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

Overview

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.

Full Title of Study: “Prospective Single Masked Study of 3% Diquafosol Topical Ophthalmic Solution in Diabetic Patients With Dry Eye.”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Supportive Care
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 31, 2022

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 (pending approval number: IRB2021.xxxxxxxxxxxxxxxx). 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.

Interventions

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

Arms, Groups and Cohorts

  • 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).

Clinical Trial Outcome Measures

Primary Measures

  • Non-invasive tear break-up time
    • Time Frame: 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
    • Time Frame: 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.
  • Tear Film Lipid Layer
    • Time Frame: 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.

Secondary Measures

  • Fluorescein and lissamine conjunctival and cornea staining
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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)
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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.

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 99 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • He Eye Hospital
  • Collaborator
    • Santen Pharmaceutical(China) Co.,LTD
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Emmanuel E Pazo, PhD, Study Chair, He Eye Hospital, Shenyang, China
  • Overall Contact(s)
    • Emmanuel E Pazo, PhD, 0086-18612782131, ericpazo@outlook.com

Citations Reporting on Results

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Weisman A, Fazli GS, Johns A, Booth GL. Evolving Trends in the Epidemiology, Risk Factors, and Prevention of Type 2 Diabetes: A Review. Can J Cardiol. 2018 May;34(5):552-564. doi: 10.1016/j.cjca.2018.03.002. Epub 2018 Mar 13. Review.

Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D, Williams R; IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract. 2019 Nov;157:107843. doi: 10.1016/j.diabres.2019.107843. Epub 2019 Sep 10.

Abdelkader H, Patel DV, McGhee CNj, Alany RG. New therapeutic approaches in the treatment of diabetic keratopathy: a review. Clin Exp Ophthalmol. 2011 Apr;39(3):259-70. doi: 10.1111/j.1442-9071.2010.02435.x. Epub 2011 Apr 4. Review.

Vieira-Potter VJ, Karamichos D, Lee DJ. Ocular Complications of Diabetes and Therapeutic Approaches. Biomed Res Int. 2016;2016:3801570. doi: 10.1155/2016/3801570. Epub 2016 Mar 28. Review.

El-Agamy A, Alsubaie S. Corneal endothelium and central corneal thickness changes in type 2 diabetes mellitus. Clin Ophthalmol. 2017 Mar 2;11:481-486. doi: 10.2147/OPTH.S126217. eCollection 2017.

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Inoue K, Okugawa K, Amano S, Oshika T, Takamura E, Egami F, Umizu G, Aikawa K, Kato S. Blinking and superficial punctate keratopathy in patients with diabetes mellitus. Eye (Lond). 2005 Apr;19(4):418-21.

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Sağdık HM, Ugurbas SH, Can M, Tetikoğlu M, Ugurbas E, Uğurbaş SC, Alpay A, Uçar F. Tear film osmolarity in patients with diabetes mellitus. Ophthalmic Res. 2013;50(1):1-5. doi: 10.1159/000345770. Epub 2013 Feb 22. Erratum in: Ophthalmic Res. 2013;50(2):134. Can, M [added]; Ugurbas, E [added]; Alpay, A [added].

Barbosa FL, Xiao Y, Bian F, Coursey TG, Ko BY, Clevers H, de Paiva CS, Pflugfelder SC. Goblet Cells Contribute to Ocular Surface Immune Tolerance-Implications for Dry Eye Disease. Int J Mol Sci. 2017 May 5;18(5). pii: E978. doi: 10.3390/ijms18050978.

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