<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01707849</url>
  </required_header>
  <id_info>
    <org_study_id>EVL-VHC-HVH.12</org_study_id>
    <nct_id>NCT01707849</nct_id>
  </id_info>
  <brief_title>The Impact of Everolimus Based Immunosuppression in the Evolution of Hepatitis C Fibrosis After Liver Transplantation</brief_title>
  <official_title>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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Vall d'Hebron</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital Vall d'Hebron</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Hepatitis C recurrence, which invariably occurs in viremic liver transplant (LT) recipients,&#xD;
      associated with accelerated liver fibrosis leading to established graft cirrhosis in 40-20%&#xD;
      of patients in 5 years with another 5% experiencing an aggressive form with cirrhosis and&#xD;
      graft loss in 1 year. Since treatment after LT has a low efficacy, the overall survival of&#xD;
      HCV-infected LT recipients is shorter than that of uninfected LT patients.&#xD;
&#xD;
      New immunosuppressive agents such as mTOR inhibitors (Everolimus/Sirolimus) reduce the risk&#xD;
      of liver graft rejection, have antifibrotic properties and do not worsen HCV recurrence.&#xD;
      Moreover new directly-acting antiviral agents have increased efficacy of interferon-based&#xD;
      treatment but their use in LT recipients may be limited by side effects.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      Use of individualized immunosuppressive regimen and early personalized anti-viral treatment&#xD;
      based on recipient and viral factors would improve outcome of HCV infected liver transplant&#xD;
      recipients.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
        1. To evaluate safety and efficacy of two steroid-free immunosuppressive regimens to reduce&#xD;
           hepatitis C recurrence associated to fibrosis progression (F≥2 under ISHAK score) at one&#xD;
           year post-transplant.&#xD;
&#xD;
        2. To identify viral and recipient factors associated with liver fibrosis progression using&#xD;
           ultra-deep pyrosequencing (UDPS).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study design:&#xD;
&#xD;
      A pilot, open-label, prospective, randomized and unicenter study. As pilot study, the number&#xD;
      of patients expected to be included is n=40.&#xD;
&#xD;
      Inclusion criteria:&#xD;
&#xD;
        -  Age≥18 years&#xD;
&#xD;
        -  First liver transplant&#xD;
&#xD;
        -  RNA-HCV positive within 12 months previous to the transplant&#xD;
&#xD;
      Exclusion criteria:&#xD;
&#xD;
        -  Multiorgan transplant&#xD;
&#xD;
        -  Split liver&#xD;
&#xD;
        -  ABO incompatible&#xD;
&#xD;
        -  HIV positive patients&#xD;
&#xD;
        -  Glomerular Filtration rate ≤60mL/min/1.73m2&#xD;
&#xD;
      Patients will receive double immunosuppression therapy at induction with tacrolimus (basal&#xD;
      dose 0.1 mg/Kg/day) and mycophenolate mofetil (MMF, basal dose 2g/day) within the first 12&#xD;
      hours after skin closure.&#xD;
&#xD;
      Patients will be randomized in one of the following groups at day 28th post-transplant:&#xD;
&#xD;
        1. MMF group (n=20): tacrolimus (levels 8-10ng/ml) and MMF (levels 1-3ng/mL).&#xD;
&#xD;
        2. EVL group (n=20): tacrolimus (levels 8-10ng/ml) and everolimus (levels 2- 4 ng/mL).&#xD;
&#xD;
      HCV monitorization:&#xD;
&#xD;
        -  HVC-RNA detection and quantification. Serum samples will be taken immediately before&#xD;
           liver transplantation, in the anhepatic phase, at the beginning and at the end of the&#xD;
           reperfusion, and at 1h, 4h, 8h, 12h, 18h, 1d, 3d, 7d, 14d, 28d, 2m, 3m, 6m, 9m and 12m.&#xD;
           Blood samples will be taken from the peripheral circulation and centrifugated within 2&#xD;
           to 3 hours after extraction, aliquoted, and frozen at -80 ºC. The concentration of&#xD;
           HCV-RNA will be determined by using a quantitative reverse-transcription polymerase&#xD;
           chain reaction (RT-PCR) assay (Cobas Ampliprep/Cobas TaqMan; Roche Molecular&#xD;
           Diagnostics, Barcelona, Spain) that achieves a sensitivity of 15 UI/mL and ultra deep&#xD;
           pyrosequencing (UDSP) protocols will be used to study DNA genomic factor and viral RNA&#xD;
           variability.&#xD;
&#xD;
        -  Serum fibrosis markers. Serum samples will be taken at 3rd, 6th and 12th months&#xD;
           post-transplant from peripheral circulation and frozen at -21ºC. Serum markers (HA,&#xD;
           PIIINP, and TIMP-1) will be analyzed by a fully automated, two-site sandwich immunoassay&#xD;
           using direct chemiluminometric technology (ADVIA Centayr XP, Siemens Healthcare&#xD;
           Diagnositics). The algorithm including the three markers (3-M-ALG) {score= -7,412 + [ln&#xD;
           (HA)x0,681] + [ln (PIIINP)x0.775] + [ln (TIMP-1)]x0,494} will be also obtained.&#xD;
&#xD;
        -  Transient elastography (FibroScan). Liver stiffness measurements using Fibroscan&#xD;
           (Echosens, Paris, France) will be performed in clinics at 6th and 12th months&#xD;
           post-transplant.&#xD;
&#xD;
        -  Liver biopsy. Liver biopsy will be performed at 12th months post-transplant. All biopsy&#xD;
           specimens will be read by a single pathologist. Necroinflammatory activity and fibrosis&#xD;
           stage will be scored using ISHAK classification.&#xD;
&#xD;
      Follow-up and clinical data:&#xD;
&#xD;
      After discharge, patients will be visited in the outpatient clinic monthly for the first 3&#xD;
      months and every 3 months thereafter during the first 12 months post-transplant, at which&#xD;
      time clinical and analytical variables will be recorded.Baseline characteristics, HCV&#xD;
      genotype and viral load before transplant, surgical variables (type of liver transplant,&#xD;
      donor age and steatosis, ischemia time), post-transplantation information and follow-up will&#xD;
      be prospectively collected in an electronic database.&#xD;
&#xD;
      Patient withdrawal:&#xD;
&#xD;
        -  No consent form given by the patient&#xD;
&#xD;
        -  Severe adverse events related to immunosuppressors used&#xD;
&#xD;
        -  Steroids are required for long period of time&#xD;
&#xD;
        -  Antiviral therapy given before during the first year post-transplant&#xD;
&#xD;
        -  Lost follow-up&#xD;
&#xD;
        -  Patient death&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">August 2016</completion_date>
  <primary_completion_date type="Actual">August 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To compare the liver fibrosis progression (F≥2 under ISHAK score) in patients who receive everolimus vs mTOR free immunosuppression</measure>
    <time_frame>One year</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To identify viral and recipient molecular predictors of fibrosis and anti-HCV treatment responses in liver transplant recipients under steroid-free immunosuppression</measure>
    <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</time_frame>
    <description>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.&#xD;
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. -&#xD;
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</description>
  </secondary_outcome>
  <other_outcome>
    <measure>To analyze liver fibrosis progression using serum markers</measure>
    <time_frame>3rd, 6th and 12th months post-transplant</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>To analyze liver fibrosis progression using liver stiffness</measure>
    <time_frame>6th and 12th months post-transplant</time_frame>
    <description>Transient elastography (FibroScan) for liver stiffness measurements will be performed in clinics.</description>
  </other_outcome>
  <other_outcome>
    <measure>To analyze the incidence of acute rejection and steroid-resistant acute rejection</measure>
    <time_frame>6th and 12th months post-transplant</time_frame>
    <description>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.</description>
  </other_outcome>
  <other_outcome>
    <measure>To analyze the timing to the first acute rejection episode in both study groups</measure>
    <time_frame>6th and 12 months post-transplant</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>To analyze need of antiviral therapy at the end of the first year post-transplant</measure>
    <time_frame>One year post-transplant</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>To analyze graft and patient survival</measure>
    <time_frame>One year post-transplant</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>To analyze the incidence of patient withdrawal</measure>
    <time_frame>One year post-transplant</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>To analyze the incidence of cardiovascular risk factors</measure>
    <time_frame>6th and 12th months post-transplant</time_frame>
    <description>Cardiovascular risk factors will be defined as follow:&#xD;
Arterial hypertension. Defined as blood pressure &gt;140/90 mmHg at two following visits according to the European Society of Hypertension criteria.&#xD;
Diabetes Mellitus. Defined as fasting plasma glucose &gt; 126 mg/dL at two following visits according to the World Health Organization.&#xD;
Dyslipidemia. Defined as hypercholesterolemia &gt; 220mg/dL and hypertriglyceridemia &gt;200mg/dL at two following visits.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Hepatitis C Recurrence After Liver Transplant</condition>
  <arm_group>
    <arm_group_label>MMF arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>MMF arm (n=20)&#xD;
They will receive immunosuppression as stipulated by hospital protocol:&#xD;
Tacrolimus (levels 8-10ng/mL) and Mycophenalate mofetil 1mg bid(levels 1-3ng/mL).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>EVL arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>EVL arm (n=20):&#xD;
Tacrolimus (levels 8-10ng/ml) + everolimus 1mg bid (levels 2-4 ng/mL)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EVL arm</intervention_name>
    <description>Patients will be randomized at day 28th post-transplant. This group will receive Tacrolimus+Everolimus.</description>
    <arm_group_label>EVL arm</arm_group_label>
    <other_name>Everolimus</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MMF arm</intervention_name>
    <description>Patients will be randomized at day 28th post-transplant. This group will continue of current immunosuppressive regimen (Tacrolimus+MMF) / no everolimus introduction.</description>
    <arm_group_label>MMF arm</arm_group_label>
    <other_name>Mofetil Mycophenolate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age≥18 years&#xD;
&#xD;
          -  First liver transplant&#xD;
&#xD;
          -  RNA-HCV positive within 12 months previous to the transplant&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Multiorgan transplant&#xD;
&#xD;
          -  Split liver&#xD;
&#xD;
          -  Fulminant hepatitis&#xD;
&#xD;
          -  ABO incompatible&#xD;
&#xD;
          -  HIV positive patients&#xD;
&#xD;
          -  Glomerular Filtration rate ≤60mL/min/1.73m2&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>68 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Itxarone Bilbao, PhD/MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of HPB Surgery and Transplant, Hospital Vall d´Hebron (Barcelona, Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ramon Charco, PhD/MD</last_name>
    <role>Study Director</role>
    <affiliation>Department of HPB and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Josep Quer, PhD/MD</last_name>
    <role>Study Chair</role>
    <affiliation>Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Francisco Rodríguez, PhD/MD</last_name>
    <role>Study Chair</role>
    <affiliation>Biochemistry Laboratory, Hospital Vall d´Hebron, Barcelona (Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Gonzalo Sapisochin, PhD/MD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of HPB Surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lluis Castells, PhD/MD</last_name>
    <role>Study Chair</role>
    <affiliation>Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Isabel Campos, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Helena Allende, PhD/MD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of Anatomo-Pathology, Hospital Vall d´Hebron, Barcelona (Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jose Luis Lazaro, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of HPB surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Cristina Dopazo-Taboada, PhD/MD</last_name>
    <role>Study Chair</role>
    <affiliation>Department of HPB and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of HPB Surgery and Transplant, Hospital Vall d´Hebron</name>
      <address>
        <city>Barcelona</city>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
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    <citation>Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009 Sep 17;461(7262):399-401. doi: 10.1038/nature08309. Epub 2009 Aug 16.</citation>
    <PMID>19684573</PMID>
  </reference>
  <reference>
    <citation>Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Muller T, Bahlo M, Stewart GJ, Booth DR, George J. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009 Oct;41(10):1100-4. doi: 10.1038/ng.447. Epub 2009 Sep 13.</citation>
    <PMID>19749758</PMID>
  </reference>
  <reference>
    <citation>Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009 Oct;41(10):1105-9. doi: 10.1038/ng.449. Epub 2009 Sep 13.</citation>
    <PMID>19749757</PMID>
  </reference>
  <reference>
    <citation>Smith KR, Suppiah V, O'Connor K, Berg T, Weltman M, Abate ML, Spengler U, Bassendine M, Matthews G, Irving WL, Powell E, Riordan S, Ahlenstiel G, Stewart GJ, Bahlo M, George J, Booth DR; International Hepatitis C Genetics Consortium (IHCGC). Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort. Genome Med. 2011 Aug 31;3(8):57. doi: 10.1186/gm273.</citation>
    <PMID>21884576</PMID>
  </reference>
  <verification_date>August 2016</verification_date>
  <study_first_submitted>October 13, 2012</study_first_submitted>
  <study_first_submitted_qc>October 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 16, 2012</study_first_posted>
  <last_update_submitted>February 6, 2018</last_update_submitted>
  <last_update_submitted_qc>February 6, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 7, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital Vall d'Hebron</investigator_affiliation>
    <investigator_full_name>Cristina Dopazo Taboada</investigator_full_name>
    <investigator_title>Liver Surgery and Transplants Consultant, PhD/MD</investigator_title>
  </responsible_party>
  <keyword>Hepatitis C</keyword>
  <keyword>Liver Fibrosis</keyword>
  <keyword>m-TOR inhibitors</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis C</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
    <mesh_term>Recurrence</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Everolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01707849
org study id: EVL-VHC-HVH.12
nct id: NCT01707849
lead sponsor: 
has dmc: Yes
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 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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: To compare the liver fibrosis progression (F≥2 under ISHAK score) in patients who receive everolimus vs mTOR free immunosuppression
time frame: One year
description: 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.
measure: 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
description: 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
measure: To analyze liver fibrosis progression using serum markers
time frame: 3rd, 6th and 12th months post-transplant
description: 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.
measure: To analyze liver fibrosis progression using liver stiffness
time frame: 6th and 12th months post-transplant
description: Transient elastography (FibroScan) for liver stiffness measurements will be performed in clinics.
measure: To analyze the incidence of acute rejection and steroid-resistant acute rejection
time frame: 6th and 12th months post-transplant
description: 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.
measure: To analyze the timing to the first acute rejection episode in both study groups
time frame: 6th and 12 months post-transplant
measure: To analyze need of antiviral therapy at the end of the first year post-transplant
time frame: One year post-transplant
description: 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
measure: To analyze graft and patient survival
time frame: One year post-transplant
measure: To analyze the incidence of patient withdrawal
time frame: One year post-transplant
measure: To analyze the incidence of cardiovascular risk factors
time frame: 6th and 12th months post-transplant
description: 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.
arm group label: MMF arm
arm group type: Active Comparator
description: 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).
arm group label: EVL arm
arm group type: Experimental
description: EVL arm (n=20):
Tacrolimus (levels 8-10ng/ml) + everolimus 1mg bid (levels 2-4 ng/mL)
intervention type: Drug
intervention name: EVL arm
description: Patients will be randomized at day 28th post-transplant. This group will receive Tacrolimus+Everolimus.
arm group label: EVL arm
other name: Everolimus
intervention type: Drug
intervention name: MMF arm
description: Patients will be randomized at day 28th post-transplant. This group will continue of current immunosuppressive regimen (Tacrolimus+MMF) / no everolimus introduction.
arm group label: MMF arm
other name: Mofetil Mycophenolate
criteria: 
gender: All
minimum age: 18 Years
maximum age: 68 Years
healthy volunteers: No
last name: Itxarone Bilbao, PhD/MD
role: Principal Investigator
affiliation: Department of HPB Surgery and Transplant, Hospital Vall d´Hebron (Barcelona, Spain)
last name: Ramon Charco, PhD/MD
role: Study Director
affiliation: Department of HPB and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)
last name: Josep Quer, PhD/MD
role: Study Chair
affiliation: Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
last name: Francisco Rodríguez, PhD/MD
role: Study Chair
affiliation: Biochemistry Laboratory, Hospital Vall d´Hebron, Barcelona (Spain)
last name: Gonzalo Sapisochin, PhD/MD
role: Study Chair
affiliation: Department of HPB Surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
last name: Lluis Castells, PhD/MD
role: Study Chair
affiliation: Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
last name: Isabel Campos, PhD
role: Study Chair
affiliation: Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
last name: Helena Allende, PhD/MD
role: Study Chair
affiliation: Department of Anatomo-Pathology, Hospital Vall d´Hebron, Barcelona (Spain)
last name: Jose Luis Lazaro, PhD
role: Study Chair
affiliation: Department of HPB surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
last name: Cristina Dopazo-Taboada, PhD/MD
role: Study Chair
affiliation: Department of HPB and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
facility: 
country: Spain
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PMID: 19684573
citation: Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Muller T, Bahlo M, Stewart GJ, Booth DR, George J. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009 Oct;41(10):1100-4. doi: 10.1038/ng.447. Epub 2009 Sep 13.
PMID: 19749758
citation: Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009 Oct;41(10):1105-9. doi: 10.1038/ng.449. Epub 2009 Sep 13.
PMID: 19749757
citation: Smith KR, Suppiah V, O'Connor K, Berg T, Weltman M, Abate ML, Spengler U, Bassendine M, Matthews G, Irving WL, Powell E, Riordan S, Ahlenstiel G, Stewart GJ, Bahlo M, George J, Booth DR; International Hepatitis C Genetics Consortium (IHCGC). Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort. Genome Med. 2011 Aug 31;3(8):57. doi: 10.1186/gm273.
PMID: 21884576
responsible party type: Principal Investigator
investigator affiliation: Hospital Vall d'Hebron
investigator full name: Cristina Dopazo Taboada
investigator title: Liver Surgery and Transplants Consultant, PhD/MD
mesh term: Hepatitis A
mesh term: Hepatitis C
mesh term: Hepatitis
mesh term: Fibrosis
mesh term: Recurrence
mesh term: Everolimus
sharing ipd: No