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

Phase 2

Terminated

Conditions: Recurrent Hepatitis C

Interventions: Drug: CsA-TAC (standard Treatment)
Drug: Everolimus

Registration Number: NCT00582738

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 43

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CsA-TAC	CsA-TAC (standard Treatment)	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.
everolimus	Everolimus	Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Fibrosis Staging Score (Measured by the Ishak-Knodell Staging Score) Between Baseline and 24 Months Post-transplant.	baseline, 24 Months	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

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in Fibrosis Metavir Scoring at 12 and 24 Months Post Randomization	Baseline, 12 months, 24 months	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
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	12 months, 24 months/EOS	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.
Comparison of the Effect of Both Regimens in the Necroinflammatory Grading Score (Ishak-Knodell) (Portal Inflammation)	baseline, 12 months, 24 months	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
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	baseline, 12 and 24 months	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)
Percentage of Patients in Each Study Arm With Increase of ≥1 Point in the Ishak-Knodell Staging Score in Fibrosis	baseline to month 24	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.
Change From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Viral Load at 12 and 24 Months Post Randomization	baseline, 12 months, 24 months/EOS	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