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    The EU Clinical Trials Register currently displays   36348   clinical trials with a EudraCT protocol, of which   5989   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2005-003561-16
    Sponsor's Protocol Code Number:TAK-242/01-04-TL-242-011
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2005-12-20
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedFinland - Fimea
    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.3.2Name or abbreviated title of the trial where available
    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 Global R&D Centre (Europe) 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.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.3.2Product code TAK-242
    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 % percent
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product Information not present in EudraCT
    D. ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D. 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
    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 8.1
    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 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 evaluate the effects of TAK-242 on organ function as measured by the Sequential Organ Failure Assessment (SOFA) score.
    - To evaluate clinical improvement as measured by Systemic Inflammatory Response Syndrome (SIRS)-free days; Vasopressor-free days; Time in ICU; Discharge location status
    - To evaluate the safety of TAK-242 administration.
    - To determine the pharmacodynamic effect of TAK-242 on the level of IL-6, IL-8, IL-10, Tumor Necrosis Factor (TNF)-alpha, Procalcitonin (PCT), and C-Reactive Protein (CRP).
    - To further characterize the pharmacokinetic (PK) profile of TAK-242, M-I and M-III in sepsis subjects.
    E.2.3Trial contains a sub-study No
    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.
    2a. 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, which must be confirmed by a core temperature).
    2b. 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.
    2c. Respiratory rate of >20 breaths/min or PaCO2 of <32 mmHg or mechanical ventilation for an acute process.
    2d. 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 or respiratory failure or both. The onset of shock or respiratory failure must be manifested within 24 hours (+12 hours, ie, up to a maximum of 36 hours) prior to the initiation of study drug infusion, which should occur as soon as possible, preferably in the first 24 hours. Subjects with septic shock that have been dependant on vasopressors for > 24 hours must be discussed in more detail with Vanderbilt Coordinating Center (VCC) and documented before randomization.
    3a. Septic shock is defined as requiring the use of vasopressors (eg, 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:
    (i) pulmonary arterial wedge pressure at least 12 mm Hg,
    (ii) central venous pressure of at least 8 mm Hg, or
    (iii) if an intravascular pressure monitoring catheter is not in place, vasopressor administration after unsuccessful fluid resuscitation.
    3b. Respiratory failure is defined as ratio of PaO2 to FIO2 <200 while mechanically ventilated.
    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, nursing and the milk is to be ingested by the infant, or the subject plans to become pregnant or nurse and the milk is to be ingested by the infant.
    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 Pre-treatment 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 (Appendix G).
    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 methemoglobin level of >5% at Pre-treatment Period or has known history of methemoglobinemia.
    10. The subject is moribund and death is considered imminent
    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, end-stage lung disease, requiring chronic home oxygen, end-stage liver disease, end-stage renal disease). Enrollment of subjects with known or suspected metastatic cancer, as well as subjects with an acute event (ie, cardiac arrest, viral encephalitis, ischemic or haemorrhagic cerebral event) within 2 weeks prior to Pre-treatment Period must be discussed with 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 (Appendix H).
    16. The subject has had acute third degree burns involving more than 30% of body surface within 120 hours prior to Pre-treatment Period.
    17. The subject has known hypersensitivity to sulfonamides.
    18. The subject has known hypersensitivity to components of TAK-242; eg, 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 a study site employee, or is an immediate family member (eg, spouse, parent, child, sibling) of a study site employee, directly involved in the conduct of the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy end point is 28-day all-cause mortality.

    The secondary efficacy endpoints of the study include the following:

    To evaluate the effects of TAK-242 on organ function (cardiovascular, respiratory, central nervous sytem, renal, coagulation and hepatic) as measured by the Sequential Organ Failure Assessment (SOFA) score.

    To evaluate clinical improvement as measured by Systemic Inflammatory Response Syndrome (SIRS)-free, vasopressor-free days, ventilator-free days, time in ICU, and discharge location status.

    To evaluate the safety of TAK-242 administration.

    To determine the pharmacodynamic effect of TAK-242 on the level of Tumour necrosis Factor (TNF)-alpha, IL-6, IL-8, IL-10, Procalcitonin (PCT) and C-Reactive Protein (CRP).

    To further characterise the pharmacokinetic profile of TAK-242, M-I and M-III.

    Exploratory endpoints include quality of life and health economic impact of TAK-242 administration.

    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 Yes
    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 Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E. 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 Yes
    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 Yes
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA95
    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
    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 months
    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) Information not present in EudraCT
    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 2005-12-20. 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. 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 state
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1390
    F.4.2.2In the whole clinical trial 2930
    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)
    Expected normal treatment.
    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 Decision2006-03-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-02-06
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2007-02-01
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