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Trial registered on ANZCTR


Registration number
ACTRN12618000196246
Ethics application status
Approved
Date submitted
17/01/2018
Date registered
7/02/2018
Date last updated
2/05/2019
Date data sharing statement initially provided
2/05/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Short term evaluation of caffeine based eye-drops in healthy volunteers.
Scientific title
Short term evaluation of the ocular response to caffeine eye-drops and caffeine plus atropine eye-drops in healthy volunteers..
Secondary ID [1] 293801 0
None
Universal Trial Number (UTN)
None
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
myopia 306216 0
Condition category
Condition code
Eye 305317 305317 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
There are 3 test eye-drops and one placebo eye-drop. The test eye-drops are 1.4% caffeine , 2.0% caffeine and 1.4% caffeine combined with atropine 0.02% eye drops. Individuals will be randomly assigned to one type of eye-drop at a time and will eventually trial all four eye-drop types on study completion. Each eye-drop will be administered by the participant with one drop per eye in the morning and evening for a minimum of 5 days and a maximum of 7 days. There will be a two day washout period between each eye-drop type. The unused volume of the eye-drop will be returned and will be measured by the investigator to determine adherence to the intervention.
Intervention code [1] 300059 0
Treatment: Drugs
Comparator / control treatment
The control treatment is a commercially available unpreserved artificial tears solution of 0.3% hydroxyl-propyl methyl cellulose.
Control group
Placebo

Outcomes
Primary outcome [1] 304480 0
To evaluate the ocular surface response to the short-term use of 1.4% caffeine, 2.0% caffeine and 1.4% caffeine plus 0.02% atropine eye-drops using established clinical grading scales for bulbar redness, limbal redness, conjunctival fluorescein staining, corneal fluorescein staining, palpebral redness and palpebral roughness. The grading will be performed by the assessment optometrist who has had concordance training and will be masked to the eye-drop used.
Timepoint [1] 304480 0
5 days from first instillation of eye-drop.
Secondary outcome [1] 342074 0
To evaluate the subjective comfort response to the short-term use of 1.4% caffeine, 2.0% caffeine, 1.4% caffeine plus 0.02% atropine eye-drops and the control eye drop, the participant will be asked the following questions at their assessment visit after 5 days of eye-drop use:

Q 1. How would you rate your ocular comfort immediately after using the eye-drop
(1 NO EFFECT – 10 MAXIMUM DISCOMFORT).

Q2. How would you rate your ocular comfort after using the eye-drops for 5 days.
(1 NO EFFECT – 10 MAXIMUM DISCOMFORT)

Q3. Did the eye-drops affect your vision after using the eye-drops for 5 days.
YES or NO.

PLEASE EXPLAIN IF YES.
Timepoint [1] 342074 0
5 days from first instillation of eye-drop.

Eligibility
Key inclusion criteria
• Able to read and comprehend English and give informed consent as demonstrated by signing a record of informed consent.
• Be at least 18 years old, male or female.
• Willing to instil each of the test eye drops daily for 5 days and follow the clinical trial visit schedule as directed by the Investigator.
• Have ocular health findings considered to be “normal”.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Any pre-existing ocular irritation, injury or condition, including infection or disease.
• Any systemic disease that adversely affects ocular health e.g. diabetes, Graves disease, and auto-immune diseases such as ankylosing spondylitis, multiple sclerosis, Sjögrens syndrome and systemic lupus erythematosus. Conditions such as systemic hypertension and arthritis do not automatically exclude prospective participants.
• Use of or a need for concurrent category S3 and above ocular medication at enrolment and/or during the clinical trial.
• Use of or a need for any systemic medication or topical medications which may alter normal ocular findings / are known to affect a participant’s ocular health / physiology or contact lens performance either in an adverse or beneficial manner at enrolment and/or during the clinical trial.
• Eye surgery within 12 weeks immediately prior to enrolment for this trial.
• Previous corneal refractive surgery.
• Contraindications to caffeine such as high blood pressure, heart conditions and ADHD
• Known allergy or intolerance to ingredients to caffeine.
Contact lens wearer
• Pregnancy and breastfeeding.*
• Currently enrolled in another clinical trial.
The Investigator may, at his/her discretion, exclude anyone who they believe may not be able to fulfil the clinical trial requirements or it is believed to be in the participant’s best interests.
*Formal testing of pregnancy is not required. A participant’s verbal report is sufficient.

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 the investigators will be masked to the study products. An unmasked person will dispense the masked products which will be packaged identically. All study products will be in identical eye-drop bottles relabelled with an opaque white sticker label by the clinical assistant. The clinical assistant who will receive the products from the compounding pharmacy, logging stock in the electronic database and performing stock control. Only the clinical assistant will have access to the secure stock-room itself. The clinical assistant will hand-over the clinical trial product to the investigator following randomisation of the assigned trial product.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation plan will be generated from http://www.randomization.com/. The website’s second random generator will be used to create a random permutation of control and test eye-drops for each participant. The random generator will allocate the order of dispensing 1 control and 3 test eye-drops for stages 1 to 4 for each participant. A randomisation list will be generated by the biostatistician and applied through the Clinic Data Management system.
The Investigator will not have access to this randomisation list until the trial is completed and final data analysis performed
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 1
Type of endpoint/s
Safety
Statistical methods / analysis
NULL HYPOTHESES
No significant difference between test and control eye drops in bulbar redness, limbal redness and corneal staining after instillation of eye drops.

DESCRIPTION
Statistical analysis is planned to commence on completion of trial monitoring and the submission of the data analysis request form. Any interim analysis will be conducted as described in this section, unless a documented request is received from the Sponsor and approved by the trial PI.

Data stored in relational databases will be imported into SPSS / STATA software for statistical purposes. Data will be investigated for quality using range checks and frequency distribution. Underlying distributions of variables will be tested. In general, variables measured on an interval scale with a sufficiently large sample size will be considered to follow a normal distribution. Outputs from the statistical analysis such as statistical tables will be copied over to Excel. Graphs will generally not be created from the statistical software. All statistical results will be reported in Excel format.

NUMBER OF PARTICIPANTS
A minimum of twenty participants are required to determine a paired difference of 0.5±0.7 in clinical grades with 80% power at the 5% level of significance. The sample size is adjusted for a 10% drop out rate.

SIGNIFICANCE
Statistical significance is set at 5%.

INTERIM ANALYSIS
No interim analysis will be employed.

ANALYSIS
Participants who have commenced the clinical trial treatment will be included in the analysis dataset. Reasons and frequency distribution of participants discontinued at baseline will be reported. The analysis of efficacy variables such as subjective ratings will employ only scheduled and evaluable visits. The analysis of safety variables such as adverse responses will include all visits, including all unscheduled visits. Efficacy primary and secondary outcome variables will be analysed in a paired format between stages. The analysis plan for each primary and secondary endpoint is described here.

Clinical Grade of Bulbar Redness, Limbal Redness and Corneal Staining
Clinical grades will be recorded on a scale of 1 to 4 on steps of 0.5. Data will be summarised as means ± standard deviations. No transformation is likely to be required. Clinical grades will be compared between test and control treatment stages and between visits using paired t-test and repeated measures ANOVA. Difference from the baseline of each stage will also be computed and compared between control and test treatment stages and visits using paired t-test and repeated measures ANOVA. Wilcoxon sign rank and Kruskal-Wallis tests may also be used as non-parametric paired tests.

Subjective Ratings
Subjective ratings will be recorded on a scale of 1 to 10 on steps of 1. Data will be summarised as means ± standard deviations. No transformation is likely to be required. Subjective ratings will be compared between test and control treatment stages and between visits using paired t-test and repeated measures ANOVA. Wilcoxon sign rank and Kruskal-Wallis tests may also be used as non-parametric paired tests.

Adverse Events
Adverse events will be recorded on a binary scale of 0 and 1, where 1 denotes the presence of the event. Data will be summarised as incidence as a percentage of participant or participant-eyes.

Other Variables
Data will be summarised as means ± standard deviations for variables measured on an interval scale and median ± interquartile range for ordinal variables and percentages for those that are categorical. Other commonly used tests of significance at each visit may include paired t-tests and group t-test for parametric data and Wilcoxon signed-rank test and rank sum test for non-parametric data. Test of other variables may also include Analysis of Variance (ANOVA) and repeated measures ANOVA to test for between-participant and within-participant factors. Test of other categorical variables may include McNemar’s, Fisher’s Exact and Chi-Square tests for within- and between-participant factors Statistical Adjustments
Difference between trial groups will be ascertained at the baseline visit. If there are significant differences, the baseline value can be used as a covariate adjustment in the statistical model. The difference from baseline can also be computed and used for further statistical analysis. If the differences are statistically significant, but of low clinical significance, the analysis can be conducted without these adjustments. However, the clinical relevance of the baseline differences will be discussed with the trial PI.

Simultaneous multiple group comparisons in a post-hoc analysis will be corrected using Bonferroni correction. No adjustments will be made for testing multiple endpoints such as multiple subjective ratings.

Deviations from Statistical Plan
The end of study analysis will be conducted as described in the protocol. Any changes to this plan will be documented in the data analysis request form and will need to be duly authorised by the study principal investigator. The data analysis request form will be retained along with other study documentation.

SUB GROUP ANALYSIS
No subgroup analysis is planned.

CRITERIA FOR TERMINATION OF THE TRIAL FOR FINAL DATA ANALYSIS
The trial will be terminated upon completion of the final visit by the last active participant or if any of the conditions for participant withdrawal are met. For example:
a participant may be discontinued due to protocol deviations and/or if exclusion criteria are met during the course of the trial, a participant is considered lost to follow-up if contact cannot be established over three documented attempts – two phone calls and one written,
or if a participant has experienced an adverse event that is continuing at the end of the clinical trial participation, the event is marked as ongoing and the participant should be followed until the event has resolved, or stabilised if there is no chance of resolution.
An active participant is one who is enrolled in the clinical trial and has not been discontinued.

PROTOCOL DEVIATION PROCESS AND ACCOUNTABILITY OF DATA
The clinical trial team will bring deviations to the attention of the PI who, pending the significance of the deviation, will discuss with the Biostatistician, and with the Sponsor, as required.

When applicable, at the end of each protocol, protocol deviations will be reviewed (masked) to determine whether any data should be excluded from the final analysis. A list of protocol deviations and a recommendation of the PI as to how to use the data collected at the respective visit will be given to the Sponsor for approval prior to data analysis.
Individual data points that are missing will be excluded from analysis involving only those specific variables. A participant’s complete visit data will not be excluded if some of the observations are missing. Data from unscheduled visits will be used only for adverse response analysis. Inclusion of outliers in the analysis will be based on the magnitude of change in test statistics with and without the outliers. Outliers will preferably be retained unless there is significant change in test results.

The Clinical Optometrist, in conjunction with the PI (Research Optometrist), may label the clinic visit as “non evaluable” on any deviations as deemed appropriate. This would then be used to exclude the clinical trial visit from the analysis. Any other variable-specific exclusion will be listed in the analysis request form and approved by the trial PI.

A list is generated of all protocol deviations reported, and this information and any subsequent analysis and comment, is included in the final “Clinical Investigation – End of Clinical trial Report”.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/03/2018
Actual
17/04/2018
Date of last participant enrolment
Anticipated
24/08/2018
Actual
29/07/2018
Date of last data collection
Anticipated
28/09/2018
Actual
14/08/2018
Sample size
Target
22
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 18584 0
2033 - Kensington

Funding & Sponsors
Funding source category [1] 298418 0
Charities/Societies/Foundations
Name [1] 298418 0
Brien Holden Vision Institute
Country [1] 298418 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Brien Holden Vision Insitute
Address
Level 4, Rupert Myers Building
Gate 14, Barker Street
UNSW Sydney NSW 2052
Country
Australia
Secondary sponsor category [1] 297636 0
None
Name [1] 297636 0
Address [1] 297636 0
Country [1] 297636 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299414 0
Bellberry Limited
Ethics committee address [1] 299414 0
Ethics committee country [1] 299414 0
Australia
Date submitted for ethics approval [1] 299414 0
17/01/2018
Approval date [1] 299414 0
07/03/2018
Ethics approval number [1] 299414 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80322 0
Dr Monica Jong
Address 80322 0
Brien Holden Vision Institute
Level 4, North Wing, RMB, Gate 14, Barker Street
UNSW
NSW 2052
Country 80322 0
Australia
Phone 80322 0
+612 93857507
Fax 80322 0
Email 80322 0
m.jong@brienholdenvision.org
Contact person for public queries
Name 80323 0
Kassandra Wagenfuehr
Address 80323 0
Brien Holden Vision Institute
Level 5, North Wing, RMB, Gate 14, Barker Street
UNSW
NSW 2052
Country 80323 0
Australia
Phone 80323 0
+612 93855934
Fax 80323 0
Email 80323 0
k.wagenfuehr@brienholdenvision.org
Contact person for scientific queries
Name 80324 0
Padmaja Sankaridurg
Address 80324 0
Brien Holden Vision Institute
Level 4, North Wing, RMB, Gate 14, Barker Street
UNSW
NSW 2052
Country 80324 0
Australia
Phone 80324 0
+612 93857507
Fax 80324 0
Email 80324 0
p.sankaridurg@brienholdenvision.org

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data will remain confidential and stored in a secure database.


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.