Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients.
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Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients. / Friman, S; Arns, W; Nashan, Björn; Vincenti, F; Banas, B; Budde, K; Cibrik, D; Chan, L; Klempnauer, J; Mulgaonkar, S; Nicholson, M; Wahlberg, J; Wissing, K-M; Abrams, K; Witte, S; Woodle, E S.
In: AM J TRANSPLANT, Vol. 11, No. 7, 7, 2011, p. 1444-1455.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Sotrastaurin, a novel small molecule inhibiting protein-kinase C: randomized phase II study in renal transplant recipients.
AU - Friman, S
AU - Arns, W
AU - Nashan, Björn
AU - Vincenti, F
AU - Banas, B
AU - Budde, K
AU - Cibrik, D
AU - Chan, L
AU - Klempnauer, J
AU - Mulgaonkar, S
AU - Nicholson, M
AU - Wahlberg, J
AU - Wissing, K-M
AU - Abrams, K
AU - Witte, S
AU - Woodle, E S
PY - 2011
Y1 - 2011
N2 - Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (± standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 ± 22.3 vs. 49.5 ± 17.7 mL/min/1.73 m(2) , p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.
AB - Sotrastaurin, a selective protein-kinase-C inhibitor, blocks early T-cell activation through a calcineurin-independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy-proven acute rejection (BPAR), graft loss, death or lost to follow-up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (± standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 ± 22.3 vs. 49.5 ± 17.7 mL/min/1.73 m(2) , p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study-medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin-inhibitor-free regimen of sotrastaurin+MPA versus the tacrolimus-based control. Ongoing studies are evaluating alternative sotrastaurin regimens.
KW - Adult
KW - Humans
KW - Male
KW - Female
KW - Quinazolines/therapeutic use
KW - Calcineurin/antagonists & inhibitors
KW - Kidney Transplantation/physiology
KW - Mycophenolic Acid/therapeutic use
KW - Protein Kinase C/antagonists & inhibitors
KW - Pyrroles/therapeutic use
KW - Tacrolimus/therapeutic use
KW - Adult
KW - Humans
KW - Male
KW - Female
KW - Quinazolines/therapeutic use
KW - Calcineurin/antagonists & inhibitors
KW - Kidney Transplantation/physiology
KW - Mycophenolic Acid/therapeutic use
KW - Protein Kinase C/antagonists & inhibitors
KW - Pyrroles/therapeutic use
KW - Tacrolimus/therapeutic use
M3 - SCORING: Journal article
VL - 11
SP - 1444
EP - 1455
JO - AM J TRANSPLANT
JF - AM J TRANSPLANT
SN - 1600-6135
IS - 7
M1 - 7
ER -
