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    Summary
    EudraCT Number:2012-002251-42
    Sponsor's Protocol Code Number:3-001
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-08-27
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2012-002251-42
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phase 3 study of ART -123 or Placebo as treatment for severe sepsis and coagulopathy
    A.4.1Sponsor's protocol code number3-001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01598831
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of Sponsor Asahi Kasei Pharma America Corporation
    B.1.3.4CountryUnited States
    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 Asahi Kasei Pharma America Corporation
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAsahi Kasei Pharma America Corporation
    B.5.2Functional name of contact pointDavid Fineberg, MD Medical Monitor
    B.5.3 Address:
    B.5.3.1Street Address200 Fifth Avenue
    B.5.3.2Town/ cityWaltham -MA
    B.5.3.3Post code02451
    B.5.3.4CountryUnited States
    B.5.4Telephone number17815307191
    B.5.5Fax number17818900660
    B.5.6E-maildfineberg@akpamerica.com
    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.3.1Product nameART-123
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous bolus use (Noncurrent)
    Intravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNthrombomodulin alfa
    D.3.9.1CAS number 120313-91-9
    D.3.9.3Other descriptive nameTHROMBOMODULIN ALFA
    D.3.9.4EV Substance CodeSUB32083
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboIntravenous bolus use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    severe sepsis and coagulopathy
    E.1.1.1Medical condition in easily understood language
    severe sepsis and coagulopathy
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To evaluate whether ART-123, when administered to subjects with bacterial infection complicated by at least one organ dysfunction (septic shock and/or respiratory failure) and coagulopathy, can reduce mortality.

    2. To evaluate the safety of ART-123 in this patient population.
    E.2.2Secondary objectives of the trial
    1. Assessment of the efficacy of ART-123 in resolution of organ dysfunction in this population.

    2. Assessment of anti-drug antibody development in subjects with coagulopathy due to bacterial infection treated with ART-123.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    This study targets critically ill subjects with severe sepsis requiring the level of care that is normally associated with treatment in an ICU setting. The inclusion criteria for organ dysfunction and coagulopathy must be met within a 24 hour period.
    1) Subjects must be receiving treatment in an ICU, or in an acute care setting (e.g., ER, Recovery Room)
    2) Subjects with:
    a. Clinical objective evidence of bacterial infection and a known site of infection
    b. Current treatment with intravenous antibiotics
    c. White Blood Cell (WBC) count greater than (>) 12,000/mm3 or less than (<) 4,000/mm3 or Bandemia greater than (>) 10%.
    d. Temperature of <36°C or fever >38°C. For hypothermia, a core reading is preferred.
    Note 1: If a subject has a Gram stain consistent with bacterial infection, positive culture from blood or an otherwise sterile body fluid, observed peritonitis, positive urinary antigen, clinical presentation of meningococcemia, or otherwise compelling evidence of infection as determined by the CCC, only one of the two inclusion criteria # 2c (WBC) or 2d (temperature) is required.
    Note 2: The presence of concurrent fungal or viral infection is allowed for the study entry, provided that the primary reason for treatment is bacterial infection.
    3) Subjects with sepsis associated organ dysfunction defined by at least one of the 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 fluid resuscitation alone does not raise MAP to >= 65 mmHg). Adequate fluid resuscitation is defined as:
    o Intravenous administration of at least 20 mL/kg crystalloid or 10 mL/kg colloid infusion within 6 hours.
    OR
    o Central Venous Pressure (CVP) greater than (>) 8 mmHg or Pulmonary Artery Wedge Pressure (PAWP) greater than ( >) 12 mmHg.
    * If dopamine is the only vasopressor used, the infusion rate must be greater than (>) 5 µg/kg/min (i.e. must be prescribed to support cardio-pulmonary perfusion). If vasopressin is used, it must be given in conjunction with another vasopressor.
    b) Respiratory Dysfunction is defined as the acute need for mechanical ventilation and PaO2/FiO2 ratio of <250 (or <200 when the lung is the site of infection). For the purposes of this protocol, mechanical ventilation is defined as any type of ventilation administered via an endotracheal tube or nasotracheal intubation. A simple administration of supplemental oxygen is NOT considered to be mechanical ventilation for the purposes of this study.
    4) Subjects with coagulopathy characterized by an INR >1.40 without other known etiology (e.g., anticoagulant therapy, chronic liver disease)
    5) Subjects with coagulopathy characterized by platelet count in the range of greater than (>) 30,000/mm3 to less than (<) 150,000/mm3 OR A greater than 30% decrease in platelets in 24 hours.
    E.4Principal exclusion criteria
    Candidates for the study will be excluded if ANY of the following criteria are present:
    1. Subject or Authorized Representative is unable or unwilling to provide initial or ongoing 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 has a positive pregnancy test
    4. Subject is <18 years of age
    5. Subject has a known 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(patients not wishing to receive CPR may qualify provided they receive all other resuscitative measures e.g. MV, vasoactive agents, cardioversion)
    8. Subject has had previous treatment with ART-123
    9. Body weight ≥ 175 kg
    10. Platelets <30,000/mm3 for any reason, PT prolongation or thrombocytopenia that is not due to sepsis
    11. 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 the first dose of study drug, 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 consent
    13. Cerebral Vascular Accident within 3 months prior to consent
    14. Any history of Intracerebral AM, cerebral aneurysm, or mass lesions of the central nervous system
    15. A history of congenital bleeding diatheses or anatomical anomaly that predisposes to haemorrhage(e.g. haemophilia, hereditary hemorrhagic telangiectasia)
    16. Significant gastrointestinal bleeding (e.g., melena, hematemesis) within 6 weeks prior to consent unless a corrective interventional procedure has been performed (i.e. therapeutic endoscopy)
    17. Subject is diagnosed with a known medical condition associated with a hypercoagulable state, including:
    a. Resistance to activated protein C or known Factor V Leiden
    b. Hereditary deficiency of protein C or protein S
    c. Presence of anticardiolipin antibody, antiphospholipid antibody, or prothrombin gene mutation
    d. Deep-vein thrombosis or pulmonary embolism within 3 months prior to consent
    e. Any disorder with a requirement for full anticoagulation
    18. History of cirrhosis or current Class C liver disease(Child-Pugh score of 10-15)
    19. Portosystemic hypertension or known history of bleeding esophageal varices
    20. History of solid organ, allogeneic bone marrow, or stem cell transplantation within the 6 months prior to consent (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 or gram stain consistent with bacterial infection. 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. Subjects with renal dysfunction defined as:
    a. Chronic renal failure requiring renal replacement therapy (RRT), or
    b. Chronic 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.
    23. Use of anticoagulants, antiplatelet agents, antithrombotics and thrombolytics within the 72 hours prior to first dose of study drug with the exception of:
    a. Heparin locks/flushes
    b. DVT Prophylaxis per prophylactic dosing on the package insert as approved in your country.
    c. Up to 325mg of aspirin daily for cardiac prophylaxis only
    d. Anticoagulants for RRT: Regional citrate is preferred. It is recommended that if unfractionated heparin or LMWH is used, that the systemic exposure be less than or equal to the DVT prophylaxis dose allowed.
    24. Life expectancy <90 days due to underlying conditions such as, but not limited to, the following: a. Poorly controlled neoplasms
    b. New York Heart Association class IV or pulmonary vascular disease resulting in severe exercise restriction or chronic restrictive or obstructive pulmonary disease that also results in severe exercise restriction, or documented chronic hypoxia, hypercapnia, secondary polycythemia, severe pulmonary or respiratory dependency
    c. Prior cardiac arrest requiring CPR without fully demonstrated neurological recovery, or subject with imminent death (in the next few hours)
    d. End-stage neurological disorders (e.g., amyotrophic lateral sclerosis – Lou Gehrig’s disease)
    25. Current use of any chemotherapy agent likely to cause myeloablation
    26. 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
    27. Confirmed or suspected endocarditis
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy

    Primary Efficacy Endpoint:
    • 28 day all-cause mortality

    Safety

    Primary Safety Endpoints:
    • Serious Adverse Events
    • Major Bleeding Events
    • Adverse Events
    E.5.1.1Timepoint(s) of evaluation of this end point
    Daily up to 28 days post dose, evaluation for mortality at Day 29
    E.5.2Secondary end point(s)
    Efficacy
    Secondary Efficacy Endpoints:
    • Follow-up of all-cause mortality at 3 months
    • Resolution of Organ Dysfunction through Day 28 as measured by
    o Shock free and alive days
    o Ventilator free and alive days
    o Dialysis free and alive days
    Safety
    Secondary Safety Endpoint:
    • Anti-drug antibodies
    E.5.2.1Timepoint(s) of evaluation of this end point
    Daily for 28 days post dose and at 3 months of post dose
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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 No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Brazil
    Bulgaria
    Canada
    Colombia
    Croatia
    Czech Republic
    Finland
    France
    Germany
    Greece
    India
    Israel
    Korea, Republic of
    Netherlands
    New Zealand
    Peru
    Russian Federation
    Spain
    Taiwan
    Turkey
    United Kingdom
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    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 No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 500
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 300
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2012-08-27. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    patient may be on a ventilator and be too ill to provide informed consent
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 400
    F.4.2.2In the whole clinical trial 800
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Follow up care by primary care physician
    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 Decision2012-09-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-02-28
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