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

Abstract

Introduction: There is a need to find alternatives to the use of human donor corneas in transplants because of the limited availability of donor organs, the incidence of graft complications, as well as the inability to successfully perform corneal transplant in patients presenting limbal deficiency, neo-vascularized or thin corneas, etc. We have designed a clinical trial to test a nanostructured fibrin-agarose corneal substitute combining allogeneic cells that mimics the anterior human native cornea in terms of optical, mechanical and biological behaviour.

Methods and analysis: This is a phase I-II, randomised, controlled, open-label clinical trial, currently ongoing in ten Spanish hospitals, to evaluate the safety and feasibility, as well as clinical efficacy evidence, of this bioengineered human 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.

Ethics and dissemination: The trial protocol received written approval by the corresponding Ethics Committee and the Spanish Regulatory Authority and is currently recruiting subjects. On completion of the trial, manuscripts with the results of phases I and II of the study will be published in a peer-reviewed journal.

Trial registration: CT.gov identifier: NCT01765244 (Jan2013). EudraCT number: 2010-024290-40 (Dec2012).

Keywords: corneal transplantation; corneal ulcer; limbal stem cell deficiency; randomized controlled trial; stromal fibrosis; tissue bioengineering.

Figure 1

Trial design and stopping rules. Within phase I of the trial, the first five eligible patients were recruited sequentially with a safety period of 45 days between each other, receiving the bioengineered corneal graft (no randomisation). When all five subjects completed a 3 month post-implantation follow-up period, safety and feasibility data generated were analysed by the trial’s Data Safety Monitoring Committee (interim analysis), according to the trial’s stopping rule. Subject enrolment was re-activated within the phase II of the study, and the remaining fifteen patients that complete the study sample size are currently being recruited and randomly allocated 2:1 to receive either the bioengineered cornea (n=10), or aminotic membrane transplantation (n=5), selected as the control treatment for trophic corneal ulcers in advanced stages. All subjects recruited in the trial will complete a 24 months follow-up period.

Figure 2

Study visits and procedures. Clinical trial visits are structured in 31 time points, that include three pre-implantation visits (screening, randomization and pre-implantation) and 27 post-implantation evaluation visits according to a decreasing frequency rate: daily (week 1), weekly (month 1), fortnightly (months 2 and 3), monthly (months 4 to 12), and quarterly (months 13 to 24). The procedures and assessments performed are detailed for each visit.