Scarlet-2: A Randomized, Double-Blind,Placebo-Controlled, Phase 3 Study to Assess The Safety And Efficacy of ART-123 in Subjects With Sepsis and Coagulopathy

The purpose of the study is to evaluate if ART-123 given to patients who have severe sepsis can decrease mortality.

开始日期2019-07-01

申办/合作机构

Asahi Kasei Pharma America Corp.

EUCTR2018-000246-19-FR / Not yet recruiting临床3期

SCARLET-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of ART-123 in Subjects with Sepsis and Coagulopathy

开始日期2018-09-24

申办/合作机构

Asahi Kasei Pharma America Corp.

EUCTR2018-000246-19-FI / Unknown status临床3期

SCARLET-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of ART-123 in Subjects with Sepsis and Coagulopathy

开始日期2018-09-03

申办/合作机构

Asahi Kasei Pharma America Corp.

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2021-12-01·Annals of Intensive Care2区 · 医学

Efficacy and safety of human soluble thrombomodulin (ART-123) for treatment of patients in France with sepsis-associated coagulopathy: post hoc analysis of SCARLET

2区 · 医学

ArticleOA

作者: François, Bruno ; Fiancette, Maud ; Vincent, Jean-Louis ; Mercier, Emmanuelle ; Helms, Julie ; Tanaka, Kosuke ; Fineberg, David ; Lascarrou, Jean-Baptiste ; Wittebole, Xavier ; Kayanoki, Toshihiko

AbstractBackgroundThe phase 3 multinational SCARLET study evaluated the efficacy and safety of a recombinant human soluble thrombomodulin (ART-123) for treatment of sepsis-associated coagulopathy (SAC), which correlates with increased mortality risk in patients with sepsis. Although no significant reduction in mortality was observed with ART-123 compared with placebo in the full analysis set (FAS), an efficacy signal of ART-123 was observed in subgroups of patients who sustained coagulopathy until the first treatment and those not administered concomitant heparin. Post hoc analysis was performed of patients treated in France, the country with the largest enrollment (19% of the FAS) and consistent patient enrollment throughout the study duration.MethodsAdult patients with SAC (international normalized ratio > 1.4; platelets > 30 × 109/L to < 150 × 109/L or platelet decrease > 30% within 24 h) and evidence of bacterial infection were included. The primary efficacy outcome was 28-day all-cause mortality. Safety outcomes included adverse, serious adverse, and major bleeding events. This analysis assessed patient characteristics and efficacy and safety outcomes in France compared with the rest of the world (ROW; excluding France). Mortality rates were assessed in patients in France or the ROW with characteristics previously associated with ART-123 efficacy.ResultsBaseline characteristics were similar between France and the ROW, but some measurements of disease severity were higher in patients in France. The 28-day all-cause mortality absolute risk reductions (ARRs) with ART-123 were 8.3% in France and 1.1% in the ROW. The greater ARR in France may be related to a higher rate of sustained coagulopathy and lower rate of heparin use. In France and the ROW, 84.6% and 78.0% of patients sustained coagulopathy from the time of initial SAC diagnosis to first treatment with the study drug, and 65.8% and 43.9% did not receive heparin, respectively. The ARRs for these subgroups of patients in France were 13.4% and 16.6%, respectively. Safety of ART-123 was comparable between France and the ROW.ConclusionsResults from this exploratory analysis suggest that patients with sustained SAC not receiving concomitant heparin may benefit from ART-123, a fact that should be confirmed in future studies with more restrictive inclusion criteria.

2019-05-28·JAMA1区 · 医学

The SCARLET Randomized Clinical Trial

1区 · 医学

Article

作者: Gorelick, Kenneth J. ; Wittebole, Xavier ; Gando, Satoshi ; Sakai, Takumi ; Russell, James A. ; Kirov, Mikhail Y. ; Fareed, Jawed ; Saito, Hidehiko ; Esmon, Charles T. ; Mercier, Emmanuelle ; Vincent, Jean-Louis ; Barie, Philip S. ; Crowther, Mark ; Mira, Jean-Paul ; Fineberg, David ; Francois, Bruno ; Levi, Marcel ; Meziani, Ferhat ; Parrillo, Joseph ; Pettilä, Ville ; Daga, Mradul Kumar ; Lobo, Suzana M. ; Lascarrou, Jean-Baptiste ; Zabolotskikh, Igor ; Tsuruta, Kazuhisa ; Opal, Steven M.

ImportancePrevious research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy.ObjectiveTo determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy.Design, Setting, and ParticipantsThe SCARLET trial was a randomized, double-blind, placebo-controlled, multinational, multicenter phase 3 study conducted in intensive care units at 159 sites in 26 countries. All adult patients admitted to one of the participating intensive care units between October 2012 and March 2018 with sepsis-associated coagulopathy and concomitant cardiovascular and/or respiratory failure, defined as an international normalized ratio greater than 1.40 without other known etiology and a platelet count in the range of 30 to 150 × 109/L or a greater than 30% decrease in platelet count within 24 hours, were considered for inclusion. The final date of follow-up was February 28, 2019.InterventionsPatients with sepsis-associated coagulopathy were randomized and treated with an intravenous bolus or a 15-minute infusion of thrombomodulin (0.06 mg/kg/d [maximum, 6 mg/d]; n = 395) or matching placebo (n = 405) once daily for 6 days.Main Outcome and MeasuresThe primary end point was 28-day all-cause mortality.ResultsAmong 816 randomized patients, 800 (mean age, 60.7 years; 437 [54.6%] men) completed the study and were included in the full analysis set. In these patients, the 28-day all-cause mortality rate was not statistically significantly different between the thrombomodulin group and the placebo group (106 of 395 patients [26.8%] vs 119 of 405 patients [29.4%], respectively; P = .32). The absolute risk difference was 2.55% (95% CI, -3.68% to 8.77%). The incidence of serious major bleeding adverse events (defined as any intracranial hemorrhage; life-threatening bleeding; or bleeding event classified as serious by the investigator, with administration of at least 1440 mL [typically 6 units] of packed red blood cells over 2 consecutive days) was 23 of 396 patients (5.8%) in the thrombomodulin group and 16 of 404 (4.0%) in the placebo group.Conclusions and RelevanceAmong patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality.Trial RegistrationClinicalTrials.gov Identifier: NCT01598831.

2018-09-01·Clinical and Applied Thrombosis/Hemostasis

Pharmacological Differentiation of Thrombomodulin Alfa and Activated Protein C on Coagulation and Fibrinolysis In Vitro

Article

作者: Tawara, Shunsuke ; Hoppensteadt, Debra ; Tsuruta, Kazuhisa ; Fareed, Jawed ; Tanaka, Kosuke

Although thrombomodulin alfa (TM alfa), recombinant human soluble thrombomodulin, exerts antithrombogenic effects through activated protein C (APC), clinical trials suggested that TM alfa has a lower bleeding risk than does recombinant human APC. To address the mechanism explaining this difference, effects of TM alfa and APC on thrombogenic, coagulation, and fibrinolytic processes were compared in vitro. TM alfa and APC inhibited generation of thrombogenic markers, thrombin, and prothrombin fragment F1+2 and prolonged coagulation parameters, activated clotting time (ACT), and activated partial thromboplastin time (APTT). Concentrations of TM alfa effective for thrombin and F1+2 generation inhibition were comparable to those of APC. However, effects of TM alfa on ACT and APTT were clearly weaker than those of APC. TM alfa significantly prolonged clot lysis time (CLT) and decreased LY30, a parameter of degree of fibrinolysis in thromboelastography, whereas APC significantly shortened CLT and increased LY30. These results suggested that while the antithrombogenic effects of TM alfa were similar to those of APC, its anticoagulant effects were lower. In addition, effects of TM alfa were antifibrinolytic, while those of APC were profibrinolytic.

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