An open-label, randomized, phase 3 study of the efficacy and safety of antithrombin gamma in patients with sepsis-induced disseminated intravascular coagulation syndrome

Abstract

Background: A recombinant form of antithrombin (AT), called AT gamma, is being developed as an alternative to AT derived from human plasma. To compare the efficacy and safety of AT gamma to plasma-derived AT (pAT), we conducted a randomized, open-label, multicenter trial in patients with sepsis-induced disseminated intravascular coagulation (DIC).

Methods: Eligible patients, recruited at 30 clinical sites, had been diagnosed with sepsis-induced DIC (by the Japanese Association for Acute Medicine [JAAM] DIC criteria) and AT activity at 70% or below. Patients were randomized 1:1 to either 36 IU/kg/day AT gamma (n = 110) or 30 IU/kg/day pAT (n = 112), both administered intravenously for 5 days. The primary endpoint was recovery from DIC at day 6 or early study withdrawal. DIC recovery was defined as a DIC score of less than four. Secondary endpoints were DIC score, outcome on day 28, sequential organ failure assessment score, acute physiology and chronic health evaluation II score (APACHE II), and plasma AT activity. Adverse events and adverse drug reactions were recorded using MedDRA/J version 16.0.

Results: Baseline patient demographics and clinical features were similar in the two treatment groups. On day 6 (or at withdrawal), DIC recovery had occurred in 62 of 110 (56.4%; 95% confidence interval, 46.6-65.8%) patients in the AT gamma group and 59 of 112 (52.7%; 95% confidence interval, 43.0-62.2%) patients in the pAT group. In both treatment groups, DIC recovery rate values tended to be higher when stratified by baseline AT activity rates. All changes in other secondary endpoints were similar in both treatment groups. Safety was also similar in the two treatment groups. Adverse events occurred in 89 of 108 (82.4%) patients in the AT gamma group and 99 of 113 (87.6%) patients in the pAT group.

Conclusions: Safety and efficacy were similar for 36 IU/kg/day AT gamma and 30 IU/kg/day pAT. These results confirm that AT gamma is an excellent alternative to pAT for improving outcomes for patients with DIC.

Trial registration: ClinicalTrials.gov identifier: NCT01384903; June 2011.

Keywords: AT activity; AT gamma; DIC; DIC recovery; JAAM DIC criteria; Potelligent®; Recombinant form of human AT; Survival.

Conflict of interest statement

This study was approved by all local ethics committees at participating institutions. All patients provided written informed consent. The protocol was approved by the institutional review boards of all participating institutes (see “Acknowledgements”).Not applicable.SE has received consulting/lecture fees and research funding from Kyowa Hakko Kirin Co., Ltd. RS is employed by Kyowa Hakko Kirin Co., Ltd.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Study design. Eligible patients were randomized 1:1 to either 36 IU/kg/day AT gamma or 30 IU/kg/day pAT administered intravenously for 5 days. After 5 days of treatment, patients were examined on day 6 to assess DIC recovery and on day 28 to assess mortality. Heparins were also administered, except in patients for whom concomitant use of heparins could have increased the risk of bleeding

Fig. 2

Patient disposition

Fig. 3

Changes in secondary endpoints during the study. The a DIC score (calculated from DIC scores for four categories [systemic inflammatory response syndrome, platelets, PT ratio, and FDP] of the JAAM DIC criteria), b plasma AT activity, c SOFA score, and d APACHE II score were assessed during the treatment and follow-up periods. The graphs show the mean values at each time point for the AT gamma (black) and pAT (gray) groups. The error bars indicate the standard deviation at each time point. APACHE, acute physiology and chronic health evaluation; AT, antithrombin; DIC, disseminated intravascular coagulation; discont., discontinuation or withdrawal; JAAM, Japanese Association for Acute Medicine; pAT, plasma-derived antithrombin; SOFA, sequential organ failure assessment