A prospective multicentre single-arm study in adults to evaluate the safety and preliminary efficacy of the autologous 3D osteogenic implant NVD-003 for bone reconstruction for the treatment of recalcitrant lower limb nonunion.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novadip Biosciences

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

2 Aug 2018 → ongoing

Decision date (initial)

2025-01-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517762-42-01

EudraCT number

2018-000299-13

ClinicalTrials.gov

NCT06335394

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Safety:
To evaluate the safety of the use of NVD-003 in patients with recalcitrant lower limb nonunion.

Secondary objectives 5

1. To assess the healing efficacy of NVD-003 by radiographic assessments.
2. To assess the healing efficacy of NVD-003 by clinical assessments.
3. To assess patient reported outcomes such as pain (pain severity and pain interference with function), quality of life and overall treatment effect.
4. To assess the local complication rate after graft implantation (i.e. revision, removal, reoperation, supplemental fixation)
5. To assess-long term safety of NVD-003

Conditions and MedDRA coding

recalcitrant lower limb nonunion

Regulatory references

Plan to share IPD

No

IPD plan description

Not applicable

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Male or female adult subject (≥18 years).
2. 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.
3. 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).
4. The impaired limb is salvageable and the patient is eligible for the intended surgical procedure according to the standard hospital practice.
5. 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.
6. 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.
7. 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.
8. Negative urinary pregnancy test for women of childbearing potential.
9. 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.
10. 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
11. 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.
12. Patient fulfils the criteria to donate his human body material (adipose tissue) and is suitable to undergo a liposuction.

Exclusion criteria 21

1. 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.
2. Multifocal or comminuted fractures.
3. A planned use of an external fixator is not allowed as of the grafting surgery (V1) until V7.
4. 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.
5. Pregnant or breast-feeding woman.
6. 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.
7. 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.
8. The subject previously received a cellular therapy treatment at any point in time (as per protocol description).
9. 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.
10. 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.
11. Known allergy to any antibiotics commonly used to treat Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus) or coagulase-negative staphylococci.
12. 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).
13. Chronic use of immunosuppressive therapy (immunosuppressant/ immunotherapy) due to inflammatory or systemic disease.
14. 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.
15. Subjects with poorly controlled diabetes mellitus type 2 as assessed by glycated haemoglobin (HbA1C) ≥ 10%.
16. Subjects with poorly controlled thyroid diseases (unstable despite proper medication).
17. Subjects with documented metabolic bone disease (based on the investigator judgment) such as, but not limited to osteogenesis imperfecta or osteomalacia.
18. 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.
19. Existing malignant tumour in the vicinity of the graft or a resected one not cured for more than 5 years.
20. Any other illness which might reduce life expectancy to less than 2 years from screening.
21. The subject is a prisoner.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety: From graft implantation until completion of visit V7  All Adverse Events (AEs) including Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI) and Procedure Related AE’s (PRAE).
2. Safety: At V2, V3, V4, V5, V6 and V7  Vital signs abnormalities.  Physical examinations abnormalities.  Safety laboratories abnormalities.

Secondary endpoints 13

1. Healing efficacy: Plain X-ray healing defined as 3 united cortices out of 4, on antero-posterior and lateral RX views, measured at 6 weeks (V3), 3 months (V4), 6 months (V5), 12 months (V6), at additional visits (V ADD, if no healing at 12 months after graft implant surgery) up to visit 7 (V7). The Radiographic Union Score (RUS) will be calculated
2. Healing efficacy: Computerized Tomography (CT)-scan healing defined as 3 united cortices out of 4, measured at 6, 12 and 24 months. The Tomography Union Score (TUS) will be calculated (see APPENDIX 7).
3. Healing efficacy: The average time from IMP grafting surgery (V1) till first observation of plain X-ray and CT-scan confirmed fracture healing (using the above definitions).
4. Healing efficacy: Investigator assessed clinical healing based on the overall clinical evaluation of the patient, including ability to bear weight, the pain score at palpation at the fracture site and the pain medication intake by the patient. Investigator assessed clinically healing will be evaluated from 6 weeks post-grafting onwards up to V7.
5. Healing efficacy: The average time from IMP grafting surgery (V1) to Investigator assessed clinical healing (time from grafting surgery till first observation of investigator assessed clinical healing).
6. Grafting Surgery parameters: Duration of surgery (V1).
7. Grafting Surgery parameters: Duration of hospitalization (V1-V2).
8. Complications: Rate of subsequent surgical interventions (e.g. revision, removal, reoperation and/or supplemental fixation) measured at 12 and 24 months post-implant surgery.
9. Quality of Life (QoL): Pain evaluation with the Brief Pain Inventory (Short Form) (BPI-SF) (see APPENDIX 3) (pain severity and pain interference with function) at screening and at 6 weeks, 3, 6, 12 and 24 months post-graft.
10. Quality of Life (QoL): QoL questionnaire EuroQol-5 Dimensions (EQ-5D- 5L) (see APPENDIX 4) measured at screening and at 6 weeks, 3, 6, 12 and 24 months post-graft.
11. Quality of Life (QoL): Overall Treatment Effect (OTE) (see APPENDIX 5) rating scale at 3, 6, 12 and 24 months post-graft.
12. General Pre-graft implantation safety: All AEs including Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI) and Procedure Related AE’s (PRAE).
13. During the extended safety follow-up period (between 24 months FU visit and 5 years post-grafting surgery in Belgium and 10 years post-grafting surgery in Luxembourg): All Serious Adverse Events (SAEs).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novadip Biosciences

Sponsor organisation

Novadip Biosciences

Address

Rue Granbonpre 11

City

Mont-Saint-Guibert

Postcode

1435

Country

Belgium

Scientific contact point

Organisation

Novadip Biosciences

Contact name

Denis Dufrane

Public contact point

Organisation

Novadip Biosciences

Contact name

Denis Dufrane

Locations

2 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 60 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications