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    Summary
    EudraCT Number:2021-005473-10
    Sponsor's Protocol Code Number:BEYOND
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-10-21
    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 ConcernedGreece - EOF
    A.2EudraCT number2021-005473-10
    A.3Full title of the trial
    BEZLOTOXUMAB YIELDED OUTCOMES BY ADDRESSING PERSONALIZED NEEDS IN CLOSTRIDIOIDES DIFFICILE INFECTION: THE BEYOND DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL
    Η ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΤΗΤΑ ΤΗΣ ΜΠΕΖΛΟΤΟΞΟΥΜΑΜΠΗΣ ΣΤΙΣ ΕΞΑΤΟΜΙΚΕΥΜΕΝΕΣ ΑΝΑΓΚΕΣ ΣΕ ΛΟΙΜΩΞΗ ΑΠΟ CLOSTRIDIOIDES DIFFICILE: Η ΜΕΛΕΤΗ BEYOND
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Bezlotoxumab for Clostridioides difficile infection
    Η χρήση μπεζλοτοξουμάμπης στην αντιμετώπιση της λοίμωξης από Clostridioides difficile
    A.4.1Sponsor's protocol code numberBEYOND
    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 str.
    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 ZINPLAVA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameBezlotoxumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for 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
    Clostridioides difficile Infection (CDI)
    Λοίμωξη από Clostridioides difficile
    E.1.1.1Medical condition in easily understood language
    Clostridioides difficile Infection (CDI)
    Λοίμωξη από Clostridioides difficile
    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 24.0
    E.1.2Level LLT
    E.1.2Classification code 10085158
    E.1.2Term Clostridioides difficile infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Previous data from our group have shown that integrated information from SNPs of the host DNA, IL-8 and the enrichment of the stool microbiome can indicate the patients with infection by Clostridioides difficile (CDI) at risk for unfavorable outcome. This integrated information is forming the BEYOND score. The aim of the BEYOND RCT is to investigate if adjunctive bezlotoxumab treatment to the current standard-of-care may decrease the likelihood of unfavorable outcome for patients who score positive by the BEYOND score.
    Πρόσφατα ερευνητικά δεδομένα δείχνουν ότι ο συνδυασμός πληροφοριών από την παρουσία μονήρων νουκλεοτιδικών πολυμορφισμών του ανθρωπίνου DNA, οι συγκεντρώσεις της ιντερλευκίνης-8 και ο εμπλουτισμός του εντερικού μικροβιώματος μπορούν να υποδείξουν τους ασθενείς με λοίμωξη από Clostridioides difficile (CDI) που βρίσκονται σε αυξημένο κίνδυνο δυσμενούς έκβασης. Αυτές οι πληροφορίες ενσωματώνονται στη βαθμολογία BEYOND. Η μελέτη BEYOND είναι διπλά-τυφλή τυχαιοποιημένη μελέτη που αποσκοπεί να διαπιστώσει αν η θεραπεία με το μονοκλωνικό αντίσωμα μπεζλοτοξουμάμπη βελτιώνει την τελική έκβαση ασθενών με CDI που βρίσκονται σε κίνδυνο όπως διαπιστώνεται από τη θετική βαθμολογία BEYOND.
    E.2.2Secondary objectives of the trial
    Not applicable
    Δεν εφαρμόζεται
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age equal or above 18 years
    2. Both genders
    3. Written informed consent provided by the patient or by their legal representative in case of patients unable to consent
    4. In case of non-menopausal women, unwillingness to become pregnant during the study period. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study.
    5. Diarrhea defined as at least 3 episodes of unformed stool in the past 24hours.
    6. Positive stool for C.difficile. This is defined as any stool sample positive for the presence of glutamate dehydrogenase (GDH) and for the presence of toxin A and/or B.
    7. Positive BEYOND score i.e. meeting any of the following:

    Gene score for susceptibility to CDI more than 53. The score is provided by the following equation:
    (Carriage of C allele of rs12148744 x 27) – (carriage of C allele of rs714024 x 27) - (carriage of C allele of rs721059 x 29) + (carriage of T allele of rs4311028 x 33) – (carriage of A allele of rs62183547 x 25) + (carriage of C allele of rs1128266 x 12) - (carriage of T allele of rs4279595 x 17) + (carriage of G allele of rs175006 x 11) + (carriage of T allele of rs3859214 x 17) + (carriage of G allele of rs7222870 x 15) – (carriage of G allele of rs5086600 x 9) + (carriage of T allele of rs7240534 x 12) + (carriage of G allele of rs20911172 x 11) - (carriage of C allele of rs17680671 x 17)
    OR
    Score provided by the following equation more than 9= [Hemoglobin <9.5 g/dl x 10] + [serum urea >64.5 mg/dl x 14] + [serum interleukin-8 >227 pg/ml x 19] – [carriage of G allele of rs2091172 x 17]
    OR
    More than 3log10 of gammaproteobacteria or Enterobacteriaceae or Enterobacteriales in the stool
    1. Ηλικία ίση ή μεγαλύτερη των 18 ετών
    2. Ασθενείς και των δύο φύλων
    3. Έγγραφη συναίνεση που δίνεται από τον ασθενή ή από το νόμιμο εκπρόσωπό του
    4. Στην περίπτωση προ-εμμηνοπαυσιακών γυναικών, απουσία επιθυμίας για εγκυμοσύνη κατά τη διάρκεια της μελέτης. Οι γυναίκες αναπαραγωγικής ηλικίας θα ελεγχθούν με δοκιμασία εγκυμοσύνης ούρων πριν την εισαγωγή τους στη μελέτη
    5. Διάρροια που ορίζεται ως τουλάχιστον 3 επεισόδια μη σχηματισμένων κενώσεων τις τελευταίες 24 ώρες
    6. Θετική δοκιμασία κοπράνων για C.difficile. Αυτή ορίζεται ως κάθε δείγμα κοπρώνων θετικών για την παρουσία της γλουταμινικής αφυδρογονάσης (GDH) και για την παρουσία των τοξινών Α και/ή Β.
    7. Θετική βαθμολογία BEYOND η οποία ορίζεται ως ένα από τα ακόλουθα:

    Γενετική βαθμολογία ευπάθειας για CDI μεγαλύτερη από 53. Η βαθμολογία δίνεται από την ακόλουθη εξίσωση:
    (Φορεία του αλληλίου C του rs12148744 x 27) – (Φορεία του αλληλίου C του rs714024 x 27) - (Φορεία του αλληλίου C του rs721059 x 29) + (Φορεία του αλληλίου Τ του rs4311028 x 33) – (Φορεία του αλληλίου Α του rs62183547 x 25) + (Φορεία του αλληλίου C του rs1128266 x 12) - (Φορεία του αλληλίου Τ του rs4279595 x 17) + (Φορεία του αλληλίου G του rs175006 x 11) + (Φορεία του αλληλίου T του rs3859214 x 17) + (Φορεία του αλληλίου G του rs7222870 x 15) – (Φορεία του αλληλίου G του rs5086600 x 9) + (Φορεία του αλληλίου T του rs7240534 x 12) + (Φορεία του αλληλίου G του rs20911172 x 11) - (Φορεία του αλληλίου C του rs17680671 x 17)
    Ή
    Βαθμολογία της ακόλουθης εξίσωσης μεγαλύτερη από 9= [αιμοσφαιρίνη <9.5 g/dl x 10] + [ουρία >64.5 mg/dl x 14] + [ιντερλευκίνη-8 ορού>227 pg/ml x 19] – [Φορεία του αλληλίου G του rs2091172 x 17]
    Ή
    Πάνω από 3log10 γαμμαπροτεοβακτήρια ή Εντεροβακτηριακά στα κόπρανα
    E.4Principal exclusion criteria
    • Age below 18 years
    • Denial for written informed consent
    • Known allergy to bezlotoxumab
    • Pregnancy or lactation. Women of child-bearing potential will be screened by a urine pregnancy test before inclusion in the study
    • Ηλικία μικρότερη από 18 έτη
    • Άρνηση έγγραφης συναίνεσης
    • Γνωστή αλλεργία στη μπεζλοτοξουμάμπη
    • Εγκυμοσύνη ή γαλουχία. Οι γυναίκες αναπαραγωγικής ηλικίας θα ελεγχθούν με δοκιμασία εγκυμοσύνης ούρων πριν την εισαγωγή τους στη μελέτη
    E.5 End points
    E.5.1Primary end point(s)
    The superiority of bezlotoxumab over placebo to reduce the incidence of unfavorable outcome. Unfavorable outcome is defined as any of the following: progression into organ dysfunction; relapse of CDI; and death. The primary endpoint is tested on Day 40 from start of blind treatment. Organ dysfunction is defined as any increase of the baseline total SOFA score by at least 2 points. Need for colectomy or admission in the Intensive Care Unit counts as organ dysfunction.
    Η ανωτερότητα της μπεζλοτοξουμάμπης συγκριτικά με την εικονική θεραπεία στην μείωση της επίπτωσης της δυσμενούς έκβασης. Η δυσμενής έκβαση ορίζεται ως η εκδήλωση οποιουδήποτε από τα: εξέλιξη σε οργανική δυσπραγία, υποτροπή της CDI ή θάνατος. Η οργανική δυσπραγία ορίζεται ως κάθε αύξηση της συνολικής βαθμολογίας SOFA μετά την εισαγωγή στη μελέτη κατά τουλάχιστον 2 βαθμούς. Η ανάγκη διενέργειας κολεκτομής ή νοσηλείας στη Μονάδα Εντατικής Θεραπείας θεωρούνται ταυτόσημες της οργανικής δυσπραγίας.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 40
    Ημέρα 40
    E.5.2Secondary end point(s)
    The superiority of bezlotoxumab over placebo when given for CDI of high likelihood for unfavorable outcome on the following:
    • Incidence of organ failure and time to first organ failure
    • Time to relapse of CDI
    • Survival time
    • Cost of hospitalization
    • Validation of the BEYOND score
    Η ανωτερότητα της μπεζλοτοξουμάμπης συγκριτικά με την εικονική θεραπεία όταν χορηγείται σε ασθενείς με CDI με υψηλό κίνδυνο δυσμενούς έκβασης στα ακόλουθα:
    • Επίπτωση οργανικής δυσπραγίας και χρόνος μέχρι την εκδήλωση της πρώτης οργανικής δυσπραγίας
    • Χρόνος ως προς την υποτροπή της CDI
    • Χρόνος επιβίωσης
    • Κόστος νοσηλείας
    • Επαλήθευση της βαθμολογίας BEYOND
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 40
    Ημέρα 40
    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 Yes
    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 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 trial2
    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 concerned18
    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 months0
    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: 22
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 22
    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 No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patients with CDI at risk for unfavorable outcome may not be able to provide informed consent. In this case, written informed consent will be provided by their legal representative.
    Οι ασθενείς με CDI και κίνδυνο δυσμενούς έκβασης μπορεί να μην δύνανται να δώσουν έγγραφη συναίνεση. Σε αυτή την περίπτωση, η γραπτή συναίνεση θα δίνεται από το νόμιμο εκπρόσωπό τους.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state44
    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)
    Not applicable
    Δεν εφαρμόζεται
    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 Decision2021-11-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-11-18
    P. End of Trial
    P.End of Trial StatusOngoing
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