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    Summary
    EudraCT Number:2021-004924-14
    Sponsor's Protocol Code Number:BSTEP
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-11-01
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-004924-14
    A.3Full title of the trial
    New treatment strategy for patients with multiple recurrent Clostridioides difficile infection with bezlotoxumab as first option
    Nieuwe behandelstrategie voor patiënten met multipel recurrente Clostridioides difficile infectie met bezlotoxumab als eerste optie
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Bezlotoxumab or fecal transplant for recurrent C. difficile infections
    Bezlotoxumab of poeptransplantatie voor terugkerende infecties met C. difficile
    A.3.2Name or abbreviated title of the trial where available
    BSTEP
    BSTEP
    A.4.1Sponsor's protocol code numberBSTEP
    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 SponsorLeiden University Medical Center
    B.1.3.4CountryNetherlands
    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 supportMERCK SHARP & DOHME CORP.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLeiden University Medical Center
    B.5.2Functional name of contact pointDepartment of Medical Microbiology
    B.5.3 Address:
    B.5.3.1Street AddressPO Box 9600
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2300 RC
    B.5.3.4CountryNetherlands
    B.5.4Telephone number00310715263931
    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 AuthorisationNetherlands
    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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    recurrent C. difficile infection
    E.1.1.1Medical condition in easily understood language
    recurrent infection of the gut by the C. difficile bacterium
    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 10009657
    E.1.2Term Clostridium difficile colitis
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10012748
    E.1.2Term Diarrhoea, Clostridium difficile
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10012734
    E.1.2Term Diarrhea, Clostridium difficile
    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
    To investigate whether a treatment strategy offering bezlotoxumab before FMT in patients suffering from multiple recurrent CDI results in equal efficacy compared with a treatment strategy with initial FMT. Strategy A includes bezlotoxumab as ancillary treatment as first option, and FMT in case of failure. Option B includes FMT as ancillary treatment as first option, and antibiotic treatment with fidaxomicin in case of failure.
    E.2.2Secondary objectives of the trial
    To provide:
    A. a point estimate of CDI recurrence (i.e. relapse within 12 weeks after initial cure,), after standard CDI ABx plus either bezlotoxumab or FMT (as initial treatment).

    To determine
    B. the initial cure rate of standard CDI ABx plus either bezlotoxumab or FMT (as initial treatment)
    C. the sustained cure rate, i.e. cure without relapse within 12 weeks, of standard CDI ABx plus either bezlotoxumab or FMT (as initial treatment).
    D. adverse events
    E. development of post-treatment irritable bowel syndrome like symptoms associated with bezlotoxumab treatment or FMT treatment
    F. duration of hospitalization
    G. use of antibiotics
    H. eradication of toxicogenic C. difficile after treatment
    I. changes in gut microbiota profiles pre- and post-treatment
    J. patient well-being before and after treatment
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - 18-90 years old
    - diarrhea (3 or more unformed stools per 24h for two consecutive days; or >= 8 unformed stools per 48h)
    - positive PCR test for toxin A/B genes and/or positive toxin EIA for current and previous episodes (low PCR cycle threshold value when only PCR performed)
    - a minimum of two prior CDI episodes
    - previous episode is maximum of 3 months prior to the current episode
    - the current episode responds well to Standard of Care treatment (vancomycin or fidaxomicin orally).
    - Assessment of the severity of the disease will be performed according to the ESCMID recommendations.
    - Both mild and severe CDI will be included
    E.4Principal exclusion criteria
    - Severe complicated CDI, i.e presence of: hypotension, septic shock, elevated serum lactate, ileus, toxic megacolon, bowel perforation, or any fulminant course of disease.
    - ICU admission for underlying disease
    - pregnancy or current desire for pregnancy
    - breastfeeding
    - (prolonged) use of antibiotics (other than for treatment of CDI) during the study period or directly after the intervention
    - previous use of bezlotoxumab or fecal microbiota transplantation
    - a history of underlying congestive heart failure (potential safety signal phase-III trail bezlotoxumab).
    - Diagnosis of inflammatory bowel disease in medical history.
    E.5 End points
    E.5.1Primary end point(s)
    Global cure of the treatment strategy. Global cure is defined as cure without relapse of CDI within 12 weeks after completion of the treatment strategy in the study arm, i.e. after completion of secondary treatment in case of failure on initial treatment.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks after completion of the treatment strategy.
    E.5.2Secondary end point(s)
    - Initial cure after treatment with bezlotoxumab or FMT.
    Defined as cure after completion of the primary CDI treatment in the study arm. Initial cure is assessed at day 2 after end of treatment.

    - Recurrence after initial treatment with bezlotoxumab or FMT.
    Defined as CDI relapse within 12 weeks, after initial cure.

    - Sustained cure after initial treatment with bezlotoxumab or FMT.
    Defined as cure without CDI relapse within 12 weeks.


    - Adverse events. Throughout the entire study all adverse events will be noted. After the final study procedure of the last patient, all adverse events will be categorized:
    1. Most likely related to ancillary CDI treatment (bezlotoxumab or FMT)
    2. May be related to ancillary CDI treatment
    3. Not related to ancillary CDI treatment

    - Development of post-treatment irritable bowel syndrome like symptoms associated with bezlotoxumab treatment or FMT treatment after treatment during 12 weeks of follow-up

    - Duration of hospitalization

    - (Rate of) use of antibiotics after treatment during 12 weeks of follow-up

    - Eradication of toxigenic C. difficile 3 weeks and 12 weeks after end of treatment assessed by PCR

    - Fecal microbiota profile pre-treatment and 3 weeks and 12 weeks after end of treatment assessed by 16S rRNA amplicon sequencing.

    - Costs per cured patient (global and sustained cure) and costs per QALY gained using the EQ-5D-5L health questionnaire

    The following data will also be collected:
    - Patients’ characteristics, i.e. age, medical history, comorbidities, comedication
    - Presence of risk factors for severe and recurrent CDI
    - Patient wellbeing as assessed by questionnaire
    - Defecation pattern during treatment and follow-up
    E.5.2.1Timepoint(s) of evaluation of this end point
    - 12 weeks follow-up
    - Initial cure is assessed at day 2 after end of treatment.
    - Global cure is assessed 12 weeks after completion of the treatment strategy in the study arm
    - Eradication of toxigenic C. difficile 3 weeks and 12 weeks after end of treatment
    - Fecal microbiota profile pre-treatment and 3 weeks and 12 weeks after end of treatment
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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
    Fecal microbiota transplantation (FMT)
    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 concerned10
    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 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 months6
    E.8.9.1In the Member State concerned days
    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: 66
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 66
    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 state66
    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 Decision2021-11-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-21
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2022-09-15
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