SOCRATES: Steroid or Cyclosporine Removal After Transplantation Using Everolimus

The glomerular filtration rate (GFR) was calculated by the Nankivell formula: GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)\^ 2 + C where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients.

Time frame: At Month 12

Population: Modified intent-to-treat (mITT)-Add population: All ITT patients who had a calculated GFR value recorded at Month 12 post-randomization including those collected after discontinuation of study medication and retrospectively collected creatinine and urea data

The glomerular filtration rate (GFR) was calculated by the Nankivell formula: GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)\^ 2 + C where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients.

Time frame: At Month 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. Missing values were imputed by last observation carried forward (LOCF) using values beyond Month 6

Measurements of bone mineral density (BMD) by Dual Energy X-ray Absorptiometry (DEXA) were done at Week 2 and Month 24. Change in BMD between week 2 and Month 24 were done for neck of femur and lumbar spine.

Time frame: Week 2, Month 24

Population: Safety population extension (SAF-EX): All patients who entered the extension period, who were treated with at least one dose of study medication during the extension period and had at least one safety/tolerability assessment after entering the extension period. Patients with week 2 and month 24 assessment for this analysis were included.

Creatinine clearance were calculated according to the Cockcroft-Gault formula: CrCl (males) = (140-A) × BW/(72 × Cr) CrCl (females) = CrCl (males) × 0.85 where A is age \[years\], BW is body weight \[kg\], and Cr is the serum concentration of creatinine \[mg/dL\]. The Cockcroft-Gault formula estimates creatinine clearance based on serum creatinine level, body weight, and age.

Time frame: At Month 12, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. Patients with data on creatinine clearance were included in this analysis. Last observation carried forward (LOCF) imputation technique was used.

Creatinine clearance were calculated according to the Cockcroft-Gault formula: CrCl (males) = (140-A) × BW/(72 × Cr) CrCl (females) = CrCl (males) × 0.85 where A is age \[years\], BW is body weight \[kg\], and Cr is the serum concentration of creatinine \[mg/dL\]. The Cockcroft-Gault formula estimates creatinine clearance based on serum creatinine level, body weight, and age.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication. Patients with 12 month data on creatinine clearance were included in this analysis.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication. Patients with 12 month data on serum creatinine were included in this analysis.

Time frame: At Month 12, 18, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. Patients with data on creatinine serum creatinine were included in this analysis. Last observation carried forward (LOCF) imputation technique was used.

SF-36 measures impact of disease on overall quality of life (QoL). 36-item survey has 8 subscales. The 8 subscales are: Physical functioning (PF), Role-physical (RP), Bodily pain (BP), General health (GH), Vitality (VT), Social functioning (SF), Role-emotional (RE) and Mental health (MH). Score for eash sub-scale has been standardized with the use of norm-based methods based on assessment of the general U.S. population free of chronic conditions. Scores range from 1-100 with a mean=50 and a standard deviation=10. A higher score indicates less impact on QoL.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication. Only those patients who had completed the QoL assessment for Month 12 were included in this analysis.

SF-36 measures impact of disease on overall quality of life (QoL). 36-item survey has 8 subscales. The 8 subscales are : Physical functioning (PF), Role-physical (RP), Bodily pain (BP), General health (GH), Vitality (VT), Social functioning (SF), Role-emotional (RE) and Mental health (MH). Score for each sub-scale has been standardized with the use of norm-based methods based on assessment of the general U.S. population free of chronic conditions. Scores range from 1-100 with a mean=50 and a standard deviation=10. A higher score indicates less impact on QoL.

Time frame: At Month 24

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This also includes patients who were randomized but were not treated with study drug. Patients with completed SF-36 assessment were included in this analysis.

Proteinuria is measured by spot morning urine Albumin/Creatinine Ratio \[ACR\]. When the ACR is more than or equal to 30 mg/mmol then it is known as proteinuria.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication. Patients with 12 month data on Proteinuria were included in this analysis.

Proteinuria is measured by spot morning urine Albumin/Creatinine Ratio \[ACR\]. When the ACR is more than or equal to 30 mg/mmol then it is known as proteinuria.

Time frame: At Month 12, 18, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment in extension period. This also includes all patients who were randomized but were not treated with study medication. Patients with ACR data at particular time point were included for analysis.

This analysis is reporting number of participants hospitalized for reasons (such as acute rejection, infection, gastrointestinal (GI) events, cardiovascular event, metabolic disorder and Other) other than primary transplantation.

Time frame: Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

This analysis is reporting number of participants hospitalized for reasons (such as acute rejection, infection, gastrointestinal (GI) events, cardiovascular event, metabolic disorder and Other) other than primary transplantation.

Time frame: Month 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

Time frame: At Month 12, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This population includes also all patients who were randomized but were not treated with study medication.

Patients with any wound healing problem such as infection related to kidney surgery, dehiscence, lymphocele, hernia, seroma, hematoma, ureteral anastomotic complication and other were reported in this analysis.

Time frame: At Month 12, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period.

The influence of demographic characteristics and comorbidities on incidence of BPAR were analyzed in the following way: Demographic characteristics were age (\<55 years, ≥55 years), Expanded criteria Donor (ECD) organ (donor age \>60 years or donor non heart-beating and donor age \>50), gender, living vs. deceased donor, Body Mass Index (BMI) classes (underweight \<18.5, normal 18.5 - \<25.0, overweight 25.0 - \<30.0, obesity 30.0 and above), years on dialysis before transplantation (\<1, 1-5, \>5 years). Comorbidities were diabetes, hypertension, cardiovascular diseases/events, nephrosclerosis, glomerulonephritis/glomerular disease, polycystic disease, and Cytomegalovirus status.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

The influence of demographic characteristics and comorbidities on incidence of BPAR were analyzed in the following way: Demographic characteristics were age (\<55 years, ≥55 years), Expanded Criteria Donor \[ECD\] organ (donor age \>60 years or donor non heart-beating and donor age \>50), gender, living vs. deceased donor, Body Mass Index (BMI) classes (underweight \<18.5, normal 18.5 - \<25.0, overweight 25.0 - \<30.0, obesity 30.0 and above), years on dialysis before transplantation (\<1, 1-5, \>5 years). Comorbidities were diabetes, hypertension, cardiovascular diseases/events, nephrosclerosis, glomerulonephritis/glomerular disease, polycystic disease, and Cytomegalovirus status.

Time frame: At Month 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This population includes also all patients who were randomized but were not treated with study medication

A biopsy-proven acute rejection is defined as a biopsy graded IA, IB, IIA, IIB, or III as per Banff 97 classification.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

A biopsy-proven acute rejection is defined as a biopsy graded IA, IB, IIA, IIB, or III as per Banff 97 classification.

Time frame: At Month 12, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This population includes also all patients who were randomized but were not treated with study medication.

Composite endpoint of treatment failure includes biopsy-proven acute rejection (BPAR), graft loss, death and loss-to-follow-up. A BPAR is defined as a biopsy graded IA, IB, IIA, IIB, or III as per Banff 97 classification. The allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was the day of graft loss.

Time frame: Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

Composite endpoint of treatment failure includes biopsy-proven acute rejection (BPAR), graft loss, death and loss-to-follow-up. A BPAR is defined as a biopsy graded IA, IB, IIA, IIB, or III as per Banff 97 classification. The allograft was presumed to be lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was the day of graft loss.

Time frame: At Month 12, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This population includes also all patients who were randomized but were not treated with study medication.

The various employment status reported are: * Employed/self employed full time * Employed part time * Unemployed * Homemaker * Volunteer * Permanently disabled * Non-permanently disable * Retired * Other

Time frame: At screening (at day 0 +/- 7 days ), At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

The various employment status reported are: * Employed/self employed full time * Employed part time * Unemployed * Homemaker * Volunteer * Permanently disabled * Non-permanently disable * Retired * Other

Time frame: At screening (at day 0 +/- 7 days ), At Month 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This population includes also all patients who were randomized but were not treated with study medication.

Time frame: Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

Time frame: Month 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This also includes patients who were randomized but were not treated with study drug.

A per-protocol biopsy was performed at Baseline and Month 12 and read by an independent blinded pathologist in order to assess chronic allograft nephropathy. Chronic rejection is characterized by a slow progressive decline in renal function and is typically preceded by the histological picture of chronic allograft nephropathy. The presence of biopsy confirmed Grade I, II or III chronic allograft nephropathy by Banff 97 criteria was assessed on all optional biopsies obtained for clinical suspicion of chronic rejection. Data summarized by 3 categories. Yes - Patients with histological evidence of CAN ; No - Patients with histological evidence of CAN and Not Done - Central protocol defined kidney allograft biopsies were not done.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication. For this analysis, only patients with available data were included. The analysis included biopsies of Month 12 visit that were done beyond month 12 cut-off date.

Chronic rejection is characterized by a slow progressive decline in renal function and is typically preceded by the histological picture of chronic allograft nephropathy. The presence of biopsy confirmed Grade I, II or III chronic allograft nephropathy by Banff 97 criteria was assessed on all optional biopsies obtained for clinical suspicion of chronic rejection. Data summarized by 3 categories. Yes - Patients with histological evidence of CAN ; No - Patients with histological evidence of CAN and Not Done - Central protocol defined kidney allograft biopsies were not done.

Time frame: At Month 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. Patients with data available at month 36 were included in this analysis.

The symptoms of new onset diabetes mellitus after transplantation (NODAT) and impaired fasting glucose are defined as any of the following conditions: 1. Patients receiving glucose lowering treatment 2. 2 fasting plasma glucose (FPG) values \>= 126 mg/dL or 2 random plasma glucose (RPG) values \>= 200 mg/dL or FPG value \>= 126 mg/dL and 1 RPG value \>= 200 mg/dL 3. Diabetes reported as treatment emergent AE with end date \> Day 15

Time frame: At Month 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This also includes patients who were randomized but were not treated with study drug.

Notable abnormal total cholesterol is defined as : High: \>= 9.1 mmol/L , normal range is 0.00 - 5.17 mmol/L Notable abnormal triglycerides is defined as : High: \>= 8.5 mmol/L, normal range is 0.30 - 2.00 mmol/L

Time frame: Overall post baseline up to month 12

Population: Safety population (SAF): All patients in whom transplantation was performed and who were treated with at least one dose of study medication and had at least one safety/tolerability assessment after randomization. Patients with serum lipid assessment anytime post baseline up to 12 month were included in this analysis.

Notable abnormal total cholesterol is defined as : High: \>= 9.1 mmol/L , normal range is 0.00 - 5.17 mmol/L Notable abnormal triglycerides is defined as : High: \>= 8.5 mmol/L, normal range is 0.30 - 2.00 mmol/L

Time frame: Overall Post Baseline up to month 36

Population: Safety population extension (SAF-EX): All patients who entered the extension period, treated with at least one dose of study medication during the extension period and had at least one safety/tolerability assessment after entering the extension period. Patients with serum lipid assessment anytime post baseline up to 36 month were included .

Notable abnormal systolic blood pressure is defined as : * Either an increase of \>=30 that results in \>=180 or \>200 (mm/Hg) * OR a decrease of \>=30 that results in \<=90 or \<75 (mm/Hg)from baseline Notable abnormal diastolic blood pressure is defined as : * Either an increase of \>=20 that results in \>=105 or \>115 (mm/Hg) * OR a decrease of \>=20 that results in \<=50 or \<40 (mm/Hg) from baseline

Time frame: Baseline, Overall post-baseline up to 12 month

Population: Safety population (SAF): All patients in whom transplantation was performed and who were treated with at least one dose of study medication and had at least one safety/tolerability assessment after randomization. Patients with baseline and overall post baseline up to 12 month assessment for this analysis were included.

Notable abnormal systolic blood pressure is defined as : * Either an increase of \>=30 that results in \>=180 or \>200 (mm/Hg) * OR a decrease of \>=30 that results in \<=90 or \<75 (mm/Hg) from baseline Notable abnormal diastolic blood pressure is defined as : * Either an increase of \>=20 that results in \>=105 or \>115 (mm/Hg) * OR a decrease of \>=20 that results in \<=50 or \<40 (mm/Hg) from baseline

Time frame: Baseline, Overall post baseline up to Month 36

Population: Safety population extension (SAF-EX): All patients who entered the extension period, treated with at least one dose of study medication during the extension period and had at least one safety/tolerability assessment after entering the extension period. Patients with baseline and overall post baseline up to month 36 assessment were included.

The symptoms of post transplant diabetes mellitus (PTDM) and impaired fasting glucose are defined as any of the following conditions: 1. Patients receiving glucose lowering treatment 2. Fasting plasma glucose (FPG) \>= 126 mg/dL on 2 separate occasions 3. Hemoglobin subtype A1c (HbA1c) \> 6.5% 4. Diabetes reported as treatment emergent AE with end date \> Day 15

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication. Patients with 12 month data on PTDM were included in this analysis.

Based on Banff 97 criteria, sub clinical acute rejection can be: GRADE IA - Cases with significant interstitial infiltration (\>25% of parenchyma affected) and foci of moderate tubulitis (\>4 mononuclear cells/tubular cross section or group of 10 tubular cells). GRADE IB - Cases with significant interstitial infiltration (\>25% of parenchyma affected) and foci of moderate tubulitis (\>10 mononuclear cells/tubular cross section or group of 10 tubular cells). GRADE IIA - Cases with significant interstitial infiltration and mild to moderate intimal arteritis (v1). GRADE IIB - Cases with moderate to severe intimal arteritis comprising \>25% of the luminal area (v2). GRADE III - Cases with transmural arteritis or fibrinoid change and necrosis of medial smooth muscle cells (v3). Borderline category is used when no intimal arteritis is present, but there are foci of mild tubulitis (1 to 4 mononuclear cells/tubular cross section).

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication. For this analysis, only patients with available data were included. The analysis included biopsies of Month 12 visit that were done beyond month 12 cut-off date.

Based on Banff 97 criteria, sub clinical acute rejection can be: GRADE IA - Cases with significant interstitial infiltration (\>25% of parenchyma affected) and foci of moderate tubulitis (\>4 mononuclear cells/tubular cross section or group of 10 tubular cells). GRADE IB - Cases with significant interstitial infiltration (\>25% of parenchyma affected) and foci of moderate tubulitis (\>10 mononuclear cells/tubular cross section or group of 10 tubular cells). GRADE IIA - Cases with significant interstitial infiltration and mild to moderate intimal arteritis (v1). GRADE IIB - Cases with moderate to severe intimal arteritis comprising \>25% of the luminal area (v2). GRADE III - Cases with transmural arteritis or fibrinoid change and necrosis of medial smooth muscle cells (v3). Borderline' category is used when no intimal arteritis is present, but there are foci of mild tubulitis (1 to 4 mononuclear cells/tubular cross section).

Time frame: At Month 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period.

Patients with any wound healing problem such as infection related to kidney surgery, dehiscence, lymphocele, hernia, seroma, hematoma, ureteral anastomotic complication and other were reported in this analysis.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

Time frame: At Month 12

Population: Intent-to-treat (ITT) population: All patients who were randomized. This population also included all patients who were randomized but were not treated with study medication.

Time frame: At Month 12, 24 and 36

Population: Intent-to-treat population extension (ITT-EX): All patients who were randomized, entered the extension period, and had at least one efficacy assessment after entering the extension period. This population includes also all patients who were randomized but were not treated with study medication.