Clinical Trial Result Information
Title of Study:
The use of daclizumab (Zenapax) and mycophenolate mofetil (CellCept) in combination with corticosteroids and Neoral (low dose versus low dose followed by complete withdrawal) to optimize renal function in recipients of renal allografts.
Fast Facts:
| Protocol number: | M67005 |
| Sponsor: | Roche Global Development |
| Company division: | Pharmaceutical |
| Product name: | CellCept |
| Generic name: | mycophenolate mofetil |
| Phase of development: | III |
| Therapeutic area, approved indication: | Kidney Transplantation |
| Date of report: | 10/2/2006 |
Clinical study summary:
This was a randomized, open-label, controlled, parallel design study in which renal transplant patients were randomized to the following treatment groups:
Group A initially received Zenapax, CellCept, corticosteroids, and low dose Neoral (CsA) (target trough level 50-100ng/mL). Beginning at the month 4 visit, patients receiving a dose of CellCept ≥1.5 g/day had their month 3 visit dose of Neoral decreased by 33% every month, until Neoral was completely withdrawn at the month 6 visit.
Group B received Zenapax, CellCept, corticosteroids, and low-dose Neoral (target trough level 50-100 ng/mL) for 12 months.
Group C received CellCept, corticosteroids, and standard-dose Neoral (target trough level 150-300 ng/mL) from baseline through the month 4 visit, and 100-200 ng/mL thereafter.
After month 12, patients entering the extension phases were encouraged, but not required, to continue with their protocol-assigned treatment regimen.
The study was prospectively planned to be 12 months in length; however after the study was started it was extended by 6 months (12-18 months extension/follow-up phase), and then by a further 18 months (18-36 months extension/follow-up phase) in order to collect long-term efficacy and safety data.
Study center(s) :
32 centers in Australia, Belgium, Canada, France, Germany, Mexico, Norway, Poland, Spain, Sweden, UK and USA.
Objectives:
Primary: Main study, 0-12 months: to compare renal function by glomerular filtration rate (GFR) at 12 months between the three treatment arms.
Extension phase 12-18 months: to compare renal function by GFR at month 18 post-transplant.
Extension phase 18-36 months: to compare renal function by GFR at month 36 post-transplant.
Follow-up phase 12-36 months: to collect basic safety data for the patients no longer on study-provided CellCept but who had been on the main study.
Secondary: Main study, 0-12 months: to compare the 3 treatment groups with regard to (1) outcomes related to rejection and graft loss; (2) post-transplant considerations related to hypertension and hyperlipidemia; and (3) TGF-β plasma protein levels and mRNA expression in renal allograft tissue; to examine the effect of the presence/absence of cyclosporine, and the cyclosporine dosage (standard-dose vs low-dose), on the pharmacokinetic parameters of MPA and its glucuronide metabolite (MPAG); to evaluate the stability of pharmacokinetic measurements of MPA and MPAG over time.
Extension phase 12-18 months: to compare the three treatment groups with regard to outcomes related to (1) renal function by calculated CrCl (2) acute and chronic rejection (3) graft loss, and death.
Extension phase 18-36 months: to compare the three treatment groups with regard to outcomes related to: (1) renal function by GFR at 24 months and calculated CrCl at 24, 30 and 36 months (2) acute and chronic rejection (3) graft loss and death (4) calcineurin inhibitor-free regimen (5) reinitiation of CsA or increase in the CsA dose above target trough levels for more than 7 consecutive days (6) initiation of tacrolimus for more than 7 consecutive days.
Methodology:
Patients were required to attend study visits at baseline (pre-transplant), and at intervals up to 12 months post-transplant (all groups). GFR and serum creatinine were recorded at months 3 and 12. All rejection episodes, renal biopsy results, treatment for acute rejection, DGF, graft loss, and serum creatinine and CsA trough and C2 levels were recorded at weeks 4 and 8, and months 3-12. Serum creatinine was also measured at baseline. The fasting lipid profile was recorded at baseline, and at months 3 and 12. TGF-β mRNA tissue expression and plasma protein levels were analyzed at baseline and month 12. Blood samples for pharmacokinetic analysis of MPA and MPAG were provided on day 7, and months 3, 7 and 12. All adverse events and concomitant medications were monitored through month 3 post-transplant. Selected adverse events, laboratory assessments, weight and vital signs, immunosuppressive therapies, and use of anti-hypertensive and/or lipid lowering medications were recorded through month 12 post-transplant.
Extension phases: GFR and serum creatinine were recorded at months 18, 24, 30 and 36. All rejection episodes, renal biopsy results, treatment of rejection, graft loss, and CsA trough and C2 levels were recorded at months 18, 24, 30 and 36. Safety measurements were recorded through 36 months post-transplant.
Follow-up phases: Patients who consented to the follow-up phases were not required to attend specific study visits but data were to be collected at 18 months and at 24, 30 and 36 months post-transplant as part of their routine post-transplant care. Immunosuppressive therapies, weight, creatinine, acute and chronic rejection, malignancies, graft loss and deaths were recorded at each visit.
Number of patients (planned/analyzed):
Main study: 535; 12-18 months: 356; 18-36 months: 331
Diagnosis and main criteria for inclusion:
Main study (months 0-12): Adult (>18 years) male or female recipients of primary allogeneic renal allografts, who were able to receive oral medication.
Extension phases (months 12-18 and 18-36): Patients who completed the 12 month study and were receiving study-provided CellCept at 12 months were encouraged to participate in an optional extension phase of the study up to 18 months and then, if still on study CellCept and willing to participate, they could continue up to 36 months post-transplant.
Follow-up phases (months 12-18 and 18-36): Patients who had already completed the 12 months study but had discontinued treatment with study-provided CellCept or had switched to commercial CellCept, were encouraged to participate in an optional follow-up phase up to 18 months and after completion of this phase, in a follow-up phase up to 36 months post-transplant. These patients received commercially available immunosuppressants of the investigator's choice during the follow-up period.
Test product, dose and mode of administration or test procedure:
Zenapax was administered intravenously (i.v.) as a loading dose (2mg/kg, minimum 100mg) within 24 hours pre-transplant, followed by 4 additional doses (1mg/kg i.v.) every 2 weeks, with the patient's baseline weight used to calculate all 5 doses of Zenapax.
CellCept was administered orally (1g bid) throughout the study, with the first dose administered within 24 hours pre-transplant.
Duration of treatment:
12 months for primary endpoint. Treatment could continue until 36 months post-transplant.
Reference therapy, dose and mode of administration or reference procedure:
N/A
Criteria for evaluation (efficacy, safety):
Efficacy: Primary: Renal function at 12 months, 18 months and 36 months post-transplant, as meausred by GFR.
Secondary: (0-12 months): Patient and graft survival by 12 months post-transplant; incidence and time to biopsy-proven acute rejections (BPAR) or treatment failure by 6 and 12 months post-transplant; proportion of patients requiring anti-lymphocyte therapy for treatment of acute rejection by 6 and 12 months post-transplant; number of acute rejection episodes per patient by 6 and 12 months post-transplant; proportion of patients reinitiating CsA or increasing the CsA dose above target trough levels, or initiating tacrolimus, for more than 7 consecutive days for acute rejection or suboptimal CellCept dose by 6 and 12 months post-transplant; number of patients with histological evidence and severity of fibrosis at time of engraftment and 12 months post-transplant; renal function as measured by serum creatinine before/after the first treated acute rejection episode during the first 12 months, and at 12 months, post-transplant; TGF-β plasma protein levels and mRNA expression in renal allograft tissue at time of engraftment and at 12 months post-transplant.
Secondary (extension phase 12-18 months): Renal function as measured by serum creatinine and calculated CrCl at 18 months post-transplant; number of acute rejections per patient during 12 to 18 months post-transplant; proportion of patients with BPAR or chronic rejection 12 to 18 months post transplant; patient and graft survival at 18 months post transplant.
Secondary (extension phase 18-36 months): Renal function as measured by GFR at 24 months post-transplant, and by serum creatinine and calculated CrCl at 24, 30 and 36 months; proportion of patients in Group A to have maintained a calcineurin-inhibitor free regimen at 24, 30 and 36 months; proportion of patients with BPAR at 24, 30 and 36 months post-transplant; proportion of patients with fibrosis (biopsy-proven chronic rejection) at 24, 30 and 36 months post-transplant; proportion of patients reinitiating CsA or increasing the CsA dose above target trough levels, or initiating tacrolimus for more than 7 consecutive days for acute rejection or suboptimal CellCept dose at 24, 30 and 36 months post-transplant; patient and graft survival at 36 months post-transplant.
Pharmacokinetics: Primary: AUC0-12 of MPA (at day 7, and months 3, 7 and 12).
Secondary: AUC0-12 of MPAG (at day 7, and months 3, 7 and 12).
Safety: 0-12 months: All adverse events and concomitant medications up to month 3, and then up to month 12, opportunistic infections, malignancies, laboratory assessments, weight and vital signs, and immunosuppressive therapies, and use of anti-hypertensive and/or lipid lowering medications at 3, 6, 9 and 12 months post-transplant.
Extension patients only, after month 12: Adverse events known to be related to CsA use, opportunistic infections, use of anti-hypertensive and/or lipid lowering medications, treatments for adverse events and opportunistic infections, vital signs and laboratory assessments.
All patients (extension and follow-up) after month 12: Deaths, malignancies, weight, and immunosuppressive therapies.
Statistical methods:
The global statistical null-hypothesis for the primary endpoint was (at month 12, 18, 24 and 36):
H0: The mean GFR was the same for all 3 treatment groups
H1: The mean GFR differed among treatment groups
The global hypothesis was tested at a two-sided α-level of 5%. If the global hypothesis was rejected, the following pair-wise comparisons of the treatment groups were to be made using a closed test procedure, at a two-sided α-level of 5%: Group A vs. C, Group B vs C, and Group A vs B. As a closed test procedure was applied, no inflation of the α-level due to multiple comparisons existed, and the two-sided α-level of 5% was maintained. However, it should be noted that no adjustment for multiple comparisons with respect to analysis at the month 18, 24 and 36 timepoints was undertaken. Since the primary timepoint in this study was at month 12, p-values were only interpreted descriptively.
Summary (efficacy, safety, other results):
Efficacy: GFR: The mean measured GFR values at 12 months after transplantation were higher in Groups A and B: 50.9 mL/min/1.73m2 than in Group C: 48.6 mL/min/1.73m2; differences were not statistically significant. At month 18, GFR was statistically significantly lower in Group A (46.8 mL/min/1.73m2) in comparison to Groups B (54.4 mL/min/1.73m2) and C (49.6 mL/min/1.73m2) (p=0.041), but at month 24 there were no statistically significant differences across the treatment groups. At month 36, mean GFR values were slightly higher in Group B (59.8 ml/min/1.73m2) than in Group A (55.5 ml/min/1.73m2) and Group C (54.0 ml/min/1.73m2), although this was not significant. At all timepoints (months 12, 18, 24, 36), mean GFR values were higher in Group B than in Groups A and C.
Calculated CrCl and serum creatinine: At month 12, mean calculated CrCl values were higher for Group B, but did not differ significantly between the three groups (67.4 mL/min, 71.7 mL/min and 66.0 mL/min respectively for Groups A, B and C). At month 36 caclulated CrCl was highest (68.4 mL/min) for Group B, followed by Group A (67.3 mL/min) and then Group C (65.4 mL/min), although differences between the groups did not reach statistical significance. Mean calculated CrCl values at months 18, 24, 30 and 36 were highest in Group B, followed by Group A and then Group C, Mean serum creatinine levels were similar for the three groups throughout the study.
Acute rejection: The incidence of first BPAR at 6 months after transplantation was not significantly different amongst the groups (Group A, 24.7%; Group B, 24.2%; Group C, 26.2%). However, at 12 months after transplantation, Group A had a significantly higher incidence of first BPAR (38%) compared with Group B (25.4%) (Odds ratio [OR] 1.85, 95%CI: 1.14–2.99; p=0.027) and Group C (27.5%) (OR 1.65, 95%CI: 1.02–2.67; p=0.040). The incidence of severe BPAR (≥ Grade IIb) was similar in Group A (3.7%), Group B (4.0%) or Group C (6.0%). The proportion of patients with any acute rejection episode (clinically suspected, biopsy proven or treated) was lowest in Group B; at month 12, the proportion was significantly higher for Group A (44.1%) versus Group B (30.1%) (OR 1.94, 95%CI:1.23–3.06; p=0.015) and Group C (34.7%) (OR 1.52, 95%CI:0.96–2.39; p=0.071).
The time to first BPAR was shorter during the first 6 months following transplantation in Group C than in Groups A or B. In Group A, there was an increased incidence of first BPAR following withdrawal of CsA.
In all three treatment groups, the majority of patients with acute rejection experienced a single rejection episode, with the incidence of patients with more than one acute rejection being higher for Groups A (13.4%) and B (12.0%) than Group C (6.9%).
At 36 months post-transplant, the incidence BPAR (excluding borderline) was highest, 36% in Group A, 26% in B, and 27% in C, although the incidence of more severe rejection was comparable across the treatment groups. Similar results were obtained at month 18 for BPAR. 4 patients experienced BPAR between months 12-18 (2 Group A, 1 Group B and 1 Group C) and 6 between months 18-36 (2 Group A, 2 Group B and 2 Group C), 3 of which were borderline.
Graft Loss: The number of patients experiencing graft loss by 12 months post-transplant was slightly lower in Group B (6) than in Group A (12) and Group B (9) with the majority of graft loss occurring early in the study (due mainly to post-surgical technical complications). At 36 months, number of patients with graft loss was again lower in Group B (8) than in Groups A (16) and C (10) - 2 graft losses occurred between 12-18 months and 5 between 18-36 months. The incidence of graft loss due to acute rejection was generally comparable across the treatment groups but graft loss due to chronic rejection was experienced only by patients in Groups A and B.
Death: The incidence of death was low and comparable between the 3 treatment groups at all timepoints. During the 12-month study period, there were 8 patient deaths (5%) in Group A, 4 (2.3%) in Group B and 5 (5.5%) in Group C. 5 deaths were considered to be related to study drug: 3 to both CellCept and Zenapax (multi-organ failure, sepsis and septic shock) and 2 to CellCept only (CNS lymphoma and meningitis). 1 death (pulmonary hemorrhage) occurred between 12-18 months in Group C. At 36 months post-transplant, there were 10 deaths (6%) in Group A, 7 (4%) in Group B and 7 (4%) in Group C, with 2, 3 and 1 deaths in Groups A, B and C respectively, occurring between months 18-36.
Other Endpoints: At both 6 and 12 months post-transplant, the incidence of treatment failure was higher in Group A compared to Groups B and C, primarily due to a higher proportion of Group A patients having their CsA dose re-initiated or increased above target trough levels (in response to acute rejection).
Time to treatment failure also appeared shorter in Group A.
In contrast to the results obtained for acute rejection, the incidence of chronic allograft nephropathy (CAN) was higher in Group C, and slightly higher in Group B, compared to Group A, at both 6 and 12 months post-transplant. CAN was comparable across the treatment groups at months 18 and 36.
A total of 13 patients (39% of those analysed) had histological evidence of fibrosis at 12 months post-transplant (all mild rejection), with the number of patients with evidence of fibrosis being slightly higher in Group C vs. B vs. A.
The numbers of patients contributing to the analysis of TGF-β plasma protein levels and mRNA expression levels in renal biopsies at time of engraftment and month 12 was too low to draw any meaningful conclusions regarding the data. The overall incidence of delayed graft function (DGF) at 12 months was slightly higher in Groups B (22%) and C (24%) than in Group A (17%), with a higher proportion of DGF patients in Group C experiencing decreased urine output or institution of dialysis.
Immunosuppression: The mean daily dose of CellCept and the mean daily dose of CsA (normalized to prednisone) were similar across the three treatment groups throughout the study. Patients in Groups A and B had similar levels of cumulative dose of CellCept.
The protocol-specified CsA trough levels were, in general, well maintained up to month 3 after transplantation. However, 26% (46/179) of patients in Group A either did not maintain their low CsA trough level or did not have CsA withdrawn continuously after month 3. Some did not have the CsA dose tapered after month 4, others had their CsA dose increased or reinitiated due to acute rejection or suboptimal dosing of CellCept (<1.5 mg/day). Some patients were changed from CsA to tacrolimus due to acute rejection or suboptimal CellCept dose: 17.3%,13.7%, 12.1% in Groups A, B, C respectively) and sirolimus was given instead of CsA to 1, 2 and 1 patients in Groups A, B, C respectively. However, at the month 12 visit, 58% of Group A patients were not receiving calcineurin inhibitor (CNI) therapy. At the month 36 visit more than half (56%) of Group A patients were off CNIs. In Group B mean CsA trough levels were maintained close to the protocol-specified targets throughout the study.
Pharmacokinetics: Reducing or eliminating CsA from the standard treatment regimen resulted in an increase in MPA exposures, and a decrease in MPAG exposures, reflecting the known drug-drug interaction between CellCept and CsA. For low-dose CsA, slightly higher MPA exposures and slightly lower MPAG exposures were observed between 3-12 months post-transplant compared to standard-dose CsA, with little evidence of an increase in MPA exposure over time, and no evidence of a decrease in MPAG exposure over time. However, in Group A there were much higher MPA exposures and much lower MPAG exposures when CsA was completely withdrawn (between months 7 and 12 post-transplant) compared to Group C (standard dose CsA), with MPA exposure increasing substantially and MPAG exposure decreasing moderately over time in Group A.
Safety:During the first 3 months post-transplant, the overall pattern of adverse events was broadly comparable for Groups A and B (low dose CsA) versus Group C (standard dose CsA). The most frequent adverse event was hypertension, the incidence of which was slightly higher in Group C (41%) vs Groups A (38%) and B (32%). The incidence of anemia, urinary tract infection, hyperkalemia, tremor, and fluid overload was also higher in Group C, while peripheral edema was more common in Groups A and B. The majority of these adverse events were considered by the investigators to be mild or moderate in intensity (93%), and unrelated to treatment with either Zenapax (>88%) or CellCept (>80%). The most frequent Zenapax-related events considered severe in intensity were infections and infestations (particularly sepsis), while the most frequent CellCept-related severe events were either gastrointestinal (particularly diarrhea), infections or infestations (particularly urinary tract infection or sepsis), or blood and lymphatic system disorders (mainly leukopenia).
The overall incidence of adverse events known or considered to be related to CsA use was also broadly comparable across the three treatment groups, except that hypertension, insomnia, tremor, hyperuricemia and hyperkalemia were slightly more common in Group C during the first 3 months post-transplant, and hypercholesterolemia and hypertension were slightly more common in Groups B and C after month 3. There was no significant difference across the 3 treatment groups in the proportion of patients requiring anti-hypertensive and/or lipid lowering medications during the first 12 months post-transplant.
During the 36 months post-transplant, adverse events known to be related to CsA use were experienced by a slightly higher proportion of patients in Group C than in Groups A and B (80% Group A, 78% Group B, 86% Group C). The incidence of hypertension (the most frequently experienced CsA-related adverse event) was also greater in Group C, followed by Group A and then Group B. Adverse events considered related to CsA use by the investigator were comparable across the three treatment groups (46% Group A, 45% Group B, 48% Group C) and there was no statistically significant difference across the treatment groups in the proportion of patients requiring anti-hypertensive and/or lipid-lowering medications at 36 months post-transplant.
Up to 12 months post-transplant, the overall incidence of opportunistic infections and of malignancies, was comparable across the 3 treatment groups (opportunistic infections: 25%, 24%, 27%, malignancies: 2%, 3% 1% in Groups A, B, C respectively). Extending out to 36 months post-transplant, the incidence of opportunistic infections and serious opportunistic infections continued to be comparable across the treatment groups (26%/11% Group A, 25%/9% Group B, 29%/8% Group C), with the most common serious opportunistic infections being CMV. Malignancies were experienced by a slightly higher proportion of patients in Group B (8%) than in Groups C (5%) and A (3%), as was the incidence of the most frequent malignancies, basal cell carcinoma and squamous cell carcinoma.
The overall incidence and pattern of serious adverse events up to 36 months post-transplant was comparable across the three treatment groups (Groups A, B, C: 65%, 65%, 62% respectively), with the majority of serious events considered mild or moderate in intensity and unrelated to Zenapax or CellCept. Serious adverse events considered severe in intensity and related to either Zenapax or CellCept were most frequently infections and infestations (particularly sepsis). A total of 49 patients (10% Group A, 9% Group B, 9% Group C) discontinued treatment with study-provided CellCept due to adverse events (mostly due to leucopenia). Most adverse events leading to discontinuation of study-provided CellCept occurred during the first 12 months.
The overall pattern of marked laboratory abnormalities was comparable across the three treatment groups, although a marked elevation in uric acid (which is associated with gout, a known CsA-related event) was higher in Group C. The average values obtained for all vital sign parameters (respiration, systolic and diastolic blood pressure, heart rate and temperature) were broadly comparable across the three groups throughout the duration of the study.
Conclusions:
In summary, low dose CsA in combination with CellCept, steroids and Zenapax induction is clinically safe and effective through 36 months post-transplant, and is clinically similar to standard dose CsA in preventing early or late acute rejection.
Publications (references, if available):
Ekberg H et al. The use of daclizumab and mycophenolate mofetil in combination with corticosteroids and cyclosporine (low dose versus low dose followed by withdrawal) to optimize renal function in recipients of renal allografts. International Conference of the Transplantation Society (ICTS), Vienna, September 2004, Poster Presentation.
Ekberg H et al. Low-dose cyclosporine in conjunction with daclizumab, mycophenolate mofetil and corticosteroids is safe and effective in contrast to early cyclosporine withdrawal. International Congress of Immunology (ICI), San Diego, December 2004, Oral Session.
Vincenti F et al.
Cyclosporine sparing with MMF and steroids to optimize renal function in renal allograft recipients 18 Month Results.
American Transplant Congress (ATC), Seattle, May 2005, Oral session.
Grinyo J et al.
Cyclosporine sparing with the use of mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients – 18 month results – the CAESAR study.
European Society for Organ Transplantation (ESOT), Geneva, October 2005, Poster presentation.
Nashan B et al.
Cyclosporine sparing with the use of mycophenolate mofetil, daclizumab and corticosteroids in renal allograft recipients - the CAESAR study 36 month results.
World Transplant Congress (WTC), Boston, July 2006, Oral session.
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