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    Summary
    EudraCT Number:2005-000412-27
    Sponsor's Protocol Code Number:ARG-CS3-001
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2005-07-25
    Trial 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 ConcernedCzechia - SUKL
    A.2EudraCT number2005-000412-27
    A.3Full title of the trial
    A Phase III International Multi-center, Prospective, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Nitric Oxide Synthase Inhibition with Tilarginine Acetate Injection in Patients with Cardiogenic Shock Complicating Acute Myocardial Infarction,
    Or, the TRIUMPH Study:
    Tilarginine Acetate Injection in a Randomized International Study in Unstable AMI Patients / Cardiogenic Shock
    A.3.2Name or abbreviated title of the trial where available
    TRIUMPH Study
    A.4.1Sponsor's protocol code numberARG-CS3-001
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberNot available
    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 SponsorArginox Pharmaceuticals, Inc.
    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
    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 numberOrphan drug status has been applied for in the EU.
    D.3 Description of the IMP
    D.3.1Product nameTilarginine Acetate Injection
    D.3.2Product code -
    D.3.4Pharmaceutical form Injection*
    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 INNTilarginine Acetate
    D.3.9.1CAS number -
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive name-
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.0
    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 placeboInjection*
    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
    It is the intent of the proposed study to further evaluate the safety and efficacy of Tilarginine Acetate Injection as a novel, mortality reducing therapeutic drug for patients with cardiogenic shock complicating acute myocardial infarction.
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to establish the efficacy of Tilarginine Acetate Injection 1.0 mg/kg IV bolus followed by 1.0 mg/kg/hr 5 hour infusion, compared to placebo in reducing all cause mortality at 30 days post randomization in patients with cardiogenic shock complicating acute myocardial infarction (MI).
    E.2.2Secondary objectives of the trial
    Secondary endpoints include the following:
    - the number of subjects demonstrating a resolution of cardiogenic shock
    - the duration (in days) of cardiogenic shock compared to placebo

    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    1. Confirmation of Acute MI
    Patients will be considered to have an acute MI if they meet both of the following criteria (a and b):
    a. Ischemic symptoms for at least 30 minutes AND
    b. Electrocardiogram (ECG) changes (at least one of the following):
    - Two or more contiguous leads with ST segment elevation
    - Evolving Q-waves
    - Left bundle branch block (LBBB)
    - ST segment depression in at least 2 contiguous leads
    In non-ST elevation MI (including old LBBB), cardiac serum markers above the upper limit of normal in the local laboratory must be confirmed prior to study entry.
    2. Confirmation of Persistent Cardiogenic Shock at Randomization
    Patients must meet all of the following shock criteria (a, b, c and d) at the time of randomization :
    a. Peripheral signs of tissue hypoperfusion such as decreased urine output and/or cool extremities AND
    b. SBP <100 mm Hg (measured with IABP paused for 60 seconds unless clinically not feasible) despite vasopressor therapy with dopamine dose at least 7 ug/kg/min, or norepinephrine / epinephrine 0.15 ug/kg/min (alone or in any combination that yields 0.15 ug/kg/min) or phenylephrine 0.7 ug/kg/min; AND
    c. Evidence of elevated LV filling pressures e.g. that the subject is not hypovolemic. Clinical examples of this would include pulmonary congestion confirmed by clinical examination or chest radiography; a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg, determined from pulmonary artery catheterization or by Doppler echocardiography (mitral E wave deceleration time ≤130ms); a left ventricular end diastolic pressure (LVEDP) at catheterization > 20 mmHg if obtained no more than 3 hours prior to randomization, or an intravenous fluid challenge. The amount of intravenous infusion that is sufficient to exclude hypovolemic will be determined by the clinical status of the subject. Evidence of a sufficient volume infusion includes an increase in central venous pressure (CVP), or development of pulmonary congestion, or resolution of hypotension and shock, AND
    d. Left ventricular ejection fraction (LVEF) <40% (measured by left ventriculography or echocardiography).
    3. Confirmation of Persistent Cardiogenic Shock Five Minutes Prior to Study Drug Administration
    Patients must meet all of the following shock criteria (a, b, and c) within 5 minutes of study drug administration:
    a. Continued signs of tissue hypoperfusion such as decreased urine output and/or cool extremities AND
    b. SBP <100 mm Hg (measured with IABP paused for 60 seconds unless clinically not feasible) despite vasopressor therapy with dopamine dose at least 7 ug/kg/min, or norepinephrine / epinephrine 0.15 ug/kg/min (alone or in any combination that yields 0.15 ug/kg/min) or phenylephrine 0.7 ug/kg/min; AND
    c. no intercurrent volume loss since randomization
    4. Confirmed Patency of the Infarct Related Artery (<70% stenosis with any TIMI flow grade)
    Infarct related artery patency must be confirmed by coronary angiography. Patency may be established by spontaneous reperfusion, fibrinolytic therapy and/or PCI. Patients with any TIMI flow or no reflow are eligible.
    5. Duration of Cardiogenic Shock and time from patency of the IRA
    The total duration of cardiogenic shock prior to randomization must be less than 24 hours.
    Subjects must remain in shock for at least 1 hour after the patency of the IRA is confirmed.
    Randomization cannot occur sooner than 1 hour after demonstration of IRA patency.

    E.4Principal exclusion criteria
    Patients will be excluded from participation in the study if ANY of the following criteria apply at the time of randomization:
    1. Suspected or documented infection; or
    2. Other causes of shock state (e.g., septic, hypovolemic, hemorrhagic, anaphylactic shock); or
    3. Shock secondary to acute severe mitral regurgitation (MR) and/or mitral apparatus rupture; or
    4. Other severe underlying valvular heart disease, e.g. aortic stenosis, mitral stenosis or aortic insufficiency; or
    5. Cardiogenic shock due to predominant RV failure or severe RV dysfunction of any cause; or
    6. Cardiogenic shock secondary to rupture of the ventricular septum or ventricular free wall; or
    7. Cardiogenic shock secondary due solely to bradyarrhythmia or tachyarrhythmia; or
    8. Aortic dissection; or
    9. Serum creatinine > 3.0 mg/dl (>264 μmol/L); or
    10. End-stage renal disease requiring dialysis; (including peritoneal dialysis); or
    11. Adult respiratory distress syndrome (ARDS); or
    12. Brain damage that precludes survival despite normalized cardiovascular status; or
    13. Irreversible multi-system failure; for example a persistent pH <7.1, or acute liver failure; or
    14. Intra-thoracic or abdominal surgical procedure within 30 days, unless procedure was coronary artery bypass grafting (CABG); or
    15. Primary pulmonary hypertension; or
    16. Age <18 years; or
    17. Requirement for emergency coronary artery bypass grafting (CABG); or
    18. IRA occlusion; or
    19. Concurrent or prior participation in another clinical trial of an investigational drug in which the last dose of study drug was administered within 5 half-lives of that drug; or
    20. Prior enrollment in this study; or
    21. CS as a consequence of PCI (iatrogenic shock) if the IRA cannot be demonstrated as patent; or
    22. Rapid resolution of cardiogenic shock between randomization and study drug administration. (The following are clinical examples of resolving shock; an SBP improvement of >20 mm Hg between randomization and initiation of study drug; a reduction of 25% or more in the dose of vasopressors administered). If there are signs of resolving shock, a 1-hour observation period for signs of further improvement should be undertaken. At the end of this hour, if SBP ≥100 mm Hg on vasopressors, no study drug should be given.
    23. A positive pregnancy test in women who are of child-bearing potential and are not surgically sterile; or women who are breast feeding.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is all cause mortality at 30 days post study drug infusion.
    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 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 Information not present in EudraCT
    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 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.8.6 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
    The study will end when all patients have completed the protocol specified procedures and a Month 6 follow-up CRF form has been completed for all patients.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    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 years2
    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.1.3Elderly (>=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 2005-07-25. 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
    Many subjects will be severely incapacitated (some unconscious) due to the AMI . Informed consent will be obtained before the subject can participate in the study from the subject, their surrogate, or their legal representatives.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state40
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 700
    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 Decision2005-07-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-07-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2006-08-02
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