A Multicentre, Randomised, Open-label, Controlled, 12-month Follow-up Study to Assess Impact on Renal Function of an Immunosuppression Regimen Based on Tacrolimus Minimisation in Association With Everolimus in de Novo Liver Transplant Recipients.
Condition: Liver Transplant
Intervention: Minimisation of TAC; TAC + MMF + corticosteroids
Intervention description: •EVR: Treatment started at a total daily dose of 2 mg within 24 hours after randomisation. The dose of EVR was adjusted upon reaching trough levels (C-0h) in whole blood of 3-8 ng/mL. The daily dose (in two administrations) of EVR may have been modified to maintain trough levels (C-0h) in whole blood of 3-8 ng/mL until Week 52 post-transplant. •TAC: Once confirmation was obtained, beginning in Week 5, that trough levels (C-0h) in whole blood of EVR were between 3-8 ng/mL, minimisation of TAC began, in order to reach trough levels (C-0h) of TAC in whole blood of ≤5 ng/mL no later than four weeks after randomisation (Week 8), which were levels that should have been maintained until Week 52 post-transplant. •MMF was withdrawn at the same time that EVR was introduced. •oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted; •Dose of TAC: Trough levels (C-0h) of TAC in whole blood should have been maintained between 6-10 ng/mL until Week 52 post-transplant. •Dose of MMF: Doses of 500-1000 mg/12 hrs was maintained until Week 52. •Corticosteroids: During the study, oral corticosteroids was administered in accordance with local clinical practice, although a therapeutic strategy free of corticosteroids was permitted (e.g. in patients with a history of HCV). It was recommended in any case that corticosteroids not be administered beyond Week 24 post-transplant except in cases of hepatopathy of autoimmune origin. At each centre all patients should have followed the same administration protocol for corticosteroids based on history of HCV.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A multicentre, randomized, open-label, controlled, exploratory clinical trial with 12-months (52 weeks) of follow-up".
Masking: None (Open Label)
Enrollment: 217.0
Sex: All
Minimum age: 18 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: De Novo Liver Transplant, Tacrolimus Minimisation, Everolimus, Renal Function, Liver transplant, allograft rejection, xenograft rejection, host vs graft disease

Summary:

      Assuming greater efficacy in the prevention of acute rejection in the EVR arm with
      minimisation of TAC levels, the hypothesis of the present trial was that the introduction of
      EVR in combination with the minimisation of TAC (rTAC) may offer improved kidney function
      compared with standard therapy with TAC-MMF.
    

Eligibility criteria:

        Screening Visit - Inclusion Criteria

          1. Recipients age 18 or over receiving a first liver transplant from a cadaver donor.

          2. Patients diagnosed with HCC must meet the Milan radiological criteria at the time of
             transplant (1 nodule ≤5 cm in diameter, or 2-3 nodules, all <3 cm in diameter) - at
             time of patient's inclusion on the waiting list.

             Anh: done.

          3. Patients who have signed the informed consent to participate in the study.

          4. Patients who by medical criteria are capable of complying with the study regimen.

        Screening Visit - Exclusion Criteria

          1. Recipients who have received multiple transplants of solid organs or pancreatic islet
             cells.

          2. Patients who have previously received an organ or tissue transplant.

          3. Patients with a combined liver-kidney transplant.

          4. Recipients of lobes or segments of liver from a live donor.

          5. A history of malignancy of any organ system in the previous 3 years according to local
             protocols (regardless of signs of local recurrence or metastasis), other than
             non-metastasising basal cell carcinoma or squamous cell carcinoma (epidermoid
             carcinoma) of the skin, or HCC.

          6. Patients with known hypersensitivity to the drugs used in the study or others of their
             class, or to any of their excipients.

          7. Recipients of ABO-incompatible transplants.

          8. Patients who test positive for HIV.

          9. Recipients of organs from donors who tested positive for the hepatitis B surface
             antigen or HIV seropositive.

         10. Patients with any medical or surgical condition that in the opinion of the
             investigator may significantly alter the absorption, distribution, metabolism or
             excretion of the study medication.

         11. Women of childbearing potential (i.e. women who are not postmenopausal with
             amenorrhoea of more than 1 year or surgically sterile) who are planning to become
             pregnant, are pregnant and/or breastfeeding, or who do not wish to use effective
             contraception, e.g. hormonal contraceptives (implantation, patches, oral) and
             double-barrier methods (any double combination of: IUD, male or female condoms with
             spermicidal gel, diaphragm, contraceptive sponge, cervical cap).

         12. Patients who are taking part in another clinical trial.

        Randomisation Visit - Inclusion Criteria

          1. Functioning allograft at the time of randomisation. A functioning allograft is defined
             as:

               1. levels of AST, ALT and total bilirubin ≤ 4 times the upper limit of normal, and

               2. levels of alkaline phosphatase and GGT ≤ 5 times the upper limit of normal.

          2. Glomerular filtrate ≥30 mL/min/1.73 m2 (calculated using the MDRD-4 equation).

        Randomisation Visit - Exclusion Criteria

          1. Patients with proteinuria ≥1.0 g/24 hrs confirmed in the urine sample
             (protein/creatinine ratio) that cannot be explained by immediate post-operative
             causes.

          2. Patients with severe hypercholesterolaemia (≥350 mg/dL; ≥9 mmol/L) or severe
             hypertriglyceridaemia (≥750 mg/dL; ≥8.5 mmol/L).

          3. Patients with a platelet count ≤50,000/mm3.

          4. Patients with an absolute neutrophil count ≤1,000/mm3 or WBC count ≤2,000/mm3.

          5. Patients who cannot take oral medication.

          6. Patients with clinically significant systemic infection who require active use of
             intravenous antibiotics.

          7. Patients who are in intensive care units and require vital support measures such as
             mechanical ventilation, dialysis, or vasoactive drugs.

          8. Patients who have required renal replacement therapy in the 7 days prior to
             randomisation.

          9. Patients who have had an episode of acute rejection and have required antibody therapy
             or who have had more than one episode of corticosteroid-sensitive acute rejection.