Evaluation of BGC101 in Peripheral Arterial Disease with Critical Limb Ischemia: A Phase 1/2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **feasibility**, safety, and efficacy of BGC101 in the treatment of patients with peripheral arterial disease (PAD) and critical limb ischemia (CLI) who have not responded to the standard of care, including prior limb revascularization, and do not have the option of further revascularization treatment. This is clinically relevant as it addresses a significant unmet need in a patient population with limited therapeutic options, potentially improving outcomes and quality of life for these individuals.

Secondary objectives include further assessment of the safety and efficacy of BGC101 versus placebo on clinical symptoms, clinical signs, and the rate of amputation. These objectives aim to provide a comprehensive understanding of the therapeutic potential and safety profile of BGC101, contributing to the overall evaluation of its clinical utility in this challenging condition.

The clinical trial involves a total of **45 participants** diagnosed with **peripheral arterial disease (PAD)** and **chronic-limb threatening ischemia (CLTI)** who have not responded to standard pharmacological treatments or risk factor control, and/or have undergone revascularization with persistent microvasculature disease, lacking further revascularization options. The study population includes both male and female subjects, aged 18 years and older, who are capable of understanding the study's purpose and complying with its instructions. Participants are required to be non-pregnant and non-lactating females, and must have clinical indications diagnostic of CLTI based on Rutherford category 4-5, with at least one hemodynamic indicator of severe peripheral arterial occlusive disease. The trial population was selected based on their inability to undergo standard revascularization due to unfavorable anatomy, high surgical risk, or previous ineffective revascularization. Lifestyle considerations such as diet and physical activity are not specified. The trial includes a vulnerable population, ensuring comprehensive evaluation of the treatment's feasibility, safety, and efficacy.

The clinical trial is designed as a **Phase 1/2**, open-label, double-blind, randomized, placebo-controlled study to evaluate the feasibility, safety, and efficacy of BGC101 in the treatment of patients with **peripheral arterial disease (PAD)** and **critical limb ischemia (CLI)**. The trial aims to assess patients who have not responded to standard pharmacological treatments or revascularization and do not have further revascularization options. The investigational product, BGC101, is an advanced therapy investigational medicinal product (ATIMP) administered via **intramuscular injection**. The trial is expected to commence recruitment on January 23, 2024, and conclude by December 31, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, clinical indications of CLI, and hemodynamic indicators of severe peripheral arterial occlusive disease. Eligible participants will be randomized into treatment or placebo groups. The trial includes regular follow-up visits to monitor safety and efficacy endpoints, such as the incidence of adverse events, vital signs, and laboratory values. The primary efficacy endpoints include the rate of major amputation and amputation-free survival at 12 months. The end-of-study visit will assess the overall outcomes and any long-term effects of the treatment.

Participant involvement is expected to last up to 12 months, with conditions for early termination including the occurrence of serious adverse events or withdrawal of consent. The trial's methodology ensures rigorous monitoring and data collection to evaluate the investigational product's impact on PAD and CLI, providing valuable insights into its potential as a treatment option for patients with limited alternatives.

The clinical trial involves the administration of an **experimental medication** identified as BGC101, which is a **suspension for injection**. This investigational product is composed of **autologous blood-derived endothelial progenitor cells, haematopoietic stem/progenitor cells, activated dendritic cells, and T helper cells**. The pharmaceutical form of BGC101 is a suspension specifically designed for **intramuscular injection**. The administration schedule and dosage frequency are determined by the study protocol, ensuring adherence to the investigational plan. The product is classified as an **Advanced Therapy Investigational Medicinal Product (ATIMP)**, highlighting its innovative approach in treating peripheral arterial disease (PAD) with critical limb ischemia (CLI). Participant compliance with the dosing regimen is monitored throughout the study to ensure the integrity of the trial data.

In addition to the experimental treatment, the study utilizes a **placebo** as a comparator to evaluate the efficacy and safety of BGC101. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's double-blind design. The placebo is formulated to match the appearance and administration route of the investigational product, ensuring that neither the participants nor the investigators can distinguish between the active treatment and the placebo. This approach is critical for maintaining the study's scientific rigor and validity.

Furthermore, the trial incorporates the use of **X-vivo 15**, a serum-free growth medium manufactured under Good Manufacturing Practice (GMP) standards and commercially available from Lonza. Although not an active treatment, X-vivo 15 is utilized in the preparation and maintenance of the cellular components used in the investigational product. Its role is essential in ensuring the viability and functionality of the cells prior to administration. The use of X-vivo 15 is consistent with the study's focus on advanced cell therapy techniques.

The efficacy of the investigational product BGC101 in the treatment of patients with peripheral arterial disease (PAD) with critical limb ischemia (CLI) will be assessed using specific primary efficacy endpoints. These endpoints include the rate of major amputation (below or above the knee) at Month 12 and the major amputation-free survival (AFS) rate at Month 12. These parameters will provide critical insights into the effectiveness of BGC101 in reducing the need for major amputations and improving survival without amputation in the target patient population.