A 24-month, multi-center, open-label, randomized, controlled trial to investigate efficacy, safety and evolution of cardiovascular parameters in de novo renal transplant recipients after early calcineurin inhibitor to everolimus conversion (CRAD001A2429, ELEVATE study)

The introduction of the immunosuppressive agent Sandimmun Neoral (cyclosporine
A, CsA) significantly improved the outcome of clinical renal transplantation in
the eighties by reducing acute rejection rates and increasing patient and graft
survival. CsA and the later introduced
drug tacrolimus, both known as calcineurin inhibitors (CNIs), are at present
the cornerstones in most of the immunosuppressive protocols used worldwide.
Although CNIs have a well documented prophylactic effect against severe acute
rejections, they do not prevent the development of chronic allograft
nephropathy (CAN)/interstitial fibrosis and tubular atrophy (IF/TA) leading to
a substantial graft loss in the long term . In addition an increased risk for
cardiovascular morbidity and of malignancies was reported as two major other
long term threads for transplanted patients, which also might be aggravated by
CNIs . The ultimate goal of immunosuppressive therapy after organ
transplantation is to provide an efficacious regimen while minimizing side
effects. By the combination of synergistic immunosuppressants it may be
possible to reduce the exposure to individual drug and therefore avoid adverse
events whilst maintaining favorable clinical outcomes. For that reason there
has been an increasing interest to explore combination of treatments that allow
for reduction in CNI exposure, as this may potentially enhance long term
outcomes. The introduction of new immunosuppressive agents may offer the
opportunity to reduce renal toxicity and cardiovascular risk factors, without
impairment of efficacy. Such recent advances in immunosuppression, especially
the introduction of mycophenolic acid (MPA) and proliferation signal inhibitors
(PSI), also called mTOR inhibitors, have led to the evaluation of new
immunosuppressive strategies with CNI minimization or elimination early post
transplantation in stable patients.
Mycophenolate mofetil (MMF) may also allow withdrawal of CNIs in maintenance
recipients . However, the addition of MMF does not permit early withdrawal or
completely CNIs-free regimens, without a significant increase in acute
rejections. In contrast, results of cyclosporine reduction in combination with
a proliferation signal inhibitor, i.e. everolimus or sirolimus based therapy
after early cyclosporine withdrawal, are particularly encouraging.
Everolimus (RAD, [40-O-[2-hydroxyethyl]-rapamycin], SDZ RAD, RAD001) is a
proliferation signal inhibitor that has been developed for use in combination
with Neoral® (cyclosporine for micro-emulsion) for the prophylaxis of acute
rejection and the prevention of chronic rejection in patients receiving
allogeneic kidney and heart transplants. There are experimental and clinical
data indicating that PSIs reduce the development of CAN/IFTA, by their
antiproliferative qualities, making CNI-reduction feasible. In heart
transplanted recipients PSIs have been shown to reduce cardiac allograft
vasculopathy. There is also evidence of anti-tumour properties of these drugs,
demonstrated in experimental as well as in clinical studies.
On the other hand PSIs have a known interaction in combination with CNIs as
they amplify the CNI-nephrotoxicity and thus requiring a thorough dosing and
monitoring of both drugs. Other side effects reported for PSIs are
hyperlipidemia and wound healing problems. There are still few number of
reports of completely CNI-free regimens, using PSIs as the initial
immunosuppression in de novo renal recipients. So it is evident that, although
CNI-free immunosuppression now is a realistic opportunity by the use of PSIs,
the optimal design of such a protocol remains to be investigated.
An alternative strategy is to delay the introduction of PSIs, until the risk of
initial wound healing problems has subsided. By then making an early and rapid
switch from CNIs to PSIs, the duration of nephrotoxic exposure would be
reduced. Such a switch has safely been made in maintenance patients, but no
controlled studies of early conversions from CNIs to PSIs are yet available.
One might assume that an early switch could cause a higher risk of acute
rejections, since this was found in studies of early CsA withdrawal in
combined treatments. However, in these withdrawal studies, MMF and anti-IL-2
induction were not used. By adding these drugs together with steroids as in the
former CNI-free protocols, one would expect that an early and rapid switch
10-14 weeks after renal transplantation from CNIs to PSIs would be possible,
without an unacceptable increase in rejection. The risk of increased rejection
rates after early elimination of CNI could be further reduced, if sensitized
patients or patients that were already treated for severe acute rejections
would be excluded from the switch.
To summarize, although PSIs may have a potential to improve the long term
condition for renal allograft recipients, by reducing CAN/IFTA, malignancies
and cardiovascular morbidity, the optimal way to use everolimus in routine
protocols for de novo transplantations still remains to be clarified. Thus, the
use of a protocol with an early conversion from CNIs to everolimus would be an
option of great potential.
Therefore, this controlled study was designed in order to test an
immunosuppressive protocol based on steroids, enteric coated Mycophenolic
Sodium and basiliximab, and an early switch from CNI to everolimus, with the
primary objective to improve the long-term function of renal allograft.

Primary objective: To demonstrate superior renal allograft function in de novo
renal transplant recipients after early CNI to everolimus conversion assessed
by Glomerular Filtration Rate (eGFR) estimated by the Modification of Diet in
Renal Disease formula 4 (MDRD4) at month 12 versus the active control.
Secundary objectives: Major: 1. To demonstrate non-inferior efficacy (defined
by a composite efficacy endpoint of treated Biopsy Proven Acute Rejection
(BPAR) * IB, graft loss or death) at month 12. 2. To demonstrate improvement of
Left Ventricular Hypertrophy as assessed by
LV mass index (LVMi) using echocardiogram at month 12. Others: after 12 and 24
months: individual components of composite endppoint, acute rejection, graft
function (various parameters), side effects, cardiovascular events.
Substudies (to be performed in all NL centres): arterial stiffness, 24 hour
blood pressure measurement, PK sodium mycophenolate.

Multicenter randomized open phase IIIB parallel group study.
Run-in period of 10-14 weeks after transplantation with standard treatment
(induction with basiliximab 20 mg infuxion on day 0 and 4, tacrolimus C0: 6-12
ng/mL, sodium mycophenolate1.08 - 1.44 g/day, steroids according to local
protocol, but at least 5 mg/day).
After 10-14 weeks randomization (1:1) to:
1. Continuation run-in treatment (however, tacrolimus C0: 5-10 ng/mL).
2. Conversion from tacrolimus to everolimus (C0 through level 6-10 ng/mL).
Overnight replacement or stepwise within 1 week.
Total study duration 2 years.
Approx. 670 patients.
Independent data safety monitoring board.

Conversion from CNI to everolimus or continuation of CNI.

Risk: side effects of study medication, renal biopsy.
Burden: 14 visits in 2 years. Physical exam and blood test during each visit
(approx. 10-30 (2x 45-50) mL/visit, approx. 400 mL in total). Screening for HIV
and hepatitis B-C.
In addition: renal biopsy 2x (plus 1 during transplantation), echocardiogram
3x, pregnancy test 2x, arterial stiffness 3x, 24 hour blood pressure
measurement (ambulatory) 3x.
2 visits with extended measurments (5-9 h) related to PK.