Clinical Trial Result Information

Title of Study:
Evaluation of renal function in liver transplant recipients receiving dacilizumab (Zenapax) and mycophenolate mofetil (CellCept, MMF) and a delayed lower dose of tacrolimus vs a standard dose tacrolimus-based regimen.

Fast Facts:

Protocol number:	M67012
Sponsor:	Hoffmann-La Roche Ltd.
Company division:	Pharmaceutical
Product name:	Zenapax
Generic name:	daclizumab
Phase of development:	III
Therapeutic area, approved indication:	Liver Transplantation
Date of report:	7/15/2005

Clinical study summary:
This was a multi-center, randomized, parallel-group, open-label comparative study to evaluate the combination of Zenapax, CellCept, tapered corticosteroids, and delayed tarcolimus therapy compared with standard-dose tacrolimus-based immunosuppressive therapy. Patients receiving a first liver transplant who were able to receive oral medication were randomized to receive Zenapax induction therapy plus delayed Tacrolimus or a standard tacrolimus-based regimen. Patients were evaluated for clinical efficacy over 12 months.

Study center(s) :
6 centers in Canada.

Objectives:
The primary objective was to evaluate the clinical benefit (a composite of stable renal function and absence of acute cellular rejection at 3 months) of the combination of Zenapax induction, CellCept, tapered corticosteroids, and a delayed and lower dose of tacrolimus vs standard-dose tacrolimus-based immunosuppression.

Secondary Objectives: (1) Incidence of acute cellular rejection, graft loss, and death; (2) Change in serum creatinine and glomerular filtration rate from baseline to Month 12; (3) Opportunistic infections, including cytomegalovirus; (4) Adverse drug effects; (5) Total days in hospital; and (6) Total days in the intensive care unit (ICU).

Methodology:
This was a multi-center, randomized, parallel-group, open-label comparative study assessing the efficacy and safety of delayed and lower doses of tacrolimus in the setting of Zenapax induction therapy in comparison with normal doses of tacrolimus in patients receiving a first cadaveric liver allograft.

Number of patients (planned/analyzed):
148 planned; 148 randomized.

Diagnosis and main criteria for inclusion:
The target population consisted of adult patients ≥18 years of age receiving a first cadaveric liver transplant with the ability to take oral medication. Key exclusion criteria were recipients of multi-organ transplants, previously transplanted organs, or an organ transplant from a living donor. Recipients who required dialysis within 30 days of transplant or whose pre-transplant serum creatinine levels were ≥180 mmol/L were also excluded.

Test product, dose and mode of administration or test procedure:
Zenapax 2 mg/kg iv 4 hours post-operatively; 1 mg/kg iv on Day 4. Tacrolimus: standard dose.

Duration of treatment:
12 months.

Reference therapy, dose and mode of administration or reference procedure:
Standard tacrolimus dosage without Zenapax.

Criteria for evaluation (efficacy, safety):
Primary efficacy parameter: Clinical benefit composite of stable renal function and absence of acute cellular rejection) at Month 3 comparing the delayed tacrolimus group with the standard tacrolimus group.

Secondary efficacy parameters: (1) Acute cellular rejection, patient survival, graft survival, and GFR at Month 12; (2) Duration of initial hospital/ICU stay, and duration of follow-up hospital stays.

Safety: (1) Adverse events; (2) Serious adverse events; and (3) Adverse events associated with the study drug and death.

Statistical methods:
Efficacy: Primary: intention-to-treat analysis. Secondary: per protocol analysis (if pertinent). Safety: Descriptive analysis based on safety population.

Summary (efficacy, safety, other results):
The primary efficacy analysis at Month 3 did not show a statistically significant difference in clinical benefit between patients in the delayed tacrolimus group (30.6%) and the standard tacrolimus group (31.6%; P=1.00). The secondary efficacy analysis at Month 12 also showed comparable 1-year patient survival (86.6% vs 92.9%; P=0.21), 1-year liver graft survival (92.5% vs 93.2%; P=0.88), duration of median hospital stays (7 vs 12 days; P=0.169), and duration of median ICU stays (2 vs 3 days; P=.183). Between baseline and Month 12, there were no statistically significant differences in the median GFR (–7 mL/minute vs –13.2 mL/minute; P=0.259). However, for patients in the standard tacrolimus group, analysis of early kidney function (GFR, blood urea nitrogen, and creatinine) showed a statistically significant decrease in renal function up to Month 1, which was most pronounced during the first week post-transplantation. Furthermore, analysis of adverse events showed a statistically significant increase in acute renal failure in patients receiving standard tacrolimus therapy (13.2%) compared with those receiving delayed tacrolimus therapy (2.8%; P=0.032).

Conclusions:
The observed primary and secondary endpoints were comparable in both treatment arms. This indicates that a regimen of delayed addition of lower-than-standard dose tacrolimus in combination with Zenapax induction is able to produce excellent results with regard to efficacy and safety.