Sunday, November 11, 2012

Certican (Everolimus) in combination with reduced exposure to Tacrolimus in Liver transplant patients reduces incidence of BPAR and provides superior renal function at end of two years

At the 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Boston, MA, USA, Novartis presented 24 month data on Certican in Liver transplant patients. The 12-month results from this study were first presented as a scientific poster at the 62nd AASLD Annual Meeting in November 2011, Certican is already approved by European Health Authorities for the prophylaxis of organ rejection in adult patients receiving a liver transplant. In the US, approval for use in liver transplant patients is expected by the end of 2012.


Clinical Trial Design 
The Phase III, multicenter, open-label, randomized, controlled study was conducted in 719 de novo liver transplant patients. Four weeks following liver transplantation, patients treated with tacrolimus and corticosteroids (with or without mycophenolate mofetil) were randomized to one of three groups:  
  1. Certican (C0 3-8ng/mL) in combination with reduced-exposure tacrolimus (C0 3-5ng/mL) (n=245), 
  2. Certican (C0 6-10ng/mL) followed by tacrolimus withdrawal at four months (n=231)
  3. Standard-exposure tacrolimus (C0 6-10ng/mL) only (control, n=243). All three study arms included twice-daily treatment
All arms included corticosteroids for at least six months post-transplant. 
Study Endpoints
The  endpoints assessed at 24 months included the 
1) Composite efficacy failure rate (treated biopsy proven acute rejection [tBPAR], graft loss, or death) and its individual components, and change in renal function. 
2)Key safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs) 
Trial Results 
Safety
At month 24, the incidence rates for Certican with reduced tacrolimus vs. the tacrolimus control group for any AEs (96.3% vs. 97.9%) and any SAEs (56.3% vs. 54.1%) were comparable.
 
Efficacy
At 24 months, the incidence of composite efficacy failure (Kaplan-Meier estimates) was numerically lower with Certican with reduced tacrolimus compared to the tacrolimus control group (10.3% vs. 12.5%; risk difference -2.2%; [97.5% CI: -8.8%, 4.4%]; p=0.452). The incidence of BPAR was significantly lower with Certican with reduced tacrolimus compared to the tacrolimus control group (6.1% vs. 13.3%; risk difference: -7.2% [95% CI: -13.5%, -0.9%]; p=0.010). The incidence rates of graft loss, death, and tBPAR were comparable between the two groups. Superior renal function was maintained at month 24 with Certican with reduced tacrolimus compared with standard tacrolimus (mean difference in eGFR change: 6.7 mL/min/1.73m2 [97.5% CI: 1.9, 11.42]; p=0.0018) (ITT population). For on-treatment patients, the difference in eGFR at month 24 was 11.5 mL/min in favor of Certican with reduced tacrolimus



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