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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00582738
First received: December 12, 2007
Last updated: August 2, 2012
Last verified: August 2012
  Purpose

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


Condition Intervention Phase
Recurrent Hepatitis C
Drug: CsA-TAC (standard Treatment)
Drug: Everolimus
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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.

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change From Baseline in Fibrosis Staging Score (Measured by the Ishak-Knodell Staging Score) Between Baseline and 24 Months Post-transplant. [ Time Frame: baseline, 24 Months ] [ Designated as safety issue: No ]

    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:
  • Change From Baseline in Fibrosis Metavir Scoring at 12 and 24 Months Post Randomization [ Time Frame: Baseline, 12 months, 24 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: 24 Months ] [ Designated as safety issue: No ]
  • Number of Patients With Events (Progression to Cirrhosis, Retransplantation, HCV Related Death, First BPAR, Graft Loss)at 12 and 24 Months [ Time Frame: 12 months, 24 months ] [ Designated as safety issue: No ]
  • Comparison of Renal Function (Glomerular Filtration Rate [GFR] Calculated Using the Modification of Diet in Renal Disease Study Group [MDRD] Formula) Between Study Groups [ Time Frame: 12 months, 24 months/EOS ] [ Designated as safety issue: No ]

    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) [ Time Frame: baseline, 12 months, 24 months ] [ Designated as safety issue: No ]
    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 [ Time Frame: baseline, 12 and 24 months ] [ Designated as safety issue: No ]

    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 [ Time Frame: baseline to month 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: baseline, 12 months, 24 months/EOS ] [ Designated as safety issue: No ]
    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


Enrollment: 43
Study Start Date: December 2007
Study Completion Date: January 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: CsA-TAC
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)
Continuation of current immunosuppressive regimen (continuation of CNI with or without MPA, with or without steroids) / no everolimus introduction.
Experimental: everolimus
Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids.
Drug: Everolimus
Hepatitis C recurrence after orthotopic liver transplantation (OLT)

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00582738

Locations
Argentina
Novartis Investigative site
Buenos Aires, Argentina
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00582738     History of Changes
Other Study ID Numbers: CRAD001H2301
Study First Received: December 12, 2007
Results First Received: January 10, 2012
Last Updated: August 2, 2012
Health Authority: Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica

Keywords provided by Novartis:
Fibrosis progression
recurrent hepatitis C
viral infection
liver transplant recipients
everolimus
Hepatitis C recurrence after orthotopic liver transplantation (OLT)

Additional relevant MeSH terms:
Fibrosis
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis C
Virus Diseases
Pathologic Processes
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on April 23, 2014