Safety and Dose-Finding Study of Activated Protein C (Drotrecogin Alfa Activated) as an Anticoagulant in End-Stage Renal Disease Patients Treated with Hemodialysis

2014 ◽  
Vol 37 (3) ◽  
pp. 243-248 ◽  
Author(s):  
Ermira Brasha-Mitchell ◽  
Ashte Collins ◽  
Lindita Shehu ◽  
Michael G. Seneff ◽  
Samir S. Patel ◽  
...  
Keyword(s):  
End Stage Renal Disease ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Dose Finding ◽  
Drotrecogin Alfa Activated ◽  
Finding Study ◽  
Dose Finding Study ◽  
Stage Renal Disease ◽  
End Stage

scholarly journals Safety and Antithrombotic Efficacy of the Recombinant Protein C Activator AB002 (E-WE Thrombin) in End Stage Renal Disease Patients on Chronic Hemodialysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2433-2433
Author(s):  
Norah G Verbout ◽  
Christina U Lorentz ◽  
Brandon D Markway ◽  
Joseph J Shatzel ◽  
Erik I Tucker ◽  
...  
Keyword(s):  
End Stage Renal Disease ◽  
Protein C ◽  
Activated Protein C ◽  
Phase 2 ◽  
Employment Equity ◽  
Equity Ownership ◽  
Stage Renal Disease ◽  
End Stage ◽  
Dose Levels ◽  
Esrd Patients

AB002 is a recombinant thrombin analog that generates endogenous activated protein C (APC) on intravascular surfaces in a thrombomodulin-dependent manner but does not promote thrombosis. Endogenously generated APC downregulates thrombin generation, thereby reducing pathological clot formation. During hemodialysis (HD), thrombi can form within the dialyzer filter and circuit, reducing dialyzer efficiency, and increasing blood loss. Heparin administration reduces clotting within the filter and circuit, but increases bleeding risk and is not tolerated in all patients. Since end-stage renal disease (ESRD) patients undergoing HD are at higher risk of both thromboembolism and bleeding, a safe, short-term and self-limiting anticoagulant alternative to heparin is currently an unmet need for this population. This is a phase 2, randomized, double-blind, placebo-controlled, single-dose study designed to evaluate the safety and efficacy of AB002 at two dose levels when administered to ESRD patients during heparin-free HD. A total of 36 adult patients are planned to be enrolled into two cohorts and dosed sequentially. Within each cohort, patients will be randomized to active drug (12) or placebo (6). Dose levels (1.5 µg/kg or 3 µg/kg; iv infusion) were based on safety data from a completed phase 1 study performed in healthy adult subjects (NCT03453060), which demonstrated that a single dose of AB002 was well tolerated, as well as based on preclinical efficacy studies performed in a baboon vascular thrombosis model. The primary objective of this phase 2 proof-of-concept study is safety and tolerability assessed as the number and severity of adverse events (AE), changes in baseline physical and lab parameters and immunogenicity of AB002. The number and severity of AE will be tabulated and summary statistics evaluated. The secondary objectives are to assess 1) pharmacodynamics using activated protein C/protein C inhibitor complexes in plasma as a surrogate marker for drug exposure, and 2) efficacy via pre-post dialyzer pressures, visual inspection of thrombus accumulation in the HD filter and dialysis efficiency based on urea kinetics. The study population includes ESRD patients on a stable outpatient HD regimen at least 3 times per week and excludes patients with history of acute vaso-occlusive thrombotic events, concomitant use of anticoagulant/antiplatelet agents immediately prior to and during the study, active cancer and bleeding disorders. This study is currently recruiting participants at one study site (Orlando Clinical Research Center) in Orlando, FL and is estimated to complete in October 2020 (NCT03963895). Disclosures Verbout: Aronora, Inc.: Employment, Equity Ownership. Lorentz:Aronora, Inc.: Employment. Markway:Aronora, Inc.: Employment. Shatzel:Aronora, Inc.: Consultancy. Tucker:Aronora, Inc.: Employment, Equity Ownership. Gruber:Aronora, Inc.: Employment, Equity Ownership.

Drotrecogin alfa activated (recombinant human activated protein C) in combination with heparin or melagatran

2004 ◽  
Vol 15 (8) ◽  
pp. 693-697 ◽  
Author(s):  
Martin Koestenberger ◽  
Gerhard Cvirn ◽  
Siegfried Gallistl ◽  
Wolfgang Muntean
Keyword(s):  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Drotrecogin Alfa Activated

Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia

Blood ◽  
2003 ◽  
Vol 102 (6) ◽  
pp. 2093-2098 ◽  
Author(s):  
Ulla Derhaschnig ◽  
Rosemarie Reiter ◽  
Paul Knöbl ◽  
Magdalena Baumgartner ◽  
Priska Keen ◽  
...  
Keyword(s):  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Host Responses ◽  
Low Grade ◽  
Human Endotoxemia ◽  
Drotrecogin Alfa Activated ◽  
Anti Inflammatory ◽  
To Receive ◽  
Thrombin Formation

Abstract Inflammatory and procoagulant host responses are closely related in sepsis. The protein C pathway serves as a regulatory pathway with anti-inflammatory and anticoagulant properties. Recently, recombinant human activated protein C (rhAPC) was shown to reduce mortality in severe sepsis. Nevertheless, the effects of rhAPC in humans are still ill defined. The infusion of low endotoxin doses into humans provides a standardized model to study inflammatory and hemostatic mechanisms. Thus, we investigated whether rhAPC acts as an anticoagulant or anti-inflammatory drug in human endotoxemia. There were 24 volunteers randomized to receive either 24 μg/kg per hour rhAPC or placebo intravenously for 8 hours. Lipopolysaccharide (LPS, 2 ng/kg) was administered 2 hours after starting the infusions. rhAPC decreased basal tissue factor (TF)–mRNA expression, and thrombin formation and action. In contrast, rhAPC did not significantly blunt LPS-induced thrombin generation. Consistently, rhAPC did not reduce LPS-induced levels of TF-mRNA or D-dimer and had no effect on fibrinolytic activity or inflammation. Finally, endogenous APC formation was enhanced during endotoxemia and appeared to be associated with inflammation rather than thrombin formation. In conclusion, even low-grade endotoxemia induces significant protein C activation. Infusion of rhAPC decreases “spontaneous” activation of coagulation but does not blunt LPS-induced, TF-mediated coagulation in healthy volunteers, which is in contrast to a number of anticoagulants.

scholarly journals Testing of anti-activated protein C antibodies in four drotrecogin alfa (activated) severe sepsis studies

Critical Care ◽  
2008 ◽  
Vol 12 (Suppl 2) ◽  
pp. P203 ◽  
Author(s):  
S Yan ◽  
J Brandt ◽  
G Vail ◽  
S Um ◽  
J Bourdage ◽  
...  
Keyword(s):  
Severe Sepsis ◽  
Protein C ◽  
Drotrecogin Alfa ◽  
Activated Protein C ◽  
Drotrecogin Alfa Activated
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