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    Summary
    EudraCT Number:2005-003561-16
    Sponsor's Protocol Code Number:TAK-242/01-04-TL-242-011
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2005-11-29
    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 number2005-003561-16
    A.3Full title of the trial
    A Pivotal, Multicentre, Multinational, Randomised, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of TAK-242 in Adults with Severe Sepsis
    A.4.1Sponsor's protocol code numberTAK-242/01-04-TL-242-011
    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 SponsorTakeda Europe R&D Centre Ltd
    B.1.3.4CountryUnited Kingdom
    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 Information not present in EudraCT
    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 Intravenous 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.3.9.2Current sponsor codeTAK-242
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number95 to 105
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 Information not present in EudraCT
    D.3.11.8Extractive medicinal product Information not present in EudraCT
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboIntravenous infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe sepsis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8
    E.1.2Level LLT
    E.1.2Classification code 10040047
    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 objectives of this study are to identify the optimal dosing regimen and to demonstrate that TAK-242 reduces 28-day all-cause mortality in subjects with severe sepsis.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are:
    To determine the pharmacodynamic (PD) effect of TAK-242 on the level of tumor necrosis factor-(TNF)-a, interleukin (IL)-6, and interleukin (IL)-8.
    To determine the effect of TAK-242 on the level of IL-10, procalcitonin (PCT) and C-reactive protein (CRP).
    To evaluate the effects of TAK-242 on organ function (cardiovascular, respiratory, hematologic, renal and hepatic) as measured by the Sequential Organ Failure Assessment (SOFA) score.
    To evaluate the safety of TAK-242 administration.
    To further characterize the pharmacokinetic (PK) profile of TAK-242 in sepsis patients.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. Clinical evidence of infection defined as the presence of a known or probable source of infection requiring the initiation of parenteral antimicrobial therapy. Examples include presence of polymorphs in a normally sterile body fluid (except blood), positive culture or Gram stain of a normally sterile body fluid, clinical focus of infection (eg, fecal peritonitis, wound with purulent discharge, pneumonia or other clinical evidence of systemic infection [eg, purpura fulminans]).

    2. The subject must meet at least 3 of the following 4 criteria for systemic inflammatory response syndrome (SIRS). The events for this criterion must be related to the onset of sepsis and not attributable to an underlying disease process or the effects of concomitant therapy.
    * A core temperature of >38°C (>100.4°F) or <36°C (<96.8°F). Core temperature is defined as rectal, central catheter, oral, tympanic or urinary temperature [oral temperature is acceptable for high temperature but not for hypothermia, to be confirmed by core temperature].
    * Heart rate of >90 beats per minute. If subject has a known medical condition (eg, heart block) or is receiving treatment (eg, beta blocker) that would prevent tachycardia, only 2 of the remaining 3 criteria for SIRS must be met.
    * Respiratory rate of >20 breaths/min or PaCO2 of <32 mmHg requiring mechanical ventilation (for the purpose of this study, mechanical ventilation is required with hyperventilation).
    * A total white blood cell (WBC) absolute count >12,000 cells/mm3 or <4,000 cells/mm3; or a WBC differential count showing >10% immature (band) forms.

    3. The subject must have sepsis with shock and/or respiratory failure. The onset of shock or respiratory failure must be manifested £36 hours prior to the initiation of study drug infusion.

    * Septic shock is defined as requiring the use of vasopressors (i.e., norepinephrine, dopamine, phenylephrine, epinephrine, vasopressin) for arterial hypotension, despite adequate fluid resuscitation for more than 1 hour, or adequate intravascular volume status. Dobutamine and dopexamine are not considered vasopressors. Arterial hypotension is defined as systolic blood pressure of <90 mm Hg (which is not the result of the subject’s underlying disease or treatment). Adequate fluid resuscitation or adequate intravascular volume status is defined as one or more of the following:

    - pulmonary arterial wedge pressure at least 12 mm Hg, or
    - central venous pressure of at least 8 mm Hg, or
    - if a pulmonary artery (PA) (Swanz-Ganz) catheter is not in place, vasopressor administration after unsuccessful fluid resuscitation.

    * Respiratory failure is defined as a ratio of PaO2 to FiO2 of <200 requiring mechanical ventilation.

    4. The subject or the subject’s legally authorized representative has provided a written informed consent, or is able to understand verbal English or a language for which a certified translation of the approved informed consent is available.
    E.4Principal exclusion criteria
    1. The subject is less than 18 years of age.
    2. If female, the subject is pregnant or lactating.
    3. The subject is receiving immunosuppressive therapy such as cyclosporine, azathioprine, or cancer-related chemotherapy.
    4. The subject has a granulocyte count of less than 1000/mm3 except if the decreased count is believed to be due to sepsis.
    5. The subject has documented or suspected acute myocardial infarction within the last 6 weeks prior to Pretreatment Period.
    6. The subject has a documented history of moderate to severe chronic heart failure as defined by New York Heart Association (NYHA) Functional Classification III or IV.
    7. The subject is known to be HIV positive with known CD4 count £50/mm3 or has known end-stage processes (eg, progressive multifocal leukoencephalopathy, systemic mycobacterium avium complex infection).
    8. The subject has known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
    9. The subject has a methemoglobin level of ³5% at Pretreatment Period or has known history of methemoglobinemia.
    10. The subject is moribund and death is considered imminent (within 24 hours of recognition of sepsis).
    11. The subject is classified as “Do Not Resuscitate” (DNR) or “Do Not Treat” or the subject’s family has not committed to aggressive management of the subject’s condition.
    12. The subject is not expected to survive for 28 days and will not likely be given life support due to a pre-existing, uncorrectable medical condition. This would include subjects with, or suspected to have, poorly controlled neoplasm or other end-stage processes (eg, end-stage cardiac disease, prior cardiac arrest within 2 weeks of Pretreatment Period, end-stage lung disease, end-stage liver disease, end-stage renal disease). Enrollment of subjects with known or suspected metastatic cancer must be approved by the Vanderbilt Coordinating Center (VCC) and documented before randomization.
    13. The subject has known esophageal varices, chronic jaundice, cirrhosis, or chronic ascites.
    14. The subject is in a chronic vegetative state or has a similar long-term neurological condition.
    15. The subject has known portal hypertension or Child-Pugh hepatic impairment class C.
    16. The subject has had acute third degree burns involving more than 30% of body surface within 120 hours prior to Pretreatment Period.
    17. The subject has known hypersensitivity to sulfonamides.
    18. The subject has known hypersensitivity to components of TAK-242; ie, is allergic to eggs, egg products, or soybeans.
    19. The subject has participated in any other investigational study (drug or device) and/or taken any investigational drug within 30 days or 5 half-lives of the drug, whichever is longer, before initiation of the study drug infusion.
    20. The subject is unwilling or the investigator feels the subject will be unable to be fully evaluated during the 28-day study period.21. The subject is an employee of a study site or is an immediate family member (eg, spouse, parent, child, sibling) of a study site employee involved in the conduct of the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is 28-day all-cause mortality. The secondary efficacy endpoints include the effects of TAK-242 on organ function (cardiovascular, respiratory, hematologic, renal and hepatic) as measured by Sequential Organ Failure Assessment (SOFA) score. Exploratory endpoints include quality of life and health economic impact of TAK-242 administration. Pharmacodynamic endpoint include TNF-a, IL-6, IL-8. The pharmacokinetic endpoints include profiles of TAK-242, M-I and M-III. The safety endpoints include adverse events, laboratory test results, vital signs, and ECG data.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    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.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    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 Information not present in EudraCT
    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
    Last visit of the last subject
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months22
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months27
    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 Information not present in EudraCT
    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 2005-11-29. Yes
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    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
    Informed consent form may be signed by subject’s legal representative if the subject is incapable.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1390
    F.4.2.2In the whole clinical trial 2930
    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 Decision2005-12-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-01-24
    P. End of Trial
    P.End of Trial StatusOngoing
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