Prova di fase 2 in aperto di un regime immunosoppressivo senza steroidi, senza CNI e basato su Belatacept

Induction with Thymoglobulin®, methylprednisolone, and maintenance immunosuppression with tacrolimus and mycophenolate mofetil (MMF)

The target dosage is 6mg/kg total over 3 to 4 days. The recommended route of administration is intravenous infusion using a high-flow vein.

• Timoglobulina®
• ATG (coniglio)

Methylprednisolone will be administered at a target dose of 500 mg beginning on the day of transplant, and tapered to 250 mg day 1 post-transplant, 125 mg day 2 post-transplant, 60 mg day 3 post-transplant, 30 mg day 4 post-transplant and day 5 post-transplant 0 mg if therapeutic tacrolimus level achieved for groups 1 and 3.

• Medrol®

Mycophenolate Mofetil will be administered at a target dose of 1000 mg orally twice a day. Myfortic® (mycophenolate sodium) may be used as a replacement for MMF. Mycophenolate sodium will be dosed at 720 mg PO BID. Mycophenolate sodium will be adjusted based on clinical complications.

• MMF
• CellCept®
• acido micofenolato

The site investigator will identify a starting tacrolimus dose at their discretion, in order to achieve the target trough levels, no later than 5 days post-transplantation. The dose will be adjusted to 5-8ng/ml for the active comparator arm (thymoglobulin + tacrolimus + MMF arm) or tapered off in the experimental arm (basiliximab + 20 weeks of tacrolimus + MMF + belatacept).

• Prograf®

Induction with Thymoglobulin®, methylprednisolone, and maintenance with belatacept and mycophenolate mofetil (MMF)

The target dosage is 6mg/kg total over 3 to 4 days. The recommended route of administration is intravenous infusion using a high-flow vein.

• Timoglobulina®
• ATG (coniglio)

Methylprednisolone will be administered at a target dose of 500 mg beginning on the day of transplant, and tapered to 250 mg day 1 post-transplant, 125 mg day 2 post-transplant, 60 mg day 3 post-transplant, 30 mg day 4 post-transplant and day 5 post-transplant 0 mg if therapeutic tacrolimus level achieved for groups 1 and 3.

• Medrol®

Mycophenolate Mofetil will be administered at a target dose of 1000 mg orally twice a day. Myfortic® (mycophenolate sodium) may be used as a replacement for MMF. Mycophenolate sodium will be dosed at 720 mg PO BID. Mycophenolate sodium will be adjusted based on clinical complications.

• MMF
• CellCept®
• acido micofenolato

Participants will receive belatacept at a dose of 10mg/kg up on day 1, 5, 14, 28, 56 and 84. After 84 days, subjects will receive a maintenance dose of 5 mg/kg every 4 weeks until completion of the trial.

• NULOJIX®

Induction basiliximab and methylprednisolone, administration of NULOJIX® (belatacept) 24 hours post reperfusion (+/-12 hrs); maintenance immunosuppression with 1. )20 week course of Prograf® (tacrolimus) or equivalent 2.) CellCept® (mycophenolate mofetil- MMF), or Myfortic® (mycophenolate sodium), or equivalent.

Subjects participating in this arm may have tacrolimus reinstated, at a dose to be determined by the site investigator, if any of the following events occur: 1 - An acute rejection episode 2- Request of the subject or site Investigator.

Methylprednisolone will be administered at a target dose of 500 mg beginning on the day of transplant, and tapered to 250 mg day 1 post-transplant, 125 mg day 2 post-transplant, 60 mg day 3 post-transplant, 30 mg day 4 post-transplant and day 5 post-transplant 0 mg if therapeutic tacrolimus level achieved for groups 1 and 3.

• Medrol®

Mycophenolate Mofetil will be administered at a target dose of 1000 mg orally twice a day. Myfortic® (mycophenolate sodium) may be used as a replacement for MMF. Mycophenolate sodium will be dosed at 720 mg PO BID. Mycophenolate sodium will be adjusted based on clinical complications.

• MMF
• CellCept®
• acido micofenolato

The site investigator will identify a starting tacrolimus dose at their discretion, in order to achieve the target trough levels, no later than 5 days post-transplantation. The dose will be adjusted to 5-8ng/ml for the active comparator arm (thymoglobulin + tacrolimus + MMF arm) or tapered off in the experimental arm (basiliximab + 20 weeks of tacrolimus + MMF + belatacept).

• Prograf®

Participants will receive belatacept at a dose of 10mg/kg up on day 1, 5, 14, 28, 56 and 84. After 84 days, subjects will receive a maintenance dose of 5 mg/kg every 4 weeks until completion of the trial.

• NULOJIX®

Basiliximab will be administered in two doses of 20 mg each.

• Simulect®

eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI):

• A score of ≥90 means kidney function is normal.
• A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease.
• Scores between 30 and 59 indicates moderately reduced kidney function.
• Scores between 15 and 29 indicate severely reduced kidney function.
• Scores below 15 indicate very severe or end stage kidney failure.

The estimated Glomerular Filtration Rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI):

• A score of ≥ 90 means kidney function is normal.
• A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease.
• Scores between 30 and 59 indicates moderately reduced kidney function.
• Scores between 15 and 29 indicate severely reduced kidney function.
• Scores below 15 indicate very severe or endstage kidney failure.

An estimate of the slope, or change over time, in eGFR was produced using standard statistical linear modeling procedures. The estimate was then re-scaled so that it could be interpreted as a change in eGFR per month. Positive numbers indicate increasing kidney function.

Larger numbers indicate greater change in kidney function.

Biopsy proven acute rejection definition: histologic evidence of a Banff grade of ≥1A per local pathologist.

eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI):

• A score of ≥90 means kidney function is normal.
• A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease.
• Scores between 30 and 59 indicates moderately reduced kidney function.
• Scores between 15 and 29 indicate severely reduced kidney function.
• Scores below 15 indicate very severe or end stage kidney failure.

The stages of Chronic Kidney Disease are defined using the participant's GFR value:

• Stage 1 if GFR value is ≥90 ( kidney function is normal)
• Stage 2 if 60 ≤ GFR < 90 (mildly reduced kidney function, pointing to kidney disease)
• Stage 3A if 45 ≤ GFR < 60*
• Stage 3B if 30 ≤ GFR < 45*
• Stage 4 if 15 ≤ GFR < 30 (severely reduced kidney function)
• Stage 5 if GFR < 15 (severe or end stage kidney failure).

Stages 3A and 3B indicate moderately reduced kidney function.*

The stages of Chronic Kidney Disease (CKD) are defined using the participant's GFR value:

• Stage 1 if GFR value is ≥ 90 (kidney function is normal)
• Stage 2 if 60 ≤ GFR < 90 (mildly reduced kidney function, pointing to kidney disease)
• Stage 3A if 45 <= GFR < 60*
• Stage 3B if 30 <= GFR < 45*
• Stage 4 if 15 ≤ GFR < 30 (severely reduced kidney function)
• Stage 5 if GFR < 15 (severe or end stage kidney failure).

Stages 3A abd 3B indicate moderately reduced kidney function.*

The estimated Glomerular Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation (MDRD):

• A score of ≥ 90 means kidney function is normal.
• A score between 60 and 89 indicates mildly reduced kidney function, pointing to kidney disease.
• Scores between 30 and 59 indicates moderately reduced kidney function.
• Scores between 15 and 29 indicate severely reduced kidney function.
• Scores below 15 indicate severe or endstage kidney failure.

Delayed grafted function is defined as dialysis in the first week on one or more occasions for any indication other than the treatment of acute hyperkalemia in the setting of otherwise acceptable renal function.

Acute cellular rejection occurs when lesions at the site of the graft characteristically are infiltrated with large numbers of lymphocytes and macrophages that cause tissue damage. Acute cellular rejection for this endpoint is defined as a grade equal to or greater than IA by Banff 2007 criteria as determined by local pathology.

Acute cellular rejection occurs when lesions at the site of the graft characteristically are infiltrated with large numbers of lymphocytes and macrophages that cause tissue damage. Acute cellular rejection for this endpoint is defined as a grade equal to or greater than IA by Banff 2007 criteria as determined by local pathology. Severity is graded as IA, IB, IIA, IIB, or III, with IA being the mildest form of cellular rejection and III being the most severe form of cellular rejection. Originally it was 2 endpoints but all participants' highest grade was also their first grade so only reporting their first grade.

Antibody mediated rejection is defined by diffusely positive staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury and was determined by local pathology.

Upon having a biopsy performed, persons often receive treatment for rejection based on the results of the biopsy, which may or may not have shown signs of rejection. Details of local biopsy findings are presented here for rejection. Acronyms and abbreviations are defined as follows:

• ACR= Acute T-Cell Mediated rejection
• AMR= Acute Antibody-mediated rejection
• Chr. AMR=Chronic Antibody Mediated Rejection
• Gd.=Grade
• IFTA=Interstitial Fibrosis and Tubular Atrophy

Upon having a biopsy performed, persons often receive treatment for rejection based on the results of the biopsy, which may or may not have shown signs of rejection. Details of treatment are presented here for rejection. Acronyms and abbreviations are defined below.

ATG=Thymoglobulin

The presence of antibodies reactive to Histocompatibility Antigen (HLA) molecules expressed on the renal allograft have been associated with both acute and chronic injury to the transplanted kidney. The development of de novo anti donor HLA antibodies may mean a person is more likely to reject the graft.

No data available.

New onset diabetes is the development of diabetes post-kidney transplant. It was identified by the clinical sites caring for each participant and reported directly in the clinical database. Impaired fasting glucose (IFG) is a determination made by referencing glucose measurements obtained from a standard chemistry panel. Any fasting glucose measure that is between 110 and 125 mg/dL is classified as IFG.

Acronyms: American Diabetes Association (ADA); World Health Organization (WHO).

Treated diabetes is defined as receipt of any oral medication or insulin for the treatment of diabetes for >14 days.

Hemoglobin A1c (HbA1c) measures the average blood glucose levels over 8-12 weeks, thus acting as a useful long-term gauge of blood glucose control:

• A value below 6.0% reflects normal levels,
• 6.0% to 6.4% reflects prediabetes, and
• a value of ≥ 6.5% reflects diabetes.

A blood pressure measurement consists of two numbers: the systolic and diastolic pressures. Systolic pressure measures the pressure in blood vessels when the heart beats. Diastolic pressure measures the pressure in blood vessels between beats of the heart.

• Systolic measures of <120 and diastolic measures of <80 are considered normal.
• Systolic measures of 120-139 and diastolic measures of 80-89 are considered at risk (or pre-hypertension).
• Systolic measures of ≥140 and diastolic measures of ≥90 are considered high.

Anti-hypertensive medications are a class of drugs that are used to treat hypertension. The medications seek to prevent the complications of high blood pressure, such as stroke and myocardial infarction.

A fasting lipid profiles measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. These measurements are used in assessing one's risk of cardiovascular disease. Target ranges for each of these measures are provided:

• Total cholesterol: 75-169 mg/dL if age ≤20; 100-199 mg/dL if age ≥ 21; high values indicate risk of cardiovascular disease
• LDL cholesterol: <70 mg/dL for people with documented cardiovascular disease or metabolic syndrome; <100 mg/dL for people considered high risk for cardiovascular disease; <130 mg/dL for people considered low risk for cardiovascular disease; high values indicate risk of cardiovascular disease
• HDL cholesterol: 40mg/dL and higher; high values indicate reduced risk of cardiovascular disease
• Non-HDL cholesterol: 30 mg/dL above the target value for LDL cholesterol; high values indicate risk of cardiovascular disease and
• Triglycerides: <150 mg/dL; high values indicate risk of cardiovascular disease.

A fasting lipid profiles measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. These measurements are used in assessing one's risk of cardiovascular disease. Target ranges for each of these measures are provided:

• Total cholesterol: 75-169 mg/dL if age ≤20; 100-199 mg/dL if age ≥ 21; high values indicate risk of cardiovascular disease
• LDL cholesterol: <70 mg/dL for people with documented cardiovascular disease or metabolic syndrome; <100 mg/dL for people considered high risk for cardiovascular disease; <130 mg/dL for people considered low risk for cardiovascular disease; high values indicate risk of cardiovascular disease
• HDL cholesterol: 40mg/dL and higher; high values indicate reduced risk of cardiovascular disease
• Non-HDL cholesterol: 30 mg/dL above the target value for LDL cholesterol; high values indicate risk of cardiovascular disease and
• Triglycerides: <150 mg/dL; high values indicate risk of cardiovascular disease.

A fasting lipid profiles measures total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. These measurements are used in assessing one's risk of cardiovascular disease. Target ranges for each of these measures are provided:

• Total cholesterol: 75-169 mg/dL if age ≤ 20; 100-199 mg/dL if age ≥ 21; high values indicate risk of cardiovascular disease
• LDL cholesterol: <70 mg/dL for people with documented cardiovascular disease or metabolic syndrome; <100 mg/dL for people considered high risk for cardiovascular disease; <130 mg/dL for people considered low risk for cardiovascular disease; high values indicate risk of cardiovascular disease
• HDL cholesterol: 40mg/dL and higher; high values indicate reduced risk of cardiovascular disease
• Non-HDL cholesterol: 30 mg/dL above the target value for LDL cholesterol; high values indicate risk of cardiovascular disease and
• Triglycerides: <150 mg/dL; high values indicate risk of cardiovascular disease.

Lipid lowering medications are used in the treatment of high levels of fats (lipids), such as cholesterol in blood.

This is a measure of the total number of pills a participant was prescribed on a given day

This measure counts deaths and graft loss occurring at any point post transplantation. Graft loss is defined as 90 days of dialysis dependency.

The number of participants who were treated by their local physician for any type of rejection including, but not limited to cellular rejection and antibody- mediated rejection of the transplanted kidney regardless of the presence of a biopsy.

Adverse events were collected systematically from enrollment through Wk 52, the last study visit. Provided are numbers of participants with ≥ 1 adverse event (serious or non-serious adverse events) by treatment arm.

Infections of certain types (i.e., excluding those identified in the protocol as occurring commonly in this study population) were required to be reported as a serious adverse event if they required either inpatient hospitalization or prolongation of a current hospitalization.

Viral infections following renal transplantation is significant source of recipient morbidity and mortality, and a significant cause of allograft dysfunction and loss. Specific viruses were monitored during the study, using participant blood samples. Displayed are counts of participants who experienced BKV and CMV viremia as adverse events by treatment arm.

Viral infections following renal transplantation, including but not limited to EBV infection, is a significant source of recipient morbidity and mortality, and a significant cause of allograft dysfunction and loss.

Temperature of >39 degrees Celsius (e.g., 102.2 degrees Fahrenheit) would be an indication of fever most often in response to an infection or illness. Systolic blood pressure <90mm Hg would be an indication of low blood pressure.