A 24 month, multicenter, randomized, open-label safety and efficacy study of concentration-controlled everolimus with reduced calcineurin inhibitor vs mycophenolate with standard calcineurin inhibitor in de novo renal transplantation- Advancing renal TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen (TRANSFORM)

In renal transplant patients, chronic allograft nephropathy (interstitial
fibrosis and tubular atrophy) is the main cause of graft failure.
Calcineurin-inhibitors (CNI*s) represent the cornerstone of immunosuppressive
therapy due to their efficacy in preventing acute rejection. However, CNIs have
nephrotoxic side effects that can directly contribute to renal dysfunction and
compromise long-term outcomes.
Several reports have shown that improvements in graft half-life are related to
conservation of renal function within the first-year post-transplantation.
Therefore, treatment strategies that allow adequate
immunosuppression to control rejection, avoid nephrotoxicity and improve
long-term outcomes are sought.
The de novo use of everolimus with CNI minimization provides an opportunity to
manage the risk of acute allograft rejection, reduce exposure to CNI
nephrotoxicity without compromising efficacy and potentially provide long-term
benefits. Studies show that a regimen with de novo everolimus and CNI
minimization is at least as effective as standard CNI-based regimens in terms
of patient and allograft survival rates, with some improvements in renal
function.
The present study builds on existing evidence and, with an innovative novel
endpoint, combining renal function and allograft rejection, aims to demonstrate
that de novo concentration-controlled everolimus, plus very low levels of CNI,
will lead to better overall graft outcomes, as compared to current standard of
care, being Mycophenolic acid (MPA) plus standard dose CNI.

Primary: to evaluate the effect of everolimus with reduced exposure CNI versus
MPA with standard exposure CNI on the binary composite of treated biopsy-proven
acute rejection (tBPAR) or eGFR < 50
mL/min/1.73m2 at Month 12 post-transplantation.
Key secondary: To evaluate everolimus with reduced exposure CNI compared to MPA
plus standard exposure CNI at 12 months post-transplantation with respect to
the composite efficacy failure rate (tBPAR, graft loss or death). To evaluate
the binary composite endpoint of tBPAR or eGFR < 50 mL/min/1.73m2 (MDRD4) Month
12 among compliant subjects.
Full listing of objectives: see protocol page 15-16.

Randomized, open-label phase IV study.
Randomization (1:1) to
* Everolimus plus low dose Tacrolimus or Cyclosporine
* Mycophenolic acid plus standard dose Tacrolimus or Cyclosporine.
Treatment duration approx. 2 years.
2040 patients.

Treatment with everolimus plus low dose Tacrolimus or Cyclosporine or treatment
with Mycophenolic acid plus standard dose Tacrolimus or Cyclosporine.

Risk: Adverse effects of study medication.
Burden: Study duration approx. 2 years. Approx. 13 visits (1-2 h).
Physical examination yearly.
Blood and urine tests every visit. Approx. 6 ml blood per occasion extra
compared to standard treatment, approx. 100 ml in total.
Pregnancy test every 6 months.
Kidney biopsy if medically indicated.
Optional tests: kidney biopsy (every year, NOT in NL), blood tests for
antibodies (yearly, 5 ml blood per occasion).