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

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ClinicalTrials.gov Identifier: NCT01707849
Recruitment Status : Completed
First Posted : October 16, 2012
Last Update Posted : February 7, 2018
Sponsor:
Information provided by (Responsible Party):
Cristina Dopazo Taboada, Hospital Vall d'Hebron

Tracking Information
First Submitted Date  ICMJE October 13, 2012
First Posted Date  ICMJE October 16, 2012
Last Update Posted Date February 7, 2018
Study Start Date  ICMJE October 2012
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2012)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT01707849 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 13, 2012)
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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 13, 2012)
  • 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.
  • 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.
  • 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.
  • To analyze the timing to the first acute rejection episode in both study groups [ Time Frame: 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
  • To analyze graft and patient survival [ Time Frame: One year post-transplant ]
  • To analyze the incidence of patient withdrawal [ Time Frame: 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE The Impact of Everolimus Based Immunosuppression in the Evolution of Hepatitis C Fibrosis After Liver Transplantation
Official Title  ICMJE 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.
Brief Summary

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).
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Hepatitis C Recurrence After Liver Transplant
Intervention  ICMJE
  • Drug: EVL arm
    Patients will be randomized at day 28th post-transplant. This group will receive Tacrolimus+Everolimus.
    Other Name: Everolimus
  • 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 Name: Mofetil Mycophenolate
Study Arms  ICMJE
  • 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).

    Intervention: Drug: MMF arm
  • Experimental: EVL arm

    EVL arm (n=20):

    Tacrolimus (levels 8-10ng/ml) + everolimus 1mg bid (levels 2-4 ng/mL)

    Intervention: Drug: EVL arm
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 2, 2016)
18
Original Estimated Enrollment  ICMJE
 (submitted: October 13, 2012)
40
Actual Study Completion Date  ICMJE August 2016
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 68 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01707849
Other Study ID Numbers  ICMJE EVL-VHC-HVH.12
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Cristina Dopazo Taboada, Hospital Vall d'Hebron
Study Sponsor  ICMJE Hospital Vall d'Hebron
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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)
PRS Account Hospital Vall d'Hebron
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP