A 24-month, multi-national, open-label, randomized (1:1:1) trial was conducted comparing two concentration-controlled everolimus regimens of 1.5 mg per day starting dose (targeting 3 to 8 ng/mL using an LC/MS/MS assay method) and 3 mg per day starting dose (targeting 6 to 12 ng/mL using an LC/MS/MS assay method) with reduced exposure cyclosporine and corticosteroids, to 1.44 g per day of mycophenolic acid with standard exposure cyclosporine and corticosteroids. The mean cyclosporine starting dose was 5.2, 5 and 5.7 mg/kg body weight/day in the everolimus 1.5 mg, 3 mg and in mycophenolic acid groups, respectively. The cyclosporine dose in the everolimus group was then adjusted to the blood trough concentration ranges indicated in Table 5, whereas in the mycophenolic acid group the target ranges were 200 to 300 ng/mL starting Day 5: 200 to 300 ng/mL, and 100 to 250 ng/mL from Month 2 to Month 12.

All patients received basiliximab induction therapy. The study population consisted of 18 to 70 year old male and female low-to-moderate risk renal transplant recipients undergoing their first transplant. Low to moderate immunologic risk was defined in the study as an ABO blood type compatible first organ or tissue transplant recipient with anti-human leukocyte antigen (HLA) Class I panel reactive antibody (PRA) less than 20% by a complement dependent cytotoxicity-based assay, or less than 50% by a flow cytometry or ELISA-based assay, and with a negative T-cell cross match. Eight hundred thirty-three (833) patients were randomized after transplantation; 277 randomized to the everolimus 1.5 mg per day group, 279 to the everolimus 3 mg per day group and 277 to the mycophenolic acid 1.44 g per day group. The study was conducted at 79 renal transplant centers across Europe, South Africa, North and South America, and Asia-Pacific. There were no major baseline differences between treatment groups with regard to recipient or donor disease characteristics. The majority of transplant recipients in all groups (70% to 76%) had three or more HLA mismatches; mean percentage of panel reactive antibodies ranged from 1% to 2%. The rate of premature treatment discontinuation at 12 months was 30% and 22% in the everolimus 1.5 mg and control groups, respectively, (p=0.03, Fisher's exact test) and was more prominent between groups among female patients. Results at 12 months indicated that everolimus 1.5 mg per day is comparable to control with respect to efficacy failure, defined as treated biopsy-proven acute rejection1, graft loss, death, or loss to follow-up. The percentage of patients experiencing this endpoint and each individual variable in the everolimus and control groups is shown in Table 7.

The estimated mean glomerular filtration rate (using the MDRD equation) for everolimus 1.5 mg (target trough concentrations 3 to 8 ng/mL) and mycophenolic acid groups were comparable at Month 12 in the ITT population (Table 8).

Two earlier studies compared fixed doses of everolimus 1.5 mg per day and 3 mg per day, without TDM, combined with standard exposure cyclosporine and corticosteroids to mycophenolate mofetil 2 g per day and corticosteroids. Antilymphocyte antibody induction was prohibited in both studies. Both were multicenter, double-blind (for first 12 months), randomized trials (1:1:1) of 588 and 583 de novo renal transplant patients, respectively. The 12-month analysis of GFR showed increased rates of renal impairment in both the everolimus groups compared to the mycophenolate mofetil group in both studies. Therefore, reduced exposure cyclosporine should be used in combination with everolimus in order to avoid renal dysfunction and everolimus trough concentrations should be adjusted using TDM to maintain trough concentrations between 3 to 8 ng/mL [see Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.6)].

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1
    Treated biopsy-proven acute rejection (tBPAR) was defined as a histologically confirmed acute rejection with a biopsy graded as IA, IB, IIA, IIB, or III according to 1997 Banff criteria that were treated with anti-rejection medication.