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

Phase 4

Terminated

• Conditions: Liver Transplant; Hepatitis C
• Interventions: Drug: Cyclosporine A; Drug: Tacrolimus

• Registration Number: NCT00260208
• Lead Sponsor: Novartis Pharmaceuticals

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 available

Study Timeline

• Study First Submitted: 2005-11-30
• Study First Submitted QC: 2005-11-30
• Study First Posted: 2005-12-01
• Study Start: 2006-01
• Primary Completion: 2010-09
• Results First Submitted: 2011-09-14
• Results First Submitted QC: 2011-09-14
• Results First Posted: 2011-10-26
• Status Verified: 2011-12
• Last Update Submitted: 2011-12-02
• Last Update Posted: 2011-12-06

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 361

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cyclosporin A	Cyclosporine 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.
Tacrolimus	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Combined Endpoint of Death or Graft Loss or Fibrosis Score (FS) ≥ 2	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	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	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	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)	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	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)	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	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	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	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	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).

Trial Locations

Locations (2)

Novartis Investigational Site; 🇨🇭 Zurich, Switzerland

Novartis Investigative Site; 🇺🇸 East Hanover, New Jersey, United States