The Effects of Dietary Supplementation With a Combination of Flaxseed Oil, Borage Oil and Fish Oil Omega-3 Fatty Acids on Ocular Comfort Including Symptoms of Dry Eye
Phase: NA
Conditions: Dry Eye
Sponsor: The University of New South Wales

 
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CLINICAL TRIAL PROTOCOL 
 
 
 
Protocol Title - Long: 
The effects of dietary supplementation with a combination of flaxseed oil, borage 
oil and fish oil omega-3 fatty acids on ocular comfort including symptoms of dry 
eye. 
Protocol Title - Short: 
Dietary supplementation and dry eye 
Protocol ID Number: 
SOVS-2016-045 
Amendment Number: 
N/A 
Version Date: 
24th January 2017 
 
 
 
 

 
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CONFIDENTIALITY 
This document is confidential and the property of the Eye Research Group at the School of Optometry and Vision Science 
(ERG@SOVS), UNSW. 
 
No part of it may be transmitted, reproduced, published, or used without prior written authorization from the Head of the ERG@SOVS, 
UNSW.  
 
 
 
 
 
APPROVALS 
 
 
 
 
 
 
 
 
 
Jacqueline Tan, Author/Principal Investigator 
 
Date 
 
 
 
 
 
 
 
 
 
 
Fiona Stapleton, Head of School  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SUMMARY OF FINAL PROTOCOL & AMENDMENTS 
Initial/ 
Amend # 
Version Date 
Author 
Main Changes 
Final 
24th January 2017 
Jacqueline Tan 
N/A 
A1 
 
 
 
A2 
 
 
 
A3 
 
 
 

 
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TABLE OF CONTENTS 
 
 
 
CONFIDENTIALITY ...................................................................................................................................... 2 
 
APPROVALS ................................................................................................................................................ 2 
 
SPONSORS .................................................................................................................................................. 3 
 
SUMMARY OF FINAL PROTOCOL AND AMENDMENTS ......................................................................... 3 
 
TABLE OF CONTENTS ................................................................................................................................ 4 
 
1.  
PROTOCOL SYNOPSIS .................................................................................................................. 7 
 
2.  
INVESTIGATOR(S) ........................................................................................................................ 10 
 
3.  
MEDICAL EXPERT ........................................................................................................................ 11 
 
4.  
BACKGROUND INFORMATION .................................................................................................. 12 
 
4.1 
Background and Clinical Rationale ................................................................................... 12 
 
4.2 
Summary ........................................................................................................................... 12 
 
 
4.2.1 
Risks and Benefits................................................................................................ 12
 
 
4.2.2 
Treatment Rationale ............................................................................................. 13 
 
 
4.2.3 
Guidelines and Regulations ................................................................................. 13 
 
 
4.2.4 
Trial Population .................................................................................................... 13 
 
 
 
5.  
STUDY OBJECTIVES AND CLINICAL HYPOTHESIS ................................................................ 14 
 
5.1 
Study Objective ................................................................................................................. 14 
 
5.2 
Clinical Hypothesis ............................................................................................................ 14 
 
6.  
STUDY DESIGN. ........................................................................................................................... 15 
 
6.1 
Methodology / Study Visits ................................................................................................ 16 
 
 
6.1.1 
Data Requirements per Visit with Visit Window ................................................... 16 
 
 
6.1.2 
Randomisation and Masking ................................................................................ 17 
 
 
6.1.3 
Clinical Trial Population ........................................................................................ 17 
 
 
6.1.4 
Trial Duration ........................................................................................................ 18 
 
 
6.1.5 
Enrolment ............................................................................................................. 19 
 
6.2 
Primary Endpoint ............................................................................................................... 19 
 
6.3 
Secondary Endpoint(s) ...................................................................................................... 19 
 
7.  
SELECTION AND WITHDRAWAL OF PARTICIPANTS .............................................................. 20 
 
7.1 
Participant Selection.......................................................................................................... 20 
 
 
7.1.1 
Inclusion Criteria................................................................................................... 20 
 
 
7.1.2 
Exclusion Criteria ................................................................................................. 20 
 
7.2 
Participant Withdrawal....................................................................................................... 21
 
7.3 
Withdrawal and Follow-Up Procedure............................................................................... 21 
 
 
7.3.1   The Final Visit ....................................................................................................... 22 
 
 
7.3.2 
Lost to Follow-up .................................................................................................. 22 
 
 
7.3.3 
Event Follow-up.................................................................................................... 22 
 
 
7.3.4  
Whether and How Participants are to be Replaced ............................................. 22 
 
7.4 
Early Termination of Trial .................................................................................................. 23 
 
 

 
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TABLE OF CONTENTS - cont 
 
8.  
NUMBERING / RANDOMISATION ............................................................................................... 24 
 
9.  
EQUIPMENT TO BE USED / STANDARD & NON-STANDARD PRACTICE PROCEDURES ... 24 
 
9.1 
Standard Equipment and Procedures ............................................................................... 24 
 
9.2 
Non-standard Equipment and Procedures ........................................................................ 25 
 
9.3 
Maintenance and Calibration of Equipment ...................................................................... 25 
 
10.  
TREATMENT OF PARTICIPANTS ............................................................................................... 26 
 
10.1 
Administration of Study Eye Drops ................................................................................... 26 
 
10.2 
Study Product Storage and Accountability ........................................................................ 26 
 
 
10.2.1 Storage Requirements ......................................................................................... 26 
 
 
10.2.2 Accountability ....................................................................................................... 26 
 
10.3 
Concomitant Therapy ........................................................................................................ 26 
 
10.4 
Participant Instructions ...................................................................................................... 27 
 
11.  
ASSESSMENT OF EFFICACY ..................................................................................................... 27 
 
11.1 
Parameters  ....................................................................................................................... 27 
 
11.2 
Methods ............................................................................................................................. 27 
 
12.  
ASSESSMENT OF SAFETY ......................................................................................................... 30 
 
12.1 
Parameters  ....................................................................................................................... 30 
 
12.2 
Methods ............................................................................................................................. 30 
 
12.3 
Definitions .......................................................................................................................... 30
 
 
12.3.1   Adverse Events .................................................................................................... 30 
 
 
12.3.2   Serious Adverse Events ....................................................................................... 31 
 
12.4 
Reporting ........................................................................................................................... 31 
 
 
12.4.1 Foreseeable Adverse Events ............................................................................... 32 
 
 
12.4.2 Other Observations .............................................................................................. 32 
 
12.5 
Follow-Up .......................................................................................................................... 32 
 
12.6 
Referrals ............................................................................................................................ 33 
 
13.  
STATISTICS 
.............................................................................................................................. 34 
13.1 
Description ........................................................................................................................ 34 
 
13.1.1 Number of Participants ......................................................................................... 34 
 
13.1.2 Significance .......................................................................................................... 34 
 
13.1.3 Analysis ................................................................................................................ 34 
13.2 
Criteria for Termination of the Trial ................................................................................... 35 
13.3 
Accountability of Data........................................................................................................ 35 
 
14.  
DATA HANDLING AND RECORD KEEPING ............................................................................... 36 
14.1 
Source Data ...................................................................................................................... 36 
14.2 
Direct Access to Source Data/Documents ........................................................................ 36 
14.3 
Database Management ..................................................................................................... 36 
14.4  
Data Archiving  .................................................................................................................. 36 
14.5 
Retention of Essential Documents .................................................................................... 37 
 
 
 

 
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TABLE OF CONTENTS - cont 
 
15.  
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 38 
15.1 
Ethical Considerations....................................................................................................... 38
 
15.1.1 Confidentiality ....................................................................................................... 38 
 
15.1.2 Informed Consent ................................................................................................. 38 
 
15.1.3 Protocol Amendments .......................................................................................... 39 
 
15.1.4 Investigator Responsibilities ................................................................................. 39 
 
16.  
FINANCING AND INSURANCE .................................................................................................... 41 
 
17.  
PUBLICATION POLICY ................................................................................................................ 41 
 
18.  
INVESTIGATOR AGREEMENT .................................................................................................... 42 
 
APPENDIX 1: Declaration of Helsinki....................................................................................................... 43 
 
APPENDIX 2: Questionnaires .................................................................................................................. 47 
 
APPENDIX 3: CCLRU Grading Scales .................................................................................................... 56 
 
APPENDIX 4: CIBA Grading Scales ........................................................................................................ 58 
 
 
 
 
 

 
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1. PROTOCOL SYNOPSIS 
 
Table 1 
Protocol Title 
The effects of dietary supplementation with a combination of flaxseed 
oil, borage oil and fish oil omega-3 fatty acids on ocular comfort 
including symptoms of dry eye. 
Protocol ID Number 
SOVS2016-045 
Trial Classification 
Evaluation 
Investigator(s)/Site(s) 
Eye Research Group @ SOVS 
The University of New South Wales 
Sydney, Australia 
Overall Duration of Trial 
1 year 
Number of Trial Participants 
Planned 
138 
Planned Start Date 
February 2017 
Primary Objective 
To investigate the efficacy of a nutraceutical formulation (combination 
of flaxseed oil, borage oil and fish oil omega-3 fatty acids) on ocular 
symptoms including dry eye, compared to a placebo control. 
Secondary Objective 
To evaluate the safety of a nutraceutical formulation (combination of 
flaxseed oil, borage oil and fish oil omega-3 fatty acids) over a 3 month 
period. 
Primary Safety Variable(s) 
Visual acuity 
Biomicroscopy: ocular redness, corneal and conjunctival staining 
Primary Efficacy/Performance 
Variable 
Subjective symptom scores measured using OSDI, OCI and DEQ-5 
Experimental design  
 Retrospective 
 Prospective 
 Single masked (Trial Participant) 
 Single masked (Investigator) 
 Double masked 
 Sponsor masked 
 Open label 
 Other 
 Single group 
 Multiple group 
 Parallel group 
 Cross over 
 Contralateral 
Inclusion criteria 
 
Able to read and comprehend English and give informed consent 
as demonstrated by signing a record of informed consent; 
 
Be at least 18 years old; 
 
Have symptoms of ocular discomfort as measured with the Ocular 
Surface Disease Index (OSDI) score of >12 at the Baseline visit; 
 
Willing to comply with the dosage and study visit schedule as 
directed by the investigator; 
 
No contact lens wear in the last 30 days and willing to refrain from 
contact lens wear for the duration of the study; 
 
No planned changes to diet and willing not to substantially alter 
their usual diet for the duration of the study, including their typical 
intake of fish; 
 
Willingness to notify the study investigator if instructed to alter their 
diet by health/medical practitioner; 
 
Willing to continue using any artificial tear supplements at the 

 
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same frequency throughout the study, as used prior to the study 
 
Have health and ocular health findings which would not prevent the 
participant from safely ingesting dietary supplementation with 
combination omega oils. 
Exclusion criteria 
 
 
 
Any systemic disease that would preclude participants from safely 
ingesting dietary supplementation with combination omega oils; 
 
Self-reported allergy/sensitivity to any of the study product 
ingredients; 
 
Use 
of 
any 
polyunsaturated 
fatty 
acid-containing 
dietary 
supplements (such as fish oil, evening primrose oil, linseed oil) up 
to 12 weeks prior to the start of the study; 
 
Use of any of the following medications (including steroids) up to 
12 weeks prior to start of the study or during the course of the 
study: 
o 
Ocular medication, category S3 and above; 
o 
Any systemic or topical medications that will affect ocular 
physiology e.g. anti-acne medications such as Roaccutane 
and corticosteroid or immunosuppressant medications such as 
Hydrocortisone, Prednisolone and antihistamine medications 
such as Claritine; 
 
Any systemic disease that may affect ocular health e.g. Graves 
disease, 
and 
auto-immune 
diseases 
such 
as 
ankolysing 
spondylitis, multiple sclerosis and systemic lupus erythematosis; 
 
Epilepsy or history of migraines exacerbated by flashing, strobe-
like lights; 
 
Eye surgery within 6 months immediately prior to enrolment for this 
study; 
 
Rigid or soft contact lens wearer, including orthokeratology in the 
last 30 days; 
 
Previous corneal refractive surgery; 
 
Pregnancy or breastfeeding; 
 
The Investigator may, at his/her discretion, exclude anyone else 
who they believe may not be able to fulfil the study requirements, 
or if it is believed to be in the participant’s best interests. 
Formulae 
 
Test capsules (per capsule) – “Supplement” 
Concentrated Omega-3 Triglycerides-fish      332 mg 
Equiv. Eicosapentaenoic Acid (EPA)             134 mg 
Equiv. Docosahexaenoic Acid (DHA)             66.8 mg 
Flax Seed Oil (Linseed Oil)                            334 mg 
Equiv. Oleic acid                                            58.5 mg 
Equiv. Linoleic acid                                        58.5 mg 
Equiv. Linolenic acid                                      192 mg 
Borago officinalis seed oil fixed (Borage)      434 mg 
Equiv. gamma-Linolenic acid                         95.5 mg 
 
Placebo control capsules (per capsule)  
Polyethylene glycol 400                                   400 mg 
Oleic acid BP/EP                                             659 mg 
Propylene glycol                                              115 mg 
 
Administration 
3 capsules per day, orally for 40 days. 
2 capsules per day, orally thereafter for approximately 50 days. 
Human Research Ethics 
Committee Status /  
This trial requires Human Research Ethics Committee approval prior 
to study initiation, any advertising, and participant consent/enrolment. 

 
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Regulatory Status  
This trial requires approval from the Therapeutic Goods 
Administration. 

 
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2. INVESTIGATOR(S) 
 
Table 2 
Name: 
Jacqueline Tan 
Title: 
Senior Research Fellow / Principal Investigator 
Site Address: 
 
Eye Research Group @ SOVS 
The University of New South Wales 
Level 3, North Wing, RMB 
Gate 14, Barker Street 
Sydney  NSW  2032 
Telephone: 
+61 2 9385 6551 
 
Name: 
Isabelle Jalbert 
Title: 
Senior Lecturer / Sub-investigator 
Site Address: 
 
The University of New South Wales 
Level 3, North Wing, RMB 
Gate 14, Barker Street 
Sydney  NSW  2032 
Telephone: 
+61 2 9385 9816 
 
Name: 
Preeji Mandathara 
Title: 
Post-doctoral Research Fellow 
Site Address: 
 
Level 3, North Wing, RMB 
Gate 14, Barker Street 
The University of New South Wales 
Sydney  NSW  2032 
Telephone: 
 
 
Name: 
Fiona Stapleton 
Title: 
Head of School 
Site Address: 
 
Level 3, North Wing, RMB 
Gate 14, Barker Street 
The University of New South Wales 
Sydney  NSW  2032 
Telephone: 
+61 2 9385 4375 
 
 

 
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3. MEDICAL EXPERT 
 
Table 3 
Name: 
The Ophthalmology Registrar 
Title: 
Ophthalmologist 
Address: 
Sydney Eye Hospital 
South Block  
Number 8 Macquarie Street 
Sydney  NSW  2000 
Telephone: 
+61 2 9382 7111 
 

 
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4. BACKGROUND INFORMATION 
 
4.1. Product 
 
The normal tear film is a relatively stable, thin film composed of a superficial lipid layer and 
an aqueous layer intermixed with a mucous gel layer, which is partially adherent to the 
corneal and conjunctival surface epithelium. Dysfunction of one or more components of the 
tear film can lead to loss of tear film stability and symptoms of dry eye. 
 
The chronicity of dry eye disease suggests that dysregulation of immune mechanisms 
leads to a cycle of continuous inflammation. Accordingly, because of better understanding 
of the inflammatory-mediated pathogenesis of dry eye disease, anti-inflammatory therapy is 
considered a causative therapeutic approach, since its objective is to interrupt the 
inflammatory cascade, rather than other treatment modalities aimed at providing 
symptomatic relief. 
 
Essential polyunsaturated fatty acids omega-3 and omega-6 are the precursors of 
eicosanoids, which are locally acting hormones that mediate the inflammatory processes. 
There is good evidence that the consumption of oily fish has a protective effect against dry 
eye, and other studies have provided evidence of the beneficial effect of supplementation 
with omega-3 essential fatty acids in the treatment of dry eye disease. 
 
However, there have been limited well designed randomised clinical trials published. 
Therefore, the purpose of this study is to conduct a randomised, placebo-controlled, 
double-masked study to investigate the effects of dietary supplementation with a 
combination of flaxseed oil, borage oil and fish oil omega-3 fatty acids on ocular comfort 
including signs and symptoms of dry eye. 
 
 
4.2. Summary 
 
 
4.2.1. Risks and Benefits 
 
Risks of the Clinical Trial 
 
It is possible that participants may have an adverse reaction to ingesting the study 
product. Potential problems associated with ingesting nutraceutical supplements 
are likely to be gastric/digestive in nature.  
 
Any untoward signs or symptoms will be treated by immediate discontinuation of 
use of the study product and participation in the study until all signs and symptoms 
have returned to normal. The participant will be referred for appropriate medical 
treatment if required.   
 
Any potential participants with a self-reported allergy/sensitivity to any of the 
ingredients in the study product will be excluded from the study.  

 
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Benefits of the Clinical Trial 
 
Participants may experience reduced symptoms of ocular discomfort and dry eye 
during the study. However, there is no guarantee or promise that the participants 
will receive any health benefits from this clinical trial. The study product and 
participants’ optometric care will be provided free of charge for the duration of the 
clinical trial.  
 
 
4.2.2. Treatment Rationale 
 
Few 
studies 
have 
investigated 
the 
potential 
for 
nutraceutical 
dietary 
supplementation to impact ocular comfort, and to date, no controlled, randomised 
clinical trials have been conducted to evaluate the “supplement” nutraceutical 
formulation.  
 
Therefore, the objective of this study is to investigate the effects of the 
“supplement” nutraceutical formulation (combination of flaxseed oil, borage oil and 
fish oil omega-3 fatty acids) on ocular symptoms including dry eye, compared to a 
placebo control. 
 
 
4.2.3. Guidelines and Regulations 
 
 
The clinical trial will be conducted in accordance with the protocol, the Declaration 
of Helsinki (see Appendix 1), ICH GCP and local regulations as applicable including 
TGA and NH&MRC guidelines. 
 
 
4.2.4. Trial Population 
 
138 participants will be enrolled.  
 
 
 

 
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5. STUDY OBJECTIVES AND CLINICAL HYPOTHESIS 
 
 
 
5.1. Study Objective 
 
The objective of this study is to evaluate ocular symptoms and signs when 
consuming the supplement nutraceutical formulation (combination of flaxseed oil, 
borage oil and fish oil omega-3 fatty acids) daily over a 3 month period, compared 
to a placebo control. 
 
5.2. Clinical Hypothesis 
 
A greater reduction in ocular discomfort and/or signs of dry eye will be observed 
after daily consumption of the supplement nutraceutical formulation (combination 
of flaxseed oil, borage oil and fish oil omega-3 fatty acids) over a 3 month period 
compared to a placebo control. 

 
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6. STUDY DESIGN 
 
 
This study will be a prospective, randomised, placebo-controlled, double masked study 
conducted over a 3-month period.  
 
One hundred and thirty-eight (138) participants who meet the inclusion / exclusion criteria 
and give informed consent will be randomised to either the test capsules containing a 
combination of flaxseed oil, borage oil and fish oil omega-3 fatty acids (“supplement”) or 
placebo capsules, identical in appearance, containing non-active ingredients polyethylene 
glycol (500mg), oleic acid (659mg) and propylene glycol (115mg) to be taken by mouth 
three times daily for 40 days and then two times daily for the remainder of the study, as 
per the manufacturer’s guidelines. Every effort will be made to stratify enrolment by 
disease severity to ensure participants with mild, moderate and severe dry eye are 
represented in the study population. Stratification will be in a 2:2:1 fashion i.e. OSDI score 
>12 (55 participants), OSDI score >20 (55 participants) and OSDI score >45 (28 
participants). Participants will be stratified according to dry eye severity prior to 
randomisation.  
 
 
There will be a total of 3 scheduled study visits over a period of approximately 3 months - 
Day 1, 1 month and 3 months. Ocular comfort and symptoms of dry eye will be assessed 
via questionnaires. The tear film and ocular surface will be assessed using specialised 
instruments (slit lamp biomicroscopy, Lipiview, Vapometer and Oculus Keratograph) and 
stains. Safety will be assessed through measurement of visual acuity, ocular redness 
(eyelid and bulbar conjunctival redness), evaluation of the ocular surface using the slit 
lamp biomicroscope and the administration of a questionnaire to assess general health 
and wellbeing. 
 
In addition, at the first visit only, body mass index and body fat composition will be 
measured to investigate the potential relationship between nutrition, body composition, 
and dry eye (Ho et al, Eye Contact Lens; Epub ahead of print 27 May 2016). 
 
All proposed procedures conform to the NHMRC Statement on Human Experimentation.   
 
Participants are considered enrolled when they have signed the informed consent form 
and are regarded as part of the clinical trial population. 
 
  

 
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6.1. Methodology / Study Visits 
 
6.1.1. Data Requirements per Visit with Visit window (± days) 
 
The data requirements for each visit are shown in Table 4. 
  
 
Table 4 
Procedures/ Data (Y/N) 
 
Visit 1 
 
BL 
Visit 2 
 
(1M from BL) 
Visit 3/Study Exit 
 
(3M from BL) 
Unscheduled / 
Adverse Events 
Visit Window 
N/A 
± 7 days 
± 14 days 
N/A 
Informed Consent 
Y 
N 
N 
N 
Meet Inclusion/Exclusion 
Criteria 
Y 
N 
N 
N 
Ocular and Medical History, 
Medications, Demographics 
Y 
N 
N 
N 
Updated History, Symptoms 
and Problems 
N 
Y 
Y 
Y 
Vision Tests (Visual Acuity) 
Y 
Y 
Y 
Y 
Symptom Survey 
Y 
Y 
Y 
* 
Nutrition Questionnaire 
Y 
N 
Y 
N 
Comfort Questionnaires 
Y 
Y 
Y 
* 
Health and Wellbeing 
Questionnaire 
N 
Y 
Y 
* 
Body Mass Index and Body Fat 
Composition 
Y 
N 
N 
N 
Tear Film Evaluation 
Y 
Y 
Y 
* 
Slit-Lamp Biomicroscopy: 
Anterior ocular health including 
evaluation of cornea & conjunctiva  
Y 
Y 
Y 
Y 
Dispense Study Product 
Y 
Y 
N 
N 
Return Unused Study Product 
N 
Y 
Y 
* 
Adverse Event Data  
(Y)** 
(Y)** 
(Y)** 
Y 
 
Y = Yes, required information, N = No, not required 
 
 
 
  
* 
At optometrists discretion 
 
 
 
 
 
  M = Month 
** 
If adverse event detected at time of visit  
 
 
 
 
    
 
 
 
 
 
 
 
 

 
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6.1.2. Randomisation and Masking 
 
Prior to initiation of study treatment, each subject who provides informed consent 
will be assigned to a subject number that will serve as the subject identification 
number on all study documents.  Subject numbers will be assigned in ascending 
order and should not be omitted or reused.  
 
Eligible subjects will be stratified according to dry eye severity (mild, moderate or 
severe) and then randomly assigned to 1 of the 2 study treatments.  A 
randomization scheme will be prepared in advance.  
 
Test and placebo capsules will be manufactured in accordance with local 
regulations including the TGA guidelines. All capsules will be identical in 
appearance as the outer capsule will be the same as the commercial test product. 
The manufacturer will code, bottle and label the test and placebo capsules to 
ensure that participants and investigators will be masked throughout the study 
duration. Both test and placebo capsules will have the same outer packaging and 
will be labelled as capsule “A” or “B”. The code will be broken after completion of 
the study and data analysis, or if required for participant safety. 
 
The recommended dosage will be 3 capsules per day by mouth to be taken with a 
meal for 40 days, and then 2 capsules per day thereafter for approximately 50 
days, as per the manufacturer’s guidelines. 
 
 
6.1.3. Clinical Trial Population 
 
A total of 138 participants will be recruited for the study, which includes allowance 
for a 10% drop-out rate).  
 
This sample size was calculated on the basis of detecting a difference in Ocular 
Surface Disease Index (OSDI) score of 10, with a standard deviation of 20, 
assuming an estimate of type 1 error a =0.05 and power of 80% for a two tailed 
test. These values were obtained from Schiffman et. al. who demonstrated a mean 
difference in OSDI score of 10 between normal subjects and those with mild to 
moderate dry eye, with a standard deviation of up to 20. 
 
Every effort will be made to stratify enrolment by disease severity to ensure 
participants with mild, moderate and severe dry eye are represented in the study 
population. Stratification will be in a 2:2:1 fashion i.e. OSDI score >12 (55 
participants), OSDI score >20 (55 participants) and OSDI score >45 (28 
participants). 
 
Trial participants will be recruited from the local population at the investigational 
site. An e-mail invitation will be circulated to all SOVS staff, the Brien Holden Vision 
Institute, the Centre for Eye Health, SOVS post-graduate students, UNSW 
administrative staff and previous study participants who have indicated their 
willingness to be contacted to participate in future research studies. Advertisements 
may also be posted in University newsletters, notice boards, websites, local 
newspapers, social media (e.g. Facebook), on the SOVS clinic TV screen and other 
local advertising and community websites. 

 
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6.1.4. Trial Duration 
 
This is a 3 month dispensing study. Participants will attend a total of 3 scheduled 
visits at Baseline, 1 month and 3 months. 
 
 
Table 5: Visits  
Visit Type: 
Abbreviation 
Baseline  
BL 
1 month 
1M 
3 months 
3M 
 
For the purpose of these studies, 1 month will be considered the same as 30 days. 
 
 

 
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6.1.5. Enrolment 
 
A study participant is considered enrolled when they have signed the Participant 
Information Statement and Consent Form.  
 
 
6.1.6. Primary Endpoint 
 
Subjective ocular comfort and symptoms assessed using validated questionnaires. 
 
6.1.7. Secondary Endpoint(s) 
 
Non-invasive tear film break-up time, tear evaporation rate, tear meniscus height, tear 
volume and lipid layer thickness. 
 

 
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7. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
 
7.1. Participant Selection  
 
One hundred and thirty-eight (138) participants, both male and female, age 18 years and 
upwards who experience symptoms of ocular dryness will be enrolled into the study.  
 
Every effort will be made to stratify enrolment by disease severity to ensure participants 
with mild, moderate and severe dry eye are represented in the study population. 
Stratification will be in a 2:2:1 fashion i.e. OSDI score >12 (55 participants), OSDI score 
>20 (55 participants) and OSDI score >45 (28 participants). 
 
Informed consent will be obtained prior to any clinical trial procedures.  
 
All participants will conform to the clinical trial entry criteria listed below: 
 
 
7.1.1. Inclusion Criteria  
 
• Able to read and comprehend English and give informed consent as 
demonstrated by signing a record of informed consent; 
• Be at least 18 years old; 
• Have symptoms of ocular discomfort as measured with the Ocular Surface 
Disease Index (OSDI) score of >12 at the Baseline visit; 
• Willing to comply with the dosage and study visit schedule as directed by the 
investigator; 
• No contact lens wear in the last 30 days and willing to refrain from contact lens 
wear for the duration of the study; 
• No planned changes to diet and willing not to substantially alter their usual diet 
for the duration of the study, including their typical intake of fish; 
• Willingness to notify the study investigator if instructed to alter their diet by 
health/medical practitioner; 
• Willing to continue using any artificial tear supplements at the same frequency 
throughout the study, as used prior to the study; 
• Have health and ocular health findings which would not prevent the participant 
from safely ingesting dietary supplementation with combination omega oils. 
 
 
7.1.2. Exclusion Criteria  
 
 Any systemic disease that would preclude participants from safely ingesting 
dietary supplementation with combination omega oils; 
 Self-reported allergy/sensitivity to any of the study product ingredients; 
 Use of any polyunsaturated fatty acid-containing dietary supplements (such as 
fish oil, evening primrose oil, linseed oil) up to 12 weeks prior to start of the 
study; 

 
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 Use of any of the following medications (including steroids) up to 12 weeks prior 
to the start of the study or during the course of the study: 
o Ocular medication, category S3 and above; 
o Any systemic or topical medications that will affect ocular physiology e.g. 
anti-acne medications such as Roaccutane and corticosteroid or 
immunosuppressant medications such as Hydrocortisone, Prednisolone and 
antihistamine medications such as Claritine; 
 Any systemic disease that may affect ocular health e.g. Graves disease, and 
auto-immune diseases such as ankolysing spondylitis, multiple sclerosis and 
systemic lupus erythematosis; 
 Epilepsy or history of migraines exacerbated by flashing, strobe-like lights; 
 Eye surgery within 6 months immediately prior to enrolment for this study; 
 Rigid or soft contact lens wearer, including orthokeratology in the last 30 days; 
 Previous corneal refractive surgery; 
 Pregnancy or breastfeeding. 
 The Investigator may, at his/her discretion, exclude anyone else who they 
believe may not be able to fulfil the study requirements, or if it is believed to be 
in the participant’s best interests.  
 
7.2. Participant Withdrawal 
 
Participants may be permanently discontinued from the clinical trial for any of the following 
reasons: 
 
If, in the Investigator’s opinion, it is in the best interest of the participant; 
 
Persistent clinical trial-related symptoms/complaints that are not correctable; 
 
Has a serious adverse event/serious adverse device event that is eye/lens/solution 
related and/or which, in the Investigator’s or Sponsor’s opinion, requires withdrawal of 
the participant; 
 
Participant voluntarily withdraws consent from the clinical trial (i.e. Revocation of 
Consent); 
 
Participant is lost to follow-up, or relocates and cannot attend the clinic; 
 
If a participant is not compliant with the clinical trial requirements and instructions e.g. 
visit schedule; 
 
Repeated protocol violations/deviations. 
 
 
7.3. Withdrawal and Follow-up Procedure  
 
 
Participants who are permanently withdrawn from the study should be seen as soon as 
possible after stopping use of the study product for a final visit to assess participant 
safety and to return any unused study product. This may be done at a routine clinic visit 
or an unscheduled visit if it occurs between routinely scheduled visits. 
 
 
 
 
 

 
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7.3.1. The Final Study Exit Visit 
 
Where possible, the data requirements for the final study exit visit are the same 
assessments as for the 3 month visit shown in Table 5. However, the minimum data 
requirements include: 
 Visual acuity 
 Slit-lamp biomicroscopy (ocular redness, corneal and conjunctival staining) 
 
For withdrawal of consent, a ‘Revocation of Consent’ document should also be 
signed, if possible. 
 
 
7.3.2. Lost to Follow-up 
 
A participant will be considered lost to follow-up, after three documented and failed 
attempts have been made to contact the participant – two phone calls and one 
written. Any contact should attempt to gain the following information:  
 reason participant has not returned to clinic 
 safety (previous/new adverse events status), and 
 concomitant therapies. 
 
 
7.3.3. Event Follow-up 
 
If a participant has experienced an adverse event that is continuing at the end of 
the study participation, the event is marked as ongoing. The Investigator should 
ensure appropriate follow-up care is arranged/provided to the participant as 
appropriate. 
 
If an adverse device event, or a serious adverse event/serious adverse device 
event has occurred and is continuing, the participant should be followed until the 
event has resolved, or stabilised if there is no chance of improvement. Source 
notes and the reporting form should be updated as appropriate, and the information 
forwarded to the Sponsor/HREC/TGA as necessary. 
 
 
 
 
7.3.4. Whether and How Participants are to be Replaced: 
 
Participants who experience an adverse response during the course of the study, 
that requires early discontinuation from the study, will not be replaced. Participants 
who are not suitable at Baseline will be replaced, until the enrolment target is 
reached. 
 
 
 
 

 
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7.4. Early Termination of Trial 
 
The trial may be stopped early for any one or more of the following reasons: 
 
If the monitoring of the clinical trial reveals unacceptable levels of device-related 
adverse events, even though some of the participants may not be affected; 
 
If the Investigator does not adhere to the protocol; 
 
If the Sponsor decides to stop the study for any reason, with appropriate notification. 
 
In the event of early termination of the trial, the HREC will be notified. 
 
 

 
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8. NUMBERING  
 
Participant numbering will occur sequentially commencing with ‘001’.   
 
 
 
9. EQUIPMENT TO BE USED / STANDARD & NON-STANDARD 
PRACTICE PROCEDURES 
 
9.1. Standard Equipment and Procedures: 
 
 
 
Visual Acuity:  Measurement of the standard of vision achieved with 
spectacles or contact lenses using standard letter charts. Measurements are 
taken under monocular and/or binocular conditions. 
 
 
Slit-Lamp Biomicroscopy:  A specialised microscope with its own light 
source is used to examine the anterior eye. 
 
 
Corneal and Conjunctival Staining:  The corneal surface is assessed by 
instilling a harmless fluorescent dye called ‘fluorescein’ using a sterile 
fluorescein strip moistened with saline. The eye is assessed with the slit-lamp 
biomicroscope using a cobalt blue filtered light and a Wratten 12 filter. The 
conjunctival surface is assessed by instilling a harmless dye called “lissamine 
green’ using a sterile lissamine green strip moistened with saline. The eye is 
assessed using the slit-lamp biomicroscope and white light. 
 
 
Questionnaires:  Questions assessing eye symptoms, diet, product usage 
and general health and wellbeing will be administered on paper forms. 
 
 
LipiView Ocular Surface Interferometer (TearScience): Will be used to 
measure the absolute thickness of the tear film lipid layer. The participant’s 
eye is positioned in front of an illumination source that is directed toward the 
tear film on the corneal surface. The camera records a 20-second video of the 
tear film interference and subsequently displays a value in interferometric 
colour units (ICU), where 1 ICU approximates 1nm of lipid layer thickness. 
 
 
Phenol red thread test: Will be used to measure tear volume.  
 
 
Participant History File:  Created at commencement of study and 
maintained throughout the trial. Contains relevant references to participant’s 
medical history (both prior to participation in the trial and ongoing throughout 
the trial); and contains details of any problems encountered during the trial 
(either through observation by the investigator or as volunteered by the 
participant). 
 
 

 
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9.2. Non-Standard Equipment and Procedures: 
 
 
Non-standard procedures that may be performed include: 
 
 
Tear Evaporation Rate:  The Vapometer is a closed chamber device which is 
used for measuring transepidermal water loss. Participants will be seated 
upright on a chair and provided with a distance fixation target. To minimize the 
effect 
of 
skin 
evaporation, 
petroleum 
jelly 
(Vaseline_, 
http://www.unilever.com.au/brands-in-action/detail/Vaseline/299339/) will be 
applied over the upper eyelid and the surrounding areas. The VapoMeter will 
then be placed over the eye and a non-invasive measurement of tear 
evaporation will be taken within 10 seconds. Participants will be instructed not 
to blink during open eye measurement and to maintain a normal straight gaze 
at the fixation target. Evaporation rates with the eyes closed will also be taken, 
in order to account for the skin evaporation from eyelids and surrounding skin 
tissue. 
 
 
Oculus Keratograph 5M (Oculus): Will be used to measure non-invasive 
tear break-up time and tear meniscus height. The participant’s eye is 
positioned in front of a placido disc illumination which allows detection of the 
tear film and tear prism non-invasively. The associated software measures 
non-invasive tear break-up time and tear meniscus height.  
 
 
Photography/Video:  A photograph of the eye will be taken, and 
photographic/video recording of any interesting/unusual findings may also be 
made for documentation and/or follow-up purposes. 
 
 
Body Mass Index (weight/height2): Will be measured using a digital scale 
(Charder Scale MS 3400; Charder Electronic Co. Ltd., Taichung City, 
Taiwan).  
 
 
Body Fat Composition: Will be measured using a Tanita monitor. This is a 
non-invasive procedure that uses bioelectrical impedance analysis and sends 
a very low, safe electrical signal from four metal electrodes through the 
participant’s feet to measure body fat composition (Tanita BC-601, Tanita, 
Australia). 
 
 
 
9.3. Maintenance and Calibration of Equipment 
 
Equipment will be monitored regularly for maintenance and calibration as per 
relevant company and product manuals. 
 

 
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10. TREATMENT OF PARTICIPANTS 
 
10.1. Administration of Study Product 
 
Participants will be instructed to take one capsule by mouth with meals, three 
times daily for 40 days, and then two times daily for the remainder of the 
study, as per the manufacturer’s recommended guidelines. 
 
  
10.2. Study Product Storage and Accountability 
 
10.2.1. Storage Requirements 
 
Study product is to be stored at room temperature in a secure 
storeroom/cupboard. The storage facility should be kept locked to prevent 
unauthorised access and to ensure accountability of the study product at all 
times. 
 
 
10.2.2. Accountability 
 
A Product Tracking spreadsheet is used for keeping track of who, where 
and when study product have been issued or dispensed to.  
 
 
Receipt of Study Product:  Once invoice has been checked, the study 
product will be entered into the Study Product Tracking spreadsheet.  
 
Issue of Study Product to Clinical Trial Participants:  The 
Optometrist is responsible for documenting the dispensing of the study 
product on the participant case record form. 
 
Disposal of Unused Supplies:  Instruction will be obtained from the 
sponsor as to how to handle returned, unused study product. 
 
 
10.3. Concomitant Therapy 
 
Whilst participating in this clinical trial participants are not permitted to enrol in other 
clinical trials.   
 
Participants must not use or have a need for any systemic or topical medications 
which may alter normal ocular findings/are known to affect a participant’s ocular 
health/physiology either in an adverse manner or risk providing a false positive. 
 
 
 

 
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10.4. Participant Instructions 
General instructions to all participants  
 Contact the clinic immediately if problems are experienced or if they have any 
questions or concerns 
 Ingest the study product daily as per manufacturer’s recommendation  
 Return the unused study product at each follow-up visit 
 Store the study product at room temperature and keep out of reach of children 
 Continue to use any artificial tear supplements at the same frequency throughout 
the study, as used prior to the study 
 Do not make any substantial changes to your intake of fish/diet for the duration of 
the study, unless instructed to do so for health/medical reasons. If so, please 
advise the study investigator as soon as possible. 
 
 
11. ASSESSMENT OF EFFICACY 
 
11.1. Parameters  
 
 
Ocular comfort  
 
Product usage 
 
Visual acuity 
 
History 
 
Tear lipid layer thickness 
 
Tear evaporation rate 
 
Non-invasive tear break-up time 
 
Tear meniscus height 
 
Tear volume (phenol red thread test) 
 
Eyelids: redness and swelling 
 
Bulbar conjunctival redness 
 
Corneal and conjunctival staining 
 
Body mass index 
 
Body fat composition 
 
 
11.2. Methods 
 
Ocular comfort and product usage will be assessed by completion of a paper 
questionnaire (Appendix II). 
 
History (including medical and general health) will be recorded on the Participant 
History File at all visits. 
 
Habitual visual acuity will be measured at each visit using standard letter charts. 
 
Tear lipid layer thickness will be measured using the LipiView Ocular Surface 

 
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Interferometer. The participant’s eye is positioned in front of an illumination source 
that is directed toward the tear film on the corneal surface. The camera records a 
20-second video of the tear film interference and subsequently displays a value in 
interferometric colour units (ICU), where 1 ICU approximates 1nm of lipid layer 
thickness. 
 
 
A photograph of the anterior eye will be taken at the Baseline visit for participants 
who are eligible to be randomised into the study. From the photograph, ocular 
surface area will be measured in order to calculate the absolute tear evaporation 
rate.  
 
Tear evaporation rate will be measured using the Vapometer. To minimize the 
effect 
of 
skin 
evaporation, 
petroleum 
jelly 
(Vaseline_, 
http://www.unilever.com.au/brands-in-action/detail/Vaseline/299339/) 
will 
be 
applied over the upper eyelid and the surrounding areas. Three measurements will 
be taken for each eye under open eye and closed eye conditions. Each 
measurement will be recorded and the absolute evaporation rate will be calculated 
for each eye.  
 
Non-invasive tear break-up time will be measured using the Oculus Keratograph 
5M. The participant’s eye is positioned in front of a placido disc illumination which 
allows detection of the tear film. Participants will be asked to blink three times and 
then to hold their eyes open for as long as possible, or until instructed to blink 
again by the study investigator. Three consecutive measurements of non-invasive 
tear break-up time will be recorded for each eye.  
 
Tear meniscus height will be measured using the Oculus Keratograph 5M. The 
participant’s eye is positioned in front of a placido disc illumination which allows 
detection of the tear film. Participants will be asked to blink once and an image of 
the tear prism will be captured immediately after the blink. Tear meniscus height 
will be obtained using the measuring guide software.  
 
Tear volume will be measured using the phenol red thread test. The folded 3mm 
end of the thread is placed at a point approximately 1/3 of the distance from the 
lateral canthus of the lower eyelid with the eye in primary position. Participants are 
instructed to look straight ahead and blink normally during the test. When 15 
seconds have elapsed, the thread is gently removed and the entire length of the 
red portion of the thread is measured in millimetres from the very tip, regardless of 
the fold.  
 
Slit lamp biomicroscopy will be performed at each visit. This will be used to assess 
the following variables and rated using the CCLRU (Appendix III) and CIBA 
Grading Scales (Appendix IV). 
 
Eyelids: redness and swelling 
 
Bulbar conjunctival redness 

 
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 
Corneal and conjunctival staining  
 
Body mass index and body fat composition will be measured at the first visit only. 
To calculate body mass index (weight/height2), participants will be asked to stand 
on a digital scale (Charder Scale MS 3400; Charder Electronic Co. Ltd., Taichung 
City, Taiwan) whereby weight and height will be measured. Body fat composition 
will be measured using a Tanita monitor (Tanita BC-601, Tanita, Australia). 
Participants will be asked to stand on the Tanita monitor, which sends a very low, 
safe electrical signal from four metal electrodes through the participant’s feet, and 
uses bioelectrical impedance analysis to calculate body fat composition.   
 

 
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12. ASSESSMENT OF SAFETY 
 
12.1. Parameters 
 
 
Discomfort 
 
History 
 
Visual acuity 
 
Ocular redness: bulbar conjunctiva 
 
Corneal and conjunctival staining 
 
Health and wellbeing questionnaire 
 
 
12.2. Methods 
 
Discomfort and Health and Wellbeing will be assessed using questionnaires and 
the Participant History File at all scheduled visits. 
 
History (including medical and general health) will be recorded on the Participant 
History File at all visits. 
 
Ocular examination using slit-lamp biomicroscopy will be carried out at Baseline 
and at every visit. Ocular bulbar conjunctival roughness and corneal and 
conjunctival staining will be assessed and recorded using the CCLRU (Appendix 
III) and CIBA Grading scales (Appendix IV).   
 
An optometrist will be available for the duration of the study. Participants will be 
advised to contact the optometrist immediately of any problem or event not 
normal with their eyes e.g. unusual redness, pain, irritation, etc. At the clinic, the 
optometrist will briefly assess the eye on a slit-lamp under low illumination to 
ascertain the nature of the condition, if any. If an adverse event occurs, the 
appropriate procedures will be conducted, including referral for medical treatment 
if necessary. Any adverse events will be followed until complete resolution to the 
reasonable satisfaction of the participant and the investigator. 
 
 
12.3. Definitions 
 
12.3.1. Adverse Events 
 
Adverse Event: Any undesirable clinical occurrence in a participant, 
whether it is considered to be device-related or not, that includes a clinical 
sign, symptom or condition and/or observation of an unintended technical 
performance or performance outcome of the device. 
 

 
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Adverse Events may be classified as Serious, Significant, Non-significant or 
Unanticipated as defined further on. 
 
 
12.3.2. Serious Adverse Events 
 
Any adverse medical occurrence that: 
 
led to death. 
 
led to a serious deterioration in health of a Participant user or other.  
This would include: 
-    a life threatening illness or injury. 
- 
a permanent impairment of body function or permanent damage to 
a body structure. 
- 
a condition requiring hospitalisation or increased length of existing 
hospitalisation. 
-    a condition requiring unnecessary medical or surgical intervention. 
-    foetal distress, foetal death or a congenital abnormality/birth  
 
   defect. 
 
might have led to death or a serious deterioration in health had 
suitable action or intervention not taken place.  This includes: 
-   a malfunction of a device such that it has to be modified or 
temporarily/permanently taken out of service. 
-   a factor (a deterioration in characteristics or performance) found on 
examination of the device. 
 
 
 
 
12.4. Reporting 
In the event of persistent irritation, redness, reduced visual acuity or any other 
unusual signs or symptoms, the participants will be advised to remove their lenses 
immediately and contact the clinic. 
Non-serious and anticipated device-related adverse events and adverse events 
should be recorded as part of Good Clinical Practice. Sponsors are expected to 
maintain up-to-date tabulations and/or line listings of all adverse device events. 
 
All Serious Adverse Events should be reported within 24 hours to the HREC as per 
their reporting requirements. This should be followed by a more detailed written 
report commenting on potential confounding factors, results of investigations, 
treatment required and outcome.  The Co-sponsor and the Principal Investigator 
should review the events in conjunction with the known information about the 
device, and make a determination as to whether the event is device-related or not. 
 
All adverse events should be reported to the Co-sponsor no later than 10 days after 
the event.  
 
 

 
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12.4.1. Foreseeable Adverse Events  
 
Risks associated with the use of the study product are likely to be 
gastric/digestive in nature and may include: 
 
• Stomach pain (<2%) 
• Diarrhoea (<1%) 
 
 
 
 
Potential risks associated with the study procedures include: 
 
• 
Eye irritation/discomfort (less than 1 in 20 chance) 
• 
Watery eyes (less than 1 in 100 chance) 
 
12.4.2. Other Observations 
 
There may be other situations that may necessitate rapid communication to 
regulatory authorities. Scientific and medical judgment should be applied for 
each situation. In general, information that might materially influence the 
benefit-risk assessment of a product or that would be sufficient to consider 
changes in product administration or in the overall conduct of a clinical 
investigation represent such situations. 
 
 
12.5. Follow-up 
 
Participants who experience an adverse response during the course of the trial will 
be followed up until the condition resolves or the participant is referred to another 
practitioner.  Permanent discontinuation:  will occur when, in the optometrist’s 
opinion (or ophthalmologist’s, if participant has been referred), continued use of the 
study product will be detrimental to ocular or general health. 
 

 
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12.6. Referrals 
 
Participants will be referred to a medical expert when judged by the optometrist to 
be necessary. After hours, participants will be referred to Sydney Eye Hospital. 
 
 
 
Table 6 
Title: 
The Ophthalmology Registrar 
Address: 
Sydney Eye Hospital 
South Block  
Number 8 Macquarie Street 
Sydney  NSW  2000 
Telephone: 
+61 2 9382 7111 

 
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13. STATISTICS 
 
13.1. Description 
 
Data stored in relational databases will be imported into SPSS software for 
statistical purposes. Statistical analysis will initially be reported in Excel. The study 
may employ at least one interim analysis. Data will be investigated for quality using 
range checks and frequency distribution. Underlying distributions of variables will be 
tested. In general, variables measured on an interval scale with a sufficiently large 
sample size will be considered to follow a normal distribution. Details of statistical 
analysis are described in Section 13.1.3.  
 
 
 
13.1.1. Number of Participants 
 
138 participants will be recruited (69 in each group, which includes allowance for a 
10% drop-out rate).  
 
This sample size was calculated on the basis of detecting a difference in OSDI score 
of 10, with a standard deviation of 20, assuming an estimate of type 1 error α =0.05 
and power of 80% for a two tailed test. These values were obtained from Schiffman 
et. al. who demonstrated a mean difference in OSDI score of 10 between normal 
subjects and those with mild to moderate dry eye, with a standard deviation of up to 
20. 
 
 
 
13.1.2. Significance 
 
A p-value less than or equal to 5% will be considered to be statistically 
significant. 
 
 
 
 
13.1.3. Analysis 
 
Participants who have commenced the study treatment will be included in 
the analysis dataset. Reasons and frequency distribution of participants 
discontinued at Baseline will be reported.  The analysis of efficacy variables 
such as subjective ratings will employ only scheduled and evaluable visits. 

 
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The analysis of safety variables such as adverse responses will include all 
visits, including all unscheduled visits. 
 
Data will be summarised as means ± standard deviations for variables 
measured on an interval scale and median ± inter-quartile range for ordinal 
variables. Statistical tests will be employed to determine significant 
differences between between visits and p ≤ 0.05 will be considered 
statistically significant. Multiple comparisons will be adjusted using 
Bonferroni’s correction. Commonly used tests of significance at each visit 
may include paired t-tests and group t-test for parametric data and Wilcoxon 
sign rank test and rank sum test for non-parametric data or repeated 
measures Analysis of Variance (ANOVA) for parametric data to determine 
differences between within-subject factors. Ranked variables will be 
analysed non-parametrically using Friedman’s analysis of variance or 
Wilcoxon Signed Rank test to determine differences. Paired categorical 
variables will be compared using McNemar’s test and grouped categorical 
variables will be analysed using Chi-Square tests. 
 
 
13.2. Criteria for Termination of the Trial 
 
The trial will be terminated upon completion of the final visit by the last active 
participant or unless any of the conditions of Section 7.4 are met. An active 
participant is one who is enrolled in the study and has not been discontinued. 
 
 
13.3. Accountability of Data 
 
 
Individual data points that are missing will be excluded from analysis involving only 
those specific variables. A participant’s complete visit data will not be excluded if 
some of the observations are missing. Data from unscheduled visits will be used 
only for adverse response analysis. Inclusion of outliers in the analysis will be 
based on the magnitude of change in test statistic with and without the outliers. 
Outliers will preferably be retained unless there is significant change in test results. 
 
 
 

 
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14. DATA HANDLING AND RECORD KEEPING 
 
14.1. Source Data 
 
The Investigator/Institution is to maintain the trial documents as specified in ICH 
GCP guidelines and as required by the applicable local regulations.  The 
Investigator/Institution is to also take measures to prevent accidental or premature 
destruction of clinical trial-related documentation. 
 
Paper Case Report Forms are utilized for this clinical trial, and will be entered into 
Excel spreadsheets for importing into statistical software. For tests conducted that 
produce printed results, these should be included in the participant’s file. Source 
data includes, but is not limited to printouts, diagrams, videos, photos, and any 
other paper, electronic or digital data that is the first recording of that information, 
and these must be maintained by the Investigator in the source files for the 
participant, or if unable to file (e.g. digital images), then reference should be made 
to their location. The clinic records will maintain a record of trial participation but will 
not be considered as the source. 
 
 
14.2. Direct Access to Source Data/Documents 
 
The Investigator will conduct this clinical trial under HREC review. As necessary the 
Investigator will provide the HREC, the Sponsor and the Sponsor’s representatives, 
and appropriate regulatory authorities direct access to source data/documents for 
review.  
 
 
14.3. Data Management 
 
The data will be accessible to study personnel only, secured and backed up 
regularly.   
 
 
14.4. Data Archiving 
 
Electronic data will be stored in a secure off-site storage facility.  Paper records are 
archived approximately 3 months after study closeout or as agreed with the 
Sponsor and/or the Principal Investigator.  The records are initially kept on site in a 
secure location, and may later be transferred to a secure off-site storage facility. 
 
 

 
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14.5. Retention of Essential Documents  
 
The Investigator/Institution is to retain essential documents until at least 2 years 
after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region. However, 
these documents should be retained for longer if required by local regulatory 
agencies or by an agreement with the Co-sponsor.  
 
The Sponsor must retain essential documents for the periods as specified above 
per ICH GCP and per TGA for 15 years following the completion of a clinical trial. 
However, per TGA requirements, essential documents may need to be retained 
longer after consideration of the following:  product liability and the potential need 
for sponsors of products to produce records at any time during, and possibly 
beyond, the life of a product in the event of a claim against the Sponsor as a result 
of an adverse outcome associated with the use of the product. 

 
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15. QUALITY CONTROL AND QUALITY ASSURANCE  
 
15.1. Ethical Considerations 
 
This trial requires HREC approval prior to start.   
 
The Investigator is to ensure that the protocol, Participant Information Statement 
and Consent Form, available safety information, information about payment and 
compensation to participants, advertising or any clinical trial specific information 
provided to participants (including potential participants), the Investigator’s CV 
and/or evidence of appropriate qualifications and any other documentation they 
may request are submitted, reviewed and approved. Any subsequent amendments 
will be reviewed and approved by an HREC prior to implementation.  
 
The HREC must be appropriately constituted, and will perform its functions in 
accordance with the applicable local regulatory requirements (TGA and NHMRC) 
and GCP. 
 
This trial will be conducted in accordance with local guidelines and requirements 
(including those of the NHMRC and TGA, as applicable). 
 
 
15.1.1. Confidentiality 
 
Confidentiality will be maintained throughout the clinical trial by all parties 
involved in accordance with guidelines under section 95 of the Privacy Act 
1998, and guidelines approved under section 95a of the Privacy Act 1998 
(December 2001). Data will be secured against unauthorised access. 
 
Privacy and confidentiality of information about each clinical trial participant 
will be preserved in the reports and any publication of the clinical 
investigation data. 
 
 
15.1.2. Informed Consent 
 
The nature and purpose of the trial will be fully explained to each participant. 
Written informed consent must be obtained from each participant prior to 
any trial procedures being performed. 
 
The informed consent documentation to be used for the trial will include all 
the elements of informed consent per GCP, and TGA requirements as 
applicable, and will be reviewed and approved by the HREC prior to use. 
 
 

 
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15.1.3. Protocol Amendments 
 
It is agreed between the Co-sponsor and the Investigator that deviations will 
be reviewed to determine the need to amend the protocol or to terminate the 
investigation.  Justification for any changes must be provided.   
 
Protocol amendments will be submitted to the Co-sponsor and HREC for 
review and approval prior to implementation, unless the change required is 
to eliminate an immediate hazard to trial participants, or involves only 
administrative and/or logistical aspects of the trial (eg. Change in contact 
numbers). 
 
 
 
15.1.4. Investigator Responsibilities 
 
The Investigator is responsible for ensuring participant safety and data 
quality by:  protocol compliance, adherence to GCP and local regulatory 
requirements, and the Declaration of Helsinki.  The Investigator should be 
appropriately qualified and legally entitled to practice, and be trained in the 
proper method of obtaining informed consent.  
 
The Investigator must have the appropriate resources to conduct the clinical 
trial, be familiar with the protocol and agree to adhere to it, support 
monitoring and auditing activities, communicate with the Sponsor regarding 
any clinical trial issues or need for protocol modifications, make the 
necessary arrangements to ensure proper conduct and completion of the 
clinical trial, and ensure the protection and welfare of the participant, 
including arranging any emergency treatment as needed. 
 
The Investigator must ensure written HREC approval is received prior to the 
start of the clinical trial, that the HREC and Sponsor is kept informed of the 
clinical trial progress, including serious/adverse events and deviations as 
required by them, and that any changes to the protocol are notified to the 
HREC and receive written approval prior to implementation. 
 
The Investigator must try to ensure adequate participant recruitment; that all 
necessary and appropriate information is given to potential participants to 
ensure informed consent; to ensure informed consent is taken and 
documented; and that clinical records indicate the participant is enrolled in a 
clinical trial.  The Investigator must ensure that clinical trial participants are 
provided with emergency contact details along with a procedure to follow in 
the case of an emergency, and that clinical trial participants are kept 
informed as pertinent new information becomes available that may affect 
their decision to participate. 
 
The Investigator has primary responsibility for the accuracy, legibility and 
security of all clinical investigation data, documents and participant records 
at the investigator site during and after the clinical trial.  Case Report Forms 
are to be signed by the Investigator, and any alterations to data are to be by 
authorised personnel, initialled and dated by same. 

 
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The Investigator must ensure that data be kept for the minimum time as 
specified by this protocol, investigational product must be accounted for (the 
quantity of the devices received must be reconciled with the quantities of the 
device used, discarded or returned), and must also be responsible for the 
supervision and assignment of duties to all responsible for the conduct and 
evaluation of the clinical trial for the investigator centre involved. 
 
 
 
 
 
 

 
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16. FINANCING AND INSURANCE 
 
Memorandum of Agreement can be provided on request. 
 
 
 
 
17. PUBLICATION POLICY 
 
 
Please refer to Memorandum of Agreement 
 
 
 
 
 

 
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INVESTIGATOR AGREEMENT 
 
 
 
 
 
“I agree to conduct the trial outlined above according to the terms and conditions of the protocol, 
Good Clinical Practice Guidelines and with the applicable regulatory requirements.  All information 
pertaining to the trial shall be treated in a confidential manner.”   
 
 
 
 
 
 
Principal Investigator’s Signature:  
_______________________   Date:______________ 
 
 
Principal Investigator’s Printed Name: 
_______________________ 
 
 

 
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APPENDIX I 
 
DECLARATION OF HELSINKI

 
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APPENDIX I:  WORLD MEDICAL ASSOCIATION DECLARATION OF  
 
 
     HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
 
The Declaration of Helsinki (Document 17.C) is an official policy document of the World Medical Association (WMA), the 
global representative body for physicians. 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 and the 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
 
A. 
 
INTRODUCTION 
1.  
The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to 
provide guidance to physicians and other participants in medical research involving human subjects. Medical 
research involving human subjects includes research on identifiable human material or identifiable data. 
2. 
It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge and 
conscience are dedicated to the fulfilment of this duty. 
3. 
The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health of 
my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A 
physician shall act only in the patient's interest when providing medical care which might have the effect of 
weakening the physical and mental condition of the patient."  
4. 
Medical progress is based on research which ultimately must rest in part on experimentation involving human 
subjects. 
5. 
In medical research on human subjects, considerations related to the well-being of the human subject should 
take precedence over the interests of science and society. 
6. 
The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and 
therapeutic procedures and the understanding of the aetiology and pathogenesis of disease. Even the best 
proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for 
their effectiveness, efficiency, accessibility and quality.  
7. 
In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures 
involve risks and burdens.  
8. 
Medical research is subject to ethical standards that promote respect for all human beings and protect their 
health and rights. Some research populations are vulnerable and need special protection. The particular needs 
of the economically and medically disadvantaged must be recognized. Special attention is also required for 
those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under 
duress, for those who will not benefit personally from the research and for those for whom the research is 
combined with care.  
9. 
Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human 
subjects in their own countries as well as applicable international requirements. No national ethical, legal or 
regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set 
forth in this Declaration. 
 
B. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10.  
It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human 
subject.  
11. 
Medical research involving human subjects must conform to generally accepted scientific principles, be based 
on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate 
laboratory and, where appropriate, animal experimentation. 
12. 
Appropriate caution must be exercised in the conduct of research which may affect the environment, and the 
welfare of animals used for research must be respected. 
13. 
The design and performance of each experimental procedure involving human subjects should be clearly 
formulated in an experimental protocol. This protocol should be submitted for consideration, comment, 
guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be 
independent of the investigator, the sponsor or any other kind of undue influence. This independent committee 
should be in conformity with the laws and regulations of the country in which the research experiment is 
performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide 
monitoring information to the committee, especially any serious adverse events. The researcher should also 
submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest and incentives for subjects.  

 
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APPENDIX I:  Declaration of Helsinki (cont.) 
 
14. 
The research protocol should always contain a statement of the ethical considerations involved and should 
indicate that there is compliance with the principles enunciated in this Declaration.  
15. 
Medical research involving human subjects should be conducted only by scientifically qualified persons and 
under the supervision of a clinically competent medical person. The responsibility for the human subject must 
always rest with a medically qualified person and never rest on the subject of the research, even though the 
subject has given consent. 
16. 
Every medical research project involving human subjects should be preceded by careful assessment of 
predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not 
preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly 
available. 
17. 
Physicians should abstain from engaging in research projects involving human subjects unless they are 
confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians 
should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive 
proof of positive and beneficial results. 
18. 
Medical research involving human subjects should only be conducted if the importance of the objective 
outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects 
are healthy volunteers.  
19. 
Medical research is only justified if there is a reasonable likelihood that the populations in which the research is 
carried out stand to benefit from the results of the research.  
20. 
The subjects must be volunteers and informed participants in the research project. 
21. 
The right of research subjects to safeguard their integrity must always be respected. Every precaution should be 
taken to respect the privacy of the subject, the confidentiality of the patient's information and to minimize the 
impact of the study on the subject's physical and mental integrity and on the personality of the subject. 
22. 
In any research on human beings, each potential subject must be adequately informed of the aims, methods, 
sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated 
benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the 
right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. 
After ensuring that the subject has understood the information, the physician should then obtain the subject's 
freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written 
consent must be formally documented and witnessed.  
23. 
When obtaining informed consent for the research project the physician should be particularly cautious if the 
subject is in a dependent relationship with the physician or may consent under duress. In that case the informed 
consent should be obtained by a well-informed physician who is not engaged in the investigation and who is 
completely independent of this relationship.  
24. 
For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a 
legally incompetent minor, the investigator must obtain informed consent from the legally authorized 
representative in accordance with applicable law. These groups should not be included in research unless the 
research is necessary to promote the health of the population represented and this research cannot instead be 
performed on legally competent persons.  
25. 
When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about 
participation in research, the investigator must obtain that assent in addition to the consent of the legally 
authorized representative. 
26. 
Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, 
should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary 
characteristic of the research population. The specific reasons for involving research subjects with a condition 
that renders them unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state that consent to remain in the 
research should be obtained as soon as possible from the individual or a legally authorized surrogate. 
27. 
Both authors and publishers have ethical obligations. In publication of the results of research, the investigators 
are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or 
otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest 
should be declared in the publication. Reports of experimentation not in accordance with the principles laid 
down in this Declaration should not be accepted for publication.  
 
 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE  
28. 
The physician may combine medical research with medical care, only to the extent that the research is justified 
by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical 
care, additional standards apply to protect the patients who are research subjects. 
29. 
The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best 
current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no 
treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists. 
 

 
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APPENDIX I:  Declaration of Helsinki (cont.) 
 
 
30. 
At the conclusion of the study, every patient entered into the study should be assured of access to the best 
proven prophylactic, diagnostic and therapeutic methods identified by the study. 
31. 
The physician should fully inform the patient which aspects of the care are related to the research. The refusal 
of a patient to participate in a study must never interfere with the patient-physician relationship. 
32. 
In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or 
have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or 
new prophylactic, diagnostic and therapeutic measures, if in the physician's judgement it offers hope of saving 
life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of 
research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, published. The other relevant guidelines of this Declaration should be followed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX II 
 
QUESTIONNAIRES 

 
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APPENDIX II:  QUESTIONNAIRES 
 
 
OCULAR COMFORT INDEX (OCI) 
 
 

 
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OCULAR SURFACE DISEASE INDEX (OSDI) 
 

 
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DRY EYE QUESTIONNAIRE 5 (DEQ-5) 
 

 
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SYMPTOM SURVEY 
Think about how your eyes have felt during a typical day in the last week. Then, using the scales provided 
below, please mark a vertical line at the place that best describes your experience with these symptoms 
during this time period: 
1. Watery Eyes 
No watering                                                                                                                 Maximum watering 
                                   
0____________________________________________________100 
 
2. Grittiness/Foreign Body Sensation 
No grittiness/foreign body sensation                                                                          
Maximum  
                                   
0____________________________________________________100 
 
3. Dryness 
No dryness                                                                                                                  Maximum dryness 
                                   
0____________________________________________________100 
 
4. Blurry/Fluctuation Vision 
No blurry/fluctuating vision                                                                                            
Maximum  
                                   
0____________________________________________________100 
 
5. Overall Ocular Pain/Discomfort 
No ocular pain/discomfort                                                                                                   
Maximum  
                                   
0____________________________________________________100 
 
6. On average, how many times per day did you use eye drops during the past week? 
_________________ 
 
 
 

 
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HEALTH AND WELLBEING SURVEY 
 
1. Since your last visit, have you: 
 
a) Been hospitalized?  
 
 
 
 
 
 
 
 
Yes / No 
b) Used any new medication or changed medication regimens? 
 
 
 
Yes / No 
c) Experienced any Gastrointestinal irritation e.g. diarrhea, heartburn, bloating or nausea?  Yes / No 
d) Experienced unusual bleeding? 
 
 
 
 
 
 
 
Yes / No 
e) If you answered yes to any of the above, please explain: 
______________________________________________________________________________________ 
______________________________________________________________________________________ 
______________________________________________________________________________________ 
______________________________________________________________________________________ 
 
2. On average, how many times per day did you ingest the study product during the past week?     
_________________ 
 
 
 
 
 
 

 
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NUTRITION QUESTIONNAIRE 
 
DIETARY SUPPLEMENTS AND OCULAR COMFORT 
 
 
 
ON AVERAGE, HOW MANY SERVES PER WEEK WOULD YOU EAT OF THE FOLLOWING  
(PLEASE REFER TO THE DIET GUIDE FOR FOOD TYPES WITHIN EACH GROUP AND SERVING SIZES.) 
 
FOOD TYPE 
SERVES PER WEEK    
CEREALS 
 
 
VEGETABLES, LEGUMES 
 
 
FRUIT 
 
 
MILK, YOGHURT, CHEESE 
 
 
LEAN MEAT, FISH, POULTRY, NUTS 
 
 
EXTRA FOODS    
(E.G. CAKES, PIES, SWEETS, SOFT DRINKS, ALCOHOL, ETC)  
 
 
 
HOW MANY TIMES PER WEEK DO YOU EAT OILY FISH (SALMON, TUNA, ETC)?:  ___________________________ 
 
 
ARE YOU VEGETARIAN OR VEGAN? 
 
NEITHER 
 
VEGETARIAN (EAT FISH) 
 
VEGETARIAN (DO NOT EAT FISH) 
 
VEGAN 
 
 

 
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APPENDIX III 
 
CCLRU GRADING SCALES 
 
 

 
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APPENDIX III:  CCLRU Grading Scales 
 
The CCLRU Grading Scale uses a 0-4 scale in 0.5 steps, as shown in the following table: 
 
 
 
Table 7 
Grade 
Description 
0 
Absent 
1 
 
 
  Very Slight 
2 
 
 
  Slight 
3 
 
 
  Moderate 
4 
 
 
  Severe 
 
The scale is to be used in conjunction with the colour photographs as a standard to compare the 
observed finding and grade accordingly. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX IV 
 
CIBA GRADING SCALES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX IV:  CIBA Grading Scales 
SLIT-LAMP QUANTIFICATION CHART 
 
BIOMICROSCOPY SIGNS 
Eyelid and Bulbar Conjunctival Redness 
 
0 
= 
None:  White and clear 
1 
= 
Trace:  Regional hyperemia 
2 
= 
Mild:  Diffuse hyperemia 
3 
= 
Moderate:  Marked regional or diffuse hyperemia 
4 
= 
Severe:  Diffuse episcleral or scleral hyperemia 
 
 
Corneal Staining 
 
0 
= 
None:  No staining 
1 
= 
Trace:  Regional superficial stippling and/or foreign body tracks 
2 
= 
Mild:  Regional or diffuse punctate staining and/or F.B. tracks 
3 
= 
Moderate:  Dense coalescent staining and/or abrasions 
4 
= 
Severe:  Epithelial loss, or full thickness abrasion 
Conjunctival Staining 
 
0 
= 
None:  No staining 
1 
= 
Trace:  Minimal regional staining 
2 
= 
Mild:  Regional or diffuse punctate staining 
3 
= 
Moderate:  Significant dense coalescent staining 
4 
= 
Severe:  Severe dense geographical staining