Effect of a Recombinant Human Soluble Thrombomodulin on Mortality in Patients With Sepsis-Associated Coagulopathy: The SCARLET Randomized Clinical Trial.

Importance: Previous research suggested that soluble human recombinant thrombomodulin may reduce mortality among patients with sepsis-associated coagulopathy. Objective: To determine the effect of human recombinant thrombomodulin vs placebo on 28-day all-cause mortality among patients with sepsis-associated coagulopathy. Design, Setting, and Participants: The 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. Interventions: Patients 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 Measures: The primary end point was 28-day all-cause mortality. Results: Among 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 Relevance: Among patients with sepsis-associated coagulopathy, administration of a human recombinant thrombomodulin, compared with placebo, did not significantly reduce 28-day all-cause mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT01598831.

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

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.

Evaluation of drug-drug interaction between the novel cPLA2 inhibitor AK106-001616 and methotrexate in rheumatoid arthritis patients.

1. Drug interaction potential between AK106-001616, a novel cytosolic phospholipase A2 inhibitor, and methotrexate (MTX) in rheumatoid arthritis patients was investigated. This trial is registered with ClinicalTrials.gov, number NCT00902369. 2. In the clinical study, the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of AUC0-t of MTX administered after AK106-001616 200 mg compared to the MTX without AK106-001616 were within 80-125%. However, administration of AK106-001616 at doses of 400 and 600 mg exceeded the 125% threshold. As small but statistically significant increases in AUC0-t were observed, we investigated the mechanism for this drug-drug interaction between MTX and AK106-001616. 3. In vitro, AK106-001616 inhibited OAT1 (IC50 = 18.4 µM, Ki = 33.6 µM) in a non-competitive manner and OAT3 (IC50 = 1.80 µM, Ki = 1.49 µM) in a competitive manner. Both transporters are involved in MTX transport in renal proximal tubules. 4. AK106-001616 has a weak drug interaction with MTX. In vitro studies provide a mechanistic understanding of the in vivo inhibition of transporters by AK106-001616.

Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment.

Thrombomodulin alfa is a soluble recombinant human thrombomodulin that was reported to enhance the reversal of disseminated intravascular coagulation (DIC) in subjects with sepsis or hematologic malignancy and reduce mortality in subjects with sepsis and DIC. Population pharmacokinetic (PK) analysis of thrombomodulin alfa was performed based on rich samples collected in 24 healthy subjects (0.02 and 0.06 mg/kg) and sparse samples collected in 368 subjects with sepsis and DIC (0.06 mg/kg). Sources of variability (baseline characteristics, markers of renal/liver function, hematocrit, and disease severity) were explored using non-linear mixed effect modeling to support dosing rationale in patients with sepsis and DIC. Plasma concentrations of thrombomodulin alfa were best fitted with a one-compartment model. Body weight and creatinine clearance were important covariates describing the PK of thrombomodulin alfa. Typical CL values in patients with normal renal function, or mild, moderate and severe renal impairment were 0.158, 0.145, 0.128, and 0.105 L/h, respectively. Based on simulations, a 0.06 mg/kg dosing of thrombomodulin alfa is expected to result in drug exposure within the therapeutic range of the product (300-5,400 ng/mL), with minimum risks of bleeding in patient with normal and impaired renal functions.

Dysregulation of inflammatory and hemostatic markers in sepsis and suspected disseminated intravascular coagulation.

Inflammatory mediators and hemostatic markers were evaluated in patients enrolled in a phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with sepsis and suspected disseminated intravascular coagulation (DIC). In contrast to controls, patients with sepsis and suspected DIC showed an increase in the circulating levels of inflammatory and fibrinolytic markers. The levels of procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), anaphylatoxin C5a, plasminogen activator inhibitor 1 (PAI-1), and myeloperoxidase were higher in the patients with sepsis and suspected DIC, whereas protein C (PrC) exhibited a significant decrease. When the patients with overt and nonovert DIC were compared, the PrC level was lower, and PCT, PAI-1, IL-6, and IL-10 levels were higher in the patients with overt DIC. These results indicate that inflammation is elevated in sepsis and suspected DIC, and inflammation, impairment of fibrinolysis, and overconsumption of PrC may play a key role in the pathogenesis of DIC.

Thrombin generation mediators and markers in sepsis-associated coagulopathy and their modulation by recombinant thrombomodulin.

Severe sepsis remains the most common cause of death in critically ill patients, and thrombin plays a crucial role in the pathogenesis of sepsis-associated disseminated intravascular coagulation (DIC). The purpose of this study was to profile prothrombin fragment (F1.2), thrombin-antithrombin complex (TAT), and d-dimer (DD) throughout the course of hospital stay in patients identified with sepsis. Plasma samples from patients enrolled in the ART-123 study, a phase 2b, international, multicenter, randomized placebo-controlled trial were analyzed for various parameters using enzyme-linked immunosorbent assay methods. Plasma levels of F1.2, DD, and TAT were measured at several time points following administration of recombinant thrombomodulin or placebo, and the results were tabulated. In the group treated with thrombomodulin, the median F1.2 levels demonstrated a 16% decrease from the baseline to day 7, while the placebo group showed an 8% increase. Both the treatment groups showed a gradual decrease in the TAT and DD, with the group treated with thrombomodulin demonstrating twice the decrease over the 7-day period. Although the data were widely scattered, these results show that DIC represents a hypercoagulable state along with other hemostatic abnormalities and the activation of the inflammatory process. Modulation of these activation processes through targets such as DD, F1.2, and TAT may play an important regulatory role in the pathogenesis of sepsis-associated coagulopathy. Moreover, this study validates the hypothesis that thrombomodulin downregulates the thrombin generation mediators/markers in sepsis-associated DIC.

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.

OBJECTIVES: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. DESIGN: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. SETTING: Two hundred and thirty-three ICUs in 17 countries. PATIENTS: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. INTERVENTIONS: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. MEASUREMENTS AND MAIN RESULTS: A total of 750 patients were randomized, nine 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 the two 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 the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, 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 greater than 1.4 at baseline. CONCLUSIONS: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

Model-based analysis of covariate effects on population pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation and normal subjects.

Thrombomodulin alfa is the recombinant extracellular domain of human thrombomodulin, which shows anticoagulation activity. To elucidate the pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation (DIC), population pharmacokinetic (PPK) analysis was performed using plasma concentration data obtained in phase 1 (20 patients, 348 time points) and phase 2 (116 patients, 305 time points) clinical trials. The actual and predicted plasma concentrations of thrombomodulin alfa based on the final PPK model showed a good linear correlation (R = 0.9504), and the pharmacokinetics of thrombomodulin alfa in DIC patients were affected by body weight, age, renal dysfunction, and hematocrit value. The distribution volume and clearance (CL) were proportional to body weight and were significantly increased in patients with lower hematocrit value (male <40%, female <35%). Furthermore, CL was decreased in patients with renal dysfunction and in elderly patients. Based on these results, the standard dose of thrombomodulin alfa is adjusted according to body weight. However, further dose adjustment is not needed based on age and hematocrit value, since these factors did not cause the large changes in plasma concentration that can affect the efficacy or safety.

Photo-electrochemical degradation of some chlorinated organic compounds on n-TiO2 electrode.

The electrolysis of some chlorinated organic compounds such as chloroacetic acids, chloromethanes and chloroethenes were carried out on a photo-irradiated n-TiO(2) electrode applied a constant potential, 1.0 V vs. Ag/AgCl, and the alternated pulse potentials of +1.0 V and various negative potentials, -1.0, -1.2 and -1.4V vs. Ag/AgCl in 0.1 mol dm(-3) Na(2)SO(4) solutions saturated with oxygen or with nitrogen. These compounds were degraded on the n-TiO(2) electrode by the photo-electrolysis and mineralized to carbon dioxide, carbon monoxide and chloride ion. When the alternated pulse potentials were applied, the mineralization yields were increased for these compounds, especially for trichloroacetic acid and carbon tetrachloride, both of which were comparatively stable to the degradation in the constant potential electrolysis. The presence of oxygen in the solution was effective for the mineralization of these compounds, while little effective for that of trichloroacetic acid and of carbon tetrachloride.