Efficacy and Safety of Allogeneic Skin-Derived ABCB5-Positive Dermal Mesenchymal Stromal Cells in Therapy-Resistant Chronic Venous Ulcers

The primary objective of this clinical trial is to evaluate the **efficacy** and **safety** of the investigational product allo-APZ2-CVU in patients with therapy-resistant non-healing **chronic venous ulcers** (CVU). Efficacy will be assessed by monitoring complete wound closure, while safety will be evaluated by monitoring adverse events (AEs). This is clinically relevant as it addresses the need for effective treatments in patients with chronic wounds that do not respond to conventional therapies, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Investigating further efficacy of one dose of 1 x 10⁶ cells/cm² of the investigational product allo-APZ2-CVU.
• Assessing the quality of life after administration of one dose of 1 x 10⁶ cells/cm² of allo-APZ2-CVU.
• Evaluating further safety of one dose of 1 x 10⁶ cells/cm² of allo-APZ2-CVU.

The clinical trial involves a total of **20 participants** diagnosed with **chronic venous ulcers (CVU)**. The study population includes both male and female subjects, aged 18 years and older, with a body mass index ranging from 15 to 50 kg/m². Participants were selected based on the presence of therapy-resistant non-healing CVU, specifically located at the lower leg and/or ankle region, with a wound size between 1 and 25 cm². The ulcers must not have been present for more than 15 years and were diagnosed through Doppler-Duplex sonography, ankle brachial index, physical examination, and dermatological review. The trial includes individuals who are able to understand the study's nature and provide informed consent. Women of childbearing potential are required to have a negative pregnancy test and must use highly effective contraceptive methods during the trial. The study does not exclude vulnerable populations, and lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is a **randomized**, **placebo-controlled**, **double-blind**, multicenter, international Phase III study designed to evaluate the efficacy and safety of the investigational product allo-APZ2-CVU in patients with therapy-resistant non-healing **chronic venous ulcers (CVU)**. The trial aims to assess the complete wound closure and monitor adverse events as primary endpoints. The study is expected to commence recruitment on September 1, 2024, and conclude by April 30, 2027.

Participants will be randomly assigned to receive either the investigational product or a placebo, both administered topically. The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, wound characteristics, and overall health status. Following the screening, participants will undergo a series of follow-up visits to monitor wound healing progress, safety, and quality of life. These visits will include assessments of wound size, quality of healing, and pain levels, as well as physical examinations and vital sign checks. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

The expected duration of participant involvement is approximately 18 weeks, with the primary efficacy endpoint being complete wound closure persisting for at least two weeks by Week 18. Secondary endpoints include wound closure at each follow-up visit, changes in wound size, and quality of life assessments. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or choose to withdraw consent. The trial will ensure that all participants provide informed consent and adhere to contraceptive guidelines if applicable.

The clinical trial involves the investigation of the experimental medication **allo-APZ2-CVU**, which is a **cutaneous suspension** containing **allogeneic skin-derived ABCB5-positive dermal mesenchymal stromal cells**. This investigational product is administered topically to the target wounds of patients with therapy-resistant non-healing chronic venous ulcers (CVU). The dosage is set at a maximum of 25 million organisms per day, with the total dose not exceeding 25 million organisms over the treatment period. The administration route is cutaneous use, and the treatment period is limited to one day. The product is of biological origin and is developed by RHEACELL GMBH & CO. KG.

The study also includes a **placebo** as a comparator treatment. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered in the same manner as the experimental medication, ensuring consistency in the administration route and frequency. The pharmaceutical form and active substance details of the placebo are not specified, as it serves as a control to evaluate the efficacy and safety of the experimental treatment.

The efficacy of the investigational product allo-APZ2-CVU in the clinical trial will be assessed primarily by monitoring **complete wound closure** at Week 18, which must persist for at least two weeks. This endpoint is crucial for evaluating the treatment's effectiveness in patients with therapy-resistant non-healing chronic venous ulcers (CVU). Secondary efficacy endpoints include the assessment of complete wound closures at each post-baseline follow-up visit, changes in wound size percentage, and the quality of wound healing. Additionally, the trial will evaluate the quality of life using the Wound-Quality of Life Questionnaire (W-QoL), EQ-5D-5L Questionnaire, and SF-36 at specified visits (V8, V11, V14, V15, V16, V17). Pain will be assessed using a numerical rating scale (NRS) at each post-baseline follow-up visit. Other secondary endpoints include the duration of wound closure, recurrence of the wound, time to complete wound closure, physical examination and vital signs at V14, and assessment of immunogenicity.