Evaluation of Lenzumestrocel on 3D Scaffold for Knee Cartilage Defects: A Randomized Controlled Trial

The primary objective of this clinical trial is to evaluate the **efficacy** of a treatment combining conventional microfracture with autologous bone marrow-derived mesenchymal stem cells (MSCs) seeded onto an acellular 3D scaffold, compared to the standard method of microfracture with scaffold application alone, in patients with knee cartilage defects. This objective is clinically relevant as it aims to determine whether the addition of MSCs can enhance cartilage repair, potentially leading to improved joint function and patient outcomes.

Secondary objectives include assessing the **safety** of autologous MSC administration. This involves collecting safety data to verify positive results observed in previous clinical trials and similar studies worldwide, thereby ensuring the treatment's safety profile in the context of knee cartilage repair.

The clinical trial involves participants diagnosed with **knee cartilage defect**, specifically targeting adult patients aged between 18 and 55 years. The study population includes both male and female subjects, with a focus on individuals who are generally healthy but have confirmed chondral defects in the weight-bearing compartment of the knee joint. The trial does not provide the total number of participants, as this information was not disclosed by the sponsor. Participants were selected based on specific criteria, including the requirement for an open knee surgery for chondral defect management, and the absence of previous knee surgeries for chondral defects. Lifestyle considerations such as diet and physical activity are not specified, but sexually active, nonsterile female participants are required to use highly effective contraception throughout the study. The trial population includes a vulnerable group, indicating careful consideration of ethical standards in participant selection.

The clinical trial is designed to evaluate the **efficacy** of autologous bone marrow-derived mesenchymal stem cells (MSCs) seeded on a 3D scaffold in the treatment of knee cartilage defects. This is a randomized, controlled, open-label, multi-centre trial. The study aims to compare the treatment efficacy of a combination of conventional microfracture and autologous MSCs seeded onto an acellular 3D scaffold against the commonly used method of microfracture and application of the scaffold alone in subjects with knee joint chondral lesions. The trial is expected to run from September 2020 to December 2026, with a primary focus on the Lysholm knee function score, KOOS value, pain according to VAS, and X-ray and MRI evaluations at 24 months post-operation.

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 chondral defects, and preoperative health status. Follow-up visits are scheduled at 6 weeks, 3, 6, 12, and 24 months post-operation to assess primary and secondary endpoints, including adverse event profiles. The end-of-study visit will occur at 24 months post-operation. The expected length of participant involvement is approximately 24 months, with conditions for early termination including withdrawal of consent or adverse events that compromise participant safety.

Inclusion criteria require adult patients aged 18 to 55 years with confirmed chondral defects of the knee joint, scheduled for open knee surgery involving microfracture and 3D scaffold application. Exclusion criteria are not specified. The investigational product, BiCure ortho MSCp, is administered via **intracartilaginous use** as a suspension for injection in a pre-filled syringe. The trial is categorized as a Phase IIb study, focusing on the advanced therapy medicinal product lenzumestrocel, a structurally diverse substance used in cell therapy. The trial is not classified as low intervention, and the maximum treatment period is one day, with a total dose amount of 5,500,000 units. Participants are required to provide written informed consent and adhere to study protocols, including the use of effective contraception for sexually active, nonsterile female participants.

The clinical trial involves the use of an **experimental medication** known as BiCure ortho MSCp, which is a **suspension for injection in a pre-filled syringe**. The active substance in this medication is **lenzumestrocel**, a structurally diverse substance used in cell therapy. Lenzumestrocel is also referred to by synonyms such as NEURONATA-R and human culture expanded autologous mesenchymal stromal cells. The medication is administered via **intracartilaginous use**, with a maximum daily and total dose amount of 5,500,000 cells. The treatment period is limited to one day. BiCure ortho MSCp is classified as an advanced therapy medicinal product and is not a pediatric formulation.

In addition to the experimental treatment, the study includes a **comparator treatment** involving the conventional method of microfracture combined with the application of an acellular 3D scaffold. This serves as the standard-of-care therapy against which the efficacy of the experimental treatment is measured. The trial is designed to assess the efficacy of autologous bone marrow-derived mesenchymal stem cells seeded on a 3D scaffold in the treatment of knee cartilage defects. Participant compliance with the dosing schedule and administration route is monitored throughout the study to ensure adherence to the protocol.

The efficacy of the treatment in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the Lysholm knee function score, the Knee injury and Osteoarthritis Outcome Score (KOOS), and pain assessment according to the Visual Analogue Scale (VAS), all evaluated at 24 months post-operation. Additionally, X-ray and MRI evaluations will be conducted at the same timepoint to assess structural changes in the knee joint.

Secondary endpoints will be measured at various intervals to provide a comprehensive evaluation of the treatment's efficacy over time. These include the Lysholm knee function score and KOOS values at 3, 6, and 12 months post-operation, as well as pain assessment according to VAS at 6 weeks, 3, 6, and 12 months post-operation. X-ray and MRI evaluations will also be performed at 12 months post-operation. Furthermore, adverse event profiles will be monitored and compared between the study arms at 6 weeks, 3, 6, 12, and 24 months post-operation.

The efficacy assessments will involve validated scales and imaging techniques to ensure accurate and reliable data collection. The comparison of score changes between the study arms will provide insights into the relative effectiveness of the treatment involving **autologous bone marrow-derived mesenchymal stem cells** seeded on a 3D scaffold versus the conventional method. The schedule for these assessments is designed to capture both short-term and long-term outcomes, contributing to a robust evaluation of the treatment's impact on knee cartilage defects.