Cell Therapy in Failure Syndromes in Limbal Stem Cells (TC181)

Thérapie Cellulaire au Cours Des Syndromes d'Insuffisance en Cellules Souches Limbiques

Transplantation of allogeneic or autologous limbal epithelial stem cells cultured on human amniotic membrane with no feeders in eyes with total limbal deficiency. Prospective non-comparative monocentric study.

Study Overview

• Status: Completed
• Conditions: Limbal Deficiency
• Intervention / Treatment: Biological: epithelial stem cells cultured; Procedure: transplantation of cultured cells

Detailed Description

The limbal stem cell deficiency syndrome is characterized by invasion of the corneal surface by an epithelium with a conjunctival differentiation, and, clinically, by opacification and vascularization of the corneal epithelium with impaired corneal epithelial cicatrisation and corneal ulcers that may lead to corneal perforation. When total, the limbal deficiency syndrome is the cause of major disability. Vision decreases largely under the legal threshold of blindness. Overall, the most frequent etiology is by far the complete loss of limbal stem cells induced by severe ocular burns. Until a rather recent date, no treatment was possible in this pathology. Progress in the comprehension of the physiology of the corneal epithelium renewal made it possible to introduce a therapeutic approach, i.e., transplantation of cultured limbal stem cells retrieved from the healthy contralateral eye (autograft, unilateral diseases) or from a cadaveric donor eye (allograft, bilateral diseases or unique eye). Techniques of cell therapy were first described in Italy, Asia and in the USA with positive clinical results. They have all different processes for preparing the cell product to be transplanted and none answers the safety criteria required by the French legislation. The investigators developed a process for preparing a cell therapy product which was accepted by the French regulation agency (AFSSaPS) for a clinical trial (TC181) which began in 2007. The aims of the study are (1) evaluation of the clinical results of this technique in terms of improvement of visual function, reduction in the handicap, improvement of the anatomical condition of the ocular surface and restitution of the physiological function of the limbal epithelium and (2) evaluation of its possible side effects. It is a biphasic monocentric non-comparative prospective study including, according to the clinical responses observed during the first phase (plane of Gehan, ß = 10%), from 15 to 50 voluntary patients with unilateral or bilateral total limbal deficiency. Patient follow-up is 3 years. The expected minimal success rate is 20% for allografts and 40% for the autografts. Monitoring is ensured by URC-Est. The grafts are prepared by culture of autologous or allogeneic limbal epithelial cells from limbal explants on human amniotic membrane. The medical safety requirements relating to transplantation of tissues and cells are reached and the cell therapy products are secured at each stage of their preparation by conventional bacteriological and fungal tests and viral and bacterial PCR. The graft quality is controlled before transplantation. The main outcome measure is survival of the grafted epithelium (Kaplan-Meier method) defined by absence of recurrence of the clinical signs of limbal deficiency (opacification of the corneal epithelium, irregularity of the corneal epithelium, surface corneal vascularization) in the central cornea. The expected repercussions are (1) restitution of a limbal epithelial function allowing a clear corneal epithelium to be obtained, with no superficial vascularization nor chronic epithelial defects, (2) improvement of vision in blind patients, and (3) obtaining a vision higher than the legal threshold of blindness after cell therapy or after subsequent corneal transplantation. If the clinical trial makes it possible to show the effectiveness of this cell therapy technique, a request for authorization of process will be made at AFSSaPS for routine use.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75012
    • CHNO des Quinze-Vingts

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient age between 18 and 70 years
• Informed consent.
• Unilateral or bilateral limbal deficiency with diffuse opacification of the corneal epithelium, and superficial (or superficial and deep) corneal vascularization, and irregular corneal epithelial surface at slit-lamp examination with fluorescein, either associated with chronic epithelial defects
• Visual acuity of the eye to be treated < 20/20.
• Absence de kératinization of the ocular surface.
• Schirmer test > 0 at 3 minutes.
• For autografts : sérology HIV -, HCV -, HBs

Exclusion Criteria:

• Age < 18 y or > 70 y.
• Absence of informed consent or imformed consent not possible.
• Partial limbal deficiency (healthy corneal epithelium persistant in at least one zone).
• Previous treatment of limbal deficiency by limbal transplantation or amniotic membrane transplantation during the last 12 months.
• Conjunctival stem cell deficiency (xerophtalmia, keratinization of the ocular surface).
• Local anesthesia impossible.
• Immune keratitis not controlled by medical treatment.
• Ocular burn during the last 2 weeks.
• Corneal anesthesia.
• Pregnancy, breast-feeding.
• Allergy to steroid eyedrops.
• Active fungal keratitis.
• For autografts : risk factor for rabbies or Creutzfeldt-Jacob disease, serology HIV +, VHC +, HBs+.
• Follow-up not possible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tranplantation of cultured LSC in stage 3 limbal deficiency; Transplantation of Allogeneic or Autologous Limbal Epithelial Stem Cells Cultured on Human Amniotic Membrane with no Feeders in stage 3 unilateral or bilateral limbal stem cell deficiency.	Biological: epithelial stem cells cultured; transplantation of allogeneic or autologous limbal epithelial stem cells cultured on human amniotic membrane with no feeders; Procedure: transplantation of cultured cells; transplantation of allogeneic or autologous limbal epithelial stem cells cultured on human amniotic membrane with no feeders

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
survival of the transplanted epithelium	survival of the transplanted epithelium defined by absence of recurrence of the clinical signs of limbal deficiency (opacification of the corneal epithelium, irregularity of the corneal epithelium, surface corneal vascularization) in the central cornea.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
visual acuity	far best spectacle-corrected LogMAR visual acuity	3 years
re-epithelialization time after keratoplasty	The healing time of corneal epithelium will be collectively assed by investigators form the CRF and the pictures taken during the study.	3 years
Symptoms	Symptoms recorded at each visit: redness : absent (0) - present (1); pain : absent (0) - present (1); burning : absent (0) - present (1); foreign body sensation : absent (0) - present (1); photophobia : absent (0) - present (1); blurred vision : absent (0) - present (1) Grading of symptoms : sum of all symptoms (0-6)	3 years
morphometric analysis of the ocular surface	the morphometric analysis of the corneal epithelial ulcerations will be assed by the CRA from the pictures of the corneal surface.	3 years

Collaborators and Investigators

• Sponsor: Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts
• Collaborators: Etablissement Français du Sang
• Investigators: Principal Investigator: Vincent M Borderie, MD, PhD, CHNO des 15-20

Publications and helpful links

General Publications

• Borderie VM, Ghoubay D, Georgeon C, Borderie M, de Sousa C, Legendre A, Rouard H. Long-Term Results of Cultured Limbal Stem Cell Versus Limbal Tissue Transplantation in Stage III Limbal Deficiency. Stem Cells Transl Med. 2019 Dec;8(12):1230-1241. doi: 10.1002/sctm.19-0021. Epub 2019 Sep 5.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 1, 2007
• Primary Completion (ACTUAL): March 6, 2017
• Study Completion (ACTUAL): March 6, 2017

Study Registration Dates

• First Submitted: May 23, 2012
• First Submitted That Met QC Criteria: June 12, 2012
• First Posted (ESTIMATE): June 14, 2012

Study Record Updates

• Last Update Posted (ACTUAL): September 3, 2019
• Last Update Submitted That Met QC Criteria: August 29, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Transplantation; Cell therapy; Limbal stem cell; Limbal deficiency
• Other Study ID Numbers: PHRC 2001 (Other Grant/Funding Number: Ministry of Health); AOM01086 (OTHER: AFSSAPS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO