A randomized, double-blind study of Neoral vs. Sandimmune in primary liver transplant recipients with two year follow up.

Abstract

46 A double-blind, multi-center, randomized, two-year trial was conducted to compare the Neoral formulation (NEO) of cyclosporine to the traditional Sandimmune formulation (SIM) in de novo liver transplant patients.Aim: The primary purpose of the study was to assess the safety of NEO relative to SIM. Methods: 325 patients from 15 centers were randomized(1:1) and received either NEO (n=161) or SIM (n=164) as primary immunosuppressive therapy. Following initial IV cyclosporine therapy, patients were started on oral cyclosporine at 10 mg/kg/day and dose titrated to target trough levels according to study protocol. Steroid and azathiprine were administred according to local protocol. No antilymphocyte preparations were used for induction. Frequent study visits to assess vital sign, laboratory values and other safety and efficacy parameters were scheduled at specified intervals. Key endpoints being patient and graft survival, acute cellular rejection episodes (ACR) and adverse event profiles. Patients who discontinued from study medication were asked to participate in a follow-up phaseof data collection to complete the two years duration of the study: These data were used for an ITT analysis. Results: Key patient demographics were comparable between the two groups. One and two year patient survival rates also did not differ between groups, (Actual 1yr patient SR = NEO 93.6%vs SIM 90.8%. Retransplantation with in 1 year: N -6.5% vs S- 6.8%. Actual 2 yr patient SR was identical N- 84.2% vs S-86.6%. Retransplantation by the end of the second year occurred in N- 9.3% vs S-7.7% (p=ns). The number of patients experiencing biopsy-confirmed ACR was comparable in the two groups - NEO = 98(62.7%) vs. SIM = 94 (59.1%), with the severity of the rejection and the incidence of steroid resistant rejection (18.5% for NEO and 20.0% for SIM) also being comparable. The incidence of major adverse events, i.e., hypertension, hyperlipidemia, renal insufficiency, infections, and neurologic symptoms were also comparable for the two groups. Patients randomized to the NEO group were weaned off cyclosporine I.V. more rapidly, median days 6 vs 7(p =0.02). Patients discontinued from study medications during the follow-up period totaled 129, 66 in the NEO group vs. 63 in the SIM group; primary reasons for discontinuations were adverse events including patient death,(N-14% vs. S-13%). Discontinuation for treatment failurewasN- 15.5% vs. S-15.8%. Mean cyclosporine doses after 24 months in study were 3.7 ±1.7 vs. 3.9 ± 2.1 mg/kg/day and trough cyclosporine levels 202 ± 95 vs. 213 ± 101 ng/mL for the NEO and SIM groups respectively.Conclusion: Excellent patient and graft survival were seen in both NEO and SIM treatments arms, with less IV. cyclosporine use in the NEO treated group. This is as good or better than any other liver recipient patient and graft survival published to date. In spite of the greater exposure provided by the NEO formulation, there were no more adverse events in the NEO group.