Clinical Trial Result Information

Protocol number
M67011

Title of Study
Multicenter, randomized, open trial, comparing the safety and efficacy of two administrations of Zenapax® versus Thymoglobulin®, both in combination with delayed introduction of Neoral®, CellCept® and steroids, in patients receiving their first renal transplantation

Sponsor
Roche SAS

Company division
Pharmaceutical

Product name
Zenapax

Generic name
daclizumab

Therapeutic area
Kidney Transplantation

Clinical study summary
This was a multicenter, randomized, open-label, parallel-group trial to compare the safety and efficacy of Zenapax and Thymoglobulin, each combined with delayed introduction of cyclosporine (Neoral), CellCept, and steroids, in patients with a first renal transplant. Patients were randomized to receive either intravenous daclizumab (Zenapax) at a maximum dose of 200 mg or intravenous antithymocyte globulin (ATG; Thymoglobulin) a minimum of 4 times and a maximum of 9 times, over 12 months.

Study center(s)
9 centers in France.

Phase of development
III

Objectives
Primary: To compare the safety of Zenapax and Thymoglobulin, in terms of CMV infection and disease during the first 6 months post-transplant.

Secondary: (1) To compare (a) Efficacy at 6 months and 12 months posttransplantation; (b) Pharmacoeconomic parameters at 6 months and 12 months posttransplantation; (2) To evaluate the pharmacokinetic parameters of 2 doses of Zenapax.

Methodology
Patients were assigned to 1 of 2 treatment groups: Zenapax group: Zenapax in 2 doses, delayed Neoral given in combination with CellCept, and steroids for 12 months. Thymoglobulin group: ATG, delayed Neoral in combination with CellCept, and steroids for 12 months. CMV infections, syndromes, and diseases during the first 6 months were assessed. Acute rejection, patient and graft survival, adverse events, and renal function blood tests were assessed at 6 and 12 months.

Number of patients (planned/analyzed)
110 planned; 115 enrolled.

Diagnosis and main criteria for inclusion
Male and female patients 18 to 65 years of age receiving a first cadaver renal allograft, able to receive immunosuppressant treatment including cyclosporine, CellCept, steroids, and either Zenapax or ATG.

Test product, dose and mode of administration or test procedure
Zenapax: 2 doses by IV infusion; first administration: 2 mg/kg during the 24 hours preceding transplantation (minimum dose: 100 mg; maximum dose: 200 mg even if weight >100 kg); second (and last) administration: 1 mg/kg on Day14 (accepted range, Day 12/Day 16).

Duration of treatment
12 months (including follow-up).

Reference therapy, dose and mode of administration or reference procedure
Thymoglobulin: First administration: IV infusion within 24 hours before transplantation or after the surgical operation. Total number of daily administrations: minimum 4, maximum 9, according to the delayed return of graft function. First dose: 1 to 1.5 mg/kg/day, then adjusted to obtain CD2/CD3 count <20/mm3.

Criteria for evaluation (efficacy, safety)
Primary: cytomegalovirus (CMV) infections, syndromes, and diseases during the first 6 months.

Secondary: Acute rejection; patient and graft survival; withdrawals (incidence and causes); number of patients who stopped steroids by Month 6; serum creatinine, creatinine clearance, and proteinuria.

Safety: At 6 and 12 months: Adverse events, including hypertension and hyperlipidemia; opportunistic infections; lymphomas and cancers; discontinuation for adverse events.

Pharmacokinetics: Zenapax serum trough levels.

Statistical methods
Calculation of the number of patients in the 2 arms developing CMV disease, CMV viral syndrome, or CMV infection during the first 6 months posttransplantation in the intent-to-treat (ITT) population, with Chi-square test and 95% confidence interval of the difference. This analysis was performed on both the ITT and PP sets. The time to onset of the first CMV infection, CMV disease, or CMV viral syndrome from the date of transplantation to the date of onset of the first episode was analyzed by the Kaplan-Meier method. The number of patients with at least 1 presumed acute rejection, and biopsy-proved acute rejection (BPAR) was compared between groups using a Fisher’s exact test. The time to onset of the first BPAR was analyzed using the Kaplan-Meier method.

Summary (efficacy, safety, other results)
Patients receiving a limited dosing regimen of Zenapax tended to have a decrease of CMV infections and a significant delayed occurrence of CMV infections. The rate of patients who developed CMV infection/syndrome/disease during the first 6 months posttransplantation in the ITT population was 40% (21 patients) in the Zenapax group and 55% (28 patients) in the Thymoglobulin group (P=0.140) (Chi-square). The types of CMV were mainly CMV infections (76%); 18% were CMV syndromes; 6% were CMV diseases. Time to onset of the first CMV episodes was significantly delayed for patients in the Zenapax group compared with the Thymoglobulin group, for any type of CMV episode, with medians of 53 (29; 164) days in the Zenapax group versus 29 (16; 89) days in the Thymoglobulin group for any CMV infection, 49 (29; 156) days versus 28 (13; 89) days, respectively, for positive antigenemia, 43 days (1 patient) versus 26 (13; 146) days, respectively, for CMV syndrome, and 130 (91; 168) days versus 30 days (1 patient), respectively, for CMV disease. The time to onset of the first episode of CMV was significantly longer (P=0.015) in the Zenapax group than in the Thymoglobulin group.

Efficacy: Rejection rates were similar in the Zenapax and Thymoglobulin groups, as were graft and patient survival rates. Acute rejection after completion of the follow-up of the last patient was reported in 39% of patients. BPAR was reported in 17 patients (9 in the Zenapax group and 8 in the Thymoglobulin group) (P=0.797). Graft survival rate: 6 patients presented a graft loss, 3 in each group (5.5%); all occurred ≤ Month 6. Return to dialysis was required for 7 patients, 2 (3.7%) in the Zenapax group and 5 (9.1%) in the Thymoglobulin group.

Safety: The overall frequency of adverse events was similar in the two groups. Adverse events reported were mostly mild to moderate in intensity. The most frequent adverse events were infections, including CMV infections (75.9%), gastrointestinal disorders such as constipation and diarrhea (55.4%), metabolism and nutritional disorders (50%), and blood and lymphatic system disorders (49.1%). Two deaths were reported: 1 in the Zenapax group during the study period (sudden death) and 1 in the Thymoglobulin group after study withdrawal (acute respiratory distress syndrome). Four patients were withdrawn from the study because of an adverse event (1 patient in the Zenapax group and 3 patients in the Thymoglobulin group).

Conclusions
These data show that a limited dosing regimen of Zenapax, in association with CellCept, cyclosporine and steroids, provides a slightly lower (though not significant) rate of CMV infection with a significantly longer delay to first CMV episode, compared to Thymoglobulin, without increasing the risk of acute rejection.

Date of report
1/1/2006