Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients

Phase 3

Completed

Conditions: Liver Transplant Recipient

Interventions: Drug: Tacrolimus (reduced tacrolimus)
Drug: Tacrolimus (tacrolimus elimination)
Drug: Tacrolimus (tacrolimus control)
Drug: Everolimus (reduced tacrolimus)
Drug: Everolimus (tacrolimus elimination)
Drug: Corticosteroids

Registration Number: NCT01150097

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The reason for this extension is to evaluate the long-term safety and efficacy of two concentration-controlled everolimus regimen in de novo liver transplant recipients. The most important long-term safety assessments include evaluation of renal function, progression of HCV related allograft fibrosis, and other treatment related effects at Month 36 post-transplantation compared to extension baseline (Months 24 post-transplantation).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 284

Inclusion Criteria

Written informed consent
Ability and willingness to adhere to study regimen
Completed core study with assigned regimen;

Exclusion Criteria

Patients fulfilling any of the following criteria are not eligible for inclusion in this study:

Severe hypercholesterolemia or hypertriglyceridemia.
Low platelet count.
Low white blood cell count.
Positive test for human immunodeficiency virus (HIV).
Systemic infection requiring active use of IV antibiotics.
Patients in a critical care setting.
Use of prohibited medication.
Use of immunosuppressive agents not utilized in the protocol.
Hypersensitivity to any of the study drugs or similar drugs.
Pregnant or nursing (lactating) women
Women of child-bearing potential not using a highly effective method of birth control.

Other protocol-defined inclusion/exclusion criteria may apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Everolimus + reduced tacrolimus	Tacrolimus (reduced tacrolimus)	Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus.
Everolimus + reduced tacrolimus	Everolimus (reduced tacrolimus)	Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus.
Everolimus + reduced tacrolimus	Corticosteroids	Participants were maintained on whole blood trough levels of 3 - 8 ng/mL everolimus and 3 - 5 ng/mL tacrolimus.
Tacrolimus elimination	Tacrolimus (tacrolimus elimination)	Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus.
Tacrolimus elimination	Everolimus (tacrolimus elimination)	Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus.
Tacrolimus elimination	Corticosteroids	Participants were maintained on a whole blood trough level of 6 - 10 ng/mL everolimus.
Tacrolimus control	Tacrolimus (tacrolimus control)	Participants were maintained on a whole blood trough level of 6 - 10 ng/mL tacrolimus.
Tacrolimus control	Corticosteroids	Participants were maintained on a whole blood trough level of 6 - 10 ng/mL tacrolimus.

Primary Outcome Measures

Name	Time	Method
Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death	from months 36 to 48	The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death	from months 36 - 48	The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.
Change in Renal Function	from months 24 to 36	Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\(C\^-1.154)\(A\^-0.203)\G\R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1.

Secondary Outcome Measures

Name	Time	Method
Incidence Rate of tBPAR	from months 24 - 36	The number of participants who had a tBPAR was analyzed. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection.