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Trial registered on ANZCTR


Registration number
ACTRN12623000830695
Ethics application status
Approved
Date submitted
28/06/2023
Date registered
2/08/2023
Date last updated
2/08/2023
Date data sharing statement initially provided
2/08/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Assessing corneal integrity in healthy eyes and eyes after laser refractive surgery
Scientific title
A randomised, controlled trial to evaluate corneal nerve function in healthy participants and in participants after laser in situ keratomileusis (LASIK) surgery
Secondary ID [1] 309990 0
None
Universal Trial Number (UTN)
U1111-1293-3499
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-LASIK 330488 0
Corneal nerve function 330606 0
Condition category
Condition code
Eye 327336 327336 0 0
Diseases / disorders of the eye
Eye 327445 327445 0 0
Normal eye development and function

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Sterile, hyperosmolar saline solution will be repeatedly applied using a pipette and single-use, sterile pipette tip to the surface of the right eye; 10 times, one drop, every 3 minutes for 30 minutes. A member of the research team will administer the saline solutions. Hence, assessing or monitoring adherence to the intervention is not required. Duration of wash-out period: 7 +/- 3 days. Note: Chemically inert eye drops are categorised as ‘medical devices’ by the TGA in Australia.
Intervention code [1] 326412 0
Treatment: Devices
Intervention code [2] 326473 0
Treatment: Other
Comparator / control treatment
Sterile, iso-osmolar saline solution (0.9%) will be repeatedly applied using a pipette and single-use, sterile pipette tip to the surface of the right eye; 10 times, one drop, every 3 minutes for 30 minutes. A member of the research team will administer the saline solutions. Hence, assessing or monitoring adherence to the intervention is not required.
Control group
Dose comparison

Outcomes
Primary outcome [1] 335207 0
Difference between the healthy and post-LASIK groups for the change from baseline in the dynamic characteristics of corneal epithelial T cells, imaged using a Heidelberg Retinal Tomograph III (HRT-III) with Rostock Corneal Module, quantified using Fiji image analysis software;
Timepoint [1] 335207 0
20 minutes after 30-minute periodic dosing of the intervention
Primary outcome [2] 335208 0
Difference between the healthy and post-LASIK groups for the change from baseline in the dynamic characteristics of corneal epithelial dendritic cells, imaged using a Heidelberg Retinal Tomograph III (HRT-III) with Rostock Corneal Module, quantified using Fiji image analysis software;
Timepoint [2] 335208 0
20 minutes after 30-minute periodic dosing of the intervention
Primary outcome [3] 335209 0
Difference between the healthy and post-LASIK groups for the change from baseline in the morphological features of stromal corneal immune cells, imaged using a Heidelberg Retinal Tomograph III (HRT-III) with Rostock Corneal Module, quantified using Fiji image analysis software;
Timepoint [3] 335209 0
20 minutes after 30-minute periodic dosing of the intervention
Secondary outcome [1] 423455 0
Difference between the healthy and post-LASIK groups for the change from baseline in the morphology of corneal epithelial T cells, imaged using a Heidelberg Retinal Tomograph III (HRT-III) with Rostock Corneal Module, quantified using the Fiji image analysis software;
Timepoint [1] 423455 0
20 minutes after 30-minute periodic dosing of the intervention
Secondary outcome [2] 423456 0
Difference between the healthy and post-LASIK groups for the change from baseline in the morphology of corneal epithelial dendritic cells, imaged using a Heidelberg Retinal Tomograph III (HRT-III) with Rostock Corneal Module, quantified using Fiji image analysis software;
Timepoint [2] 423456 0
20 minutes after 30-minute periodic dosing of the intervention
Secondary outcome [3] 423457 0
Difference between the healthy and post-LASIK groups for the change from baseline in corneal immune cell density, measured as cells/mm-squared, imaged using a Heidelberg Retinal Tomograph III (HRT-III) with Rostock Corneal Module, quantified using Fiji image analysis software;
Timepoint [3] 423457 0
20 minutes after 30-minute periodic dosing of the intervention
Secondary outcome [4] 423458 0
Difference between the healthy and post-LASIK groups for the change from baseline in corneal epithelial immune cell instantaneous speed, quantified as the change in pre- versus post-interaction with a corneal nerve, imaged using a Heidelberg HRT-III with Rostock Corneal module;
Timepoint [4] 423458 0
20 minutes after 30-minute periodic dosing of the intervention
Secondary outcome [5] 423459 0
Difference between the healthy and post-LASIK groups for the change from baseline in the subjective sensory response of ocular stinging sensation, measured using a visual analogue scale (0 – 100 mm);
Timepoint [5] 423459 0
After 30-minute periodic dosing of the intervention
Secondary outcome [6] 423460 0
Difference between the healthy and post-LASIK groups for the change from baseline in the subjective sensory response of ocular burning sensation, measured using a visual analogue scale (0 – 100 mm);
Timepoint [6] 423460 0
After 30-minute periodic dosing of the intervention
Secondary outcome [7] 423461 0
Difference between the healthy and post-LASIK groups for the change from baseline in the subjective sensory response of ocular discomfort sensation, measured using a visual analogue scale (0 – 100 mm);
Timepoint [7] 423461 0
After 30-minute periodic dosing of the intervention
Secondary outcome [8] 423462 0
Difference between the healthy and post-LASIK groups for the change from baseline in tear protein levels, quantified using proteomic assays;
Timepoint [8] 423462 0
15 minutes after 30-minute periodic dosing of the intervention

Eligibility
Key inclusion criteria
1. Written informed consent and documentation, in accordance with privacy requirements, obtained prior to performing any study procedures in the healthy and post-LASIK population;
2. Ability to understand and follow study instructions, with the intention of completing all of the required study visits in the healthy and post-LASIK population;
3. Distance best-corrected visual acuity of at least 6/9 Snellen equivalent in each eye using a standard visual acuity chart in the healthy and post-LASIK population;
4. Post-LASIK population: participants who underwent LASIK, 6 months to 1 year prior to enrolment, for the correction of myopia;
Minimum age
18 Years
Maximum age
45 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
i) Healthy and post-LASIK population:
1. Females who are currently pregnant or breastfeeding;
2. Diagnosis of a systemic disease known to affect small nerve fibres or the health of the ocular surface;
3. Current, or recent (within last 3 months), use of any agent (by any route of administration) known to substantially affect ocular surface health;
4. Active ocular inflammation, allergy or infection;
5. Any ocular surface condition or history of surgery that may adversely alter corneal nerves;
6. Participants with a scheduled corneal surgery over the course of the study;
7. Known allergy to, or previous reaction to, any agents required to be used for the study;
8. History of chronic migraine
ii). Healthy population: Clinically significant dry eye disease, as specified in the TFOS DEWS II definition;
iii) Post-LASIK population: Post-LASIK ectasia; history of any surgery, other than a single LASIK surgery, that might affect the health of the ocular surface;

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is concealed using sealed opaque envelopes by investigators not involved in participant recruitment or data collection.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
A randomised allocation sequence will be generated, in advance, by one of the investigators not involved with participant recruitment or data collection. The sequence will be designed to assign equal numbers of control and post-LASIK participants to first receive one of the two treatments with an 1:1 allocation, via a computer-generated randomisation schedule.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Crossover
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
Sample size: As this is an exploratory, proof-of-concept study, it is not possible to calculate a sample size using conventional statistical methods (which require a reliable estimate of effect size and variability). The nominated sample size of 15 participants in each participant group is based on the rationale that this number of population samples will achieve the reasonable expectations for an analysis based upon the normal distribution (z-test) to be valid. Recruitment feasibility is also supported by this estimate.

Corneal nerve parameters will be quantified from IVCM images using ACCMetrics (University of Manchester, UK), a free, validated software program to derive quantitative corneal nerve parameters. Fiji image analysis software will be used to quantify the dynamics, density and morphology of corneal immune cells. Study groups/exposure conditions will be compared with parametric or non-parametric tests, as appropriate to the data, for the listed outcome measures.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
7/08/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24992 0
The University of Melbourne - Parkville
Recruitment postcode(s) [1] 40649 0
3010 - Parkville

Funding & Sponsors
Funding source category [1] 314169 0
Charities/Societies/Foundations
Name [1] 314169 0
Rebecca L Cooper Medical Research Foundation
Country [1] 314169 0
Australia
Primary sponsor type
University
Name
The University of Melbourne
Address
The University of Melbourne
Parkville
Victoria, Australia 3010
Country
Australia
Secondary sponsor category [1] 316085 0
None
Name [1] 316085 0
Address [1] 316085 0
Country [1] 316085 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313297 0
Office of Research Ethics and Integrity (OREI), University of Melbourne
Ethics committee address [1] 313297 0
Office of Research Ethics and Integrity (OREI),
University of Melbourne,
Parkville, Victoria, 3010
Ethics committee country [1] 313297 0
Australia
Date submitted for ethics approval [1] 313297 0
03/06/2023
Approval date [1] 313297 0
09/06/2023
Ethics approval number [1] 313297 0
2023-13783-41230-3

Summary
Brief summary
Corneal nerve disease (neuropathy) can negatively impact quality-of-life due to associated ocular surface disease, which promotes chronic pain and impaired vision, particularly in severe cases. Corneal neuropathy impairs the trophic and sensory functions of the corneal nerves, leading to reduced corneal sensitivity and disruptions to ocular surface integrity. The currently available techniques to measure corneal nerve function and structure are available only in research settings. Moreover, the techniques measuring corneal nerve function are primarily a measure of mechanical corneal sensation and not a composite measure of the corneal sensations. This is a major barrier to early-stage diagnosis and management of corneal neuropathy. So, robust measures of corneal nerve integrity that could be performed routinely in the clinic need to be developed.

The main aim of this project is to investigate a new method for assessing corneal nerve integrity. Our approach involves quantifying subjective corneal sensory responses and the interaction between immune cells and nerves in the cornea (using non-invasive corneal imaging) in response to stimulating the cornea with sterile salt solutions. These approaches will be compared between healthy (control) corneas and corneas with nerve changes from LASIK. These findings will provide a foundation for determining whether these aspects of corneal nerve function might have the potential to be used in the future as a marker of corneal neuropathy. The identification of a suitable non-invasive biomarker of corneal nerve fibre integrity has the capacity to be translated into the clinic, for enhanced early detection of corneal nerve damage.
Trial website
Trial related presentations / publications
Public notes
Key exclusion criteria (Healthy and post-LASIK population):
Recent COVID-19 infection (i.e., a positive rapid antigen or PCR test within 14 days of planned enrolment);

Contacts
Principal investigator
Name 127650 0
A/Prof Associate Professor Laura Downie
Address 127650 0
Department of Optometry and Vision Sciences
University of Melbourne
200 Berkeley Street, Carlton VIC 3053
Country 127650 0
Australia
Phone 127650 0
+61 3 9035 3043
Fax 127650 0
Email 127650 0
ldownie@unimelb.edu.au
Contact person for public queries
Name 127651 0
A/Prof Associate Professor Laura Downie
Address 127651 0
Department of Optometry and Vision Sciences
University of Melbourne
200 Berkeley Street, Carlton VIC 3053
Country 127651 0
Australia
Phone 127651 0
+61 3 9035 3043
Fax 127651 0
Email 127651 0
ldownie@unimelb.edu.au
Contact person for scientific queries
Name 127652 0
A/Prof Associate Professor Laura Downie
Address 127652 0
Department of Optometry and Vision Sciences
University of Melbourne
200 Berkeley Street, Carlton VIC 3053
Country 127652 0
Australia
Phone 127652 0
+61 3 9035 3043
Fax 127652 0
Email 127652 0
ldownie@unimelb.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
Current human ethics approval does not allow for data sharing. Any potential data sharing beyond the investigator team would be subject to achieving HREC approval for this process.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.