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Trial registered on ANZCTR


Registration number
ACTRN12620001346965p
Ethics application status
Submitted, not yet approved
Date submitted
16/09/2020
Date registered
14/12/2020
Date last updated
14/12/2020
Date data sharing statement initially provided
14/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Systane hydration on ocular comfort and ocular surface damage among type 2 diabetics with dry eye disease and diabetic neuropathy
Scientific title
Effect of Systane hydration on ocular comfort and ocular surface damage among type 2 diabetics with dry eye disease and diabetic neuropathy
Secondary ID [1] 302332 0
None
Universal Trial Number (UTN)
U1111-1258-3516
Trial acronym


Linked study record


Health condition
Health condition(s) or problem(s) studied:
Dry eye disease 319096 0
Diabetes 319097 0
Diabetic neuropathy 319098 0
Condition category
Condition code
Eye 317051 317051 0 0
Diseases / disorders of the eye
Metabolic and Endocrine 317052 317052 0 0
Diabetes
Neurological 317367 317367 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
One drop will be instilled per eye, four times a day. Compliance will be monitored by counting the number of vials used.
There will be a two week washout between treatments.



In phase 1, a sample of 60 participants with type 2 diabetes will be tested for the signs of dry eye disease and neuropathy. We estimate that approximately half will have the signs and symptoms of dry eye disease. This group will proceed to the next phase of the study, that is treatment. In phase 2, 30 participants will be randomised to Systane Hydration or saline for one month and a further one month with the alternate drop. One drop will be instilled per eye, four times a day. Compliance will be monitored by counting the number of vials used. There will be a two week washout between treatments.
Intervention code [1] 318619 0
Treatment: Drugs
Comparator / control treatment
The control being used is saline eye drops. One drop will be instilled per eye, four times a day. Compliance will be monitored by counting the number of vials used.
Control group
Placebo

Outcomes
Primary outcome [1] 325147 0
Comfort will be assessed with the OSDI questionnaire
Timepoint [1] 325147 0
1 and 2 months post intervention commencement
Primary outcome [2] 325405 0
ocular surface damage (corneal and conjunctival staining)
Timepoint [2] 325405 0
1 and 2 months post intervention commencement
Primary outcome [3] 325705 0
Comfort will be assessed using the DEQ-5 questionnaire
Timepoint [3] 325705 0
1 and 2 months post treatment commencement
Secondary outcome [1] 386999 0
- Tear film break-up time (TBUT)
Timepoint [1] 386999 0
1 and 2 months post intervention commencement
Secondary outcome [2] 387806 0
Corneal dendritic cell density will be assessed using in vivo corneal confocal microscopy
Timepoint [2] 387806 0
1 and 2 months post commencement of intervention
Secondary outcome [3] 387807 0
Osmolarity will be assessed using the ipen
Timepoint [3] 387807 0
1 and 2 months post intervention commencement
Secondary outcome [4] 387808 0
Gland expressibility will be assessed using slit-lamp biomicroscopy
Timepoint [4] 387808 0
1 and 2 months post commencement
Secondary outcome [5] 387809 0
- Tear volume (phenol red thread)
Timepoint [5] 387809 0
1 and 2 months post intervention commencement
Secondary outcome [6] 387811 0
Lipid layer thickness will be assessed using the LipiView interferometer
Timepoint [6] 387811 0
1 and 2 months post commencement of intervention
Secondary outcome [7] 388819 0
Comfort will be assessed using the OPAS questionnaire
Timepoint [7] 388819 0
1 and 2 months post commencement of intervention - this is a primary outcome
Secondary outcome [8] 389779 0
Comfort will be assessed using the DEQ-5
Timepoint [8] 389779 0
1 and 2 months post intervention commencement

Eligibility
Key inclusion criteria
For the first phase of the study, participants with type 2 diabetes will be recruited and examined for the signs and symptoms of dry eye disease. Participants will be at least 18 years of age.
To be included in the second phase of the study, participants will need to have neuropathy AND an OSDI score greater than or equal to 12, as well as one of the following: the presence of either corneal or conjunctival staining, a tear break-up time of <10 seconds, or osmolarity greater than or equal to 308 mOsm/L in either eye or interocular difference > 8mOsm/L. An approximately equal number of mild, moderate and severe dry eye participants will be recruited based on the OSDI scores (mild >12-17; moderate 18-35; severe 36-100). The group receiving Systane Hydration first and the group receiving saline first will be age-matched, with similar body mass index (BMI), duration of diabetes, neuropathy severity and gender distribution and will be recruited from the Diabetes Centre at the Prince of Wales Hospital, Sydney, Australia. We have shown that age can impact on both the signs and symptoms of dry eye disease as well as the presence of corneal nerves and dendritic cells. Therefore age will be carefully controlled between groups.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded from the study if they have a history of other medical illnesses known to be associated with neuropathy. Exclusion criteria include malignant disease, connective tissue disease or infectious disease, neurotoxin exposure, deficiency of vitamin B12, family history of neuropathy or active diabetic foot ulcers. Patients will also be excluded from the study if they present with current eye infections, corneal abrasions, or a history of refractive surgery, eye surgery within 12 weeks immediately prior to study enrolment, contact lens wear, anterior segment trauma or are taking ocular medication category S3.

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)
The participants and investigator will be blinded, dispensed by the stock coordinator at UNSW Pharmacy. The Systane Hydration drops will have labels removed and the saline will be delivered in unlabelled bottles indistinguishable from the Systane Hydration. Unmasking will only occur in the case of an adverse event if knowledge of the trial treatment would alter the plan of care for the participant. If at all possible (if time permits) the Sponsor / Principal Investigator will be consulted prior to unmasking. Thorough documentation will occur, and exposure to treatment knowledge should be limited only to those who must know.
Provided “unmasking” has not occurred, the Principal Investigator will not have access to the randomization code until the trial is completed and final data analysis is performed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The participant will be randomized at the initial study visit, after they have provided informed consent and once it is clear that they have met the study criteria for phase 2. At this visit the participant will be randomized to the initial arm of the study (intervention or placebo) and will receive a Randomization Number, allocated by the NHRMC Clinical Trials Centre.
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
The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Once all the data will be collected they are going to be subjected to different tests to establish if they follow normal distributions. Namely, the Shapiro-Wilk test and the determination of heteroscedasticity, which is when the variability of a dependent variable is unequal across the range of values of an independent variable that predicts it. Then, the data will be compared by groups using parametric tests such as the independent t-test, and paired student-t-test for within groups acoss time. Chi-square continuity statistics will be used for continuous and non-continuous variables collected at least twice, longitudinally in time, respectively. If the data do not follow normal distributions, they will be compared by groups using non-parametric tests such as the Kruskal-Wallis test or multiple analyses of variance (MANOVA).

Recruitment
Recruitment status
Not yet 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 postcode(s) [1] 31282 0
2031 - Randwick

Funding & Sponsors
Funding source category [1] 306755 0
Commercial sector/Industry
Name [1] 306755 0
Alcon Laboratories Pty Ltd
Address [1] 306755 0
15 Talavera Rd, Macquarie Park NSW 2113
Country [1] 306755 0
Australia
Primary sponsor type
University
Name
UNSW
Address
Level 3, North Wing, Rupert Myers Building, UNSW NSW 2052
Country
Australia
Secondary sponsor category [1] 307309 0
Hospital
Name [1] 307309 0
Prince of Wales Hospital
Address [1] 307309 0
320-346 Barker St, Randwick NSW 2031
Country [1] 307309 0
Australia

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 306926 0
South Eastern Sydney Local Health District Ethics committee
Ethics committee address [1] 306926 0
15 O'Keefes Ln, Kogarah NSW 2217
Ethics committee country [1] 306926 0
Australia
Date submitted for ethics approval [1] 306926 0
09/09/2020
Approval date [1] 306926 0
Ethics approval number [1] 306926 0

Summary
Brief summary
Dry eye disease affects between 5 and 50% of the population. In many cases, dry eye disease is idiopathic, however dry eye disease secondary to systemic disease has been identified as a major risk factor in the 2017 Tear Film and Ocular Surface Dry Eye Workshop II (TFOS DEWSII) report. In a study of 199 patients with type 2 diabetes, 54.3% were found to have dry eye disease, with dry eye frequency correlating with the duration of diabetes, where a 100% frequency was reported in patients who had a history of diabetes of greater than 15 years. The concurrent presence of dry eye disease in diabetes poses an additional risk to a potentially already compromised ocular surface: diabetes is known to increase the risk of corneal erosion formation, neurotrophic ulceration and persistent epithelial defects.
Diabetes is currently estimated to affect 1.7 million Australians, with this figure predicted to rise to 3 million by 2025. It is associated with a multitude of microvascular and macrovascular complications due to the widespread effects of hyperglycaemia on the body’s various systems. The most commonly recognized diabetes-related complications are diabetic retinopathy and diabetic peripheral neuropathy. The prevalence of diabetic neuropathy is 26.4%15-70% depending on the method of detection used. The prevalence rises to 50% following 10 years of disease duration in type 2 diabetes. The clinical consequences are neuropathic pain, weakness with an increased risk of falls, and loss of sensation which may progress to foot ulceration and even amputation. The cornea, being one of the most densely innervated tissues, contains myelinated A-d and unmyelinated C fibers and has been advocated as a surrogate measure of peripheral neuropathy. We, and others, have previously reported a reduction in corneal nerve fiber length, fiber density and branch density with increasing neuropathic severity in both type 1 and type 2 diabetes.
We hypothesize that the presence of neuropathy will increase the prevalence and severity of dry eye disease among those with diabetes. We further hypothesize that treating those with secondary dry eye disease with Systane Hydration will reduce these signs and symptoms, whether or not there is existing neuropathy.
Primary Objective: This study will establish the odds of dry eye disease in diabetes when neuropathy is present, compared to diabetes without neuropathy (phase 1).
Secondary objectives: This study will establish whether regular ocular lubrication with Systane Hydration can alleviate the signs and symptoms of secondary dry eye disease, whether it be due to diabetes alone or diabetic neuropathy (phase 2).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105474 0
Dr Maria Markoulli
Address 105474 0
Gate 14, Barker St, Level 3, North Wing, Rupert Myers Building, UNSW NSW 2052
Country 105474 0
Australia
Phone 105474 0
+612 9065 7355
Fax 105474 0
Email 105474 0
m.markoulli@unsw.edu.au
Contact person for public queries
Name 105475 0
Dr Maria Markoulli
Address 105475 0
Gate 14, Barker St, Level 3, North Wing, Rupert Myers Building, UNSW NSW 2052
Country 105475 0
Australia
Phone 105475 0
+612 9065 7355
Fax 105475 0
Email 105475 0
m.markoulli@unsw.edu.au
Contact person for scientific queries
Name 105476 0
Dr Maria Markoulli
Address 105476 0
Gate 14, Barker St, Level 3, North Wing, Rupert Myers Building, UNSW NSW 2052
Country 105476 0
Australia
Phone 105476 0
+612 9065 7355
Fax 105476 0
Email 105476 0
m.markoulli@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD and data dictionaries will not be made available
What supporting documents are/will be available?
No other documents available
Summary results
No Results