NVD-003 in the Treatment of Congenital Pseudarthrosis of the Tibia

Study Overview
=================
Brief Summary
-----------------
A single arm, multi-country, multi-center study in pediatric patients, suffering from congenital pseudarthrosis of the tibia (CPT), treated during the primary surgical intervention with NVD-003, an autologous 3D scaffold free osteogenic graft.

Detailed Description
-----------------
Congenital pseudarthrosis is a rare disorder of unknown aetiology and variable history that manifests itself as a non-union or pseudarthrosis of fractures that develop spontaneously or following minor trauma. It can be defined as a disorder of the diaphysis which is revealed by either pseudarthrosis at birth or by a pathological fracture presenting in bone with modifications such as bowing, narrowing of the medullary canal or a cyst. Although uncommon, CPT is the most frequently observed type of congenital pseudarthrosis. Its incidence is reported to be between 1:140,000 to 1:250,000 live births. Autologous bone grafting is considered the gold standard approach as this material vascularizes and integrates with surrounding bone, minimizing the risk of infection, dislodgement, or break-down. NVD-003 is a scaffold free 3D osteogenic graft derived from autologous adipose stem cells which become embedded in their extracellular matrix and combined with hydroxyapatite/beta-tricalcium phosphate (HA/βTCP) particles. NVD-003 is intended to promote bone formation, supporting the physiological bone healing process in severe pathophysiological conditions such as hypoxia, lack of mineralized callus formation, bone resorption and low osteogenicity.

Official Title
-----------------
A Proof-of-concept Study With NVD-003, an Autologous Osteogenic Bone Graft, in the Treatment of Congenital Pseudarthrosis of the Tibia in Pediatric Patients.

Conditions
-----------------
Congenital Pseudarthrosis of Tibia

Intervention / Treatment
-----------------
* Biological: NVD-003, an autologous 3D scaffold free osteogenic graft


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosed with congenital pseudarthrosis of the tibia (with or without NF1) and presenting with a non-healing Paley type 3 or 4 fracture. Minimum weight of 5kg/11lbs. Maximum 2 previous failed surgical orthopaedic interventions to treat the primary CPT fracture. Acceptable serology and molecular test results excluding the presence of viruses Satisfactory general health condition to undergo surgeries (ATC and GS) with anaesthesia as per local standards. The patient's parent(s) and/or legal guardian(s) provided written informed consent and accepted the participation of the patient in the trial. Exclusion Criteria: Bilateral CPT. Presence of CPT without a fracture of the tibia (Paley type 1 and 2). More than 2 failed surgical attempt(s) to treat the primary tibial fracture. Evidence of plexiform neurofibroma of any size or nodular fibroma ≥ 1.2in/3cm on the ipsilateral leg. Clinically significant infection at the target grafting site or systemic infection. Presence of clinically significant hematologic, renal, hepatic, and coagulation laboratory abnormalities (i.e., CBC, PT/INR, Chem-7, and LFTs, etc.). Presence of any auto-immune disease, with exception of well controlled diabetes type 1 or auto-immune thyroid disorders. Any history of experimental therapy with another investigational drug within 60 days prior to screening. Presence of active tumour. Documented metabolic bone disease or any disorder, such as but not limited to osteogenesis imperfecta and osteomalacia, that could interfere with the bone healing and bone metabolism. Chronic, ongoing, or planned use of medications that might affect bone metabolism or bone quality such as bisphosphonates, steroids, methotrexate, anticoagulant therapies, immunosuppressant therapy or immunotherapy.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 8 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: A single arm, multi-country, multi-center study in pediatric patients, suffering from congenital pseudarthrosis of the tibia (CPT), treated during the primary surgical intervention with NVD-003, an autologous 3D scaffold free osteogenic graft.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NVD-003 bone graft implant<br>The study includes 2 important surgical procedures, the Adipose Tissue Collection (ATC) and the Grafting Surgery (GS) and 3 stages Stage 1: A screening, adipose tissue collection & NVD 003 manufacturing period. Stage 2: Grafting surgery and 12-month post-GS follow-up period. Stage 3: long-term safety follow-up period (from post-month 12 to month 24). | Biological: NVD-003, an autologous 3D scaffold free osteogenic graft<br>* Bone correction and grafting surgery<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary objective: safety short (≤3 months) and mid long-term (>3-12 months): : Descriptive analysis | Assess number of patients with NVD-003 related (S)AEs | Up to 12 months post-grafting surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Long term Safety long-term (>12-24 months): Descriptive analysis | Assess number of patients with NVD-003 related SAEs | 12-24 months post grafting surgery | 
| Tibial length evaluation | Assess evolution tibial length (using CT-Scan) | 3-, 6-, 12- and 24-months post-GS | 
| Bone formation | Assess changes in bone formation (Using Lane and Sandhu Scoring on CT-Scan) | 3-, 6-, 12- and 24-months post-GS | 
| Bone remodeling | Assess changes in bone remodeling (using Lane and Sandhu Scoring on CT-scan) Based on Dual Energy CT-scan (DECT or Spectral CT), information of low- and high-energy photons is collected, allowing to uncover differences in energy-dependent attenuation, facilitating composition of NVD 003 and surrounding tissue and define bone mineral density) at 3-, 6-, and 12-months post-GS | 3-, 6-, 12- and 24-months post-GS | 
| Bone union | Assess changes in bone union (using Lane and Sandhu Scoring on CT-scan) | 3-, 6-, 12- and 24-months post-GS | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tissue Engineered Therapy, bone graft, autologous, pediatric, congenital, non-union, pseudarthrosis, Cellular therapy