E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
RENAL FUNCTION IN LIVER TRANSPLANT RECIPIENT RECEIVING AN IMMUNOSUPPRESSIVE REGIMEN OF ADVAGRAF (IMMEDIATELY OR DELAYED POST-TRANSPLANT) AND MMF WITH OR WITHOUT SIMULECT |
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E.1.1.1 | Medical condition in easily understood language |
Prevention of liver transplant rejection |
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E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Surgical Procedures, Operative [E04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
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 |
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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 aim of this study is to compare three therapy regimens with regard to renal function. This study has been designed to determine whether delayed administration of Advagraf in the immediate period post liver transplantation and lowered Advagraf exposure may provide a benefit upon subsequent renal function. The three treatment arms are: Arm 1: Advagraf + MMF + Corticosteroids (Bolus) Arm 2: Advagraf (lower dose) + MMF + Basiliximab + Corticosteroids (Bolus) Arm 3: Advagraf (5 days delay) + MMF + Basiliximab + Corticosteroids (Bolus) Treatment Arm 1 will serve as the reference arm for the study, the combination of tacrolimus and MMF has a proven efficacy and safety profile. In addition the combination of Advagraf and MMF allows the minimisation of steroids and a potential reduction in associated infectious and metabolic complications. Treatment Arm 2 will have a lower tacrolimus exposure and Treatment Arm 3 will have a delayed Advagraf administration and each will... |
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E.2.2 | Secondary objectives of the trial |
The secondary aim of this study is to compare the efficacy and safety profiles of the three therapy regimens as described in A10. The efficacy of the three therapy regimens will be measured from the following variables: Efficacy failure rate: measured by the incidence of graft loss or biopsy confirmed acute rejection and the time to the first incidence of the composite (more than one variable) event. In this case graft loss is defined as re-transplantation or death. Renal function: • Glomerular filtration rate (GFR) at 24 Weeks after transplantation measured by Iothalamate clearance. • GFR at 24 Weeks after transplantation estimated using a Cystatin C based formula. • Creatinine clearance at 24 Weeks after transplantation estimated using the Cockcroft and Gault formula… |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PHARMACOKINETICS OF ADVAGRAF IN DE-NOVO LIVER TRANSPLANT SUBJECTS WHEN ADMINISTERED VIA NASOGASTRIC TUBE. PMR-EC-1107 (DIAMOND France Study) dated 7th June 2010 (Final Version). Due to French administrative requirements the PMR-EC-1107 study is organized as a sub-study of the PMR-EC-1106 study. The two protocols have the same objectives. |
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E.3 | Principal inclusion criteria |
Inclusion Criteria: A subject is eligible for the study if all of the following apply: 1. Age ≥ 18 years. 2. Undergoing orthotopic liver or split liver allograft transplantation. 3. Female subject of childbearing potential must have a negative serum or urine pregnancy test at enrollment and must agree to maintain effective birth control during the study. 4. Capable of understanding the purpose and risks of the study, fully informed and given written informed consent (signed Informed Consent has been obtained). |
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E.4 | Principal exclusion criteria |
Exclusion Criteria A subject will be excluded from participation if any of the following apply: 1. Receiving a multi-organ transplant or having previous received an organ transplant (including liver re-transplantation). 2. Receiving an auxiliary graft or in whom a bio-artificial liver (cell system) has been used. 3. Receiving ABO incompatible graft or a graft from a non heart beating donor. 4. Ongoing dosing with systemic corticosteroids. 5. Subjects with systemic infection requiring treatment except viral hepatitis. 6. Diagnosis of new-onset malignancy prior to transplantation, with the exception of basocellular or squamous cell carcinoma of the skin which had been treated successfully. However, subjects with primary liver carcinoma can be included if they meet the following criteria: • < or equal to 3 nodules • no nodule larger than 5 cm • no metastases • no vascular tumoral invasion 7. Significant, uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or active peptic ulcer. 8. Subject or donor known to be HIV positive. 9. Known allergy or intolerance to tacrolimus, macrolide antibiotics, corticosteroids, Basiliximab or mycophenolate mofetil or any of the product excipients. 10. Pregnant woman or breast-feeding mother. 11. Currently participating in another clinical trial, and/or has taken an investigational drug within 28 days prior to enrollment. 12. Unlikely to comply with the Visits scheduled in the protocol. 13. Any unstable medical condition that could interfere with the study objectives in the opinion of the Investigator. 14. Receiving prohibited concomitant therapy, or received prohibited concomitant therapy within 28 days prior to enrollment. 15. Any form of substance abuse, psychiatric disorder or condition which, in the opinion of the Investigator, may complicate communication with the Investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point of this study is to demonstrate the non-inferiority of the two experimental Advagraf arms (Arm 2 and Arm 3), each compared separately to the control Advagraf Arm 1, 24 Weeks after liver transplantation with regard to kidney function. The primary endpoint of the study is graft dysfunction (defined as glomerular filtration rate (GFR) < 22.5mL/min/1.73m2 estimated by MDRD4 formula 24 weeks after transplantation). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
● Efficacy Failure Rate, composite endpoint consisting of graft loss (defined as re-transplantation or death) or biopsy confirmed acute rejection. ● Renal function (assessed by Iohexol clearance, Cystatin C based formula and Cockcroft and Gault formula) ● Acute Rejection Episodes Incidence and Time to (both Corticosteroid sensitive and resistant) • Biopsy Confirmed Acute Rejection Episodes - Incidence, Time to and Severity (both corticosteroid sensitive and resistant) ● Subject and graft survival. ● Incidence of Adverse Events ● Laboratory Parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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 | 3 |
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 | 70 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Belarus |
Brazil |
Canada |
Colombia |
Mexico |
Russian Federation |
South Africa |
Switzerland |
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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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The end of study is defined as the last subject’s last protocol-defined assessment(performance of End of Study Visit or follow-up Visit in the case of withdrawn subjects). |
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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 | 7 |
E.8.9.1 | In the Member State concerned days | 29 |
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 | 7 |
E.8.9.2 | In all countries concerned by the trial days | 29 |