Evaluation of Allogeneic Nanostructured Artificial Cornea in Advanced Corneal Trophic Ulcers Refractory to Conventional Treatment

The primary objective of this multicenter clinical trial is to evaluate the **safety**, feasibility, and clinical efficacy of a human artificial nanostructured lamellar cornea model in patients with severe corneal disease, specifically corneal trophic ulcers refractory to conventional treatment. This is clinically relevant as these patients currently lack effective therapeutic options, and the development of a viable artificial cornea could significantly improve their treatment outcomes.

Secondary objectives include:

• Generating artificial corneas that are nanostructured and lamellar, derived from human allogeneic sources, specifically from cadaver donors using sclero-corneal limbus and biomaterials.
• Implementing these nanostructured artificial corneas in a randomized group of patients with severe corneal disease, assessing their integration and functionality.
• Evaluating the biosafety of the implanted nanostructured artificial corneas to rule out severe and unexpected adverse reactions, ensuring patient safety and the viability of the treatment.

The clinical trial involves participants diagnosed with **corneal trophic ulcers** that are refractory to conventional treatment or have sequelae from previous ulcers, such as stromal thinning or fibrosis, potentially associated with limbal insufficiency. The study population includes both male and female subjects aged 18 years and older, with no upper age limit specified. Participants are required to have normal laboratory parameters, including leukocytes ≥ 3000, neutrophils ≥ 1500, platelets ≥ 100000, AST/ALT ≤ 1.5 ULN, and creatinine ≤ 1.5 mg/dL. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include patients with stage 3 Mackie corneal ulcers unresponsive to conventional medical treatment, potentially secondary to various conditions such as Riley-Day syndrome, diabetes, or autoimmune disorders. Participants must have a minimum disease duration of six weeks and no active ocular infection. Lifestyle factors such as diet, physical activity, or habits are not specified as relevant considerations for this trial.

The clinical trial is designed to evaluate the safety and feasibility of an allogeneic tissue-engineered product, specifically a **nanostructured artificial cornea**, in patients with advanced corneal trophic ulcers that are refractory to conventional ophthalmic treatment. This trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The trial is expected to span from January 17, 2014, to February 17, 2027, allowing for comprehensive data collection and analysis over an extended period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as the presence of stage 3 Mackie corneal ulcers unresponsive to conventional treatment and the absence of active ocular infections. Following successful screening, participants will be randomized to receive either the investigational product or a comparator. Subsequent follow-up visits will be scheduled to monitor the incidence of adverse events, graft conditions, and signs of infection, as well as to assess secondary endpoints like ulcer persistence, visual acuity, and corneal transparency. The end-of-study visit will conclude the participant's involvement, summarizing the outcomes and any adverse events experienced during the trial.

The expected length of participant involvement is contingent upon the individual's response to treatment and the absence of any conditions that may necessitate early termination, such as severe adverse events or non-compliance with study protocols. Participants will be closely monitored throughout the trial to ensure their safety and the integrity of the data collected. The trial aims to provide valuable insights into the potential of the investigational product as a therapeutic option for patients with severe corneal disease lacking effective treatment alternatives.

The clinical trial involves the use of two experimental treatments, both classified as **living tissue equivalents**. The first treatment is the **amniotic membrane**, a human-derived product utilized for its regenerative properties. This treatment is administered via **implantation**. The amniotic membrane serves as a **transplant** and is not a pediatric formulation. The product is developed by the RED ANDALUZA DE DISEÑO Y TRASLACIÓN DE TERAPIAS AVANZADAS - FUNDACIÓN PROGRESO Y SALUD. The administration schedule and dosage are determined based on the specific requirements of the trial, with compliance monitored through standard clinical trial procedures.

The second experimental treatment is a combination of **allogenic sclerocorneal limbus stem-derived adult limbal cells, ex-vivo expanded**, and **allogenic corneal-derived adult keratocytes, ex-vivo expanded**. This advanced therapy medicinal product is also administered through **implantation**. The product is designed to address severe corneal diseases and is not intended for pediatric use. Like the amniotic membrane, this treatment is developed by the same organization, ensuring consistency in the quality and origin of the substances used. The dosing schedule and participant compliance are managed according to the trial's protocol, ensuring adherence to the study's objectives.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial data. The focus remains on evaluating the safety and feasibility of these innovative tissue-engineered products in patients with advanced corneal trophic ulcers that are refractory to conventional ophthalmic treatments.

The efficacy of the investigational product in this clinical trial will be assessed using both primary and secondary endpoints. Primary endpoints include the incidence of adverse events and severe adverse events related to the investigational medicinal product (IMP), the condition of the graft (artificial cornea) in terms of integrity, survival, or reabsorption, signs of local, regional, or systemic infection, and induced corneal vascularization. These parameters will provide a comprehensive evaluation of the safety and feasibility of the treatment.

Secondary endpoints will focus on the clinical efficacy of the treatment, including the persistence or regeneration of the corneal stroma, improvement in visual acuity, and corneal transparency. Additionally, the quality of life will be assessed using the EQ5, part I and II, and the characterization of the corneal surface will be conducted through impression cytology and OCT mapping. These assessments will be conducted at specified intervals throughout the trial to monitor changes and improvements in the condition of the patients with advanced corneal trophic ulcers.