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    Summary
    EudraCT Number:2017-002171-26
    Sponsor's Protocol Code Number:PROVIDE
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-07-06
    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 ConcernedGreece - EOF
    A.2EudraCT number2017-002171-26
    A.3Full title of the trial
    A PERSONALIZED RANDOMIZED TRIAL OF VALIdATION AND RESTORATION OF IMMUNE DYSFUNCTION IN SEVERE INFECTIONS AND SEPSIS: THE PROVIDE TRIAL
    ΜΙΑ ΔΙΠΛΗ-ΤΥΦΛΗ ΤΥΧΑΙΟΠΟΙΗΜΕΝΗ ΜΕΛΕΤΗ ΑΞΙΟΛΟΓΗΣΗΣ ΚΑΙ ΑΠΟΚΑΤΑΣΤΑΣΗΣ ΤΗΣ ΑΝΟΣΙΑΚΗΣ ΔΙΑΤΑΡΑΧΗΣ ΣΤΙΣ ΣΟΒΑΡΕΣ ΛΟΙΜΩΞΕΙΣ ΚΑΙ ΣΤΗ ΣΗΨΗ: Η ΜΕΛΕΤΗ PROVIDE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A TRIAL FOR IMMUNOMODULATION IN SEPSIS
    ΜΙΑ ΜΕΛΕΤΗ ΑΝΟΣΟΤΡΟΠΟΠΟΙΗΣΗΣ ΣΤΗ ΣΗΨΗ
    A.3.2Name or abbreviated title of the trial where available
    PROVIDE
    A.4.1Sponsor's protocol code numberPROVIDE
    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 SponsorHellenic Institute for the Study of Sepsis
    B.1.3.4CountryGreece
    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 supportHellenic Institute for the Study of Sepsis
    B.4.2CountryGreece
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHellenic Institute for the Study of Sepsis
    B.5.2Functional name of contact pointPresident of the Board
    B.5.3 Address:
    B.5.3.1Street Address88 Michalakopoulou Street
    B.5.3.2Town/ cityAthens
    B.5.3.3Post code11528
    B.5.3.4CountryGreece
    B.5.4Telephone number00302107480662
    B.5.5Fax number00302107480662
    B.5.6E-mailinsepsis@otenet.gr
    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 Kineret
    D.2.1.1.2Name of the Marketing Authorisation holderSwedish Orphan Biovitrum AB
    D.2.1.2Country which granted the Marketing AuthorisationGreece
    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 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 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.IMP: 2
    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 Imukin
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim A.E
    D.2.1.2Country which granted the Marketing AuthorisationGreece
    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 Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    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.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
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInjection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    A TRIAL FOR IMMUNOMODULATION IN SEPSIS
    ΜΙΑ ΜΕΛΕΤΗ ΑΝΟΣΟΤΡΟΠΟΠΟΙΗΣΗΣ ΣΤΗ ΣΗΨΗ
    E.1.1.1Medical condition in easily understood language
    A TRIAL FOR IMMUNOMODULATION IN SEPSIS
    ΜΙΑ ΜΕΛΕΤΗ ΑΝΟΣΟΤΡΟΠΟΠΟΙΗΣΗΣ ΣΤΗ ΣΗΨΗ
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10040047
    E.1.2Term Sepsis
    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
    Our aim is to conduct one RCT of personalized immunotherapy in sepsis targeting patients who lie either on the predominantly hyper-inflammatory arm or on the predominantly hypo-inflammatory arm of the spectrum of the host response. These patients will be selected by the use of a panel of biomarkers and laboratory findings and they will be allocated to placebo or immunotherapy treatment according to their needs.
    Πρόκειται για τυχαιοποιημένη κλινική μελέτη προσωποποιημένης ανοσοθεραπείας σε σηπτικούς ασθενείς που βρίσκονται είτε στο υπερφλεγμονώδες άκρο είτε στο υποφλεγμονώδες άκρο του φάσματος της ανοσιακής απόκρισης. Οι ασθενείς αυτοί θα επιλέγονται με τη χρήση μιας ομάδας βιολογικών δεικτών και εργαστηριακών ευρημάτων και θα λαμβάνουν ανοσοθεραπεία ή εικονικό φάρμακο.
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age equal to or above 18 years
    • Male or female gender
    • In case of women, unwillingness to remain pregnant during the study period.
    • Written informed consent provided by the patient or by legal representative in case of patients unable to consent
    • Community-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP) or ventilator-associated pneumonia (VAP) or primary bacteremia (BSI) or acute cholangitis (AC).
    • Septic shock defined by the Sepsis-3 definitions.
    • Patients with either signs of MALS or hypo-inflammation
    • Ηλικία μεγαλύτερη ή ίση των 18 ετών
    • Και τα δύο φύλα
    • Προκειμένου για γυναίκες αναπαραγωγικής ηλικίας, πρέπει να χρησιμοποιούν ή να είναι πρόθυμες να χρησιμοποιήσουν διπλή αντισυλληπτική μέθοδο κατά τη διάρκεια της μελέτης. Προ της εισαγωγής στη μελέτη θα διενεργείται δοκιμασία (τεστ) κύησης ούρων προς αποκλεισμό εγκυμοσύνης.
    • Έγγραφη συγκατάθεση που παρέχεται από τον ασθενή ή από το νόμιμο εκπρόσωπο σε περίπτωση που ο ασθενής δεν είναι δυνατό να συναινέσει.
    • Πνευμονία κοινότητας ή ενδονοσοκομειακή πνευμονία ή πνευμονία σχετιζόμενη με μηχανικό αερισμό ή πρωτοπαθής βακτηριαιμία ή οξεία χολαγγειίτιδα.
    • Σηπτική καταπληξία, όπως ορίζεται από τους ορισμούς κατά Sepsis-3.
    • Ασθενείς που παρουσιάζουν είτε σημεία ΣΟΕΜ είτε υποφλεγμονή
    E.4Principal exclusion criteria
    • Age below 18 years
    • Denial for written informed consent
    • Acute pyelonephritis or intraabdominal infection other than AC, meningitis or skin infection. It is explicitly stated that in the case of a patient with both AC and any other type of intraabdominal infection, the patient cannot be enrolled.
    • Any stage IV malignancy
    • Any do not resuscitate decision
    • In the case of BSI, patients with blood cultures growing coagulase-negative staphylococci or skin commensals or catheter-related infections cannot be enrolled.
    • Active tuberculosis (TB) as defined by the co-administration of drugs for the treatment of TB
    • Infection by the human immunodeficiency virus (HIV)
    • Any primary immunodeficiency
    • Oral or IV intake of corticosteroids at a daily dose equal or greater than 0.4 mg/kg prednisone or greater the last 15 days.
    • Any anti-cytokine biological treatment the last one month
    • Medical history of systemic lupus erythematosus
    • Medical history of multiple sclerosis or any other demyelinating disorder.
    • Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
    • Ηλικία κάτω των 18 ετών
    • Άρνηση για έγγραφη συγκατάθεση
    • Οξεία πυελονεφρίτιδα ή ενδοκοιλιακή λοίμωξη διαφορετική από οξεία χολαγγειίτιδα, μηνιγγίτιδα ή λοίμωξη δέρματος και μαλακών μορίων. Αναφέρεται ρητά ότι σε περίπτωση που ένας ασθενής πάσχει ταυτόχρονα από οξεία χολαγγειίτιδα και από οποιοδήποτε άλλη μορφή ενδοκοιλιακής λοίμωξης, δεν μπορεί να ενταχθεί στη μελέτη.
    • Κακοήθεια σταδίου IV
    • Οποιαδήποτε περίπτωση ασθενούς, όπου έχει ληφθεί απόφαση να μην γίνει αναζωογόνηση
    • Στην περίπτωση βακτηριαιμιών, ασθενείς με καλλιέργειες αίματος όπου καλλιεργούνται στελέχη Staphylococcus αρνητικά κατά κοαγκουλάση ή συμβιωτικά μικρόβια του δέρματος ή ασθενείς που έχουν λοίμωξη που σχετίζεται με κεντρικό καθετήρα, δεν μπορούν να ενταχθούν.
    • Ενεργός φυματίωση όπως ορίζεται από την συγχορήγηση φαρμάκων για τη θεραπεία της
    • Λοίμωξη από τον ιό της ανθρώπινης ανοσοανεπάρκειας (HIV)
    • Οποιαδήποτε πρωτοπαθής ανοσοανεπάρκεια
    • Από του στόματος ή ενδοφλέβια λήψη κορτικοστεροειδών σε καθημερινή δόση ίση ή μεγαλύτερη από 0,4mg/kg ισοδυνάμου πρεδνιζόνης για περισσότερο από τις τελευταίες 15 ημέρες.
    • Χορήγηση οποιασδήποτε βιολογικής θεραπείας που στοχεύει έναντι κυτταροκινών τον τελευταίο μήνα
    • Ιατρικό ιστορικό συστηματικού ερυθηματώδους λύκου
    • Ιατρικό πολλαπλής σκλήρυνσης ή οποιαδήποτε άλλης απομυελινωτικής διαταραχής.
    • Εγκυμοσύνη ή γαλουχία. Προκειμένου για γυναίκες αναπαραγωγικής ηλικίας προ της εισαγωγής στη μελέτη θα διενεργείται τεστ κύησης ούρων προς αποκλεισμό εγκυμοσύνης
    E.5 End points
    E.5.1Primary end point(s)
    The primary study endpoint will be the comparative efficacy of the applied immunotherapy versus standard therapy on mortality after 28 days
    Το πρωτογενές καταληκτικό σημείο είναι η συγκριτική θνητότητα μετά από 28 ημέρες μεταξύ της ομάδας της εφαρμοζόμενης ανοσοθεραπείας και της ομάδας της καθιερωμένης θεραπείας.
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days
    28 ημέρες
    E.5.2Secondary end point(s)
    • Mortality after 90 days
    • Time to decrease of SOFA score by more than 50%
    • Time to infection resolution
    • Duration of hospitalization
    • Development of secondary infections
    • Change of cytokine stimulation between days 0 and 4 and between days 0 and 7
    • Change of gene expression between days 0 and 7
    • Change of gut microbiome between days 0 and 7
    • Epigenetic changes on day 7
    • Classification of the immune function of screened patients not characterized with MALS neither with hypo-inflammation
    • Θνητότητα μετά από 90 ημέρες
    • Χρόνος ως μείωση της βαθμολογίας SOFA κατά τουλάχιστον 50%
    • Χρόνος ως λύση της λοίμωξης
    • Ανάπτυξη δευτεροπαθών λοιμώξεων
    • Διάρκεια νοσηλείας
    • Διαφοροποίηση της διέγερσης παραγωγής κυτταροκινών μεταξύ των ημερών 0 και 4 και μεταξύ των ημερών 0 και 7
    • Διαφοροποίηση στην έκφραση των γονιδίων μεταξύ των ημερών 0 και 7
    • Διαφοροποίηση στο μικροβίωμα του εντέρου μεταξύ των ημερών 0 και 7
    • Επιγενετικές αλλαγές την ημέρα 7
    • Ταξινόμηση της ανοσιακής λειτουργίας των ασθενών που ελέγχονται για εισαγωγή σητ μελέτη και οι οποίοι δεν μπορούν να ταξινομηθούν ως πάσχοντες ούτε από ΣΟΕΜ ούτε από υποφλεγμονή
    E.5.2.1Timepoint(s) of evaluation of this end point
    7 days, 90 days
    7 ημέρες, 90 ημέρες
    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 Yes
    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) No
    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 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 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 concerned9
    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 No
    E.8.7Trial has a data monitoring committee No
    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
    τελευταία επίσκεψη τελευταίου ασθενούς
    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 months2
    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: 78
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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 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
    Patients under anesthesia and/or mechanically ventilated, patients unable to read and/or write
    Ασθενείς υπό καταστολή ή/και μηχανικό αερισμό και ασθενείς που δε δύνανται να διαβάσουν ή/και να γράψουν
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state278
    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 Decision2017-10-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-09-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-12-31
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