Liver Fibrosis in Patients Transplanted for Hepatitis C Receiving Either Cyclosporine Microemulsion or Tacrolimus

This study has been terminated.
(Study was prematurely terminated due to poor recruitment.)
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00260208
First received: November 30, 2005
Last updated: December 2, 2011
Last verified: December 2011
  Purpose

Following a transplant for hepatitis C cirrhosis, the infection comes back in 70-90% of cases and over time causes fibrosis and eventually cirrhosis of the new liver. The aim of this study was to see if the frequency of liver fibrosis was different with cyclosporine microemulsion than tacrolimus


Condition Intervention Phase
Liver Transplant
Hepatitis C
Drug: Cyclosporine A
Drug: Tacrolimus
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: A Multicenter, Randomized, Open-label Study to Compare the Development of Liver Fibrosis at 12 Months After Transplantation for Hepatitis C Cirrhosis in Patients Receiving Either Cyclosporine Microemulsion or Tacrolimus

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: No ]
    Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. Logistic regression on the presence of IK>=2 was applied based on central biopsy readings only.


Secondary Outcome Measures:
  • Number of Participants With Combined Endpoint of Death or Graft Loss or Fibrosis Score (FS) ≥ 2 [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
    The number of participants with combined end point of death or graft loss or presented with a Ishak-Knodell fibrosis score (FS) ≥2 was calculated. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had liver retransplant or died. Assessment of hepatic fibrosis was performed with liver biopsies read centrally. Ishak-Knodell FS was used to stage liver disease; 0=none; 1=portal fibrosis (some); 2=portal fibrosis (most); 3=bridging fibrosis (few); 4=bridging fibrosis (many); 5=Incomplete cirrhosis; 6=cirrhosis. Higher score indicates greater fibrosis.

  • Number of Participants With Fibrosing Cholestatic Hepatitis [ Time Frame: 1 year post-transplantation ] [ Designated as safety issue: No ]
    Fibrosing cholestatic hepatitis (FCH) is characterized by progressive jaundice with a rapid decline in liver function leading to liver failure, most often associated with markedly elevated viral levels detected in the bloodstream (e.g. more than 20 times pre-liver transplantation levels) and in the liver tissue as well. The presence of FCH was reported based on the diagnosis given by the investigator.

  • Number of Participants With Death, Graft Loss, Death or Graft Loss, Graft Loss With Re-transplantation [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
    Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.

  • Number of Participants With Treated Acute Rejection, Biopsy Proven Acute Rejection (BPAR), and Sub-clinical Rejection [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
    Treated acute rejection is defined as an acute rejection, clinically suspected, whether biopsy-proven or not, which has been treated and confirmed by the investigator according to the response to therapy. BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. A sub-clinical rejection was defined as a rejection identified by center driven biopsy, i.e. a biopsy performed routinely at some pre-defined time points after transplantation as per center practice in the absence of any clinical signs of rejection.

  • Number of Participants With Combined Endpoint of Death or Graft Loss or Biopsy Proven Acute Rejection (BPAR) [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
    BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.

  • Number of Participants With Death or Re-transplantation Due to Recurrence of Hepatitis C Cirrhosis [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: Yes ]
    Cirrhosis was resulted due to the recurrence of the hepatitis C virus infection in the transplanted liver.

  • Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant (Intent to Treat Population) [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: No ]
    Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis.

  • Mean Value of Liver Function Tests at 1 Year Post-transplantation [ Time Frame: 1 year post-transplant ] [ Designated as safety issue: No ]

    The mean value (in Units per liter, IU/L) of following tests were calculated at 1 year post-transplant:

    • Serum glutamic pyruvic transaminase (SGPT)
    • Serum Glutamic Oxaloacetic Transaminase (SGOT)
    • Bilirubin
    • Alkaline Phosphate
    • γ-Glutamyltransferase (GGT)

  • Log-transformed Hepatitis C Virus Ribonucleic Acid (HCV RNA) Values up to 1 Year Post Transplant [ Time Frame: Pre-transplant (Day 1), Day , Day 8, Day 29, Month 6 and 12 post- transplant ] [ Designated as safety issue: No ]
    HCV RNA was measured (IU/µL)centrally pre-transplant (Day 1) and at 48 hours (Day 3), Day 8 and 29, Month 6 and 12 post-transplant and concomitantly to any additional biopsies performed.

  • Percentage of Participants With an Increase of at Least 1 Stage in Fibrosis [ Time Frame: Between 1 and 2 years ] [ Designated as safety issue: No ]
    Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. An increase of at least 1 stage demonstrated a worsening of the disease, i.e. the transition from one score to the next higher one.

  • Mean Fibrosis Score [ Time Frame: At 1and 2 years and its evolution over time ] [ Designated as safety issue: No ]
    Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. The mean score was equivalent to mean of IK at 1 and 2 years (evolution over time).


Enrollment: 361
Study Start Date: January 2006
Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Cyclosporin A

The first administration of Cyclosporin A (CsA) was within the first 24 hours post-transplantation at an initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout the study period. During the study, the dose of CsA was adjusted, as necessary, to achieve and maintain the C2 or C0 blood CsA concentration within the target ranges.

Before enrolling the first patient, each center chose the adjunct immunosuppressive (IS) regimen between:

  • Steroids administered and tapered as per local practice
  • interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice.

The regimen selected by the center was to be given to all patients enrolled in the trial from this center.

Drug: Cyclosporine A
Initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v.) within the first 24 hours post-transplantation.
Other Name: Neoral
Active Comparator: Tacrolimus

Tacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses (twice daily at 12-hour interval) either orally or via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout study period. Throughout the study, the dose of tacrolimus was adjusted as necessary to achieve and maintain C0 tacrolimus concentrations within target ranges.

Before enrolling the first patient, each center chose adjunct immunosuppressive (IS) regimen between:

  • Steroids administered and tapered as per local practice
  • interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice.

The regimen selected by center was to be given to all patients enrolled in trial from this center.

Drug: Tacrolimus
Tacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses either orally or via a nasogastric (NG) tube or intravenously (i.v).

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Reason for transplant is end-stage liver disease due to hepatitis C cirrhosis
  • Patients receiving a first liver transplant from a deceased or living donor
  • Patients in whom biopsies will be possible

Exclusion criteria

  • Recipients of a liver from an hepatitis C virus positive (HCV+), human immunodeficiency virus positive (HIV+) or hepatitis B virus positive (HBV+) donor
  • Patients with any severe coexisting disease or suffering any unstable medical condition or co-infected with HBV or HIV
  • Patients with co-existing alcoholic disease who have not been abstinent for at least 6 months
  • Transplanted for liver cancer exceeding a pre-defined size
  • Pregnant or nursing women

Other protocol-defined inclusion/exclusion criteria may apply

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00260208

Locations
United States, New Jersey
Novartis Investigative Site
East Hanover, New Jersey, United States
Switzerland
Novartis Investigational Site
Zurich, Switzerland, 8091
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: NCT00260208     History of Changes
Other Study ID Numbers: COLO400A2426
Study First Received: November 30, 2005
Results First Received: September 14, 2011
Last Updated: December 2, 2011
Health Authority: United States: Institutional Review Board

Keywords provided by Novartis:
Liver transplant, adults, hepatitis C, liver fibrosis, cyclosporine microemulsion, tacrolimus

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Fibrosis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Pathologic Processes
Cyclosporins
Cyclosporine
Tacrolimus
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on September 18, 2014