SOCRATES: Steroid or Cyclosporine Removal After Transplantation Using Everolimus

Study Overview
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Brief Summary
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The aim of this study is to assess the safety and efficacy of corticosteroid discontinuation versus cyclosporine micro emulsion discontinuation in recipients receiving reduced exposure cyclosporine micro emulsion and corticosteroids plus enteric-coated mycophenolate sodium (EC-MPS) initially, changed to everolimus at 2 weeks post-transplant. These two groups will be compared to a third control group, who will receive treatment consisting of cyclosporine micro emulsion, enteric-coated mycophenolate sodium (EC-MPS) and steroids.

Official Title
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A Prospective, Open-label, Controlled Multicenter Trial to Assess the Efficacy and Safety of an Induction Regimen of Cyclosporine Micro Emulsion, Enteric-coated Mycophenolate Sodium (EC-MPS) and Corticosteroids, Followed by Administration of Everolimus and Enteric-coated Mycophenolate Sodium (EC-MPS), With Either the Withdrawal of Cyclosporine Micro Emulsion or Corticosteroids in de Novo Kidney Transplant Recipients

Conditions
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Renal Transplanted Recipients

Intervention / Treatment
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* Drug: Everolimus (RAD001)
* Drug: Cyclosporine (Calcineurin Inhibitor (CNI))
* Drug: Methylprednisone/prednisone
* Drug: Mycophenolate sodium (MPA)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Males and females aged 18-65 years inclusive. First time recipients of cadaveric, living unrelated or living related donor kidney transplants. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained. Exclusion criteria Patients who are recipients of multiple organ transplants, including more than one kidney, kidney and pancreas, or previous transplant with any organ other than kidney. Patients at high immunological risk of graft loss, indicated by peak PRA >50% or loss of a previous renal allograft within the first 6 months of transplantation due to acute rejection. Patients who have received an investigational drug within 4 weeks prior to the screening visit. Presence of any severe allergy or hypersensitivity to drugs similar to everolimus (e.g. antibiotics such as Clindamycin) Other protocol-defined inclusion/exclusion criteria may applied

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Calcineurin Inhibitor (CNI) Withdrawal<br>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 | Drug: Everolimus (RAD001)<br> <br> * Other names: Certican®;Drug: Cyclosporine (Calcineurin Inhibitor (CNI))<br> <br> * Other names: Neoral®;Drug: Methylprednisone/prednisone<br> <br> Drug: Mycophenolate sodium (MPA)<br> <br> * Other names: myfortic®;|
| Experimental: Steroid Withdrawal<br>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 | Drug: Everolimus (RAD001)<br> <br> * Other names: Certican®;Drug: Cyclosporine (Calcineurin Inhibitor (CNI))<br> <br> * Other names: Neoral®;Drug: Methylprednisone/prednisone<br> <br> Drug: Mycophenolate sodium (MPA)<br> <br> * Other names: myfortic®;|
| Active Comparator: CNI+MPA+ Steroid<br>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. | Drug: Cyclosporine (Calcineurin Inhibitor (CNI))<br> <br> * Other names: Neoral®;Drug: Methylprednisone/prednisone<br> <br> Drug: Mycophenolate sodium (MPA)<br> <br> * Other names: myfortic®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculated Glomerular Filtration Rate (cGFR) After Kidney Transplant to Evaluate Kidney Function (12 Months Analysis) | 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. | At Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Calculated Glomerular Filtration Rate (cGFR) After Kidney Transplant to Evaluate Kidney Function (36 Months Analysis) | 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. | At Month 24 and 36 | 
| Number of Participants With Biopsy Proven Acute Rejection (BPAR) Per Treatment Group (12 Months Analysis) | A biopsy-proven acute rejection is defined as a biopsy graded IA, IB, IIA, IIB, or III as per Banff 97 classification. | At Month 12 | 
| Number of Participants With Biopsy Proven Acute Rejection (BPAR) Per Treatment Group (36 Months Analysis) | A biopsy-proven acute rejection is defined as a biopsy graded IA, IB, IIA, IIB, or III as per Banff 97 classification. | At Month 12, 24 and 36 | 
| Number of Participants With Composite Endpoint of Treatment Failure (12 Months Analysis) | 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. | Month 12 | 
| Number of Participants With Composite Endpoint of Treatment Failure (36 Months Analysis) | 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. | At Month 12, 24 and 36 | 
| Number of Participants With Histological Evidence Chronic Allograft Nephropathy (CAN) (12 Months Analysis) | 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. | At Month 12 | 
| Number of Participants With Histological Evidence Chronic Allograft Nephropathy (CAN) (36 Months Analysis) | 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. | At Month 36 | 
| Number of Participants With Sub Clinical Acute Rejection (12 Months 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). | At Month 12 | 
| Number of Participants With Sub Clinical Acute Rejection (36 Months 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). | At Month 36 | 
| Mean Serum Creatinine (12 Months Analysis) |  | At Month 12 | 
| Mean Serum Creatinine (36 Months Analysis) |  | At Month 12, 18, 24 and 36 | 
| Creatinine Clearance (CrCl) Calculated by the Cockcroft-Gault Formula (12 Months Analysis) | 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. | At Month 12 | 
| Creatinine Clearance Calculated by the Cockcroft-Gault Formula (36 Months Analysis) | 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. | At Month 12, 24 and 36 | 
| Mean Urine Albumin/Creatinine Ratio (ACR) as Measurement of Proteinuria (12 Months 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. | At Month 12 | 
| Mean Urine Albumin/Creatinine Ratio [ACR] as Measurement of Proteinuria (36 Months 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. | At Month 12, 18, 24 and 36 | 
| Number of Participants With Post Transplant Diabetes Mellitus (PTDM) and Impaired Fasting Glucose (12 Months Analysis) | The symptoms of post transplant diabetes mellitus (PTDM) and impaired fasting glucose are defined as any of the following conditions: Patients receiving glucose lowering treatment Fasting plasma glucose (FPG) >= 126 mg/dL on 2 separate occasions Hemoglobin subtype A1c (HbA1c) > 6.5% Diabetes reported as treatment emergent AE with end date > Day 15 | At Month 12 | 
| Number of Participants With New Onset Diabetes Mellitus After Transplantation (NODAT) and Impaired Fasting Glucose (36 Months Analysis) | The symptoms of new onset diabetes mellitus after transplantation (NODAT) and impaired fasting glucose are defined as any of the following conditions: Patients receiving glucose lowering treatment 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 Diabetes reported as treatment emergent AE with end date > Day 15 | At Month 36 | 
| Number of Participants With Notable Abnormal Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) as Measurement of Effect of Treatment on Cardiovascular Health (12 Months Analysis) | 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 | Baseline, Overall post-baseline up to 12 month | 
| Number of Participants With Notable Abnormal Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) as Measurement of Effect of Treatment on Cardiovascular Health (36 Months Analysis) | 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 | Baseline, Overall post baseline up to Month 36 | 
| Number of Participants With Erythropoietin Usage (12 Months Analysis) |  | Month 12 | 
| Number of Participants With Erythropoietin Usage (36 Months Analysis) |  | Month 36 | 
| Mean Short-form 36 Health Survey (SF-36) Score as a Measure of Quality of Life Assessment (12 Months 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 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. | At Month 12 | 
| Mean Short-form 36 Health Survey (SF-36) Score as a Measure of Quality of Life Assessment (36 Months 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. | At Month 24 | 
| Number of Participants Hospitalized for Reasons Other Than Primary Transplantation (12 Months 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. | Month 12 | 
| Number of Participants Hospitalized for Reasons Other Than Primary Transplantation (36 Months 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. | Month 36 | 
| Number of Participants With Employment Status (12 Months Analysis) | The various employment status reported are: Employed/self employed full time Employed part time Unemployed Homemaker Volunteer Permanently disabled Non-permanently disable Retired Other | At screening (at day 0 +/- 7 days ), At Month 12 | 
| Number of Participants With Employment Status (36 Months Analysis) | The various employment status reported are: Employed/self employed full time Employed part time Unemployed Homemaker Volunteer Permanently disabled Non-permanently disable Retired Other | At screening (at day 0 +/- 7 days ), At Month 36 | 
| Number of Participants With Wound Problems(12 Months Analysis) | 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. | At Month 12 | 
| Number of Participants With Any Wound Problems (36 Months Analysis) | 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. | At Month 12, 24 and 36 | 
| Number of Participants With Notable Abnormalities in Total Cholesterol and Triglycerides as Measurement of Effect of Treatment on Cardiovascular Health (12 Months 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 | Overall post baseline up to month 12 | 
| Number of Participants With Notable Abnormalities in Total Cholesterol and Triglycerides as Measurement of Effect of Treatment on Cardiovascular Health (36 Months 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 | Overall Post Baseline up to month 36 | 
| Number of Participants With Antibody-mediated Rejection Per Treatment Group (12 Months Analysis) |  | At Month 12 | 
| Number of Participants With Antibody-mediated Rejection Per Treatment Group (36 Months Analysis) |  | At Month 12, 24 and 36 | 
| Number of Participants With Biopsy Proven Acute Rejection (BPAR) Influenced by Demographic Characteristics and Morbidities (12 Months Analysis) | 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. | At Month 12 | 
| Number of Participants With Biopsy Proven Acute Rejection (BPAR) Influenced by Demographic Characteristics and Morbidities (36 Months Analysis) | 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. | At Month 36 | 
| Number of Patient Survival and Graft Survival (12 Months Analysis) |  | At Month 12 | 
| Number of Patient Survival and Graft Survival (36 Months Analysis) |  | At Month 12, 24 and 36 | 
| Change in Bone Mineral Density Between Week 2 and Month 24 (36 Months Analysis) | 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. | Week 2, Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplantation, everolimus, Immunosuppressants