Efficacy of Everolimus as Inhibitor of Fibrosis Progression in Liver Transplant Patients With Recurrence of Hepatitis C Viral Infection

Study Overview
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Brief Summary
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This study will assess the efficacy of everolimus as an inhibitor of fibrosis progression in liver transplant patients who have a recurrence of hepatitis C viral infection in the transplant

Official Title
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A Randomized, Controlled, Open Label, Two Arms, Exploratory Study to Evaluate the Effect of Everolimus on Histologically Assessed Fibrosis Progression (Ishak-Knodell) in Liver Transplant Recipients With Recurrent Hepatitis C Viral Infection as Compared to Standard Treatment.

Conditions
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Recurrent Hepatitis C

Intervention / Treatment
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* Drug: CsA-TAC (standard Treatment)
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients 18 - 65 years of age Recipients of deceased or living donors Patients who had undergone primary liver transplantation at least 6 months before enrolment Recurrent Hepatitis C viral infection and histologically confirmed liver fibrosis (stage I-IV in the Ishak-Knodell scale) obtained at baseline or within the previous 6 months to the date of enrolment Patients receiving tacrolimus or cyclosporine micro-emulsion with or without - Mycophenolic acid (MPA), with or without steroids. Absence of acute rejection episodes within the previous 6 months to the date of enrolment Patient in whom an allograft biopsy will not be contraindicated Patient willing and capable of giving written informed consent for study participation and able to participate in the study for 24 months Patients with Hepatocellular carcinoma (HCC) within the University California, San Francisco (UCSF) Criteria and no recurrence for at least 18 months after OLT. Exclusion Criteria: Recipients of multiple organ transplants or patients who have undergone retransplantation Current biliary complications History of drug or alcohol abuse within 1 year before enrolment Patients treated with anti-hepatitis C virus treatment at the time of enrollment or within the previous month to the date of enrolment Co-infection with Hepatitis B virus (HBV) or Human Immunodeficiency Virus (HIV) Patients with Leukocyte count (WBC) < 3000/mm3, platelet count < 75000/mm3 or Hemoglobin (Hb) < 8 g/dl Patients with proteinuria >1g/24 hours Patient with a current severe systemic infection Other protocol defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CsA-TAC<br>Continuation of current immunosuppressive regimen (continuation of Calcineurin Inhibitor [CNI] with or without Enteric-coated mycophenolate sodium (myfortic) or mycophenolate mofetil(Cellcept)[MPA], with or without steroids) / no everolimus introduction. | Drug: CsA-TAC (standard Treatment)<br>* Continuation of current immunosuppressive regimen (continuation of CNI with or without MPA, with or without steroids) / no everolimus introduction.<br>|
| Experimental: everolimus<br>Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids. | Drug: Everolimus<br>* Hepatitis C recurrence after orthotopic liver transplantation (OLT)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fibrosis Staging Score (Measured by the Ishak-Knodell Staging Score) Between Baseline and 24 Months Post-transplant. | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite Decrease in score from baseline indicates improvement | baseline, 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fibrosis Metavir Scoring at 12 and 24 Months Post Randomization | Metavir Score: F0=No fibrosis; F1=Portal fibrosis without septa; F2=Portal fibrosis with rare septa; F3=Numerous septa without cirrhosis Decrease in score from baseline indicates improvement | Baseline, 12 months, 24 months | 
| Percentage of Patients With Death, Graft Loss and Biopsy Proven Acute Rejection (BPAR) Between Study Groups |  | 24 Months | 
| Number of Patients With Events (Progression to Cirrhosis, Retransplantation, HCV Related Death, First BPAR, Graft Loss)at 12 and 24 Months |  | 12 months, 24 months | 
| Comparison of Renal Function (Glomerular Filtration Rate [GFR] Calculated Using the Modification of Diet in Renal Disease Study Group [MDRD] Formula) Between Study Groups | GFR Month 9 value if available, otherwise minimal first year post-randomization available value. Imputation rule of missing Month 24 GFR values: GFR Month 18 value if available, otherwise Month 12 GFR is used. Least square means are from an ANCOVA model containing treatment as factor and baseline eGFR as a covariate. | 12 months, 24 months/EOS | 
| Comparison of the Effect of Both Regimens in the Necroinflammatory Grading Score (Ishak-Knodell) (Portal Inflammation) | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite | baseline, 12 months, 24 months | 
| Comparison of the Effect of Both Regimens on the Inflammatory (Acti-test) and Fibrosis (Fibro-test) Components of Fibrosure, and on Fibrosis Area Assessed by Histomorphometry | The Fibrosure test is the combination of Fibro-test + Acti-test. FibroTest (FT) was for the assessment of fibrosis. Fibro test was calculated using an original combination of five highly concentrated serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin and gammaglutamyltransferase (GGT). FibroTest scores range from 0.00 to 1.00 where 0.0-0.21 is no fibrosis and >= 0.59 is cirrhosis. Acti-test was calculated using 6 serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT and alanine aminotransferase (ALT). ActiTest (AT) was used for the assessment of necroinflammatory activity. Test score ranges from 0.00 to 1.00, where 0.00-0.17 indicates no necrosis and >= 0.61 indicates severe necrosis If 12-month Actitest value was the last available assessment, the value is used to impute the final staging score(End of Study) | baseline, 12 and 24 months | 
| Percentage of Patients in Each Study Arm With Increase of ≥1 Point in the Ishak-Knodell Staging Score in Fibrosis | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite. | baseline to month 24 | 
| Change From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Viral Load at 12 and 24 Months Post Randomization | End of Study (EOS) endpoint is the last available assessment on or after Month 12. A reduction of at least two logs in HCV RNA viral load was considered as success | baseline, 12 months, 24 months/EOS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibrosis progression, recurrent hepatitis C, viral infection, liver transplant recipients, everolimus, Hepatitis C recurrence after orthotopic liver transplantation (OLT)