Evaluation of Nanostructured Fibrin-Agarose Artificial Cornea (NANOULCOR) in Severe Corneal Ulcers Using Allogenic Limbal Cells and Keratocytes

The primary objective of this clinical trial is to determine the **clinical efficacy** of NANOULCOR, a nanostructured fibrin-agarose artificial cornea model, in patients with severe **corneal ulcers**. The study aims to evaluate the regeneration of the trophic defect in comparison to a control group. This is clinically relevant as severe corneal ulcers can lead to significant visual impairment and current treatments may not be effective for all patients.

Secondary objectives include assessing the effectiveness of NANOULCOR by measuring the reduction in time to healing, improvement in visual acuity, and reduction of corneal complications according to the SOTOZONE scale. Additionally, the study will evaluate the improvement in the patient's quality of life. Safety objectives involve ratifying the safety data of NANOULCOR, as demonstrated in a previous trial. Feasibility objectives aim to confirm the feasibility data of NANOULCOR, also demonstrated in a prior trial, to ensure its clinical implementation in the healthcare system.

The clinical trial focuses on evaluating the efficacy of NANOULCOR in patients with severe **corneal ulcers**. The study population includes both male and female participants over the age of 18, with no upper age limit specified. Participants are required to have trophic corneal ulcers that are refractory to conventional medical treatment, and they may present with sequelae such as corneal thinning or clouding. The trial does not involve a vulnerable population. Participants must have had the disease causing the corneal ulcer for at least three weeks. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants of childbearing age must agree to use safe methods of birth control throughout the study and follow-up period. The selection criteria ensure that participants are willing and able to comply with the study's visit schedule, treatment plan, and procedures.

The clinical trial is a **Phase IIb**, randomized, controlled, unblinded, multicenter study designed to evaluate the clinical efficacy of a nanostructured fibrin-agarose artificial cornea model in patients with severe **corneal ulcers**. The primary objective is to assess the ability of the investigational product, NANOULCOR, to regenerate the trophic defect compared to a control group. The trial will involve the implantation of **allogenic sclerocorneal limbus stem-derived adult limbal cells** and **allogenic corneal-derived adult keratocytes**, both ex-vivo expanded, in a biological matrix. The study is expected to commence recruitment on November 1, 2023, and conclude by November 1, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as the presence of trophic corneal ulcers refractory to conventional treatment and the ability to comply with study procedures. Following the screening, participants will be randomized into either the treatment or control group. The study will include regular follow-up visits to monitor the status of the trophic defect, assess healing time, changes in visual acuity, and any corneal complications. The occurrence of adverse events (AEs) and serious adverse events (SAEs) will also be recorded. The end-of-study visit will evaluate the overall treatment efficacy and safety, including the integrity of the implanted corneal construct.

Participant involvement is expected to last throughout the treatment period and a six-month follow-up. Conditions that may lead to early termination from the study include non-compliance with the visit schedule, treatment plan, or any significant adverse events that compromise participant safety. The trial's primary endpoint is the percentage of patients in whom the epithelial defect disappears, while secondary endpoints include time to healing, changes in quality of life, and the feasibility of the treatment process. The study aims to provide valuable insights into the potential of advanced therapy products in treating severe corneal ulcers.

The clinical trial involves the use of an **experimental medication** known as "Alogenic sclerocorneal limbus stem adult limbal cells expanded combined with alogenic corneal differentiated adult keratocytes expanded in biological matrix." This product is classified as a **living tissue equivalent** and is an advanced therapy product. The active substances in this medication include **allogenic sclerocorneal limbus stem-derived adult limbal cells, ex-vivo expanded**, and **allogenic corneal-derived adult keratocytes, ex-vivo expanded**. These substances are derived from cell therapy and are structurally diverse. The medication is administered via **implantation**. The dosage is set at a maximum of one unit per day, with a total maximum dose of one unit over the treatment period, which is limited to one day.

In this study, there is no mention of a **non-experimental treatment** such as a placebo or comparator treatment. The focus is solely on evaluating the clinical efficacy of the experimental medication, NANOULCOR, in patients with severe corneal ulcers. The trial aims to assess the regeneration of the trophic defect in these patients. Participant compliance with the dosing schedule will be monitored to ensure adherence to the treatment protocol. The trial is designed as a Phase IIb, randomised, controlled, unblinded, multicentre study.

Efficacy in this clinical trial will be assessed by evaluating the capacity of the investigational product, NANOULCOR, to regenerate the **trophic defect** in patients with severe corneal ulcers. The primary endpoint will focus on the percentage of patients in whom the epithelial defect disappears, comparing the treatment group with the control group. This assessment will be conducted at all scheduled visits throughout the trial.

Secondary endpoints will include the time to healing, changes in visual acuity, and the incidence of corneal complications as measured by the SOTOZONE scale. Additionally, changes in the patient's quality of life will be evaluated. The status of the implanted corneal construct will also be monitored, specifically its integrity, detachment, or resorption. The occurrence of adverse events (AE) and serious adverse events (SAE) will be recorded to assess safety. Furthermore, the feasibility of treatment with NANOULCOR will be documented by recording the percentage of patients for whom the treatment process was feasible.