Sepsis, defined by the presence of infection and host inflammation, is a lethal clinical syndrome. In severe disease, the coagulation system becomes diffusely activated, with consumption of multiple clotting factors resulting in Disseminated Intravascular Coagulation (DIC). MedDRA version: 20.0 Level: PT Classification code 10053840 Term: Bacterial sepsis System Organ Class: 10021881 - Infections and infestations MedDRA version: 20.0 Level: PT Classification code 10009802 Term: Coagulopathy Sy
Conditions
Interventions
Product Name: ART-123
Product Code: ART-123
Pharmaceutical Form: Lyophilisate and solvent for solution for injection
INN or Proposed INN: ART-123
CAS Number: 120313-91-9
Current Sponsor code: ART-123
Sponsors
Asahi Kasei Pharma America Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.Subjects must be receiving treatment in an ICU or in an acute care setting (e.g.,Emergency Room, Recovery Room). 2.Subjects with either compelling evidence of infection OR clinical syndromes highly likely to be bacterial in origin, as follows: a.Compelling objective evidence of bacterial infection and a known site of infection. Objective evidence would be met with a grossly purulent site of infection, Gram stain evidence, culture, rapid immunoassay or genomic based rapid diagnostic assays confirming a bacterial pathogen from normally sterile fluids (blood, urine, cerebrospinal fluid (CSF), peritoneal fluid, etc.), having either: •White Blood Cell (WBC) count greater > 12,000/mm3 or 10% bands within 36 hours of randomization OR •Temperature 38°C b.Clinical syndromes highly likely to be bacterial in origin but not compelling •White Blood Cell (WBC) count greater > 12,000/mm3 or 10% bands within 36 hours of randomization AND •Temperature 38°C 3.Current treatment with intravenous antibiotics for the acute bacterial infection(i.e. not prophylactic antibiotics) 4.Subjects with sepsis associated organ dysfunction defined by at least one ofthe following: a.Cardiovascular Dysfunction defined as requiring both adequate fluid resuscitation and vasopressors* to maintain Mean Arterial Pressure(MAP) greater than or equal to (=) 65 mmHg (implies fluidresuscitation alone does not raise MAP to = 65 mmHg), with onset time being the time vasopressors are initiated (end of surgery if initiated in surgery), with adequate fluid resuscitation defined as: •Intravenous administration of at least 20 mL/kg crystalloid or 10 mL/kg colloid infusion within 6 hours. OR •Central Venous Pressure (CVP) of greater than (>) 8 mmHg or Pulmonary Artery Wedge Pressure (PAWP) of greater than ( >) 12 mmHg. *If dopamine is the only vasopressor used, the infusion ratemust be greater than (>) 5 µg/kg/min (i.e., must be prescribedto support cardio-pulmonary perfusion). If vasopressin is used,it must be given in conjunction with another vasopressor. b.Respiratory Dysfunction defined as the acute need for mechanical ventilation and PaO2/FiO2 ratio of 1.40 without other known etiology (e.g., anticoagulant therapy, chronic liver disease), and having an onset at the time of the first local laboratory blood draw yielding a qualifying result (point of care device INR results must be confirmed by local laboratory). 6.Subjects with coagulopathy characterized by platelet count that meets any of the below criteria, and having an onset at the time of the first blood draw yielding a qualifying result. a.= 20,000/mm3 and 30,000/mm3 (qualifying at the time of the first blood draw yielding a result = 20,000/mm3 and = 30,000/mm3). b.> 30,000/mm3 to 30% decrease in platelet count within 24 hours 7.First and last qualifying criteria of sepsis associated organ dysfunction, platelet count, and INR (results from local or transferring hospita
Exclusion criteria
Exclusion criteria: 1.Subject or Authorized Representative is unable or unwilling to provide informed consent (as applicable per local and country regulations) 2.Subject is pregnant (positive serum or urine human Chorionic Gonadotropin(hCG)) or breastfeeding or intends to get pregnant within 28 days of enrollinginto the study 3.Subject is 30,000/mm3 9.Elevated INR, leukopenia, or thrombocytopenia that is not due to sepsis, (e.g. patients treated by chemotherapy agent). Please refer to Appendix C of the protocol as an example of agents known to cause myelosuppression that should be evaluated as the potential cause of leukopenia or thrombocytopenia 10.Inability to randomize patients in = 12 hours after meeting Inclusion # 7 (onset time requirements for sepsis associated organ dysfunction, INR, and platelet count) 11.= 8 hours remaining from the end of a major surgery having a high risk of post-operative bleeding and randomization (e.g. extensive intraabdominal orintrathoracic dissection, debridement of a large surface area of tissue, complications arising during surgery, problems with hemostasis during surgery, surgeries of long duration, surgeries with large estimated blood loss). a.Ensures all randomized surgical subjects with a high risk of post-operative bleeding can be dosed no earlier than 12 hours post-operatively, as described in Section 2.6.3. (minimum 8 hour delay before randomization and 4 hour maximum time to dose after randomization) 12.Stroke within 3 months prior to consent, trauma or major surgery within 3 months prior to consent that may increase the risk of bleeding 13.Known bleeding diatheses or anatomical anomaly that predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia, esophageal varices, arteriovenous malformation) 14.Gastrointestinal bleeding (e.g. melena, hematemesis) or genitourinary bleeding within 6 weeks prior to consent unless a corrective interventional procedure has been performed (i.e. therapeutic endoscopy), or there is evidence of complete resolution 15.Known thrombophilia or a history of deep-vein thrombosis or pulmonary embolism within 3 months prior to consent 16.Need for full dose anticoagulation therapy other than IV unfractionated heparin discontinued > 12 hours prior to randomization, full dose or catheter directed thrombolysis, aspirin at a daily dose > 325 mg, long-acting antiplatelet drugs (e.g. clopidogrel, prasugrel, or ticagrelor), dual antiplatelet therapy, and doses of anticoagulants exceeding thromboprophylaxis doses within 72 hours prior to the first dose of study drug 17.Acute liver failure not due to sepsis, sepsis associated acute liver failure in any patient with a history of cirrhosis, Class C Chronic liver disease (Child-Pughscore of 10-15) 18.Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture or Gram stain consistent with bacterial infection. Also, in the opinion of the treating physician the subject is
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •To evaluate whether ART-123, when administered to subjects with bacterial infection complicated by at least one organ dysfunction (cardiac or respiratory)and coagulopathy, can reduce mortality. •To evaluate the safety of ART-123 in this population.;Secondary Objective: •Assessment of the efficacy of ART-123 in resolution of organ dysfunction(ventilator, dialysis, shock) in this population. •Assessment of anti-drug antibody development in subjects with coagulopathy due to bacterial infection treated with ART-123.;Primary end point(s): Primary Efficacy Endpoint: • 28 day (Day 29) all-cause mortality Primary Safety Endpoints: •Serious Adverse Events •Major Bleeding Events •Adverse Events;Timepoint(s) of evaluation of this end point: Please refer to the Schedule of Activities (SOA): Table 1: Visit Schedule and Assessments | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints: •Follow-up of all-cause mortality at 3 months •Resolution of Organ Dysfunction through 28 days (Day 29) as measured by: oShock free and alive days oVentilator free and alive days oDialysis free and alive days Secondary Safety Endpoint: •Anti-drug antibodies (ADA) to ART-123;Timepoint(s) of evaluation of this end point: Please refer to the Schedule of Activities (SOA): Table 1: Visit Schedule and Assessments | — |
Countries
Australia, Belgium, Brazil, Canada, Czech Republic, Finland, France, Germany, Israel, Netherlands, Spain, United Kingdom, United States
Contacts
Public ContactMedical Monitor
Asahi Kasei Pharma America Corporation
Outcome results
None listed