SOCRATES: Steroid or Cyclosporine Removal After Transplantation Using Everolimus

Every randomized patient in this group received

Day 1 - Day 14: cyclosporine as Calcineurin Inhibitor (CNI) 5 mg/kg twice daily (b.i.d.), dose adjusted to achieve C2 target of 1,500 ng/mL (range 1,400-1,600 ng/mL) + mycophenolate sodium (MPA)720 mg b.i.d. + methylprednisone/prednisone 500 mg intra-operatively, 250 mg on day 1, then 10-30 mg/day prednisone

Day 15 - Day 60: everolimus 1.5 mg b.i.d. to achieve target 6-10 ng/mL + cyclosporine decrease dose as per protocol guideline + MPA 720 mg b.i.d. until everolimus trough >6 ng/mL, then MPA was stopped + prednisone 10-30mg/day

Day 61 - Day 120: everolimus dose adjusted to achieve target 6-10 ng/mL + cyclosporine 25% dose reduction per fortnight, to be discontinued by day 120 as per protocol (or commence reduction by day 120 at discretion of investigator, to be completed within 2 months of commencement) + prednisone 10-30mg/day Day 121 - Month 36: everolimus dose adjusted to achieve target 8-12 ng/mL + prednisone 5-10 mg/day

• Certican®

• Neoral®

• myfortic®

Every randomized patient in this group received

Day 1 -14: cyclosporine 5 mg/kg b.i.d., dose adjusted to achieve C2 target as per protocol + mycophenolate sodium (MPA) 720 mg b.i.d. + methylprednisone/prednisone 500 mg intra-operatively, 250 mg on day 1, then 10-30 mg prednisone per day

Day 15 - 60: everolimus 1.5 mg b.i.d. to achieve target 6-10 ng/mL + cyclosporine decrease dose as per protocol guideline + MPA 720 mg b.i.d. until everolimus trough >6 ng/mL, then MPA was stopped + prednisone 10-30mg per day

Day 61 - 120: Everolimus dose adjusted + cyclosporine adjust dose according protocol guideline (or commence reduction by day 120 at discretion of Investigator, to be completed within 2 months of commencement) + gradual withdrawal of prednisone by 1 mg/week to be discontinued by Day 120.

Day 121 - Month 36: At Day 121, Month 7 and Month 13 Everolimus dose was adjusted to achieve target 6-10 ng/mL + Cyclosporine adjust dose to achieve C2 target as per protocol

• Certican®

• Neoral®

• myfortic®

Patients randomized to this group received:

Day 1 - Month 36: cyclosporine 5 mg/kg b.i.d., dose adjusted to achieve the protocol defined C2 Targets + mycophenolate sodium 720mg b.i.d. + Methylprednisone/prednisone 500mg intra-operatively, 250mg on day 1, 10-30mg prednisone per day until month 12 (as per local practice), 5-10mg/day months 13-36.

• Neoral®

• myfortic®

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.

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.

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.

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.

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).

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).

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.

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.

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

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

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

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

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.

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.

The various employment status reported are:

• Employed/self employed full time
• Employed part time
• Unemployed
• Homemaker
• Volunteer
• Permanently disabled
• Non-permanently disable
• Retired
• Other

The various employment status reported are:

• Employed/self employed full time
• Employed part time
• Unemployed
• Homemaker
• Volunteer
• Permanently disabled
• Non-permanently disable
• Retired
• Other

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

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