Conversion from Calcineurin Inhibitor- to Belatacept-Based Maintenance Immunosuppression in Renal Transplant Recipients: A Randomized Phase 3b Trial

Abstract

Background: Calcineurin inhibitors (CNIs) are standard of care after kidney transplantation, but they are associated with nephrotoxicity and reduced long-term graft survival. Belatacept, a selective T cell costimulation blocker, is approved for the prophylaxis of kidney transplant rejection. This phase 3 trial evaluated the efficacy and safety of conversion from CNI-based to belatacept-based maintenance immunosuppression in kidney transplant recipients.

Methods: Stable adult kidney transplant recipients 6-60 months post-transplantation under CNI-based immunosuppression were randomized (1:1) to switch to belatacept or continue treatment with their established CNI. The primary end point was the percentage of patients surviving with a functioning graft at 24 months.

Results: Overall, 446 renal transplant recipients were randomized to belatacept conversion ( n =223) or CNI continuation ( n =223). The 24-month rates of survival with graft function were 98% and 97% in the belatacept and CNI groups, respectively (adjusted difference, 0.8; 95.1% CI, -2.1 to 3.7). In the belatacept conversion versus CNI continuation groups, 8% versus 4% of patients experienced biopsy-proven acute rejection (BPAR), respectively, and 1% versus 7% developed de novo donor-specific antibodies (dnDSAs), respectively. The 24-month eGFR was higher with belatacept (55.5 versus 48.5 ml/min per 1.73 m 2 with CNI). Both groups had similar rates of serious adverse events, infections, and discontinuations, with no unexpected adverse events. One patient in the belatacept group had post-transplant lymphoproliferative disorder.

Conclusions: Switching stable renal transplant recipients from CNI-based to belatacept-based immunosuppression was associated with a similar rate of death or graft loss, improved renal function, and a numerically higher BPAR rate but a lower incidence of dnDSA.Clinical Trial registry name and registration number: A Study in Maintenance Kidney Transplant Recipients Following Conversion to Nulojix® (Belatacept)-Based, NCT01820572.

Graphical abstract

Figure 1.

The trial profile of patient disposition shows 446 patients randomized to belatacept conversion (n=223) or CNI continuation (n=223); these patients constituted the ITT population. The 24-month treatment period was completed by 87% of patients in the belatacept group and 83% in the CNI group. ITT, intention to treat.

Figure 2.

Kaplan-Meier analysis of the time to first occurrence of death or graft loss of the ITT population showed a similar time to death or graft loss in the belatacept conversion group and in the CNI continuation group. No patient was imputed as having graft loss or death due to loss of follow-up.

Figure 3.

Treatment effect on time and incidence of BPAR. (A) The Kaplan-Meier analysis of time to first BPAR event showed an HR of 2.09 (95% CI, 0.94 to 4.65) for belatacept conversion relative to CNI continuation. (B) The incidence of BPAR at 24 months was 8% in the belatacept conversion group and 4% in the CNI continuation group. In the belatacept group, all episodes occurred during the first 7 months after randomization, whereas in the CNI group, the rate was 2% at month 12 and 4% at month 24. HR, hazard ratio.

Figure 4.

Plots of adjusted mean eGFR over time from randomization (solid lines) and month 3 (dotted lines) indicated a sustained improvement in renal function in the belatacept conversion group during the 24-month period. The trend in baseline-adjusted mean eGFR over 24 months showed an estimated positive slope of 0.68 ml/min per 1.73 m² in the belatacept group and a negative slope of −0.11 ml/min per 1.73 m² in the CNI group. For patients who died or had graft loss, missing eGFR values were imputed to zero. Adjusted mean eGFR values (error bars representing 95% CIs) over time are shown along with trend lines on the basis of a linear mixed model using treatment group, baseline eGFR, month (continuous), and interaction term treatment by month as fixed effects. These models also included a random intercept and slope for month. A separate model was fitted for the trend analysis from baseline (shown as solid lines) and month 3 (shown as dashed lines).

Figure 5.

Analysis of the prevalence of dnDSAs indicated that 1% of patients in the belatacept group and 7% of patients in the CNI group developed dnDSAs at 24 months postrandomization.