Mechanisms of Light-based Therapies for Dry Eye Disease

Study Overview
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Brief Summary
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Dry eye disease is a common condition affecting millions worldwide and costing millions in healthcare due to reduced work productivity and quality of life. The disruption of oil glands in our eyelids known as Meibomian glands, which produce the oily layer of our tears to protect it from evaporating, is one of the most common contributors of dry eye disease. Much effort has been put into developing effective treatments for this condition as new treatments are constantly being introduced to the market. The purpose of this clinical trial is to investigate how proven light-based therapies work in treating dry eye disease and oil gland disruption. These therapies include intense-pulsed light therapy (IPL) which uses a series of light flashes on the facial skin surface, and low-level light therapy (LLLT) which uses a mask with a series of light-emitting diodes (LEDs) to warm the body cells. The main questions it aims to answer are: What are the short- and long-term changes associated with these treatments on the eyelids and surface of the eyes? Does LLLT alone work better than IPL+LLLT in treating dry eye disease and oil gland disruption? Participants with dry eye disease and oil gland disruption will receive four treatments with these light-based therapies each separated by two to three weeks apart, and followed up two to three weeks and three months after the final treatment session. One eye of the participant will receive intense pulsed light together with low-level light therapy, while the other eye will receive only low-level light therapy with a sham intense pulsed light treatment so that the researchers can compare if clinical signs and symptoms improve in one eye more than the other.

Detailed Description
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This study will be a randomized, double-masked, paired-eye clinical study to assess the potential difference in impact between the two treatment modalities. Each eye of the participant will be randomized to receive either IPL+LLLT or sham IPL+LLLT. The whole study involves a total of 6 visits (consisting of 4 treatment visits, and 2 follow-up visits). All visits will be conducted at the Aston Dry Eye Clinic in Aston University, Birmingham, United Kingdom.

Official Title
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Mechanisms of Action of Light-based Therapies in the Management of Dry Eye Disease and Meibomian Gland Dysfunction

Conditions
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Dry Eye Syndromes, Meibomian Gland Dysfunction

Intervention / Treatment
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* Device: Actual IPL
* Device: Sham IPL
* Device: LLLT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals with dry eye disease symptoms (Ocular Surface Disease Index questionnaire (OSDI) score ≥ 13 or Dry Eye Questionnaire (DEQ5) score > 6) and signs (tear film instability measured with non-invasive tear break-up time < 10 s or ocular surface damage measured using special dyes placed on the front surface of the eyes that temporarily stains any aggravated or damaged cells: > 5 corneal spots, > 9 conjunctival spots or lid margin staining ≥ 2mm in length and ≥ 25% in width) (Wolffsohn et al., 2017) Individuals need to also have Meibomian gland dysfunction. The diagnosis of Meibomian gland dysfunction depends on how many of 5 glands in the central lower eyelid can express oil, and the quality of the oil. A diagnosis is made if there is decreased expressibility (grade 1-3 on the Pflugfelder scale) and reduced quality of oil (grade 1-3 on Bron scale). Any presence of gland blockage and/or loss of oil glands grade 2 to grade 4 of either eyelid [Pult and Reide-Pult, 2013]) will also justify a diagnosis of Meibomian gland dysfunction Age ≥ 18 years, male or female Able to provide written consent in English Able to attend multiple visits (4 treatment visits) and followed up for 2 weeks and 3 months after final treatment Exclusion Criteria: Pregnancy Contraindications to IPL treatment (Individuals with darker skin types - Fitzpatrick skin type V or VI, photosensitive epilepsy, tattoos, implants, electrical or acoustic prosthetics, semi-permanent make-up, pigmented lesions or skin cancer in the treatment area, pacemakers, use of photosensitising medication the past 3 months or during treatment period) Facial or ocular IPL or LLLT treatment within the past 6 months or during study period in addition to those provided in the study Use of topical medical eyedrops in the past 3 months or during study period Contact lens wear in the past 2 weeks or during study period Systemic conditions that can cause dry eye disease or corneal nerve loss including diabetes and Sjögren's syndrome Other active ocular surface diseases or history of ocular surgery or corneal infections Individuals with 1 eye

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: One eye of the participant is randomised to receiving IPL and LLLT, while the other eye of the same participant will receive sham intense pulsed light therapy and low-level light therapy.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Actual IPL and LLLT<br>IPL and LLLT will be administered using the Espansione Group Ltd Eye-light unit. Five pulses of IPL will be administered along the lower lid region of the eye after the Pult meiboscore and Fitzpatrick skin grading has been entered into the unit. LLLT consisting of a wearable facial mask with red LEDs is then administered for 15 minutes. | Device: Actual IPL<br>* Five light pulses along lower lid region of one eye of the participant ranging from 59 to 69 Joules (J) over an area of 2.5cm by 4.5cm for each pulse<br>Device: LLLT<br>* Mask with LEDs transferring a total of about 32 J/cm^2 of energy to facial and eyelids region with their eyes closed<br>|
| Sham Comparator: Sham IPL and LLLT<br>Sham IPL will be administered by placing a separate empty IPL cartridge on the lower eyelid regions of the patient's other eye while a working IPL cartridge (Espansione Group Ltd Eye-light unit) simulates a light pulse pointed away from the patient's face, after entering the Pult meiboscore and Fitzpatrick skin grading into the unit. Five simulated pulses will be administered. LLLT consisting of a wearable facial mask with red LEDs is then administered for 15 minutes. | Device: Sham IPL<br>* Simulated five light pulses along lower lid region of the other eye of the same participant<br>Device: LLLT<br>* Mask with LEDs transferring a total of about 32 J/cm^2 of energy to facial and eyelids region with their eyes closed<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Non-invasive Tear Break Up Time to the Final Follow-up 3 Months After Final Treatment Session | Measure of the stability of tears and how fast the tears evaporate in seconds using the Oculus Keratograph 5M instrument. An average of 3 measurements is obtained. | Baseline and 3 months after final treatment session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Ocular Surface Disease Index scores to the Final Follow-up 3 Months After Final Treatment Session | Validated questionnaire for assessing dry eye symptom severity and impact. Scores range from 0 indicating no dry eye symptoms to 100 with severe dry eye symptoms and impact (Schiffman et al, 2000). | Baseline up to 3 months after final treatment session | 
| Change from Baseline in 5-Item Dry Eye Questionnaire scores to the Final Follow-up 3 Months After Final Treatment Session | Validated questionnaire for assessing dry eye symptom severity and frequency. Scores range from 0 indicating no dry eye symptoms to 22 with severe dry eye symptoms (Chalmers et al, 2010). | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Tear Meniscus Height to the Final Follow-up 3 Months After Final Treatment Session | Measure of the volume of tears in mm using the Oculus Keratograph 5M instrument. An average of 3 measurements is obtained. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Lipid Layer Pattern Grading to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of the appearance of the lipid layer pattern as a surrogate measure of its thickness using the Oculus Keratograph 5M instrument. This ranges from Grade 1 indicating very thin lipid layer to Grade 6 indicating very thick lipid layer. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Bulbar Conjunctival Hyperaemia to the Final Follow-up 3 Months After Final Treatment Session | Automated objective grading of the bulbar conjunctival redness using the Oculus Keratograph 5M instrument. This ranges from Grade 0 indicating no redness to Grade 4 indicating substantial redness. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Blink Rate to the Final Follow-up 3 Months After Final Treatment Session | Manual subjective count of the number of blinks using the Oculus Keratograph 5M instrument. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Visual Acuity to the Final Follow-up 3 Months After Final Treatment Session | Subjective measure of visual acuity using Logarithm of the Minimum Angle Resolution (logMAR) scoring, ranging from -0.30 which signify the ability to be able to resolve the smallest letters, to 1.00 which signify the ability to resolve only the largest letters. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Fluorescein Corneal Staining to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of the amount of corneal staining using fluorescein instillation, cobalt blue light illumination and the Oxford grading scale. This ranges from 0 with no staining to 5 with intense staining. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Lissamine Green Bulbar Conjunctival Staining to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of the amount of bulbar conjunctival staining using lissamine green instillation, white light illumination and the Oxford grading scale. This ranges from 0 with no staining to 5 with intense staining. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Lissamine Green Lid Wiper Epitheliopathy to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of the amount of lid wiper epitheliopathy using lissamine green instillation and white light illumination. This grading ranges from 0 with no lid wiper epitheliopathy to 4 with severe lid wiper epitheliopathy | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Meibography Meiboscore to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of the amount of Meibomian gland loss using infrared imaging and the Pult meiboscore. This grading ranges from 0 with no gland loss to 4 with severe gland loss (Pult and Reide-Pult, 2013). | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Demodex Presence to the Final Follow-up 3 Months After Final Treatment Session | Subjective assessment of the amount of Demodex present at the base of the lashes using slit lamp biomicroscopy and white light illumination (Muntz et al, 2020). | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Number of Blocked or Capped Meibomian Glands to the Final Follow-up 3 Months After Final Treatment Session | Subjective assessment of the number of blocked or capped Meibomian Glands using slit lamp biomicroscopy and white light illumination. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Lid Margin Telangiectasia Grading to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of the amount of telangiectasia at the lid margins using slit lamp biomicroscopy and white light illumination. This grading ranges from 0 with no telangiectasia to 3 with severe telangiectasia (Arita et al, 2016). | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Meibum Expressibility to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of meibum expressibility of lower eyelids using slit lamp biomicroscopy and white light illumination. This grading ranges from 0 with all glands being expressible to 3 with no glands being expressible (Tomlinson et al, 2011). | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Meibum Quality to the Final Follow-up 3 Months After Final Treatment Session | Subjective grading of meibum quality of lower eyelids using slit lamp biomicroscopy and white light illumination. This grading ranges from 0 with clear fluid being expressed to 3 with inspissated toothpaste-like expression (Tomlinson et al, 2011). | Baseline up to 3 months after final treatment session | 
| Number of Participants with Dry Eye Disease and Meibomian Gland Dysfunction | The number of participants diagnosed with dry eye disease and Meibomian gland dysfunction according to established clinical diagnostic criteria (Wolffsohn et al, 2017 ; Tomlinson et al, 2011). | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Total Corneal Nerve Length to the Final Follow-up 3 Months After Final Treatment Session | Measure of total corneal nerve length of sub-basal nerve plexi images obtained from in-vivo corneal confocal microscopy. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Blood Flow to the Final Follow-up 3 Months After Final Treatment Session | Measure of blood flow using laser doppler flowmetry instrument. | Baseline up to 3 months after final treatment session | 
| Change from Baseline in Tear Constituent to the Final Follow-up 3 Months After Final Treatment Session | Measure of tear constituent using Schirmer strip tear sampling technique. | Baseline up to 3 months after final treatment session | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intense pulsed light therapy, Low-level light therapy