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    Summary
    EudraCT Number:2018-003801-24
    Sponsor's Protocol Code Number:P160925J
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2019-05-29
    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 ConcernedFrance - ANSM
    A.2EudraCT number2018-003801-24
    A.3Full title of the trial
    A multicenter, prospective, randomized, placebo-controlled, double-blind, multi-arm, multi-stage clinical trial of Ivabradine for heart Rate control In Septic shock
    L’ivabradine pour le contrôle de la fréquence cardiaque au cours du choc septique : un essai clinique multicentrique, prospectif, randomisé, multi-bras et multi-stades, en double insu contre placebo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A multicenter, prospective, randomized, placebo-controlled, double-blind, multi-arm, multi-stage clinical trial of Ivabradine for heart Rate control In Septic shock
    L’ivabradine pour le contrôle de la fréquence cardiaque au cours du choc septique : un essai clinique multicentrique, prospectif, randomisé, multi-bras et multi-stades, en double insu contre placebo.
    A.3.2Name or abbreviated title of the trial where available
    IRISS
    A.4.1Sponsor's protocol code numberP160925J
    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 SponsorAssistance Publique - Hôpitaux de Paris
    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 supportMinistry of Health (PHRC - N)
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAssistance Publique - Hôpitaux de Paris
    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 number+330144841747
    B.5.5Fax number+330144841701
    B.5.6E-mailcandy.estevez@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 PROCORALAN 5 mg
    D.2.1.1.2Name of the Marketing Authorisation holderLes Laboratoires Servier
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 namePROCORALAN 5 mg
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPEnteral use (Noncurrent)
    Oral use
    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) 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 No
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Trial subjects are adult patients with septic shock.
    E.1.1.1Medical condition in easily understood language
    septic shock.
    E.1.1.2Therapeutic area Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10040070
    E.1.2Term Septic shock
    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
    The primary objective is to assess the efficacy of ivabradine in controlling heart rate and improving 28-day survival in patients with septic shock.
    These objectives will be assessed via a two-stage trial: activity (focused on heart rate control) and efficacy (focused on mortality).
    E.2.2Secondary objectives of the trial
    -determine the tolerance of ivabradine;
    -evaluate the impact of ivabradine-driven heart rate control on systemic hemodynamics, myocardial stress, organ dysfunction, morbidity, and intensive care mortality;
    -determine the pharmacokinetics of ivabradine.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    It is an ancillary study integrated into the protocol.
    Objectives : scrutinize the pharmacokinetic profile of ivabradine in critically ill patients.. This ancillary study will be undertaken in centers of Greater Paris (Henri Mondor, Pitié-Salpétrière, Bicêtre, Ambroise Paré, Tenon, HEGP, Lariboisière, Cochin, Bichat, Foch, Marne-la-Vallée, Sud Francilien).
    E.3Principal inclusion criteria
    -18 years of age or older;
    -Proven or suspected site of infection;
    -Septic shock (defined as hypotension unresponsive to fluid resuscitation and requiring vasopressor treatment to maintain adequate blood pressure) for at least 6 hours and less than 24 hours;
    -In sinus rhythm with heart rate ≥ 95 bpm at time of randomization;
    -Informed consent obtained in accordance with local regulations;
    -Affiliation to a social security regime.
    E.4Principal exclusion criteria
    -Age < 18 years,
    -Cardiac arythmia, conduction disorder, sinus syndrome ("sick sinus syndrome"), sino-atrial block; 3rd degree atrioventricular block;
    -Cardiogenic shock or unstable or acute heart failure, without proven or suspected infection;
    -Acute myocardial infarction with angiographic documentation; CCS class ≥ II angina pectoris;
    -Refractory shock with systolic arterial pressure <90 mm Hg despite the use of high doses of vasopressors (,norepinephrine BASE or epinephrine BASE > 2.4 µg/kg/min; these doses should be multiplied by two for noradrenaline salt (tartrate or bitartrate).
    -Co-treatment with drugs inducing bradycardia, QT lengthening or strong inhibition of CYP4503A4, pacemaker, defibrillator, kalemia <3 mM
    -Known pregnancy, breast feeding, women with of childbearing potential will be tested for pregnancy and excluded if pregnant
    -Known allergy to ivabradine or to any of the excipients, retinitis pigmentosa, congenital galactosemia, lactase deficiency, glucose or galactose malabsorption
    -Severe renal failure (creatinine clearance <15 ml/min) or hepatic failure (prothrombin time <20%),
    -Enteral feeding impossible, vomiting, congenital galactosemia, lactase deficiency, glucose-galactose malabsorption syndrome.
    -Tachycardia due to hyperthyroidism, pheochromocytoma or severe anemia (<7 g/dL)
    -Prior enrolment in the trial, participation in another interventional study on septic shock,
    -Known legal incapacity (patients under guardianship or curatorship),
    -Decision to limit full care taken before obtaining informed consent.
    -Patient under AME (state emergency medical help)
    E.5 End points
    E.5.1Primary end point(s)
    There are two primary endpoints:
    -for activity and treatment selection at interim analysis: the percentage of patients with heart rate within the predefined threshold (80-94 bpm) at hour-48;
    -for efficacy and the final analysis: 28-day mortality.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - At hour-48
    - At day-28
    E.5.2Secondary end point(s)
    a) Tolerance of ivabradine: percentage of patients with bradycardia, atrial fibrillation, phosphenes or blurred vision up to day-17;
    b) Percentage of patients with a heart rate within the target range (80-94 bpm) at hour-72; percentage of heart rate measurements (assessed every 3 to 4 hours) within the target range at hour-72; changes in heart rate, mean arterial pressure and cardiac output evaluated by the area under the curve (AUC) versus time;
    c) Organ failures free days (SOFA<3 for each organ) at day-14 and day-28, number of vasopressor- and mechanical ventilation-free days at day-14 and day-28, lactate clearance at day-2 and day-3;
    d) Repeated echocardiographies [to assess left ventricle systolic (ejection fraction, s wave at mitral annulus by tissue Doppler, and global longitudinal strain if available), and diastolic (early and late mitral inflow by pulse and tissue Doppler) functions] and biomarker assessment (natriurectic peptide and troponin);
    e) Pharmacokinetics of ivabradine;
    f) Mortality at ICU discharge, hospital discharge, and day-90; ICU- and hospital-free days at day-28 and day-90
    E.5.2.1Timepoint(s) of evaluation of this end point
    - day 17
    - 72 hours
    - day 14
    - day 28
    - day 2
    - day 3
    - day 90
    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 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) Yes
    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 trial3
    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 concerned17
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA18
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years2
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months3
    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: 215
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 215
    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 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 Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Justification: i) septic shock is a life-threatening situation with a high risk of mortality ; ii) in order to improve hemodynamics and patient outcome, heart rate control should be initiated as early as possible after septic shock onset.
    F.3.3.7Others Yes
    F.3.3.7.1Details of other specific vulnerable populations
    women with childbearing potential with negatif test for pregnancy
    F.4 Planned number of subjects to be included
    F.4.1In the member state380
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 429
    F.4.2.2In the whole clinical trial 429
    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 Decision2019-07-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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