Sotrastaurin in calcineurin inhibitor-free regimen using everolimus in de novo kidney transplant recipients.
Tedesco-Silva H, Kho MM, et al.American Journal of Transplantation 2013; 13(7):1757-68.
Aims
To investigate the efficacy and safety of two doses of sotrastaurin 300mg b.i.d. or 200mg b.i.d. against cyclosporine A (CsA) in low-risk de novo kidney transplant recipients receiving basiliximab induction, everolimus (EVR) and corticosteroids.
Interventions
The trial was a two stage study. In stage 1 patients received sotrastaurin 300mg b.i.d. or CsA combined with EVR. In stage 2 participants received sotrastaurin 300mg b.i.d. or 200mg b.i.d. or CsA combined with EVR.
Participants
Adult primary renal allograft recipients; 131 patients in stage 1 and 180 patients in stage 2
Outcomes
The primary outcomes included composite efficacy failure defined as treated biopsy proven acute rejection grade ≥1A, graft loss, death or lost to follow up. Secondary endpoints included incidences of individual components of composite efficacy failure, treated acute rejections and chronic allograft nephropathy. The safety outcomes included renal function, adverse events, gastrointestinal events, haematological adverse events, infection and heart rate.
Follow-up
3 months in stage 1 and 6 months in stage 2.
CET Conclusions
This two-stage phase II trial investigated the efficacy (stage 1) and dose range (stage 2) of the Protein Kinase C inhibitor Sotrastaurin in a CNI-free regimen of Basiliximab, corticosteroids and everolimus compared to CNI treatment with cyclosporin. The trial was open-label, and recruited only low-risk (first transplant, no DCD donors) recipients. Whilst there were numerically higher rates of efficacy failure in the Sotrastaurin arms in both stages of the trial (mainly due to increased rates of BPAR), none of these differences achieved statistical significance. There was a significant early improvement in renal function with Sotrastaurin, particularly at the higher (300mg) dose, compared to CsA/Everolimus, although this benefit reduced over time. Interestingly, there was an unexplained increase in treatment failure rates in both the CsA and Sotrastaurin arms between stage 1 and 2 of the trial, despite the same doses being employed. This does cast some doubt on the validity of the results observed. Given the lack of statistical significance in any of the reported outcomes, the authors perhaps overstate the increased risk of treatment failure with Sotrastaurin. The control-arm of everolimus and cyclosporin would not be regarded as “standard†immunosuppression in most units, and as such the results of the phase II trial comparing Sotrastaurin with Tac/MPA reported by Russ et al in the same issue of AJT is probably of more interest.
Data analysis
Available case analysis
Trial registration
ClinicalTrials.gov - NCT00504543