Efficacy and Safety of Autologous Adipose-Derived Stem Cells (NVD003) Versus Iliac Crest Bone Graft in Pediatric Congenital Pseudarthrosis of the Tibia

The primary objective of this study is to assess the **efficacy** of NVD003 for the surgical treatment of congenital pseudarthrosis of the tibia (CPT) in pediatric participants. This is clinically relevant as CPT is a challenging condition to treat, often requiring surgical intervention, and the use of NVD003, an implant derived from autologous adipose-derived stem cells, may offer a novel therapeutic approach.

Secondary objectives include: - Evaluating the efficacy of NVD003 with respect to individual components of overall healing. - Assessing the **safety** of NVD003 for the surgical treatment of CPT in pediatric participants. - Further evaluating the efficacy of NVD003 based on other measures of bone healing. - Evaluating the effects of NVD003 on quality of life (QoL).

The clinical trial involves a total of **4 participants** diagnosed with **congenital pseudarthrosis of the tibia** (CPT), with or without neurofibromatosis type 1 (NF1). The study population includes pediatric participants of any sex, aged 17 years or younger, who are candidates for surgical treatment using an internal fixation approach. Both male and female subjects are included, and the trial population is considered vulnerable due to the pediatric nature of the participants. Participants were selected based on their diagnosis of CPT, the presence of a non-healing Paley type 3 or 4 diaphyseal fracture, and their general health status, which allows for surgical intervention. All participants have undergone serology and molecular testing to exclude infections such as human T-cell lymphoma virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and syphilis. Additionally, participants must weigh at least 5 kg (11 lb) and are not pregnant or lactating. The trial requires that participants and their parent(s) or legal guardian(s) provide informed consent and are willing to comply with study visits and follow-up evaluations. The sponsor has not provided specific information regarding lifestyle considerations such as diet or physical activity.

The clinical trial is a **Phase 3 randomized, controlled study** designed to evaluate the efficacy and safety of NVD003, an **implant** containing **autologous adipose-derived stem cells**, compared to iliac crest bone graft in pediatric participants undergoing surgical treatment for **congenital pseudarthrosis of the tibia**. The trial employs a double-blind methodology to ensure unbiased results, with participants and investigators unaware of the treatment assignments. The estimated duration of the trial is from October 2025 to October 2027, with participant involvement expected to last approximately 12 months from the date of 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. This visit will include serology and molecular tests to exclude certain infections. Following the screening, eligible participants will be randomized to receive either the investigational product or the control treatment. The primary endpoint of the study is overall healing at 12 months, assessed through radiographic and clinical evaluations, and the absence of secondary interventions. Secondary endpoints include assessments of adverse events, blood transfusion requirements, and functional outcomes.

Study visits will occur at baseline, and at 3, 6, and 12 months post-surgery, with evaluations including radiological assessments and functional walking tests. The end-of-study visit will coincide with the 12-month follow-up, where final assessments of healing and quality of life will be conducted. Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial aims to provide comprehensive data on the potential benefits and risks of NVD003 in treating this rare pediatric condition.

The clinical trial involves the use of an experimental medication known as **NVD003**, which is an **implant** containing **autologous adipose-derived stem cells**. This investigational product is designed as an osteogenic graft derived from the patient's own adipose stem cells. The pharmaceutical form of NVD003 is an implant, and it is administered via **implantation**. The maximum daily dose and total dose amount are both set at 31 units, with the treatment period limited to a maximum of one day. The product is classified under the ATC code M05, which pertains to drugs for the treatment of bone diseases. NVD003 is designated as an orphan drug, indicating its use in rare conditions, specifically for the surgical treatment of congenital pseudarthrosis of the tibia in pediatric participants.

In this study, the comparator treatment is the **iliac crest bone graft**, which serves as the standard-of-care therapy. This non-experimental treatment involves the surgical harvesting of bone from the iliac crest to be used as a graft. The trial aims to compare the efficacy and safety of NVD003 against this established method. Participant compliance with the treatment protocol will be monitored throughout the study to ensure adherence to the dosing schedule and administration procedures.

The efficacy of the investigational product, NVD003, will be assessed in a Phase 3 randomized, controlled study involving pediatric participants undergoing surgical treatment for **Congenital Pseudarthrosis of the Tibia (CPT)**. The primary endpoint for evaluating efficacy is overall healing at 12 months. This is defined as a binary outcome (yes/no) based on three criteria: radiographic healing, clinical healing, and the absence of secondary interventions to promote or accelerate bone healing. Radiographic healing will be determined using the modified Radiological Union Scale for Tibia (mRUST) scale, with a score of 13 or higher indicating healing, as assessed by independent central readers (ICRs). Clinical healing will be measured by the absence of pain during weight-bearing, as evaluated by a clinician. All three criteria must be met to achieve a "yes" for overall healing.

Secondary endpoints will also be evaluated at 12 months post-surgery with NVD003. These include radiographic and clinical healing, non-use of secondary interventions, and several safety and procedural parameters such as the number and severity of adverse events (AEs) and serious adverse events (SAEs) related to NVD003, units of blood transfused perioperatively, duration of general surgery (GS), duration of hospitalization post-GS, and incidence of recurrent fractures within 12 months. Additionally, radiological bone union status will be assessed at 3, 6, and 12 months using the total extended Lane and Sandhu scoring (eLSS) method, and functional walking outcomes will be evaluated using the timed 10-meter walking test. Quality of life (QoL) changes from baseline to 6 and 12 months post-GS will be measured using the Pediatric Outcomes Data Collection Instrument (PODCI) parent report for children aged 2 years and above.