Clinical trial NCT01707849: The Impact of Everolimus Based Immunosuppression in the Evolution of Hepatitis C Fibrosis After Liver Transplantation
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis C Recurrence After Liver Transplant
Keywords: Hepatitis C
Liver Fibrosis
m-TOR inhibitors
Lead sponsor: Hospital Vall d'Hebron
Sponsor class: OTHER
First posted: 2012-10-16
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 68
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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

Eligibility criteria: 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

Primary outcomes:
measure: To compare the liver fibrosis progression (F≥2 under ISHAK score) in patients who receive everolimus vs mTOR free immunosuppression
timeFrame: One year
Secondary outcomes:
measure: To identify viral and recipient molecular predictors of fibrosis and anti-HCV treatment responses in liver transplant recipients under steroid-free immunosuppression
timeFrame: 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 outcomes:
measure: To analyze liver fibrosis progression using serum markers
timeFrame: 3rd, 6th and 12th months post-transplant
measure: To analyze liver fibrosis progression using liver stiffness
timeFrame: 6th and 12th months post-transplant
measure: To analyze the incidence of acute rejection and steroid-resistant acute rejection
timeFrame: 6th and 12th months post-transplant
measure: To analyze the timing to the first acute rejection episode in both study groups
timeFrame: 6th and 12 months post-transplant
measure: To analyze need of antiviral therapy at the end of the first year post-transplant
timeFrame: One year post-transplant
measure: To analyze graft and patient survival
timeFrame: One year post-transplant
measure: To analyze the incidence of patient withdrawal
timeFrame: One year post-transplant
measure: To analyze the incidence of cardiovascular risk factors
timeFrame: 6th and 12th months post-transplant
Locations:
city: Barcelona
country: Spain
facility: Department of HPB Surgery and Transplant, Hospital Vall d´Hebron
Study officials:
affiliation: Department of HPB Surgery and Transplant, Hospital Vall d´Hebron (Barcelona, Spain)
name: Itxarone Bilbao, PhD/MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of HPB and Transplants, Hospital Vall d´Hebron (Barcelona, Spain)
name: Ramon Charco, PhD/MD
role: STUDY_DIRECTOR
affiliation: Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
name: Josep Quer, PhD/MD
role: STUDY_CHAIR
affiliation: Biochemistry Laboratory, Hospital Vall d´Hebron, Barcelona (Spain)
name: Francisco Rodríguez, PhD/MD
role: STUDY_CHAIR
affiliation: Department of HPB Surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
name: Gonzalo Sapisochin, PhD/MD
role: STUDY_CHAIR
affiliation: Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
name: Lluis Castells, PhD/MD
role: STUDY_CHAIR
affiliation: Hepatology Unit, Department of Internal Medicine, Hospital Vall d´Hebron, CIBERehd, Barcelona (Spain)
name: Isabel Campos, PhD
role: STUDY_CHAIR
affiliation: Department of Anatomo-Pathology, Hospital Vall d´Hebron, Barcelona (Spain)
name: Helena Allende, PhD/MD
role: STUDY_CHAIR
affiliation: Department of HPB surgery and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
name: Jose Luis Lazaro, PhD
role: STUDY_CHAIR
affiliation: Department of HPB and Transplant, Hospital Vall d´Hebron, Barcelona (Spain)
name: Cristina Dopazo-Taboada, PhD/MD
role: STUDY_CHAIR
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