A Two Comparator, Controlled Phase 3 Study of OM3 Tear Formulation Versus OPTIVE ADVANCED Unit Dose and OPTIVE Unit Dose Eye Drops in Patients With and Without Evaporative Dry Eye.
Phase: PHASE3
Conditions: Dry Eye Syndromes
Sponsor: The University of New South Wales

 
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CLINICAL TRIAL PROTOCOL 
 
 
 
Protocol Title - Long: 
A two comparator, controlled phase 3 study of OM3 Tear formulation versus 
OPTIVE ADVANCED Unit Dose and OPTIVE Unit Dose eye drops in patients 
with and without evaporative dry eye. 
Protocol Title - Short: 
Omega 3 Tear 
Protocol ID Number: 
SOVS-2016-040 
Amendment Number: 
N/A 
Version Date: 
14th July 2016 
 
 
 
 

 
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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 
 
 
 
 
 
 
Mark Willcox, Professor/Sub-investigator  
 
Date 
 
 
 
 
 
 
 
Fiona Stapleton, Head of School  
 
Date 
 
 
 
 
 
 
 
Peter Simmons, Allergan Inc. 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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SPONSOR 
Sponsor: 
 
Address: 
 
University of New South Wales (UNSW) 
 
Sydney, NSW 2052 
Australia 
CO-SPONSOR 
Sponsor: 
 
Address: 
 
Allergan Singapore Pty Ltd. 
20 Pasir Panjang Road, 
Mapletree Business City  
West Building, #09-25 
Singapore 117439 
 
SUMMARY OF FINAL PROTOCOL & AMENDMENTS 
Initial/ 
Amend # 
Version Date 
Author 
Main Changes 
Final 
14th July 2016 
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) ........................................................................................................................ 11 
 
3.  
MEDICAL EXPERT ........................................................................................................................ 12 
 
4.  
BACKGROUND INFORMATION .................................................................................................. 13 
 
4.1 
Background and Clinical Rationale ................................................................................... 13 
 
4.2 
Summary ........................................................................................................................... 13 
 
 
4.2.1 
Risks and Benefits................................................................................................ 13
 
 
4.2.2 
Treatment Rationale ............................................................................................. 14 
 
 
4.2.3 
Guidelines and Regulations ................................................................................. 14 
 
 
4.2.4 
Trial Population .................................................................................................... 14 
 
 
 
5.  
STUDY OBJECTIVES AND CLINICAL HYPOTHESIS ................................................................ 15 
 
5.1 
Study Objective ................................................................................................................. 15 
 
5.2 
Clinical Hypothesis ............................................................................................................ 15 
 
6.  
STUDY DESIGN. ........................................................................................................................... 16 
 
6.1 
Methodology / Study Visits ................................................................................................ 16 
 
 
6.1.1 
Data Requirements per Visit with Visit Window ................................................... 16 
 
 
6.1.2 
Randomisation and Masking ................................................................................ 18 
 
 
6.1.3 
Clinical Trial Population ........................................................................................ 18 
 
 
6.1.4 
Trial Duration ........................................................................................................ 18 
 
 
6.1.5 
Enrollment ............................................................................................................ 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 ................................................................................................. 21 
 
7.2 
Participant Withdrawal....................................................................................................... 21
 
7.3 
Withdrawal and Follow-Up Procedure............................................................................... 22 
 
 
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 ............................................. 23 
 
7.4 
Early Termination of Trial .................................................................................................. 23 
 
 

 
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TABLE OF CONTENTS - cont 
 
8.  
NUMBERING / RANDOMISATION ............................................................................................... 23 
 
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 ........................................................................................................ 27 
 
10.4 
Participant Instructions ...................................................................................................... 27 
 
11.  
ASSESSMENT OF EFFICACY ..................................................................................................... 28 
 
11.1 
Parameters  ....................................................................................................................... 28 
 
11.2 
Methods ............................................................................................................................. 28 
 
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
 
12.5 
Follow-Up .......................................................................................................................... 32 
 
12.6 
Referrals ............................................................................................................................ 32 
 
13.  
STATISTICS 
.............................................................................................................................. 33 
13.1 
Description ........................................................................................................................ 33 
 
13.1.1 Number of Participants ......................................................................................... 33 
 
13.1.2 Significance .......................................................................................................... 33 
 
13.1.3 Analysis ................................................................................................................ 33 
13.2 
Criteria for Termination of the Trial ................................................................................... 34 
13.3 
Accountability of Data........................................................................................................ 34 
 
14.  
DATA HANDLING AND RECORD KEEPING ............................................................................... 35 
14.1 
Source Data ...................................................................................................................... 35 
14.2 
Direct Access to Source Data/Documents ........................................................................ 35 
14.3 
Database Management ..................................................................................................... 35 
14.4  
Data Archiving  .................................................................................................................. 35 
14.5 
Retention of Essential Documents .................................................................................... 36 
 
 
 

 
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TABLE OF CONTENTS - cont 
 
15.  
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................... 37 
15.1 
Ethical Considerations....................................................................................................... 37
 
15.1.1 Confidentiality ....................................................................................................... 37 
 
15.1.2 Informed Consent ................................................................................................. 37 
 
15.1.3 Protocol Amendments .......................................................................................... 38 
 
15.1.4 Investigator Responsibilities ................................................................................. 38 
 
16.  
FINANCING AND INSURANCE .................................................................................................... 40 
 
17.  
PUBLICATION POLICY ................................................................................................................ 40 
 
18.  
INVESTIGATOR AGREEMENT .................................................................................................... 41 
 
APPENDIX 1: Declaration of Helsinki....................................................................................................... 42 
 
APPENDIX 2: CCLRU Grading Scales .................................................................................................... 46 
 
APPENDIX 3: CIBA Grading Scales ........................................................................................................ 48 
 
 
 
 

 
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1. PROTOCOL SYNOPSIS 
 
Table 1 
Protocol Title 
A two comparator, controlled phase 3 study of OM3 Tear formulation versus 
OPTIVE ADVANCED Unit Dose and OPTIVE Unit Dose eye drops in patients 
with and without evaporative dry eye. 
Background 
 
o 
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 
o 
Dysfunction of one or more components of the tear film can lead to loss of 
tear film stability and symptoms of dry eye 
o 
The majority of patients with dry eye are prescribed artificial tears to 
alleviate symptoms and maintain a healthy ocular surface 
o 
OM3 Tear is a new unit dose emulsion, containing flaxseed/castor oil, 
which is being developed by Allergan. It is desirable to understand the 
effect that this new emulsion has on tear film evaporation and tear lipid 
profile via interferometry, in patients with evaporative dry eye (EDE) and 
those without (non-EDE). It would also be valuable to evaluate the 
retention time of the lipid components of the new emulsion via tear 
collection and analysis in EDE and non-EDE patients 
 
Study Design 
Single centre, double-masked, randomized, 3 arm comparison of OM3 Tear 
eye drops to two comparators. 
Aims and Objectives 
To measure tear film evaporation rate, tear lipid profile via interferometry and 
tear lipid components before and 15 mins, 1 hour and 4 hours after the first 
dose, and again after 4 weeks of use of the emulsion OM3 Tear eye drops, 
compared to two comparators (Optive Advanced Unit Dose and Optive Unit 
Dose). 
Recruitment 
September 2016 
Study Start & End Dates 
September 2016 – April 2017 
Sample size 
 
Up to 40 participants will be recruited (approx. 20 EDE and 20 non-EDE 
subjects). This sample size was calculated on the basis of detecting a 
difference in:  
o 
tear evaporation rate between the eye drops of 36 gm-2/h where the 
expected standard deviation of the measurement is 50 gm-2/h, assuming  
an estimate of type 1 error α =0.05 and power of 80% for a two tailed test1 
 
Subject Source 
UNSW and general community 

 
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Selection criteria 
 
General Inclusion Criteria  
o 
Able to read and comprehend English and give informed consent as 
demonstrated by signing a record of informed consent; 
o 
Over 18 years of age; 
o 
Not wearing contact lenses in the past 3 months before enrolling 
o 
Willing to use eye drops and comply with the study visit schedule as 
directed by the Investigator; 
o 
Habitual (corrected or uncorrected) visual acuity of 6/9.5 or better in each 
eye; 
o 
At the Screening visit (Day -14), patients must have Ocular Surface 
Disease Index (OSDI) score >18 (0 to 100 scale). At Baseline (Day 1) 
visits, patients must have OSDI score > 12 to continue in the study. 
o 
TBUT≤10sec in at least 1 eye at Screening visit and Baseline visit 
o 
Corneal sodium fluorescein staining score ≥ 1 and <4 (Oxford scheme) at 
Screening and Baseline visit.  
 
 
Additional Inclusion Criteria for EDE Classification  
o 
Tear Evaporation Rate (TER) ≥ 110 - To be confirmed (TBC) 
Additional Inclusion Criteria for non-EDE Classification  
o 
Tear Evaporation Rate (TER) < 110 (TBC) 
For patients who have one eye meeting EDE criteria, and other eye meeting 
non-EDE criteria, their Schirmer score will be used to determine the 
classification.  If their Schirmer score is >10 in both eyes, they will be 
classified in the EDE group.   
 
General Exclusion Criteria 
o 
Schirmer test (with anesthesia) ≤ 2 mm in either eye at Screening 
o 
Patients who are currently using topical ocular medication or have used 
topical ocular medication within 2 weeks of the Screening visit. Patients 
who are being treated bilaterally with a marketed artificial tear for dry eye 
can be considered, provided they discontinue use at the Screening visit; 
o 
Any active anterior segment disease excluding blepharitis; 
o 
Any systemic disease that may affect ocular health e.g. Graves disease, 
and auto-immune diseases such as ankylosing spondylitis, multiple 
sclerosis and systemic lupus erythematosus; 
o History of epilepsy or migraines exacerbated by flashing, strobe-like lights; 
o 
Rigid or soft contact lens wearer, including orthokeratology; 
o 
History of eye surgery within 6 months prior to enrolment in the study; 
o 
Previous corneal refractive surgery. 
 
Visit Schedule – 3 arm 
study 
 
Visit 1 (Day -14): Screening visit, dispensing run-in product (Refresh Plus) 
 
ARM 1: 
 
Visit 2a (Day 1): Pre-instillation and 15 min (± 5 min) post-instillation 
assessment - Eye Drop #1  
 
Visit 2b (Day 1): 1 hour (± 15 min) post-instillation assessment - Eye Drop #1 
 
Visit 2c* (Day 1): 4 hour (± 30 min)  post-instillation assessment - Eye Drop #1 
 
Visit 3 (4 weeks): 4 week assessment - Eye Drop #1  
 
ARM 2: (after minimum 2 week wash-out period using run-in product Refresh 
Plus) 
 

 
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Visit 4a ([6 weeks): Pre-instillation and 15 min (± 5 min) post-instillation 
assessment - Eye Drop #2 
 
Visit 4b (6 weeks): 1 hour (± 15 min) post-instillation assessment - Eye Drop 
#2 
 
Visit 4c* (6 weeks): 4 hour (± 30 min) post-instillation assessment - Eye Drop 
#2 
 
Visit 5 (10 weeks): 4 week assessment - Eye Drop #2  
 
ARM 3: (after minimum 2 week wash-out period using run-in product Refresh 
Plus) 
 
Visit 6a (12 weeks): Pre-instillation and 15 min (± 5 min) post-instillation 
assessment - Eye Drop #3 
 
Visit 6b (12 weeks): 1 hour (± 15 min) post-instillation assessment - Eye Drop 
#3 
 
Visit 6c* (12 weeks): 4 hour (± 30 min) post-instillation assessment - Eye Drop 
#3 
 
Visit 7 (16 weeks): 4 week assessment Eye Drop #3  
 
Note: Subjects are NOT to instil any eye drops within 3 hours prior to the 
scheduled visits 
 
* 4 hour assessments will only be conducted on participants who are able to 
attend this additional visit on the same day as the initial assessment 
 
Procedure 
Standard ocular examination and non-standard ocular examination procedures 
will be carried out at the scheduled visits. 
 
Standard optometric procedures may include: 
o 
Subjective questionnaires (OSDI, Likert and VAS) 
o 
Corneal and conjunctival staining (Fluorescein and Lissamine Green) 
Non-standard optometric procedures may include: 
o 
Tear evaporation rate (Modified Vapometer, Delphin Technologies) 
o 
Tear Break-Up Time (with fluorescein) and lipid layer grade  
o 
Tear film lipid layer thickness (LipiView Interferometer) 
o 
Tear collection using Schirmer strips. The tear lipidome will be 
characterized using targeted chip-based nanoelectrospray tandem mass 
spectrometry (ESI/MS), per our previous methods. Levels of peroxidised 
lipids will be evaluated using ELISA. 
Study Endpoints 
 
The primary endpoint is a measurable difference in tear evaporation rate 
between the eye drops after initial application (15 min) and/or after 1 hour 
and/or 4 hours of application and/or after 4 weeks of daily use. 
 
The secondary endpoints are (i) a measurable difference in TBUT between the 

 
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eye drops after initial application (15 min) and/or after 1 hour and/or 4 hours of 
application and/or after 4 weeks of daily use and (ii) a measurable difference 
in symptom improvement between the eye drops after initial application (15 
min) and after 4 weeks of daily use.  
 
Statistical 
Considerations 
 
Paired t-tests, repeated measures ANOVA or linear mixed model analysis 
using Bonferroni adjustment for multiple comparisons and p value set at 
p<0.05. Mann Whitney U test will be used to compare tear film lipidome 
between the eye drops.  
 
IRB Status & Details 
 
This clinical research study requires approval from the Human Research 
Ethics Committee at the University of New South Wales prior to study 
initiation, any advertising, and participant enrolment. 
 
o 
HREC meetings held monthly 
o 
Lead time for new applications: approx. 2 months 
Dissemination of 
Results 
 
o 
Publication in peer-reviewed journals 
o 
Presentation at International conferences 
 

 
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2. INVESTIGATOR(S) 
 
Table 2 
Name: 
Jacqueline Tan 
Title: 
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: 
Katherine Wong 
Title: 
Research Optometrist 
Site Address: 
 
Level 1, North Wing, RMB 
Gate 14, Barker Street 
The University of New South Wales 
Sydney  NSW  2032 
Telephone: 
+61 2 9385 4721 
 
Name: 
Patricia Arthur 
Title: 
Research Optometrist 
Site Address: 
 
Level 2, North Wing, RMB 
Gate 14, Barker Street 
The University of New South Wales 
Sydney  NSW  2032 
Telephone: 
+61 2 9385 4503 
 
Name: 
Simin Masoudi 
Title: 
Research Fellow 
Site Address: 
 
Level 2, North Wing, RMB 
Gate 14, Barker Street 
The University of New South Wales 
Sydney  NSW  2032 
Telephone: 
+61 2 9385 4503 
 
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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Name: 
Mark Willcox 
Title: 
Professor 
Site Address: 
 
Level 3, North Wing, RMB 
Gate 14, Barker Street 
The University of New South Wales 
Sydney  NSW  2032 
Telephone: 
+61 2 9385 4164 
 
 
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. Background and Clinical Rationale 
 
 
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 majority of 
patients with dry eye are prescribed artificial tears to alleviate symptoms and maintain a 
healthy ocular surface. 
 
The purpose of this study is to evaluate the retention time of the lipid components of the 
new emulsion OM3 Tear eye drops via tear collection and analysis in evaporative dry eye 
(EDE) and non-EDE patients. Tear film evaporation rate, tear lipid profile via interferometry 
and tear lipid components will be evaluated before and 15 mins, 1 hour and 4 hours after 
the first dose, and again after 4 weeks of use of the emulsion OM3 Tear eye drops, 
compared to two comparators (Optive Advanced Unit Dose and Optive Unit Dose).  
 
 
 
4.2. Summary 
 
 
4.2.1. Risks and Benefits 
 
Risks of the Clinical Trial 
 
It is possible that participants may have an allergic reaction to any the study eye 
drops. Signs of ocular allergy (e.g. redness, itching and watering) will be treated by 
immediate discontinuation of use of the study eye drops and participation in the 
study. However, participants will be monitored until ocular signs and symptoms 
have returned to normal. Topical and/or oral antihistamines may be prescribed if 
deemed appropriate. The participant will be referred for appropriate medical 
treatment if required.   
 
Any potential participants with a self-reported allergy/sensitivity to any of the study 
eye drops will be excluded from the study.  
 
The Lipiview Ocular Surface Interferometer uses flashing strobe-like lights which 
may have an adverse effect on participants with a history of epilepsy or migraines. 
Any potential participants with epilepsy or a history of migraines exacerbated by 
flashing, strobe-like lights will be excluded from the study.  

 
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Benefits of the Clinical Trial 
 
Participants will receive ocular lubricant treatment for their dry eye condition. 
However, there is no guarantee or promise that the participants will receive any 
health benefits from this clinical trial. The study eye drops and participants’ 
optometric care will be provided free of charge for the duration of the clinical trial.  
 
 
4.2.2. 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. 
 
 
4.2.3. Trial Population 
 
40 participants will be recruited (approx. 20 EDE and 20 non-EDE subjects).  
 
 
 

 
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5. STUDY OBJECTIVES AND CLINICAL HYPOTHESIS 
 
 
 
5.1. Study Objective 
 
The objective of this study is to measure tear film evaporation rate, tear lipid profile 
via interferometry and tear lipid components with the use of the emulsion OM3 
Tear eye drops, compared to two comparators (Optive Advanced Unit Dose and 
Optive Unit Dose) in subjects with EDE and those without (non-EDE) 
 
5.2. Clinical Hypothesis 
 
Tear evaporation rate as measured with the Vapometer is better (i.e. lower) with 
the emulsion OM3 Tear formulation compared to at least one of the two 
comparators at one or more of the post eye drop instillation time-points. 

 
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6. STUDY DESIGN 
 
 
This study is a single centre, double-masked, randomized, 3-arm comparison of emulsion 
OM3 eye drops compared to two comparators.  All study subjects will attend a Screening 
visit and receive REFRESH PLUS® for 2 weeks during a run-in period prior to 
randomization.  Subjects will be randomized as to the order of allocation to use the OM3 
Tear eye drop and the two comparators.  For each arm of the study, assessments will be 
conducted prior to eye drop instillation and 15 min, 1 hour and 4 hours post-instillation. 
Subjects will then be dispensed with the randomized study eye drop and instructed to 
instill 1 to 2 drops of their assigned study product in each eye, as needed, but at least 
twice daily, for 4 weeks.  Subjects will attend a 4 week visit assessment and then undergo 
a minimum 2 week wash-out period using run-in product REFRESH PLUS® before 
returning to complete the next arm of the study. These procedures will be repeated until 
the subjects have completed all 3 arms of the study.  
The primary endpoint is a measurable difference in tear evaporation rate between the eye 
drops after initial application (15 min) and/or after 1 hour and/or 4 hours of application 
and/or after 4 weeks of daily use.  
 
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. 
 
  
 
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. 
  
 

 
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Table 4 
 
 
Visit 1 
Visit 
2a 
Visit 
2b* 
Visit 
2c 
Visit 
3a 
Visit 
3b*  
Visit 
3c 
Visit 
4a 
Visit 
4b* 
Visit 
4c 
Timeline 
Day -
14 
Day 1 
#1 
Day 1 
#1 
4 
weeks 
#1 
6 
weeks 
#2 
6 
weeks 
#2 
10 
weeks 
#2 
12 
weeks 
#3 
12 
weeks 
#3 
16 
weeks 
#3 
Procedure 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
Y 
N 
N 
N 
N 
N 
N 
N 
N 
N 
Inclusion/Exclusion 
criteria 
Y 
Y 
N 
N 
N 
N 
N 
N 
N 
N 
Ocular, medical 
history, 
medications, 
demographics 
Y 
N 
N 
N 
N 
N 
N 
N 
N 
N 
Updated history, 
symptoms, 
problems 
Y 
Y 
N 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Vision tests 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Biomicroscopy 
(ocular health, 
staining) 
Y 
Y 
N 
Y 
Y 
N 
Y 
Y 
N 
Y 
Meibomian gland 
assessment 
Y 
N 
N 
N 
N 
N 
N 
N 
N 
N 
Schirmer test 
(eligibility) 
Y 
N 
N 
N 
N 
N 
N 
N 
N 
N 
Instill eye drops 
Y 
Y 
N 
N 
Y 
N 
N 
Y 
N 
N 
Tear evaporation 
rate 
N 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Eye photo (ocular 
surface area) 
Y 
N 
N 
N 
N 
N 
N 
N 
N 
N 
Schirmer test (tear 
collection) 
N 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
LipiView 
N 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
TBUT (fluorescein) 
N 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Questionnaires 
(OSDI, VAS) 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
 
 
Y = Yes, required information, N = No, not required 
 
 
 
  
# = eye drop 
a = Baseline and 15 min post-eye drop assessment  
b = 3-5 hour post-eye drop assessment  
c = 4 week post-eye drop assessment 
 
 
 
 
    
 
 
*Visits 2b, 3b and 4b are scheduled 4 hours (± 30 mins) after the corresponding visits 2a, 
3a and 4a on the same day, and therefore are not compulsory for all study participants to 
attend. Only those who are able to attend this visit will complete the assessment visits 2b, 
3b and 4b. 

 
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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. 
At the Screening visit (Visit 1), all eligible subjects will receive run-in product 
(REFRESH PLUS) for use during the 14-day run-in period.  The clinical site will 
dispense the run-in product.  At the time of randomization (Visit 2, Arm 1), eligible 
subjects will be randomly assigned to 1 of the 3 treatments.  A randomization 
scheme will be prepared in advance.  
Study product will be labeled with study product kit numbers.  At Visit 2 (Arm 1), the 
specific study product kit number for each randomized subject will be dispensed by 
unmasked administrative study personnel and all study measurements will be 
conducted by the masked investigator. Unused study product will be returned at the 
4 week follow-up visit and the run-in product will be dispensed to be used during 
the wash-out period. This procedure will be repeated until all arms of the study 
have been completed.  
 
The emulsion OM3 Tear formulation and the two comparator unit dose eye drops 
will be provided in similar 0.4 mL unit-dose vials (comparator products will have 
commercial labeling). 
 
 
6.1.3. Clinical Trial Population 
 
40 participants (approx. 20 EDE and 20 non-EDE subjects) will be recruited for the 
study. 
 
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.  
 
 
6.1.4. Trial Duration 
 
This study is a randomized 3-arm comparison of emulsion OM3 eye drops 
compared to two comparators. Participants will attend a Screening visit (Day -14) 
and up to 3 scheduled visits for each eye drop. It will take participants 

 
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approximately 18 weeks to complete all 3 arms of the study. 
Table 5: Visits  
Visit Type: 
Visit No: 
Study Arm 
Screening (Day -14)  
1 
- 
Eye Drop #1: Baseline and 15 min assessment 
2a 
1 
Eye Drop #1: 3-5 hour assessment 
2b 
1 
Eye Drop #1: 4 week assessment 
2c 
1 
Eye Drop #2: Baseline and 15 min assessment 
3a 
2 
Eye Drop #2: 3-5 hour assessment 
3b 
2 
Eye Drop #2: 4 week assessment 
3c 
2 
Eye Drop #3: Baseline and 15 min assessment 
4a 
3 
Eye Drop #3: 3-5 hour assessment 
4b 
3 
Eye Drop #3: 4 week assessment and Exit 
4c 
3 
 
 
All study participants will attend a Screening visit and receive REFRESH PLUS® for 
 
2 weeks during a run-in period prior to randomization at Visit 2a. After the 4 week 
 
assessment, all study participants will undergo a minimum 2 week wash-out period 
 
using run-in product REFRESH PLUS® before returning to complete the next arm of 
 
the study. These procedures will be repeated until the subjects have completed all 
 
3 arms of the study. 
 
6.1.5. Enrolment 
 
A study participant is considered enrolled when they have signed the Participant 
Information Statement and Consent Form.  
 
 
6.2. Primary Endpoint 
 
The primary endpoint is a measurable difference in tear evaporation rate (Vapometer) 
between the eye drops after initial application (15 min) and/or after 1 hour and/or 4 hours 
of application and/or after 4 weeks of daily use. 
 
 
 
6.3. Secondary Endpoint(s) 
 
Tear break-up time (TBUT) with fluorescein, subjective comfort scores and lipid layer 
thickness (LipiView). 
 

 
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7. SELECTION AND WITHDRAWAL OF PARTICIPANTS 
 
7.1. Participant Selection  
 
Only subjects who have signs and symptoms of dry eye disease (EDE or non-EDE) will be 
enrolled. 
 
Participants will be pre-screened for suitability by way of a general phone questionnaire.  
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  
 
 
The following are requirements for entry into the study:  
1. Male or female, ≥ 18 years of age;  
2. Able to read and comprehend English and give informed consent as demonstrated by 
signing a record of informed consent; 
3. Not wearing contact lenses in the past 3 months before enrolling; 
4. Willing to use eye drops and comply with the study visit schedule as directed by the 
Investigator; 
5. Habitual (corrected or uncorrected) visual acuity of 6/9.5 or better in each eye; 
6. At the Screening visit (Day -14), patients must have Ocular Surface Disease Index 
(OSDI) score >18 (0 to 100 scale). At Baseline (Day 1) visits, patients must have OSDI 
score > 12 to continue in the study; 
7. TBUT≤10sec in at least 1 eye at the Screening visit; 
8. Corneal sodium fluorescein staining score ≥ 1 and <4 (Oxford scheme) at screening and 
baseline visit; 
9. If using RESTASIS® cyclosporine ophthalmic emulsion, subjects must be using drops for 
≥ 3 months prior to Screening. 
10. Subjects with primary open-angle glaucoma or ocular hypertension (OHT) may be 
included provided they are on stable monotherapy bilaterally, with both eyes IOP 
controlled (≤ 21 mm Hg).  Any topical IOP-lowering medications must have a start date 
of ≥ 3 months prior to Screening date and dosage is not expected to change during the 
study.  The type of medication will be recorded at the Screening visit along with other 
concomitant medications; 
11. Ability to follow study instructions and likely to complete all required visits. 
 
Additional Inclusion Criteria for EDE Classification: 
• 
Tear Evaporation Rate (TER) ≥ 110 (TBC) 

 
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Additional Inclusion Criteria for non-EDE Classification: 
• 
Tear Evaporation Rate (TER) < 110 (TBC) 
 
 
For patients who have one eye meeting EDE criteria, and other eye meeting non-EDE 
 
criteria, their Schirmer score will be used to determine the classification.  If their Schirmer 
 
score is >10 in both eyes, they will be classified in the EDE group. 
 
7.1.2. Exclusion Criteria  
 
  
The following are criteria for exclusion from participating in the study: 
1. Schirmer test (with anesthesia) ≤ 2 mm in either eye at Screening; 
2. Patients who are currently using topical ocular medication or have used topical ocular 
medication within 2 weeks of the Screening visit. Patients who are being treated 
bilaterally with a marketed artificial tear for dry eye can be considered, provided they 
discontinue use at the Screening visit; 
3. Any active anterior segment disease excluding blepharitis; 
4. Any systemic disease that may affect ocular health e.g. Graves disease, and auto-
immune diseases such as ankylosing spondylitis, multiple sclerosis and systemic lupus 
erythematosus; 
5. History of epilepsy or migraines exacerbated by flashing, strobe-like lights; 
6. Rigid or soft contact lens wearer, including orthokeratology; 
7. History of eye surgery within 6 months prior to enrolment in the study; 
8. Previous corneal refractive surgery; 
9. Known allergy or sensitivity to the study product(s) or its components; 
10. Females who are pregnant (self-report), nursing, or planning a pregnancy. 
 
 
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 an adverse event that is related to the study eye drops 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; 

 
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 
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 eye drops for a final visit to assess participant 
safety and to return any unused study eye drops. This may be done at a routine clinic 
visit or an unscheduled visit if it occurs between routinely scheduled visits. 
 
 
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 4 week assessment (Visit 4c) 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 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 

 
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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 Screening will be replaced, until the enrolment target is 
reached. 
 
 
 
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 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. 
 
 
 
 
8. NUMBERING  
 
Participant numbering will occur sequentially commencing with ‘001’.   
 
 
 

 
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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 using standard letter charts. Measurements are taken under 
monocular conditions. 
 
 
Slit-Lamp Biomicroscopy:  A specialised microscope with its own light 
source is used to examine the anterior eye including the Meibomian glands. 
 
 
Fluorescein Assessment:  The ocular surface is assessed by instilling a 
harmless fluorescent dye called ‘fluorescein’ directly to the inferior bulbar 
conjunctiva using a sterile strip impregnated with fluorescein and moistened 
with sterile saline. The eye is assessed with the slit-lamp biomicroscope using 
a cobalt blue filtered light and a Wratten 12 filter. 
 
 
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. 
 
 
Questionnaires:  Questions assessing eye symptoms and product usage will 
be administered on paper forms. 
 
 
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 will be performed include: 
 
 
Tear Evaporation Rate:  The Vapometer is a closed chamber device which is 
used for measuring transepidermal water loss. 
 
 
Tear Collection: A sample of tears will be taken from each eye using Schimer 
strips.  
 
 
Photography/Video:  A photograph of the eye will be taken at the first visit, 
and photographs and video recording of any interesting/unusual findings may 
also be made for documentation and/or follow-up purposes at other visits. 
 
 
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 Eye Drops 
 
The study eye drops will be dispensed to each randomized subject at Visits 
2a, 3a and 4a. Run-in product will be dispensed at Visits 1, 2c and 3c.  Each 
subject will be instructed by the investigator to instill 1 to 2 drops in each eye, 
as needed, but at least 2 times daily.  The same vial can be used for both 
eyes, and should be used one time only.  The vial should be discarded after 
each usage. If the subject is concurrently using approved Restasis or 
glaucoma therapy drops during the study and run-in period, they should be 
instructed to wait a minimum of 15 minutes between drop instillations. 
Subjects should be instructed not to instill any eye drops within 3 hours prior 
to their scheduled study visits. 
 
  
10.2. Study Product Storage and Accountability 
 
10.2.1. Storage Requirements 
 
 
 
 
The study product must be stored in a secure area.  Only assigned study  
 
 
 
personnel authorized by the investigator may have access to study product.  
 
 
 
Study product  can be administered only to subjects entered into the clinical 
 
 
 
study, at no cost to the subject, in accordance with the conditions specified 
 
 
 
in this protocol.  
Study product must be stored at room temperature. 
 
 
10.2.2. Accountability 
 
A Study Product Tracking spreadsheet is used for keeping track of who, 
where and when study product has been issued or dispensed to.  
 
 
Receipt of Study Product:  Once invoice has been checked, the study 
eye drops 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 and in the Study Product 
Tracking spreadsheet. 
 
Disposal of Unused Supplies:  Instruction will be obtained from the 
sponsor as to how to handle returned, unused study product. 

 
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10.3. Concomitant Therapy 
 
10.3.1. Permissible Medications/Treatments 
 
Therapy considered necessary for the subject's welfare may be given at the 
discretion of the investigator.  Systemic medications that do not cause or affect dry 
eye, dry mouth, changes in vision or other ocular changes are considered 
permissible medications.  No topical ocular medication is allowed during the study, 
except for subjects meeting all inclusion and exclusion criteria for their use of 
monotherapy for glaucoma or OHT, or RESTASIS cyclosporine ophthalmic 
emulsion drops.  Subjects using monotherapy for glaucoma or OHT, or RESTASIS, 
should continue to use their drops at the same dose and frequency for the duration 
of the study.  If the permissibility of a specific medication/treatment is in question, 
please contact Allergan. 
 
10.3.2. Prohibited Medications/Treatments 
 
 
 
Contact lens use is prohibited during the study.  Subjects are not allowed to have 
 
 
any scheduled or planned ocular or systemic surgery or procedure during the study 
 
 
that in the investigator’s opinion may inhibit the subject’s study participation.  
 
 
Subjects are not allowed to receive temporary or permanent occlusion or   
 
 
cauterization of the lacrimal puncta during the study.  After Screening, subjects  
 
 
should not begin or stop the use of any systemic medications that may affect a dry 
 
 
eye condition or affect vision (e.g. may cause blurred vision, cataracts, or   
 
 
glaucoma).  Sites should look up the potential adverse reactions of each medication 
 
 
to ensure they do not fall within these exclusionary drug families.  In addition,  
 
 
subjects should not begin using any topical ophthalmic medications such as topical 
 
 
cyclosporines, ophthalmic steroids, or glaucoma drops while enrolled in the study.   
 
  
The decision to administer a prohibited medication/treatment is done with the safety 
 
  
of the study participant as the primary consideration.  When possible, Allergan  
 
  
should be notified before the prohibited medication/treatment is administered 
 
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 
 Use the study eye drops provided only as instructed over the course of the study 
 Instill 1 to 2 drops in each eye, as needed, but at least 2 times daily 
 The same vial can be used for both eyes, and should be used one time only. The 
vial should be discarded after each usage. 

 
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11. ASSESSMENT OF EFFICACY 
 
11.1. Parameters  
 
 
Subjective comfort 
 
History 
 
Visual acuity 
 
Eye photo 
 
Tear evaporation rate 
 
Lipid layer thickness 
 
Tear break-up time 
 
Bulbar conjunctival redness 
 
Corneal and conjunctival staining 
 
Tear film collection 
 
Product usage 
 
 
11.2. Methods 
 
Ocular comfort will be assessed by completion of paper-based questionnaires 
(Ocular Surface Disease Index and Visual Analogue Scales). 
 
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. 
 
A photograph of the anterior eye will be taken at the Screening visit only for 
participants who are eligible to continue into the randomization phase of 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.  
 
Tear lipid layer thickness will be measured using the LipiView Ocular Surface 
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 

 
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interferometric colour units (ICU), where 1 ICU approximates 1nm of lipid layer 
thickness 
 
Slit lamp biomicroscopy will be performed at each visit. This will be used to assess 
the following variables and rated using the CCLRU (Appendix II) and CIBA grading 
scales (Appendix III). 
 
Bulbar conjunctival redness 
 
Corneal and conjunctival staining (in conjunction with fluorescein and a 
Wratten 12   filter) 
 
Tear break-up time (TBUT) will be performed with the application of fluorescein 
and a yellow barrier filter. A stopwatch will be used to record the first occurrence of 
true tear break-up, not just local thinning or tear film irregularity. Three consecutive 
TBUTs will be performed per eye and the time in seconds for each of the three 
measurements will be recorded.  
  
Small volumes of tears will be collected using Schirmer strips. A single Schirmer 
strip will be placed in the lower outer canthus of each eye for 5 minutes. Upon 
removal of the Schirmer strips, the tear volume in millimetres (mm) will be 
recorded. Strips from the left and right eyes will be stored in separate vials in -80 
ºC until processed for either tear lipidome characterization using mass 
spectrometry or peroxidised lipids levels using ELISA. 

 
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12. ASSESSMENT OF SAFETY 
 
12.1. Parameters 
 
 
Discomfort 
 
History 
 
Habitual visual acuity 
 
Biomicroscopy  
 
Corneal and conjunctival staining 
 
 
12.2. Methods 
 
Discomfort 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 redness (bulbar) and corneal and conjunctival staining 
will be assessed and recorded using the CCLRU (Appendix II) and CIBA grading 
scales (Appendix III). 
 
An optometrist will be available for the duration of the study. Participants will be 
advised to contact the optometrist immediately of any unusual event 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 
 
The principal investigator, or designated personnel determined to be 
medically qualified by the principal investigator, will question the subject 
about adverse events.  All adverse events will be documented.   

 
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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.   
 
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 immediately cease 
use of the study eye drops and contact the clinic. 
Non-serious adverse events should be recorded as part of Good Clinical Practice. 
 
All Serious Adverse Events (SAEs) will be reported to the Co-Sponsor (Allergan) 
within 24 hours of first knowledge of the event, even if the information is incomplete, 
using the SAE report form. This procedure is required regardless as to the causal 
relationship to the study eye drops and also relates to SAEs which are 
spontaneously reported to investigators from patients taking Allergan products 
which are not being investigated as part of the study. 
 
 
 
 
 
 
Allergan Serious Adverse Event Reporting 
Fax Number(s): 
+1-714-796-9504 
(Back Up Fax No.: +1-714-246-5295) 
Allergan Medical Safety Physician Contact Information: 
Undraa Altangerel, MD 
Tel (office): 1-908-203-2633 
Cell or Mobile Phone: 1-908-255-5912 
FAX (office): 1-714-571-2587 
Email address: Altangerel_Undraa@Allergan.com 
 
SAEs will also be reported to the HREC as per their reporting requirements and to 
other regulatory authorities as applicable under local regulations. This should be 
followed by a more detailed written report commenting on potential confounding 
factors, results of investigations, treatment required and outcome.  The Sponsor 

 
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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.  
 
The investigator agrees to provide written notice to Allergan of any SAEs before 
publishing any such findings.  
 
All other adverse events should be reported to the Sponsor no later than 10 days 
after the event.  
 
 
12.4.1. Foreseeable Adverse Events  
 
Risks associated with the use of the study products are likely to be allergic 
in nature and include: 
 
• Eye irritation (<1%) 
• Eye itching (<1%) 
• Eye/eyelid swelling (<1%) 
• Eye redness (<1%) 
 
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 eye drops will be detrimental to ocular health. 
 
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 
 
Up to 40 participants will be recruited (approx. 20 EDE and 20 non-EDE subjects). 
This sample size was calculated on the basis of detecting a difference in:  
tear evaporation rate between the eye drops of 36 gm-2/h where the expected 
standard deviation of the measurement is 50 gm-2/h, assuming  an estimate of type 1 
error α =0.05 and power of 80% for a two tailed test. 
 
 
 
 
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 the Screening visit will be reported.  The analysis of efficacy 
variables such as subjective ratings will employ only scheduled and 
evaluable visits. The analysis of safety variables such as adverse responses 
will include all visits, including all unscheduled visits.  
 

 
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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. Mann Whitney U test will 
be used to compare tear film lipidome between the eye drops. 
 
 
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 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. 
 

 
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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. 
 
 
15.1.3. Protocol Amendments 
 
It is agreed between the 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 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 (e.g. 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 

 
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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. 
 
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 
 
CCLRU GRADING SCALES 
 
 

 
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APPENDIX II:  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 III 
 
CIBA GRADING SCALES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX III:  CIBA Grading Scales 
SLIT-LAMP QUANTIFICATION CHART 
 
BIOMICROSCOPY SIGNS 
 
Bulbar 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 
 
Epithelial 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