A partially blinded, prospective, randomized multicenter study evaluating efficacy, safety and tolerability of oral sotrastaurin plus standard or reduced exposure tacrolimus vs. myfortic plus tacrolimus in de novo renal transplant recipients (CAEB071A2214)

Over the past decades, organ allotransplantation has become a common medical
procedure with considerable impact on extending and improving the quality of
life of patients with end stage renal, cardiac, hepatic or pulmonary failure.
To maximize efficacy and minimize adverse effects, current immunosuppressant
(IS) regimens use combinations of IS drugs. Care is taken to achieve synergy or
additive immunosuppressive effects via the administration of sub-maximal doses
of agents with different mechanism of action while avoiding overlapping
toxicities. Most regimens currently include a regimen of a calcineurin
inhibitor (CNI) such as cyclosporine or tacrolimus, together with a lymphocyte
proliferation inhibitor such as mycophenolic acid or mycophenolate mofetil.
Sotrastaurin (STN) is a novel IS that blocks early T-cell activation via
inhibition of protein kinase C (PKC). It is a highly potent and selective
inhibitor of the classical (α, β) and novel (δ, *, *, *) PKC isoforms (Ki
values range from 0.2 to 3.2nM). The role of PKC isoforms in immune cell
signaling is still under intense investigation. At the cellular level, early
T-cell activation, but not T-cell proliferation, is strongly inhibited by
sotrastaurin as assessed by interleukin-2 (IL-2) secretion.

Primary objectives
The primary objective of the study is demonstrate that at least one of the
sotrastaurin treatment arms is non-inferior to the active control regimen
myfortic + tacrolimus with respect to composite efficacy failure (treated BPAR
of grade IA or higher, graft loss, death or lost to follow up) at Month 6
post-transplantation.
Secondary objectives
• Evaluate renal function at Months 6, 12, 24 and 36 post-transplantation using
o Estimated GFR (eGFR) by MDRD formula (eGFRMDRD),
o A composite renal function endpoint defined as eGFRMDRD < 60 mL/min/1.73 m2
at Month 12, or a decrease from Month 3 to Month 12 >= 10 mL/min/1.73 m2 in each
sotrastaurin treatment arm relative to the control regimen (Month 12 analysis
only),
o Estimated creatinine clearance using the Cockcroft-Gault formula.
• Evaluate the composite efficacy endpoint in the sotrastaurin arms and the
control arm at Months 12, 24 and 36 post-transplantation.
• Evaluate individual components (and combinations of the individual
components) of the composite efficacy endpoint in the sotrastaurin arms and the
control arm at Months 6, 12, 24 and 36 post-transplantation.
• Evaluate safety and tolerability between the sotrastaurin arms and the
control arm, including infections, GI tolerability, ECG parameters, and
hematological parameters (e.g. neutrophils) at Months 6, 12, 24 and 36
post-transplantation.

This study is a 3-year, randomized, multicenter, partially blinded, 4-arm study
comparing the efficacy and evaluating the safety of oral sotrastaurin +
standard or reduced exposure tacrolimus versus the active control myfortic +
standard exposure tacrolimus for initial and maintenance prophylaxis of organ
rejection in adult de novo renal transplant patients.
Upon meeting inclusion-exclusion criteria, approximately 300 patients
(approximately 75 per treatment arm) will be randomized (1:1:1:1) within 24
hours following transplantation. Randomization will be stratified by donor
source (living vs. deceased donor) using a
centralized randomization procedure:
• Arm 1: sotrastaurin 100 mg b.i.d. + standard exposure tacrolimus
• Arm 2: sotrastaurin 200 mg b.i.d. + standard exposure tacrolimus
• Arm 3: sotrastaurin 300 mg b.i.d. + reduced exposure tacrolimus
• Arm 4 (control arm): myfortic 720 mg b.i.d. + standard exposure tacrolimus
The daily dose of tacrolimus will be adjusted to maintain target concentrations:
• Standard exposure tacrolimus (whole blood trough levels > 5 - 12 ng/mL)
• Reduced exposure tacrolimus (whole blood trough levels 2 - 5 ng/mL).
The combination of STN + Tac and myfortic + Tac will be considered as study
drugs. All patients will receive induction treatment with basiliximab 20 mg on
study Day -1 (the day of kidney transplant surgery) and Day 4 (or on the day of
discharge if sooner than Day 4) and will receive corticosteroids through Month
36.
• Patients randomized to Arms 1 and 2 will receive blinded sotrastaurin 100 mg
b.i.d. or 200 mg b.i.d., plus matching placebo
• Patients randomized to Arm 3 (sotrastaurin + reduced exposure tacrolimus)
will receive open-label sotrastaurin 300 mg b.i.d.
• Patients randomized to Arm 4 will receive blinded myfortic 720 mg b.i.d.,
plus matching placebo.
Data Monitoring Committee.

Treatment with sotrastaurin + tacrolimus or standard treatment mycophenolic
acid + tacrolimus.

Risk: Adverse events of study treatment. Insufficient efficacy of (one of) the
experimental treatment arms.
Burden: 21 visits in 3 yearss. All visits: vital signs and blood draws (10-15
ml per visit, 300 ml in total). 11x physical examinations, 21x EKG, 11x
pregnancy test (if applicable).
The study burden is not significantly different from regular treatment.
Basiliximab infusions (2) are also given during regular care.
Optional PK substudy: not in NL.