Everolimus in de Novo Liver Transplantation: a Multicentre Randomized Study (EPOCAL)

Terapia Con Everolimus Nel Trapianto de Novo di Fegato: Uno Studio Multicentrico Randomizzato

Safety and Efficacy of Everolimus in adult de novo liver transplant recipients.

Study Overview

• Status: Unknown
• Conditions: Liver Diseases; Liver Failure; Liver Cirrhosis; Liver Neoplasms
• Intervention / Treatment: Drug: Everolimus

Detailed Description

This prospective study was designed to evaluate the feasibility and effectiveness of the use of Everolimus in the minimization and possible suspension of calcineurin inhibitors in adult liver transplant patients. The study will take into account a control group (standard immunosuppression with tacrolimus and steroids) after induction with anti-IL2 Antibodies.

• Study Type: Interventional
• Enrollment (Anticipated): 117
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Laura Saracino, MSc; Phone Number: +390498218624; Email: lasaracino@gmail.com

Study Locations

• Italy
  • BG
    • Bergamo, BG, Italy, 24128
      • Recruiting
      • Ospedali Riuniti - Bergamo
      • Contact: Michele Colledan, MD; Phone Number: +39 035 269111; Email: mcolledan@ospedaliriuniti.bergamo.it
      • Contact: Vittorio Corno, MD; Phone Number: +39 035 269111; Email: vcorno@ospedaliriuniti.bergamo.it
      • Principal Investigator: Michele Colledan, MD
      • Sub-Investigator: Vittorio Corno, MD
  • MI
    • Milano, MI, Italy, 20122
      • Recruiting
      • IRCCS Ospedale Maggiore Policlinico di Milano
      • Contact: Giorgio Rossi, MD; Phone Number: +39 02 55031; Email: giorgio.rossi@unimi.it
      • Contact: Paolo Reggiani, MD; Phone Number: +39 02 55031; Email: paolo.reggiani@policlinico.mi.it
      • Principal Investigator: Giorgio Rossi, MD
      • Sub-Investigator: Paolo Reggiani, MD
    • Milano, MI, Italy, 20162
      • Recruiting
      • Ospedale Ca' Granda-Niguarda - Milano
      • Contact: Luciano De Carlis, MD; Phone Number: +39 02 64441; Email: Luciano.DeCarlis@ospedaleniguarda.it
      • Contact: Jacopo Mangoni, MD; Phone Number: +39 02 64441; Email: jacopo.mangoni@libero.it
      • Principal Investigator: Luciano De Carlis, MD
      • Sub-Investigator: Jacopo Mangoni, MD
  • PD
    • Padua, PD, Italy, 35128
      • Recruiting
      • Azienda Ospedaliera di Padova
      • Sub-Investigator: Roberto Marchini, MD
      • Sub-Investigator: Angelica Magrofuoco, CCTC
      • Sub-Investigator: Laura Saracino, MSc
  • RM
    • Roma, RM, Italy, 00168
      • Recruiting
      • Policlinico Universitario Gemelli di Roma
      • Contact: Salvatore Agnes, MD; Phone Number: +39 06 3550 1928; Email: salvatoreagnes@rm.unicatt.it
      • Contact: Erida Nure, MD; Phone Number: +39 06 3550 1928; Email: eridanure@yahoo.it
      • Sub-Investigator: Erida Nure, MD
      • Principal Investigator: Salvatore Agnes, MD
  • TO
    • Torino, TO, Italy, 10126
      • Recruiting
      • A.O. Universitaria S. Giovanni Battista-Molinette Di Torino
      • Contact: Mauro Salizzoni, MD; Phone Number: +39 011 633 1633; Email: msalizzoni@molinette.piemonte.it
      • Contact: Francesco Lupo, MD; Phone Number: +39 011 633 1633; Email: flupo@molinette.piemonte.it
      • Principal Investigator: Mauro Salizzoni, MD
      • Sub-Investigator: Francesco Lupo, MD
  • UD
    • Udine, UD, Italy, 33100
      • Recruiting
      • A.O. Universitaria S. Maria Della Misericordia Di Udine
      • Contact: Fabio Bresàdola, MD; Phone Number: +39 0432 5521; Email: fabrizio.bresadola@dsc.uniud.it
      • Contact: Umberto Baccarani, MD; Phone Number: +39 0432 5521; Email: umberto.baccarani@dsc.uniud.it
      • Sub-Investigator: Umberto Baccarani, MD
      • Principal Investigator: Fabio Bresàdola, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients between 18 and 70 years of age,
• Patients undergoing de novo liver transplantation from cadaveric donor with a functional graft at the time of randomization,
• Transplantation from cadaveric donor whole or split liver,
• Patients able to communicate properly with the study investigators, to understand and respond to the needs of the protocol and who have given written consent
• Cold ischemia time <12 hours

Exclusion Criteria:

• Physical or laboratory abnormalities or mental illness within 2 weeks before randomization such that, in the opinion of the investigator, may interfere with participation in the study
• Women who are pregnant (positive test with hCG values> 5mUI/ml) or breast-feeding
• Women of childbearing potential, with the following exceptions: a) women in menopause (spontaneous amenorrhea for at least 12 months, spontaneous amenorrhea for at least 6 months with FSH levels >40 mIU/ml, surgical bilateral oophorectomy at least 6 weeks before baseline, with or without hysterectomy) b) women who use one or more reliable and approved methods of contraception for the duration of the study and for the three months following discontinuation of study treatment.
• Patients who undergo transplantation or multivisceral transplantation of pancreatic islets, or who have previously undergone organ transplantation or tissue.
• Patients who undergo combined liver-kidney transplantation
• Patients who undergo living donor liver transplantation
• Patients who undergo ABO-incompatible liver transplantation
• Patients who undergo transplantation from donors positive for HBV surface antigen or HIV
• History of malignant disease at any site in the 3 year period prior, regardless of whether or not there is evidence of recurrence or metastasis. (Except non-metastatic skin cancers such as basal cell or squamous cell carcinoma of the skin, or hepatocellular carcinoma)
• Patients receiving other investigational drugs within 4 weeks before baseline or who are currently enrolled in other clinical trials
• Patients who show hypersensitivity to the drug (or drugs similar to Everolimus - Former macrolides) or class or pharmaceutical excipients. Also, when there are contraindications
• A history of coagulopathy or the presence of any medical condition that requires long-term anticoagulant therapy after transplantation (The use of low-dose ASA is admissible)
• Platelet count <=40.000/mm3 or WBC count <2000/mm3 or hemoglobin <=7g/dl at the time of randomization
• Severe systemic infections
• High cholesterol levels (>350mg/dl) or severe hypertriglyceridemia (>500mg/dl). Patients with compensated hyperlipidemia are eligible.
• Diagnosis of pre-transplant autoimmune liver disease (PBC, sclerosing cholangitis)
• Acute Liver Failure

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control; Standard immunosuppression protocol with Tacrolimus, maintaining trough levels between 6 and 12 ng/ml in the first month, in association with steroids (20 mg/day with subsequent weaning within 3 months after transplantation).
Experimental: Everolimus; Administration of Everolimus in association with Tacrolimus and steroids.	Drug: Everolimus; Administration of Everolimus within 24 hours from the time of randomization (7 days from the time of transplantation) in association with Tacrolimus and steroids. The first dose level of the trough will be performed at day 7 after initiation of therapy. After the reaching an Everolimus trough level of >5ng/ml (final target 6-12 ng/ml), there will be a gradual weaning of tacrolimus (bringing Tacrolimus blood levels <5 ng/ml) with discontinuation of Tacrolimus within 30 days after transplantation when possible.; Other Names: Afinitor; Certican; Zortress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biopsy-proven rejection episodes (BPAR)		3 months
Graft survival		3 months
Patient post-Liver Transplantation survival		3 months
Everolimus monotherapy	Patients not requiring calcineurin inhibitors (CNI)	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal function evaluation	Impact of therapy on renal function, evaluated by creatinine clearance according to the Modification of Diet in Renal Disease (MDRD) Study.	24 months
Requests for dialysis		24 months
Incidence of Adverse Events	Evaluation of common post Liver Transplantation Adverse Events: wound healing, bone marrow depression, hyperlipidemia, proteinuria, diabetes mellitus, diagnosed hypertension, infections, levels of HCV.	24 months

Collaborators and Investigators

• Sponsor: Azienda Ospedaliera di Padova

Publications and helpful links

Helpful Links

• Hepatobiliary surgery and Liver Transplantation Unit, University Hospital of Padua (Italy)

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Anticipated): January 1, 2014
• Study Completion (Anticipated): January 1, 2014

Study Registration Dates

• First Submitted: August 25, 2011
• First Submitted That Met QC Criteria: August 25, 2011
• First Posted (Estimate): August 26, 2011

Study Record Updates

• Last Update Posted (Estimate): July 18, 2012
• Last Update Submitted That Met QC Criteria: July 17, 2012
• Last Verified: July 1, 2012

More Information

Terms related to this study

• Keywords: Immunosuppression; Gastroenterology; Organ Transplantation; Graft Rejection; Liver Transplantation; Graft Survival; Transplantation Immunology; Anti-Rejection Therapy; Host vs Graft Reaction; Hepatology
• Additional Relevant MeSH Terms: Digestive System Diseases; Hepatic Insufficiency; Pathologic Processes; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Fibrosis; Liver Diseases; Liver Failure; Liver Cirrhosis; Liver Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: 1956P; 2009-016176-78 (EudraCT Number)