Allogeneic Tissue Engineering (Nanostructured Artificial Human Cornea) in Patients With Corneal Trophic Ulcers in Advanced Stages, Refractory to Conventional (Ophthalmic) Treatment

Study Overview
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Brief Summary
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This is a prospective, phase I-II, randomised, open-label clinical trial that will evaluate the safety and feasibility, as well as clinical efficacy evidence, of a bioengineered anterior corneal substitute in adults with severe trophic corneal ulcers. This model of human anterior allogeneic cornea will provide an alternative approach in cases where human donor keratoplasty is not an option.

Detailed Description
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This is a phase I-II, randomised, controlled, open-label clinical trial, currently ongoing in eleven Spanish hospitals, to evaluate the safety and feasibility, as well as clinical efficacy evidence, of a bioengineered human anterior corneal substitute in adults with severe trophic corneal ulcers refractory to conventional treatment, or with sequelae of previous ulcers. In the initial phase of the trial (n=5), patients were sequentially recruited, with a safety period of 45 days, receiving the bioengineered corneal graft. In the second phase of the trial (currently ongoing), subjects are block randomised (2:1) to receive either the corneal graft (n=10), or amniotic membrane (n=5), as the control treatment. Adverse events, implant status, infection signs and induced neovascularization are evaluated as determinants of safety and feasibility of the bioengineered graft (main outcomes). Study endpoints are measured along a follow-up period of 24 months, including 27 post-implant assessment visits according to a decreasing frequency. Intention to treat, and per protocol, and safety analysis will be performed.

Official Title
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Multicenter Clinical Trial to Evaluate the Safety and Feasibility of an Allogeneic Tissue Engineered Drug (Nanostructured Artificial Human Cornea) in Patients With Corneal Trophic Ulcers Refractory to Conventional Treatment

Conditions
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Severe Trophic Corneal Ulcers Refractory to Conventional Treatment, Sequelae of Previous Trophic Corneal Ulcers

Intervention / Treatment
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* Drug: Anterior lamellar nanostructured artificial human cornea.
* Other: Amniotic membrane transplantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Man or woman aged≥18, with no upper age limit. Patients that give their informed consent for study participation. Stage 3 Mackie corneal ulcers that do not respond to conventional medical treatment, or patients having undergone previous stage 3 Mackie corneal ulcers,33 currently suffering sequelae such as stromal fibrosis or corneal thinning, having no effective therapeutic alternative. Stromal involvement, not reaching the Descemet membrane. Central or peripheral localization. Minimum duration of the disease causing the corneal ulcer: 6 weeks. No active ocular infection. Patients with normal laboratory parameters as defined by: Leukocytes≥3000 cells/µL; Neutrophils≥1500 cells/µL; Platelets≥100 billion/L; AST/ALT≤1.5 ULN; Creatinine≤1.5 mg/dL. Exclusion Criteria: Absence of stromal involvement. Good response to standard medical treatments for corneal disease in less than 3 to 5 weeks. Bullous keratopathy or other endothelial decompensations. Active ocular infection. Positive serology to HBV, HCV, HIV or any other pathology that may interfere with correct patient follow-up. Pregnant or breast-feeding women or childbearing-age women that do not consent the use of contraceptive methods approved in the protocol. Medical history of active neoplasia within the past 5 years. Participation in other clinical trials in 3 months previous to inclusion, or in the previous 5 years for trials with advanced therapies.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Bioengineered anterior human corneal substitute Amniotic membrane corneal graft
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anterior lamellar nanostructured artificial human cornea<br>Anterior lamellar nanostructured artificial human cornea with allogenic from dead donor and cultured in its inside and allogeneic corneal epithelium cultured in its surface | Drug: Anterior lamellar nanostructured artificial human cornea.<br>* Implantation of an anterior lamellar nanostructured artificial human cornea with allogeneic cells from dead donors embedded in a fibrin-agarose scaffold<br>* Other names: Bioengineered human anterior corneal substitute;|
| Active Comparator: Amniotic membrane transplantation<br>Amniotic membrane transplantation as conventional treatment of corneal trophic ulcers. | Other: Amniotic membrane transplantation<br>* Implantation of an amniotic membrane graft to cover the corneal scarring using the mixed graft/patch technique.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events (and serious adverse events) causally related to experimental treatment. |  | 24 months | 
| Implant status (integrity, detachment and reabsorption) |  | 24 months | 
| Local, regional or systemic infections related with the implant |  | 24 months | 
| Induced corneal neovascularization |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ulcer persistency or relapse and corneal stromal repair |  | 24 months | 
| Visual acuity |  | 24 months | 
| Corneal transparency |  | 24 months | 
| Tear function (TBUT and Schirmer) |  | 24 months | 
| Quality of life (EQ-5) |  | 24 months | 
| Induced chronic ocular complications |  | 24 months | 
| In vivo confocal microscopy (IVCM) analysis of the grafted bioengineered cornea (and AM) |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Corneal trophic ulcers, limbal deficiency, cornea blindness