A Randomized, Double-Blind, Placebo-Controlled, Phase-2B Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients with Sepsis and Suspected Disseminated Intravascular Coagulation

Severe sepsis remains the most common cause of death in critically ill patients (1) and new therapeutic approaches are urgently needed. DIC is also a frequent complication of severe sepsis (3), and when present is associated with increased mortality in these patients (4, 5). Current management of DIC is primarily focused on treating any associated underlying medical condition, although use of supplemental clotting factors or platelets, or anticoagulant therapy may occasionally be required (6). ART-123 (Artisan Pharma, Waltham, MA, USA) is a soluble recombinant human thrombomodulin that acts by reducing thrombin-mediated clotting and enhancing protein C activation at the site of clotting. We sought to determine the safety and efficacy of ART-123 when combined with standard care in patients with sepsis-associated DIC.

This study was a Phase 2b, multicenter, international double-blind, randomized, placebo-controlled, parallel group trial, conducted in compliance with the ethical principles of the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. Two hundred and thirty intensive care units (ICUs) in seventeen countries enrolled 750 adult patients with sepsis and suspected DIC as assessed using a modified international society of hemostasis and thrombosis score. Patients were randomized to receive intravenous ART-123 (0.06 mg/kg/day) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt DIC and reduction in disease severity. Patients were randomized to receive intravenous ART-123 (0.06 mg/kg/day) for 6 days or placebo, in addition to standard of care. Blood samples were also obtained at different time points to measure various coagulation and inflammatory biomarkers. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt DIC and reduction in disease severity.

A total of 750 patients were randomized, 9 of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p-value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event free and alive days between groups. D-dimer, F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between groups in bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio >1.4 at baseline.

Administration of ART-123 at a dose of 0.06 mg/kg/day for a 6-day treatment period was associated with clear pharmacologic effects (lower D-dimer, F1.2 and TATc levels) and plausible probability of efficacy. ART-123 was found to be a safe intervention in critically ill patients with coagulopathy due to sepsis, even in settings where patients are administered prophylactic doses of heparin, with no difference in bleeding complications between ART-123 and placebo-treated patients. These findings provide support for undertaking a phase III study, based on the population identified from the post hoc analyses, to extend these observations. Future trials using ART-123 should also be designed to better characterize the complex interactions present within the coagulation cascade in septic patients and to enable a description of the interactions between ART-123 and other anticoagulant modalities in these patients.

Kaul:Asahi Kasei Pharma America Corporation: Employment. Tsuruta:Asahi Kasei Pharma America Corporation: Employment. Gorelick:Asahi Kasei Pharma America Corporation: Employment. Osawa:Asahi Kasei Pharma America Corporation: Employment. Vincent:Asahi Kasei Pharma America Corporation: Employment.