The randomized population included 364 patients of which 303 patients (83.2%) completed the study protocol (Table
). There were more patients prematurely withdrawn from the high level FK778 group (42.5%) than from the mid level FK778 group (35.9%), with a comparable percentage of patients withdrawn from the low level FK778 and MMF groups (22.8% and 23.7%, respectively). The majority of patients (70) were withdrawn due to adverse events which were related to study drug dose (Table
Disposition of Kidney Transplant Recipients Patients receiving Tacrolimus combined with Three Different Doses of FK778 or with MMF
Patient baseline characteristics were well balanced across groups with the exception of a slightly lower proportion of male recipients and donors in the high level FK778 group (Table
). Male Caucasian patients predominated, mean age was 47, and all patients had a PRA
50% and were ABO compatible to their donors. Of the patients with a recorded viral status at baseline, more than half were CMV-positive and approximately 50% were EBV-positive. The most common underlying pathologies leading to chronic renal failure were glomerulonephritis, polycystic disease, uropathy, and nephrosclerosis.
Demographics and Transplantation Information
During the first weeks after transplantation, tacrolimus trough levels were similar across all 4 treatment groups (Figure ). Higher mean daily doses of tacrolimus were required in the high and mid level FK778 groups, particularly during the first 24
weeks, to maintain targeted tacrolimus trough levels (Figure ).
Figure 1 Mean Tacrolimus Trough Levels during the Study presented for Patients included in the Intent to Treat Population. With the exception of some variability during the first weeks after transplantation, where tacrolimus levels were highest in the MMF and (more ...)
Figure 2 Mean Total Daily Dose (mg/kg) of Tacrolimus taken by Patients included in the Intent to Treat Population. The mean tacrolimus dose differed across the treatment groups throughout the study being generally highest in the high level FK778 group and lowest (more ...)
Median FK778 trough levels were within the targeted ranges of 150–200
μg/mL (high level FK778), 100–150
μg/mL (mid level FK778) and 50–100
μg/mL (low level FK778) by days 3, 4, and 5 in all dose groups and maintained to week 4 as protocol-specified (Figure ). After week 4, daily doses of FK778 were reduced to attain protocol-defined target trough ranges which were maintained until month 12.
Figure 3 Mean FK778 Trough Levels during the Study in Patients included in the Intent to Treat Population. Initial target plasma FK778 trough levels were 150–200μg/mL (high level FK778), 100 –150μg/mL (mid level (more ...)
All patients in the MMF group received at least 1
g/day of MMF by day 1 and were receiving a mean (SD) daily dose of 1
g (0.12) at month 12.
The incidence of BPAR (local evaluation) at 24
weeks, the study primary endpoint, was significantly higher in the high level FK778 group than in the MMF group (P
0.010, Fisher’s exact test) (Table
). The difference in incidence between the high level FK778 and MMF group was 17.3% (95% CI, 4.7 to 29.9%). Differences between the mid and low level FK778 groups and the MMF group were 12.1% and 5.6%, respectively, and did not reach statistical significance. No linear dose–response relationship of FK778 treated groups was found (P
0.954; Cochran-Armitage trend test stratified by donor type).
Results from the Intent to Treat Population for Primary and Secondary Efficacy Variables
The incidence of BPAR (local evaluation) at 12
months was highest in the high and mid level FK778 groups (Table
). While the incidence of corticosteroid resistant BPAR was comparable for the FK778 treatment groups, it was lower in the MMF group. The difference in incidence was significantly greater in the high level FK778 group compared with the MMF group (P
0.007, Fisher’s exact test). More mild (Banff I) rejections were reported in the mid level FK778 group than in the other groups. One severe (Banff III) rejection was reported in the high level FK778 group.
Results of central biopsy evaluation of rejection showed lower incidences of acute rejection in all treatment groups in comparison to biopsy results of local evaluation (Table
Kaplan-Meier survival estimates for freedom from BPAR (local evaluation) at 12
months were lower for the high and mid level FK778 groups than for the low level and MMF groups but comparable between low level FK778 and MMF (Figure ).
Figure 4 Estimated Rate of Patients Free from Local Biopsy-proven Acute Rejection (Kaplan-Meier Method). Differences in the estimated rate of patients free from biopsy proven acute rejection at week 24 between the high level FK778 (62.3%) vs. MMF (82%) groups (more ...)
The incidence of treatment failure at 12
months was highest in the high and mid level FK778 groups but comparable between the low level and MMF groups (Table
). The primary contributor to treatment failure was BPAR in all groups. Kaplan-Meier estimated survival rates from treatment failure at 12
months were lowest in the high and mid level FK778 groups (Table
CADI scores did not indicate a protective effect of FK778 against chronic allograft nephropathy. Renal function, as measured by calculated creatinine clearance, was better in the MMF group compared to the high and mid level FK778 groups. The difference in median values between the low level FK778 and MMF groups was minimal.
One patient in the mid level FK778 group died during the study (death on day 4 due to cardiac arrest) and nine patients died after premature study withdrawal (six patients in the high and two in the low level FK778 groups and one patient in the MMF group). There were no statistically significant differences in patient and graft survival estimates across the treatment groups. Patient survival at 12
months (Kaplan Meier method) was lower for the high (88.4%) compared to the mid (99%) and low (98%) level FK778 groups and the MMF group (99%).
The incidence of adverse events and serious adverse events during the study was generally comparable across groups. At least one adverse event was reported in the majority of patients and a causally-related adverse event in approximately 75% of patients in each treatment group. Adverse events leading to withdrawal were highest in the high and mid level FK778 groups (Table
). Across all treatment groups, the most common adverse events leading to premature study withdrawal were leukopenia (1–3.4%) and graft dysfunction (0–4.3%).
The most frequently reported adverse event regardless of relationship to study medication was anemia (Table
). Adverse events associated with a significant difference across treatment groups were thrombocytopenia, chest pain, and hypoalbuminemia (P
0.05, Fisher’s exact test) (Table
). The incidence of leucopenia, diarrhea, constipation, insomnia and hyperlipidemia was lower in all FK778 groups compared to the MMF group.
Most Frequently Reported Adverse Events
The incidence of CMV infections was 4.6% in the high level FK778 group with a two-fold higher incidence in the low level FK778 and MMF groups (9.8% and 10.8%, respectively). The plasma CMV DNA load and the plasma and urine polyomavirus BK DNA load were comparable for all treatment groups with similar use of antiviral medication reported across groups (36–41.3%). A malignancy was diagnosed during the study in 5 patients: 3 patients in the high level FK778 group (adenocarcinoma [not further specified], bladder neoplasm, and malignant ascites), 1 patient in the mid level FK778 group (Kaposi’s sarcoma), and 1 patient in the MMF group (malignant neoplasm of the tongue [histology not specified]).
Mean total cholesterol and triglyceride levels were consistently lower in the FK778 groups compared with the MMF group. Overall, the use of lipid-lowering medications was lower in the FK778 groups (26– 28.3%) compared to the MMF group (40%).