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

Sponsor

He Eye Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05193331

Collaborator

Santen Pharmaceutical(China) Co.,LTD (Industry)

Enrollment

Location

Arm

Anticipated Duration (Days)

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Eye Problems	Drug: 3% Diquafosol tetrasodium	N/A

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Prospective studyProspective study

Masking:

None (Open Label)

Primary Purpose:

Supportive Care

Official Title:

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

Anticipated Study Start Date :

Apr 1, 2022

Anticipated Primary Completion Date :

Apr 30, 2022

Anticipated Study Completion Date :

May 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DQS group 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 3% Diquafosol tetrasodium eye drops will be used to assess its usefulness in diabetic dry eye symptoms Other Names: Diquas

Arm

Intervention/Treatment

Experimental: DQS group

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

3% Diquafosol tetrasodium eye drops will be used to assess its usefulness in diabetic dry eye symptoms

Other Names:

Diquas

Outcome Measures

Primary Outcome Measures

Non-invasive tear break-up time [Day-0 (baseline), day-14, and day-28]
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 day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
SPEED Questionnaire Score [Day-0 (baseline), day-14, and day-28]
Chinese translated version of the questionnaire will be used to assess the subjective dry eye symptoms. Changes at day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined. The participants grades the severity of their symptoms on a scale of zero to four with zero being no symptoms and four being intolerable symptoms. The total score can range from 0 to 28 that is the result of 8 items that assess frequency and severity of symptoms.
Tear Film Lipid Layer Score [Day-0 (baseline), day-14, and day-28]
Tear Film Lipid Layer interferometry will be assessed using DR-1 (Kowa, Nagoya, Japan). Changes at day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined. 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.

Secondary Outcome Measures

Fluorescein and lissamine conjunctival and cornea staining [Day-0 (baseline), day-14, and day-28]
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). Changes at day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
Tear meniscus height [Day-0 (baseline), day-14, and day-28]
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. Changes at day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
Quality of meibum grade [Day-0 (baseline), day-14, and day-28]
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 day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
Expressibility of meibum grade [Day-0 (baseline), day-14, and day-28]
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 day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
Conjunctivocorneal epithelial staining grade [Day-0 (baseline), day-14, and day-28]
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 day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
Conjunctival hyperemia (RS score) [Day-0 (baseline), day-14, and day-28]
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 day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
Corneal nerves and immune/inflammatory cells change [Day-0 (baseline), day-14, and day-28]
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. Changes at day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
MMP-9 detection [Day-0 (baseline), day-14, and day-28]
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. Changes at day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.
Corneal sensitivity score [Day-0 (baseline), day-14, and day-28]
Corneal sensitivity was determined by an esthesiometer (Cochet and Bonnet, Boca Raton, Florida), with the end point of blinking; 4 measurements will be taken for each eye and averaged. The values were determined directly from the protocol supplied by the manufacturer. Measurements of sensitivity will be conducted prior to other ocular tests. Changes at day-14 and day-28 will be compare with baseline measurements. Comparison between groups at baseline, day-14 and day-28 will also be examined.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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