Clinical Trial Result Information

Title of Study:
Open-label, comparative study of daclizumab in combination with mycophenolate mofetil and tacrolimus versus tacrolimus in combination with steroids for the prevention of acute rejection in recipients of allogenic liver transplants.

Fast Facts:

Protocol number:	M67014
Sponsor:	F. Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	CellCept
Generic name:	mycophenolate mofetil
Phase of development:	IV
Therapeutic area, approved indication:	Liver Transplantation
Date of report:	7/1/2005

Clinical study summary:
This was an open-label, comparative, randomized, multicenter study comparing the efficacy of combination treatment with daclizumab (Zenapax), mycophenolate mofetil (CellCept) and tacrolimus with that of tacrolimus plus steroids in preventing acute transplant rejection in allogenic liver transplant recipients. Patients were treated for 24 weeks, with a follow-up visit at 52 weeks.

Study center(s) :
14 centers in Spain.

Objectives:
Primary: To evaluate the efficacy of Zenapax in combination with CellCept and tacrolimus versus standard treatment (tacrolimus and steroids) for the prevention of acute rejection episodes in recipients of allogenic liver transplants.

Secondary: (1) Proportion of biopsy-confirmed acute rejection within 52 weeks post-transplant; (2) Patient and transplanted organ survival at 24 and 52 weeks of transplant; (3) Proportion of patients developing chronic rejection; (4) Proportion of patients requiring OKT3/ATG for treatment of the acute rejection episode; (5) Number of cycles of high-dose corticosteroids and/or antilymphocyte therapy for treatment of the rejection episode; (6) Time to first rejection episode; (7) Number of acute rejection episodes per patient; (8) Hepatic function, evaluated by laboratory tests: AST, ALT, GGT, alkaline phosphatase and total bilirubin at 24 and 52 weeks post-transplant; (9) Renal function, evaluated by serum creatinine at 24 and 52 weeks; (10) Proportion of HCV+ patients in which specific follow-up, consisting of determination of genotype and viral load (PCR) in the pre-transplant period, viral load (PCR) at Weeks 4 and 52, and a biopsy at Week 53, was performed.

Safety: To compare the safety profile of the combination in recipients of primary allogenic liver transplants.

Methodology:
Patients were randomized to one of 2 treatment groups: Zenapax + CellCept + tacrolimus, or tacrolimus + steroids. Efficacy and safety were compared after 24 weeks of treatment. Follow-up was carried out until Week 52 post-transplant.

Number of patients (planned/analyzed):
159 enrolled; 157 in the intent-to-treat (ITT) population; 103 in the per-protocol analysis.

Diagnosis and main criteria for inclusion:
Male and female patients between 18 and 70 years of age who were recipients of a single-organ (liver only) primary allogenic liver transplant. Patients with prior organ transplant or an organ from a living donor, and those who had had former treatment with Zenapax or CellCept, were excluded.

Test product, dose and mode of administration or test procedure:
Zenapax, 25 mg/5mL vials (2mg/kg 6 hours post-transplant, 1mg/kg on day 7 post-transplant); CellCept, vials of 500 mg in powder to prepare solution for infusion; CellCept, tablets of 500mg (2g/day)

Duration of treatment:
24 weeks.

Reference therapy, dose and mode of administration or reference procedure:
Tacrolimus (at an initial dose of 0.05mg/kg bid) in combination with steroids (at an initial dose of 15-20g/day).

Criteria for evaluation (efficacy, safety):
Rejection rate, patient survival, graft survival, biopsy-proven acute cellular rejection rate. Hepatic function: AST, ALT, GGT, alkaline phosphatase, and total bilirubin. Renal function: serum creatinine. Adverse event rate, serious adverse event rate, opportunistic infection rate, blood pressure, diabetes incidence.

Statistical methods:
Chi-square tests were used to determine statistically significant differences between the 2 treatment groups for efficacy and safety variables. Differences between groups in time to rejection were determined by log-rank test. Significant differences in total bilirubin levels between groups were determined by ANOVA.

Summary (efficacy, safety, other results):
A total of 157 patients (of 159 included) were considered for the ITT population and 103 for the per-protocol analysis. The Zenapax + CellCept + tacrolimus group had a statistically significant lower rejection rate at 24 weeks from transplant than the tacrolimus + steroids group (11.5% vs 26.6%, respectively; Chi-square; P=0.017). There were no differences between treatment groups for patient survival (Chi-square; P=0.515) or for graft survival (Chi-square; P=0.684), but the Zenapax + CellCept + tacrolimus group had a statistically significant later time to rejection than did the tacrolimus + steroids group (log-rank; P=0.044). The biopsy-proven acute cellular rejection at 52 weeks in the Zenapax + CellCept + tacrolimus group was statistically lower than the rate in the tacrolimus + steroids group (14.1% vs 27.8%, respectively; Chi-square; P=0.035).

Although the baseline total bilirubin levels were statistically higher in the tacrolimus + steroids group (4.76 vs 3.12; ANOVA; P=0.046), the hepatic function recovered very early (1 month after the baseline visit), with no statistically significant differences between treatment groups in bilirubin and AST levels. Recovery of ALT was not so evident, GGT level increased in both groups, and alkaline phosphatase increased in the Zenapax + CellCept + tacrolimus group, but decreased in the tacrolimus + steroids group. Creatinine levels increased in both treatment groups within 1 month after baseline. There were no statistical differences between treatment groups in either the adverse event rate (Chi-square; P=0.210), the related adverse event rate (Chi-square; P=0.882), or the serious adverse event rate (Chi-square; P=0.233). There were a total of 13 deaths, 12 of which occurred after the start of treatment. Causes of death were sepsis (5), multiorgan failure (4), digestive hemorrhage, cerebral infarction, consumption coagulopathy and cardiac arrhythmia.Distribution by treatment groups was similar. The most frequently related adverse event for Zenapax + CellCept + tacrolimus was leukopenia (32.1%), and for tacrolimus + steroids was renal impairment (26.6%). Although not statistically significantly different, the Zenapax + CellCept + tacrolimus group had a higher opportunistic infection rate than the tacrolimus + steroids group (19.2% vs 11.4%, respectively; Chi-square; P=0.172). Blood pressure (both systolic and diastolic) increased statistically throughout the study in both treatment groups. Although not statistically significantly different, the tacrolimus + steroids group had a higher incidence of diabetes than did the Zenapax + CellCept + tacrolimus group (13.9% vs 6.4%; respectively; Chi-square; P=0.120).

Conclusions:
Zenapax in combination with CellCept and tacrolimus had a confirmed lower rejection rate versus standard treatment (tacrolimus + steroids) in allogenic liver transplant recipients after 24 months and 52 months. The test combination had a confirmed longer time to rejection versus the standard treatment (P=0.044). The safety profiles were very similar, with no major differences between treatment groups in the incidence of adverse events, related adverse events, deaths, or any other serious adverse events. The efficacy and safety results confirm the combination of Zenapax and CellCept and tacrolimus for the prevention of acute rejection episodes in recipients of allogenic liver transplants.

Publications (references, if available):
bstract in Transplant International 2005;18 (suppl. 1), 116