Phase 3 Safety and Efficacy Study of ART-123 in Subjects With Severe Sepsis and Coagulopathy

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

Detailed Description
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Study is to evaluate if ART-123 given to patients who have severe sepsis complicated by at least one organ dysfunction and coagulopathy can decrease mortality.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study to Assess the Safety and Efficacy of ART-123 in Subjects With Severe Sepsis and Coagulopathy.

Conditions
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Severe Sepsis, Coagulopathy

Intervention / Treatment
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* Drug: ART-123
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be receiving treatment in an ICU, or in an acute care setting (e.g., ER, RR) Clinical objective evidence of bacterial infection and a known site of infection. Cardiovascular dysfunction or Respiratory Failure due to sepsis. Coagulopathy characterized by an INR >1.40 without other known causes. Exclusion Criteria: Subject or Authorized Representative is unable to provide informed consent. Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of enrolling into the study. Subject is of childbearing potential and does not have a negative pregnancy test. Subject is < 18 years of age. Subject has a known allergy to ART-123 or any components of the drug product. Subject is unwilling to allow transfusion of blood or blood products. Subject has an advance directive to withhold life-sustaining treatment. Subject has had previous treatment with ART-123. Body weight ≥ 175 kg. Platelets < 30,000/ mm3 for any reason, PT prolongation or thrombocytopenia that is not due to sepsis. Any surgery that is potentially hemorrhagic (e.g. intra-thoracic, intra-abdominal or non-traumatic orthopedic surgery of the femur or pelvis) that is completed within 12 hours prior to first dose of study drug, or ongoing impairment of hemostasis as a result of one of these procedures History of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to consent. Cerebral Vascular Accident (CVA) within 3 months prior to consent. Any history of intracerebral arteriovenous malformation (AVM), cerebral aneurysm, or mass lesions of the central nervous system. History of congenital bleeding diathesesor anatomical anomaly that predisposes to hemorrhage (e.g. hemophilia, hereditary hemorrhagic telangiectasia). Significant gastrointestinal bleeding within 6 weeks prior to consent. Subject is diagnosed with a known medical condition associated with a hypercoagulable state. Child-Pugh score of 10-15 (Class C) Portosystemic hypertension or known history of bleeding esophageal varices. History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 6 months prior to consent. Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture or gram stain consistent with bacterial infection. Subjects with renal dysfunction defined as (a) Chronic renal failure requiring renal replacement therapy (RRT), or (b) Acute renal failure with onset of oliguria (urine output < 0.3 ml/kg/hr) > 48 hours prior to first dose of study drug whether receiving RRT or not Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first does of study drug. Life expectancy < 90 days. Current use of any chemotherapy agent likely to cause myeloablation (severe or complete depletion of bone marrow). Participation in another research study involving an investigational agent within 30 days prior to consent or projected study participation during the 28 days post study randomization. Confirmed or suspected endocarditis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ART-123<br> | Drug: ART-123<br>* Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days<br>* Other names: thrombomodulin alfa;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Dose: 0.06 mg/kg/day up to a maximum dose of 6 mg/day for 6 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 28-Day All-cause Mortality | 28-Day All-cause Mortality | 28 days | 
| Number of Participants With On-Treatment Serious Major Bleeding Events | On-treatment Serious Major Bleeding Events collected as Serious Adverse Events and defined as: any intracranial hemorrhage, any life-threatening bleeding, any bleeding event classified as serious by the Investigator (e.g., resulting in permanent morbidity), or any bleeding that required the administration of 1440 ml (typically 6 units) of packed red cells over two consecutive days. (Investigator assessment for seriousness criteria.) | Through Study Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Follow up All-cause Mortality at 3 Months | Follow up all-cause mortality at 3 months | 3 months | 
| Number of Event Free and Alive Days to Measure Resolution of Organ Dysfunction | Resolution of organ dysfunction as measured through day 28 by shock free, ventilator free, dialysis free plus alive days. | 28 days | 
| Number of Participants With Anti-drug Antibodies | Presence of Anti-drug antibodies up to 18 months | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sepsis