A Phase II Study of Belatacept (BMS-224818) With a Steroid-free Regimen in Subjects Undergoing Kidney Transplantation

AR is clinicopathological event requiring clinical evidence and biopsy confirmation by central pathologist. One or more conditions were met and a renal biopsy revealed histologic evidence of rejection: unexplained rise of serum creatine (SCr) greater than or equal to 25% from baseline plus one or more of the following: unexplained decreased urine output; fever, graft tenderness; SCr that remained elevated 14 days post-transplantation and clinical suspicion of AR; other reason and participant treated for episode. Day 1=transplantation. Banff 97 working classification of kidney transplant pathology: Type I=tubulointerstitial AR without arteritis (IA: interstitial infiltration with \>25% of parenchyma affected and moderate tubulitis with \>4 mononuclear cells/tubular cross section; IB: \>10 mononuclear cells; Type II vascular AR with (IA) intimal arteritis (IIA=mild - moderate; IIB=severe; Type III=severe rejection with transmural arterial changes, necrosis of smooth muscle cells.

Time frame: Day 1 to Month 6 post-transplantation

Population: Participants with more than one episode of AR were counted once only and the episode with the worst grade was used. For 95% Confidence Interval (CI) within each group, normal approximation was used if N greater than, or equal to (\>=) 5. Otherwise, exact method was used. ITT population defined as all randomized and transplanted participants.

Baseline (BL) was value obtained day prior to transplantation. Lipid values measured in milligrams/deciliter (mg/dL) included: high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), non-HDL cholesterol (non-HDL-C), total cholesterol (TC), triglycerides. Intent to treat population included all participants randomized and transplanted.

Time frame: Baseline to Month 12

Population: 33, 26, 30 participants were included in the ITT population. Number of participants analyzed for HDL-C = 26, 22, 26; non-HDL-C = 26, 22, 26; LDL-C = 20, 14, 21; TC = 26, 22, 26; triglycerides = 20, 14, 21, in belatacept/MMF, belatacept/sirolimus, and tacrolimus/MMF arms, respectively.

Blood urea nitrogen (BUN) in mg/dL; Albumin (Alb) in g/dL;Serum creatinine (SCr) in mg/dL; Age in years. Glomerular filtration rate (GFR) was calculated based upon serum creatinine (SCr) using the Modification of Diet in Renal Disease (MDRD) formula as suggested by Levey et al: MDRD GFR = 170 x \[SCr/0.95\]\^(-0.999) x \[Age\]\^(-0.176) x \[0.762 if participant was female\] x \[1.180 if participant was black\] x \[BUN\]\^(-0.170) x \[Alb\]\^(+0.318). Intent to Treat (ITT) population is defined as all participants randomized and transplanted.

Time frame: Months 3, 6 and 12 post transplantation

Population: Month 12 n presented above. Calculated GFR, values \>180 mL/min/1.73 m2 (beyond upper limit of biologic plausibility)were truncated at 180 mL/min/1.73 m\^2. Based on median (SD) GFR of 83 (50).

GFR was calculated based upon serum creatinine (SCr) using the Modification of Diet in Renal Disease (MDRD) formula as suggested by Levey et al: MDRD GFR = 170 x \[SCr/0.95\]\^(-0.999) x \[Age\]\^(-0.176) x \[0.762 if participant was female\] x \[1.180 if participant was black\] x \[BUN\]\^(-0.170) x \[Alb\]\^(+0.318). Age in years, Alb = Albumin in g/dL; SCr = in mg/dL; BUN =Blood urea nitrogen in mg/dL. Intent to Treat population is defined as all participants randomized and transplanted.

Time frame: Months 24, 36 and 48 post transplantation

Population: N=All participants who were randomized, transplanted, in the LTE and had data available at the specific time point.

Systolic, diastolic and mean arterial blood pressures were measured in millimeters of mercury (mm Hg). Baseline was defined as value obtained before transplantation. Intent to treat population included all participants randomized and transplanted.

Time frame: Baseline and 12 months post transplantation

Population: Number analyzed at baseline presented above. Number analyzed at Month 12: 28, 22, 29 in belatacept/MMF, belatacept/sirolimus, and tacrolimus/MMF treatment arms,respectively. Measurements obtained immediately after drug infusion were excluded from analysis.

Participants were said to be corticosteroid-free at Month 6 if they were not receiving corticosteroids for greater than (\>) 7 consecutive days during Days 141 through Days 196, and at Month 12 if not receiving corticosteroids for \> 7 days during Days 337 through 392. Intent to treat population included all randomized and transplanted participants.

Time frame: Day 1 through Month 12

Population: For 95% CI within each group, normal approximation was used if N greater than, equal to (\>=)5. Otherwise, exact method was used. Numbers of participants analyzed at Month 6 in each arm were 33, 26, 30 and numbers of participants analyzed at Month 12 were 32, 26, 30, in belatacept/MMF, belatacept/sirolimus, and tacrolimus/MMF arms, respectively.

In the LTE, a participant was considered corticosteroid-free if they were not receiving corticosteroids for \>7 consecutive days during Day 701 and Day 756, Day 1065 and Day 1120, as well as Day 1429 and Day 1484, respectively.

Time frame: End of Month 12 to end of Long Term Extension (Year 4)

Population: N= All participants who completed the ST period, were eligible and accepted to enter the LTE by signing a new informed consent form, and had data available at the specific time point were analyzed.

Participants using \> = 1 antihyperlipidemic medication at Month 12.

Time frame: Month 12

Population: Analysis based on all participants who were followed up at least 364 days.

Long Term extension was the period from the end of Month 12 to the end of Month 48 post transplantation and the completion of the study 31 July 2012. At any time in the study, participants who were unable to tolerate MMF in the Bela-MMF and Tac-MMF groups could discontinue (DC) MMF and switch to sirolimus and remain in the study and those in the Bela-Siro group who were unable to tolerate sirolimus could DC sirolimus and switch to MMF and remain in the study. Study completion=data base (DB) lock.

Time frame: End of Month 12 to end of Study (Month 48)

Population: N= All participants who completed the ST period, were eligible and accepted to enter the LTE by signing a new informed consent form

Baseline was defined as day prior to transplantation. Number of anti-hypertension medications taken were categorized from 1 to 6 and greater than (\>)6. Intent to treat population included all participants randomized and transplanted.

Time frame: Baseline and Month 12

Population: ITT population, 33, 26, 30 for each arm, respectively, was used for each time point (baseline and Month 12). At baseline, 2 participants in each arm were not using at least one medication. 8, 6, and 10 participants in each arm respectively, were not using at least one medication at Month 12.

Participants were considered corticosteroid-free at Months 24, 36, and 48 if they were not receiving corticosteroids for \>7 consecutive days during Day 701 and Day 756, Day 1065 and Day 1120, as well as Day 1429 and Day 1484, respectively. Participants were considered CNI-free at Months 24, 36, and 48 if they were not receiving CNI during Day 701 and Day 756, Day 1065 and Day 1120, as well as Day 1429 and Day 1484, respectively. Participants in the tacrolimus arm were not relevant to this analysis because tacrolimus is a calcinurin inhibitor.

Time frame: Months 24, 36, 48

Population: N= All participants who completed the ST period, were eligible and accepted to enter the LTE by signing a new informed consent form, and had data available at the specific time point were analyzed.

Participants were said to be CNI-free at Month 6 or 12 if they were not receiving a CNI during Day 141 to Day 196, or Day 337 to Day 392. Participants in the tacrolimus arm were not relevant to this analysis because tacrolimus is a calcinurin inhibitor. Participants were corticosteroid-free (CS-free) at Month 6 if they were not receiving corticosteroids for \> 7 consecutive days during Days 141 through Days 196, and at Month 12 if not receiving corticosteroids for \> 7 days during Days 337 through 392. Day 1 was day of transplantation. Intent to treat population included all randomized and transplanted participants.

Time frame: Day 1 to Month 12 post transplantation

Population: Analysis on both CNI-free and CS-free participants based on all followed up at least 151 days for Month 6 or 347 days for Month 12. One participant in the tacrolimus arm was counted as CNI-free since he discontinued tacrolimus on Day 2 of transplant and no data were available regarding immunosuppressive therapy after discontinuation.

AR defined as a clinicopathological event requiring clinical evidence and biopsy confirmation by central pathologist. One or more conditions were met and a renal biopsy revealed histologic evidence of rejection: unexplained rise of serum creatine (SCr) \>= 25 % from baseline plus one or more of the following: unexplained decreased urine output; fever and graft tenderness; a SCr that remained elevated within 14 days after transplantation and clinical suspicion of AR; reason other than those listed and participant was treated for this episode. Day 1 was day of transplantation. Banff grade used Banff 97 working classification of kidney transplant pathology. ITT population was all randomized and transplanted participants.

Time frame: End of Month 12 to end of Month 48 Post Transplantation

Population: All participants who completed the short term (ST) period, were eligible and accepted to enter the LTE by signing a new informed consent form.

AR defined as a clinicopathological event requiring clinical evidence and biopsy confirmation by central pathologist. One or more conditions were met and a renal biopsy revealed histologic evidence of rejection: unexplained rise of serum creatine (SCr) \>= 25 % from baseline plus one or more of the following: unexplained decreased urine output; fever and graft tenderness; a SCr that remained elevated within 14 days after transplantation and clinical suspicion of AR; reason other than those listed and participant was treated for this episode. Day 1 was day of transplantation. Banff grade used Banff 97 working classification of kidney transplant pathology. ITT population was all randomized and transplanted participants.

Time frame: Day 1 to Month 12 post transplantation

Population: For 95% CI within each group, normal approximation was used if N greater than, equal to 5. Otherwise, exact method was used.

Subjects with graft loss or death prior to Month 12 were considered having an event of AR, therefore, the incidence of AR was reported as a composite of AR, death, and graft loss.

Time frame: Day 1 up to Month 12

Participants with graft loss or death prior to Month 6 were considered having an event of AR, therefore, the incidence of AR was reported as a composite of AR, death, and graft loss.

Time frame: Day 1 up to Month 6

Population: Intent to treat population included all randomized and transplanted participants.

Delayed graft function (DGF) is defined as participant requiring dialysis within the first week (Day 1-8) post transplantation. Participants losing their graft less than 48 hours post transplant and receiving chronic dialysis were not considered as having DGF. Day 1 was day of transplantation. Intent to treat population defined as all participants randomized and transplanted

Time frame: From Day 1 up to and including Day 8 post transplantation

Graft loss was defined as either functional loss or physical loss. Functional loss was defined as either: sustained level of SCr greater than or equal to (\>=) 6.0 mg/dL (530 micromoles/Liter; micromol/L) for \>= 4 weeks as determined by the local laboratory; regularly scheduled dialysis treatments over a period of 56 days; impairment of renal function to such a degree that the participant undergoes re-transplant. Day 1 was day of transplantation. ITT population defined as all participants randomized and transplanted.

Time frame: End of Month 12 to end of Long Term Extension (Year 4)

Population: N=participants randomized and transplanted and in LTE.

Graft loss was defined as either functional loss or physical loss. Functional loss was defined as either: sustained level of SCr greater than or equal to (\>=) 6.0 mg/dL (530 micromoles/Liter; micromol/L) for \>= 4 weeks as determined by the local laboratory; regularly scheduled dialysis treatments over a period of 56 days; impairment of renal function to such a degree that the participant undergoes re-transplant. Day 1 was day of transplantation. ITT population defined as all participants randomized and transplanted.

Time frame: Day 1 to Month 6 and Month 12 post transplantation

Population: Participants surviving with a functioning graft were 30, 24, 30 in belatacept/MMF, belatacept/sirolimus, tacrolimus/MMF arms, respectively. Participant who died had functioning graft at time of death.

Baseline defined as day before transplantation. A participant who did not have diabetes prior to randomization and received an antidiabetic medication for a duration of at least 30 days or a participant who meets the following criteria and did not have diabetes prior to randomization: Symptoms of diabetes plus casual plasma glucose (PG) concentration ≥ 200 mg/dL (11.1 mmol/L); or fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L); or 2-hour PG ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test and a confirmatory laboratory test based on measurements of venous PG must have been done on another day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation. Intent to treat population included all participants randomized and transplanted.

Time frame: Baseline to Month 12