Roche trials database

Protocol number:

ML17521

Title of Study:

An exploratory study to evaluate the efficacy, safety, particularly renal function, and tolerability of 3 regimes of immunosuppressive therapy, in patients who have undergone liver transplantation.

Sponsor:

F Hoffman-La Roche Ltd

Company division:

Pharmaceutical

Product name:

Zenapax

Generic name:

daclizumab

Therapeutic area:

• Liver Transplantation

Clinical study summary:

This was a prospective, randomized, open-label, parallel group, multicenter study in patients who had undergone liver transplantation. Patients were randomized in a 1:1:1 fashion to one of three immunosuppressive regimens: Group A (standard dosage of tacrolimus [trough level >10 ng/mL] for the first 30 days after transplantation, thereafter dosed according to documented center practice, and corticosteroids), Group B (reduced dosage of tacrolimus [trough level ≤8 mg/mL], CellCept (MMF) and corticosteroids), or Group C (reduced dosage tacrolimus [as Group B] introduced at day 5 post-transplantation, plus CellCept, Zenapax (daclizumab) and corticosteroids initiated immediately post-transplant).

Study center(s):

28 centers in Belgium, Finland, France, Germany, Norway, Spain, Sweden, Switzerland and United Kingdom

Phase of development:

III

Objectives:

The primary objective was to assess renal function (calculated creatinine clearance) in patients receiving tacrolimus in standard dosage (without CellCept) or reduced dosage (with CellCept) or those whose treatment with tacrolimus was delayed under the protection of CellCept and Zenapax, each in combination with corticosteroids.
Secondary objectives were to collect efficacy, safety and tolerability data.

Methodology:

This was a, prospective, randomized, open-label, parallel group, multicenter study in patients who had undergone liver transplantation. Patients were randomized in a 1:1:1 fashion to one of the three immunosuppressive regimens. A total of 9 study visits were performed over a 52 week period plus a safety follow-up visit. For children who withdrew from the study before completing the full 52 weeks of protocol treatment, selected information was collected between withdrawal and 52 weeks post-transplant.

Number of patients (planned/analyzed):

525 planned; 517 enrolled and treated

Diagnosis and main criteria for inclusion:

Male or female patients ≥16 years of age who were first time orthotopic (whole or split) liver transplant patients.

Test product, dose and mode of administration or test procedure:

Zenapax (daclizumab) was administered to Group C patients at a dose of 2 mg/kg given within 12 hours of transplantation with a second dose of 1 mg/kg given 7 days after the first dose.

Duration of treatment:

Minimum of 52 weeks

Reference therapy, dose and mode of administration or reference procedure:

Tacrolimus was administered as follows:

Group A:
Initial recommended oral dose: 0.10 – 0.15 mg/kg/day in 2 divided doses
Initial recommended IV dose: 0.01 – 0.05 mg/kg/day 24-hour infusion
Group B:
Initial recommended oral dose: 0.05 – 0.10 mg/kg/day in 2 divided doses
Initial recommended IV dose: 0.008 – 0.04 mg/kg/day 24-hour infusion
Group C:
Initial recommended oral dose: 0.05 – 0.10 mg/kg/day in 2 divided doses
Initial recommended IV dose: 0.008 – 0.04 mg/kg/day 24-hour infusion

CellCept (MMF) was administered 1 g bid IV until at least day 5 post-transplantation. From day 5 onwards, patients received MMF tablets 1 g bid.

Corticosteroids were administered according to the investigational centers documented standard practice.

Criteria for evaluation (efficacy, safety):

Efficacy: Change from baseline at Week 52 for calculated creatinine clearance; change from baseline for serum creatinine at 13, 26 and 52 weeks post-transplantation; change from baseline for calculated creatinine clearance at 13 and 26 weeks post-transplantation; requirement for renal dialysis occurring between 2 and 52 weeks post-transplantation; biopsy proven acute rejection requiring pulse immunosuppression therapy up to 26 weeks and 52 weeks post-transplantation; biopsy-proven acute rejection requiring pulse immunosuppression therapy; graft loss (defined as death or retransplantation); or requirement to adjust tacrolimus levels outside of the target range (during the first 26 and 52 weeks post-transplantation); composite endpoint, 20% (or greater) decrease from baseline in calculated creatinine clearance, or acute rejection, or graft loss or death; biopsy-proven acute rejection during 26 and 52 weeks post-transplantation; acute rejection requiring pulse immunosuppressant therapy during 26 and 52 weeks; episodes of biopsy-proven or presumed acute rejection during the first 26 and 52 weeks post-transplantation; time to first biopsy-proven acute rejection requiring pulse immunosuppression therapy up to 52 weeks; patient and graft survival at 52 weeks post-transplantation; time to graft loss or death up to 52 weeks; incidence of histologically determined recurrence of underlying liver disease post-transplantation.
Safety parameters were adverse events, laboratory test parameter abnormalities, incidence of hypertension, diabetes, hyperlipidemia, diarrhea and leukopenia and incidence of protocol-defined opportunistic infections up to Week 52.

Statistical methods:

Two comparisons were performed for the primary efficacy endpoint, Group A vs Group B, and Group A vs Group C. Analysis of covariance was performed with treatment group, center and baseline calculated creatinine clearance as factors in the model. Estimates of the population marginal means were presented for each treatment group, together with the p-value for difference between treatment groups.

Summary (efficacy, safety, other results):

Efficacy: At week 52, the change from baseline in the rate of calculated creatinine clearance was significantly less (p=0.012) for patients in Group C than for patients in Group A (reference group). The change from baseline in the rate of calculated creatinine clearance for patients in Group B was similar to that for patients in Group A at week 52. This significant reduction in the decline of renal function in Group C was also noted for weeks 13 and 26. For Group B, the change from baseline in calculated creatinine clearance was significantly smaller than for Group A at week 13 only.
The change from baseline in serum creatinine levels was also significantly less in Group C at week 13 (mean 0.11 mg/dL; p=0.006), week 26 (0.11 mg/dL; p=0.017) and week 52 (0.12 mg/dL; p=0.020) compared with Group A (0.22, 0.23 and 0.23 mg/dL, respectively). The change from baseline in serum creatinine levels was also significantly less at week 13 and 52 in patients in Group B than in patients in Group A.
Significantly fewer (p=0.0367) patients in Group C required renal dialysis between weeks 2 and 52 (4.2%) compared with patients given a standard dose of tacrolimus (Group A; 9.9%).
Significantly fewer (p=0.0396) patients in Group C (14.9%) compared with Group A (23.2%) experienced biopsy-proven acute rejection liver requiring pulse immunosuppression therapy at week 26 post-transplantation. Fewer patients in Group C (16.7%) than Group A (24.3%) experienced this type of rejection at week 52 as well, although the difference did not achieve statistical significance (p=0.0643).
Fewer patients in Group C had biopsies graded moderate or severe during acute rejection than in Groups A or B.
A similar percentage of patients (6-7%) experienecd graft loss in the 3 treatment regimens, mainly during the study as opposed to after withdrawal. A slightly greater percentage of patients died in Group s A (9.4%) and B (11.3%) than patients in Group C (6.5%).
The recurrence of liver disease up to week 52 occurred in significantly more (p=0.0466) patients in Group C (22.1%) than in Group A (9.7%). Hepatitis C was the most frequently recurring liver disease. More patients in Group C (14; 35.9%) compared with Group A (7; 19.4%) had recurring Hepatitis C, although the difference was not statistically significant (p=0.2871).
A composite endpoint was used to assess renal function and graft related outcomes: those patients who experienced a≥20% decrease from baseline in calculated creatinine clearance, or acute rejection, graft loss, or death. Significantly fewer patients (p=0.0001) in Group C (77.4%) compared with patients in Group A (92.3%) experienced such an event as assessed by the composite endpoint. The time to event was also significantly longer (p<0.0001) for patients in Group C (median 21.5 days) than for patients in Group A (median 7.0 days).

Safety: The safety findings were consistent with the known safety profiles of CellCept, tacrolimus and Zenapax and with the safety findings in transplant patients in general. The number of patients who experienced AEs and SAEs was similar between the 3 groups. Most AEs were mild or moderate in intensity. The number of deaths was higher in Groups A (8.8%) and B (9.5%) than in Group C (4.1%). The most frequently reported SAEs leading to death in Groups A, B and C were infections and infestations (1.1%, 3.0% and 2.4%, respectively).
More patients in Group A (30.2%) withdrew because of AEs than in Groups B and C (approximately 20%). The most common AEs leading to withdrawal in Groups A, B and C were renal insufficiency (6.0%, 1.2% and 0%, respectively) and graft dysfunction (3.3%, 2.4% and 3.0%, respectively).
The most frequently reported AEs considered by the investigator as causally related to Zenapax were hypertension (8.9%), although Group C showed lowest hypertension rates, diabetes mellitus (8.3%) and cytomegalovirus syndrome (5.9%).
The most common SAEs in Groups A, B and C were graft dysfunction (4.4%, 4.7% and 3.6%, respectively) and renal insufficiency (4.4%, 2.4% and 2.4%, respectively). There was a numerically greater incidence of bile duct stenosis in Group A (5.5%) than in Groups B (1.2%) or C (2.4%).
The most common opportunistic infections were CMV infection/disease, which were reported with a similar incidence in the 3 groups (12.1%, 13.0% and 13.6% of patients in Groups A, B, and C, respectively) and Candida infections (7.7%, 10.7% and 8.3% of patients, respectively).
A low level of malignancies was noted in Groups A, B and C during the study (2.2%, 0.6% and 1.8%, respectively).

Conclusions:

An immunosuppressive regimen consisting of a delayed and reduced tacrolimus dose regimen under the protection of CellCept and Zenapax was associated with less impairment of renal function than standard dose tacrolimus or reduced dose tacrolimus plus CellCept 12 months after liver transplantation.
In addition, the delayed reduced-dose tacrolimus regimen in combination with CellCept and Zenapax appeared to protect against acute rejection, at least for the first 26 weeks post-transplant and this effect lasted for at least 1 year post transplant.
Patient death, graft loss and patient safety were not adversely affected compared with standard dose tacrolimus or reduced dose tacrolimus with CellCept therapy.
The safety findings in this study were consistent with the known safety profiles of CellCept, tacrolimus and Zenapax. No unexpected safety issues were identified. Overall the regimen of delayed and reduced tacrolimus, CellCept, Zenapax and corticosteroids offers a clinical advantage to the reference regimen of tacrolimus and corticosteroids due to a benefit of less decline in renal function without adverse consequences in acute rejection and overall mortality.

Publications (references, if available):

None

Date of report:

15.10.2008

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