| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prophylaxis of heart, liver and kidney tranpslant rejection in paediatrics |
| profilassi del rigetto d’organo dopo trapianto di cuore, fegato e rene pediatrico |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prevention of heart, liver and kidney transplant in children |
| Prevenzione della perdita del cuore, fegato e rene trapiantato nei bambini |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007611 |
| E.1.2 | Term | Cardiac transplant |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| 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 | 10024716 |
| E.1.2 | Term | Liver transplantation |
| 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 compare the systemic exposure (AUC0-24h) of tacrolimus for Advagraf versus Prograf after the first dose and following repeated administration in pediatric subjects undergoing de novo allograft transplantation of kidney, liver or heart. |
| Confrontare l’esposizione sistemica (AUC0-24h) di tacrolimus per Advagraf con quella per Prograf dopo la somministrazione della prima dose e successivamente a dosi ripetute in soggetti pediatrici sottoposti ad allotrapianto de novo di rene, fegato o cuore. |
|
| E.2.2 | Secondary objectives of the trial |
| To observe the long-term safety and efficacy profile of tacrolimus for Advagraf with that of Prograf in pediatric subjects undergoing de novo allograft transplantation of kidney, liver or heart. |
| Confrontare,a lungo termine,il profilo di sicurezza e di efficacia di tacrolimus per Advagraf con quello per Prograf in soggetti pediatrici sottoposti ad allotrapianto de novo di rene,fegato o cuore. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subject is eligible for the study if all of the following apply:
1. The subject is aged < 16 years of age, undergoing primary liver, kidney or heart allograft transplantation.
2. The subject must be able to swallow intact Prograf or Advagraf capsules.
3. Female subjects of child bearing potential must provide a negative urine or serum pregnancy test prior to enrolment in the study.
4. Male and female subjects that are sexually active must agree to practice effective birth control during the study. (An effective method of birth control is defined as those which result in a low failure rate (ICH M3(R2)) of less than 1% per year when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomized partner).
5. The subject’s parent(s), or their legal representative(s), has been fully informed and has given written informed consent to participate in the study. The subject has given assent where applicable.
Additional Inclusion Criteria on Day 1 (Heart transplant subjects):
6. Subjects, treated since transplantation with Basiliximab or ATG/ Mycophenolate Mofetil (MMF)/steroids, whose gastric motility has resumed and whose renal function is adequate on Day 1. |
Il soggetto sarà arruolabile nello studio nei seguenti casi:
1. Soggetto di età inferiore a 16 anni, sottoposto a trapianto primario allografico di fegato, rene o cuore.
2. Soggetto in grado di inghiottire capsule integre di Prograf o Advagraf
3. I soggetti di sesso femminile potenzialmente fertili devono presentare un test di gravidanza negativo su siero o urine al momento dell’arruolamento.
4. I soggetti di sesso maschile e femminile che siano sessualmente attivi devono acconsentire a mantenere un metodo altamente efficace di controllo delle nascite durante lo studio (per “metodo altamente efficace di controllo delle nascite” si intende uno di quei metodi che risultano avere un basso tasso di fallimenti (ICH M3(R2)), meno dell’1% all’anno, se usati in maniera costante e corretta come impianti, metodi iniettabili, contraccettivi orali combinati, alcuni dispositivi intrauterini (IUDs), astinenza da rapporti sessuali o il partner vasectomizzato).
5. Il/I genitore/i del soggetto, o il/i loro rappresentante/i legale/i, è stato completamente informato e ha dato il suo consenso informato scritto a partecipare allo studio. Se applicabile, il soggetto stesso ha dato il proprio assenso.
Criteri di Inclusione aggiuntivi al Giorno 1 (soggetti sottoposti a trapianto di cuore):
6. Soggetti, trattati con Basiliximab o ATG/MMF/steroidi sin dal giorno del trapianto, con ripresa della motilità gastrica e adeguata funzionalità renale al Giorno 1. |
|
| E.4 | Principal exclusion criteria |
Subject will be excluded from participation if any of the following apply at baseline:
1. Subject is receiving a multi-organ transplant or has previously received an organ transplant (including re-transplantation).
2. Subject with pulmonary vascular resistance 4 Wood units despite medication.
3. Subject with significant renal impairment, defined as having serum creatinine ≥230 μmol/l (≥2.6 mg/dl) pre-transplantation. (Not applicable for renal transplanted subjects)
4. Subject with significant liver disease, defined as having continuously elevated SGPT/ALT and/or SGOT/AST and/or total bilirubin levels of ≥3 times the upper value of the normal range of the investigational site during the past 28 days. (Not applicable for liver transplanted subjects)
5. Subject with malignancies or a history of malignancy within the last 5 years, with the exception of those with basalioma or squamous cell carcinoma of the skin that has been treated successfully. (Not applicable for transplanted subjects with a primary organ diagnosis of cancer)
6. Subject with significant, uncontrolled concomitant infections and/or severe diarrhoea, vomiting, active upper gastrointestinal disorder that may affect the absorption of tacrolimus or active peptic ulcer.
7. Subject requiring systemic immunosuppressive medication for any other indication than transplantation.
8. Subject or donor known to be HIV or HCV or HBV positive.
9. Subject is allergic or intolerant to steroids, macrolide antibiotics, MMF or tacrolimus.
10. Subject is pregnant or breast-feeding.
11. Subject is unlikely to comply with the visits scheduled in the protocol.
12. Subject has any form of substance abuse, psychiatric disorder or condition which, in the opinion of the Investigator, may complicate communication with the Investigator.
13. Subject is participating or has participated in another clinical trial and/or those taking or having taken an investigational/non-registered drug in the past 28 days.
14. Subject is taking or requiring to be treated with medication or substances known to interfere with tacrolimus metabolism and listed in section below ‘Prohibited Concomitant Medication’ or having taken such medication within 28 days prior to inclusion. |
Il soggetto verrà escluso dalla partecipazione allo studio nei seguenti casi:
1. Il soggetti sta per ricevere un trapianto multi-organo o ha precedentemente ricevuto un trapianto d’organo (incluso un ritrapianto).
2. Soggetto con resistenza vascolare polmonare >4 unità Wood nonostante terapia.
3. Soggetto con compromessa funzionalità renale significativa, definita come creatinina sierica > 230 μmol/l (> 2.6 ml/dl) pre-trapianto (eccetto i soggetti sottoposti a trapianto di rene).
4. Soggetto con epatopatia significativa, definita come livelli di SGPT/ALT e/o SGOT/AST continuativamente elevati e/o livelli di bilirubina totale ≥ 3 volte il limite superiore della norma del centro sperimentale negli ultimi 28 giorni (eccetto i soggetti sottoposti a trapianto di fegato).
5. Soggetto con neoplasia maligna o storia clinica di neoplasia maligna entro gli ultimi 5 anni, ad eccezione del carcinoma basocellulare o a cellule squamose della pelle trattato con successo (eccetto i soggetti sottoposti a trapianto con diagnosi primaria di tumore).
6. Soggetto con infezioni concomitanti significative e non controllate e/o grave diarrea, vomito, disordini attivi del tratto gastrointestinale superiore tali da avere effetto sull’assorbimento di tacrolimus o ulcera peptica attiva.
7. Soggetto che richieda la somministrazione di un immunosoppressore sistemico per qualsiasi indicazione diversa dal trapianto.
8. Soggetto o donatore notoriamente HIV o HCV o HBV positivo.
9. Soggetto allergico o intollerante a steroidi, antibiotici macrolidi, MMF o tacrolimus.
10. Soggetto in stato di gravidanza o allattamento.
11. Soggetto verosimilmente poco in grado di aderire allo schema delle visite previsto dal protocollo.
12. Soggetto con qualunque forma di abuso di sostanze, disturbo psichiatrico o condizione che, a giudizio dello sperimentatore, possa complicare la comunicazione con lo sperimentatore.
13. Soggetto che stia attualmente partecipando o abbia partecipato ad un’altra sperimentazione clinica e/o stia assumendo o abbia assunto un farmaco sperimentale negli ultimi 28 giorni.
14. Soggetto che stia assumendo o che necessiti di essere trattato con farmaci o sostanze note per interferire con il metabolismo di tacrolimus ed elencate nella sezione “Farmaci Concomitanti Proibiti” o che abbia assunto tali farmaci nei 28 giorni precedenti alla data di inclusione. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Pharmacokinetic Variables
• The systemic exposure (AUC0-24h at each of Day 1, Day 7 and Day 28) of tacrolimus after first dose and under steady state conditions.
Primary Safety Variables
• AEs
• Laboratory parameters
• Vital signs |
Variabile Primaria di Farmacocinetica
L’esposizione sistemica (AUC0-24h al Giorno 1, Giorno 7 e Giorno 28) di tacrolimus dopo la prima dose e in condizioni di steady state
Variabili Primarie di Sicurezza
Incidenza di Eventi Avversi (AE)
Parametri di Laboratorio
Segni vitali |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
AUC0-24h at each of Day 1, Day 7 and Day 28
Long term safety at 2, 3, 6, and 12 months |
AUC0-24h al Giorno 1, Giorno 7 e Giorno 28
Sicurezza a lungo termine a 2, 3, 6 e 12 mesi |
|
| E.5.2 | Secondary end point(s) |
Secondary Pharmacokinetic Variables
The following PK parameters for tacrolimus will be determined for each profile
• Cmax
• tmax
• C24
Efficacy Variables
• Rejection episodes
• Subject and graft survival |
Variabili Secondarie di Farmacocinetica
Saranno determinati per tacrolimus i seguenti parametri di PK per ciascun profilo
Cmax
tmax
C24
Variabili di Efficacia
Episodi di Rigetto
Sopravvivenza dell’organo e del paziente |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK variables at Day 1, Day 7 and Day 28
Long term efficacy variables at 2, 3, 6 and 12 months |
Variabili di farmacocinetica al Giorno 1, Giorno 7 e Giorno 28
Variabili di efficacia a lungo termine a 2, 3, 6 e 12 mesi |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| 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) | 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 | 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) | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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
|
| The study will not be discontinued early based on the results of PK data. Part B, including baseline characteristics, safety and efficacy data from Part A, will be reported once the one year follow up has been completed |
| Lo studio non sarà interrotto anticipatamente sulla base dei risultati dei dati di farmacocinetica.Il report relativo alla Parte B sarà fornito al completamento del periodo di follow-up di un anno. |
|
| 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 | 24 |
| 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 | 24 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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