Clinical Trial Result Information
Protocol number
PA16522
Title of Study
An Exploratory Study to Evaluate the Pharmacokinetics, Efficacy, Safety and Tolerability of Mycophenolate Mofetil (CellCept) in Liver Transplant Patients Receiving Standard or Reduced Levels of Tacrolimus (Prograf).
Sponsor
Roche Global Development
Company division
Pharmaceutical
Product name
CellCept
Generic name
mycophenolate mofetil
Therapeutic area
Liver transplantation
Clinical study summary
This was a randomized, parallel group, open label, multi center study.
Patients were randomized (1:1) to the following treatment groups:
Group A: CellCept (1g b.i.d.) + standard level of tacrolimus (10-15 ng/mL) + corticosteroids
Group B: CellCept (1g b.i.d.) + reduced level of tacrolimus (5-8 ng/mL) + corticosteroids
The duration of the study was 52 weeks.
Study center(s)
Total of 11 centers in Canada, France, Germany, Spain, Switzerland and UK.
Phase of development
II
Objectives
To characterize the pharmacokinetics of mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) in the presence of standard or reduced levels of tacrolimus over a 52 week period in de novo liver transplant recipients; to assess preliminary data on the efficacy, safety and tolerability of CellCept (mycophenolate mofetil (MMF)) in combination with tacrolimus over a 26 week and 52 week period in de novo liver transplant recipients.
Methodology
Patients were required to attend study visits at screening and post transplant days 1, 2, 4 10, 14 and at intervals up to week 52. CellCept 1g i.v. b.i.d. was administered via central or peripheral venous catheters as a 2 hour infusion for the first 4 to 10 days post transplant, and CellCept 1g orally b.i.d. was given after a minimum of 4 days of i.v. therapy. Blood samples for PK analysis were obtained following the last a.m. i.v. dose (on day 4 to 10 post transplantation), the first a.m. oral dose (on day 5 to 11 post transplantation), and up to week 52 post-transplantation. Rejection data, graft and patient survival and AEs were collected throughout the study.
Number of patients (planned/analyzed)
60 patients were randomized.
Diagnosis and main criteria for inclusion
Adult (aged ≥18 years), male or female single organ recipients of primary hepatic allografts, excluding patients with hepatocellular carcinoma who had at least one nodule >5 cm in diameter or more than 3 nodules >3 cm in diameter or vascular invasion or any signs of metastases.
Test product, dose and mode of administration or test procedure
CellCept (mycophenolate mofetil) [1g every 12 hours] was administered intravenously for 4-10 days post-transplantation and orally thereafter, up to 52 weeks post-transplant.
Tacrolimus (Prograf®) [Group A: 10 15 ng/mL, Group B: 5 8 ng/mL], the first dose was administered orally at least 6 hours but no more than 48 hours post transplant. The dose could be adjusted by the investigator from 26 weeks post transplantation as long as the trough was maintained above 2ng/mL.
Corticosteroids (commercial supply) were provided by each center. They were administered according to center practice but all patients were to remain on at least 0.1 mg/kg/day of prednisone equivalent for 26 weeks post transplantation.
Duration of treatment
52 weeks
Reference therapy, dose and mode of administration or reference procedure
N/A
Criteria for evaluation (efficacy, safety)
Efficacy: Primary Parameter: Proportion of biopsy proven acute rejections requiring treatment with pulse immunosuppression therapy or graft loss (defined as death or re transplantation) during the first 26 weeks post transplant.
Secondary Parameters: Proportion of biopsy proven acute rejections requiring treatment with pulse immunosuppression therapy or graft loss during the first 52 weeks post transplant; time to first biopsy proven acute rejections requiring treatment with pulse immunosuppression therapy or graft loss over 26 and 52 weeks; patient and graft survival at 26 and 52 weeks post transplant; renal function; treatment failure or graft loss by the end of week 26 post transplant, or a change in the target tacrolimus range.
Pharmacokinetics: Primary Parameter: AUC0-12 of mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG); AUClast, Cmax and Tmax were also calculated for MPA and MPAG.
Safety: Adverse events, deaths and serious adverse events (SAEs); laboratory parameters and vital signs; rejection data, graft and patient survival; concomitant medications and immunosuppressive therapies.
Statistical methods
All pharmacokinetic, efficacy and safety variables were summarized descriptively by treatment arm.
Summary (efficacy, safety, other results)
Efficacy: By week 26 post transplant, the incidence of biopsy proven acute rejection requiring treatment with pulse immunosuppression or graft loss was higher in Group B compared to Group A (17.2% Group A, 25.9% Group B) in the ITT population; the difference was largely due to more patients requiring treatment with graft loss in Group B (3.4% Group A, 7.4% Group B). There was 1 death in Group A and 2 in Group B. In the PP population, the incidence of biopsy proven acute rejection or graft loss was also higher in Group B compared to Group A and the difference between the two treatment groups was greater than in the ITT population (12.0% Group A, 30.0% Group B).
At week 52 post transplant, the incidence of biopsy proven acute rejection requiring treatment with pulse immunosuppression or graft loss remained higher in Group B compared to Group A (17.2% Group A, 26.9% Group B) in the ITT population and as at week 26, the difference was largely due to more patients requiring treatment with graft loss in Group B (3.4% Group A, 7.7% Group B). There were no additional patient deaths from week 26 to 52. In the PP population, the percentages of biopsy proven acute rejections and death remained the same as those at week 26.
In the ITT population, the majority of patients who experienced a biopsy proven acute rejection had their first rejection episode in the first 8 weeks post transplant in both treatment groups. In the PP population, all patients in Group A and 5 of the 6 in Group B who had a biopsy proven acute rejection had their first one by 4 weeks post transplant.
Patient and graft survival in the ITT population at weeks 26 and 52 was 96.6% in Group A at both time points, and 92.6% and 92.3% respectively in Group B). All patients had a surviving graft at weeks 26 and 52. In the PP population, all patients in Group A and 90.0% in Group B were alive with functioning graft at weeks 26 and 52.
In the ITT population, the median calculated creatinine clearance values showed Group B to have better renal function both at screening and throughout the study. In the PP population, the median calculated creatinine clearance values showed Group B to have better renal function at all visits except week 4.
Pharmacokinetics: Following administration of CellCept in combination with tacrolimus, MPA concentrations rose rapidly. Median time to peak was between 1.0 1.5 hours for Group A and 0.88 1.98 hours for Group B, and was similar between the two groups at each visit. There was no major difference between mean dose normalized Cmax of MPA upon switching from i.v. to oral CellCept. There was also no major difference between the two groups at any visit; however, both groups showed a trend towards an increase in Cmax of MPA over time.
Dose normalized AUC0-12 of MPA was only calculated for last i.v., first oral and week 26. No difference was noted upon changing from last i.v. to first oral. Dose normalized AUClast of MPA was similar upon switching from i.v. to oral CellCept and AUClast was similar between groups at all visits.
Median time to peak MPAG concentrations was similar in both groups ranging from between 2.0 to 4.0 hours. The mean dose normalized Cmax concentrations for MPAG were similar upon switching from i.v. to oral CellCept. There was no significant difference between the two groups at any visit; however as with MPA both groups showed a trend towards an increase in Cmax over time. Dose normalized AUC0-12 for MPAG was only calculated for last i.v., first oral and week 26. No difference was noted upon changing from last i.v. to first oral.Values of dose normalized AUClast for MPAG were similar upon switching from i.v. to oral CellCept, and AUClast was similar between groups at all visits.
No interaction was observed between tacrolimus and MPA exposure (trough level and AUClast). Different levels of tacrolimus had no major influence on MPA pharmacokinetics.
Safety: The overall intensity of AEs was broadly comparable between the two treatment groups, with the majority of AEs either mild or moderate in intensity, and unrelated to treatment. AEs occurring in more patients in Group A than Group B included vomiting (31.0% vs 10.3%), headache (31.0% vs 17.2%), upper abdominal pain (17.2% vs 0%), abdominal pain (24.1% vs 10.3%) and peripheral edema (20.7% vs 6.9%). Conversely, AEs occurring in more patients in Group B than Group A included cholangitis (13.8% vs 0%), fatigue (13.8% vs 0%), anemia (44.8% vs 34.5%), diabetes mellitus (20.7% vs 10.3%) and thrombocytopenia (20.7% vs 10.3%). AEs related to treatment were mostly gastrointestinal disorders (in particular diarrhea) and blood and lymphatic disorders (mainly anemia and leucopenia). A total of 44.8% of patients in each group had a related gastrointestinal disorder, and 37.9% a blood and lymphatic system disorder.The pattern of AEs up to 52 weeks post-transplantation was similar to that seen after 26 weeks.
A total of 12 patients in Group A and 10 patients in Group B had at least one opportunistic infection up to 26 weeks post transplant. There were 2 additional patients in Group A and 1 in Group B with opportunistic infections at 52 weeks. The most frequent opportunistic infection at 26 weeks was cytomegalovirus (CMV), the incidence of which was higher in Group B (17.2% Group A, 31.0% Group B), followed by herpes simplex and candida. The trend continued at 52 weeks post transplant.
There was 1 death in Group A (multi-organ failure) and 2 deaths in Group B (multi-organ failure, and septic shock) up to 26 weeks post transplant. No additional deaths occurred up to 52 weeks post-transplantation.
A higher number of SAEs were reported by patients in Group B than in Group A (23 vs 33 at 26 weeks, and 25 vs 38 at 52 weeks). However, the overall pattern of SAEs reported up to 26 weeks post transplant was comparable across the two treatment groups. The most common SAEs were infections and infestations (particularly cytomegaloviral infections) and hepatobiliary disorders (especially biliary tract disorders and cholangitis). At week 52, the overall pattern remained the same. Most SAEs reported in this study were unrelated to study treatment, but 4 SAEs in Group A and 2 in Group B up to 26 weeks post-transplant were considered related to CellCept. In Group A, there were single instances of diarrhea, dyspepsia, klebsiella bacteremia, and leukopenia. In Group B, there were single instances of gastrointestinal hemorrhage and Escherichia urinary tract infection. There was one additional SAE considered related to CellCept in each group up to 52 weeks post transplant (oesophagitis in Group A and dehydration in Group B).
A total of 4 patients in Group A and 6 patients in Group B experienced at least one serious opportunistic infection up to 26 weeks post transplant, comprising CMV, herpes zoster and pneumocystis carinii infection; no additional serious opportunistic infections occurred up to 52 weeks post-transplant.
One patient in Group A and 3 patients in Group B had AEs that led to withdrawal from study treatment up to 26 weeks post transplant. In Group A, 1 patient was withdrawn due to severe encephalopathy. In Group B, 2 patients were withdrawn due to severe CMV viremia and 1 patient was withdrawn due to a gastrointestinal hemorrhage of moderate intensity, which was possibly related to study drug. Up to 52 weeks post transplant, an additional 3 patients were withdrawn, 1 due to CMV viremia, 1 due to diarrhea and 1 due to neutropenia, the latter two conditions being considered possibly related to study drug.
Mean changes in laboratory parameters from baseline were generally similar between the two treatment groups. Patients in Group A had greater shifts from baseline (decreases) in the following parameters: neutrophils, eosinophils, creatinine, carbon dioxide and fasting glucose. Patients in Group B had greater shifts from baseline (decreases) in the following parameters: hemoglobin, hematocrit, RBC and lymphocytes. The most frequent marked laboratory abnormalities were low levels of lymphocytes, hemoglobin, RBC, platelets, total protein and hematocrit.
Conclusions
When CellCept was co-administered with tacrolimus and corticosteroids to hepatic transplant patients, the incidence of biopsy-proven acute rejection requiring treatment with pulse immunosuppression or graft loss was relatively low and patients had good long term graft survival. The incidence of biopsy-proven acute rejections requiring treatment with pulse immunosuppression or graft loss was greater in Group B who received the reduced level of tacrolimus (5-8 ng/mL). There was no correlation between the dose of tacrolimus and systemic exposure of MPA or MPAG confirming that there is no drug-drug interaction between tacrolimus and CellCept. The efficacy and safety profiles were generally similar to previously reported data.
Date of report
6/12/2006
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