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

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

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.

Study Overview

• Status: Completed
• Conditions: Severe Trophic Corneal Ulcers Refractory to Conventional Treatment; Sequelae of Previous Trophic Corneal Ulcers
• Intervention / Treatment: Drug: Anterior lamellar nanostructured artificial human cornea.; Other: Amniotic membrane transplantation

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Spain
  • Bormujos, Spain
    • Hospital San Juan de Dios
  • Cádiz, Spain, 11009
    • University Hospital Puerta del Mar
  • Córdoba, Spain
    • Hospital Universitario Reina Sofía
  • Córdoba, Spain
    • Hospital La Arruzafa
  • Granada, Spain, 18012
    • University Hospital San Cecilio
  • Granada, Spain, 18014
    • University Hospital Virgen de las Nieves
  • Marbella, Spain
    • Hospital Costa del Sol
  • Málaga, Spain
    • Marina Rodriguez Calvo-Mora
  • Sevilla, Spain, 41009
    • University Hospital Virgen Macarena
  • Sevilla, Spain
    • Hospital Nuestra Senora de Valme
  • Sevilla, Spain, 41013
    • University Hospital Virgen de Rocío

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	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 Names: Bioengineered human anterior corneal substitute
ACTIVE_COMPARATOR: Amniotic membrane transplantation; Amniotic membrane transplantation as conventional treatment of corneal trophic ulcers.	Other: Amniotic membrane transplantation; Implantation of an amniotic membrane graft to cover the corneal scarring using the mixed graft/patch technique.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Andalusian Initiative for Advanced Therapies - Fundación Pública Andaluza Progreso y Salud
• Collaborators: Iniciativa Andaluza en Terapias Avanzadas
• Investigators: Study Director: Santiago Medialdea, MD, PhD, Hospital U Virgen de las Nieves; Study Chair: Miguel Alaminos, MD, PhD, Universidad de Granada

Publications and helpful links

General Publications

• 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.

Helpful Links

• Andalusian Initiative for Advanced Therapies

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 17, 2014
• Primary Completion (ACTUAL): January 14, 2021
• Study Completion (ACTUAL): January 14, 2021

Study Registration Dates

• First Submitted: January 9, 2013
• First Submitted That Met QC Criteria: January 9, 2013
• First Posted (ESTIMATE): January 10, 2013

Study Record Updates

• Last Update Posted (ACTUAL): January 20, 2021
• Last Update Submitted That Met QC Criteria: January 19, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Corneal trophic ulcers, limbal deficiency, cornea blindness
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Eye Diseases; Keratitis; Corneal Diseases; Eye Infections; Ulcer; Corneal Ulcer
• Other Study ID Numbers: CAH/Ulc/2010; 2010-024290-40 (EUDRACT_NUMBER)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No