence of the AE are not reasonably related in time, OR exposure to IP 
has not occurred. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that 
the IP caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. Types of evidence that would suggest a 
causal relationship between the IP and the AE event include: a single occurrence of an 
event that is uncommon and known to be strongly associated with IP exposure (e.g., 
angioedema, hepatic injury, Stevens-Johnson Syndrome); one or more occurrences of an 
event that is not commonly associated with IP exposure, but is otherwise uncommon in 
the population exposed to the IP (e.g., tendon rupture); an aggregate analysis of specific 
events observed in a clinical trial (such as known consequences of the underlying disease 
or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more 
frequently in the IP-treatment group than in a concurrent or historical control group. 
9.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
 Unexpected: An AE that is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed. 
 Expected:  An AE that is listed in the IB at the specificity and severity that has been 
observed. 
 Not applicable: An AE unrelated to the IP. 
AE events that are mentioned in the IB as occurring with a class of products or as 
anticipated from the pharmacological/mechanical (or other) properties of the product, but 
are not specifically mentioned as occurring with the particular product under 
investigation are to be considered unexpected. 


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The investigator should initially classify the expectedness of an AE, but the final 
classification is subject to the Medical Monitor’s determination. 
9.2 
Serious Adverse Events 
An AE is considered serious if, in the view of the investigator, it results in any of the 
following outcomes: 
 Death; 
 A life-threatening AE; 
Note: An AE is considered “life-threatening” if, in the view of the investigator its 
occurrence places the subject at immediate risk of death. It does not include an AE that, 
had it occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if less 
than 24 hours). For chronic or long-term inpatients, inpatient admission includes transfer 
within the hospital to an acute/intensive care inpatient unit. Inpatient hospitalization does 
not include: emergency room visits; outpatient/same-day/ambulatory procedures; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the 
initial admission as determined by the investigator or treating physician. 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
Note: A serious adverse event (SAE) specifically related to visual threat would be 
interpreted as any potential impairment or damage to the subject’s eyes (e.g., 
hemorrhage, retinal detachment, central corneal ulcer or damage to the optic nerve). 
 A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
9.3 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to Ora and the IRB/IEC as required by the 
IRB/IEC, federal, state, or local regulations and governing health authorities and recorded 
on the appropriate CRF. AE’s will be collected from first dose of study drug to 30 days 
after treatment discontinuation.   


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9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora and the IRB/IEC 
as required by the IRB/IEC, federal, state, or local regulations and governing health 
authorities. 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported. All information relevant to the SAE must be recorded on the 
appropriate CRFs. The investigator is obligated to pursue and obtain information 
requested by Ora in addition to that information reported on the CRF. All subjects 
experiencing a SAE must be followed up and the outcome reported. 
In the event of a SAE, the investigator must notify Ora immediately; obtain and maintain 
in his/her files all pertinent medical records, information, and medical judgments from 
colleagues who assisted in the treatment and follow-up of the subject; provide Ora with a 
complete case history, which includes a statement as to whether the event was or was not 
suspected to be related to the use of the IP; and inform the IRB of the SAE within their 
guidelines for reporting SAEs. 
Contact information for reporting SAEs and ADEs: 
 
Clinical Project Manager: Phoebe Carter 
Company: 
Ora, Inc. 
Office Telephone:  
(978) 685-8900 x9496 
Alternative Telephone: 
(978) 409-0955 
Office Facsimile: 
(978) 849-7371 
 
 
9.4 
Procedures for Unmasking (if applicable) 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment arm has been assigned to a subject. 
When possible (i.e., in non-emergent situations), Ora should be notified before 
unmasking study drug. Ora must be informed immediately about any unmasking event. 
If the investigator identifies a medical need for unmasking the treatment assignment of a 
subject, he should contact Ora prior to unmasking the identity of the IP, if possible. Ora 
will ask the site to complete and send them the Unmasking Request Form. Ora will 


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determine if the unmasking request should be granted. The result of the request will be 
documented on the Unmasking Request Form. If approval is granted to unmask a subject, 
written permission via the Unmasking Request Form will be provided to the investigator. 
The investigator will unmask the subject using the unmasking report. The investigator 
will complete the Unmasking Memo form and include it in the subject’s study file and 
provide a copy for the Trial Master File (TMF). For each unmasked request, the reason, 
date, signature, and name of the person who unmasked the subject, must be noted in the 
subject’s study file. Unmasked subjects will be discontinued from the study. 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the investigator does not expect any further 
improvement or worsening of the AE. If the subject is lost to follow-up, the investigator 
should make 3 reasonable attempts to contact the subject via telephone, post, or certified 
mail. All follow-up will be documented in the subject’s source document. Non-serious 
AEs identified on the last scheduled contact must be recorded on the AE CRF with the 
status noted.  
If the investigator becomes aware of any new information regarding an existing SAE 
(i.e., resolution, change in condition, or new treatment), a new SAE/Unanticipated Report 
Form must be completed and faxed to Ora within 24 hours of the site’s awareness of the 
new information. The original SAE form is not to be altered. The report should describe 
whether the event has resolved or continues and how the event was treated. 
10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
Analysis Populations 
 Modified Intent-to-Treat Population – The modified intent-to-treat (mITT) 
population includes all randomized subjects with at least one post visit 2 study 
assessment. Efficacy analysis will be performed on the mITT population. 
Subjects in the mITT population will be analyzed as randomized. 
 
 Safety Population – The safety population includes all subjects who have 
received at least one dose of the investigational product. Subjects in the Safety 
population will be analyzed as treated.  
The statistical analysis of safety data will be performed for the safety population. The 
analysis of baseline and all efficacy data will be performed for the mITT population.  
Sample Size: 


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With a sample size of 60 subjects in the Safety and Efficacy Assessment, the study 
will have 79% probability of detecting AEs occurring at a rate of 5% or more in either 
treatment arm. 
Multiplicity Consideration: 
There will be no adjustments for multiple endpoints or multiple treatment 
comparisons for this early phase, exploratory study. 
Safety Variables: 
Frequencies and percentages of subjects with treatment-emergent adverse events 
(TEAEs), serious TEAEs, and TEAEs causing premature discontinuation will be 
provided by treatment group. An AE is treatment emergent if it occurs or worsens 
after the first dose of study treatment. Separate summaries will be provided for ocular 
specific and all AEs (including systemic). 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, corneal 
sensitivity, dilated fundoscopy, intraocular pressure will be summarized by treatment 
group and visit using descriptive statistics.  Changes or shifts from baseline will also 
be summarized where appropriate. For assessments performed by eye, study eye and 
fellow eye may be summarized separately. Summaries of the comfort data from the 
Comfort Assessment of the study will be performed on the safety population from 
that Assessment. The statistical analysis of safety data will be performed for the 
safety population, separately for the Comfort Assessment and the Safety and Efficacy 
Assessment of the study. The analysis of baseline and all efficacy data in the Safety 
and Efficacy Assessment of the study will be performed for the mITT population.  
The efficacy analyses may also be performed on the PP population as sensitivity 
analyses. 
 
10.2 Statistical Hypotheses 
For each efficacy endpoint and time point, the statistical hypotheses are as follows: 
H0: There is no difference between the Naltrexone Ophthalmic Solution treatment 
group and placebo for the respective endpoint. 
H1: There is a difference between the Naltrexone Ophthalmic Solution treatment 
group and placebo for the respective endpoint. A difference in favor of Naltrexone 
Ophthalmic Solutions will be considered a success for that endpoint. 
10.3  Sample Size 
The study is not powered to show statistical differences for any of the efficacy 
endpoints. The sample size was determined based on prior clinical trial experience 
with in subjects with dry eye syndrome and is deemed to be robust sufficient to 


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evaluate the safety and tolerability of Naltrexone Ophthalmic Solution in this 
population and to gather efficacy data that will aid in powering future clinical trials. 
With a sample size of 60 subjects in the Safety and Efficacy Assessment, the study 
will have 79% probability of detecting AEs occurring at a rate of 5% or more in either 
treatment arm.  
10.4 Statistical Analysis 
10.4.1 General Considerations 
The quantitative variables will be summarized using number of subjects 
(n), mean, median, standard deviation, minimum and maximum. The 
qualitative variables will be summarized using counts and percentages.  
All summaries will be presented by treatment group.. Summaries will be 
provided for demographics, baseline medical history, concurrent therapies, 
and subject disposition. 
Baseline measures are defined as the last measure prior to the initiation of 
study treatment, usually at Visit 2.  
10.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, 
the unit of analysis will be the worst eye. 
10.4.3 Missing Data 
The efficacy analyses will be performed using observed data.         
10.4.4 Multiplicity Consideration 
There will be no adjustments for multiple endpoints or multiple treatment 
comparisons for this early phase, exploratory study. 
10.4.5 Safety Variables 
Frequencies and percentages of subjects with treatment-emergent adverse 
events (TEAEs), serious TEAEs, and TEAEs causing premature 
discontinuation will be provided by treatment group. An AE is treatment 
emergent if it occurs or worsens after the first dose of study treatment. 
Separate summaries will be provided for ocular specific and all AEs 
(including systemic). 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, 
corneal sensitivity, dilated fundoscopy, intraocular pressure will be 
summarized by treatment group and visit using descriptive statistics.  
Changes or shifts from baseline will also be summarized where 
appropriate. For assessments performed by eye, study eye and fellow eye 


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may be summarized separately. Summaries of the comfort data from the 
Comfort Assessment of the study will be performed on the safety 
population from that Assessment. The statistical analysis of safety data 
will be performed for the safety population, separately for the Comfort 
Assessment and the Safety and Efficacy Assessment of the study. The 
analysis of baseline and all efficacy data in the Safety and Efficacy 
Assessment of the study will be performed for the mITT population.  The 
efficacy analyses may also be performed on the PP population as 
sensitivity analyses. 
10.4.6 Efficacy Analyses 
The continuous and ordinal secondary efficacy variables collected at each 
visit will be summarized descriptively (n, mean, standard deviation, 
median, min and max), and analyzed with two-sample t-tests comparing 
each of the active treatment groups to placebo. All visit-based data will be 
analyzed at each visit and change from baseline. A Wilcoxon rank sum 
test and an ANCOVA model adjusting for baseline may be assessed where 
appropriate.  
A full statistical analysis plan (SAP) will be finalized before database lock 
and unmasking.   
10.4.7 Interim Analyses 
No interim analyses are planned. 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonisation (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki. In addition, all 
applicable local, state, and federal requirements relevant to the use of IP in the countries 
involved will be adhered to. 
11.1 
Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures are 
initiated. Signed and dated written informed consent must be obtained from each subject 
and/or from the subject’s parent or legal guardian prior to enrollment into the study. If the 
subject is under the legal age of consent, the consent form must be signed by a legal 
guardian or as required by state and/or local laws and regulations. 
All informed consent/assent forms must be approved for use by Ora and receive 
approval/favorable opinion from an IRB/IEC prior to their use. If the consent form 


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requires revision (e.g., due to a protocol amendment or significant new safety 
information), it is the investigator’s responsibility to ensure that the amended informed 
consent is reviewed and approved by Ora prior to submission to the governing IRB/IEC 
and that it is read, signed and dated by all subjects subsequently enrolled in the study as 
well as those currently enrolled in the study. 
If informed consent is taken under special circumstances (oral informed consent), then 
the procedures to be followed must be determined by Ora and provided in writing by Ora 
prior to the consent process. 
11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 
56.103). The investigator must obtain appropriate IRB approval before initiating the 
study and re-approval at least annually. 
Only an IRB/IEC approved version of the informed consent form will be used. 
11.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
11.3 
Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora and the IRB/IEC 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the subject’s original 
medical and study records for verification of the data and/or clinical trial procedures. 
Access to this information will be permitted to the aforementioned individuals to the 
extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed, but the subject’s 
identity will not be disclosed in these documents. 
11.4 
Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s study subject files, as well as the results of diagnostic tests such as X-
rays, laboratory tests, and EKGs. The investigator’s copy of the CRFs serves as the 
investigator’s record of a subject’s study-related data. 


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11.4.1 Retention of Documentation 
All study related correspondence, subject records, consent forms, record of the 
distribution and use of all IP, and copies of CRFs should be maintained on file for at least 
two years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region; or until at 
least two years have elapsed since the formal discontinuation of clinical development of 
the IP. These documents will be retained for a longer period if required by the applicable 
regulatory requirements. 
If the investigator retires, relocates, or for other reasons withdraws from the responsibility 
of keeping study records, custody must be transferred to a person who will accept the 
responsibility.  
11.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product 
11.5.1 Labeling/Packaging 
For the run-in period, 1 bottle of will be dispensed for two weeks of BID dosing. 
Investigational drug will be packaged and labeled into clinical kits. Study drug will be 
provided as subjects’ kits containing 1 bottle of Naltrexone Ophthalmic Solution or 
Vehicle Ophthalmic Solution. The required medication until the next visit will be 
dispensed to the subject (see Section 7.1.2 for details). The kit with remaining medication 
will be kept at the site. 
11.5.2 Storage of Investigational Product 
The IP must be stored in a secure area accessible only to the investigator and his/her 
designees. The IP will be administered only to subjects entered into the clinical study, in 
accordance with the conditions specified in this protocol. 
Study drug must be refrigerated, protected from light, and secured at the investigational 
site in a locked container. Subjects should be instructed to store study drug in the same 
manner, but at room temperature, at home. 
11.5.3 Accountability of Investigational Product 
The IP is to only be prescribed by the principal investigator or his/her named sub-
investigator(s), and is to only be used in accordance with this protocol. The IP must only 
be distributed to subjects properly qualified under this protocol to receive IP. 
The investigator must keep an accurate accounting of the IP received from the supplier. 
This includes the amount of IP dispensed to subjects, amount of IP returned to the 
investigator by the subjects, and the amount returned or disposed upon the completion of 
the study. A detailed inventory must be completed for the IP. 


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11.5.4 Return or Disposal of Investigational Product 
All IP will be returned to the sponsor or their designee or destroyed at the study site. The 
return or disposal of IP will be specified in writing. 
11.6 
Recording of Data on Source Documents and Case Reports Forms (CRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s CRF, source document, and all study-related material. All 
study data should also be attributable, legible, contemporaneous, and original. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g., by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when, by adding to the correction 
his/her initials as well as the date of the correction. 
11.7 
Handling of Biological Specimens 
Not Applicable.  
11.8 
Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study.  
 
 
 
 
 
 
 
 
 


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REFERENCES 
Liang D, Sassani JW, McLaughlin PJ, Zagon IS. Topical Application of Naltrexone to 
the Ocular Surface of Healthy Volunteers: A Tolerability Study. J Ocul Pharmacol Ther. 
2016 Mar;32(2):127-32. doi: 10.1089/jop.2015.0070. Epub 2016 Jan 7. 
Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM. Prevalence of dry eye among an 
elderly Chinese population in Taiwan: the Shihpai Eye Study. Ophthalmology. 2003 
Jun;110(6):1096-101. 
McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The 
epidemiology of dry eye in Melbourne, Australia. Ophthalmology. 1998 
Jun;105(6):1114-9. 
Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome 
among US women. Am J Ophthalmol. 2003 Aug;136(2):318-26. 
Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among 
US men: estimates from the Physicians' Health Studies. Arch Ophthalmol. 2009 
Jun;127(6):763-8. doi: 10.1001/archophthalmol.2009.103. 
 
 


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13 
APPENDICES 
APPENDIX 1: SCHEDULE OF VISITS AND MEASUREMENTS 
Procedure 
Visit 1 
Day-10 
±1 
Visit 2 
Day 1 
Visit 3 
Day 8 ± 1 
Visit 4 
Day 15 ± 
1 
Visit 5 
Day 29 
±2 
Informed Consent 
X 
 
 
 
 
Demographic Data 
X 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
Medical/Medication History 
Update 
 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
Urine pregnancy test 
X 
 
 
 
X 
OSDI© questionnaire 
X 
X 
X 
X 
X 
Ora Calibra® Ocular Discomfort 
Scale 
X 
X 
X 
X 
X 
Ora Calibra® Ocular Discomfort 
& 4 Symptom Questionnaire 
X 
X 
X 
X 
X 
Visual Acuity Scale (VAS) 
X 
X 
X 
X 
X 
BCVA 
X 
X 
X 
X 
X 
Slit lamp biomicroscopy 
X 
X 
X 
X 
X 
Ora Calibra® Conjunctival 
redness 
X 
X 
X 
X 
X 
Corneal Sensitivity (Cochet-
Bonnet) 
X 
X 
X 
X 
X 
Tear Osmolarity 
 
X 
 
 
X 
InflammaDry® (MMP-9) testing 
 
X 
 
 
X 
TFBUT 
X 
X 
X 
X 
X 


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Corneal and conjunctival 
fluorescein staining 
X 
X 
X 
X 
X 
Corneal and conjunctival 
lissamine green staining 
X 
X 
X 
X 
X 
Schirmer’s Test 
 
X 
X 
X 
X 
IOP 
 
X 
 
 
X 
Dilated Fundoscopy 
 
X 
 
 
X 
ENK blood draw (optional) 
 
 
 
 
X 
Review Eligibility Criteria 
X 
X 
X 
X 
X 
Run-in (vehicle) instillation at 
study site 
X 
 
 
 
 
Study drug/placebo instillation at 
study site 
 
X 
X 
X 
X 
Run-in (vehicle) Dispensed 
X 
 
 
 
 
Run-in (vehicle) Returned  
 
X 
 
 
 
Adverse Event Query 
X 
X 
X 
X 
X 
Investigational Product 
Dispensed 
 
X 
X 
X 
 
Investigational Product Returned 
 
 
X 
X 
 X 
Dosing Diary Dispensed  
X 
X 
X 
X 
 
Exit from Study 
 
 
 
 
X 


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APPENDIX 2: EXAMINATION PROCEDURES, TESTS, EQUIPMENT, AND 
TECHNIQUES  
Visual Acuity Procedures (ETDRS Chart) 
LogMAR visual acuity (VA) must be assessed using an Early Treatment Diabetic 
Retinopathy Study (ETDRS) chart. The procedure used will be consistent with the 
recommendations provided for using the ETDRS eye chart. VA should be evaluated at 
the beginning of each visit in the study (i.e., prior to slit-lamp examination). VA testing 
should be done with most recent correction. 
Equipment 
The VA chart to be used is the ETDRS chart. If smaller reproduction (18" by 18", e.g., 
from Prevent Blindness) wall charts are used, the subject viewing distance should be 
exactly 10 feet (or as specified by the manufacturer). In ALL cases, for purposes of 
standardizing the testing conditions during the study, all sites must use only the 'R' charts, 
and the right eye should be tested first. For reflectance (wall) charts, the chart should be 
placed frontally and well-illuminated. 
Measurement Technique 
The chart should be at a comfortable viewing angle. The right eye should be tested first. 
The subject should attempt to read each letter, line-by-line, left to right, beginning with 
line 1 at the top of the chart. The subject should be told that the chart has letters only, no 
numbers. If the subject reads a number, he or she should be reminded that the chart 
contains no numbers, and the examiner should then request a letter in lieu of the number. 
The subject should be asked to read slowly, so as to achieve the best identification of 
each letter. He/she is not to proceed to the next letter until he/she has given a definite 
response. 
If the subject changes a response (e.g., that was a "C" not an "O") before he has read 
aloud the next letter, then the change must be accepted. If the subject changes a response 
having read the next letter, then the change is not to be accepted. The examiner should 
never point to the chart or to specific letters on the chart during the test. 
A maximum effort should be made to identify each letter on the chart. When the subject 
says he or she cannot read a letter, he or she should be encouraged to guess. If the subject 
identifies a letter as 1 of 2 letters, he or she should be asked to choose 1 letter and, if 
necessary, to guess. When it becomes evident that no further meaningful readings can be 
made, despite encouragement to read or guess, the examiner should stop the test for that 
eye. However, all letters on the last line should be attempted as letter difficulties vary and 
the last may be the only one read correctly. The number of letters missed or read 
incorrectly should be noted. 
 


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LogMAR Visual Acuity Calculations 
The last line in which a letter is read correctly will be taken as the base logMAR reading. 
To this value will be added the number "N x 0.02" where 'N' represents the total number 
of letters missed up to and included in the last line read. This total sum represents the 
logMAR VA for that eye. 
For example: Subject correctly reads 4 of 5 letters on the 0.2 line, and 2 of 5 letters on the 
0.1 line. 
Base logMAR 
= 0.1 
N (total number of letters incorrect on line 0.2 as 
well as 0.1) 
= 4 
N x T (T=0.02) 
= 0.08 
Base logMAR + (N x T) 
= 0.1 + 0.08 
logMAR VA 
= 0.18 
Repeat the procedure for the left eye. 
In order to provide standardized and well-controlled assessments of VA during the study, 
all VA assessments at a single site must be consistently done using the same lighting 
conditions and same correction if possible during the entire study. If the same correction 
cannot be used (i.e., a subject forgets his glasses), the reason for the change in correction 
should be documented. 
Note: A clinically significant visual acuity decrease (defined as an increase of 0.22 or 
greater in logMAR score) from baseline (Visit 1) will be considered an Adverse Event. 
Slit Lamp Biomicroscopy Procedures 
Slit lamp biomicroscopic observations will be graded as Normal or Abnormal. Abnormal 
findings will be categorized as clinically significant (findings that may interfere with 
study parameters or otherwise confound the data as determined by the investigator) or not 
clinically significant (NCS). The following will be examined:  
 Cornea  
 Conjunctiva 
 Anterior Chamber 
 Iris 
 Lens 


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 Eyelid 
External magnification and biomicroscopy will be performed using a slit-lamp. 
Magnification will be consistent with standard clinical practice. The subject will be 
seated. 
Dilated Fundoscopy 
Dilated fundus exams will be performed using indirect ophthalmoscopy. The investigator 
will make observations of the vitreous, retina, macula, choroid and optic nerve.   
Observations will be graded as Normal or Abnormal. Abnormal findings that are 
clinically significant (as determined by the investigator that may interfere with study 
parameters or otherwise confound the data) and those that are not clinically significant 
will be described. An indirect Fundoscopy examination should be performed if retinal 
disease is detected. A 78 or 90 diopter lens should also be used as needed.  
 Vitreous: Examination should emphasize the visual axis.  
 Retina, Macula, Choroid: Include an observation of the retina and its blood 
vessels. Eyes should be excluded from the study if active inflammation is present.  
 Optic Nerve: Significant damage or cupping to the optic nerve should be noted. 
 
It is recommended that tropicamide 1% ophthalmic solution be used to dilate subjects. 
The use of cyclopentolate 1% ophthalmic solution is recommended as secondary dilating 
medication, should the need arise.   
Intraocular Pressure 
Intraocular pressure (IOP) will be measured in each eye by contact tonometry by the 
examiner and the results will be recorded in mmHg.  A single measurement is made to 
obtain a determination of IOP.  The same tonometer employing the investigator’s 
standard technique will be used throughout the study.  In addition, all reasonable efforts 
will be made to have the same examiner obtain all IOP measurements for a given subject. 
 


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InflammaDry® 
Levels of MMP-9 will be measured in each eye using InflammaDry at Visit 1, Visit 3 and 
Visit 5. The test will be recorded as either positive or negative. Sample should not be taken 
within two hours of any medication being instilled in either eye. 
1. Open the Sterile Sample Collector (Package I) 
2. Use the sampling fleece, gently dab along the palpebral conjunctiva until saturated 
3. Open the Test Cassette (Package II), remove the protective cap, and insert the sampling 
fleece where indicated, ensuring to press down to hear the double click. 
4. Place the absorbent tip in the buffer solution for at least 20 seconds. 
5. Put the protective cover back over the Test Cassette and lay flat for at least 10 minutes 
before interpreting results. 
6. Repeat test in other eye. 
 


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Tear Osmolarity 
Tear osmolarity will be measured in each eye using the TearLab© osmolarity system.  Tear 
osmolarity will be taken once from the temporal canthus of each eye and the measurement 
will be recorded. A second reading may be taken if first reading is out of range.  A 
maximum of 2 attempts will be made per eye. Tear osmolarity will be measured in 
mOsm/L. 
 
1. Turn the Reader on. 
 
2. Remove a Test Card from its package. 
 
3. Attach a Test Card by sliding the wings of the Test Card onto the TearLab Pen. The 
Pen will light up and beep when the card is attached properly. The green light will stay on 
until you collect tears or the Pen times out (after two minutes). 
 
4. While holding the Test Card wings, remove the protective cover from the Test Card 
just before tear collection. 
 
5. Collect a tear fluid sample as described in the TearLab Osmolarity System User 
Manual or Quick Reference Guide. IMPORTANT: Any Test Card that does not contain a 
protective cover should not be used for subject testing. 
 
6. Dock the Pen into the Reader within 40 seconds. Do NOT remove the Test Card from 
the Pen before docking or all data will be lost. 
 
7. Locate the code on the top of the Test Card. Press the RECALL key below the up or 
down arrows on the Reader keypad to match the Test Card code. Press OK or wait eight 
seconds for the Reader to accept the code. 
 
8. The Reader will display the Test Result in a few seconds. Record the Test Result in the 
source document. 
 
9. Remove the Test Card by pressing your thumb forward on top of the Test Card. Do not 
pull from the wings. Dispose in an appropriate container. 
 
10. Repeat in the other eye for a total of 2 measurements. 
 
 


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Ora Calibra® Ocular Discomfort Scale for Dry Eye 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
Ocular discomfort scores will be subjectively graded by the subjects according to the 
following scale, rating each eye separately.   
0 
No discomfort 
1 
Intermittent awareness 
2 
Constant awareness 
3 
Intermittent discomfort 
4 
Constant discomfort 
 
Ora Calibra® Ocular Discomfort & 4-Symptom Questionnaire for Dry Eye 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
Subjects will rate the severity of each of the following symptoms, with regard to how 
both their eyes feel, in general – overall ocular discomfort, burning, dryness, grittiness 
and stinging according to the following 6-point (0 to 5) scale where 0 = none and 5 = 
worst. 
0 
 
1 
 
2 
 
3 
 
4 
 
5 
(None)  
 
 
 
 
 
 
 
      (Worst) 
 
 
 
 
 
 
 


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Visual Analogue Scale (VAS) 
Subjects will be asked the following questions regarding ocular discomfort (unrelated to 
study drug instillation) at all visits.  
The subject will be asked to rate each ocular symptom due to ocular dryness by placing a 
vertical mark on the horizontal line to indicate the level of discomfort. 0% corresponds to 
“no discomfort” and 100% corresponds to “maximal discomfort” 
 
 
 
 


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Ocular Surface and Disease Index (OSDI) © for Dry Eye 
 
 


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Ora proprietary scales – Not for distribution without permission 
Ora Calibra® Conjunctival Redness Scale for Dry Eye 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
None  
0 = Normal, without vasodilation 
Trace  
1 = Trace ciliary or conjunctival vasodilation 
Mild  
2 = Broad ciliary vasodilation; 
Moderate  
3 = Broad ciliary and slight, horizontal conjunctival vasodilation 
Severe  
4 = Broad ciliary and prominent, horizontal conjunctival 
vasodilation 
Half (0.5) unit increments are allowed. 
 
Ora proprietary scale – Not for distribution without permission 
Tear Film Break-Up Time (TFBUT)  
The examiner will instill 5 L of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye.  To thoroughly mix the fluorescein with 
the tear film, the subject will be instructed to blink several times.  In order to achieve 
maximum fluorescence, the examiner should wait approximately 30 seconds after 
instillation before evaluating TFBUT.    
With the aid of a slit-lamp, the examiner will monitor the integrity of the tear film, noting 
the time it takes to form micelles from the time that the eye is opened.  TFBUT will be 
measured in seconds using a stopwatch and a digital image recording system for the right 
eye followed by the left eye.  A Wratten #12 yellow filter will be used to enhance the 
ability to grade TFBUT.   
For each eye, 2 measurements will be taken and averaged unless the 2 measurements are 
> 2 seconds apart and are each < 10 seconds, in which case, a third measurement would 
be taken and the 2 closest of the 3 would be averaged. 


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Fluorescein Staining  
The examiner will instill 5 L of 2% preservative-free sodium fluorescein solution into 
the inferior conjunctival cul-de-sac of each eye. In order to achieve maximum 
fluorescence, the examiner should wait approximately 3-5 minutes after instillation 
before evaluating fluorescein staining. A Wratten #12 yellow filter will be used to 
enhance the ability to grade fluorescein staining. The staining will be graded with the Ora 
Calibra® Corneal and Conjunctival Staining Scale and NEI scale. Digital images of 
fluorescein staining may be taken for digital analysis. 
 
Ora proprietary scale – Not for distribution without permission 
Ora Calibra® Corneal and Conjunctival Staining Scale for Grading of Fluorescein 
Staining 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
The following scale will be used to grade staining of the ocular surface (areas A, B, C, D, 
and E). Half (0.5) grade increments may be used.  
None  
0 = no staining 
Trace  
1 = occasional 
Mild  
2 = countable 
Moderate  
3 = uncountable, but not confluent 
Severe  
4 = confluent 
Staining areas: 
 
 
 


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Staining Areas Ocular Structure 
Position 
A – Inferior 
Cornea 
4-8 o’clock, extending 2 mm onto the 
conjunctiva 
Limbus/Conjunctiva 
4-8 o’clock, extending 2 mm towards 
the center 
B – Superior 
Cornea 
8-4 o’clock, extending 3 mm onto the 
conjunctiva 
Limbus/Conjunctiva 
8-10 o’clock and 2-4 o’clock, extending 
1 mm onto the conjunctiva; 
10-2 o’clock, extending 2 mm onto the 
conjunctiva 
C – Central 
Cornea 
Central cornea 
D – Temporal 
Conjunctiva 
Triangular wedge of temporal 
conjunctiva 
E – Nasal 
Conjunctiva 
Triangular wedge of nasal conjunctiva 
 
NEI/Industry Workshop Scale for Grading of Fluorescein Staining 
Score each of 5 areas on the cornea of each eye.  
Diagram of the division of the corneal surface for measuring fluorescein uptake. A 
standardized grading system of 0-3 is used for each of the 5 areas on each cornea. Grade 
0 will be specified when no staining is present. The maximum score is 15. 


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Ora proprietary scale – Not for distribution without permission 
Lissamine Green Staining  
The Investigator will instill 10 L of lissamine green solution into the inferior 
conjunctival cul-de-sac and wait approximately 30 seconds before evaluating staining. 
The subject will be instructed to blink several times to distribute the lissamine green. The 
staining will be graded with the Ora Calibra® Corneal and Conjunctival Staining Scale as 
well as the NEI scale. Digital images of lissamine green staining may be taken for digital 
analysis. 
Ora Calibra® Corneal and Conjunctival Staining Scale for Grading of Lissamine 
Green Staining 
This procedure will be performed according to Ora, Inc. SOPs and/or guidance 
documents. 
The following scale will be used to grade staining of the ocular surface (areas A, B, C, D, 
and E). Half (0.5) grade increments may be used.  
None  
0 = no staining 
Trace  
1 = occasional 
Mild  
2 = countable 
Moderate  
3 = uncountable, but not confluent 
Severe  
4 = confluent 
Staining areas: 
 
 
 


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Staining Areas Ocular Structure 
Position 
A – Inferior 
Cornea 
4-8 o’clock, extending 2 mm onto the 
conjunctiva 
Limbus/Conjunctiva 
4-8 o’clock, extending 2 mm towards 
the center 
B – Superior 
Cornea 
8-4 o’clock, extending 3 mm onto the 
conjunctiva 
Limbus/Conjunctiva 
8-10 o’clock and 2-4 o’clock, extending 
1 mm onto the conjunctiva; 
10-2 o’clock, extending 2 mm onto the 
conjunctiva 
C – Central 
Cornea 
Central cornea 
D – Temporal 
Conjunctiva 
Triangular wedge of temporal 
conjunctiva 
E – Nasal 
Conjunctiva 
Triangular wedge of nasal conjunctiva 
NEI/Industry Workshop Scale for Grading of Lissamine Green Staining 
The nasal and temporal conjunctivae are divided into 3 segments as diagrammed. Score 
each of the 6 areas of the conjunctiva of each eye.  
1 – Temporal 
2 – Superior Temporal 
3 – Inferior Temporal 
4 – Superior Nasal 
5 – Inferior Nasal 
6 – Nasal 


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Right Eye 
Left Eye 
 
 
A standardized grading system of 0 - 3 is used for each of the 6 areas on each 
conjunctiva. Grade 0 will be specified when no staining is present. The maximum score is 
18. 
Unanesthetized Schirmer’s Test 
Schirmer Tear Test will be performed according to the following procedure: 
 Using a sterile Tear Flo Schirmer test strip (Rose Enterprises), a bend in the strip 
will be made in line with the notch in the strip. 
 The subject will be instructed to gaze up and in. 
 The Schirmer test strip will be placed in the lower temporal lid margin of each 
eye such that the strip fits tightly. Subjects will be instructed to close their eyes. 
 After 5 minutes have elapsed, the Schirmer strip will be removed. The length of 
the moistened area will be recorded (mm) for each eye. 
Corneal Sensitivity  
The aesthesiometer (Cochet–Bonnet) is a nylon thread contained in a pen–like case that 
can be extended specific distances from the tip of the case. The following steps will be 
followed by the examiner for evaluating corneal sensitivity: 
1. Remove Cochet–Bonnet from box. 
 
2 
4 
 1 
3 
5 
6 
  
4 
2 
6 
5 
3 
1 


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2. Extend the filament to 60 mm (the filament should not have bends in it – if it does, 
the readings will be incorrect and the filament should not be used). 
3. The examiner will inform the subject that a thin delicate plastic filament will be used 
to test their corneal sensitivity and that they will feel the sensation similar to a strand 
of hair on their eye. (If the subject is hesitant, a spot on the subject’s hand will be 
cleaned with an alcohol pad and the filament touched to the hand to demonstrate the 
painless contact). 
4. The examiner will instruct the subject to say “Yes” when they feel sensation on their 
eyeball.  
5. The examiner will place their free hand on the cheek below the eye being measured to 
stabilize subject’s head position. 
6. The examiner will position their hand with the device such that the filament is normal 
(90 degree angle with corneal surface). The device should be between the examiner’s 
index, middle finger, and thumb. 
7. The examiner will extend fingers such that the filament applies gentle pressure on the 
central corneal surface. The examiner will then ask subject if they can perceive the 
filament touching the central corneal surface. 
If the subject responds “Yes”, the examiner will ensure the response is valid by 
performing a sham (not touching the cornea) application and also confirm that 
response was not due to eyelids touching the filament.  
If the subject responds “No”, then the filament is shortened the length by 5mm and 
reapplied to the cornea. 
If the subject responds “Yes”, record length; if the subject responds “No”, go to  
step b. 
Step 7 is repeated 3 times. 
The filament is retracted such that only 10 mm are exposed. 
The tip is wiped with an alcohol pad gently ENSURING that it does NOT bend the 
filament.  
The alcohol is allowed to dry before reusing device (alcohol can cause corneal abrasions). 
 
 


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Enkephalin Blood Draw (optional) 
Subjects may have their blood drawn at Visit 5 for testing of enkephalin levels. It is 
estimated that 1-2 mLs will be drawn for analysis. Further details on sample processing 
will be provided in a separate manual as applicable.  
 
 
 
 
 


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APPENDIX 3: SUBJECT DIARY  
 


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APPENDIX 4: AMENDMENT SUMMARY  
 
 


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APPENDIX 5: APPROVALS 
 
Protocol Title: 
A Single-Center, Randomized, Double Masked, Placebo 
Controlled Clinical Study to Assess the Safety and Efficacy of 
Topical Naltrexone Ophthalmic Solution on the Signs and 
Symptoms of Dry Eye in Diabetic Subjects 
Protocol Number: 
DDES001 
Final Date: 
21 June 2018 
This clinical study protocol was subject to critical review and has been approved by the 
investigator. The following personnel contributed to writing and/or approving this 
protocol. 
Signed: 
 
 
Date:  
 
Mike Shine 
CEO, Ocunova  
Signed: 
 
 
Date:  
 
George W. Ousler, III 
VP, Dry Eye, Ora, Inc.  
 
Signed: 
 
 
Date:  
 
Michael Watson  
Director, Dry Eye, Ora, Inc.  
Signed: 
 
 
Date:  
 
Phoebe Carter 
Clinical Project Manager, Dry Eye, Ora, Inc.  
Signed: 
 
 
Date:  
 
Eugene McLaurin, MD 
Total Eye Care, PA 
 
 


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APPENDIX 6: INVESTIGATOR’S SIGNATURE 
 
Protocol Title: 
A Single-Center, Randomized, Double Masked, Placebo 
Controlled Clinical Study to Assess the Safety and Efficacy of 
Topical Naltrexone Ophthalmic Solution on the Signs and 
Symptoms of Dry Eye in Diabetic Subjects 
Protocol Number: 
DDES001 
Final Date: 
21 June 2018  
I agree to implement and conduct the study diligently and in strict compliance with the 
protocol, good clinical practices and all applicable laws and regulations. I agree to 
maintain all information supplied by Ora and the sponsor in confidence and, when this 
information is submitted to an Institutional Review Board (IRB), Ethical Review 
Committee (ERC) or another group, it will be submitted with a designation that the 
material is confidential. 
I have read this protocol in its entirety, including the above statement, and I agree to all 
aspects. 
Signed: 
 
 
Date:  
 
Dr. Eugene McLaurin 
Principal Investigator  
Total Eye Care, PA 
6060 Primacy Pkwy, Memphis, TN 38119 
 (901) 761-4620