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

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.

Time frame: 1 year post-transplant

Population: The modified intent-to-treat population (mITT) included patients treated with study drug at least up to 30 days before Month 12 visit and a liver biopsy had to be performed at this visit. Also included were patients with an earlier biopsy that showed an Ishak-Knodell fibrosis score ≥2 and treated at least up to 30 days before that biopsy was taken.

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.

Time frame: Pre-transplant (Day 1), Day , Day 8, Day 29, Month 6 and 12 post- transplant

Population: Intent-to-treat (ITT) population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment. n in each of the categories is the number of participants with data at the given time point.

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).

Time frame: At 1and 2 years and its evolution over time

Population: This outcome was not analyzed because of premature termination of study.

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)

Time frame: 1 year post-transplant

Population: Intent-to-treat (ITT) population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment. n is number participants with assessable data in each category.

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.

Time frame: 1 year post-transplant

Population: Intent-to-treat (ITT) population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment.

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.

Time frame: 1 year post-transplant

Population: Intent-to-treat (ITT) population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment.

Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.

Time frame: 1 year post-transplant

Population: Intent-to-treat (ITT) population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment.

Cirrhosis was resulted due to the recurrence of the hepatitis C virus infection in the transplanted liver.

Time frame: 1 year post-transplant

Population: Intent-to-treat (ITT) population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment.

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.

Time frame: 1 year post-transplantation

Population: Intent-to-treat population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment.

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.

Time frame: 1 year post-transplant

Population: The Intent-To-Treat (ITT) population consisted of all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment.

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.

Time frame: 1 year post-transplant

Population: Intent-to-treat (ITT) population: all patients as randomized that were transplanted, received at least one dose of study drug and had at least one post-baseline efficacy assessment.

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.

Time frame: Between 1 and 2 years

Population: The outcome measure was not analyzed because of premature termination of study.