Clinical Trial Result Information

Title of Study:
A prospective, open label, randomized, multicenter, multinational study evaluating the overall efficacy and safety including the effect on renal function of sirolimus (Rapamune®) replacing CNI in a standard care regimen of CNI, mycophenolate mofetil (MMF) and steroids in heart transplant patients.

Fast Facts:

Protocol number:	MT18328
Sponsor:	Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	CellCept
Generic name:	mycophenolate mofetil
Phase of development:	IV
Therapeutic area, approved indication:	Heart Transplantation
Date of report:	8/1/2006

Clinical study summary:
This was a prospective, open label, randomized, multicenter, multinational, two parallel arm study. The study was prematurely terminated in response to a higher than expected early incidence of grade IIIA acute rejection in patients who were randomized to sirolimus (Arm A).

Study center(s) :
15 sites in Australia, the Czech Republic, France, Germany, Spain, and the USA.

Objectives:
The primary objective was to evaluate efficacy and safety, including the effect on renal function, of sirolimus (Rapamune®) replacing calcineurin inhibitor (CNI) after 3 months in a standard care regimen of CNI, CellCept (MMF) and steroids (Arm A) compared with a standard care regimen of CNI, CellCept and steroids (Arm B) in heart transplant patients.

Methodology:
At study entry, 4-6 weeks after transplantation, patients were entered into the study and continued on a standard care regimen of CNI, CellCept and steroids. At 12 weeks after transplantation, patients were randomized into either Arm A (sirolimus) or Arm B (continuation of CNI), both in combination with CellCept and steroids.
For patients randomized to Arm A, CNI was discontinued on the day of randomization and sirolimus introduced 12-24 hours after the last CNI dose, with a single loading dose of 6 mg. This was followed by 2-3 mg/day administered in a single daily dose adjusted to maintain whole blood trough concentrations of 5-10 ng/mL. CellCept was administered at 1.5 g twice daily and mycophenolic acid (MPA) levels were monitored after conversion from CNI to sirolimus until a minimum trough level of 2.0 µg/mL was obtained.
For patients randomized to Arm B, CNI was administered following center practice, and CellCept was given at 1.5 g twice daily. In both arms, corticosteroids were given following center practice with a minimum dose of 5 mg/day for 1 year.

Number of patients (planned/analyzed):
35 enrolled, 15 randomized.

Diagnosis and main criteria for inclusion:
Patients aged ≥18 years who had received their first heart transplant (single organ transplant), and were on a standard care regimen of CNI, CellCept and steroids since transplantation.

Test product, dose and mode of administration or test procedure:
Sirolimus (Rapamune®) 6 mg single loading dose followed by 2-3 mg/day adjusted to maintain whole blood trough concentrations of 5-10 ng/mL, plus CNI, CellCept and corticosteroids (see below for dosages).

Duration of treatment:
2 years + (planned)

Reference therapy, dose and mode of administration or reference procedure:
CNI – administered following standard center practice; CellCept – 1.5 g twice daily; Corticosteroids – administered following standard center practice with a minimum dose of 5 mg/day for the first year.

Criteria for evaluation (efficacy, safety):
Efficacy: The intended primary endpoints were: Renal function (% change from randomization assessed by calculated glomerular filtration rate (GFR) at 24 months post transplantation (PT) (21 months post-randomization) and a composite endpoint of incidence of biopsy proven acute rejection (BPAR) or hemodynamic compromise (HDC), or graft loss (re-transplantation or death) or lost to follow-up in the interval between randomization and 12 months PT (9 months post-randomization).
Due to the early termination of this study, only the following variables were assessed: The number and percentage of patients with BPAR ≥ISHLT grade III, HDC, graft loss (re-transplantation or death) or loss to follow-up at study cessation, overall and by baseline CNI type.
The number and percentage of patients with: BPAR from study entry to randomization and from randomization to study cessation; HDC treated with pulse immunosuppression from study entry to randomization and from randomization to study cessation. The number and percentage of deaths until study cessation. Average daily dose of corticosteroids from transplant to study cessation. Steroids to treat rejection and maintenance steroids were summarized separately.
Safety: The following variables were assessed: Duration of exposure to study drugs; use of other immunosuppressant treatments; incidence of adverse events, including serious adverse events; incidence of opportunistic infections (OIs); laboratory variables.

Statistical methods:
As the study was prematurely terminated, no statistical testing of hypotheses of treatment differences were performed.
Data were summarized using descriptive statistics for continuous variables and counts, percentages, and confidence intervals (CIs) for categorical variables. These summaries were derived for patients in the following groups: enrolled but not randomized; randomized group sirolimus (Arm A); randomized group CNI (Arm B).

Summary (efficacy, safety, other results):
Efficacy: This report has focused on safety given the small number of patients who were randomized. However, the efficacy variables that were considered to be of clinical importance to these patients in the short time that they were in the study have been summarized.
Four patients (57.1%) in Arm A had BPAR, and one of these had HDC. There were no patients with graft loss and none was lost to follow-up after randomization (95% CI for the proportion of patients with an event: 0.18, 0.90). Of the patients who experienced rejection, three were receiving cyclosporine and one was receiving tacrolimus. The rejections occurred from 2-5 weeks following the switch from CNI to sirolimus. No patient in Arm B had any of these events after randomization (95% CI for the proportion of patients with an event: 0.00, 0.37).

Safety: More than half the patients in Arm A and Arm B (57.1% and 62.5%, respectively) received at least one other immunosuppressant therapy (IST) for transplant, ie, for induction or renal insufficiency. In Arm A, one patient received other ISTs for renal insufficiency and three patients received other ISTs for induction. In Arm B, one patient received other ISTs for renal insufficiency and four patients received other ISTs for induction.
The overall incidence of post-randomization adverse events was higher in Arm B (62.5%) compared with Arm A (42.9%). However, no particular adverse event occurred at sufficient frequency for meaningful interpretation. In Arm A, one patient had a serious adverse event of sepsis, which began 19 days after the last dose of sirolimus; the patient died during the follow-up period of the study. No other patients died before study cessation.
No post-randomization or serious OIs were reported during this study.
In general, there were no important differences in laboratory tests between the groups. However, the mean serum creatinine levels were consistently higher across all time points from baseline to the last assessment in Arm B compared with Arm A, with Arm B levels tending to increase from baseline and Arm A levels tending to decrease.
The mean urea levels were also consistently higher across all time points from baseline to the last assessment in Arm B compared with Arm A, with Arm B levels tending to increase from baseline and Arm A levels tending to decrease.
There were no clinically significant changes in vital signs or clinically significant abnormal echocardiograms during the study.

Conclusions:
The study was stopped because the incidence of acute early rejection in patients in Arm A was higher than expected. There were no rejections in Arm B. However, there are not enough data to allow a firm conclusion to be drawn regarding the unexpected difference in rejection rate between the two treatment arms.
No rejections ≥grade IIIA were observed in Arm B, in which the standard care regimen consisting of CNI, CellCept and steroids was given. Thus, in this patient population, no specific safety concern was noticed regarding the use of CellCept in patients receiving the standard care regimen.

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