Clinical trial NCT04181593
Conditions: Dry Eye
Keywords: Dry Eye Disease Ocular Surface Disease
Sponsor: OmegaD LLC
Start date: 2019-11-18; Completion date: 2021-02-28
Enrollment: 322 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 (mineral oil ) dosed orally BID for 84 days. Approximately 300 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 at least moderate ocular surface disease (OSDI ≥ 20) 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 Screening and the Schirmer's test score in both eye(s) must be ≥ 5 mm at Screening.

Approximately 300 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: Omega 3 fatty acid intervention 2: Placebos
Intervention descriptions: intervention 1: Omega 3 fatty acid Softgels intervention 2: Mineral oil Softgels

Protocol documents:
Prot_000.pdf: 
CLINICAL TRIAL PROTOCOL 
OmegaD-2019-002 
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: 
07 October 2019 
Amended Protocol V2.0: 
28 October 2019 
Amended Protocol V3.0: 
18 December 2019 
Amended Protocol V4.0: 
05 May 2020 
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 protocol might be 
subject to change and revision. Any conclusion regarding efficacy and safety must be considered 
provisional. 


Om egaD softgels 
Protocol Omega D-2019-002 
Study Title: 
SPONSOR SIGNATURE 
A Randomized, Multicenter, Double-Masked, Placebo-
OmegaD LLC 
!NO 130264 
Controlled Study of the Safety and Efficacy ofOmegaD Softgels 
in the Treatment of Dry Eye Disease 
Study Number: 
OmegaD-2019-002 
Amended Protocol: 
05 May 2020 
Person authorized to sign the protocol and protocol amendment(s) for the Sponsor, OmegaD 
LLC: 
S. Gregory Smith, MD 
Chief Executive Officer, OmegaD LLC 
302-383-3948 (Mobile) 
5 /('f4d-7 ~fr\0 
Signature 
Date 
Medical Monitor 
Charles Slonim, MD 
Oculos Development Services, LLC 
813-690-0255 (Mobile) 
Email: chuck.slonim@oculoscr.com 
Signature 
Date 


OmegaD softgels 
Protocol Omega D-20 19-002 
Study Title: 
SPONSOR SIGNATURE 
A Randomized, Multicenter, Double-Masked, Placebo-
OmegaD LLC 
IND 130264 
Controlled Study of the Safety and Efficacy of Om egaD Softgels 
in the Treatment of Dry Eye Disease 
Study Number: 
OmegaD-20 19-002 
Amended Protocol: 
05 May 2020 
Person authorized to sign the protocol and protocol amendment(s) for the Sponsor, OmegaD 
LLC: 
S. Gregory Smith, MD 
Chief Executive Officer, OmegaD LLC 
302-383-3948 (Mobile) 
Signature 
Date 
Medical Monitor 
Charles Slonim, MD 
Oculos Development Services, LLC 
813-690-0255 (Mobile) 
Email: chuck.slonim@oculoscr.corn 
~~ 
Signature 
Date 
1 


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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-2019-002 
Amended Protocol: 
05 May 2020 
 
I have read the OmegaD-2019-002 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 Council for 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 Development Services, LLC 
586-212-0237 (Mobile) 
Email: roselyn.judd@oculoscr.com 
Medical Monitor 
Charles Slonim, MD 
Oculos Development Services, LLC 
813-690-0255 (Mobile) 
Email: chuck.slonim@oculoscr.com 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: OmegaD LLC 
Name of Investigational Products: 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 subject enrolled: November 2019 
Estimated date last subject completed: July 2020 
Phase of Development:  
3 
Objectives:  
The primary objective of this study is to evaluate the safety and efficacy of once daily 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 =150 subjects): 4 softgels to be taken daily at bedtime. No other 
orally taken medications (including vitamins) should be taken within 2 hours of taking 
the study medication. If necessary to minimize any digestive upset, subjects may take 2 
softgels twice daily (BID), provided that dosing of study medication is not within 2 hours 
of a meal or orally taken administration of other medications, including vitamins. Under 
these circumstances, the first dose should be taken between meals and the second dose 
should be taken at bedtime 
• 
Placebo softgels (N =150 subjects): 4 softgels to be taken daily at bedtime. No other 
orally taken medications (including vitamins) should be taken within 2 hours of taking 
the study medication. If necessary to minimize any digestive upset, subjects may take 2 
softgels BID, provided that dosing of study medication is not within 2 hours of a meal or 
orally taken administration of other medications, including vitamins. Under these 
circumstances, the first dose should be taken between meals and the second dose should 
be taken at bedtime  
Comparisons of OmegaD softgels to placebo will be double-masked; OmegaD softgels and placebo 
will be identically 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 (Ocular Surface Disease Index [OSDI] 
questionnaire [to be completed by subjects], tear osmolarity testing, meibomian gland dysfunction 
grading, tear break-up time [TBUT], Schirmer’s test [anesthetized]), 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 1) and the 
site will update concomitant medications, perform a urine pregnancy test (women of childbearing 
potential only), and conduct baseline examinations. Continuing eligibility for enrollment will require 
a negative pregnancy test result (if performed), 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 


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and Baseline, TBUT ≤ 7 seconds in both eyes at Screening, Schirmer’s test score (anesthetized) at 
Screening must be ≥ 5 mm in both eyes, and OSDI score at Screening must be ≥ 20. 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 
higher tear osmolarity score; if both eyes score equally on tear osmolarity, the eye with the lower 
TBUT 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 HS-Omega-3 
Index score will be assessed via fingerstick blood sample and site personnel will dispense 
investigational product (IP) and a daily IP diary and assess AEs. 
Subjects will take 4 softgels daily at bedtime. Daily reminders to take the medication will be 
provided, and subjects will document their compliance in terms of number of softgels taken in the IP 
diary on a daily basis. 
Each subject will return to the site at Day 42 (± 7 days) along with all unused IP and the IP diary. The 
subject will complete an OSDI questionnaire, and site personnel will update concomitant medications, 
conduct a slit lamp examination, dispense new IP, assess AEs, and perform IP accountability and 
diary review.  
Subjects will return to the site at Day 84 (± 7 days), along with all unused IP and the IP diary, for 
final safety and efficacy evaluations. The subject will complete an OSDI questionnaire and answer a 
question to establish their compliance with dosing of any vitamins (to be taken more than 2 hours 
before or after study medication) during the study. Site personnel will update concomitant 
medications, perform a urine pregnancy test (women of childbearing potential only), conduct all 
specified ophthalmic assessments, assess the HS-Omega-3 Index score via fingerstick blood sample, 
assess AEs, and perform IP accountability and diary review.  
Both eyes will be assessed at each visit. AEs and concomitant medications will be documented from 
signing of informed consent at Screening to Day 84. 
Subjects who have already completed their Day 84 Final Study Visit at the time of this Protocol 
Amendment (V4.0) will be contacted by the site to establish their compliance with dosing of any 
vitamins (to be taken more than 2 hours before or after study medication) during the study. 
Number of Subjects (Planned):  
Approximately 300 subjects are planned to be enrolled, with approximately 150 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. Noncompliance will be defined as a 
total of 28 missed softgels in a 6-week period. 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. 
At least moderate ocular surface disease as measured by an OSDI score ≥ 20 at Screening. 
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. 
Schirmer's test score (anesthetized)  5 mm in both eyes at Screening. 
7. 
TBUT  7 seconds in both eyes at Screening.  


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8. 
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. 
Exclusion Criteria:  
1. 
Any previous reconstructive or cosmetic eyelid surgery that may, in the Investigator’s 
opinion, affect the normal function of the lids (eg, blepharoplasty, ptosis repair, 
entropion/ectropion repair) that could affect study parameters/assessments.  
2. 
Cataract extraction, with or without minimally invasive glaucoma surgery (eg, iStent®), 
within 90 days prior to Screening. 
3. 
Any previous invasive glaucoma surgery (eg, trabeculectomy, shunts, valves) and/or corneal 
surgery (eg, penetrating keratoplasty, lamellar keratoplasty, Descemet’s stripping endothelial 
keratoplasty [DSEK]). 
4. 
 Lid scrubs with over-the-counter (OTC) products (eg, OCuSOFT® lid scrub, SteriLid®, baby 
shampoo, etc.) and/or warm compresses within 14 days prior to Screening and throughout the 
study period.  
5. 
Prescription and OTC ophthalmic mast cell stabilizers and antihistamines within 21 days prior 
to Screening and throughout the study period (systemic mast cell stabilizers are allowed, and 
systemic antihistamines are permitted with certain restrictions [see exclusion criterion #16]). 
6. 
Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 
systemic narcotics for any chronic pain syndrome (eg, fibromyalgia, rheumatoid arthritis, 
etc.) during the study period. Short-term, as-needed dosing of a systemic narcotic for ≤ 72 
hours is allowed, but not at Screening or on the day of the study visit. 
7. 
Allergy to fish oil or mineral oil (component of placebo softgels) or any component of the 
softgel material. 
8. 
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. 
9. 
Active or anticipated seasonal and/or perennial allergic conjunctivitis or rhinitis. 
10. 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 or 
inflammation of the eye and ocular surface scarring. 
11. History or presence of abnormal nasolacrimal drainage. 
12. Laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) 
performed within one year prior to Screening and throughout the study period. 
13. Ophthalmic artificial tear drop use within 2 hours prior to any study visit. Any OTC artificial 
tear (preserved or unpreserved) should be continued at the same frequency and with no 
change in drop brand. 
14. Contact lens wear within 12 hours prior to Screening or any study visit; subjects determined 
to have worn contact lenses within 12 hours must be rescheduled. 
15. History of cauterization of the punctum or existing silicone punctal plug(s); history of silicone 
plug removal or collagen plug insertion or removal within 12 months prior to Screening and 
throughout the study period. 
16. Started or changed the dose of systemic medications known to affect tear production 
(including immunomodulators, tricyclic antidepressants, diuretics, and corticosteroids) within 
30 days prior to Screening and throughout the study period. However, one short (≤ 72 hour) 


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course of a systemic medication that affects tear production (including immunomodulators, 
tricyclic antidepressants, diuretics, and corticosteroids) or systemic antihistamines is allowed 
but not within 30 days of Screening or on the day before or the day of any other study visit. 
Any chronic use of systemic antihistamines within 30 days prior to Screening and throughout 
the study period is prohibited.  
17. Use of any topical prescription ophthalmic medications (including cyclosporine [Restasis®, 
Cequa®] or topical lifitegrast [Xiidra®], steroids, nonsteroidal anti-inflammatory drugs 
[NSAIDs], anti-glaucoma medications, anti-microbials), topical macrolides, or oral 
nutraceuticals (fish, flax, black currant seed oils, etc.) within 21 days prior to Screening and 
throughout the study period. 
18. Use of oral tetracyclines or oral macrolides within 21 days prior to Screening and throughout 
the study period; use of isotretinoin (Accutane®) within 90 days prior to Screening and 
throughout the study period. 
19. 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 of any dosage is permitted. 
20. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable form of birth control. Acceptable methods include the use of at 
least one of the following: intrauterine device (IUD), hormonal (oral, injection, patch, 
implant, ring), barrier with spermicide (condom, diaphragm), or abstinence. An adult woman 
is considered to be of childbearing potential unless she is 1 year postmenopausal or post-
surgical hysterectomy. All women of childbearing potential, including those post-tubal 
ligation, must have a negative urine pregnancy test result at Visit 1 (Screening), Visit 2 
(Baseline), and Visit 4 (Day 84) examinations and must intend to not become pregnant during 
the study. 
21. 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: 4 softgels to be taken daily at bedtime. No other orally taken medications 
(including vitamins) should be taken within 2 hours of taking the study medication. If necessary to 
minimize any digestive upset, subjects may take 2 softgels BID, provided that dosing of study 
medication is not within 2 hours of a meal or orally taken administration of other medications, 
including vitamins. Under these circumstances, the first dose should be taken between meals and the 
second dose should be taken at bedtime. 
Reference Therapy, Dosage and Mode of Administration:  
Placebo softgels: 4 softgels to be taken daily at bedtime. No other orally taken medications (including 
vitamins) should be taken within 2 hours of taking the study medication. If necessary to minimize any 
digestive upset, subjects may take 2 softgels BID, provided that dosing of study medication is not 
within 2 hours of a meal or orally taken administration of other medications, including vitamins. 
Under these circumstances, the first dose should be taken between meals and the second dose should 
be taken at bedtime. 
Duration of Treatment:  
84 days (12 weeks) 
Study Procedures:  
Visit 1 (Day -7 to Day -1): Screening Visit 


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The site will obtain signed informed consent, demographics, medical/ocular/concomitant medication 
histories, perform a urine pregnancy test (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 (anesthetized) ≥ 5 mm in both eyes, OSDI score ≥ 20), 
review inclusion/exclusion criteria, and assess AEs. The qualifying osmolarity level and meibomian 
orifice size grade must be present in the same eye at the Screening Visit if only one eye qualifies. 
Visit 2 (Day 1): Baseline Visit 
The site will update concomitant medications, perform a urine pregnancy test (women of childbearing 
potential only), conduct baseline examinations including tear osmolarity testing, meibomian gland 
dysfunction grading, and slit lamp examination and then review inclusion/exclusion criteria. 
Site personnel will then randomize eligible subjects, perform the HS-Omega-3 Index Test via 
fingerstick blood sample, dispense/document IP and a daily IP diary and provide instructions for use, 
and assess AEs. 
Subjects should be reminded to bring all IP and the IP diary to the clinical site at Visit 3 (Day 42). If 
the IP 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 IP and the IP diary, update concomitant medications, conduct OSDI 
questionnaire (overseeing subject completion) and slit lamp examination, dispense IP, assess AEs, 
and conduct IP accountability and diary review. 
Subjects should be reminded to bring all IP and the IP diary to the clinical site at Visit 4 (Day 84). If 
the IP and diary are not brought to the site, the visit must be rescheduled. 
Visit 4 (Day 84 ± 7 days): Final Study Visit 
The site will collect unused IP and the daily IP diary, update concomitant medications, perform a 
urine pregnancy test (women of childbearing potential only), conduct final ophthalmic examinations 
(OSDI questionnaire [overseeing subject completion], tear osmolarity, meibomian gland dysfunction 
grading, slit lamp examination, TBUT, and Schirmer’s test [anesthetized]), HS-Omega-3 Index Test 
via fingerstick blood sample, assess AEs, record subject’s answer to yes/no question, “During the 
study, did you regularly take any vitamins within 2 hours of taking your study medication?”, and 
conduct final IP accountability and diary review. 
Clinical site personnel will document all received and returned IP at each visit and review the IP 
diary. IP accountability will be conducted by the monitor at each applicable monitoring visit. 
If a subject is discontinued from IP 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. 
Subjects who have already completed their Day 84 Final Study Visit at the time of this Protocol 
Amendment (V4.0) will be contacted by the site to establish their compliance with dosing of any 
vitamins (to be taken more than 2 hours before or after study medication) during the study. 
Efficacy Assessments:  
Signs: Tear osmolarity, meibomian gland dysfunction grading, TBUT, Schirmer’s test (anesthetized)  
Symptoms: OSDI questionnaire 
Pharmacokinetics: HS-Omega-3 Index Test 
Safety Assessments:  
Safety assessments will include slit lamp examination and collection of AEs. 


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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 tear osmolarity in the study eye at Visit 4 (Day 84) 
• 
Mean change from Screening 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 2 endpoints will be tested sequentially in the order 
described above. If the null hypothesis for the tear osmolarity endpoint can be rejected at P ≤ 0.05, 
OSDI endpoint will be tested at P ≤ 0.05.  
Secondary Efficacy Endpoints:  
• 
Mean change from baseline in TBUT 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) 
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) 
Safety Endpoint: 
• 
Incidence of AEs 
Statistical Methods: 
Analysis Populations: 
• 
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 IP. 
Efficacy analysis will be conducted on the ITT population and on the PP population. Safety analyses 
will be performed using the safety analysis population. 
Statistical Analyses: 
Analysis of TBUT, meibomian gland dysfunction, tear osmolarity, and Schirmer’s test scores 
(anesthetized) will utilize the designated study eye (worse eye at Baseline as defined by higher tear 
osmolarity score; if both eyes score equally on tear osmolarity, the eye with the lower TBUT 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 an analysis of covariance using 
treatment, center, and baseline values as covariates. 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 (SD) 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. 
A comprehensive Statistical Analysis Plan will be completed prior to completion of data collection. 


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Sample Size:  
A total of 150 subjects per groups is planned. Power considerations for each endpoint are described 
below.  
Tear osmolarity: In the initial placebo-controlled trial of OmegaD, the change from baseline in tear 
osmolarity was -13 (SD=22). Two natural history studies in dry eye suggest that changes in tear 
osmolarity can become less or more severe. The former trial reported a mean decrease of 6 mOsm/L, 
whereas the latter trial reported a mean increase of approximately 20 mOsm/L. A sample size of 150  
in each group will have 95% power to detect a difference in changes in tear osmolarity means of 8 
mOsm/L (-13 mOsm/L for OmegaD and -5 mOsm/L for placebo), assuming that the common SD of 
change is 19, using a two-group t-test with a 0.05 two-sided significance level.  
OSDI: As OSDI is a subjective subject-reported outcome, some degree of improvement is expected 
from trial participation. In the initial placebo-controlled trial of OmegaD, the change from baseline in 
OSDI was -13 points (SD=20). In natural history studies, changes from baseline in OSDI were -7 
and -10 points (SD≈16). A sample size of 150 in each group will have approximately 95% power to 
detect a difference in change in mean OSDI scores of 7 points (-13-point change for OmegaD and -6-
point change for placebo), assuming that the common SD of change in OSDI is 17.0, using a two-
group t-test with a 0.05 two-sided significance level.  
TBUT: In the initial placebo-controlled trial of OmegaD, the change from baseline in TBUT was 1.4 
seconds with a SD of 2.8. In natural history studies, changes from baseline in TBUT were 0.4 and 0 
seconds (SD≈1.9). A sample size of 150 in each group will have approximately 95% power to detect 
a difference in changes in mean TBUT of 1 second (1.4-second change for OmegaD and 0.4-second 
change for placebo), assuming that the common SD of change in TBUT is 2.4, using a two-group 
t-test with a 0.05 two-sided significance level. 


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Table 2: 
Schedule of Procedures 
Procedures 
Visit 1 
Screening 
Visit 2 
Baseline 
Visit 3 
Safety and Accountability 
Visit 4 
Final Study/Early Discontinuation 
Days 
-7 to -1 
1 
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 
 
X 
Ocular Surface Disease Index Questionnaire 
X 
 
X 
X 
Tear osmolarity b 
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 
X 
Tear break-up time  
X 
 
 
X 
Schirmer’s test (anesthetized)                                          
X 
 
 
X 
Review inclusion/exclusion criteria 
X 
X 
 
 
Randomization 
 
X 
 
 
HS-Omega-3 Index Test (fingerstick) 
 
X 
 
X 
IP distribution  
 
X 
X 
 
IP diary distribution 
 
X 
 
 
Unused IP and diary collection 
 
 
X 
X 
IP accountability c 
 
X 
X 
X 
IP diary review 
 
 
X 
X 
Vitamin dosing compliance 
 
 
 
X 
AE assessment d 
X 
X 
X 
X 
AE, adverse event; IP, investigational product. 
a Women of childbearing potential only. 
b Investigators can use up to 3 attempts to obtain a valid reading (with a 10-minute waiting period between attempts). No other diagnostic examinations can be 
performed until a valid reading is obtained. 
c Clinical site personnel will document all dispensed or returned IP as applicable at Baseline Visit and at Days 42 and 84 Visits. 
d Collection of AEs extends from signing of informed consent until the last study visit. 


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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 ..................................................12 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................16 
4. 
INTRODUCTION ......................................................................................................18 
4.1. 
Background Information .............................................................................................18 
4.2. 
Rationale for the Development of OmegaD Softgels for the Treatment of 
Dry Eye .......................................................................................................................18 
4.3. 
Justification for Dose, Regimen, and Treatment Period .............................................19 
4.4. 
Good Clinical Practice Statement ...............................................................................20 
4.5. 
Population to Be Studied ............................................................................................20 
5. 
TRIAL OBJECTIVES AND PURPOSE ....................................................................21 
5.1. 
Primary Objective .......................................................................................................21 
6. 
INVESTIGATIONAL PLAN .....................................................................................22 
6.1. 
Overall Study Design ..................................................................................................22 
6.2. 
Number of Subjects ....................................................................................................23 
6.3. 
Criteria for Study Termination ...................................................................................23 
7. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................24 
7.1. 
Subject Inclusion Criteria ...........................................................................................24 
7.2. 
Subject Exclusion Criteria ..........................................................................................24 
7.3. 
Withdrawal Criteria ....................................................................................................26 
8. 
TREATMENT OF SUBJECTS ..................................................................................27 
8.1. 
Description of Investigational Product .......................................................................27 
8.1.1. 
Investigational Product ...............................................................................................27 
8.1.2. 
Reference Therapy ......................................................................................................27 
8.2. 
Randomization and Masking ......................................................................................27 
8.2.1. 
Unmasking During the Study Period ..........................................................................27 
8.3. 
Concomitant Medications ...........................................................................................28 
8.3.1. 
Permitted Medications and Treatments ......................................................................28 
8.3.2. 
Prohibited Medications ...............................................................................................28 


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8.4. 
Treatment Compliance ................................................................................................29 
8.5. 
Discontinuation of Investigational Product ................................................................29 
8.6. 
Investigational Product Materials and Management ..................................................30 
8.6.1. 
Packaging and Labeling ..............................................................................................30 
8.6.2. 
Storage ........................................................................................................................30 
8.6.3. 
Administration ............................................................................................................30 
8.6.4. 
Dispensing ..................................................................................................................30 
8.6.4.1. 
Interim COVID-19 Pandemic Dispensing Procedures ...............................................30 
8.6.5. 
Investigational Product Accountability ......................................................................31 
9. 
STUDY ASSESSMENTS ..........................................................................................32 
9.1. 
Demographic and Background Characteristics ..........................................................32 
9.1.1. 
Demographic Information ..........................................................................................32 
9.1.2. 
Medical/Ocular History ..............................................................................................32 
9.1.3. 
Concomitant Medications History ..............................................................................32 
9.1.4. 
Urine Pregnancy Test .................................................................................................32 
9.2. 
Efficacy Assessments .................................................................................................32 
9.2.1. 
Signs ...........................................................................................................................32 
9.2.1.1. 
Tear Osmolarity ..........................................................................................................32 
9.2.1.2. 
Meibomian Gland Dysfunction Grading ....................................................................33 
9.2.1.3. 
Tear Break-Up Time ...................................................................................................33 
9.2.1.4. 
Schirmer’s Test (Anesthetized) ..................................................................................34 
9.2.2. 
Symptoms ...................................................................................................................34 
9.3. 
Safety Assessments .....................................................................................................34 
9.3.1. 
Slit Lamp Examination ...............................................................................................34 
9.4. 
Pharmacokinetic Assessment ......................................................................................34 
9.4.1. 
HS-Omega-3 Index Test .............................................................................................34 
9.5. 
Other Assessment .......................................................................................................34 
9.5.1. 
Vitamin Dosing Compliance Question .......................................................................34 
9.6. 
Adverse and Serious Adverse Events .........................................................................35 
9.6.1. 
Definition of Adverse Events .....................................................................................35 
9.6.1.1. 
Adverse Event .............................................................................................................35 
9.6.1.2. 
Serious Adverse Event ................................................................................................35 


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9.7. 
Relationship to Investigational Product ......................................................................36 
9.8. 
Recording Adverse Events .........................................................................................36 
9.9. 
Reporting Adverse Events ..........................................................................................37 
10. 
STUDY ACTIVITIES ................................................................................................39 
10.1. 
Visit 1 (Day -7 to Day -1)/Screening ..........................................................................39 
10.2. 
Visit 2 (Day 1)/Baseline .............................................................................................40 
10.3. 
Visit 3 (Day 42)/Safety and Accountability Visit .......................................................40 
10.4. 
Visit 4 (Day 84)/Final Study/Early Discontinuation Visit .........................................41 
11. 
STATISTICS ..............................................................................................................42 
11.1. 
General Considerations ...............................................................................................42 
11.2. 
Handling of Missing Data ...........................................................................................42 
11.3. 
Determination of Sample Size ....................................................................................42 
11.4. 
Analysis Populations ..................................................................................................43 
11.4.1. 
Populations for Efficacy Analysis ..............................................................................43 
11.4.1.1. 
Intent-to-Treat Population ..........................................................................................43 
11.4.1.2. 
Per Protocol Population ..............................................................................................43 
11.4.2. 
Safety Analysis Population .........................................................................................43 
11.5. 
Demographics and Baseline Characteristics ...............................................................43 
11.6. 
Efficacy Analysis ........................................................................................................43 
11.6.1. 
Primary Efficacy Endpoints ........................................................................................44 
11.6.2. 
Secondary Efficacy Endpoints ....................................................................................44 
11.6.3. 
Exploratory Efficacy Endpoint ...................................................................................44 
11.7. 
Safety Analyses ..........................................................................................................44 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................45 
12.1. 
Interim COVID-19 Pandemic Monitoring Procedures ...............................................45 
13. 
ADMINISTRATIVE CONSIDERATIONS ..............................................................46 
13.1. 
Institutional Review Board .........................................................................................46 
13.2. 
Ethical Conduct of the Study ......................................................................................46 
13.3. 
Written Informed Consent ..........................................................................................46 
13.3.1. 
Version 3.0 Reconsent ................................................................................................46 
13.4. 
Subject Confidentiality and Confidentiality of Data ..................................................47 
13.5. 
Study Monitoring ........................................................................................................47 


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13.5.1. 
Interim COVID-19 Pandemic Monitoring Procedures ...............................................48 
13.6. 
Case Report Forms and Study Records ......................................................................48 
13.7. 
Protocol Violations/Deviations ...................................................................................48 
13.8. 
Access to Source Documentation ...............................................................................48 
13.9. 
Data Generation and Analysis ....................................................................................49 
13.9.1. 
Retention of Data ........................................................................................................49 
13.10. 
Publication and Disclosure Policy ..............................................................................49 
14. 
LIST OF REFERENCES ............................................................................................50 
APPENDIX A. OCULAR SURFACE DISEASE INDEX QUESTIONNAIRE ........................52 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Procedures ...............................................................................................11 
Table 3: 
Abbreviations ..............................................................................................................16 
 


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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 
DSEK 
Descemet’s stripping endothelial keratoplasty 
eCRF 
electronic case report form 
eDC 
electronic data capture 
EPA 
eicosapentaenoic acid 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IL-1 
interleukin 1 
IL-1β 
interleukin 1 beta 
IRB 
Institutional Review Board 
IP 
investigational product 
ITT 
intent-to-treat 
IUD 
intrauterine device 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LASIK 
laser-assisted in situ keratomileusis 
LTB4 
leukotriene B4 
MMP-3 
matrix metalloproteinase 3 
MMP-9 
matrix metalloproteinase 9 
NSAID 
nonsteroidal anti-inflammatory drug 
OSDI 
Ocular Surface Disease Index 
OTC 
over-the-counter  
PGE1 
prostaglandin E1 
PGE2 
prostaglandin E2 
PGE3 
prostaglandin E3 
PP 
per protocol 
PRK 
photorefractive keratectomy 


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Abbreviation 
Explanation 
PRN 
Physician Recommended Nutriceuticals 
SAE 
serious adverse event 
SD 
standard deviation 
SOP 
standard operating procedure  
TBUT 
tear break-up time  
TNF-α 
tumor necrosis factor alpha 
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 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 metalloproteinases 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 
(prostaglandin E1 [PGE1]) and weakly inflammatory (prostaglandin E3 [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 interleukin 1 
beta (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 (anesthetized) 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 LLC 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 softgels 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, with 4 subjects in each treatment group reporting 
adverse events (AEs; Omega Benefits 7.5%, placebo 8.0%). All the AEs reported for the Omega 
Benefits group were mild and 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, having identical amounts of EPA and 
DHA. 
Omega D LLC conducted a multicenter, placebo-controlled, double-masked, randomized clinical 
trial in subjects with dry eye disease. One hundred and eighty (180) subjects were randomized 
(OmegaD, n=89; placebo, n=91), with 173 subjects completing the study (OmegaD, n=85; 
placebo, n=88). After 84 days of treatment, the results of the study showed that although 
treatment with OmegaD softgels achieved an approximate 30% change from baseline in both 
TBUT and OSDI, there was no significant difference between OmegaD and placebo for either of 
these parameters [TBUT (P = 0.54), OSDI (P = 0.52)]. The lack of significant difference was 
considered primarily due to the unexpectedly high placebo response rates. The Omega-3 Index 
score was significantly increased in the OmegaD group compared with placebo (P < 0.0001), 
showing that omega-3 fatty acids in the RBC membranes had increased over the duration of the 
study in those subjects receiving OmegaD softgels. The safety profile of OmegaD softgels in this 
study was similar to the previous PRN study. There were no serious adverse events (SAEs) in 
either group and a total of 56 AEs were reported in 39 subjects (OmegaD, 31 AEs in 23 subjects 
[25.8%]; placebo, 25 AEs in 16 subjects [17.6%]). Of these, only diarrhea (n=4 subjects), 
abdominal discomfort (n=2), abdominal pain (n=2), and upper respiratory tract infection (n=4) 
were reported in more than one subject in either group (> 2%). All AEs were either mild or 
moderate in intensity. Four subjects in the OmegaD group and 1 subject in the placebo group 
withdrew from the study due to AEs and 1 further subject in the OmegaD group had study drug 
interruption. 
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 only supported by general health claims. While these omega-3 
supplements were subject to Food and Drug Administration (FDA) regulation as food 
supplements, the clinical data to support activity in dry eye disease may not have been reviewed 
by the FDA. 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-2019-002, 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 (Epitropoulos, 


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2016). This dose also 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 Practice Statement 
This study will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and in compliance with International Council for 
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 an OSDI score ≥ 20 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 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 Screening, and Schirmer’s test 
score (anesthetized) in both eyes must be ≥ 5 mm at Screening. 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 once daily 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 =150 subjects): 4 softgels to be taken daily at bedtime. No other 
orally taken medications (including vitamins) should be taken within 2 hours of 
taking the study medication. If necessary to minimize any digestive upset, subjects 
may take 2 softgels twice daily (BID), provided that dosing of study medication is not 
within 2 hours of a meal or orally taken administration of other medications, 
including vitamins. Under these circumstances, the first dose should be taken between 
meals and the second dose should be taken at bedtime. 
• Placebo softgels (N =150 subjects): 4 softgels to be taken daily at bedtime. No other 
orally taken medications (including vitamins) should be taken within 2 hours of 
taking the study medication. If necessary to minimize any digestive upset, subjects 
may take 2 softgels BID, provided that dosing of study medication is not within 2 
hours of a meal or orally taken administration of other medications, including 
vitamins. Under these circumstances, the first dose should be taken between meals 
and the second dose should be taken at bedtime. 
Comparisons of OmegaD softgels to placebo will be double-masked; OmegaD softgels and 
placebo will be identically 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 [anesthetized], and 
OSDI), 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 1) and 
the site will update concomitant medications, perform a urine pregnancy test (women of 
childbearing potential only), and conduct baseline examinations. Continuing eligibility for 
enrollment will require a negative pregnancy test result (if performed), 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 
Screening, Schirmer’s test score (anesthetized) must be ≥ 5 mm in both eyes at Screening, and 
OSDI score must be ≥ 20 at Screening. 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 higher tear osmolarity 
score; if both eyes score equally on tear osmolarity, the eye with the lower TBUT 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 HS-Omega-3 Index score will be 
assessed via fingerstick blood sample and site personnel will dispense investigational product 
(IP) and a daily IP diary and assess AEs. 


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Subjects will take 4 softgels daily at bedtime. Daily reminders to take the medication will be 
provided, and subjects will document their compliance in terms of number of softgels taken in 
the IP diary on a daily basis. 
Each subject will return to the site at Day 42 (± 7 days) along with all unused IP and the IP diary. 
The subject will complete an OSDI questionnaire, and site personnel will update concomitant 
medications, conduct a slit lamp examination, dispense IP, assess AEs, and perform IP 
accountability and diary review.  
Subjects will return to the site at Day 84 (± 7 days), along with all unused IP and the IP diary, for 
final safety and efficacy evaluations. The subject will complete an OSDI questionnaire and 
answer a question to establish their compliance with dosing of any vitamins (to be taken more 
than 2 hours before or after study medication) during the study. Site personnel will update 
concomitant medications, perform a urine pregnancy test (women of childbearing potential 
only), conduct all specified ophthalmic assessments, assess the HS-Omega-3 Index score via 
fingerstick blood sample, assess AEs, and perform IP accountability and diary review.  
Both eyes will be assessed at each visit. AEs and concomitant medications will be documented 
from signing of informed consent at Screening to Day 84. 
Note: For those subjects unable or unwilling to attend a scheduled study visit in-person during 
the COVID-19 pandemic, a “phone visit” will be conducted to allow collection of as many data 
points as possible, including changes to concomitant medication, AE inquiries, OSDI 
questionnaire responses, and response to the vitamin dosing compliance question. Subjects who 
are willing and able will be asked to come into the office for the Final Study Visit, during which 
all scheduled assessments will be conducted. Additional subject enrollment will occur to 
compensate for those subjects unable or unwilling to attend their Final Study Visit, to ensure a 
minimum of 300 evaluable subjects.  
6.2. 
Number of Subjects 
Approximately 300 subjects are planned to be enrolled, with approximately 150 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. Noncompliance will be defined 
as a total of 28 missed softgels in a 6-week period. 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. 
Note: Due to the COVID-19 pandemic, some subjects may be unable or unwilling to attend their 
Final Study Visit (see Section 6.1). Additional subject enrollment will occur to compensate for 
these subjects, to ensure a minimum of 300 evaluable subjects. 
6.3. 
Criteria for Study Termination 
The study may be terminated at any time by OmegaD LLC, following appropriate notification of 
FDA, the Institutional Review Board (IRB), sites/investigators, and subjects.


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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. At least moderate ocular surface disease as measured by an OSDI score ≥ 20 at 
Screening. 
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. Schirmer's test score (anesthetized)  5 mm in both eyes at Screening. 
7. TBUT  7 seconds in both eyes at Screening.  
8. 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. 
7.2. 
Subject Exclusion Criteria 
1. Any previous reconstructive or cosmetic eyelid surgery that may, in the Investigator’s 
opinion, affect the normal function of the lids (eg, blepharoplasty, ptosis repair, 
entropion/ectropion repair) that could affect study parameters/assessments.  
2. Cataract extraction, with or without minimally invasive glaucoma surgery (eg, iStent®), 
within 90 days prior to Screening. 
3. Any previous invasive glaucoma surgery (eg, trabeculectomy, shunts, valves) and/or 
corneal surgery (eg, penetrating keratoplasty, lamellar keratoplasty, Descemet’s stripping 
endothelial keratoplasty [DSEK]). 
4.  Lid scrubs with over-the-counter (OTC) products (eg, OCuSOFT® lid scrub, SteriLid®, 
baby shampoo, etc.) and/or warm compresses within 14 days prior to Screening and 
throughout the study period.  
5. Prescription and OTC ophthalmic mast cell stabilizers and antihistamines within 21 days 
prior to Screening and throughout the study period (systemic mast cell stabilizers are 
allowed, and systemic antihistamines are permitted with certain restrictions [see 
exclusion criterion #16]). 
6. Chronic daily use (defined as > 7 consecutive days at the recommended dosing 
frequency) of systemic narcotics for any chronic pain syndrome (eg, fibromyalgia, 
rheumatoid arthritis, etc.) during the study period. Short-term, as-needed dosing of a 


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systemic narcotic for ≤ 72 hours is allowed, but not at Screening or on the day of the 
study visit. 
7. Allergy to fish oil or mineral oil (component of placebo softgels) or any component of 
the softgel material. 
8. 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. 
9. Active or anticipated seasonal and/or perennial allergic conjunctivitis or rhinitis. 
10. 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 or inflammation of the eye and ocular surface scarring. 
11. History or presence of abnormal nasolacrimal drainage. 
12. Laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) 
performed within one year prior to Screening and throughout the study period. 
13. Ophthalmic artificial tear drop use within 2 hours prior to any study visit. Any OTC 
artificial tear (preserved or unpreserved) should be continued at the same frequency and 
with no change in drop brand. 
14. Contact lens wear within 12 hours prior to Screening or any study visit; subjects 
determined to have worn contact lenses within 12 hours must be rescheduled. 
15. History of cauterization of the punctum or existing silicone punctal plug(s); history of 
silicone plug removal or collagen plug insertion or removal within 12 months prior to 
Screening and throughout the study period.  
16. Started or changed the dose of systemic medications known to affect tear production 
(including immunomodulators, tricyclic antidepressants, diuretics, and corticosteroids) 
within 30 days prior to Screening and throughout the study period. However, one short 
(≤ 72 hour) course of a systemic medications that affect tear production (including 
immunomodulators, tricyclic antidepressants, diuretics, and corticosteroids) or systemic 
antihistamines is allowed but not within 30 days of Screening or on the day before or the 
day of any other study visit. Any chronic use of systemic antihistamines within 30 days 
prior to Screening and throughout the study period is prohibited. 
17. Use of any topical prescription ophthalmic medications (including cyclosporine 
[Restasis®, Cequa®] or topical lifitegrast [Xiidra®], steroids, nonsteroidal anti-
inflammatory drugs [NSAIDs], anti-glaucoma medications, anti-microbials), topical 
macrolides, or oral nutraceuticals (fish, flax, black currant seed oils, etc.) within 21 days 
prior to Screening and throughout the study period. 
18. Use of oral tetracyclines or oral macrolides within 21 days prior to Screening and 
throughout the study period; use of isotretinoin (Accutane®) within 90 days prior to 
Screening and throughout the study period. 
19. 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 


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study period must be discussed with the Medical Monitor. Aspirin of any dosage is 
permitted. 
20. Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not 
using a medically acceptable form of birth control. Acceptable methods include the use of 
at least one of the following: intrauterine device (IUD), hormonal (oral, injection, patch, 
implant, ring), barrier with spermicide (condom, diaphragm), or abstinence. An adult 
woman is considered to be of childbearing potential unless she is 1 year postmenopausal 
or post-surgical hysterectomy. All women of childbearing potential, including those post-
tubal ligation, must have a negative urine pregnancy test result at Visit 1 (Screening), 
Visit 2 (Baseline), and Visit 4 (Day 84) examinations and must intend to not become 
pregnant during the study. 
21. 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 subject is lost to follow-up at any point during the study period, attempts to contact the 
subject must be documented. 
If a subject is discontinued from IP before Visit 4 (Day 84) 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 (Day 84) procedures at the visit the subject is 
discontinued. 


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Investigational Product 
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 mineral oil in a softgel shell composed of gelatin, glycerin, and 
colorant.  
8.2. 
Randomization and Masking 
An Interactive Web Response System (IWRS)/Interactive Voice Response System (IVRS) will 
assign a kit number to subjects who qualify for randomization. IP 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), they will be randomly assigned to IP at the Baseline Visit. Clinical sites will utilize the 
IWRS to assign kits to subjects. The IP kit randomization number will be recorded in the 
subject’s eCRF. 
A supply of randomized IP 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 IP 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 IP 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 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 10.4) should be completed. 


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4. The Investigator should contact Oculos Development Services, LLC (Oculos), the 
contract research organization, at OmegaD-safety@oculoscr.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 IP 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. Permitted concomitant orally administered medications (including 
vitamins) should not be taken within 2 hours of study medication dosing. 
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. 
The initiation or dose modification of systemic medications known to affect tear production is 
prohibited within 30 days prior to Screening and throughout the study period, but short-term, as-
needed dosing of a systemic medication is allowed with certain restrictions. One short 
(≤ 72 hour) course of a systemic medication that affects tear production (including 
immunomodulators, tricyclic antidepressants, diuretics, and corticosteroids) or systemic 
antihistamines is allowed but not within 30 days of Screening or on the day before or the day of 
any other study visit. Any chronic use of systemic antihistamines within 30 days prior to 
Screening and throughout the study period is prohibited. 
Prescription and OTC ophthalmic mast cell stabilizers and antihistamines are prohibited within 
21 days prior to Screening and throughout the study period (systemic mast cell stabilizers are 
allowed, and systemic antihistamines are permitted with the restrictions outlined above).  
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 of any dosage 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 (ie, Restasis and Cequa) 
• Lifitegrast (Xiidra) 
• Steroids 
• NSAIDs 
• Antiglaucoma medications 
• Anti-microbials 
• Macrolides 
Additionally, oral nutraceuticals (fish, flax, black currant seed oils, etc.), oral tetracyclines, and 
oral macrolides are prohibited within 21 days prior to Screening and throughout the study period. 
Isotretinoin (Accutane®) is also prohibited within 90 days prior to Screening and throughout the 
study period. 
Contact lens and ophthalmic drop use (eg, 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 
• History of cauterization of the punctum or existing silicone punctal plug(s); history of 
silicone plug removal or collagen plug insertion or removal within 12 months prior to 
Screening and throughout the study period.  
8.4. 
Treatment Compliance 
Treatment compliance will be monitored by IP accountability and subjects’ daily IP diaries. The 
amount of unused softgels returned at the Day 42 and Day 84 Visits (IP accountability) and the 
information provided in the IP diaries by subjects will be documented by study site personnel in 
the electronic data capture (eDC) system. 
8.5. 
Discontinuation of Investigational Product 
Subjects may be discontinued from IP for either 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 


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− 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 IP 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 in Section 7.3. 
8.6. 
Investigational Product Materials and Management 
8.6.1. 
Packaging and Labeling 
IP will be packaged and labeled at a central packaging facility. Each subject kit will consist of a 
single box with 5 bottles of IP. Upon randomization, each eligible subject will receive 2 bottles 
of IP. The study site will retain 3 bottles, 2 of which will be dispensed at the Day 42 Visit, and 1 
extra bottle will be maintained at the site in case of loss or damage.  
8.6.2. 
Storage 
Store at 15° to 25°C (59° to 77°F). Do not freeze. Keep out of reach of children. 
8.6.3. 
Administration 
Following randomization, site personnel will dispense IP and instruct the subject on 
administration procedures. The daily dose is 4 softgels to be taken at bedtime. No other orally 
taken medications (including vitamins) should be taken within 2 hours of taking the study 
medication. If necessary to minimize any digestive upset, subjects may take 2 softgels BID, 
provided that dosing of study medication is not within 2 hours of a meal or orally taken 
administration of other medications, including vitamins. Under these circumstances, the first 
dose should be taken between meals and the second dose should be taken at bedtime. 
8.6.4. 
Dispensing 
At randomization, a kit with 2 bottles of IP (sufficient IP to last until the Day 42 Visit with a 
little overage) and a IP diary will be dispensed to the subject with instructions to return the kit 
along with all unused IP and the completed study diary at the Day 42 Visit. At the Day 42 Visit, 
the unused IP will be counted, and the site will dispense 2 bottles of IP (sufficient IP to last until 
the Day 84 Visit with a little overage) and the IP diary with instructions to return the kit along 
with all unused IP and the completed study diary at the Day 84 Visit.  
8.6.4.1. 
Interim COVID-19 Pandemic Dispensing Procedures 
During the COVID-19 pandemic, sites may dispense to subjects as much IP as necessary 
(including the fifth/reserve bottle) to allow the subjects to continue to take their study medication 
until they are able to return for a final visit. In addition, subjects will be dispensed an extra diary 
with blank study dosing days to be completed if they take IP for more days than originally 
intended in order to allow continued dosing through to the Final Study Visit. 


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For those subjects entering the study prior to the pandemic who have not received the remainder 
of the IP, they can receive the IP and an extra diary with blank study dosing days in any of the 
following ways: 
• In-person during an already scheduled study visit 
• In-person pick-up by the subject, or designee, if the subject is unwilling or unable to keep 
a previously scheduled study visit 
• IP and extra diary delivered to the subject by study staff 
• IP and extra diary shipped overnight to the subject by study staff 
Regardless of the method utilized, study drug accountability records will be maintained, and 
delivery methods will be documented by the site. 
8.6.5. 
Investigational Product Accountability 
The Investigator or designee (eg, study coordinator or pharmacist) will maintain a full 
accountability record for the IP and will be responsible for recording the receipt, dispensing, and 
returning all supplies of the IP using the inventories supplied by Oculos. Clinical site personnel 
will document all dispensed and returned IPs at Baseline (Day 1), Day 42, and Day 84, and IP 
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 IP and the IP 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 will note any discrepancies. 
All IP 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 IRB-approved version of the informed consent form (ICF). 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 (eg, 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. 
9.1.4. 
Urine Pregnancy Test 
A urine pregnancy test will be performed at Screening, at Baseline, and at the Final Study 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 Visit 4), and the subject must 
refrain from administering any tear supplements within 2 hours prior to the tear osmolarity test. 
The testing must follow the protocol specified in the Study Procedures Manual. If an invalid 
reading is obtained (< 275 or > 400 mOsm/L), the investigator should wait at least 10 minutes to 
retest tear osmolarity. No other diagnostic examinations can be administered until a valid tear 
osmolarity reading is obtained. Investigators can use up to 3 attempts to obtain a valid reading 
(with a 10-minute waiting period between attempts). 


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9.2.1.2. 
Meibomian Gland Dysfunction Grading 
Using a slit lamp at a magnification of 10X 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 subject 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 Altafluor is added to the eye and the subject may blink for 2 seconds 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. If there is break-up in the tear film 
immediately after the blink, this shall be registered as 0. 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 (see Study Procedures Manual). 
 


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9.2.1.4. 
Schirmer’s Test (Anesthetized) 
An anesthetized Schirmer’s test will be performed to ensure that only basal tear secretion is 
being measured and to prevent tearing due to the irritation from the filter paper (the eyes will 
already have been anesthetized for the TBUT procedure). Schirmer strips will be placed in both 
eyes on the lower eyelid margins at the same time. The eyes are closed for 5 minutes. The strips 
are then removed and the amount of moisture on each strip in millimeters (mm) is measured and 
recorded in the eCRF (see Study Procedures Manual). 
9.2.2. 
Symptoms 
A laminated copy of the OSDI questionnaire (Appendix A) will be provided to the subject, who 
will be asked to point to 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. 
HS-Omega-3 Index Test 
The HS-Omega-3 Index Test measures the concentration of 2 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 2 of blood on a collection card. Each card is 
identified and packaged to be submitted to OmegaQuant (Sioux Falls, SD) for analysis. 
9.5. 
Other Assessment 
9.5.1. 
Vitamin Dosing Compliance Question 
At the Final Study Visit, subjects will be asked the yes/no question, “During the study, did you 
regularly take any vitamins within 2 hours of taking your study medication?” Subjects who have 
already completed their Day 84 Final Study Visit at the time of this Protocol Amendment (V4.0) 
will be contacted by the site to establish their compliance with dosing of any vitamins (to be 
taken more than 2 hours before or after study medication) during the study. 


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9.6. 
Adverse and Serious Adverse Events 
9.6.1. 
Definition of Adverse Events 
9.6.1.1. 
Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject administered an IP 
(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 IP, whether 
or not related to the IP. IP 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. 
9.6.1.2. 
Serious Adverse Event  
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening or sight-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. 


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All SAEs that are ongoing at the time of completion or discontinuation from the study will be 
followed until stabilization (ie, no other change in the condition is expected) or resolution of the 
event. 
9.7. 
Relationship to Investigational Product 
The relationship of AEs to the IP should be assessed by the Investigator using the definitions 
below. 
Not suspected: The temporal relationship of the event to the IP 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 IP 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 IP and the occurrence of the AE, then the AE should be considered 
“suspected.” 
If the relationship between the AE/SAE and the IP is determined by the Sponsor or designee to 
be “suspected,” the event will be considered to be related to the IP for the purposes of expedited 
regulatory reporting (see Section 9.9). 
9.8. 
Recording Adverse Events 
AEs 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 IP 
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 ICF 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 IP will be summarized separately from AEs that occur from the first 
dose of double-masked treatment on Day 1 to the Day 84 Visit. Following Visit 4 (Day 84), all 
AEs “suspected” to be related to the IP should be followed until resolution. 
Medical conditions/diseases occurring before the first dose of IP during Visit 2 (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 
• Resolution date 
• Severity grade (mild, moderate, severe) 
• Relationship to IP (not suspected, suspected) 


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• Action taken (none, IP temporarily interrupted, IP 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 9.6.1.2. 
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 IP may have interfered with the 
effectiveness of a contraceptive medication. 
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. 
9.9. 
Reporting Adverse Events 
All SAEs (suspected and not suspected) will be recorded from signing of informed consent until 
the Final Study Visit (Visit 4/Day 84), following the end of treatment exposure. Any SAEs 
“suspected” to be related to the IP 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@oculoscr.com. The Investigator must assess the SAE relationship and complete 
the SAE form. Oculos may request additional information. Follow-up information (eg, discharge 
summary) will be retained in the subject’s chart and a copy will be emailed to OmegaD-safety@ 
oculoscr.com. 
In addition, all SAEs should be recorded on the AE 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. 


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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 or unexpected (based on the available information in 
the Investigator’s Brochure). 
Any death occurring during the study or 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 IP, 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 (Table 2). 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. 
Note: For those subjects unable or unwilling to attend a scheduled study visit in-person during 
the COVID-19 pandemic, a “phone visit” will be conducted to allow collection of as many data 
points as possible, including changes to concomitant medication, AE inquiries, OSDI 
questionnaire responses, and response to the vitamin dosing compliance question. Subjects who 
are willing and able will be asked to come into the office for the Final Study Visit, during which 
all scheduled assessments will be conducted. Additional subject enrollment will occur to 
compensate for those subjects unable or unwilling to attend their Final Study Visit, to ensure a 
minimum of 300 evaluable subjects. 
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 will participate in screening procedures to 
establish eligibility for the study. Procedures performed at Screening will include the following: 
• Obtain written informed consent 
• Demographics 
• Medical and ocular histories 
• Concomitant medication history 
• Urine pregnancy test (women of childbearing potential only) 
• OSDI 
• Tear osmolarity test 
• Meibomian gland dysfunction grading 
• Slit lamp examination 
• TBUT 
• Schirmer’s test (anesthetized) 
• Review inclusion/exclusion criteria 
• AE assessment 
Only subjects with a score on the OSDI ≥ 20, tear osmolarity ≥ 312 mOsm/L and meibomian 
gland dysfunction grade 1 or 2 on the meibomian orifice size scale in at least one eye, TBUT 
≤ 7 seconds in both eyes and Schirmer’s test score (anesthetized) ≥ 5 mm in both eyes will be 
scheduled to return to the clinical site for Visit 2 (Day 1). The qualifying osmolarity level and 
meibomian orifice size grade must be present in the same eye at Screening if only one eye 
qualifies. 


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10.2. 
Visit 2 (Day 1)/Baseline 
At Visit 2 (Day 1)/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 IP. Procedures performed at Baseline 
include: 
• Concomitant medication review 
• Urine pregnancy test (women of childbearing potential only) 
• Tear osmolarity test 
• Meibomian gland dysfunction grading 
• Slit lamp examination 
• 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 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 Screening (TBUT is not conducted at 
Baseline) 
− Schirmer’s test score (anesthetized) at Screening must be ≥ 5 mm in both eyes 
(Schirmer’s test is not conducted at Baseline) 
− OSDI ≥ 20 points at Screening 
• Randomization 
• HS-Omega-3 Index Test (fingerstick blood sample) 
• Dispense and document dispensing of IP and provide instructions for administration 
• Dispense IP 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 IP and the IP 
diary to Visit 3 (Day 42). If the IP 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: 
• Concomitant medication review 
• OSDI 


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• Slit lamp examination 
• Dispense IP for the remainder of the study  
• Collect unused IP and IP diary  
• Conduct IP accountability and review IP diary 
• AE assessment 
10.4. 
Visit 4 (Day 84)/Final Study/Early Discontinuation 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 IP 
and the IP diary to Visit 4 (Day 84). If the IP and diary are not brought to the site, the visit must 
be rescheduled. Due to the COVID-19 pandemic precautions, the Final Study Visit may be 
extended until the subject can safely attend the visit. 
At Visit 4 (Day 84), the Final Study Visit, subjects will participate in final efficacy and safety 
evaluations. Procedures/assessments performed at Day 84 will include the following, regardless 
of whether the subject had participated in a “phone visit” during the COVID-19 pandemic: 
• Concomitant medication review 
• Vitamin dosing compliance question  
• Urine pregnancy test (women of childbearing potential only) 
• OSDI  
• Tear osmolarity test 
• Meibomian gland dysfunction grading 
• Slit lamp examination 
• TBUT 
• Schirmer’s test (anesthetized) 
• HS-Omega-3 Index Test (fingerstick blood sample)  
• Collect unused IP and IP diary 
• Conduct IP accountability and review IP diary 
• AE assessment 


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11. 
STATISTICS 
A comprehensive Statistical Analysis Plan will be completed prior to completion of data 
collection. 
11.1. 
General Considerations 
This is a randomized, multicenter, double-masked, placebo-controlled study to evaluate the 
safety and efficacy of once daily 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 =150 subjects); 4 softgels at bedtime 
• Placebo softgels (N = 150 subjects); 4 softgels at bedtime 
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 11.4. 
The study eye will be the worse of qualifying eyes at Baseline as defined by the higher tear 
osmolarity; if both eyes score equally on tear osmolarity, the eye with the lower TBUT 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 
A total of 150 subjects per group is planned. Power considerations for each endpoint are 
described below.  
Tear osmolarity: In the initial placebo-controlled trial of OmegaD, the change from baseline in 
tear osmolarity was -13 (standard deviation [SD]=22). Two dry eye natural history studies 
(Smith, data on file and Sullivan, 2012) suggest that changes in tear osmolarity can become less 
or more severe. The former trial reported a mean decrease of 6 mOsm/L, whereas the latter 
reported a mean increase of approximately 20 mOsm/L. A sample size of 150 in each group will 
have 95% power to detect a difference in change in tear osmolarity means of 8 mOsm/L (-13 
mOsm/L for OmegaD and -5 mOsm/L for placebo), assuming that the common SD of change is 
19, using a two-group t-test with a 0.05 two-sided significance level.  
OSDI: As OSDI is a subjective subject-reported outcome, some degree of improvement is 
expected from trial participation. In the initial placebo-controlled trial of OmegaD, the change 
from baseline in OSDI was -13 points (SD=20). In the natural history studies described above, 
changes from baseline in OSDI were -7 and -10 points (SD≈16). A sample size of 150 in each 


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group will have approximately 95% power to detect a difference in change in mean OSDI scores 
of 7 points (-13-point change for OmegaD and -6-point change for placebo), assuming that the 
common SD of change in OSDI is 17.0, using a two-group t-test with a 0.05 two-sided 
significance level.  
TBUT: In the initial placebo-controlled trial of OmegaD, the change from baseline in TBUT was 
1.4 seconds (SD=2.8). In the natural history studies described above, changes from baseline in 
TBUT were 0.4 and 0 seconds (SD≈1.9). A sample size of 150 in each group will have 
approximately 95% power to detect a difference in change in mean TBUT of 1 second (1.4-
second change for OmegaD and 0.4-second change for placebo), assuming that the common SD 
of change in TBUT is 2.4, using a two-group t-test with a 0.05 two-sided significance level.  
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 
(Day 84) 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 IP. 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 (anesthetized) 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.  


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Statistical significance for the comparison of means will utilize an analysis of covariance using 
treatment, center, and baseline values as covariates. 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, 
SD 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. 
11.6.1. 
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 tear osmolarity in the study eye at Visit 4 (Day 84) 
• Mean change from Screening 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 2 endpoints will be tested sequentially in the order 
described above. If the null hypothesis for the tear osmolarity endpoint can be rejected at 
P ≤ 0.05, OSDI endpoint will be tested at P ≤ 0.05.  
11.6.2. 
Secondary Efficacy Endpoints 
• Mean change from baseline in TBUT 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) 
11.6.3. 
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) 
11.7. 
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 ensure compliance with GCP and all applicable regulatory requirements, the 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 ICFs, medical records, and regulatory 
documentation; an assessment of study conduct and protocol compliance; and a review of the IP 
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. 
12.1. 
Interim COVID-19 Pandemic Monitoring Procedures 
  
• All onsite monitoring visits will be suspended until further notice. 
• ICFs will be uploaded to DataTrak by the sites for remote review by Oculos. 
 


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13. 
ADMINISTRATIVE CONSIDERATIONS 
13.1. 
Institutional Review Board  
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 ICF 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 ICF 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 ICFs 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 ICF. The original ICF is to be retained by the study site, and a copy 
is to be given to the subject. 
13.3.1. 
Version 3.0 Reconsent 
All newly consented subjects will follow the usual, in-person consenting procedures. Due to the 
nature of Version 3.0 involving a dosing change, it is important that the change is implemented 
as soon as possible for currently enrolled subjects. All efforts will be made to have the subject 
come to the site and complete the reconsenting procedures in person. If in-person consent cannot 
be obtained, remote consent may be completed as outlined below: 
 


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• Designated site staff will contact the subject to explain that the site will be sending an 
updated ICF and dosing instructions. 
• Once received, the subject will contact the site to set up a time to discuss the dosing 
changes with the Principal Investigator or Study Coordinator and will be given ample 
time and opportunity to ask questions. 
• If the subject agrees to the new dosing schedule, the subject will sign the ICF and 
send it back to the site.   
• Upon receipt at the site, the person who performed consenting procedures via phone 
will sign and date with the current date at the time of signature. 
• A copy of the fully signed ICF will be mailed to the subject or given to them at their 
next scheduled visit and the original will be retained onsite. 
• The consenting process should be documented in the subject’s file and include a 
notation indicating that the subject’s consent was obtained remotely in order to 
explain the discrepancy between the participant’s date of documents and staff’s date 
of documents. 
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 
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. 


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During visits to the study site, the monitor may review the source documents including, but not 
limited to, signed ICFs, IP diaries, IP 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 (closeout) visit to the site. 
The objectives of this visit are to ascertain that all regulatory records and reports are complete, 
verify that the IP 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. 
13.5.1. 
Interim COVID-19 Pandemic Monitoring Procedures 
  
• All onsite monitoring visits will be suspended until further notice. 
• ICFs will be uploaded to DataTrak by the sites for remote review by Oculos. 
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 (eg, discharge summaries, etc.) will be 
retained at the study site. 
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 ICFs, medical 
records, and regulatory documentation; an assessment of study conduct and protocol compliance; 
and a review of the IP receipt, storage, and administration. 


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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 Development Services, LLC, 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. 
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;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;63(1):116-22. 
Donnenfeld ED, Holland EJ, Bucci FA Jr, et al. Effect of oral re-esterified omega-3 nutritional 
supplementation on dry-eye disease: double-masked randomized placebo-controlled study. In 
ASCRS ASOA Symposium and Congress 2015 Apr 17-21 San Diego, CA.  
Epitropoulos AT, Donnenfeld E, Shah ZA, et al. Effect of oral re-esterified omega-3 nutritional 
supplementation on dry eyes. Cornea. 2016;35(9):1185-91. 
Investigator’s Brochure. OmegaD softgels for the treatment of dry eye disease. 28 August 2019. 
James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory 
mediator production. Am J Clin Nutr. 2000;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;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;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;137(2):337-42. 
Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among 
US women. Am J Ophthalmol. 2003;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;127(6):763-8.  
Data on file. Smith G. A longitudinal natural history study of the signs and symptoms of dry eye 
disease. 2017. 
Sullivan BD, Crews LA, Sönmez B, et al. Clinical utility of objective tests for dry eye disease: 
variability over time and implications for clinical trials and disease management. Cornea. 
2012;31(9):1000-8. 


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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;30(3):308-14. 


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APPENDIX A. OCULAR SURFACE DISEASE INDEX QUESTIONNAIRE 
 


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SAP_001.pdf: 
Statistical Analysis Plan 
 OmegaD-2019-002 
SAP version Draft 0.3 
July 16, 2020 
Page 1 of 17 
 
Statistical Analysis Plan 
 
TRIAL FULL TITLE 
A Randomized, Multicenter, Double-Masked, Placebo-Controlled 
Study of the Safety and Efficacy of OmegaD Softgels in the 
Treatment of Dry Eye Disease 
SAP VERSION 
1 
SAP VERSION DATE 
November 5, 2020 
TRIAL STATISTICIAN 
Mark Scott PhD 
Protocol Version (SAP 
associated with) 
4.0 
TRIAL PRINCIPAL 
INVESTIGATOR 
Charles Slonim, MD 
 
SAP AUTHOR(s) 
Mark Scott PhD 
 
1 
Signatures ...................................................................................................................... 3 
2 
Abbreviations and Definitions ......................................................................................... 3 
3 
Introduction.................................................................................................................... 4 
3.1 
Preface ...............................................................................................................................4 
3.2 
Scope of the analyses ..........................................................................................................4 
4 
Study Objectives and Endpoints ...................................................................................... 4 
4.1 
Study Objectives .................................................................................................................4 
4.2 
Endpoints ............................................................................................................................4 
5 
Study Methods ............................................................................................................... 5 
5.1 
General Study Design and Plan ............................................................................................5 
5.1.1 
Inclusion-Exclusion Criteria ..............................................................................................5 
5.1.1.1 
Inclusion ..........................................................................................................................5 
5.1.1.2 
Exclusion .........................................................................................................................5 
5.2 
Randomization and Masking................................................................................................7 
5.3 
Study Assessments ..............................................................................................................7 
6 
Sample Size .................................................................................................................... 9 
7 
General Analysis Considerations ................................................................................... 10 
7.1 
Timing of Analyses ............................................................................................................ 10 


Statistical Analysis Plan 
 OmegaD-2019-002 
SAP version Draft 0.3 
July 16, 2020 
Page 2 of 17 
 
7.2 
Analysis Populations ......................................................................................................... 10 
7.2.1 
Full Analysis Population (or Intention to Treat or Modified Intention to Treat) ................................... 10 
7.2.2 
Per Protocol Population ......................................................................................................................... 10 
7.2.3 
Safety Population ................................................................................................................................... 10 
7.3 
Covariates and Subgroups ................................................................................................. 10 
7.4 
Missing Data ..................................................................................................................... 11 
7.5 
Interim Analyses and Data Monitoring (as applicable) ........................................................ 12 
7.6 
Multiple Testing ................................................................................................................ 12 
8 
Summary of Study Data ................................................................................................ 12 
8.1 
Subject Disposition ............................................................................................................ 12 
8.2 
Derived variables .............................................................................................................. 13 
8.3 
Protocol Deviations ........................................................................................................... 13 
8.4 
Demographic and Baseline Variables ................................................................................. 13 
8.5 
Concurrent Illnesses and Medical Conditions ..................................................................... 13 
8.6 
Treatment Compliance ...................................................................................................... 13 
9 
Efficacy Analyses .......................................................................................................... 13 
9.1 
Primary Efficacy Analysis ................................................................................................... 14 
9.2 
Secondary Efficacy Analyses .............................................................................................. 15 
9.3 
Exploratory Efficacy Analyses ............................................................................................ 15 
10 
Safety Analyses ......................................................................................................... 15 
10.1 
Extent of Exposure ............................................................................................................ 15 
10.2 
Adverse Events .................................................................................................................. 15 
10.3 
Deaths, Serious Adverse Events and other Significant Adverse Events................................. 15 
10.4 
Pregnancies....................................................................................................................... 15 
10.5 
Clinical Laboratory Evaluations .......................................................................................... 15 
10.6 
Prior and Concurrent Medications ..................................................................................... 15 
10.7 
Other Safety Measures ...................................................................................................... 15 
11 
Pharmacokinetics (N/A) ............................................................................................ 16 
12 
Other Analyses .......................................................................................................... 16 
13 
Reporting Conventions .............................................................................................. 16 
14 
Quality Assurance of Statistical Programming (As Applicable) ................................... 16 
15 
Summary of Changes to the Protocol and/or SAP ....................................................... 16 
16 
References ................................................................................................................ 17 


Statistical Analysis Plan 
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1 Signatures 
 
I give my approval for the statistical analysis plan (SAP).  
 
Statistician (Author) 
Name:  Mark Scott PhD 
 
Signature: 
 
 
 
Date: 
 
        January 16, 2021 
 
Principal Investigator 
Name:      Charles Slonim, MD 
 
Signature: 
 
 
 
 
 
Date: 
 
16Jan2021 
 
2 Abbreviations and Definitions 
Abbreviation 
Explanation 
AE 
adverse event 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
IP 
investigational product 
ITT 
intent-to-treat 
IWRS 
Interactive Web Response System 
LASIK 
laser-assisted in situ keratomileusis 
NSAID 
nonsteroidal anti-inflammatory drug 
OSDI 
Ocular Surface Disease Index 
OTC 
over-the-counter  
PP 
per protocol 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
TBUT 
tear break-up time  
US 
United States  
 


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3 Introduction 
3.1 Preface 
Dry eye disease is a common multifactorial ophthalmologic disorder of the tears and ocular surface.  
Inflammation is an integral component of this disease.  Restasis® (cyclosporine ophthalmic emulsion, 
0.05%), is a drug that targets the immune system. It was the first Food and Drug Administration (FDA)-
approved and most commonly prescribed drug product for patients with dry eye disease. It is indicated 
for 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 patients1. However, 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. More recently Xiidra® (lifitegrast) was approved for the treatment of the 
signs and symptoms of dry eye disease but there remains a clear medical need for additional therapies2.  
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 therefore important to evaluate 
whether omega-3 supplementation can improve dry eye disease signs, symptoms, and associated 
measures of inflammation.   
3.2 Scope of the analyses 
These analyses will assess the efficacy and safety of OmegaD softgels in comparison with a placebo 
control and will be included in the clinical study report. 
4 Study Objectives and Endpoints 
4.1 Study Objectives 
The primary objective of this study is to evaluate the safety and efficacy of once daily dosing of OmegaD 
softgels in subjects with dry eye disease.     
4.2 Endpoints 
The two primary efficacy endpoints include mean change from baseline in tear osmolarity in the study 
eye at Visit 4 (Day 84) and mean change from Screening in Ocular Surface Disease Index (OSDI) score at 
Visit 4 (Day 84).  Secondary efficacy endpoints include mean change from baseline in tear break-up time 
(TBUT) in the study eye at Visit 4 (Day 84) and mean change from Screening in Schirmer’s test 
(anesthetized) score in the study eye at Visit 4 (Day 84).  The 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) is an exploratory endpoint.   
 
Safety of OmegaD softgels will be assessed by examination of proportions of subjects experiencing an 
adverse event during the trial.     
 
 


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5 Study Methods 
5.1 General Study Design and Plan 
● 
This is a randomized, multicenter, double-masked, placebo-controlled study.  
● 
Primary efficacy comparison is assessing superiority of OmegaD softgels over placebo softgels.   
● 
Placebo Control with doubling masking of trial materials.   
● 
Randomization is performed by blocks within each center.   
● 
Subjects will be screened within 7 days of baseline.  Subjects meeting screening criteria will be 
evaluated for randomization at the baseline visit (Day 1).  Randomized subjects are to receive 
trial treatments for 84 days with an interim clinic visit at Day 42.    
5.1.1 Inclusion-Exclusion Criteria 
5.1.1.1 Inclusion  
● 
Subjects age ≥ 18 years and ≤ 90 years on the date of informed consent. 
● 
All subjects must provide signed written consent prior to participation in any study-related 
procedures. 
● 
At least moderate ocular surface disease as measured by an OSDI score ≥ 20 at Screening. 
● 
Clinical diagnosis of dry eye disease supported by global clinical assessment. 
● 
Presence of tear osmolarity in at least one eye ≥ 312 mOsm/L at both Screening and Baseline. 
● 
Schirmer's test score (anesthetized) ≥ 5 mm in both eyes at Screening. 
● 
TBUT ≤ 7 seconds in both eyes at Screening.   
● 
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. 
5.1.1.2 Exclusion 
● 
Any previous reconstructive or cosmetic eyelid surgery that may, in the Investigator’s opinion, 
affect the normal function of the lids (eg, blepharoplasty, ptosis repair, entropion/ectropion 
repair) that could affect study parameters/assessments.  
● 
Cataract extraction, with or without minimally invasive glaucoma surgery (eg, iStent®), within 90 
days prior to Screening. 
● 
Any previous invasive glaucoma surgery (eg, trabeculectomy, shunts, valves) and/or corneal 
surgery (eg, penetrating keratoplasty, lamellar keratoplasty, Descemet’s stripping endothelial 
keratoplasty [DSEK]). 
● 
Lid scrubs with over-the-counter (OTC) products (eg, OCuSOFT® lid scrub, SteriLid®, baby 
shampoo, etc.) and/or warm compresses within 14 days prior to Screening and throughout the 
study period. 
● 
Prescription and OTC ophthalmic mast cell stabilizers and antihistamines within 21 days prior to 


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Screening and throughout the study period (systemic mast cell stabilizers are allowed, and 
systemic antihistamines are permitted with certain restrictions. 
● 
Chronic daily use (>7 consecutive days at the recommended dosing frequency) of systemic 
narcotics for any chronic pain syndrome (e.g. fibromyalgia, rheumatoid arthritis, etc.) during the 
study period. Short-term, as needed dosing of a systemic narcotic for ≤ 72 hours is allowed, but 
not at Screening or on the day of the study visit. 
● 
Allergy to fish oil or mineral oil (component of placebo softgels) or any component of the softgel 
material. 
● 
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. 
● 
Active or anticipated seasonal and/or perennial allergic conjunctivitis or rhinitis. 
● 
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 or 
inflammation of the eye and ocular surface scarring. 
● 
History or presence of abnormal nasolacrimal drainage. 
● 
Laser-assisted in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) performed 
within one year prior to Screening and throughout the study period. 
● 
Ophthalmic artificial tear drop use within 2 hours prior to any study visit. Any OTC artificial tear 
(preserved or unpreserved) should be continued at the same frequency and with no change in 
drop brand. 
● 
Contact lens wear within 12 hours prior to Screening or any study visit; subjects determined to 
have worn contact lenses within 12 hours must be rescheduled. 
● 
History of cauterization of the punctum or existing silicone punctal plug(s); history of silicone 
plug removal or collagen plug insertion or removal within 12 months prior to Screening and 
throughout the study period. 
● 
Started or changed the dose of systemic medications known to affect tear production (including 
immunomodulators, tricyclic antidepressants, diuretics, and corticosteroids) within 30 days prior 
to Screening and throughout the study period.  A short (≤ 72 hour) course of a systemic 
medications that affect tear production (including immunomodulators, tricyclic antidepressants, 
diuretics, and corticosteroids) or systemic antihistamines is allowed but not within 30 days of 
Screening or on the day before or the day of any other study visit. Any chronic use of systemic 
antihistamines within 30 days prior to Screening and throughout the study period is prohibited. 
● 
Use of any topical prescription ophthalmic medications (including cyclosporine [Restasis®, 
Cequa®] or topical lifitegrast [Xiidra®], steroids, nonsteroidal anti-inflammatory drugs [NSAIDs], 
anti-glaucoma medications, anti-microbials), topical macrolides, or oral nutraceuticals (fish, flax, 
black currant seed oils, etc.) within 21 days prior to Screening and throughout the study period. 
● 
Use of oral tetracyclines or oral macrolides within 21 days prior to Screening and throughout the 
study period; use of isotretinoin (Accutane®) within 90 days prior to Screening and throughout 
the study period. 
● 
Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 


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oral NSAIDs during the study period. ANY use of oral NSAIDs during the study period must be 
discussed with the Medical Monitor. Aspirin of any dosage is permitted. 
● 
Women of childbearing potential who are pregnant, nursing, planning a pregnancy, or not using 
a medically acceptable form of birth control. Acceptable methods include the use of at least one 
of the following: intrauterine device (IUD), hormonal (oral, injection, patch, implant, ring), 
barrier with spermicide (condom, diaphragm), or abstinence. An adult woman is considered to 
be of childbearing potential unless she is 1 year postmenopausal or post-surgical hysterectomy. 
All women of childbearing potential, including those with post-tubal ligation, must have a 
negative urine pregnancy test result at Visit 1 (Screening), Visit 2 (Baseline), and Visit 4 (Day 84) 
examinations and must intend to not become pregnant during the study. 
● 
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.   
 
5.2 Randomization and Masking 
An Interactive Web Response System (IWRS) assigned a kit number to subjects qualifying for 
randomization. Subjects were randomized in a 1:1 ratio (OmegaD to placebo). A randomized block 
design (balanced blocks within the Clinical Site) was used. 
 
Subjects meeting eligibility criteria at Screening and at Baseline were randomly assigned to trial therapy 
at the Baseline Visit. Clinical sites utilized the IWRS to assign kits to subjects. The investigational product 
(IP) kit randomization number was recorded in the subject’s electronic case report form (eCRF). 
 
OmegaD softgels are identical in appearance to placebo softgels.   
 
5.3 Study Assessments  
 
 
Visit 1/(Screening) 
Visit 2(Baseline) 
Visit 3 
Visit 4 
 
(Day -7 to Day -1) 
Day 1 
Day 42 
Day 84 
Obtain written informed consent 
x 
 
 
 
Demographics 
x 
 
 
 
Medical and ocular histories 
x 
 
 
 
Concomitant medication history 
(review) 
x 
x 
x 
x 
Urine pregnancy test (women of 
childbearing potential only) 
x 
x 
 
x 
OSDI 
x 
 
x 
x 
Tear osmolarity test 
x 
x 
 
x 
Meibomian gland dysfunction 
grading 
x 
x 
 
x 


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Visit 1/(Screening) 
Visit 2(Baseline) 
Visit 3 
Visit 4 
 
(Day -7 to Day -1) 
Day 1 
Day 42 
Day 84 
Slit lamp examination 
x 
x 
x 
x 
TBUT 
x 
 
 
x 
Schirmer’s test (anesthetized) 
x 
 
 
x 
Review inclusion/exclusion criteria 
x 
x* 
 
 
AE assessment 
x 
x 
x 
x 
Randomization 
  
x 
 
 
HS-Omega-3 Index Test (fingerstick 
blood sample) 
 
x 
 
x 
Dispense and document dispensing 
of IP and IP diary  
 
x 
x 
 
Collect unused IP and IP diary  
 
 
x 
x 
Conduct IP accountability and 
review IP diary 
 
 
x 
x 
Assess compliance with dosing of 
any vitamins with respect to study 
medication. 
 
 
 
x 
Note(*) 
• 
Subjects must have tear osmolarity ≥ 312 mOsm/L and meibomian gland dysfunction grade as defined by a grade 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 Screening (TBUT is not conducted at Baseline) 
• 
Schirmer’s test score (anesthetized) at Screening must be ≥ 5 mm in both eyes (Schirmer’s test is not conducted at Baseline) 
• 
OSDI ≥ 20 points at Screening 
 
The occurrence of interim visits necessitating efficacy assessments is unlikely.  Subjects having efficacy 
data collected outside these time windows will be considered for inclusion in the per protocol 
population.   
Visit (target day) 
Lower bound (days) 
Upper bound (days) 
Baseline (0) 
N/A 
N/A 
Day 42 
35 
49 
Day 84 
77 
91 
 
Tear osmolarity and OSDI are the primary efficacy assessments.  Secondary efficacy endpoints include 
TBUT and Schirmer’s Test.   The study eye will be the worse eye at Baseline as defined by higher tear 
osmolarity score; if both eyes score equally on tear osmolarity, the eye with the lower TBUT score will 
be chosen, and if still equal, the right eye will be the study eye.     
 
Tear osmolarity will be measured at Screening, Baseline and at Day 84.  Tear osmolarity will be assessed 
using the TearLab Osmolarity Test.  Subjects will require tear osmolarity values ≥ 312 mOsm/L in the 
study eye at both Screening and Baseline.  Subjects must have tear osmolarity ≥ 312 mOsm/L and 
meibomian gland dysfunction grade as defined by a grade 1 or 2 on the meibomian orifice size scale in 


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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.  
 
OSDI will be measured at Screening, Day 42 and Day 84.  OSDI is assessed on a scale of 0 to 100, with 
higher scores representing greater disability.  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.  
At screening subjects must have OSDI scores ≥20.  This represents at least moderate dry eye disease.  
OSDI at screening was the pretherapy assessment and will be used as the Baseline value.  OSDI was an 
eligibility criterium and so the screening visit was taken as the baseline value to prevent any issues 
regarding learning that can occur from repeat testing in a short space of time.  It was recognized that 
OSDI could fluctuate day-to-day.  As potential fluctuations were prior to randomization any change 
would not introduce bias.   
 
TBUT is determined by measuring the interval between instillation of topical fluorescein and appearance 
of the first dry spots on the cornea.  Three consecutive measurements are taken, and the time is 
averaged to obtain the TBUT.  A TBUT value of less than 10 seconds is considered abnormal.  TBUT will 
be measured at Screening and at Day 84. 
 
Schirmer’s test determines whether a subject’s eye produces enough tears to keep their eye moist and 
healthy. To conduct a Schirmer’s test, filter paper is applied inside the lower eyelid of both eyes and the 
subject closes their eyes.  After 5 minutes, filter paper is removed.   How far the tears have travelled on 
the paper is the measurement.  In general, the smaller the amount of moisture on the paper, the fewer 
tears that person has produced.  Results from Schirmer’s test will be available at Screening and at Day 
84.  
6 Sample Size  
A total of 150 subjects per group is planned.   No interim analyses are contemplated.  The target 
recruitment of 300 randomized subjects was increased to 320 to account for a number of subjects not 
being able to attend visits due and hence being dropped due to COVID-19.      
 
Power considerations for each of the primary endpoints are described below.  
Tear osmolarity: In the initial placebo-controlled trial of OmegaD (OmegaD-2016-0013), the change from 
baseline in tear osmolarity was -13 (standard deviation [SD]=22). Two dry eye natural history studies 
(Smith, data on file4 and Sullivan, 20125) suggest that changes in tear osmolarity can become less or 
more severe. The former trial reported a mean decrease of 6 mOsm/L, whereas the latter reported a 
mean increase of approximately 20 mOsm/L.  A sample size of 150 in each group will have 95% power to 
detect a difference in change in tear osmolarity means of 8 mOsm/L (-13 mOsm/L for OmegaD and -5 
mOsm/L for placebo), assuming that the common SD of change is 19, using a two-group t-test with an 
a=0.05 two-sided significance level.  
OSDI: As OSDI is a subject-reported outcome, some degree of improvement is expected from trial 
participation. In study OmegaD-2016-001, the change from baseline in OSDI was -13 points (SD=20). In 
the natural history studies described above, changes from baseline in OSDI were -7 and -10 points 
(SD≈16). A sample size of 150 in each group will have approximately 95% power to detect a difference in 


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change in mean OSDI scores of 7 points (-13-point change for OmegaD and -6-point change for placebo), 
assuming that the common SD of change in OSDI is 17.0, using a two-group t-test with an a=0.05 
two-sided significance level.  
 
Although not a primary endpoint, sample size calculations for TBUT are included.  TBUT: In study 
OmegaD-2016-001, the change from baseline in TBUT was 1.4 seconds (SD=2.8). In the natural history 
studies described above, changes from baseline in TBUT were 0.4 and 0 seconds (SD≈1.9). A sample size 
of 150 in each group will have approximately 95% power to detect a difference in change in mean TBUT 
of 1 second (1.4-second change for OmegaD and 0.4-second change for placebo), assuming that the 
common SD of change in TBUT is 2.4, using a two-group t-test with an a=0.05 two-sided significance 
level.  
 
7 General Analysis Considerations 
7.1 Timing of Analyses 
The statistical analysis will be conducted after the data base has been locked.  This will include all data 
on all randomized subjects with completed follow-up. 
7.2 Analysis Populations 
7.2.1 
Full Analysis Population (or Intention to Treat or Modified Intention to Treat) 
● All subjects who were randomized and received any IP.    
7.2.2 
Per Protocol Population 
● All subjects meeting protocol entry criteria, compliant with protocol procedures and 
investigational product and did not receive prohibited medications thought to affect objective 
and subjective dry eye measurements.  (See Section 7.2 of protocol).  Early terminations include 
subject withdrawing due to Adverse Events, COVID-19 (including subjects without data at Visit 4 
and those having Visit 4 assessments telephonically), Subject Withdrawal, Lost to Follow-up and 
Efficacy Assessments greater than 7 days from last IP dose. 
● This population will be determined prior to unmasking of the trial.     
7.2.3 
Safety Population 
● All subjects who received at least one dose of IP  
 
The primary efficacy analysis is based on the full analysis population.   The safety assessment will use 
data from the safety population.  Supportive analysis will use the Per Protocol Population.   
7.3 Covariates and Subgroups 
 
The primary analysis will use a statistical model that adjusts for trial center as well as the pre-
randomization value of the efficacy variable.  The effects of center will be examined and potential 
interactions between centers and IP.   
 


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15 Centers with 20 subjects per center are planned.  In the event of underperformance (<6 per center) 
in recruitment among a number of centers, the underperforming centers will be pooled.  The strategy 
for pooling will consider location of the center (academic or clinic) and geography.  The pooling will be 
decided prior to unmasking of the data.        
 
There are no a priori subgroups considered for inclusion in the statistical analyses.  However, treatment 
outcomes by gender and age will be displayed.    
7.4 Missing Data 
The protocol requires that, for subject discontinuation before Visit 4 (Day 84), 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 (Day 84) procedures at the visit the subject is discontinued.   Also, due to COVID-19, 
subjects nearing the Day 84 assessment, but not allowed to attend clinic, were allowed to continue IP 
until a final visit could occur.  The visit times may be well over the times in the nominal visit window but 
data from these visits will be included provided that the subject continued to dose IP and was dosing IP 
for at least 7 days prior to their V4 visit.  For these subjects those data will not be considered missing 
and used in the primary analyses for the Full Analysis Population.   
     
Efficacy data (osmolarity and/or OSDI) for subjects receiving IP may be missing for Day 84 (e.g. failure to 
return, Adverse Event).  A priori assumptions are that these will be few.  The missing data handling 
method for the primary endpoints, based on the population of randomized and treated subjects, will be 
as follows:  Regression and propensity scores methods of multiple imputation will be used for missing 
OSDI and tear osmolarity scores at Visit 4 (week 12).   As data will only be missing at visit 4, monotone 
missingness will be assumed.  OSDI and Total Osmolarity will be assessed separately.         
 
The PROC MI procedure in SAS will be used.  In addition to the regression method, propensity scores will 
also be employed.  The output of interest from PROC MI is a data set containing multiple repetitions of 
the original data set, along with the newly imputed values.   Each of these output datasets will be 
analyzed using the statistical model that adjusts for trial center as well as the pre-randomization value of 
the efficacy variable.   The MIANALYZE procedure in SAS will be used to combine the results from output 
datasets from PROC MI.   
 
The model structure in SAS for the OSDI endpoint will be as follows for the regression and propensity 
scores (similar models for Total Osmolarity will be generated): 
 
DATA OSDI_CH; set omegad.osdi_CH; keep trt subject center osdi_v1 
osdi_v4 trt; 
proc mi data=osdi_CH seed=501213 nimpute=5  out=OSDI_outreg; 
class center trt; 
monotone reg (OSDI_v4=osdi_v1 center trt); 
var center trt OSDI_v1 OSDI_v4; 
run; 
proc mi data=osdi_CH  seed=501213 nimpute=5  out=OSDI_outprop; 
class center trt; 
monotone propensity (OSDI_v4=osdi_v1 center trt); 
var center trt OSDI_v1 OSDI_v4; 
run; 


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Here OSDI_V1 and OSDI_V4 are OSDI values at visits 1 and 4 respectively; trt and center are 
classification variables for trt and center.   OMEGAD.osdi_CH will be the final analysis data set for OSDI.        
 
As a sensitivity check these outcomes will be compared to the results using a last value carried forward 
approach on the Intention-to-Treat Population and results from the per-protocol population.   
Differences in approaches will be assessed and reported.             
 
A detailed table will be provided listing subjects screened, attending baseline, randomized and 
randomized and completed to describe the extent of missing data.    
7.5 Interim Analyses and Data Monitoring (as applicable) 
No Interim Analysis is planned. 
7.6 Multiple Testing 
The primary efficacy endpoints (Mean change from baseline in tear osmolarity in the study eye at Day 
84 and Mean change from Screening in OSDI score Day 84) comprise a set of hypotheses that will be 
tested in a hierarchical fashion using Hochberg’s procedure.  The Hochberg procedure is a step-up 
procedure.  The procedure starts with the largest p-value, which is compared to the largest endpoint-
specific critical value (α=0.05). If the largest p-value is less 0.05, then the method concludes that there 
are significant treatment effects for all endpoints.   
 
The differences between the 2 treatment groups for these endpoints will be tested with a significance 
level of 0.05. In order to control the Type I error rate these 2 endpoints will be tested sequentially in the 
method described above.  For instance, if significance level for the null hypothesis for the tear 
osmolarity endpoint is the largest and is less than 0.05, OSDI endpoint will also declared significant at P 
≤ 0.05. 
 
8  Summary of Study Data 
All continuous variables will be summarized using the following descriptive statistics: n (non-missing 
sample size), mean, SD, median, maximum and minimum. The frequency and percentages (based on 
the non-missing sample size) of observed levels will be reported for all categorical measures. In 
general, all data will be listed, sorted by center, treatment and subject, and when appropriate by 
visit number within subject. All summary tables will be structured with a column for each treatment 
in the order (Placebo, OmegaD) and will be annotated with the total population size relevant to that 
table/treatment, including any missing observations. 
8.1 Subject Disposition 
 
A CONSORT diagram will be included delineating subjects screened, randomized and followed will be 
included. 
 


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8.2  Derived variables 
Changes from Baseline are the derived variables.    
8.3 Protocol Deviations 
 
From Section 7.2 in the protocol the following are deviations that may be associated with subject 
withdrawal during the post randomization period as they may affect efficacy assessments.  
 
• 
Use of Lid scrubs with over-the-counter products and/or warm compresses. 
• 
Chronic daily use of systemic narcotics for any chronic pain syndrome  
• 
LASIK or photorefractive keratectomy  
• 
Ophthalmic artificial tear drop use within 2 hours prior to any study visit.  
• 
Contact lens wear within 12 hours of any study visit. 
• 
Cauterization of the punctum or existing silicone punctal plug(s); silicone plug removal or 
collagen plug insertion or removal  
• 
Started or changed the dose of systemic medications known to affect tear production  
• 
Any chronic use of systemic antihistamines  
• 
Use of any topical prescription ophthalmic medications, topical macrolides, or oral 
nutraceuticals (fish, flax, black currant seed oils, etc.)  
• 
Use of oral tetracyclines or oral macrolides; use of isotretinoin. 
• 
Chronic daily use (defined as > 7 consecutive days at the recommended dosing frequency) of 
oral NSAIDs  
• 
Becoming Pregnant.    
• 
Participation in any other drug or device clinical investigation. 
• 
Lack of compliance with respect to timing of dosing of vitamins relative to investigational 
product.   
 
Subjects with these deviations will be examined and data may be excluded from the per-protocol 
analysis.   
8.4 Demographic and Baseline Variables 
Demographic variables include age, gender and clinical site.   
8.5 Concurrent Illnesses and Medical Conditions 
Medical History and Ocular History are coded with MedDRA V22.1.  Concomitant Medications are coded 
with WHO Drug v. September 2019.  
8.6 Treatment Compliance 
Compliance will be assessed as the percent of Soft-Gels returned versus dispensed.   For those subjects 
delaying clinic visits due to COVID-19, additional IP was provided as needed. 
     
9 Efficacy Analyses 
All efficacy variables will be listed by subject within study center. Data will be summarized by 
treatment group. N, Mean, Median, SD, Minimum and Maximum will summarize continuous efficacy 


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variables, whereas number and percent will summarize categorical efficacy variables. 
 
As per E9 Statistical Principles for Clinical Trials, the main treatment effect will be estimated using Model 
(1) that allows for center differences but does not include a term for treatment-by-center interaction.  In 
the presence of a significant treatment effect, heterogeneity of the treatment effect will be explored by 
adding treatment by center interaction terms (Model (2)).  If no statistically significant interaction is 
seen, then the estimated treatment effect from Model (1) will be provided.  If an interaction between 
treatment and center is present the nature of the interactions will be explored (quantitative or 
qualitative) and reported.   
Model (1):  yijk=𝜇𝜇+ 𝑐𝑐𝑖𝑖+ 𝑡𝑡𝑗𝑗+ 𝜉𝜉𝑖𝑖𝑖𝑖𝑖𝑖, where: 
𝑐𝑐𝑖𝑖 is fixed effect of the ith center 
𝑡𝑡𝑗𝑗 is the fixed effect of the jth treatment 
yijk is the response of the kth subject in jth treatment group within the ith center 
𝜉𝜉𝑖𝑖𝑖𝑖𝑖𝑖 is the random measurement error in observing yijk  
µ is a constant effect common to all responses 
i=1, . . . , c, j=1 or 2 and k=1, . . . , nij. 
Model (2): yijk=𝜇𝜇+ 𝑐𝑐𝑖𝑖+ 𝑡𝑡𝑗𝑗+ (ct)𝑖𝑖𝑖𝑖+ 𝜉𝜉𝑖𝑖𝑖𝑖𝑖𝑖 where (ct)𝑖𝑖𝑖𝑖 is the fixed interaction effect between the ith 
center and jth treatment.   
Analyses will be using the SAS system.        
9.1 Primary Efficacy Analysis 
 
The null and alternative hypotheses for this model are H0: α=0 versus α≠0. Treatment will be tested at 
the 2-sided 5% significance level.  A test for interaction will be performed if the overall effect for 
investigational product in the model for main effects is significant.  In the event of a lack of interaction 
between center and investigational product the results from the main effect model will be reported (IP 
and Center).  If a beneficial treatment effect is observed for both primary variables (OSDI/tear 
osmolarity) then OmegaD would be declared effective in dry eye disease.  
 
Box plots will be used to check for normality prior to analysis.  Transformations may be used to allow for 
conformance to normality.  Data from previously reported clinical trials in dry eye disease, examining 
changes in both OSDI and tear osmolarity, were used in estimating sample sizes. Methods sections and 
results from publications examining these outcomes reflect use of data without need for 
transformations to achieve normality.  However, in the event that normality is not observed, the van 
Elteren test will be employed in the event of nonnormal distributions.  The van Elteren test is an 
extension of the Wilcoxon rank sum test for detecting differences in the distributions of the response of 
interest between groups in a stratified experiment.   
 
Statistical tests will be two-sided.  Methods for handling missing data are described in Section 8.4.     
All assumptions for regression models will be assessed by viewing plots of the residual values. 


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9.2  Secondary Efficacy Analyses 
Slit lamp examinations, TBUT and Schirmer’s test will be analyzed as secondary endpoints using the 
model above on both the per-protocol and intention-to-treat populations.  Results from the 
secondary endpoints will be reported.  No formal inferences are planned for secondary endpoints.    
9.3  Exploratory Efficacy Analyses 
Meibomian gland dysfunction grading will be analyzed as an exploratory endpoint using the model 
above. 
10 Safety Analyses 
Adverse event (AE) data will be listed by subject within study center and IP.  Tables of proportions of AEs 
by IP within body system, severity and relationship to IP will be provided.   
 
Tables of All-Cause Mortality and Serious Adverse Events (SAE) will also be included.   
 
No formal statistical analyses of AE data are planned.    
 
10.1 Extent of Exposure 
Exposure in days will be summarized by IP using N, Mean, Median, SD, Minimum and Maximum. 
10.2  Adverse Events 
All AEs will be reported and summarized as proportions with event by IP.   
10.3 Deaths, Serious Adverse Events and other Significant Adverse Events 
These events, if any, will be tabulated. 
10.4  Pregnancies  
Pregnancies during the study will be tabulated  
10.5  Clinical Laboratory Evaluations 
Not Collected.   
10.6 Prior and Concurrent Medications  
Medications received prior and during the study will be summarized.   
10.7  Other Safety Measures 
N/A 
 
 


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11  Pharmacokinetics (N/A) 
N/A 
12 Other Analyses 
N/A 
13 Reporting Conventions 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, SD, and any other statistics other than quantiles, will be reported to one 
decimal place greater than the original data. Quantiles, such as median, or minimum and maximum 
will use the same number of decimal places as the original data. Estimated parameters, not on the 
same scale as raw observations (e.g. regression coefficients) will be reported to 3 significant figures.  
14 Quality Assurance of Statistical Programming (As Applicable) 
The SAS system will be used to created analysis data sets, statistical analyses and summary tables and 
listings.   
 
Any population to be used in a table, analysis or graphical display will be explicitly set at the start of a 
block of code that computes the output.    
 
Any outputs will have the 
  
● date and time included  
● the name of the code file that produced the analysis  
● the author  
 
At the start of any code file there will be a set of comments that give 
  
● the author  
● the date and time of writing  
● references to inputs and outputs  
● reference to any parent code file that runs the child code file  
15 Summary of Changes to the Protocol and/or SAP 
As of this date no changes to the protocol have been made that materially affect the statistical methods 
section in the protocol.   
 


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16 References 
1 Restasis® (cyclosporine ophthalmic emulsion, 0.05%) US Prescribing Information. 
2 XIIDRA® (lifitegrast ophthalmic solution), US Prescribing Information, Initial U.S. Approval: 2016  
 3Study of the Safety and Efficacy of OmegaD Softgels in the Treatment of Dry Eye Disease:   
ClinicalTrials.gov Identifier: NCT02980224 
4Smith, data on file.   
5Sullivan BD et al, An objective approach to dry eye disease severity.  Invest Ophthalmol Vis Sci. 2010 
Dec; 51(12):6125-30.