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    Summary
    EudraCT Number:2018-000816-96
    Sponsor's Protocol Code Number:P160924
    National Competent Authority:Slovenia - JAZMP
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-12-21
    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 ConcernedSlovenia - JAZMP
    A.2EudraCT number2018-000816-96
    A.3Full title of the trial
    A reduced dose of thrombolytic treatment for patients with intermediate high-risk acute pulmonary embolism: a randomized controlled trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A reduced dose of thrombolytic treatment for patients with intermediate high-risk acute pulmonary embolism
    A.3.2Name or abbreviated title of the trial where available
    PEITHO 3
    A.4.1Sponsor's protocol code numberP160924
    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 SponsorAP-HP/ DRCI
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportASSISTANCE PUBLIQUE-HOPITAUX DE PARIS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAPHP/DRCI
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street Address1 avenue Claude Vellefaux
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number33144841798
    B.5.5Fax number33144841701
    B.5.6E-mailaurelie.guimfack@aphp.fr
    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 Yes
    D.2.1.1.1Trade name ACTILYSE 50mg
    D.2.1.1.2Name of the Marketing Authorisation holderBOEHRINGER INGELHEIM FRANCE
    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 and solvent for solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameALTEPLASE FOR INJECTION
    D.3.9.4EV Substance CodeSUB126952
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number0.6 mg/kg (maximu to 50
    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.3.11.13.1Other medicinal product typerecombinant human tissue-type plasminogen activator
    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 placeboPowder and solvent for solution for injection/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
    Intermediate high-risk acute pulmonary embolism
    E.1.1.1Medical condition in easily understood language
    Intermediate high-risk acute pulmonary embolism
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the efficacy of reduced dose thrombolytic therapy in patients with acute intermediate-high-risk pulmonary embolism at day 30.
    E.2.2Secondary objectives of the trial
    •To assess the safety of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism
    •To assess the net clinical benefit of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism
    •To assess the effect of reduced dose thrombolytic therapy on overall mortality of patients with intermediate-high-risk acute pulmonary embolism
    •To assess the effect of reduced dose thrombolytic therapy on long-term mortality, functional impairment, residual right ventricular (RV) dysfunction and chronic thromboembolic pulmonary hypertension
    •To assess the effect of reduced-dose thrombolytic therapy on utilization of health care resources
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age 18 years or older
    • Objectively confirmed acute PE with first symptoms occurring 2 weeks or less before randomization. Objective confirmation is based on at least one of the following criteria: (a) at least one segmental ventilation-perfusion mismatch on lung scanning; (b) computed tomography pulmonary angiography (CTPA) or selective pulmonary angiography showing a filling defect or an abrupt obstruction of a segmental or more proximal pulmonary artery
    • Αcute PE confirmed within 24 hours prior to randomization;
    • Elevated risk of early death, or of hemodynamic collapse, or PE recurrence, indicated by at least one of the following criteria: (a) systolic blood pressure (SBP) ≤ 110 mm Hg upon enrolment, (b) temporary need for fluid resuscitation and/or treatment with low dose catecholamines because of arterial hypotension at presentation, provided that the patient could be stabilized within 2 hours of admission and maintains SBP of ≥ 90 mmHg and adequate organ perfusion without catecholamine infusion; (c) respiratory rate > 20/min or SpO2 <90% (or partial arterial oxygen pressure < 60 mmHg) at rest while breathing room air, (d) history of chronic heart failure defined as previous diagnosis of heart failure (i.e. heart failure with reduced, moderately reduced or preserved ejection fraction) or treatment for heart failure at any time during the past 12 months;
    • RV dysfunction indicated by RV/LV diameter ratio >1.0 on echocardiography apical four- chamber or subcostal four-chamber view or on CTPA (transverse plane)
    • Serum troponin I or T concentration above the upper limit of local normal using a high-sensitivity assay
    • Abiltity to randomize patient within 6 hours after the investigator receives the result of the second of the two criteria for RV dysfunction (RV/LV diameter ratio >1.0) and myocardial injury (serum troponin I or T concentration above the upper limit of local normal), whichever comes the latest.
    • Signed informed consent form
    • [France] Patient insured under a social security system
    E.4Principal exclusion criteria
    • Hemodynamic instability, defined by at least one of the following criteria
    - cardiac arrest;
    - obstructive shock, defined as: (i) SBP <90 mmHg, or vasopressors required to achieve a SBP ≥90 mmHg despite an adequate filling status; and (ii) end-organ hypoperfusion (altered mental status; cold, clammy skin; oliguria/anuria; increased serum lactate);
    - isolated persistent hypotension (SBP <90 mmHg, or a systolic pressure drop ≥40 mmHg for >15 min), if not caused by new-onset arrhythmia, hypovolemia, or sepsis
    • Active bleeding
    • History of non-traumatic intracranial bleeding, any time
    • Acute ischemic stroke within the previous 6 months
    • Known central nervous system neoplasm/metastasis
    • Neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery or trauma within the previous 3 weeks
    • Platelet count < 100 x 109/L
    • INR > 1.4
    • Treatment with antiplatelet agents other than (a) acetylsalicylic acid (ASA) ≤ 100 mg once daily or (b) clopidogrel 75 mg once daily or (c) a single loading dose of ASA or clopidogrel. Dual anti-platelet therapy (ASA + clopidogrel) is not allowed.
    • Any direct oral anticoagulant within 12 hours of inclusion
    • Uncontrolled hypertension > 180/90 mm Hg at the time of inclusion
    • Known significant bleeding risk according to the investigator's judgement
    • Administration of thrombolytic agents within the previous 4 days
    • Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days
    • Current participation in another interventional clinical study
    • Previous enrolment in this study
    • Known hypersensitivity to alteplase, gentamicin (a residue of the Actilyse® manufacturing process present in trace amounts), any of the excipients of Actilyse®, or low-molecular weight heparin (LMWH)
    • Known previous immune heparin-induced thrombocytopenia
    • Known severe liver disease (grade ≥ 3) including liver failure, cirrhosis, portal hypertension (esophageal varices) and active hepatitis
    • Acute symptomatic pancreatitis
    • Gastrointestinal ulcers or esophageal varices, documented within the past 3 months
    • Known arterial aneurysm, arterial or venous malformations
    • Pregnancy or parturition within the previous 30 days or current breastfeeding.
    • Women of childbearing potential who do not have a negative pregnancy test and do not use one of the following methods of birth control: hormonal contraception or intrauterine device or bilateral tubal occlusion
    • Any other condition that in investigator'opinions would place the patient at increased risk upon start of the investigational treatment
    • Life expectancy of less than 6 months or inability to complete 6-month follow-up.
    • Patient under legal protection
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the composite of (1) death from any cause or (2) hemodynamic decompensation or (3) objectively confirmed recurrent PE at day 30.
    E.5.1.1Timepoint(s) of evaluation of this end point
    day 30 ; day 180; 2 years
    E.5.2Secondary end point(s)
    The following key secondary outcomes will be included in a hierarchical analysis:
    1) Fatal or GUSTO severe or life-threatening bleeding within 30 days
    2) Net clinical benefit defined as the composite of the primary efficacy outcome and GUSTO severe or life-threatening bleeding within 30 days
    3) All-cause mortality within 30 days
    The following secondary outcomes are not entered in the hierarchical analysis:
    4) PE-related death within 30 days
    5) Hemodynamic decompensation within 30 days
    6) Need for rescue thrombolysis, catheter-directed treatment or surgical embolectomy within 30 days
    7) Recurrent PE within 30 days
    8) Ischemic or hemorrhagic stroke within 30 days
    9) Serious adverse events within 30 days
    10) All-cause mortality at two years
    11) Dyspnea assessed by the Medical Research Council scale at day 180 and at two years
    12) Functional outcome using the post-VTE functional scale at day 180 and at 2 years
    13) Persistent RV dysfunction at day 180 and at 2 years
    14) Confirmed chronic thromboembolic pulmonary hypertension at 2 years
    Utilization of health care resources within 30 days and 180 days post randomization.
    E.5.2.1Timepoint(s) of evaluation of this end point
    2 years
    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 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 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) Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA90
    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
    Serbia
    Austria
    Belgium
    Canada
    Germany
    Italy
    Netherlands
    Poland
    Portugal
    Romania
    Slovenia
    Spain
    Switzerland
    France
    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 years
    E.8.9.1In the Member State concerned months72
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months72
    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: 586
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 64
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 600
    F.4.2.2In the whole clinical trial 650
    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)
    None
    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 Decision2022-05-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-05-16
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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