Efficacy of sotrastaurin plus tacrolimus after de novo kidney transplantation: randomized, phase II trial results.
Russ GR, Tedesco-Silva H, et al.American Journal of Transplantation 2013; 13(7):1746-56.
Aims
To investigate the efficacy and safety of sotrastaurin with tacrolimus in a dose-ranging non-inferiority study of renal transplant recipients.
Interventions
The four treatment groups included (1) sotrastaurin (STN) 100mg b.i.d. + standard tacrolimus (sTAC); (2) STN 200mg b.i.d.+ sTAC:; (3) STN 300mg b.i.d. + reduced tacrolimus ); (4) mycophenolic acid 720mg b.i.d. + sTAC All patients received basiliximab and corticosteroids.
Participants
298 adult first or second renal transplant patients.
Outcomes
The primary outcomes include the composite of treated biopsy proven acute rejection of grade IA or higher, graft loss, death or loss to follow up at 6 months post transplant. Secondary outcomes included the incidence of composite efficacy endpoint and the individual components at month 12 and combinations of individual components at months 6 and 12.
Follow-up
36 months.
CET Conclusions
This somewhat complex phase II trial investigated the role of the Protein Kinase C inhibitor Sotrastaurin at various doses in combination with Basiliximab, steroids and tacrolimus following renal transplantation. Results are difficult to interpret due to the varying doses of Sotrastaurin and Tacrolimus employed in the four arms, and the varying statistical models used to analyse the data. The use of low dose (100mg) Sotrastaurin was discontinued after 12 months due to an excess of biopsy-proven acute rejection (BPAR). Both 200mg Sotrastaurin with standard tacrolimus dosing, and 300mg Sotrastaurin with reduced tacrolimus dosing, appear as effective at preventing BPAR as a standard dose tacrolimus and mycophenolate regimen. Whilst the 300mg group demonstrated non-significantly improved 12 month renal function, there was a dose-related increase in adverse events including anaemia, tachycardia and gastrointestinal side effects. It should be noted that the trial included only low risk recipients (and excluded DCD donors), and was only partially blinded. Due to the limited benefits seen over standard immunosuppression in this and other phase II trials, development of Sotrastaurin has been halted.
Data analysis
Available case analysis
Trial registration
ClinicalTrials.gov - NCT01064791