AUTOLOGOUS ADIPOSE-DERIVED STEM CELLS for Recalcitrant lower limb nonunion

Inclusion criteria

• {"criterion_text":"- Male or female adult subject (≥18 years).\n- 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.\n- 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).\n- The impaired limb is salvageable and the patient is eligible for the intended surgical procedure according to the standard hospital practice.\n- 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.\n- 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.\n- 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.\n- Negative urinary pregnancy test for women of childbearing potential.\n- 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.\n- 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\n- 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.\n- Patient fulfils the criteria to donate his human body material (adipose tissue) and is suitable to undergo a liposuction."}

Exclusion criteria

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

Primary endpoints

• {"endpoint_text":"- 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).","definition_or_measurement_approach":"All AEs, SAEs, AESI and procedure-related AEs will be collected from graft implantation until completion of visit V7 (safety monitoring period defined in protocol)."}
• {"endpoint_text":"- Safety: At V2, V3, V4, V5, V6 and V7  Vital signs abnormalities.  Physical examinations abnormalities.  Safety laboratories abnormalities.","definition_or_measurement_approach":"Assessment of vital signs, physical examination findings, and safety laboratory abnormalities at visits V2, V3, V4, V5, V6 and V7 as recorded in case report forms."}

Secondary endpoints

• {"endpoint_text":"- 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","definition_or_measurement_approach":"Plain X-ray assessment using definition of 3 united cortices out of 4 on AP and lateral views at specified visits; Radiographic Union Score (RUS) calculated."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"CT-scan assessment using 3 of 4 united cortices definition at 6, 12 and 24 months; Tomography Union Score (TUS) calculated."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Time (days) from grafting surgery (V1) to first radiographic/CT confirmation of union per definitions above."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Investigator clinical assessment of healing including weight-bearing, palpation pain score and analgesic use assessed from 6 weeks post-grafting through V7."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Time (days) from grafting surgery to first investigator-determined clinical healing."}
• {"endpoint_text":"- Grafting Surgery parameters: Duration of surgery (V1).","definition_or_measurement_approach":"Measured operative time at V1 (grafting surgery)."}
• {"endpoint_text":"- Grafting Surgery parameters: Duration of hospitalization (V1-V2).","definition_or_measurement_approach":"Length of hospital stay measured from V1 to V2."}
• {"endpoint_text":"- Complications: Rate of subsequent surgical interventions (e.g. revision, removal, reoperation and/or supplemental fixation) measured at 12 and 24 months post-implant surgery.","definition_or_measurement_approach":"Incidence rate of subsequent surgical interventions recorded at 12 and 24 months post-implant."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Patient-reported BPI-SF scores collected at screening and specified post-graft timepoints."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"EQ-5D-5L questionnaire scores collected at screening and specified post-graft visits."}
• {"endpoint_text":"- Quality of Life (QoL): Overall Treatment Effect (OTE) (see APPENDIX 5) rating scale at 3, 6, 12 and 24 months post-graft.","definition_or_measurement_approach":"OTE rating scale collected at 3, 6, 12 and 24 months post-graft."}
• {"endpoint_text":"- General Pre-graft implantation safety: All AEs including Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESI) and Procedure Related AE’s (PRAE).","definition_or_measurement_approach":"Collection of AEs, SAEs, AESI and PRAE in pre-graft period per safety reporting."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"SAEs collected during extended follow-up: up to 5 years post-grafting in Belgium and up to 10 years post-grafting in Luxembourg."}

Belgium

Earliest CTIS Part Ii Submission Date

16-01-2025

Latest Decision Or Authorization Date

23-01-2025

Processing Time Days

7

Number Of Sites

4

Number Of Participants

8

Luxembourg

Earliest CTIS Part Ii Submission Date

16-01-2025

Latest Decision Or Authorization Date

04-09-2025

Processing Time Days

231

Number Of Sites

1

Number Of Participants

3

Primary sponsor

Full Name

Novadip Biosciences

Organisation Type

Pharmaceutical company

Country Of Registered Address

Belgium