E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Sepsis and disseminated intravascular coagulation. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013442 |
E.1.2 | Term | Disseminated intravascular coagulation |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and activity of ART-123 in reducing mortality in subjects with disseminated intravascular coagulation (DIC) due to sepsis, |
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E.2.2 | Secondary objectives of the trial |
To assess the efficacy of ART-123 in resolution of DIC in this population To establish the predictive value of a modified DIC score based on platelet count and INR compared with the ISTH DIC criteria. To evaluate several coagulation parameters in predicting response to ART-123 To obtain an accurate estimate of the risk of death in subjects with DIC due to sepsis. To assess the safety of ART-123 in subjects with DIC due to sepis.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Candidates for this study must meet ALL of the following criteria:
1. Clinical objective evidence of bacterial infection and being treated with antimicrobial medication (s). Evidence would include but is not limited to: • Physical exam findings (i.e. cellulitis or abscesses) • Cultures • Gram stains • Radiographic studies • Surgical pathology specimens ** Note: A positive culture is not required for eligibility
2. DIC score of ≥3 using a modified ISTH algorithm documented within 24 hours of study drug administration.
3. Subject presents with 2 or more of the following sepsis related SIRS criteria within 24 hours prior to any particular qualifying DIC score, with one of the two criteria being either temperature or WBC: a. Temperature >38ºC or <36ºC (core temperature for low range temperature) b. WBC >12,000 or <4,000 cells/μL or >10% Band forms c. Heart Rate >90 BPM (This criterion cannot be used if the subject is treated with β-blockers or heart rate is pacemaker dependent) d. Respiratory Rate >20 BPM or PaCO2<32 mmHg or mechanically ventilated subject |
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E.4 | Principal exclusion criteria |
Candidates for the study will be excluded if ANY of the following criteria are present: 1. Subject or Legally Authorized Representative is unable to provide informed consent 2. Subject is pregnant or breastfeeding or intends to get pregnant within 28 days of enrolling into the study 3. Subject is of childbearing potential and does not agree to use a medically acceptable form of contraception for the duration of the trial (28 days or 22 days post the last dose of study drug administration). (see protocol for further details) 4. Subject is < 18 years of age 5. Allergy to ART-123 or any components of the drug product 6. Subject is unwilling to allow transfusion of blood or blood products 7. Presence of an advance directive to withhold life-sustaining treatment, with the exception of cardiopulmonary resuscitation (CPR) 8. Previous treatment with ART-123 9. Body weight ≥ 175kg 10. PT prolongation or thrombocytopenia that is not due to sepsis (see protocol for further details) 11. Intra-thoracic, intra-abdominal, or intra-cranial surgery, within the previous 12 hours to randomization, or ongoing impairment of hemostasis as a result of one of these procedures 12. A history of head trauma, spinal trauma, or other acute trauma with an increased risk of bleeding within 3 months prior to enrollment (see protocol for further details) 13. Cerebral Vascular Accident (CVA) within 3 months prior to enrollment 14. Any history of intracerebral arteriovenous malformation (AVM), cerebral aneurysm, or mass lesions of the central nervous system 15. A history of congenital bleeding diatheses 16. Gastrointestinal bleeding within 6 weeks prior to enrollment unless a corrective interventional procedure has been performed 17. Known medical conditions associated with a hypercoagulable state, including: a. Resistance to activated protein C or known Factor V Leiden b. Hereditary deficiency of protein C, protein S or antithrombin III c. Presence of anticardiolipin antibody, antiphosopholipid antibody, lupus anticoagulant, prothrombin gene mutation, or homocysteinemia d. Deep-vein thrombois or pulmonary embolism within 3 months prior to enrollment (if evaluation is in progress, this should be completed before consideration for this trial) e. History of idiopathic thrombosis 18. Known or suspected severe liver disease, as defined by a score of 10-15 (class C) using the Child-Pugh Classification (see Appendix G of protocol) 19. Portosystemic hypertension or known history of bleeding esophageal varices 20. History of solid organ, allogeneic bone marrow, or stem cell transplantation within 6 months of enrollment (uncomplicated kidney and autologous stem cell/bone marrow transplant subjects may be enrolled at any time after they have recovered from their transplant procedure) 21. Acute pancreatitis where infection has not been documented by a positive blood or abdominal fluid culture. Also, in the opinion of the treating physician the subject is at an increased risk for developing hemorrhagic pancreatitis over the duration of the study. 22. Severe renal failure characterized by chronic or acute need of hemodialysis, hemofiltration or peritoneal dialysis. 23. Use or intended use of Xigris® (drotrecogin alfa [activated]) within the 24 hours prior of enrollment 24.Use or intended use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 24 hours prior to study dosing with the exception of: a. Heparin locks/flushes b. DVT Prophylaxis with either unfractionated heparin at total daily doses no higher than 10000 U SQ or LMWH at a total daily dose no higher than 15000 U SQ (no switching or alternating between unfractionated heparin and LMWH is allowed during treatment and up to Study Day 14) c. Up to 325 mg of aspirin daily for cardiac prophylaxis 25. Platelet count <20,000 OR platelet count <30,000 after platelet transfusion 26. Life expectancy <90 days due, but not limited to, the following conditions: a. Poorly controlled neoplasms b. New York Heart Association class IV subjects or pulmonary vascular disease resulting in severe exercise restriction (i.e., unable to climb stairs or perform household duties), or chronic restrictive or obstructive pulmonary disease that also results in severe exercise restriction, or documented chronic hypoxia, hypercapnia, secondary polycythemia, severe pulmonary hypertension (mean arterial pulmonary pressure >40 mm Hg) or respirator dependency c. Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery, or subject with imminent death d. End-stage neurological disorders (e.g., amyotrophic lateral sclerosis – Lou Gehrig’s disease) 27. Use of any chemotherapy agent 28. Participation in another research study involving an investigational agent within 30 days prior to enrollment
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be all cause mortality through D28. Date of death will be recorded. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The last patient's last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |