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Trial registered on ANZCTR


Registration number
ACTRN12621001468819
Ethics application status
Approved
Date submitted
8/08/2021
Date registered
27/10/2021
Date last updated
27/10/2021
Date data sharing statement initially provided
27/10/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Handheld thermal pulsation vs Standard of Care in Meibomian Gland Dysfunction Management
Scientific title
Tear Film Quality following handheld thermal pulsation vs Standard of Care in Meibomian Gland Dysfunction Management in Adults
Secondary ID [1] 302668 0
None
Universal Trial Number (UTN)
U1111-1264-6534
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Dry eye disease 320894 0
Evaporative dry eye 320895 0
Meibomian gland dysfunction 320896 0
Condition category
Condition code
Eye 318710 318710 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention comprises a single treatment session with the iLux, a hand-held device that utilises thermal pulsation therapy to encourage unblocking of the meibomian glands in evaporative dry eye.
The single treatment session involves up to 30 minutes application of the iLux device by a third-party, unmasked clinically trained investigator, who is uninvolved with research data collection. The clinician accurately positions the device relative to the participant’s eyelid, and applies heat directly to the eyelid, melting the trapped oils within the glands. After warming, focus-guided compressions are performed to encourage release of the melted oils from the glands.
Intervention code [1] 319832 0
Treatment: Devices
Comparator / control treatment
The comparator treatment is current standard of care therapy comprising daily: 1) patient-applied warm compress (MGDRx Eyebags®, Eyebag® Company, UK) and 2) gland expression via a silicone eyelid massager (Eyepeace, Cathedral Eye Care, UK). The warmed compress will be administered by participants themselves for 10 minutes, once daily, and will be immediately followed by gentle massage of the eyelids for 15-30 seconds per eye with the silicone device. This daily standard of care therapy will be applied for the entire study duration (6 months). Compliance will be recorded by patient-report at each monthly visit.

Participants randomised to the standard of care group, will be offered the opportunity to receive the study treatment (iLux) free of charge at the end of the study.
Control group
Active

Outcomes
Primary outcome [1] 326645 0
Lipid layer grade (LLG) as measured by the Oculus Keratograph 5M and Tearcheck device.
Timepoint [1] 326645 0
Measurements will be recorded at baseline and at monthly follow-up visits (1 month, 2 months, 3 months, 4 months, 5 months and 6 months) after assignment of treatment. The primary study endpoint is 6 months following intervention.

Secondary outcome [1] 392266 0
Change in non-invasive tear breakup time (NIKBUT) as measured by the Oculus Keratograph 5M.
Timepoint [1] 392266 0
Measurements will be recorded at baseline and at monthly follow-up visits (1 month, 2 months, 3 months, 4 months, 5 months and 6 months) after assignment of treatment.
Secondary outcome [2] 392267 0
Evaluation of meibomian gland expressibility with slit lamp biomicroscopy and a diagnostic expression instrument (Korb Meibomian Gland Evaluator).
Timepoint [2] 392267 0
Measurements will be recorded at baseline and at monthly follow-up visits (1 month, 2 months, 3 months, 4 months, 5 months and 6 months) after assignment of treatment.
Secondary outcome [3] 392268 0
Change in Symptom Assessment in Dry Eye (SANDE) questionnaire score, which comprises of two questions that use a 100 mm horizontal linear visual analogue scale to quantify both severity and frequency of dry eye symptoms.
Timepoint [3] 392268 0
Measurements will be recorded at baseline and at monthly follow-up visits (1 month, 2 months, 3 months, 4 months, 5 months and 6 months) after assignment of treatment.
Secondary outcome [4] 392269 0
Change in Ocular Surface Disease Index (OSDI) questionnaire score.
Timepoint [4] 392269 0
Measurements will be recorded at baseline and at monthly follow-up visits (1 month, 2 months, 3 months, 4 months, 5 months and 6 months) after assignment of treatment. .
Secondary outcome [5] 392270 0
Change in Standardised Patient Evaluation of Eye Dryness (SPEED) questionnaire score.
Timepoint [5] 392270 0
Measurements will be recorded at baseline and at monthly follow-up visits (1 month, 2 months, 3 months, 4 months, 5 months and 6 months) after assignment of treatment.
Secondary outcome [6] 399345 0
Evaluation with standard clinical dyes (sodium fluorescein and lissamine green) that assess the health of ocular surface.
Timepoint [6] 399345 0
Measurements will be recorded at baseline and at monthly follow-up visits (1 month, 2 months, 3 months, 4 months, 5 months and 6 months) after assignment of treatment.
Secondary outcome [7] 399346 0
Clinical evaluation of tear osmolarity, using the TearLab device.
Timepoint [7] 399346 0
Measurements will be recorded at baseline and 6 months after assignment of treatment.

Eligibility
Key inclusion criteria
Key inclusion criteria: Participants with symptomatic dry eye due to evaporative causes (e.g. meibomian gland dysfunction).

Participants will be required to:
• Meet criteria for TFOS DEWS II dry eye diagnosis
• Be willing and able to follow the protocol accurately
• Be willing to minimise application of dry eye treatments beyond the study treatment

Inclusion criteria:
• Age 18 years or older, able and willing to comply with study instructions
• Minimum of 6 months since onset of self-reported dry eye symptoms
• Normal lid architecture, and closure
• Dry eye diagnosis according to the TFOS DEWS II diagnostic criteria (Symptoms: DEQ5 equal or greater than 6, or OSDI equal or greater than 13. Signs: equal or greater than 1 positive finding on NIKBUT (less than 10 s) / osmolarity (equal or greater than 308mOsm/L or interocular difference of greater than 8mOsm/L) / staining (greater than 5 corneal spots, 9 conjunctival spots; or lid wiper epitheliopathy of equal or greater than 2mm length and equal or greater than 25% lid margin width)
• Evidence of meibomian gland dysfunction (lipid layer grade equal or less than 2, meibomian gland capping grade equal or greater than 1, and/or meibomian gland expressibility score of equal or greater than grade 2)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:
• Patients with a small interpalpebral fissure unable to house the The Smart Tip Patient Interface
• Patients whose pupils have been pharmaceutically dilated, since the aversion response (i.e., rapid pupil constriction) may be diminished.
• Lid surface abnormalities (e.g., entropion, ectropion, tumor, edema, blepharospasm, lagophthalmos, severe trichiasis, severe ptosis) that affect lid function in either eye.
• Inability or unwillingness to commit to 6-month trial
• Refusal or inability to refrain from topical eye drop use, including artificial tear supplements, for equal or greater than 48 hours prior to baseline visit or within 24 hours of any subsequent study visit
• Refusal to limit topical supplement use to ‘rescue use’ only
• Refusal to be advised of incidental findings
• Wear of contact lenses within 48 hours of study commencement or during the study
• Warm compress therapy within 30 days of the screening visit
• Prior iLux or Lipiflow treatment
• Punctal plugs, unless non-dissolvable (silicone plugs or cautery of equal or greater than 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 (equal or 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 equal or greater than 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)
Treatment allocation will be randomised and prospectively investigator-masked to minimize risk of bias in clinical data interpretation. Randomisation to one of the two treatment groups (iLux or standard of care) will be derived by computer-generated random number allocation and applied to sequentially enrolled participants at each site. The randomisation schedule will be pre-determined prior to patient recruitment, such that the investigator involved in baseline participant assessment will have no influence in treatment allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Prospective, randomised, investigator-masked, parallel group, 6-month efficacy trial comparing a key Alcon treatment device to the existing standard of care (daily patient-applied warm compress and gland expression).
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size:
68 (34 in each group), bilateral evaluation. It is anticipated that 76 participants will be recruited in order to obtain the necessary sample size by 3 months, allowing for a 12% drop out. It is acknowledged that, due to the nature of the study, further drop out by the 6-month time point may occur. The statistics will be adjusted accordingly.

Justification:
Sample size requirements were determined from non-parametric adjusted power calculations conducted using NCSS PASS 2002 (Utah, USA), with lipid layer grade as the designated outcome, and the standard deviation estimated to be around 1 grade. The power calculation showed that a minimum of 34 participants per treatment group, or 68 participants in total, are required to detect a clinically significant difference of 1 lipid layer grade, with 80% power (ß equal 0.2), at a two-sided statistical significance level of 5% (a equal 0.05) and permit subgroup analysis according to severity. Allowing for a 12% participant dropout rate or loss to follow-up by 3-month review, this would mean that a total of 76 participants will need to be recruited (38 per group).

Statistical 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 greater than 0.05). Non-normally distributed continuous (NIKBUT) and ordinal data (LLG, gland expressibility score and LWE) will be converted to rank-values prior to undergoing analysis. Pre-specified multiplicity-adjusted post-hoc assessment of individual treatment and time effects will be conducted using Sidak's test. Categorical data (treatment satisfaction) will be compared using Fisher's exact test. All tests will be two-tailed and p less than 0.05 considered significant.

Analysis for time-course of improvement will be based on between-group comparisons. Whether maximal clinical improvement in signs and symptoms of meibomian gland dysfunction and dry eye disease observed between the two treatments might be influenced by the severity of baseline signs and symptoms (as defined by the TFOS DEWS II dry eye disease diagnostic criteria and meibomian gland dysfunction diagnostic criteria as described in the TFOS MGD report), 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.

The full 6-month data will inform the anticipated manuscript arising from this study.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2021
Actual
Date of last participant enrolment
Anticipated
1/05/2022
Actual
Date of last data collection
Anticipated
1/11/2022
Actual
Sample size
Target
76
Accrual to date
Final
Recruitment outside Australia
Country [1] 23487 0
New Zealand
State/province [1] 23487 0
Auckland region

Funding & Sponsors
Funding source category [1] 307107 0
Commercial sector/Industry
Name [1] 307107 0
Alcon Laboratories, Pty Ltd.
Country [1] 307107 0
Australia
Primary sponsor type
University
Name
The University of Auckland
Address
Private Bag 92019, Auckland 1142
Country
New Zealand
Secondary sponsor category [1] 310344 0
None
Name [1] 310344 0
Address [1] 310344 0
Country [1] 310344 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307221 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 307221 0
Ethics committee country [1] 307221 0
New Zealand
Date submitted for ethics approval [1] 307221 0
10/06/2021
Approval date [1] 307221 0
13/09/2021
Ethics approval number [1] 307221 0
21/NTB/159

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

Contacts
Principal investigator
Name 106458 0
Prof Jennifer P. Craig
Address 106458 0
Department of Ophthalmology, The University of Auckland, Private Bag 92019, Auckland 1142
Country 106458 0
New Zealand
Phone 106458 0
+64 09 923 8173
Fax 106458 0
Email 106458 0
jp.craig@auckland.ac.nz
Contact person for public queries
Name 106459 0
Jennifer P. Craig
Address 106459 0
Department of Ophthalmology, The University of Auckland, Private Bag 92019, Auckland 1142
Country 106459 0
New Zealand
Phone 106459 0
+64 09 923 8173
Fax 106459 0
Email 106459 0
jp.craig@auckland.ac.nz
Contact person for scientific queries
Name 106460 0
Jennifer P. Craig
Address 106460 0
Department of Ophthalmology, The University of Auckland, Private Bag 92019, Auckland 1142
Country 106460 0
New Zealand
Phone 106460 0
+64 09 923 8173
Fax 106460 0
Email 106460 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 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.