Avoidance of CNI and steroids using belatacept-Results of the Clinical Trials in Organ Transplantation 16 trial

Abstract

Immunosuppression devoid of corticosteroids has been investigated to avoid long-term comorbidities. Likewise, alternatives to calcineurin inhibitors have been investigated as a strategy to improve long-term kidney function following transplanion. Costimulatory blockade strategies that include corticosteroids have recently shown promise, despite their higher rates of early acute rejection. We designed a randomized clinical trial utilizing depletional induction therapy to mitigate early rejection risk while limiting calcineurin inhibitors and corticosteroids. This trial, Clinical Trials in Organ Transplantation 16 (CTOT-16), sought to evaluate novel belatacept-based strategies employing tacrolimus and corticosteroid avoidance. Sixty-nine kidney transplant recipients were randomized from 4 US transplant centers comparing a control group of with rabbit antithymocyte globulin (rATG) induction, rapid steroid taper, and maintenance mycophenolate and tacrolimus, to 2 arms using maintenance belatacept. There were no graft losses but there were 2 deaths in the control group. However, the trial was halted early because of rejection in the belatacept treatment groups. Serious adverse events were similar across groups. Although rejection was not uniform in the belatacept maintenance therapy groups, the frequency of rejection limits the practical implementation of this strategy to avoid both calcineurin inhibitors and corticosteroids at this time.

Keywords: clinical research/practice; clinical trial; costimulation; immunosuppressant - fusion proteins and monoclonal antibodies: belatacept; immunosuppression/immune modulation; kidney transplantation / nephrology; rejection: T cell-mediated (TCMR).

Figure 1:

Study design and therapy. Consort diagram of study design and enrollment (A). Assignments were made randomly to one of the groups (B), all of which received mycophenolate and rapid corticosteroid taper.

Figure 2.

Renal function during the first year post-transplant. A. Mean values (with standard deviation bars) of estimated glomerular filtration rate (eGFR) using the CKD-EPI equation are plotted over time for groups 1 (blue), 2 (red), and 3 (green). Individual eGFR values are plotted as circles within each group. A repeated measures linear mixed model yielded an estimated mean of 58.4 mL/min/1.73m² for group 1, 61.9 mL/min/1.73m² for group 2, and 63.2 mL/min/1.73m² for group 3 at week 52. The model resulted in an estimated treatment group difference at 52 weeks for group 2 vs. group 1 of 3.5 mL/min/1.73m² with 95% CI of (−8.0, 15.0), p=0.54, and for group 3 vs. group 1 of 4.8 mL/min/1.73m² with 95% CI of (−10.5, 20.1), p=0.53. B. eGFR at 52 weeks in each treatment group. The asterisks (*) indicate which subjects had rejection during the first year of enrollment.

Figure 3.

Freedom from biopsy-proven acute cellular rejection (≥ Banff grade IA rejection based on local read) by treatment group. Number of subjects at risk is presented at selected days post-transplant. Subjects are censored at day of last follow-up or death. Follow-up truncated at day 370 for illustration purposes. CI=confidence interval.