| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple non-infected delayed-union fractures |
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| E.1.1.1 | Medical condition in easily understood language |
| Multiple 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 | 19.1 |
| 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 is to assess the safety and efficacy of single administration of ALLOB® into minimum 2 and maximum 4 delayed-union fracture sites affecting long bones, with a maximal dose of 200 million ALLOB® cells.
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 (vital signs), and laboratory measurements.
Efficacy: The success will be based on the percentage of treated fractures and 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 pain at palpation (VAS) performed by the physician but assessed by the patient has not improved by at least 25% on at least 2 of possible 4 targeted sites and the TUS as assessed by CT scan has not increased by at least 2 points (versus baseline) on at least 2 of the possible 4 targeted sites. |
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| E.2.2 | Secondary objectives of the trial |
The efficacy of ALLOB® will be assessed over time versus baseline in terms of efficacy using:
- Global Disease Evaluation as perceived by the physician (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 and during activities ) (at 6 Months and over time)
- Weight-bearing using a Likert Scale (at 6 Months and over time)
- Quantitative radiological changes using the mRUS as assessed by X-ray (at 6 Months and over time)
-Assessment of biomarkers
-Evolution from baseline to each time point of the TUS and/or mRUS score(s) of untreated fractured neigbouring bones (e.g., fibula left untretaed when the tibia is the target bone of the study) as assessed by CT scan and/or X-ray |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female patient aged between 18 to 70 years inclusive
- Patient diagnosed with a minimum of 2 non-infected DU fracture (see definition on page 21 of the clinical study protocol) affecting one or more long bones (femur, tibia, fibula, humerus, ulna, radius) documented by an X-Ray and/or a CT-scan showing delayed healing as judged by the investigator.
- Modified Radiographic Union Scale (mRUS) absolute score at screening visit lower than 10 for at least 2 DU fracture sites.
- Global Disease Evaluaton Score as assessed by the patient of 20 mm or higher on Visual Analogue Scale
- Patient capable to understand and comply with study requirements and capable to provide a written, dated, and signed informed consent prior to any study procedure for participation in the study and transmission of personal "anonymized" data. |
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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
- Patients for whom 2 of the DU targeted sites occur on both humerus
- Osteosynthesis material revision or a surgery at the fracture site that can have a significant impact on the delayed union fracture healing, as judged by the Investigator
- Active bone infection (at site)
- Femoral neck fracture, if the femur is the target bone of the study
- 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 pain assessments during the study, as judged 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 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 with childbearing potential not willing or able to use or present:
- 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).
- Present negative Urine Pregnancy tests at Visit #1. If a Urine Pregnancy test is positive, the patient is excluded from the study.
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 Endpoints:
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…).
Efficacy Endpoints:
A patient will be considered as failed under treatment if, at Month 6, the pain at palpation (performed by the physician and assessed by the patient) score as perceived by the patient has not improved by at least 25% on at least 2 of possible 4 targeted sites and the TUS as assessed by CT scan has not increased by at least two points for at least two of the maximum four targeted fracture sites. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Clinical Efficacy and safety variables will be determined at each scheduled visit over the 6-month study period (at 2 weeks, 1, 3 and 6 months). Radiological variable will be based on X-Ray performed at screening, 3 and 6 months. CT scan will be performed only at screening and month 6. A safety follow up at (6), 12 and 24 months after the end of the study follow-up will also be conducted by phone call, the data of which will be reported as Annexes and Supplementary Data to the final CSR.
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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 Investigator
- Evolution from baseline to each time point of Pain VAS at rest and during activities 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 for the treated fracture sites (independently) assessed by conventional X-ray
- Assessment of biomarkers
- Evolution from baseline to each time point of the TUS and/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 | 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) | No |
| E.7.1.1 | First administration to humans | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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