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    Summary
    EudraCT Number:2006-002873-35
    Sponsor's Protocol Code Number:LEO 90010-I21
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2007-02-26
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2006-002873-35
    A.3Full title of the trial
    Exploratory efficacy and safety, pharmacokinetics and dose-finding study of ATryn® (antithrombin alfa) in patients with disseminated intravascular coagulation associated with severe sepsis
    A.4.1Sponsor's protocol code numberLEO 90010-I21
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorLEO Pharmaceutical Products Ltd A/S (LEO Pharma A/S)
    B.1.3.4CountryDenmark
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNantithrombin alfa
    D.3.9.1CAS number 84720-88-7
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number175
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Disseminated intravascular coagulation associated with severe sepsis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10013442
    E.1.2Term Disseminated intravascular coagulation
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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 continuous intravenous (IV) infusion over five days.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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) related to the current sepsis episode 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/microlitre or < 4000 cells/microlitre (if a medical condition or medication prevents tachycardia, two SIRS criteria are acceptable) and b. Minimum one sustained organ failure (respiratory failure, renal dysfunction, hepatic dysfunction, or metabolic acidosis or septic 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. Maximum time from diagnosis of first organ failure to randomisation: 48 hours. Maximum time from diagnosis of DIC to randomisation: 24 hours.
    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. At the time of enrolment there has to be intent by physicians and families to aggressively treat the patient
    E.4Principal 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 and INR above 1.5
    6. Treatment with: clopidogrel, glycoprotein IIb/IIIa inhibitors or acetylsalicylic acid at doses >325 mg/day within 5 days prior to randomisation
    7. Anticoagulant treatment with pentasaccharide (e.g. fondaparinux) within 7 days prior to randomisation
    8. Conditions other than sepsis anticipated to be terminal within 6 months
    9. Known bleeding disorder other than DIC
    10. Chronic vegetative state
    11. Incurable malignancy with documented metastases
    12. Haematological neoplasia where cytostatic treatment has been administered within two months prior to randomisation
    13. Bone marrow aplasia or treatment induced low platelet count (due to immunosuppressive medication)
    14. Preexisting dialysis-dependent renal failure
    15. Known advanced chronic liver disease corresponding to Child-Pugh class C (measured prior to ICU admission outside the current sepsis episode) or any history of bleeding from oesophageal varices
    16. Overt, ongoing serious haemorrhage
    17. Advanced directive to withhold life-supporting treatment (except cardiopulmonary resuscitation)
    18. Major burns involving > 20% of the body surface
    19. Platelet count < 20000/microlitre (patients should not be included if they require a platelet transfusion to bring their platelet level above 20000/microlitre just prior to randomisation)
    20. Acute Myocardial Infarction within 7 days prior to randomisation. Please note that troponin levels may be elevated due to sepsis
    21. Recent (within 30 days prior to randomisation) or planned (during 6 days post randomisation) heart surgery with cardio-pulmonary bypass
    22. Transplantation within 30 days prior to randomisation
    23. History of stroke within the last 90 days prior to randomisation
    24. Severe cranial or spinal trauma within the last 90 days before randomisation or known cranial or spinal space occupying lesion, intracerebral arteriovenous malformation or cerebral aneurysm
    25. Epidural catheter within 12 hours before randomisation or planned epidural catheter during 6 days post randomisation
    26. Recent (within 30 days prior to randomisation) or planned (during 6 days post randomisation) cranial or spinal surgery (except nontraumatic lumbar puncture)
    27. Any major surgery with increased high risk of bleeding within 12-hours before randomisation or planned major surgery with increased high risk of bleeding during 6 days post randomisation (except tracheostomy)
    28. Trauma patients with increased risk of bleeding e.g. significant contusion to lung, liver or spleen, retroperitoneal bleed, pelvic fracture or compartment syndrome within 48 hour before randomisation
    29. Known or suspected hypersensitivity to component(s) of investigational products or known or suspected hypersensitivity to goats or goat products
    30. Current participation in any other interventional clinical trial .
    31. 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
    32. Previously enrolled in any trial of ATryn®
    E.5 End points
    E.5.1Primary 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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Dose escalation in 3 steps
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Best standard treatment for the underlying condition i.e. severe sepsis
    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.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA63
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Yes
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Women of childbearing potential must have a negative urine or serum pregnancy test before entering the study.

    For subjects incapable of giving consent personally, his/her legally acceptable representative must give the informed consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 200
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2007-03-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2007-04-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-03-18
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