E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Disseminated intravascular coagulation associated with severe sepsis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10013442 |
E.1.2 | Term | Disseminated intravascular coagulation |
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E.1.2 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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to explore the efficacy and safety of ATryn® for the treatment of disseminated intravascular coagulation (DIC) associated with severe sepsis, when administered by continous intravenous (IV) infusion over five days.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to obtain pharmacokinetic data in patients with DIC associated with severe sepsis and to establish an appropriate dose regimen for phase III. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Signed informed consent has been obtained from the patient or his/her legally acceptable representative 2. Severe sepsis defined as: a. Systemic inflammatory response syndrome (SIRS) with at least three of the following clinical findings: body temperature (rectal, ear or core) > 38°C or < 36°C; heart rate > 90 beats/minute; hyperventilation (evidenced by a respiratory rate of > 20 breaths/minute or a PaCO2 of < 32 mmHg) or mechanical ventilation; leucocyte count > 12000 cells/mgl or < 4000 cells/mgl and b. Minimum two organ failures (respiratory failure, renal dysfunction, hepatic dysfunction, or metabolic acidosis) or refractory shock and c. Clinical signs of infection caused by a bacterial or fungal pathogen 3. Disseminated intravascular coagulation (>= 5 points on overt or non overt DIC score) 4. Predicted mortality between 30 and 60% (43 to 56 points on Simplified Acute Physiology Score II (SAPS II)) 5. At least 18 years of age 6. Males or non-pregnant females. Females of child bearing potential should have a negative urine or serum pregnancy test within 24 hours prior to drug administration 7. Any ethnic origin 8. Patient hospitalised at an intensive care unit (ICU) 9. Maximum time from diagnosis of first organ failure to randomisation: 48 hours. Maximum time from diagnosis of second organ failure or septic shock to randomisation: 24 hours. 10. At the time of enrolment there has to be intent by physicians and families to aggressively treat the patient
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E.4 | Principal exclusion criteria |
1. Previous treatment with an antithrombin concentrate or recombinant human activated protein C (rhAPC) within the current sepsis episode 2. Treatment with unfractionated heparin (UFH) or low molecular weight heparin (LMWH) at any dose within the last 6 or 18 hours before randomisation, respectively 3. Anticipated need for treatment with UFH/LMWH, pentasaccharide (e.g. fondaparinux), oral anticoagulants or thrombolytic agents during 6 days post randomisation (e.g. current VTE, atrial fibrillation, ongoing VTE prophylaxis or hypercoagulable state) 4. Intended treatment with rhAPC during 6 days post randomisation 5. Treatment with oral anticoagulants within the last 48 hours before randomisation or currently indicated 6. Anticoagulant treatment with pentasaccharide (e.g. fondaparinux) within 7 days prior to randomisation or currently indicated 7. Conditions other than sepsis anticipated to be terminal within 6 months 8. Known bleeding disorder other than DIC 9. Chronic vegetative state 10. Incurable malignancy with documented metastases 11. Haematological neoplasia during cytostatic treatment 12. Bone marrow aplasia 13. Preexisting dialysis-dependent renal failure 14. Known advanced chronic liver disease corresponding to Child-Pugh class B or C (measured prior to ICU admission outside the current sepsis episode) or any history of bleeding from oesophagus varices 15. Overt, ongoing serious haemorrhage 16. Advanced directive to withhold life-supporting treatment (except cardiopulmonary resuscitation) 17. Major burns involving > 20% of the body surface 18. Platelet count < 30000/mgl (unsupported) 19. Acute Myocardial Infarction within 7 days prior to randomisation having led to cardiogenic shock 20. Recent (within 30 days prior to randomisation) or planned (during 6 days post randomisation) heart surgery with cardio-pulmonary bypass 21. Transplantation within 30 days prior to randomisation 22. History of stroke within the last 90 days prior to randomisation 23. Severe cranial or spinal trauma within the last 90 days before randomisation or known cranial or spinal space occupying lesion 24. Recent (within 30 days prior to randomisation) or planned (during 6 days post randomisation) cranial or spinal surgery (except nontraumatic lumbar puncture) 25. Planned major surgery during 6 days post randomisation except tracheostomy 26. Known or suspected hypersensitivity to component(s) of investigational products or known or suspected hypersensitivity to goats or goat products 27. Current participation in any other interventional clinical trial . 28. Patients who have received treatment with any non-marketed drug substance (i.e., an agent which has not yet been made available for clinical use following registration) within the last 30 days prior to randomisation 29. Previously enrolled in this trial |
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E.5 End points |
E.5.1 | Primary end point(s) |
Patients alive on day 28, having had an improvement in the DIC score (overt or non-overt) by at least 2 points between baseline and day 6 and having had no worsening of the Sepsis-related Organ Failure Assessment (SOFA) score between baseline and day 6. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Dose escalation in 3 steps |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Best standard treatment for the underlying condition i.e. severe sepsis |
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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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 28 |
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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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 | 3 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |