Clinical Trial Result Information
Title of Study:
Multicentre, prospective, randomized, controlled, open-label trial evaluating the benefit on renal function of an introduction of CellCept combined with a half-dose of cyclosporine versus a group with usual doses of cyclosporine in renal transplant recipients with altered renal function.
Fast Facts:
| Protocol number: | M55018 |
| Sponsor: | Roche SAS |
| Company division: | Pharmaceutical |
| Product name: | CellCept |
| Generic name: | mycophenolate mofetil |
| Phase of development: | III |
| Therapeutic area, approved indication: | Kidney Transplantation |
| Date of report: | 5/1/2006 |
Clinical study summary:
Multicentre, randomized, controlled, open-label trial in two treatment arms. Patients satisfying the selection criteria and with no episode of acute rejection during the three months preceding inclusion in the trial were randomized to one of the following groups:
CellCept group: CellCept 2 g/day + half-dose cyclosporine alone or in combination with corticosteroids (according to the centre’s usual practice).
Cyclosporine group: cyclosporine (regardless of the dose, but with a plasma trough level before the dose not less than 100 ng/mL) + azathioprine (AZA), or cyclosporine + corticosteroids, or cyclosporine + AZA + corticosteroids (CellCept or Prograf were prohibited).
Study center(s) :
12 centres in France.
Objectives:
Primary objective: to evaluate the efficacy and safety of introduction of CellCept combined with half-dose cyclosporine on the course of renal function at the end of phase II of the study (96th week).
Secondary objectives: to describe and evaluate the following parameters at the end of phase II of the study:
1) Incidence of presumed or biopsy-proven acute graft rejection; 2) Incidence of treatment failure, defined by graft loss or patient's death, time to return to dialysis and drop-out for any cause; 3) Safety, and incidence of adverse events; 4) Cardiovascular risk factors: hypertension, lipids.
Methodology:
Phase I (8 weeks): Patients in the CellCept group received increasing daily doses (1 g, then 1.5 g, then 2 g) of CellCept over four weeks. The 2 g dose of CellCept was reached at the end of the 4th week. From the beginning of the 5th week, the dosage of cyclosporine was reduced by 25% every two weeks to reach half of the week 4 dose at the end of the 8th week, or was immediately reduced by 50%. Patients in the cyclosporine group continued the centre’s usual treatment regimen throughout this 8-week period.
Phase II (88 weeks): Phase II began the 9th week after randomization, when patients of the CellCept group were treated with half-dose cyclosporine and continued for 88 weeks in both groups.
This report describes the analysis of the primary endpoint and secondary endpoints performed at the end of phase II, at the 96th week.
Phase III (post-trial follow-up): a three-year post-trial follow-up was initiated to evaluate the benefit of long-term treatment on patient and graft survival. No trial treatment was defined during this follow-up period. Patients were able to continue the treatment attributed in the initial study, or immunosuppressive treatment could be modified at the investigator's discretion and/or according to the centre’s usual practice. Patients were therefore to be followed for a total of five years after introduction of CellCept.
Number of patients (planned/analyzed):
103 randomized. 101 in ITT population.
Diagnosis and main criteria for inclusion:
Male or female patients, aged 18 to 65 years, transplanted with a first or second cadaveric or living related donor kidney for at least 12 months and less than 10 years; patients with serum creatinine between 150 and 300 µmol/L; patients receiving cyclosporine-based immunosuppressive therapy for at least three months with a trough level greater than or equal to 100 ng/mL; patients who did not present any episode of acute rejection during the three months preceding inclusion in the trial.
Test product, dose and mode of administration or test procedure:
CellCept: mycophenolate mofetil, 500 mg tablets, administered orally before meals (CellCept group only). For the first week, CellCept was administered at the dose of 1 g/day: one tablet in the morning and one tablet in the evening. The dose was then increased to 1.5 g/day for the second week (one tablet in the morning, two tablets in the evening). In the third week, a total dose of 2 g/day was administered: two tablets in the morning and two tablets in the evening. The cyclosporine dose reduction phase was started when CellCept at the dose of 2 g/day was well tolerated at the end of the 4th week.
Duration of treatment:
The duration of the initial study, was 96 weeks (two years) per patient.
Reference therapy, dose and mode of administration or reference procedure:
Patients in the control group (cyclosporine group) continued to take cyclosporine according to the standard treatment modalities in each centre, at an adapted dose, provided that trough levels were greater than or equal to 100 ng/ml. These patients were allowed to receive any immunosuppressive other than CellCept or Prograf.
Criteria for evaluation (efficacy, safety):
Primary endpoint: course of renal function at the end of phase II of the trial (between the 9th and 96th weeks), evaluated by the slope of the curve of the inverse of serum creatinine (1/SeCr) as a function of time, during phase II.
Secondary efficacy endpoints: Variation of other renal function parameters defined by glomerular filtration rate and calculated value of creatinine clearance; incidence of presumed or biopsy-proven acute rejection; loss of graft or patient's death; incidence and time to return to dialysis; comparison of the slopes of 1/SeCr as a function of time between the two groups before inclusion and at the end of the trial (end of phase II).
Statistical methods:
Statistical analysis was performed with two-tailed tests at a limit of 5% throughout the trial. The main efficacy analysis was performed on the ITT population, completed by analyses on secondary populations (PP, complete ITT and complete PP) for the main efficacy parameters. Analysis of safety was performed on the safety population.
Efficacy: The main efficacy analysis compared the slopes of regression of the inverse of serum creatinine during phase II between the two groups using a mixed effects model. Several variance-covariance matrices were tested and the best model was adopted. Other analyses of the primary endpoint were performed on the other defined populations.
The other efficacy analyses concerned other criteria evaluating renal function:
The inverse of serum creatinine; creatinine clearance and serum creatinine; glomerular filtration rate; the course of proteinuria.
Finally, other efficacy analyses concerned biopsy-proven Chronic Allograft Nephropathies (NCA), biopsy-proven chronic graft rejections especially ≥ grade II, biopsy-proven acute rejection, graft loss, return to dialysis and any deaths. Biopsies were not performed systematically, but only in case of suspicion of acute rejection or in case of suspected renal function degradation.
Safety: Safety parameters were analysed descriptively.
Summary (efficacy, safety, other results):
Efficacy: Primary Endpoint: At the inclusion visit, the mean inverse of serum creatinine was 0.0054 (± 0.0009) in the CellCept group and 0.0056 (± 0.0009) in the cyclosporine group.
During Phase II, values for this parameter increased in the CellCept group to a mean of 0.0060 (± 0.0011) at Visit 6, 0.0063 (± 0.0012) at Visit 10, and 0.0067 (± 0.0016) at the end of Phase II (Visit 13), while, in the cyclosporine group, this parameter remained stable and even tended to decrease during Phase II, with a mean of 0.0057 (± 0.0009) at Visit 6, 0.0054 (± 0.0014) at Visit 10, and 0.0057 (± 0.0014) at Visit 13.
The group x time interaction was significant at the limit of 5% (p=0.003); there was therefore a statistically significant difference between the slopes of the two regression lines during Phase II of the study, indicating that the difference between treatment groups varied over time: increasing slope in the CellCept group, and stable or even slightly decreasing slope in the cyclosporine group, indicating better renal function in the CellCept group than in the cyclosporine group.
The final model adjusted for the baseline inverse of serum creatinine gave similar results to the model without covariable.
Secondary Endpoints: These results were confirmed by the secondary analysis on the PP population and were also confirmed on analysis of the secondary endpoints (inverse of serum creatinine over 96 weeks/during the first six months/during the first year, creatinine clearance, serum creatinine).
At the end of phase II: Proteinuria greater than 0.3 g/24h was observed in 39% of patients in the CellCept group versus 62% of patients in the cyclosporine group. Chronic allograft nephropathies (NCA) were observed in all patients in whom biopsies were performed during the study, 6 patients (9%) in the CellCept group and 5 patients (16%) in the cyclosporine group (p=0.305). Chronic graft rejection was observed in 10 of the 11 patients in whom biopsies were performed during the study. Chronic graft rejection ≥ grade II was observed in 7 patients, 4 patients (6%) of the CellCept group and 3 patients (10%) of the cyclosporine group (p=0.673). One patient in the CellCept group had a suspected acute rejection not confirmed by biopsy. Graft loss was observed in one patient in the CellCept group after 678 days and also in one patient in the cyclosporine group after 518 days. These 2 patients returned to dialysis, as did a second patient in the cyclosporine group who returned to dialysis before study withdrawal but lost his graft after study withdrawal. No deaths were reported.
Safety: Adverse events: During the study, 465 adverse events (AE) were reported in 89 patients, with 342 AEs in 62 patients (89%) in the CellCept group and 123 AEs in 27 patients (82%) in the cyclosporine group.
During Phase I, 71% of patients in the CellCept group and 39% of patients in the cyclosporine group experienced at least one AE (p=0.002). The majority of AEs (70%) were mild.
In the CellCept group, the AEs most frequently observed were expected AEs, essentially gastrointestinal disorders (diarrhoea, dyspepsia, nausea) and anaemia. In the cyclosporine group, the AEs most frequently observed were also expected AEs, essentially disorders of metabolism and nutrition (gout).
Overall, 53% of patients in the CellCept group experienced at least one AE attributable to CellCept; among the 80 AEs attributable to CellCept, only five AEs led to permanent discontinuation of CellCept (including only two AEs classified as SAEs and exclusively attributable to CellCept: one case of diarrhoea and one case of dyspepsia). AEs attributable to cyclosporine were observed in 36% of patients in the CellCept group and 27% of patients in the cyclosporine group; none of the AEs attributable to cyclosporine led to permanent discontinuation of cyclosporine.
Only one patient in the cyclosporine group developed an opportunistic infection (Herpes zoster).
Finally, seven patients in the CellCept group experienced at least one serious adverse event (SAE) versus one patient in the cyclosporine group. SAEs in the CellCept group consisted of diarrhoea and dyspepsia attributable to CellCept and primary graft dysfunction attributable to cyclosporine, while the other four SAEs (gastroenteritis, bronchitis, renal impairment and gout) were not treatment-related. The SAE in the cyclosporine group consisted of chest pain not related to treatment.
During Phase II of the study, the majority of AEs were also mild: 66% of AEs in the CellCept group and 53% in the cyclosporine group .
The AEs most frequently observed during Phase II in the CellCept group were expected AEs, as during Phase I, and essentially consisted of infections (bronchitis, sinusitis, nasopharyngitis, gastroenteritis), gastrointestinal disorders (diarrhoea, abdominal pain) and anaemia. The AEs most frequently observed during Phase II in the cyclosporine group were also expected AEs, essentially infections (bronchitis), disorders of metabolism and nutrition (disorders of lipid metabolism) and general manifestations (peripheral oedema).
Overall, 53% of patients in the CellCept group experienced at least one AE attributable to CellCept; among the 104 AEs attributable to CellCept, only four AEs led to permanent discontinuation of CellCept. (Only one AE, granulocytopenia, was classified as a SAE and exclusively attributable to CellCept). AEs attributable to cyclosporine were observed in 47% of patients in the CellCept group and 49% of patients in the cyclosporine group; among the 114 AEs attributable to cyclosporine, only three AEs (classified as SAEs) led to permanent discontinuation of treatment with cyclosporine: two SAEs in the CellCept group (renal impairment exclusively attributable to cyclosporine, and elevation of serum creatinine not related to CellCept and corticosteroids), and one SAE in the cyclosporine group (renal impairment not related to both treatments of this group). Six patients in the CellCept group developed an opportunistic infection (Herpes virus infections).
Finally, 22 patients (31%) in the CellCept group experienced at least one SAE versus nine patients (27%) in the cyclosporine group. In the CellCept group, there were 11 SAEs in nine patients attributable to CellCept, including three SAEs exclusively attributable to CellCept (granulocytopenia, alteration of general state and anaemia) and eight SAEs attributable to the three treatments); 10 SAEs in nine patients were attributable to cyclosporine, including two SAEs exclusively attributable to cyclosporine (acute renal failure, renal impairment); 12 SAEs in 11 patients were attributable to corticosteroids.
In the cyclosporine group, there were six SAEs in five patients attributable to cyclosporine, including one SAE exclusively attributable to cyclosporine (elevated serum creatinine). The others were attributable to cyclosporine and corticosteroids. Six SAEs in five patients were attributable to corticosteroids. No death was reported during Phases I and II of the study.
These data confirm the good general safety profile of CellCept in renal transplant recipients.
Conclusions:
These results show that in renal transplant recipients with altered renal function, the introduction of CellCept combined with ½ dose of cyclosporine, resulted, after 2 years, in a significant improvement in renal function and was well tolerated, in comparison to cyclosporine administered at usual doses.
An additional 3-year follow-up is ongoing.
Click here for the protocol registry listing of this trial.
