In a phase 2 multi-center open label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas-kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI) based immunosuppressive regimen (tacrolimus) (n=21) or an investigational arm using low-dose CNI plus co-stimulation blockade (belatacept) with intended CNI withdrawal (n=22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium or mycophenolate
mofetil, and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled. At that time the rate of biopsy proven acute rejection (BPAR) of the pancreas was low in both groups until CNI was withdrawn, with four of the five pancreas rejections occurring during or after CNI withdrawal. The rate of BPAR of kidney allografts was low in both control (9.5%) and investigational (9.1%) arms. Pancreas graft survival at 52 weeks, defined by insulin independence, was 21 (100%) in the control group and 19 (86%) in the investigational arm. One subject in the investigational arm died with functioning pancreas and kidney grafts. Renal function at week 52 was similar in both arms. Costimulation blockade with belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing CNI withdrawal.
Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This is a well conducted multicentre study in simultaneous pancreas-kidney transplantation, a field in which RCTs are few and far between. A study-wide suspension of CNI withdrawal was taken during an interim safety review; 8 of 22 enrolled subjects in the investigational arm had pancreas rejection, all but one shortly after or during CNI withdrawal. Blockade of T-cell co-stimulation with belatacept did not enable CNI to be safely withdrawn in SPK. Low dose CNI however, alongside belatacept and mycophenolate, could prevent rejection of both kidney and pancreas, but with a higher risk of opportunistic infection.
The aim of this study was to assess the long term effects of a calcineurin inhibitor (CNI)-free, corticosteroid-free belatacept (NULOJIX®) based regimen on the graft function of simultaneous pancreas and kidney (SPK) transplant recipients.
Participants were randomized at a 1:1 ratio to either the NULOJIX®-based maintenance immunosuppressive regimen arm or the CNI-based regimen arm
Simultaneous pancreas and kidney transplant recipients.
The primary endpoint was the assessment of mean glomerular filtration rate (GFR) at 52 weeks. The secondary endpoints were additional measures of kidney function and injury, metabolic and cardiovascular parameters, and measures of pancreatic function and injury at 52 weeks post transplant. The anti-donor reactivity and the occurrence and severity of rejection were also measured.