This was expected, given that there is no exposureCresponse relationship in the kidney transplant setting, such that therapeutic drug monitoring is not needed with belatacept treatment. While preservation of renal function was a key getting in the pivotal phase III clinical trials of belatacept in renal transplant recipients, the magnitude of the renal function difference in the current study highlights the capacity Soyasaponin BB for DLL1 native kidneys to recover substantial function following LT in the absence of CNI exposure. The tendency toward more viral and fungal Soyasaponin BB infections observed in belatacept-treated patients raises the possibility of overimmunosuppression in some patients, as observed with regimens that include MMF (27). belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15C34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated. pneumonia. Outcomes The primary end point was the composite incidence of AR, graft loss and death at 6 months after transplantation. AR was included in the composite end point if it was clinically suspected and confirmed via biopsy. All biopsies for suspected AR were assessed by a central histopathologist blinded to treatment assignment using the Banff schema for grading of LT rejection and rejection activity index for staging (19). Graft loss was defined as impairment of liver function that resulted in individual death or re-transplantation. Secondary end points included the incidence, severity, treatment and end result of AR by 12 months; graft loss and death by 12 months; switch in renal function over time as determined by measured GFR (mGFR) and calculated GFR (cGFR; MDRD methodology); incidence of HCV recurrence by 12 months, defined as histologic confirmation on liver biopsy scored by the Ishak (altered Knodell) system, a score of 5 of 18 on altered histological activity index grading, and a fibrosis score of 2 of 6 (20). Incidence rates of cardiovascular and metabolic comorbidities (i.e. posttransplant diabetes mellitus, dyslipidemia and hypertension) and the overall safety of the belatacept-based regimens were also evaluated. Liver allograft biopsies (confirmed by a central pathology laboratory) were obtained at baseline and at 12 months to assess histology. Biopsies were also performed in patients who met protocol-specified criteria for clinical suspicion of AR or HCV recurrence. Statistical analyses A statistical analysis plan was prepared prior to unblinding this study. The purpose of the study was to provide initial clinical experience regarding the efficacy and security of belatacept in LT recipients and identify a belatacept-based regimen with an acceptable composite rate of AR, graft loss and death. Therefore, statistical screening was not prespecified and the study was not powered to demonstrate a difference between treatment groups. A calculated sample size of 50 patients per treatment group Soyasaponin BB was decided to provide initial data regarding security and efficacy. If the observed primary end point (composite incidence of AR, graft loss and death by 6 months) for any belatacept-based group was Soyasaponin BB 40%, it was estimated that this two-sided 95% confidence interval (CI) of this incidence would lengthen from 26.4% to 53.6%, which would be within the general range observed in large LT studies that used CNI-based immunosuppression (21,22). Analyses were performed around the intent-to-treat populace (i.e. those who were randomized and received a transplant). Most analyses were descriptive in nature, using point estimates and 95% CIs. mGFR was assessed via iothalamate at months 2 (baseline) and 12. cGFR was assessed pretransplant and at 1, 2, 3, 6 and 12 months. Results A total of 260 patients at 39 centers worldwide were randomized, of whom 250 received a transplant and were treated. A total of 164 patients completed 12 months of Soyasaponin BB treatment (Physique 1). Demographic and baseline characteristics were generally comparable across treatment groups (Table ?(Table2).2). The mean age was 54 years, and 46% of patients were HCV-positive. The primary reasons for discontinuing treatment, as defined by the study investigators, were AEs and lack of efficacy in the belatacept groups and AEs in the tacrolimus groups. Table 2 Demographic characteristics of recipients by treatment group DSA in all groups. Table 6 DSA: quantity of patients with detectable antidonor HLA antibodies DSA1 by month 123/47 (6)1/47 (2)1/43 (2)6/52 (12)3/45 (7) Open in a separate windows DSA, donor-specific.