A Study of BMS-224818 (Belatacept) in Patients Who Have Undergone a Kidney Transplant and Are Currently on Stable Cyclosporine or Tacrolimus Regimen With or Without Corticosteroids

Calculated GFR assessment used the modification of diet in renal disease (MDRD) formula. GFR was measured as mL/min/1.73 m^2. For death or graft loss participants, calculated GFR (cGFR) value 10 was used, for other participants who had a post baseline cGFR value missing, but had baseline value and at least 2 post baseline values available, which were at least 120 days apart, linear regression model was used to impute the cGFR value. Baseline = value at screening.

AR defined: if either a or b was satisfied: a: the reason for clinical suspicion was reported to be an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; or an unexplained decreased urine output; or fever and graft tenderness and the episode was a case of biopsy proven AR (AR of Banff histopathologic classification Grade IA or higher as assessed by the blinded central pathologist); b: the reason for clinical suspicion was reported to be something other than: an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; or an unexplained decreased urine output; or fever and graft tenderness; the episode was a case of biopsy proven AR, and the participant was treated for this episode. Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. AR is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection.

Graft loss was defined as either functional loss or physical loss. Functional loss was defined as a sustained level of serum creatinine (SCr) ≥ 6.0 mg/dL (530 μmol/L) for ≥ 4 weeks or administration of a maintenance dialysis regimen for at least 56 days or impairment of renal function to such a degree that the participant undergoes re-transplantation.

Reasons for study drug dose modification included categories of decline in renal function (as determined by the investigator), treatment of acute rejection, and other reasons. More than 1 reason could be given for dose alteration.

Percentage=number with composite divided by number randomized. Graft loss was functional loss or physical loss. Functional loss = sustained level of serum creatinine (SCr) ≥ 6.0 mg/dL for ≥ 4 weeks or administration of a maintenance dialysis regimen for at least 56 days or impairment of renal function to such a degree that participant undergoes re-transplantation. AR: if either a or b: (a) the reason for clinical suspicion was reported to be an unexplained rise of serum creatinine ≥ 25% from baseline; or an unexplained decreased urine output; or fever and graft tenderness and the episode was a case of biopsy-proven AR (grade IA or higher as assessed by the blinded central pathologist); (b) the reason for clinical suspicion was reported to be something other than: an unexplained rise of serum creatinine ≥ 25% from baseline; or an unexplained decreased urine output; or fever and graft tenderness; the episode was a case of biopsy-proven AR, and the participant was treated for it.

A participant who did not have diabetes prior to randomization is determined to have new onset diabetes mellitus if they received an antidiabetic medication for a duration of at least 30 days or at least two fasting plasma glucose (FPG) tests indicated that FPG is >=126 mg/dL. Percentage was the number of participants with new onset of diabetes mellitus divided by the number of participants without pre-randomization diabetes.

Samples were obtained at Day 1 (first dose), Week 24, and Week 52 (or end of therapy). This was a cumulative summary in that once a participant was positive, that participant remained positive for later time points. Evaluation of anti-donor HLA antibodies was performed by an external laboratory (Emory University, Atlanta, Georgia).

Baseline was value at screening or prior to first dose of study drug. Serum creatinine was measured in milligrams per deciliter (mg/dL). Baseline = value at screening.

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug.

SF-36 was a Participant-Reported Quality of Life (QoL) Short Form (SF) questionnaire. The subscale in the mental component (MCS) part of the instrument ranged from 1 to 6 with 1=all of the time and 6= none of the time. The subscale for physical component (PCS) ranged from 1 to 3 with 1=Yes, limited a lot and 3=No, not limited at all. The subscale for the extent that physical health or emotional problems interfered with normal activities ranged from 1 to 5 with 1=not at all and 5= extremely. Baseline was at randomization or prior to first dose. Baseline = value at screening. The subscale scores were transformed using norm-based methods that standardized the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores range from a minimum of 0 to a maximum of 100, with a higher score indicating better quality of life.

SF-36 was a Participant-Reported Quality of Life (QoL) Short Form (SF) questionnaire measuring health-related quality of life (HRQL) covering 8 domains of physical and mental component summaries: physical function, role limitations due to physical problems, pain, general health perception, and vitality, social function, role limitations due to emotional problems, and mental health.

All domains were scored using norm-based methods that standardized the scores to a mean of 50 and a standard deviation of 10 in the general population. The scores range from a minimum of 0 to a maximum of 100, with a higher score indicating better quality of life.

The Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) was used to assess the occurrence (never, occasionally, regularly, almost always, always) and distress (0=no distress to 4=terrible distress) of symptoms associated with immunosuppressive therapies. Ridit (relative to an identified distribution) analysis (Fleiss JL. Statistical methods for rates and proportions. New York: John Wiley \& Sons, Inc. 1991) was used. Ridit scores were calculated at 12 months for overall symptom occurrence score and overall symptom distress. The Ridit score reflects the probability that a score observed for an individual randomly selected from a group would be higher (worse symptom) than a score observed for a randomly selected individual from the reference group. The reference group was constituted by the frequency distribution of the responses of all participants on all items at baseline. The ridit of the reference group is by definition, 0.5.

Upper limits of normal (ULL). Leukocytes: < 2.0*10^3 cells per microliter (c/µL); Lymphocytes (absolute): < 0.5*10^3 c/µL; bilirubin: > 3.0*ULN milligrams per deciliter (mg/dL); Potassium: < 3.0 milliequivalents per liter (meq/L) or > 6.0 meq/L; Magnesium >2.6 meq/L; Sodium: < 130 meq/L; Phosphorus: < 2.0 mg/dL; Uric Acid: > 10 mg/dL. Baseline = value at screening.

ITT=participants randomized to their original treatment arm and who entered the LT period are presented. Baseline=value at screening. Calculated GFR assessment used the MDRD formula. GFR was measured as mL/min/1.73 m^2. For death or graft loss participants, calculated GFR (cGFR) value of 0 was imputed and carried forward after death or graft loss up to the end of the analysis period. Sponsor discontinued the CNI treatment arm in Year 3, and participants treated with CNI could elect to switch to belatacept. If a participant did not switch to belatacept, they were required to discontinue from the study. Therefore, efficacy results from Month 36 through Month 54 are difficult to interpret. No formal comparisons were planned between the belatacept and CNI treatment groups post Month 36, and the data up to the final database lock should be interpreted with caution.

AR was defined: if either a or b was satisfied: (a) the reason for clinical suspicion was reported to be an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; or an unexplained decreased urine output; or fever and graft tenderness and the episode was a case of biopsy proven AR (AR of Banff histopathologic classification grade IA or higher as assessed by the blinded central pathologist); (b) the reason for clinical suspicion was reported to be something other than: an unexplained rise of serum creatinine ≥ 25% from baseline creatinine; or an unexplained decreased urine output; or fever and graft tenderness; the episode was a case of biopsy proven AR, and the participant was treated for this episode. Banff 97 working classification of kidney transplant pathology was used to categorize the severity of the AR.

Graft loss = either pure graft loss (participant survived to the end of the study period after graft loss) or death with functioning graft. Pure graft loss = either functional loss or physical loss. Functional loss = a sustained level of serum creatinine (SCr) ≥ 6.0 mg/dL (530 μmol/L) for ≥ 4 weeks or administration of a maintenance dialysis regimen for at least 56 days or impairment of renal function to such a degree that the participant undergoes re-transplantation. The table was designed with built-in redundancy to capture all possible combinations of death and/or graft loss, but not all lines can be summed to reach the total number surviving and the total number who die and/or lose grafts. If a participant experiences pure graft loss and dies at a later date independent of the graft loss event, they are counted only once in the cumulative tabulation of death or graft loss. Only the first event experienced by the participant counted toward the cumulative total.

A participant who did not have diabetes prior to randomization is determined to have new onset diabetes mellitus if they received an antidiabetic medication for a duration of at least 30 days or at least two fasting plasma glucose (FPG) tests indicated that FPG is >=126 mg/dL. Percentage was the number of participants with new onset of diabetes mellitus divided by the number of participants without pre-randomization diabetes.

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug.

Prospectively identified events of special interest which were a subset of all AEs, and were either SAEs or non-serious AEs, included the following categories: Serious Infections, Thrombolic/embolic events, Autoimmune Disease, Malignancy, Peri-infusional reactions (only belatacept treatment group was IV) , Acute Peri-infusional events occurring within 24 hours of injection, Pulmonary Edema and Congestive Heart Failure. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization.

Baseline was value at screening. Serum creatinine was measured in mg/dL. Only participants who entered into Long Term Period were included in the analysis.

Upper limits of normal (ULN). Hemoglobin: < 8 g/dL; Platelet count: < 50*10^9 c/L; Leukocytes: < 2.0*10^3 c/µL; Lymphocytes (absolute): < 0.5*10^3 c/µL; Neutrophils: < 1.0*10^3 c/µL; Alanine Aminotransferase (ALT): > 5.0*ULN Units per liter (U/L); bilirubin: > 3.0*ULN mg/dL; Creatinine: > 3.0*ULN mg/dL; Calcium: < 7 mg/dL; Bicarbonate: > 12.5 mg/dL; Potassium: < 3.0 meq/L or > 6.0 meq/L; Magnesium >2.6 meq/L; Sodium: < 130 meq/L; Phosphorus: < 2.0 mg/dL; Uric Acid: > 10 mg/dL.

Blood pressure was measured while the participant was sitting quietly for 5 minutes and was measured in millimeters of mercury (mmHg). Baseline was value at screening. Only those participants who entered long term period were evaluated.

Blood pressure was measured while the participant was sitting quietly for 5 minutes and was measured in mmHg. Baseline was value at screening. Only those participants who entered long term period were evaluated.

Calculated GFR assessment used the MDRD formula. GFR was measured as mL/min/1.73 m^2. For death or graft loss participants, calculated GFR (cGFR) value 10 was used, for other participants who had a post baseline cGFR value missing, but had baseline value and at least 2 post baseline values available, which were at least 120 days apart, linear regression model was used to impute the cGFR value. Day of Switch = the first belatacept infusion day.

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Day of Switch = the first belatacept infusion day.