The Effect of Manuka Eye Drops on Tear Film Properties
Phase: NA
Conditions: Dry Eye Syndrome
Sponsor: The University of New South Wales

 
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CLINICAL TRIAL PROTOCOL 
 
 
 
Protocol Title - Long: 
The Effect of Manuka Eye Drops on Tear Film Properties 
Protocol Title - Short: 
The effect of Manuka eyedrops on the tear film  
Protocol ID Number: 
SOVS2018-501 
Amendment Number: 
N/A 
Version Date: 
21st March 2018 
 
 
 
 
 
School of Optometry and  
Vision Science 

 
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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, Sub-Investigator 
 
Date 
 
 
 
 
 
 
Fiona Stapleton, Principal Investigator  
 
Date 
 
 
 
 
 
 
 
 
 

 
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SPONSOR 
Sponsor: 
 
Address: 
 
University of New South Wales (UNSW) 
 
Sydney, NSW 2052 
Australia 
 
SUMMARY OF FINAL PROTOCOL & AMENDMENTS 
Initial/ 
Amend # 
Version Date 
Author 
Main Changes 
Final 
21 March 2018 
Jacqueline Tan 
N/A 
A1 
 
 
 
A2 
 
 
 
A3 
 
 
 

 
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TABLE OF CONTENTS 
 
1. 
PROTOCOL SYNOPSIS .......................................................................................................................... 6 
2. 
INVESTIGATOR(S) .................................................................................................................................. 8 
3. 
MEDICAL EXPERT .................................................................................................................................. 9 
4. 
BACKGROUND INFORMATION ............................................................................................................ 10 
4.1 Product .......................................................................................................................................... 10 
4.2 Summary ....................................................................................................................................... 10 
4.2.1. Risks and Benefits ............................................................................................................... 10 
4.2.2. Treatment Rationale ............................................................................................................ 10 
4.2.3. Guidelines and Regulations ................................................................................................ 11 
4.2.4. Trial Population ................................................................................................................... 11 
5. TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS ................................................................................ 12 
5.1. Trial Objective ............................................................................................................................... 12 
5.2. Clinical Hypothesis ........................................................................................................................ 12 
6. TRIAL DESIGN ........................................................................................................................................... 13 
6.1. Methodology / Study Visits ............................................................................................................ 13 
6.1.1. Data Requirements per Visit ............................................................................................... 13 
6.1.2. Randomisation and Masking ............................................................................................... 14 
6.1.3. Clinical Trial Population ....................................................................................................... 15 
6.1.4. Trial Duration ....................................................................................................................... 15 
6.1.5. Enrolment ............................................................................................................................ 15 
6.2. Primary Endpoint ............................................................................................................................ 15 
6.3. Secondary Endpoint(s) .................................................................................................................. 15 
SELECTION AND WITHDRAWAL OF PARTICIPANTS ................................................................................ 16 
7.1. Participant Selection ...................................................................................................................... 16 
7.1.1. Inclusion Criteria .................................................................................................................. 16 
7.1.2. Exclusion Criteria ................................................................................................................ 16 
7.2. Participant Withdrawal ................................................................................................................... 17 
7.3. Withdrawal and Follow-up Procedure ........................................................................................... 17 
7.4. Early Termination of Trial .............................................................................................................. 17 
8. 
NUMBERING .......................................................................................................................................... 17 
9. 
EQUIPMENT TO BE USED / STANDARD & NON-STANDARD PRACTICE PROCEDURES ............. 18 
9.1. Standard Equipment and Procedures: .......................................................................................... 18 
9.2. Non-Standard Equipment and Procedures: .................................................................................. 18 
9.3. Maintenance and Calibration of Equipment .................................................................................. 18 
10. TREATMENT OF PARTICIPANTS ........................................................................................................ 19 
10.1. 
Administration of drops ............................................................................................................ 19 
10.2. 
Drop Storage and Accountability ............................................................................................. 19 
10.2.1. Storage Requirements ...................................................................................................... 19 
10.2.2. Accountability .................................................................................................................... 19 
10.3. 
Concomitant Therapy .............................................................................................................. 19 
10.4. 
Participant Instructions ............................................................................................................ 19 
11. ASSESSMENT OF EFFICACY .............................................................................................................. 20 
11.1. 
Parameters .............................................................................................................................. 20 
11.2. 
Methods ................................................................................................................................... 20 

 
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12. ASSESSMENT OF SAFETY .................................................................................................................. 21 
12.1. 
Parameters .............................................................................................................................. 21 
12.2. 
Methods ................................................................................................................................... 21 
12.3. 
Definitions ................................................................................................................................ 21 
12.3.1. Adverse Events ................................................................................................................. 21 
12.3.2. Serious Adverse Events .................................................................................................... 21 
12.3.3. Significant Adverse Events ............................................................................................... 23 
12.3.4. Non-Significant Adverse Events ........................................................................................ 23 
12.3.5. Unanticipated Adverse Events .......................................................................................... 23 
12.3.6. Event Severity ................................................................................................................... 23 
12.4. 
Reporting ................................................................................................................................. 23 
12.4.1. Expedited Reporting .......................................................................................................... 24 
12.4.2. Foreseeable Adverse Events ............................................................................................ 24 
12.4.3. Other Observations ........................................................................................................... 24 
12.5. 
Follow-up ................................................................................................................................. 25 
12.6. 
Referrals .................................................................................................................................. 25 
13. STATISTICS ........................................................................................................................................... 26 
13.1. 
Description ............................................................................................................................... 26 
13.1.1. Number of Participants ...................................................................................................... 26 
13.1.2. Significance ....................................................................................................................... 26 
13.1.3. Analysis ............................................................................................................................. 26 
13.2. 
Criteria for Termination of the Trial .......................................................................................... 26 
13.3. 
Accountability of Data .............................................................................................................. 26 
14. DATA HANDLING AND RECORD KEEPING ........................................................................................ 27 
14.1. 
Source Data ............................................................................................................................. 27 
14.2. 
Direct Access to Source Data/Documents .............................................................................. 27 
14.3. 
Data Management ................................................................................................................... 27 
14.4. 
Data Archiving ......................................................................................................................... 27 
14.5. 
Retention of Essential Documents .......................................................................................... 27 
15. QUALITY CONTROL AND QUALITY ASSURANCE ............................................................................. 28 
15.1. 
Ethical Considerations ............................................................................................................. 28 
15.1.1. Confidentiality .................................................................................................................... 28 
15.1.2. Informed Consent .............................................................................................................. 28 
15.1.3. Protocol Amendments ....................................................................................................... 28 
15.1.4. Investigator Responsibilities .............................................................................................. 29 
16. FINANCING AND INSURANCE ............................................................................................................. 30 
17. PUBLICATION POLICY ......................................................................................................................... 30 
REFERENCES ................................................................................................................................................ 36 
 
 

 
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1. PROTOCOL SYNOPSIS 
 
Table 1: 
Protocol synopsis 
Protocol Title 
The Effect of Manuka Eye Drops on Tear Film Properties 
Protocol ID Number 
SOVS2018-501 
Trial Classification 
Evaluation 
Investigator(s)/Site(s) 
Eye Research Group @ SOVS 
The University of New South Wales 
Sydney, Australia 
Overall Duration of Trial 
4 months 
Number of Trial Participants 
Planned 
48 
Planned Start Date 
June 2018 
Primary Objective 
To compare the effect on tear film properties and dry eye signs and 
symptoms of Optimel Manuka eye drops compared to Systane Ultra 
tear supplement after one month of daily use.  
Secondary Objectives 
• 
To compare the effect on ocular signs and symptoms. 
Primary Safety Variable(s) 
Visual acuity 
Biomicroscopy: ocular redness, corneal details and staining 
Primary Efficacy/Performance 
Variable 
Lipid layer thickness, tear evaporation rate and fluorescein tear 
breakup time up 
Experimental design  
 Retrospective 
 Prospective 
 Single masked (Trial Participant) 
 Single masked (Investigator) 
 Double masked 
 Sponsor masked 
 Open label 
 Other: randomised 
 Single group 
 Multiple group 
 Parallel group 
 Cross over 
 Contralateral 
Study product details - test 
Name 
Optimel™ Manuka+™ Dry Eye Drops 
Manufacturer 
Melcare Biomedical Pty Ltd 
Study product details - control 
Name 
Systane Ultra 
Manufacturer 
Alcon Laboratories 
Inclusion criteria 
o Able to read and comprehend English and give informed consent 
as demonstrated by signing a record of informed consent; 
o General population aged 18 years and over; 
o In good general health; 
o Subjectively experiencing dry eye symptoms (e.g. burning, 
irritation, and discomfort due to dryness of the eye or exposure to 
wind or sun). Participants will be selected based on a minimum 
OSDI score of 13 points (1). 
o Willing to discontinue CL wear for 1 week before first visit and 
continue to do so until the conclusion of the study; 
o Participant is willing to discontinue their use of any previous 
conventional dry eye treatment method commenced before the 
study throughout the study; 
o Willing to comply with the dosage and study visit schedule as 
directed by the investigator; 
o No planned changes to diet and willing not to substantially alter 

 
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their usual diet for the duration of the study, including their typical 
intake of fish, green tea or oral supplements known to have anti-
inflammatory properties; 
o Willingness to notify the study investigator if instructed to alter their 
diet by health/medical practitioner.  
Exclusion criteria 
 
 
o 
Allergy to benzoic acid preservatives; 
o 
Allergy to honey products; 
o 
Active anterior eye disease/ infection, inflammation/allergy that 
requires ocular medical treatment; 
o 
Eye injury or surgery in the past 6 months  including chemical 
burns, penetrating injuries, traumatic iritis, orbital fractures, laser 
surgery, strabismus surgery, cataract or any other intraocular 
surgeries; 
o 
Soft contact lens, rigid gas permeable, orthokeratology lens 
wearer within one week prior to the study and during the study. 
o 
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: 
-         Ocular medication, category S3 and above; 
-         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; 
o 
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; 
o 
Epilepsy or history of migraines exacerbated by flashing, strobe-
like lights; 
o 
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. 
 
Human Research Ethics 
Committee Status /  
Regulatory Status  
This trial requires Human Research Ethics Committee approval prior 
to study initiation, any advertising, and participant consent/enrolment. 
The study products are commercially available in Australia and are 
approved by the Therapeutic Goods Administration. 
 

 
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2. INVESTIGATOR(S) 
 
Table 2: List of investigators 
Name: 
Jacqueline Tan 
Title: 
Senior Research Fellow  
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: 
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: Medical Expert 
Name: 
Emergency Department 
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 
Optimel Manuka eye drops (MelCare Biomedical Pty Ltd., Australia) is at present the only 
available manuka based eye drop commercially available in Australia. It is available both as 16% 
eye drop as well as 98% gel form 1. Presently, a growing number of studies are exploring ocular 
benefits of the drop, based on extensive evidence of antimicrobial, antioxidant, and anti-
inflammatory effects of Manuka honey 2-4.  
Systane Ultra lubricant eye drops (Alcon Laboratories, Inc., Forth Worth, Tx) is a new generation 
ocular lubricant that has been developed with a unique intelligent delivery system for the treatment 
of dry eye symptoms.5, 6 It is an aqueous solution composed of polyethylene glycol (0.4%) and 
propylene glycol (0.3%) as demulcents and incorporates the benefits of hydroxypropyl guar as 
gelling agent.  
4.2 
Summary 
This study is potentially significant in its demonstration of the benefits of Manuka honey eye drops 
in altering the physiological properties of the tear film, thereby improving ocular comfort and 
reducing dry eye. These findings will aid in informing practitioners about the benefits of considering 
Manuka eye drops in the alleviation and treatment of dry eye disease, whilst adding credibility to 
the Optimel Manuka eye drops range and growing its potential market opportunities globally. 
4.2.1. Risks and Benefits 
 
Risks of the Clinical Trial 
 
Although unlikely, it is possible that participants may be allergic to any of the ingredients in the 
study eye drops. Signs of ocular allergy include swelling, redness, itching and watering of the 
eyes. Subjects with a known allergy to the study eye drops will not be enrolled. Subjects who 
experience an allergic reaction will be treated by thoroughly rinsing the eye with preservative free 
unit-dose saline, continuous monitoring until ocular signs and symptoms have returned to normal, 
and immediate discontinuation from the study. Subjects may also be referred to the Sydney Eye 
Hospital for treatment, if required. 
 
Benefits of the Clinical Trial 
 
There is no guarantee or promise that the participants will receive any benefits from this clinical 
trial.  
4.2.2. Treatment Rationale 
This is a prospective, randomized, double-masked, single centre study. All eligible participants 
were randomized into one of the treatment groups. One group received Optimel Manuka eye 
drops (Leptospermum spp. honey 160 mg/g, water, sodium chloride, benzoic acid 0.2 per cent) 
(Optimel 16 percent), (Melcare, Australia) and the other group received a non-lipid based 
conventional ocular lubricant, Systane Ultra (Polyethylene Glycol 400 0.4%, Propylene Glycol 
0.3%, aminomethylpropanol, boric acid, hydroxypropyl guar, POLYQUAD® (polyquaternium-1) 
0.001% preservative, potassium chloride, purified water, sodium chloride, sorbitol)(Alcon 

 
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Laboratories, USA). Participants were asked to instill one drop into each eye, three times a day for 
twenty-eight days (±4 days). 
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 
Thirty-eight (38) participants aged 18 years or above who were assessed to have mild to severe 
dry eye are required to complete the study. Taking into consideration a 20% drop out rate, 
approximately 48 subjects will be enrolled in this study. 
 
 
 
 

 
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5. TRIAL OBJECTIVES AND CLINICAL HYPOTHESIS 
5.1. Trial Objective 
To compare the effects of Optimel Manuka eye drops and Systane Ultra on symptomology 
assessed using the OSDI questionnaire, and objective tear film properties such as lipid layer 
thickness and tear break-up time will be measured 4 weeks after use of treatment drops in dry eye 
participants.  
5.2. Clinical Hypothesis 
We hypothesize that the:  
- 
Measurable differences in the subjective symptomatology and in objective tear film 
parameters will be apparent after 4 weeks of use with the Optimel Manuka and Systane 
Ultra eye drop treatments. 

 
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6. TRIAL DESIGN 
 
This will be a prospective, randomized, single centre, double-masked, randomized dispensing 
study. There will be 2 visits in total:  
(i) 
Baseline (Week 0): Screening, randomization, informed consent, habitual visual 
acuity, OSDI, symptom survey, biomicroscopy, tear film assessment and 
dispensing eye drops. 
(ii) 
28 days of treatment ± 4 days (Week 4): habitual visual acuity, OSDI, symptom 
survey, biomicroscopy, tear film assessment and study exit.  
 
Standard ocular examination and non-standard ocular examination procedures will be carried out 
at the scheduled visits. 
 
Standard optometric procedures at each visit include: 
 
o Habitual visual acuity 
o Slit lamp evaluation including corneal details  
o Subjective questionnaire: Ocular Surface Disease Index (OSDI) 
o Tear breakup time 
o Tear lipid layer thickness 
Non-standard optometric procedures may include: 
 
o Tear evaporation rate  
6.1. Methodology / Study Visits 
6.1.1. Data Requirements per Visit 
 
This study requires 2 visits of approx. 1-hour duration each. The data requirements for each visit 
are shown in Table 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 4: Data requirements 
 
Procedures/ Data (Y/N) 
 
Visit 1 
Screening / Baseline 
Visit 2 
28 days ± 4 days 
Informed Consent 
Y 
N 
Meet Inclusion/Exclusion Criteria 
Y 
N 
Ocular and Medical History, Medications, Demographics 
Y 
Y 
Vision Tests (Visual Acuity) 
Y 
Y 
Randomization (to eye drop) 
Y 
N 
Slit-Lamp Biomicroscopy 
Y 
Y 
Subjective questionnaire 
Y 
Y 
Tear evaporation rate 
Y 
Y 
Tear break-up time 
Y 
Y 
Tear lipid layer thickness 
Y 
Y 
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.  
 
Participants will be randomly assigned to the eye drop type to be dispensed (Optimel Manuka+ 
16% eye drops or Systane Ultra eye drops). A randomization scheme will be prepared in advance.  
 
The Investigator will provide instructions to the study participants as to the drop instillation 
technique but will not be cognizant to the randomisation schedule and will not be present during 
the drop dispensation to maintain masking.   

 
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6.1.3. Clinical Trial Population 
A total of 46 participants with dry eye disease will be required to complete 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, and previous study participants and/or Optometry Clinic 
patients 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 requires 2 visits of approx. 1-hour duration each. The study duration for each participant 
will be approximately 28 days.  
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 lipid layer thickness between Optimel 
Manuka eye drops and Systane Ultra eye drops after 4 weeks of daily use. 
6.3. Secondary Endpoint(s) 
The secondary endpoints are: a measurable difference in tear parameters such as tear breakup 
time and tear evaporation rate, and subjective symptoms after 4 weeks of daily use.  

 
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SELECTION AND WITHDRAWAL OF PARTICIPANTS 
7.1. Participant Selection  
 
Participants with dry eye disease will be enrolled. Informed consent will be obtained prior to any 
clinical trial procedures being conducted. 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; 
 Adults aged 18 years and over with symptoms of dry eye; 
 Ocular Surface Disease Index score of >12 at Screening; 
 Not wearing contact lenses for 1 week prior to the study and for the duration of the study; 
 Willing to use the study eye drops and refrain from using any other eye drops for the 
duration of the study; 
 Willing to refrain from using the study eye drops within 4 hours prior to each study visit; 
 Willing to comply with the study visit schedule and adhere to instructions as directed by the 
Investigator.  
7.1.2. Exclusion Criteria  
 
Any active anterior segment disease excluding blepharitis; 
 
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. 
 
Use of any polyunsaturated fatty acid-containing dietary supplements (such as fish oil, 
evening primrose oil, linseed oil) for less than 12 weeks prior to the start of the study; 
 
Planned changes to intake of polyunsaturated fatty acid-containing dietary supplements 
and/or diet (including typical intake of fish) for the duration of the study; 
 
Use of any at-home eyelid warming treatments for less than 12 weeks prior to the start of 
the study, or planned changes to routine usage over the course of the study; 
 
Use of any of the following dry eye treatments up to 6 months prior to the start of the study 
or during the course of the study: 
o Intense Pulsed Light (IPL) therapy; 
o Blephasteam; 
o LipiFlow Thermal Pulsation treatment; 
o Punctal plugs. 
 
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; 
 
History of eye surgery within 6 months prior to enrolment in the study; 

 
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 
Epilepsy or history of migraines exacerbated by flashing, strobe-like lights; 
 
Any known allergy to the ingredients in Systane Complete; 
 
Pregnancy or breastfeeding. 
 
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 event that is eye related and/or which, in 
the Investigator’s opinion, requires withdrawal of the participant; 
 
Participant voluntarily withdraws consent from the clinical trial (i.e. Revocation of 
Consent); 
 
If a participant is not compliant with the clinical trial requirements and instructions; 
 
Protocol violations/deviations. 
7.3. Withdrawal and Follow-up Procedure  
This study comprises four visits for each participant. Any participants who wish to be withdrawn 
from the study will be exited upon request. 
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 or 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 ‘01’.   
 
 
 

 
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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 and/or binocular 
conditions. 
 Slit-Lamp Biomicroscopy:  A specialised microscope with its own light source is used to 
examine the anterior eye. 
 Subjective questionnaire: The “ocular surface disease index” questionnaire will be 
administered. This consists of 12 questions relating to the participant’s dry eye symptoms.  
 Lipid layer thickness: The LipiView® Ocular Surface Interferometer (TearScience®) 
measures the absolute thickness of the tear film lipid layer by analyzing more than one 
billion data points of the interferometric image of the tear film. The patient’s eye is 
positioned in front of an illumination source that is directed toward the tear film on the 
corneal surface. Light from this source passes through the tear film and is specularly 
reflected into a camera. The camera records a 20-second video of the tear film interference 
and subsequently displays a value in interferometric colour units (ICUs) where 1 ICU 
approximates 1 nm of lipid layer thickness. 
 Tear Break-Up Time: Following instillation of fluorescein, tear break up time will be 
measured. 
 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. 
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.  
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 drops 
 
The Investigator will provide instructions to the study participants as to the drop instillation 
technique but will not be cognizant to the randomisation schedule and will not be present during 
the dispensing of the drops to maintain masking.   
10.2. Drop Storage and Accountability 
10.2.1. Storage Requirements 
Drops will be stored at room temperature in a secure storeroom/cupboard. The storage facility 
should be kept locked to prevent unauthorized access and to ensure accountability of the study 
lenses at all times. 
10.2.2. Accountability 
An Eye Drop Tracking spreadsheet is used for keeping track of who, where and when drops have 
been issued or dispensed to.  
 
Receipt of drops:  Once invoice has been checked, the drops will be entered into the Eye 
Drop Tracking spreadsheet. 
 
 
Issue of Drops to Clinical Trial Participants:  The Optometrist is responsible for 
documenting the dispensing of the drops on the Eye Drop Tracking spreadsheet. 
 
Disposal of Unused Supplies:  Instruction will be obtained from the Sponsor as to how to 
handle returned, unused drops. 
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. 
 
Participants will be instructed to refrain from wearing contact lenses for 1 week prior to the study 
and for the duration of the study. 
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. 
 

 
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11. ASSESSMENT OF EFFICACY 
11.1. Parameters  
A measurable difference in subjective symptoms and/or objective tear lipid layer thickness or tear 
breakup time between Optimel Manuka eye drops and Systane Ultra Eye drops after 4 weeks of 
daily use. 
 
11.2. Methods 
Subjective symptoms will be measured using the OSDI questionnaire. 
 
Tear film inferior lipid layer thickness (LLT; nm) will be measured using the LipiView II (Johnson 
and Johnson Vision, USA). 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. 
 
Fluorescein tear break-up time (TBUT; sec) (Opti-Strip-FL, Optimed, Lane Cove West, NSW, 
Australia) was measured viewed with a yellow Wratten filter (No. 12, Kodak) and cobalt light of the 
slit lamp biomicroscope. Three consecutive TBUT measurements for each eye were taken by a 
single masked investigator. 
 

 
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12. ASSESSMENT OF SAFETY 
12.1. Parameters 
 
Visual acuity  
 
History 
 
Ocular health 
 
Corneal staining 
 
12.2. Methods 
Visual acuity will be measured using standard letter charts. The study participant’s habitual visual 
acuity will be assessed. 
 
History (including medical and general health) will be recorded at the study visit. 
 
Slit lamp biomicroscopy will be assessed to evaluate ocular surface health.   
 
An optometrist will be available for the duration of the study. Participants will be advised to contact 
the Optometrist immediately of any event not normal 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, that includes a clinical sign, 
symptom or condition and/or observation of an unintended technical performance or performance 
outcome. 
 
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. 

 
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- 
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.   
 
Specifically for the eye, Serious Adverse Events include but are not limited to: 
 
permanent decrease in best-corrected visual acuity (≥2 lines) 
 
central corneal opacities 
 
central corneal neovascularisation – in the central 4mm of the cornea 
 
central corneal opacities – in the central 4mm of the cornea 
 
infectious corneal ulcers 
 
uveitis 
 
iritis 
 
endophthalmitis 
 
hypopyon 
 
hyphema 
 
penetration of bowman’s membrane 
 
persistent epithelial defect 
 
limbal cell damage leading to conjunctivalisation. 
 
 
Serious adverse events are reportable. 
 
 
 

 
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12.3.3. Significant Adverse Events 
 
Significant Adverse Events are those that are symptomatic (excluding serious adverse events 
noted above).  They include, but are not limited to: 
 
 
Infiltrative keratitis: Inflammatory reaction of the cornea characterised by anterior stromal 
infiltrates with or without epithelial involvement. Symptoms include mild to moderate irritation, 
and redness. Staining may be slight to moderate. 
 
 
Conjunctivitis: Inflammatory reaction of the conjunctiva characterised by discharge, grittiness, 
redness and swelling. 
 
 
Corneal Erosion: Full thickness epithelial loss over a discrete area.    
 
12.3.4. Non-Significant Adverse Events 
 
Non-significant Adverse Events are those that treatment, if needed, is usually with over the 
counter products. They include, but are not limited to: 
 
asymptomatic infiltrative keratitis 
 
blepharitis 
 
meibomitis 
 
contact dermatitis 
 
localised allergic reactions. 
 
12.3.5. Unanticipated Adverse Events 
Adverse events or serious adverse events are considered “unexpected” or “unanticipated” if they 
do not appear listed in the technical manuals to date. These events require expedited reporting. 
 
12.3.6. Event Severity 
Events should be rated by a study investigator according to their severity: 
Mild:  
No treatment required 
Moderate:   
Treatment required. 
Severe:  
Requires referral to and treatment by an ophthalmologist. 
 
 
 
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 contact the investigators immediately. 
 

 
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Non-serious and anticipated 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 events. 
 
All Serious Adverse Events should be reported 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.   
 
12.4.1. Expedited Reporting 
UNSW, via the Principal Investigator (PI) of the clinical trial is required to report to the Therapeutic 
Goods Administration (TGA) single cases of serious and unanticipated adverse events.   
 
Fatal or life-threatening unexpected adverse events – the TGA 
should be notified as soon as possible but no later than 7 calendar days after first knowledge 
by the PI that the case qualifies, followed by a complete report as possible within eight 
additional calendar days. 
 
All other serious, unexpected adverse events – TGA notification as 
soon as possible but no later than 15 calendar days after first knowledge by the PI that the 
case meets the minimum criteria for expedited reporting. 
 
In the case of an unexpected and serious adverse event that occurs outside Australia with use of 
the same product, the TGA and HREC should also be notified. The time frame for this reporting 
should be within 72 hours of any significant safety issue which has arisen from an analysis of 
overseas reports or action which has been taken by another country’s regulatory agency. This 
advice must include the basis for such action. Investigators should also be notified, who must in 
turn notify the HREC. 
  
Reports should be on the ‘Medical Incident Report Form’ located on the TGA website 
(http://www.tga.gov.au/docs/html/forms/iris_mdir.htm) or similar format, and clearly marked 
‘Clinical Trial Adverse Event’ and sent to: 
 
 
 
 
 
The Medical Officer 
 
 
 
Office of Devices, Blood and Tissues 
 
 
 
Therapeutic Goods Administration 
 
 
 
PO Box 100 
 
 
 
Woden  ACT  2606 
12.4.2. Foreseeable Adverse Events  
Risks associated with the use of the study eye drops include: 
 
 Eye discomfort/stinging (<30%) 
 Eye redness (<10%) 
 Blurry vision (<10%) 
12.4.3. 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 

 
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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 will be discontinued from the study and followed 
up until the condition resolves or the participant is referred to another practitioner.   
 
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 5). 
 
 
 
 
Table 5: Sydney Eye Hospital 
 
Title: 
Emergency Department 
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. Data will be investigated for quality using 
range checks and frequency distribution. Underlying distributions of variables will be tested. 
Details of statistical analysis are described in Section 13.1.3.  
13.1.1. Number of Participants 
38 participants will be required to complete the study.  
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 complete the study treatment will be included in the analysis dataset. Reasons 
and frequency distribution of participants discontinued will be reported.   
 
 
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 in tear parameters, subjective symptoms and other parameters 
between Optimel Manuka+ Eye Drops and Systane Ultra eye drops. Normality will be assessed 
using the Shapiro-Wilk test. Independent t-tests will be used for comparison of continuous 
normally distributed data between the test and control groups. Non-parametric data will be 
analysed using Mann-Whitney U test. Proportions will be compared using χ2 tests and 
associations will be examined using Pearson’s correlation. The level of significance is set at 
alpha=0.05. Statistical analysis will be performed using SPSS software V.22.0. The difference 
between the 28 days and baseline data will be used to quantify the treatment effect. 
 
13.2. Criteria for Termination of the Trial 
The trial will be terminated upon completion of the final study visit by the last 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. 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 will be 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 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.  The records are initially kept on site in a secure 
location, and may later be transferred to a secure off-site storage facility. 
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.  
 
The Investigator/Institution must also retain essential documents for 15 years as per TGA 
requirements following the completion of a clinical trial. However, essential documents may need 
to be retained longer after consideration of the following:  product liability and the potential need to 
produce records at any time during, and possibly beyond, the life of a product in the event of a 
claim 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. 
15.1.3. Protocol Amendments 
The Investigator will review deviations to determine the need to amend the protocol or to terminate 
the investigation.  Justification for any changes will be provided.   
 
Protocol amendments will be submitted to the 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). 

 
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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, 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 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. 
 
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 received must be reconciled with the 
quantities 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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Cokcetin N, Pappalardo M, Campbell L, et al. The Antibacterial Activity of 
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Almasaudi SB, El-Shitany NA, Abbas AT, et al. Antioxidant, Anti-inflammatory, and 
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Kading D. A two-week clinical evaluation of the safety of Systane Ultra in contact 
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6. 
Springs C. Novel ocular lubricant containing an intelligent delivery system: details of 
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Miller K, Walt, J., Mink, D. et al. Minimal Clinically Important Difference for the 
Ocular Surface Disease Index. Arch Ophthalmol 2010;128:94.