A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation

Abstract

A previous nonblinded, randomized, single-center renal transplantation trial of single-dose rabbit anti-thymocyte globulin induction (SD-rATG) showed improved efficacy compared with conventional divided-dose (DD-rATG) administration. The present multicenter, double-blind/double-dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD-rATG versus DD-rATG induction for noninferiority in early (7-day) safety and tolerability. Ninety-five patients (randomized 1:1) received 6 mg/kg SD-rATG or 1.5 mg/kg/dose DD-rATG, with tacrolimus-mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12-month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD-rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD-rATG induction to be noninferior to DD-rATG induction in early tolerability and equivalent in 12-month safety. (Clinical Trials.gov #NCT00906204.).

Figure 1

CONSORT (Consolidated Standards of Reporting Trials) chart of patient flow through the study. Included patients were 18‐ to 70‐year‐old primary kidney recipients of ABO (A, B, or O blood type)‐compatible living, deceased, or extended‐criteria donors with Nyberg scores ≤30 25. Additional requirements were panel reactive antibody (PRA) <75%, cold ischemic time <30 h, and, if pumped, kidney resistance <0.35 mmHg/mL/min with flow rate >60 mL/min.

Figure 2

Primary and secondary end points. (A) Occurrence of primary composite end point events among study patients. (B–E) Posttransplant assessments of secondary (12‐month) safety end point data on days 21, 42, 90, 180, 270, and 365.

Figure 3

Hematologic effects of rabbit anti–thymocyte globulin ( rATG ) induction regimen. The same patients provided data for all six graphs. There was generally more rapid (but not statistically significant) immune cell count recovery among the single‐dose (SD) group.