Evaluation of Safety and Preliminary Efficacy of Autologous 3D Osteogenic Implant NVD-003 in Recalcitrant Lower Limb Nonunion in Adults
- Trial ID
- 2024-517762-42-01
- Protocol
- NVD003-CLN01
- Sponsor
- Novadip Biosciences
Trial statistics
Objectives
The primary objective of this study is to evaluate the **safety** of the autologous 3D osteogenic implant NVD-003 in patients with recalcitrant lower limb nonunion. This is clinically relevant as ensuring the safety of the implant is crucial for its potential use in bone reconstruction, particularly in challenging cases where traditional treatments have failed.
Secondary objectives include:
- Assessing the healing efficacy of NVD-003 through radiographic and clinical assessments.
- Evaluating patient-reported outcomes such as pain severity, pain interference with function, quality of life, and overall treatment effect.
- Determining the local complication rate post-graft implantation, including revision, removal, reoperation, and supplemental fixation.
- Assessing the long-term safety of NVD-003.
Participants
The clinical trial involves **adult** participants, both male and female, aged 18 years and older, who are diagnosed with **recalcitrant lower limb nonunion**. The sponsor has not provided the total number of participants. The study population was selected based on specific inclusion criteria, including the ability to donate adipose tissue and suitability for liposuction, as well as documented normal or low bone density. Participants must have radiographic confirmation of lower limb nonunion and be eligible for the intended surgical procedure. The trial excludes vulnerable populations and requires participants to be psychosocially, mentally, and physically able to comply with the protocol. Women of childbearing potential must use effective birth control and have a negative pregnancy test. The trial does not specify any particular lifestyle considerations such as diet or physical activity.
Plans and Procedures
The clinical trial is a **prospective multicentre single-arm study** designed to evaluate the safety and preliminary efficacy of the autologous 3D osteogenic implant NVD-003 for bone reconstruction in adults with **recalcitrant lower limb nonunion**. The trial is structured as a Phase I/IIa study, focusing on the safety of the NVD-003 implant, which is derived from **autologous adipose-derived stem cells**. The trial is expected to run from August 2018 to May 2030, with participant involvement lasting up to 24 months post-graft, followed by an extended safety follow-up period.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, serology tests, and radiographic evidence of nonunion. Following the screening, the initial visit (V1) involves the grafting surgery, where the NVD-003 implant is administered via **implantation**. Subsequent follow-up visits are scheduled at 6 weeks (V3), 3 months (V4), 6 months (V5), and 12 months (V6) post-surgery, with additional visits if necessary, up to the final visit (V7) at 24 months. These visits will assess safety through monitoring of adverse events, vital signs, and laboratory results, as well as efficacy through radiographic and clinical evaluations of bone healing.
The primary endpoint focuses on safety, tracking all adverse events from graft implantation until the completion of visit V7. Secondary endpoints include healing efficacy, assessed through X-ray and CT-scan evaluations, and quality of life measures using standardized questionnaires. Participants may be terminated early from the study if they experience significant adverse events or fail to comply with study procedures. The trial aims to provide valuable insights into the potential of NVD-003 as a treatment for challenging bone conditions, with a comprehensive assessment of both safety and preliminary efficacy.
Treatment
The clinical trial involves the use of an experimental medication known as **NVD-003**, which is an osteogenic graft derived from **autologous adipose-derived stem cells**. This investigational product is developed by NOVADIP BIOSCIENCES and is classified under the ATC code M05, indicating its use in the treatment of bone diseases. The pharmaceutical form of NVD-003 is an **implant**, specifically designed for implantation into the body. The route of administration is through **implantation**, and the product is not formulated for pediatric use. The primary objective of the trial is to evaluate the safety and preliminary efficacy of NVD-003 in adults with recalcitrant lower limb nonunion.
In this study, NVD-003 is the sole investigational treatment, and there are no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments mentioned. The trial does not specify a maximum daily dose, total dose, or treatment period for NVD-003, indicating that dosing schedules may be individualized based on the specific needs of the participants. Compliance with the treatment regimen will be monitored throughout the study to ensure adherence to the protocol. The trial aims to provide insights into the safety profile of NVD-003 and its potential efficacy in promoting bone reconstruction in the specified patient population.
Efficacy
The efficacy of the autologous 3D osteogenic implant NVD-003 for bone reconstruction in the treatment of recalcitrant lower limb nonunion will be assessed through several parameters. The primary efficacy endpoint involves the evaluation of healing efficacy using radiographic assessments. Plain X-ray healing is defined as the presence of 3 united cortices out of 4 on antero-posterior and lateral views, measured at specific timepoints: 6 weeks, 3 months, 6 months, 12 months, and additional visits if necessary, up to visit 7. The **Radiographic Union Score (RUS)** will be calculated to quantify healing. Additionally, Computerized Tomography (CT)-scan healing will be assessed using the same criteria at 6, 12, and 24 months, with the **Tomography Union Score (TUS)** being calculated.
Secondary efficacy endpoints include the average time from the investigational medicinal product (IMP) grafting surgery to the first observation of fracture healing confirmed by X-ray and CT-scan, as well as investigator-assessed clinical healing. Clinical healing will be evaluated based on the patient's ability to bear weight, pain score at the fracture site, and pain medication intake, starting from 6 weeks post-grafting up to visit 7. The duration of surgery and hospitalization, as well as the rate of subsequent surgical interventions, will also be recorded. Quality of life will be assessed using the Brief Pain Inventory (Short Form) and the EuroQol-5 Dimensions questionnaire at screening and at various intervals post-graft, including 6 weeks, 3, 6, 12, and 24 months. The Overall Treatment Effect rating scale will be used at 3, 6, 12, and 24 months post-graft.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Male or female adult subject (≥18 years).
- Radiographic images not older than 3 months, confirming lower limb nonunion, defined as the absence of clinical and radiographic progression towards healing over 3 consecutive months on serial radiographs and minimum 9 months after the first attempt of surgical bone repair, or minimum 6 months after the second (or any subsequent) attempt of surgical bone repair.
- Radiologic single, meta- and/or diaphyseal bone defect with a maximum size of 4 cm (in case of a void that does not transverse the whole width of the bone, the total volume cannot exceed the volume corresponding to the 4 cm gap).
- The impaired limb is salvageable and the patient is eligible for the intended surgical procedure according to the standard hospital practice.
- Documented normal or low bone density: Bone density scan determined by Dual Energy X-Ray Absorptiometry DEXA scan on lumbar spine and hip (bone mineral density T-scores above -2.5). An examination ≤ 1-year-old before screening is acceptable.
- The subject is, in the Investigator’s opinion, psychosocially, mentally and physically able to fully comply with this protocol, including the postoperative regimen and followup visits.
- Use of an effective birth control method for 2 months prior to the date of the intended surgical intervention up to Visit V7 for women of childbearing potential.
- Negative urinary pregnancy test for women of childbearing potential.
- At screening, safety local laboratory test results are medically acceptable to undergo surgery (see Section 7.3.2) and serology results are in accordance with country specific requirements for donation of Human Body Material.
- At time of adipose tissue collection, central laboratory serology and molecular tests panel for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and syphilis are in accordance with Belgian specific requirements for release of Human Body Material
- The subject has understood the nature of the study, agrees to its provisions, and has accepted to participate in the study and to follow all study procedures. This is acknowledged by signing the informed consent as approved by the required Institutional Review Board/Ethics Committee and the national competent authorities.
- Patient fulfils the criteria to donate his human body material (adipose tissue) and is suitable to undergo a liposuction.
Exclusion Criteria
- The subject has a body mass index (BMI) ≤ 20 kg/m² or ≥ 40 kg/m², or of ≥35 kg/m² with obesity-related health conditions, such as high blood pressure or diabetes.
- Multifocal or comminuted fractures.
- A planned use of an external fixator is not allowed as of the grafting surgery (V1) until V7.
- Documented osteoporosis: bone density determined using DEXA scan on lumbar spine and hip: bone mineral density T-scores of -2.5 and below. An examination ≤ 1-year-old before screening is acceptable.
- Pregnant or breast-feeding woman.
- The subject shows signs of an active drug or alcohol dependence, serious current illness, mental illness or any other factors which, in the opinion of the investigator, will interfere with study conduct or the interpretation of the results.
- The patient has a history of solid organ transplant at any point in the past or is on the waiting list for future organ transplantation.
- The subject previously received a cellular therapy treatment at any point in time (as per protocol description).
- Previous exposure to any experimental therapy with another investigational drug within 60 days prior to screening or enrolment in any concurrent study that may confound the results of this study.
- Any signs or suspicion of an active local (area of the future surgical site), or systemic infection before the induced membrane surgery or the grafting surgery.
- Known allergy to any antibiotics commonly used to treat Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus) or coagulase-negative staphylococci.
- Diagnosis of HIV, HBV (HBsAg or PCR positive), HCV, Human T-cell Lymphotropic Virus (HTLV) 1 or 2, or syphilis infection (as confirmed by serology and nucleic acid test (NAT) by Tissue Establishment).
- Chronic use of immunosuppressive therapy (immunosuppressant/ immunotherapy) due to inflammatory or systemic disease.
- Any clinically relevant chronic disease associated with renal or hepatic insufficiency or any chronic disease of such severity that surgery could be detrimental to the survival of the patient.
- Subjects with poorly controlled diabetes mellitus type 2 as assessed by glycated haemoglobin (HbA1C) ≥ 10%.
- Subjects with poorly controlled thyroid diseases (unstable despite proper medication).
- Subjects with documented metabolic bone disease (based on the investigator judgment) such as, but not limited to osteogenesis imperfecta or osteomalacia.
- Chronic, current or planned during study use of any medications that might affect bone metabolism or the quality of bone formation such as but not limited to bisphosphonates, steroids, methotrexate, anticoagulant therapies, immunosuppressant therapy or immunotherapy. However, short lasting surgery related prophylactic treatments such as antibiotics, analgesics and low molecular heparin drugs may be administered according to hospital recommendations.
- Existing malignant tumour in the vicinity of the graft or a resected one not cured for more than 5 years.
- Any other illness which might reduce life expectancy to less than 2 years from screening.
- The subject is a prisoner.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 02 Aug 2018 | 8 |
 Luxembourg | Recruiting | 02 Aug 2018 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
NVD003 | Test | IMPLANT | IMPLANTATION | — | — | PRD5906702 |