E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Early avascular necrosis of the femoral head (MRI diagnosis): Ficat and Arlet 0, 1, or 2 (Steinberg stages 0, I, IIA, IIB, or IIC) |
Necrosi avascolare della testa del femore in fase precoce (diagnosticata con MRI): Ficat e Arlet 0, 1, or 2 (Steinberg stages 0, I, IIA, IIB, o IIC) |
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E.1.1.1 | Medical condition in easily understood language |
Avascular necrosis of the femoral head |
Necrosi avascolare della testa del femore |
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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 | 14.1 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10028395 |
E.1.2 | Term | Musculoskeletal and connective tissue disorders |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10003860 |
E.1.2 | Term | Avascular necrosis femoral head |
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 |
To evaluate the safety and feasibility of the treatment of early avascular necrosis of the femoral head with expanded bone marrow autologous stem cells to enhance bone healing, after core decompression through percutaneous forage |
Valutare la sicurezza e la fattibilità del trattamento della necrosi avascolare della testa del femore in fase precoce con cellule staminali mesenchimali autologhe espanse per potenziare la guarigione ossea, dopo decompressione attraverso iniezione percutanea. |
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E.2.2 | Secondary objectives of the trial |
To obtain bone healing, without increasing the complication rate, of early avascular necrosis of the femoral head treated by standard care procedures plus percutaneous injection of autologous stem cells derived from bone marrow and expanded under GMP conditions. |
Ottenere la guarigione dell’osso senza aumento del tasso di complicazioni della necrosi avascolare della testa del femore in fase precoce trattata con procedure standard ed iniezione percutanea di cellule staminali autologhe derivate da midollo osseo ed espanse in condizioni GMP. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Age 18 to 65, both sexes
-Early avascular necrosis of the femoral head (MRI diagnosis): Ficat and Arlet 0, 1, or 2 (Steinberg stages 0, I, IIA, IIB, or IIC)
-Symptomatic osteonecrosis with less than 6 months of evolution
-Able to provide informed consent, and signed informed consent
-Medical health care coverage
-Able to understand and accept the study constraints
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- Età18-65 anni, entrambi i sessi
- Necrosi avascolare della testa del femore in fase precoce (diagnosticata con MRI): Ficat e Arlet 0, 1, or 2 (Steinberg stages 0, I, IIA, IIB, o IIC)
- Osteonecrosi sintomatica con meno di sei mesi di evoluzione
- in grado di fornire consenso e di firmare i consenso informato
- copertura di spese mediche
- in grado di capire ed accettare i vincoli dello studio
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E.4 | Principal exclusion criteria |
-Pregnancy, breast feeding women and women who are of childbearing age and not practicing adequate birth control.
-Participation in another therapeutic trial in the previous 3 months
-Stages 3 or more (Ficat and Arlet) or III or more (Steinberg) of severe femoral head osteonecrosis, primarily based on diagnosis by imaging (X-Rays, MRI).
-Flattening or collapse of the femoral head (Steinberg stage IV) or articular cartilage collapse at the time of core decompression surgery.
-Septic arthritis.
-Stress fracture.
-Non-osteonecrosis metabolic bone diseases (particularly Paget's disease of bone, osteogenesis imperfecta, primary hyperparathyroidism, fibrous dysplasia monostotic, polyostotic McCune-Albright syndrome] and osteopetrosis).
-Any active bisphosphonate treatment or any history of intravenous (IV) treatment.
-History of prior or concurrent diagnosis of HIV-, Hepatitis-B- or Hepatitis-C-infection (confirmed by serology or PCR)
-Active hepatitis B or hepatitis C infection at the time of screening. Known allergies to products involved in the production process of MSC.
-History of neoplasia or current neoplasia in any organ.
-Corticoid or immunosuppressive therapy more than one week in the two months prior to study inclusion
-Patients who will require continuous, systemic, high dose corticosteroid therapy (more than 7.5 mg/day) within 6 months after surgery.
-Patients who are in active treatment for cancer or blood dyscrasia, or have received chemotherapy, radiotherapy or immunotherapy in the past 2 years.
-History of regular alcohol consumption exceeding 2 drinks/day (1 drink = 150 mL of wine or 360 mL of beer or 45 mL of hard liquor) within 6 months of screening and/or history of illicit drug use.
-Serum AST (SGOT)/ALT (SGPT) > 2.5 X (institutional standard range).
-MRI-incompatible internaldevices (pacemakers, aneurysm clips, etc).
-Body mass index (BMI) of 40 kg/m² or greater.
-Patients unable to tolerate general anesthesia defined as an American Society of Anesthesiologists (ASA) criteria of > 2.
-Insulin dependent diabetes
-Patients with poorly controlled diabetes mellitus (HbA1C > 8%), or with peripheral neuropathy, or known concomitant vascular problems.
-Patients receiving treatment with hematopoietic growth factors or anti-vasculogenesis or antiangiogenesis treatment.
-Traumatic osteonecrosis.
-Adult in the care of a guardian (Subject legally protected)
-Impossibility to meet at the appointments for the clinical follow up.
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- Gravidanza, donne che stanno allattando, donne che sono in eta’ fertile ma che non pratichino adeguate misure contraccettive.
- Partecipazione ad un altro studio terapeutico nei 3 mesi precedenti
- Stadi 3 o superiori (Ficat and Arlet) o III o superiori (Steinberg) di osteonecrosi severa della testa femorale, fondamentalmente ottenuta mediante diagnosi strumentale (X-Ray, MRI).
- Appiattimento o crollo della testa femorale (Steinberg stage IV) o crollo della cartilagine articolare al momento dell’intervento di ‘core decompression’.
- Artrite settica
- Frattura da stress.
- Malattie metaboliche dell’osso senza osteonecrosi (in particolare malattia di Paget’s, osteogenesi imperfetta, iperparatiroidismo primario, displasia fibrosa monostotica, sindrome polistotica di McCune-Albright e osteopetrosi).
- Ogni trattamento di bifosfonato attivo o ogni storia clinica di trattamento intravenoso (IV)
- Diagnosi precedente o contemporanea di infezione da HIV, da Epatite-B o Epatite-C (confermata mediante indagine sierologica o PCR)
- Infezione da Epatite-B o Epatite-C attiva al momento dell’inclusione
- Allergie documentate a prodotti utilizzati nel processo di produzione delle MSCs.
- Precedente neoplasia o neoplasia in corso in qualunque organo.
- Terapia corticosteroidea o immunosoppressiva per più di 1 settimana nei due mesi precedenti l’inclusione nello studio
- Pazienti che necessiteranno di terapia continuata, sistemica, ad alte dosi di farmaci corticosteroidei (più di 7,5 mg/giorno) entro 6 mesi dopo l’intervento
- Pazienti che sono in trattamento attivo per neoplasia o discrasia ematica, o sottoposti a chemioterapia, radioterapia o immunoterapia negli ultimi due anni.
- Storia clinica di regolare assunzione di alcol superiore a due bicchieri al giorno (1 bicchiere = 150 ml di vino o 360 ml di birra o 45 ml di liquore) nei 6 mesi precedenti l’inclusione e/o storia clinica di uso di droghe illecite.
- AST (SGOT)/ALT (SGPT) seriche > 2.5 X (range standard dell’istituto ).
- Dispositivi endocorporei incompatibili con la MRI (pacemakers, clips aneurismatiche, ecc).
- Indice di massa corporea (BMI) di 40 kg/m² o superiore.
- Pazienti incapaci di sopportare l’anestesia generale, definiti, in base ai criteri della American Society of Anesthesiologists (ASA) , come > 2.
- Diabete insulino-dipendente
- Pazienti con diabete mellito scarsamente controllato (HbA1C > 8%), o con neuropatia periferica, o con accertati problemi vascolari concomitanti.
- Pazienti che stiano ricevendo trattamenti con fattori di crescita ematopoietici, di antivasculogenesi, di antiangiogenesi.
- Osteonecrosi traumatica
- Adulto affidato a un tutore (soggetto legalmente protetto)
- impossibilita’ di presenziare agli appuntamenti per la valutazione clinica
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety endpoints include:
-Early local complication rate, as the percentage of patients with local complications within three months after surgery.
- Global complication rate, as the percentage of patients with local or general complications at 52 weeks
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- tasso di complicazioni precoce definto come percentuale di pazienti con complicazioni locali entro 3 mesi dopo l’intervento.
- tasso di complicazioni globali definto come percentuale di pazienti con complicazioni locali o generali dopo 52 settimane.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Complication rates at weeks : 6, 12, 24, 52 |
tasso di complicazioni alle settimane 6, 12, 24, 52 |
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E.5.2 | Secondary end point(s) |
-Local and general complication rate at 104 weeks regarding potential effects in the FU of patients after introducing MSCs
-Number of patients with no progression to the next stage (defined as 0 to 1, 1 to 2, 2 to 3) at 12 months.
-Number of patients with no radiological or MRI progression at 6 weeks (X-ray), 12 weeks (X-ray, MRI), 24 weeksX-ray), and 52 weeks (X-ray, MRI), in proportion of the recruited, treated patients. Data and images will be reviewed by an adjudication committee at the end of the study following a pre established procedure
-Amount of necrotic bone in the femoral head at 12 weeks and 52 weeks in MRI, compared with preoperative status. This will be measured according to a standardised protocol.
-Changes in serum levels of bone turnover markers(in a centralized laboratory) at 12 and 24 weeks after treatment
-Pain assessed by a Visual Analogue Scale at 12 , 24 and 52 weeks
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- Tasso di complicazioni locali e generali dopo 104 settimane riguardo potenziali effetti nel follow up dei pazienti dopo l’introduzione delle cellule staminale mesenchimali.
- Numero di pazienti con nessuna progressione allo stadio successivo (definito come da 0 a 1, da 1 a 2, da 2 a 3) ai 12 mesi
- Numero di pazienti con nessuna progressione verificata radiologicamente (X-ray) o con risonanza magnetica (MRI) a 6 settimane (X-ray), 12 settimane (X-ray, MRI), 24 settimane (X-ray), e 52 settimane (X-ray, MRI), in proporzione ai pazienti arruolati, e trattati. I dati e le immagini saranno analizzati da una commissione giudicante al termine dello studio mediante una procedura prestabilita.
- Quantità di tessuto necrotico nella testa femorale a 12 e 52 settimane valutata mediante MRI, a confronto con la condizione pre-operatoria. Questa verrà misurata mediante un protocollo standardizzato.
- Alterazioni nei livelli serici degli indici di rimodellamento osseo (laboratorio centralizzato) dopo 12 e 24 settimane dal trattamento.
- Dolore valutato con ‘Visual Analogue Scale’ a 12, 24 e 52 settimane.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
6, 12, 24, 52 and 104 weeks
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6, 12, 24, 52, 104 settimane |
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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 | 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
| 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 | 6 |
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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |