| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-infected delayed-union fractures |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-infected delayed-union fractures |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10017081 |
| E.1.2 | Term | Fracture delayed union |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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| 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 |
The primary objective of the main study is to assess the safety and efficacy of ALLOB® single percutaneous implantation in healing delayed-union fractures at the end of the study period (Month 6).
Safety:
Subjects will be systematically assessed for the potential occurrence of any AE or SAE, related to the product or related to the procedure, using patient open questionnaires, physical examination, (including vital signs), and laboratory measurements.
Efficacy:
The success will be based on the percentage of treated patients (ALLOB®) not failing under treatment.
A patient will be considered as failed under a treatment if, at the end of the study period (Month 6), the patient had required a rescue surgery or the Global Disease Evaluation score (VAS) as perceived by the patient has not improved by at least 25% and the TUS as assessed by CT scan has not increased by at least two points (versus baseline). |
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| E.2.2 | Secondary objectives of the trial |
The efficacy of ALLOB® will also be evaluated on other efficacy parameters:
- Global Disease Evaluation as perceived by the Investigator (at 6 Months and over time) and by the patient (over time) using a Visual Analogue Scale
- Pain using a visual analogue scale (at rest, during activities and at palpation) (at 6 Months and over time)
- Weight-bearing using a Likert Scale (at 6 Months and over time)
- Radiological improvement using the TUS as assessed by CT scan over time
- Radiological improvement using the mRUS as assessed by X-ray (at 6 Months and over time)
- Biodistribution of ALLOB®
- Evolution of bone metabolism
- Variations in the biomarkers
- Radiological improvement of untreated fractured neigbouring bone using TUS and/or mRUS as assesssed by CT scan and X-ray, respectively |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biodistribution Sub-study
Title : ALLOB® biodistribution (version 04, dated Jul 29, 2015)
The aim of this sub-study is to follow the biodistribution of radiolabelled ALLOB® cells and to study the bone metabolism after administration at the fracture site. This sub-study is planned on a maximum of 8 patients in a single centre. About 10% of the injected ALLOB® cells will be labeled with indium oxinate, and mixed with unlabeled ALLOB® cells before being injected to the patient. Images will be acquired at 4 or 6 (if feasible), 24 and 48 and 72 hours after the injection at the site of the fracture. Planar whole body images and SPECT/CT volumetric images of the region of interest will be obtained using the SPECT/CT bone scintigraphy. The bone metabolism assessment can be
performed independently from the biodistribution study using
radiolabelled ALLOB® cells.
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| E.3 | Principal inclusion criteria |
- Patient aged 18 to 80 years inclusive
- Patient diagnosed with a non-infected delayed-union fracture of a long bone (femur, tibia, fibula, humerus, ulna, radius) of minimum 3 months and maximum 7 months (± 2 weeks) without signs of healing over the last 4 weeks at the time of screening
- Modified Radiographic Union Score (mRUS)* < 10
- Global Disease Evaluation Score as assessed by the patient ≥ 20 mm on a Visual Analogue Scale
- Patient (or patient’s legally acceptable representative) capable to provide a written, dated, and signed informed consent prior to any study procedure.
*In case the mRUS is not assessable, the Tomographic Union Score (TUS) could be used instead (judged by the independent Reader)
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|
| E.4 | Principal exclusion criteria |
Current symptoms and/or signs related to the disease under study
- Fracture interline > 2.5 cm, as defined by the Independent Radiologist
- Insufficient reduction of the fracture
- Insufficient fracture stability defined as osteolysis at the level of the nails/screws and/or defect and/or mobility of the osteosynthesis material at physical examination, as assessed by the Investigator
- Osteosynthesis material revision or surgery (i) performed less than 2 months from the screening visit at the fracture site or (ii) performed less than 4 weeks from the screening visit at distance of the fracture site.
- Active bone infection (at site)
- Femoral neck fracture, if the femur is the target bone of the study
- Multifocal fracture (e.g., more than one fracture site on the studied bone)
- Symptomatic delayed/non-union fracture on the neighbouring bone , as judged by the Investigator
- Severe nerve damage and/or neuropathic/neuropathic-like pain at fracture site, that may interfere with assessment during the study, as appreciated by the Investigator
- Severe tendon lesion (e.g., rupture or enthesopathy) at fracture site, that may interfere with assessment during the study, as appreciated by the Investigator
Current or previous diagnoses, signs and/or symptoms
- Positive serology for HIV (defined as positive Anti-HIV 1 and/or 2 and/or positive PCR)
- Active hepatitis B (defined as positive HBs Ag and/or positive PCR)
- Active hepatitis C (defined as positive Anti-HCV and/or positive PCR)
- Global sepsis
- Renal impairment, defined as serum creatinine >2 mg/dl or 176 µmol/L
- Hepatic impairment, defined as alanine aminotransferase or aspartate aminotransferase ≥ 3 times the upper normal limit
- Poorly controlled diabetes mellitus (defined as HbA1C >8%)
- Known allergy to gentamicin
- History of hypersensitivity to human biological material including blood and blood derived products, documented clinically or by laboratory tests
- Current or past history of solid or haematological neoplasia
- History of organ or bone marrow transplantation
- Active autoimmune disease (e.g., sclerodermia, Sjögren syndrome, lupus,...)
- Any concomitant disease that could interfere with the evaluation of efficacy, as judged by the Investigator, including but not limited to local or metabolic bone diseases
- Life expectancy less than 6 months
Current or previous treatment
- Patients who have previously been treated with ALLOB®
- Participation in another clinical study involving a pharmacological treatment within 3 months prior to screening
- Current (or within 1 month of screening) treatment with calcitonin, raloxifen, teriparatide, and/or strontium ralenate
- Current (or within 6 months of screening) illicit drug abuse (as per local law)
Safety aspects concerning female subjects of childbearing potential
- Pregnancy
- Breast-feeding
- Woman not willing or able to use a reliable contraceptive method for at
least 6 weeks prior to screening and during the whole study period.
Reliable contraceptive methods include orally administered hormonal
contraceptives, surgical intervention (e.g., tubal ligation), and
intrauterine device (IUD).
- Woman with positive urine pregnancy tests at Visits #1 and/or #2.
Other exclusion criteria
- Body Mass Index (BMI) of 35 kg/m2 or greater
- Unable to undergo general anaesthesia or a surgical intervention
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Criteria :
In addition to standard pharmacovigilance requirements, particular attention will be given to AE suggesting immune-mediated reactions, such as: general discomfort, uneasiness, ill feeling, pain or swelling in the implanted area, fever and any inflammatory reactions, flu-like symptoms (e.g., chills, body aches, shortness of breath, cutaneous rashes…). All severe AEs potentially related to the IMP and in particular those potentially related to the allogeneic reactions will be managed by the safety monitoring committee (SMC) who will analyse and report these events in a timely manner consistent with the safety of patient recruitment scheme.
Efficacy Criteria:
A patient will be considered as failed under treatment if, at Month 6, the patient had required a rescue surgery or has the Global Disease Evaluation Score (as perceived by the patient) has not improved by at least 25% and the Tomographic Union Score (TUS) as assessed by CT scan has not increased by at least two points. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy and safety endpoints will be determined at each scheduled visit over the 6-month follow-up period (at 2 weeks, 1, 3 and 6 months).
The interim report and the decision for continuation will be established on the first 16 assessable patients after 6 months of follow-up and the final Clinical Study Report (CSR) will be established at 6 months (end of study) after treatment for all patients, as applicable.
Moreover, selected clinical efficacy and safety parameters will also be investigated throughout an additional safety follow-up period at (6) 12 and 24 months after the end of the study.
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| E.5.2 | Secondary end point(s) |
Other efficacy endpoints:
- Evolution from baseline to each time point of the Global Disease Evaluation score (VAS) as perceived by the patient and physician
- Evolution from baseline to each time point of the TUS score as assessed by CT scan
- Evolution from baseline to each time point of Pain VAS at rest, during activities and at palpation (as performed by the physician) as assessed by the patient
- Evolution from baseline to each time point of Weight-Bearing score
- Evolution from baseline to each time point mRUS score assessed by conventional X-ray
- Evolution from baseline to each time point of the biodistribution of the ALLOB® cells
- Evolution from baseline to each time point of the bone metabolism
- Evolution from baseline to each time point of the biomarkers
- Evolution from baseline to each time point of the TUS and/or mRUS score(s) of untreated fractured neighbouring bones (e.g., fibula left untreated when the tibia is the target bone of the study) as assessed by CT scan and/or X-ray |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoints will be determined at each scheduled visit over the 6-month follow-up period (at 2 weeks, 1, 3 and 6 months).
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 15 |
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