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

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ClinicalTrials.gov Identifier: NCT00260208
Recruitment Status : Terminated (Study was prematurely terminated due to poor recruitment.)
First Posted : December 1, 2005
Results First Posted : October 26, 2011
Last Update Posted : December 6, 2011
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE November 30, 2005
First Posted Date  ICMJE December 1, 2005
Results First Submitted Date  ICMJE September 14, 2011
Results First Posted Date  ICMJE October 26, 2011
Last Update Posted Date December 6, 2011
Study Start Date  ICMJE January 2006
Actual Primary Completion Date September 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 14, 2011)
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 ]
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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 2, 2011)
  • Number of Participants With Combined Endpoint of Death or Graft Loss or Fibrosis Score (FS) ≥ 2 [ Time Frame: 1 year post-transplant ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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).
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Liver Fibrosis in Patients Transplanted for Hepatitis C Receiving Either Cyclosporine Microemulsion or Tacrolimus
Official Title  ICMJE 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
Brief Summary 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
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Liver Transplant
  • Hepatitis C
Intervention  ICMJE
  • 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
  • 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).
Study Arms  ICMJE
  • 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.

    Intervention: Drug: Cyclosporine A
  • 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.

    Intervention: Drug: Tacrolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 14, 2011)
361
Original Enrollment  ICMJE Not Provided
Study Completion Date  ICMJE Not Provided
Actual Primary Completion Date September 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland,   United States
Removed Location Countries Germany
 
Administrative Information
NCT Number  ICMJE NCT00260208
Other Study ID Numbers  ICMJE COLO400A2426
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date December 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP