OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation

Abstract

Background: The once-daily (QD), prolonged-release formulation of tacrolimus has been shown to improve adherence versus twice-daily (BD) tacrolimus. Treatment nonadherence in transplant recipients has been associated with poor graft outcomes.

Methods: This open-label, parallel-group study randomized adults with end-stage renal disease undergoing primary kidney transplantation or retransplantation to an initial dose of tacrolimus BD 0.2 mg/kg per day (Arm 1; n=309), QD 0.2 mg/kg per day (Arm 2; n=302), QD 0.3 mg/kg per day (Arm 3; n=304) all with mycophenolate mofetil and corticosteroids (tapered) over 24 weeks, or tacrolimus QD 0.2 mg/kg per day with mycophenolate mofetil, basiliximab, and corticosteroids given only perioperatively (Arm 4; n=283). The primary composite endpoint (efficacy failure; per protocol set) was defined as graft loss, biopsy-confirmed acute rejection, or graft dysfunction at week 24. Graft dysfunction was defined as estimated glomerular filtration rate Modification of Diet in Renal Disease-4 formula of less than 40 mL/min/1.73 m(2). The prespecified noninferiority margin was 12.5%.

Results: The per protocol set included 976 patients: 237, 263, 246, and 230 patients in Arms 1 to 4, respectively. Noninferiority of the composite endpoint was demonstrated for Arm 2 versus Arm 1; Kaplan-Meier estimates of efficacy failure were 42.2% and 40.6%, respectively (difference, -1.6%; 95% confidence interval [CI], -12.2% to 9.0%). Noninferiority to Arm 1 was not confirmed for Arm 3 (difference, -3.5%; 95% CI, -13.6% to 6.6%) or Arm 4 (difference, -7.1%; 95% CI, -16.1% to 1.9%). Graft dysfunction (estimated glomerular filtration rate <40 mL/min/1.73 m(2)) was the main determinant of composite-endpoint efficacy failure across all arms.

Conclusions: In patients representative of the European kidney transplant population, tacrolimus QD-based immunosuppression (0.2 mg/kg/day), without induction, showed similar efficacy to 0.2 mg/kg per day tacrolimus BD.

Trial registration: ClinicalTrials.gov NCT00717470.

FIGURE 1

Patient populations and reasons for discontinuation. Patients were excluded from the PPS for major protocol violations; the rate of exclusion ranged from 13.6% to 22.2% across arms. The most commonly reported protocol violation was a deviation of the initial dose of study drug that was either greater than or less than 10% of the recommended dose. Bas, basiliximab; FAS, full anaysis set; PPS, per protocol set; SAF, safety set.

FIGURE 2

Primary endpoint: (A) efficacy failure rates (PPS) and (B) efficacy failure rates (FAS). Data represent the first event for each patient. BCAR, biopsy-confirmed acute rejection; CS, corticosteroid; FAS, full analysis set; PPS, per protocol set.

FIGURE 3

Measurements of (A) eGFR at 24 weeks (FAS), (B) time course of eGFR in patients who received a kidney from a deceased donor (FAS), and (C) time course of eGFR in patients who received a kidney from a living donor (FAS). The least-squares mean values for eGFR were 48.3, 45.7, and 45.9 mL/min/1.73 m² in Arms 1 to 3, respectively, versus 41.7 mL/min/1.73 m² in Arm 4 (P<0.001). Bas, basiliximab; CS, corticosteroid; MMF, mycophenolate mofetil; Tac, tacrolimus.