Use of 3% Diquafosol Topical Ophthalmic Solution for Diabetic Dry Eye

Study Overview
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Brief Summary
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Diquafosol ophthalmic solution (DQS) stimulates P2Y2 receptors on the ocular surface, which enhances mucin secretion from goblet cells. Therefore, tear film stability and hydration of the ocular surface can be achieved independent from lacrimal glands function. This prospective, open label pilot study will include 140 eyes of 70 diabetic patients diagnosed with DED and will be consecutively assigned to DQS (n=140 eyes). Participants in the DQS group will receive 3% Diquafosol ophthalmic solution. The dosage of 3% Diquafosol will be one drop, six times per day for 4 weeks. Tear film lipid layer (TFLL), non-invasive breakup time (NITBUT), corneoconjunctival staining score (CS), meibum gland (MG), conjunctival hyperemia (RS score), ocular surface disease index (OSDI) will be assessed and compared at baseline, day-14, and day-28.

Detailed Description
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This study will be conducted in compliance with the tenets of the Declaration of Helsinki and the Institutional Review Board of He Eye Specialist Hospital, Shenyang, China [ethics approval number: IRB(2022)K002.01] Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic illness that causes relative insulin insufficiency in target organs owing to pancreatic β-cell dysfunction and insulin resistance. Shift to sedentary lifestyle, ageing population and obesity has significantly contributed to the global rise in the prevalence of T2DM. In 2019 the prevalence of diabetes was documented to be 9.3% (463 million people) and in 2030 it is estimated to rise to 10.2% (578 million) and T2DM accounts for approximately 90% of all diabetic occurrence. Negative alterations to the tear film, corneal epithelium, corneal endothelium, and corneal nerves have been observed in 47-64% of patients with diabetes. Ocular surface manifestation of signs and symptoms secondary to DM has been termed as diabetic keratopathy (DK). DK has been documented to increase central corneal thickness[6], decrease in endothelial cell density, leads of superficial punctate keratitis[8], delay and impede wound repair[9], and decrease in corneal sensitivity due to neuropathy. Additionally, DM patients have also been noted to have compromised tear quantity and quality due to conjunctival goblet cell loss as documented on cytologic analysis. Goblet cells secrete mucin, which stabilizes the tear film, minimizes tear evaporation, and reduces mechanical friction. Goblet cell loss in animal models suggests that it disrupts the ocular surface's immune tolerance and increased expression of inflammatory cytokines in the conjunctiva. 0.1% hyaluronate (HA) used in artificial tears have been reported to promote corneal re-epithelium and improve corneal healing. Diquafosol tetrasodium is a dinucleotide polyphosphate which a purinoceptor agonist, when administered to the ocular surface, it binds to P2Y2 receptors and stimulates mucin and tear secretion. The corneal epithelium, conjunctival epithelium, lacrimal gland ductal epithelium, meibomian gland sebaceous cells, and meibomian gland ductal cells all express the P2Y2 receptor. Subsequently, enhanced secretion of mucin and tear secretion due to Diquafosol tetrasodium ophthalmic solution (DQS) stabilize the tear film, minimizes tear evaporation, and reduces mechanical friction thereby protecting the corneal epithelium [23]. Various reports have concluded that that 3% DQS is effective in the treatment of dry eye disease and the year 2020's findings suggest that DQS improves corneal epithelial damage in T2DM rat model. However, the effect of DQS on the tear film of T2DM humans has not been previously assessed. Therefore, the purpose s to assess subjective and objective diabetic dry eye findings after using 3% DQS topical eye drops.

Official Title
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3% Diquafosol Topical Ophthalmic Solution in Diabetic Patients With Dry Eye

Conditions
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Diabetic Eye Problems

Intervention / Treatment
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* Drug: 3% Diquafosol tetrasodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Clinical diagnosed and confirmed with type 2 diabetes for one year or more Able and willing to comply with the treatment/follow-up schedule Bilateral signs and symptoms of dry eye disease Exclusion Criteria: Participants with systemic immune-mediated illnesses, such as secondary Sjögren's syndrome or graft-versus-host disease Patients using topical medication(s) for the treatment of ocular disorders such as glaucoma or allergic conjunctivitis were excluded from the study. Previous ocular surgery or trauma 1-month history of blepharal and periorbital skin disease or allergies Severe dry eyes with corneal epithelial defect Limbic keratitis Pterygium Corneal neovascularization Glaucoma Breastfeeding Rheumatic immune systemic diseases Herpes zoster infection Pregnant women Allergic to fluorescein Contact lens wearers

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Supportive Care
Intervention Model: Single Group Assignment
Interventional Model Description: Prospective study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DQS group<br>Participants in DQS group will be administered one drop of 3% DQS (Diquas, Santen Pharmaceutical Co., Ltd., Osaka, Japan) six times per day for 4 weeks (28 days). | Drug: 3% Diquafosol tetrasodium<br>* 3% Diquafosol tetrasodium eye drops will be used to assess its usefulness in diabetic dry eye symptoms<br>* Other names: Diquas;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-invasive tear break-up time | Non-invasive initial tear film breaking time will be assessed using the Keratograph 5M (Oculus, Germany) topographer. Three sequentially readings will be captured, and the median value will be included in the final analysis. The median value will be recorded. | Day-0 (baseline), 4-weeks and 8-weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fluorescein and lissamine conjunctival and cornea staining | Fluorescein and lissamine staining of the ocular surface will be divided into three zones comprising nasal conjunctival, corneal, and temporal conjunctival areas. The staining score ranged from 0 to 3 for each zone, yielding a total score of 0-9 for the ocular surface (Uchino et al., 2012). | Day-0 (baseline), 4-weeks and 8-weeks | 
| Tear Film Lipid Layer Score | Tear Film Lipid Layer interferometry will be assessed using DR-1 (Kowa, Nagoya, Japan). - Tear Film Lipid Layer will be scored as follows: grade 1, somewhat gray color, uniform distribution; grade 2, somewhat gray color, nonuniform distribution; grade 3, a few colors, nonuniform distribution; grade 4, many colors, nonuniform distribution; grade 5, corneal surface partially exposed. | Day-0 (baseline), 4-weeks and 8-weeks | 
| Corneal Sensitivity Score | Corneal Sensitivity Score measured with Cochet-Bonnet esthesiometer (in mm filament length) two times (the measurements will be done immediately before starting the medication, including 3 measurements each time. | Day-0 (baseline), 4-weeks and 8-weeks | 
| MMP-9 detection | InflammaDry, (Rapid Pathogen Screening Inc., Sarasota, FL, USA) is a patented and proprietary modification of a traditional lateral flow device and uses direct sampling microfiltration technology. Two antigen-specific antibodies capture MMP-9 antigens in the sample, and this complex is captured in a proprietary mode at the test result line, giving rise to a visually observable signal. | Day-0 (baseline), 4-weeks and 8-weeks | 
| Tear meniscus height | Non-invasive first tear film breakup time using the Keratograph 5M (Oculus, Germany) topographer will be measured three times consecutively and the median value was recorded. of the three values was calculated. | Day-0 (baseline), 4-weeks and 8-weeks | 
| Conjunctival hyperemia (RS score) | Conjunctival hyperemia (RS score) will be assessed by keratograph image (Oculus, Germany) of 1156*873 pixels, redness score (RS) (accurate to 0.1 U) was displayed on the computer screen that ranged from 0.0 to 4.0. | Day-0 (baseline), 4-weeks and 8-weeks | 
| Meibomian gland function and secretion quality | Meibum quality will be assessed under a slit-lamp: Five meibomian gland in the middle parts of the eyelid will be assessed using a scale of 0 to 3 for each gland (0 represented clear meibum; 1 represented cloudy meibum; 2 represented cloudy and granular meibum; and 3 represented thick, toothpaste like consistency meibum). | Day-0 (baseline), 4-weeks and 8-weeks | 
| Corneal nerves and immune/inflammatory cells change | HRT III RCM, (Heidelberg Engineering GmbH, Dossenheim, Germany) will be used to record corneal nerves and immune/inflammatory cells change. A total of 5-8 sequence/volume scans were taken from the center of each cornea, focusing on all corneal layers: superficial, intermediate, and basal epithelial layers, sub-basal nerve plexus, anterior, central and posterior stroma, and endothelium. Special attention was given to the basal epithelial layer and sub-basal nerve plexus area to evaluate the nerve plexi and epithelial DC density. Three representative images of the sub-basal nerve plexus and epithelial DCs were selected for analysis for each eye, considering criteria such as whole image in the same layer, best focus and good contrast. | Day-0 (baseline), 4-weeks and 8-weeks | 
| Dry eye Questionnaire Score | Chinese translated version of the questionnaire will be used to assess the subjective dry eye symptoms. | Day-0 (baseline), 4-weeks and 8-weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dry eye, Diquafosol, Hyaluronate, Diabetic dry eye