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Trial registered on ANZCTR


Registration number
ACTRN12624000444583
Ethics application status
Approved
Date submitted
7/12/2023
Date registered
10/04/2024
Date last updated
10/04/2024
Date data sharing statement initially provided
10/04/2024
Date results provided
10/04/2024
Type of registration
Retrospectively registered

Titles & IDs
Public title
The impact of probiotics and prebiotics on dry eye disease
Scientific title
Investigating the effect of probiotics and prebiotics on signs and symptoms of dry eye disease in adults
Secondary ID [1] 295954 0
None
Universal Trial Number (UTN)
U1111-1219-6583
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dry eye discomfort 309464 0
Condition category
Condition code
Eye 308298 308298 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study was conducted as a double-masked, randomised controlled clinical trial involving 41 patients experiencing dry eye discomfort. Using a web-based system, participants were randomly assigned to one of two groups. The treatment group received both oral capsules and sachets, capsules of MULTIBIOTIC™ probiotics ( containing 21 billion colony forming units (CFU) capability of human probiotic isolates of lactic acid bacteria (LAB) and Bifidobacteria including beneficial strains of Lactobacillus Acidophilus Lactobacillus Bifidus and S. Thermophilus) and sachets of NutriKane D as the prebiotics. The control group was given placebo capsules and sachets, both containing Maltodextrin. The duration of the treatment for both groups was four months with the following dosing schedule:

The schedule of capsules and sachets, both placebo and treatment is as follows:

• One capsules daily
• Two sachets daily, one morning and another one evening


Participants in this treatment arm will consume both capsules and sachets.

An optometrist investigator was conducted the visit

Study visits:
The study will divide to 5 visits. Visits 1,3,4,5 take between 1.5 -2 hours.
Visit 1: Baseline visit at this visit, participants will be randomized to receive the placebo or the treatments. Baseline measurements will also be taken.
Visit 2: 1-month visit (1 month±7 days from visit 1)
Visit 3: 4-month visit and tablet return visit (4 months ± 7 days from visit 1)
Visit 4: follow-up visit (1 month±7 days from visit 4)

1. Comfort
2. Inflammation: tear film inflammatory mediators, neuromediators and clinical parameters
3. Corneal nerve morphology and migration
4. Systemic microbiome changes.
Intervention code [1] 312279 0
Treatment: Other
Comparator / control treatment
Sachets and capsules of Maltodextrin used as prebiotics and probiotics supplements placebo prepared by ACP compounding pharmacy
Control group
Placebo

Outcomes
Primary outcome [1] 307269 0
Any change in dry eye discomfort was assessed using the Ocular Surface Disease Index (ODSI) questionnaire
Timepoint [1] 307269 0
Baseline, 1 month, 4 months (the primary timepoint), 5 months post-randomisation
Secondary outcome [1] 353516 0
Any change in dry eye signs was assessed using the OCULUS Keratograph and LipiView
Timepoint [1] 353516 0
Baseline, 1 month, 4 months, 5 months post-randomisation
Secondary outcome [2] 431879 0
Any change in tear film inflammatory mediators was assessed by ELISA
Timepoint [2] 431879 0
Baseline, 1 month, 4 months, 5 months post-randomisation
Secondary outcome [3] 431881 0
Any change in corneal immune cells and nerve morphology and migration assessed by In vivo confocal microscopy (IVCM)
Timepoint [3] 431881 0
Baseline, 4 months post-randomisation.
Secondary outcome [4] 431883 0
Any change in the systemic microbiome changes by collecting of two sample types, (1) stool samples and assessed by independent methods (16s rRNA sequencing). and (2) nasal swabs assessed by culture-dependent ( Chocolate agar (CA) medium for the isolation and identification of bacteria).
Timepoint [4] 431883 0
Baseline, 4 months post-randomisation
Secondary outcome [5] 432962 0
For the purpose of evaluating any changes in the ocular microbiome, ocular swabs were collected from the ocular surface of participants. The swabs were assessed by culture-dependent and culture-independent methods.

1. Culture-Dependent Method:
Our culture-dependent analysis involves the use of the Chocolate Agar (CA) medium. CA is particularly chosen for its capacity to support the growth of a wide range of bacterial pathogens, including those fastidious in nature. Once the ocular swabs were collected, they were inoculated onto CA plates under optimal growth conditions. Following incubation, bacterial colonies were identified based on colony morphology, colour, and further biochemical testing as necessary. This traditional method allows for the isolation and identification of bacteria, enabling detailed analysis of specific pathogens present on the ocular surface.

2. Culture-Independent Method:
16s rRNA sequencing was used as the culture-independent method, to assess the bacterial composition of the ocular microbiome. This technique involves extracting total DNA from the swab samples and amplifying the 16S rRNA gene, which is highly conserved among bacteria. Sequencing of this gene segment allows for the identification and quantification of bacterial taxa present in the sample without the need for culture. This method provides a comprehensive view of the bacterial community structure, including non-culturable organisms, thus offering a more complete picture of the ocular microbiome.
Timepoint [5] 432962 0
Baseline, 4 months post-randomisation

Eligibility
Key inclusion criteria
Inclusion criteria:
- be able to read and comprehend English and give informed consent as demonstrated by signing a record of informed consent
- No previous probiotic or fermented product intake in the last three months
- Currently have been diagnosed with dry eye disease
- Be at least 18 years old
- Be willing to comply with the consuming probiotic product and clinical trial visit schedule
- Be willing to discontinue all ophthalmic preparations including artificial tears during the study and 72 hours before screening
Minimum age
18 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Currently taking probiotics or other fermented products. Participants will be advised not to change their diet for the duration of the study.
- Any systemic or topical medications that will affect ocular physiology or tear film layer e.g. anti-acne medications such as Roaccutane and corticosteroids or immunosuppressant medications such as Hydrocortisone, Prednisolone.
- Any systemic disease that may affect ocular health e.g. diabetes, Graves’ disease, and auto-immune diseases such as ankylosing spondylitis, multiple sclerosis, Sjögren’s syndrome, Crohn’s disease, elevated CRP, IBS, Inflammatory bowel disease and systemic lupus erythematosus.
- Eye surgery within 12 weeks immediately prior to enrolment for this trial
- Previous corneal refractive surgery
- Active corneal infection or any active ocular disease such as iritis, corneal edema or corneal dystrophies, including anterior membrane dystrophy
- Any current ocular injury
- Taking oral or topical antibiotics
- Be currently enrolled in another clinical trial or have participated in a clinical trial within the previous 2 weeks.
- pregnant or lactating

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)
Allocation is concealed by use of identical bottles containing either treatment or placebo which will be labelled A and B. The investigator determining eligibility of the subjects will be masked to the code for placebo and control.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be carried out through a web based randomisation system
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
A sample of 55 participants in each group (total 110) will have 95% power at the 5% level of significance to detect a group difference of 10±12 units using the OSDI questionnaire for dry eye patients. This sample is adjusted for a 20% discontinuation rate. The group standard deviation of 11 is based on prior studies using the OSDI questionnaire.
Summary statistics and graphical representations will be produced for relevant variables. All statistical tests will be performed using Statistical Package for Social Sciences (IBM SPSS Statistics 22, Armonk, NY). A linear mixed model will be developed to compare the effect of probiotics and placebo treatments on clinical and functional variables. Nonparametric tests will be utilized for categorical variables

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
9/05/2019
Date of last participant enrolment
Anticipated
Actual
1/07/2021
Date of last data collection
Anticipated
Actual
1/12/2021
Sample size
Target
110
Accrual to date
Final
41
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment postcode(s) [1] 24575 0
2052 - Unsw Sydney

Funding & Sponsors
Funding source category [1] 300552 0
University
Name [1] 300552 0
UNSW School of Optometry and Science Vision
Country [1] 300552 0
Australia
Funding source category [2] 301077 0
Charities/Societies/Foundations
Name [2] 301077 0
Brien Holden Vision Institute
Country [2] 301077 0
Australia
Primary sponsor type
University
Name
UNSW School of Optometry and Science Vision
Address
Gate 14, Barker St, North Wing, Rupert Myers Building, School of Optometry and Vision ScienceUNSW SYDNEY NSW 2052 AUSTRALIA
Country
Australia
Secondary sponsor category [1] 300034 0
None
Name [1] 300034 0
Address [1] 300034 0
Country [1] 300034 0
Other collaborator category [1] 280417 0
Charities/Societies/Foundations
Name [1] 280417 0
Brien Holden Vision Institute
Address [1] 280417 0
Gate 14, Barker St, North Wing, Rupert Myers Building, Brien Holden Vision Institute UNSW SYDNEY NSW 2052 AUSTRALIA
Country [1] 280417 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301346 0
UNSW Human Research Ethics Committee
Ethics committee address [1] 301346 0
Ethics committee country [1] 301346 0
Australia
Date submitted for ethics approval [1] 301346 0
04/11/2018
Approval date [1] 301346 0
21/01/2019
Ethics approval number [1] 301346 0
HC180853

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

Contacts
Principal investigator
Name 86686 0
Dr Maria Markoulli
Address 86686 0
Gate 14, Barker St,North Wing, Rupert Myers BuildingSchool of Optometry and Vision ScienceUNSW SYDNEY NSW 2052 AUSTRALIA
Country 86686 0
Australia
Phone 86686 0
+61 2 9065 7355
Fax 86686 0
Email 86686 0
m.markoulli@unsw.edu.au
Contact person for public queries
Name 86687 0
Azadeh Tavakoli
Address 86687 0
Gate 14, Barker St,North Wing, Rupert Myers BuildingSchool of Optometry and Vision ScienceUNSW SYDNEY NSW 2052 AUSTRALIA
Country 86687 0
Australia
Phone 86687 0
+61 4 23264890
Fax 86687 0
Email 86687 0
a.tavakkolinasab@unsw.edu.au
Contact person for scientific queries
Name 86688 0
Maria Markoulli
Address 86688 0
Gate 14, Barker St,North Wing, Rupert Myers BuildingSchool of Optometry and Vision ScienceUNSW SYDNEY NSW 2052 AUSTRALIA
Country 86688 0
Australia
Phone 86688 0
+612 9 065 7355
Fax 86688 0
Email 86688 0
m.markoulli@unsw.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All individual participant data collected during the trial, after deidentification
When will data be available (start and end dates)?
Beginning one year and ending five years following publication
Available to whom?
Researchers who provide a sound methodological reason by way of written proposal
Available for what types of analyses?
To achieve aims stated in the methodological reason
How or where can data be obtained?
proposals should be directed to Dr Maria Markoulli (m.markoulli@unsw.edu.au) for access. Data will be available through the UNSW secure data-centre


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.