Phase III Multicenter Randomized Controlled Trial Evaluating Efficacy and Safety of Bilayer Engineered Collagen Hydrogel-Based Skin Graft in Deep Partial and Full-Thickness Burns

The primary objective of this study is to confirm the **efficacy** and functionality of denovoSkin™ in achieving wound closure and reducing scarring in patients with deep partial and full-thickness burns, as compared to split-thickness skin grafts (STSG). This is clinically relevant as effective wound closure and minimized scarring are critical outcomes in the management of severe burns, impacting both the physical recovery and quality of life of patients.

Secondary objectives include:

• To confirm the donor-site sparing effect of denovoSkin™ by comparing the difference in the expansion ratio between the investigational medicinal product (IMP) and STSG.
• To confirm the limitation of scar contracture by comparing the size of the area grafted with IMP and STSG over time.
• To confirm the progression and quality of burn wound and donor site wound healing after denovoSkin™ grafting as compared to meshed STSG.

The clinical trial involves a total of **7 participants** who are being studied to evaluate the efficacy and functionality of denovoSkin™ in achieving wound closure and reducing scarring in patients with **deep partial and full-thickness burns**. The study population includes both male and female subjects aged **12 years and older**. Participants were selected based on the presence of deep partial or full-thickness thermal burns covering **20% or more of the total body surface area (TBSA)**, for which excision and standard of care (STSG) are clinically indicated. The trial includes a vulnerable population, and informed consent was obtained from the patients or their legally authorized representatives. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status of the participants.

The clinical trial is designed as a **randomized**, controlled, Phase III study to evaluate the efficacy and safety of a bilayer engineered collagen hydrogel-based skin graft composed of autologous keratinocytes and fibroblasts for the treatment of patients with deep partial and full-thickness burns. The trial will involve intra-patient comparisons to confirm the product's effectiveness in achieving wound closure and reducing scarring compared to standard treatment with split-thickness skin grafts (STSG). The study is expected to commence recruitment in August 2024 and conclude by January 2028.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as having deep partial or full-thickness thermal burns covering at least 20% of the total body surface area and being aged 12 years or older. Informed consent must be obtained from the patient or their legally authorized representative. Following the inclusion visit, participants will receive the investigational product through **implantation**. Subsequent follow-up visits will occur at 4 and 10 weeks, and at 3, 6, 12, and 24 months post-grafting to assess primary and secondary endpoints, including wound closure, scar quality, and graft take.

The primary endpoint is a composite measure of wound closure, defined as at least 95% epithelialization at 10 weeks post-grafting, and a POSAS v2.0 overall opinion score of at most 5 at 6 months post-grafting. Secondary endpoints include the ratio of covered surface area to biopsy site surface area, limitation of scar contracture, and assessments of infection and scar quality at various time points. The expected duration of participant involvement is up to 24 months, with conditions for early termination including withdrawal of consent or adverse events that contraindicate continued participation.

The clinical trial involves the use of an **experimental medication** known as EHSG-KF, which is a **bilayer engineered collagen hydrogel-based skin graft** composed of autologous keratinocytes and fibroblasts. This product is developed by CUTISS AG and is classified as an Advanced Therapy Medicinal Product (ATMP). The pharmaceutical form of EHSG-KF is a **hydrogel**, and it is administered via **implantation**. The maximum daily dose is 336 cm², with the same amount being the maximum total dose allowed. The treatment period is limited to one day. EHSG-KF is not a pediatric formulation and has been designated as an orphan drug under the designation number EU/3/15/1596.

In this study, EHSG-KF is compared to the standard treatment of split-thickness skin grafts (STSG) for patients with deep partial and full-thickness burns. The trial aims to confirm the efficacy and safety of EHSG-KF in achieving wound closure and reducing scarring. The comparator treatment, STSG, is a well-established standard-of-care therapy for burn patients, providing a benchmark against which the experimental treatment's performance is measured. Participant compliance with the treatment protocol is monitored throughout the study to ensure adherence to the dosing schedule and administration route.

Efficacy in this clinical trial will be assessed using a composite primary endpoint, which includes two specific criteria: wound closure, defined as at least 95% epithelialization at 10 weeks post-grafting, and the overall opinion score from the observer part of the Patient and Observer Scar Assessment Scale (POSAS) v2.0, which should be at most 5 at 6 months post-grafting. Secondary endpoints will further evaluate efficacy through various measures, including the ratio of covered surface area to biopsy site/donor site surface area at 4 weeks post-grafting, and the limitation of scar contracture by assessing the size of the grafted areas at 6, 12, and 24 months post-grafting.

Additional secondary endpoints include the percentage of epithelialization at 3 and 6 months post-grafting, graft take at 14 and 21 days post-grafting, and the assessment of donor sites and grafted burn wound areas for infection and scar quality at multiple timepoints: 4 and 10 weeks, and 3, 6, 12, and 24 months post-grafting. The POSAS v2.0 questionnaire will be utilized for both patient and observer assessments of scar quality. These efficacy parameters will be collected and analyzed according to the specified schedule to determine the effectiveness of the bilayer engineered collagen-based skin graft, denovoSkin™, in treating patients with deep partial and full-thickness burns.