Evaluation of NVD-003 Autologous Osteogenic Bone Graft for Congenital Pseudarthrosis of the Tibia in Pediatric Patients

The primary objective of this study is to evaluate the **safety** of NVD-003, an autologous osteogenic bone graft, in the treatment of congenital pseudarthrosis of the tibia in pediatric patients. This involves a comprehensive assessment of both clinical and radiological safety, focusing on short, mid, and long-term outcomes. The evaluation includes the safety of the adipose tissue collection procedure and the NVD-003 grafting surgery. This is clinically relevant as it addresses the potential risks associated with the use of autologous adipose-derived stem cells in a vulnerable pediatric population, aiming to ensure that the treatment does not introduce adverse effects.

Secondary objectives include:

• To centrally assess the efficacy of NVD-003 radiologically, focusing on bone formation, union, and remodeling.
• To locally assess the clinical efficacy of NVD-003.

The clinical trial involves a total of **2 participants** diagnosed with **congenital pseudarthrosis of the tibia**, a rare orthopedic condition. The study population comprises both male and female pediatric patients, specifically within the age range of **2 to 8 years**. Participants were selected based on their diagnosis and the presence of a non-healing Paley type 3 or 4 fracture, with a minimum weight requirement of 5 kg (11 lbs). The trial includes individuals who have undergone a maximum of two previous failed surgical orthopedic interventions for the primary fracture. Participants are required to be in satisfactory general health to undergo surgical procedures with anesthesia, as per local standards. The trial population is characterized by the ability to obtain a minimum of 2cc of adipose tissue for the study procedures. Additionally, participants must have serology and molecular test results excluding infections such as HTLV1/2, HIV 1/2, HBV, HCV, and syphilis. The study involves a vulnerable population, and informed consent was obtained from the patients' parents or legal guardians.

The clinical trial is designed to evaluate the safety of **NVD-003**, an autologous osteogenic bone graft, in pediatric patients diagnosed with **congenital pseudarthrosis of the tibia**. This proof-of-concept study employs a randomized, double-blind, controlled trial design to ensure the reliability and validity of the results. The trial is expected to span from November 2022 to January 2026, with participant involvement lasting up to 24 months post-grafting surgery.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, weight, and health status. The inclusion criteria require patients to be between 2 and 8 years old, with a minimum weight of 5 kg, and to have a non-healing Paley type 3 or 4 fracture. The screening visit will also involve serological and molecular tests to exclude infections such as HIV and hepatitis. Following the screening, participants will undergo the adipose tissue collection (ATC) and grafting surgery (GS), with subsequent follow-up visits scheduled at hospital discharge, 6 weeks, and 3, 6, 12, and 24 months post-GS.

The primary endpoints focus on assessing the short, mid, and long-term safety of the NVD-003 treatment, including any adverse events (AEs) related to the graft and surgical procedures. Secondary endpoints involve the analysis of bone formation, union, and remodeling through imaging techniques such as CT scans and X-rays, as well as the evaluation of clinical outcomes using the Clinical Global Impression scales. The expected length of participant involvement is contingent upon the successful completion of all scheduled visits and assessments. However, conditions such as the occurrence of serious adverse events or non-compliance with study protocols may lead to early termination from the study.

The clinical trial involves the use of **NVD-003**, an experimental medication designed as an osteogenic graft derived from **autologous adipose-derived stem cells**. This product is developed by NOVADIP BIOSCIENCES and is classified under the ATC code M05, which pertains to drugs for the treatment of bone diseases. The pharmaceutical form of NVD-003 is an **implant**, and it is administered via **implantation**. The primary objective of the trial is to assess the safety of NVD-003 in the treatment of congenital pseudarthrosis of the tibia in pediatric patients. The trial will evaluate both clinical and radiological safety, focusing on short, mid, and long-term outcomes, including the safety of the adipose tissue collection procedure and the grafting surgery.

In this study, NVD-003 is the sole investigational product, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial does not include a pediatric formulation, and the product is not classified as an orphan drug. The administration of NVD-003 is conducted through a surgical procedure, where the implant is placed at the site of the bone defect. The study protocol does not specify a maximum daily dose, total dose, or treatment period, indicating that the dosing schedule is likely determined by the surgical procedure and the specific needs of the patient. Participant compliance is monitored through clinical and radiological assessments to ensure the safety and efficacy of the treatment.

The clinical trial will assess the efficacy of NVD-003, an autologous osteogenic bone graft, in the treatment of congenital pseudarthrosis of the tibia in pediatric patients. Efficacy will be evaluated through both primary and secondary endpoints. The primary endpoints focus on the safety of the treatment, including the assessment of short-term, mid long-term, and long-term safety. Short-term safety will be evaluated by monitoring adverse events (AEs) related to the adipose tissue collection (ATC) and NVD-003 between screening and 3 months post-grafting surgery (GS). Mid long-term safety will be assessed by examining the NVD-003 graft implantation, related AEs, and the surgical reintervention rate from 3 to 12 months post-GS. Long-term safety will be evaluated by monitoring serious adverse events (SAEs) related to NVD-003 from 12 to 24 months post-GS.

Secondary endpoints will include the analysis of bone formation and remodeling using imaging techniques such as CT scans and X-rays. CT scans will be used to centrally analyze tibial length differences and bone formation at various timepoints, including 3, 6, and 12 months post-GS. X-rays will be utilized to assess the positioning of the graft, alignment of bones, and fixation devices at 6 weeks and 24 months post-GS. Additionally, the clinical evolution of the patient will be assessed using the "Clinical Global Impression" Severity Scale (CGI-S) and Improvement Scale (CGI-I) at multiple timepoints, including screening, hospital discharge, and at 6 weeks, 3, 6, 12, and 24 months post-grafting. These assessments will focus on general functioning, walking ability, weight bearing, presence of pain, appearance of the leg, and social activities.