Table 1.

Examples of knowledge gaps in key clinical trials and potential next steps

Trial NameKey FindingsGaps/OpportunitiesFuture Strategies (Applicable to All Studies)
SymphonyTacrolimus superior to cyclosporin or sirolimus for the end points of 1-yr acute rejection, GFROptimal MMF dose unknownRisk stratify patients for enrollment into minimization/withdrawal studies not only on the basis of traditional clinical and immunologic risk factors but also on novel immunologic assessments (e.g., baseline T cell reactivity, epitope matching).
Using nondepleting induction, no DSA assessment
TRANSFORMEverolimus/low calcineurin inhibitor/prednisone is noninferior to standard calcineurin inhibitor/mycophenolate/prednisoneNo long-term outcomes of DSA, proteinuria, GFR
BENEFITBelatacept with superior GFR despite higher AR rates than cyclosporinControl arm not standard of careInvestigate endpoints beyond one-year graft survival, patient survival, rejection (e.g. iBox, GFR, histological endpoints)
Astellas corticosteroid withdrawalTacrolimus/mycophenolate with comparable graft survival and GFR despite higher AR than tacrolimus/mycophenolate/prednisoneDetails regarding rejection and effect on outcomes not described
No DSA data or formal histologic assessmentsUtilize emerging biomarker assessments to risk stratify patients for enrollment and randomization to determine timing of protocol-specified immunosuppression change/increase/decrease, and as surrogate end points (e.g., blood genomic profiling, molecular assessment of kidney transplant biopsy tissue, urinary chemokines and mRNA, blood donor–derived cell-free DNA).
CONVERTCalcineurin inhibitor to sirolimus conversion at 6–120 mo was associated with inferior outcomes in those with GFR<40 and proteinuria in those above GFR 40Randomized by GFR and not by histologic features (e.g., IFTA with lack of glomerulosclerosis)
ZEUSCyclosporin to everolimus conversion at 4.5 mo was associated with higher GFR but more rejection and higher discontinuation rateNo DSA data or formal histologic assessments
BESTBelatacept/early steroid withdrawal with depleting antibody induction was not superior to TAC/early steroid withdrawalNo long-term GFR follow-up or formal histologic assessments
  • MMF, mycophenolate; DSA, donor-specific antibody; AR, acute rejection; IFTA, interstitial fibrosis and tubular atrophy; TAC, tacrolimus.