Clinical Trial Result Information
Title of Study:
A pilot study of the pharmacokinetics, safety and efficacy of mycophenolate mofetil (CellCept) and sirolimus (Rapamune) in renal transplantation when used in conjunction with daclizumab (Zenapax) and corticosteroids.
Fast Facts:
| Protocol number: | PA16290 |
| Sponsor: | Hoffmann-La Roche Inc |
| Company division: | Pharmaceutical |
| Product name: | CellCept |
| Generic name: | mycophenolate mofetil |
| Phase of development: | II |
| Therapeutic area, approved indication: | Kidney Transplantation |
| Date of report: | 11/1/2004 |
Clinical study summary:
This was a randomized, open-label, parallel design study in renal transplant patients, to study the safety, efficacy and pharmacokinetics of Rapamune in combination with CellCept, Zenapax and corticosteroids, and to compare combination treatment containing Rapamune versus cyclosporine.
Study center(s) :
6 centers in the USA.
Objectives:
To characterize the pharmacokinetics (PK) of CellCept (mycophenolic acid [MPA] and its glucuronide metabolite [MPAG]) and Rapamune over a period of 6 months post-transplant in renal transplant recipients treated with Zenapax, CellCept, Rapamune and corticosteroids. To compare the PK of CellCept in the presence of Rapamune versus cyclosporine. To describe the safety and efficacy of Rapamune versus cyclosporine in combination with Zenapax, CellCept and corticosteroids in renal transplant recipients.
Methodology:
Patients were required to attend study visits at baseline, and on post-transplant days 1, 4 and 7, weeks 2, 4, 6 and 8, and months 3, 4, 5 and 6. Sirolimus and cyclosporine trough levels were measured at each visit from day 7 through month 6. Blood samples for PK analysis at a central laboratory were collected on days 4 and 7, week 4, and months 3 and 6. Episodes of acute rejection, treatment for rejection, and graft loss were recorded throughout the study. Serum creatinine was measured at baseline, and at intervals to month 6. Glomerular filtration rate (GFR) was measured at month 6. Adverse events and concomitant treatments were recorded throughout the study. Fasting lipid profile, laboratory safety assessments, weight and vital signs were recorded at baseline and at intervals to month 6.
Number of patients (planned/analyzed):
45 patients.
Diagnosis and main criteria for inclusion:
Adult (aged 18-75 years), male or female single organ recipients of primary renal allografts, excluding recipients of HLA-identical living-related kidney transplants.
Test product, dose and mode of administration or test procedure:
Zenapax (daclizumab) supplied in single use 5mL glass vials for reconstitution (25mg daclizumab reconstituted in 5mL).
CellCept (mycophenolate mofetil) supplied as 250mg capsules, and as powder for i.v. administration (500mg in 20mL vials).
Rapamune oral solution (sirolimus) supplied in either 60 or 150 mL glass bottles for reconstitution (1mg per 1mL).
Rapamune tablets (sirolimus) supplied as 1 mg tablets in bottles (100 tablets per bottle).
Neoral (or therapeutic cyclosporine A equivalent) was provided by each center.
Corticosteroids were provided by each center.
Duration of treatment:
6 months
Reference therapy, dose and mode of administration or reference procedure:
Not applicable
Criteria for evaluation (efficacy, safety):
Pharmacokinetics: Primary Parameter: AUC0-12 of MPA and MPAG and AUC0-24 of sirolimus. Secondary Parameters: PK parameters (except AUC), including Cmax, Tmax and Cmin.
Efficacy: Biopsy-proven acute rejection or treatment failure at 6 months; biopsy-proven acute rejection (BPAR) at 6 months; time to BPAR; patient and graft survival at 6 months; renal function, as measured by calculated creatinine clearance (CrCL) and measured glomerular filtration rate (GFR) at 6 months.
Safety: Adverse events (including opportunistic infections and malignancies), deaths and serious adverse events; laboratory parameters, vital signs and weight; incidence of failure to achieve primary closure of transplant surgical wound at 1 month post-transplant; incidence of lymphocele requiring intervention during the first 6 months post-transplant.
Statistical methods:
All PK parameters were listed and summarized descriptively. Dose normalized AUC0-12 (MPA and MPAG) and AUC0-24 (sirolimus) were used in the analyses.
The efficacy and safety data were summarized descriptively, with no formal statistical tests applied to the data.
Summary (efficacy, safety, other results):
Pharmacokinetic: Following administration of Rapamune in combination with CellCept, concentrations of sirolimus rose rapidly, with a median time to peak concentration of 1.25 – 2 hours over the three PK visits, and with a slight trend towards an increase between week 4 and months 3 and 6 in sirolimus Cmax and AUC0-24h levels. Target trough levels were achieved by 59-69.2% patients across visits.
Following administration of CellCept in combination with either Rapamune (Group A) or cyclosporine (Group B), MPA concentrations rose rapidly, with median Tmax values in Groups A and B ranging across visits from 0.67 – 1.21 h and 1.25 – 1.31 h, with a trend towards increasing MPA levels through month 6. Overall, MPA Cmax, Cmin and AUC0-12h was slightly decreased, and Tmax slightly increased, in the presence of cyclosporine compared to sirolimus. MPA exposure was reduced across visits by 39 50%, and Day 4 mean MPA trough levels also appeared to be slightly lower, in the presence of cyclosporine compared to sirolimus.
MPAG concentrations rose less rapidly, with median Tmax values in Groups A and B of 2.00 h and 2.00 3.00 h; MPAG Tmax, Cmax Cmin and AUC0-12h were slightly increased in the presence of cyclosporine compared to sirolimus, with approximate increases in MPAG exposure of 27% at day 7, 28% at week 4, 25% at month 3 and 52% at month 6. Day 4 mean MPAG trough levels were also slightly higher in Group B compared to Group A.
Efficacy: By 6 months post-transplant, the incidence of biopsy-proven acute rejection or treatment failure was higher in Group A (Rapamune) compared to Group B (cyclosporine) [40% vs. 13.3% (including borderline rejection), respectively]. In Group A, 11 patients experienced biopsy-proven acute rejection and 3 patients experienced treatment failure. In contrast, only 2 patients in Group B experienced biopsy-proven acute rejection, and no patient experienced treatment failure. All 13 biopsy-proven acute rejection episodes, and all 3 treatment failure episodes, occurred within the first 4 months post-transplant, with early acute rejections (within the first 2 months) more common in Group A compared to Group B (6 vs. 0 patients, respectively). In addition, 1 patient (in Group A) experienced acute rejection which was not confirmed by biopsy.
Renal function at 6 months post transplant appeared to be slightly better in Group A compared to Group B (mean serum creatinine 1.2 mg/dL vs. 1.5 mg/dL, and mean creatinine clearance 82.7 mL/min vs. 77.8 mL/min, respectively). However, glomerular filtration rate (GFR) values for the two treatment groups appeared more comparable (mean GFR 54.6 mL/min/1.73 m2 in Group A vs. 55.2 mL/min/1.73 m2 in Group B).
None of the patients died or experienced graft loss during the study. One patient (in Group B) had evidence of chronic rejection (mild interstitial fibrosis) on day 2 post-transplant, but this probably reflected the condition of the donor organ. A total of 9 patients experienced delayed graft function (DGF), with the overall incidence being higher in Group A compared to Group B (23.3% vs. 13.3%, respectively). Of these 9 patients, 7 (6 in Group A, 1 in Group B) experienced protocol-defined DGF, while 2 (one in each group) had DGF recorded as an adverse event. Only 1 patient (Group B) required induction therapy for DGF. None of the 9 patients who experienced DGF lost their graft, and only 2 patients with DGF (both in Group A) experienced biopsy-proven acute rejection.
Safety: Adverse events known to be associated with cyclosporine use were more common in Group B, including hypertension, tremor and, hirsutism,... However, diarrhea was more frequent in Group A as was anemia, and to a lesser extent leucopenia. The incidence of thrombocytopenia was low but nevertheless slightly higher in Group A as was the incidence of other events associated with Rapamune, including hyperlipidemia, and pneumonia. Hypercholesterolemia was also slightly more frequent in Group A.
A higher proportion of patients in Group A than Group B failed to achieve primary closure of their surgical wound by 1 month post-transplant (37% / 13%), and the incidence of hernias was also slightly higher in Group A than Group B (13% / 7%). Only 1 patient (Group A) experienced lymphocele during the study.
The majority of AEs which occurred during the study were considered either mild or moderate in intensity and unrelated to study treatment. The most frequent AEs considered Zenapax-related were pyrexia, upper respiratory and urinary tract infections, while the most frequent CellCept-related AEs were diarrhea, dyspepsia, leukopenia, anemia and thrombocytopenia. Rapamune-related AEs were most commonly anemia, leucopenia, thrombocytopenia, hyperlipidemia, hypercholesterolemia, diarrhea and stomatitis, while the most common cyclosporine-related AEs were tremor, headache, parasthesia, dizziness, hirsutism, hyperlipidemia, hypertension and leukopenia .
The overall incidence of opportunistic infections by 6 months post-transplant was slightly higher in Group A (17%) than in Group B (7%). The most frequent opportunistic infection (OI) was candida, the incidence of which was slightly higher in Group A, followed by cytomegalovirus (CMV) and herpes simplex. No malignancies were recorded up to 6 months post-transplant, and there were no deaths during the study. A total of 23 patients (57% Group A, 40% Group B) experienced at least one serious adverse event (SAE) during the study, with the most common being CMV and candidal infections, or renal and urinary disorders. The majority of SAEs were considered unrelated to study treatment.
A total of 5 patients (all in Group A) discontinued treatment with study drug due to AEs. Two patients withdrew from CellCept (one due to leukopenia and one due to diarrhea), two patients from Rapamune (one due to wound dehiscence, and one due to interstitial nephritis and renal tubular necrosis), and one patient withdrew from CellCept and Rapamune (due to human polyoma virus infection). There were no withdrawals from Zenapax due to AEs. A total of 26 patients (70% Group A, 33% Group B) experienced at least one AE leading to dose modification or interruption of at least one of the drugs in their immunosuppressive regimen.
The most frequent marked laboratory abnormalities were hypophosphatemia, low hemoglobin and lymphopenia. The incidence of marked thrombocytopenia, an event associated with Rapamune use, was higher in Group A than Group B (23% / 0%). The incidence of marked hypercholesterolemia was slightly higher in Group A (17% Group A, 7% Group B). In both treatment groups, the majority of patients remained within ± 5% of their baseline weight throughout the study, and vital signs were also broadly comparable in the two treatment groups for the duration of the study.
Conclusions:
When CellCept was coadministered with cyclosporine, exposure to MPA was decreased by 39 – 50% and exposure to MPAG was increased by 25 – 52%, compared to when CellCept was coadministered with Rapamune. These results are consistent with a drug-drug interaction, whereby cyclosporine inhibits or interferes with the enterohepatic recycling of MPA, inhibiting MPAG excretion from the liver to the bile, resulting in decreased MPAG conversion back to MPA in the gut lumen and decreased MPA re-absorption.
Although the patient numbers were small in this study, when CellCept was coadministered with Rapamune rather than cyclosporine, renal function was slightly improved, but the incidence of acute rejection was increased, as was the incidence of diarrhea, anemia, leukopenia, thrombocytopenia, hyperlipidemia, hypercholesterolemia and impaired wound healing. The increase in acute rejection did not, however, affect graft loss or patient survival by 6 months post transplant.
Publications (references, if available):
M. Pescovitz et al. Pharmacokinetics, safety and efficacy of mycophenolate mofetil in combination with sirolimus vs. cyclosporine in renal transplant patients. American Transplant Congress (ATC), Boston, USA, May 2004, Oral Presentation.
Click here for the protocol registry listing of this trial.
