Rationale and design of the DIRECT study: a comparative assessment of the hyperglycemic effects of tacrolimus and cyclosporine following renal transplantation

Abstract

Increased risk of cardiovascular disease contributes significantly to the higher rate of mortality seen in kidney transplant patients compared to the general population. New-onset diabetes mellitus (NODM) is a major risk factor for cardiovascular disease, as well as being associated with significantly increased graft loss and higher health care costs compared to the nondiabetic transplant population. Evidence from large-scale analyses of registry databases has shown that the calcineurin inhibitor, tacrolimus, is associated with approximately a 50% increase in the risk of NODM compared to the microemulsion formulation of cyclosporine (CsA); but to date, little robust evidence is available from clinical trials. The DIRECT (Diabetes Incidence after REnal transplantation: Neoral® C 2 monitoring versus Tacrolimus) study will be the first prospective trial to compare directly the impact of tacrolimus and CsA microemulsion on glucose metabolism in kidney transplant recipients. DIRECT is a 6-month, parallel-group, open-label, randomized trial for which approximately 700 patients will be recruited at around 70 transplant centers worldwide. Patients will be randomized to tacrolimus or CsA microemulsion (using C 2 monitoring), with mycophenolate mofetil or enteric-coated mycophenolic acid, steroids, and basiliximab. Primary endpoints are: (a) a composite of NODM or impaired fasting glucose among patients who are nondiabetic at time of transplantation; and (b) combined incidence of biopsy-proven acute rejection, graft loss, or death with CsA microemulsion C 2 monitoring compared to tacrolimus trough monitoring . Full results are expected in 2006, with interim results available by the end of 2004, and will be awaited with interest by the transplant community.