| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| renal transplantation |
| Trapianto di rene |
|
| MedDRA Classification |
| 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 | 10023438 |
| E.1.2 | Term | Kidney transplant |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 demonstrate superior renal allograft function in de novo renal transplant recipients after early conversion from CNI to everolimus, assessed by Glomerular Filtration Rate (eGFR) estimated by the Modification of Diet in Renal Disease formula 4 (MDRD4) at Month 12 versus the active control. |
| • dimostrare la superiorita' in termini di funzionalita' renale nei pazienti trapiantati di rene de novo dopo conversione precoce da inibitori della calcineurina ad everolimus misurata come velocita' di filtrazione glomerulare (eGFR) calcolata con la formula MDRD4 (Modification of Diet in Renal Disease) dopo 12 mesi rispetto al controllo attivo. |
|
| E.2.2 | Secondary objectives of the trial |
| - To demonstrate non-inferior efficacy (defined by a composite efficacy endpoint of treated Biopsy Proven Acute Rejection (BPAR) ≥ IB, graft loss or death) at Month 12. - To demonstrate improvement of Left Ventricular Hypertrophy (LVH) in comparable patients (assessed by LV mass index, LVMi) by echocardiogram at Month 12. |
| • dimostrare la non inferiorita' in termini di efficacia (definita come endpoint composito di efficacia valutata da rigetto acuto trattato confermato da biopsia (tBPAR) ≥ IB, perdita del trapianto o morte) a 12 mesi • dimostrare un miglioramento della Ipertrofia Ventricolare Sinistra (LVH) misurata con l’indice di massa del ventricolo sinistro (LVMi) utilizzando un ecocardiogramma a 12 mesi |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Inclusion criteria at Baseline: (Day of transplantation) • Male or female renal allograft recipients at least 18 years old. • Patients who have given written informed consent to participate in the study. If consent cannot be expressed in writing, it must be formally documented and witnessed, ideally via an independent trusted witness. • Patient who has received a primary or secondary kidney transplant from a cadaveric or living unrelated-/related donor. • Recipient of a kidney allograft with a cold ischemia time (CIT) < 24 hours. • Female patients must have a negative pregnancy test prior to study enrollment. Inclusion criteria at Randomization: (Week 10-14 after transplantation) • Patients on CNI (tacrolimus or Neoral) + Myfortic + steroids. • Patients with an acceptable allograft function defined by a serum creatinine < 2.8 mg/dL (250 μmol/L) and an actual eGFR (MDRD4) ≥ 25 mL/min/1.73m2 (without renal replacement therapy). |
| Principali criteri di inclusione alla randomizzazione (10-14 settimane dopo trapianto): • Pazienti in terapia con inibitori della calcineurina (tacrolimus o Neoral) + Myfortic + steroidi • Pazienti con una funzionalita' dell’organo trapiantato accettabile definita come creatinina sierica < 2.8 mg/dL (250 μmol/L) e una eGFR attuale (MDRD4) ≥ 25 mL/min/1.73m2 (senza un trattamento renale sostitutivo) |
|
| E.4 | Principal exclusion criteria |
| Exclusion criteria at Baseline: (Day of transplantation) • Recipient of multiple organ transplants. • Recipient of ABO incompatible allograft or a positive cross-match. • Patient with most recent Panel Reactive Antibodies (PRA) level ≥ 30 % or a positive luminex test for any permitted antigen of the recipient. • Patient who is human immunodeficiency virus (HIV) positive. • Patient who received an allograft from a Hepatitis B surface Antigen (HBsAg) or a Hepatitis C Virus (HCV) positive donor. • HBsAg and/or a HCV positive patient with evidence of elevated LFTs (ALT/AST levels ≥ 2.5 times ULN). Viral serology results obtained within 6 months prior to randomization are acceptable. • Patient with severe restrictive or obstructive pulmonary disorders. • Patient with severe allergy requiring acute (within 4 weeks of baseline) or chronic treatment that would prevent patient from potential exposure to everolimus, or with hypersensitivity to drugs similar to everolimus (e.g. macrolides). • Patients with a known hypersensitivity/contraindication to any of the immunosuppressants or their classes, or to any of the excipients. • Patient with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled. • Patient with white blood cell (WBC) count ≤ 2,000 /mm3 or with platelet count ≤ 50,000 /mm3. • History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. Exclusion criteria at Randomization: (Week 10-14 after transplantation) • Graft loss. • Patient on renal replacement therapy. • Patient who experienced severe humoral and/or cellular rejection (BANFF ≥ IIb). • Patient with ≥ 2 episodes of AR or an AR episode that needed antibody treatment. • Patient with ongoing or currently treated AR (2 weeks prior to randomization). • Proteinuria > 1 g/day (as calculated from the urinary protein-to-creatinine ratio). • Patients with recurrence of Focal Segmental Glomerulosclerosis (FSGS). • Patient with white blood cell (WBC) count ≤ 2,000 /mm3, an absolute neutrophil count of ≤ 1,500 /mm3, with a platelet count ≤ 50,000 /mm3, or hemoglobin < 8 g/dL. • Evidence of severe liver disease (incl. abnormal liver function tests, i.e. AST, ALT or total bilirubin > 2.5 times ULN). • Patient who has a current severe systemic infection according to the investigator judgment requiring continued therapy that would interfere with the objectives of the study. • Patient with severe hypercholesterolemia or hypertriglyceridemia that cannot be controlled. • Patients with ongoing wound healing problems, clinically significant infection requiring continued therapy or other severe surgical complication in the opinion of the investigator. PLS SEE PROTOCOL |
| Principali criteri di esclusione al basale ( giorno del trapianto): • Pazienti riceventi trapianto multiorgano • Pazienti riceventi trapianto ABO incompatibile o trapianto con crossmatch positivo • Pazienti con anticorpi anti-pannello (PRA) ≥ 30% o con test Luminex positivo a uno qualsiasi degli antigeni del ricevente • Pazienti positivi al virus dell’immunodeficienza umana (HIV) • Pazienti riceventi un organo da un paziente positivo all’antigene di superficie del virus dell’epatite B (HBsAg+), o al virus dell’epatite C (HCV+) • Pazienti HBsAg+, o HCV+ con alterazione degli enzimi epatici (LFTs) (AST, ALT ≥ 2.5 volte il limite superiore della norma. I valori della sierologia virale saranno considerati accettabili se effettuati entro 6 mesi prima della randomizzazione. • Pazienti con una nota ipersensibilita'/controindicazione ad un solo immunosoppressore o a tutta la classe o ad uno qualsiasi degli eccipienti • Pazienti con importanti problemi polmonari di tipo restrittivo o ostruttivo • Pazienti con allergie di grado severo (entro 4 settimane dalla visita basale) che richiedono un trattamento acuto o cronico che potrebbe impedire al paziente una potenziale esposizione all’everolimus o pazienti che hanno una accertata ipersensibilita' a farmaci simili all’everolimus (es.macrolidi) • Pazienti con ipercolesterolemia o ipertrigliceridemia non controllata • Pazienti con conta leucocitaria (WBC) ≤ 2000/mm3 o con conta piastrinica ≤ 50.000/mm3 • Anamnesi positiva per neoplasie, entro i 5 anni precedenti, trattate o non trattate, con o senza evidenza di recidiva locale o metastasi, con l’eccezione di carcinomi cutanei basocellulari localizzati. Principali criteri di esclusione alla randomizzazione (10-14 settimane dal trapianto): • Perdita del trapianto • Pazienti in terapia renale sostitutiva • Pazienti che hanno avuto un rigetto umorale e/o cellulare (BANFF ≥ IIb) • Pazienti con ≥ 2 episodi di rigetto acuto o episodio di rigetto acuto che ha richiesto trattamento con anticorpi • Pazienti con episodio di rigetto acuto in corso o in trattamento (2 settimane precedenti alla randomizzazione) • Proteinuria >1 g / die (calcolata come rapporto tra le proteine urinarie e la creatinina) • Pazienti con recidiva di Glomerulosclerosi Segmentale Focale (FSGS) • Pazienti con conta leucocitaria (WBC) ≤ 2000/mm3, conta neutrofilica ≤ 1500/mm3 con conta piastrinica ≤ 50.000/mm3 o emoglobina < 8 g/dL • Evidenza di malattia epatica severa (incluso anomalie nei test di funzionalita' epatica, es. AST,ALT o bilirubina totale > 2.5 volte il limite superiore della norma • Pazienti che secondo il parere del medico responsabile dello studio hanno in corso una infezione sistemica grave che richiedono di continuare la terapia che potrebbe interferire con l’obiettivo dello studio • Pazienti con ipercolesterolemia o ipertrigliceridemia non controllata • Pazienti con difficolta' di guarigione della ferita, con infezione clinicamente significativa che richiede una terapia continuativa o altra complicanza chirurgica severa secondo l’opinione del medico responsabile dello studio • Pazienti con complicanze o effetti collaterali non trattabili alla terapia immunosoppressiva • Pazienti in terapia con anticoagulanti che impediscono esecuzione della biopsia renale |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| To demonstrate superior renal allograft function in de novo renal transplant recipients after early CNI to everolimus conversion assessed by Glomerular Filtration Rate (eGFR) estimated by the Modification of Diet in Renal Disease formula 4 (MDRD4) at Month 12 versus the active control. |
| Dimostrare la superiorita' in termini di funzionalita' renale nei pazienti trapiantati di rene de novo dopo conversione precoce da inibitori della calcineurina ad everolimus misurata come velocita' di filtrazione glomerulare (eGFR) calcolata con la formula MDRD4 (Modification of Diet in Renal Disease) dopo 12 mesi rispetto al controllo attivo. |
|
| 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) | 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 | 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 95 |
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 43 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 54 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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