Diquafosol Ophthalmic Solution for Dry Eye Symptoms

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. While it has been observed that 0.1 percent hyaluronate (HA) in artificial tears promotes corneal re-epithelium and improves corneal healing.This prospective, open label pilot study will include 60 eyes of 30 diabetic patients diagnosed with DED and will be randomly assigned to either DQS (n=30 eyes) or ATD group (n=30 eyes). Participants in the DQS group will receive 3% Diquafosol ophthalmic solution, while HA group will receive 0.1% Sodium hyaluronate artificial tears. The dosage for both drugs 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 (approval number: IRB2019.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 [1]. Shift to sedentary lifestyle, ageing population and obesity has significantly contributed to the global rise in the prevalence of T2DM [2]. 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[3]. Negative alterations to the tear film, corneal epithelium, corneal endothelium, and corneal nerves have been observed in 47-64% of patients with diabetes[4] [5]. 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[7], leads of superficial punctate keratitis[8], delay and impede wound repair[9], and decrease in corneal sensitivity due to neuropathy[10]. Additionally, DM patients have also been noted to have compromised tear quantity and quality[11][12] due to conjunctival goblet cell loss as documented on cytologic analysis [13]. 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 [14] and increased expression of inflammatory cytokines in the conjunctiva[15]. 0.1% hyaluronate (HA) used in artificial tears have been reported to promote corneal re-epithelium and improve corneal healing[16]. Additionally, HA has been reported to decrease the rate of tear evaporation and enhance the stability of tear film [17]. 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[18-20]. The corneal epithelium, conjunctival epithelium, lacrimal gland ductal epithelium, meibomian gland sebaceous cells, and meibomian gland ductal cells all express the P2Y2 receptor. [21,22]. 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 [24-26] and Dota et al.'s [19] 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 or 0.1% HA topical eye drops.

Official Title
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Impact of Diquafosol Ophthalmic Solution on Tear Film and Dry Eye Symptom in Type 2 Diabetic Dry Eye: A Four-week Randomized Control, Single Masked Pilot Study.

Conditions
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Diabetic Eye Problems

Intervention / Treatment
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* Drug: 3% Diquafosol tetrasodium
* Drug: 0.1% hyaluronate


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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, comparative pilot study
Masking: Triple


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 8 weeks. | 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;|
| Active Comparator: HA group<br>Participants in HA group will be administered one drop of 0.1% Sodium hyaluronate artificial tears (preservative free) six times per day for 8 weeks. | Drug: 0.1% hyaluronate<br>* 0.1% hyaluronate eye drops will be used to assess its usefulness in diabetic dry eye symptoms and compared to 3% Diquafosol tetrasodium eye drops.<br>* Other names: Artificial tears;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-invasive tear break-up time | Changes in 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. Changes at 4-weeks and 8-weeks will be compare with baseline measurements. Comparison between groups at baseline, 4-weeks and 8-weeks will also be examined | Day-0 (baseline), 4-weeks, 8-weeks | 
| Tear Film Lipid Layer | Tear Film Lipid Layer interferometry will be assessed using DR-1 (Kowa, Nagoya, Japan). Changes at 4-weeks and 8-weeks will be compare with baseline measurements. Comparison between groups at baseline, 4-weeks and 8-weeks will also be examined | Day-0 (baseline), 4-weeks, 8-weeks | 
| OSDI Score | Chinese translated, and validated OSDI (Allergan Inc, Irvine, USA) version will beused to assess and quantify DE symptom. The 12 items of the questionnaire can be tabulated into a score that ranges from 0 (no symptoms) to 100 (severe symptoms) points Changes at 4-weeks and 8-weeks will be compare with baseline measurements. Comparison between groups at baseline, 4-weeks and 8-weeks will also be examined | Day-0 (baseline), 4-weeks, 8-weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. Changes at 4-weeks and 8-weeks will be compare with baseline measurements. Comparison between groups at baseline, 4-weeks and 8-weeks will also be examined | Day-0 (baseline), 4-weeks, 8-weeks | 
| Quality of meibum grade | 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). Changes at 4-weeks and 8-weeks will be compare with baseline measurements. Comparison between groups at baseline, 4-weeks and 8-weeks will also be examined | Day-0 (baseline), 4-weeks, 8-weeks | 
| Expressibility of meibum grade | Meibum expressibility will be assessed under a slit-lamp: Eight meibomian glands in the middle part will be evaluated on a scale of 0 to 3 (0 denoted that all glands expressible; 1 denoted that 3 to 4 glands expressible; 2 denoted those 1 to 2 glands expressible; and 3 denoted that no glands were expressible). The overall score was computed using the mean scores of these eight glands. Changes at 4-weeks and 8-weeks will be compare with baseline measurements. Comparison between groups at baseline, 4-weeks and 8-weeks will also be examined | Day-0 (baseline), 4-weeks, 8-weeks | 
| Conjunctivocorneal epithelial staining grade | Conjunctivocorneal epithelial staining will be assessed under a slit-lamp: Conjunctivocorneal epithelial staining will be assess corneal and conjunctival epithelium damage. Double vital staining approach with two microliters of a preservative-free solution containing 1% lissamine green and 1% sodium fluorescein will be instilled in the conjunctival sac. The eye will be sectioned into three equal pieces (temporal conjunctiva, cornea, and nasal conjunctiva). Each region receives a maximum staining score of three points and a minimum of zero points. The combined scores from all three parts were then recorded on a scale ranging from 0 (normal) to 9 (severe). Changes at 4-weeks and 8-weeks will be compare with baseline measurements. Comparison between groups at baseline, 4-weeks and 8-weeks will also be examined | Day-0 (baseline), 4-weeks, 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