Phase II Evaluation of Autologous Skin-Derived Keratinocytes and Fibroblasts in Fibrin Matrix for Reconstructive Surgery in Basal Cell Carcinoma

The primary objective of this Phase II clinical trial is to evaluate the **safety** and **feasibility** of using nanostructured autologous artificial skin, based on a fibrin matrix combined with agarose or hyaluronic acid, in reconstructive surgery for basal cell carcinoma. The safety assessment focuses on the incidence of adverse events related to the investigational products during implantation and subsequent follow-up. The feasibility aspect examines the surgical implant's suturability, its ability to attach to the recipient tissue, maintain integrity, and facilitate re-epithelialization of the surgical wound. This is clinically relevant as it aims to provide a safer and potentially more effective alternative to traditional autografts in reconstructive surgery.

Secondary objectives include:

• Analyzing the efficacy of the investigational products in terms of epithelialization 21 days post-surgery, compared to autografts.
• Evaluating the clinical safety profile of the new treatment, including adverse effects, graft adhesion, infection, necrosis, and epithelialization over time.
• Comparing histological characteristics of the bioimplanted PHA and autograft using optical microscopy and immunohistochemical studies.
• Studying skin homeostasis parameters such as pH, temperature, transepidermal water loss, and elasticity using non-invasive probes.
• Analyzing ultrasound differences in the dermis and epidermis across study arms.
• Comparing the safety of PHA and autografts in terms of pain from the intervention.
• Assessing the aesthetic quality of scars and their impact on quality of life using specific questionnaires.
• Conducting a comparative economic evaluation of the three treatment types used in the trial.

The clinical trial involves participants undergoing **reconstructive skin surgery** for basal cell carcinoma, specifically Mohs surgery. The study population includes adults aged 18 years and older, encompassing both male and female subjects of any racial origin. Participants are required to have a clinical and dermatoscopic diagnosis of basal cell carcinoma with lesions located on the scalp, torso, or extremities, where direct suture or flap closure is not feasible. The trial does not involve a vulnerable population. Participants must provide informed consent and, if of childbearing potential, commit to using medically proven contraceptives. The sponsor has not provided information regarding the total number of participants. Lifestyle factors such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the safety and efficacy of a tissue-engineered autologous skin substitute for reconstructive surgery in patients with **basal cell carcinoma**. This is a Phase II, randomized, double-blind, controlled trial. The trial will involve the implantation of a **living tissue equivalent** composed of autologous skin-derived adult keratinocytes and fibroblasts expanded in a fibrin-agarose or fibrin-hyaluronic acid biological matrix. The trial is expected to run from January 21, 2022, to January 21, 2026, with participant involvement lasting up to one year.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of basal cell carcinoma, and consent to use effective contraceptives if applicable. Following successful screening, participants will be randomized to receive either the investigational product or a **skin autograft** as a comparator. The primary endpoint will focus on safety, assessing adverse events and reactions related to the investigational products during implantation and follow-up. Secondary endpoints will evaluate efficacy, including the percentage of epithelialization, time to complete healing, and quality of life assessments.

Study visits will include follow-up assessments to monitor the surgical site and donor area for complications such as hematoma, infection, and graft loss. The end-of-study visit will evaluate the long-term outcomes, including the aesthetic appearance of the lesion and any rescue surgeries performed. Participants may be withdrawn from the study if they experience severe adverse events, fail to comply with study procedures, or withdraw consent. The trial aims to provide comprehensive data on the feasibility and safety of the investigational product, contributing to the advancement of reconstructive surgical options for basal cell carcinoma patients.

The clinical trial involves the use of an **experimental medication** known as "Autologous skin differentiated adult keratinocytes and fibroblasts cell-sheet expanded in a fibrin-agarose biological matrix." This product is classified as a **living tissue equivalent** and is administered via **implantation**. The active substances include **autologous skin-derived adult keratinocytes expanded** and **autologous skin-derived adult fibroblasts expanded**. The maximum daily and total dose is 144 cm², with a treatment period of up to one day. This product is categorized as an **advanced therapy medicinal product** and is not formulated for pediatric use.

Another **experimental medication** used in the trial is "Autologous skin differentiated adult keratinocytes and fibroblasts cell-sheet expanded in a fibrin-hialuronic acid biological matrix." Similar to the previous product, it is a **living tissue equivalent** administered through **implantation**. It contains the same active substances: **autologous skin-derived adult keratinocytes expanded** and **autologous skin-derived adult fibroblasts expanded**. The dosing parameters are identical, with a maximum daily and total dose of 144 cm² and a treatment period of one day. This product is also classified as an **advanced therapy medicinal product** and is not intended for pediatric use.

The **comparator treatment** in the study is a "Skin autograft," which is also a **living tissue equivalent** administered via **implantation**. The active substance is **skin autograft**, and the maximum daily and total dose is one dosage form, with a treatment period of one day. This treatment is categorized as a **transplant** and is not designed for pediatric patients.

The efficacy of the investigational products in this Phase II clinical trial will be assessed through several primary and secondary endpoints. The primary efficacy endpoint focuses on the feasibility of the surgical procedure, specifically evaluating the surgical suturability and the ability of the nanostructured autologous artificial skin to adhere to the recipient tissue, maintain its integrity, and facilitate re-epithelialization of the surgical wound. Secondary efficacy endpoints include the percentage of epithelialization of the lesion three weeks post-intervention, the time until removal of stitches, and the time until complete epithelialization. Additionally, the degree of pain will be assessed using a visual analogue scale, and the aesthetic appearance of the lesion will be evaluated using the POSAS scale. Quality of life will be measured using the DLQI and SCI indices.

Complementary assessments will involve measuring structural characteristics, molecular, and functional properties of the skin in the surgical injury using various techniques such as Doppler ultrasound, cutaneous homeostasis study, and histological tests of skin biopsies with optical microscopy. These assessments aim to provide a comprehensive evaluation of the efficacy of the tissue-engineered autologous skin substitute in reconstructive surgery for **basal cell carcinoma**. The schedule for these assessments includes specific timepoints, such as three weeks after the intervention, to ensure consistent and reliable data collection throughout the trial.