Overview

This trial is active, not recruiting.

Condition liver transplantation
Treatments everolimus + reduced tacrolimus, standard tacrolimus
Phase phase 3
Targets mTOR, FKBP-12
Sponsor Novartis Pharmaceuticals
Start date September 2013
End date October 2017
Trial size 286 participants
Trial identifier NCT01888432, 2010-024527-25, CRAD001H2307

Summary

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

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Everolimus + reduced tacrolimus ± corticosteroids
everolimus + reduced tacrolimus
Everolimus will be initiated at Week 4 post transplantation. The dose will be adjusted to maintain the everolimus trough blood levels between 3-8 ng/mL for the duration of the study. Tacrolimus will be reduced to 3-5 ng/mL.
(Active Comparator)
Standard tacrolimus ± corticosteroids
standard tacrolimus
Tacrolimus will be initiated as soon as possible after transplantation according to approved labeling recommendations. The trough level should be 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.

Primary Outcomes

Measure
Composite efficacy failure of treated biopsy proven acute rejection, graft loss or death in everolimus with reduced tacrolimus group compared to standard tacrolimus
time frame: at 12 months post transplantation

Secondary Outcomes

Measure
Renal function by estimated Glomerular Filtration Rate
time frame: Randomization, Month 12
Compare incidence of a composite of tBPAR, graft loss, death. Incidenceof each component of the composite. Incidenceof a composite of death or graft loss. Incidence of BPAR, tAR and AR.
time frame: Month 12 and Month 24 post transplantation
Compare tBPAR and tAR by severity (RAI grading) as well as diagnosis leading to transplantation
time frame: Month 6, Month 12 and Month 24
Incidence of treated BPAR by time to event, severity, and diagnosis leading to transplantation
time frame: Month 12 and Month 24
Compare evolution of post-randomization renal function over time assessed by the change by eGFR
time frame: Randomization, Month 12 and Month 24
Renal function and change in eGFR in subgroups
time frame: Randomization, Month 6 and 12
Urinary protein/creatinine ratio at various time points
time frame: Month 24
Compare rate of recurrence and time to recurrence of HCC in subjects with a diagnosis of HCC at the time of liver transplantation
time frame: Randomization, Month12 and Month 24
Compare tumor-free survival in subjects with a diagnosis of HCC at the time of liver transplantation
time frame: Randomization, Month 24
Compare HCV viral load (overall and by genotype).
time frame: Month 12 and 24
Compare rate of progression of HCV related allograft fibrosis.
time frame: Randomization, Month 24
Compare incidence of AEs and SAEs including infections and serious infections, overall, by body system and preferred term
time frame: Month 24

Eligibility Criteria

Male or female participants at least 18 years old.

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. Other protocol-defined inclusion/exclusion criteria may apply. 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

Additional Information

Official title A 24 Month, Randomized, Controlled, Study to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus Plus Reduced Tacrolimus Compared to Standard Tacrolimus in Recipients of Living Donor Liver Transplants and Long Term Extension to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus Plus Reduced Tacrolimus Compared to Standard Tacrolimus in Recipients of Living Donor Liver Transplants in Japan.
Description This study is 24 month, multicenter study in 280 living donor liver transplant patients from Asia, Europe and Canada. The study also have an long term extension in Japan and approximately 28 patients will be included to evaluate the long-term efficacy and safety of concentration-controlled everolimus regimen plus reduced tacrolimus compared to standard tacrolimus in recipients of living donor liver transplants in Japan who have participated in the CRAD001H2307 study.
Trial information was received from ClinicalTrials.gov and was last updated in September 2016.
Information provided to ClinicalTrials.gov by Novartis.