The Impact of Everolimus Based Immunosuppression in the Evolution of Hepatitis C Fibrosis After Liver Transplantation - Full Text View

Purpose

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:

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.
To identify viral and recipient factors associated with liver fibrosis progression using ultra-deep pyrosequencing (UDPS).

Condition	Intervention	Phase
Hepatitis C Recurrence After Liver Transplant	Drug: EVL arm Drug: MMF arm	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Basic Science
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. Personalized Management of Hepatitis C Virus.

Resource links provided by NLM:

MedlinePlus related topics: Hepatitis Hepatitis A Hepatitis C Liver Transplantation

Drug Information available for: Mycophenolic acid Mycophenolate sodium Sirolimus Mycophenolate mofetil hydrochloride Mycophenolate mofetil Everolimus Temsirolimus Hepatitis A Vaccines

U.S. FDA Resources

Further study details as provided by Hospital Vall d'Hebron:

Primary Outcome Measures:

To compare the liver fibrosis progression (F≥2 under ISHAK score) in patients who receive everolimus vs mTOR free immunosuppression [ Time Frame: One year ] [ Designated as safety issue: No ]
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.

Secondary Outcome Measures:

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 ] [ Designated as safety issue: No ]
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

Other Outcome Measures:

To analyze liver fibrosis progression using serum markers [ Time Frame: 3rd, 6th and 12th months post-transplant ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: Yes ]
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 ] [ Designated as safety issue: Yes ]
To analyze need of antiviral therapy at the end of the first year post-transplant [ Time Frame: One year post-transplant ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: Yes ]
To analyze the incidence of patient withdrawal [ Time Frame: One year post-transplant ] [ Designated as safety issue: Yes ]
To analyze the incidence of cardiovascular risk factors [ Time Frame: 6th and 12th months post-transplant ] [ Designated as safety issue: Yes ]
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.

Estimated Enrollment:	40
Study Start Date:	October 2012
Estimated Study Completion Date:	November 2015
Estimated Primary Completion Date:	November 2013 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
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 Name: 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 Name: Everolimus

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 68 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01707849

Contacts

Contact: Cristina Dopazo-Taboada, PhD/MD

+34932746113

cdopazo@vhebron.net

Locations

Spain
Department of HPB Surgery and Transplant, Hospital Vall d´Hebron	Recruiting
Barcelona, Spain, 08035
Contact: Cristina Dopazo-Taboada, PhD/MD +3493746113 cdopazo@vhebron.net
Sub-Investigator: Cristina Dopazo-Taboada, PhD/MD

Sponsors and Collaborators

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)

More Information

Publications:

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Neef M, Ledermann M, Saegesser H, Schneider V, Reichen J. Low-dose oral rapamycin treatment reduces fibrogenesis, improves liver function, and prolongs survival in rats with established liver cirrhosis. J Hepatol. 2006 Dec;45(6):786-96. Epub 2006 Sep 22. Erratum in: J Hepatol. 2007 Aug;47(2):310.

Patsenker E, Schneider V, Ledermann M, Saegesser H, Dorn C, Hellerbrand C, Stickel F. Potent antifibrotic activity of mTOR inhibitors sirolimus and everolimus but not of cyclosporine A and tacrolimus in experimental liver fibrosis. J Hepatol. 2011 Aug;55(2):388-98. Epub 2010 Dec 17.

Bilbao I, Sapisochin G, Dopazo C, Lazaro JL, Pou L, Castells L, Caralt M, Blanco L, Gantxegi A, Margarit C, Charco R. Indications and management of everolimus after liver transplantation. Transplant Proc. 2009 Jul-Aug;41(6):2172-6.

Wagner D, Kniepeiss D, Schaffellner S, Jakoby E, Mueller H, Fahrleitner-Pammer A, Stiegler P, Tscheliessnigg KH, Iberer F. Sirolimus has a potential to influent viral recurrence in HCV positive liver transplant candidates. Int Immunopharmacol. 2010 Aug;10(8):990-3. Epub 2010 May 17.

McKenna GJ, Trotter JF, Klintmalm E, Onaca N, Ruiz R, Jennings LW, Neri M, O'Leary JG, Davis GL, Levy MF, Goldstein RM, Klintmalm GB. Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression. Am J Transplant. 2011 Nov;11(11):2379-87. doi: 10.1111/j.1600-6143.2011.03767.x. Epub 2011 Oct 3.

Carrión JA, Torres F, Crespo G, Miquel R, García-Valdecasas JC, Navasa M, Forns X. Liver stiffness identifies two different patterns of fibrosis progression in patients with hepatitis C virus recurrence after liver transplantation. Hepatology. 2010 Jan;51(1):23-34.

Pungpapong S, Nunes DP, Krishna M, Nakhleh R, Chambers K, Ghabril M, Dickson RC, Hughes CB, Steers J, Nguyen JH, Keaveny AP. Serum fibrosis markers can predict rapid fibrosis progression after liver transplantation for hepatitis C. Liver Transpl. 2008 Sep;14(9):1294-302.

Nobili V, Parkes J, Bottazzo G, Marcellini M, Cross R, Newman D, Vizzutti F, Pinzani M, Rosenberg WM. Performance of ELF serum markers in predicting fibrosis stage in pediatric non-alcoholic fatty liver disease. Gastroenterology. 2009 Jan;136(1):160-7. Epub 2008 Sep 20.

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Responsible Party:	Cristina Dopazo Taboada, Liver Surgery and Transplants Consultant, PhD/MD, Hospital Vall d'Hebron
ClinicalTrials.gov Identifier:	NCT01707849 History of Changes
Other Study ID Numbers:	EVL-VHC-HVH.12
Study First Received:	October 13, 2012
Last Updated:	October 31, 2012
Health Authority:	Spain: Agencia Española de Medicamentos y Productos Sanitarios Spain: Departament de Salut de la Generalitat de Catalunya Spain: Ethics Committee

Keywords provided by Hospital Vall d'Hebron:

Hepatitis C
Liver Fibrosis
m-TOR inhibitors

Additional relevant MeSH terms:

Fibrosis
Hepatitis
Hepatitis A
Hepatitis C
Recurrence
Pathologic Processes
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Disease Attributes

Mycophenolic Acid
Sirolimus
Mycophenolate mofetil
Everolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on May 21, 2013