Optimization of NULOJIX® Usage As A Means of Avoiding CNI and Steroids in Renal Transplantation

GFR 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.

Time frame: Week 52

Population: Intent-to-treat population with measurable data at Week 52

CAN/IFTA grades reflect the severity of interstitial fibrosis and tubular atrophy present in the tissue obtained during a kidney biopsy. Higher grades indicate greater severity in interstitial fibrosis and tubular atrophy present the kidney biopsy tissue. The aim of this measure was to compare central lab reviewed pre-implantation biopsies to post-transplant biopsies, as pre-specified per protocol; however, the central lab had an inadequate set of biopsies to proceed with evaluation.

Time frame: Week 52, Week 104, and Week 156

Population: There was an insufficient number of biopsies collected for the summarized data to be reliable.

The stages of Chronic Kidney Disease are defined using the participant's GFR value as indicated below: Stage 1 if GFR value is ≥90; Stage 2 if GFR value is ≥60 and \< 90; Stage 3A if 45 ≤GFR \< 60; Stage 3B if 30 ≤ GFR \< 45; Stage 4 if 15 ≤GFR \< 30;l Stage 5 if GFR \< 15. Stage 1 means kidney function is normal. Stage 2 indicates mildly reduced kidney function, pointing to kidney disease. Stages 3A and 3B indicate moderately reduced kidney function. Stage 4 indicates severely reduced kidney function. Stage 5 indicates very severe or end stage kidney failure.

Time frame: Week 52, Week 104, and Week 156

Population: Intent-to-treat population with available data at Weeks 52, 104 and 156

Acute cellular rejection is 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 ≥ IA by Banff 2007 criteria. 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, this endpoint was worded as The severity of first and highest acute cellular rejection within the first 52 weeks. But since the highest grade for each subject coincided with the first ACR episode for each subject, only a summary of severity of the first episode is presented here.

Time frame: Transplantation through Week 52

Population: Intent-to-treat

Acute cellular rejection is 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 ≥ IA by Banff 2007 criteria.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

Antibody mediated rejection (AMR) is defined as diffusely positive staining for C4d, presence of circulating anti-donor antibodies and morphologic evidence of acute tissue injury.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

Biopsy proven acute rejection was defined as histologic evidence of borderline or higher cellular rejection per local pathologist.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

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 this study using participant blood samples. Acronyms: BK Polyoma Virus (BKV); Cytomegalovirus (CMV).

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

CAN/IFTA grades were determined per local pathology interpretations of biopsy tissue. These grades reflect the severity of interstitial fibrosis and tubular atrophy present in the tissue obtained during a kidney biopsy. Higher grades indicate greater severity in interstitial fibrosis and tubular atrophy present the kidney biopsy tissue.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

The stages of Chronic Kidney Disease are defined using the participant's GFR value as indicated below. Stage 1 if GFR value is ≥90; Stage 2 if 60 ≤ GFR \< 90; Stage 3A if 45 ≤ GFR \< 60; Stage 3B if 30 ≤ GFR \< 45; Stage 4 if 15 ≤ GFR \< 30; Stage 5 if GFR \< 15. Stage 1 means kidney function is normal. Stage 2 indicates mildly reduced kidney function, pointing to kidney disease. Stages 3A abd 3B indicate moderately reduced kidney function. Stage 4 indicates severely reduced kidney function. Stage 5 indicates very severe or end stage kidney failure.

Time frame: Week 52, Week 104, and Week 156

Population: Intent-to-treat population with available data at Weeks 52, 104 and 156

Delayed graft 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

Time frame: Any time within the first week post-transplant

Population: Intent-to-treat

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.

Time frame: Week 52

Population: Intent-to-treat

Viral infections following renal transplantation is a significant source of recipient morbidity and mortality, and a significant cause of allograft dysfunction and loss. Specific viruses were monitored during this study using participant blood samples. Acronym: Epstein-Barr virus (EBV)

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

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).

Time frame: Week 52

Population: Intent-to-treat

GFR 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. This measure specifically looked at participants with scores less than 60.

Time frame: Week 52, Week 104, and Week 156

Population: Intent-to-treat population with available data at Weeks 52, 104 and 156.

Temperature of \>39 degrees Celsius 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.

Time frame: 24 hours after transplantation

Population: Intent-to-treat

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 of prolongation of a current hospitalization.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

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.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

Treated diabetes is defined as the receipt of oral medication or insulin for \>14 days between 14 days and 52 weeks post-transplant

Time frame: Day 14 to Week 52

Population: Intent-to-treat with available data

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 stoke and myocardial infarction.

Time frame: Week 52

Population: Intent-to-treat with available data at Week 52

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

Time frame: Baseline, Week 24, Week 52, Week 104, Week 156

Population: Intent-to-treat

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 detailed below. 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 Triglycerides: \<150 mg/dL; high values indicate risk of cardiovascular disease

Time frame: Baseline, Week 24, Week 52, Week 104, Week 156

Population: Intent-to-treat

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.

Time frame: Day 28, Day 84, Week 24, Week 36, Week 52, Week 72, Week 104, Week 156

Population: Intent-to-treat with available data

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 very severe or endstage kidney failure.

Time frame: Week 52, Week 104, and Week 156

Population: Intent-to-treat population with available data at Weeks 52, 104 and 156

Adverse events were collected systematically from enrollment through last study visit. Displayed below are counts of all adverse events per treatment group (including both serious and non-serious adverse events). Separately counts of all adverse events determined to be serious are displayed per treatment group. More detail about adverse events for this trial is displayed in the 'Adverse Event' section.

Time frame: Enrollment through last study visit (up to week 156)

Population: Intent-to-treat

This measure counts deaths and graft loss occurring at any point post transplantation. Graft loss is defined as need for dialysis for greater than 30 days duration, allograft nephrectomy, or retransplantation.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat

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.

Time frame: Week 52

Population: Intent-to-treat with available data at Week 52

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 can be interpreted as a change in eGFR per month. Positive numbers indicate increasing kidney function. Larger numbers indicate greater change in kidney function.

Time frame: Week 52, Week 104, and Week 156

Population: Intent-to-treat with available data

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

Time frame: Day 28, Day 84, Week 24, Week 36, Week 52, Week 72, Week 104, Week 156

Population: Intent-to-treat with available data

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 biopsy findings and corresponding treatment are presented here for each instance of treatment for rejection. Acronyms and abbreviations are defined below. ACR=Acute Cellular Rejection ATG=Anti-thymocyte globulin therapy Chr. AMR=Chronic Antibody Mediated Rejection Gd.=Grade IFTA=Interstitial Fibrosis and Tubular Atrophy IVIG=Intravenous Immunoglobulin therapy. Only 'for cause' biopsies were performed post-transplant; thus, it is possible for a participant to be included in the analysis population and not have a biopsy for this outcome measure.

Time frame: Transplantation through last study visit (up to week 156)

Population: Intent-to-treat