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Trial registered on ANZCTR


Registration number
ACTRN12619000390189
Ethics application status
Approved
Date submitted
3/03/2019
Date registered
12/03/2019
Date last updated
28/05/2019
Date data sharing statement initially provided
12/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Developing evidence-based guidance for the treatment of dry eye disease (DED) with artificial tear supplements
Scientific title
Exploring changes in tear film stability and dry eye symptoms following 6 months Systane® artificial tear supplement application for dry eye disease (DED)
Secondary ID [1] 297532 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dry eye disease 311751 0
Condition category
Condition code
Eye 310377 310377 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Brief name: artificial tear supplement instillation of Systane Ultra (SU) and Systane Complete (SC) (Alcon, Inc.)

Participants will be randomized to self administer 1-2 drops (20-40 microlitres) of either SU or SC topically, a minimum of four times daily in both eyes for a 6-month period. Drops can be instilled as often as needed (no maximum), as per the instructions provided by the manufacturers for this product. Compliance will be assessed by weighing bottles before and after use. Application of 1- 2 drops increases the chance of application to the intended area. The eye can hold only 1 drop at any one time therefore any excess fluid in the eye will spill over or be expelled by blinking.

Systane Ultra contains:
Active ingredients: Polyethylene Glycol 400 0.4%Lubricant
Propylene Glycol 0.3%
Inactive ingredients: Aminomethylpropanol, boric acid, hydroxypropyl guar, POLYQUAD® (polyquaternium-1)0.001% preservative, potassium chloride, purified water, sodium chloride, sorbitol. May contain hydrochloric acid and/or sodium hydroxide to adjust pH.

Systane Complete contains:
Active ingredient: Propylene Glycol 0.6%
Inactive ingredient: boric acid, dimyristoyl phosphatidylglycerol, edatate disodium, hydroxypropyl guar, mineral oil, polyoxl 40 stearate, POLYQUAD® (polyquaternium-1) 0.001% preservative, sorbitan tristearate, sorbitol and purified water. May contain hydrochloric acid and/or sodium hydroxide to adjust pH.
Intervention code [1] 313773 0
Treatment: Drugs
Comparator / control treatment
Active control: Systane Ultra (SU) (reference comparator) (Alcon, Inc.)
Control group
Active

Outcomes
Primary outcome [1] 319253 0
Change in tear film stability measured objectively as the non invasive keratograph break up time (NIKBUT)
Timepoint [1] 319253 0
Baseline, and 1, 2, 3, 4, 5 and 6 months (primary timepoint)
Primary outcome [2] 319254 0
Change in symptom score according to the Symptom Assessment iN Dry Eye questionnaire (SANDE)
Timepoint [2] 319254 0
Baseline, and 1, 2, 3, 4, 5 and 6 months (primary timepoint)
Primary outcome [3] 319255 0
Change in symptoms according to the Ocular Surface Disease Index (OSDI) Questionnaire
Timepoint [3] 319255 0
Baseline, and 1, 2, 3, 4, 5 and 6 months (primary timepoint)
Secondary outcome [1] 367480 0
Lipid layer grade (LLG) evaluated from masked grading of interferometric patterns recorded with the Oculus Keratograph 5M
Timepoint [1] 367480 0
Baseline, and 1, 2, 3, 4, 5, and 6 months
Secondary outcome [2] 367481 0
Change in lid wiper epitheliopathy (LWE) visualised with slit lamp biomicroscopy following application of vital dyes (sodium fluorescein, lissamine green)

Timepoint [2] 367481 0
Baseline, and 1, 2, 3, 4, 5, and 6 months
Secondary outcome [3] 367482 0
Change in tear meniscus height (TMH) measured with digital callipers from a still image captured under infra red illumination with the Oculus Keratograph 5M
Timepoint [3] 367482 0
Baseline, and 1, 2, 3, 4, 5, and 6 months
Secondary outcome [4] 367483 0
Change in bulbar hyperemia measured objectively by the Oculus Keratograph 5M
Timepoint [4] 367483 0
Baseline, and 1, 2, 3, 4, 5, and 6 months
Secondary outcome [5] 367484 0
Change in tear osmolarity evaluated with the TearLab Osmometer
Timepoint [5] 367484 0
Baseline, and 1, 2, 3, 4, 5, and 6 months
Secondary outcome [6] 367485 0
Change in blink rate (blinks per minute) by masked observation of infrared videos captured under infrared illumination
Timepoint [6] 367485 0
Baseline, and 1, 2, 3, 4, 5, and 6 months
Secondary outcome [7] 367486 0
Change in ocular surface staining highlighted by application of vital dyes (sodium fluorescein, lissamine green) and visualised by slit lamp biomicroscopy
Timepoint [7] 367486 0
Baseline, and 1, 2, 3, 4, 5, and 6 months
Secondary outcome [8] 367487 0
Change in meibomian gland expressibility evaluated with the application of a consistent pressure from the Meibomian Gland Evaluator
Timepoint [8] 367487 0
1, 2, 3, 4, 5 and 6 months from baseline
Secondary outcome [9] 367722 0
Change in percentage meibomian gland drop out, assessed by a masked observed from infrared images captured with the Oculus Keratograph 5M.
Timepoint [9] 367722 0
6 months from baseline
Secondary outcome [10] 367787 0
Change in blink quality (blink completeness) by masked observation of infrared videos captured under infrared illumination
Timepoint [10] 367787 0
1, 2, 3, 4, 5 and 6 months from baseline

Eligibility
Key inclusion criteria
• Able and willing to comply with study instructions
• Minimum of 6 months since onset of self-reported DED
• Normal lid architecture, and eyelid closure
• Dry eye diagnosis according to the TFOS DEWS II diagnostic criteria (Symptoms: DEQ5 or OSDI and Signs: at least 1 positive finding on NIKBUT/osmolarity/staining).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Non-normal lid architecture affecting lid closure/blink
• Inability or refusal to commit to 6-month trial
• Refusal or inability to refrain from topical eye drop use, including artificial tear supplements, for at least 48 hours prior to baseline visit
• Refusal to restrict topical eye drop use to only the study tear supplement
• Refusal to be advised of incidental findings
• Wear of contact lenses within 48 hours of study commencement or during the study
• Warm compress therapy, unless performed regularly, for a minimum of 30 days, and maintained at the same frequency throughout the course of the trial
• Punctal plugs, unless non-dissolvable (silicone plugs or cautery of at least 3 months duration)
• History of ocular surgery (such as refractive or cataract surgery) in either eye within 3 months of the screening visit
• History or presence of any ocular disorder or condition in either eye that would likely interfere with the interpretation of the study results or patient safety. This includes but is not limited to significantly reduced visual acuity (less than 20/200), significant corneal or conjunctival scarring, pterygium or nodular pinguecula; current ocular infection or inflammation unrelated to dry eye; anterior (epithelial) basement membrane corneal dystrophy or other clinically significant corneal dystrophy or degeneration; ocular herpetic infection
• Use of topical medications that might interfere with the study outcomes, or deemed to be contraindicated for participation
• A systemic condition or disease considered unstable or judged by the investigator to be incompatible with participation in the study (including but not limited to current systemic infection, uncontrolled autoimmune disease, uncontrolled immunodeficiency disease, history of myocardial infarction)
• Self-reported pregnancy or lactation
• Active or uncontrolled severe systemic allergy, chronic seasonal allergies, rhinitis or sinusitis requiring treatment (with antihistamines, decongestants, oral or aerosol steroids) at the time of screening
• Use of medication known to cause ocular drying (including but not limited to antihistamines, tricyclic antidepressants, anxiolytics, antimuscarinics, beta-blocking agents, diuretics, phenothiazines, steroids) within 30 days of the screening visit
• Use of oral medications not associated with ocular drying, unless stable dose for at least 3 months and continued at the same dose throughout trial
• Participation in any clinical trial with a new active substance or a new device within 30 days of the screening visit

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Product allocation will be randomised and prospectively double-masked to minimize risk of bias. Products will be over labelled to obscure contents. Randomisation schedules for the total sample will be derived at the primary site, by computer-generated random number allocation, and applied to sequentially enrolled participants for the four individual sites. The randomisation schedule will be pre-determined prior to patient recruitment, such that the investigator involved in baseline participant assessment will have no involvement in treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer software (i.e. computerised sequence generation) will be used to generate a randomisation schedule for each individual site. Participants at these individual sites will be assigned treatment according to sequential enrolment.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The significance of overall treatment, time, and treatment-by-time interaction effects will be assessed using repeated measures two-way analysis of variance (ANOVA) for continuous variables with normal distributions confirmed by Kolmogorov-Smirnov testing (p > 0.05). Non-normally distributed continuous data (NIKBUT) will be logarithmically transformed, and ordinal data (LLG) converted to rank-values before analysis. Pre-specified multiplicity-adjusted post-hoc assessment of individual treatment and time effects will be conducted using Sidak's test. Categorical data (treatment preference) will be compared using Fisher's exact test. All tests will be two-tailed and p < 0.05 considered significant. Analysis for objectives 1 and 2 (time course of improvement) will be based on between-group comparisons. Whether maximal clinical improvement in signs and symptoms of dry eye disease observed between the two products might be influenced by the severity of global dry eye signs and symptoms (as defined by the TFOS DEWS II dry eye disease diagnostic criteria), as well as evaporative and aqueous deficient subtype classification markers (as defined by the TFOS DEWS II dry eye disease subtype classification testing scheme), will be assessed on the basis of within-group changes from baseline.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment outside Australia
Country [1] 21312 0
New Zealand
State/province [1] 21312 0
Auckland
Country [2] 21313 0
Canada
State/province [2] 21313 0
Ontario
Country [3] 21314 0
United Kingdom
State/province [3] 21314 0
Birmingham

Funding & Sponsors
Funding source category [1] 302090 0
Commercial sector/Industry
Name [1] 302090 0
Alcon Inc.
Address [1] 302090 0
Unit 10/25 Frenches Forest Road East, Frenchs Forest, NSW 2086
Country [1] 302090 0
Australia
Primary sponsor type
University
Name
The University of Auckland
Address
Private Bag 92019
Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 301911 0
University
Name [1] 301911 0
University of Waterloo
Address [1] 301911 0
Centre for Ocular Research & Education (CORE)
University of Waterloo
200 Columbia St W,
Waterloo,
ON
N2L 3G1,
Canada
Country [1] 301911 0
Canada
Secondary sponsor category [2] 301925 0
University
Name [2] 301925 0
University of New South Wales
Address [2] 301925 0
School of Optometry and Vision Science
University of New South Wales
Rupert Myers Building,
Barker St,
Kensington
NSW 2033,
Australia
Country [2] 301925 0
Australia
Secondary sponsor category [3] 301926 0
University
Name [3] 301926 0
Aston University
Address [3] 301926 0
Aston Triangle,
Birmingham
B4 7HT
Country [3] 301926 0
United Kingdom

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302769 0
The University of Auckland Human Participants Ethics Committee
Ethics committee address [1] 302769 0
Private Bag 92019
Auckland 1142
Ethics committee country [1] 302769 0
New Zealand
Date submitted for ethics approval [1] 302769 0
22/11/2018
Approval date [1] 302769 0
07/12/2018
Ethics approval number [1] 302769 0
022493
Ethics committee name [2] 302793 0
University of Waterloo Office of Research
Ethics committee address [2] 302793 0
200 University Ave West
N2L3G1 Waterloo
Canada
Ethics committee country [2] 302793 0
Canada
Date submitted for ethics approval [2] 302793 0
Approval date [2] 302793 0
Ethics approval number [2] 302793 0
Ethics committee name [3] 302795 0
Aston University Research Ethics Committee
Ethics committee address [3] 302795 0
Aston University,
Aston St,
Birmingham
B4 7ET,
UK
Ethics committee country [3] 302795 0
United Kingdom
Date submitted for ethics approval [3] 302795 0
29/11/2018
Approval date [3] 302795 0
19/02/2019
Ethics approval number [3] 302795 0
#1452
Ethics committee name [4] 302796 0
UNSW Human Research Ethics Committee
Ethics committee address [4] 302796 0
UNSW Research Ethics & Compliance Support
The University of New South Wales
Sydney NSW 2052 Australia
Ethics committee country [4] 302796 0
Australia
Date submitted for ethics approval [4] 302796 0
Approval date [4] 302796 0
Ethics approval number [4] 302796 0

Summary
Brief summary
The ability of artificial tear supplements, that are commercially available ‘over-the-counter’, to improve tear film stability and reduce symptoms of dry eye will be evaluated. Specifically the clinical course of artificial tear supplement effects, including how quickly improvements in signs and symptoms occur and the time taken to reach maximal treatment effect will be assessed. The outcomes relative to dry eye subtype, such as those deficient in tear volume or those who exhibit poor tear quality at baseline, will be evaluated.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91338 0
A/Prof Jennifer P Craig
Address 91338 0
Department of Ophthalmology
The University of Auckland
Private Bag 92019
Auckland 1142
Auckland
Country 91338 0
New Zealand
Phone 91338 0
+6499238173
Fax 91338 0
Email 91338 0
jp.craig@auckland.ac.nz
Contact person for public queries
Name 91339 0
Dr Alex Muntz
Address 91339 0
Department of Ophthalmology
The University of Auckland
Private Bag 92019
Auckland 1142
Auckland
Country 91339 0
New Zealand
Phone 91339 0
+6493737599
Fax 91339 0
Email 91339 0
a.muntz@auckland.ac.nz
Contact person for scientific queries
Name 91340 0
A/Prof Jennifer P Craig
Address 91340 0
Department of Ophthalmology
The University of Auckland
Private Bag 92019
Auckland 1142
Auckland
Country 91340 0
New Zealand
Phone 91340 0
+6499238173
Fax 91340 0
Email 91340 0
jp.craig@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results