Tacrolimus QD Is Equivalent to Tacrolimus BID in All Measures of Clinical Efficacy

Abstract

Introduction: Two large prospective studies of tacrolimus prolonged release (QD) versus tacrolimus immediate release (BID) were performed in de novo renal transplantation. Both studies were designed as non-inferiority trials of tacrolimus QD and tacrolimus BID in combination with mycophenolate mofetil and low-dose corticosteroids. The first study (12-03) was a double-blind, double-dummy, randomized controlled trial, and the second study (OSAKA) was an open-label, parallel-group trial. In these studies, efficacy was assessed after 6 months (24 weeks) in terms of biopsy-confirmed acute rejection rates (BCAR; Study 12-03) and a composite endpoint following EMA guidelines (graft loss, BCAR, renal dysfunction at the end-of-study visit; Study OSAKA). The present analyses investigate different efficacy parameters on the basis of a combined database. Methods: Data from both studies (full analysis sets) were combined to one common database. In these studies, patient and graft survival, BCAR (local pathology), and renal function (eGFR; MDRD4-algorithm) data at end-of-study, follow-up or last visit were assessed. For the present analyses, data were collected up to the formal end-of-study visit or the follow-up visit. In these analyses, evaluation was performed according to the single endpoint of BCAR, the US FDA composite endpoint (graft loss, BCAR, loss to follow-up) and the EMA composite endpoint. Renal dysfunction was defined as eGFR < 40mL/min/1.73m2. The 95% confidence intervals were calculated taking a 10% margin for non-inferiority. Results: The combined database included 633 patients receiving tacrolimus QD (331 patients from study 12-03, 302 from OSAKA) and 645 patients receiving tacrolimus BID (336 patients from 12-03, 309 from OSAKA). Treatment group demographics were well balanced with the majority of organs from deceased male donors aged < 60 years. The rate of study completers was 78.5% (497/633) in the tacrolimus QD group and 83.1% (536/645) in the tacrolimus BID group. The incidence of BCAR was 13.9% versus 14.1% in the tacrolimus QD and BID groups, respectively. The US FDA composite endpoint was reached by 21.5% of tacrolimus QD-treated and 19.8% of tacrolimus BID-treated patients, and the EMA composite endpoint was reached by 40.3% of patients in the tacrolimus QD group and 38.3% in the tacrolimus BID group. Differences in incidence were between -0.2% and +2.0% and the 95% confidence intervals were between -4.0% and +7.4% (Table).Conclusions: Results from a combined database including data from a double-blind study and data from an open-label study reveal that standard efficacy endpoints (BCAR, US FDA and EMA composite endpoints) demonstrate non-inferiority of tacrolimus prolonged-release versus tacrolimus immediate-release treatment.