Clinical Trial Result Information

Protocol number
M55021

Title of Study
An open, pilot, parallel group, randomized clinical trial to evaluate pharmacokinetic variability of mycophenolate mofetil in association with cyclosporine and corticosteriods administered for 9 months following a dose controlled or a concentration controlled 3 months regimen in primary orthotopic heart transplant recipients.

Sponsor
F. Hoffmann-La Roche Ltd

Company division
Pharmaceutical

Product name
CellCept

Generic name
mycophenolate mofetil

Therapeutic area
Heart Transplantation

Clinical study summary
This was a prospective, randomized, open-label, multicenter pharmacokinetic study of CellCept (mycophenolate mofetil) administered either as a fixed dose or a controlled concentration, in primary heart transplant recipients.

Study center(s)
4 centers in Italy.

Phase of development
II

Objectives
Primary: To evaluate the rate of patients reaching a MPA AUC_0-12 of 40μg*h/mL +/- 10μg*h/mL in the fixed CellCept (mycophenolate mofetil) dose group; to evaluate the dose range needed to achieve an MPA AUC_0-12 of 40μg*h/mL in the concentration controlled group; to correlate the pharmacokinetics of mycophenolate mofetil in terms of MPA AUC_0-12 with the incidence of acute and chronic rejection in both patient groups.
Secondary: To evaluate the optimum sampling timing to reliably predict MPA AUC_0-12; to evaluate the safety of CellCept in both groups, in terms of incidence of infection, adverse events and malignancies.

Methodology
Patients were randomized (post operatively within 72 hours of skin closure) either to a fixed dose group, Group A (to be treated with CellCept 3g/day), or a concentration controlled group, Group B (to be treated with a CellCept dosage adequate to achieve and maintain an AUC_0-12 of 40μg*h/mL). Oral administration of CellCept was started within the fifth day after transplantation; the drug was given twice daily at least one hour before or more than 3 hours after meals. AUC_0-12 was determined at week 1, 2, 4, 8 and 12, with patients in the concentration-controlled group having the dose increased in case of MPA AUC_0-12 <30μg*h/mL or decreased in case of MPA AUC_0-12 >50μg*h/mL. Graft assessment with check for rejection episodes and endomyocardial biopsy were performed at intervals up to week 36 and at the end of treatment, with laboratory tests repeated and adverse events, including opportunistic infection, checked. Within week 8 and at the end of treatment coronary angiography was carried out. If required, CsA trough levels and dose adjustment as well as steroid dose adjustment were to be implemented.

Number of patients (planned/analyzed)
50 patients planned, 54 patients recruited.

Diagnosis and main criteria for inclusion
Patients aged 18-65 undergoing orthotopic heart transplantation who had not experienced previous or multiple organ transplant.

Test product, dose and mode of administration or test procedure
CellCept (mycophenolate mofetil) was administered p.o. at a dose of 1.5g b.i.d. ≥1 hour before or >3 hours after meals. Following AUC_0-12 determination at week 1, 2, 4, 8 and 12, patients in the concentration-controlled group were to have the dose increased in case of MPA AUC_0-12 <30μg*h/mL or decreased in case of MPA AUC_0-12 >50μg*h/mL. The study duration in each patient was 1 year, with CellCept dosage reached by month 3 to be administered up to study end. Apart from above, no CellCept dose increase was to be applied, while a decrease of 500mg/day was to be considered in case of suspected drug toxicity.

Duration of treatment
1 year

Reference therapy, dose and mode of administration or reference procedure
N/A.

Criteria for evaluation (efficacy, safety)
Efficacy: Primary efficacy parameters included acute rejection within week 12 and over the study period (identified on the basis of myocardial biopsy grading and need for treatment) and chronic rejection (identified from coronary angiography at end of treatment vs. baseline).
Pharmacokinetics: MPA AUC_0-12 values at intervals up to week 12, with patients classified according to a target value of MPA AUC_0-12 of 40μg*h/mL +/- 10μg*h/mL.
Safety: AEs, laboratory assessments; chest X-ray.

Statistical methods
Primary efficacy variables were analysed in the ITT and PP populations.
Secondary efficacy values were analysed in the ITT population.
No statistical hypothesis testing was planned; data analysis was of an exploratory nature, with descriptive summary statistics used to describe the primary and secondary efficacy parameters. As for primary efficacy parameters, frequency of patients reaching a MPA AUC_0-12 of 40μg*h/mL +/- 10μg*h/mL and relationship between MPA AUC_0-12 and the incidence of acute rejection were analysed. For both acute and chronic rejection, frequency over the study period by treatment group was calculated. Safety analyses included total frequency of AEs, SAEs , acute reaction-related and study medication-related AEs. Relationship between MPA-AUC_0-12 and the incidence of AEs up to week 12 was also analysed.

Summary (efficacy, safety, other results)
Efficacy: Group A and B received similar CellCept daily doses up to week 4, while at week 8-12 between-treatment differences became more evident, with a CellCept median daily dose of 3g in group A and of 2.5 - 2g in group B. However, mean CellCept daily dose up to week 12 was only slightly lower in group B (2.74g, SD 0.44) than in group A (2.91g, SD 0.18). Over the whole study period, treatment length was almost identical in the two groups (median values of 366 and 365 days in group A and B, respectively), while cumulative doses were lower in the concentration controlled group than in the fixed dose group.
In the ITT population, acute rejection episodes with cardiac biopsy grading ≥1B occurred at least once during the study period in 44.0% vs. 65.5% of patients in group A and B respectively, with non significant between-treatment differences (p=0.15, χ² test), and with 28.0% vs. 27.6% of patients with at least one acute rejection requiring therapy in the two groups (p=0.32, χ² test). From the Kaplan-Meier analysis, mean acute reaction probability time was somewhat smaller in group A (161.9 days, SE 22.4) than in group B (210.8 days, SE 30.8), with non significant differences in the log-rang test (p=0.41). In both groups most acute reactions occurred within the initial 12 weeks of treatment, with 36.0% and 48.3% of patients in group A and group B, respectively, showing the above signs at cardiac biopsy (p=0.43, χ² test).
Among the 53 patients with both assessments, the three MPA AUC_0-12 classes were unequally represented, with most patients (71.7%) clustering in the target class, with only 1.9% and 26.4% of patients being included in the below and above target class, respectively. At least one acute rejection within week 12 was seen in 35.8% of cases, mostly (26.4%) associated with MPA AUC_0-12 values within target, with remaining cases observed with MPA AUC_0-12 values above target (9.4%). Absence of acute reaction also clustered (45.3%) in the MPA AUC_0-12 target class, with remaining cases somewhat more frequent at MPA AUC_0-12 values above target (17.0%) than below target (1.9%). No significant association between occurrence of acute reaction and MPA AUC_0-12 class emerged (p=0.27, χ² test).
AEs occurred by week 12 in 96.2% of the 53 patients with both evaluations, 69.8% with MPA AUC_0-12 values within target range, 24.5% with values above target range and 1.9% with values below target range. Drug related AEs occurred in 11.5% of patients, with 4.8% of the cases concomitant with MPA AUC_0-12 target values, 2.4% with below target, and 4.4% with above target values. Absence of drug related AEs also clustered in patients with average MPA AUC_0-12 within target (50.2%), remaining cases being somewhat more frequent at MPA AUC_0-12 values above target (23.9%) that below target (14.3%). Differences in the frequency distribution were not statistically significant (p=0.29, χ² test). On the whole, therefore, the observed data do not provide any indication of a relationship between emergence of AEs and MPA AUC_0-12 class.
On the basis of the per protocol definition chronic rejection was detected at end of treatment in one patient per group.

Pharmacokinetic: MPA AUC_0-12 average values showed a limited and similar increase in the two groups at weekly evaluations, with week 12 values only negligibly lower in group B than in group A, and with week 1-12 average values within target range in both groups. PK end-point analysis showed a 66.7% target rate in group A vs. 75.9% in group B, with non-significant between-group differences (p=0.46, χ² test). Non-target patients mostly showed MPA AUC_0-12 average values above the target range in both group A (33.3%) and group B (20.7%), with MPA AUC_0-12 average values below the target range seen in only one group B patient.
In both groups most patients were within the MPA AUC_0-12 target values up to week 8, while at week 12 this was the case in group B (60.7% of the 28 assessed cases), but not in group A (40.9% of the 22 assessed cases), with MPA AUC_0-12 values above target being prevalent in the latter group (50.0%).

Safety: Three patients died during the study period, one due to cardiogenic shock and one to septic shock after intestinal occlusion (group A, both events being judged unrelated to study medication), and one due to kidney cancer (group B, judged possibly related to study medication). In addition, AEs caused treatment discontinuation in one group A patient due to gingival hypertrophy, and three group B patients, two due to leukocytopenia and one due to arm/leg pain, accompanied by chest pain of suspected viral etiology. During the whole study period a total of 51 SAEs were reported in 21 patients, mostly including events related to infective disorders (18 events in 12 patients, with CMV infections in 9 cases), to cardiovascular or to metabolic disorders (9 events in 6 patients for each category), or to hemopoietic disorders (4 events in 3 patients). Clinical AEs occurred in 88.0% of group A and 79.3% of group B patients, being judged drug related in 56.0% of group A and 55.2% of group B patients. Laboratory AEs occurred in 96.0% of group A and 96.6% of group B patients, being judged drug related in 60.0% and 72.4% of group A and B patients, respectively.
Most frequent AEs related to laboratory abnormalities (>10% of patients in at least one group) included hemoglobin decrease, occurring in 64.0% and 72.4% of group A and B patients, increased triglycerides (20.0% and 58.6%), increased bilirubin (48.0% and 34.5%), increased serum creatinine (28.0% and 48.3%), decreased leucocytes (32.0% and 34.5%), ALT increase (28.0% and 20.7%), AST increase (32.0% and 10.3%), increased cholesterol (12.0% and 24.1%), hyperglycemia (24.0% and 17.2%), BUN and γGT increase (16.0% and 17.2%), uric acid increase (12.0% and 13.8%), increased CPK (12% and 10.3%), and lymphopenia (8.0% and 10.3%). Most frequent clinical AEs included CMV infection and hypertension (12.0% and 20.7% of group A and B patients), and oedema (8.0% and 10.3%).
No clinically relevant changes in laboratory parameters were apparent, apart from a marked decrease vs. baseline in hematological parameters immediately after surgery, with slow recovery to baseline values thereafter. Among blood chemistry parameters, only total bilirubin showed a slight average increase in the immediate post-surgery period with recovery to baseline average values thereafter. Laboratory abnormalities with maximum WHO grade 3 or 4 were reported in a limited number of cases, most frequently including hemoglobin decrease, bilirubin increase and hyperglycemia (5 cases each), as well as lymphocytopenia and leucopenia (3 cases each), with all other events recorded in ≤2 patients.

Conclusions
In conclusion, the results of the study do not provide indication of PK/PD differences of relevance between the fixed dosing and the concentration controlled dosing, in terms of short term CellCept dosing, efficacy and safety. The two approaches showed similar long term efficacy and safety. Both regimens proved feasible in terms of tolerability and safety, in association with CsA and corticosteroids.

Date of report
4/2/2007

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