Clinical trial NCT04995926: Labial Mucosal Epithelium Grafting for Corneal Limbus Substitution
Official title: Efficiency and Safety of Labial Mucosal Epithelium Grafting for Corneal Reepithelization in Patients With Bilateral Non-immunogenic Limbal Stem Cell Deficiency
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Limbal Stem-cell Deficiency
Keywords: Limbal Stem Cell Deficiency
Lead sponsor: The S.N. Fyodorov Eye Microsurgery State Institution
Sponsor class: OTHER_GOV
First posted: 2021-08-09
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Earlier approaches for cornea reepithelization in patients with bilateral LSCD included allogeneic corneal limbus grafting from postmortem donor or livingrelated relatives with concomitant systemic immunosuppression (Cheung and Holland, 2017) and cultivated oral mucosal epithelial transplantation (COMET) (Nishida et al., 2004).

The novel surgical technique for corneal re-epithelization were described by Liu et al. (2011) and Choe et al. (2019). In both clinical studies, the autologous labial mucosal epithelium graft was transplanted as a surrogate corneal limbus for purpose of treatment the LSCD. Authors reported positive outcomes in terms of anatomical success and corneal status improvement.

The purpose of the study is to evaluate the feasibility of the novel surgical intervention in clinical use.

Detailed description: Earlier approaches for cornea reepithelization in patients with bilateral LSCD included allogeneic corneal limbus grafting from postmortem donor or livingrelated relatives with concomitant systemic immunosuppression (Cheung and Holland, 2017) and cultivated oral mucosal epithelial transplantation (COMET) (Nishida et al., 2004).

The novel surgical technique for corneal re-epithelization were described by Liu et al. (2011) and Choe et al. (2019). In both clinical studies, the autologous labial mucosal epithelium graft was transplanted as a surrogate corneal limbus for purpose of treatment the LSCD. Authors reported positive outcomes in terms of anatomical success and corneal status improvement.

Lip oral mucosa is a promising autologous source of epithelial cell for the trial because it has similar histological characteristic as the normal corneal. In particular, lip oral mucosal epithelium is stratified squamous and nonkeratinized.

The indicated histological and molecular features of the lip oral mucosal epithelium predetermined the use of labial mucosal epithelial graft for treatment patients with bilateral LSCD.

The purpose of the study is to confirm the validity of the hypothesis about the possibility of re-epithelialization diseased cornea using labial mucosal epithelium graft as a surrogate limbus in patients with bilateral LSCD.

Eligibility criteria: Inclusion Criteria:

* Man or woman 18 years and older.
* Signed informed consent, given by the participant or his/her legal representative.
* Ability to understand Russian spoken and written language.
* Sanitated oral cavity.
* Bilateral limbal stem cell deficiency diagnosed by two or more symptoms during slit-lamp examination: corneal conjunctivalization, absence of palisades of Vogt, superficial corneal neovascularization, recurrent or persistent corneal epithelium erosion.
* Bilateral limbal stem cell deficiency non-immunogenic etiology (burns, irradiation, contact lens related, etc.).
* Best-corrected visual acuity less than 0.3 (6/18 Snellen chart)
* Intraocular pressure in normal range.
* Schirmer's test I more than 5 mm.

Exclusion Criteria:

* Inability to give signed informed consent.
* Age under 18 years.
* Pregnancy and/or breastfeeding.
* Hormonal contraceptives intake.
* History of allergic reactions to antibiotics, glucocorticosteroids, remedies for treatment dry eye syndrome, medications for local and general anesthesia.
* Participation in other clinical trials.
* Systemic immunosuppression intake.
* Diagnosed neoplastic process or treatment for it.
* Positive tests for infectious: HIV, syphilis, Hepatitis B, Hepatitis C.
* Any medical, psychiatric and/or condition, including cachexia, or social conditions that the investigator believes would interfere with or contraindicate adherence to the research protocol or the ability to provide signed informed consent.
* Immune-mediated limbal stem cell deficiency (Stevens-Johnson syndrome, ocular cicatricial pemphigoid and other.), unknown and/or inherited etiology.
* Best-corrected visual acuity more than 0.3 (6/18 Snellen chart)
* Ocular burns earlier than 12 months.
* Keratoplasty earlier than 12 months.
* Limbal grafting (from postmortem or living-related donors).
* Keratoprosthetic device or history of its implantation.
* Cellular therapy for treatment of limbal stem cell deficiency.
* Cellular transplantation for treatment of limbal stem cell deficiency.
* Active ophthalmic infection.
* Symblepharon, ectropion, trichiasis, lagophthalmos and/or other lid and/or conjunctival fornixes abnormalities.
* Surgery on ocular adnexa earlier than 9 months.
* Corneal stromal thickness less than 300 mkm.
* Dry eye with Schirmer test I less than 5 mm and/or keratinized ocular surface.
* Uncontrolled glaucoma and/or presents of a glaucoma drainage device.
* Retinal defunctioning (no light perception and/or retinal detachment).
* Absence of the electric activity of the optic nerve and/or retina.

Primary outcomes:
measure: Anatomical success
timeFrame: 12 months
Secondary outcomes:
measure: Number of participants with improvement in corneal status
timeFrame: 12 months
measure: Functional success
timeFrame: 12 months
measure: Rate of complications
timeFrame: 12 months
Other outcomes:
Locations:
city: Moscow
country: Russian Federation
facility: The S. Fyodorov Eye Microsurgery Federal State Institution
Study officials:
affiliation: The S. Fyodorov Eye Microsurgery Federal State Institution
name: Boris E Malyugin, MD PhD Prof
role: PRINCIPAL_INVESTIGATOR
References:
citation: Malyugin B.E., Borzenok S.A., Gerasimov M.Y. Clinical outcomes of autologous cultured oral mucosal epithelium transplantation for treatment of limbal stem cell deficiency. Fyodorov Journal of Ophthalmic Surgery. 2020;(4):77-85. (In Russ.) doi:10.25276/0235-4160-2020-4-77-85
citation: Borzenok S.A., Gerasimov M.Yu., Ostrovskiy D.S., Malyugin B.E. Culture of human labial mucosal epithelial cell for use in patients with bilateral limbal stem cell deficiency. Russian Journal of Transplantology and Artificial Organs. 2019;21(3):111-120. doi:10.15825/1995-1191-2019-3-111-120
citation: Cabral JV, Jackson CJ, Utheim TP, Jirsova K. Ex vivo cultivated oral mucosal epithelial cell transplantation for limbal stem cell deficiency: a review. Stem Cell Res Ther. 2020 Jul 21;11(1):301. doi: 10.1186/s13287-020-01783-8.
citation: Campbell JDM, Ahmad S, Agrawal A, Bienek C, Atkinson A, Mcgowan NWA, Kaye S, Mantry S, Ramaesh K, Glover A, Pelly J, MacRury C, MacDonald M, Hargreaves E, Barry J, Drain J, Cuthbertson B, Nerurkar L, Downing I, Fraser AR, Turner ML, Dhillon B. Allogeneic Ex Vivo Expanded Corneal Epithelial Stem Cell Transplantation: A Randomized Controlled Clinical Trial. Stem Cells Transl Med. 2019 Apr;8(4):323-331. doi: 10.1002/sctm.18-0140. Epub 2019 Jan 28.
citation: Choe HR, Yoon CH, Kim MK. Ocular Surface Reconstruction Using Circumferentially-trephined Autologous Oral Mucosal Graft Transplantation in Limbal Stem Cell Deficiency. Korean J Ophthalmol. 2019 Feb;33(1):16-25. doi: 10.3341/kjo.2018.0111.
citation: Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JAP, Pellegrini G, Shimmura S, Kruse FE; and The International Limbal Stem Cell Deficiency Working Group. Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea. 2019 Mar;38(3):364-375. doi: 10.1097/ICO.0000000000001820.
citation: Deng SX, Kruse F, Gomes JAP, Chan CC, Daya S, Dana R, Figueiredo FC, Kinoshita S, Rama P, Sangwan V, Slomovic AR, Tan D; and the International Limbal Stem Cell Deficiency Working Group. Global Consensus on the Management of Limbal Stem Cell Deficiency. Cornea. 2020 Oct;39(10):1291-1302. doi: 10.1097/ICO.0000000000002358.
citation: Holland EJ, Mogilishetty G, Skeens HM, Hair DB, Neff KD, Biber JM, Chan CC. Systemic immunosuppression in ocular surface stem cell transplantation: results of a 10-year experience. Cornea. 2012 Jun;31(6):655-61. doi: 10.1097/ICO.0b013e31823f8b0c.
citation: Inamochi A, Tomioka A, Kitamoto K, Miyai T, Usui T, Aihara M, Yamagami S. Simple oral mucosal epithelial transplantation in a rabbit model. Sci Rep. 2019 Dec 2;9(1):18088. doi: 10.1038/s41598-019-54571-7.
citation: Li W, Li Q, Wang W, Li K, Ling S, Yang Y, Liang L. A rat model of autologous oral mucosal epithelial transplantation for corneal limbal stem cell failure. Eye Sci. 2014 Mar;29(1):1-5.
citation: Liu J, Sheha H, Fu Y, Giegengack M, Tseng SC. Oral mucosal graft with amniotic membrane transplantation for total limbal stem cell deficiency. Am J Ophthalmol. 2011 Nov;152(5):739-47.e1. doi: 10.1016/j.ajo.2011.03.037. Epub 2011 Jul 30.
citation: Nakamura T, Endo K, Cooper LJ, Fullwood NJ, Tanifuji N, Tsuzuki M, Koizumi N, Inatomi T, Sano Y, Kinoshita S. The successful culture and autologous transplantation of rabbit oral mucosal epithelial cells on amniotic membrane. Invest Ophthalmol Vis Sci. 2003 Jan;44(1):106-16. doi: 10.1167/iovs.02-0195.
citation: Nishida K, Yamato M, Hayashida Y, Watanabe K, Yamamoto K, Adachi E, Nagai S, Kikuchi A, Maeda N, Watanabe H, Okano T, Tano Y. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N Engl J Med. 2004 Sep 16;351(12):1187-96. doi: 10.1056/NEJMoa040455.
citation: Oliva J, Bardag-Gorce F, Niihara Y. Clinical Trials of Limbal Stem Cell Deficiency Treated with Oral Mucosal Epithelial Cells. Int J Mol Sci. 2020 Jan 9;21(2):411. doi: 10.3390/ijms21020411.