The Impact of Everolimus Based Immunosuppression in the Evolution of Hepatitis C Fibrosis After Liver Transplantation

February 6, 2018 updated by: Cristina Dopazo Taboada, Hospital Vall d'Hebron

An Unicenter, Prospective, Randomized, Pilot Study Comparing the Effect of Everolimus-containing Versus mTOR Inhibitor Free Immunosuppression in the Evolution of Hepatitis C Fibrosis After Liver Transplantation.

Background:

Hepatitis C recurrence, which invariably occurs in viremic liver transplant (LT) recipients, associated with accelerated liver fibrosis leading to established graft cirrhosis in 40-20% of patients in 5 years with another 5% experiencing an aggressive form with cirrhosis and graft loss in 1 year. Since treatment after LT has a low efficacy, the overall survival of HCV-infected LT recipients is shorter than that of uninfected LT patients.

New immunosuppressive agents such as mTOR inhibitors (Everolimus/Sirolimus) reduce the risk of liver graft rejection, have antifibrotic properties and do not worsen HCV recurrence. Moreover new directly-acting antiviral agents have increased efficacy of interferon-based treatment but their use in LT recipients may be limited by side effects.

Hypothesis:

Use of individualized immunosuppressive regimen and early personalized anti-viral treatment based on recipient and viral factors would improve outcome of HCV infected liver transplant recipients.

Objectives:

  1. To evaluate safety and efficacy of two steroid-free immunosuppressive regimens to reduce hepatitis C recurrence associated to fibrosis progression (F≥2 under ISHAK score) at one year post-transplant.
  2. To identify viral and recipient factors associated with liver fibrosis progression using ultra-deep pyrosequencing (UDPS).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Study design:

A pilot, open-label, prospective, randomized and unicenter study. As pilot study, the number of patients expected to be included is n=40.

Inclusion criteria:

  • Age≥18 years
  • First liver transplant
  • RNA-HCV positive within 12 months previous to the transplant

Exclusion criteria:

  • Multiorgan transplant
  • Split liver
  • ABO incompatible
  • HIV positive patients
  • Glomerular Filtration rate ≤60mL/min/1.73m2

Patients will receive double immunosuppression therapy at induction with tacrolimus (basal dose 0.1 mg/Kg/day) and mycophenolate mofetil (MMF, basal dose 2g/day) within the first 12 hours after skin closure.

Patients will be randomized in one of the following groups at day 28th post-transplant:

  1. MMF group (n=20): tacrolimus (levels 8-10ng/ml) and MMF (levels 1-3ng/mL).
  2. EVL group (n=20): tacrolimus (levels 8-10ng/ml) and everolimus (levels 2- 4 ng/mL).

HCV monitorization:

  • HVC-RNA detection and quantification. Serum samples will be taken immediately before liver transplantation, in the anhepatic phase, at the beginning and at the end of the reperfusion, and at 1h, 4h, 8h, 12h, 18h, 1d, 3d, 7d, 14d, 28d, 2m, 3m, 6m, 9m and 12m. Blood samples will be taken from the peripheral circulation and centrifugated within 2 to 3 hours after extraction, aliquoted, and frozen at -80 ºC. The concentration of HCV-RNA will be determined by using a quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay (Cobas Ampliprep/Cobas TaqMan; Roche Molecular Diagnostics, Barcelona, Spain) that achieves a sensitivity of 15 UI/mL and ultra deep pyrosequencing (UDSP) protocols will be used to study DNA genomic factor and viral RNA variability.
  • Serum fibrosis markers. Serum samples will be taken at 3rd, 6th and 12th months post-transplant from peripheral circulation and frozen at -21ºC. Serum markers (HA, PIIINP, and TIMP-1) will be analyzed by a fully automated, two-site sandwich immunoassay using direct chemiluminometric technology (ADVIA Centayr XP, Siemens Healthcare Diagnositics). The algorithm including the three markers (3-M-ALG) {score= -7,412 + [ln (HA)x0,681] + [ln (PIIINP)x0.775] + [ln (TIMP-1)]x0,494} will be also obtained.
  • Transient elastography (FibroScan). Liver stiffness measurements using Fibroscan (Echosens, Paris, France) will be performed in clinics at 6th and 12th months post-transplant.
  • Liver biopsy. Liver biopsy will be performed at 12th months post-transplant. All biopsy specimens will be read by a single pathologist. Necroinflammatory activity and fibrosis stage will be scored using ISHAK classification.

Follow-up and clinical data:

After discharge, patients will be visited in the outpatient clinic monthly for the first 3 months and every 3 months thereafter during the first 12 months post-transplant, at which time clinical and analytical variables will be recorded.Baseline characteristics, HCV genotype and viral load before transplant, surgical variables (type of liver transplant, donor age and steatosis, ischemia time), post-transplantation information and follow-up will be prospectively collected in an electronic database.

Patient withdrawal:

  • No consent form given by the patient
  • Severe adverse events related to immunosuppressors used
  • Steroids are required for long period of time
  • Antiviral therapy given before during the first year post-transplant
  • Lost follow-up
  • Patient death

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Barcelona, Spain, 08035
        • Department of HPB Surgery and Transplant, Hospital Vall d´Hebron

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age≥18 years
  • First liver transplant
  • RNA-HCV positive within 12 months previous to the transplant

Exclusion Criteria:

  • Multiorgan transplant
  • Split liver
  • Fulminant hepatitis
  • ABO incompatible
  • HIV positive patients
  • Glomerular Filtration rate ≤60mL/min/1.73m2

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: MMF arm

MMF arm (n=20)

They will receive immunosuppression as stipulated by hospital protocol:

Tacrolimus (levels 8-10ng/mL) and Mycophenalate mofetil 1mg bid(levels 1-3ng/mL).
Drug: MMF arm
Patients will be randomized at day 28th post-transplant. This group will continue of current immunosuppressive regimen (Tacrolimus+MMF) / no everolimus introduction.
Other Names:
  • Mofetil Mycophenolate
Experimental: EVL arm

EVL arm (n=20):

Tacrolimus (levels 8-10ng/ml) + everolimus 1mg bid (levels 2-4 ng/mL)
Drug: EVL arm
Patients will be randomized at day 28th post-transplant. This group will receive Tacrolimus+Everolimus.
Other Names:
  • Everolimus

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To compare the liver fibrosis progression (F≥2 under ISHAK score) in patients who receive everolimus vs mTOR free immunosuppression
Time Frame: One year
Liver biopsy will be performed at 12th months post-transplant. All biopsy specimens will be read by a single pathologist. Necroinflammatory activity and fibrosis stage were scored using ISHAK classification.
One year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To identify viral and recipient molecular predictors of fibrosis and anti-HCV treatment responses in liver transplant recipients under steroid-free immunosuppression
Time Frame: Immediately before liver transplantation, in the anhepatic phase, at the beginning and at the end of the reperfusion, and at 1h, 4h, 8h, 12h, 18h, 1dy, 3dy, 7dy, 14dy, 28dy, 2mo, 3mo, 6mo, 9mo and 12mo post-transplant

Serum samples from the recipient will be taken immediately before liver transplantation, in the anhepatic phase, at the beginning and at the end of the reperfusion, and at 1h, 4h, 8h, 12h, 18h, 1d, 3d, 7d, 14d, 28d, 2m, 3m, 6m, 9m and 12m. Blood samples will be taken from the peripheral circulation and centrifugated within 2 to 3 hours after extraction, aliquoted, and frozen at -80 ºC.

  • The concentration of HCV-RNA will be determined by using a quantitative reverse-transcription polymerase chain reaction (RT-PCR) assay (Cobas Ampliprep/Cobas TaqMan; Roche Molecular Diagnostics, Barcelona, Spain) that achieves a sensitivity of 15 UI/mL. -
  • DNA will be extracted from the liver donor and the recipient to characterize DNA polymorphisms. RNA Viral population complexity and presence of resistant mutations will be also studied using ultra-deep pyrosequence using eithre GS-Junior or GS-FLX platforms
Immediately before liver transplantation, in the anhepatic phase, at the beginning and at the end of the reperfusion, and at 1h, 4h, 8h, 12h, 18h, 1dy, 3dy, 7dy, 14dy, 28dy, 2mo, 3mo, 6mo, 9mo and 12mo post-transplant

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
To analyze liver fibrosis progression using serum markers
Time Frame: 3rd, 6th and 12th months post-transplant
Serum samples will be taken from peripheral circulation an frozen at -21ºC. Serum markers (HA, PIIINP, and TIMP-1) are analyzed by a fully automated, two-site sandwich immunoassay using direct chemiluminometric technology (ADVIA Centayr XP, Siemens Healthcare Diagnositics). The algorithm including the three markers (3-M-ALG) {score= -7,412 + [ln (HA)x0,681] + [ln (PIIINP)x0.775] + [ln (TIMP-1)]x0,494} will be also obtained.
3rd, 6th and 12th months post-transplant
To analyze liver fibrosis progression using liver stiffness
Time Frame: 6th and 12th months post-transplant
Transient elastography (FibroScan) for liver stiffness measurements will be performed in clinics.
6th and 12th months post-transplant
To analyze the incidence of acute rejection and steroid-resistant acute rejection
Time Frame: 6th and 12th months post-transplant
Rejection will be suspected in patients with an increase in the levels of bilirrubin, transaminases or alkaline phosphatase. Doppler ultrasound will be performed in order to discard biliary dilation and to confirm portal and arterial flow patency. A liver biopsy will be performed and graft rejection will be defined and stratified according to the BANFF criteria.
6th and 12th months post-transplant
To analyze the timing to the first acute rejection episode in both study groups
Time Frame: 6th and 12 months post-transplant
6th and 12 months post-transplant
To analyze need of antiviral therapy at the end of the first year post-transplant
Time Frame: One year post-transplant
Antiviral treatment will be considered at the end of the 12-months study period if moderated fibrosis (F≥2 under ISHAK score)is diagnosed and the patient do not have any contraindications to therapy
One year post-transplant
To analyze graft and patient survival
Time Frame: One year post-transplant
One year post-transplant
To analyze the incidence of patient withdrawal
Time Frame: One year post-transplant
One year post-transplant
To analyze the incidence of cardiovascular risk factors
Time Frame: 6th and 12th months post-transplant

Cardiovascular risk factors will be defined as follow:

Arterial hypertension. Defined as blood pressure >140/90 mmHg at two following visits according to the European Society of Hypertension criteria.

Diabetes Mellitus. Defined as fasting plasma glucose > 126 mg/dL at two following visits according to the World Health Organization.

Dyslipidemia. Defined as hypercholesterolemia > 220mg/dL and hypertriglyceridemia >200mg/dL at two following visits.
6th and 12th months post-transplant

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital Vall d'Hebron

Investigators

  • Principal Investigator: Itxarone Bilbao, PhD/MD, Department of HPB Surgery and Transplant, Hospital Vall d´Hebron (Barcelona, Spain)
  • Study Director: Ramon Charco, PhD/MD, Department of HPB and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)
  • Study Chair: Josep Quer, PhD/MD, Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
  • Study Chair: Francisco Rodríguez, PhD/MD, Biochemistry Laboratory, Hospital Vall d´Hebron, Barcelona (Spain)
  • Study Chair: Gonzalo Sapisochin, PhD/MD, Department of HPB surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
  • Study Chair: Lluis Castells, PhD/MD, Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
  • Study Chair: Isabel Campos, PhD, Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
  • Study Chair: Helena Allende, PhD/MD, Department of Anatomo-Pathology, Hospital Vall d´Hebron, Barcelona (Spain)
  • Study Chair: Jose Luis Lazaro, PhD, Department of HPB surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
  • Study Chair: Cristina Dopazo-Taboada, PhD/MD, Department of HPB and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2012

Primary Completion (Actual)

August 1, 2016

Study Completion (Actual)

August 1, 2016

Study Registration Dates

First Submitted

October 13, 2012

First Submitted That Met QC Criteria

October 13, 2012

First Posted (Estimate)

October 16, 2012

Study Record Updates

Last Update Posted (Actual)

February 7, 2018

Last Update Submitted That Met QC Criteria

February 6, 2018

Last Verified

August 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EVL-VHC-HVH.12

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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