| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-infected hypotrophic non-union fractures of long bones |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-infected non-union fractures |
|
| 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 | 16.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10048617 |
| E.1.2 | Term | Pseudarthrosis |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| 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 main objectives of the study are to demonstrate the non-inferiority of PREOB® implantation over bone autograft in terms of safety and efficacy at Month 12 clinically on the basis of the global disease evaluation score (as assessed by visual analogue scales) and radiologically on the basis of the percentage of patients with radiological improvement as assessed by RUST score determined by CT Scan. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective is to compare PREOB® and Bone Autograft in terms of efficacy using:
- Global Disease Evaluation as perceived by the physician using a Visual Analogue Scale
- Pain using a visual analogue scale (at rest, during activities and at palpation)
- Weight-bearing using a Likert Scale
- Well-being score as assessed by the SF-12 questionnaire
- Radiological improvement using the RUS(T) as assessed by X-ray. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patient diagnosed with a non-infected hypotrophic (atrophic and oligotrophic) non-union fracture of a long bone which will be of a minimum 6 months without signs of evolution over the last 3 months at the time of randomisation/baseline
- Patient aged 18 to 65 years inclusive
- Patient capable to understand and comply with study requirements
- Patient 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.
- Normal haematology function, defined in a peripheral blood testing as leukocytes >3000/mm³, absolute neutrophils count >1500/mm³ and platelets >140,000/mm³
Female patients must be:
- Post-menopausal (defined as at least 12 month post-cessation of menses), or
- Surgically sterile, or
- For women with childbearing potential:
1. Using 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).
2. Present negative Urine Pregnancy tests at Visit #1 and Visit #2. If a Urine Pregnancy test is positive at any other of the following visits, the patient is excluded from the study.
|
|
| E.4 | Principal exclusion criteria |
- Non-union interline > 1 cm as defined by the independent radiologist
- Insufficient reduction of the fracture with displaced fragments
- Insufficient fracture stability due, for example, to an osteolysis at the level of the nails/screws and/or defect and/or mobility of the osteosynthesis material at physical examination, as judged by the Investigator
- Osteosynthesis material revision performed less than 3 months from the randomization/baseline visit for simple revision without surgery or bone graft at the non-union site or less than 6 months from the randomization/baseline visit for revision with surgery or bone graft on the non-union site
- Osteosynthesis materials at the non-union site other than intramedullary nails, screws, plates or external fixation
- Open fracture with septic local infection and/or abnormal CRP and/or abnormal skin and scar, at the point of screening
- Bone infection at site
- Femoral neck fracture
- Multifocal fracture/non-unions (i.e., more than one non-union fracture site on the studied bone)
- Non-union or non-consolidated fracture on the neighbouring bone (i.e., at radius/ulna or at tibia/fibula)
- RUS(T) > 9 as assessed by conventional X-ray
- Global disease evaluation as assessed by the patient lower than 20 mm on a visual analogue scale
- Nerve damage and/or neuropathic/neuropathic-like pain at non-union fracture site
- Tendon lesion (e.g., rupture or enthesopathy) at non-union fracture site
- Positive serology for hepatitis B
- Positive serology for hepatitis C
- Positive serology for HIV
- Positive serology for syphilis
- Positive serology for HTLV-1
- Presence, or previous history, of risks factors for diseases caused by prions, including patients diagnosed with Creutzfeldt-Jakob disease, or variant Creutzfeldt-Jakob disease (including bovine spongiform encephalopathy), or having a family history of non-iatrogenic Creutzfeldt-Jakob disease; patients with a history of rapid progressive dementia or degenerative neurological disease (including those of unknown origin); recipients of hormones derived from the human pituitary gland (such as growth hormones); and recipients of grafts of cornea, sclera, and dura mera)
- Global sepsis, including, but not limited to brucellosis, typhus, leprosy, relapsing fever, melioidosis and tularaemia
- Haemoglobin level <10 g/dl
- History of blood loss exceeding 450 ml (incl. blood donations) within 1 month before screening
- 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%)
- Clinically relevant abnormal ECG (> 6-lead or according to standard of care at the hospital) at screening, as judged by the Investigator
- Known history of severe acute or chronic allergy requiring medical therapy
- Known allergy to Gelfoam® (i.e., porcine collagen)
- Known allergy to gentamicin
- Current or past history of solid or haematological neoplasia or bone marrow transplantation
- Life expectancy less than 6 months
- Current medical disease that could interfere with the evaluation of efficacy, as judged by the investigator, including but not limited to local or metabolic bone diseases (e.g., osteogenesis imperfecta, primary hyperparathyroidism, renal osteodystrophy, fibrous dysplasia [monostotic, polyostotic McCune-Albright syndrome] and osteopetrosis), Paget’s disease, fibromyalgia, hemochromatosis, acromegaly, ochronotic arthritis, heritable disorder, and collagen gene mutations
- Known severe osteoporosis, as defined by T-score < -2.5 at the lumbar spine or at the hip, or by the occurrence of a low trauma fracture in the medical history of the patient
- Patients who have previously been treated with PREOB®
- Participation in another clinical study involving a pharmacological treatment within 3 months prior to screening
- Current or past treatment for cancer or blood dyscrasia, including any chemotherapy, radiotherapy, immunotherapy, biotherapy, haematopoietic growth factors, anti-vasculogenesis, and/or anti-angiogenesis treatment
- Current (or within 1 month of screening) anticoagulants, including intravenous, intramuscular, subcutaneous, and oral anticoagulation at any therapeutic dosage (but not prophylactic use)
- Current or past intravenous bisphosphonate therapy (e.g., zoledronic acid)
- Current (or within 6 months of screening) oral bisphosphonate therapy
- 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
- Pregnancy
- Breast-feeding
- Woman not willing or able to use a contraceptive method, which the investigator considers reliable (see inclusion criteria)
- Body Mass Index (BMI) of 35 kg/m2 or greater
- Patients unable to undergo general anaesthesia |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Global disease evaluation as perceived by the patients using a visual analogue scale
- Radiological healing progression using the RUS(T) as assessed by CT scan
At each follow-up visit, subjects will be assessed for the potential occurrence of any AE or SAE, related to the product or related to the procedure, using patient open non-directive questionnaire, vital signs and laboratory measurements. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Efficacy endpoints will be determined at each scheduled visit over the 12-month follow-up period (notably at 1, 3, 6, 9 and 12 months) for patients in the PREOB® implantation or in the Bone Autograft groups. |
|
| E.5.2 | Secondary end point(s) |
- Pain using visual analogue scale
- Weight bearing using a likert scale
- Well-being score as assessed by SF 12
- Global disease evaluation as perceived by the physician using a visual analogue scale
- Radiological improvements using the RUS(T) as assessed by X-Ray
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Efficacy endpoints will be determined at each scheduled visit over the 12-month follow-up period (notably at 1, 3, 6, 9 and 12 months) for patients in the PREOB® implantation or in the Bone Autograft groups. |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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
|
| Last visit of the last subject undergoing the trial |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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