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    Summary
    EudraCT Number:2019-003016-32
    Sponsor's Protocol Code Number:APHP180690
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-11-18
    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 number2019-003016-32
    A.3Full title of the trial
    Impact of aminoglycosides-based antibiotics combination and protective isolation on outcomes in critically-ill neutropenic patients with sepsis:A randomized 2 by 2 factorial design randomized pragmatic trial
    Influence de la bithérapie antibiotique par aminosides et de l’isolement protecteur sur le devenir des patients neutropéniques admis en réanimation avec un sepsis :
    étude randomisée double plan factoriel
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NA
    NA
    A.3.2Name or abbreviated title of the trial where available
    Combination-Lock01
    A.4.1Sponsor's protocol code numberAPHP180690
    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 supportDGOS - PHRC
    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 pointKarine SEYMOUR
    B.5.3 Address:
    B.5.3.1Street Address1 avenue Claude Vellefaux - 75475 Paris cedex 10
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75475
    B.5.3.4CountryFrance
    B.5.4Telephone number0144841742
    B.5.5Fax number0144841701
    B.5.6E-mailkarine.seymour@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 AMIKACINE
    D.2.1.1.2Name of the Marketing Authorisation holderMylan
    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 nameAMIKACINE
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    neutropenic patients with sepsis
    patients neutropéniques admis en réanimation avec un sepsis
    E.1.1.1Medical condition in easily understood language
    NA
    NA
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    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 evaluate the impact on day-90 mortality of two strategies, separately, using a 2x2 factorial design RCT:
    • Intervention 1 - routine association of aminoglycoside to initial antibiotic therapy when compared to standard of care
    • Intervention 2 - lack of routine use of protective isolation when compared to standard of care
    Évaluer l'impact sur la mortalité à J90 de deux stratégies, séparément, en utilisant un plan factoriel 2x2 :
    - Intervention 1 - association systématique d'aminoglycosides à l'antibiothérapie initiale par rapport à la norme de soins
    - Intervention 2 - Absence de recours systématique à l'isolement protecteur par rapport à la norme de soins
    E.2.2Secondary objectives of the trial
    To evaluate the impact of the studied interventions, on
    - Day-28 and hospital outcome
    - Incidence, severity and duration of AKI
    - Rate of adherence of hand hygiene
    - Rate of selected adverse events
    - Rate of nosocomial bacterial, viral and fungal infection episodes
    - Organ support during ICU stay and organ support duration
    - Failure of initial antibiotic therapy
    - Antibiotic duration
    - Rate of aminoglycosides overdosage and overuse
    Evaluer l’impact des stratégies testées :
    - Mortalité à J28 et à l’hôpital
    - Incidence, sévérité et durée de l’insuffisance rénale aiguë
    - Adhésion à l’hygiène des mains
    - Taux d’évènement indésirable
    - Taux d’infection nosocomiale bactérienne, virale et fongique
    - Suppléances vitales et durée de ces dernières
    - Echec de l’antibiothérapie
    - Durée d’antibiothérapie
    - Quantité d’aminosides reçues et surdosages
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Age ≥ 18 years
    - Sepsis or septic shock as defined by SEPSIS3 definition
    - Underlying tumor, allogeneic stem cell transplantation or hematological malignancy
    - Neutropenia (defined by either absolute neutrophil count <500/mm3 or leucocytes <1000/mm3) related to an underlying malignancy or its treatment
    - Informed or deferred consent
    - Age ≥ 18 ans
    Admission en réanimation
    - Sepsis ou choc septique selon la définition SEPSIS3
    - Tumeur solide, greffe de moelle ou maladie hématologique tumorale
    - Neutropénie (PNN <500/mm3 ou leucocytes <1000/mm3) en lien avec le traitement de l’hémopathie
    - Consentement du patient, du proche ou inclusion selon un critère d’urgence


    E.4Principal exclusion criteria
    - Pregnancy and breastfeeding
    - Moribund patients (death expected within 48 hours by attending physician)
    - Previous participation to this study
    - No affiliation to social security
    - Patients under legal protection according to French Law
    - Patient having received more than 1 injection of aminoglycosides in the 3 days preceding ICU admission
    - Hypersensitivity to amikacin, to other antibiotics from the aminoglycoside family, or to any excipient from the amikacin used.
    - Patients with documented allergy to aminoglycosides
    - Delay between admission for a new sepsis and inclusion>24 hours or (in patients previously admitted in the ICU for another reason) delay between new sepsis in study inclusion >24h
    - Grossesse ou allaitement
    - Survie attendue <48h
    - Participation antérieure à l’étude
    - Absence d’affiliation à un régime de sécurité social
    - Patient majeur protégé ou privé de liberté
    - Patient ayant reçu plus d'une injection d'aminoglycosides dans les 3 jours précédant
    - Hypersensibilité aux aminosides ou à l'un des excipients de l'amikacine.
    - Délai entre l'admission pour sepsis et l'inclusion> 24 heures ou (chez les patients admis en réanimation pour une autre raison), délai entre le sepsis et l’inclusion > 24h
    E.5 End points
    E.5.1Primary end point(s)
    Day-90 mortality
    Mortalité à J90
    E.5.1.1Timepoint(s) of evaluation of this end point
    NA
    NA
    E.5.2Secondary end point(s)
    - Day-28 and hospital mortality
    - Incidence and severity of AKI.
    - Major Adverse Kidney Events at day-28 and day 90.
    - Rate of adherence to adequate hand hygiene as assessed by external observer.
    - Incidence density of selected serious adverse events including unexpected cardiac arrest.
    - Incidence density of new bacterial, viral or fungal episode.
    - Number of days free from organ support therapy (mechanical ventilation, vasopressors or RRT) at day 28
    - Rate of clinical cure
    - Frequency of initial antibiotic therapy inadequate as regard to microbiological documentation.
    - Number of day free of antibiotic therapy at day-28
    - Duration of aminoglycoside therapy, rate of aminoglycoside overdosage according to residual concentration and overuse when compared to experts recommendations
    - Mortalité à J28 et en réanimation
    - Incidence et sévérité de l’IRA.
    - Major Adverse Kidney Events à J28 et J90.
    - Taux d’hygiène des mains répondant aux crtéres de bonne qualité tel qu’evalué par un observateur extérieur.
    - Densité d’incidence d’évènement indésirable sévère dont l’arrêt cardiaque non anticipé.
    - Densité d’incidence des nouveaux épisodes d’infections bactérienne, viral et fongique.
    - Nombre de jour vivant libre de suppléance vitale (ventilation mécanique, amines et épuration extra-rénale).
    - Taux de guérison de l’infection motivant l’admission.
    - Taux d’antibiothérapie inadéquate.
    - Nombre de jours vivant sans antibiotique à J28
    - Durée du traitement par aminoside, taux de surdosage définit selon le taux résiduel et taux d’utilisation considérée comme excessive lorsque comparé aux recommandations.
    E.5.2.1Timepoint(s) of evaluation of this end point
    NA
    NA
    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 No
    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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    • Intervention 1 – Absence d’adjonction systématique d’aminoside • Intervention 2 – Isolement prote
    • Intervention 1 - Antibiotic therapy without systematic adjunction of aminoglycosides • Interventi
    E.8.2.4Number of treatment arms in the trial1
    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 concerned14
    E.8.5The trial involves multiple Member States No
    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 Information not present in EudraCT
    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 follow-up of the last patient
    Dernier suivi du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years12
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned 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: 255
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 85
    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 2019-11-18. 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.3.3.6.1Details of subjects incapable of giving consent
    NA
    Dans un contexte d’urgence vital, certains patients seront inclus dans ce protocole avec l’accord d’un proche ou d’une personne de confiance désigné au préalable.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state340
    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
    Non
    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 Decision2020-01-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-12-12
    P. End of Trial
    P.End of Trial StatusOngoing
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