Efficacy and Safety of Everolimus in Liver Transplant Recipients of Living Donor Liver Transplants
Condition: Liver Transplantation
Intervention: Everolimus + reduced tacrolimus; Standard tacrolimus
Intervention description: Everolimus was initiated at Week 4 post transplantation. The dose was adjusted to maintain the everolimus trough blood levels between 3-8 ng/mL for the duration of the study. Tacrolimus was reduced to 3-5 ng/mL.; Tacrolimus was initiated as soon as possible after transplantation according to approved labeling recommendations. The trough level should've been 5-15 ng/mL until randomization, 8-12 ng/mL from randomization until month 4 and after month 4 until end of study reduced to 6 -10 ng/mL.
Intervention MeSH terms: Everolimus; Tacrolimus
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This was a 24-month, multicenter, open-label, randomized, controlled study. It included the extension to the 24-month, randomized, controlled, open-label CRAD001H2307 study in recipients of living donor liver transplants in Japan.
Masking: Single (Care Provider)
Enrollment: 285.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: liver transplantation; everolimus; tacrolimus; reduced calcineuron inhibitor; renal function; living donor; RAD001H2307; RAD001H

Summary:

      The purpose of this trial was to demonstrate the efficacy and safety of everolimus in
      combination with reduced tacrolimus, compared to tacrolimus control, in living donor liver
      transplant recipients.
    

Eligibility criteria:

        Inclusion criteria:

          -  Written informed consent

          -  Subject aged ≥18 years of a primary, orthotopic liver allograft, from a living donor

          -  Subject negative for HIV

        Incusion criteria at Randomization:

        - Subject was initated on tacrolimus-based immunosuppressive regimen with steroids and
        other immunosuppression

        Exclusion criteria:

          -  Subjects transplanted for acute liver failure

          -  HCV negativesubjects receiving a transplant from HCV positive donor

          -  Subjects receiving multiple solid organ (including multiple liver lobes/segments) or
             islet cell tissue transplants, or have previously received an organ or tissue
             transplant.

          -  Subjects receiving an ABO incompatible allograft.

          -  MELD-score > 35 within 1 month prior to transplantation.

          -  Use of immunosuppressive or antibody induction agents not specified in the protocol.

          -  History of malignancy of any organ system (except hepatocellular carcinoma or
             localized basal cell carcinoma of the skin)

          -  Hepatocellular carcinoma with extrahepatic spread or macrovascular invasion

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive hCG laboratory test.

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             during dosing and for 2 weeks after the last dose of study medication

          -  History of hypersensitivity to any of the study drugs or to drugs with similar
             chemical class, or to any of the excipients

        Exclusion criteria at Randomization:

          -  Any post-transplant history of thrombosis, occlusion or stent placement in any major
             hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time during
             the run-in period prior to randomization.

          -  Subjects with a confirmed spot urine protein/creatinine ratio that indicates ≥ 1.0
             g/24 hrs of proteinuria

          -  Subjects who have severe hypercholesterolemia (>350 mg/dL; >9.1 mmol/L) or
             hypertriglyceridemia (>500 mg/dL; >5.6 mmol/L) at randomization.

          -  Subjects with platelet count < 30,000/mm3.

          -  Subjects with an absolute neutrophil count of < 1,000/mm³ or white blood cell count of
             < 2,000/mm³.

          -  Subjects with systemic infection requiring active use of IV antibiotics.

          -  Subjects requiring life support measures such as ventilation, dialysis, vasopressor
             agents.

          -  Subjects who require renal replacement therapy within 7 days prior to randomization.

          -  Subjects with detectable HBV DNA at time of randomization

          -  Subjects meeting the following criteria for acute rejection during the run in period:

               -  Any acute rejection in the week prior to randomization.

               -  2 treated acute rejections.

               -  Any rejection requiring antibody treatment.

               -  Any severe cellular (and/or any humoral) rejection.

        Long term extension for patients in Japan:

        Inclusion criteria

          -  Written informed consent must be obtained before any extension specific assessment is
             performed.

          -  Ability and willingness to adhere to study regimen.

          -  Completed Month 24 visit of core study and continuously being treated with assigned
             regimen.

        Exclusion criteria:

          -  Use of medication that is prohibited by the study protocol at Month 24.

          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive hCG laboratory test.

          -  History of hypersensitivity to any of the study drugs or to drugs with similar
             chemical class, or to any of the excipients