E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with documented recalcitrant lower limb nonunion, meaning a single, diaphyseal nonunion defect of femur or tibia after at least one failed reconstructive surgical attempt. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with recalcitrant bone non-union affecting lower limb long bones (tibia, femur). |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety of the use of NVD-003 in patients with recalcitrant lower limb nonunion. |
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E.2.2 | Secondary objectives of the trial |
To assess the healing efficacy of NVD-003 by radiographic assessments. To assess the healing efficacy of NVD-003 by clinical assessments. To assess patient reported outcomes such as pain (pain severity and pain interference with function), quality of life and overall treatment effect. To assess the local complication rate after graft implantation (i.e. revision, removal, reoperation, supplemental fixation).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female adult subject (≥18 years). - Lower limb nonunion defined as the absence of clinical and radiographic signs of union in the last 3 months 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, diaphyseal bone defect ≤4 cm. - 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 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 follow-up visits. - Use of an effective birth control method for 2 months prior to the date of the intended surgical intervention and throughout the study duration for women of childbearing potential. - Negative urinary pregnancy test for women of childbearing potential. - Safety laboratory test results and serology at screening are medically acceptable to undergo surgery. - Serology panel for Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and syphilis must be negative at screening. - 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. |
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E.4 | Principal 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. - 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 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. - Active local or systemic infection, including infection around (area of) the future surgical site. - Known allergy to any antibiotics commonly used to treat Staphylococcus aureus (including methicillin-resistant Staphylococcus aureus) or coagulase-negative staphylococci. - Diagnosis of HIV, HBV, 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. - Any other illness which might reduce life expectancy to less than 2 years from screening. - The subject is a prisoner. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- All Serious Adverse Events (SAEs). - All Adverse Events (AEs) (only up to V6, 12 months after graft implant surgery). - Adverse Events of Special Interest (AESI): - Local: bone resorption, soft tissue calcification/ossification and tumor growth observed on CT and conventional radiographic images (RX). - General: ectopic bone formation or tumor growth on Chest X-Ray. - Vital signs abnormalities. - Physical examinations abnormalities. - Safety laboratories abnormalities.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After graft implantation (V1) until end of study (EOS) visit (V7). The study duration per patient will not exceed 24 months post-implantation. |
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E.5.2 | Secondary end point(s) |
- Healing efficacy - Surgical parameters - Complications - Quality of Life - General safety reporting (pre-graft implantation) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Healing efficacy (After graft implantation (V1) until end of study (EOS) visit (V7). The study duration per patient will not exceed 24 months post-implantation). - Surgical parameters (During implantation surgery and during hospitalization when implantation occurs). - Complications (12 months post-implantation surgery and at EOS visit). - Quality of Life (at screening and at 6 weeks, 3 months, 6 months, 12 months post-graft and EOS visit). - General safety reporting (from screening to pre-graft implantation). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Luxembourg |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |