Clinical trial NCT02980224
Conditions: Dry Eye
Sponsor: OmegaD LLC
Start date: 2016-10-01; Completion date: 2017-02-01
Enrollment: 180 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3 study to evaluate the safety and efficacy of OmegaD softgels for the treatment of dry eye disease. A daily dose of 2 OmegaD softgels dosed orally BID will be compared to 2 placebo softgels dosed orally BID for 84 days. Approximately 164 subjects will be evaluated for their signs and symptoms of dry eye disease and for safety throughout the study.

Detailed description:
Inflammation is a key component of dry eye disease. Increasing the systemic levels of omega-3 fatty acids relative to omega-6 levels can mediate immune responses. Evaluating whether omega-3 supplementation can improve dry eye disease signs, symptoms and associated measures of inflammation may present a new therapeutic option for dry eye disease.

The primary objective of this study is to evaluate the safety and efficacy of twice daily (BID) dosing of OmegaD softgels in subjects with dry eye disease.

Male and female subjects between 18 years and 90 years of age, with patient-reported dry eye symptoms and a clinical diagnosis of dry eye disease supported by global clinical assessment will be screened and enrolled. Each subject must have, in at least one eye, tear osmolarity of ≥ 312 mOsm/L and meibomian gland dysfunction as defined by a grade of 1 or 2 on the meibomian orifice size scale at both Screening and Baseline in at least one eye. In addition, Tear break up time (TBUT) must be ≤ 7 seconds in both eyes at both Screening and Baseline and the Schirmer's test score in both eye(s) must be ≥ 5 mm at Baseline.

Approximately 164 subjects will be randomized (1:1) to 1 of 2 treatment arms and treated for 84 days (12 weeks) with either OmegaD softgels; 2 softgels BID or placebo softgels; 2 softgels BID. The study will be double-masked with OmegaD and placebo being identical-appearing softgels.

Subjects will participate in safety and efficacy assessments throughout the study. Efficacy assessments will include, tear osmolarity, meibomian gland dysfunction grading, TBUT, Schirmer's Test, and dry eye symptoms based on the OSDI questionnaire, Safety assessments will include, slit lamp examination and adverse events.

Arms: arm 1: OmegaD Softgels arm 2: Placebo Softgels
Interventions: intervention 1: OmegaD intervention 2: Placebo
Intervention descriptions: intervention 1: OmegaD Softgels intervention 2: Placebo Softgels

Protocol documents:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
OmegaD-2016-001 
A Randomized, Multicenter, Double-Masked, Placebo-
Controlled Study of the Safety and Efficacy of OmegaD 
Softgels in the Treatment of Dry Eye Disease 
Study Phase: 
Phase 3 
Product Name: 
OmegaD softgels 
Indication: 
Treatment of dry eye disease 
Sponsor: 
OmegaD LLC 
740 Nine Gates Road  
Yorklyn, DE 19736 
Medical Monitor: 
Charles Slonim, MD 
Original Protocol: 
24 June 2016 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is confidential and proprietary property of OmegaD 
LLC. Neither this document nor the information contained herein may be divulged, transmitted, 
reproduced, published, or otherwise used by others without the express written permission of 
OmegaD LLC. Investigators are cautioned that the information given in this brochure might be 
subject to change and revision. Any conclusion regarding efficacy and safety must be considered 
provisional. 
 
 
 
 
 




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INVESTIGATOR’S AGREEMENT 
 
Study Title: 
A Randomized, Multicenter, Double-Masked, Placebo-Controlled 
Study of the Safety and Efficacy of OmegaD Softgels in the 
Treatment of Dry Eye Disease 
Study Number: 
OmegaD-2016-001 
Original Protocol: 
24 June 2016  
 
I have read the OmegaD-2016-001 protocol. The signature below constitutes the approval of this 
protocol and the attachments, and provides the necessary assurances that this trial will be 
conducted according to all stipulations of the protocol, including all statements regarding 
confidentiality, and in compliance with International Conference of Harmonisation (ICH) 
Guidelines, and all applicable United States (US) Federal Regulations and local legal and 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Clinical Study Leader 
Roselyn Judd 
Oculos Clinical Research 
615-962-8698 (Office) 
586-212-0237 (Mobile) 
Email: rjudd@pointguardllc.com 
Medical Monitor 
Charles Slonim, MD 
Oculos Clinical Research 
813-690-0255 (Mobile) 
813-443-5865 (Fax) 
Email: cslonim@pointguardllc.com 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: OmegaD LLC 
Name of Investigational Product: OmegaD softgels and placebo softgels 
Name of Active Ingredient: Eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA), Omega-3 
fatty acids in the triglyceride form 
Title of Study: A Randomized, Multicenter, Double-Masked, Placebo-Controlled Study of the Safety 
and Efficacy of OmegaD Softgels in the Treatment of Dry Eye Disease 
Studied Period (Years):  
Estimated date first patient enrolled: September 2016 
Estimated date last patient completed: May 2017 
Phase of Development:  
3 
Objectives: The primary objective of this study is to evaluate the safety and efficacy of twice daily 
(BID) dosing of OmegaD softgels in the treatment of subjects with dry eye disease. 
Methodology: This will be a randomized, multicenter, double-masked, placebo-controlled study. 
Subjects will be randomized to 1 of 2 treatment arms and treated for 84 days (12 weeks) as follows: 
• 
OmegaD softgels (N = 82 subjects); 2 softgels BID (2 softgels 5 – 10 minutes before 
breakfast and 2 softgels 5 – 10 minutes before dinner) for 84 days 
• 
Placebo softgels (N = 82 subjects); 2 softgels BID (2 softgels 5 – 10 minutes before 
breakfast and 2 softgels 5 – 10 minutes before dinner) for 84 days 
Comparisons of OmegaD softgels to placebo will be double-masked; OmegaD softgels and placebo 
will be identical-appearing softgels. 
At Screening (Day -7 to Day -1), sites will obtain signed informed consent, demographic information, 
medical/ocular and concomitant medication histories, perform a urine pregnancy test (women of 
childbearing potential only), conduct screening examinations (tear osmolarity testing, meibomian gland 
dysfunction grading, tear break-up time (TBUT), Schirmer’s test), and assess adverse events (AEs). 
Inclusion/exclusion criteria will then be reviewed. 
Subjects who meet eligibility criteria at Screening will return to the site at Baseline (Day 0) and the site 
will update concomitant medications and conduct baseline examinations (Ocular Surface Disease Index 
(OSDI) questionnaire, tear osmolarity, meibomian gland dysfunction grading, slit lamp examination, 
TBUT). Continuing eligibility for enrollment will require tear osmolarity ≥ 312 mOsm/L and 
meibomian gland dysfunction as defined by a grade of 1 or 2 on the meibomian orifice size scale in at 
least one eye at both Screening and Baseline, TBUT ≤ 7 seconds in both eyes at both Screening and 
Baseline, and the Schirmer’s test score from Screening must be ≥ 5 mm in both eyes. The qualifying 
osmolarity level and meibomian orifice size grade must be present in the same eye at both Screening 
and Baseline if only one eye qualifies. After inclusion/exclusion criteria are reviewed, the site will 
randomize eligible subjects. The Omega-3 Index score will be assessed via fingerstick blood sample 
and site personnel will dispense study medication and a daily study medication diary and assess AEs. 
Subjects will take 2 softgels twice daily 5 to 10 minutes before a meal (ie, 2 softgels 5 – 10 minutes 
before breakfast and 2 softgels 5 – 10 minutes before dinner). Daily reminders to take the medication 
will be provided, and subjects will document their compliance in terms of number of softgels taken in 
the study medication diary on a daily basis. 


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Methodology (Continued): 
Each subject will return to the site at Day 42 (± 7 days) along with all unused study medication and the 
study medication diary and site personnel will update concomitant medications, conduct a slit lamp 
examination, dispense study medication, assess AEs, and perform study medication accountability and 
diary review.  
Subjects will return to the site at Day 84 (± 7 days), along with all unused study medication and the 
study medication diary, for final safety and efficacy evaluations. Site personnel will update 
concomitant medications, perform a urine pregnancy test (women of childbearing potential), conduct 
all ophthalmic assessments as specified in the Schedule of Procedures, the Omega-3 Index via 
fingerstick blood sample, assess AEs, and perform study medication accountability and diary review.  
Both eyes will be assessed at each visit. Adverse events and concomitant medications will be 
documented from signing of informed consent at Screening to Day 84. 
Number of Patients (Planned): Approximately 164 subjects are planned to be enrolled; 
approximately 82 subjects in each treatment arm at approximately 15 clinical sites; however, when 
90 subjects have completed treatment a review of treatment compliance will be conducted. If more than 
10% of subjects have protocol deviations for treatment compliance, the study will be resized to achieve 
a study population in which 90% are compliant. 
Diagnosis and Main Criteria For Inclusion: 
Inclusion Criteria: 
1. Subjects age ≥ 18 years and ≤ 90 years on the date of informed consent. 
2. All subjects must provide signed written consent prior to participation in any study related 
procedures. 
3. Patient-reported dry eye symptoms.  
4. Clinical diagnosis of dry eye disease supported by global clinical assessment. 
5. Presence of tear osmolarity in at least one eye ≥ 312 mOsm/L at both Screening and 
Baseline. 
6. Presence of meibomian gland dysfunction as defined by a grade of 1 or 2 on the meibomian 
orifice size scale in at least one eye at both Screening and Baseline. The qualifying 
osmolarity level and meibomian orifice size grade must be present in the same eye at both 
Screening and Baseline if only one eye qualifies. 
7. Female subjects of childbearing potential must have a negative urine pregnancy test at 
Screening. Women of childbearing potential (i.e., women who are not either postmenopausal 
for one year or surgically sterile) must use an acceptable form of contraception throughout the 
study. 
Exclusion Criteria:  
1. Allergy to fish oil or safflower oil (component of placebo softgels) or any component of the 
softgel material. 
2. Schirmer’s test score < 5 mm at Screening in either eye. 
3. Tear break-up time > 7 seconds at Screening or Baseline in either eye. 
4. Clinically significant eyelid deformity or eyelid movement disorder that is caused by 
conditions such as notch deformity, incomplete lid closure, entropion, ectropion, hordeolum, 
or chalazion. 
5. Active seasonal and/or perennial allergic conjunctivitis or rhinitis. 


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Diagnosis and Main Criteria For Inclusion: 
Exclusion Criteria (Continued):  
6. Previous ocular disease leaving sequelae or requiring current topical eye therapy other than for 
dry eye disease, including, but not limited to: active corneal or conjunctival infection of the 
eye and ocular surface scarring. 
7. History or presence of abnormal nasolacrimal drainage. 
8. Laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) performed 
within one year prior to Screening and throughout the study period. 
9. Ophthalmic drop use within 2 hours prior to any study visit. Any over-the-counter (OTC) 
artificial tear should be continued at the same frequency and with no change in drop brand. 
10. Contact lens wear within 12 hours prior to any study visit; subjects determined to have worn 
contact lenses within 12 hours must be rescheduled.  
11. Punctal cauterization or punctal plug placement within 60 days prior to Screening and 
throughout the study period. 
12. Started or changed the dose of systemic medications known to affect tear production within 
30 days prior to Screening and throughout the study period. These include but are not limited 
to the following medications: 
• 
Immunomodulators 
• 
Antihistamines 
• 
Tricyclic antidepressants  
• 
Diuretics 
• 
Corticosteroids (intranasal, inhaled, topical dermatological, and perianal steroids are 
permitted). 
13. Use of any topical prescription ophthalmic medications (including cyclosporine [Restasis®, 
steroids, nonsteroidal anti-inflammatory drugs [NSAIDS], anti-glaucoma medications), oral 
tetracyclines or topical macrolides, oral nutraceuticals [fish, flax, black currant seed oils, etc.] 
within 21 days prior to Screening and throughout the study period.  
14. Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 
oral NSAIDs during the study period. ANY use of oral NSAIDS during the study period must 
be discussed with the Medical Monitor. Aspirin is permitted. 
15. Participation in any drug or device clinical investigation within 30 days prior to entry into this 
study and/or during the period of study participation. 
Investigational Product, Dosage and Mode Of Administration: OmegaD softgels, 2 softgels BID 
(ie, 2 softgels 5 – 10 minutes before breakfast and 2 softgels 5 – 10 minutes before dinner). 
Reference Therapy, Dosage and Mode Of Administration: Placebo softgels, 2 softgels BID (ie, 
2 softgels 5 – 10 minutes before breakfast and 2 softgels 5 – 10 minutes before dinner). 
Duration of Treatment: 84 days (12 weeks) 
Study Procedures: Note: Ophthalmic examinations should be conducted in the order listed in the 
Schedule of Procedures. All ophthalmic examinations are conducted in both eyes. Study medication 
accountability (documentation of dispensed/returned study medication) will be conducted at each study 
visit beginning at Baseline. 
Visit 1 (Day -7 to Day -1): Screening 
The site will obtain signed informed consent, demographics, medical/ocular/concomitant medication 


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histories, perform a urine pregnancy test (for women of childbearing potential only), conduct screening 
ophthalmic examinations (tear osmolarity ≥ 312 mOsm/L and meibomian gland dysfunction as defined 
by a grade of 1 or 2 on the meibomian orifice size scale in at least one eye, TBUT ≤ 7 seconds in both 
eyes, Schirmer’s test score ≥ 5 mm in both eyes), review inclusion/exclusion criteria, and assess AEs. 
The qualifying osmolarity level and meibomian orifice size grade must be present in the same eye at 
Screening if only one eye qualifies. 
Visit 2 (Day 0): Baseline 
The site will update concomitant medications, conduct baseline examinations including the OSDI, tear 
osmolarity testing, meibomian gland dysfunction grading, slit-lamp examination, and TBUT and then 
review inclusion/exclusion criteria. 
In order to meet inclusion requirements, subjects must have tear osmolarity ≥ 312 mOsm/L and 
meibomian gland dysfunction as defined by a grade of 1 or 2 on the meibomian orifice size scale in at 
least one eye at both Screening and Baseline, TBUT ≤ 7 seconds in both eyes at both Screening and 
Baseline, and the Schirmer’s test score from Screening must be > 5 mm in both eyes. The qualifying 
osmolarity level and meibomian orifice size grade must be present in the same eye at both Screening 
and Baseline if only one eye qualifies. The study eye will be the worse eye at Baseline as defined by 
lower TBUT score; if both eyes score equally on TBUT, the eye with the higher tear osmolarity score 
will be chosen, and if still equal, the right eye will be the study eye. Site personnel will then randomize 
eligible subjects, perform the HS-Omega-3 Index Test will be via fingerstick blood sample, 
dispense/document study medication and a daily study medication diary and provide instructions for 
use, and assess AEs. 
Subjects should be reminded to bring all study medication and the study medication diary to the 
clinical site at Visit 3 (Day 42). If the study medication and diary are not brought to the site, the visit 
must be rescheduled. 
Visit 3 (Day 42 ± 7 days): Safety and Accountability Visit 
The site will collect unused study medication and the study medication diary, update concomitant 
medications, perform a slit-lamp examination, dispense study medication, assess AEs, and conduct 
study medication accountability and diary review. 
Subjects should be reminded to bring all study medication and the study medication diary to the 
clinical site at Visit 4(Day 84). If the study medication and diary are not brought to the site, the visit 
must be rescheduled. 
Visit 4 (Day 84 ± 7 days): Final Treatment Visit 
The site will collect unused study medication and the daily study medication diary, update concomitant 
medications, perform urine pregnancy test, conduct final ophthalmic examinations (OSDI, tear 
osmolarity, meibomian gland grading, slit-lamp examination, TBUT, and Schirmer’s test), Omega-3 
Index via fingerstick blood sample, assess AEs, and conduct final study medication accountability and 
diary review. 
Clinical site personnel will document all received and returned study medication at each visit and 
review the study medication diary. Study medication accountability will be conducted by the monitor at 
each applicable monitoring visit. 
If a study subject is discontinued from study medication before Visit 4 or is generally noncompliant 
with the protocol, every effort should be made to keep the subject in the study and conduct all study 
visits as scheduled or, failing that, to perform all Visit 4 procedures at the visit the subject is 
discontinued. 


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Efficacy Assessments:  
Signs: TBUT, tear osmolarity, meibomian gland dysfunction grading, Schirmer’s test (anesthetized).  
Symptoms: OSDI questionnaire. 
Pharmacokinetics: Omega-3 Index Test 
Safety Assessments: Safety assessments will include slit-lamp examination, collection of AEs, and 
documentation of concomitant medications. 
Criteria for Evaluation: 
Primary Efficacy Endpoints:  
The primary efficacy endpoints comprise a set of hypotheses that will be tested in a hierarchical 
fashion. 
• 
Mean change from baseline in TBUT in the study eye at Visit 4 (Day 84). 
• 
Mean change from baseline in OSDI score at Visit 4 (Day 84) 
The differences between the 2 treatment groups will be tested with a significance level of 0.05. In order 
to control the Type I error rate these two endpoints will be tested sequentially in the order described 
above. If the null hypothesis for the TBUT endpoint can be rejected at P ≤ 0.05, the OSDI endpoint 
will be tested at P ≤ 0.05.  
Exploratory Efficacy Endpoint: 
• 
Proportion of subjects with meibomian gland dysfunction grade of 0 on both meibomian 
orifice size and telangiectasia scales in the study eye at Visit 4 (Day 84). 
Secondary Efficacy Endpoint(s):  
• 
Mean change from baseline in tear osmolarity in the study eye at Visit 4 (Day 84). 
• 
Mean change from Screening in Schirmer’s test (anesthetized) score in the study eye at 
Visit 4 (Day 84). 
Safety Endpoint: 
• 
Incidence of adverse events. 
Statistical Methods: 
Analysis Population: 
• 
Intent-to-treat (ITT): The ITT population will include all randomized subjects. 
• 
Per protocol (PP): The PP population will include all ITT subjects who remain in the study 
through Visit 4 and who did not deviate from the protocol in any way likely to seriously affect 
the primary outcome of the study. 
• 
Safety: The safety population will include all subjects who have received at least one dose of 
the study medication. 


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Statistical Methods (Continued): 
Statistical Analyses: 
Analysis of TBUT, meibomian gland dysfunction, tear osmolarity, and Schirmer’s test scores will 
utilize the designated study eye (worse eye at Baseline as defined by lower TBUT score; if both eyes 
score equally on TBUT, the eye with the higher tear osmolarity score will be chosen, and if still equal 
the right eye will be the study eye) to assess the significance of the differences between OmegaD and 
placebo. The unit of analysis for OSDI symptoms will be the subject.  
Statistical significance for the comparison of means will utilize the t-test or analysis of covariance. 
Statistical significance for binary data will be assessed by a chi-square, Fisher's exact, or 
Cochran-Mantel-Haenszel test. 
Descriptive statistics will be used to summarize continuous outcomes (number of subjects, mean, 
standard deviation or standard error of the mean, median, maximum, and minimum) and categorical 
variables (frequency and percentage) at each assessment time point. All summary tables will be 
supported with individual subject data listings. 
Sample Size:  
TBUT: A sample size of 82 in each group will have 95% power to detect a difference in means of 
2.07 seconds assuming that the common standard deviation is 3.5 using a two-group t-test with a 0.05 
two-sided significance level.  
OSDI: A sample size of 82 in each group will have approximately 95% power to detect a difference in 
means of 11.390 assuming that the common standard deviation is 20.0 using a two-group t-test with a 
0.05 two-sided significance level. 
When 90 subjects have completed treatment a review of treatment compliance will be conducted. If 
more than 10% of subjects have protocol deviations for treatment compliance, the study will be resized 
to achieve a study population in which 90% are compliant. 


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Table 2: 
Schedule of Procedures 
Procedures 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4/Early 
Discontinuation 
Days 
-7 to -1 
0 
42 ± 7 days 
84 ±7 days 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical/ocular history 
X 
 
 
 
Concomitant medication history/review 
X 
X 
X 
X 
Urine pregnancy test a  
X 
 
 
X 
Ocular Surface Disease Index Questionnaire 
 
X 
 
X 
Tear osmolarity 
X 
X 
 
X 
Meibomian gland dysfunction grading at slit-lamp using 
meibomian orifice size and telangiectasia scales 
X 
X 
 
X 
Slit-lamp examination 
 
X 
X 
X 
Tear break-up time (TBUT) 
X 
X 
 
X 
Schirmer’s test (anesthetized)                                                     
X 
 
 
X 
Review inclusion/exclusion criteria 
X 
X 
 
 
Randomization 
 
X 
 
 
HS-Omega-3 Index Test (fingerstick) 
 
X 
 
X 
Study medication and study medication diary distribution 
 
X 
X 
 
Adverse event assessment b 
X 
X 
X 
X 
Study medication accountability c 
 
X 
X 
X 
Study medication diary review 
 
 
X 
X 
a Women of childbearing potential only. 
b Collection of AEs extends from signing of informed consent until the last study visit. 
c Clinical site personnel will document all dispensed or returned study medication as applicable at Baseline, and Days 42 and 84.


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2. 
TABLE OF CONTENTS AND LIST OF TABLES  
TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS AND LIST OF TABLES ..................................................11 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................15 
4. 
INTRODUCTION ......................................................................................................17 
4.1. 
Background Information .............................................................................................17 
4.2. 
Rationale for the Development of OmegaD softgels for the Treatment of Dry 
Eye ..............................................................................................................................17 
4.3. 
Justification for Dose, Regimen, and Treatment Period .............................................18 
4.4. 
Good Clinical Practices Statement .............................................................................18 
4.5. 
Population to Be Studied ............................................................................................18 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................20 
5.1. 
Primary Objective .......................................................................................................20 
6. 
INVESTIGATIONAL PLAN .....................................................................................21 
6.1. 
Overall Study Design ..................................................................................................21 
6.2. 
Number of Subjects ....................................................................................................22 
6.3. 
Criteria for Study Termination ...................................................................................22 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................23 
7.1. 
Subject Inclusion Criteria ...........................................................................................23 
7.2. 
Subject Exclusion Criteria ..........................................................................................23 
7.3. 
Withdrawal Criteria ....................................................................................................24 
8. 
TREATMENT OF SUBJECTS ..................................................................................25 
8.1. 
Description of Study Drug ..........................................................................................25 
8.1.1. 
Investigational Product ...............................................................................................25 
8.1.2. 
Reference Therapy ......................................................................................................25 
8.2. 
Randomization and Masking ......................................................................................25 
8.2.1. 
Unmasking During the Study Period ..........................................................................25 
8.3. 
Concomitant Medications ...........................................................................................26 
8.3.1. 
Permitted Medications and Treatments ......................................................................26 
8.3.2. 
Prohibited Medications ...............................................................................................26 


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8.4. 
Treatment Compliance ................................................................................................27 
8.5. 
Discontinuation of Study Medication .........................................................................27 
8.6. 
Study Medication Materials and Management ...........................................................28 
8.6.1. 
Packaging and Labeling ..............................................................................................28 
8.6.2. 
Storage ........................................................................................................................28 
8.6.3. 
Administration ............................................................................................................28 
8.6.4. 
Dispensing ..................................................................................................................28 
8.6.5. 
Study Medication Accountability ...............................................................................28 
9. 
STUDY ASSESSMENTS ..........................................................................................30 
9.1. 
Demographic and Background Characteristics ..........................................................30 
9.1.1. 
Demographic Information ..........................................................................................30 
9.1.2. 
Medical/Ocular History ..............................................................................................30 
9.1.3. 
Concomitant Medications History ..............................................................................30 
9.1.4. 
Urine Pregnancy Test .................................................................................................30 
9.2. 
Efficacy Assessments .................................................................................................30 
9.2.1. 
Signs ...........................................................................................................................30 
9.2.1.1. 
Tear Osmolarity ..........................................................................................................30 
9.2.1.2. 
Meibomian Gland Dysfunction Grading ....................................................................31 
9.2.1.3. 
Tear Break-Up Time ...................................................................................................31 
9.2.1.4. 
Schirmer’s Test (Anesthetized) ..................................................................................31 
9.2.2. 
Symptoms ...................................................................................................................32 
9.3. 
Safety Assessments .....................................................................................................32 
9.3.1. 
Slit-Lamp Examination ...............................................................................................32 
9.4. 
Pharmacokinetic Assessment ......................................................................................32 
9.4.1. 
Omega-3 Index Test ...................................................................................................32 
9.5. 
Adverse and Serious Adverse Events .........................................................................32 
9.5.1. 
Definition of Adverse Events .....................................................................................32 
9.5.1.1. 
Adverse Event (AE) ....................................................................................................32 
9.5.1.2. 
Serious Adverse Event ................................................................................................33 
9.6. 
Relationship to Study Drug ........................................................................................33 
9.7. 
Recording Adverse Events .........................................................................................34 
9.8. 
Reporting Adverse Events ..........................................................................................35 


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10. 
STUDY ACTIVITIES ................................................................................................36 
10.1. 
Visit 1 (Day -7 to Day -1)/Screening ..........................................................................36 
10.2. 
Visit 2 (Day 0)/Baseline .............................................................................................36 
10.3. 
Visit 3 (Day 42)/Safety and Accountability Visit .......................................................37 
10.4. 
Visit 4 (Day 84)/Final Study Visit ..............................................................................38 
10.5. 
Early Discontinuation .................................................................................................38 
11. 
STATISTICS ..............................................................................................................40 
11.1. 
General Considerations ...............................................................................................40 
11.2. 
Handling of Missing Data ...........................................................................................40 
11.3. 
Determination of Sample Size ....................................................................................40 
11.4. 
Analysis Populations ..................................................................................................41 
11.4.1. 
Populations for Efficacy Analysis ..............................................................................41 
11.4.1.1. 
Intent-to-Treat Population ..........................................................................................41 
11.4.1.2. 
Per Protocol Population ..............................................................................................41 
11.4.2. 
Safety Analysis Population .........................................................................................41 
11.5. 
Demographics and Baseline Characteristics ...............................................................41 
11.6. 
Efficacy Analysis ........................................................................................................41 
11.6.1. 
Primary Efficacy Endpoints ........................................................................................42 
11.6.2. 
Exploratory Efficacy Endpoint ...................................................................................42 
11.6.3. 
Secondary Efficacy Endpoints ....................................................................................42 
11.7. 
Safety Analyses ..........................................................................................................42 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................43 
13. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................44 
13.1. 
Institutional Review Board (IRB) ...............................................................................44 
13.2. 
Ethical Conduct of the Study ......................................................................................44 
13.3. 
Written Informed Consent ..........................................................................................44 
13.4. 
Subject Confidentiality and Confidentiality of Data ..................................................44 
13.5. 
Study Monitoring ........................................................................................................45 
13.6. 
Case Report Forms and Study Records ......................................................................45 
13.7. 
Protocol Violations/Deviations ...................................................................................46 
13.8. 
Access to Source Documentation ...............................................................................46 
13.9. 
Data Generation and Analysis ....................................................................................46 


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13.9.1. 
Retention of Data ........................................................................................................46 
13.10. 
Publication And Disclosure Policy .............................................................................46 
14. 
LIST OF REFERENCES ............................................................................................48 
APPENDIX A. OCULAR SURFACE DISEASE INDEX (OSDI) QUESTIONNAIRE ...........49 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Procedures ...............................................................................................10 
Table 3: 
Abbreviations ..............................................................................................................15 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations are used in this study protocol. 
Table 3: 
Abbreviations  
Abbreviation 
Explanation 
AA 
Arachidonic acid  
AE 
Adverse event 
BID 
Twice daily 
DHA 
Docosahexaenoic acid 
eCRF 
Electronic case report form 
eDC 
Electronic data capture 
EPA 
Eicosapentaenoic acid 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LASIK 
Laser-assisted in situ keratomileusis 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
Matrix metalloproteinase 
NSAID 
Nonsteroidal anti-inflammatory drug 
OSDI 
Ocular Surface Disease Index 
OTC 
Over-the-counter  
PGE 
Prostaglandin E 
PP 
Per protocol 
PRK 
Photorefractive keratectomy 
PRN 
Physician Recommended Nutriceuticals 
PT 
Preferred terms 
SAE 
Serious adverse event 
SOC 
System organ class 
SOP 
Standard operating procedures  
TBUT 
Tear break-up time  


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Abbreviation 
Explanation 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumor necrosis factor 
US 
United States  


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4. 
INTRODUCTION 
4.1. 
Background Information 
Dry eye disease is a common multifactorial ophthalmologic disorder of the tears and ocular 
surface. Dry eye affects approximately 4.9 million people (3.2 million women and 1.7 million 
men) 50 years and older in in the United States (US) (Schaumberg et al, 2003; Schaumberg et al, 
2009). Inflammation is an integral component of this disease, as shown by increased expression 
of inflammatory mediators on the ocular surface such as interleukin 1 (IL-1), tumor necrosis 
factor alpha (TNF-α) and matrix metalloproteinase 3 and 9 (MMP-3, MMP-9) (Pflugfelder, 
2004). This is supported by the observation that Restasis® (cyclosporine ophthalmic emulsion, 
0.05%), a drug that targets the immune system, is approved for the indication of increased tear 
production in patients whose tear production is presumed to be suppressed due to ocular 
inflammation associated with keratoconjunctivitis sicca and effectively treats these symptoms in 
some patients. The efficacy of Restasis is considered to be modest and ocular burning after 
instillation, the most common adverse reaction, sometimes limits patient compliance and leads to 
discontinuation of the drug. There is a clear medical need for more effective therapies. 
4.2. 
Rationale for the Development of OmegaD softgels for the Treatment 
of Dry Eye 
Among alternative drug treatments for dry eye, oral treatment with omega-3 fatty acid 
supplements, in particular the marine omega-3s eicosapentaenoic acid (EPA) and 
docosahexaenoic acid (DHA), appears to be promising. Essential fatty acids have been shown to 
diminish inflammatory responses in many human inflammatory diseases.  
EPA and DHA compete for the same enzymes as the omega-6 fatty acid, arachidonic acid (AA). 
As omega-3 levels increase relative to omega-6 levels, the competition for cyclooxygenase and 
5-lipoxygenase suppresses AA synthesis of inflammatory mediators prostaglandin E2 (PGE2) and 
leukotriene B4 (LTB4), and increases EPA and DHA synthesis of anti-inflammatory (PGE1) and 
weakly inflammatory (PGE3) mediators. This shifts the balance to a less inflammatory mixture 
of eicosanoids (James et al, 2000). EPA and DHA supplementation also decreases monocyte 
synthesis of cytokines TNF-α and IL-1β, with cytokine synthesis decreasing as cellular EPA 
concentrations increase (Caughey et al, 1996). More recently, EPA and DHA derivatives, 
resolvins and protectins, have been shown to act to initiate the resolution of inflammation by 
enhancing macrophage clearance of leukocytes (Kohli and Levy, 2009).  
Because inflammation is a key component of dry eye disease and increasing the systemic levels 
of omega-3 fatty acids relative to omega-6 levels can mediate immune responses, it is important 
to evaluate whether omega-3 supplementation can improve dry eye disease signs, symptoms and 
associated measures of inflammation. In clinical studies conducted with patients with dry eye, 
oral supplementation with omega-3s has been found to produce significant improvement in dry 
eye symptoms, and improvement in various dry eye signs has been observed, most often 
increased tear break-up time (TBUT), with increased Schirmer’s test scores and improved 
meibum characteristics reported by several investigators (Bhargava et al, 2013; Kangari et al, 
2013; Kawakita et al, 2013; Macsai, 2008; Oleñik et al, 2013; Wojtowicz et al, 2011). 


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On the basis of the clinical development conducted by Physician Recommended Nutriceuticals 
(PRN) with PRN Dry Eye Omega Benefits®, OmegaD is now developing OmegaD softgels. A 
randomized, masked clinical trial was conducted with 105 subjects with dry eye who were 
randomized to 4 Dry Eye Omega Benefits or placebo (safflower oil) softgels daily and treated for 
3 months. Statistically significantly decreased tear osmolarity and dry eye Ocular Surface 
Disease Index (OSDI) symptoms, and significantly increased TBUT were observed for subjects 
who received Dry Eye Omega Benefits versus placebo (Donnenfeld et al, 2015). The safety 
profile appeared to be satisfactory; 4 subjects in each treatment group reported adverse events 
(AEs) (Omega Benefits 7.5%, placebo 8.0%). All the AEs reported for the Omega Benefits 
group were mild, these included stomach upset (2 subjects), diarrhea, headache, upper 
respiratory infection, and flu. The stomach upset reported for one subject and the diarrhea 
reported for another were considered possibly related to study drug. OmegaD softgels is a 
formulation that is similar to Dry Eye Omega Benefits with only slightly different amounts of 
EPA and DHA. 
Although numerous clinical studies have been conducted to study the efficacy of various doses 
and formulations of omega-3 fatty acids, the commercially available omega-3 supplements used 
for dry eye disease are supported by general health claims, and while subject to Food and Drug 
Administration (FDA) regulation as food supplements, the FDA may not have reviewed the 
clinical data to support activity in dry eye disease. OmegaD LLC plans to conduct a clinical 
program to evaluate the safety and efficacy of a controlled, pharmaceutical grade omega-3 oral 
supplement for dry eye disease. 
4.3. 
Justification for Dose, Regimen, and Treatment Period 
The omega-3 daily dose to be utilized in OmegaD-2016-001, 1680 mg of EPA and 560 mg of 
DHA, is the same dose utilized in the PRN study in which significant separation was observed 
between OmegaD and placebo in OSDI symptoms, TBUT, and tear osmolarity (Donnenfeld et 
al, 2015), and it appeared to be well tolerated based on the low number of AEs reported 
(unpublished data). The daily amount of omega-3 in OmegaD is less than that present in Lovaza® 
capsules (1860 mg of EPA and 1500 mg of DHA), the FDA-approved EPA/DHA product 
indicated for the reduction of triglyceride levels in adults with severe hypertriglyceridemia, the 
safety of which was established in the clinical trials conducted in support of approval. The 
treatment period of 3 months is considered sufficient to evaluate the efficacy and safety of 
OmegaD softgels and is a standard study duration in trials of dry eye disease.  
4.4. 
Good Clinical Practices Statement 
This study will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and in compliance with International Conference of 
Harmonisation (ICH) guidelines, and all applicable US federal regulations and local legal and 
regulatory requirements. 
4.5. 
Population to Be Studied 
Study subjects will be ≥ 18 years and ≤ 90 years of age, with patient-reported dry eye symptoms 
and a clinical diagnosis of dry eye disease supported by global clinical assessment. Each subject 
must have, in at least one eye, tear osmolarity of ≥ 312 mOsm/L and meibomian gland 


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dysfunction as defined by a grade of 1 or 2 on the meibomian orifice size scale at both Screening 
and Baseline in at least one eye. In addition, TBUT must be ≤ 7 seconds in both eyes at both 
Screening and Baseline and the Schirmer’s test score in both eye(s) must be ≥ 5 mm at Baseline. 
The qualifying osmolarity level and meibomian orifice size grade must be present in the same 
eye at both Screening and Baseline if only one eye qualifies. See Section 7 for inclusion and 
exclusion criteria. 


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5. 
TRIAL OBJECTIVES AND PURPOSE 
5.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of twice daily (BID) 
dosing of OmegaD softgels in subjects with dry eye disease. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This will be a randomized, multicenter, double-masked, placebo-controlled study. Subjects will 
be randomized to 1 of 2 treatment arms and treated for 84 days (12 weeks) as follows: 
• OmegaD softgels (N = 82 subjects); 2 softgels BID (2 softgels 5 – 10 minutes before 
breakfast and 2 softgels 5 – 10 minutes before dinner) for 84 days 
• Placebo softgels (N = 82 subjects); 2 softgels BID (2 softgels 5 – 10 minutes before 
breakfast and 2 softgels 5 – 10 minutes before dinner) for 84 days 
Comparisons of OmegaD softgels to placebo will be double-masked; OmegaD softgels and 
placebo will be identical-appearing softgels. 
At Screening (Day -7 to Day -1), sites will obtain signed informed consent, demographic 
information, medical/ocular and concomitant medication histories, perform a urine pregnancy 
test (women of childbearing potential only), conduct screening examinations (tear osmolarity 
testing, meibomian gland dysfunction grading, TBUT, Schirmer’s test), and assess AEs. 
Inclusion/exclusion criteria will then be reviewed. 
Subjects who meet eligibility criteria at Screening will return to the site at Baseline (Day 0) and 
the site will update concomitant medications and conduct baseline examinations beginning with 
the OSDI questionnaire. Continuing eligibility for enrollment will require tear osmolarity 
≥ 312 mOsm/L and meibomian gland dysfunction grade 1 or 2 on the meibomian orifice size 
scale in at least one eye at both Screening and Baseline, TBUT ≤ 7 seconds in both eyes at 
both Screening and Baseline, and the Schirmer’s test score from Screening must be ≥ 5 mm in 
both eyes. The qualifying osmolarity level and meibomian orifice size grade must be present in 
the same eye at both Screening and Baseline if only one eye qualifies. The study eye will be the 
worse eye at Baseline as defined by lower TBUT score; if both eyes score equally on TBUT, the 
eye with the higher tear osmolarity score will be chosen, and if still equal, the right eye will be 
the study eye. After inclusion/exclusion criteria are reviewed, the site will randomize eligible 
subjects. The Omega-3 Index score will be assessed via fingerstick blood sample and site 
personnel will dispense study medication and a daily study medication diary and assess AEs. 
Subjects will take 2 softgels twice daily 5 to 10 minutes before a meal (ie, 2 softgels 
5 - 10 minutes before breakfast and 2 softgels 5 – 10 minutes before dinner). Daily reminders to 
take the medication will be provided, and subjects will document their compliance in terms of 
number of softgels taken in the study medication diary on a daily basis. 
Each subject will return to the site at Day 42 (± 7 days) along with all unused study medication 
and the study medication diary and site personnel will update concomitant medications, conduct 
a slit-lamp examination, dispense study medication, assess AEs, and perform study medication 
accountability and diary review.  
Subjects will return to the site at Day 84 (± 7 days), along with all unused study medication and 
the study medication diary, for final safety and efficacy evaluations. Site personnel will update 
concomitant medications, perform a urine pregnancy test (women of childbearing potential 


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only), conduct all specified ophthalmic assessments, assess the Omega-3 Index score via 
fingerstick blood sample, assess AEs, and perform study medication accountability and diary 
review. 
Both eyes will be assessed at each visit. Adverse events and concomitant medications will be 
documented from signing of informed consent at Screening to Day 84 
6.2. 
Number of Subjects 
Approximately 164 subjects are planned to be enrolled; approximately 82 subjects in each 
treatment arm at up to 15 clinical sites; however, when 90 subjects have completed treatment a 
review of treatment compliance will be conducted. If more than 10% of subjects have protocol 
deviations for treatment compliance, the study will be resized to achieve a study population in 
which 90% are compliant. 
6.3. 
Criteria for Study Termination 
The study may be terminated at any time by OmegaD LLC, following appropriate notification.


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Subject Inclusion Criteria 
1. Subjects age ≥ 18 years and ≤ 90 years on the date of informed consent. 
2. All subjects must provide signed written consent prior to participation in any study 
related procedures. 
3. Patient-reported dry eye symptoms. 
4. Clinical diagnosis of dry eye disease supported by global clinical assessment. 
5. Presence of tear osmolarity in at least one eye ≥ 312 mOsm/L at both Screening and 
Baseline. 
6. Presence of meibomian gland dysfunction as defined by a grade of 1 or 2 on the 
meibomian orifice size scale in at least one eye at both Screening and Baseline. The 
qualifying osmolarity level and meibomian orifice size grade must be present in the same 
eye at both Screening and Baseline if only one eye qualifies. 
7. Female subjects of childbearing potential must have a negative urine pregnancy test at 
Screening. Women of childbearing potential (i.e., women who are not either 
postmenopausal for one year or surgically sterile) must use an acceptable form of 
contraception throughout the study. 
7.2. 
Subject Exclusion Criteria 
1. Allergy to fish oil or safflower oil (component of placebo softgels) or any component of 
the softgel material. 
2. Schirmer's test score < 5 mm at Screening in either eye. 
3. Tear break-up time > 7 seconds at Screening or Baseline in either eye. 
4. Clinically significant eyelid deformity or eyelid movement disorder that is caused by 
conditions such as notch deformity, incomplete lid closure, entropion, ectropion, 
hordeolum or chalazion. 
5. Active seasonal and/or perennial allergic conjunctivitis or rhinitis. 
6. Previous ocular disease leaving sequelae or requiring current topical eye therapy other 
than for dry eye disease, including, but not limited to: active corneal or conjunctival 
infection of the eye and ocular surface scarring. 
7. History or presence of abnormal nasolacrimal drainage. 
8. Laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) 
performed within one year prior to Screening and throughout the study period. 
9. Ophthalmic drop use within 2 hours prior to any study visit. Any over-the-counter (OTC) 
artificial tear should be continued at the same frequency and with no change in drop 
brand. 


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10. Contact lens wear within 12 hours prior to any study visit; subjects determined to have worn 
contact lenses within 12 hours must be rescheduled. 
11. Punctal cauterization or punctal plug placement within 60 days prior to Screening and 
throughout the study period. 
12. Started or changed the dose of systemic medications known to affect tear production 
within 30 days prior to Screening and throughout the study period. These include but are 
not limited to the following medications: 
• Immunomodulators 
• Antihistamines 
• Tricyclic antidepressants  
• Diuretics 
• Corticosteroids (intranasal, inhaled, topical dermatological, and perianal steroids are 
permitted). 
13. Use of any topical prescription ophthalmic medications (including cyclosporine 
[Restasis®, steroids, nonsteroidal anti-inflammatory drugs [NSAIDs], anti-glaucoma 
medications), oral tetracyclines or topical macrolides, oral nutraceuticals [fish, flax, black 
currant seed oils, etc.] within 21 days prior to Screening and throughout the study period. 
14. Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 
oral NSAIDs during the study period. ANY use of oral NSAIDS during the study period 
must be discussed with the Medical Monitor. 
15. Participation in any drug or device clinical investigation within 30 days prior to entry into 
this study and/or during the period of study participation. 
7.3. 
Withdrawal Criteria 
The following are the criteria for considering withdrawal from the study: 
• Withdrawal of subject consent. 
• Subject is lost to follow-up. 
If a subject withdraws or is withdrawn from the study, the principal reason for withdrawal will 
be recorded in the electronic case report form (eCRF).   
If a study subject is lost to follow up at any point during the study period, attempts to contact the 
subject must be documented. 
If a study subject is discontinued from study medication before Visit 4 or is generally 
noncompliant with the protocol, every effort should be made to keep the subject in the study and 
conduct all study visits as scheduled or, failing that, to perform all Visit 4 procedures at the visit 
the subject is discontinued. 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Drug 
8.1.1. 
Investigational Product 
The daily dose of OmegaD softgels, 4 softgels, contains 1680 mg of EPA and 560 mg of DHA, 
with other naturally occurring omega-3 fatty acids, an antioxidant (alpha tocopherol), and a 
flavoring agent in a softgel shell composed of gelatin, glycerin, and colorant. The softgel is 
formulated with the omega-3 fatty acids in the triglyceride form. 
8.1.2. 
Reference Therapy 
The placebo softgels contain safflower oil in a softgel shell composed of gelatin, glycerin, and 
colorant.  
8.2. 
Randomization and Masking 
Study medication will be randomized in a 1:1 ratio (OmegaD to placebo). A randomized block 
design will be used, and the randomization will be created by the biostatistician. 
If subjects meet eligibility criteria at Screening and at Baseline (see Section 7 for eligibility 
criteria), subjects will be randomly assigned to study medication at the Baseline visit. Clinical 
sites will assign the next subject kit, taken sequentially, from the lowest to the highest numbered 
kits from within each shipment of study medication. The drug kit randomization number will be 
recorded in the subject’s eCRF. 
A supply of randomized study medication from the assigned kit sufficient to last until Day 42 
will be dispensed to the subject at the Baseline visit; and at the Day 42 visit a supply of 
randomized study medication from the assigned kit sufficient to last until Day 84 will be 
dispensed. 
8.2.1. 
Unmasking During the Study Period 
Should it be necessary to unmask a subject’s treatment assignment in case of emergency, the 
investigator may obtain the treatment code for a given randomized subject from the 2-part 
tear-off label from the subject’s study medication kit. The randomization code is to be obtained 
only if a medical emergency exists and knowledge of the medication being taken will influence 
the medical management of the subject. In the event of emergency or life-threatening condition, 
the investigator may need to unmask the subject. The following procedure should be followed: 
1. The Investigator should contact the Medical Monitor via phone immediately before 
unmasking a subject, unless it is not possible to do so without risk to the subject. 
2. The Investigator should document the serious adverse event (SAE) and justification for 
unmasking in the Study Summary and Comments pages of the eCRF.  
3. The Subject may continue to participate in the study at the Investigator’s discretion. If the 
subject is to be discontinued from study participation, then ALL procedures described in 
the Early Discontinuation Visit (Section 10.5) should be completed. 


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4. The Investigator should contact Oculos Clinical Research, the clinical research 
organization, at OmegaD-safety@pointguardllc.com within 24 hours with the 
randomization number, subject initials, details of the AE or SAE, any action taken, and 
whether the subject is continuing in the study. 
8.3. 
Concomitant Medications 
8.3.1. 
Permitted Medications and Treatments 
Therapy considered necessary for the subject’s welfare that will not interfere with the evaluation 
of the study medication may be given at the discretion of the Investigator. If there is any question 
as to whether the medication may interfere, the Investigator should contact the Medical Monitor 
or Sponsor. Whenever possible, medications should be administered in dosages that remain 
constant throughout the study duration. 
Artificial tear use is permitted during the study period, but it should be continued at the same 
frequency and with no change in drop brand. 
8.3.2. 
Prohibited Medications 
The Medical Monitor should be notified before prohibited medication or therapy is administered 
unless the safety of the subject requires immediate action. The decision to administer a 
prohibited medication or therapy should be done with the safety of the subject as the primary 
consideration. The Medical Monitor MUST be contacted to determine the permissibility of a 
specific medication or therapy and whether or not the subject should continue with study 
participation. 
For systemic medications known to affect tear production, any new medication or change in the 
dose of the medication within 30 days prior to Screening and throughout the study period is 
prohibited as follows: 
• Immunomodulators 
• Antihistamines 
• Tricyclic antidepressants 
• Diuretics 
• Corticosteroids (intranasal, inhaled, topical dermatological, and perianal steroids are 
permitted). 
Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 
oral NSAIDs during the study period is prohibited. ANY use of oral NSAIDS during the study 
period must be discussed with the Medical Monitor. Aspirin is permitted. 


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Prohibited ophthalmic medications and therapies within 21 days prior to Screening and 
throughout the study period include the use of any topical prescription ophthalmic medications 
as follows: 
• Cyclosporine (i.e., Restasis) 
• Steroids 
• NSAIDs 
• Antiglaucoma medications 
• Macrolides 
Additionally, oral nutraceuticals [fish, flax, black currant seed oils, etc.] are prohibited within 
21 days prior to Screening and throughout the study period. 
Contact lens and ophthalmic drop use (e.g., artificial tears), while permitted during the study 
period, are prohibited within designated time periods prior to any study visit. Contact lens wear 
is prohibited within 12 hours prior to any study visit (subjects determined to have worn contact 
lenses within 12 hours must be rescheduled), and ophthalmic drop use is prohibited within 2 hours 
prior to any study visit.  
The following procedures are prohibited as specified:  
• LASIK or PRK performed within one year prior to Screening and throughout the 
study period. 
• Punctal cauterization or punctal plug placement within 60 days prior to Screening and 
throughout the study period. 
8.4. 
Treatment Compliance 
Treatment compliance will be monitored by study medication accountability and subjects’ daily 
study medication diaries. The amount of unused softgels returned at the Day 42 and Day 84 
visits and the information provided in the study medication diaries by subjects will be 
documented by study site personnel in the electronic data capture (eDC) system. 
8.5. 
Discontinuation of Study Medication 
Subjects may be discontinued from study medication for any of the following reasons: 
• The subject has a clinically significant or serious AE that would not be consistent 
with continuation in the study, as determined by the Investigator or Medical Monitor 
− It is possible for subjects to experience a skin rash or other allergic reaction 
related to the components of the softgels; if this occurs, the subject should 
discontinue the medication. 
• Pregnancy 
If a subject is discontinued from study medication or is generally noncompliant with the 
protocol, every effort should be made to encourage the subject to continue to attend study visits 


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to be followed for safety, rather than withdrawing the subject from the study. Reasons for 
considering subject withdrawal from the study are discussed in Section 7.3. 
8.6. 
Study Medication Materials and Management 
8.6.1. 
Packaging and Labeling 
Study medication will be packaged and labeled at a central packaging facility. Each subject kit 
will consist of a single box with 5 bottles of study medication. Upon randomization each eligible 
subject will receive 2 bottles of study medication. The study site will retain 3 bottles, 2 of which 
will be dispensed at the Day 42 visit, and 1 extra bottle in case of loss or damage.  
8.6.2. 
Storage 
Store at controlled room temperature: 15° to 30°C (59° to 86°F). Do not freeze. Keep out of 
reach of children. 
8.6.3. 
Administration 
Following randomization, site personnel will dispense study medication and instruct the subject 
on administration procedures. The daily dose is 4 softgels daily, which is recommended to be 
taken as 2 softgels 5 – 10 minutes before breakfast and 2 softgels 5 – 10 minutes before dinner. 
Taking the softgels just before meals is important to minimize any digestive upset, such as 
belching and indigestion. If the subject can tolerate it, all 4 softgels may be taken 5 - 10 minutes 
before a single meal; the timing of the dose is not as important as taking all 4 softgels. 
8.6.4. 
Dispensing 
At randomization, a kit with 2 bottles of study medication (sufficient study medication to last 
until the Day 42 visit with a little overage) and a study medication diary will be dispensed to the 
subject with instructions to return the kit along with all unused study medication and the 
completed study diary at the Day 42 visit. At the Day 42 visit, the unused study medication will 
be counted, and the site will dispense 2 bottles of study medication (sufficient study medication 
to last until the Day 84 visit with a little overage) and the study medication diary with 
instructions to return the kit along with all unused study medication and the completed study 
diary at the Day 84 visit. 
8.6.5. 
Study Medication Accountability 
The Investigator or designee (e.g., study coordinator or pharmacist) will maintain a full 
accountability record for the study medication and will be responsible for recording the receipt, 
dispensing, and return of all supplies of the study medication using the inventories supplied by 
Oculos. Clinical site personnel will document all dispensed and returned study medications at 
Baseline (Day 0), Day 42, and Day 84 and study drug accountability will be conducted by the 
monitor at each applicable monitoring visit. 
As described in Section 8.6.4, the subject will return all unused study medication and the study 
medication diary at Days 42 and 84. The monitor will review dispensing and drug accountability 
records during site visits and at the completion of the study and note any discrepancies. 


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All investigational study medication must be stored in a secure facility, with access limited to the 
Investigator and authorized staff. 


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9. 
STUDY ASSESSMENTS 
Prior to entry into the study or initiation of any study-related procedures, the subject must read, 
sign, and date the current Institutional Review Board (IRB)-approved version of the informed 
consent form. A full discussion of informed consent is presented in Section 13.3. 
9.1. 
Demographic and Background Characteristics 
9.1.1. 
Demographic Information 
Demographic information including date of birth, gender, race, ethnicity, and date of informed 
consent will be recorded. 
9.1.2. 
Medical/Ocular History 
Clinically significant medical and ophthalmic history will be documented and will include any 
previously diagnosed ophthalmic abnormalities and ocular surgeries, including laser and 
non-laser procedures. 
9.1.3. 
Concomitant Medications History 
All concomitant medications (prescription and OTC) taken at Screening and for 3 months prior 
to Screening and throughout the course of the study will be recorded in the Concomitant 
Medications page of the eCRF. Information regarding the dates of first and last dose, site of 
dosing (e.g., right eye, left eye, both eyes, systemic), and the reason the concomitant medication 
is being taken must be recorded in the eCRF. When a concomitant medication has been taken at 
a stable dose for longer than 6 months, an estimation of the start date is adequate. Standard 
procedural medications will not go into the eCRF but are recorded on a standard procedural 
medication log provided by Oculos Clinical Research. 
9.1.4. 
Urine Pregnancy Test 
A urine pregnancy test will be performed at Screening and repeated at the End of Treatment Visit 
(Day 84) or the Early Discontinuation Visit for women of childbearing potential only. 
9.2. 
Efficacy Assessments 
9.2.1. 
Signs 
9.2.1.1. 
Tear Osmolarity 
Tear osmolarity will be tested via the TearLab Osmolarity Test. The osmolarity testing must 
precede all other diagnostic examinations (except the OSDI at Visits 2 and 4), and the subject 
must refrain from administrating any tear supplements within two hours prior to the tear 
osmolarity test.  


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9.2.1.2. 
Meibomian Gland Dysfunction Grading 
Using a slit-lamp at a magnification of 10 to 16X, the eyelids of each eye will be evaluated 
utilizing the following scales: 
Meibomian Gland Dysfunction Grading Scales 
A. Meibomian Orifice Size Scale 
GRADE 
EYELID MARGIN MEIBOMIAN ORIFICE SIZE FINDINGS 
0 
Orifice barely visible.  
1 
Orifice easily visible in at least 5 orifices. 
2 
Orifice dilated with meibum plug which may extend above the lid margin in at least 
5 orifices. 
3 
Orifice keratinized over in at least 5 orifices. 
A grade of 1 or 2 in meibomian orifice size in at least one eye is required for eligibility into the 
study. A grade of 0 or 3 in both eyes excludes the patient from study participation. The 
qualifying osmolarity level and meibomian orifice size grade must be present in the same eye at 
both Screening and Baseline if only one eye qualifies. 
B. Telangiectasia Scale 
GRADE 
EYELID MARGIN TELANGIECTASIA FINDINGS 
0 
No blood vessels present between meibomian glands. 
1 
One (1) blood vessel present between 4 pairs of glands/orifices 
2 
More than 1 vessel between 4 pairs of glands/orifices 
3 
More than 1 vessel with vasodilation between 4 pairs of glands/orifices. 
4 
More than 1 vessel with vasodilation between 4 pairs of glands/orifices with erythema of 
the tissue. 
A certain score on the telangiectasia scale is not required for study entry, nor is it an exclusion 
criterion. The telangiectasia and meibomian orifice size scales will provide additional detailed 
information with which to track the progress/resolution of meibomian gland disease. 
9.2.1.3. 
Tear Break-Up Time 
A drop of Fluress® is added to the eye and the patient may blink once to disperse it. Then while 
the subject avoids blinking, the tear film is observed under the slit-lamp through a cobalt blue 
filter and timed until tiny dry spots develop. The procedure is conducted 3 times for each eye and 
the TBUT for each is measured in seconds and recorded in the eCRF. The average for each eye 
will be calculated by the eDC system. 
9.2.1.4. 
Schirmer’s Test (Anesthetized) 
An anesthetized Schirmer’s test will be performed to insure that only basal tear secretion is being 
measured and to prevent tearing due to the irritation from the filter paper (the eyes will already 


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have been anesthetized for the TBUT procedure). Filter paper strips will be placed in both eyes 
inside the lower eyelid (conjunctival sac) at the same time. The eyes are closed for 5 minutes. 
The paper is then removed and the amount of moisture on each strip in millimeters (mm) is 
measured and recorded in the eCRF. 
9.2.2. 
Symptoms 
The OSDI questionnaire (Appendix A) will be provided to the study subject, who will be asked 
to circle the number that corresponds with the frequency of dry eye symptoms experienced over 
the past week. Site personnel will enter the scores in the eCRF. The eDC system will 
automatically calculate the final score. 
9.3. 
Safety Assessments 
9.3.1. 
Slit-Lamp Examination 
A routine slit-lamp examination will be performed to evaluate the anterior segment of the eye, 
including lids, cornea, conjunctiva, anterior chamber, iris, and lens. Abnormalities will be 
documented. 
9.4. 
Pharmacokinetic Assessment 
9.4.1. 
Omega-3 Index Test 
The Omega -3 Index Test measures the concentration of two specific omega-3 fatty acids, EPA 
and DHA, as a percent of total fatty acids in red blood cell membranes. This test is performed by 
using a contact-activated lancet to collect a drop or two of blood on a collection card. Each card 
is identified and packaged to be submitted to OmegaQuant (Sioux Falls, SD) for analysis. 
9.5. 
Adverse and Serious Adverse Events 
9.5.1. 
Definition of Adverse Events 
9.5.1.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
study medication (pharmaceutical/biological product) that does not necessarily have a causal 
relationship to this medication. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of the study medication, whether or not related to the study medication. Study medication 
includes the investigational drug under evaluation and the comparator product or vehicle placebo 
that is given during any phase of the study. 
Medical conditions/diseases present before starting the investigational treatment are only 
considered AEs if they worsen after starting the investigational treatment. Abnormal test results 
constitute AEs only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
The occurrence of AEs should be sought by open-ended questioning of the subject at each visit 
during the study. At each clinic visit, study personnel should ask the following question: "Have 


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you had any problems since your last visit?” AEs also may be detected when they are 
volunteered by the subject during or between visits or through study assessments. 
9.5.1.2. 
Serious Adverse Event  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
Note: The term "life-threatening" refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
• Results in persistent or significant disability/incapacity (excluding 
progression/outcome of the disease under study); 
• Is a congenital anomaly/birth defect, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Is medically significant; ie, defined as an event that jeopardizes the health of the 
subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Treatment on an outpatient emergency basis that does not result in hospital admission, or a 
hospitalization that is elective or is a preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start of the study, is not 
considered an SAE. 
All SAEs that are ongoing at the time of completion or discontinuation from the study will be 
followed until stabilization (i.e., no other change in the condition is expected) or resolution of the 
event. 
9.6. 
Relationship to Study Drug 
The relationship of AEs to the study medication should be assessed by the Investigator using the 
definitions below. 
Not suspected: The temporal relationship of the event to the study medication makes a causal 
relationship unlikely, or, other drugs, therapeutic interventions or underlying conditions provide 
a sufficient explanation for the observed event. 
Suspected: The temporal relationship of the event to the study medication makes a causal 
relationship possible or other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the study medication and the occurrence of the AE, then the AE should be 
considered “suspected.” 


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If the relationship between the AE/SAE and the investigational product is determined by the 
Sponsor or designee to be “suspected” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting (see Section 9.8). 
9.7. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation, regardless of severity or potential 
association with the study medication or study procedures, will be recorded in the eCRF. 
Clinically significant changes in blood pressure and heart rate should be reported as AEs; 
however, Omega-3 treatment has been demonstrated to have beneficial effects on blood pressure 
and heart rate. Only clinically significant changes (increase or decrease) in heart rate should be 
reported as AEs. All AEs that occur after a subject has signed the informed consent form until 
the final study visit, Visit 4 (Day 84), should be collected and recorded on the AE eCRF page. 
AEs that occur after informed consent is provided but before the first dose of study medication 
will be summarized separately from AEs that occur from the first dose of double-masked 
treatment on Day 0 to the Day 84 visit. Serious adverse events will be followed until the event is 
resolved or stabilized. 
Medical conditions/diseases occurring before the first dose of study medication during Visit 1 
(Day 1) should be collected on the medical/ocular history pages of the eCRF. 
The AE term should be reported in standard medical terminology when possible. For each AE, 
the Investigator will evaluate and report the following: 
• Onset (date and time); 
• Resolution (date and time); 
• Severity grade (mild, moderate, severe); 
• Relationship to study medication (not suspected, suspected); 
• Action taken (none, study medication temporarily interrupted, study medication 
permanently discontinued; concomitant medication taken; hospitalization/prolonged 
hospitalization; other); 
• Serious outcome (yes/no). 
The severity grade should be determined by the Investigator using the definitions below. 
• Mild: Discomfort noticed but no disruption of normal daily activity  
• Moderate: Discomfort sufficient to cause interference with normal daily activity  
• Severe: Incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
(as defined directly above) whereas seriousness is defined by the criteria under Section 9.5.1.2 . 
An AE of severe intensity may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the pregnancy form. Pregnancy in 
itself is not regarded as an AE unless there is a suspicion that an investigational product may 
have interfered with the effectiveness of a contraceptive medication. 


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The outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth or 
congenital abnormality) must be followed up and documented even if the subject was 
discontinued from the study. 
9.8. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded from signing of informed consent until the 
final study visit, Visit 3 (Day 42), following the end of treatment exposure. Any SAEs 
“suspected” to be related to the investigational product and discovered by the Investigator at any 
time after the study should be reported to Oculos.  
Any SAE that occurs must be reported to Oculos within 24 hours of its occurrence or within 
24 hours of learning of its occurrence. Recurrent episodes, complications, or progression of the 
initial SAE must be reported to Oculos as follow-up to the original episode within 24 hours of 
the Investigator receiving the information. Information about all SAEs will be collected and 
recorded on the SAE form. All pertinent medical records and information collected during the 
treatment and follow-up of the subject should be maintained at the site with a copy emailed to 
OmegaD-safety@pointguardllc.com. The Investigator must assess the SAE relationship and 
complete the SAE form. Oculos may request additional information. Follow-up information 
(e.g., discharge summary) will be retained in the subject’s chart and a copy will be emailed to 
OmegaD-safety@ pointguardllc.com. 
In addition, all SAEs should be recorded on the Adverse Event eCRF page with the serious 
question marked “Yes”. 
It is the investigator’s responsibility to notify the approving IRB of any SAEs on a timely basis 
as instructed by the Sponsor or designee following the Sponsor’s determination of causality. 
All subjects who experience an SAE should be followed clinically and undergo the appropriate 
diagnostic evaluations until stabilization or resolution of the event. 
Oculos will report all SAEs to the US FDA on the appropriate schedule depending if the event is 
drug related or not drug related, expected, unexpected (based on the available information in the 
Investigator’s Brochure). 
Any death occurring during the study and follow up period should be reported as an SAE. For 
any death occurring through the end of the study, regardless of the degree of relationship to study 
drug, the SAE resulting in the death must be reported to Oculos. A death occurring after 
completion of the study at Visit 4 (Day 84) does not require completion of the SAE form. 
 


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10. 
STUDY ACTIVITIES 
Note: Ophthalmic examinations should be conducted in the order listed in the Schedule of 
Procedures. All ophthalmic examinations are conducted in both eyes. Subjects must not have 
used any ophthalmic drop within 2 hours and must not have worn contact lenses within 12 hours 
of the study visit. Subjects determined to have used ophthalmic drops or worn contacts within the 
specified durations prior to study visits must be rescheduled. 
10.1. 
Visit 1 (Day -7 to Day -1)/Screening 
At Visit 1 (Day -7 to Day -1)/Screening subjects will provide written informed consent before 
any study-related procedures are conducted and participate in screening procedures to establish 
eligibility for the study. Procedures performed at Screening will include the following: 
• Obtain written informed consent 
• Inclusion/exclusion criteria 
• Demographics 
• Medical and ocular histories 
• Concomitant medication history 
• Urine pregnancy test (women of childbearing potential only) 
• Tear osmolarity test 
• Meibomian gland dysfunction grading 
• TBUT 
• Schirmer’s test (anesthetized) 
• Review inclusion/exclusion criteria 
• AE assessment 
Only subjects with tear osmolarity ≥ 312 mOsm/L and meibomian gland dysfunction grade 1 or 
2 on the meibomian orifice size scale in at least one eye, and TBUT ≤ 7 seconds and Schirmer’s 
test score ≥ 5 mm in both eyes will be scheduled to return to the clinical site for Visit 2. The 
qualifying osmolarity level and meibomian orifice size grade must be present in the same eye at 
Screening if only one eye qualifies. 
10.2. 
Visit 2 (Day 0)/Baseline 
At Visit 2 (Day 0)/Baseline the site will conduct confirmatory examinations of eligibility and 
subjects who continue to meet eligibility criteria will participate in baseline dry eye disease 
examinations, be randomized, and receive a supply of study medication.  Procedures performed 
at Baseline include: 
• Concomitant medication review 
• OSDI questionnaire 


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• Tear osmolarity test 
• Meibomian gland dysfunction grading 
• Slit-lamp examination 
• TBUT 
• Review inclusion/exclusion criteria to confirm eligibility. Subjects who do not meet 
the following criteria will be considered to have failed screening at this point:  
− Subjects must have tear osmolarity ≥ 312 mOsm/L and meibomian gland 
dysfunction grade as defined by a grade of 1 or 2 on the meibomian orifice size 
scale in at least one eye at both Screening and Baseline. The qualifying 
osmolarity level and meibomian orifice size grade must be present in the same 
eye at both Screening and Baseline if only one eye qualifies.  
− TBUT ≤ 7 seconds in both eyes at both Screening and Baseline 
− The Schirmer’s test score from Screening must be ≥ 5 mm in both eyes 
(Schirmer’s test is not conducted at Baseline). 
• Randomization 
• Omega-3 Index test (fingerstick blood sample) 
• Dispense and document dispensing of study medication and provide instructions for 
administration 
• Dispense study medication diary and provide instructions for use 
• AE assessment 
10.3. 
Visit 3 (Day 42)/Safety and Accountability Visit 
Subjects should be reminded at scheduling and confirmation to bring all unused study 
medication and the study medication diary to Visit 3. If the study medication and diary are not 
brought to the site, the visit must be rescheduled.  
Procedures performed at Visit 3 (Day 42), a mid-treatment safety and accountability visit, will 
include the following: 
• Collect unused study medication and study medication diary  
• Concomitant medication review 
• Slit-lamp examination 
• Dispense study medication for the remainder of the study  
• AE assessment 
• Conduct study medication accountability and review study medication diary 


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10.4. 
Visit 4 (Day 84)/Final Study Visit 
Subjects should be reminded at scheduling and confirmation not to use ophthalmic drops within 
2 hours or wear contact lenses within 12 hours prior to the study visit and to bring all unused 
study medication and the study medication diary to Visit 4. If the study medication and diary are 
not brought to the site, the visit must be rescheduled. 
At Visit 4 (Day 84), the final study visit, subjects will participate in final efficacy and safety 
evaluations. Procedures performed at Day 84 will include the following: 
• Collect unused study medication and study medication diary 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• OSDI  
• Tear osmolarity test 
• Meibomian gland dysfunction grading 
• Slit-lamp examination 
• TBUT 
• Schirmer’s test (anesthetized) 
• Omega-3 Index test (fingerstick blood sample)  
• AE assessment 
• Conduct study medication accountability and review study medication diary 
10.5. 
Early Discontinuation 
If the subject discontinues the study early, procedures performed will include the following: 
• Collect all unused study medication materials and the study medication diary, if 
available; otherwise arrange for the subject to return them  
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• OSDI  
• Tear osmolarity test 
• Meibomian gland dysfunction grading 
• Slit-lamp examination 
• TBUT 
• Schirmer’s test (anesthetized) 
• Omega-3 Index test (fingerstick blood sample)  


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• AE assessment 
• Conduct study medication accountability and review study medication diary 


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11. 
STATISTICS 
11.1. 
General Considerations 
This is a randomized, multicenter, double-masked, placebo-controlled study to evaluate the 
safety and efficacy of BID dosing of OmegaD softgels for 84 days (12 weeks) in the treatment of 
subjects with dry eye disease.  
Subjects will be randomized in a 1:1 ratio as follows: 
• OmegaD softgels (N = 82 subjects); 2 softgels BID 
• Placebo softgels (N = 82 subjects); 2 softgels BID 
A biostatistician will perform statistical analyses as agreed with the Sponsor according to the 
Statistical Analysis Plan. Any additional or supplemental data analysis performed independently 
by an Investigator shall be submitted to the Sponsor for review. 
Efficacy analysis will be conducted on the intent-to-treat (ITT) population and on the per 
protocol (PP) population. Safety analyses will be performed using the safety analysis population. 
Definitions for all of the analysis populations can be found in Section 11.3. 
The study eye will be the worse of qualifying eyes at Baseline as defined by lower TBUT score; 
if both eyes score equally on TBUT, the eye with the higher tear osmolarity score will be chosen, 
and if still equal the right eye will be the study eye. 
11.2. 
Handling of Missing Data 
The planned statistical methods use all available data. To account for the presence of missing 
data, multiple imputation may be used for ITT analyses on the primary endpoints. Multiple 
imputation will be carried out using the SAS procedures. 
11.3. 
Determination of Sample Size 
TBUT: A sample size of 82 in each group will have 95% power to detect a difference in means 
of 2.07 seconds assuming that the common standard deviation is 3.5 using a two-group t-test 
with a 0.05 two-sided significance level. 
OSDI: A sample size of 82 in each group will have approximately 95% power to detect a 
difference in means of 11.390 assuming that the common standard deviation is 20.0 using a 
two-group t test with a 0.05 two-sided significance level. 
When 90 subjects have completed treatment a review of treatment compliance will be conducted. 
If more than 10% of subjects have protocol deviations for treatment compliance, the study will 
be resized to achieve a study population in which 90% are compliant. 


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11.4. 
Analysis Populations 
11.4.1. 
Populations for Efficacy Analysis 
11.4.1.1. Intent-to-Treat Population 
The ITT population is defined as all randomized subjects. The primary efficacy analysis will be 
performed on the ITT population. 
11.4.1.2. Per Protocol Population 
The PP population will include all ITT subjects who remain in the study through Visit 4 and who 
did not deviate from the protocol in any way likely to seriously affect the primary outcome of the 
study. Secondary efficacy analyses will be performed on the PP population. 
11.4.2. 
Safety Analysis Population 
The safety population will include all subjects who have received at least one dose of the study 
medication. All safety analyses will utilize the safety population. 
11.5. 
Demographics and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for the ITT analysis 
population; however, should there be a reasonable difference in the size of the ITT and safety 
analysis populations, demographic and baseline characteristics will be summarized for both. The 
comparability of groups used in comparison analyses will be characterized in tables of 
demographic data. Summary tables will be supported with individual subject data listings. 
11.6. 
Efficacy Analysis 
Primary efficacy analyses will be performed on the ITT population. Analysis of TBUT, 
meibomian gland dysfunction, tear osmolarity, and Schirmer’s test scores will utilize the 
designated study eye (worse eye at Baseline as defined by lower TBUT; if both eyes score 
equally on TBUT the eye with the higher tear osmolarity score will be chosen, and if still equal 
the right eye will be the study eye) to assess the significance of the differences between OmegaD 
and placebo. The unit of analysis for OSDI symptoms will be the subject.  
Statistical significance for the comparison of means will utilize the t-test or analysis of 
covariance. Statistical significance for binary data will be assessed by a chi-square, Fisher's 
exact, or Cochran-Mantel-Haenszel test. 
Descriptive statistics will be used to summarize continuous outcomes (number of subjects, mean, 
standard deviation or standard error of the mean, median, maximum, and minimum) and 
categorical variables (frequency and percentage) at each assessment time point. All summary 
tables will be supported with individual subject data listings. 


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11.6.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoints comprise a set of hypotheses that will be tested in a hierarchical 
fashion. 
• TBUT in the study eye 
• OSDI score 
The differences between the 2 treatment groups will be tested with a significance level of 0.05. 
In order to control the Type I error rate these two endpoints will be tested sequentially in the 
order described above. If the null hypothesis for the TBUT endpoint can be rejected at P  ≤ 0.05, 
OSDI endpoint will be tested at P ≤ 0.05.  
11.6.2. 
Exploratory Efficacy Endpoint 
• Proportion of subjects with meibomian gland dysfunction grade of 0 on both 
meibomian orifice size and telangiectasia scales in the study eye at Visit 4 (Day 84). 
11.6.3. 
Secondary Efficacy Endpoints 
• Mean change from baseline in tear osmolarity in the study eye at Visit 4 (Day 84). 
• Mean change from Screening in Schirmer’s test (anesthetized) score in the study eye 
at Visit 4 (Day 84). 
11.7. 
Safety Analyses 
Safety data will be presented in tables of descriptive statistics and frequency distribution. All 
summary tables will be supported with individual subject data listings. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Oculos/OmegaD LLC and/or their contracted agents utilize standard operating procedures 
(SOPs) designed to ensure that research procedures and documentation are consistently 
conducted/prepared to the highest quality standards. These SOPs require compliance with FDA 
regulations and the ICH Good Clinical Practice (GCP) guidance. 
The study will be monitored by Oculos to verify that the rights and well-being of human subjects 
are being protected, the reported data are accurate, complete, and verifiable, and that the conduct 
of the study is in compliance with the currently approved protocol, with ICH GCP, and with the 
applicable regulatory requirements. 
To insure compliance with GCP and all applicable regulatory requirements, Sponsor or its agent 
may conduct a quality assurance audit at any time during or after completion of a study. The 
investigator will be given adequate notice if he/she is selected for an audit. The audit will 
include, but is not limited to: a review of all informed consent forms, medical records, and 
regulatory documentation; an assessment of study conduct and protocol compliance; and a 
review of the investigational drug product receipt, storage, and administration. At the conclusion 
of an audit, the auditor will conduct a brief meeting with the investigator to review the findings 
of the audit. 


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13. 
ADMINISTRATIVE CONSIDERATIONS 
13.1. 
Institutional Review Board (IRB) 
The IRB must review, approve, and provide continuing review of the clinical study protocol, 
protocol amendments, the informed consent documents, subject recruitment advertisements, and 
any other written information to be provided to the subjects. Initial IRB approval is an 
affirmative decision that the clinical study has been reviewed and may be conducted at the study 
site within the constraints set forth by the IRB, the institution, GCP, and applicable regulatory 
requirements. A copy of the IRB approval letter for the protocol, the informed consent, the 
intended advertising, and any written material to be provided to the subject must be submitted to 
Oculos prior to release of investigational supplies to the study site. Progress reports and 
notifications of serious adverse drug reactions will be provided to the IRB according to local 
regulations and guidelines. The IRB must be notified of completion or termination of the study. 
The study site must maintain an accurate and complete record of all reports, documents, and 
other submissions made to the IRB concerning this protocol. 
13.2. 
Ethical Conduct of the Study 
The study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and in compliance with ICH guidelines, and all applicable US federal 
regulations and local legal and regulatory requirements. 
13.3. 
Written Informed Consent 
A sample informed consent form containing the required elements of informed consent will be 
provided by Oculos. Any changes made to this sample must be approved by Oculos prior to 
submission to the IRB. After approval by Oculos, the informed consent form must be submitted 
to and approved by the IRB. The informed consent must be written in a language in which the 
subject is fluent. Regulations require that foreign language informed consent forms be submitted 
to the IRB for approval. The foreign language translation is required to contain a statement of 
certification of the translation. The investigator must forward a copy of the consent forms, the 
certified foreign language translation, and an IRB approval letter to Oculos. 
It is the responsibility of the Investigator to inform each subject of the purpose of this clinical 
trial, including possible risks and benefits, and to document the informed consent process. Prior 
to undergoing any study-related procedures, the subject must read, sign, and date the current 
IRB-approved version of the informed consent form. The original informed consent form is to be 
retained by the study site, and a copy is to be given to the subject. 
13.4. 
Subject Confidentiality and Confidentiality of Data 
Data generated for the study should be stored in a limited-access file area and be accessible only 
to representatives of the study site, Oculos/OmegaD LLC, the IRB, and FDA/relevant regulatory 
agencies. Medical information resulting from a subject’s participation in this study may be given 
to the subject’s personal physician or to the appropriate medical personnel responsible for the 
subject’s welfare. No information that can be related to a specific individual subject will be 


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released or used in any fashion without the signed written consent of that subject. All reports and 
communications relating to study subjects will identify subjects only by initials and subject 
identification number. Complete subject identification will be kept by the Investigator for 
purposes of long-term follow-up, if needed. This information will be treated with strict 
adherence to professional standards of confidentiality. 
13.5. 
Study Monitoring 
The study will be monitored by Oculos on behalf of OmegaD LLC in accordance with current 
GCP to assure compliance with the study protocol and the quality of the data collected. 
Monitoring visits will occur as required and could include a study initiation visit, a monitoring 
visit, and a study close-out visit. Training will be provided for key investigative personnel in all 
aspects of study conduct. The Investigator will be responsible for making sure that clinical site 
personnel are provided adequate training on conducting their designated tasks. 
This study will utilize eDC to optimize the eCRF source verification process with limited 
separate source documentation. Monitors will review e-source data and overall study 
data/consistency remotely and query discrepancies based upon eCRF entries (eCRF initial entry 
is the source). During this monitoring, data are reviewed as entered by the site, and the monitors 
will flag any abnormalities, trends, or safety signals for Medical Monitor review and monitor 
follow-up onsite, if necessary. 
During visits to the study site, the monitor may review the source documents including but not 
limited to signed informed consent forms, study medication diaries, study medication 
accountability and storage, and the reporting procedures for AEs and SAEs. All data generated 
during this study and the medical records/documents from which they originated are subject to 
inspection by Oculos, the study Sponsor, the FDA, and other regulatory agencies. The 
investigator must notify Oculos promptly of any inspections scheduled by regulatory authorities. 
Upon completion of the study, the clinical monitor will conduct a final visit (closeout) to the site. 
The objectives of this visit are to ascertain that all regulatory records and reports are complete, 
verify that the study drug and other supplies have been accounted for, and ensure that the 
Investigators are aware of their responsibilities once the study ends.  
The Investigator is responsible for permitting Oculos direct access to any study documents for 
monitoring and auditing purposes, for providing adequate space for monitoring, and for 
addressing any questions or issues that might be raised by the monitor or auditor on a timely 
basis. 
13.6. 
Case Report Forms and Study Records  
All data relating to study procedures will be entered by site personnel directly onto eCRFs 
provided by Oculos. The eCRF is the first place the majority of the study data will be recorded; 
and therefore, considered to be the source document. In general, paper source documents will not 
be created, but when generated, source documents (e.g., discharge summaries, etc.) will be 
retained at the study site. 


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13.7. 
Protocol Violations/Deviations 
The Investigator should not deviate from the requirements of this protocol without prior written 
approval of the Medical Monitor at Oculos, with the exception of a medical emergency. 
A significant protocol violation must be reported to Oculos upon discovery. Protocol deviations 
should be reported to the IRB in accordance with IRB guidelines. 
All changes to the protocol will be made by Oculos, or designee as an approved amendment to 
the protocol, submitted to the FDA, and approved by the IRB prior to implementation.  
13.8. 
Access to Source Documentation 
A trial-related monitoring audit, review by the IRB, and/or regulatory inspection may be 
conducted at any time during or after completion of a study (Section 12). The Investigator will 
be given adequate notice if he/she is selected for an audit and must provide direct access to study 
documentation. The audit may include, but is not limited to, a review of all informed consent 
forms; a review of medical records; a review of regulatory documentation; an assessment of 
study conduct and protocol compliance; and a review of the investigational drug product receipt, 
storage, and administration. 
13.9. 
Data Generation and Analysis 
Management of data and the production of the clinical study report will be the responsibility of 
Oculos or its designee. 
During the course of the trial, data queries will be generated for data items that are potentially 
erroneous and require appropriate clarification or correction. Such clarifications and corrections 
will be discussed with and approved by study site personnel and appropriately documented. Prior 
to database lock, data listings will be generated and anomalous values investigated. 
13.9.1. 
Retention of Data 
Investigators should retain study-related records at the site until informed by the Sponsor. The 
Investigator will not discard any records without notifying OmegaD, LLC. If the Principal 
Investigator moves from the current clinical site, OmegaD LLC should be notified of the name of 
the person who will assume responsibility for maintenance of the records at the clinical site or 
the new address at which the records will be stored. The Investigator will notify OmegaD, LLC 
as soon as possible in the event of accidental loss or destruction of any study documentation. If it 
becomes necessary for Oculos Clinical Research, OmegaD LLC, or the FDA or relevant 
regulatory authorities to review any documentation relating to the study, the Investigator must 
permit access to such records. 
13.10. 
Publication And Disclosure Policy 
All information concerning OmegaD softgels and the operations of OmegaD LLC, such as patent 
applications, formulas, manufacturing processes, basic scientific data or formulation information 
not previously published, are considered CONFIDENTIAL and shall remain the sole property of 
OmegaD LLC. The Investigator agrees to use this information only in accomplishing this study 
and will not use it for other purposes without the written consent of OmegaD LLC 


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The publication policy is addressed in a separate agreement. 


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14. 
LIST OF REFERENCES 
Bhargava R, Kumar P, Kumar M, Mehra N, Mishra A. A randomized controlled trial of omega-3 
fatty acids in dry eye syndrome. Int J Ophthalmol. 2013 Dec 18;6(6):811-6. 
Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ. The effect on human tumor 
necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from 
vegetable oil or fish oil. Am J Clin Nutr. 1996 Jan;63(1):116-22. 
James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory 
mediator production. Am J Clin Nutr. 2000 Jan;71(1 Suppl):343S-8S. 
Kangari H, Eftekhari MH, Sardari S, Hashemi H, Salamzadeh J, Ghassemi-Broumand M, et al. 
Short-term consumption of oral omega-3 and dry eye syndrome. Ophthalmology. 2013 
Nov;120(11):2191-6. 
Kawakita T, Kawabata F, Tsuji T, Kawashima M, Shimmura S, Tsubota K. Effects of dietary 
supplementation with fish oil on dry eye syndrome subjects: randomized controlled trial. Biomed 
Res. 2013;34(5):215-20. 
Kohli P, Levy BD. Resolvins and protectins: mediating solutions to inflammation. Br J 
Pharmacol. 2009 Oct;158(4):960-71. 
Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian gland 
dysfunction (an AOS thesis). Trans Am Ophthalmol Soc. 2008;106:336-56. 
Oleñik A, Jiménez-Alfaro I, Alejandre-Alba N, Mahillo-Fernández I. A randomized, double-
masked study to evaluate the effect of omega-3 fatty acids supplementation in meibomian gland 
dysfunction. Clin Interv Aging. 2013;8:1133-8. 
Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol. 2004 Feb;137(2):337-
42. 
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.  
Wojtowicz JC, Butovich I, Uchiyama E, Aronowicz J, Agee S, McCulley JP. Pilot, prospective, 
randomized, double-masked, placebo-controlled clinical trial of an omega-3 supplement for dry 
eye. Cornea. 2011 Mar;30(3):308-14. 


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APPENDIX A. OCULAR SURFACE DISEASE INDEX (OSDI) 
QUESTIONNAIRE 
 


Ocular Surface Disease Index© (OSDI©)2
Ask your patient the following 12 questions, and circle the number in the box that best represents
each answer. Then, fill in boxes A, B, C, D, and E according to the instructions beside each.
HAVE YOU EXPERIENCED ANY OF THE FOLLOWING DURING THE LAST WEEK:
All of
the time
Most of
the time
Half of
the time
Some of
the time
None of
the time
1. Eyes that are sensitive to light?
4
3
2
1
0
2. Eyes that feel gritty?
4
3
2
1
0
3. Painful or sore eyes?
4
3
2
1
0
4. Blurred vision?
4
3
2
1
0
5. Poor vision?
4
3
2
1
0
Subtotal score for answers 1 to 5
HAVE PROBLEMS WITH YOUR EYES LIMITED YOU
IN PERFORMING ANY OF THE FOLLOWING DURING THE LAST WEEK:
All of
the time
Most of
the time
Half of
the time
Some of
the time
None of
the time
6. Reading?
4
3
2
1
0
N/A
7. Driving at night?
4
3
2
1
0
N/A
8. Working with a computer  
4
3
2
1
0
N/A
or bank machine (ATM)?
9. Watching TV? 
4 
3 
2 
1 
0
N/A
Subtotal score for answers 6 to 9
HAVE YOUR EYES FELT UNCOMFORTABLE
IN ANY OF THE FOLLOWING SITUATIONS DURING THE LAST WEEK:
All of
the time
Most of
the time
Half of
the time
Some of
the time
None of
the time
10. Windy conditions?
4
3
2
1
0
N/A
11. Places or areas with 
4
3
2
1
0
N/A
low humidity (very dry)?
12. Areas that are air conditioned?
4
3
2
1
0
N/A
Subtotal score for answers 10 to 12
Please turn over the questionnaire to calculate the patient’s final OSDI© score.
(A)
(B)
(C)
(D)
(E)
ADD SUBTOTALS A, B, AND C TO OBTAIN D
(D = SUM OF SCORES FOR ALL QUESTIONS ANSWERED)
TOTAL NUMBER OF QUESTIONS ANSWERED
(DO NOT INCLUDE QUESTIONS ANSWERED N/A)


Evaluating the OSDI© Score1
The OSDI© is assessed on a scale of 0 to 100, with higher scores representing greater disability.
The index demonstrates sensitivity and specificity in distinguishing between normal subjects and
patients with dry eye disease. The OSDI© is a valid and reliable instrument for measuring dry eye 
disease severity (normal, mild to moderate, and severe) and effect on vision-related function.
Assessing Your Patient’s Dry Eye Disease1,2
Use your answers D and E from Side 1 to compare the sum of scores for all questions
answered (D) and the number of questions answered (E) with the chart below.*
Find where your patient’s score would fall. Match the corresponding shade of red to the 
key below to determine whether your patient’s score indicates normal, mild, moderate, 
or severe dry eye disease.
Patient’s Name:
Date:
How long has the patient experienced dry eye?
Eye Care Professional’s Comments:
Tear and place in patient’s chart for follow-up care on next visit.
Number of Questions Answered
(E from Side 1)
Sum of Scores for All Questions Answered 
(D from Side 1)
12
11
10
9
8
7
6
5
4
3
2
1
5
48
45
40
35
30
25
20
15
10
10.4
11.4
12.5
13.9
15.6
1 7.9
20.8
25.0
31.3
41.7
62.5
20.8
22.7
25.0
27.8
31.3
35.7
41.7
50.0
62.5
83.3
31.3
34.1
37.5
41.7
46.9
53.6
62.5
75.0
93.8
41.7
45.5
50.0
55.6
62.5
71.4
83.3
100.0
52.1
56.8
62.5
69.4
78.1
89.3
100.0
62.5
68.2
75.0
83.3
93.8
100.0
72.9
79.5
87.5
97.2
100.0
83.3
90.9
100.0
93.8
100.0
100.0
Normal
Mild
Moderate
Severe
10.4
11.4
12.5
13.9
15.6
1 7.9
20.8
25.0
31.3
41.7
62.5
20.8
22.7
25.0
27.8
31.3
35.7
41.7
50.0
62.5
83.3
31.3
34.1
37.5
41.7
46.9
53.6
62.5
75.0
93.8
41.7
45.5
50.0
55.6
62.5
71.4
83.3
100.0
52.1
56.8
62.5
69.4
78.1
89.3
100.0
62.5
68.2
75.0
83.3
93.8
100.0
72.9
79.5
87.5
97.2
100.0
83.3
90.9
100.0
93.8
100.0
100.0
*Values to determine dry eye disease severity
calculated using the OSDI© formula:
OSDI©= (sum of scores) x 25
(# of questions answered)
Reference: 1. Schiffman RM, Christianson MD,
Jacobsen G, Hirsch JD, Reis BL. Reliability and validity 
of the Ocular Surface Disease Index. Arch Ophthalmol.
2000;118:615-621. 2. Data on file, Allergan, Inc.
©2004 Allergan, Inc., Irvine, CA 92612               Re-order: 4941843

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STATISTICAL ANALYSIS PLAN 
 
PROTOCOL TITLE: 
A Randomized, Multicenter, Double-Masked, Placebo-
Controlled Study of the Safety and Efficacy of OmegaD 
Softgels in the Treatment of Dry Eye Disease 
PROTOCOL NUMBER: 
OmegaD-2016-001 
STUDY DRUG: 
OmegaD Softgels 
DEVELOPMENT PHASE: 
Phase 3 
SPONSOR: 
OmegaD LLC 
 
740 Nine Gates Road  
Yorklyn, DE 19736 
 
VERSION: 
1.3 
 
VERSION DATE:  
06 June 2017 
 
 
 
 
 
 
  




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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ........................................................................................................7 
1.1. 
Rationale for the Development of OmegaD softgels for the Treatment of Dry 
Eye ................................................................................................................................7 
2. 
STUDY DESCRIPTION ..............................................................................................9 
2.1. 
Primary Objective .........................................................................................................9 
2.2. 
Study Design .................................................................................................................9 
2.3. 
Inclusion Criteria ........................................................................................................10 
2.4. 
Exclusion Criteria .......................................................................................................10 
2.5. 
Permitted Medications and Treatments ......................................................................11 
2.6. 
Prohibited Medications and Treatments .....................................................................12 
2.7. 
Treatment Compliance ................................................................................................13 
2.8. 
Withdrawal from Study and Discontinuation of Study Medication ...........................13 
3. 
STUDY ASSESSMENTS ..........................................................................................14 
3.1.1. 
Demographic Information ..........................................................................................14 
3.1.2. 
Medical/Ocular History ..............................................................................................14 
3.1.3. 
Concomitant Medications History ..............................................................................14 
3.1.4. 
Urine Pregnancy Test .................................................................................................14 
3.2. 
Efficacy Assessments .................................................................................................14 
3.2.1. 
Signs ...........................................................................................................................14 
3.2.1.1. 
Tear Osmolarity ..........................................................................................................14 
3.2.1.2. 
Meibomian Gland Dysfunction Grading ....................................................................14 
3.2.1.3. 
Tear Break-Up Time ...................................................................................................15 
3.2.1.4. 
Schirmer’s Test (Anesthetized) ..................................................................................15 
3.2.2. 
Symptoms ...................................................................................................................15 
3.3. 
Safety Assessments .....................................................................................................15 
3.3.1. 
Slit-Lamp Examination ...............................................................................................15 
3.4. 
Pharmacokinetic Assessment ......................................................................................16 


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3.4.1. 
Omega-3 Index Test ...................................................................................................16 
3.5. 
Adverse and Serious Adverse Events .........................................................................16 
3.5.1. 
Definition of Adverse Events .....................................................................................16 
3.5.1.1. 
Adverse Event (AE) ....................................................................................................16 
3.5.1.2. 
Serious Adverse Event ................................................................................................16 
3.6. 
Relationship to Study Drug ........................................................................................17 
3.7. 
Recording Adverse Events .........................................................................................17 
4. 
SAMPLE SIZE AND POWER CONSIDERATIONS ...............................................20 
5. 
ANALYSIS POPULATIONS ....................................................................................21 
5.1.1. 
Populations for Efficacy Analysis ..............................................................................21 
5.1.1.1. 
Intent-to-Treat Population ..........................................................................................21 
5.1.1.2. 
Per Protocol Population ..............................................................................................21 
5.1.2. 
Safety Analysis Population .........................................................................................21 
6. 
HANDLING OF MISSING DATA ............................................................................22 
7. 
STATISTICAL ANALYSIS ......................................................................................23 
7.1. 
Subject Disposition .....................................................................................................23 
7.2. 
Demographic and Baseline Characteristics ................................................................24 
7.3. 
Treatment Compliance and Exposure .........................................................................24 
7.4. 
Study Endpoints ..........................................................................................................24 
7.4.1. 
Primary Efficacy Endpoints ........................................................................................24 
7.4.2. 
Exploratory Efficacy Endpoint ...................................................................................25 
8. 
SAFETY EVALUATIONS ........................................................................................26 
8.1. 
Adverse Events ...........................................................................................................26 
8.2. 
Concomitant Medications ...........................................................................................26 
8.3. 
Ocular and Other Medical History .............................................................................27 
8.4. 
Ophthalmoscopy/Dilated Fundoscopy ........................................................................27 
9. 
CHANGES FROM THE PROTOCOL ......................................................................28 
10. 
INTERIM ANALYSIS ...............................................................................................29 
11. 
TABLES, LISTINGS AND FIGURES ......................................................................30 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Explanation 
AA 
Arachidonic acid  
AE 
Adverse event 
ATC-WHO-DD 
Anatomical Therapeutic Chemical World Health 
Organization Drug Dictionary 
BID 
Twice daily 
DHA 
Docosahexaenoic acid 
DOB 
Date of birth 
eCRF 
Electronic case report form 
eDC 
Electronic data capture 
EPA 
Eicosapentaenoic acid 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LASIK 
Laser-assisted in situ keratomileusis 
LTB4 
Leukotriene B4  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
Matrix metalloproteinase 
NSAID 
Nonsteroidal anti-inflammatory drug 
OSDI 
Ocular Surface Disease Index 
OTC 
Over-the-counter  
PGE 
Prostaglandin E 
PP 
Per protocol 
PRK 
Photorefractive keratectomy 
PRN 
Physician Recommended Nutriceuticals 
PT 
Preferred term 
SAE 
Serious adverse event 


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Abbreviation 
Explanation 
SOC 
System organ class 
SOP 
Standard operating procedures  
TBUT 
Tear break-up time  
TEAE 
Treatment-emergent adverse event 
TNF-α 
Tumor necrosis factor alpha 
US 
United States  
 


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1. 
INTRODUCTION 
Dry eye disease is a common multifactorial ophthalmologic disorder of the tears and ocular 
surface. Dry eye affects approximately 4.9 million people (3.2 million women and 1.7 million 
men) 50 years and older in in the United States (US). Inflammation is an integral component of 
this disease, as shown by increased expression of inflammatory mediators on the ocular surface 
such as interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-α) and matrix metalloproteinase 3 
and 9 (MMP-3, MMP-9). This is supported by the observation that Restasis® (cyclosporine 
ophthalmic emulsion, 0.05%), a drug that targets the immune system, is approved for the 
indication of increased tear production in patients whose tear production is presumed to be 
suppressed due to ocular inflammation associated with keratoconjunctivitis sicca and effectively 
treats these symptoms in some patients. The efficacy of Restasis is considered to be modest and 
ocular burning after instillation, the most common adverse reaction, sometimes limits patient 
compliance and leads to discontinuation of the drug. There is a clear medical need for more 
effective therapies. 
1.1. 
Rationale for the Development of OmegaD softgels for the Treatment 
of Dry Eye 
Among alternative drug treatments for dry eye, oral treatment with omega-3 fatty acid 
supplements, in particular the marine omega-3s eicosapentaenoic acid (EPA) and 
docosahexaenoic acid (DHA), appears to be promising. Essential fatty acids have been shown to 
diminish inflammatory responses in many human inflammatory diseases.  
EPA and DHA compete for the same enzymes as the omega-6 fatty acid, arachidonic acid (AA). 
As omega-3 levels increase relative to omega-6 levels, the competition for cyclooxygenase and 
5-lipoxygenase suppresses AA synthesis of inflammatory mediators prostaglandin E2 (PGE2) and 
leukotriene B4 (LTB4), and increases EPA and DHA synthesis of anti-inflammatory (PGE1) and 
weakly inflammatory (PGE3) mediators. This shifts the balance to a less inflammatory mixture of 
eicosanoids. EPA and DHA supplementation also decreases monocyte synthesis of cytokines 
TNF-α and IL-1β, with cytokine synthesis decreasing as cellular EPA concentrations increase. 
More recently, EPA and DHA derivatives, resolvins and protectins, have been shown to act to 
initiate the resolution of inflammation by enhancing macrophage clearance of leukocytes.  
Because inflammation is a key component of dry eye disease and increasing the systemic levels 
of omega-3 fatty acids relative to omega-6 levels can mediate immune responses, it is important 
to evaluate whether omega-3 supplementation can improve dry eye disease signs, symptoms and 
associated measures of inflammation. In clinical studies conducted with patients with dry eye, 
oral supplementation with omega-3s has been found to produce significant improvement in dry 
eye symptoms, and improvement in various dry eye signs has been observed, most often 
increased tear break-up time (TBUT), with increased Schirmer’s test scores and improved 
meibum characteristics reported by several investigators. 
On the basis of the clinical development conducted by Physician Recommended Nutriceuticals 
(PRN) with PRN Dry Eye Omega Benefits®, OmegaD is now developing OmegaD softgels. A 
randomized, masked clinical trial was conducted with 105 subjects with dry eye who were 
randomized to 4 Dry Eye Omega Benefits or placebo (safflower oil) softgels daily and treated for 


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3 months. Statistically significantly decreased tear osmolarity and dry eye Ocular Surface 
Disease Index (OSDI) symptoms, and significantly increased TBUT were observed for subjects 
who received Dry Eye Omega Benefits versus placebo. The safety profile appeared to be 
satisfactory; 4 subjects in each treatment group reported adverse events (AEs) (Omega Benefits 
7.5%, placebo 8.0%). All the AEs reported for the Omega Benefits group were mild; these 
included stomach upset (2 subjects), diarrhea, headache, upper respiratory infection, and flu. The 
stomach upset reported for one subject and the diarrhea reported for another were considered 
possibly related to study drug. OmegaD softgels is a formulation that is similar to Dry Eye 
Omega Benefits with only slightly different amounts of EPA and DHA. 
Although numerous clinical studies have been conducted to study the efficacy of various doses 
and formulations of omega-3 fatty acids, the commercially available omega-3 supplements used 
for dry eye disease are supported by general health claims, and while subject to Food and Drug 
Administration (FDA) regulation as food supplements, the FDA may not have reviewed the 
clinical data to support activity in dry eye disease. OmegaD LLC plans to conduct a clinical 
program to evaluate the safety and efficacy of a controlled, pharmaceutical grade omega-3 oral 
supplement for dry eye disease. 


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2. 
STUDY DESCRIPTION 
2.1. 
Primary Objective 
The primary objective of this study is to evaluate the safety and efficacy of twice daily (BID) 
dosing of OmegaD softgels in subjects with dry eye disease. 
2.2. 
Study Design 
This will be a randomized, multicenter, double-masked, placebo-controlled study. Subjects will 
be randomized to 1 of 2 treatment arms and treated for 84 days (12 weeks) as follows: 
 OmegaD softgels (N = 82 subjects); 2 softgels BID (2 softgels 5 – 10 minutes before 
breakfast and 2 softgels 5 – 10 minutes before dinner) for 84 days 
 Placebo softgels (N = 82 subjects); 2 softgels BID (2 softgels 5 – 10 minutes before 
breakfast and 2 softgels 5 – 10 minutes before dinner) for 84 days 
At Screening (Day -7 to Day -1), sites will obtain signed informed consent, demographic 
information, medical/ocular and concomitant medication histories, perform a urine pregnancy 
test (women of childbearing potential only), conduct screening examinations (tear osmolarity 
testing, meibomian gland dysfunction grading, TBUT, Schirmer’s test), and assess AEs. 
Inclusion/exclusion criteria will then be reviewed. 
Subjects who meet eligibility criteria at Screening will return to the site at Baseline (Day 0) and 
the site will update concomitant medications and conduct baseline examinations beginning with 
the OSDI questionnaire. Continuing eligibility for enrollment will require tear osmolarity 
≥ 312 mOsm/L and meibomian gland dysfunction grade 1 or 2 on the meibomian orifice size 
scale in at least one eye at both Screening and Baseline, TBUT ≤ 7 seconds in both eyes at 
both Screening and Baseline, and the Schirmer’s test score from Screening must be ≥ 5 mm in 
both eyes. The qualifying osmolarity level and meibomian orifice size grade must be present in 
the same eye at both Screening and Baseline if only one eye qualifies. The study eye will be the 
worse eye at Baseline as defined by lower TBUT score; if both eyes score equally on TBUT, the 
eye with the higher tear osmolarity score will be chosen, and if still equal, the right eye will be 
the study eye. After inclusion/exclusion criteria are reviewed, the site will randomize eligible 
subjects. The Omega-3 Index score will be assessed via fingerstick blood sample and site 
personnel will dispense study medication and a daily study medication diary and assess AEs. 
Subjects will take 2 softgels twice daily 5 to 10 minutes before a meal (i.e., 2 softgels before 
breakfast and 2 softgels before dinner). Subjects will document their compliance in terms of 
number of softgels taken in the study medication diary on a daily basis. 
Each subject will return to the site at Day 42 (± 7 days) along with all unused study medication 
and the study medication diary and site personnel will update concomitant medications, conduct 
a slit-lamp examination, dispense study medication, assess AEs, and perform study medication 
accountability and diary review.  
Subjects will return to the site at Day 84 (± 7 days), along with all unused study medication and 
the study medication diary, for final safety and efficacy evaluations. Site personnel will update 


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concomitant medications, perform a urine pregnancy test (women of childbearing potential 
only), conduct all specified ophthalmic assessments, assess the Omega-3 Index score via 
fingerstick blood sample, assess AEs, and perform study medication accountability and diary 
review. 
Both eyes will be assessed at each visit. Adverse events and concomitant medications will be 
documented from signing of informed consent at Screening to Day 84. 
Approximately 164 subjects are planned to be enrolled; approximately 82 subjects in each 
treatment arm at up to 15 clinical sites; however, when 90 subjects have completed treatment a 
review of treatment compliance will be conducted. If more than 10% of subjects have protocol 
deviations for treatment compliance, the study will be resized to achieve a study population in 
which 90% are compliant. 
2.3. 
Inclusion Criteria 
1. Subjects age ≥ 18 years and ≤ 90 years on the date of informed consent. 
2. All subjects must provide signed written consent prior to participation in any study 
related procedures. 
3. Patient-reported dry eye symptoms. 
4. Clinical diagnosis of dry eye disease supported by global clinical assessment. 
5. Presence of tear osmolarity in at least one eye ≥ 312 mOsm/L at both Screening and 
Baseline. 
6. Presence of meibomian gland dysfunction as defined by a grade of 1 or 2 on the 
meibomian orifice size scale in at least one eye at both Screening and Baseline. The 
qualifying osmolarity level and meibomian orifice size grade must be present in the same 
eye at both Screening and Baseline if only one eye qualifies. 
7. Female subjects of childbearing potential must have a negative urine pregnancy test at 
Screening. Women of childbearing potential (i.e., women who are not either 
postmenopausal for one year or surgically sterile) must use an acceptable form of 
contraception throughout the study. 
2.4. 
Exclusion Criteria 
1. Allergy to fish oil or safflower oil (component of placebo softgels) or any component of 
the softgel material. 
2. Schirmer's test score < 5 mm at Screening in either eye. 
3. Tear break-up time > 7 seconds at Screening or Baseline in either eye. 
4. Clinically significant eyelid deformity or eyelid movement disorder that is caused by 
conditions such as notch deformity, incomplete lid closure, entropion, ectropion, 
hordeolum or chalazion. 
5. Active seasonal and/or perennial allergic conjunctivitis or rhinitis. 


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6. Previous ocular disease leaving sequelae or requiring current topical eye therapy other 
than for dry eye disease, including, but not limited to: active corneal or conjunctival 
infection of the eye and ocular surface scarring. 
7. History or presence of abnormal nasolacrimal drainage. 
8. Laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) 
performed within one year prior to Screening and throughout the study period. 
9. Ophthalmic drop use within 2 hours prior to any study visit. Any over-the-counter (OTC) 
artificial tear should be continued at the same frequency and with no change in drop 
brand. 
10. Contact lens wear within 12 hours prior to any study visit; subjects determined to have worn 
contact lenses within 12 hours must be rescheduled. 
11. Punctal cauterization or punctal plug placement within 60 days prior to Screening and 
throughout the study period. 
12. Started or changed the dose of systemic medications known to affect tear production 
within 30 days prior to Screening and throughout the study period. These include but are 
not limited to the following medications: 
 Immunomodulators 
 Antihistamines 
 Tricyclic antidepressants  
 Diuretics 
 Corticosteroids (intranasal, inhaled, topical dermatological, and perianal steroids are 
permitted). 
13. Use of any topical prescription ophthalmic medications (including cyclosporine 
[Restasis®, steroids, nonsteroidal anti-inflammatory drugs [NSAIDs], anti-glaucoma 
medications), oral tetracyclines or topical macrolides, oral nutraceuticals [fish, flax, black 
currant seed oils, etc.] within 21 days prior to Screening and throughout the study period. 
14. Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 
oral NSAIDs during the study period. ANY use of oral NSAIDS during the study period 
must be discussed with the Medical Monitor. 
15. Participation in any drug or device clinical investigation within 30 days prior to entry into 
this study and/or during the period of study participation. 
2.5. 
Permitted Medications and Treatments 
Therapy considered necessary for the subject’s welfare that will not interfere with the evaluation 
of the study medication may be given at the discretion of the Investigator. If there is any question 
as to whether the medication may interfere, the Investigator should contact the Medical Monitor 
or Sponsor. Whenever possible, medications should be administered in dosages that remain 
constant throughout the study duration. 


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Artificial tear use is permitted during the study period, but it should be continued at the same 
frequency and with no change in drop brand. 
2.6. 
Prohibited Medications and Treatments 
The Medical Monitor should be notified before prohibited medication or therapy is administered 
unless the safety of the subject requires immediate action. The decision to administer a 
prohibited medication or therapy should be done with the safety of the subject as the primary 
consideration. The Medical Monitor MUST be contacted to determine the permissibility of a 
specific medication or therapy and whether or not the subject should continue with study 
participation. 
For systemic medications known to affect tear production, any new medication or change in the 
dose of the medication within 30 days prior to Screening and throughout the study period is 
prohibited as follows: 
 Immunomodulators 
 Antihistamines 
 Tricyclic antidepressants 
 Diuretics 
 Corticosteroids (intranasal, inhaled, topical dermatological, and perianal steroids 
are permitted). 
Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 
oral NSAIDs during the study period is prohibited. ANY use of oral NSAIDS during the study 
period must be discussed with the Medical Monitor. Aspirin is permitted. 
Prohibited ophthalmic medications and therapies within 21 days prior to Screening and 
throughout the study period include the use of any topical prescription ophthalmic medications 
as follows: 
 Cyclosporine (i.e., Restasis) 
 Steroids 
 NSAIDs 
 Antiglaucoma medications 
 Macrolides 
Additionally, oral nutraceuticals [fish, flax, black currant seed oils, etc.] are prohibited within 
21 days prior to Screening and throughout the study period. 
The following procedures are prohibited as specified:  
 LASIK or PRK performed within one year prior to Screening and throughout the 
study period. 
 Punctal cauterization or punctal plug placement within 60 days prior to Screening 
and throughout the study period. 


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2.7. 
Treatment Compliance 
Treatment compliance will be monitored by study medication accountability and subjects’ daily 
study medication diaries. The amount of unused softgels returned at the Day 42 and Day 84 
visits and the information provided in the study medication diaries by subjects will be 
documented by study site personnel in the electronic data capture (eDC) system. 
2.8. 
Withdrawal from Study and Discontinuation of Study Medication 
The following are the criteria for considering withdrawal from the study: 
 Withdrawal of subject consent. 
 Subject is lost to follow-up. 
Subjects may be discontinued from study medication for any of the following reasons: 
 The subject has a clinically significant or serious AE that would not be consistent 
with continuation in the study, as determined by the Investigator or Medical Monitor 
 It is possible for subjects to experience a skin rash or other allergic reaction 
related to the components of the softgels; if this occurs, the subject should 
discontinue the medication. 
 Pregnancy 
If a subject is discontinued from study medication or is generally noncompliant with the 
protocol, every effort should be made to encourage the subject to continue to attend study visits 
to be followed for safety, rather than withdrawing the subject from the study. Reasons for 
considering subject withdrawal from the study are discussed above. 


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3. 
STUDY ASSESSMENTS 
3.1.1. 
Demographic Information 
Demographic information including date of birth, gender, race, ethnicity, and date of informed 
consent will be recorded. 
3.1.2. 
Medical/Ocular History 
Clinically significant medical and ophthalmic history will be documented and will include any 
previously diagnosed ophthalmic abnormalities and ocular surgeries, including laser and 
non-laser procedures. 
3.1.3. 
Concomitant Medications History 
All concomitant medications (prescription and OTC) taken at Screening and for 3 months prior 
to Screening and throughout the course of the study will be recorded in the Concomitant 
Medications page of the electronic case report form (eCRF). Information regarding the dates of 
first and last dose, site of dosing (e.g., right eye, left eye, both eyes, systemic), and the reason the 
concomitant medication is being taken must be recorded in the eCRF. When a concomitant 
medication has been taken at a stable dose for longer than 6 months, an estimation of the start 
date is adequate. 
3.1.4. 
Urine Pregnancy Test 
A urine pregnancy test will be performed at Screening and repeated at the End of Treatment Visit 
(Day 84) or the Early Discontinuation Visit for women of childbearing potential only. 
3.2. 
Efficacy Assessments 
3.2.1. 
Signs 
3.2.1.1. 
Tear Osmolarity 
Tear osmolarity will be tested via the TearLab Osmolarity Test.  
3.2.1.2. 
Meibomian Gland Dysfunction Grading 
Using a slit-lamp at a magnification of 10 to 16X, the eyelids of each eye will be evaluated 
utilizing the following scales: 


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Meibomian Gland Dysfunction Grading Scales 
A. Meibomian Orifice Size Scale 
GRADE 
EYELID MARGIN MEIBOMIAN ORIFICE SIZE FINDINGS 
0 
Orifice barely visible.  
1 
Orifice easily visible in at least 5 orifices. 
2 
Orifice dilated with meibum plug which may extend above the lid margin in at least 
5 orifices. 
3 
Orifice keratinized over in at least 5 orifices. 
B. Telangiectasia Scale 
GRADE 
EYELID MARGIN TELANGIECTASIA FINDINGS 
0 
No blood vessels present between meibomian glands. 
1 
One (1) blood vessel present between 4 pairs of glands/orifices 
2 
More than 1 vessel between 4 pairs of glands/orifices 
3 
More than 1 vessel with vasodilation between 4 pairs of glands/orifices. 
4 
More than 1 vessel with vasodilation between 4 pairs of glands/orifices with erythema of 
the tissue. 
3.2.1.3. 
Tear Break-Up Time 
The TBUT procedure is conducted 3 times for each eye and the TBUT for each is measured in 
seconds and recorded in the eCRF. The average for each eye will be calculated by the eDC 
system. 
3.2.1.4. 
Schirmer’s Test (Anesthetized) 
An anesthetized Schirmer’s test will be performed and the amount of moisture on each strip in 
millimeters (mm) will be measured and recorded in the eCRF. 
3.2.2. 
Symptoms 
The OSDI questionnaire will be provided to the study subject, who will be asked to circle the 
number that corresponds with the frequency of dry eye symptoms experienced over the past 
week. Site personnel will enter the scores in the eCRF. The eDC system will automatically 
calculate the final score. 
3.3. 
Safety Assessments 
3.3.1. 
Slit-Lamp Examination 
A routine slit-lamp examination will be performed to evaluate the anterior segment of the eye, 
including lids, cornea, conjunctiva, anterior chamber, iris, and lens. Abnormalities will be 
documented. 


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3.4. 
Pharmacokinetic Assessment 
3.4.1. 
Omega-3 Index Test 
The Omega -3 Index Test measures the concentration of two specific omega-3 fatty acids, EPA 
and DHA, as a percent of total fatty acids in red blood cell membranes. This test is performed by 
using a contact-activated lancet to collect a drop or two of blood on a collection card. Each card 
is identified and packaged to be submitted to OmegaQuant (Sioux Falls, SD) for analysis. 
3.5. 
Adverse and Serious Adverse Events 
3.5.1. 
Definition of Adverse Events 
3.5.1.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
study medication (pharmaceutical/biological product) that does not necessarily have a causal 
relationship to this medication. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of the study medication, whether or not related to the study medication. Study medication 
includes the investigational drug under evaluation and the comparator product or vehicle placebo 
that is given during any phase of the study. 
Medical conditions/diseases present before starting the investigational treatment are only 
considered AEs if they worsen after starting the investigational treatment. Abnormal test results 
constitute AEs only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
The occurrence of AEs should be sought by open-ended questioning of the subject at each visit 
during the study. At each clinic visit, study personnel should ask the following question: "Have 
you had any problems since your last visit?” AEs also may be detected when they are 
volunteered by the subject during or between visits or through study assessments. 
3.5.1.2. 
Serious Adverse Event  
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
Note: The term "life-threatening" refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe. 
 Results in persistent or significant disability/incapacity (excluding 
progression/outcome of the disease under study); 
 Is a congenital anomaly/birth defect, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, or 


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 Is medically significant; i.e., defined as an event that jeopardizes the health of the 
subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Treatment on an outpatient emergency basis that does not result in hospital admission, or a 
hospitalization that is elective or is a preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start of the study, is not 
considered an SAE. 
All SAEs that are ongoing at the time of completion or discontinuation from the study will be 
followed until stabilization (i.e., no other change in the condition is expected) or resolution of the 
event. 
3.6. 
Relationship to Study Drug 
The relationship of AEs to the study medication should be assessed by the Investigator using the 
definitions below. 
Not suspected: The temporal relationship of the event to the study medication makes a causal 
relationship unlikely, or, other drugs, therapeutic interventions or underlying conditions provide 
a sufficient explanation for the observed event. 
Suspected: The temporal relationship of the event to the study medication makes a causal 
relationship possible or other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 
If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the study medication and the occurrence of the AE, then the AE should be 
considered “suspected.” 
If the relationship between the AE/SAE and the investigational product is determined by the 
Sponsor or designee to be “suspected” the event will be considered to be related to the 
investigational product for the purposes of expedited regulatory reporting (see Section 9.8). 
3.7. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation, regardless of severity or potential 
association with the study medication or study procedures, will be recorded in the eCRF. 
Clinically significant changes in blood pressure and heart rate should be reported as AEs; 
however, Omega-3 treatment has been demonstrated to have beneficial effects on blood pressure 
and heart rate. Only clinically significant changes (increase or decrease) in heart rate should be 
reported as AEs. All AEs that occur after a subject has signed the informed consent form until 
the final study visit, Visit 4 (Day 84), should be collected and recorded on the AE eCRF page. 
AEs that occur after informed consent is provided but before the first dose of study medication 
will be summarized separately from AEs that occur from the first dose of double-masked 
treatment on Day 0 to the Day 84 visit. Serious adverse events will be followed until the event is 
resolved or stabilized. 


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Medical conditions/diseases occurring before the signing of Informed Consent Form during Visit 
1 (Screening) should be collected on the medical/ocular history pages of the eCRF. 
The AE term should be reported in standard medical terminology when possible. For each AE, 
the Investigator will evaluate and report the following: 
 Onset (date and time); 
 Resolution (date and time); 
 Severity grade (mild, moderate, severe); 
 Relationship to study medication (not suspected, suspected); 
 Action taken (none, study medication temporarily interrupted, study medication 
permanently discontinued; concomitant medication taken; hospitalization/prolonged 
hospitalization; other); 
 Serious outcome (yes/no). 
The severity grade should be determined by the Investigator using the definitions below. 
 Mild: Discomfort noticed but no disruption of normal daily activity  
 Moderate: Discomfort sufficient to cause interference with normal daily activity  
 Severe: Incapacitating, with inability to perform normal activities 


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Table 2: 
Schedule of Procedures 
 
Procedures 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Visit 4/Early 
Discontinuation 
Days 
-7 to -1 
0 
42 ± 7 days 
84 ±7 days 
Informed consent 
X 
 
 
 
Demographics 
X 
 
 
 
Medical/ocular history 
X 
 
 
 
Concomitant medication history/review 
X 
X 
X 
X 
Urine pregnancy test a  
X 
 
 
X 
Ocular Surface Disease Index Questionnaire 
 
X 
 
X 
Tear osmolarity 
X 
X 
 
X 
Meibomian gland dysfunction grading at slit-
lamp using meibomian orifice size and 
telangiectasia scales 
X 
X 
 
X 
Slit-lamp examination 
 
X 
X 
X 
Tear break-up time (TBUT) 
X 
X 
 
X 
Schirmer’s test (anesthetized)                                 
X 
 
 
X 
Review inclusion/exclusion criteria 
X 
X 
 
 
Randomization 
 
X 
 
 
HS-Omega-3 Index Test (fingerstick) 
 
X 
 
X 
Study medication and study medication diary 
distribution 
 
X 
X 
 
Adverse event assessment b 
X 
X 
X 
X 
Study medication accountability c 
 
X 
X 
X 
Study medication diary review 
 
 
X 
X 
a Women of childbearing potential only. 
b Collection of AEs extends from signing of informed consent until the last study visit. 
c Clinical site personnel will document all dispensed or returned study medication as applicable at Baseline, and 
Days 42 and 84. 
 


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4. 
SAMPLE SIZE AND POWER CONSIDERATIONS 
TBUT: A sample size of 82 in each group will have 95% power to detect a difference in 
means of 2.07 seconds assuming that the common standard deviation is 3.5 using a 
two-group t-test with a 0.05 two-sided significance level. 
OSDI: A sample size of 82 in each group will have approximately 95% power to detect a 
difference in means of 11.390 assuming that the common standard deviation is 20.0 using 
a two-group t test with a 0.05 two-sided significance level. 
When 90 subjects have completed treatment a review of treatment compliance will be 
conducted. If more than 10% of subjects have protocol deviations for treatment 
compliance, the study will be resized to achieve a study population in which 90% are 
compliant. 


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5. 
ANALYSIS POPULATIONS 
5.1.1. 
Populations for Efficacy Analysis 
5.1.1.1. 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is defined as all randomized subjects. The primary 
efficacy analysis will be performed on the ITT population. 
5.1.1.2. 
Per Protocol Population 
The per protocol (PP) population will include all ITT subjects who remain in the study 
through Visit 4 and who did not deviate from the protocol in any way likely to seriously 
affect the primary outcome of the study. Secondary efficacy analyses will be performed 
on the PP population. 
5.1.2. 
Safety Analysis Population 
The safety population will include all subjects who have received at least one dose of the 
study medication. All safety analyses will utilize the safety population. 


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6. 
HANDLING OF MISSING DATA 
The planned statistical methods use all available data. To account for the presence of 
missing data, multiple imputation may be used for ITT analyses on the primary 
endpoints. Multiple imputation will be carried out using the SAS procedures. 
 


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7. 
STATISTICAL ANALYSIS 
Efficacy analysis will be conducted on the ITT population and on the PP population. 
Safety analyses will be performed using the safety analysis population. 
The study eye will be the worse of qualifying eyes at Baseline as defined by lower TBUT 
score; if both eyes score equally on TBUT, the eye with the higher tear osmolarity score 
will be chosen, and if still equal the right eye will be the study eye. All statistical analyses 
and reporting will be performed using the SAS® System Version 9.3 or later.  
Unless otherwise specified, continuous variables will be summarized with descriptive 
statistics (n, mean, median, standard deviation, standard error, minimum, and maximum), 
and categorical variables will be summarized with counts and percentages. 
Definition of Baseline:  
Baseline measurements will be the last measurement for the corresponding variable prior 
to the first randomized dose on Visit 2, Day 0. 
Out of Window and Unscheduled Visits: 
The protocol defined windows for scheduled visits will not be used in the analyses by 
visit. Data will be assigned to the scheduled visit closer in time to the scheduled visit. 
Unscheduled visit data will only be used in an analysis if there is no other available data 
closer in time to a scheduled visit. All unscheduled visit data will be included in data 
listings. 
7.1. 
Subject Disposition 
Subject disposition, including the number of subjects randomized, treated, and 
completing the study (and completing each study visit), will be tabulated by treatment 
group. The percentage of subjects treated and completing the study will be based on the 
total number randomized. A subject data listing will be provided. 
Eligibility criteria exemptions and major protocol deviations will be summarized by 
treatment group and presented in a listing. Major protocol deviations may include, but are 
not limited to the following: violation of inclusion or exclusion criteria, using prohibited 
medications, non-adherence to study treatment schedule. A guideline for classification of 
patients as belonging to the per protocol analysis dataset will be documented prior to 
database unmasking as will the masked review of patient data for purposes of 
classification. 
The total number and percentage of subjects included in each of the analysis datasets will 
be summarized by treatment group, with percentages based on the total number of 
randomized subjects. A subject data listing will be provided. 
Discontinuations and the reasons for discontinuation from the study will be summarized 
for all randomized subjects. Summaries will include the number and percentage of 
subjects within each treatment group.  


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Reasons for discontinuation following the receipt of study drug will include the 
following: 
 Withdrawal of subject consent. 
 Adverse event(s). 
A subject data listing will be provided. 
7.2. 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for the ITT analysis 
population; however, should there be a reasonable difference in the size of the ITT and 
safety analysis populations, demographic and baseline characteristics will be summarized 
for both. The comparability of groups used in comparison analyses will be characterized 
in tables of demographic data. Summary tables will be supported with individual subject 
data listings. 
Continuous variables such as age will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum), and categorical variables 
such as gender, race, ethnicity, and iris color will be summarized using counts and 
percentages of subjects.  
Age will be determined as the whole integer number of years from the date of birth 
(DOB) to the date of the screening visit, i.e., the truncated integer difference between the 
DOB and Visit 1. 
7.3. 
Treatment Compliance and Exposure 
The duration of drug exposure and % compliance will be summarized by visit and 
treatment group. Compliance over all visits will also be summarized. 
Duration of drug exposure will be calculated for each subject as the last date of dosing 
minus the first date of dosing + 1. The number and percentage of subjects by treatment 
group will be summarized according to the following duration-of-exposure categories: 
‘< 1 wk’, ‘1 to < 9 wks’, ’9 to < 13 wks’, and ≥ 13 wks’. 
A subject data listing will be provided. 
7.4. 
Study Endpoints 
7.4.1. 
Primary Efficacy Endpoints 
The primary efficacy endpoints comprise a set of hypotheses that will be tested in a 
hierarchical fashion. 
1. Mean change from baseline in average of the 3 TBUT measures in the study 
eye at Visit 4 (Day 84)  
2. Mean change from baseline in OSDI score at Visit 4 (Day 84) 
3. Mean change from Screening in Schirmer’s test (anesthetized) score in the 
study eye at Visit 4 (Day 84). 


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4. Mean change from baseline in tear osmolarity in the study eye at Visit 4 (Day 
84). 
Groups will be compared using an analysis of covariance model where treatment group is 
a fixed factor and baseline score is a covariate. The treatment difference will be estimated 
by the adjusted least squares mean. The 95% confidence on the difference will be 
provided. 
The differences between the 2 treatment groups will be tested with a significance level of 
0.05. In order to control the Type I error rate these endpoints will be tested sequentially in 
the order described above.  Testing will halt at the first p-value >0.05. 
7.4.2. 
Exploratory Efficacy Endpoint 
 Proportion of subjects with meibomian gland dysfunction grade of 0 on both 
meibomian orifice size and telangiectasia scales in the study eye at Visit 4 
(Day 84). Statistical significance will be assessed by a chi-square, Fisher's 
exact, or Cochran-Mantel-Haenszel test. 
Groups will be compared using an analysis of covariance model where treatment group is 
a fixed factor and baseline score is a covariate. The treatment difference will be estimated 
by the adjusted least squares mean. The 95% confidence on the difference will be 
provided. 
 


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8. 
SAFETY EVALUATIONS 
8.1. 
Adverse Events 
Treatment-emergent adverse events (TEAEs) are those with onset after randomization or 
if occurring prior to randomization, worsened after randomization. Only treatment-
emergent events will be summarized. All events in the clinical database regardless of 
when they occurred will be provided in data listings. Adverse events will be classified 
according to the Medical Dictionary for Regulatory Activities (MedDRA) system to the 
levels of System Organ Class (SOC) and primary Preferred Term (PT). 
An overall summary will be presented which gives the number and percentage of subjects 
within each treatment group that experienced any TEAE, experienced any treatment 
related TEAE, permanently discontinued treatment due to a TEAE, experienced a 
treatment emergent SAE, and that died. 
In summary tables, AEs occurring in both eyes will be summarized once at the greater 
intensity and relationship to study drug.  
Events that are possibly or probably related will be counted as an event related to study 
drug.  
The number and percentage of subjects experiencing one or more events within a 
MedDRA SOC and PT class without regard to intensity, relationship, or seriousness will 
be tabulated by treatment group. In addition, tables will display events by SOC, PT, and 
maximum intensity or closest relationship to treatment. 
The number of deaths and SAEs will also be presented, and AEs leading to premature 
discontinuation from the study will be listed and tabulated. 
A glossary listing that shows the verbatim terms assigned to each SOC and PT will be 
provided.  
A listing of TEAEs by treatment group ordered by subject, SOC, PT, and onset date will 
be provided. 
A listing of serious TEAEs by treatment group ordered by subject, SOC, PT, and onset 
date will be provided. 
8.2. 
 Concomitant Medications 
All concomitant medications listed on the case report form will be provided in data 
listings in the clinical study report. Each medication will be mapped to their 
corresponding Preferred Term from the ATC-WHO-DD (Anatomical Therapeutic 
Chemical World Health Organization Drug Dictionary) A frequency distribution of all 
concomitant medications used during the study will be provided for each treatment 
group. Medications used prior to randomization but stopped prior to randomization will 
be summarized separately from those used concomitantly. A subject data listing will be 
provided. 


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8.3. 
Ocular and Other Medical History 
History terms will be classified according to the MedDRA system to the levels of SOC 
and primary PT. 
An overall summary will be presented which gives the number and percentage of subjects 
within each treatment group that experienced each condition or procedure. A subject data 
listing will be provided. 
8.4. 
Ophthalmoscopy/Dilated Fundoscopy 
The observations of ocular ophthalmoscopy and dilated fundoscopy will be summarized 
in frequency tables based on the ordinal or categorical scales for each measure for each 
eye by time point and treatment group. A subject data listing will be provided. 
 


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9. 
CHANGES FROM THE PROTOCOL 
TBD 


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10. 
INTERIM ANALYSIS 
No interim analyses are planned. 


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11. 
TABLES, LISTINGS AND FIGURES 
Table, listing and figure shells are provided in the Appendix.