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Drug Information for Simulect (Novartis Pharmaceuticals Corporation): CLINICAL STUDIES
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The safety and efficacy of Simulect®(basiliximab) for the prophylaxis of acute organ rejection in adults following cadaveric- or living-donor renal transplantation were assessed in four randomized, double-blind, placebo-controlled clinical studies (1,184 patients). Of these four, two studies (Study 1 [EU/CAN] and Study 2 [US Study]) compared two 20-mg doses of Simulect with placebo, each administered intravenously as an infusion, as part of a standard immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids. The other two controlled studies compared two 20-mg doses of Simulect with placebo, each administered intravenously as a bolus injection, as part of a standard triple-immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED), corticosteroids and either azathioprine or mycophenolate mofetil (Study 3 and Study 4, respectively). The first dose of Simulect or placebo was administered within 2 hours prior to transplantation surgery (Day 0) and the second dose administered on Day 4 post-transplantation. The regimen of Simulect was chosen to provide 30-45 days of IL-2Rα saturation.
729 patients were enrolled in the two studies using a dual maintenance immunosuppressive regimen comprised of cyclosporine, USP (MODIFIED) and corticosteroids, of which 363 patients were treated with Simulect and 358 patients were placebo-treated. Study 1 was conducted at 21 sites in Europe and Canada (EU/CAN Study); Study 2 was conducted at 21 sites in the USA (US Study). Patients 18-75 years of age undergoing first cadaveric- (Study 1 and Study 2) or living-donor (Study 2 only) renal transplantation, with ≥1 HLA mismatch, were enrolled.1,2
The primary efficacy endpoint in both studies was the incidence of death, graft loss or an episode of acute rejection during the first 6 months post-transplantation. Secondary efficacy endpoints included the primary efficacy variable measured during the first 12 months post-transplantation, the incidence of biopsy-confirmed acute rejection during the first 6 and 12 months post-transplantation, and patient survival and graft survival, each measured at 12 months post-transplantation. Table 1 summarizes the results of these studies. Figure 1 displays the Kaplan-Meier estimates of the percentage of patients by treatment group experiencing the primary efficacy endpoint during the first 12 months post-transplantation for Study 2. Patients in both studies receiving Simulect experienced a significantly lower incidence of biopsy-confirmed rejection episodes at both 6 and 12 months post-transplantation. There was no difference in the rate of delayed graft function, patient survival, or graft survival between Simulect-treated patients and placebo-treated patients in either study.
There was no evidence that the clinical benefit of Simulect was limited to specific subpopulations based on age, gender, race, donor type (cadaveric or living donor allograft) or history of diabetes mellitus.
Table 1. Efficacy Parameters (Percentage of Patients) Dual-therapy Regimen (cyclosporine* and corticosteroids) Study 1 Study 2 Placebo(N=185) Simulect®(N=190) p-value Placebo(N=173) Simulect®(N=173) p-value Primary endpointDeath, graft loss or acute rejection episode (0-6 months) 57% 42% 0.003 55% 38% 0.002 Secondary endpointsDeath, graft loss or acute rejection episode (0-12 months) 60% 46% 0.007 58% 41% 0.001 Biopsy-confirmed rejection episode (0-6 months) 44% 30% 0.007 46% 33% 0.015 Biopsy-confirmed rejection episode (0-12 months) 46% 32% 0.005 49% 35% 0.009 Patient survival (12 months) 97% 95% 0.29 96% 97% 0.56 Patients with functioning graft (12 months) 87% 88% 0.70 93% 95% 0.50
* USP (MODIFIED)
Two double-blind, randomized, placebo-controlled studies (Study 3 and Study 4) assessed the safety and efficacy of Simulect for the prophylaxis of acute renal transplant rejection in adults when used in combination with a triple immunosuppressive regimen. In Study 3, 340 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and azathioprine (AZA), of which 168 patients were treated with Simulect and 172 patients were treated with placebo. In Study 4, 123 patients were concomitantly treated with cyclosporine, USP (MODIFIED), corticosteroids and mycophenolate mofetil (MMF), of which 59 patients were treated with Simulect and 64 patients were treated with placebo. Patients 18-70 years of age undergoing first or second cadaveric or living donor (related or unrelated) renal transplantation were enrolled in both studies.
The results of Study 3 are shown in Table 2. These results are consistent with the findings from Study 1 and Study 2.
Table 2. Efficacy Parameters (Percentage of Patients) Study 3: Triple-therapy Regimen (cyclosporine*, corticosteroids, and azathioprine) Placebo Simulect® (N=172) (N=168) p-value Primary endpoint Acute rejection episode (0-6 months) 35% 21% 0.005 Secondary endpoints Death, graft loss or acute rejection episode (0-6 months) 40% 26% 0.008 Biopsy-confirmed rejection episode (0-6 months) 29% 18% 0.023 Patient survival (12 months) 97% 98% 1.000 Patients with functioning graft (12 months) 88% 90% 0.599
In Study 4, the percentage of patients experiencing biopsy-proven acute rejection by 6 months was 15% (9 of 59 patients) in the Simulect group and 27% (17 of 64 patients) in the placebo group. Although numerically lower, the difference in acute rejection was not significant.
In a multicenter, randomized, double-blind, placebo-controlled trial of Simulect for the prevention of allograft rejection in liver transplant recipients (n=381) receiving concomitant cyclosporine, USP (MODIFIED) and steroids, the incidence of the combined endpoint of death, graft loss, or first biopsy-confirmed rejection episode at either 6 or 12 months was similar between patients randomized to receive Simulect and those randomized to receive placebo.
The efficacy of Simulect for the prophylaxis of acute rejection in recipients of a second renal allograft has not been demonstrated.
Long Term Follow-up
Five-year patient survival and graft survival data were provided by 71% and 58% of the original subjects of Study 1 and Study 2, respectively. Subjects in both studies continued to receive a dual-therapy regimen with cyclosporine, USP (MODIFIED) and corticosteroid. No difference was observed between groups in the 5-year graft survival in either Study 1 (91% Simulect group, 92% placebo group) or Study 2 (85% Simulect group, 86% placebo group). In Study 1, patient survival was lower in the Simulect-treated patients compared to the placebo-treated patients (142/163 [87%] vs. 156/164 [95%], respectively). The cause of this difference in survival is unknown. The data do not indicate an increase in malignancy- or infection-related mortality. In Study 2, patient survival in the placebo group (90%) was the same compared to Simulect group (90%).
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