Clinical Trial Result Information

Title of Study:
A double-blind, placebo-controlled, randomized study to assess the efficacy and safety of Zenapax in combination with CellCept, cyclosporine, and corticosteroids in patients undergoing cardiac transplantation

Fast Facts:

Protocol number:	NR15880
Sponsor:	Roche Laboratories Inc.
Company division:	Pharmaceutical
Product name:	Zenapax
Generic name:	daclizumab
Phase of development:	IV
Therapeutic area, approved indication:	Heart Transplantation
Date of report:	3/21/2003

Clinical study summary:
This double-blind, randomized, placebo-controlled, multi-center study was designed to evaluate the efficacy and safety of Zenapax in combination with mycophenolate mofetil (MMF) (CellCept) cyclosporine, and corticosteroids in the prevention of acute rejection in primary cardiac transplant recipients. All patients were to receive a total of 5 doses of Zenapax or placebo during the study. The first dose of study medication was administered at 1 mg/kg by intravenous (iv) infusion within 12 hours after transplantation. The subsequent 4 doses of 1 mg/kg iv (≤100 mg) were administered every 2 weeks.

Study center(s) :
31 centers: 26 in the United States, 2 in Canada, 2 in Germany, and 1 in Sweden.

Objectives:
The primary objective was to compare the proportion of patients treated with Zenapax versus placebo in combination with CellCept, cyclosporine, and corticosteroids who had acute rejection within the first 6 months post-transplantation. Secondary objectives for this study were to compare between treatment groups: (1) Acute rejection rate at 12 months post-transplantation; (2) Number of acute rejection episodes per patient within the first 6 months and within the first 12 months post-transplantation; (3) Patient and graft survival at 6 and 12 months, post-transplantation; (4) Distribution of the worst International Society of Heart and Lung Transplantation (ISHLT) biopsy grade, at 6 and 12 months post-transplantation; (5) Time to first acute rejection episode within 6 and 12 months post-transplantation; (6) Proportion of patients to whom OKT3/ATGAM was administered in the first 6 months post-transplantation; (7) Maintenance doses of MMF and cyclosporine and cumulative dose of corticosteroids at 6 and 12 months post-transplantation; and (8) Assessment of change from baseline for each component of the lipid profile (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL] , LDL/HDL ratio, triglycerides) at 3 and 6 months post-transplantation.

Methodology:
Eligible patients were screened up to 48 hours prior to cardiac transplantation. They were randomized to receive either Zenapax or placebo in combination with MMF, cyclosporine and corticosteroids. Patients were seen weekly for 1 month, bi-weekly for an additional 2 months, monthly for 3 months, and every other month for the remainder of the year, for clinical evaluations, measurement of laboratory parameters and diagnostic tests.

Number of patients (planned/analyzed):
434 enrolled: 216 randomized to receive Zenapax and 218 randomized to placebo.

Diagnosis and main criteria for inclusion:
Males or females ≥13 years of age who are recipients of a first cardiac allograft.

Test product, dose and mode of administration or test procedure:
Zenapax iv 1 mg/kg within 12 hours of transplantation.

Duration of treatment:
Subsequent doses administered on Days 8, 22, 36, and 50 (total of 7 weeks) post-transplantation.

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

Criteria for evaluation (efficacy, safety):
The primary efficacy parameter was a composite endpoint of acute rejection and treatment failure within 6 months (no earlier than Day 180).

Secondary efficacy parameters: (1) Proportion of patients who experienced an acute rejection within the first 12 months after transplantation; (2) Number of acute rejection episodes per patient within the first 6 months and first 12 months post-transplantation; (3) Patient and graft survival at 6 and 12 months, post-transplantation; (4) Number of patients categorized by their worst ISHLT biopsy grade in the first 6 months post-transplantation and within the first 12 months; (5) Time to first acute rejection within the first 6 months and first 12 months; (6) Use of OKT3 or ATGAM in the first 6 months post-transplantation; (7) Maintenance doses of MMF and cyclosporine, and cumulative dose of corticosteroids, at 6 and 12 months post-transplantation; (8) Change from baseline for lipid profile.

Safety parameters: Safety assessments included: (1) Clinical assessments, including weight and vital signs; (2) Incidences of adverse events, malignancies, opportunistic infections, and premature withdrawal resulting from adverse events (AEs). (3) Collection of selected concomitant medications and immunosuppressive therapies; (4) Laboratory assessments; and (5) Graft loss and death.

Vital signs were noted pre-infusion, immediately post-infusion, and 15 minutes post-infusion of study medication.

Statistical methods:
Sample size: The sample size was based on the primary efficacy parameter. A 40% rejection rate was assumed for the placebo arm, and the level of significance was 2-sided at an alpha level of 2.5% (a/2=.0125). A total of 173 patients per arm were required to detect a 40% reduction (relative to the placebo arm) in rejection rate for the Zenapax arm with 80% power. A 20% dropout rate was assumed, and therefore, a total of 217 patients per arm, or 434 patients in all, were needed. The sample size was calculated using the normal approximation to the binomial with continuity correction.

Primary endpoint: A Mantel-Haenszel general association test was used for hypothesis testing, which investigated any association between treatment and rejection rate. Logistic regression was used to detect any interaction between treatment and rejection rate. A 95% confidence interval was calculated for the weighted average of the difference in rejection rate at 6 months between treatment groups.

Secondary endpoints: (1) Acute rejection rate at 12 months: the same methods as for primary endpoint were used; (2) The association of number of acute rejection episodes with treatment, by 6 and 12 months, was tested using the Mantel-Haenszel row mean score test; the rate of rejection, was analyzed by Poisson regression using a log linear model; (3) Patient survival and time to first acute rejection, by 6 and 12 months, were estimated by the Kaplan-Meier method and the survival curves were plotted and compared using the log-rank test; (4) The association of severity of biopsy grade with treatment was tested using the Mantel-Haenszel row mean score test; (5) The maintenance dose of MMF and cyclosporine, and the cumulative dose of corticosteroids, were analyzed using the Wilcoxon rank-sum test.

The changes from baseline for lipid profile were investigated using analysis of covariance (ANCOVA), with terms for treatment, baseline, and baseline-by-treatment interaction. A nonparametric test, analysis of variance using the rank transformation, was used to confirm the results of ANCOVA.

Summary (efficacy, safety, other results):
Efficacy– Overall, patients treated with Zenapax, combined with a regimen of MMF at 3 g/day, cyclosporine and corticosteroids, had statistically significantly fewer rejections than patients in the placebo group.

The difference of –12% in the weighted average of the percentage of patients with acute rejection during 6 months post-transplantation in the Zenapax and placebo groups was statistically significant (P=0.007). These results were also confirmed in the per-protocol population. The overall proportion of patients meeting the primary endpoint of acute rejection in the Zenapax and placebo groups was 35.6% and 47.7%, respectively, with an incidence of first biopsy-proven acute rejection of 25.5% and 41.3%, respectively. The proportion of patients in the Zenapax and placebo groups experiencing hemodynamic compromise was 2.8% and 1.4%, respectively. The difference of –8.6% in the weighted average of the percentage of patients with acute rejection during 12 months post-transplantation in the Zenapax and placebo groups was of borderline statistical significance (P=0.063). In the per-protocol population, the difference of –9.7% was statistically significant in the weighted average of the percentage of patients with acute rejection during 12 months post-transplantation in the Zenapax and placebo groups (P=0.049).

Safety – The proportion of patients in the Zenapax and placebo groups who died was 6.5% and 3.2%, respectively. Results were similar in the per-protocol population. Two hundred fourteen (214) of 216 patients (99%) in the Zenapax treatment group and all 207 of patients (100%) in the placebo group experienced AEs between the time of first study drug intake and Day 210 (6-month window). There were 8 AEs with a difference in incidence between treatment groups of >5%. The incidence of upper respiratory tract infection and pleural effusion was approximately 6% greater in the Zenapax group compared with the placebo group, and the incidence of muscle cramps, fluid overload, anxiety, hyperglycemia, nausea, and hypertension was 5%–9% higher in the placebo group compared with the Zenapax group.

A similar proportion of patients in the Zenapax and placebo groups experienced serious adverse events up to Day 210 (50% and 49%, respectively) or serious opportunistic infections (6.9% and 7.7%, respectively). Mortality in the safety population for the Zenapax and placebo groups was 7.4% and 4.8%, respectively, at 6 months, and 9.7% and 5.3%, respectively, at 12 months. Although the difference in mortality did not reach statistical significance, the study was not powered to show a difference and at 12 months the lower limit of the confidence interval of the difference in mortality rates was close to 0. More infectious deaths occurred in the Zenapax group; with this exception, the causes of death were generally similar in the 2 groups.

Conclusions:
Zenapax in combination with 3 g/day of MMF plus cyclosporine and corticosteroids provided better prophylaxis for acute cellular rejection than placebo following cardiac transplantation. However, when additional immunosuppression was given, such as antilymphocyte therapy, patients may have been over-immunosuppressed, as evidenced by more deaths associated with infection in such patients treated with Zenapax. Zenapax and placebo were very similar with respect to other AEs, including opportunistic viral and fungal infections, and changes in laboratory parameters.

This is the largest, controlled, double-blind, cardiac transplantation trial with Zenapax in combination with 3 g/day of MMF plus cyclosporine and corticosteroids. The results cannot be taken as proof that Zenapax in such a setting is unsafe; however, the results do warrant further study of such a combination in this setting. It is possible that such a combination places a patient at a higher risk for over-immunosuppression, especially if additional immunosuppression is required during a patient’s post-transplant course.

Publications (references, if available):
1) Hershberger RE et al. Daclizumab to prevent rejection after cardiac transplantation. New Engl J Med 2005; 352 (26): 2705-13 2) Hosenpud JD. Immunosuppression in cardiac transplantation. New Engl J Med 2005; 352 (26): 2749-50