A twelve-month, multicenter, open-label, randomized study of the safety, tolerability and efficacy of Certican* with Simulect, corticosteroids and two different exposure levels of tacrolimus in de novo renal transplant recipients

Kidney transplantation without immunosupression is unfortunately not possible.
Almost all immunopsupressives have side-effects. The standard-of-care therapy
at this moment at the UMC Utrecht consists of tacrolimus, mycophenolate
mofetil, and, for a number of months, prednisone.

In patients who are at increased immunsupressive risk, or who are receiving
their third transplant, an IL-2 receptor antagonist is added.

One of the most unfortunate side-effects is the nephrotoxicity of calcineuron
inhibitors (tacrolimus and cyclosporine). In this protocol we attempt to
achieve better kidney function by reducing the dose of tracrolimus. Because we
nevertheless wish to provide adequate immunosuppression, other
immunospuressives must be prescribed. In this protocol we use a combination
made up of basiliximab (Simulect®), tacrolimus, everolimus (Certican*) and
prednisone in dosages which were recently used with success in a study by
Cooper et al. Data from this study has been included with application.

A similar study has also already been performed with cyclosporine as
calcineuron inhibitor. In most study centers, with Utrecht and Maastricht
included, tacrolimus is chosen over cyclosporine because tacrolimus does not
induce gingival hyperplasia and also does raises the patient*s blood pressure
with less severity.

This study is designed, therefore, to see if fit is possible to lower the
tacrolimus dosage even further after three months.

With the goal of improving kidney function and without causing an increased
number of rejections, is it possible to reduce tacrolimus dosage through the
use of the previously-mentioned immunosupressives after month three.

12 months, multicenter, randomized, open-label.

There are two phases:
In the first three months, the patients are proscribed an accepted treatment
consisting of an induction therapy of basiliximab 20 mg at day 0 and 4,
everolimus dosed at trough levels of 3 to 8 ng/mL, tacrolimus dosed at a
trough level of 4 to 7 ng/mL and a 100 mg pre-operative dose of prednisone,
followed by 20 mg per day to eventually tapered to a maintenance dose of 5 mg
by 2 months.

After three months, the control arm (B) has their medication continued in this
fashion while the study arm (A) has their tacrolimus dosing lowered to a trough
level of 1.5-3 ng/mL.

At month 3, the tacrolimus dosage in the study arm (A) is lowered.

Extra procedures
There are no visits or blood draws for study subjects on top of the regular
kidney transplant follow-up, except a 5ml tube of blood to be taken at 13
visits throughout the trial, with the purpose of determining the everolimus
trough level.

Risks
As everolimus is a new medicine, this study may bring to light new side-effects
that are presently unknown or not expected. Unexpected side effects of
immunosupressives are, among others, temporary hormonal changes, lever function
abnormalities, bone marrow suppression and increased susceptibility for
infection. In a multiple dose study of everolimus in humans it was noted that
in some subjects the platelet count (blood cells which stop bleeding) and in
some others the white blood cell count dropped. Further, there is the
possibility that the triglyceride/cholesterol level will rise. Subjects will,
however, receive a low dose of everolimus and should their doctor consider it
necessary, they will also receive a lipid-lowering agent (HMG-CoA reductase
inhibitor) which will reduce the chance of a raised cholesterol level.

The number of tacrolimus-related side effects will, however, be lower due to
the reduced dose. Further, subjects will not experience side effects from
mycophenolate mofetil, the medicine usually given concomitantly with
tacrolimus.

With every change in the immunosupressive protocol there is a chance for an
increased incidence of acute organ rejections. The chance of this is not large
during this period (months 4-12), however, and such rejections are nearly
always treatable with the standard therapies available (methylsolumedrol and
ATG).