A Randomized, Double-Blind, Placebo-Controlled, Phase 2b Study to Assess the Safety and Efficacy Effects of ART-123 on Subjects with Sepsis and Disseminated Intravascular Coagulation

开始日期2007-11-21

申办/合作机构

Artisan Pharma, Inc.

NCT00487656 / Completed临床2期

A Randomized, Double-Blind, Placebo-Controlled, Phase-2B Study to Assess the Safety and Efficacy Effects of ART-123 on Subjects With Sepsis and Disseminated Intravascular Coagulation

The purpose of this study is to see if ART-123 (recombinant human soluble thrombomodulin) decreases the number of people who die as a result of Disseminated Intravascular Coagulation (DIC) complication of sepsis.

开始日期2007-07-01

申办/合作机构

Artisan Pharma, Inc.

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2011-11-18·Blood

Thrombin Generation Mediators and Markers in Sepsis Associated Coagulapathy,

作者: Litinas, Evangelos ; Fareed, Jawed ; Khan, Hussein ; Kaul, Inder ; Cunanan, Josephine ; Sharma, Gautam ; Hoppensteadt, Debra

AbstractAbstract 3341Thrombin 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), fibrinopeptide A (FPA) and thrombin antithrombin complex (TAT), along with tissue factor (TF), microparticles (MP), D-dimer (DD) and antithrombin (AT). Baseline plasma samples from one hundred patients diagnosed with sepsis associated DIC were analyzed for various parameters by using ELISA methods. The MP levels were measured by using a functional method utilizing annexing trapping whereas the antithrombin was measured using both the functional and immunologic methods. Plasma samples from 50 normal male and female individuals comprised the control group. The results are tabulated in the following table. Both TF and MP levels were markedly elevated in comparison to the control group. All of the other markers of thrombin generation showed elevated levels F1.2 (3.4 fold), FPA (4.3 fold) and TAT (4.0 fold). Marked elevation of D-dimer was also noted (5.0 fold). Both the immunologic and functional levels of AT were also decreased. While the data was 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 such as the antithrombin, thrombomodulin and TFPI may play an important regulatory role in the pathogenesis of this syndrome.MarkerNormal ControlsDIC BaselineF 1.2 (pM)108.6+12.3473.7+320FPA (ng/ml)1.6+0.86.8+3.1MP (nM)8.47+1.124.56+2.1AT (% NHP)94.2+2.780.4+3.1DD (ng/ml)415.4+65.23685+112TAT (ng/ml)3.4+0.317.0+3.1Disclosures:No relevant conflicts of interest to declare.

2011-11-18·Blood

Identification of Unique Biomarkers in Sepsis Associated Coagulopathy

作者: Sharma, Gautam ; Bijlani, Rahul ; Cunanan, Josephine ; Litinas, Evangelos ; Hoppensteadt, Debra ; Sharma, Gautum ; Khan, Hussein ; Kaul, Inder ; Fareed, Jawed

AbstractAbstract 1237Introduction:Disseminated Intravascular Coagulation represents a complex multi-factorial pathophysiological process in which protease disregulation along with other pathologic processes play an important role. The uncontrolled protease activities result in generation of several mediators which are not fully characterized. Biomarker profiling using protein chip array technology has been used in the identification of unique mediators in various diseases. Surface Enhanced Laser Desorption Ionisation(SELDI) is an ionization method in mass spectrometry that is used for the analysis of protein mixtures and correspondingly in the profiling of biomarkers in various diseases. Purpose: The purpose of this study was to profile and identify unique biomarkers in hospitalized patients with sepsis associated coagulopathy. Study design: There were 385 plasma samples included in this study. Baseline protein chip array profile in Molecular weight range of 0–200 kDa was carried out using SELDI technique employing gold chips. Plasma samples from normal humans (n=100) and pooled preparation from both the normal (NHP) and suspect liver disease/coagulopathy were utilized as controls. Results: Of the 385 baseline samples analyzed 371 patients (96.86%) exhibited the presence of a unique biomarker at 11.6 kDa. In addition down regulation of a biomarker at 56.4 kDa was also noted in 218 of patients (56.74%) In the normal human pooled plasma the 11.6 kDa peak was nearly absent. However in Pathological pooled plasma a distinct biomarker at 11.6 kDa with a much lower intensity was noted. Additional markers in baseline samples in 1–10 kDa range were also noted. Conclusions: These observations suggest that sepsis associated coagulopathy results in the generation of specific unique biomarker at 11.6kDa which requires further characterization. The downregulation of biomarker at 56.4 kDa and the apparent reduction levels during hospitalization require further investigations.Disclosures:No relevant conflicts of interest to declare.

2011-11-18·Blood

Biochip Array Analysis of Various Mediators of Inflammation in Disseminated Intravascular Coagulation

作者: Fareed, Jawed ; Kaul, Inder ; Hoppensteadt, Debra ; Sadeghi, Nasir ; Davis, Rachael ; Rahman, Saud ; Cunanan, Josephine

AbstractAbstract 2302Disseminated intravascular coagulation is a polypathologic syndrome which involves blood, endothelial and target organ dysfunction resulting in the generation of various mediators of vascular dysfunction, hemostatic aberrations and hemodynamic disturbances. In addition, various disorders of target organs such as kidney, liver, heart and brain are observed. Uncontrolled protease generation results in the formation of various mediators of inflammation such as neuron specific enolase (NSE), neutrophil gelatinase associated lipocalin (NGal) and soluble tumor necrosis factor receptor 1 (TNF R1). Endothelial damage results in the generation of thrombomodulin (TM) and endogenous coagulation/fibrinolysis results in D- Dimer formation. In order to study the circulating levels of these mediators, a Biochip array method (Randox, Oceanside, CA) was utilized with samples obtained from clinically diagnosed DIC (n=100) and normal individuals (n=10). The results are summarized in the following table. Circulating levels of these mediators were markedly increased in DIC patients in comparison to normals. The most striking increase was noted in NGal (4–6 fold) and TNF R1 (10 fold). Other mediators were also increased in the DIC group, however the data was broadly scattered. These results indicate that beside the aberration in the hemostatic system NGal and TNF R1 along with other inflammatory mediators may play a major role in the pathophysiology of DIC.MarkerNormal ControlsDIC BaselineCRP (ug/ml)3.47 + 0.913.11 + 0.2*NSE (ng/ml)6.11 + 8.610.78 + 1.6*NGAL(ng/ml)306.45 + 25.51376.56 + 48.5*TNFR1 (ng/ml)0.35 + 0.013.89 + 0.3*DD (ng/ml)232.8 + 74.41318.94 + 80.5*TM (ng/ml)3.4 + 0.33.16 + 0.2P=<0.05Disclosures:No relevant conflicts of interest to declare.

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