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

Overview

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.

Full Title of Study: “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”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 14, 2021

Detailed Description

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.

Interventions

  • Drug: Anterior lamellar nanostructured artificial human cornea.
    • Implantation of an anterior lamellar nanostructured artificial human cornea with allogeneic cells from dead donors embedded in a fibrin-agarose scaffold
  • Other: Amniotic membrane transplantation
    • Implantation of an amniotic membrane graft to cover the corneal scarring using the mixed graft/patch technique.

Arms, Groups and Cohorts

  • Experimental: Anterior lamellar nanostructured artificial human cornea
    • Anterior lamellar nanostructured artificial human cornea with allogenic from dead donor and cultured in its inside and allogeneic corneal epithelium cultured in its surface
  • Active Comparator: Amniotic membrane transplantation
    • Amniotic membrane transplantation as conventional treatment of corneal trophic ulcers.

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Andalusian Initiative for Advanced Therapies – Fundación Pública Andaluza Progreso y Salud
  • Collaborator
    • Iniciativa Andaluza en Terapias Avanzadas
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Santiago Medialdea, MD, PhD, Study Director, Hospital U Virgen de las Nieves
    • Miguel Alaminos, MD, PhD, Study Chair, Universidad de Granada

References

Gonzalez-Andrades M, Mata R, Gonzalez-Gallardo MDC, Medialdea S, Arias-Santiago S, Martinez-Atienza J, Ruiz-Garcia A, Perez-Fajardo L, Lizana-Moreno A, Garzon I, Campos A, Alaminos M, Carmona G, Cuende N. A study protocol for a multicentre randomised clinical trial evaluating the safety and feasibility of a bioengineered human allogeneic nanostructured anterior cornea in patients with advanced corneal trophic ulcers refractory to conventional treatment. BMJ Open. 2017 Sep 24;7(9):e016487. doi: 10.1136/bmjopen-2017-016487.

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