Clinical Trial Result Information

Title of Study:
Two-arm, open-label, randomized, multi-center study of the addition of CellCept (MMF, mycophenolate mofetil) to a tacrolimus-based immunosuppressive regimen for the prevention of acute rejection in hepatic allografts recipients.

Fast Facts:

Protocol number:	M55026
Sponsor:	Shanghai Roche Pharmaceuticals Ltd.
Company division:	Pharmaceutical
Product name:	CellCept
Generic name:	mycophenolate mofetil
Phase of development:	III
Therapeutic area, approved indication:	Liver Transplantation
Date of report:	1/26/2005

Clinical study summary:
This randomized, open-label, multi-center study evaluated the efficacy of CellCept (0.5–1 g twice daily) in addition to a tacrolimus-based immunosuppressive regimen compared to tacrolimus-based immunosuppression alone, for the prevention of acute rejection in recipients of hepatic allografts. Patients were followed for a total of 24 weeks, and the proportion of patients experiencing an acute rejection reaction was recorded.

Study center(s) :
9 sites in China.

Objectives:
To evaluate the efficacy of the adding of oral CellCept 0.5–1.0 g bid (fasting) for 24 weeks to a tacrolimus-based immunosuppressive regimen for the prevention of acute rejection episodes after liver transplantation.

Methodology:
Patients were randomized to received either CellCept plus tacrolimus (initial dose 0.04–0.10 mg/kg daily) plus corticosteroids, or tacrolimus (initial dose 0.10–0.15 mg/kg daily) plus corticosteroids. Clinical assessments were completed at screening, baseline, and at intervals up to week 24. Safety was assessed through the monitoring of adverse events, graft and patient survival, opportunistic infections, malignancies, vital signs and physical examination.

Number of patients (planned/analyzed):
72 planned, 64 completed the study.

Diagnosis and main criteria for inclusion:
Patients in receipt of hepatic allografts were eligible for this study.

Test product, dose and mode of administration or test procedure:
CellCept 0.5–1.0 g/bid/po + tacrolimus 8-15ng/mL and corticosteroids at the dose normally given at each participating centre.

Duration of treatment:
24 weeks.

Reference therapy, dose and mode of administration or reference procedure:
Tacrolimus 8–15 ng/mL and corticosteroids at the dose normally given at each participating center.

Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: The proportion of patients experiencing ≥1 episode of acute rejection in 24 weeks.

Secondary efficacy parameters: (1) Number of patients treated requiring treatment following an episode of acute rejection; (2) Number of biopsy-proven acute rejection episodes during the study; (3) Renal function (4) Liver function; (5) Pancreatic function(6) Graft and patient survival; (7) Adverse events; (8) Opportunistic infections; (9) Malignancies; (10) Bone marrow suppression

Statistical methods:
The analysis was performed for both ITT and per-protocol patients. Efficacy data were performed per protocol by a 2-sided test. Confidence intervals for binomial proportions were computed for other parameters. Actuarial analysis of survival was performed by the Kaplan-Meier method, with P-values generated by the Wilcoxon test. The values of descriptive variables between groups were compared with the nonparametric Wilcoxon rank-sum test. The chi-squared test or Fisher’s exact test was used to evaluate the independence of the group.

Summary (efficacy, safety, other results):
Efficacy – One of 25 patients in the CellCept group experienced a single incident of acute rejection, compared with 4 of 18 patients in the control group.

Safety – Hemoglobin levels: Reductions in hemoglobin levels were found in the CellCept group at the end of Week 1-2 post transplantation. Peripheral platelet levels: At the end of Week 8 post-transplantation, peripheral platelet levels were higher in the CellCept group, with levels in both groups being significantly higher than those pre-transplant. Prothrombin time: There was a significant difference between the 2 groups at the end of Week 4 , favouring the control group. ALT/AST: Marked increases in ALT/AST levels were found in the control group at the end of Week 4 post-transplantation. Blood sugar/triglyceride levels: Notable increases were found in the control group. Total cholesterol levels: Total cholesterol levels were lower before transplantation; there were no significant difference between the 2 groups post-transplantation. Blood bilirubin, inosine, and urea nitrogen levels: There was no difference between both groups at any time point. There is no difference in the incidence of adverse events between the 2 groups.

Conclusions:
At the early stage of post-liver transplantation, CellCept produced an immunosuppressive effect on the prevention of acute liver rejection. No fatal adverse events were observed, and no significant liver or kidney toxicity was found.