Diquafosol Ophthalmic Solution for Dry Eye Symptoms

Diabetic Eye Problems Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04980144
• Other study ID #: DMDEDQS-2021-1
• Status: Not yet recruiting
• Phase: N/A
• Start date: March 3, 2023
• Est. completion date: November 1, 2023

Study information

• Verified date: January 2023
• Source: He Eye Hospital
• Contact: Emmanuel Eric E Pazo, PhD
• Phone: 0086-18612782131
• Email: ericpazo[@]outlook.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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. 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.

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 (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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 101
• Est. completion date: November 1, 2023
• Est. primary completion date: August 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetic Eye Problems
• Dry Eye Syndromes
• Keratoconjunctivitis Sicca

Intervention

Drug:
• 3% Diquafosol tetrasodium
3% Diquafosol tetrasodium eye drops will be used to assess its usefulness in diabetic dry eye symptoms
• 0.1% hyaluronate
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.

Locations

Country	Name	City	State
China	He Eye Hospital	Shenyang	Liaoning

Sponsors (1)

Lead Sponsor	Collaborator
He Eye Hospital

Country where clinical trial is conducted

China, 

References & Publications (26)

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. — View Citation

Amano S, Inoue K. Effect of topical 3% diquafosol sodium on eyes with dry eye disease and meibomian gland dysfunction. Clin Ophthalmol. 2017 Sep 14;11:1677-1682. doi: 10.2147/OPTH.S148167. eCollection 2017. — View Citation

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):978. doi: 10.3390/ijms18050978. — View Citation

Chatterjee S, Khunti K, Davies MJ. Type 2 diabetes. Lancet. 2017 Jun 3;389(10085):2239-2251. doi: 10.1016/S0140-6736(17)30058-2. Epub 2017 Feb 10. Erratum In: Lancet. 2017 Jun 3;389(10085):2192. — View Citation

Cowlen MS, Zhang VZ, Warnock L, Moyer CF, Peterson WM, Yerxa BR. Localization of ocular P2Y2 receptor gene expression by in situ hybridization. Exp Eye Res. 2003 Jul;77(1):77-84. doi: 10.1016/s0014-4835(03)00068-x. — View Citation

Dogru M, Katakami C, Inoue M. Tear function and ocular surface changes in noninsulin-dependent diabetes mellitus. Ophthalmology. 2001 Mar;108(3):586-92. doi: 10.1016/s0161-6420(00)00599-6. — View Citation

Dota A, Sakamoto A, Nagano T, Murakami T, Matsugi T. Effect of Diquafosol Ophthalmic Solution on Airflow-Induced Ocular Surface Disorder in Diabetic Rats. Clin Ophthalmol. 2020 Apr 1;14:1019-1024. doi: 10.2147/OPTH.S242764. eCollection 2020. — View Citation

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. — View Citation

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. doi: 10.1038/sj.eye.6701497. — View Citation

Jeon HS, Hyon JY. The Efficacy of Diquafosol Ophthalmic Solution in Non-Sjogren and Sjogren Syndrome Dry Eye Patients Unresponsive to Artificial Tear. J Ocul Pharmacol Ther. 2016 Sep;32(7):463-8. doi: 10.1089/jop.2015.0081. Epub 2016 Jun 13. — View Citation

Ji YW, Kim HM, Ryu SY, Oh JW, Yeo A, Choi CY, Kim MJ, Song JS, Kim HS, Seo KY, Kim KP, Lee HK. Changes in Human Tear Proteome Following Topical Treatment of Dry Eye Disease: Cyclosporine A Versus Diquafosol Tetrasodium. Invest Ophthalmol Vis Sci. 2019 Dec — View Citation

Jumblatt JE, Jumblatt MM. Regulation of ocular mucin secretion by P2Y2 nucleotide receptors in rabbit and human conjunctiva. Exp Eye Res. 1998 Sep;67(3):341-6. doi: 10.1006/exer.1998.0520. — View Citation

Kaido M, Kawashima M, Shigeno Y, Yamada Y, Tsubota K. Randomized Controlled Study to Investigate the Effect of Topical Diquafosol Tetrasodium on Corneal Sensitivity in Short Tear Break-Up Time Dry Eye. Adv Ther. 2018 May;35(5):697-706. doi: 10.1007/s12325 — View Citation

Kulkarni AA, Trousdale MD, Stevenson D, Gukasyan HJ, Shiue MH, Kim KJ, Read RW, Lee VH. Nucleotide-induced restoration of conjunctival chloride and fluid secretion in adenovirus type 5-infected pigmented rabbit eyes. J Pharmacol Exp Ther. 2003 Jun;305(3): — View Citation

Lee JS, Oum BS, Choi HY, Lee JE, Cho BM. Differences in corneal thickness and corneal endothelium related to duration in diabetes. Eye (Lond). 2006 Mar;20(3):315-8. doi: 10.1038/sj.eye.6701868. — View Citation

Marko CK, Menon BB, Chen G, Whitsett JA, Clevers H, Gipson IK. Spdef null mice lack conjunctival goblet cells and provide a model of dry eye. Am J Pathol. 2013 Jul;183(1):35-48. doi: 10.1016/j.ajpath.2013.03.017. Epub 2013 May 10. — View Citation

Murphy PJ, Patel S, Kong N, Ryder RE, Marshall J. Noninvasive assessment of corneal sensitivity in young and elderly diabetic and nondiabetic subjects. Invest Ophthalmol Vis Sci. 2004 Jun;45(6):1737-42. doi: 10.1167/iovs.03-0689. — View Citation

Ohashi Y, Munesue M, Shimazaki J, Takamura E, Yokoi N, Watanabe H, Nomura A, Shimada F. Long-Term Safety and Effectiveness of Diquafosol for the Treatment of Dry Eye in a Real-World Setting: A Prospective Observational Study. Adv Ther. 2020 Feb;37(2):707- — View Citation

Park Y, Song JS, Choi CY, Yoon KC, Lee HK, Kim HS. A Randomized Multicenter Study Comparing 0.1%, 0.15%, and 0.3% Sodium Hyaluronate with 0.05% Cyclosporine in the Treatment of Dry Eye. J Ocul Pharmacol Ther. 2017 Mar;33(2):66-72. doi: 10.1089/jop.2016.00 — View Citation

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 fo — View Citation

Sagdik HM, Ugurbas SH, Can M, Tetikoglu M, Ugurbas E, Ugurbas SC, Alpay A, Ucar 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):13 — View Citation

Shih KC, Lam KS, Tong L. A systematic review on the impact of diabetes mellitus on the ocular surface. Nutr Diabetes. 2017 Mar 20;7(3):e251. doi: 10.1038/nutd.2017.4. — View Citation

Tanioka H, Kuriki Y, Sakamoto A, Katsuta O, Kawazu K, Nakamura M. Expression of the P2Y(2) receptor on the rat ocular surface during a 1-year rearing period. Jpn J Ophthalmol. 2014 Nov;58(6):515-21. doi: 10.1007/s10384-014-0342-4. Epub 2014 Sep 2. — View Citation

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Yuko, T.S.; NAKAMURA, M. Stimulatory Effect of Diquafosol Tetrasodium on the Expression of Membrane-Binding Mucin Genes in Cultured Human Corneal Epithelial Cells. Journal of the eye 2011, 28, 425-429.

* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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